Anesthesiology News - April 2011 - Digital Edition by McMahon Group

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The Independent Monthly Newspaper for Anesthesiologists AnesthesiologyNews.com • A p r i l 2 0 1 1 • Volume 37 Number 4

Simple Protocol Cuts PropofolInfusion Syndrome Retrospective study of trauma patients found 90% lower incidence

More Data, but few Answers, For Anesthesia Safety in Peds Second FDA panel ends with many questions, no conclusions

simple screening protocol can reduce the incidence of propofol-infusion syndrome in critically ill patients with traumatic brain injury by up to 90%, according to study results presented at the 2011 annual meeting of the Society of Critical Care Medicine (abstract 53). Based on the findings, the investigators have urged

Silver Spring, Md.—Four years after the FDA convened a panel of experts to discuss a possible relationship between general anesthesia and cognitive damage, experts say there still is not enough scientific evidence to define anesthetic drugs’ effects on children’s development or recommend any changes in anesthesiology practice. A panel of about 30 academic and government physicians and scientists met at the FDA March 10, to review a variety of clinical and

see syndrome page 24

see FDA page 26

INside

As Florida Eyes Mandatory Urine Drug Testing, Experts Weigh in on Ethics, Role

n January, the Florida Board of Medicine passed a new rule setting up standards of practice for pain physicians in the state. Designed to rein in “pill mills,” the new rule mandates a set of clinical steps that every pain physician in Florida would have to take with their patients. One major component of the rule is mandatory urine drug testing (UDT), both at the initial intake visit and at least twice randomly throughout the year. The rule requires that “evidence or behavioral indications of diversion shall

be followed by discontinuation of controlled substance therapy and the patient shall be discharged.” In other words, patients can and should be “fired” if their UDT results are abnormal. Days before the rule was set to take effect, a last-minute act by the state’s legislature held it up—not because elected officials disagreed with the provisions, but because any rule made by a state agency costing small businesses more than $1 million would now require legislative review. Individual

22 | technology The Wii Fit test for post-op balance.

UDTs can cost between $200 and $1,200 per test, so the costs to the health care system could be significant. Florida’s part-time legislators then closed their session, causing the rule to remain in legislative limbo. If passed, the new standards would be far-reaching, and include step-bystep instructions to help physicians assess their patients. Aggressive Tack The testing rule is among the

31 | PRN Improving the journal club.

38 | POLICY & MANAGEMENT A guide to RFPs—getting to know the enemy.

49 | Pain Medicine Poor mental health linked to persistent pain after knee arthroplasty.

62 | COMMENTARY The case for evidence-based guidelines in subspecialty care.

55 | CME—PreAnesthetic Assessment Lesson 291: PreAnesthetic Assessment of the Patient With Systemic Lupus Erythematosus

see UDT page 45

Newproduct

Featuredproduct

The A5 from Mindray, see pages 17 and 34.

SonoPlex from Pajunk Medical Systems, see pages 21, 23 and 38.

Educationalreview

Ultrasound-guided Central Blocks in Infants, Children, and Adolescents, see insert at page 32.

Can a nurse practitioner perform the post-anesthesia evaluation? Find the answer at: www.anesthesiallc.com/an-apr11

4 I AnesthesiologyNews.com

April 2011

Discuss these and other articles @ AnesthesiologyNews.com.

Heard Here First: One of the things that really angers adolescents is when you pretend to engage them while blowing them off and not giving them credit.

So don’t do it.

April 2011

The five most-viewed articles last month on AnesthesiologyNews.com 1. Sedation in the ICU: Shifts and Strategies (Educational Review)

If you’re going to overrule them, don’t even go through the farce, because you’re only going to make things worse.

2. More Retractions in Boldt Case (Web Exclusive) 3. For Anesthesiologists, Defining Value May Be Key to Future

See article on page 34.

4. Wrong-Site Blocks Vex OR Safety Efforts 5. February Issue Recap (Podcast)

Alan Kaye, PhD, MD, New Orleans, LA Robert S. Lagasse, MD, New Haven, CT Alex Macario, MD, MBA, Stanford, CA The Independent monthly Newspaper for Anesthesiologists

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MICHAEL F. ROIZEN, MD, Cleveland, OH JOAN E. SPIEGEL, MD, Boston, MA Susan T. Verghese, MD, Washington, DC Eugene R. Viscusi, MD, Philadelphia, PA

Correction: Due to a technical problem, the title of the review article on page 42 of the March issue was rendered incorrectly. The correct title is “IV Fluid Administration and the Elderly.” Anesthesiology News regrets the error.

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e nt n se rta tio se po ma ea Im or Pl sed Inf y clo fet en Sa w Ne

WHEN CHOOSING AN IV SEDATIVE

Different situations require different solutions

Precedex : A right ﬁt ®

FOR TODAY’S SEDATION MANAGEMENT PRACTICES

e nt n se rta tio se po ma ea Im or Pl sed Inf y clo fet en Sa w Ne

DIFFERENT SITUATIONS REQUIRE DIFFERENT SEDATIVE SOLUTIONS The ﬁrst and only alpha2 agonist indicated for sedation1,2 —Nonintubated patients prior to and during surgical and other procedures1 —Intubated and mechanically ventilated patients during treatment in an intensive care setting1 Can be used alone or in combination with other sedatives or opioid analgesics to provide sedation and added patient comfort.1 Should be administered by continuous infusion not to exceed 24 hours.1 Effective for intubated patients not just before—but also during—and after extubation.1 More than 4.5 million vials administered to millions of patients since launch.3

IMPORTANT PRECEDEX SAFETY INFORMATION Clinically signiﬁcant episodes of bradycardia, sinus arrest and hypotension have been associated with Precedex infusion and may necessitate medical intervention. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex. Please see the brief summary of Prescribing Information on adjacent page.

Important New Safety Information In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours in duration, with maintenance doses of 0.2 to 1.4 mcg/kg/hr. Precedex® was not shown to be superior to midazolam for the primary efﬁcacy endpoint, the percent of time patients were adequately sedated (81% with Precedex versus 81% with midazolam). Precedex is indicated for administration by continuous infusion not to exceed 24 hours. The approved maintenance dosages are 0.2 to 0.7 mcg/kg/hr for ICU sedation and 0.2 to 1 mcg/kg/hr for procedural sedation. The safety information highlighted below applies to the use of Precedex outside of its currently approved dosages and duration.

Warnings and Precautions Withdrawal With administration up to 7 days, regardless of dose used, 12 (5%) Precedex subjects experienced at least 1 event related to withdrawal within the ﬁrst 24 hours after discontinuation and 7 (3%) experienced at least 1 event 24 to 48 hours after stopping treatment. The most common events related to withdrawal were nausea, vomiting and agitation. Tachycardia and hypertension requiring intervention in the ﬁrst 48 hours following study drug discontinuation occurred at frequencies of less than 5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex, supportive therapy is indicated. Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated with tolerance, tachyphylaxis and a dose-related increase in adverse reactions [see Table 1 and Table 2]. Adverse Reactions Adverse reactions associated with infusion in ICU patients for periods greater than 24 hours in duration include ARDS, respiratory failure and agitation [see Table 1].

Adverse Event Hypotension1 Hypotension requiring intervention Bradycardia2 Bradycardia requiring intervention Systolic Hypertension3 Tachycardia4 Tachycardia requiring intervention Diastolic Hypertension3 Hypertension3 Hypertension requiring intervention† Hypokalemia Pyrexia Agitation Hyperglycemia Constipation Hypoglycemia Respiratory Failure Renal Failure Acute Acute Respiratory Distress Syndrome Generalized edema Hypomagnesemia

Dexmedetomidine (N=244) 56% 28% 42% 5% 28% 25% 10% 12% 11% 19% 9% 7% 7% 7% 6% 5% 5% 2% 2% 2% 1%

Midazolam (N=122) 56% 27% 19% 1% 42% 44% 10% 15% 15% 30% 13% 2% 6% 2% 6% 6% 3% 1% 1% 6% 7%

e nt n se rta tio se po ma ea Im or Pl sed Inf y clo fet en Sa w Ne

TABLE 1: KEY TREATMENT-EMERGENT ADVERSE EVENTS OCCURRING IN DEXMEDETOMIDINE- OR MIDAZOLAM-TREATED PATIENTS IN THE RANDOMIZED ACTIVE COMPARATOR CONTINUOUS INFUSION LONG-TERM ICU SEDATION STUDY

Includes any type of hypertension. 1. Hypotension was defined in absolute terms as systolic blood pressure of <80 mmHg or diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2. Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3. Hypertension was defined in absolute terms as systolic blood pressure >180 mmHg or diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4. Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.

†

The following adverse events occurred between 2 and 5% for Precedex and midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%) and respiratory failure (4.5%, 3.3%). TABLE 2: PERCENT OF SUBJECTS WHO HAD A DOSE-RELATED INCREASE IN TREATMENT-EMERGENT ADVERSE EVENTS BY MAINTENANCE ADJUSTED DOSE RATE RANGE IN THE PRECEDEX GROUP Precedex mcg/kg/hr Adverse Event Constipation Agitation Anxiety Oedema peripheral Atrial ﬁbrillation Respiratory failure Acute respiratory distress syndrome

0.7* N=95

! 0.7 to * N=78

! * N=71

6% 5% 5% 3% 2% 2% 1%

5% 8% 5% 5% 4% 6% 3%

14% 14% 9% 7% 9% 10% 9%

* Average maintenance dose over the entire study drug administration.

Ne enc Pl w los ea Sa ed se fet Im se yI p e nfo ort rm ant ati on

The right ﬁt FOR TODAY’S SEDATION MANAGEMENT PRACTICES

For step-by-step instructions on how to start using Precedex and what to expect, please visit us at www.Precedex.com. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex.1 Clinically signiﬁcant episodes of bradycardia and sinus arrest have occurred in young, healthy volunteers with high vagal tone or with different routes of administration such as rapid intravenous or bolus administration.1 Transient hypertension has been observed primarily during the administration of the loading dose. Treatment has generally not been necessary, although a reduction in loading dose infusion rate may be desirable.1

Hypotension and bradycardia can occur and may necessitate medical intervention such as —Decreasing or stopping Precedex infusion —Increasing rate of IV ﬂuid administration —Elevating lower extremities —Administering pressor agents such as atropine, ephedrine or glycopyrrolate1 Use with caution in patients with advanced heart block or severe ventricular dysfunction.1 The most common adverse effects (incidence >2%) are hypotension, bradycardia and dry mouth.1

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2010. 2. Kamibayashi T, Maze M. Clinical uses of α2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349. 3. Data on file. Hospira, Inc.

Hospira, Inc. 275 North Field Drive, Lake Forest, IL 60045 P10-3082-Dec., 10. Printed in the USA.

Advancing Wellness™

For more information on Advancing WellnessTM, contact your Hospira representative at 1-877-9HOSPIRA (1-877-946-7747) or visit www.hospira.com.

Reference EN-2680

Precedex®

(dexmedetomidine hydrochloride) injection

For Intravenous Use Rx only

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 1 1.1

INDICATIONS AND USAGE Intensive Care Unit Sedation Precedex® is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Precedex should be administered by continuous infusion not to exceed 24 hours. Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation. 1.2 Procedural Sedation Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Drug Administration Precedex should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously monitored while receiving Precedex. 5.2 Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration in young, healthy volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration. Reports of hypotension and bradycardia have been associated with Precedex infusion. If medical intervention is required, treatment may include decreasing or stopping the infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because Precedex has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of Precedex-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering Precedex to patients with advanced heart block and/or severe ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients. In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with Precedex. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Precedex. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable. 5.4 Arousability Some patients receiving Precedex have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. 5.5 Withdrawal Intensive Care Unit Sedation With administration up to 7 days, regardless of dose, 12 (5%) Precedex subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex subjects experienced at least 1 event 24 to 48 hours after end of

study drug. The most common events were nausea, vomiting, and agitation. Tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated. Procedural Sedation Withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours). 5.6 Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see Adverse Reactions (6.1)]. 5.7 Hepatic Impairment Since Precedex clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Use of Precedex has been associated with the following serious adverse reactions: • Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)] • Transient hypertension [see Warnings and Precautions (5.3)] Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth. Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1007 patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)]. Table 2: Adverse Reactions With an Incidence >2%— Intensive Care Unit Sedation Population <24 hours*

Adverse Event Hypotension Hypertension Nausea Bradycardia Atrial fibrillation Pyrexia Dry mouth Vomiting Hypovolemia Atelectasis Pleural effusion Agitation Tachycardia Anemia Hyperthermia Chills Hyperglycemia Hypoxia Post-procedural hemorrhage Pulmonary edema Hypocalcemia Acidosis Urine output decreased Sinus tachycardia Ventricular tachycardia Wheezing Edema peripheral

All Randomized Precedex Precedex Placebo Propofol (N = 1007) (N = 798) (N = 400) (N = 188) (%) (%) (%) (%) 25% 12% 9% 5% 4% 4% 4% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2%

24% 13% 9% 5% 5% 4% 3% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2%

12% 19% 9% 3% 3% 4% 1% 5% 2% 3% 1% 3% 4% 2% 3% 3% 2% 2%

13% 4% 11% 0 7% 4% 1% 3% 5% 6% 6% 1% 1% 2% 0 2% 3% 3%

2% 1% 1% 1%

3% 1% 0 1%

4% 3% 2% 2%

1% 1%

0 1%

2% 2%

<1% <1% <1%

1% 1% 0

1% 0 1%

5% 2% 2%

* 26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24 hours.

Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex for sedation in the surgical intensive care unit setting in which 387 patients received Precedex for less than 24 hours. The most frequently observed treatmentemergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3). Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Patients in the Randomized Placebo-controlled Continuous Infusion <24 Hours ICU Sedation Studies Adverse Event

Randomized Dexmedetomidine (N = 387)

Placebo (N = 379)

28% 16% 11% 7% 5% 4% 4% 4% 3% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2% 2%

13% 18% 9% 3% 4% 6% 3% 4% 5% 4% 2% 1% 3% 3% 3% 2% 2% 2% 1% <1% <1%

Hypotension Hypertension Nausea Bradycardia Fever Vomiting Atrial Fibrillation Hypoxia Tachycardia Hemorrhage Anemia Dry Mouth Rigors Agitation Hyperpyrexia Pain Hyperglycemia Acidosis Pleural Effusion Oliguria Thirst

In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex group is provided in Table 5. Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study* Adverse Event Hypotension1 Hypotension requiring intervention Bradycardia2 Bradycardia requiring intervention Systolic Hypertension3 Tachycardia4 Tachycardia requiring intervention Diastolic Hypertension3 Hypertension3 Hypertension requiring intervention† Hypokalemia Pyrexia Agitation Hyperglycemia Constipation Hypoglycemia Respiratory Failure Renal Failure Acute Acute Respiratory Distress Syndrome Generalized edema Hypomagnesemia

Dexmedetomidine (N=244)

Midazolam (N=122)

56%

28% 42%

27% 19%

5% 28% 25%

1% 42% 44%

10% 12% 11%

10% 15% 15%

19% 9% 7% 7% 7% 6% 5% 5% 2%

30% 13% 2% 6% 2% 6% 6% 3% 1%

2% 2% 1%

1% 6% 7%

† Includes any type of hypertension. 1 Hypotension was defined in absolute terms as Systolic blood

pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.

The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 5. Number (%) of subjects who had a dose-related increase in Treatment Emergent Adverse Events by maintenance adjusted dose rate range in the Precedex group Precedex mcg/kg/hr Adverse Event

≤ 0.7* N = 95

> 0.7 to ≤ 1.1* N = 78

> 1.1* N = 71

6% 5% 5% 3% 2% 2%

5% 8% 5% 5% 4% 6%

14% 14% 9% 7% 9% 10%

Constipation Agitation Anxiety Oedema peripheral Atrial fibrillation Respiratory failure Acute Respiratory Distress Syndrome

*Average maintenance dose over the entire study drug administration

Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation in which 318 patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, 30% ≥65 years of age, 52% male and 61% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between Precedex and comparator groups in both studies. Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population

Adverse Event Hypotension1

Respiratory depression2 Bradycardia3 Hypertension4 Tachycardia5 Nausea Dry mouth Hypoxia6 Bradypnea

Precedex N = 318 (%)

Placebo N = 113 (%)

54% 37% 14% 13% 5% 3% 3% 2% 2%

30% 32% 4% 24% 17% 2% 1% 3% 4%

Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg.

Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.

Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.

Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg.

Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.

Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.

Postmarketing Experience The following adverse reactions have been identified during post approval use of Precedex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex during post approval use of the drug.

Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex Body System

Preferred Term

Body as a Whole

Fever, hyperpyrexia, hypovolemia, light anesthesia, pain, rigors

Cardiovascular Disorders, General

Blood pressure fluctuation, heart disorder, hypertension, hypotension, myocardial infarction

Central and Peripheral Nervous System Disorders

Dizziness, headache, neuralgia, neuritis, speech disorder, convulsion

Gastrointestinal System Disorders

Abdominal pain, diarrhea, vomiting, nausea

Heart Rate and Rhythm Disorders

Arrhythmia, ventricular arrhythmia, bradycardia, hypoxia, atrioventricular block, cardiac arrest, extrasystoles, atrial fibrillation, heart block, t wave inversion, tachycardia, supraventricular tachycardia, ventricular tachycardia

Liver and Biliary System Disorders

Increased gamma-glutamyl transpepsidase, hepatic function abnormal, hyperbilirubinemia, alanine transaminase, aspartate aminotransferase

Metabolic and Acidosis, respiratory acidosis, Nutritional Disorders hyperkalemia, increased alkaline phosphatase, thirst, hypoglycemia Psychiatric Disorders

Agitation, confusion, delirium, hallucination, illusion

Red Blood Cell Disorders

Anemia

Renal Disorders

Blood urea nitrogen increased, oliguria

Respiratory System Disorders

Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion

Skin and Appendages Disorders

Increased sweating

Vascular Disorders

Hemorrhage

Vision Disorders

Photopsia, abnormal vision

OVERDOSAGE The tolerability of Precedex was studied in one study in which healthy subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute. Five patients received an overdose of Precedex in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted Precedex (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

6.2

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Licensed from: Orion Corporation Espoo, Finland Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA

April 2011

AnesthesiologyNews.com I 13

COR R ESPONDENCE Editor’s note: A version of this letter also appears in the April 2011 issue of our sister publication, Gastroenterology & Endoscopy News.

To the Editor:

ince the completion of our gastroenterology fellowships in 1978 and 1990, we have worked in a community-based 100% GI practice on Long Island. For the last 20 years, we have been routinely utilizing anesthesiology services in our office with propofol administration. Until now, we have remained on the sidelines, well aware of the raging propofol debate and the extensive literature about same. However, at this point, we feel it is time for community-based gastroenterologists to finally take a position in these discussions, and to have our voices heard. There is a mandate for colorectal cancer screening in appropriate populations.

Among the many barriers to screening include the fears that such examinations may be painful and/or result in complications. In most gastroenterologists’ experiences, patient satisfaction is highest when propofol, either as monotherapy or in combination with other medications, is administered. In turn, patients are more likely to undergo subsequent procedures when they are satisfied with their initial examination. In an era when the number of gastroenterologists available to perform such screening is inadequate, and hospital endoscopy suites and ambulatory surgery centers (ASCs) have been overwhelmed, many GI practices, including ours, rely primarily on office-based endoscopy. In New York, legislation has mandated that all facilities be accredited by a certifying organization, either the Joint Commission, AAAHC or AAAASC.

Readers Respond

he three-part series, “Life in a Fix,” by Joel Freedland, DO, prompted a range of comments from readers. Reactions varied from admiration at Dr. Freeland’s candid depiction of his struggle with addiction and his criminal behavior, to outrage at his actions and their consequences. Below are a few of the posts we received on AnesthesiologyNews.com. (These comments have been edited for spelling, punctuation and grammar. E-mail addresses have been truncated to preserve author privacy.)

oung doctors who work for this type of clinic manager end up with him using you and your ID and billing rights to feed his habit. He will report you as billing and stealing money from him when [in reality] he did it to you. And if you leave, he has all that he needs to feed him ... and accuse you of doing illegal billing … and not seeing patients and it is federal investigations … and you cannot work or bill Medicaid until this issue has been resolved under your billing name. HE MADE YOU HIS SLAVE … and ruined your life … like Don King said, ONLY IN AMERICA. jotto...

As we are not partners in an ASC, and our hospitals cannot easily accommodate the needs of our patients and practice, we attained Joint Commission certification. When reviewing the options of undergoing procedures, our patients generally prefer the friendlier, less intimidating atmosphere, and the convenience, of the office to the hospitals. Patient safety and comfort are paramount, and the office-based setting lends itself to increased efficiency. New York law and propofol labeling information do not permit non-anesthesiologists to administer propofol. When nurse anesthetists administer propofol, there must be an anesthesiologist physically present overseeing that provider. In hospital and ASC settings, there is an anesthesiology presence, often with many other medical professionals, including physicians, nurses, see propofol page 14

would like to commend Dr. Freedland for his courage in sharing this story. Physician addiction is an under-recognized, understudied and undertreated problem with significant consequences for the physicians and their loved ones, as well as for public health and safety. More effort is needed to raise awareness of this critical problem, to improve addiction education for medical students and physicians and to destigmatize physicians’ attempts to obtain treatment for addiction. Recent research studies have demonstrated that (1) rates of prescription drug misuse are particularly high among physicians, (2) physicians feel unprepared to intervene when they suspect a colleague is impaired by substance abuse, and (3) participation in physician health programs (i.e., state monitoring programs for impaired physicians) is associated with successful recovery for the overwhelming majority of physicians. When addicted physicians share their stories, others may benefit from learning that treatment actually can help the physician return to a productive life and regain what has been lost. All physicians and their colleagues would benefit from knowing more about addiction assessment, treatment and monitoring options coordinated by their state physician health program. Lisa J. Merlo, PhD, MPE

Assistant professor of psychiatry, University of Florida College of Medicine, director of research, Professionals Resource Network, Inc., Gainesville, Fla.

s a recovering addict myself, I applaud Dr. Freedland’s courage in telling his life story. It takes a great determination and recovery processes to come out of the closet

and to show who he really is. His discovery of true life and his existence as a plain human being humble me. How many people would really understand why he did what he did and why he started destroying himself when he

had other options to become successful. I do! That’s why [the American Medical Association] defined addiction as a disease in 1953. Truly remarkable! bkim1...

14 I AnesthesiologyNews.com

April 2011

COR R ESP ONDENCE Propofol continued from page 13

metropolitan New York, it has become the standard of care for anesthesiolomedical assistants and house staff, avail- gists to be involved with all patients able in case an emergency arises. undergoing endoscopic procedures. In In the community setting, we are our opinion, ACLS certification, which “an island,” with a smaller margin for entails learning various arrhythmia and error, often without many of those airway algorithms, working on a manother back-up resources. Most com- nequin and passing an examination, in munity gastroenterologists do not feel no way makes us comfortable or even comfortable administering propofol qualified to take care of that occasional and/or being solely responsible for car- patient who is in trouble. Neither does diopulmonary issues that might arise taking a weekend course or being procduring the course of procedures. In tored for some length of time by an

“expert.” The potential FDA approval of an automated propofol administering and monitoring device does not make patient care “dummy-proof ” or safest for a given patient, because in the event of a misadventure, a “rescue expert” is not immediately available to assist. It is ludicrous to assume that such training or new technology will render community gastroenterologists as competent as anesthesia professionals. As community gastroenterologists, we are also concerned about the

THE

FLEXTIP PLUS DIFFERENCE

A UNIQUE DESIGN…SUPPORTED BY EVIDENCE

According to a meta-analysis that evaluated strategies to avoid epidural vein cannulation, “the effect size is so large that other techniques for reducing the risk of intravascular cannulation may be irrelevant if a wire-embedded polyurethane catheter is used.”1

Trust the evidence: Catheter design matters. Teleflex’s Arrow ® FlexTip Plus Epidural Catheter with its unique wire-embedded polyurethane design has been clinically proven to virtually eliminate the incidence of intravascular cannulation1,2,3 and effectively reduce transient paresthesia.2,4 The FlexTip Plus Difference: A wire-embedded polyurethane design. Other springwound catheters are made of nylon. When compared to nylon catheters, this unique design was associated with: 3,4 3,4 1,2,3,4 4 3,4

Call Teleflex customer service at 866.246.6990 today to experience the FlexTip Plus Difference. 1. Mhyre, Jill M., et al. A Systematic Review of Randomized Controlled Trials That Evaluate Strategies to Avoid Epidural Vein Cannulation During Obstetric Epidural Catheter Placement. Anesthesia & Analgesia 2009; 108 (4): 1232-1242. 2. Banwell B.R., et al. Decreased incidence of complications in parturients with the Arrow (FlexTip Plus™) epidural catheter. Canadian Journal of Anaesthesia 1998; 45 (4): 370-372. 3. Cohen S., et al. Sutured Epidural Catheter for Epidural Block in obstetric Patients:“Arrow” versus “B. Braun”. Anesthesiology 2006;105: A904. 4. Cohen S., et al. Arrow versus B. Braun Epidural Catheter for Epidural Block in Obstetric Patients. Anesthesiology 2004; 101: A1199.

Caution: Federal law restricts this device to sale by or on the order of a physician. Arrow, FlexTip Plus, and Teleflex are registered trademarks of Teleflex Incorporated or its affiliates. ©2010 Teleflex Incorporated. All rights reserved. 2010-0383 v1

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medicolegal risks of having a complication in the office setting, especially one that might have been more quickly recognized and successfully handled by an anesthesia professional. Very few practitioners will closely adhere to practice guidelines when a potential catastrophic outcome can result in litigation. In addition, we are more likely to discover advanced colorectal neoplasia when our attention remains focused on the job at hand. We should keep both eyes on the video screen and have the anesthesia professional monitor the patients. It is only a matter of time before lawsuits are brought for missed neoplasms that arguably may have been (partially) caused by the gastroenterologists’ attention being diverted by monitoring the patient and/or administering anesthesia themselves. The argument to “turn back the clock” by some prominent gastroenterologist proponents of nonanesthesiologist-administered propofol (NAAP) is reminiscent of the debate regarding performance of liver biopsies. We recall the time when we regularly performed liver biopsies ourselves, without radiologic guidance or sedation. However, after many recognized that the procedure could be done more safely and comfortably by interventional radiologists, and after a spate of lawsuits for misadventures that might have been avoided by using the technology and expertise at hand, most gastroenterologists in our community no longer perform that procedure, despite the greater costs that are incurred as a result. Certainly we need to remain vigilant regarding the ever-increasing costs of health care, and to identify and implement ways to rein in such costs. However, as medical science marches forward, cost containment remains problematic, particularly in the absence of tort reform. Although we fully anticipate reading a lot more about NAAP and automated propofol machines that have the potential to marginalize anesthesiologists, there are numerous barriers to community gastroenterologists implementing same. Our GI societies and leaders do not seem to comprehend that medicine is not “one size fits all,” that hospital-based physicians and those of us who do much of our work in office-based facilities have disparate needs, experiences, back-up systems and comfort levels. We must all persevere in our quest to do what we feel is in the best interest of our patients. —Perry J. Milman, MD, and Steven P. Goldenberg, MD The authors practice in Lake Success, N.Y.

April 2011

AnesthesiologyNews.com I 15

COR R ESPONDENCE

—Timothy Flint, MS, CRNA Mr. Flint is director of anesthesia at Lexington Medical Center in West Columbia, S.C. The author has no financial conflicts of interest to disclose pertaining to the content of this letter.

Contact the editor of Anesthesiology News

ama rcu s

To the Editor: read with interest the article on the cost of volatile anesthetics (Anesthesiology News, November 2010, page 11). My institution also was able to control our expenditures on these drugs, without altering our choice of agent. As with all anesthesia departments, pharmaceuticals are our highest nonlabor supply expense. Volatile agents accounted for 96% of our overall drug budget. During the initial investigation into our outlays, we discovered that our anesthesia machine had a feature that we were not taking full advantage of. The feature we discovered is a program within the machine that helps to reduce waste and better preserve patient temperature, while also lowering drug costs. The software shows practitioners when the flows are too high, when they’re too low and when they are efficient for individual patients. We tested the effect of the software by comparing data between October 2008 to March 2009, before we used the feature, and October 2009 to March 2010, after we began using it routinely. We instructed our anesthesia providers to keep their maintenance flows in the efficient zone, but to choose the volatile agent they felt was best suited for the patient. To minimize any confounding data, we also reviewed our case volume and type of anesthetics in both time frames. Case volume did not change significantly across the study period, with volume holding steady at about 7,700 cases every six months. The percentage of general anesthetic cases remained the same, at 79% for both time frames. The type of anesthetic agent used also remained consistent, with desflurane (Suprane, Baxter) chosen 76% of the time for all general anesthetic cases before and after the intervention. The major impact, however, was in cost. By using the low-flow feature, we cut our monthly expenditure on anesthetic agents by an average of $8,800— or $105,600 per year. This savings has been consistent since we started the program and has more than met our goal to reduce pharmaceutical costs without limiting our drug options.

onmed.com mah c m @

NAROPIN® delivers a faster return of motor function than bupivacaine.1,2 A Block Well Done. NAROPIN provides 8 to 10 hours faster return of motor function following total knee replacement than bupivacaine (P<0.05).1 To learn more about the clinical beneﬁts of NAROPIN, visit www.naropin-us.com.

Using NAROPIN beyond recommended doses to increase motor block or duration of sensory block may negate its favorable cardiovascular advantages, in the event that an inadvertent intravascular injection occurs. Like all amide-type local anesthetics, NAROPIN may be associated with adverse reactions. In clinical trials, side effects were mild and transient and may reﬂect the procedures, patient health status, and/or other medications used. Adverse events reported at a rate of ≥5%: hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain. Important Safety Information There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. NAROPIN is not approved for this use. Please see dosage and administration details in Prescribing Information at www.naropin-us.com. Please see accompanying brief summary of Prescribing Information. www.naropin-us.com

NAROPIN is indicated for the production of regional or local anesthesia for surgery and for acute pain management. References: 1. Beaulieu P, Babin D, Hemmerling T. The pharmacodynamics of ropivacaine and bupivacaine in combined sciatic and femoral nerve blocks for total knee arthroplasty. Anesth Analg. 2006;103:768-774. 2. Morrison LM, Emanuelsson BM, McClure JH, et al. Efﬁcacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth. 1994;72:164-169. Naropin® and logo are registered trademarks of APP Pharmaceuticals, LLC. and APP ® are registered trademarks of APP Pharmaceuticals, LLC. ©2011, APP Pharmaceuticals, LLC. All Rights Reserved. 0155-NAR-05-2/11

WHY COMPROMISE?

16 I AnesthesiologyNews.com

April 2011

IN B R I E F

Meta-analyses Ignore Financial Conflicts in Trials

ooled analyses of randomized controlled drug trials rarely if ever specify whether the original research had ties to pharmaceutical companies with a stake in the findings. That’s the conclusion of a recent study that found that only two of 29 meta-analyses (7%) reported the funding sources of the 509 drug trials they covered and none offered information about whether the authors of

Naropin

(ropivacaine HCl) Injection

The study, published in the March 9 issue of the Journal of the American Medical Association, found that 219 of 318 (69%) trials in the meta-analyses that identified their funding sources had received support from pharmaceutical companies. Only about 25% of the 509 studies provided financial disclosures for the authors involved in the work. Of those that did so, 69% listed at least one

the pooled studies worked for or had received funding from industry. The researchers focused on metaanalyses published in 2009 in major journals with high-impact factors. They looked at trials of patented drugs in five clinical areas—oncology, cardiology, respiratory medicine, endocrinology and gastroenterology— known for strong sales of prescription medication.

BRIEF SUMMARY INDICATIONS AND USAGE Naropin is indicated for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration. Acute Pain Management: epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration. CONTRAINDICATIONS Naropin is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type. WARNINGS In performing Naropin blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of Naropin for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. Naropin should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/ circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously. Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an i.v. line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies that may arise from the block to be employed, and then only after ensuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies (See also ADVERSE REACTIONS, PRECAUTIONS, and MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2-3 minutes, extended to the T10 level in 10-13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive. PRECAUTIONS: General: The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions, which contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Administration of higher than recommended doses of Naropin to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block. Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (MH). Amide-type local anesthetics are not known to trigger this reaction. However, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for MH management should be available. Epidural Anesthesia: During epidural administration, Naropin should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When clinical conditions permit, the test dose should contain an appropriate dose of epinephrine to serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart should be continuously monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a rise in systolic blood pressure. A test dose of a shortacting amide anesthetic such as lidocaine is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Use in Brachial Plexus Block: Ropivacine plasma concentrations may approach the threshold for central nervous system toxicity after the administration of 300 mg of ropivacaine for brachial plexus block. Caution should be exercised when using the 300 mg dose. (See OVERDOSAGE.) The dose for a major nerve block must be adjusted according to the site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used. Use in Peripheral Nerve Block: Major peripheral nerve blocks may result in the administration of a large volume of local anesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations. Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) Use in Ophthalmic Surgery: The use of Naropin in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of Naropin for such surgery is not recommended. Drug Interactions: Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (e.g., amiodarone) have not been performed, but caution is advised (see WARNINGS). Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Naropin, can interact with Naropin leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. Pregnancy Category B: There are no adequate or well-controlled studies in pregnant women of the effects of Naropin on the developing fetus. Naropin should only be used during pregnancy if the benefits outweigh the risk. Labor and Delivery: Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and PHARMACOKINETICS). The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia with Naropin for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural anesthesia has been reported to prolong the second stage of labor by removing the patient’s reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving Naropin than in those receiving

bupivacaine. Nursing Mothers: Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total Naropin dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see Precautions). Pediatric Use: The safety and efficacy of Naropin in pediatric patients have not been established. Geriatric Use: Of the 2,978 subjects that were administered Naropin Injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older, which includes 127 patients (4%) 75 years of age and over. Naropin Injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function. (See PHARMACOKINETICS, Elimination.) ADVERSE REACTIONS Reactions to ropivacaine are characteristic of those associated with other amidetype local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation. The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to Naropin at concentrations up to 1.0% in clinical trials. Each patient was counted once for each type of adverse event. Incidence ≥5%: For the indications of epidural administration in surgery, cesarean section, postoperative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥5% in all clinical studies (N=3988): hypotension (37.0%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8.0%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5.0%). Incidence 1-5%: Urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection. Incidence in Controlled Clinical Trials: The reported adverse events are derived from controlled clinical studies with Naropin (concentrations ranged from 0.125% to 1.0% for Naropin and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Tables 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin-treated patients in these studies. The majority of patients receiving concentrations higher than 5.0 mg/mL (0.5%) were treated with Naropin.

author with a financial tie to the drug industry, according to the researchers. In seven cases, every study in the meta-analysis disclosed at least one potential conflict of interest—such as sponsorship by a drug maker or an author employed by the company whose drug product was being studied. But one of those meta-analyses noted the sources of funding and none reported any of the financial ties or employment connections, the researchers said. “Without acknowledgment of [conflicts of interest] due to industry funding or author–industry financial ties” in the studies that meta-analyses cover, “readers’ understanding and appraisal of the evidence from the meta-analysis may be compromised,” the authors wrote. (And yes, the authors of the JAMA study provided a lengthy disclosure statement at the end of their article.) —Adam Marcus

Table 3A Adverse Events Reported in ≥1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Post-Operative Pain Management, Peripheral Nerve Block and Local Infiltration)

Adverse Reaction Hypotension Nausea Vomiting Bradycardia Headache Paresthesia Back pain Pain Pruritus Fever Dizziness Rigors (Chills) Postoperative complications Hypoesthesia Urinary retention Progression of labor poor/failed Anxiety Breast disorder, breast-feeding Rhinitis

N 536 283 117 96 84 82 73 71 63 61 42 42 41 27 23 23 21 21 18

Naropin total N=1661

(%) (32.3) (17.0) (7.0) (5.8) (5.1) (4.9) (4.4) (4.3) (3.8) (3.7) (2.5) (2.5) (2.5) (1.6) (1.4) (1.4) (1.3) (1.3) (1.1)

N 408 207 88 73 68 57 75 71 40 37 23 24 44 24 20 22 11 12 13

Bupivacaine total N=1433

(%) (28.5) (14.4) (6.1) (5.1) (4.7) (4.0) (5.2) (5.0) (2.8) (2.6) (1.6) (1.7) (3.1) (1.7) (1.4) (1.5) (0.8) (0.8) (0.9)

Table 3B Adverse Events Reported in ≥1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies)

Adverse Reaction Fetal bradycardia Neonatal jaundice Neonatal complication-NOS Apgar score low Neonatal respiratory disorder Neonatal tachypnea Neonatal fever Fetal tachycardia Fetal distress Neonatal infection Neonatal hypoglycemia

N 77 49 42 18 17 14 13 13 11 10 8

Naropin total N=1661

(%) (12.1) (7.7) (6.6) (2.8) (2.7) (2.2) (2.0) (2.0) (1.7) (1.6) (1.3)

N 68 47 38 14 18 15 14 12 10 8 16

Bupivacaine total N=1433

(%) (11.9) (8.2) (6.6) (2.4) (3.1) (2.6) (2.4) (2.1) (1.7) (1.4) (2.8)

OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered, or large doses administered, during therapeutic use of local anesthetics or to unintended subarachnoid or intravascular injection of local anesthetic solution. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES: Therapy with Naropin should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with Naropin; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of Naropin, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic and during continuous infusion. At the first sign of change in mental status, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Circulation should be assisted as necessary. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control convulsions. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, nonpregnant and pregnant sheep were 4.9, 6.1 and 5.9 mg/kg, respectively. These doses were associated with peak arterial total plasma concentrations of 11.4, 4.3 and 5.0 μg/mL, respectively. In human volunteers given intravenous Naropin, the mean (min-max) maximum tolerated total and free arterial plasma concentrations were 4.3 (3.4-5.3) and 0.6 (0.3-0.9) μg/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted. Clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen, which may avoid cardiac arrest. If difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated, endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of nonpregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts.

APP Pharmaceuticals, LLC

0155-NAR-05-2/11

Rev. 11/08

Could a VAD Cause vWD?

hile more treatments for von Willebrand disease (vWD) flow through the pipeline, other state-of-the-art medical therapeutics may be creating new cases of the disease. Recent studies point to particular risks associated with ventricular assist devices (VADs). “Bleeding after VAD implantation is becoming a problem following the introduction of the continuous flow VAD design,” said Sheri Crow, MD, of Mayo Clinic, in Rochester, Minn. “Understanding why these patients bleed and finding ways to prevent it will help ensure that they continue to experience the quality of life they have come to enjoy postVAD,” added Dr. Crow, who recently led two studies on the potential link (ASAIO J 2010:56:441-445; Ann Thorac Surg 2010:90:1263-1269). Dr. Crow and colleagues studied 51 patients who received VADs and found that all of them acquired an abnormality in the von Willebrand factor after implantation. Although not all of the patients had bleeding complications, the researchers suggest that the clotting dysfunction could be associated with a higher risk. The non-pulsatile flow generated by a VAD might result in gastrointestinal

April 2011

AnesthesiologyNews.com I 17

IN BR IE F

New Substance Abuse/Addiction Teaching Resources Available From NIDA

ow much are medical students taught about substance abuse and addiction? Would young clinicians be able to tell if a patient was at risk for addiction? Unfortunately, medical school curricula and commitment to the subject of addiction vary widely. To improve drug abuse and addiction training of future physicians, the National Institute on Drug Abuse (NIDA) recently released three new teaching resources through its physician outreach initiative NIDAMED. The new teaching tools include: • an objective structured clinical examination from Boston University School of Medicine on opioid risk management that covers how to initiate and manage longterm opioid therapy in patients with chronic pain, and how to discuss the risks and benefits of opioids with patients; • a lecture presentation from the University of North Dakota School of Medicine & Health Sciences on how to talk to patients about sensitive subjects, including drug/alcohol use and abuse,

vascular changes, Dr. Crow explained, which could make patients particularly vulnerable to bleeding. But she also highlighted the need for more research to clarify the link and to understand the best management for the problem. “Currently, there are no clear therapies that will treat the von Willebrand factor destruction,” said Dr. Crow, noting that replacement clotting factors hadn’t proven useful. “The most common management is to reduce or stop anticoagulation until the bleeding stops. “Patients who present with bleeding should have a thorough workup to identify and treat anatomical bleeding sources,” she said. ”Transfusion and bleeding time correction should be applied as needed to maintain blood pressure stability in the face of bleeding.” —Lynne Peeples

intimate partner violence and sexual history/concerns; and • a methamphetamine lecture and a design for a clinical interclerkship for third-year medical students, developed by Creighton University, that introduces medical students to methamphetamine abuse and dependence, including its mechanism of action, short- and long-term effects and treatment.

The NIDA curriculum resources are offered in multiple formats, including a Web module, an objective structured clinical examination, an interclerkship, problem- and case-based studies, lectures and a faculty workshop—all of which can be incorporated into existing medical school instruction. The NIDAMED program offers physicians and other health care providers evidence-based tools to enable

them to be the first line of defense against substance abuse and addiction and to increase awareness of the likely impact of substance abuse on a patient’s overall health. For more information, go to http:// www.drugabuse.gov/coe/cr-overview. htm. —Based on a press release from NIDA

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TECHNOLOGY

Strengthening Strategies To Deter Drug Diversion

ast October, Philadelphia’s Temple University Health System paid a $130,000 fine to the U.S. government and saw the drug conviction of two of its anesthesiologists. The hospitals, according to the feds, hadn’t done enough to try to prevent physicians from pocketing controlled substances intended for patients. The guilty medical centers are not alone. The rate of drug and alcohol addiction among practicing physicians is estimated to be between 10% and 12%, a figure similar to the general population. Around 7% of nurses are thought to misuse prescription drugs, and approximately 6% of pharmacists in one study identified themselves as drug abusers at some point in their careers (J Am Pharm Assoc 2001;41:392-400). Although it is difficult to know just how frequently drug diversion occurs, experts have put the figure between 1% and 2%. Increasingly sophisticated tools, such as automated drug dispensing cabinets and software that mines the cabinet’s data in search of abnormalities, have helped a growing number of U.S. hospitals with the difficult task of tracking drug diversion. But even the facilities that now use some form of the technology— including the approximately 85% that have the kiosks to store, dispense, control and track medications near the point of care—cannot rest assured that narcotics or sedatives will always make the full journey from pharmacy to patient. “We have the same cross-section of people who work in a hospital that we do in life. Not everybody is perfect,” said Ray Vrabel, PharmD, senior director for medication systems strategy at Omnicell, Inc. “And no matter how hard we work at having tight systems, it’s a continuous effort to try to outsmart people who are trying to beat the system.” Omnicell recently announced its acquisition of Pandora Data Systems, a leading developer of analytic software for medication diversion detection. Dr. Vrabel said he is hopeful that the union will result in more powerful tools to outsmart drug diverters than could be produced by the two individually. Two decades ago, before the advent of computerized tracking, drug diversion was extremely difficult to detect, let alone control. A locked box full of medicine generally sat in a nursing unit, with one shared key. Nurses were supposed to record in a ledger every dose removed from the box and given to a patient. “Filling out the ledger wasn’t exactly

Nurse Jane is the nurse? Is Nurse Joe taking stuff out and keeping some for himself, and thereby endangering his patients, himself and those that might cross his path on his drive home?” Carl Washburn, PharmD, pharmacy director at Dominican Santa Cruz Hospital, in California, has several years of experience with both Omnicell and Pandora technologies. The hospital curDrug Task Force rently uses the duo prospectively every John Burke, now commander of the month to look for evidence of anything Warren County Ohio Drug Task Force, going wrong. Dr. Washburn noted that probably knows the evolution of drug the system highlights a person of interdiversion tracking better than anyone. est four to six times a year, with about After more than 20 years with the Cin- half of them going on to some form of cinnati police, he formed and, from rehabilitation. When they find something, they look 1990 to 1999, headed the division’s their highest priority,” recalled Dr. Vrabel, who also is a 40-year veteran pharmacist. “Discrepancies resulted from even the best of them.” But just how often drugs were diverted is hard to know. Only when a nurse or other health care worker was caught would the ledgers be studied for evidence.

‘Dispensing cabinets and analytic software [are] tremendous tools … if you’ve got a [drug] diversion and are trying to shore down the investigation to who might be responsible.’ —John Burke

Pharmaceutical Diversion Squad. His team’s work originally entailed thumbing through piles of papers, looking for clues. “The age of computerization really changed the job. The dispensing cabinets and analytic software became tremendous tools to be proactive, or reactive if you’ve got a diversion and are trying to shore down the investigation to who might be responsible,” said Cmdr. Burke, whose unit was arresting a nurse every seven days in Cincinnati at the time he left. Continuous surveillance via the cabinets and coupled software can offer hints of abnormal drug movement, such as high usage and wastage, as well as drugs withdrawn from the cabinet after cases are finished or for patients to whom the dispensing provider was not assigned. “These reporting solutions can look at behaviors of people handling controlled substances to determine whether or not their behaviors are different from the norm,” noted Dr. Vrabel. “Why is it when Nurse Joe is the nurse his patients seem to be in pain more than when

deeper and then try to intervene early. Of course, just because someone gets flagged as having unusually high numbers of dispensed drugs, doesn’t mean there has been any wrongdoing, Dr. Washburn noted. One individual’s work schedule, for example, may simply be different from that of their colleagues. The challenging investigative work has become further complicated in recent years with the shortage of nurses. Rather than sticking with one unit, nurses now frequently work several, which means the use of several different dispensing cabinets. Perhaps even more difficult to track now is the behavior of traveling nurses. Most of their contracts last only 13 weeks, noted Dr. Washburn, while the reports generally don’t have the power to detect anomalies without at least 90 days of data. Not all hospitals are as cooperative as Dominican Santa Cruz in reporting diversion, despite the fact that the failure to do so is a federal crime. Rules and regulations vary by state, but the

U.S. Drug Enforcement Administration requires hospitals and nursing homes to report any loss of controlled substances, which account for most of the diversion. Cmdr. Burke pointed out that diversion is not necessarily something that hospitals want to publicize to their potential customers. “It’s often the case that the perpetrating nurse just gets fired, which doesn’t help the nurse, and allows him or her to just go on to the next facility and endanger other patients,” he said. “If a hospital doesn’t put emphasis on this, the facility will eventually get filled with people who are diverting drugs. “Diversion happens every day in this country, in multiple places, and is often not reported. We really need to drive home the message that we’re serious about reporting these diversions,” he added. “Then maybe we’ll get a better handle on the numbers, better protect patients, and catch addicts earlier so they can go into successful rehab.” Enhanced Drug Tracking With the Omnicell-Pandora merger, Dr. Vrabel said he anticipates fewer gaps for abusers to slip through. One of the new features is the tracking of the final leg of a drug’s journey: administration to a patient. “At end of the day, the health care provider that has the drugs in their hand to administer has an opportunity that no other people have, because that patient will not necessarily know if they got exactly what they were supposed to get,” Dr. Vrabel said. “That’s been one of the missing pieces of the puzzle.” Obtaining these new data would entail linking the cabinet’s dispensing data with electronic documentation of drug administration, which is currently available in about 45% of hospitals and expected to reach 100% in the next two years due to new federal requirements. When what was dispensed, wasted and returned doesn’t match up with what was administered, a report will be triggered just as it is for the currently retrievable clues of abnormal behavior. “These reporting and analytical solutions create an environment in which a good person, who might stray to sneak through a red light if there wasn’t a camera, will likely be a lot more cautious,” Dr. Vrabel said. “That’s what we want,” he added, “to keep good people good and delivering care to patients. And then if someone bad comes along, we can catch them.” —Lynne Peeples

Please visit us at the ASRA Booth #212

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Sedation Resource

The following advertorial is provided as a service to our valued advertisers. It is designed to support the advertisement presented below.

Q. What is the Sedation Stethoscope?

mobility you want with the continuous monitoring you need.

A. The Sedation Stethoscope is an amplified Bluetooth® wireless stethoscope used to monitor ventilation. The Piezo version of the Sedation Stethoscope has the microphone built into the chest piece, which reduces ambient noise and produces diagnostic quality sound. With the Sedation Stethoscope Classic, the microphone is built into the line, which allows the interchange of various sizes of Wenger chest pieces or use of an esophageal probe. With either type of Sedation Stethoscope, you can obtain the

Q. How is the Sedation Stethoscope different from a traditional precordial/ pretracheal stethoscope? A. The Sedation Stethoscope provides amplified auscultation with the mobility of a wireless headset or speaker. Bluetooth® technology removes the tether previously associated with a traditional precordial stethoscope. The range of sound

is approximately 30 feet, enabling the clinician to move about the procedure room while continuously monitoring the patient.

Q. How does the Sedation Stethoscope help anesthesiologists monitor patients? A. Foundational monitoring of ventilation is listening to breath sounds. Traditionally, the clinician was tethered to the patient with a short length of tubing, but many clinicians abandoned the use of

precordial stethoscopes when capnographs were introduced. Bluetooth® technology and the amplification of the Sedation Stethoscope is allowing anesthetists to return to the standard principle of listening to the airway for those subtle clues that tell when a patient is about to obstruct.

Q. How does monitoring with the Sedation Stethoscope compare with capnography? A. Capnography is an effective tool; however, it cannot reveal the slight airway changes that can occur during a procedure. The anesthesiologist is still the most important monitor in the room and the type of equipment chosen should extend his or her senses. The Sedation Stethoscope allows clinicians to move about freely and still have early warning of potential airway difficulties even before the patient moves, coughs or obstructs. Continuous auscultation should be the first line of defense against life-threatening respiratory distress.

Q. How can the Sedation Stethoscope save lives? A. When listening to your patients’ breathing, it is not necessary to watch a waveform or wait for an alarm to realize they are having respiratory difficulty. Because of this, the Sedation Stethoscope has become an invaluable tool in many teaching institutions across the country. The instructor can monitor ventilation alongside the student, helping to ensure the patient’s airway patency and increasing instructional opportunities. Critical incidents have been documented where an attending physician was on the opposite side of the room and was able to detect problems. Using the Bluetooth® Sedation Stethoscope, the physicians have been able to intervene early and prevent the patient from respiratory distress, which could have resulted in a more negative outcome.

Q. How does the Sedation Stethoscope support regulatory compliance? A. The Sedation Stethoscope’s noninvasive method of monitoring breath sounds is compliant with the guidelines for monitoring respiratory functions during anesthesia, which require ventilation to be monitored continually (periodically) during moderate sedation and continuously (uninterrupted) during deep sedation and general anesthesia.

Our Customer Service Policy Sedation Resource brings a fresh and innovative approach to the sedation market with a goal to be the most honest and ethical trade partner of choice—consistently providing superior service, and creating an atmosphere that encourages new ideas, innovations and growth. Please feel free to call for more information (800) 753-6376, or visit us at www.sedationstethoscope.com.

April 2011

AnesthesiologyNews.com I 21

TECHNOLOGY

Smart Pump Libraries Not Optimized at Many Centers Anaheim, Calif.—Despite their potential benefits, such as reduced errors as well as improved efficiency and convenience, infusion pump libraries are not yet optimized at many hospitals, according to a presentation during the Safety and Quality Pearls session at the 2010 American Society of Health-System Pharmacists Midyear Clinical Meeting. “This is a key safety feature of intravenous infusion pumps that is completely under-utilized,” said presenter Elisabeth Mouw, PharmD, clinical coordinator of NICU/Pediatrics at the University of Chicago Medical Center (UCMC). When such libraries are implemented and used optimally, they maintain dosing guidelines based on concentrations and dose limits. Drug libraries that are unit-specific can reduce the number of medication choices visible to the end user, reducing confusion and delays, Dr. Mouw noted. Various units use “different medications and different concentrations,” she said, “so you can develop libraries for specific units that will help reduce the number of medications visible to the end user. The nurses will thank you when they are not floating through 10 different pages of medications to see what they need.” UCMC started using smart pumps in 2006, but had not initially optimized the pump libraries, according to Dr. Mouw. To facilitate improved use of the pump libraries, in November 2009, the medical center established a multidisciplinary team, with pharmacy playing a leadership role. The team developed different medication libraries for 11 patient care areas, evaluating all the intravenous fluids infused in those settings. They reviewed the fluids for appropriateness and simplicity with respect to weight-based dosing, maximum and minimum rates and standard admixtures, incorporating dosing tools to facilitate appropriate medication initiation as well as soft and hard upper and lower medication dose limits. Each library was set up to accommodate the preferences of the nurses in that particular patient care area, while attempting to minimize human factors that could affect library use. The team educated staff about the new medication libraries, and before rollout the hospital’s nurses had the opportunity to test pumps programmed with the new libraries.

The team assessed pump library use before and after implementation and found that it varied widely across patient care areas. Overall, use of the libraries rose from 2% to 25% before implementation to 7% to 89% 12 months after implementation. The big success story was in the NICU, which had the highest use of the pump libraries. The Women’s Care unit had the second-highest use of the libraries, at 66%. The reasons the nurses reported for not using the library included medication not located in the library, difficulty selecting the medication due to too many medication choices presented, concentration did not match that sent from the pharmacy, difficulty when patients changed care areas, and too time-consuming to use the library. Given the mixed success, the hospital is conducting an extensive re-education effort. It also has earmarked funding to update the smart pumps with wireless features and software upgrades. Once these upgrades are completed, the multidisciplinary team plans to update the libraries and educate the staff for a second time. Learning from the libraries with the highest use, Dr. Mouw said that the biggest benefit of using infusion pump libraries is reduced administration errors related to incorrect dose calculations. Additionally, she said, these libraries allow pharmacists to programin hard stop alerts to forestall programming errors. Lastly, she noted that the libraries provide an opportunity for data collection to allow for future improvements to the pumps. Dr. Mouw pointed out that infusion pump libraries are not static and may need to be modified based on several factors. Drug availability issues such as during drug shortages may require the use of concentrations that staff are not accustomed to using. Prescribing patterns as well as nursing and physician preferences also can necessitate adjustments to drug libraries. It is important to work closely with the nursing staff to ensure that the library is meeting all of their needs. Dr. Mouw said, “You do need to have the ability to modify your pump libraries as practice issues arise and formulary agents change.” —Sarah Tilyou

SonoPlex – THE Ultrasound Nerve Block Cannula With SonoPlex, PAJUNK® has developed a new cannula-generation, an innovation, which for the first time facilitates the unerring localization by means of ultrasound technology. The distal end of the cannula shaft has been equipped with a circumferential array of reflectors. The nature of the „Corner Stone“ reflectors renders optimal reflection properties in any position, at steep and at flat puncture angles as well.

Visible cannula tip The distal end has been provided with two pattern-embossed sections, each having a length of 10 mm and separated from each other by a blank zone, which provides for additional orientation. The visibility of the cannula therefore covers a total length of 20 mm, and it is thus distinctively recognizable.

The reﬂection guarantee The embossed indentations at the tip of the cannula are shaped as if the corner of a cube had been impressed into the surface: This renders three surfaces which respectively coincide in 90° angles. The surface is thereby enlarged in such way to permit the - direct or indirect - reﬂection of the ultrasound waves from almost every angle of incidence.

100 % reflection - thanks to „Corner Stone“ reflectors The „Corner Stone“ reflectors reflect ultrasound waves in a spectrum of incidence angles ranging from 60° to -20°. The visibility of the cannula is therefore guaranteed at a flat puncture angle, and at a steep puncture angle as well.

Pioneering medical technology

Please e-mail us for a free sample Kit or visit our website for more information richard.ﬁscher@pajunk-usa.com www.sonoplexusa.com Please visit us at the ASRA Booth #300

Regional Anaesthesia • Laparoscopy • Biopsy • Worldwide

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TECHNOLOGY

Gaming Unit Could Help Prevent Post-procedure Falls Researchers use Wii Fit to measure balance after emergence from sedation

intendo probably has no plans now or ever to make a “PACU Challenge” game for its popular Wii Fit console, but that hasn’t stopped a group of researchers from using the device as a testing tool to see if patients emerging from anesthesia or sedation are ready to leave the hospital.

Jeffrey Mandel, MD, MS, of the University of Pennsylvania School of Medicine, and colleagues in Helsinki, Finland, have found that the Wii Fit can collect useful data about stability among patients in the recovery suite. Such information, they said, could help clinicians predict which patients may be likely to fall after a procedure.

Between 70% and 80% of surgeries are performed on an outpatient basis. Both the government and the Joint Commission have targeted falls in the health care setting as a significant problem. But predicting which patients are ready to walk out of the hospital without assistance is far from an exact science.

“Time to ambulation is such a subjective measure,” Dr. Mandel said. Holding someone in the recovery suite too long is a waste of time and resources. “If you test people too early and they fall over, that’s not good either,” he said. Now, he said, “we think we have a test where we can say fairly easily that your postural stability has not recovered and therefore you’re not ready to go out.” Kirk Shelley, MD, PhD, professor of anesthesiology at Yale University School of Medicine in New Haven, Conn., and president of the Society for Technology in Anesthesia (STA), called the new research “a stroke of genius” with true clinical consequences. “There’s not an ambulatory center I know of where someone hasn’t had a major injury getting up and falling over,” Dr. Shelley told Anesthesiology News. He also commended the investigators for coming up with a bargain-basement approach to what is a typically high-cost proposition. “They’ve gotten the setup much cheaper but made the mathematics more complex. That’s exactly what you want to be able to do.” Nuclear Medicine The study, which was presented at the 2011 annual meeting of the STA (abstract 25), emerged from the confluence of two seemingly far-flung research interests: Dr. Mandel’s quest for a mathematically rigorous way to determine whether a patient recovering from surgery truly is steady on his or her feet, and a project by the Finnish scientists to assess the effects of fatigue on the balance of engineers in nuclear power plants. In either case, a misstep can have major consequences. Looking through the literature, Dr. Mandel discovered studies conducted in Japan reporting that a measure of entropy in posture—called fuzzy sample entropy—akin to that Table. Patient Characteristics Patients (42 men, 61 women) Age, y

57±12

Height, cm

169±10

Weight, kg

83±19

Midazolam, mcg/kg

63±22

Fentanyl, mcg/kg

1.5±0.5

Diphenhydramine, mg/kg

0.49±0.18

April 2011

AnesthesiologyNews.com I 23

TECHNOLOGY used in some brain monitors could be a marker of recovery from medication. But the Japanese researchers had used a piece of extremely expensive, highly sophisticated posturographic equipment. Although Dr. Mandel had access to such an instrument, it was unsuitable for his purposes. “It’s a big thing, it costs maybe $50,000, and you need 0.35

Fuzzy Sample Entropy

0.30

0.25

0.20

0.15

0.10

0.05

Pre

Post

Figure 1. Postural stability on the Wii Fit system in relation to sedation.

Sensitivity

0.8

0.6

0.4

0.2

0.4

0.6

0.8

Specificity Figure 2. Area under the curve indicating statistical significance for the stability data from the Wii Fit.

a place to put it,” he said. “It’s never where patients are coming out of the recovery room.” Then he read a paper from the Helsinki group, which had described using a Wii Fit device to collect balance data on sleep-starved students. He contacted the team, and one of the researchers, a doctoral candidate, came to Philadelphia and helped Dr. Mandel perform the project. The study included 103 men and women, aged 23 to 83 years, who were scheduled to undergo a colonoscopy or endoscopy with midazolam and fentanyl for sedation (Table). The subjects were asked to stand on the Wii Fit balance pad for one minute prior to receiving sedation and for one minute prior to being released from the recovery suite. After compiling the before-andafter balance data, the researchers used fuzzy sample entropy to calculate the “sway signal” for each patient (Figure 1), then used the information to generate a receiver operating characteristic curve—a statistical tool for determining whether two populations can be differentiated meaningfully (Figure 2). They found that the area under the curve was 0.85, suggesting that the balance board was providing statistically significant information. “What we now know is that we can differentiate people who get conscious sedation for endoscopy quite sensitively,” Dr. Mandel said. He recently submitted a paper showing a “night-and-day difference” on balance between patients given propofol and those who received midazolam for endoscopic procedures. “The people who are getting discharged on propofol are pretty close to being completely recovered. But on midazolam, they’re still pretty impaired,” he said. Although anesthesiologists know the difference from experience, “it was nice that we could separate the two out mathematically,” he added. The researchers are conducting a follow-up study in 105 patients undergoing ambulatory surgery. “I can’t tell you what the right thing to do is— stay in the hospital or get wheeled out to the car and driven home—but I can tell you that you’re not ready to ambulate yet,” he said. “I’m not saying this is the perfect instrument, but it’s an instrument that’s relatively easy to implement,” Dr. Mandel said. And at a few hundred dollars, it costs a sliver of the price tag for a sophisticated posture analyzer. —Adam Marcus

SonoLong – The new revolutionary echogenic catheter kit equipped with “3D Cornerstone” reflectors PAJUNK® has, as the first and only manufacturer, initiated a system, by which the catheter is introduced under sterile conditions directly from a cassette through the TRUE echogenic SonoPlex cannula. The SonoPlex cannula is equipped with “3D Cornerstone” reflectors, which render optimal reflection properties at steep and shallow puncture angles. This SonoLong kit is perfectly suitable for the optimal ultrasound guided continuous nerve block.

Visibility – regardless of the puncture angle

The distal end of the SonoPlex cannula is equipped with a pattern embossed section over the ﬁrst 20 mm. This new feature provides optimal visibility of the cannula tip, which can be identiﬁed with absolute certainty, regardless of steep or shallow puncture angles.

Maximum stability and improved echogenicity – through steel stylet

The catheter of the SonoLong kit has been provided with a steel stylet, which gives the catheter maximum stability and improves echogenicity. It is removed after catheter insertion.

Optimal ﬂow and localization – through central opening and depth graduations

The distal end of the radiopaque catheter is open. This ensures the free ﬂow of the anesthetic – particularly in connection with the post-operative injection pump. In addition, the 50 cm long catheter, has been provided with ascending depth graduations at intervals of 5 cm. Therefore its exact position can be determined at any time. Please e-mail us for a free sample kit or visit our website for more information richard.ﬁscher@pajunk-usa.com www.sonoplexusa.com

Pioneering medical technology Please visit us at the ASRA Booth #300

Regional Anaesthesia • Laparoscopy • Biopsy • Worldwide

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CL IN I C A L A NESTHES IOLOGY In the study, Dr. Schroeppel and his colleagues compared mortality rates related to propofol-infusion syndrome in 222 patients treated in 2005 for traumatic brain injury with 700 patients who were treated for traumatic brain injury after January 2006—at which time Dr. Schroeppel and colleagues had begun ordering propofol cessation if serum lactate levels rose above 3 mmol/L or CPK exceeded 5,000 U/L. Patients who died within 24 hours

of initial trauma were excluded from the study, along with patients who received less than 100 mL of propofol or received the agent only during surgery. Patients were diagnosed with propofol-infusion syndrome if they met two of the following criteria: cardiac arrhythmia or collapse; metabolic acidosis; or rhabdomyolysis that otherwise could not be explained. Dr. Schroeppel’s group analyzed possible associations between propofolinfusion syndrome and demographic

INDICATION EXALGO® tablets are an extended release oral formulation of the opioid agonist hydromorphone hydrochloride that is indicated for once daily administration for the management of moderate to severe pain in opioid p tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time. IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE

Syndrome continued from page 1 physicians to discontinue propofol infusion in such patients when levels rise above 5,000 U/L of creatine phosphokinase (CPK) and 3 mmol/L of serum lactate. Michael E. Johnson, MD, PhD, a Mayo Clinic anesthesiologist who was not involved in the research, said the study not only demonstrated the benefits of following a basic protocol for the prevention of propofol-related complications, but in doing so, provided further evidence that propofol-infusion syndrome is a very real clinical entity. “The study is significant in justifying the need for a screening protocol for intensive care patients receiving propofol infusions, and for documenting the efficacy of such a screening protocol,” Dr. Johnson said. “My own personal decision would be to discontinue propofol and switch to alternative agents such as midazolam and fentanyl in any patient found to have possible propofol-infusion syndrome as defined by the screening protocol used.” Thomas Schroeppel, MD, assistant professor of surgery at the University of Tennessee Health Science Center, in Memphis, who led the study, said that apart from anecdotal case reports little is known about the risk factors for propofol-infusion syndrome and its incidence in critical care patients with traumatic brain injury.

Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Proper p Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/ hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer. EXALGO is for use in opioid tolerant patients only. Fatal respiratory depression could occur in patients who are not opioid tolerant. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone. Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain. EXALGO is not intended for use as an as-needed analgesic. EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone. • EXALGO is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia. - have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites. • Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. EXALGO may impair the ability to drive a car or operate machinery. • Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prosthetic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment. • Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness. Serious adverse events could also include head injury, hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal. • Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention. • Do not abruptly discontinue EXALGO Please see brief summary of Full Prescribing Information, including boxed warning on following pages. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG. EXALGO is a registered trademark of Mallinckrodt Inc. © 2011 Mallinckrodt Inc., a Covidien company. MK20024 January 2011 Printed in USA.

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CLIN IC A L A NESTHES IOLOGY ‘The study is significant in justifying the need for a screening protocol for intensive care patients receiving propofol infusions.’ —Michael E. Johnson, MD, PhD

characteristics, medications, injury severity score, Glasgow Coma Scale score, intracranial pressure, infusion time and dose, infusion rates and serum sodium levels and dose. Six (2.7%) of the 222 patients treated before the screening protocol was implemented developed propofol-infusion syndrome; two of the 700 patients (<0.3%) treated after implementation of the screening protocol also developed the condition. Those two cases resulted from the only two protocol

violations during the post-implementation period, Dr. Schroeppel said. Patients who developed propofolinfusion syndrome had higher injury severity scores, but the difference was not statistically significant. According to Dr. Schroeppel, CPK and serum lactate levels have been described as useful predictors of the syndrome, but their efficacy in a prevention protocol has not been studied. He said the current findings are definitive in demonstrating that a screening protocol

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using these measures is necessary to ensure safe use of propofol. “The bottom line is that propofol is a very effective agent in the trauma population when used appropriately,” Dr. Schroeppel told Anesthesiology News. “But when it is used inappropriately in high-risk patients, such as those with traumatic brain injury, it can push them over the edge and result in propofol-infusion syndrome.” —David Wild

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CL IN I C A L A NESTHES IOLOGY FDA continued from page 1

children would experience, and the few human studies so far have conflicting animal studies published on this topic results. since their initial meeting in 2007. The “Although we have made some progpanelists agreed that although several ress since the last committee meeting, studies have indicated that exposure to the progress hasn’t been huge,” said anesthetic agents during periods of sig- panel chair Jeffrey Kirsch, MD, pronificant brain development in young fessor and chair of anesthesiology children can result in neuronal cell and perioperative medicine at Oredeath or later cognitive deficits, it’s gon Health & Science University, in difficult to generalize the results. Ani- Portland. mal studies may have exposed subjects The panel recommended that the to longer periods of anesthesia than FDA conduct a survey to determine

areas in need of research, establish standard practice in the United States and globally find the “low-hanging fruit,” and focus research on areas that will have the biggest impact on numbers of patients. Studies should carefully note drug dosages, ages of children studied, their duration of exposure to anesthetic agents and measure children’s function prior to anesthesia exposure, to best define the short- and long-term effects of surgical and anesthetic interventions.

BRIEF SUMMARY - Consult full prescribing information before use. EXALGO® (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)]. Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)]. EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)]. Fatal respiratory depression could occur in patients who are not opioid tolerant. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)]. Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)]. EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)]. EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)]. CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant. Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia. Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus. Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction. Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)]. WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning]. EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning]. EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone. Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion. Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)]. If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration. Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose. Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)]. Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone. Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations. The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition. It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Special Risk Groups EXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)]. EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis. EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings. Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery. Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)]. Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.3)] • Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.6)] • Gastrointestinal Effects [see Warnings and Precautions (5.7)] • Cardiac Arrest [see Overdosage (10)] • Precipitation of Withdrawal [see Warnings and Precautions (5.13)]

Panelist Susan Swedo, MD, chief of pediatrics and neurodevelopmental science at the National Institute of Mental Health, in Bethesda, Md., said she read minutes from the 2007 committee “and at least on the preclinical side, I would say that 90% of what they had identified would still be true today. We need more data in the area of currently used agents in real-dose situations, and I would like to have the brain-behavior literature much more richly described.”

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year. The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients. A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1. Table 1. Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2. Table 2. Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) a 272 (11) Asthenia Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) 139 (6) Anorexia b Dry Mouth 121 (5) 115 (5) Abdominal Pain c Anxiety 95 (4) Back Pain 95 (4) d 88 (4) Dyspepsia Depression 81 (3) 76 (3) Dyspnea e Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) 51 (2) Chest Discomfort f a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

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CLIN IC A L A NESTHES IOLOGY Panelist Jayant Deshpande, MD, MPH, senior vice president, chief quality officer and associate medical director of Arkansas Children’s Hospital in Little Rock, said he was concerned that most of the preclinical data looked at only ketamine and isoflurane, and no other anesthetics. Even in the human studies, Dr. Deshpande added, “multiple exposures to anesthetics are associated with neurodevelomental problems, not necessarily can be detrimental. I think it’s important to parse those words.”

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)]. Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment. Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended. Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)]. Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day). Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis. Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day). Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Experts advised partnering with large physician groups or ongoing studies with large patient registries— such as the Anesthesia Quality Institute (sidebar)—or pregnancy cohorts, and asking them to include variables helpful to assess children administered short- or long-term anesthetics. Or, as oncology groups do, conduct studies that randomly assign patients to a specific anesthetic regimen and study the patients prospectively. The experts recommended that professional

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate. However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk. Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established. Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose. Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital. Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)]. Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)]. DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse. Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. “Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances. With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

anesthesiology and other physician organizations keep their members apprised of ongoing research. The panel did recommend postponing elective procedures, whenever possible, to age 4 years or older. They also agreed that anesthesiologists should use the lowest dose possible of anesthetics for the least amount of time, and address parental concerns by saying they would not give any anesthetics to patients that they wouldn’t use on their own children. Panelists did

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)]. OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours. Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose. Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use. OROS is a registered trademark of ALZA Corporation. EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

Mallinckrodt

not feel the FDA needed to include any warnings in anesthetic package labeling for now. “I’m not in favor of a boxed warning for anesthetic agents—that would be a mistake,” Dr. Kirsch said. “I also don’t believe that there’s any one sentinel study that is definitively clear on the true impact of anesthetic agents on patients,” that should be added to drug labels. The meeting coincided with an editorial published the same day in The New England Journal of Medicine, by Bob Rappaport, MD, director of the FDA’s Division of Anesthesia and Analgesia Products, and colleagues, describing the difficulties defining the safe use of anesthesia in children. “We need to definitively answer the questions of whether anesthetic use in children poses a risk to their development and, if so, under what circumstances,” the authors wrote. “If anesthetic agents are found, in certain cases, to affect the developing brain, strategies for mitigating and managing such risks can be implemented.”

‘This [meeting] was a summary of what we know and don’t know. We just wanted to get it out there to the medical community so people think about it.’ —Bob Rappaport, MD A possible tie between general anesthesia and cognitive damage has been suggested for more than a decade, starting with a seminal 1999 study in Science showing that rat pups exposed to N-methyl-d-aspartic acid (NMDA) antagonists produced neuronal cell death through apoptosis. Those findings prompted the FDA to form an expert working group and to sponsor studies to evaluate the potential neurotoxic effects of NMDA antagonists, such as ketamine, on the developing brain. Each year, more than one million children aged 4 years and younger undergo surgical procedures that require anesthesia, according to the International Anesthesia Research Society (IARS). Thousands more are anesthetized for imaging tests such as magnetic resonance imaging or dental procedures to keep them still, panelists noted. see FDA page 28

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CL IN I C A L A NESTHES IOLOGY FDA continued from page 27 One brain growth spurt during which scientists have been concerned about exposure to anesthetics occurs from gestation through 9 months after birth. Panelists also questioned whether adolescence is another critical period of brain development that could be adversely affected by anesthetics, but there are no studies of anesthetics’ effects in that population. Animal Data Conflict At the FDA meeting, Merle Paule, PhD, director of the Division of Neurotoxicology at the agency’s National Center for Toxicological Research, discussed his work exposing rhesus monkeys aged 5 days to a dose of ketamine sufficient to produce a light surgical plane of anesthesia for 24 hours, then following them starting at 7 months old in a series of tests designed to assess short-term memory, learning and attention. Monkeys given ketamine had lower training scores than those not exposed to the drug, and they never caught up developmentally. Similar studies of primates exposed to isoflurane are ongoing. John Olney, MD, professor of psychiatry, pathology and immunology at Washington University in St. Louis, presented data from his work with scientists at Oregon Health & Science University, exposing fetal and neonatal rhesus monkeys to isoflurane, ketamine or propofol for five hours, and examining the animals’ brains for evidence of cell death three hours afterward. The researchers found highly organized patterns of dead neurons and glial cells in the animals exposed to anesthetics. Ketamine was found to be most toxic for fetuses, whereas isoflurane was most toxic for neonates. Another study in infant mice found that caffeine, when added to anesthetics as is sometimes the practice in neonatal intensive care units to prevent cerebral palsy, may be helpful when combined with minimal anesthesia but harmful when combined with maximal anesthesia. K.J.S. “Sunny” Anand, MBBS, DPhil, division chief of pediatric critical care medicine at the University of Tennessee at Memphis, reviewed several studies of ketamine and neonatal brains of rats and humans, in which he found that neural stem cells are resistant to the neurotoxic effects of ketamine at low or clinically relevant doses (10 mcMol), and that ketamine enhances the neuronal differentiation of neural stem cells. “We don’t yet know what the animal data means, so it’s not the time to cause major changes,” Dr. Rappaport told Anesthesiology News. “This [meeting] was a summary of what we know and don’t know. We just wanted to get it out there to the medical community so people think about it.” As an outcome from the 2007 meeting, the FDA in 2009 partnered with the IARS to launch the SmartTots (Strategies for Mitigating AnesthesiaRelated neuroToxicity in Tots) program (formerly called SAFEKIDS), to fund research into whether anesthetic exposure causes harmful side effects in young children and potentially foster development of new, safer anesthetic drugs. The FDA recently funded three projects related to SmartTots: Children’s Hospital of Harvard

AQI Head on Anesthetic Safety in Children

Richard Dutton, MD, executive director of the Anesthesia Quality Institute

e are very interested in the topic of anesthetic safety in children, but it is obviously very complex. At present we have no good way to gather long-term outcomes from pediatric exposure to anesthetics, especially because testing is itself controversial and nonstandard. A lot of data will be required to answer the basic question: Does anesthetic exposure influence later intellectual development? (Or the similar question for adults: Does anesthetic exposure influence the development of Alzheimer’s disease?) Consider the risk adjustment required: Children who require surgery are already “not normal” in some way, and that “not-normalness” may have impact on their later development. This can be a direct genetic connection or a secondary result of the disease (e.g., children with frequent ear infections do worse in school). Sorting this out will be very challenging. In the retrospective cohort study from Minnesota [Anesthesiology 2009;110:796-804] that started this discussion, I believe that children who had only one or two anesthesia exposures had normal educational results years later, whereas those with multiple exposures did poorly. In the long term, a lifelong universal health care identifier and a fully realized interconnected digital future will make any association between anesthesia and cognitive deficits obvious. It’s going to take us a while to get there, though. In the short term, our best bet is prospective funded research cohort studies (similar to Framingham Heart) that will gather good data longitudinally, but will be expensive and slow to produce results. In the mid-term, the Anesthesia Quality Institute (AQI) will be able to contribute good data on anesthesia exposure (and other risk factors) to investigators that will link it to other databases examining intellectual outcomes. These will be retrospective, administrative studies that might demonstrate

University, in Boston, is coordinating an international study of neurodevelopment outcomes in 660 infants administered regional or general anesthesia while undergoing inguinal hernia repair; Columbia University in New York City, is coordinating a multicenter study comparing neurocognitive, emotional and behavioral outcomes in pediatric patients who have and have not been exposed to anesthesia; and researchers at Mayo Clinic in Rochester, Minn., are studying long-term cognitive development following exposure to general anesthetic agents in infancy. This spring, SmartTots is launching a $30 million fundraising campaign to support additional studies, said Lowry Champion, director of research programs for the consortium, who estimates that it could be another decade before these studies are published. Mark Singleton, MD, chair of the American Society of Anesthesiologists’ Committee on Pediatric Anesthesia, told Anesthesiology News that many

associations but will not be definitive as to cause and effect. Any quality/safety study involves three components: risk factors, process and outcome. AQI is working with participating practices (now 64 groups) to capture all three things, but the ability to do so is variable. It depends on how good their information technology is, how the practice relates to the hospital or facility and whether someone in the group has pushed the need to capture outcomes. Risk factors—age, sex, ASA (American Society of Anesthesiologists) physical status—are universally captured. Diagnostic codes, body mass index, allergies, chronic medications, and lab values are contributed by some participants and not others (based on how “wired” their hospital has become). Process factors—anesthesia type, surgical and anesthesia diagnostic codes, and provider—are universally captured. Those practices that have anesthesia information management systems in place contribute a lot more: specific medications and doses, fluid management, continuous vital signs and so on. At present this is about 25% of the AQI groups, but will eventually be everyone. Regarding outcomes, only major intraoperative events are universally captured. All other reporting is variable, and this is what AQI is working hardest on right now. At present I am emphasizing 24-hour postoperative capture of major complications and patient-centered metrics (nausea, pain management, satisfaction). Long-term follow-up is extremely hard for anesthesia groups and is only seen in niche practices (such as congenital cardiac surgery). But this is a desirable future goal. The ASA and I are promoting AQI participation for any anesthesia group, anywhere, with any kind of data infrastructure. In the long term, this is going to be the standard for our profession for benchmarking performance. ■

prominent pediatric anesthesiologists are conducting additional studies but until results are in, anesthesiologists should not make any statements. “We would worry that people would be unnecessarily withholding important care, and have kids get hearing loss instead of ear tubes or have trouble in school because of obstructive sleep apnea.” Richard Kaplan, MD, professor and chief of anesthesiology and pain medicine at Children’s National Medical Center, in Washington, D.C., who attended the meeting, said he and his colleagues frequently have discussed the potential for cognitive damage “because we are concerned about our patients’ development and the multiple polypharmacy we employ. “We are starting to get parents who are very knowledgeable and ask [for] our thoughts,” Dr. Kaplan said. “We tell them, ‘these are the best, safest medications available for children who need anesthesia.’ ” —Karen Blum

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Where the Patients Are: 2011

urgery, it seems, has at least one thing in common with the real estate business: Location is key. Depending on where in the country a person lives, the rate of several common elective surgeries can vary dramatically, according to a new report from the Dartmouth Atlas Project. The report, “Improving Patient Decision-Making in Health Care,” used Medicare data to plot maps of procedures by geographic area. It concludes that “for many conditions—especially those that can be treated with elective surgery—the treatment a patient receives depends more on the physician’s recommendations than the patient’s preferences.” Here we present three maps in the report of procedures that constitute a significant share of the anesthesiology caseload. The rates are calculated for patients per 1,000 Medicare beneficiaries in each region, adjusted for age, sex and race (reprinted with permission from the Dartmouth Atlas Project). —AN

Coronary artery bypass graft surgery per 1,000 Medicare beneficiaries among hospital referral regions (2003-2007) The highest rate (8.9 per 1,000 Medicare beneficiaries), was seen in McAllen, Texas. That figure was nearly five times greater than that in the region encompassing Pueblo, Colo. (1.9 per 1,000). The national average rate of CABG was 4.6 per 1,000.

Back surgery per 1,000 Medicare beneficiaries among hospital referral regions (2003-2007) The highest rate (10 surgeries per 1,000 beneficiaries) was seen in Casper, Wyo. This rate was nearly six times higher than the lowest rate (1.7 per 1,000), seen in the Honolulu area. The average rate of back surgery in the United States was 4.3 per 1,000.

Cholecystectomy per 1,000 Medicare beneficiaries among hospital referral regions (2003-2007) The highest rate for cholecystectomy was 6.8 procedures per 1,000 Medicare beneficiaries in the McAllen, Texas, region. The lowest rate (2.4 per 1,000), was seen in the region that includes Mason City, Iowa—a nearly threefold difference. The average rate of gallbladder surgery in the entire United States was 4 per 1,000.

April 2011

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Successful Journal Clubs Guide Residents’ Growth

Take Charge of Your Life. Ensure Your Future.

New York—Journal clubs are ubiquitous features of medical education, but a recent study highlighted several ways that the anesthesia-based programs can be improved. Marek Brzezinski, MD, PhD, associate professor of anesthesia at University of California School of Medicine, in San Francisco, and his colleagues conducted a nationwide survey of 117 directors of anesthesia residency programs. The survey participants were asked for details on their programs’ journal clubs; 80 programs (68%) responded, of which 96% regularly conducted a journal club. The study results were presented at the 2010 annual PostGraduate Assembly in Anesthesiology (abstract 9150).

establishing a system to evaluate and change an existing program, according to the authors. Alan Schwartz, MD, MSEd, director of education and program director of pediatric anesthesiology fellowships at the Children’s Hospital of Philadelphia, said that journal clubs have great potential in anesthesia education but generally rely on substantial faculty involvement in order to succeed. “They’re great; the residents love them, but it depends on how well they’re implemented,” Dr. Schwartz told Anesthesiology News. “And that depends on a champion, a faculty champion. For anything that we do educationally, it works better when there is a champion.” Dr. Brzezinski’s study showed that whereas faculty involvement helped attendance, the most successful journal clubs were those in which the residents were involved in the club’s organization. Journal clubs in which more than five faculty members attended also were 1. Create online checklists and well attended by residents. appraisal tools To encourage participation in a journal club, the authors sug2. Set explicit goals gested creating online checklists 3. Evaluate routinely and appraisal tools, explicit goal-setting, routine evalu4. Make participation mandatory ations of a program, man5. Acknowledge individual datory participation and contributions acknowledgment of individual contribu6. If it’s broke, fix it tions. Dr. Brzezinski said that the main focus should be to “change the mentality: The faculty are there to lay the foundation and facilitate the disThe researchers found that a faculty cussion, but the long-term success of member (instead of a resident) often journal clubs is based on active involveis the primary organizer of a journal ment of the residents.” club, and that faculty leaders moderAlso, because the majority of journal ated 70% of the programs and selected clubs have not changed substantively in articles for review in 93% of the pro- recent years, consideration of alternative grams. The more successful journal formats in struggling programs could clubs—measured by greater than 50% increase success. Possibilities include attendance—had mandatory atten- journal club meetings that are more dance (P=0.02), involved residents in frequent but last a shorter time, invitaa journal club organization (P=0.02) tions to nonresident presenters and speand reviewed more articles per session cialists to discuss particular articles and (P=0.01). formation of Web-based clubs. “As we Interestingly, the journal clubs that embark on creating the new generation had recently undergone a change in of leaders in anesthesia,” Dr. Brzezinski format also were very well attended said, “we need to better equip the resi(P=0.0001); 24% of the journal clubs dents with the necessary tools to critihad implemented such a recent change. cally appraise scientific papers, and not With that finding in mind, the 60% of expect them to just know it.” programs without a formal evaluation process might improve attendance by —Dave Levitan

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More Evidence of a ‘Weekend Effect’

patients presenting on the weekend are sicker than their weekday counterparts or maybe they delay their decision Two studies highlight risk for patients with dangerous hypertension or emboli to go to the hospital by a few hours because they know their disease is that n what is a further indictment of admitted counterparts to experience MD, executive vice chair of anesthesiol- much more likely to result in a poor a medical system that is letting severe complications or succumb to ogy at Mount Sinai Medical Center, in outcome on the weekend.” weekend admissions down, a pair their illnesses. New York City, who was not involved Other likely factors include staffing of recent retrospective studies shows Multiple studies have unearthed a in the new research. and supervision issues and a “weekend that patients admitted during the growing pool of victims of the euphe“Many variables that could not be mentality,” including “a tendency to do weekend for hypertensive emergencies mistically named “weekend effect,” but controlled for in studies like these may less until Monday, when specialists are or acute pulmonary emboli are signifi- experts have yet to identify the likely be contributing to this phenomenon,” present,” Dr. Leibowitz said. Raising cantly more likely than their weekday- suspects, said Andrew B. Leibowitz, Dr. Leibowitz noted. “It may be that compensation rates for weekend work may attract a larger number of more experienced staff, and might help improve the situation, he suggested.

Improved Ultrasound Needles for Nerve Blocks & Pain Injections At the Same Low Price!

Prior Links Links between weekend admissions, higher complication rates and lower survival rates have been established in patients undergoing emergency surgery and those with myocardial infarction, among other patient groups. In the two latest studies, lead investigator Sandeep Markan, MD, MBBS, associate professor of anesthesiology at the Medical College of Wisconsin, in Milwaukee, and colleagues analyzed weekend and weekday complication and mortality rates using data from the Nationwide Inpatient Sample Database, which was compiled between 2000 and 2008. They compared 264,689 patients admitted for hypertensive emergencies between midnight Friday and midnight Sunday with 949,480 similar patients admitted during the week, and 148,888 weekend patients admitted for acute pulmonary embolism with data from 535,143 weekday admissions with the same condition. Dr. Markan and his team examined rates of in-hospital mortality, acute myocardial infarction, acute aortic dissection, stroke and hypertensive encephalopathy. They also conducted multivariate regression analyses to control for the effects of older age, hospital

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Ultrasound-guided Central Blocks in Infants, Children, and Adolescents

ISABELLA MUKHERJI, MD Attending Anesthesiologist

CHANDRA CASTRO, MD Fellow in Pediatric Anesthesiology

SANTHANAM SURESH, MD Vice Chairman Department of Pediatric Anesthesiology Director Pain Management Services and Research Children’s Memorial Hospital Northwestern University Feinberg School of Medicine Chicago, Illinois The authors have received research support from Philips Healthcare and SonoSite, Inc.

Introduction

egional anesthesia is part of the curriculum for anesthesia training programs.

Although the use of regional anesthesia in children has been limited, the field holds clear promise. The introduction of ultrasound (US) guidance,

along with numerous focused workshops at major specialty meetings, have altered

the outlook and increased participation and use of regional anesthesia in pediatric practice. This article will review the use of US-guided central neuraxial blocks as they apply to practice in infants, children, and adolescents. In particular, it will focus on 3 US-guided regional techniques—the caudal block, epidural analgesia, and the paravertebral block (PVB)—that are gaining popularity in this patient population.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

A N E ST H E S I O LO GY N E WS • A P R I L 2 0 1 1

Figure 1a. Caudal block under ultrasound guidance. A midline scan using a linear probe is performed; after the caudal space is accessed with a blunt styletted needle, local anesthetic solution spread is visible.

hernia repairs, urologic procedures, and procedures performed on the lower extremities. A single-shot caudal anesthetic provides relatively brief analgesia, on the order of 4 to 8 hours depending on the agents used, and is appropriate for inpatient and outpatient management strategies. A successful caudal anesthetic blockade affords the anesthesiologist the opportunity to reduce intraoperative use of volatile anesthetic agents and to use a narcotic-sparing approach that ultimately may benefit the patient while providing a better postoperative course with less nausea and vomiting. Although the block typically is performed with a loss-of-resistance technique using a blunt needle, the use of US not only allows the space to be identified but permits visualization of the spread of the local anesthetic solution.

Ultrasound-guided Caudal Anesthesia Recent advances in the use of US-guided approaches to regional anesthesia have occurred across the spectrum of adult and pediatric patients. The use of US in neuraxial blockade has had limited success in adult patients because of poor penetration through calcified bony structures. In contrast, potentially promising uses of the imaging technology exist for the pediatric population. Younger children are less likely to have bony ossification, and US may serve as an invaluable tool in the placement of caudal blocks and epidural catheters originating from the caudal space.1

ANATOMIC

Figure 1b. Ultrasound paramedian scan of the lumbosacral area; note the spinous process of L5 and the visualization of the dura mater. Local anesthetic injection can be visualized by anterior displacement of the dura mater.

Caudal Epidural Anesthesia Caudal epidural anesthesia is an important tool for pain control and anesthetic management in children undergoing surgical procedures below the umbilicus. Caudal anesthesia is the most frequently used regional anesthetic technique in pediatric patients (Pediatric Regional Anesthesia Network; S. Suresh, personal communication) and is one of the most common blocks taught in anesthesia training programs in the United States.

INDICATIONS Caudal epidural blocks have numerous indications, including abdominal operations below the umbilicus,

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AND

TECHNICAL CONSIDERATIONS

Ultrasound imaging of the caudal region is best performed in both the transverse axial and longitudinal paramedian or midline positions (Figure 1a).1 This technique aids identification of the sacral cornu, sacrococcygeal ligament, and dural sac. A higher-frequency (13-6 MHz) â&#x20AC;&#x153;hockey stickâ&#x20AC;? probe is a good choice for the transverse axial view. Placement of the probe at the level of the coccyx, with subsequent scanning toward the sacral canal, will help the clinician localize important landmarks. A larger, lower-frequency probe may be more desirable for the longitudinal paramedian view, which has a large field of interest. A midline axial transverse scan demonstrates a reasonable representation of the sonoanatomy at the level of the sacral hiatus with the sacral cornu located laterally and the sacrococcygeal ligament shown as the collection of hyperechoic lines (Figure 1b). The sacral hiatus is inferior to the ligament and appears hypoechoic. When the probe is placed in a midline longitudinal position, the sacrococcygeal ligament and dorsal surface of the sacrum can be discerned. The sacral cornua are seen as humps. The sacrococcygeal ligament appears as a hyperechoic membrane between the sacral cornua. The ligament extends as a thick band beyond the end of the dorsal aspect of the sacrum. The image is clearer in neonates and infants but seldom is so distinct in children over the age of 6 years, in whom the sacrococcygeal ligament is likely to have ossified.

Once the caudal needle has pierced the skin, both transverse and longitudinal views can confirm placement. Case reports detail the use of transverse imaging for visualizing the sacral hiatus anatomy and noting the injection of local anesthetic into the caudal space. Schwartz et al. have described the transverse view of injected local anesthetic as dilation of the caudal space and turbulence (Table). Color flow or Doppler imaging may enhance viewing the solution. Roberts et al. described their approach to visualization of a saline test bolus in the caudal space under US guidance. They used the longitudinal view cephalad to the catheter insertion site (1 cm) to observe anterior movement of the posterior aspect of the dura.2 Visualization of the needle as it enters the sacral canal may be accomplished with the probe in a longitudinal position similar to an in-plane approach for other peripheral nerve blocks. This view may aid in making adjustments to the needle angle to avoid penetration of surrounding bony structures and help prevent intraosseous injection of local anesthetic. As discussed by Tsui and Suresh, initial use of the longitudinal view may aid in assessment of the needle puncture and angle and depth of the needle, and a transition to a transverse view may permit the visualization of the spread of local anesthetic solution.1 When introducing a catheter into the caudal space, a technique similar to the one described above works well. However, injecting saline into the area as the space is accessed directly with a paramedian view of the spinous process affords the easiest visualization of the spread of the local anesthetic solution. Surrogate markers of the anterior displacement of the dura mater usually are a good sign when placing catheters under US guidance. Compared with the “swoosh test”—an audible spread of local anesthetic up the epidural space—US guidance can better capture the spread of local anesthetic solution.3 The difference is even more marked with the use of Doppler ultrasound.

COMPLICATIONS There is a chance, albeit small, that these blocks may fail after improper needle placement or alteration of needle position once initial loss of resistance has been obtained. The implications of failure are magnified in neonates or young infants, for whom the margin of error in dosing is minimal. In addition, bloody punctures and intravascular events have been reported and must be carefully monitored4; test dosing prior to injection should be performed. In general, major complications of caudal anesthesia in pediatric patients are uncommon. The risk of greatest concern to the anesthesiologist is the inadvertent injection of local anesthetic into a vascular space, which may lead to central nervous system dysfunction and cardiovascular compromise. Electrocardiographic changes involving an increase in T-wave amplitude of more than 25% are highly predictive of intravascular injection.5

Figure 2a. A high-frequency ultrasound scan using the paramedian view generates the best views for epidural analgesia. However, a transverse axial scan also can enable adequate measurement of the epidural space.

Figure 2b. A paramedian scan using a linear high-frequency ultrasound probe demonstrates the spinous process (sawtooth appearance) and the dura mater as a hyperechoic shadow between the bony spinous process. Correct placement of the local anesthetic solution in the epidural space is demonstrated by anterior displacement of the dura mater.

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Efforts should be made to avoid the test dose during periods of light anesthesia or when other stimulation is occurring. Inadvertent dural entry is unusual, provided close attention is paid to the depth of the needle. Other rare complications include epidural abscess, epidural hematoma, dural puncture, subdural injection, air embolism, total spinal, and other adverse events associated with epidural anesthesia. The incidence of systemic toxicity is higher with caudal blocks than with epidural blockade at other levels.

Epidural Analgesia

Figure 3a. A linear ultrasound probe is placed lateral to the spinous process; the transverse process can be viewed and the pleura can be visualized easily.

Epidural analgesia has been an important dimension of pediatric practice for nearly 2 decades. Many studies have assessed the efficacy as well as the pharmacokinetics of local anesthetic solutions in infants and children. Detecting the epidural space through US guidance initially was part of a preprocedure scan and delivered excellent results, particularly in obese parturients.6 The technique can be applied in neonates and infants with ease, as the posterior vertebral column in infants is cartilaginous and thus effectively transparent to the US beam. The advantages of US guidance are manifold in this population: The epidural space is superficial and errors are likely to be made with access; dosing parameters can easily be exaggerated with the use of loss of resistance; loss of resistance with air may lead to a potential for air embolism, raising the risk for further complications.

SONOANATOMY

Figure 3b. Ultrasound image using a linear high-frequency probe in the paramedian view; the pleura and transverse processes appear as hyperechoic shadows. The inner intercostal membrane is above the pleura and the paravertebral space can be accessed easily using an in- or out-of-plane approach. Anterior movement of the pleura demonstrates the presence of the local anesthetic solution in the paravertebral space.

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A high-frequency probe (13-6 MHz) typically works best for US-guided epidural analgesia. With the paramedian view, structures are identified more readily, although a transverse axial scan can adequately measure the epidural space (Figures 2a-b). With the paramedian scan, a large acoustic window enables visualization of several vertebral spaces, and also the intervertebral spaces. Clinicians may choose the transverse axial view, but the decreasing depth of the epidural space limits the utility of the image. A prospective study in infants found a linear hockey stick probe provided easy visualization of neuraxial structures, the lumbar spine being more acoustic than the thoracic spine.7 The dura mater is often more readily visible than the ligamentum flavum. The study also found the visibility of the epidural space to be greater in infants under 3 months of age, which is similar to our own experience. Kil et al. corroborated these findings,8 and a subsequent study from Austria demonstrated the ability to differentiate the dura mater as well as the ligamentum flavum in infants who were placed lateral with caudal hip flexion.9 It is crucial to remember that loss of resistance must be carried out with saline, as air will obliterate the image that is obtained. US guidance has been shown to provide better visualization for catheter placement in infants under 6 months of age than in older infants.10 A study by Rapp

et al. found that US imaging of the catheter was possible in 19 of 23 patients studied; however, multiple planes were required to visualize the catheter placement.11 The Austrian group noted that with the patient flexed at the hip and in the lateral position with a paramedian scan of the spine, placement of the epidural catheter was not obvious. However, anterior displacement of the dura mater was clear,9 again similar to our own experience of catheter placement. The study by Rapp et al. also found a significant correlation between the measured epidural depth and the depth at which loss of resistance was obtained.11 The US-guided technique led to less bone–needle contact (17% vs 71%) and shortened the procedure time (162 vs 234 sec).12 Although the study did not demonstrate greater success in the US group, the added safety of knowing the depth of the epidural space and the ability to determine proper placement outweighs the extra effort required to use US guidance. Indeed, US guidance soon may prove to be the only method for successful cannulation of the epidural space, providing greater comfort for patients and a teaching tool for residents and fellows in anesthesia.

Figure 3c. An oblique transverse view of the paravertebral space, demonstrating the pleura and inner intercostal membrane, as well as the costotranverse ligament. An inor out-of-plane approach can be used for accessing the paravertebral space.

Paravertebral Blocks PVBs produce ipsilateral analgesia by injection of local anesthetic solution alongside the body of the vertebra. They have been used for pain control in patients undergoing thoracotomies, chest wall trauma, breast reconstructive surgery, cholecystectomy, herniorrhaphy, and renal surgery. Bilateral PVBs may be needed in some cases to provide adequate analgesia.13,14 Paravertebral blockade may be administered either as a single injection or by a catheter that can provide continuous or bolus administration of a local anesthetic.15 PVBs provide nerve blockade to the roots of nerve plexus or spinal nerves soon after their emergence from the spinal canal. However, often they are not categorized as a peripheral nerve block as they share characteristics of neuraxial blocks. They have been described as “paraneuraxial” epidural blocks, because the nerves they affect are enclosed by dura mater extending from dura lining the spinal cord.16 It is important to understand that PVBs are performed in close proximity to nerve roots surrounded by dura mater and their complications may be similar to those associated with central neuraxial blocks. PVBs may be classified as a family of 4 related blocks. Baumgarten et al.17 subdivides PVBs by their location into these regions: cervical, thoracic (T1-10), thoracolumbar or hernia region (T11-L2), and lumbar or psoas compartment (L2-5).

HISTORY Sellheim is credited with performing the first PVB in 1905, while searching for an alternative to spinal anesthesia and its associated dangers of hemodynamic and respiratory complications. In the early part of the

Table. Suggested Steps for Caudal Blocks In Pediatric Patients 1. Appreciate the sacral space using an axial transverse scan. 2. If possible, view the direct entry of the needle as it is placed in the caudal epidural space. 3. Visualize the spread of the local anesthetic solution directly, or look for the anterior displacement of the dura mater.

century, PVB was used for relief of surgical pain, angina pectoris, intractable pain of malignancy, ischemic limb pain (including causalgia), and reflex sympathetic dystrophy.18 The technique experienced a brief popularity in the 1920s and 1930s but almost completely disappeared from the literature in the 1950s and 1960s. In 1979, Eason et al. reestablished the safety and efficacy of thoracic PVBs in cadaver studies, and since then numerous authors have refined the technique. Boezaart discussed the use of continuous cervical PVB and PV approaches to the brachial plexus.16 In 1997, Weltz et al. demonstrated enhanced patient satisfaction and the safety of thoracic PVBs in surgery for breast malignancy, which has become a leading indication for the block.19

APPLIED ANATOMY The PV space is located on either side of the vertebral column anterior to the transverse process and posterior to the parietal pleura. In the thorax, it is wedge-shaped

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and bounded posteriorly by the superior costotransverse ligament, which connects the corresponding upper and lower borders of the transverse process, and anterolaterally by the parietal pleura. The base is formed by posterolateral aspect of the vertebral body, intervertebral disk, and intervertebral foramina.13,20 The PV has no lateral limit, and depending on the level of injectate, local anesthetic can provide cervical, stellate, brachial plexus, intercostal, and lumbar plexus blockade. The PV communicates medially with the epidural space through the intervertebral foramina and can connect with the contralateral PV space through the prevertebral or epidural space. It can track along the PV gutter to the ipsilateral PV spaces above and below. The endothoracic fascia is interposed between the parietal pleura in front and costotransverse ligament behind and divides the PV space into the anterior extrapleural and posterior subendothoracic PV compartments. The thoracic PV space contains the spinal (intercostal) nerve, dorsal ramus, intercostal vessels, rami communicantes, and the sympathetic chain.21 Lonnqvist et al. studied the caudal limit of thoracic PV space in cadavers and observed that it was limited by the origin of the psoas limiting spread below the 12th thoracic vertebra.22 However, cadaver studies by Saito et al. revealed the presence of a communication between the thoracic and lumbar PV regions.23 Local anesthetic spread through the medial and lateral arcuate ligaments to the anterior surface of the psoas major and quadratus lumborum muscles, where it contacted the peripheral nerves originating from the lumbar plexus. The question of whether a single- or multiple-level PV injection should be used is controversial. Multiplelevel thoracic injection avoids large doses of anesthetic and therefore may prevent intravascular or intrathecal injections.17 However, multilevel injections may provide a more reliable distribution of drug.24 Single-level injection may be more desirable for both patients and clinicians as it reduces procedure time, patient discomfort, and the incidence of needle-related complications.25 For these reasons, among others, Ben-David et al. have advocated the placement of a single PV catheter instead of multiple blocks.15

PARAVERTEBRAL BLOCKS

CHILDREN

PVBs in children are effective and safe, and provide prolonged blockade. Splinter et al. studied 36 children undergoing appendectomy under general anesthesia with or without a PVB (right PVB at T11, 12, and L1 level with 0.2% ropivacaine at a dose of 0.25 mg/kg). They found no difference in side effects between the 2 groups of patients, but those who received a PVB reported superior pain relief.26

CONTRAINDICATIONS

AND

COMPLICATIONS

Contraindications to PVBs are similar to those relating to central neuraxial blocks. They include infection at the site of needle insertion, empyema, and a history of

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local anesthetic toxicity. The presence of coagulopathy is a relative contraindication, as a paravertebral hematoma may have milder neurologic consequences than extradural hematoma.22 Caution to avoid pleural puncture should be exercised in patients with kyphoscoliosis or who have had a previous thoracotomy. The overall failure rate reported by Lonnqvist et al. is 10% in adults and 6% in children.30 Complications include hypotension (4.6%), vascular puncture (3.8%), pleural puncture (1.1%), and pneumothorax (0.5%). These rates compare favorably with other regional techniques. A bilateral PVB can double the incidence of vascular puncture and raise the risk for pneumothorax 8-fold compared with a unilateral block.31 The high incidence of vascular puncture and pneumothorax was associated with bilateral, multiple-level injections, however, and would not apply to bilateral single-level blocks. Transient ipsilateral Horner syndrome can result from the cephalad spread of local anesthetic to the cervical segment and is not a cause for concern in patients undergoing PVBs. Bilateral Horner syndrome can result from spread anterior to vertebra or from crossover sympathetic fibers. It may be associated with bilateral phrenic or recurrent nerve blocks.30

ULTRASOUND-GUIDED PARAVERTEBRAL BLOCKS The introduction of US guidance has increased the potential for PVBs to be placed in younger children with fewer complications.32 This technique is the preferred approach in our institution for infants, children, and adolescents undergoing major surgical procedures including pyeloplasty, thoracotomy, breast augmentation, and

Case Studies 1. A 10-year-old girl undergoing forequarter amputation for osteosarcoma of the humerus received a high continuous PVB at C5 and T2. Brachial plexus block was divided and resected during surgery and was not an option. The patient experienced excellent postoperative analgesia with no need for opioids in the immediate postoperative period.27 2. Single-injection PVBs were used as an adjunct to general anesthesia in 24 children undergoing major renal surgery. Low thoracic PVB was employed with levobupivacaine (0.5 mg/kg) and epinephrine (5 mcg/mL). The blocks were successful in 23 of 24 children, providing a median duration of analgesia of 600 minutes. The incidence of vascular puncture (8.3%) was high.28 3. Continuous PVBs were used for post-thoracotomy pain in 15 children. Excellent analgesia was obtained without pulmonary complications or complications related to the continuous infusion of bupivacaine.29

video-assisted thoracoscopic surgery. Initial work done by Lonnqvist et al. in the area of PVBs using the loss-ofresistance technique has now been complemented with the use of US guidance by Karmarkar et al. There are 2 ways of recognizing the PV space— a midline paramedian or an oblique transverse view (Figures 3a-c). Our preference is the paramedian view, as it can provide the easiest way to access the PV space in a child. Injection of local anesthetic in the correct area leads to a downward movement of the pleura. An M-mode is applied to the US machine to determine if the pleura has been rent, as demonstrated by the maintenance of the “sea shore” sign.

Conclusions Recent anesthetic literature has shown that caudal anesthesia and PVBs are effective and safe for use in children, with complication rates comparable to other regional techniques. They have relatively few contraindications, are easy to perform, and can be used in a wide variety of clinical situations. They have a low sideeffect profile and are becoming more acceptable to the anesthetic community with a resurgence of interest and research in this technique. The use of US for determining the epidural space may become the standard of care as more anesthesiologists receive training in the art of reading US imaging. The result likely will be safer practice in pediatric patients.

References 1.

Ecoffey C, Lacroix F, Giaufre E, Orliaguet G, Courreges P. Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth. 2010; 20(12):1061-1069.

2. Tsui BC, Suresh S. Ultrasound imaging for regional anesthesia in infants, children, and adolescents: a review of current literature and its application in the practice of neuraxial blocks. Anesthesiology. 2010;112(3):719-728. 3. Raghunathan K, Schwartz D, Connelly NR. Determining the accuracy of caudal needle placement in children: a comparison of the swoosh test and ultrasonography. Paediatr Anaesth. 2008; 18(7):606-612.

10. Chawathe MS, Jones RM, Gildersleve CD, Harrison SK, Morris SJ, Eickmann C. Detection of epidural catheters with ultrasound in children. Paediatr Anaesth. 2003;13(8):681-684. 11. Rapp HJ, Folger A, Grau T. Ultrasound-guided epidural catheter insertion in children. Anesth Analg. 2005;101(2):333-339. 12. Willschke H, Marhofer P, Bosenberg A, et al. Epidural catheter placement in children: comparing a novel approach using ultrasound guidance and a standard loss-of-resistance technique. Br J Anaesth. 2006;97(2):200-207. 13. Lonnqvist PA, Olsson GL. Paravertebral vs epidural block in children. Effects on postoperative morphine requirement after renal surgery. Acta Anaesthesiol Scand. 1994;38(4):346-349. 14. Ben-David B, Merman R, Chelly JE. Paravertebral blocks in thoracoscopy: single no, continuous yes. Anesthesiology. 2007;106(2):398. 15. Ben-David B, Swanson J, Nelson JB, Chelly JE. Multimodal analgesia for radical prostatectomy provides better analgesia and shortens hospital stay. J Clin Anesth. 2007;19(4):264-268. 16. Boezaart AP, Lucas SD, Elliott CE. Paravertebral block: cervical, thoracic, lumbar, and sacral. Curr Opin Anaesthesiol. 2009;22(5):637-643. 17. Baumgarten RK, Greengrass RA, Wesen CA. Paravertebral block: the holy grail of anesthesia for hernia surgery? Anesth Analg. 2007;104(1):207. 18. Richardson J, Jones J, Atkinson R. The effect of thoracic paravertebral blockade on intercostal somatosensory evoked potentials. Anesth Analg. 1998;87(2):373-376. 19. Weltz CR, Klein SM, Arbo JE, Greengrass RA. Paravertebral block anesthesia for inguinal hernia repair. World J Surg. 2003;27(4):425-429. 20. Richardson J, Lonnqvist PA. Thoracic paravertebral block. Br J Anaesth. 1998;81(2):230-238. 21. Karmakar MK, Booker PD, Franks R. Bilateral continuous paravertebral block used for postoperative analgesia in an infant having bilateral thoracotomy. Paediatr Anaesth. 1997;7(6):469-471. 22. Lonnqvist PA. Continuous paravertebral block in children. Initial experience. Anaesthesia. 1992;47(7):607-609. 23. Saito T, Den S, Tanuma K, Tanuma Y, Carney E, Carlsson C. Anatomical bases for paravertebral anesthetic block: fluid communication between the thoracic and lumbar paravertebral regions. Surg Radiol Anat. 1999;21(6):359-363. 24. Naja Z, Ziade MF, Lonnqvist PA. Bilateral paravertebral somatic nerve block for ventral hernia repair. Eur J Anaesthesiol. 2002; 19(3):197-202. 25. Thavaneswaran P, Rudkin GE, Cooter RD, Moyes DG, Perera CL, Maddern GJ. Brief reports: paravertebral block for anesthesia: a systematic review. Anesth Analg. 2010;110(6):1740-1744.

4. Roberts SA, Guruswamy V, Galvez I. Caudal injectate can be reliably imaged using portable ultrasound—a preliminary study. Paediatr Anaesth. 2005;15(11): 948-952.

26. Splinter WM, Thomson ME. Somatic paravertebral block decreases opioid requirements in children undergoing appendectomy. Can J Anesth. 2010;57(3):206-210.

5. Freid EB, Bailey AG, Valley RD. Electrocardiographic and hemodynamic changes associated with unintentional intravascular injection of bupivacaine with epinephrine in infants. Anesthesiology. 1993;79(2):394-398.

27. Koyyalamudi VB, Elliott C, Gibbs CP, Boezaart AP. Perioperative analgesia for forequarter amputation in a child: a dual paravertebral approach. Anesth Analg. 2010;110(3):761-763.

6. Wallace DH, Currie JM, Gilstrap LC, Santos R. Indirect sonographic guidance for epidural anesthesia in obese pregnant patients. Reg Anesth. 1992;17(4):233-236. 7.

Marhofer P, Bosenberg A, Sitzwohl C, Willschke H, Wanzel O, Kapral S. Pilot study of neuraxial imaging by ultrasound in infants and children. Paediatr Anaesth. 2005;15(8):671-676.

8. Kil HK, Cho JE, Kim WO, Koo BN, Han SW, Kim JY. Prepuncture ultrasound-measured distance: an accurate reflection of epidural depth in infants and small children. Reg Anesth Pain Med. 2007;32(2):102-106. 9. Willschke H, Bosenberg A, Marhofer P, et al. Epidural catheter placement in neonates: sonoanatomy and feasibility of ultrasonographic guidance in term and preterm neonates. Reg Anesth Pain Med. 2007;32(1):34-40.

28. Berta E, Spanhel J, Smakal O, Smolka V, Gabrhelik T, Lonnqvist PA. Single injection paravertebral block for renal surgery in children. Paediatr Anaesth. 2008;18(7):593-597. 29. Shah R, Sabanathan S, Richardson J, Mearns A, Bembridge J. Continuous paravertebral block for post thoracotomy analgesia in children. J Cardiovasc Surg (Torino). 1997;38(5):543-546. 30. Lonnqvist PA, MacKenzie J, Soni AK, Conacher ID. Paravertebral blockade. Failure rate and complications. Anaesthesia. 1995;50(9):813-815. 31. Lonnqvist PA. Entering the paravertebral space age again? Acta Anaesthesiol Scand. 2001;45(1):1-3. 32. Hara K, Sakura S, Nomura T, Saito Y. Ultrasound guided thoracic paravertebral block in breast surgery. Anaesthesia. 2009;64(2):223-225.

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PR N Table. Rates of Complications Varied for Patients With Hypertensive Emergency Admitted on Weekends or Weekdays Acute Myocardial Acute Aortic Stroke, % Hypertensive Infarction, % Dissection, % Encephalopathy, % Weekend

3.1

0.31

11.3

2.6

Weekday

2.5

0.23

9.2

2.3

characteristics and comorbidities. For patients with acute pulmonary embolism, they also compared time to placement of inferior vena cava filters and scores on the Pulmonary Embolism Severity Index (PESI). As they suspected, mortality rates between both groups of weekend admissions were higher than among weekday admissions. Specifically, patients with hypertensive emergencies had a mortality rate of 3.1% if admitted over the weekend, whereas only 2.5% of those admitted during the week died in the hospital (Table; odds ratio [OR] for weekend vs. weekday, 1.22; 95% confidence interval [CI], 1.16-1.30; P<0.001). After controlling for other risk factors, Dr. Markan reported, weekend patients were about 17% more likely to die in the hospital than weekday admits (95% CI, 1.08-1.26; P<0.001). Complication rates also were significantly higher among hypertensive emergency patients admitted during a weekend, Dr. Markan found. “The reasons for this phenomenon likely include a sicker patient population admitted over weekends, relative unavailability of investigative procedures, inappropriate hospital staffing patterns, untimely recognition of acute disease and underutilization of lifesaving procedures,” said Dr. Markan, who presented the findings at the 2011 annual meeting of the Society of Critical Care Medicine (abstracts 10 and 43). Among patients admitted during a weekend for acute pulmonary embolism,

he incidence of bloodstream infections involving central lines among patients in the intensive care unit dropped by nearly 60% between 2001 and 2009, to roughly 18,000 cases, according to the Centers for Disease Control and Prevention. Infections linked to Staphylococcus aureus saw a 73% reduction, the sharpest decline for any pathogen (left).

the rate of in-hospital deaths was nearly 20% higher than that among similar weekday admissions, Dr. Markan’s group found (4.84% vs. 4.11%, respectively;

OR,1.2; 95% CI, 1.13-1.31; P<0.05). Patients admitted over the weekend for acute pulmonary embolism also had more cardiac arrests, required more mechanical ventilation, had a higher rate of acute renal failure, more upper gastrointestinal bleeds and required more blood products during their hospital stay, the researchers found. Patients with pulmonary embolism who were admitted over the weekend received inferior vena cava filters an average of 0.19 days later than weekday

Closed.

patients, possibly accounting for part of the increased mortality, Dr. Markan said. He added that although in-hospital mortality rates among patients with pulmonary embolism in general had declined during the years his group examined, “the weekend effect has persisted and the odds for mortality among weekend admissions with pulmonary embolism are no different in the year 2008 than they were in 2000.” —David Wild

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April 2011

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Fourteen—A Magic Number for Clinical Care? One peds specialist sees bright line emerge for consent in early adolescence San Diego—When is a child an adult? The answer, of course, depends on context. But when it comes to making decisions about treatment, Harvard anesthesiologist David B. Waisel, MD, has an answer: 14. Yet as Dr. Waisel explained, the decision to honor or overrule an adolescent’s wishes with respect to anesthesia care is a complex one. Choosing treatment options for children and adolescents begins with an assessment of whether the child has the ability to decide for himself or herself. Children under the age of 6 years are not considered responsible for their actions. Between 7 and 13 years old, they can distinguish right from wrong, but they lack the ability to weigh these conflicting realities and anticipate the implications of their actions. When children reach age 14, however, they can consider and balance varied ideas, anticipate outcomes, have some sense of probability and can articulate their reasoning. Sarah Walton, MD, a pediatric anesthesiologist and medical ethicist at the University of Michigan Health System, in Ann Arbor, offered two pieces of advice for her colleagues. The first: “Absolutely know your state laws,” Dr. Walton said. The fastest way to find them will be to contact the hospital’s legal division, which ought to have copies of the latest statutes on file. Second: “Use sound clinical judgment”—and know the relevant state law. “No matter how old a teen is, if he or she doesn’t appear to be making rational or reasonable decisions, the hospital attorney is your best resource,” Dr. Walton said. Dr. Walton added that most pediatric anesthesiologists likely were not exposed to these sorts of ethical Advertisement

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questions during their training. “I didn’t learn any of this in medical school and I learned very little of it in my residency,” she said. Case Study To help demonstrate the complexity of such situations, Dr. Waisel described the case of a 14-year-old girl undergoing surgery in which an epidural is a possible—although not exclusive—analgesic option. In one scenario, the girl does not want the epidural; her parents do. “If we give her the epidural, we are taking away her voice,” Dr. Waisel said. “This is a young woman who’s going to be in the medical system all her life. If I take away her ability to be heard, she may forgo the medical system in the future.” Such decisions are relatively easy in situations for which other treatment options exist. Yet when patients refuse treatments that are clearly beneficial, physicians need to consider the impli‘I have a bit of a problem with someone cations of informed refusal. “We have an obligation, when we think somesaying they will accept risks that are not one is making a poor decision, to go the extra mile and make sure they actually considered beneficial by national standards. understand what the experience will be like,” noted Dr. Waisel, who discussed So in this case, listening to the teen does issues of assent and consent at the 2010 not override standard medical practice. annual meeting of the American Society of Anesthesiologists. “This is especially Just like you wouldn’t let an adult override true when that someone is a teenager.” What if the adolescent wants an epistandard medical practice, you wouldn’t dural and the parents do not? “From where I’m sitting, I’ve got to get that kid let a teen do the same thing, either.’ an epidural, as long as I think it’s a good idea,” Dr. Waisel said. “I need to work —David B. Waisel, MD with the parents to get them on board, because all of us shoulder a fair amount of angst if we disregard the parents on this.” you call in an ethics consult and you call in legal.” If the adolescent wants the epidural placed while Monica S. Vavilala, MD, associate professor of anesshe’s asleep, a whole new set of issues arises for the thesiology and pediatrics at the University of Washanesthesiologist. In this case, clinicians need to ington, in Seattle, said she prefers to judge each decide if they are comfortable assuming the risk for a adolescent on maturity rather than age. “I believe procedure whose benefits have not been overwhelm- these decisions should be based on the child’s develingly documented in the literature. opmental age,” Dr. Vavilala told Anesthesiology News. “I have a bit of a problem with someone saying they “You can have a 14-year-old who thinks like a 20-yearwill accept risks that are not considered beneficial by old or a 14-year-old who thinks like an 8-year-old.” national standards,” Dr. Waisel explained. “So in this Dr. Vavilala said she believes one of the most imporcase, listening to the teen does not override standard tant aspects of working with adolescents is ensuring medical practice. Just like you wouldn’t let an adult they feel heard with respect to their wishes. “I think override standard medical practice, you wouldn’t let a the ideal situation is to have a conversation with the teen do the same thing, either.” adolescent as well as the parent, because it provides Perhaps the most complex situation occurs when them with a sense of empowerment,” she said. “I think a treatment is essential to the adolescent’s well the mistake that physicians often make is to only being, but neither the patient nor the parents want speak to the parents, not realizing that some adolesit. “You need help,” Dr. Waisel said. “You’re going cents have their own opinions about things.” to face decisions in complex situations where you are just not going to know what to do. This is when —Michael Vlessides

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t is very important to assess the emotional and developmental maturity of the patient in question. I don’t believe there is an absolute age at which this can be defined. It can occur anytime from approximately age 12 until some time in the patient’s mid-20s, depending on the individual, the environment in which he or she is raised and many other contributing factors. The American Academy of Pediatrics considers age 14 to be a good average age at which a minor can be deemed sufficiently mature to understand the risks and benefits of medical procedures, and thus recommends that his or her “assent” to medical procedures be obtained in addition to the “informed consent” of the patient’s parents. In the example given in this article, if the patient adamantly refuses the epidural but the parents provide consent by proxy, the refusal—although not deemed the ideal decision by the health care provider—is not unreasonable by societal standards. The procedure carries inherent risks. An adult patient has the right to refuse the procedure, so the adolescent, too, should be afforded this right. We must give adolescents reasonable autonomy with their health care decisions. A study by Lewis et al. in Pediatric Anesthesiology (2007;17:11341142) addresses the issue of anesthesiologists’ comfort level with patient coercion for anesthetics. Most anesthesiologists would not override an adolescent’s refusal of elective procedures despite parental consent. If the opposite were the case, in which the patient desired a procedure that the parents refused, then it would be critical for the anesthesiologist to make every effort to convince the parents that the adolescent was making a safe and reasonable choice. If the issue becomes contentious, it would be necessary to involve legal services and allow the patient the opportunity to petition for medical emancipation for this particular case. It

The Ethicist Is in: Sarah Walton, MD would necessitate postponing the elective procedure until the legal decision can be made. In cases involving reproductive health, the adolescent is emancipated automatically in a majority of the states. One more issue to consider is that some institutions are starting to create adolescent “peer groups.” Adolescent patients

who have undergone procedures and treatments are asked by their medical providers to be available to talk to new patients who may be scheduled to undergo similar care in order to let them know what to expect, tell them what options they chose and relate how those choices worked for them. Often adolescents are more open

to hearing advice from their own cohort rather than being counseled by parents or health care providers. Sarah Walton, MD, is clinical assistant professor at C.S. Mott Hospital, part of the University of Michigan Health System, in Ann Arbor.

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Electronic Chart Could Spare Patients, Providers the Pain of Dental Trauma During Surgery

ental trauma during surgery is a leading cause of malpractice claims against anesthesiologists. But a research group from Taiwan has found that an electronic checklist can take a big bite out of the incidence of such injuries—and, by implication,

the risk that anesthesia providers will end up getting sued for causing them. The charting system prompts clinicians to examine a patient’s dentition prior to a procedure. The Taiwanese team found that after implementing the checklist, they cut the rate of dental

trauma in half. “The introduction of [a] preoperative standardized electronic dental chart might keep anesthesiologists alert about dental status before anesthesia and reduces incidence of anesthesiarelated dental trauma,” according to the

investigators, who presented their findings at the 2010 annual meeting of the American Society of Anesthesiologists (ASA; abstract A1657). Led by David Vi Lu, MD, of the anesthesiology department at Kaohsiung Municipal Hsiao-Kang Hospital, the researchers compared the incidence of dental trauma in patients undergoing general anesthesia before and after implementing the chart. During the 38-month study period, four of the 12,480 patients (0.03%) experienced dental trauma; three received an endotracheal tube and one a laryngeal mask airway. But the incidence became sharply lower after the charting system began, falling from 0.04% to 0.02% (P<0.001), according to Dr. Lu and his colleagues. Dr. Lu’s group said it recommends the chart be used for every patient receiving a preoperative evaluation.

ClipChart Michigan: A systematic, statewide effort to cut down on ventilatorassociated pneumonia in the intensive care unit has paid dividends with a 70% reduction in the rate of the complication. The program, funded by the Agency for Healthcare Research and Quality, pushed clinicians to use a checklist, practice appropriate hand hygiene and take other steps to prevent the spread of pathogens in the ICU. During the 2.5 years of follow-up, clinicians increased their routine use of five evidence-based measures to avoid ventilator-related complications more than twofold, from 32% to 84%, according to the study. The findings appeared in a recent issue of Infection Control and Hospital Epidemiology.

Lexington, Ky: Anesthesiologist John H. Eichhorn, MD, was honored with the 2010 John M. Eisenberg Patient Safety and Quality Award for his work in reducing potentially life-threatening episodes related to anesthesia during surgery. The award is given jointly by the National Quality Forum and the Joint Commission.

April 2011

AnesthesiologyNews.com I 37

POL ICY & M A N A GE MENT But Daniel L. Orr II, DDS, PhD, JD, MD, a dentist and anesthesiologist (and attorney) in Las Vegas, stifled a yawn over the study. “Anesthesiologists don’t need to chart teeth that might be a little looser or otherwise more compromised than normal. They are trained to avoid all teeth,” Dr. Orr said. “The poster does allude to identifying removable dental prostheses, which is good for physician anesthesiologists, mainly because they aren’t dentists.” However, Dr. Orr said, most anesthesiologists can identify potential dental problems without a formal charting system simply by noting in the preanesthesia record details such as “teeth WNL [within normal limits]” or “avoid central incisors if possible.” “It sounds like a lot of busywork to me, and fodder for my attorney colleagues. I’ve seen physicians call a loose denture an LF I facial fracture,” Dr. Orr added. “And even if an anesthesiologist was able to accurately delineate between +2 and +3 mobility or if a tooth had previously had a root canal or not, how would that possibly change

Boston: A Boston University anesthesiologist has received a letter of commendation from the World Health Organization for his creation of a video to promote the spread of pulse oximetry in the developing world. Rafael Ortega, MD, and colleagues spent two years developing the video, which is available in French, Spanish, Arabic, Russian, Mandarin Chinese and English. It contains both real and simulated scenes from the operating room, along with computer animation instruction on how to use a pulse oximeter.

the treatment plan? Plus, I suspect the reaction of a dentist to an anesthesiologist’s dental chart would likely be similar to an anesthesiologist looking at a non–anesthesia-trained dentist’s anesthesia chart—a loud guffaw.” Karen Domino, MD, who directs the ASA’s Closed Claims Project, said that although dental injuries are the most frequent source of liability suits against anesthesiologists, the database does not include them because their mechanism is straightforward.

Wade Willard, JD, vice president of claims for Preferred Physicians Medical, a Shawnee Mission, Kan.-based firm that specializes in providing malpractice insurance to anesthesiologists, said his group has handled 308 dental claims and suits between 2000 and late 2010. Of those, 99% closed without payment, Mr. Willard said, while the average indemnity payment was $1,100. The reason for the heavily skewed stats? “The vast majority of claimants have a pre-existing dental condition

that predisposes them to this type of injury,” Mr. Willard said. “An important aspect of this investigation is the documentation by the anesthesia care provider and the informed consent process the patient has been provided. If no evidence is found that the anesthesia care was below the standard of care, coupled with the fact that dental injury is a known risk and complication of the administration of anesthesia, the claim will be denied.” —Adam Marcus

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How To Navigate the Rising Tide of Aggressive RFPs

ospitals increasingly are disrupting their relationships with their longstanding anesthesia groups as they seek to cut stipends and get more for nothing. The favored tool? The request for proposal, or RFP. Consider the prototypical “Springdale Anesthesia” and its 20-odd anesthesiologists, which held the exclusive contract with Quad Cities Regional Medical Center for almost three decades. As the facility grew so did Springdale and its expertise, recruiting subspecialty-trained physicians to the practice despite the hospital’s less than desirable location and, in some subspecialty practice areas, lack of sufficient case volume. The symbiosis between the group and the facility was enhanced by the coverage stipend Quad Cities paid, and by the fact that both the breadth and depth of coverage provided by the fully board-certified group had enabled the hospital to recruit surgeons to expand into profitable service lines. As the years passed, contract term seemed to meld into contract term. To be true, there were simple negotiations around renewal time and, on occasion, a bump or two over demands for new coverage or more money. But as the years progressed the pats on the back for jobs well done became more and more hearty. Advertisement

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Until one day, as on the neck of a turkey fattened for months and months prior to Thanksgiving, the ax fell. Called to a meeting with Quad City’s chief executive officer, Springdale’s president was handed a notice with the three dreaded letters: RFP. Later, Springdale’s leader recalled having heard the CEO say, “We hope that Springdale submits a proposal.” For the moment, he still had need of a shirt collar. Unfortunately, this scene is playing out with increasing frequency, as if the tactic were viral, or at least the topic of a detailed briefing at a hospital association conference. Of course, the concept of an RFP is not new; it has been used for decades across many industries and by governmental agencies. But as opposed to its traditional use—identifying vendors for discrete supply orders or for a one-time project—the current RFPs for anesthesia services are increasingly being used as clubs to beat down the expectations of the present provider group. The Three RFPs Having dealt with anesthesia RFPs over four decades, I’ve classified them into three distinct categories. 1. True RFPs: These are genuine searches for the best-quality provider with a favorable ratio of quality to cost. This type of RFP is the closest in relationship to the traditional form used in industry and government. It is commonly seen in situations in which the current, or sometimes very recently former group, has “blown up” and can no longer provide coverage. It’s also frequent in scenarios where the current group has completely lost the facility’s trust. 2. Fictitious RFPs: These RFPs belie the fact that hospital administrators are not interested in the merits of any response; they have already decided to whom they will award the contract. Yet, for one political reason or another, they’ve decided to issue a phony RFP to project a patina of “fairness” to the medical staff, to the hospital’s own board, to some third party—or perhaps to you. 3. Fulcrum RFPs: Consider this the weaponized RFP. As the name implies, the increasingly common fulcrum RFPs are designed to create leverage. The facility intends on renewing with the present group but uses the RFP as a tool to dictate terms by fiat and to pressure the group into negotiating against its own best interests out of fear of replacement. Nonetheless, the facility is open to competing proposals. Category Dictates Strategy It’s essential that a group understand in any particular situation what type of RFP it is dealing with to calculate its response, or, in some cases, to determine whether to respond at all. It also is necessary to develop very good intelligence to identify the other responding parties. For example, why should a group incur the cost of responding to a fictitious RFP if it won’t be the

anointed one? After all, the fix is already in; don’t become a bit player in someone else’s show. The only reward will be significant expense at considerable effort. Or, in connection with a Mark F. Weiss, JD true RFP, especially in situations in which so-called anesthesia staffing companies are “bidding,” it’s vital to weigh the possibility that the process will simply result in a race to the lowest bottom line. Will the former accountant turned staffing company executive care if his group’s proposal does not make economic sense if holding the contract will increase the company’s market share? The strategy involved in a potential response and the tactics a group will employ depend on a proper assessment of the RFP’s character and on the likely competitors for the contract. Lastly, the fulcrum RFP situation requires the most advanced strategic thinking and tactical awareness on the part of the group. Groups must deploy both defensive and offensive tactics: On the defense, it’s imperative to hold the group together under the strain of what is a violent attack. On the offense, in launching this type of RFP, the hospital has left itself vulnerable as its preference is not to replace the current group. This leaves open the possibility that the current group can transform the situation into an even stronger position, through a strategy executed both within and outside the RFP process to demonstrate the unique benefits provided by the group and the loss that would result to the facility if the relationship did not continue. Of course, the best strategy for any group includes the creation of an experience monopoly for the hospital, surgeons and patients that results in a situation that the hospital would be foolish to disrupt. Even if the hospital does turn to the use of an RFP, it would be comparing a proven, successful package to untested alternatives. But, just as some hospitals are run by fools who know price but not value, the best strategy also includes never being wed to serve only one facility. As financial pressures on hospitals increase and as commoditization of anesthesia services continues, the trend toward RFPs will intensify. Develop and implement a strategy now for dealing with them now, preferably years before you find yourself on the receiving end of an RFP designed to replace you, to force disadvantageous terms, or, even worse, to have you offer to cut your own economic throat in the mistaken belief that a slow bleed is better than a quick chop. —Mark F. Weiss, JD Mark F. Weiss is an attorney who specializes in the business and legal issues affecting anesthesia and other physician groups on a national basis. He holds an appointment as clinical assistant professor of anesthesiology at University of Southern California’s Keck School of Medicine and practices with the Advisory Law Group, a firm with offices in Los Angeles and Santa Barbara, Calif., representing clients across the country. He can be reached by e-mail at markweiss@advisorylawgroup.com.

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40 I AnesthesiologyNews.com

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Did FDA Do Right by Cutting Acetaminophen Dose in Rx Products? One safety advocate offers guarded support but points to remaining OTC threat

linicians striving to provide patients with pain relief, without risking toxicity, received some support from federal officials in January, when the FDA recommended limiting the dose of acetaminophen

to 325 mg in combined prescription products. But the extent of the toxicity risk, as well as how much to limit patient access, remains a divisive subject, with more federal direction likely to come.

At issue is how best to balance the risks and benefits of a pain reliever that is sold in billions of doses. The new limit, which FDA officials say will be phased in over three years, is the first response to a series of acetaminophen recommendations issued by an advisory committee meeting in June 2009. The federal agency also announced in January that it is requiring a boxed warning on the prescription products to warn consumers of risk for severe liver injury. FDA officials also left the door open to later action regarding over-the-counter (OTC) products, saying they were continuing to evaluate various options. The new 325-mg limit stopped short of the advisory committee’s recommendation, by a narrow margin, to eliminate the prescription products. Narcotic products containing acetaminophen comprise 11 billion of the 28 billion OTC and prescription doses that consumers purchased in 2005, according to data cited by FDA officials. Charles Seifert, PharmD, FCCP, BCPS, described it as a thoughtful approach. “If you reduce the amount of acetaminophen in those products, that’s a really nice middle ground, if you will,” said Dr. Seifert, professor of pharmacy practice in the School of Pharmacy at Texas Tech University Health Sciences Center in Lubbock. “Now you can still get them as Schedule III. But you hope that, as you increase the narcotic component, the acetaminophen doesn’t exceed 4 g a day.” Will Rowe, chief executive officer of the American Pain Foundation, is not as sanguine, and is worried about unintended ripple effects. The nonprofit organization favors better education of patients and clinicians rather than regulatory changes that might limit access. Once the acetaminophen amount is restricted in the combined prescription products, patients might consume more OTC acetaminophen, thus pumping up their total consumption, Mr. Rowe said. “That person is at risk

April 2011

AnesthesiologyNews.com I 41

POL ICY & M A N A GE MENT because they don’t know what is a good [acetaminophen] supplement here and how much,” he said. “You may be creating a greater harm than good and that’s something to be very cautious and wary about.” Sidney Wolfe, MD, director of Public Citizen’s Health Research Group and a longtime critic of the FDA’s oversight of pain medications, agreed that clinicians should be concerned about the dangers posed by OTC acetaminophen products. “It is inexcusably poor judgment on the part of the [FDA] to have failed to take action concerning this major source of acetaminophen consumption and toxicity,” he wrote in a blog posted to Public Citizen’s Web site on Jan. 13. Dr. Wolfe pointed out that during the 2009 advisory committee meeting, members “overwhelmingly” voted to recommend that the OTC dose of acetaminophen be lowered. “If the FDA [in 2011] needed to set a priority … between acting on prescription or OTC products first, the agency should have first addressed the OTC category,” he wrote. [For more of Dr. Wolfe’s views on the controversy, see sidebar.] Weighing Risk As for the advisory committee’s vote on prescription acetaminophen products, no specific vote was actually taken to cap the acetaminophen dosage at 325 mg. But the committee did overwhelmingly vote 36 to 1 in favor of putting a boxed warning on the prescription combination products. By a far narrower margin (20 to 17), they sided with eliminating those products. Another voting option, to jettison nonprescription combination products, was rejected. Only 13 committee members voted in favor; 24 were opposed. In outlining their decision in the Federal Register, FDA officials cited several studies linking excessive acetaminophen intake with liver toxicity. It’s difficult to predict the precise impact of the lower 325-mg dose, they wrote. But to provide a sense of what that impact might be, they extrapolated data from a study published in 2005, showing that the median dose of those suffering liver toxicity was 7,500 mg per day (Hepatology 2005;42:13641372). Assuming that those pills were 500 mg apiece, the most common dosage, converting that number to 325mg pills could result in a total intake of 4,875 mg, “a level at which death or

liver failure is unlikely to occur in most people,” federal officials wrote. Still, only time will illuminate the clinical impact, said Brian Hemstreet, PharmD, associate professor in the Department of Clinical Pharmacy at the University of Colorado School of Pharmacy, Denver. “The biggest issue will be whether or not decreasing the [acetaminophen] dose will make a clinically significant dent in liver injury,” he said. Dr. Seifert, who co-presented with Dr. Hemstreet about acetaminophen

dosing at last year’s American College of Clinical Pharmacy annual meeting in Austin, Texas, also questioned whether a single threshold daily limit of 4 g made sense for all patients. “Four grams for everybody is ridiculous,” he said, adding that more studies were needed to assess toxicity based on weight. A daily dose that might be safe for him, he said, could be excessive for a slight, elderly woman. In interviews, it’s clear that clinicians are struggling with the balance between

risk and efficacy of the popular pain reliever. Kelly Jones, PharmD, BCPS, is one who believes that the pendulum is swinging too far toward regulation. “We are trying to control tiny risks—I think that gets dangerous after a while,” said Dr. Jones, associate professor of family medicine at the McLeod Family Medicine Center in Florence, S.C. In an analysis published last year in the Annals of Pharmacotherapy (2010; 44:737-739), Dr. Jones calculated the see acetaminophen page 42

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P OLI CY & M ANAGEMENT Acetaminophen continued from page 41

induced,” he said. “The intention of taking a prescription or OTC drug, in rate of unintentional acute liver fail- contrast, is that it is going to improve ure from acetaminophen to be 1 per your health. But with acetaminophen, 850,000 people, lower than the risk that’s often not the case; it actually for dying in a car crash or from a fall harms patients when misused.” or a gunshot wound. In an interview, In fact, “liver toxicity from acetaminDr. Jones put it far more colorfully. “I ophen is largely a preventable disease,” think you are more likely to be hit by a Dr. Wolfe added. “If we can get rid of bus going backward on I-95.” the 500-mg OTC pill and change it Dr. Wolfe said that he took issue to 325 mg, and in the process reduce with the bus-accident analogy, “because by about a third the amount of drug such events, albeit rare, are externally that is going to be ingested, you’ll

drastically reduce the amount of liver toxicity, liver failure and deaths seen in this country annually.” Boosting Education Patients will likely double up to ease their pain, no matter how products are designed, said Kennon Heard, MD, a Colorado emergency physician who also runs the medical toxicology training program at the Rocky Mountain Poison and Drug Center, in Denver. He described a patient he had seen that

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Public Citizen’s Take On Acetaminophen Toxicity

idney Wolfe, MD, director of the Health Research Group at Public Citizen, a Washington, D.C.-based consumer health advocacy organization, has been fighting for decades to ensure that FDA-approved medications strike the right balance between safety and efficacy. In June 2009, as a member of the agency’s Drug Safety and Risk Management advisory committee, Dr. Wolfe was asked to review acetaminophencontaining medications. He and his colleagues recommended several steps for reducing a major risk related to the painkillers: liver toxicity. At press time, many of those steps still had not been acted upon by the FDA. In an interview with Anesthesiology News, Dr. Wolfe expressed his frustrations with the agency’s efforts to tame acetaminophen toxicity and outlines what else needs to be done to protect consumers from “this continuing threat to public health.” AN: You made it pretty clear in a recent blog that you weren’t happy with the fact that the FDA, at least to date, has only implemented a 325-mg dosage cap on prescription acetaminophen products, while leaving OTC dosages of the painkiller essentially unchanged. What’s your primary concern with that decision? Dr. Wolfe: The main problem is that the OTC formulation accounts for nearly 80% of all acetaminophen product sales and causes up to 60% of all cases of liver toxicity in the United States annually. So by only acting on the prescription painkiller, the agency has left a major portion of the risk equation for this medication completely unaddressed. As I noted in my blog, I really do feel that this constitutes inexcusably poor judgment on the part of the FDA. The risks posed by OTC products should have been a larger priority for the agency. AN: In the days after you posted your blog, the FDA was quoted in media reports saying that it was still considering placing new limits on OTC acetaminophen products. But an agency spokeswoman said “there are more complexities” in the rule-making

day who was seeking help for severe abdominal pain. In the few days prior, she had been consuming as much as 12 g of acetaminophen daily in search of relief. Dr. Heard worries that the 325-mg limit could backfire, if patients perceive the new combined products as

April 2011

AnesthesiologyNews.com I 43

POL ICY & M A N A GE MENT process when it comes to OTCs, and that process “occurs over a longer time frame.” What’s your view on that? Dr. Wolfe: It’s true that regulating OTCs is somewhat more complex. But it’s not as though the FDA has not had time to work on this. Remember, our advisory committee met in June 2009. That’s more than 18 months ago. If the FDA had made both prescription and OTC acetaminophen products a priority from the start, there is no reason why they could not be ready today, or at least very soon, to place a maximum daily dose on OTC products. For some reason, the agency decided they wanted us to choose one product class over the other. Well, we did that; but we voted overwhelmingly (24 of 37 members) to set the maximum on OTC products first, then to tackle the prescription products. Obviously, the agency chose to go in another direction. As a result, now you have this really dangerous, paradoxical situation where the allowable dose in prescription products—325 mg—is lower than the 500mg “maximum-strength” OTC dose that you can buy in the supermarket or gas station. AN: In the past, when you’ve seen documented risks posed by medications, you’ve advocated pulling them from the market. Do you think acetaminophen needs to just go? Dr. Wolfe: Acetaminophen is a perfectly good drug; we never considered taking it off the market. But every string should be pulled to minimize the amount of damage that it can cause, and having around these 500-mg OTC pills that are essentially 1.5 times more pill than you’d get in 325-mg prescription product means that most people are taking more acetaminophen than they need to be. Now, based on the FDA’s actions, or lack thereof, the attendant risk will be reduced in the prescription drug arena but not in the OTC arena. That just makes no sense. It’s also important to remember that the majority of people suffering from acetaminophen-induced liver toxicity are not attempting suicide. Tragically, most of these cases are due to unintentional overdoses from either the OTC or prescription formulations—or both, taken together. And so many of these cases are avoidable, if only the FDA had used a two-pronged attack on this. —David Bronstein

acetaminophen—and other pain relievers like nonsteroidal anti-inflammatory drugs, for that matter—they are taking. Only 45% of patients know that Tylenol contains acetaminophen, according to results published in the Emergency Medicine Journal (2008;25:213-216). Far fewer were aware that medications like Percocet (oxycodone and acetaminophen) or Vicodin (hydrocodone bitartrate and acetaminophen) also contain the painkiller—18% and 10%, respectively.

Clinicians also should emphasize that if the recommended dose is not effective, the patient should return for further evaluation and help, Dr. Heard said. To improve education, the American Pain Foundation has launched an initiative called PainSAFE (http://www. painfoundation.org/painsafe) with information for providers and patients. Details about OTC pain relievers will be available by spring, according to Mr. Rowe.

FDA officials have been involved in public education as well, dating back to 2004. But continued toxicity experience shows that education alone is not sufficient, FDA officials said, in explaining their January decision. Dr. Hemstreet agreed. “We are still seeing people showing up with liver injury and liver failure, even with these added warnings in the last few years and even with education by pharmacists.” —Charlotte Huff

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Opioid Imbalance

he California Workers’ Compensation Institute recently reported that 3% of physicians who prescribe opioids to injured workers in that state write more than half of such prescriptions. California has seen a surge in opioid orders for workers’ compensation claims, from 1.4% of all prescriptions in 2005 to 7.2% of prescriptions in 2009, the group said. Meanwhile, payments for such drugs rose 531% over the same period. (Tables reprinted with permission from the California Workers’ Compensation Institute. The full report is available at www.cwci.org/research.html.)

Table 1. Distribution of Claims, Schedule II Prescriptions and Schedule II Payments by Diagnosis Category—Claims With at Least One Schedule II Opioid Prescription

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Schedule II Opioid Payments, %

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Schedule II Opioid Prescriptions, %

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STATUS & HISTORY

Schedule II Opioid Claims, %

FILE SLUG

Medical Back Problems w/o Spinal Cord Involvement

35.7

47.1

50.2

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Each installment contains articles from the current month’s issue ahead of print, as well as links to podcasts and other Web-exclusive content

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Circulation

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Spine Disorders w/ Spinal Cord or Root Involvement

11.3

15.1

16.1

Cranial & Peripheral Nerve Disorders

5.0

6.8

6.5

Degenerative, Infective & Metabolic Joint Disorders

9.3

6.1

5.4

Other Injuries, Poisonings & Toxic Effects

5.5

5.9

6.8

Ruptured Tendon, Tendonitis, Myositis & Bursitis

6.0

3.6

2.7

Sprain of Shoulder, Arm, Knee or Lower Leg

6.8

3.2

2.8

Wound, Fracture of Shoulder, Arm, Knee or Lower Leg

6.3

2.7

1.6

Other Mental Disturbances

1.2

1.7

1.5

Other Diagnoses of Musculoskeletal System

1.5

1.4

1.1

Head & Spinal Injury w/o Spinal Cord Involvement

1.1

0.9

0.7

Carpal Tunnel Syndrome

1.1

0.8

0.7

Subtotal: Top 12 Diagnosis Categories

90.8

95.3

96.2

All Other Diagnosis Categories

9.2

4.7

3.8

Total

100

Table 2. California WC Schedule II Prescriptions, Payments and Average Number of Schedule II Opioid Prescriptions Per Claim (Top 10% of Schedule II Prescribing Physicians)

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Physician Ranking Based on No. of Schedule II Scripts Writtena

Cumulative Percentage of All Schedule II Opioid Prescriptions

Cumulative Percentage of All Schedule II Opioid Morphine Equivalents

Cumulative Percentage of All Schedule II Opioid Payments

Top 1.0%

33.1

41.0

42.4

Top 2.0%

46.2

53.6

55.8

Top 3.0%

54.9

62.4

64.7

Top 4.0%

61.3

69.0

70.8

Top 5.0%

66.0

74.1

76.3

Top 6.0%

69.7

77.9

80.1

Top 7.0%

72.7

80.9

83.1

Top 8.0%

75.2

83.3

85.1

Top 9.0%

77.3

85.3

86.8

Top 10.0%

79.2

86.8

88.2

All Other Physicians

20.8

13.2

11.8

Total

100

Each percentile includes approximately 93 physicians, so the top 1% represents 93 physicians, the top 2% represents 186 physicians, the top 3% represents 279 physicians, etc.

April 2011

AnesthesiologyNews.com I 45

Pai n Me d i ci n e UDT continued from page 1 most aggressive by a state medical board in the United States. Although many Florida physicians support some form of increased regulation, the idea that patients should be discharged for an unexpected UDT result raises a number of ethical concerns about the role that drug testing should play in pain clinics. “One of the requirements is that upon any evidence of diversion, the patient has to be immediately discharged or the physician risks being held in violation of state rules. The problem is how it’s written,” said Warren Pearson, executive director of the Florida Society of Pain Management Providers, an organization that advises pain clinics on compliance with state rules. “To be beyond a reasonable doubt, you have to be 99% sure, and to meet the clear and convincing [criterion] you have to be more than 50% sure that someone is guilty. But there is a lot that qualifies as some evidence of diversion and many patients will be needlessly subjected to the trauma of separation from their physician with absolutely no

mechanism in place to treat their continuing pain or addiction.” Even without a state law, patients are routinely dismissed after an abnormal UDT. “It’s fairly common for patients to fail a drug test and be fired from a pain clinic,” said Gary Reisfield, MD, assistant professor of psychiatry at the University of Florida in Gainesville, who specializes in pain management and addiction. “We see patients in our clinic at least weekly who have been fired from their previous pain physician or primary care physician on the basis of a single failed test. “But I feel very strongly that an unexpected urine drug test result should not be the end of the therapeutic relationship,” he added. “Rather, it should be the beginning of a conversation between physician and patient to discern the meaning of the test result.” UDT is perceived as the most objective measure a physician can use to assess a patient’s compliance. “In terms of adherence monitoring, we know unequivocally that patients’ selfreport about their use is unreliable,” Dr. Reisfield said. “We also know that

400

Anesthesia

Please visit us at the ASRA Booth #117

behavioral observations only go so far.” Doug Gourlay, MD, a pain and chemical dependency consultant to the Wasser Pain Management Centre in Toronto, Ontario, Canada, agreed that “[urine drug analysis] brings a level of objectivity to help you verify information that otherwise is difficult to verify by other means. It adds a level of honesty to the interaction that you might hope is implicit, but the reality is that sometimes people [with drug problems] don’t know just how big an issue drug use is in their lives.”

monitoring and urine testing along with other types of measurements,” said Joseph Pergolizzi, MD, adjunct assistant professor in the Department of Medicine at Johns Hopkins University, in Baltimore, with a private practice in Naples, Fla. He tells his higher-risk patients, “If you’re a patient in my practice, once a year we are going to have random urine drug testing and the goal is to support assessment and diagnosis to see how well you’re doing.” “By using urine drug testing in a matter-of-fact fashion, you normalize it; you just make it part of the assessAssessing When To Use UDT ment,” said Dr. Gourlay, who added Nevertheless, urinalysis use is far that he believes that the possibility from universal. Although a growing of UDT should be discussed with all number of pain physicians routinely patients. use UDT in their practice, concerns UDTs for patients on chronic opiover the proper interpretation of the oid therapy are less common among results remain a common question primary care physicians because pain for clinicians, said Dr. Gourlay. In physicians appear to worry less about some pain clinics, UDT is rolled into creating an adversarial relationship a universal precautions strategy that with a patient, whereas primary care incorporates a constellation of risk doctors will discharge a patient only assessment measures. under extreme conditions, like when “Urine drug testing is part of an entire they are concerned about possible integrated drug compliance system, violence. see UDT page 46 where you want to incorporate patient

46 I AnesthesiologyNews.com

April 2011

P A IN M ED I C I NE UDT continued from page 45

approaches, experts say. One major problem is that once a patient “beats” a test for a substance abuse disorder, the patient–physician dynamic shifts. Over time, the patient becomes aware that the system isn’t foolproof. “When a clinician overly relies on urine drug testing, it can convey to the patient that [the physician] may not really know as much about this [area] as they think,” Dr. Gourlay said. “And once it becomes apparent that you can use a drug and the drug won’t show up

in the urine for various reasons, then the patient may feel, ‘Well, these people don’t really know how to manage risk here at all,’ or that they ‘have an advantage over the clinical team.’ ” So when should UDT be done? “It should not be wielded as a weapon, but should be regarded as a diagnostic tool,” Dr. Reisfield said.

using UDT. “Urine drug testing use has to be predicated on the initial ques“I think some primary care providtion, ‘What information do you hope ers tend to be uncomfortable with the to get out of it?’ What is your testing idea of urine drug testing because it strategy?” said Dr. Gourlay. “You betdoes, in some physicians’ minds, stigter have a plan and the plan better have matize patients and I think physicians clinical relevance. And, in fact, in medview urine drug testing as an adversaricine you should never do a test where ial behavior,” Dr. Reisfield said. you don’t know how to interpret the Although UDT is probably underresults.” Interpreting the Results used, it doesn’t mean that it should This last part is key, because studbe universally employed, but should A physician needs to ascertain, on ies have demonstrated that many phybe used in conjunction with other a patient-by-patient basis, why they’re sicians do not, in fact, know how to correctly interpret UDT results. With UDT, Dr. Reisfield said, “there are a plethora of unknown unknowns; that is, many physicians don’t know what they don’t know.” Dr. Pergolizzi added that “some individuals have a relatively high understanding and others don’t, but there really is no standard that’s come out for urine drug testing.” The result is that testing knowledge is “all over the board.” A lack of understanding can create any number of problems. “It’s dangerous in two directions,” said Dr. Gourlay. “It can give you a false sense of security if in fact [a test] looks normal but is not, but equally, it can result in people who do nothing wrong [being accused of diversion] simply because the test result came back negative for the drug that is prescribed.” As a basic example, quantitative tests have a threshold that defines a positive result. Patients who are just below that threshold may come back negative for their prescribed opioid, even though they’ve been compliant, or simply missed a dose. On a more complex level, opioids Donald J. Palmisano, MD, JD, FACS metabolize in many different ways. For Board of Governors, The Doctors Company Past President, American Medical Association example, oxycodone is poorly crossreactive with most antibody-based screening assays, which are designed to detect morphine and codeine. Similarly, fentanyl and methadone are undeThe Doctors Company is devoted to helping doctors avoid potential lawsuits. For us, this starts with patient tectable because the structures of these synthetic opioids differ radically from safety. In fact, we have the largest Department of Patient Safety/Risk Management of any medical malpractice those of commonly prescribed opiates. insurer. And, local physician advisory boards across the country. Why do we go this far? Because sometimes “Patients are fired for the ‘absence’ of oxycodone fairly frequently,” Dr. Reisthe best way to look out for the doctor is to start with the patient. To learn more about our medical field said. professional liability program and the beneﬁts that have made us the nation’s leading writer of anesthesiologists, There also are a host of drug–drug conversions during metabolism. Oxycall (800) 352-0320 or visit us at www.thedoctors.com. codone metabolizes to oxymorphone, codeine metabolizes to morphine and hydrocodone. Testing techniques using chromatography and mass spectroscopy will detect parent drugs and metabolites. “There are numerous other examples, but the point is that there are biologic interconversions of opioids. If the

We hate lawsuits. We loathe litigation. We help doctors head off claims at the pass. We track new treatments and analyze medical advances. We are the eyes in the back of your head. We make CME easy, free, and online. We do extra homework. We protect good medicine. We are your guardian angels. We are The Doctors Company.

see UDT page 62

April 2011

AnesthesiologyNews.com I 47

Pai n Me d i ci n e

High Morbidity Accompanies Nonmedical Use of Prescription Opioids

he rate of opioid-related deaths in individuals taking the drugs for nonmedical reasons continues to rise unabated. Between 1999 and 2006, the number of poisoning-related deaths in the United States increased by 85% (from 20,000 to 37,000 deaths per year), with the largest increase attributed to opioid use (National Center for Health Statistics data brief, No. 22; available at www. cdc.gov/nchs/data/databriefs/db22. pdf; Figure). Nonmedical prescription opioid use is a growing part of the problem, but there is limited information on the costs associated with it. In a new report, investigators estimated the economic burden from nonmedical use of prescription opioids in the United States, using data from National Household Survey on Drug Abuse, which captures information on 60,000 to 70,000 people annually (about 0.022% to 0.023% of the U.S. population). The authors evaluated the economic burden in terms of four major categories: substance abuse treatment, medical complications, lost productivity and criminal activity (Clin J Pain 2011;27:194-202). According to the study, in 2006, the total cost of nonmedical use of prescription opioids reached $53.4 billion. Of this amount, $42 billion (79%) could be attributed to lost productivity, $8.2 billion (15%) to crime-related    

40,000 35,000

No drug involved Specified drug(s) other than opioid analgesics Only nonspecified drug(s) Any opioid analgesic

costs, $2.2 billion (4%) to drug abuse treatment and $944 million to medical complications (2%). The opioids oxycodone, hydrocodone, propoxyphene and methadone accounted for twothirds of the total economic burden. The authors also acknowledged

several constraints of the study, most notably that the data included in the household survey were limited. “Our study suggests that the costs of nonmedical use of prescription opioids in the United States are substantial,” the authors wrote. “Our estimates

are consistent with prior estimates for all drug misuse reported by [the Office of National Drug Control Policy], but much higher than a prior published estimate specific to prescription opioids.” But given several limitations of the methods and sources included in the study, the authors concluded that “our results should be interpreted with caution and regarded as approximations only.” —Victoria Stern

30,000 34%

Deaths

25,000

ChloraPrep® skin antiseptic has consistently outperformed iodine-based products.2,3,4,5 In a landmark study published in The New England Journal of Medicine, ChloraPrep reduced total surgical site infections by

20,000 14%

22%

15,000 10,000 37%

18%

References: 1. Wenzel RP. Minimizing surgical-site infections. N Engl J Med. 2010;362(1):75-7. 2. Darouiche R, Wall M Jr, Itani M, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010;362:18-26. 3. Saltzman MD, Nuber GW, Gryzlo SM, Marecek GS, Koh JL. Efﬁcacy of surgical preparation solutions in shoulder surgery. J Bone Joint Surg Am. 2009;91(8):1949-1953. 4. Ostrander RV, Botte MJ, Brage ME. Efﬁcacy of surgical preparation solutions in foot and ankle surgery. J Bone Joint Surg Am. 2005;87:980-985. 5. Chaiyakunapruk N, Veenstra DL, Lipsky BA, Saint S. Chlorhexidine compared with povidone-iodine solution for vascular cathetersite care: a meta-analysis. Ann Intern Med. 2002;136(11):792-801.

chloraprep.com | 800.523.0502

21%

41% versus povidone-iodine [9.5% vs 16.1%, respectively].2 It’s one more reason why ChloraPrep is the proven way to prep.™

47%

5,000

Set the new standard every time you prep with ChloraPrep.®

1999 2000 2001 2002 2003 2004 2005 2006

Year Figure. Poisoning deaths involving opioid analgesics, other drugs and no drugs: United States, 1999-2006.

48 I AnesthesiologyNews.com

April 2011

P A IN M ED I C I NE

REMS: Symptom or Cure?

isk associated with drug toxicity is a prominent national health care issue that must be addressed. But will the FDA’s Risk Evaluation and Mitigation Strategies (REMS) be the cure we are hoping for? Will REMS lead to less risk and better outcomes for patients, or further overwhelm our health care system to the point of failure? Certainly, it is understandable why the FDA is looking to REMS to further reduce the risks posed by certain medications. Advances in technology, drug development and medication delivery, as well as increasing globalization of health care, are driving us to new levels of complexity—all factors that can increase the potential for drug mishaps. The proactive nature of REMS also makes sense: As scientists, we understand it is better to prevent a problem than to resolve one. More importantly, we know that progress arises when people are interconnected, share knowledge and work together. But is the REMS program, as currently constructed, built for success? Let’s begin by discussing the core concept behind REMS—mitigation, which is defined as the act of decreasing or reducing something in such a way that it appears less serious. If drug toxicity is a real threat to a patient, can we be satisfied with mitigation? With modern knowledge and technology, why can’t we build systems that prevent avoidable risks and appropriately anticipate and manage unavoidable toxicity? Anything less should be unacceptable. The National Comprehensive Cancer Network (NCCN) recently convened an “all-stakeholders” task force to survey attitudes toward the REMS program (J Natl Compr Canc Netw 2010;8:7-27). The results suggest several potential trouble spots. For example, only 39% of the respondents, which included prescribers, providers, manufacturers, payers, distributors, regulators and patients, were moderately or highly familiar with REMS requirements. Only 52% agreed that REMS will better inform patients, and 66% agreed REMS would improve safety. Perhaps of greatest concern are the opinions expressed that REMS will alter prescribing patterns and lead to disparities in care. A majority of practitioners indicated they will register to prescribe REMS drugs only when no alternatives are available (74%) and when the process is not burdensome (59%). Fewer than 21% of all responders disagreed that REMS will interfere with the provision of care, drive utilization toward non-REMS drugs and create disparities in care. Stakeholders in the survey agreed that an effective REMS program must be standardized for efficient processing, user-friendly, supported by informatics systems, supportive of therapy adherence and patient-centric, as well as able to provide balanced and objective information. Stakeholders agreed that REMS should not create a barrier to accessing drugs, but should have methods for sharing data and should define methods and metrics for determining effectiveness. Stakeholders agreed that they should be involved in determining which drugs require REMS and have input into each program’s design. Additionally, all stakeholders were concerned about the added

cost and time this “unfunded mandate” requires and the impact on other essential services. For now, we must adhere to established regulations approved by the FDA. There seems to be general agreement that the best practice includes building REMS criteria into the drug formulary and drug ordering process and that mandatory education should be part of practitioner credentialing. Is REMS a Symptom or a Cure? To put this in perspective, I will borrow from The Watchman’s Rattle: Thinking Our Way Out of Extinction, by Rebecca Costa (New York, NY: Vanguard Press; 2010). According to Costa, major civilizations fail when faced with an overwhelming complexity of issues. Prior civilizations such as the Mayans and the Romans had technology to reach an advanced state and maintain themselves for thousands of years, but eventually succumbed to a variety of issues that emerged over time. They could have used their techFuture Clinical Decisions?

Indications for Use (Evidence-Based)

All Drugs Compendia (Strength of Evidence Rated)

Toxicity/Risk (Evidence-Based)

Decision Algorithm/Treatment Guidelines Decision Points (Start, Change, Stop)

Measure Outcomes (Efficacy, Toxicity, Quality of Life, Cost)

Comparative Effectiveness Feedback

to identify when the patient becomes at risk for drug toxicity. Given that ever-advancing technology facilitates personalized monitoring, the better way to deal with the risk for Philip E. Johnson, drug toxicity is to build it into MS, RPh a comprehensive process for total and personalized patient care. Start With Education The REMS approach is correct in identifying the importance of education. However, education provided to professionals must be provided at the highest evidentiary level and be traceable. Patient education must be objective, balanced and easily understood. I propose that in an ideal model, education also must be: • Based on guidance from an interdisciplinary advisory board to ensure the quality and appropriateness of the education; • Provided in accord with the Accreditation Council for Continuing Medical Education and the Accreditation Council for Pharmacy Education, both of which are proven entities that have requested this role in a public record; and • Not only eligible for continuing education credits, but eventually participation also will be searchable so we can verify practitioner and patient completion. Build Risk Into the Total Treatment Plan I believe a comprehensive care plan is more effective than addressing individual components separately. There is currently wide acceptance of evidence-based compendia for determining appropriate use (NCCN, Gold Standard, MicroMedex). Such compendia are supported by several payers when determining therapy is appropriate and authorized. Evidence-based compendia can (and should) include evidence-based risk factors and toxicity trigger points. When risk factors are built into total patient care algorithms, several important things happen: Risk and prevention are both part of a consolidated care plan; all care-related issues can be anticipated, monitored and managed; outcomes of care can be determined while considering all relevant variables, thus supporting true comparative effectiveness evaluation; and new knowledge becomes available for use in a continuous feedback loop to enhance and advance the patient care algorithm. The accompanying schematic shows how this process could be designed for the future. I believe the creation of the current REMS process is a symptom of the overwhelming complexity we are facing in health care, not a solution to the problem. A comprehensive, personalized patient care approach using modern technology and evidence-based protocols is necessary to provide optimally safe and effective care. It won’t be easy, but innovation through collaboration will bring the ultimate resolution to the problems we face in health care today, including the problem of risks presented to patients by drugs.

nology and advanced knowledge to work through the problems, but unfortunately they reached a “cognitive threshold” that led to a mental gridlock. They were so overwhelmed with complexity they turned to desperate survival tactics (wars to claim needed resources) or unsubstantiated solutions such as human sacrifice. Applying this to REMS, more than 160 drugs have been identified as high risk, and the prescribed solution is to hold the pharmaceutical companies responsible for an education strategy that will mitigate the problem. This strategy is worrisome because it directly opposes the modern concept of personalized medicine. When looking at the current list of REMS drugs, some may assume that high-risk drugs that are not on the list such as digoxin, phenytoin and warfarin will now be considered “risk-free.” Health care —Philip E. Johnson, MS, RPh professionals know that not all drugs present risk for all patients. By monitoring the “whole patient” appro- Mr. Johnson is pharmacy advocacy director at the Moffitt Cancer priately, any health care practitioner should be able Center and Research Institute, in Tampa, Fla.

April 2011

AnesthesiologyNews.com I 49

Pai n Me d i ci n e

Poor Mental Health Linked to Persistent Pain After TKA San Diego—An estimated 300,000 Americans undergo total knee replacement surgery each year, many to relieve pain from osteoarthritis. Although the procedure is effective for most patients, as many as 20% experience persistent pain for as long as six months after surgery. New evidence from Rush University Medical Center in Chicago, points to an association between lingering postoperative pain and poor mental health. “One of the most significant consequences that can occur after primary total knee replacement is pain,” said Mario Moric, MS, research coordinator in the Department of Anesthesiology at Rush. “Investigators have hinted that persistent postoperative pain may affect mental health, but it hasn’t really been examined in depth.” Mr. Moric and colleagues enrolled 31 patients undergoing primary total knee arthroplasty (TKA) into the study. Persistent postoperative pain was defined as pain occurring in the operative knee three to six months after surgery and rated 4 or higher on a 10-point numerical rating scale. Other possible causes of pain were excluded. Two measures were used to assess mental health: the Knee injury 100

KOOS Score (0-100)

* 20

 No PPP  PPP * Significant between groups at P<0.05

0 0

Time (months postoperative) Figure 1. KOOS subscale of quality of life in TKA patients. PPP, persistent postoperative pain; TKA, total knee arthroplasty

and Osteoarthritis Outcome Score (KOOS) quality-of-life subscale and the Short Form (SF)-36 mental health subscale. For each measure, the researchers calculated a normalized score, with 100 signifying no symptoms and 0 indicating extreme symptoms. Scores on the two scales were compared between patients with and

without persistent postoperative pain at three, six and 12 months after surgery. As Mr. Moric reported at the 2010 annual meeting of the American Society of Anesthesiologists (abstract A159), KOOS quality-of-life values were lower in patients who had persistent postoperative pain than in those without such pain (45±3 vs. 75±2),

a pattern that held throughout the follow-up period. These differences were statistically significant at three months, but not after (Figure 1). Scores on the SF-36 mental health subscale also were significantly compromised throughout the postoperative period in patients with persistent postoperative pain (70±4 vs. 84±2; see TKA page 50

50 I AnesthesiologyNews.com

April 2011

P A IN M ED I C I NE TKA continued from page 49

‘We know this is something that all pain physicians have

Figure 2). These differences were statistically significant only at 12 months after surgery. “This study has demonstrated that persistent postoperative pain is associated with compromised mental health,” Mr. Moric said. Cognitive-behavioral therapy may prevent persistent postoperative pain, thereby improving quality of life, he noted. “We are performing another study,

observed. I’m sure if we examined a pool of people who

Qutenza® (capsaicin) 8% patch

continued pain processes and significant or debilitating psychosocial issues as described in this study.’ —Alan Kaye, MD, PhD Other Adverse Reactions Observed During the Clinical Studies of Qutenza: General Disorders and Administration-Site Conditions: application-site urticaria, application-site paresthesia, application-site dermatitis, application-site hyperesthesia, application-site excoriation, application-site warmth, application-site anesthesia, application-site bruising, application-site inflammation, application-site exfoliation, peripheral edema Nervous System Disorders: headache, burning sensation, peripheral sensory neuropathy, dizziness, dysgeusia, hyperesthesia, hypoesthesia Respiratory, Thoracic, and Mediastinal Disorders: cough, throat irritation Skin and Subcutaneous Tissue Disorders: abnormal skin odor

DESCRIPTION Qutenza (capsaicin) 8% patch contains capsaicin in a localized dermal delivery system. The capsaicin in Qutenza is a synthetic equivalent of the naturally occurring compound found in chili peppers. INDICATIONS AND USAGE Qutenza is indicated for the management of neuropathic pain associated with postherpetic neuralgia. WARNINGS AND PRECAUTIONS Eye and Mucous Membrane Exposure: Do not apply Qutenza to the face or scalp to avoid risk of exposure to the eyes or mucous membranes. Aerosolization of Capsaicin: Aerosolization of capsaicin can occur upon rapid removal of Qutenza patches. Therefore, remove Qutenza patches gently and slowly by rolling the adhesive side inward. If irritation of eyes or airways occurs, remove the affected individual from the vicinity of Qutenza. Flush eyes and mucous membranes with cool water. Inhalation of airborne capsaicin can result in coughing or sneezing. Provide supportive medical care if shortness of breath develops. Unintended Skin Exposure: If skin not intended to be treated comes in contact with Qutenza, apply Cleansing Gel for one minute and wipe off with dry gauze. After the Cleansing Gel has been wiped off, wash the area with soap and water. Application-Associated Pain: Even following use of a local anesthetic prior to administration of Qutenza, patients may experience substantial procedural pain. Prepare to treat acute pain during and following the application procedure with local cooling (such as an ice pack) and/or appropriate analgesic medication, such as opioids. Opioids may affect the ability to perform potentially hazardous activities such as driving or operating machinery. Increase in Blood Pressure: In clinical trials, increases in blood pressure occurred during or shortly after exposure to Qutenza. The changes averaged less than 10 mm Hg, although some patients had greater increases and these changes lasted for approximately two hours after patch removal. Increases in blood pressure were unrelated to the pretreatment blood pressure but were related to treatment-related increases in pain. Monitor blood pressure during the treatment and provide adequate support for treatment-related pain. Patients with unstable or poorly controlled hypertension, a recent history of cardiovascular or cerebrovascular events may be at an increased risk of adverse cardiovascular effects. Consider these factors prior to initiating Qutenza treatment. ADVERSE REACTIONS The following serious adverse reactions are discussed in Warnings and Precautions: ApplicationAssociated Pain and Increase in Blood Pressure. Clinical Trials Experience: Across all controlled and uncontrolled trials, more than 1,600 patients have received Qutenza. A total of 394 patients received more than one tre atment application and 274 patients were followed for 48 weeks or longer. In controlled clinical studies, 98% of patients completed ≥ 90% of the intended patch application duration. Among patients treated with Qutenza, 1% discontinued prematurely due to an adverse event. Controlled Clinical Studies: Common Adverse Reactions: adverse reactions occurring in ≥ 5% of patients in the Qutenza group and at an incidence greater than in the control group were application-site erythema, application-site pain, application-site pruritus and application-site papules. Table 1 summarizes all adverse reactions, regardless of causality, occurring in ≥ 1% of patients with postherpetic neuralgia in the Qutenza group for which the incidence was greater than in the control group. The majority of application-site reactions were transient and self-limited. Transient increases in pain were commonly observed on the day of treatment in patients treated with Qutenza. Pain increases occurring during patch application usually began to resolve after patch removal. On average, pain scores returned to baseline by the end of the treatment day and then remained at or below baseline levels. A majority of Qutenza-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate.” TABLE 1: Treatment-emergent adverse reaction incidence (%) in controlled trials in postherpetic neuralgia (events in ≥ 1% of Qutenza-treated patients and at least 1% greater in the Qutenza group than in the control group)

DRUG INTERACTIONS No clinical drug interaction studies have been performed. Data from in vitro cytochrome P450 inhibition and induction studies show that capsaicin does not inhibit or induce liver cytochrome P450 enzymes at concentrations which far exceed those measured in blood samples. Therefore, interactions with systemic medicinal products are unlikely. USE IN SPECIFIC POPULATIONS Pregnancy - Category B There are no adequate and well-controlled studies evaluating Qutenza in pregnant women. There was no evidence of fetal teratogenicity in embryofetal developmental toxicological studies conducted in pregnant rats and rabbits in which Qutenza patches (rats) or liquid (rabbits) were applied once daily for a 3-hour duration during the period of fetal organogenesis up to doses corresponding to an 11-fold margin over the maximum recommended human dose [MRHD] based on a Cmax exposure comparison. A peri- and post-natal reproduction toxicology study in rats showed no effects on survival, growth, learning and memory tests, sexual maturation, mating, pregnancy, and fetal development in the offspring of mothers treated with capsaicin up to an 11-fold margin over the MRHD. Labor and Delivery: The effects of Qutenza on labor and delivery are unknown. Nursing Mothers: There are no adequate and well-controlled studies in nursing women. Studies in rats have demonstrated capsaicin is excreted into breast milk of this species. It is unknown whether capsaicin is excreted in human breast milk. Because Qutenza is administered as a single 60-minute application and capsaicin is rapidly cleared from the bloodstream, mothers can reduce infant exposure by not breast-feeding after treatment on the day of treatment. Pediatric Use: The safety and effectiveness of Qutenza in patients younger than 18 years of age have not been studied. Geriatric Use: In controlled clinical studies of Qutenza in neuropathic pain associated with postherpetic neuralgia, 75% of patients were 65 years and older and 43% of patients were 75 years and older. Safety and effectiveness were similar in geriatric patients and younger patients. No dose adjustments are required in geriatric patients. OVERDOSAGE There is no clinical experience with Qutenza overdose in humans. There is no specific antidote for overdose with capsaicin. In case of suspected overdose, remove patches gently, apply Cleansing Gel for one minute, wipe off with dry gauze and gently wash the area with soap and water. Use supportive measures and treat symptoms as clinically warranted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Adequate carcinogenicity studies have not been conducted with Qutenza or capsaicin. Capsaicin was not mutagenic in the Ames, mouse micronucleus and chromosomal aberration in human peripheral blood lymphocytes assays. As with other catechol-containing compounds (eg, dopamine), capsaicin showed a weak mutagenic response in the mouse lymphoma assay. A fertility and reproductive toxicology study was conducted in rats with exposure to Qutenza patches daily for 3 hours/day beginning 28 days before cohabitation, through cohabitation and continuing through the day before sacrifice (approximately 49 days of treatment). The results revealed a statistically significant reduction in the number and percent of motile sperm. Sperm motility obtained from the vas deferens was reduced in all capsaicin treatment groups (16, 24, and 32 mg capsaicin patch/rat/day). Though a “no effect” level was not determined, dose levels used in the study correspond to a 13- to 28-fold exposure margin over the mean Cmax associated with the maximal human recommended dose. Sperm counts were reduced in the vas deferens or cauda epididymis in the 24 and 32 mg capsaicin patch/rat/day dose groups (79 and 69%, respectively) compared to the placebo-patch-treated control group; however, these reductions did not adversely affect fertility. As this animal model has a large excess of sperm-generating capacity relative to the threshold necessary for fertilization, the lack of an effect on fertility in this species is of unknown significance for human risk assessment. DOSAGE AND ADMINISTRATION Special precautions: • Only physicians or health care professionals under the close supervision of a physician are to administer Qutenza. • Use only nitrile gloves when handling Qutenza, and when cleaning capsaicin residue from the skin. • Immediately after use, dispose of used and unused patches, cleansing gel, and other treatment materials in accordance with the local biomedical waste procedures. • Use Qutenza only on dry, intact (unbroken) skin. Dosing: The recommended dose of Qutenza is a single, 60-minute application of up to four patches. Treatment with Qutenza may be repeated every three months or as warranted by the return of pain (not more frequently than every three months).

Qutenza 60 minutes (N = 622) %

Control 60 minutes (N = 495) %

Application-Site Erythema

Application-Site Pain

Application-Site Pruritus

Application-Site Papules

Application-Site Edema

Application-Site Swelling

Application-Site Dryness

HANDLING AND DISPOSAL Qutenza contains capsaicin capable of producing severe irritation of eyes, skin, respiratory tract, and mucous membranes. Do not dispense Qutenza to patients for self-administration. It is critical that health care professionals who administer Qutenza have completely familiarized themselves with proper dosing, handling, and disposal procedures before handling Qutenza to avoid accidental or inadvertent capsaicin exposure to themselves or others [see Dosage and Administration]. Do not touch Qutenza, treatment areas, and all used supplies or other materials placed in contact with the treatment area without wearing nitrile gloves. Wear nitrile gloves at all times while handling Qutenza and cleaning treatment areas. Do NOT use latex gloves. Do not hold Qutenza near eyes or mucous membranes. Immediately after use, dispose of used and unused patches, patch clippings, unused Cleansing Gel, and associated treatment supplies in accordance with local biomedical waste procedures.

Nasopharyngitis

Bronchitis

PATIENT COUNSELING INFORMATION See Patient Counseling Information section of the full package insert.

Sinusitis

Nausea

Vomiting

GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS

Infections and Infestations

Gastrointestinal Disorders

Skin and Subcutaneous Tissue Disorder Vascular Disorders Hypertension

Manufactured for NeurogesX, Inc., San Mateo, CA 94404, USA by Lohmann Therapie-Systeme AG (LTS), Andernach, Germany www.Qutenza.com Qutenza® is a registered trademark of NeurogesX, Inc. © NeurogesX, Inc. 2010 Rev. November 2009 109270-1

SF-36 Score (0-100)

we would also find a clear association between

BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete prescribing information please see package insert.)

Pruritus

had unsuccessful hip replacement surgery, for example,

Rx Only

Body System Preferred Term

100

 No PPP  PPP * Significant between groups at P<0.05

Time (months postoperative) Figure 2. SF-36 subscale of mental health in TKA patients. PPP, persistent postoperative pain; TKA, total knee arthroplasty

in which we’re looking at preoperative factors that affect persistent postoperative pain,” Mr. Moric added. “We have found some indication that preoperative mental health scores may predict persistent postoperative pain at six months. So the idea here is that if you can improve affect—the psychological profile—preoperatively, maybe it will lower long-term persistent postoperative pain.” Alan Kaye, MD, PhD, chair of anesthesiology and director of pain services at Louisiana State University in New Orleans, said that total knee replacement patients who continue to suffer pain after surgery present with the same features as any other chronic pain patient. “In this case, the pain itself becomes the disease,” said Dr. Kaye, a member of the editorial board of Anesthesiology News. “There‘s a huge component of psychosocial issues that go along with this, including depression, insomnia and marital stress, to name a few. “This abstract is excellent,” Dr. Kaye continued, “because we know this is something that all pain physicians have observed. I’m sure if we examined a pool of people who had unsuccessful hip replacement surgery, for example, we would also find a clear association between continued pain processes and significant or debilitating psychosocial issues as described in this study.” —Michael Vlessides

April 2011

AnesthesiologyNews.com I 51

Pai n Me d i ci n e

Michigan Headache and Neurological Institute Taking Mystery Out of Head Pain

n George Cruikshank’s 1819 caricature “Head ache,” demons gleefully drive stakes, drill holes and jab spears into a helpless man’s skull. It’s probably still an apt image for the more than 45 million Americans who suffer chronic headaches. But at the Michigan Headache and Neurological Institute (MHNI), the nation’s first comprehensive head pain treatment and research center, headaches aren’t caused by demons, but by wide-ranging, elusive and complicated elements that require exact diagnosis and comprehensive treatment plans. “There is no condition of such magnitude and influence over the lives of patients that is more associated with myths, misunderstanding and mistreatment than headaches,” said Joel Saper, MD, founder and director of MHNI. MHNI has sought to unravel the myths about headaches for more than three decades. Headquartered in Ann Arbor, it is the only center of its kind to earn national accreditation by both the Joint Commission and the Commission on Accreditation of Rehabilitation Facilities. In 2010, the American Pain Society selected it for a Center of Excellence award, the first given to a primary head pain center. Daunting Challenge Headaches pose a real challenge for physicians because there are so many varieties—both primary, of which migraine is the most well known, and secondary, which can be a symptom for more than 300 other medical conditions. “Headache also is elusive because you can’t investigate the head the same as you do an arm or lower back,” Dr. Saper explained. “Give a patient with a pure migraine a [magnetic resonance imaging scan], and the results will probably be normal, no matter how bad the pain.” Effective treatment can prove a complex undertaking, too. “With migraine headaches, for instance, it is a chemical event in the brain that creates the pain,” pointed out Cindy Bruggner, RN, BSN, MHNI’s head nurse. “Pain medications don’t improve that.” In fact, ordinary pain medicines used too frequently can make migraines worse, and actually cause changes in the brain that increase its vulnerability to pain. “That’s why we don’t use opioids,”

said Dr. Saper. “They can change brain cells and physiology.” Experience and Commitment Headaches take a tremendous annual toll on society. In the United States, headaches cause approximately 157 million lost workdays, $50 billion in health care expenses and 10 million visits to physicians each year. Since opening its doors in 1978, MHNI has provided more than 500,000 visits to head pain patients from around the world, often taking on difficult cases that have perplexed other clinicians. MHNI uses a multidisciplinary team of specially trained neurologists, anesthesiologists, physician assistants, psychologists, registered nurses, physical therapists, technicians and administrative staff to provide coordinated care. Most of the team has been with MHNI for more than 15 years. This experienced team addresses any symptom, physical or psychological, that may cause a patient’s pain. The team employs broad diagnostic tools through MHNI’s laboratory division, accredited by the Commission on Office Laboratory Accreditation and repeatedly recognized for excellence. MHNI’s physicians use conservative therapies first, but if ineffective, they offer interventional techniques, such as trigger point injections; occipital nerve blocks; cryoneurolysis; radiofrequency nerve ablation; peripheral nerve and spinal cord stimulation; intradiscal electrothermal therapy; and intrathecal drug delivery. Because the causes of one patient’s headache often differ from another patient, education is a critical component of MHNI’s treatment regimen. “Our patients get more than just a prescription,” said Marjorie Winters, RN, BSN, head of research and education. “They need to understand the brain is a complex organ, and that medications can affect various nerve transmitters and components of brain function in various ways. They also need to understand how triggers set off headaches and how treatments work.” MHNI’s educational endeavors are not limited to just patients, but extend to the public and medical professionals. It conducts seminars for patient groups, as well as national and statewide pain see MHNI page 52

Figure 1. MHNI Director Joel R. Saper, MD, second from right, and Robert Hamel, PA.-C., right, confer with the institute’s inpatient unit staff at nearby Chelsea Community Hospital.

Figure 2. MHNI’s Mary Burnett, RN, handles patient inquiries on the institute’s “Phone Nurse” system.

Figure 3. MHNI board-certified anesthesiologist Shamas Moheyuddin, MD, performs a procedure at Chelsea Community Hospital.

52 I AnesthesiologyNews.com

April 2011

P A IN M ED I C I NE MHNI continued from page 51

including diagnostic, treatment and consultative services. awareness campaigns. For the past “So much of our work is helping 12 years, it has held an annual headache patients manage the stress they feel, pain symposium for clinicians, which understanding how disturbed they draws more than 500 health profes- can become emotionally by headache sionals from all over the country. pain,” said Alvin Lake III, PhD, division director of behavioral medicine at Mind and Body MHNI. Management Tools In outcomes studies, he said, stress Because stress is a key trigger of reduction therapies, including psyheadaches, MHNI provides a broad chotherapy, cognitive-behavioral therrange of behavioral medicine resources, apy and biofeedback, have improved

Please visit us at the SCA Booth #221

headache pain by 35% to 55%, when combined with appropriate medications. “And it’s not just avoiding stress, but patients must learn how to confront it,” said Dr. Lake. “We might teach a patient assertiveness skills to help him or her cope with situations that trigger headache.” MHNI psychologists also treat associated psychological conditions caused by or accompanying headache pain— such as depression and anxiety—and

fully address the impact recurring head pain has on patients’ families. Physical therapy plays an important role in MHNI’s treatment approach, too. According to Ms. Bruggner, many patients don’t realize how the muscles and joints in the neck can refer pain to the head. For example, upper trapezius shoulder muscles when overused, such as by constant computer work, can cause head pain. Tightness in the muscles of the cervical spine can trigger migraines. MHNI physical therapists treat neck and spine joints, ligaments, muscles, nerves and other soft tissue structures to restore function, eliminate movement restrictions and reduce pain. What really sets MHNI apart from other headache pain clinics, however, is that it is the only one in the country with a dedicated, 20-bed inpatient unit, located at nearby Chelsea Community Hospital. Created by Dr. Saper, the inpatient Head Pain Treatment Unit has become a model for treating severe or advanced head, neck and other pain conditions that don’t respond to outpatient treatment. “It is a comprehensive inpatient unit, with its own staff,” Dr. Saper said. “About 30% of our patients require hospitalization. These patients include people dependent on pain medications or [who are] excessively medicated, sometimes [to a] toxic [level]; those with other medical problems that make treating their headache more difficult; or those needing certain procedures or IV therapies that can’t be performed safely in an outpatient setting.” Investigating Pain and Its Mechanisms Research into headaches has become very intensive over the past few years. “It is one of the major frontiers not fully explored,” said Dr. Saper. “The potential of the brain to feel and think, and turn pain on and off, is of great interest because of the problems of impairment and disability.” “We focus primarily on treatments,” Ms. Winters said of MHNI’s clinical investigation program, “evaluating pharmaceuticals or device interventions for not only headache, but pain disorders in general. While the unique aspect of the anatomy and physiology of migraine remains our primary target, we feel it is important to have a broad vision of pain mechanisms and the peripheral and central nervous systems, and how they work. You can’t research one without the other. A lot of medicine for general pain has applications for headache and vice versa.”

April 2011

AnesthesiologyNews.com I 53

Pai n Me d i ci n e Right now, MHNI has approximately 20 investigations under way, such as studies into neuropathic pain, postherpetic neuralgia, diabetic neuropathy, osteoarthritis and menstrual migraines. On the pharmaceutical front, MHNI researchers are investigating drugs to block calcitonin generelated peptide, a brain chemical involved in transmitting pain signals

during migraine headache. They are hoping to help find pharmacotherapies with fewer side effects and safety concerns than current migraine medicines. MHNI researchers also are examining innovative delivery systems (nasal sprays, inhalers, skin patches, autoinjectors) that will deliver medications more efficiently and effectively.

uniquely trained in headache, continues to make diagnostic and therapeutic inroads and offers real hope for patients suffering these serious medical conditions. “We’ve gone from believing demons inhabited the head, and we had to cut holes in the skull to let them out, to believing most patients with headaches were neurotic and couldn’t hanHope on the Horizon dle stress, to now recognizing that MHNI’s state-of-the-art care from headaches are disturbances on a molecits experienced and committed staff, ular level in the brain that produce

a vulnerability with little provocation,” said Dr. Saper. “As science shows us what’s going on in the brain, it will open doors on how to control or even fix it. In the near future, research will make available very specific drugs to correct biological disturbances, novel ways to deliver headache medicine and advances in understanding how electrical and magnetic stimulation alters brain physiology, as well as ways to harness them as therapy.” —Tom McDonough

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Once you use it, it’s hard to imagine ever working without it. Figure 4. An MHNI patient undergoes physical therapy at the institute.

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Figure 5. MHNI Inpatient Head Pain Treatment Unit has been treating patients with severe head pain since 1978. Here, in the early 1990s, MHNI Director Joel R. Saper, MD, attends to a patient.

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CONTINUING MEDICAL EDUCATION

April 2011

Lesson 291: PreAnesthetic Assessment of the Patient With Systemic Lupus Erythematosus Written by:

call For Writers

Sharon Carrilloa and Alan D. Kaye, MD, PhDb a Medical student, Louisiana State University School of Medicine, in New Orleans, Louisiana. Dr. Carrillo is now a resident in anesthesiology with Ochsner Clinic Foundation, in New Orleans. b Professor and chairman, Department of Anesthesiology, Louisiana State University School of Medicine, New Orleans, Louisiana

If you would like to write a CME lesson for Anesthesiology News, please send an e-mail to Elizabeth A.M. Frost, MD, at ElzFrost@aol.com.

revieWed by:

learning objectives

Elizabeth A.M. Frost, MD Clinical professor, Department of Anesthesia, Mount Sinai Medical Center, New York, New York

At the end of this activity, the participant should be able to: 1. Define SLE. 2. Review the pathophysiology and anesthetic implications of SLE. 3. Describe the mucocutaneous and systemic manifestations seen in patients with SLE. 4. Explain the pathogenesis of SLE. 5. Apply appropriate preoperative testing and evaluation of patients. 6. Evaluate laboratory findings. 7. Present an anesthetic and analgesic plan. 8. Outline treatment options. 9. Cite the incidence and prevalence of SLE. 10. Anticipate, recognize, and manage likely perioperative complications.

date revieWed: March 2011 disclosures Dr. Kaye has disclosed that he is a member of the Baxter speaker’s bureau. Dr. Carrillo and the reviewer have no relationships with pharmaceutical companies or manufacturers of products to disclose. This educational activity may contain discussion of published and/or investigational uses of agents for the treatment of disease. Some uses of these agents have not been approved by the FDA. Please refer to the official prescribing information for each product for approved indications, contraindications, and warnings.

needs statement Systemic lupus erythematosus (SLE) is an autoimmune, connective tissue disorder with multiple manifestations that complicate the functionality of key target organs. Persistent autoantibodies cause pathologic processes in systems that affect anesthetic practice. Anesthesiologists should be able to appropriately manage patients with SLE perioperatively. Drugs used in treating SLE and associated organ dysfunctions—particularly cardiac, neuromuscular, pulmonary, renal, hepatic, and hematologic—influence management of anesthesia.

target audience Anesthesiologists

case History A 32-year-old woman with long-standing SLE presented to the preoperative area with newonset kidney failure. She was scheduled for surgery to create an arteriovenous shunt and place a temporary dialysis catheter. Electrolyte analyses were normal. Hemoglobin and hematocrit levels were 13 g/dL and 39.1%, respectively. Blood urea nitrogen and creatinine levels were 54 and 3.8 mg/dL, respectively. Vital signs were within normal limits and oxygen saturation by pulse oximetry (SpO2) on room air was 99%. The patient had received glucocorticoid therapy in the past. Recently, she had been taking 200 mg of celecoxib once daily for joint pain. She had never before undergone surgery.

ystemic lupus erythematosus (SLE) is a complex disorder characterized by dysregulation of pathogenic autoantibodies and immune complexes that leads to multisystem chronic inflammatory processes.1 SLE is not a rare condition; the estimated prevalence is 100 physician-diagnosed patients per 100,000 people. The disease may present at any age, although it primarily affects women of reproductive ages. The ratio of female to male patients is 9:1. The prevalence of SLE is described as having an ethnic component, with black women affected 3 times more than whites2; in addition, blacks and Hispanics are reported to have higher rates of morbidity.3 Although a classical presentation of SLE has been described, clinically there are many variations of the disease. For example, elderly patients tend to have a less-severe form involving fewer organ systems overall; men usually experience less photosensitivity but have a higher rate of mortality.4,5 SLE was first documented in the Middle Ages when it was termed lupus (“wolf” in Latin) to describe the

PREANESTHETIC ASSESSMENT Dr. Elizabeth A.M. Frost, who is the editor of this continuing medical education series, is clinical professor of anesthesiology at the Mount Sinai School of Medicine in New York City. She is the author of Clinical Anesthesia in Neurosurgery (ButterworthHeinemann, Boston) and numerous articles. Dr. Frost is past president of the Anesthesia History Association and former editor of the journal of the New York State Society of Anesthesiologists, Sphere. She is also editor of the book series based on this CME program, Preanesthetic Assessment, Volumes 1 through 3 (Birkhäuser, Boston) and 4 through 6 (McMahon Publishing, New York City).

A C our s e of s tudy for AMA/Pr A C Ate gor y 1 C r e dit Read this article, reflect on the information presented, then go online (www.mssm.procampus.net) and complete the lesson post-test and course evaluation before April 30, 2012. (CME credit is not valid past this date.) You must achieve a score of 80% or better to earn CME credit. t iMe to C oMPle te A C tivity : 2 hours r e le As e d Ate : April 2011 t e r MinAtion d Ate : April 30, 2012 A C C r e ditAtion s tAte Me nt The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

appearance of the classical facial (malar) rash. It was suggested that the rash resembled the fur on the forehead and muzzle of the wolf. Others have suggested that the disease may have been named after a veil (loup) used by women in France to cover facial blemishes. It was not until 1872 that Móric Kaposi, a Hungarian dermatologist, began to recognize and describe the systemic manifestations of the disease.6 A groundbreaking advance in the study of lupus was made when Malcolm Hargraves, a hematologist at Mayo Clinic in 1948, described the lupus erythematosus or LE cell found in the bone marrow of patients. Ten years later, George Friou, MD, developed a test using fluorescent antihuman globulin demonstrating the antigen–antibody reaction, thus advancing the immunologic study of the disease.7 Although SLE is largely attributed to autoimmune processes, its pathogenesis can be induced by drugs. This feature of SLE was discovered at the Cleveland Clinic in 1954, when a patient who was treated with hydralazine for hypertension subsequently developed SLE.8

C r e dit d e s ignAtion s tAte Me nt The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance, independence, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

CONTINUING MEDICAL EDUCATION

This lesson is available online at www.mssm.procampus.net

Butterfly rash

Pleural effusions Heart problems

Lupus nephritis

Arthritis

Raynaud’s phenomenon

Figure. Clinical manifestations of systemic lupus erythematosus can vary widely between individuals.

Clinical Manifestations Considerable variation exists in the clinical presentation of SLE, ranging from acute features with the classical malar, erythematous “butterfly rash” to a progressive fatal illness most commonly caused by complications of renal, cardiovascular, pulmonary, and central nervous system (CNS) pathologies.9 Across all age groups, SLE is characterized by chronic, inflammatory, multiorgan symptoms caused by immune complexes and antibodies against cell surface molecules or serum constituents.10 The level of involvement of each organ system varies (Figure). Mucocutaneous involvement is the most commonly reported clinical feature. It can appear as a rash (acute to chronic), alopecia, photosensitivity, and pathology of mucous membranes.4 These manifestations are secondary to activation of the membrane attack complex and immune complex deposition.11 Musculoskeletal symptoms play a major role in the pathogenesis of SLE, affecting 53% to 95% of cases.4 These include arthritic, arthropathic, myositic, and necrotic processes. Some complications arise from immunoglobulin deposition; others may be a result of corticosteroid treatment or hematologic pathogenesis. Hematologic involvement is a common characteristic of SLE. It is defined variously as anemia, leukopenia, thrombocytopenia, and antiphospholipid syndrome. Most patients with SLE have anemia secondary to many causes,

including immune-mediated hemolysis, chronic disease, renal insufficiency, aplastic anemia, hypersplenism, blood loss, myelodysplasia, myelofibrosis, and medication use. Thrombocytopenia in these patients can result from platelet destruction, microangiopathic hemolytic anemia, hypersplenism, bone marrow suppression, and thrombopoietin antibodies. SLE is commonly complicated by leukopenia— either neutropenia or lymphocytopenia. Antiphospholipid syndrome may coexist with SLE, causing thrombosis and vascular disease.4 Renal symptoms affect 40% to 70% of patients.4 Mild, asymptomatic disorders of the urinary system affect many patients. A small percentage of cases progress to chronic renal insufficiency, a renal vasculitis syndrome, or severe lupus glomerulonephritis.12 Perhaps the most debilitating complications seen in SLE are those affecting the peripheral nervous system and CNS. The American College of Rheumatology (ACR) classifies these manifestations as neuropsychiatric systemic lupus erythematosus syndromes (NPSLE).13 The ACR has designated 19 syndromes within the NPSLE group. CNS syndromes include cerebrovascular disease, demyelinating syndrome, myelopathy, seizure disorder, psychosis, and aseptic meningitis. Peripheral nervous system syndromes include Guillain-Barré syndrome, mononeuropathy, myasthenia gravis, and cranial neuropathy.4 Cardiovascular involvement is variable. Approximately 25% of patients with SLE develop pericarditis, whereas myocardial pathology is reported in less than 5% of patients.4 There is a correlation between early, severe atherosclerosis and SLE, leading to an increased prevalence of coronary artery disease, myocardial infarction, and stroke in these patients.14 Additionally, SLE increases the risk for valvular heart disease defined as aortic and mitral valve thickening, vegetations, regurgitation, and stenosis.15 Pulmonary involvement includes pleural, parenchymal, vascular, and muscular manifestations. The most common respiratory finding is pleuritic pain. Pleuritis is reported in more than 50% of patients with SLE. Clinically insignificant pleural effusions often are diagnosed. A more debilitating complication, although rare, is interstitial lung disease; its severity ranges from mild inflammation to extensive fibrosis.16 Reports of other types of parenchymal involvement include acute pneumonitis secondary to alveolar wall necrosis, bronchiolitis obliterans, pulmonary hypertension, and infection due to immunosuppression.17 Perhaps most worrisome is pulmonary hemorrhage secondary to inflamed capillaries, a relatively rare complication that has a mortality rate as high as 90%.18 A late pulmonary consequence of SLE is diaphragmatic pathology. This complication, known as “shrinking lung syndrome,” causes decreased total lung capacity and volume.19 As supported by recent evidence, patients with SLE have an increased risk for cancer, including non-Hodgkin’s lymphoma and lung, breast, and cervical malignancies. Although there is an association between malignancy and SLE, the pathogenic mechanisms are unknown. It has been suggested that genetic and environmental factors play a role.20

Pathogenesis The pathogenesis of SLE is complex. Main factors include genetic patterns, gender, and environmental risks. Despite the different presentations of SLE, each patient shares a common dysregulation of autoantibody activity and an increased amount of immune complexes. Functionality at every level of the immune system is affected. Abnormalities in B cells, T cells, and immunoregulatory pathways have been described. The unchecked production of these

April 2011

Table 1. Environmental Factors Associated With Pathogenesis of SLE Ultraviolet B light Epstein-Barr virus Estrogen and prolactin: Predilection for females (9:1 ratio, female:male) Lupus-inducing medications Hydralazine Procainamide Isoniazid Hydantoins Chlorpromazine Methyldopa Penicillamine Minocycline Tumor necrosis factor-α inhibitors Interferon-α Dietary factors: Alfalfa sprouts and related sprouted foods containing canavanine, pristane Infectious agents other than Epstein-Barr virus Bacterial DNA Human retroviruses Endotoxins, bacterial lipopolysaccharides SLE, systemic lupus erythematosus Adapted from reference 1.

self-destructing molecules causes widespread inflammatory processes leading to a common theme of damaged organ systems. In SLE, many autoantibodies have a pathogenic role, targeting DNA, RNA, cell membrane structures, the cellular surface, and intracellular molecules.1 The most prevalent self-destructing molecules are within the antinuclear antibody (ANA) group. The hypothesis supported by increasing evidence is that these antibodies originate from antinucleosomal antibodies.21 A main concern is the effect of the anti-DNA antibodies on renal parenchyma. The antibodies directly bind to or form complexes with various renal components, such as heparin sulfate proteoglycan, laminin, α-actinin, histone proteins, and glomerular basement membrane collagen.22,23 In SLE, anti-DNA molecules also attack the CNS. These antibodies target neurons and cause apoptosis, leading to cognitive impairment, altered mental status, and deterioration in mood.24 Other autoantibodies specific to cellular types cause complications in patients. A common self-destructing molecule with up to 25% prevalence is the anti-Smith autoantibody, another ANA subtype. Highly specific for SLE, this autoantibody acts as an accelerator of disease.1 Similarly, anti-Ro autoantibody has a particularly important part in the pathogenesis of SLE and is associated with nephritis, dermatitis, vasculitis, neonatal lupus, and Sjögren’s syndrome.1 With a variable severity of disease, some autoantibodies cause hematologic pathology; antibodies against platelets cause thrombocytopenia. More specifically, these antibodies are targeted against platelet cytoplasmic and surface components, including phospholipids and glycoproteins II and III.25 The immunoglobulin G non-Rhesus antibody against an erythrocyte surface molecule contributes to SLE by causing hemolysis and anemia.26 Additionally, anticardiolipin antibody and lupus anticoagulant target phospholipids, inducing vascular thrombosis.1

CONTINUING MEDICAL EDUCATION

April 2011

Table 3. Clinical Manifestations and Associated Autoantibodies in SLE

Table 2. ACR Classification Criteria for SLE Criteria

Description

ANA

Abnormal titer of ANA by immunofluorescence or equivalent assay at any time and in the absence of drugs known to be associated with drug-induced lupus syndrome

Arthritis

Non-erosive arthritis involving 2 or more peripheral joints and characterized by tenderness, swelling, or effusion

Discoid rash

Erythematous, raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring occurs in older lesions

Hematologic disorder

Hemolytic anemia with reticulocytosis, or Leukopenia: <4,000/mm3, or Lymphopenia: <1,500/mm3, or Thrombocytopenia: <100,000/mm3 in the absence of contributing medications

Immunologic disorder

Anti-DNA: antibody to native DNA in abnormal titer, or Anti-Smith: presence of antibody to Smith nuclear antigen, or Positive finding of antiphospholipid antibodies based on: 1) abnormal serum concentration of IgG or IgM anticardiolipin antibodies; 2) positive test result for lupus anticoagulant using a standard method; or 3) false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

Malar rash

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Neurologic disorder

Seizures in the absence of contributing medication or known metabolic derangements (eg, uremia, acidosis, or electrolyte imbalance) Psychosis in the absence of contributing medication or known metabolic derangements (eg, uremia, acidosis, or electrolyte imbalance)

Oral ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Photosensitivity

Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation

Renal disorder

Persistent proteinuria, >0.5 g per day, >3+ if quantitation is not performed, or Cellular casts: may be red blood cell, hemoglobin, granular tubular, or mixed

Serositis

Pleuritis: convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion, or Pericarditis documented by ECG or rub or evidence of pericardial effusion

ACR, American College of Rheumatology; ANA, antinuclear antibody; ECG, electrocardiography; Ig, Immunoglobulin; SLE, systemic lupus erythematosus Adapted from reference 29.

Numerous genetic factors affect pathogenesis of SLE. Monozygotic twins appear to have an increased prevalence of SLE.27 First-degree relatives have a reported 29-fold relative risk.28 A predisposition to develop SLE is thought to involve expression of multiple genes and gene regions, including autoantibody production, several human leukocyte antigens, and non-leukocyte antigens.1 The clinical picture of each patient differs according to unique and multiple stimuli, and the pathogenesis of the disease may be influenced by a number of environmental factors.1 These include exposure to viruses (most notably Epstein-Barr), ultraviolet light, certain medications (including procainamide, hydralazine, isoniazid, hydantoins, chlorpromazine, methyldopa, penicillamine, minocycline, tumor necrosis factor blockers, and interferon-α), and certain dietary components (Table 1).

Diagnosis The ACR has established clinical criteria for the diagnosis of SLE (Table 2). A patient must exhibit at least 4 of the following 11 features: serositis, manifested as pleuritis or pericarditis; oral ulcers, including nasopharyngeal lesions; arthritis; photosensitivity; hematologic abnormalities, including hemolytic anemia or any blood component

deficiency; renal pathology, such as proteinuria or cellular casts; presence of antinuclear antibodies, such as anti-Smith, anti–double-stranded DNA (anti-dsDNA), antihistone, anti-U1RNP, anti-Ro/SSA, or anti-La/SSB; immunologic disorders; neurologic disorders; malar rash; and discoid rash. These standard criteria confer 95% specificity and 85% sensitivity for SLE diagnosis.29 Diagnosing SLE may be a tedious process; however, many laboratory studies, imaging studies, and histologic tests are available. A Coombs’ test measures erythrocytespecific antibodies in patients with anemia. Anti-histone screening may confirm drug-induced lupus in a patient whose prescription history is pertinent.1 Other tests are used to determine levels of certain biological markers to support the diagnosis. For example, an increased level of creatine kinase supports myositis; an elevated C-reactive protein level or erythrocyte sedimentation rate indicates an inflammatory state; and depressed levels of the complement proteins C3 and C4 suggest immune complex activity. The use of various molecular biology techniques to test for antibodies coupled with the clinical picture may distinguish SLE from other connective tissue disorders or determine coexisting disease. For example, the presence of anti-Ro/SSA or anti-La/SSB indicates Sjögren’s syndrome

Manifestation

Autoantibody

Nephritis

Anti-dsDNA Anti-Ro Anti-C1q

Dermatitis

Anti-Ro Anti-dsDNA

Vasculitis

Anti-Ro

CNS

Anti-ribosomal P Antineuronal Anti-NR2

Hematologic Lymphopenia Hemolysis Thrombocytopenia Clotting

Antilymphocyte Antierythrocyte Antiplatelet Antiphospholipid

Fetal loss

Antiphospholipid

Sjögren’s syndrome

Anti-Ro

Neonatal lupus

Anti-Ro

CNS, central nervous system; dsDNA, double-stranded DNA; SLE, systemic lupus erythematosus Adapted from reference 1.

and is associated with neonatal lupus. Anti-RNP antibodies suggest scleroderma, whereas anti-cardiolipin antibodies have been described in the pathogenesis of antiphospholipid antibody syndrome1 (Table 3).

Prognosis and Treatment Prior to advancements in screening tests, diagnostic laboratory studies, and treatment options, the prognosis was dismal for patients with SLE. Currently, the survival rate exceeds 90% in patients diagnosed 10 years previously.30 Although the pathogenesis of SLE is different for each patient, there is an established correlation of increased mortality with infection, accelerated atherosclerosis, CNS involvement, and renal disease. For the younger patient, infection seems to be a main cause of death, whereas complications related to atherosclerosis decrease survival in older patients.4 Etiologic factors that increase mortality include age greater than 50 years, male gender, and low socioeconomic status.31 The treatment and management of patients with SLE varies. Disease severity and organ involvement determine a suitable treatment regimen. Treatment is induced during relapses in an effort to prevent exacerbations. Patients with mild SLE, defined by musculoskeletal and cutaneous involvement, generally are treated with antimalarials, glucocorticoids, and nonsteroidal anti-inflammatory agents. Patients in whom there is major organ involvement, including renal, hematologic, pulmonary, cardiac, and nervous systems, are considered to have moderate to severe SLE. These patients benefit from more intense treatment with immunosuppressive, cytotoxic, and biologic agents.4 Clinical guidelines set forth by the ACR recommend drug therapy with azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, and cyclosporine, with appropriate monitoring for toxicity.4 In addition, a new drug belimumab, a monoclonal antibody, was recently FDA-approved for treating patients with SLE.

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Anesthetic Considerations Preoperative Assessment Because of extensive, multiple organ dysfunction that can develop in SLE, the preoperative assessment of a patient with this disease may be extensive. Patient history, thorough physical examination, laboratory testing, and imaging are indicated. Cardiovascular function should be assessed with chest radiography, echocardiography, and electrocardiography to determine the presence of pericarditis, endocarditis, myocarditis, congestive heart failure, and conduction blocks. In addition to cardiovascular evaluation, pulmonary function and arterial blood gas tests should be conducted if respiratory symptoms are present. Other complications such as lupoid hepatitis can be uncovered by liver function tests, a gastrointestinal series, and determination of albumin/globulin ratios and bilirubin levels. Anemia, thrombocytopenia, and leukopenia can be assessed by hematologic studies, including complete blood count, platelet count, prothrombin time, and partial thromboplastin time. For CNS involvement, electroencephalography and a

computed tomography scan may be necessary. Renal involvement can be evaluated by urinalysis, renal ultrasound and scan, blood urea nitrogen level, and creatinine, albumin, and total serum protein levels.32 Identifying specific organ dysfunctions and the clinical picture will determine the appropriate anesthetic plan (Table 4). Intraoperative Assessment There are many perioperative issues to consider in the patient with SLE—from organ pathology to anatomic change. As mentioned, multiple manifestations of the disease may alter anesthetic management of the patient. Renal or hepatic involvement may affect the metabolism and efficacy of common drugs, including IV and inhaled anesthetics, analgesics, neuromuscular inhibitors, cholinesterase inhibitors, and muscarinic antagonists. Patients treated with cyclophosphamide may require a longer period of anesthesia induction because of an inhibitory effect on cholinesterase that may lengthen the response to succinylcholine.33 Intubation, extubation, and maintaining an airway may be difficult in some patients because of SLE-induced upper airway obstruction and laryngeal involvement.10

April 2011

Airway Maintenance Airway protection is a major concern in all patients undergoing anesthesia. Patients with SLE may have mucosal ulceration, cricoarytenoid arthritis, laryngeal pathology including recurrent laryngeal nerve palsy, or temporomandibular joint dysfunction that results in a difficult intubation.10 Avoiding intubation when possible or using fiber-optic techniques are alternative approaches.32 Pulmonary In patients with SLE, respiratory involvement may include acute pneumonitis, chronic alveolar infiltrates, and recurrent infectious pneumonia.4 Perioperatively, pulmonary function and oxygenation should be carefully assessed. Avoidance of hypoxia, hypercapnia, and catecholamine release maintains pulmonary blood flow and reduces pulmonary vascular resistance. Arterial cannulation for blood gas analyses, and placement of a pulmonary artery catheter to assess pulmonary hypertension, may be indicated.32 A rare complication in these patients is alveolar hemorrhage, in which case pulmonary capillary exchange, oxygenation, and airway pressure must be monitored; suction should be readily available.

Table 4. Preoperative Assessment of the Patient With SLE System

Effects

Assessment by History

Physical Examination

Tests

Cardiovascular

Pericarditis Endocarditis Myocarditis CHF Conduction blocks

Chest pain Palpitations

Murmur Effusion Diastolic noncompliance Pericardial friction rub

ECG CXR Echocardiography

Respiratory

Infiltrates Restrictive PFTs  a-a gradient Atelectasis

Pleuritic pain Dyspnea Cough Hemoptysis

Friction rub Effusion Cyanosis Normal peak flow

CXR PFTs ABGs

Gastrointestinal

Perforated viscus Pseudo-obstruction Liver congestion Lupoid hepatitis

Nausea/vomiting Peritonitis Pancreatitis Abdominal pain Ileus

Dilated loops of bowel Peritoneal free air Hepatomegaly Jaundice

Gastrointestinal series LFTs Bilirubin level A/G ratio

Hematologic

Hemorrhage Thromboembolism Anemia

Bruising Thrombosis

Lymphadenopathy Splenomegaly Anemia

CBC Platelet count PT, PTT

Renal

Glomerulitis Nephrotic syndrome Renal insufficiency Renal failure

Polyuria Oliguria Hematuria Fever

Costophrenic tenderness Edema

Urinalysis Renal US Renal scan BUN, Cr, TP, albumin

CNS

Confusion Hallucinations Psychoses Seizures

Paranoid states Hyperirritability Numbness Hemiparesis

Psychosis Nystagmus, ptosis, diplopia Aphasia Peripheral neuropathy

EEG CT scan Neurologic, psychiatric evaluations

Vasculitis Symmetric arthritis Joint immobility Aseptic necrosis

Photosensitivity Atrophic/scarred lesions Ecchymosis Purpura Joint pain Immobility

Malar or butterfly rash Perioral ulcerations Reduced range of motion Hip pain

Hip x-rays Antinuclear antibody

Musculoskeletal and dermatologic

a-a, alveolar-arterial; ABG, arterial blood gas; A/G, albumin/globulin; BUN, blood urea nitrogen; CBC, complete blood count; CHF, congestive heart failure; CNS, central nervous system; Cr, creatinine; CT, computed tomography; CXR, chest x-ray; ECG, electrocardiography; EEG, electroencephalography; LFT, liver function test; PFT, pulmonary function test; PT, prothrombin time; PTT, partial thromboplastin time; SLE, systemic lupus erythematosus; TP, total protein; US, ultrasound Adapted from Robinson DM. Systemic lupus erythematosus. In: Roizen MF, Fleisher LA, eds. Essence of Anesthesia Practice. 2nd ed. Philadelphia, PA: WB Saunders; 2002.

Renal Glomerulitis, nephrotic syndrome, renal insufficiency, and renal failure may develop. Renal involvement poses a significant challenge in patients with SLE and may alter standard administration of anesthetics.32 Drugs requiring renal excretion, including some opioids, benzodiazepines, and neuromuscular blocking agents, may accumulate. The lingering, toxic metabolites lead to prolonged sedation, paralysis, and an increased recovery period. Additionally, the kidneys or other organ systems may be further damaged. In cases of extreme endorgan damage, the use of remifentanil and cisatracurium—both metabolized via processes that are end organ–independent—is indicated. Cardiovascular Premature and accelerated atherosclerosis increases the risk for cardiovascular disease.34 Patients are predisposed to potentially catastrophic events such as intraoperative myocardial infarction. Every effort should be made to maintain hemodynamic stability.

Management of the Case Presented A detailed medical history of the patient was obtained, and a physical examination completed. Her airway was characterized as Mallampati class II with good cervical range of motion. Her lungs were clear to auscultation; heart sounds were regular without murmurs. Other findings of the physical examination were within normal limits, except for alopecia, which was moderate. After a discussion with the patient about the risks and benefits of general anesthesia, regional anesthesia, and supplemented local anesthesia, the latter was chosen. After IV administration of 2 mg of midazolam and 50 mcg of fentanyl, the surgeon locally injected

CONTINUING MEDICAL EDUCATION

April 2011

a mixture of bupivacaine and lidocaine. A propofol infusion of 40 mcg/kg per minute was started. The patient also received 4 mg of ondansetron. The procedure lasted 45 minutes. The patient was discharged to undergo dialysis, and later to home.

Conclusion SLE is a complicated autoimmune disease with variable systemic manifestations. Because of the complexity and potentially wide-ranging clinical presentations of SLE, anesthetic management of patients is challenging. The inherent heterogeneity of SLE necessitates extensive preoperative assessments of patients, in addition to obtaining detailed histories and physical examinations. Careful anesthetic planning and intraoperative monitoring of all affected organ systems—particularly renal, pulmonary, and cardiovascular function—are required.

References 1.

Hahn B, Tsao B. Pathogenesis of systemic lupus erythematosus. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1233-1262.

Ward MM. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the Third National Health and Nutrition Examination Survey. J Womens Health (Larchmt). 2004;13(6):713-718.

Rivest C, Lew RA, Welsing PM, et al. Association between clinical factors, socioeconomic status, and organ damage in recent-onset systemic lupus erythematosus. J Rheumatol. 2000;27(3):680-684.

Tassiulas I, Boumpas D. Clinical features and treatment of systemic lupus erythematosus. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1263-1296.

Miller MH, Urowitz MB, Gladman DD, Killinger DW. Systemic lupus erythematosus in males. Medicine (Baltimore). 1983;62(5):327-334.

Hochberg MC. The history of lupus erythematosus. Md Med J. 1991;40(10):871-873.

Hargraves MM. Discovery of the LE cell and its morphology. Mayo Clin Proc. 1969;44(9):579-599.

Lee SL, Rivero I, Siegel M. Activation of systemic lupus erythematosus by drugs. Arch Intern Med. 1966;117(5):620-626.

Cassidy JT. Systemic lupus erythematosus, juvenile dermatomyositis, scleroderma, and vasculitis. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1677-1681.

10. Hines RL, Greene NM, Marschall KE. Skin and musculoskeletal diseases: systemic lupus erythematosus. In: Hines RL, Marschall KE, eds. Stoelting’s Anesthesia and Co-existing Disease. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2008:445-446. 11. Biesecker G, Lavin L, Ziskind M, Koffler D. Cutaneous localization of the membrane attack complex in discoid and systemic lupus erythematosus. N Engl J Med. 1982;306(5):264-270. 12. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521530. 13. [No authors listed.] The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42(4):599-608. 14. Björnådal L, Yin L, Granath F, Klareskog L, Ekbom A. Cardiovascular disease, a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population-based study, 1964-95. J Rheumatol. 2004;31(4):713-719. 15. Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. 1996;335(19):1424-1430. 16. Keane MP, Lynch JP 3rd. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax. 2000;55(2):159-166. 17. Myers JL, Katzenstein AA. Microangiitis in lupus-induced pulmonary hemorrhage. Am J Clin Pathol. 1986;85(5):552-556. 18. Badsha H, Teh CL, Kong KO, Lian TY, Chng HH. Pulmonary hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum. 2004;33(6):414-421. 19. Karim MY, Miranda LC, Tench CM, et al. Presentation and prognosis of the shrinking lung syndrome in systemic lupus erythematosus. Semin Arthritis Rheum. 2002;31(5):289-298. 20. Ben-Menachem E. Review article: systemic lupus erythematosus: a review for anesthesiologists. Anesth Analg. 2010;111(3):665-676. 21. Burlingame RW, Rubin RL. Autoantibody to the nucleosome subunit (H2A-H2B)– DNA is an early and ubiquitous feature of lupus-like conditions. Mol Biol Rep. 1996;23(3-4):159-166. 22. Chan TM, Leung JK, Ho SK, Yung S. Mesangial cell-binding anti-DNA antibodies in patients with systemic lupus erythematosus. J Am Soc Nephrol. 2002;13(5):1219-1229.

Visit www.mssm.procampus.net today for instant online processing of your CME post-test and evaluation form. There is a registration fee of $15 for this non–industry-supported activity. For assistance with technical problems, including questions about navigating the Web site, call toll-free customer service at (888) 345-6788 or send an e-mail to Customer.Support@ProCEO.com.

23. Deocharan B, Qing X, Lichauco J, Putterman C. Alpha-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J Immunol. 2002;168(6):30723078. 24. Maddison PJ, Reichlin M. Deposition of antibodies to a soluble cytoplasmic antigen in the kidneys of patients with systemic lupus erythematosus. Arthritis Rheum. 1979;22(8):858-863. 25. Rioux JD, Zdárský E, Newkirk MM, Rauch J. Anti-DNA and anti-platelet specificities of SLE-derived autoantibodies: evidence for CDR2H mutations and CDR3H motifs. Mol Immunol. 1995;32(10):683-696. 26. Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis. 2006;65(2):144-148. 27. Järvinen P, Kaprio J, Mäkitalo R, Koskenvuo M, Aho K. Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features. J Intern Med. 1992;231(1):67-72. 28. Alarcón-Segovia D, Alarcón-Riquelme ME, Cardiel MH, et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52(4):1138-1147. 29. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. 30. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore). 2006;85(3):147-156. 31. Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus: results from a single center; I: causes of death. J Rheumatol. 1995;22(7):1259-1264. 32. Cuenco J, Tzeng G, Wittles B. Anesthetic management of the parturient with systemic lupus erythematosus, pulmonary hypertension, and pulmonary edema. Anesthesiology. 1999;91(2):568-570. 33. Dierdorf S, Walton S. Rare and coexisting disease. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Clinical Anesthesia. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:638-639. 34. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349(25):2399-2406.

For inquiries about course content only, send an e-mail to ram.roth@mssm.edu. Ram Roth, MD, is director of PreAnesthetic Assessment Online and assistant professor of anesthesiology at The Mount Sinai School of Medicine, New York, NY.

Post-Test 1. How is the diagnosis of systemic lupus erythematosus (SLE) established? a. By a positive test for serum antinuclear antibody b. Only by the presence of lupus nephritis c. By the coexistence of 4 of the 11 criteria set forth in the American College of Rheumatology guidelines d. By the presence of the characteristic malar rash

2. Which is the most common clinical feature of SLE? a. Mucocutaneous involvement b. Renal involvement c. Pulmonary involvement d. Cardiovascular involvement

3. Which demographic group has the highest prevalence of SLE? a. Hispanic female b. White male c. Black female d. None of the above

4. SLE is distinguished by the presence of which antibody? a. Antimitochondrial b. Anti-basement membrane c. Antinuclear d. Antiphospholipid

5. Pulmonary abnormalities associated with SLE include all of the following, except: a. intra-alveolar blood b. necrotizing granulomas c. atelectasis d. alveolar infiltrates

6. All of the following agents may be used in the treatment of SLE, except: a. procainamide b. cyclophosphamide c. belimumab d. methotrexate

7. In patients with SLE, the following are important anesthetic considerations, except: a. upper airway obstruction b. current medications c. genetic studies d. kidney function

8. Which of the following plays an extensive role in the pathogenesis of SLE? a. Gender b. Epstein-Barr virus c. Alfalfa sprouts d. Ultraviolet B light

9. All of the following drugs have shown evidence of causing lupus, except: a. hydralazine b. isoniazid c. methyldopa d. cyclosporine

10. The presence of which antibody is characteristic of drug-induced lupus? a. Anti-histone b. Anti-Ro c. Anti-La d. Anti-DNA

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Written by a team of residents from St. Luke’s-Roosevelt Hospital Center, this is a high-yield “insider’s guide” to success on the anesthesia boards and in-service exams. The books presents quick, frequently tested, high-yield facts based on the most recently administered exams. Students will find this great for initial and last-minute exam review and anesthesiologists will find it valuable as a refresher before recertification.

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COMM ENT A R Y

The Evidence for Evidence-based Guidelines

here are two words with rather straightforward definitions: Evidence: Something that furnishes proof Based: The point or line from which a start is made in an action or undertaking Yet, when used together and preceding the words “medicine” or “guidelines,” they are recognized to imply a superior approach to health care delivery. The concept of a practitioner who employs “evidence” in the selection of treatment with a serious medical condition, such as cancer, is a powerful one. Who would not want to be treated based on “evidence”? But what exactly does the expression “evidence-based medicine” really mean, specifically in the context of management of an individual patient? It is perhaps most appropriate to begin this discussion with a less abstract concept. Level of evidence is an expression used to convey a defined hierarchy of the quality of certain “evidence.” Randomized trials and meta-analyses of multiple such studies are considered the highest level of evidence. Anecdotal case reports (at the alternative extreme) represent a far lower degree of evidence on which to potentially base medical decisions. It is likely there would be little (if any) debate regarding either the reliability or wisdom of using this general conceptual approach to assist busy clinicians in their decision-making process. Recently, however, the use of the term evidence has evolved from this rather narrow concept to define the overall quality of data to the establishment of “treatment guidelines,” where acceptable levels of evidence are used to select therapy for an individual patient in a particular clinical setting. Such recommendations often are defined very specifically and at times rather rigidly. It is important to note that those engaged in what might reasonably be described as a meaningful peerto-peer educational exercise designed to optimize the quality of patient care did not necessarily intend for their efforts to be used to either directly select or

UDT continued from page 46 physician isn’t savvy to this [he or she] can make assumptions that patients are using nonprescribed opioids and falsely accuse a patient,” Dr. Reisfield said. When a UDT does come back negative, or positive for an illegal substance, experts agreed unanimously that patients should not be discharged immediately. “I think you have to be very careful,” said Dr. Pergolizzi. “The knee-jerk reaction is to discharge the patient.” The first step, Dr. Pergolizzi said, is to determine exactly what’s happening. It’s possible that there’s a benign explanation for a negative result, for example. If there are underlying signs pointing to addiction, managing the patient becomes more complex. For example,

potentially routinely deny care for individual patients felt to be medically appropriate by their own physicians. Unfortunately, this is precisely how some organizations (including third-party medical insurance carriers) have elected to employ these documents. But what is the evidence supporting the fundamental objectivity of these so-called “evidence-based guidelines”? Is it appropriate to state these current efforts represent a “high level” of evidence? In fact, despite the good intentions of those who have accepted the challenge to develop therapeutic guidelines, the existing data suggest these efforts are far from what a truly objective, disinterested observer would reasonably classify as being “evidence-based.” For example, a recent report of an analysis of “levels of evidence” supporting guidelines produced by the Infectious Diseases Society of America found that only 14% of the recommendations were based on at least one “properly conducted randomized trial” (level 1 evidence).2 Furthermore, the majority of the recommendations in these guidelines (55%) were based on level 3 evidence (“evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees”).2 A similar outcome was noted in an analysis of guidelines in the cardiology arena.3 And a recent review of National Comprehensive Cancer Network clinical practice guidelines found that, overall, less than 10% of therapeutic recommendations were classified as category 1 evidence (“high level of evidence such as randomized controlled trials with uniform consensus”).4 Additionally, other concerns have been expressed regarding the medical guideline development process. These include potential conflict of interest among individuals designing the guidelines and the appropriate composition of specific guideline committees.3 Finally, very serious questions have been appropriately raised regarding the actual quality of the individual randomized trials and meta-analyses that form

patients often will admit recreational drug use. Dr. Gourlay said colleagues often ask him how to manage patients who genuinely have real, bona fide pain, and the medication prescribed is genuinely helpful to them, but they do cocaine periodically. The only thing certain in this situation is that the patient acknowledges using cocaine, along with a self-report of opioid efficacy. “It’s a no-brainer. A person is entitled to have more than one problem but they can’t pick and choose what problems to deal with—ongoing cocaine use is a pretty strong contraindication for the continued prescription of controlled substances,” Dr. Gourlay said. The consequences don’t have to be draconian. If the patient wants to continue treatment for pain, ideally he or she should be referred to counseling

the foundation for any claim that a particular guideline is “evidence-based.”5,6 These data, and the issues they raise, present a rather disconcerting Maurie Markman, MD challenge to the fundamental legitimacy of establishing a solidly “evidence-based” therapeutic guideline development process. In summary, it is perhaps most reasonable to conclude at the present time that “guideline development” in medicine, in general, and oncology, in particular, is a true early work in progress. It is both premature and inaccurate to classify the effort as satisfying objective valid criteria for being “evidence-based.” Or, one might conclude, as noted in a recent commentary, that “we should exercise caution when using guidelines as the sole source guiding patient care decisions. Especially for subspecialists, guidelines may provide a starting point for searching for information, but they are not the finish line.”3 —Maurie Markman, MD Dr. Markman is vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America, in Philadelphia.

References

1. Webster’s New Collegiate Dictionary. Springfield, MA: G. & C. Merriam Co; 2010. 2. Lee DH, Vielmeyer O. Analysis of overall level of evidence behind Infectious Diseases Society of America Practice Guidelines. Arch Intern Med. 2011;171:18-22. 3. Powers JH. Practice guidelines: belief, criticism, and probability. Arch Intern Med. 2011;171:15-16. 4. Poonacha TK, Go RS. Level of scientific evidence underlying recommendations arising from the National Comprehensive Cancer Network Clinical Practice Guidelines. J Clin Oncol. 2011;29:186-191. 5. Robinson KA, Goodman SN. A systemic examination of the citation of prior research in reports of randomized, controlled trials. Ann Intern Med. 2011;154:50-55. 6. Booth A, Clarke M, Ghersi D, Moher D, Petticrew M, Stewart L. An international registry of systemic-review protocols. Lancet. 2011;377:108-109.

for addiction and transitioned into another mode of pain therapy that does not include controlled substances. But, in some cases, there are no referral options. “In a perfect world, it’d be great if we could increase the amount of referral opportunities to qualified individuals for these types of patients, but in reality, there aren’t enough of them,” said Dr. Pergolizzi. Physicians should have a clearly defined exit strategy, particularly when dealing with high-risk patients or with patients demonstrating a series of aberrant behaviors that point to misuse or abuse. When it comes to prescribing controlled substances, “You shouldn’t take off if you don’t know how to land,” said Dr. Gourlay, adding that inappropriate opioid withdrawal can punish patients. “If a doctor has a patient with

pain and a substance abuse problem, that’s a challenge for the doctor, but if that patient doesn’t have a doctor, they become an unanchored problem in the community.” The pending law in Florida suggests that urine drug screening may become a mandatory standard of practice in many pain clinics. If that’s the case, many more physicians will be negotiating the nuances of unexpected drug test results. “Urine drug screening is an important part of risk management and if we recognize that urine drug screening is a fact, then doesn’t it behoove us to do it well?” said Dr. Gourlay. “[Shouldn’t we] do it in a patient-centered fashion to ensure that patients who need help get help and patients who are doing well are recognized for it.” —Gabriel Miller

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