March 2014 by McMahon Group

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For Tracheostomy, Better Late Than … Early?

oughly one-third of patients who undergo mechanical ventilation in the ICU undergo a tracheostomy. The procedure is thought to improve comfort and decrease the duration of mechanical ventilation, sedation, exposure and length of stay in the unit. For years, clinicians have been debating whether tracheostomies should be performed early or late, but what constitutes “early” or “late” has not been clear. Two studies presented at the 2014 annual meeting of the Society of Critical Care Medicine came to different conclusions regarding the benefits of early tracheostomy in patients undergoing mechanical ventilation.

Hypoxia After Surgery Much More Common Than Previously Believed Study finds high rate of prolonged bouts of desaturation on wards

surprisingly largge fraction of patients exxperiences prrolonged periods of hyypoxemia whille recovering from surgery, n new research shows. Although the impliccations of the findings for patients are n not yet clear, exxperts said results suggest that efforts too monitor oxygen saturation on the ward are not nearly as effective as cllinicians might assume. “The way we’re doing it now is not proviiding physicians with what they reaally want, which is an early warning sign of respiratory distress,” said Daniel I. Sesssler, MD, chair of the

see early page 28

see hypoxia page 24

“I Felt Like an Old Fool”: Poor decisions and the loss of a medical career

fter the state medical board he would be back with an order to revoke my controlled substance cerinvestigator’s second visit, I tificate, and in that case I would not was growing concerned. The charts he requested were patients who get it back for two years. After talking with my attorney, I decided to sign it. were somewhat problematic. Several months after I submitted a second I was in shock, but my main conPart 2 of 3 cern was for the patients who were group of charts, he came back with an depending on me for pain medicine. official board document. The agent told me that I could voluntarily surrender my state Another local physician who was willing to treat pain controlled substance certificate; I would have to pres- took a small number of my patients, but posted a sign ent my case at a hearing to see whether I could get saying he was not accepting any more from me. The it back. He said that if I did not sign the document, see taboo page 10

PRN

Trauma patients exposed to increasing amounts of radiation.

CLINICAL ANESTHESIOLOGY

Ultrasound guides percutaneous tracheostomy to better outcomes.

CLINICAL ANESTHESIOLOGY

Managing pain after anorectal surgery— the surgeon’s take.

POLICY & MANAGEMENT

Particulate steroids: too risky to use? A debate.

EDUCATIONAL REVIEW Nerve Monitors and Peripheral Blockade: Assuring Optimal Needle Placement, see insert at page 22.

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see pages 24 and 43

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E-NEWSLETTER Scan to register

ourself nY ti

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April 11-13, 2014

The Cosmopolitan of Las Vegas Topics Featured at the 2014 Advanced Institute for Anesthesia Practice Management As a busy professional you realize it’s imperative to keep informed on the latest topics of interest to Anesthesiologists, Practice Administrators, CRNAs and others in the anesthesia marketplace.

20 CME Credits

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Tulane University Health Sciences Center designates this live activity for a maximum of 20 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This program has been prior approved by the American Association of Nurse Anesthetists for 18 CE Credits; Code Number 1029059; Expiration Date 04/13/14 This program has prior approval of the American Academy of Professional Coders (AAPC) for 19 Continuing Education Units (CEUs). Granting prior approval in no way constitutes endorsement by the Academy of the program, content or the program sponsor. This conference has been pre-approved by the Board of Medical Specialty Coding (BMSC) for 18 Continuing Education Units (CEUs) towards the maintenance of the ACS-AN and/or SCP-AN credential.

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The Advanced Institute for Anesthesia Practice Management, to be held April 11-13, 2014 at The Cosmopolitan of Las Vegas, offers a chance to experience the following topics, led by industry-renown experts. What Anesthesiologists Need to Know About ACOs High Reliability Organizing: A New Cultural Model Trends in Anesthesia-Hospital Relations (and Employment) Preparing for ICD-10 Quality’s Impact on the Bottom Line Pain Management Practice Efficiencies Perioperative Surgical Home and other Pathways into the Future Getting the Most out of the Anesthesia Record Mergers are Back Private Equity’s Interest in Anesthesia The AIAPM conference also includes numerous talks on anesthesia and pain billing and coding, charge capture and compliance. Please join us for an informative meeting and exceptional educational experience.

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Make An Educated Decision Information You Need To Be Informed and Stay Competitive Anesthesia Business Consultants (ABC) believes the more you know, the better the decisions you can make. ABC places the highest value on continuing education. As the health care world continues to evolve, offering new technological advances and business models, along with changing laws and regulations, it’s imperative to keep informed. We provide our clients and associates regular updates on what is happening in the world of anesthesiology through our weekly eAlerts. These Alerts highlight the very latest in developments, changing requirements and opportunities and are a complimentary service. If you are interested in receiving these Alerts just send your name, e-mail address, the name of your practice or company, city and state to info@anesthesiallc.com. ABC is also pleased to offer the Communiqué, our quarterly newsletter, to interested individuals. It is available electronically as well as in print. The Communiqué features articles written by industry leaders focusing on the latest hot topics in group management, compliance and future business models for anesthesiologists, nurse anesthetists, pain management specialists and anesthesia practice administrators. We look forward to providing you with many more years of practice management news through the Communiqué and our weekly Alerts. Please log on to ABC’s web site at www.anesthesiallc.com and click on the “Publications” link to view the electronic version of the Communiqué online or to see copies of our previous Alerts. ABC does not share this list with any third parties nor use it for purposes other than distributing the Alerts, the quarterly Communiqués and the very occasional special announcement. If you have any questions or would like additional information please call 517-787-6440 x 4113, send an email to info@anesthesiallc.com, or visit our website at www.anesthesiallc.com. This communication is for educational informational purposes only and is not intended or offered as legal advice.

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MARCH 2014

Comment on these and other articles @ AnesthesiologyNews.com.

Heard Here First: We discovered that anesthesiologists were not reversing [neuromuscular blockade] in the operating room. When we asked

March 2014

‘Some of the nurses asked us not to.’

The five most-viewed articles last month on AnesthesiologyNews.com

them why, they said,

1. ‘I Broke the Ultimate Taboo’: A Physician’s Downward Spiral 2. Current Concepts in the Management of Malignant Hyperthermia (Educational Review)

The nurses wanted patients to stay sedated

3. Awake Fiber-optic Intubation Made Rapid and Reliable: an Interview With Scott Miller, MD (Blog Post)

until they could get them settled in.

4. New Acetaminophen Warnings Build on Previous FDA Actions (Web Exclusive)

SEE ARTICLE ON PAGE 26.

5. Study Supports Adductor Canal Blocks After TKA

ACT NOW!

Renew your free print subscription to Looking for a PreAnesthetic Assessment CME lesson? Visit www.mssm.procampus.net.

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The McGRATH® MAC video laryngoscope complies with EN 60601-1 and EN 60601-1-2 safety standards. The CE mark indicates that it meets the requirements of European Council Directive 93/42/EEC concerning medical devices. The device is regulated in the USA under FDA Regulation Number 868.5540 and device listed under the name “McGRATH MAC”. “McGRATH” and “Aircraft” are registered trademarks of Aircraft Medical Limited. “CameraStick” is a trademark of Aircraft Medical Limited. COVIDIEN, COVIDIEN with logo, Covidien logo and positive results for life are U.S. and internationally registered trademarks of Covidien AG. ©2013, 14 Covidien. 13-AW-0007b

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C OMM E NT A R Y

On Bricks and Mortar Boards A glimpse into the future of medical education By Stephen S. Kron, MD

recent article in Anesthesiology News (Brave New Word, January 2014, page 6) decrying that “anesthesia care teams” do not require medical doctors as leaders got me thinking. As most of us have heard, in the near future, no longer satisfied with awarding master’s degrees, schools training certified registered nurse anesthetists (CRNAs) and other advanced practice nurses (APRNs) will be presenting their graduates doctorates in nursing. However, unlike the conventional PhDs with which we are familiar, these degrees may be earned by merely accumulating class credits. The need to do original research, write a doctoral thesis intended to increase the body of knowledge and defend it before a panel of experts, has been eliminated. (As an aside, the Connecticut state legislature has mandated that hospital identification badges state DOCTOR or NURSE in large red block letters below the provider’s name. I wonder how this will be dealt with as APRNs get their doctoral certificates). Further investigation revealed that far from only being a nursing tactic, similar doctorates are being awarded in many diverse fields of endeavor. My health club trainer, for example, is well on the way to earning her doctorate … perhaps in Zumba. Even more surprising, many of these degrees may be obtained through the new buzzword in higher education—distance learning. My initial shock at this realization was gradually replaced by grudging respect. Just as health care was late to computers and the Internet and, with the introduction of electronic medical records, is just beginning to catch up to other industries, medical education is still stuck in the ossified conventional classroom model of the 20th century.

To the Editor: read with interest the article entitled “Liposomal Bupivacaine Boosts TAP Block” (December 2013, page 36), and wish to make several comments. My comments are based on data reported in the meeting abstract and the article in Anesthesiology News. In the report, the research was presented as a study; however, it would be more accurately described as a case series of 13 patients. I am somewhat surprised that Anesthesiology News chose to report such a small case series as evidence for the efficacy of liposomal bupivacaine in the setting of TAP blocks. Before clinicians consider applying these findings to their clinical

Dr. Kron is an anesthesiologist in Hartford, Conn., and a frequent contributor to Anesthesiology News.

Using only a computer, a smartphone, a threedimensional (3D) printer and some raw meat, our profession can leap into the 2100s as doctors are homeschooled and brickk and-mortar medical schools wind up in the rubble of history. The nonclinical first two years of medical school will be easy to duplicate at home: Lectures, exams, papers and homework are readily produced on any desktop, laptop or tablet. Virtual laboratory classes would not be complex to manage. Microscopic images and x-rays surely lend themselves to this concept. Indeed, the teaching of gross and neuroanatomy would even be improved thanks to 3D silicone cadavers and brains, correct to every anatomic detail but not pickled in nasty formaldehyde, that can lie in perpetually pristine state on a kitchen table for convenient dissection.

Why stop there? With some minor tweaks, internship and residency programs can follow this plan as well. The simulation of life-threateningg situations can be accomplished with existing infrastructure developed for all those required maintenance of certification courses; a schedule would have to be created with occasional, randomly timed sleep-disruptingg robo calls. This plan has many advantages over the stodgy status quo. Most significantly, the cost of medical education and training would be dramatically slashed. Furthermore, because tele-students never have to leave their homes, they could become physicians with minimal interference with their other lifestyle choices and responsibilities such as part-time work, giving back, child raising, caring for pets. And because their education may be taken anywhere in the world, even the more fortunate who have the means and lack of struggles would benefit. Imagine learning orthopedics on an iPod at the peak of Annapurna or taking that gynecology elective on a Kindle Fire while vacationing in South Beach! Lastly, the traditional time commitment of medical schooling and residency could be tailored: increased or decreased to suit an individual trainee’s needs. The slower learnSmartphones held by rounding attendings or ers could take a few extra years earning their MDs. strapped to their heads during surgeries, deliveries The brighter could graduate early or even ape their or other procedures that occupy their hands would nursing colleagues and add a PhD. facilitate the students’ clinical rotations. Basic techniAs my plan is put into practice, there is no doubt cal ability—starting IVs, tying surgical knots, locating that unexpected developments and difficulties will structures on ultrasound—would be developed on arise but we must start it to find out what’s in it. I chicken parts. The advanced student would perform am confident that with good old bipartisan Amerminor operations, deliveries and other procedures on ican know-how, w we will overcome whatever prob3D plastic anatomic models. lems arise.

practice, I think several points of the study should be considered. The study had a number of fundamental flaws that do not allow any clear conclusions to be drawn. The study was not randomized or controlled; the cases were subjectively selected without clear inclusion or exclusion criteria; there was no comparative placebo or active (standard bupivacaine) control group; primary outcome for successful analgesia was not adequately defined; and the follow-up (daily, non-standardized phone call without sensory testing of block efficacy) was inadequate. The authors claimed the drug led to 72 hours of pain relief, stating that “it lasted about three days in most

patients.” However, if success is defined by no analgesic requirements, then seven of 13 patients (46%) failed; one patient’s block failed immediately and six others required analgesia in the first 24 hours. Similarly, if analgesic success was defined as no or minimal pain scores, then the liposomal bupivacaine TAP block was not as effective as stated. Based on the reported 72-hour pain scores (99% confidence interval, 0-5.8), several patients were in the moderate pain score range, and therefore successful pain relief should not be concluded. The report also does not mention that liposomal bupivacaine is only FDAapproved for administration into the surgical site to produce postsurgical

analgesia. It currently is not FDAapproved for perineural administration or TAP blocks. In conclusion, little evidence presented in this case series supports claims of efficacy made by the authors of this study, which was funded by Pacira Pharmaceuticals, the maker of liposomal bupivacaine (Exparel). We should await further studies before considering the use of liposomal bupivacaine for TAP blocks. —Brendan Carvalho, MBBCh, FRCA Department of Anesthesia Stanford University Medical Center Stanford, Calif. Editor’s note: The authors of the study on which this letter comments declined to respond.

Different situations require different sedative solutions The ﬁrst and only alpha2 agonist indicated for sedation1-2

Important Precedex Safety Information

Nonintubated patients prior to and during surgical and other procedures.1 Initially intubated and mechanically ventilated patients during treatment in an intensive care setting.1 Administer Precedex™ by continuous infusion not to exceed 24 hours.1

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. Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a doserelated increase in adverse events.

Learn more at precedex.com

A right ﬁt for today’s sedation management practices

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2013. 2. Kamibayashi T, Maze M. Clinical uses of α2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P14-0182-5-10.5x13-Jan., 14 Printed in the USA.

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

BRIEF SUMMARY OF PRESCRIBING INFORMATION PLEASE SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION.

Precedex™ (dexmedetomidine hydrochloride) Injection For intravenous use.

Precedex™ (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection

Rx Only

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 adult 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 1. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)]. Table 1: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation Population <24 hours*

1 INDICATIONS AND USAGE 1.1 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.

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 adult 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 adult subjects experienced at least 1 event related to withdrawal within the ﬁrst 24 hours after discontinuing study drug and 7 (3%) Precedex adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation. In adult subjects, 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 In adult subjects, 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) in full prescribing information].

All Precedex Adverse Event

(N = 1007) (%)

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

25% 12% 9% 5% 4% 4% 4% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2% 2% 1% 1% 1% 1% 1% <1% <1% <1%

Randomized Precedex (N = 798) (%) 24% 13% 9% 5% 5% 4% 3% 3% 3% 3% 2% 2% 2% 2% 2% 2% 2% 2% 2% 1% 1% 1% 1% 1% 1% 1% 0

Placebo

Propofol

(N = 400)

(N = 188)

(%)

12% 19% 9% 3% 3% 4% 1% 5% 2% 3% 1% 3% 4% 2% 3% 3% 2% 2% 3% 1% 0 1% 0 1% 1% 0 1%

13% 4% 11% 0 7% 4% 1% 3% 5% 6% 6% 1% 1% 2% 0 2% 3% 3% 4% 3% 2% 2% 2% 2% 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 adult patients received Precedex for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 2). Table 2: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies Adverse Event Hypotension Hypertension Nausea Bradycardia Fever Vomiting Atrial Fibrillation Hypoxia Tachycardia Hemorrhage Anemia Dry Mouth Rigors Agitation Hyperpyrexia Pain

Randomized Dexmedetomidine

Placebo

(N = 387) 28% 16% 11% 7% 5% 4% 4% 4% 3% 3% 3% 3% 2% 2% 2% 2%

(N = 379) 13% 18% 9% 3% 4% 6% 3% 4% 5% 4% 2% 1% 3% 3% 3% 2%

Table 2: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies (continued) Adverse Event Hyperglycemia Acidosis Pleural Eﬀusion Oliguria Thirst

Randomized Dexmedetomidine

Placebo

(N = 387) 2% 2% 2% 2% 2%

(N = 379) 2% 2% 1% <1% <1%

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 5. 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 5: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population

Adverse Event In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. 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 3. 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 4.

Hypotension1 Respiratory Depression2 Bradycardia3 Hypertension4 Tachycardia5 Nausea Dry Mouth Hypoxia6 Bradypnea

Table 3: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study Adverse Event Hypotension

Dexmedetomidine

Midazolam

(N = 244)

(N = 122)

56%

28%

27%

42%

19%

28%

42%

Hypotension Requiring Intervention Bradycardia2 Bradycardia Requiring Intervention Systolic Hypertension3 4

Precedex

Placebo

(N = 318)

(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 prestudy 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.

25%

44%

10%

12%

15%

11%

15%

19%

30%

Hypokalemia

13%

6.2 Postmarketing Experience

Pyrexia

Agitation

Hyperglycemia

Constipation

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.

Tachycardia

Tachycardia Requiring Intervention Diastolic Hypertension3 Hypertension

Hypertension Requiring Intervention†

Hypoglycemia

Respiratory Failure

Renal Failure Acute

Acute Respiratory Distress Syndrome

Generalized Edema

Hypomagnesemia

Table 6: 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

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%).

Metabolic and Nutritional Disorders

Acidosis, respiratory acidosis, hyperkalemia, increased alkaline phosphatase, thirst, hypoglycemia

Table 4. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex Group

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

†

Includes any type of hypertension.

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.

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

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.

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

Precedex mcg/kg/hr Adverse Event Constipation Agitation Anxiety Edema Peripheral Atrial Fibrillation Respiratory Failure Acute Respiratory Distress Syndrome

≤0.7*

>0.7 to ≤1.1*

>1.1*

(N = 95)

(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 Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation in which 318 adult patients received Precedex.

Adapted from: EN-3411; Revised 12/2013 Manufactured and Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA Licensed from: Orion Corporation, Espoo, Finland P14-0164-5-10.5x13-Feb.,14 Printed in USA Hospira, Inc., Lake Forest, IL 60045 USA

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CONTINUED FROM PAGE 1

board’s action resulted in a number of my patients going through significant opioid withdrawal, and five of them were hospitalized. The board’s action had harmed my patients, not protected them. I spent a lot of time on the phone dealing with opioid withdrawal symptoms that developed over the next month. I was otherwise powerless to help. My practice volume was cut in half; I did not realize that I had that many pain patients. A Nightmare Affair Meanwhile, another drama was playing out. DeeDee and I had texted about getting together. We arranged a late-night rendezvous. When that night actually came, I had second thoughts. About 15 minutes after the time we had chosen, I got a text message asking, “Are you still coming?” My resistance collapsed, and I went to the office to meet her. We met several more times over the next couple months. Then things started to get complicated. At first she just asked for some additional medication, then she started making demands. Soon she was threatening me with lawsuits and to report me to the medical board. Never assume that you can keep anything like that a secret. DeeDee had sent me some very explicit text messages at about 2 a.m. while I was sound asleep. I was awakened by an enraged wife; she had read the messages. That basically doomed the marriage. Things were very frosty at home after that. Somehow even in the office rumors were flying, and were very close to the truth. Soon I was served with divorce papers. My wife said I had threatened her and I received an order to vacate. I had two weeks to get out of the house. Just when I thought things couldn’t get any worse, the investigator for the board came back. This time he had a subpoena requiring a copy of DeeDee’s chart. As I was reading the subpoena I had a feeling close to terror. I knew my medical license was now in serious danger. The investigator explained that he had received a tip to look in the courthouse. When he searched there, he easily found the divorce petition, which mentioned DeeDee. He then searched the state drug database where he found the prescriptions I had written for her and confirmed that I had had been having sexual relations with a patient. To make matters worse, as I was copying the chart I realized I had kept copies of more prescriptions for DeeDee that I had intended to put in, with a note about why they were written. I never had. ‘I Looked Pretty Bad’ I still had a hearing scheduled with the state medical board. I spent a day meeting with my attorney, and reviewing my charts. He had earlier helped me write a letter to the medical board in which I admitted my affair with DeeDee, but put it in the best possible light. When we reviewed her chart, and the prescriptions she had received, he sat there in silence for a minute before announcing it indefensible. He asked me how aggressively I wanted to fight. I knew that my treatment of DeeDee and several other patients was going to be controversial and difficult to defend because they were on multiple opioids; I had

I got a text message asking, ‘Are you still coming?’ My resistance collapsed, and I went to the office to meet her. gradually titrated their dosages to control their pain based on their verbal reports of pain. We didn’t have any expert witnesses on my behalf. The attorney didn’t think that calling any of the patients as witnesses would be helpful. We really didn’t have much to fight with to prepare a defense. Instead I would concede some points, and hope for the best. I know now that was a poor choice, and I should have contested the case more vigorously. The board’s expert was going to be a pharmacologist who did not treat patients. My lawyer had encountered the expert before, and knew she would be a tough witness. Right before the hearing started, my lawyer negotiated with the board’s attorney. We planned to acknowledge immediately that some of my treatment decisions were inappropriate. He wanted to keep the board’s witness from having to testify at all. I was seated at the head of a very long table and placed under oath. Then we got into a discussion about JC, my patient who had also been an informant for the Drug Enforcement Administration. They also brought up several other patients I was not expecting to discuss. Again I looked pretty bad. At one point, I had casually told the investigator that I had learned a lot by reading about pain management in a specific publication. That detail was twisted to make it sound like that was all the training I had in pain management, completely discounting my years of practice experience, other reading and CME activities on the subject. At the end of my testimony, one of the board members pointed out that I had not mentioned “improving function” at all in my testimony. I did not get a chance to refute this. If they had looked at my charts, they would have seen that I had always tried to discuss this, as well as mentioning pain scores in my progress notes. I really did not know what to expect after the hearing; I did know that it had not gone very well. Still, I was hopeful that the board would not be too hard

on me. About a month later, I received a certified letter. My state controlled substances certificate was revoked. I would have to wait for two years by statute before applying to get it back. My actions had caused a lot of problems for my patients. Many were without pain meds. No local physicians wanted to see them. If a patient even mentioned pain, they would often be labeled an addict. Several had been forced to go to the local methadone clinic and lie about being addicted, just to get pain medication. Some of them were driving more than 100 miles to find a doctor who would prescribe opioids. One patient committed suicide the following year. DeeDee lost interest in me almost immediately after I lost the ability to prescribe controlled substances. She asked for money several times but I refused. She had seduced and conned me at the same time. I felt like an old fool, losing my head over a younger woman. I was the professional and I knew what I was doing was wrong. I knew that I would have another hearing to face. I didn’t have to wait very long. The investigator came back with another document, this time a “Voluntary Agreement Not to Practice.” Either I signed it, or my license would be revoked. I had to stop seeing patients immediately, and wait for a hearing to determine my licensure status. I sent a letter to my patients stating that I would be taking some time off from my practice. I did not give any details, and I did not say for how long. Then I went home. I lay there for several hours in shock. I wasn’t ready for retirement. I didn’t know how I would survive financially. Being separated from my wife had already doubled our living expenses. Revenue from my practice had dried up. At the end of the month, I moved out of my office and put everything into storage. —Name Withheld

MARCH 2014

AnesthesiologyNews.com I 11

TE CH N OL OG Y

The Surgical Robot: A Tool? A Toy? An Advance? [[A caveatt: This is an overview of a relatively new technology and a new surgical endeavor. r It is not an exhaustive review and it is not meant as a substitute for a scientific evaluation. It is a practical look at a new surgical world. d What follows is an attempt to raise many questions and provide a few answers. The article is part fact, part observation and part editorial.]

he mere mention of robotic-assisted surgery evokes strong passions. “Love” and “hate” are words heard when discussions turn toward the robot in the operating room. Logic becomes murky as the debate rages. But one thing is clear: The technology works. And not only does it work, it works beautifully in every sense of the word. The surgical robot represents the intersection of science and art; a surgeon-controlled machine directed toward delicate human dissection. Talk about “no touch” technique. This is it. To watch one robotic operation, guided by a skilled surgeon, is to see surgery at its finest; to see it as we picture it. The technology works. So what? To ask whether the technology works, or whether we should allot dollars to robotic surgery, is to ask important questions. However, these may not be the bigger, more important questions. Let’s look first at surgical history, and at the smaller questions.

Confusion and Fear If you are a “traditional” surgeon (insert your own age here), then you may feel somewhat antiquated in the present-day, y high-tech operating room. Fast forward. It gets worse. You are about to feel like a dinosaur. Stand in an operating room with an operating robot docked comfortably at the side of the patient who is lying on the operating table. Watch as the surgeon, dressed in a traditional sterile surgical gown and gloves, places several instruments and readies the operative field. So far, so good. But just as you are beginning to feel comfortable in this new world, beginning to think that you are not really the ghost of the operating room past, and that you might actually fit in here, the surgeon abruptly turns, walks away, removes the sterile gown, snaps off the gloves and sits down at a console in the corner. Before you blurt out “Where are you going?” you realize that you have just stepped far out of your comfort zone and through the door marked “tomorrow,” today. If you are a “young” surgeon (insert your own age here), this new world is the same old world of your present-dayy operating room. The transition likely will be but a small blip on your lifetime learning curve. But, if you are that “traditional” surgeon, you are going to begin to ask yourself a lot of questions. The answers to these questions may bother you or elate you. The answers are as much about your mind as they are about the operating room. The answers are about more than the date on your residency certificate or the date on your maintenance of certification certificate. You are about to find out if you are “traditional” or “young.” Perhaps you are both. And should you become concerned that you, the surgeon, are about to become expendable, take heart. With all of the automation in our modern aircraft cockpits, two pilots guide and control the plane. Two pilots make sure that each of us arrives safely at our destination. The pilot, not the robot, is responsible for our safety. As with aircraft avionics, the surgical robot works for us. You are not expendable … yet.

Is This the Future? The confined space of the human pelvis can hamper visibility and maneuverability in the operative field. Both laparoscopic and robotic systems are touted as helping the surgeon overcome this space limitation. This has spurred the explosive growth of minimally invasive technologies. Robotic surgery was originally developed by the military for remote surgical use. Subsequently, its use was found to be more applicable as an on-site tool. The first robotic procedure, a prostate operation, was performed in 1992. To date, more than 1.5 million robotic procedures have been performed worldwide. In 2000, the FDA approved the da Vinci robotic system for use in intra-abdominal surgery. The initial popularity of robotic systems was for use in urologic and gynecologic procedures. Robotic colorectal surgery was first performed in 2001. Only six reported robotic colectomies were performed between December 2001 and April 2002 despite literature demonstrating the feasibility and safety of the da Vinci system. Fifty-three robotic colorectal procedures were performed between 2001 and 2003, with 22 of these cases being for malignancy. The general consensus was that robotic techniques could achieve the same operative and postoperative results when compared with conventional laparoscopic techniques. According to one review, the use of robotic surgery in colorectal operations increased by 100% from 1,188 cases in 2009 to 2,380 cases in 2010. In contrast, the use of laparoscopy increased only by 1.15%. Colorectal surgeons were thoughtfully slow to adopt robotic technology. Questions arose as to what, if any, were the advantages of robot-assisted colorectal surgery. In contradistinction to the improved, hand-sewn, robot-guided urethral anastomosis, the stapled colorectal anastomosis performed during robot-assisted surgery was no different from the stapled anastomosis performed during laparoscopic procedures. And then, there was the issue of cost. New systems were expensive to purchase or lease, and to maintain, to say nothing of the cost of the disposable items for each case. And, what about the steep learning curve? With the inevitable development of new equipment and experience, coupled with a never-ending drive to advance in fertile directions, surgeons and industry have begun to look again at robotic technology. Costs have come down and instruments are being made to better fit the needs of the colorectal surgeon and the general surgeon, as well as various other surgical specialists. The surgical community has begun to re-evaluate robotic-assisted technology and operative strategies. Does the improved experience in urologic surgery translate to colorectal surgery? To other specialties? Specifically, in colorectal surgery, current robotic techniques are focused on the treatments of

rectal cancer, rectal prolapse, enterocele repair and diverticulitis. Laparoscopic vs. Robotic As in laparoscopic surgery, robotic surgery makes use of small incisions. In both techniques, patients recover faster compared with recovery times following open operations. With a more rapid recovery, needed chemotherapy can begin sooner when laparoscopic or robotic surgery is used for rectal cancer. In surgery for very low rectal tumors, the increased visibility using modern optic systems and improved precision and access to the most distal surgical sites— allowing for increased rates of sphincter-sparingg procedures—could potentially decrease the permanent ostomy rate. Postoperative pain is minimized by an extraction site incision of just 6 to 8 cm (and in some cases even shorter) compared with an incision length of 15 to 20 cm in open surgery. Large, comparative clinical trials are under way, and results thus far indicate that robotic surgery is as effective as open surgery, and yields results “no worse” than the results in laparoscopic surgical procedures. Bells and Whistles The robotic system has certain benefits for both the surgeon and the patient. These are: Three-dimensional high-definition vision. The robotic system has two high-definition cameras that provide the surgeon with a magnified, stereoscopic view of the surgical site, combining accurate depth perception with a sharp image. see robot page 12

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CONTINUED FROM PAGE 11

An additional arm. This additional arm, which can be used to hold a retractor or other surgical instruments, gives the surgeon 50% more operating capability. Instant image referencing (“TilePro”). This feature allows the surgeon to display up to two diagnostic ultrasound or computed tomographic (CT) images taken before surgery, inside the da Vinci console monitor, directly alongside the view of the realtime procedure, providing a critical extra reference when necessary. Extra-mobile “wrist action.” The mechanical wrists, which can hold a wide array of specialized instruments, function just like a human wrist, but with even greater range of motion. This facilitates a relative ease of intracorporeal suturing. Scalability and dexterity. This innovation allows the surgeon to calibrate the robot’s arm to move a fraction of an inch for every inch that the surgeon’s hand moves, simplifying the most complex movements, including delicate resections, suturing and knot-tying. With the robotic system, movements are smooth and without awkwardness. Natural tremor is eliminated. Anastomotic vascular perfusion. Following the injection of indocyanine green, vascularized tissues are seen as green under fluorescent light, whereas underperfused or nonperfused tissues are seen as grey or black. (Presently, it is not known whether this technology is predictive of the anastomotic leak rate and more study is needed to evaluate this technology.) A related technology, real-time, fluorescent, near-infraredd cholangiography also may image the biliary tree. Visualization of the pelvic nerve plexus. Using the high-definition magnification of the robotic optical system, the pelvic plexus of nerves can be seen and protected. The thought is that protecting this delicate and critical latticework of autonomic nerves will preserve continence and sexual functioning. This has yet to be proven in clinical trials. Laparoscopic surgeons will point out that the nerves are seen during laparoscopic interventions as well, thus negating the promoted critical view of the autonomic plexus in robotic procedures. More study is needed to clarify this point.

depending on factors related to training and personal preference. The use of catheters also may be related to the surgeon’s initial comfort with robot-assistedd procedures. The use of ureteral catheters may decrease over time. More study is needed to evaluate the use and safety of robotic colon procedures with respect to genitourinary complications. A dedicated team must be assembled and trained to allow for consistency, safety and reliability in the conduct of the operation. The robot is an expensive system. A new system can cost up to $1.5 million to purchase, and, as in laparoscopic surgery, each operation can require the use of more expensive, single-use equipment. Service contracts are required. As of now, the manufacturer has no competitor and no competitive pricing pressure beyond the current regulatory forces. Clearly, there is a financial impact of added operating time, materials and personnel needs. Studies show that the results after robotic procedures are “no worse” than laparoscopic procedures. However, no prospective, randomized controlled trials have demonstrated a clear-cut advantage of this new technology when compared with the now “traditional” laparoscopic technology. Unlike a urethral anastomosis, the colorectal anastomosis is no different between laparoscopic and robotic techniques, negating an important potential advantage of the robotic system. The Smaller Questions Surgeons are now performing most colorectal procedures using either laparoscopic or robotic technology. Our surgical group is transitioning to performing an ever-increasingg number of robotic-assisted operations. New technologies usually engender new questions. Are there challenges in colorectal procedures that can be overcome, or

Weaknesses and Drawbacks The robotic system has a few drawbacks. An important clinical drawback is the lack of both tactile sensation and tensile feedback to the surgeon. Thus, tissue damage can occur unintentionally during traction by the robotic arm and during movement of the robotic instrument. Learning safe robotic surgery is associated with a steep learning curve. Importantly, robotic technology seems to put the eyes of the surgeon closer to the operative field; an advantage and a drawback as the view of the operative field is often “too close” and a larger frame of reference is required in order to get the “big picture.” Ureteral catheters may be placed before beginning the robot-assisted operation. As robot-assisted procedures are associated with limited tactile sensation, lighted catheters may better improve ureteral identification. The catheters may assist in visual confirmation, identification and added protection of the ureters. This practice varies by institution and by surgeon, The da Vinci Surgical System by Intuitive Surgical.

clinical outcomes that can be improved by using robotic techniques? In both laparoscopic and robotic systems, the technical aspects of the operation are similar. Surgical principles remain unchanged. It is our (mechanical) hands that are different in robotassisted operations. The view and clarity of the operative field and the precision of the surgeon’s movements are unrivaled. In many instances, the robotic optical view is improved over the view during laparoscopic procedures. Dissection is delicate and atraumatic. However, is one technology better than the other? Is robotic colorectal technology an advance? Are we improving the results for our patients? Can hospitals and society afford the expensive robotic system? And, specifically in colorectal surgery, are we on the cusp of another surgical revolution? Is robotic surgery a fancy gimmick and sales tool, or perhaps a technology looking for another diseased organ system to repair? Many questions, few answers … so far. The Big Questions In science, a properly framed question is worth more than a king’s ransom. It is worth more than all of the equipment in all of the labs in all of our research facilities. Frame your question wrong, and you might as well not even take the first step down the road of experimentation. The game is over before the first reagent hits the first test tube. But, frame your question well, frame it in your mind before even putting pen to paper or fingers to keyboard, and the results will jump out at you in ways almost unimaginable. And so it is with robotic surgery. Everyone has an opinion and an answer. To be sure, all questions about patient care are important. And as robotic technology spreads into new arenas, new questions must be asked as old questions resurface. However, the top-level questions must be asked first in order to appropriately frame the subsequent debate and evaluation. So, here are the top-levell questions: Should the robot be allowed into our surgical thinking and then into our operating rooms? Here are the top-levell answers: Yes and yes. And here is why: It does not matter at all what the robot can do for us today. It matters a heck of a lot what the robot might do for us tomorrow. We explore space, we explore the ocean’s depths and we explore our bodies down to our electrons. We do these things because we are curious and because we can. And, from this curiosity we have penicillin and xx rays. We have stethoscopes and ophthalmoscopes, and all of the incredible tools of our craft. We have automobiles, although horses worked just fine. We have computers and software for all kinds of problems. We have telescopes in space. And we have pacemakers, electron microscopes, CT scanners and magnetic resonance scanners. We have artificial joints coated with Trabecular Metal. The list is endless and is a catalogue of human advances. In fact, everything that we have today exists because we invented it all yesterday. Think of robotic-assisted surgery as an experiment—an experiment that may or may not yield results. It might prove meaningless. Or, it might lead to the development of artificial intelligence see robot page 14

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T E C H NO L O G Y ROBOT

questions. And from this questioning will come small and large advances algorithms that will save lives, maybe for all of us. We need to advance. To even save lives in remote locations or stand still is … to stand still. We need remote planets. Who knows? But it is to keep moving forward, because we worth trying. It matters that in devel- can. Robotic technologies are a part of oping robotic technologies, we might this progress. just invent something totally unexRobots R Us? A Few More pected, something that none of us can Answers (Beginning see now through our short-term lenses. With the Big Answer) We must think longer term. We must Should we be using the robot in look further. We must go beyond small questions to big questions, to huge the operating room? Yes. We may not CONTINUED FROM PAGE 12

know where this technology will lead us, but the story of mankind runs in lockstep with invention and exploration of all of our frontiers. Is performing a robotic colorectal procedure exciting and fun? Yes. Are robotic-assisted d procedures being performed in our community and at our hospital? Yes. Surgeons of many specialties are in various stages of learning and adoption, and are evaluating the clinical applications of roboticassistedd operations. It is an intensive

learning process, and the field of robotic surgery is a rapidly evolving work in progress at both the national and personal levels. Is robotic surgery safe? Yes, in trained surgical hands. (Remember, first do no harm.) What about the learning curve? It is steep, very steep. For “traditional” surgeons, it involves didactic training, much practical training and “muscle memory” retraining. The curve is likely not as steep for the “younger surgeons” who already live in a high-tech, surgical and video game world. Is laparoscopic surgery presently the most commonly used surgical system in minimally invasive general surgical and colorectal operations? Yes. Will laparoscopic, minimally invasive surgery remain the most commonly used system in minimally invasive general surgical and colorectal operations for some time to come? Yes. Is today’s robotic colorectal surgery an advance over our current

FDA Seeks Electronic Records for Drug Safety Data

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s part of the FDA’s ongoing efforts to evaluate the safety of drugs and biological products, the agency quietly began a search for access to electronic health records (EHRs) in December. The agency plans to use the information gleaned from EHR data to augment its MedWatch reporting system and other actions taken by the FDA’s Office of Surveillance and Epidemiology. In a notice posted to Federal Business Opportunities, a website used by government agencies looking to contract outside vendors, the FDA wrote that it is seeking direct and continued access to EHR data. The agency said it is “not interested [in] developing this database,” because the successful contractor would have to provide the health information for at least 10 million patients. At a minimum, 5 million of these patients would be currently active in the EHR system, and the majority of patients must have been continuously enrolled in the system for three years or longer. The FDA emphasized that the identities of all patients would be obscured. The Prescription Drug User Fee

MARCH 2014

AnesthesiologyNews.com I 15

TE CH N OL OG Y laparoscopic techniques? Yes, in certain clinical situations. Does robotic surgery have the potential to become the procedure of choice for the resection of pelvic tumors, left-sided d tumors and complicated resections or reoperative resections, as well as in intra-abdominal rectocele repair and enterocele repair? Yes. Do colorectal robotic systems allow for better clinical outcomes when compared with laparoscopic procedures? Possibly, for certain clinical applications. Much study is needed to clarify this point, however. Are the results using robotic tools “no worse” than the results in laparoscopic surgery? Yes. (Remember, first do no harm.) Is the promoted advantage of “greater visibility” using robotic technology an operating room advance when used in colorectal surgery? Possibly, especially if it turns out that nerve visualization and protection, and intraoperative vascular anastomotic

Act (PDUFA) gives the FDA the legal authority to compile this database information, the agency said in the notice. It cited a provision in PDUFA that enables the FDA to “continue the Agency’s efforts on the standardsbased information systems to support how FDA obtains and analyzes postmarket drug safety data and manages emerging drug safety information.” The data provided by the contractor will allow reviewers to “evaluate drugrelated safety issues of high regulatory priority in a timely manner” and assess several risk factors. In the notice, the FDA said it sees benefit from access to longitudinal information regarding the patient population. The agency is looking for real-time access to a database that includes demographic and diagnostic information; laboratory test orders and results; drug and biological agent use; the National Death Index; and health history, including visits to hospitals and specialists. On Jan. 8, the response date for the EHR notice had passed, and three contractors had posted to the website expressing their interest. In a separate notice, the FDA also sought database access to demographic information regarding over-the-counter drug purchases.

perfusion evaluation are found to relate to improved clinical outcomes. Again, more study is needed to look at clinical outcomes. Finally, is someone, somewhere working on an artificial intelligence program that will guide the robotsurgeon (or surgeon-robot) through an operation? Yes.

system in the operating room will depend on a clinical benefit analysis. There appears to be increasing acceptance and use of robotic technologies in many common operative interventions. The technology has improvements and advances over open surgical procedures and laparoscopic technologies as well. However, it will take the combined evaluations of both “traA Tool, a Toy and an Advance ditional” and “young” surgeons to Ultimately, as with any new inter- decide if the robot is a tool, a toy or an vention, the decision to use a robotic advance.

—Gary H. Hoffman, MD, Eiman Firoozmand, MD, Liza M. Capiendo, MD, Stephen Yoo, MD, Allen Kamrava, MD The authors are surgeons at Los Angeles Colon and Rectal Surgical Associates (www. lacolon.com) and instructors in the Division of Colon and Rectal Surgery and in the Colorectal Surgery Fellowship of Cedars-Sinai Medical Center, Los Angeles, California. The authors report no financial relationship with Intuitive Surgical.

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ASHP’s Top Tips for Safer Insulin Treatment Plans Orlando, Fla.—The American Society of Health-System Pharmacists (ASHP) Foundation has issued 10 clinical recommendations it believes can substantially reduce the incidence of in-hospital insulin-related adverse events (AEs) if implemented. The strategies, which target errors during all stages of insulin use, “have several strong advantages,” said Joshua Neumiller, PharmD, assistant professor in the Department of Pharmacotherapy at Washington State University’s College of Pharmacy, in Spokane. “One thing is that they [the recommendations] stress the need for standardized, evidencebased, protocol-driven order sets for insulin use and they also recommend transitioning from reactive to proactive glycemic management approaches,” said Dr. Neumiller,r who was not involved in developing the recommendations. Other organizations have published safe insulin-use guidelines ((J Clin Endocrinol Metab 2012;97:16-38; ACE/ ADA Task Force consensus statement Endocr Pract 2006;12[suppl 3]:4-13).

Nevertheless, insulin-related AEs remain unacceptably high, according to Table. Highest-Priority Insulin Errors* Daniel Cobaugh, PharmD, lead author • Incorrect dosage/irrational orders of the recommendations and vice presi• Nomenclature-related errors dent of the ASHP Research and Educa• Incorrect transcription of verbal or telephone orders tion Foundation, in Bethesda, Md. To • Transcription of incorrect dose develop these new recommendations, • Failure to double-check insulin products before the ASHP Foundation commissioned administration the Institute for Safe Medication Prac• Confusion with look-alike containers tices (ISMP) to review the published • Unsecure storage in patient care and pharmacy areas literature and the ISMP National Medication Error Reporting Program to • Administration of incorrect doses identify in-hospital insulin-use errors. • Incorrect use of insulin pens Based on the findings, Dr. Cobaugh • Failure to match insulin to nutritional status or intake and his colleagues generated a 60-item • Failure to appropriately monitor for insulin effects and survey, which they disseminated to adjust dose accordingly a 21-member panel asked to rank * List not in order of priority Source: ASHP the three highest-priorityy errors they thought should be addressed (Table). Dr. Cobaugh said the broadly representative panel—including pharmacists, physicians, nurses and consumer advoThe 10 recommendations were concentrations for insuulin cacy groups—will help drive adoption developed from the panel’s input and infusions. “There can be b of the recommendations. “This is the include the following: confusion and errors iff concentrations are not standarrdized,” first time an interprofessional panel Prescribing has issued insulin safety use recomDr. Cobaugh explainedd. • In both computerized prescriber mendations,” he stressed. Administering g order entry systems and paper med• Because insulin infusioons preical record systems, replace the use of free-text insulin orders with pared by clinicians poteentially evidence-based, protocol-driven can be diluted to incorrect or order sets for specific insulin uses. nonstandard concentrations, The sets should include guidance leading to medication errors, limit for glucose monitoring and decision preparation of bolus and infusion support, and should take into coninsulin to the pharmacy. sideration a patient’s nutritional sta- • Develop policies and procedures and tus (see the American Association provide staff education to ensure insulin pens are not reused in multiof Clinical Endocrinologists’ Diabetes Resource Center for sample ple patients. Pens have been found to contain blood cells and tissue followorder sets at http://inpatient.aace. ing a single use, and therefore present com/protocols-and-order-sets). • Eliminate routine administraan infection risk if reused in another tion of sliding-scale insulin doses patient. Both the FDA and the ISMP as a primary treatment strategy for have warned of this risk (see “Inforhyperglycemia. mation for healthcare professionals: risk of transmission of blood-borne Storing and Dispensing pathogens from shared use of insulin • Store only U-100 concentrapens” at www.fda.gov and the ISMP’s tion insulin, and ensure the insu“Reuse of insulin pen for multiple lin and administration devices kept patients risks transmission of bloodin patient care areas are securely borne disease” at www.ismp.org). stored. There have been cases in Monitoring which U-500 insulin was inadver• Ensure insulin use is linked to a tently used instead of U-100 insulin, leading to a fivefold increase in patient’s nutritional status and coorinsulin concentrations and severe dinate meal delivery, point-off care hypoglycemia (Am ( J Health Syst glucose testing and insulin administration in a standardized fashion. Pharm 2011;68:63-68). There also • Educate patients and their caregivers have been reports of insulin being confused with other medications to request rapid-actingg insulin at the such as heparin (see, e.g., Pennsylbeginning of a meal, because administering rapid-actingg insulin along vania Patient Safety Authority Pa Patient Saf Advis 2010;7:9-17). with meals decreases the risk for • Develop hospital-wide standard insulin-related hypoglycemia.

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• IIn patients with variablee nutritional intake, delayy administration of prandial in nsulin until meals are coompleted. • Develop protocoldriven and evidence-based order sets for insulin use and blood glucose monitoring for use specifically during enteral (EN) aand parenteral nutrition (PN N) interruptions (see J Hosp Med 20099;4:3-15 for EN- and PNspecific oorder sets). Evaluating • Prospeectively document hypoglycemia and hyperglycemia rates. Monitor iinsulin use, coordinated insulin addministration, glucose testing and nutritional delivery. The Surgical C Care Improvement Project (http:://www.jointcommission .org/surgiical_care_improvement_ project) and a the Partnership for Patients ( partnershipforpatients. cms.gov) are two collaborations that provide n national quality measure outcomess for comparison. • P Provide id real-time, hospital-wide glucose reports to health care teams to ensure appropriate surveillance and management of patients with unexpected hypoglycemia (blood glucose ≤40 mg/dL) and hyperglycemia (blood glucose ≥180 mg/dL). Planning • Provide standardized education, including competency assessments, to all hospital-based health professionals responsible for insulin use. Gregory A. Maynard, MD, MSc, who co-authored the recommendations and presented them at the ASHP 2013 midyear clinical meeting, said the recommendations include a heavy emphasis on physician insulin prescribing as well as nursing care. “We found some of the most common causes of insulin-related errors were inappropriate prescribing, failure to adjust insulin dosing in response to unexpected nutrition interruption and mismatch between carbohydrate intake and insulin intake,” said Dr. Maynard, who is the director of the Center for Innovation and Improvement Science at the University of California, San Diego. He added that caregivers also need to improve how and when they assess initial insulin events. “We don’t do a good enough job at

looking at why hypoglycemia occurs, and this doesn’t allow us to deter recurrences,” Dr. Maynard d said. Scott Mathis, PharmD, director of pharmacy at Monmouth Medical Center, in Long Branch, N.J., applauded the guidelines for being “more focused on safety than previous guidelines. “They use an objective and structured approach based on tracking and

trending of actual adverse events,” said Dr. Mathis, who was not involved in the development of the recommendations. “One thing I like is that they allow use of insulin pens in hospital,” he said. “In my experience, having nurses draw up doses from vials in syringes leads to a large potential for errors, especially 10-fold dosing errors due to incorrect volume being drawn up.”

The recommendations were also published in the ASHP journal earlier in 2013 (Am ( J Health Syst Pharm 2013;70:1404-1413). —David Wild Dr. Cobaugh reported receiving funding from Sanofi for the development of the recommendations. Drs. Maynard, Mathis and Neumiller reported no relevant conflicts of interest.

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Reference: 1 4th National Audit Project of the Royal College of Anesthetists and the Difﬁcult Airway Society: Major complications of Airway Management in the United Kingdom. Report and ﬁndings: March 2011. Editors: Dr. Tim Cook, Dr. Nick Woodall, and Dr. Chris Frerk.

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Better Package Design Helps Prevent Drug Errors

fforts by manufacturers to improve the way they label and package drugs—prompted by new guidelines issued by the FDA just over a year ago—have been largely successful, according to the Institute for Safe Medication Practices (ISMP). The recommendations have made many companies prioritize the information on labels, avoid too similar designs among

different products and standardize ways to indicate drug strengths. “Poor design of container labels and carton labeling can obscure critical safety information,” said Irene Z. Chan, PharmD, a safety evaluator in the FDA’s Division of Medication Error Prevention and Analysis, during a recent online conference hosted by the ISMP.

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Problematic names, labels and packaging contribute to 33% of all medication errors—including a proportionate number of fatalities—out of the annual total of 400,000 errors in the United States, according to a 2006 estimate by the Institute of Medicine. To address this problem, the FDA issued a series of guidelines to drug manufacturers, beginning in December

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2012. They describe ways to properly design drug products, cartons and container labels. The final recommendation, to be released this year, will address naming conventions for proprietary drugs. Manufacturers’ recent steps to improve labeling safety have a long precedent, according to Michael R. Cohen, RPh, MS, ScD (hon.), FASHP, the president of the ISMP. “We feel pretty proud of the progress that’s been made over the last 20 years,” Dr. Cohen said during the Web conference. He attributed much of this progress to clinicians and patients who have reported problems to the ISMP and the FDA’s MedWatch. “I believe we have the safest drug product labeling and packaging around the world,” he said. What Hospitals Can Do There are several proactive steps that health systems can take to decrease errors related to drug labels, according to Kelly J. Besco, PharmD, a medication safety coordinator at OhioHealth in Columbus, Ohio, who was not involved with the ISMP conference. Various barcodingg technologies, for example, can “ensure you’re putting the right drug in the right location on an inpatient care unit, or ensure you are giving the correct medication by scanning the drug against a patient’s ID band prior to administration,” she said. A cost-benefit analysis of the bar code system at Brigham and Women’s Hospital, in Boston, found an annual reduction of 517 adverse drug events, saving $2.2 million per year ((Arch Intern Med 2007;167:788-794). Such interventions, however, aren’t always sufficient to overcome poorly constructed containers or imprecise labels, Dr. Chan noted. “What we’ve found is that product design features that predispose end users to errors can often withstand interventions,” she said, including those efforts “focused on product labeling or education of health care providers or patients.” That’s why the FDA has chosen to focus on the source of the problem— manufacturers with poorly designed labels—rather than on end users. Medication packaging and labels need to reflect the variety of factors that can influence an end user’s behaviors, Dr. Chan said. If manufacturers do not anticipate multiple environments of use, from hospital pharmacies to local drugstores, the lack of foresight can compound poor design problems, she said.

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PR N What’s in a Name? Labeling-related medication safety issues also can arise when clinicians have difficulty discerning between drug names or packaging. In the event that one drug is mistaken for another, Dr. Besco said, OhioHealth’s medication safety team will partner with pharmacy purchasers to determine if an alternative manufacturer offers the drug in a more distinctive container. Otherwise, the purchasers will try to obtain the drugs in different delivery systems,

Old (left) and new versions of heparin injection label. Both vials hold the same amount of medication.

such as a prefilled syringe. “There can be so many distractions on a label: corporate logos, different colors, highly stylized graphics,” Dr. Cohen said. Companies need to be willing to “work with front-line practitioners to test their products prior to marketing,” so pharmacists have a chance to evaluate how well these products are packaged. —Ben Guarino No sources reported relevant financial conflicts of interest.

Source: NAN Alert, June 10, 2013.

Effects of Poor Labeling Such faulty packaging has led to a variety of problems, including people ingesting topical Benadryl sold in drugstores. The container’s shape seemed to indicate it was intended for oral use, Dr. Besco said, and the description “Topical Analgesic” was written in “very, very small” letters on the original labels. “This was the most important piece of information for the consumer to acknowledge prior to taking the medication, and could have prevented the errors from occurring.” In May 2010, the FDA reported that ingesting Benadryl Extra Strength Itch Stopping Gel caused cases of hallucinations and unconsciousness; in response, Benadryl maker Johnson & Johnson added a sticker with “For Skin Use Only” in large type on the cap. In a clinical environment, improper type size also can cause harm. Dr. Chan cited the example of a vial of heparin that, with a quick glance at the large bold number on the label, appeared to contain 1,000 units. In fact, the bold number listed the units per milliliter, and the full 30-mL vial totaled 30,000 units of heparin. “We have run into problems where people see concentration per milliliter and that doesn’t represent the whole content of vial,” Dr. Chan said. “That has led to overdoses.” Indeed, several high-profile cases of heparin overdoses—some fatal— have occurred in recent years due to such confusion. The FDA responded by recommending that manufacturers follow the guidelines laid out in U.S. Pharmacopeial Convention Chapter <1>. The USP chapter stipulates that small-volume parenteral product labels should state the quantity of a drug per total volume before listing the per milliliter concentration (see photo). Several heparin vial manufacturers have revised their labeling to comply with that directive.

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Bariatric Surgery May Stunt Aging Mechanism

ariatric surgery may reverse the shrinkage of telomeres, the caps on the ends of each strand of DNA that are considered markers for biological aging, according to a small, preliminary study. “This is the first study to demonstrate that surgical weight loss leads to decreased aging by increasing telomere length,” said lead author John M. Morton, MD, MPH, director of bariatric surgery, at Stanford University, in Stanford, Calif. He and his colleagues presented the findings at Obesity Week, the first annual joint meeting of the American Society for Metabolic and Bariatric Surgery and The Obesity Society. Often likened to the tips on the ends of shoelaces, telomeres are responsible for maintaining chromosome stability. Every time cells replicate, the telomere frays and shortens, losing some genetic material in the process. Shortened telomeres have been linked to higher rates of cancer, neurodegenerative diseases and mortality. But although researchers understand more about what happens as telomeres lose integrity, little is known about how to prevent the degradation. It is believed that interventions to prevent telomere shortening could increase longevity and decrease the incidence of age-related dementia (Arch ( Neurol 2012;69:1332-1339). Obesity is one of the drivers of telomere shortening, and experiments in mice suggest that obesity increases the formation of reactive oxygen species in fat cells and shortens telomeres (Nat Med 2009;15:996-997). Based on these findings, Dr. Morton and his colleagues set out to look at

whether weight loss induced by bariatric surgery could influence telomere length. They studied 55 patients with a mean age of 48.5 years who underwent laparoscopic gastric bypass for obesity and telomere analysis by Telomere Diagnostics, Inc. Overall, patients’ telomere length remained relatively stable, measuring 0.987 (relative to 1.0) preoperatively and 0.982 one year after surgery (P=0.764). But specific groups of patients showed remarkable improvements in telomere length, particularly those with the highest preoperative levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP). Patients with high preoperative CRP, defined as 7 at baseline, demonstrated a 2.83% increase in telomere length one year after surgery. Patients with high LDL-C preoperatively, defined as greater than 140 at baseline, showed a 1.62% increase in telomere length. “I look at it this way: It’s the sickest patients—those with the worst cholesterol, the most inflammation— who got the most benefit,” Dr. Morton explained. The findings suggest that there may be a way to determine who will have the best results from bariatric surgery, an issue that will become even more important in the next few years under health care reform, said Bruce Wolfe, MD, professor of surgery at Oregon Health & Science University, in Portland. Dr. Wolfe was not involved with the study. “A fundamental question in bariatric surgery is how can we determine beforehand who will have a very good operation so we can focus the selection of patients,” he said.

“What th his is study show weed, as I interpret et it, is that th the gastric byppaass ss and resulltan nt weight loss led too restoration of tel elloo-mere fun ction an nd chromosom mal preservatiion n. If indeed the he weight loss does have a positive effect on preservation of DNA and how it functions, that is a remarkable finding.” Dr. Wolfe cautioned that although the study provides proof of concept, much more information is needed. Currently, the investigators have expanded the study and plan to conduct telomere analysis on more than 1,500 patients who underwent gastric bypass as part of the National Institutes of Health research consortium on bariatric surgery, known as LABS. Such a study would provide more information on what happens to the telomeres of bariatric surgery patients, particularly in the long term. Dr. Wolfe is co-chair of LABS. It is unknown if telomere erosion itself contributes to aging or if it is a reflection of the aging process. That’s a question for future research, Dr. Morton said. —Christina Frangou Dr. Morton has served as a consultant to Covidien and Ethicon. Dr. Wolfe reported no relevant financial conflicts of interest.

Trials, Data Needed To Guide Biosimilar Adoption

ffectively integrating biosimilar drugs into the U.S. market will require careful collaboration between manufacturers and regulators, according to clinicians who spoke during a recent Web conference hosted by the Institute for Safe Medication Practices (ISMP). For a number of blockbuster biologic drugs, the road ahead leads to the so-called patent cliff. Several drugs will lose their market protection within the next decade, including adalimumab in 2016 (Humira, Abbott) and trastuzumab in 2019 (Herceptin, Genentech). At the same time, the market for biologics is booming, with worldwide sales climbing from $46 billion in 2002 to $169 billion in 2012, an IMS Health report estimated. As the demand for biologics continues to grow, physicians, regulators and patients are looking to biosimilars, the offf patent compounds that are

comparable to biologics—although not identical copies—to help rein in costs. “We definitely need biosimilars as a strategy to reduce our health care costs,” said Edward Li, PharmD, associate professor of pharmacy practice at the University of New England, in Portland, Maine, who spoke during the ISMP seminar. The pathways to approval for biosimilars and generic drugs run parallel, with a few key distinctions. Under the Biologics Price Competition and Innovation (BPCI) Act, part of the Affordable Care Act, a manufacturer can apply to the FDA for a shortened approval process. In 1984, the U.S. Drug Price Competition and Patent Term Restoration Act created a standard method of approving nonbranded medication through an Abbreviated New Drug Application. At that time, however, Congress excluded biologic

drugs from the abbreviated pathway, citing the difficulty of manufacturing these compounds. “When you consider small molecule drugs,” Dr. Li said, “those are relatively simple [to produce] compared to a biologic manufacturing process.” Part of the challenge arises from the extreme disparity in size of the compounds. With a sequence of 165 amino acids, epoetin, for example, has a molecular mass of about 30,000 Da, hundreds of times larger than inorganic compounds such as the chemotherapy agent cisplatin. And unlike the chemical production of a small molecule compound, creating a large biologic drug requires living cells. “It’s not quite like synthesizing something in a test tube,” said Leonard Zwelling, MD, MBA, a clinical oncologist and professor of medicine and pharmacology at the University of Texas MD Anderson Cancer Center, in Houston, who

was not involved with the ISMP Web seminar. Because biosimilars are the product of living systems, it will be impossible for other manufacturers to perfectly match the structure of a brand-name biologic. A biosimilar could have many of the same chemical constituents as a reference drug, but post-translational modifications such as protein folding or other biological quirks of a cell line may affect a biosimilar agent’s efficacy. Dr. Li noted that the complexity of producing biosimilars would keep the costs of these drugs higher than the price of traditional generic pharmaceuticals. “But we are going to see some savings compared to the reference product,” he said during the Web conference. “Hopefully, that will increase access to expensive therapies.” John Mbagwu, PharmD, a clinical pharmacist for the medical consulting group Optum, said that, on the high

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PR N end, estimates for the manufacture of a biosimilar would be about $250 million. Although this is a fraction of the average $1.2 billion cost of bringing a new drug to market, compared with a generic drug, a biosimilar requires more rigorous safety and efficacy data to earn approval. Ensuring Biosimilar Safety Approval for generic drugs must show bioequivalence in form, safety and route of administration, and the agents are not required by the FDA to undergo comparative clinical trials. Biosimilars, however, must demonstrate that they are “highly similar.” To guide manufacturers looking to bring biosimilars to market, the FDA has released three draft recommendations. In a 2012 draft guidance, the agency said that approval of a biosimilar must be based on “data derived from analytical studies, animal studies and a clinical study or studies,” under the BPCI Act. Because biologic drugs are manufactured in cells derived from hamsters, rabbits and other organisms, they pose varying risks for immunogenicity. A patient’s immune system may produce antibodies that neutralize the biologic, or develop antibodies that trigger antibody-mediated disease or other adverse reactions. Dr. Li cited an increase in the number of cases of pure red cell aplasia linked to biologic erythropoietin products in the 1990s. “The whole point of this abbreviated biosimilar [approval] pathway is [to allow] the FDA [to] prospectively review these agents, so we don’t have immunogenicity issues in the future,” Dr. Li said. To that end, the FDA has recommended comparative parallel studies in its guidances. But the requirement for clinical data increases the projected costs of biosimilars. Although generic drugs can be purchased for as little as 20% of the cost of a branded drug, a 2011 review reported that estimates for biosimilars prices would be 15% to 30% less than the reference drug (Clinicoecon Outcomes Res 2011;3:29-36). In June, the chief executive officer of Celltrion announced that the biosimilar version of infliximab, Remsima, would be more than 30% cheaper than Johnson & Johnson’s Remicade. Celltrion is seeking approval for Remsima in Europe, where more than a dozen biosimilars have been approved by the European Medicines Agency. In the European Union, biosimilars saved an estimated $2.6 billion (1.9 billion euros) in 2009, according to the European Generic Medicines Association.

Prescriber Skepticism When biosimilars become available in the United States, a large body of clinical data will be needed to help overcome another hurdle—prescriber skepticism. Additional clinical data also will enable certain biosimilars to be labeled “interchangeable,” a term that has already come under fire in the United States. Under a provision of the BPCI, biosimilars deemed interchangeable by the FDA can be substituted without a pharmacist notifying the prescribing physician.

A bill passed by California’s state Senate would have voided that provision, requiring pharmacists to notify prescribers which biosimilar drug they had dispensed. Responding to calls from the Generic Pharmaceutical Association and other critics, Gov. Edmund G. Brown vetoed the bill, stating that “to require physician notification at this point strikes me as premature.” The question to ask becomes not when biosimilars will become available in the United States,

Dr. Zwellingg said, but when doctors will prescribe them. “Until I see a trial in which the biosimilar and the [reference] drug are compared head to head, in real patients with real cancer,” he said, “I wouldn’t prescribe it, and I wouldn’t let my mother take it.” —Ben Guarino Dr. Zwelling reported no relevant financial disclosures. Dr. Li has served on advisory boards for Amgen and Hospira.

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Trauma Patients See Rise in Radiation Exposure to a growing body of research on inpatient radiation exposure, reflects the belief that “we are submitting our trauma patients to a tremendous amount of radiation,” said Michel Wagner, MD, a trauma and critical care surgeon at Creighton University Medical Center in Omaha, Neb., and a coauthor of the study. Dr. Wagner presented the results of

this research at the 2014 annual meeting of the Society of Critical Care Medicine (abstract 257). “I think that this is a little bit of a warning bell.” Using patient records from a database at a Nebraska trauma center, the researchers retrospectively determined which radiologic exams clinicians had ordered for patients between 2001 and 2010. For 7,661 trauma patients who

Exposure in mSv

rauma patients at a Nebraska hospital who underwent computed tomography (CT) scans and other diagnostic tests faced an upswing in radiation exposure over the past decade, adding to concerns that radiologic procedures may pose a greater carcinogenic risk to patients than previously understood. The recent study, which contributes

0 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘08 ‘09 ‘10

Year

Figure. Average Radiation Exposure Per Year The average trauma patient’s radiation exposure climbed from 2001 to 2010. (Based on Wagner et al. SCCM abstract 257)

were admitted to the hospital during that period, the authors evaluated the amount of radiation each patient received based on dose estimates for 416 different radiologic procedures. “The goal was to come up with a standard metric of comparison,” said Jonathan Vonk, a medical student at the Roy J. and Lucille A. Carver College of Medicine in Iowa City, Iowa, who helped conduct the research. “In reality, the actual received dose is highly dependent on body composition.” Radiation exposure among trauma patients rose significantly over the 10-year period, increasing by an estimated 6.7 to 12.8 mSv. In 2001, the average radiation exposure was 14.9 mSv per trauma patient, the authors calculated. By 2010, the mean dose of radiation had increased to about 24.6 mSv per patient (Figure). In contrast, the total radiation dosage for an average American, including exposure from background radiation and medical procedures, is 6.2 mSv per year, according to a 2011 report from the U.S. Nuclear Regulatory Commission. “As this study and many other studies show, our reliance on medical radiation continues to grow for diagnostic and therapeutic measures,” said Deborah Rohner, MD, assistant professor in the Department of Anesthesiology at the University of Kentucky College of Medicine, in Lexington, who was not involved with the research. “Therefore,” she said, “the potential iatrogenic cancer burden is expected to increase.” The commonly accepted model is a linear relationship between radiation dose and cancer risk, Mr. Vonkk said, but

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ACLU To Fight Indiana’s New Drug Testing Rule

he American Civil Liberties Union is taking aim at a new rule that mandates drug testing for certain patients with chronic pain in Indiana. The state’s medical licensing board now requires urine and saliva drug-monitoringg tests for any patient who, for at least three months, receives more than 60 opioid-containingg pills per month or a daily dose of opioids equivalent to more than 15 mg of morphine. As of December 2013, patients who are prescribed opioid regimens that meet these conditions must undergo a drug test at the beginning of their treatment plans and at least once a year thereafter. By filing a lawsuit on Jan. 8, Wierciak, et al. v. Individual Members of the Medical Licensing Board of Indiana, the ACLU seeks to stop the licensing board’s testing requirement. In an accompanying statement, the ACLU asserted that these tests are “not medically indicated,” and that patients should not be forced to consent to the increased monitoring efforts to receive treatment. “The Fourth Amendment protects all of us from government-mandated searches unless there is cause or justification,” stated Kenneth J. Falk, legal director of the ACLU’s Indiana chapter. “The mandatory drug testing simply goes too far.” Earlier in 2013, the Indiana General Assembly had authorized the state licensing board to enact emergency

the researchers could not verify if the increase in radiation had a detrimental effect within the study population. The clinical significance of radiation doses less than 100 mSv remains controversial, Dr. Rohnerr said. She also noted that the allowable exposure to radiation workers in the United States is 50 mSv per year. Exposure to 100 mSv of radiation is associated with a 1% increase in lifetime risk for developing cancer, according to a 2006 report from the Board on Radiation Effects Research VII. Physicians may be reluctant to limit the number of CT scans ordered, out of concern that injuries will go undetected. But clinicians should be willing to reassess the risks and benefits of diagnostic plans, Dr. Wagnerr said. CT scans are easy to order, he said, but they are not without risk. —Ben Guarino

rules, as part of a broader legislative action to curb opioid abuse in Indiana. Prescription drug overdoses in that state were associated with 14.4 deaths per 100,000 people in 2010, according to data of the Centers for Disease Control and Prevention. Kentucky’s medical licensing board undertook similar action to restrict opioid abuse in 2012, when it began

to require urine screenings for chronic opioid users in a “random manner at appropriate times.” Pharmacies in Indiana consequently may be forcing primary care doctors to reduce the opioid dosages prescribed to patients, said Julie Reed, general counsel for the Indiana State Medical Association (ISMA), in a statement on Jan. 27. “The ISMA is receiving

many reports from all across the state that pharmacies and pharmacists are increasingly placing barriers between doctors and their patients who have been issued controlled substance prescriptions,” she said. “Most of these pharmacy issues are pretty new, and they may be getting worse.” —Ben Guarino

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Department of Outcomes Research at Cleveland Clinic, in Ohio, who helped conduct the study. “I’m guessing that in 10 years, maybe even in five years, continuous pulse oximetry will be the standard of care on hospital wards because hypoxia is so common,” Dr. Sesslerr said. The prospective observational study, which Dr. Sessler, Andrea Kurz, MD, and their colleagues presented at the 2013 annual meeting of the American Society of Anesthesiologists (abstract BOC12) was a subanalysis of the VISION study, which looked at 40,000 patients over 45 years old undergoing noncardiac inpatient surgery. Patients were included if they were over age 45 and were admitted for inpatient procedures at Cleveland Clinic and a second hospital. The roughly 1,500 patients in the substudy had continuous pulse oximetry from the time they left the postanesthesia care unit or the intensive care unit for up to 48 hours. Unlike previous studies of continuous pulse oximetry, the Cleveland Clinic researchers masked the monitors and muted their alarms to blind clinicians to their output. “They thus had no way of knowing the saturations we recorded,” Dr. Sesslerr said, although they were permitted to perform their own clinical routines. That blinding was important, Dr. Sessler added, because “if alarms go off, people come in and do things. You can’t then ask how long patients would otherwise have remained hypoxic.”

Patients, %

HYPOXIA

Episode Duration >10 minutes >20 minutes >30 minutes >60 minutes >90 minutes >120 minutes >180 minutes

40 30 20 10 0 75

Threshold Defining Hypoxia Figure. Incidence of contiguous hypoxic episodes of varying duration, under a range of progressive SpO2 thresholds defining hypoxia.

Eugene Viscusi, MD, professor and director of acute pain management at Thomas Jefferson University Hospitals, in Philadelphia, said the study raised cause for concern. “Generally, we would think of 85% saturation as needing treatment. We consider these patients to be on the cusp of disaster, which I don’t deny. However, it is interesting that there were no catastrophic results. “I see two lines of questions here,” Dr. Viscusi added. “One is the above: Just how risky is this hypoxia? Can we quantify the risk of these progressing to a bad outcome? The second question is how to predict which patients will become this hypoxic,” which boils down to demographics that aren’t yet clear. Elizabeth A. M. Frost, MD, clinical professor of anesthesiology at Icahn School of Medicine at Mount Sinai, in New York City, wondered if transient hypoxia is really so harmful. “Does desaturation lead to respiratory arrest? I suppose at the end of the day it would, but how often are patients somewhat hypoxic after surgery and nothing happens?” Dr. Frost asked. Evidence suggests that patients who do not receive oxygen during transport to the postanesthesia care unit arrive there hypoxic. “But there do not seem to be any adverse consequences,” she noted. Finally, she said, “We know that REM/NREM [rapid eye movement/non-REM] sleep patterns are disturbed for several days postoperatively. Is this what causes hypoxia? And how many patients actually desaturate during sleep normally, without surgery? Are they at risk for arrest?”

Although the researchers did not evaluate clinical sequelae of hypoxic episodes—and the study wasn’t powered to do so—Dr. Sessler said the implications are concerning. “Most people don’t think that it’s a good thing to have prolonged periods of desaturation.” One likely consequence, he noted, is poor wound healing because adequate tissue oxygenation is key to both healing and fighting infection. Opioids surely contribute to postoperative hypoxia, Dr. Sessler said. Another obvious cause is sleep apnea. Indeed, the Cleveland group is now evaluating the relationship between sleep apnea and hypoxia in hospitalized patients. Dr. Sessler and his colleagues also are comparing “Sobering” Results nursing reports with their continuous pulse oximetry The results, he said, were “pretty sobering”: Approx- results. “We think there’s a huge discrepancy there. —Adam Marcus imately 21% of patients averaged at least 10 minutes Nurses wake patients up and start taking vital signs, per hour with SpO2 values below 90%, and approxi- and by then people are breathing fine. Then they go Drs. Viscusi and Frost are members of the editorial board of Anesthesiology News. mately 8% of patients averaged at least 20 minutes per back to sleep and start desaturating.” hour. Approximately 8% of patients averaged at least 5 minutes per hour with SpO2 less than 85%. Advertisement ACTion Pain Pump MultiBolus II, from Ambu Inc. The new MultiBolus II from Ambu is the only disposable bolus that has been truly designed for regional anesthesia. A quick delivery of medication, similar to that of syringe, allows the medication to be delivered in less than one minute. The easy-to-pull handle allows the patient to self-administer the bolus with minimal effort. MultiBolus II is a truly adjustable parallel bolus from 0-6 mL per hour while offering a continuous basal flow to the patient. Ambu Inc 6740 Baymeadow Dr. Glen Burnie, MD 21060 (800) 262-8462 dct@ambu.com www.ambuusa.com See our ad on page 43.

Improved Rapid-Sequence Intubation atients undergoing rapid-sequence intubation (RSI) are more likely to receive sedation if a pharmacist is present during intubation, University of California, San Francisco researchers reported at the American Society of Health-System Pharmacists 2013 midyear clinical meeting (poster 3-069). Lead investigator Zlatan Coralic, PharmD, an emergency medicine pharmacist at UCSF, reviewed medical records from 499 patients who underwent RSI at the university’s emergency department between 2008 and 2012 and found many were not receiving appropriate sedation and analgesia. Specifically, 55.7% (278 of 499) did not receive post-RSI analgesia and 25.7% (128 of 499) were not given sedatives during their stay in the ED. “Intubation hurts, and analgesia and sedation need to be administered,” Dr. Coralic said. “There are very few instances where these should not be administered.” Further analyses revealed two interesting findings: 60.8% and 28.3% of a subset of patients given rocuronium for RSI did not receive analgesia and sedation, respectively, compared with 48.6% and 15.6% of those administered succinylcholine (P≤ P 0.004 for both). “There may be a false sense that patients are sedated with rocuronium,” Dr. Coralic said. “It is a much longeracting paralytic than succinylcholine but it is just that—a paralytic. It does not provide any analgesia or sedation.” In contrast, the effect of succinylcholine diminishes after

five to 10 minutes, “unmasking a patient’s agitation and prompting providers to administer analgesia and sedation much sooner than with rocuronium.” On average, recipients of succinylcholine received analgesia and sedatives 20 minutes sooner than patients on rocuronium, he found. Further analyses showed that only 19% of rocuronium recipients were left unsedated when an ED pharmacist was present during RSI compared with 35% who were unsedated when a pharmacist was not present (P=0.01). P “I think that pharmacists are aware of rocuronium’s pharmacokinetics and its duration of action, and they prompt providers to order analgesia and sedation,” Dr. Coralic said. He added that pharmacist attendance did not correlate with analgesia use in rocuronium recipients or with both analgesia and sedation in succinylcholine recipients. Although his was a single-center study, the findings are not unique to UCSF, Dr. Coralic said. A retrospective analysis of data from more than 1 million patients included in the National Hospital Ambulatory Medical Care Survey found that fewer than half of ED patients who underwent RSI received appropriate sedation (Am J Emerg Med d 2013;31:222-226). “There is plenty of room for improvement in every emergency department,” he said. —AN Staff

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CL IN ICA L A N E STH E SIOL OG Y

Surgical Patients Show Higher Mortality From Harm, Study Finds

esearchers have long known that postsurgery recovery is a vulnerable time for patients, but a new study goes a step toward quantifying that risk. Michigan investigators assessed patients who experienced similar harms in the hospital—such as infection, pressure ulcers or renal failure— and found surgical patients represented a significantly higher percentage of overall mortality from harm than the rest of the inpatient population (73.2% vs. 37.0%, respectively; P<0.001). A variety of factors could contribute to the disparity in mortality rates, said Zachary M. Bauman, DO, a critical care surgeon at Henry Ford Health System, in Detroit, who presented the findings at the 2014 meeting of the Society of Critical Care Medicine (abstract 31). One factor, he said, “is the surgery itself.” Surgical patients may experience more pain and require more narcotics than patients who do not undergo surgery, Dr. Bauman said, which could lead to more severe harm from naloxone or other medications. To determine the effect of inpatient harm on patient mortality, Dr. Bauman and his colleagues retrospectively reviewed the records of 114,677 patients admitted to a hospital in the Henry Ford Health System from 2009 to 2011. For each of the 11 inpatient harms assessed, the authors found significantly higher mortality rates among surgical patients injured in the hospital (P<0.001 for each harm reviewed). The three incidents with the highest mortality rates for surgical patients and patients who did not undergo surgery were adverse reactions to medication (32.0% vs. 13.1%, respectively), renal failure (23.5% vs. 8.3%) and hypoglycemia (20% vs. 9.9%). Procedural harm had the largest proportional difference in mortality rate—a roughly sevenfold increase—in surgical patients compared with nonsurgical patients (19.4% vs. 2.8%, respectively). “Even one complication puts [a patient] at risk for a completely different trajectory,” said Ilan S. Rubinfeld, MD, MBA, a specialist in trauma and emergency surgery at Henry Ford Hospital who helped conduct the study. Martin A. Makary, MD, MPH, associate professor of surgery at Johns Hopkins University, in Baltimore, who was not involved with the research, agreed. “A single event can set off a cascade of subsequent harms,” Dr. Makaryy said. Determining the consequences of having a specific harm remains a

challenge. “Are some of these harms more important, or more a bellwether of bad things to come?” Dr. Rubinfeld asked. “We can’t say that for sure, but we all have our suspicions.” He added that ongoing studies would address these questions in more detail. Differences in patient characteristics could impact the way harmful incidents affect mortality. The authors

found that surgical patients had fewer comorbidities than nonsurgical patients, with a lower average Elixhauser Comorbidity Index (3.57 vs. 5.52, respectively; P<0.001). But why a patient was admitted to the surgical floor could “very well have been more serious,” Dr. Makaryy said, than the reason a nonsurgical patient was admitted to the hospital.

high in botic risk is When throm thrombin deficiency ti hereditary an

Clinicians also suggested that stress could play a role. Dr. Makaryy pointed out that even minor stressors have been linked to physical conditions, such as acne or cold sore outbreaks. Surgical patients, he said, are encountering one of the “greatest physiologic stress events in medicine: an operation.” —Ben Guarino

To learn more, visit www.thrombate.com

FELY PROCEED SA

Thrombate III® (antithrombin III [human])—proven effective for patients with hereditary antithrombin (AT) deficiency during surgery, childbirth, and in the prevention and treatment of thromboembolism1 Thrombate III provides predictable amounts of AT to replace what is normally present in the body t AT concentrate purified from human plasma and pasteurized to inactivate viruses, with no confirmed cases of virus transmission t In clinical studies, no cases of thrombotic complications during surgical and obstetrical procedures were reported

Easy to administer1

Convenient to store and reconstitute1

t One dosing formula t Bolus intravenous infusion (not continuous infusion) t Pregnancy category B

t 500 IU vials with sterile water for injection t Filter and transfer needles provided t Room temperature storage

Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia. The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identified for Thrombate III. Please see brief summary of Thrombate III complete Prescribing Information on adjacent page. Reference: 1. Thrombate III® (antithrombin III [human]) [prescribing information]. Research Triangle Park, NC: Grifols Inc; 2012. © 2013 Grifols Inc.

February 2013

TH05-0113

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Multidisciplinary Program Improves Extubation Rates Raleigh, were an alarmingly low 14.4%. That figure had earned WakeMed a single star from the National Quality Forum. In response, a team of nurses, respiratory therapists, anesthesiologists, surgeons and intensivists began working together to assess the problem and develop protocols to improve extubation rates.

THROMBATE

III®

Antithrombin III (Human) BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

FOR INTRAVENOUS USE ONLY DESCRIPTION Antithrombin III (Human), THROMBATE IIIw is a sterile, nonpyrogenic, stable, lyophilized preparation of purified human antithrombin III (ATIII). THROMBATE III is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0–7.5, a sodium content of 110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M, and a heparin content of not more than 0.1 IU heparin/IU ATIII. THROMBATE III contains no preservative and must be administered by the intravenous route. Each vial of THROMBATE III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm. The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. CLINICAL PHARMACOLOGY Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by ATIII proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect in vivo of heparin is mediated by ATIII, heparin is ineffective in the absence or near absence of ATIII. The prevalence of the hereditary deficiency of ATIII is estimated to be one per 500 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40%–60% of normal. These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary ATIII deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episode by the age of 50 years. In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of ATIII, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals. In clinical studies of THROMBATE III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days. In clinical studies of THROMBATE III, none of the 13 patients with hereditary ATIII deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism. During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for ⱖ 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B. INDICATIONS AND USAGE THROMBATE III is indicated for the treatment of patients with hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

“The reason our program was so successful was that it was truly a multidisciplinary effort,” said Lisa Soltis, a cardiovascular critical care clinical nurse specialist at WakeMed who helped lead the study. Ms. Soltis and her colleagues presented their findings at the 2014 annual meeting of the Society of Critical Care Medicine (abstract 319).

Subjects with ATIII deficiency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease. The diagnosis of hereditary antithrombin III (ATIII) deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. ATIII in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary ATIII deficiencies. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. CONTRAINDICATIONS None known. WARNINGS Because THROMBATE III is made from human plasma, it may carry a risk of transmitting infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for THROMBATE III. Inform patients that THROMBATE III is made from human plasma and may contain infectious agents that can cause disease. While the risk that THROMBATE III can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics Inc. [1-800-520-2807]. The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. PRECAUTIONS General 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution. 2. Administer only by the intravenous route. 3. THROMBATE III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions. 4. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in sharps container after single use. Discard all equipment including any reconstituted THROMBATE III product in accordance with biohazard procedures. The diagnosis of hereditary ATIII deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. Laboratory Tests It is recommended that ATIII plasma levels be monitored during the treatment period. Functional levels of ATIII in plasma may be measured by amidolytic assays using chromogenic substrates or by clotting assays. Drug Interactions The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III. It is not known whether THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. ADVERSE REACTIONS In clinical studies involving THROMBATE III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were dizziness (8), chest discomfort (3), nausea (3), dysgeusia (3), chills (2), pain (cramps) (2), dyspnoea (1), chest pain (1), vision blurred (1), intestinal dilatation (1), urticaria (1), pyrexia (1), and wound secretion and hematoma (1). If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate. CAUTION & only U.S. federal law prohibits dispensing without prescription.

Grifols Therapeutics Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1871

In some cases, poor communication during physician handoff slowed extubations. Other times, a history of significant pulmonary illness, the run length of cardiopulmonary bypass, anesthesia reversal or personnel workload led to subpar extubation rates. “We discovered that anesthesiologists were not reversing [neuromuscular blockade] in the operating room. When we asked them why, they said, ‘Some of the nurses asked us not to.’ The nurses wanted patients to stay sedated until they could get them settled in,” Ms. Soltis said. The team solved this problem by educating nurses and therapists about the importance of timely and complete reversal of neuromuscular blockade. The new respiratory extubation protocol improved communication among practitioners and encourage weaning progression. And new tools and protocols improved patient management when potential problems were identified after extubation. New tools and protocols improved patient management when potential problems were identified after extubation. For example, a new extubation evaluation form helped clinicians collect data on patients who were intubated for more than six months, such as the names of the physicians involved; the sedatives and narcotics given to the patient; and the reasons for being unable to extubate. “The form helped us identify the fact that we had some patients that were experiencing shunt from the nitroprusside, so we added nicardipine [Cardene, Cornerstone Therapeutics] to our postoperative order set,” Ms. Soltis said. 80%

Post-intervention

% <6 h Linear (% <6 h)

70% 70 60%

Intervention 50% 40% 30%

Pre-intervention

North Carolina hospital has dramatically increased rates of early extubation after cardiac surgery, reduced patient returns to the ICU and shortened patient stays in the hospital. The multidisciplinary effort was born of the realization a few years ago that extubation rates at the facility, WakeMed Health and Hospitals in

28.6 20% 10% 0%

14.4

2011

2012

2013 Q1

2013 Q2

2013 Q3

Figure. The extubation protocol increased the percentage of extubations in under six hours ... 08941115-BS

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CL IN ICA L A N E STH E SIOL OG Y The team also developed algorithms for a progressive care unit to facilitate the management of patients experiencing hypotension, bradychardia, tachycardia and hypoxia. A rounding nurse was assigned to follow patients who were at high risk for returning to the ICU, based on criteria including a complicated postoperative course and high risk for chronic obstructive pulmonary disease. A multidisciplinary team of clinicians started meeting daily to discuss high-riskk patients. The new program launched in July 2012. Regular progress reports helped motivate staff. “We did our own internal audit to make sure we could get real-time data, rather than saying, ‘three months ago, you didn’t extubate this patient, what happened?’ There was a group who were collecting data on every patient, every day,” Ms. Soltis said. “Every week, we would send out an update on the cases and say, ‘congratulations to these nurses,’ and [list] their times. There was some push back at first, but when clinicians started to see the results, the buyy in was really there.” In roughly one year, implementation of the protocols increased the number of patients extubated in less than six hours (14.4% vs. 45%), decreased the number of patients intubated for more than 24 hours (15.4% vs. 9%), decreased returns to the ICU (7% vs. 4.5%; Figure) and reduced returns to the ICU related to pulmonary complications (60% vs. 27%). The protocols also significantly decreased the ICU length of stay and overall length of stay by two days. Those gains helped WakeMed earn back its two stars from the National Quality Forum.

Prolonged intubations (>24 h)

Pre-intervention

Linear (Prolonged intubations >24 h)

16 15.7

Intervention

14 12 11.5

Post-intervention

8.8

7 5

4 2 0

2012 Q2

2012 Q3

2012 Q4

2013 Q1

2013 Q2

and reduced the number of iintubations t b ti llasting ti more th than 24 hours.

2013 Q3

Kevin Lobdell, MD, director of quality at the Sanger Heart & Vascular Institute, in Charlotte, N.C., said early extubation is important because mechanical ventilation is ubiquitous in cardiac surgery and positive pressure ventilation is not physiologically normal. “In most situations, our cardiopulmonary physiology is better with negative pressure ventilation than positive pressure mechanical ventilation,” said Dr. Lobdell, whose institute is part of the Carolinas HealthCare System.

“Additionally, the endotracheal tube utilized for positive pressure mechanical ventilation bypasses standard host defenses that prevent organisms access directly into our lungs.” The national average for prolonged ventilation after coronary artery bypass surgery is about 10%, Dr. Lobdelll said— meaning WakeMed’s rates are better than average. It appears that when programs improve early extubation rates, their prolonged ventilation rates also improve, he added.

“The importance of focusing on a single important metric, like early extubation, is commonly overlooked in clinical medicine,” Dr. Lobdelll said. “It indicates that a team has mitigated risk and improved operations, since it requires proper selection of patients for surgery, along with timing of operation and sound technical performance in the operating room, as well as a reliable process to extubate in the ICU. It is not simply removing endotracheal tubes early.” —Kate O’Rourke

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The only thing on which researchers seem to agree is that more research is needed. To Wait … In one analysis (abstract 395), researchers searched 13 databases from 1980 to October 2013 to identify studies of ICU patients requiring prolonged mechanical ventilation for 24 hours to 21 consecutive days. Fifteen studies were included in the meta-analysis, and investigators divided patients into two cohorts. Patients who had a tracheostomy within seven days of intubation were considered to fall into the early tracheostomy cohort (n=1,166). The late tracheostomy cohort consisted of patients who had a prolonged period of endotracheal intubation with the potential for a tracheostomy to be placed after seven days (n=1,214). In the late cohort, 797 patients never received a tracheostomy. The investigators found no difference in mortality between the two groups of patients. “Tracheostomy within the first seven days of mechanical ventilation is not associated with improved outcomes, whilst the increased procedure rate could result in short and long-term complications,” said Tamas Szakmany, MD, PhD, a consultant in intensive care and anesthesia at Cardiff University, in the United Kingdom, who presented the results. “The striking finding is that in those studies where patients had the option of late tracheostomy, only a small proportion actually received it. They were extubated and weaned or died before the late tracheostomy could happen.” Although patients receiving early tracheostomy also received less sedation, this did not translate into an earlier weaning from the ventilator. According to Dr. Szakmany, y early tracheostomy should be avoided.

performing a tracheostomy after intubation for prolonged mechanical ventilation (abstract 364). Bess Storch, MD, a resident from New York University conducting research at Weill Cornell Medical College, in New York City, presented the results. Dr. Storch and her colleagues analyzed records for all hospital admissions involving an insertion of an endotracheal tube (ETT) and a temporary tracheostomy in New York, California and Florida, between 2006 and 2011. The patient sample was derived from state and federal databases. Of the 1,070,213 patients identified who received an ETT, 8.8% underwent a temporary tracheostomy placement, with a median interval of 11 days between the two procedures. In-hospitall mortality peaked as the interval between ETT insertion and tracheostomy placement widened, the researchers found, with a proportional increase of 96.5% (14.5% to 28.4%) as the interval increased from days 1 to 20. The likelihood that patients would be discharged home decreased from 13.2% to 3.9%, as the interval from intubation to tracheostomy increased from days 1 to 20. “This is a retrospective study, and there certainly could be selection differences in these patients as the time interval increases that could account for some of the results,” said Kane Pryor, MD, director of clinical research and director of education at Weill Cornell, and a member of the study team. “It would be stretching at this point to say clinical practice should change based on the work that we have done. Nonetheless, we feel that this study should be a piece of information that is used to help drive further study.” If further analysis suggests that differences in morbidity cannot account for the results, Dr. Pryorr said, Weill Cornell clinicians would integrate that information into their decision making.

attended the Triologic Society annual meeting, where researchers presented a retrospective review of an inpatient sample in which early tracheostomy was defined as less than 10 days. “Their conclusion was that early tracheostomy is associated with improved mortality, length of stay and charges,” Dr. Bhatti said. The definition of early tracheostomy is also problematic. The meaning of “early” has ranged from insertion within 48 hours to up to 10 days. Definitions of “late” have ranged from eight to 28 days. “My frustration is that there is not a universal definition of what early tracheostomy is, whether it is within the first four days or seven days or 10,” Dr. Bhatti said. His group has published data showing that early tracheostomy in patients who were mechanically ventilated in a neuro-intensive care setting is beneficial ((Anaesth Intensive Caree 1997;25:365-368). Last spring, the Journal of the American Medical Association published results from a randomized clinical trial, conducted between 2004 and 2011, that addressed the tracheostomy timing issue (2013;309:2121-2129). The study involved 909 adult patients who were breathing with the aid of mechanical ventilation for less than four days and were identified by their physician as likely to require at least seven days more of mechanical ventilation. Patients were randomized to receive early tracheostomy within four days, or late tracheostomy after 10 days if still indicated. Early tracheostomy was not associated with improvement in 30-dayy mortality or other important secondary outcomes. The study also concluded that “the ability of clinicians to predict which patients required extended ventilatory support was limited.” “This is a very controversial subject,” Dr. Bhatti said. “My personal bias is toward early tracheostomy, but I completely understand that the jury is still indecisive about whether early tracheostomy is beneficial or not.”

Lack of a Standard Or Not To Wait Nasir Bhatti, MD, director of the Johns Hopkins —Kate O’Rourke In a second study presented at the meeting, an anal- Hospital Adult Tracheostomy and Airway Service, ysis of community hospital data suggested that in- said studies have shown conflicting results about the Drs. Szakmany, Storch, Pryor and Bhatti reported no relevant hospitall mortality increases the longer clinicians delay benefits of early versus late tracheostomies. He recently disclosures.

Opioid Prescriptions Common for Pregnant Women

ore than 14% of pregnant women in a recent study received an opioid prescription for pain at some point during their pregnancy. The study results, posted in the online version of the journal Anesthesiology, y left its researchers “surprised,” and calling for further study to accurately assess the risk to unborn children. Using a commercial insurance plan database of more than 530,000 women, investigators assessed the pain treatment given during pregnancy between 2005 and 2011. Specifically, they looked at each type of pain treated with opioids and how frequently prescriptions were written and filled both regionally and overall. Of the 76,742 women included in the study (average age, 31 years), 14.4% received opioid prescriptions during their pregnancy, most for short durations (less

than a week in most cases). Opioids were prescribed in the first and second trimesters in 5.7% of the women, and 6.5% were prescribed opioids in the third trimester. More than 2% of the women were prescribed opioids at least three times during pregnancy. Thirty-seven percent of opioids were prescribed for low back pain. Other conditions treated with opioids included abdominal pain, migraine, joint pain and fibromyalgia. “Nearly all women experience some pain during pregnancy,” said Brian Bateman, MD, MSc, assistant professor, Harvard Medical School, in Boston, and study author, in a written statement. “However, the safety of using opioids to manage their pain remains unclear. Ultimately, we need more data to assess the risk–benefit ratio

of prescribing these drugs to women and how it may affect their babies.” American Society of Anesthesiologists Committee on Obstetric Anesthesia Chair Edward A. Yaghmour, MD, stressed that careful assessment of treatment is needed to reduce risk to mother and child, as is first-line treatment with something other than opioids whenever possible. “We would never stop giving antiseizure medication or medication for diabetes,” he said. “The danger in those situations is clear. With opioids, there are simply not enough data to have a clear answer. Untreated severe pain in the mother may also be harmful to the fetus.” The researchers further found that rates of opioid use during pregnancy are “significantly higher” in the United States than in Europe. In the United States, use peaked in the South and was at its lowest point in the Northeast, they noted. Commenting on the study online for Anesthesiology, Pamela Flood, MD,

professor of anesthesiology, Pain and Perioperative Medicine at Stanford University, Stanford, Calif., stated that “the risk to the fetus of short-term exposure to prescription opioids under medical supervision is difficult to assess and needs to be carefully examined in future studies.” Studies conducted in the late 1950s through the 1980s found little evidence of a link between opioid use and birth defects. The 1997-2005 U.S. National Birth Defects Prevention Study showed connections between the use of opioids, specifically codeine, and birth defects (e.g., atrial and ventricular septal defects, hypoplastic left heart syndrome, spina bifida, gastroschisis in newborns). The National Birth Defects Prevention Study also found longterm use during pregnancy to be a known risk for neonatal opioid dependence. —AN Staff Based on a press release from Anesthesiology.

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Ultrasound: The New Standard of Care for Percutaneous Dilatational Tracheostomy?

eal-time ultrasound guidance during percutaneous dilatational tracheostomy (PDT) can decrease the rate of significant complications, Michigan researchers have found. The study showed that patients who received ultrasound-guided PDT were 10 times less likely to experience a problem related to the procedure as those who had the conventional approach. Experts said the eight-year retrospective chart review suggests that ultrasound should become a routine part of PDT, and possibly the standard of care. “I think there is very little reason not to add ultrasound to the other tools we use today to make tracheostomy safer,” said Krishna Rajajee, MD, associate

professor in neurosurgery and neurology at the University of Michigan Medical School, in Ann Arbor, who helped conduct the study. Dr. Rajajee presented the findings at the 2014 annual meeting of the Society for Critical Care Medicine (abstract 365). Since the introduction and widespread acceptance of percutaneous techniques in the ICU setting, the number of critically ill patients undergoing tracheostomy has increased steadily. The procedure, however, is not without risks. A study estimated that one in 600 patients who undergo PDT die from the procedure (Crit Caree 2013;17:R258). Early complications of PDT include bleeding, loss of airway, injury to anatomic structures, too high or too low placement, infection and dislodgement. Late complications include tracheo-innominate fistula, tracheal granuloma, tracheomalacia, tracheal stenosis, and tracheoesophageal and trachea-cutaneous fistulas. Real-time ultrasound can help clinicians maneuver around vascular structures, cannulate at the correct level and confirm the position of the guide wire (Figure). It also can help clinicians measure the distance between the skin and the anterior tracheal wall, assess the need for an extended length of tube, and appropriately position the endotracheal tube. Until now, however, there was little evidence that ultrasound can improve clinical outcomes when it is added to bronchoscopy in patients undergoing PDT. In the new study, the researchers reviewed the medical records for all PDTs performed between July 2005 and July 2013 in the neuro-ICU at the University of Michigan Health System. Patients with less than 30 days of follow-up were excluded from the study. In the majority of cases, residents and fellows performed the PDT under the supervision of an attending physician. Bronchoscopy was used in all cases. Real-time ultrasound guidance, left to the discretion of the attending physician, was used in 107 patients. Roughly one-third of the Figure. Top: Sonographic view of the trachea in axial section patients (32%) had clotting disordemonstrates the needle (arrow) at the anterior tracheal wall ders, cervical spine immobilization, in real-time. Real-time guidance facilitates tracheal puncture at morbid obesity, previous trachethe desired level in the midline. Bottom: Sonographic duplex ostomy and unfavorable anatomy, image of the trachea in axial section demonstrates the inferior which put them at risk for worse thyroid veins on either side of the midline. Imaging in real-time outcomes with PDT. may facilitate avoidance of injury to vascular structures in the The primary outcome was a coagulopathic patient undergoing percutaneous tracheostomy. composite of 11 complications,

Table. Composite of 11 Complications Related to Nonuse of Ultrasound in PDT • • Bleeding • Infection • Posterior wall injury • Pneumothorax/Pneumomediastinum • Inability to complete procedure • Conversion to surgical tracheostomy • Early dislodgement • Need for revision of tracheostomy • Tracheoinnominate, trachea-esophageal or trachea-cutaneous fistula • Tracheomalacia, tracheal stenosis PDT, percutaneous p dilatational tracheostomyy

including loss of airway during the procedure, bleeding, infection and posterior wall injury (Table). Patients who did not receive ultrasound were 10 times more likely to experience complications as those who received it (95% confidence interval, 1.2-86.2; P=0.032). With the current evidence, Dr. Rajajee said, all clinicians should use ultrasound when performing PDT. Despite this, he acknowledged that randomized clinical trials are needed to determine if ultrasound should be the standard of care, as it already is with central venous catheter placement. “As with any other procedure, this particular technique of tracheostomy does require a minimum number of supervised attempts before an operator becomes comfortable with the relevant anatomy on ultrasound and the procedure itself,” Dr. Rajajee said. Nasir Bhatti, MD, director of the Johns Hopkins Hospital Adult Tracheostomy and Airway Service, in Baltimore, applauded the study design and said he supported the use of ultrasound by nonsurgeons, such as intensivists and pulmonologists, performing PDTs. “I see an increasing trend in the use of ultrasound for tracheostomies,” Dr. Bhatti said. “But because we use video bronchoscopy for this procedure and we take other precautions to make the procedure safe, we don’t use it. It’s like belts and suspenders. If you have a belt, then you don’t necessarily need to use the suspenders.” Dr. Bhatti said for clinicians who have less experience, however, ultrasound makes sense. “For teaching institutions and in situations where people don’t have extensive experience with these procedures, I think one has to consider using ultrasound [for PDT],” he said. —Kate O’Rourke Drs. Rajajee and Bhatti reported no relevant disclosures.

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References 1. Wong CA, Ratliff JT, Sullivan JT, et al. A randomized comparison of programmed intermittent epidural bolus with continuous epidural infusion for labor analgesia. Anesth Analg. 2006;102:904-909. 2. Leo S, Ocampo CE, Lim Y, et al. A randomized comparison of automated intermittent mandatory boluses with a basal infusion in

combination with patient-controlled epidural analgesia for labor and delivery. Int J Obstet Anesth. 2010;19:357-364. 3. Capogna G, Camorcia M, Stirparo S, et al. Programmed intermittent epidural bolus versus continuous epidural infusion for labor analgesia: the effects on maternal motor function and labor outcome. A randomized

double-blind study in nulliparous women. Anesth Analg. 2011;113:826-831. 4. Hogan Q. Distribution of solution in the epidural space: examination by cryomicrotome section. Reg Anesth Pain Med. 2002;27:150-156.

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Study Finds Gaps in Knowledge of Opioid-Induced Constipation

ore than 3% of all Americans use opioids for chronic pain relief, and many experience constipation as a side effect. When opioids interact with the gastrointestinal tract, the drugs can trigger opioid-inducedd constipation (OIC), which poses a serious obstacle to effective pain management. However, data from a recent study showed that about half of physicians who prescribe opioids for long-term use do not prescribe prophylaxis for OIC. “Constipation is a top side effect” of opioid use, said study author Sharon Hwang, MD, MPH, medical director of CE Outcomes, a health care research firm in Birmingham, Ala. “Among surveyed clinicians, there was a lot of varied understanding of OIC,” she said, specifically citing differences in knowledge of the condition between nurse practitioners, primary care physicians and pain specialists. The results of these surveys were presented at the 2013 PAINWeek meeting (abstract 54). With support from Takeda Pharmaceuticals, which is developing a drug, Amitiza, for the market, Dr. Hwangg posed a series of questions to clinicians to ascertain their perceptions of OIC. Based on responses of more than 300 health care professionals, Dr. Hwangg and her colleagues observed “many gaps in the care of patients with chronic pain and OIC.” For example, they found that only half of primary care physicians and pain specialists regularly

prescribe a prophylaxis regimen for opioid users. Alternatively, about three-fourths of nurse practitioners prescribe prophylactic medication to long-term opioid users more than 40% of the time. Dr. Hwangg noted that some survey respondents had not considered OIC as a side effect of treatment with opioids. She believes that nurse practitioners, by virtue of the increased time they spend with patients, are the most likely to recognize OIC and prescribe prophylactics accordingly. “You have to ask the right question,” to determine if patients are suffering from OIC, Dr. Hwangg said— and not all clinicians take that step. “The first step is making everyone aware this is a big issue,” said Gyanprakash Ketwaroo, MD, a gastroenterologist at Beth Israel Deaconess Medical Center, in Boston. “There are multiple approaches, but no real comparison studies yet.”

effects of OIC. In the first year of the trial, 29 palliative care patients were eligible for the initiative; of these, 25 (86%) had bowel movements within 72 hours after treatment (PAINWeek 2013, abstract 33). The second trial demonstrated similar results, with 24 of 31 patients achieving laxation within 72 hours.

‘The first step is making everyone aware this is a big issue.’ —Gyanprakash Ketwaroo, MD

Once a regimen is recommended, clinicians at Abington Memorial Hospital rely on several techniques for treating OIC. A typical regimen begins with the use of a stimulant and stool softener combination. Depending on the patient, Dr. Foyy said, she might titrate up to nine tablets of senna per day— Prophylaxis Pays Off three tablets, three times daily. One approach to managing OIC is under way “Most people wouldn’t think of going that high,” at Abington Memorial Hospital, near Philadelphia, Dr. Foyy said, but she maintains that it is a safe and where Maria Foy, PharmD, a clinical specialist in effective way to manage constipation. If laxatives are insufficient, next steps include tap pain management, has enacted a prophylactic bowel regimen in the palliative care unit. water enemas and suppositories. After 72 to 96 hours Over two yearlong trials, from November 2011 to of constipation and failure of rectal treatments, cliFebruary 2012 and April 2012 to March 2013, clini- nicians may administer methylnaltrexone (Relistor, cians carried out the regimen, aimed at reducing the Salix).

Following a Surgical Checklist Improves Patient Care Study shows OR form leads to changes that avoid morbidity

he minority of U.S. hospitals may be using surgery checklists, but doing so in the operating room immediately before a procedure can have a significant effect on patient safety, recent research shows. A review by investigators at Georgetown University in Washington, D.C., found that nearly half of 233 patients had changes to their care as a result of the checklist. As the World Health Organization (WHO) suggested, checklists lower mortality and morbidity by reducing the number of communication failures and promoting proactive and collaborative team communication. “Many of us have read ‘The Checklist Manifesto’ by Atul Gawande,” said Brent A. Gilmore, MD, a resident at Georgetown. “It made me realize that we should start looking into the utility of our department’s checklist. We use one that is very similar to that proposed by the WHO. So although the idea of a checklist wasn’t necessarily new for us, we wanted to find out if it

changed anything in terms of patients’ care.” Dr. Gilmore and his colleagues noted if a change was made to the patient’s intraoperative management based on the use of the checklist. Types of changes were identified, along with how such changes affected postoperative course and resultant patient outcomes. As Dr. Gilmore reported at the 2013 annual meeting of the International Anesthesia Research Society (abstract S-275), 113 of the 233 patients (48%) had changes made to their care as a result of the checklist; the total number of changes was 132. The majority of changes to care occurred when antibiotics were held or administered (73 of 132). Changes made related to anemia, involving type and screen or transfusion, also were common, comprising 27 of the 132 changes. Other observed care changes included modifications made regarding anticoagulation; β-blockers being held; and a category labeled “other.” Finally,

Brent A. Gilmore, MD.

allergies were identified as triggering seven of the 132 changes (5%). “Given our results, I find it concerning that only about 20% of hospitals in the United States are using some version of the safe surgery checklist,” Dr. Gilmore said, “because we know that there’s information out there from many other technical fields that

shows that we can benefit from using a checklist. Certainly we shouldn’t feel above having to go through a form to improve communication and standardization just because we’re doctors. “Although antibiotics changes were the most common, a fair criticism was that we were only looking at patients in our limb salvage center,” Dr. Gilmore

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CL IN ICA L A N E STH E SIOL OG Y For example, when she encounters a patient who hasn’t had a bowel movement in about 10 days, Dr. Foy said, “I will use Relistor right off the bat.” Although effective, methylnaltrexone is a restricted-use drug at Abington Memorial Hospital because of its cost. The average price for a single-use vial of methylnaltrexone is $48, and a seven-dose kit is $336 ((Am Fam Physician 2010;82:678-681). The high cost of laxatives isn’t the only way that OIC can put a squeeze on budgets. Based on a retrospective review of Medicare and commercial claims data from more than 16,000 chronic opioid users, researchers at Pharmerit International in Bethesda, Md., and Takeda found that patients who developed OIC had higher than average health care costs compared with patients without constipation. The average annual cost of health care (including inpatient and outpatient care) for a nonelderly patient with OIC was more than $23,000, significantly higher than the $13,000 average annual cost for a patient without OIC (P<0.001; PAINWeek, abstract 133). The same study revealed that clinicians prescribed laxatives to significantly more patients with

added. “So this is a group of patients where it makes sense that there were frequent changes in antibiotics. That being said, if it wasn’t for the formal checklist and a structured conversation between surgery and anesthesia, they may have been missed.” One of the shortcomings of the study—and of checklists in general— is that the forms can filled out without the items being completed, said Yiliam F. Rodriguez, MD, assistant professor of clinical anesthesiology at the University of Miami, in Florida. “People could just go through and it would be difficult to tell if they actually performed the items or not. Nevertheless, at our institution we take these checklists very seriously.” But Dr. Gilmore said his group had evidence that clinicians were not simply going through the motions. “We had situations where we picked up allergy discrepancies in the OR during the time-out that we hadn’t before,” Dr. Gilmore said. “So that’s someone who has already gone through preoperative screening; everyone’s talked to the patient, but they’re still making it to the OR and the allergy is only being recognized during the checklist.” —Michael Vlessides

OIC compared with non-OIC patients (8.8% vs. 0.8%, respectively; P<0.001). The Pharmerit and Takeda researchers also found that the incidence of OIC among chronic opioid users without cancer ranges from 2.9% among nonelderly patients to 6.6% among elderly patients, and up to 15% in long-term care patients without cancer.

Clinicians should try to do more, he said, to increase awareness about OIC. As a gastroenterology fellow, he receives a “fair amount” of tertiary care referrals for OIC, but practitioners in community care may not be as cognizant of the side effect, he said. “Everything has its own side effects,” Dr. Ketwaroo said. “Can we minimize the number of opioids we are prescribEye-Opening Findings ing? I think that’s a fair question to ask.” Dr. Ketwaroo described the prevaHalf of the clinicians who spoke lence of OIC as “somewhat eye-opening.” with Dr. Hwangg voiced concern that

constipation or sedation, as side effects of treatment with opioids, would result in poor adherence or discontinuation of the drugs for long-term pain management. “If we can control constipation in clinical opioid use,” Dr. Hwangg said, “we can optimize patient adherence.” —Ben Guarino Drs. Ketwaroo and Foy reported no relevant financial conflicts of interest. Dr. Hwang, as an employee of CE Outcomes, received support from Takeda Pharmaceuticals.

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Postoperative Pain Management in Anorectal Surgery New Techniques: Antidotes or Anecdotes—the Surgeon’s Perspective

norectal surgery: often a painful cure; and worse, the performance of the curative operation is only 50% of the battle. Sleepless nights await both the patient and the surgeon once the cure has been inflicted. Postoperative pain relief represents the other 50% of the battle. Thirty-five million ambulatory surgical procedures are performed annually in the United States.1 Effective pain control is essential for recovery, improved wound healing and reduced hospital admission rates. In evaluating hospital admission data for 20,817 patients undergoing same-dayy surgery, 1.5% returned to the hospital in the postoperative period.2 Pain was the most common reason. There has been little progress in addressing this challenge.

Can We Do Better? Surveys from 1993, 2003 and 2012 have demonstrated that postsurgical pain is common and that a similar distribution of the quality of perceived pain has remained unchanged.3-5 Patient pain scores are now being used as metrics in measuring the adequacy of care. Surveys from the Hospital Consumer Assessment of Healthcare Providers and Systems during 2008 and 2009 confirmed the need for improving postoperative pain management. Mean pain management scores were 68 of 100 in 3,765 participating hospitals. The government and other third-party payors may use data of this type in determining reimbursement rates. Surgeons and hospitals alike are being pushed to demonstrate improvement. Educating Patients Several areas of improvement can help to reduce postsurgical pain. A first line of defense involves managing patient expectations. Patient education goes far in this regard. Preoperatively, patients should be advised that their postoperative discomfort may occur along a spectrum of intensity, and that their pain intensity and frequency may change constantly until healing is final. Allowing patients to “prepare for the worst” actually helps with their expectations rather than hinders them. A frank discussion about postoperative pain management options reassures patients and helps them to understand that relief is available. With the advent of newer pain management techniques, procedures are available that may allow for sophisticated postoperative strategies to handle any discomfort. Transdermal patches, epidural injections and new oral pain medications are but a few strategies that will allow the patient and the surgeon to sleep in the days and weeks following anorectal surgery. A preoperative consultation with a pain management specialist may be worth its weight in sleep. Initiating the use of stool softeners before the operation may help in easing the pain of the first postoperative bowel movement. Educating the Operating Team Urinary retention is the bane of the anorectal surgeon. The discomfort of urinary retention adds to the pain from the operation. It is recommended that

the operation be performed using a safe but limited volume of IV fluids. Should retention be encountered postoperatively, an attempt to void while sitting in a warm tub may be all that is necessary to achieve symptomatic relief. However, prolonged urinary retention may worsen matters and might indicate a more serious underlying problem. Patients should be instructed to contact their surgeon earlier rather than later in their course.

to opioids have been reported in 12% to 48% of patients.6 In the inpatient setting, opioid-related AEs account for a 3.3-dayy increase in hospital length of stay. Several options exist to help decrease the dependence on narcotics. Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP) have been shown to help control postoperative pain. NSAIDs may be started before surgery and continued through the recovery period. Many studies have demonstrated a diminution in pain scores when up Educating the Surgeon to 1,000 mg of APAP, 600 mg of ibuprofen or 30 mg Another area of improvement has evolved through of intravenous ketorolac were given immediately after the efforts of surgeons and industry working together surgery.7 NSAIDs aid in reducing and managing the to develop less traumatic procedures. An example of inflammatory response. Cyclooxygenase-2 inhibithis collaboration has been in the area of the hem- tors, ketamine, clonidine and steroids also have demorrhoidectomy. Procedure for prolapse and hem- onstrated benefit. Many surgeons have patients begin taking NSAIDs preoperatively pre and continue taking the medication m throughout the recovery peeriod. As NSAIDs may be To date, 100% of our associateed with postoperative bleedpatients have been ing, th heir use must be evaluated with h a preoperative assessment almost pain-free for of vvarious patient risk factors. SSome institutions are using the entire six-day gaabapentin/pregabalin in f -track recovery protofast period. Opioid use ccols for abdominal surgery. SSeveral studies have demhas been minimal oonstrated that administering i 1,200 mg of gabapentin both during the sixorr 300 mg of pregabalin preday period and after operatively yields a decrease in addjunctive narcotic requirethe six-day period. ments.8 Some surgeons will administer the medication for up to two to three days postopeeratively. Larger doses have orrhoids (PPH) and transarterial nsarterial hemorrhoidal been associated with sed sedation and dizziness. There dearterialization (THD) have been associated with are no established studies evaluating the use of these diminishing, although not vanishing, postoperative medications after anorectal surgery. Anecdotal pain. Procedures such as these are performed proxi- reports abound, however, testifying to their effectivemal to the dentate line and result in less pain because ness. This is an area ripe for larger, randomized trials. of the paucity of pain fibers in this region. These Local Pain Control: The Basics procedures require careful patient selection and are Any anesthetic agent that is able to inhibit the best suited for stage II/III hemorrhoids with prolapse and a limited external hemorrhoidal compo- excitatory process in the nerve ending will block the nent. When PPH and THD are compared with perception of pain. The nerve membrane is a lipid the Milligan-Morgan technique for stage IV hem- and protein structure. The two key elements in pain orrhoids, the duration and depth of pain after the control are the anesthetic potency and duration of excisional hemorrhoidectomy (Milligan-Morgan action. These are related to the lipid and protein technique) is typically longer and more severe. structure of the nerve membrane. Anesthetic potency Although considered to be an advance in hemor- is correlated with lipid solubility. Anesthetic durarhoidal operations, the adoption of these newer tion is related to the degree of protein binding at the techniques has been slow because special training is membrane level, with a longer duration of anesthesia required. being the result of a greater binding activity. Both pH and the type and size of the nerve fibers Traditionally, multimodality and multidisciplinary pharmacologic techniques have been used to help in also play roles in the anesthetic effects of various the management of the patient’s recovery. Opioids agents. Local anesthetics are more effective in more have been a cornerstone in the management of postop- basic pH environments. Smaller nerves with lighter erative pain. However, narcotics may be accompanied myelin coatings are more easily blocked than are by numerous well-known adverse events (AEs) such as larger, more heavily myelinated nerves. Pain is most nausea, vomiting, constipation, respiratory depression, commonly the first sensation to be blocked and the ileus, itching and dependence/tolerance. AEs related see anorectal page 36

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last to recover, followed by temperature sensation, touch and pressure. Anesthetic agents can be degraded by hydrolysis or enzymatic activity. As bupivacaine is metabolized slowly, its anesthetic effects are longer lasting. Lidocaine is rapidly metabolized and is a short-actingg agent. These two drugs are the most common local anesthetic agents used in anorectal procedures.

Local anesthetics are used routinely and are extremely effective for completely blocking pain sensation intraoperatively. Administered in the form of a pudendal block, coupled with direct injections into the operative sites before beginning the operation, local anesthetics also are effective in managing pain in the postoperative setting. Their benefit, however, is limited by their duration of effectiveness. Bupivacaine and lidocaine have established durations of action of less than

12 hours, even with the use of epinephrine. Because of this, there have been attempts to improve the duration profile of local anesthetics. Elastomeric pain pumps and catheter systems have been shown to help ameliorate the pain for several days postoperatively. Ideally, the pumps should deliver a steady dose of the anesthetic for one to seven days, depending on the size of the pump. However, there have been technical problems reported, including catheter dislodgement and infections.9

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Epidural anesthesia is a reliable way to ensure a pain-free postoperative recovery. The catheters can remain in place for up to five days after a procedure. Although most often used in the hospital setting, it is theoretically possible to use this type of system on an outpatient basis. Adoption of this technique has been hampered by the need for periodic infusion of the anesthetic, catheter dislodgement, various systemic side effects and the potential for a delay in the diagnosis of a possibly serious catheter-related infection. The topical application of local anesthetics is of marginal and unpredictable efficacy. A Leap Forward? More Basics Liposomal depot formulations of bupivacaine have shown promise in the management of postoperative pain.10,11 Liposomes are laboratoryprepared, microscopic lipid bilayer membranes that encapsulate an aqueous core. A lipid bilayer is essentially a double-thickness layer of phospholipid molecules. Each of the two layers is one molecule in thickness. This duallayer system is common in nature and serves to keep substances positioned where they are needed, thus preventing these substances (proteins or ions) from diffusing away from their target area. Cell membranes are composed of lipid bilayers. The idea behind using a liposomal system is that the liposomes can be formulated into a multivesicular system, with the active anesthetic agent being held in each vesicle and slowly released to the target area over time. The anesthetic agent, bupivacaine, is not new; the delivery system is the apparent innovation. The anesthetic system is marketed under the name of Exparel (Pacira Pharmaceuticals). The microvesicular liposomal preparation theoretically results in a drug release pattern showing an increased stability and a prolonged duration of medication release. The pharmacokinetics result in a sevenfold increase in the Tmax, and a 9.8 times increase in the halff life of the medication. The manufacturer states that the medication has a duration of up to 72 hours of delivery and effectiveness. The onset of action is immediate, as there is free bupivacaine in the solution along with the microvesicular preparation. The Antidote? Recent FDA approval of the liposomal bupivacaine formulation has been granted for use in hemorrhoidectomies and bunionectomies. Gorfine et

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CL IN ICA L A N E STH E SIOL OG Y al performed a multicenter, doubleblind, placebo-controlled study in patients undergoing hemorrhoidectomies.12 The use of 300 mg of the liposomal bupivacaine was compared with a saline placebo, and evaluated over a period of 72 hours. Pain intensity scores were significantly lower in the extended-release (ER) group versus the placebo group. At 12 hours, 59% of patients in the ER group were opioidfree compared with 14% in the placebo group. At 72 hours, 28% of patients in the ER group were opioid-free compared with 10% in the placebo group. In patients requiring opioids, median time to first use was 14.3 hours in the liposomal bupivacaine group compared with 1.2 hours for the placebo group. Ultimately, a 30% reduction in cumulative pain and a 45% reduction in opioid consumption were seen in the study. The safety profile of the formulation has been studied in dose levels of 66 to 532 mg (with the FDAapproved dose at 266 mg), and cardiac safety has been demonstrated in supratherapeutic doses as high as 665 mg in healthy volunteers. Studies evaluating ER bupivacaine in the setting of open and laparoscopic colectomies, ileostomy reversal, breast augmentation, inguinal hernia repairs and total knee replacement demonstrated similar favorable results.13-17 It seems that the medication may be of benefit in many procedures requiring the use of local anesthesia. Practical Considerations Liposomal bupivacaine comes in single-use 20-cc vials containing 266 mg of bupivacaine that must be stored between 36 F and 46 F. A temperature indicator will change from green to white if the medication has been exposed to excessively low or high temperatures. The medication may be stored at room temperature for up to 30 days. The liposomal structure may be altered if the preparation is exposed to lidocaine or other anesthetics, and liposomal bupivacaine should not be mixed with other preparations. Liposomal bupivacaine may be used without dilution or may be mixed with up to 280 cc of preservative-free, sterile saline. It should not be diluted with water or any other hypotonic solution that might disrupt the delivery system. The profile of AEs for liposomal bupivacaine is that of the parent drug, bupivacaine, and clincians must be familiar with the AE profile and treatment of bupivacaine-related AEs.

The Anecdote About the Antidote: Curbside Consultations and Operating Room Experience The use of liposomal bupivacaine has been the topic of many surgical lounge discussions and intraoffice surgical debates. As Exparel is expensive, much thought has gone into the decision to purchase and use it clinically. We have discussed this topic with colleagues, drug representatives and the surgeons in our group. We decided to

try liposomal bupivacaine in our own, unscientific trial. Our results have been impressive. Our protocol has been to administer the medication in the more dilute form using a pudendal block and a local infiltration in the perianal area and around the anal verge. The medication is typically diluted 2:1 and infiltrated just after the surgical time-out is performed, with the patient under IV sedation. We have not experienced any anesthetic failures during the

intraoperative period. At the conclusion of the procedure, a bolus of 30 mg ketorolac is given by IV route to those patients without any contraindications to its use. In the first three postoperative days, no oral or other adjunctive medications are used unless the patient feels the need for supplemental pain relief. After three days, patients are given ketorolac, 10 mg orally every six hours for 12 doses. To date, 100% of our patients have been almost pain-free see anorectal page 38

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C LIN I C A L A N ES THES IO LO G Y The Tale of the Traveling Salesman Perhaps most interesting is one of for the entire six-dayy period. Opioid use has been minimal both during the our patients, a traveling salesman. He six-dayy postoperative period and after was due to leave town immediately the six-dayy period. In all of our cases, after his office visit, for an important the operative anorectal procedures three-day sales trip. The pain from have been extensive. We have not used his acute thrombotic hemorrhoid liposomal bupivacaine in procedures had almost crippled him. Because of that we considered to be of a minor his impending trip, he was not amenature. nable to surgical drainage or removal. Our patients have not experienced He was desperate for pain relief and any AEs. refused to consider canceling his trip.

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He was offered an injection of liposomal bupivacaine and he agreed to try it. The medication was diluted to 40 cc and the local injection was made through a 25-gauge needle around and deep to the thrombotic hemorrhoid. The injection of most local anesthetics in an awake patient is uncomfortable at best and the salesman’s expletives attested to this. Fortunately his office visit was at the end of the day when no other patients were nearby to hear his rather loud

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comments during the injection. Yet, he left the office without any pain. He returned three days later in a mood bordering on euphoria. He had had no pain since the initial injection. Unfortunately for him, he lost the sale. Because he had incorrectly accounted for the time zone change during his flight, he arrived an hour late for his presentation and was denied a chance to make his pitch. This time, however, his expletives were directed at himself rather than the injection of analgesia. Surgeons cannot fix everything. Antidote or Anecdote? Judge for Yourself We have been happy with our results to date. Patients have been happy with their results to date. But our trial is only anecdotal. Although supported by clinical trials, our results may not be the same as those of other surgeons. Time and experience will be the final arbiter of clinical efficacy. But liposomal bupivacaine, although expensive, may be a useful medication in combating pain following anorectal operations. —Gary H. Hoffman, MD and Stephen Yoo, MD, Los Angeles Colon and Rectal Surgical Associates

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Dr. Hoffman is attending surgeon in the Dvision of Colorectal Surgery at Cedars-Sinai Medical Center, and attending surgeon in the Division of General Surgery and associate clinical professor of surgery at the David Geffen School of Medicine of the University of California, Los Angeles. He is a senior member of Los Angeles Colon and Rectal Surgical Associates. Dr. Yoo is attending surgeon in the Division of Colorectal Surgery at Cedars-Sinai Medical Center and associate clinical professor of surgery at the David Geffen School of Medicine. He is a member of Los Angeles Colon and Rectal Surgical Associates. The authors have no financial or other relationships with any of the manufacturers of any of the drugs mentioned in this review.

References 1.

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2. Coley KC, Williams BA, DaPos SV, et al. Retrospective evaluation of unanticipated admissions and readmissions after same day surgery and associated costs. J Clin Anesth. 2002;14:349-353. 3. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology. y 1995;83:1090-1094.

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4. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534-540.

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CLINICAL ANESTHESI OLOGY 5. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract]. Presented at: Annual Fall Pain Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine; November 15-18, 2012; Miami Beach, FL. 6. Oderda G, Gan T. Effect of opioid-related adverse events on outcomes in selected surgical patients. J Pain Palliat Care Pharmacother.r 2013;27:62-70. 7. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21:185-211. 8. Dauri M, Faria S, Gatti A, et al. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716-733. 9. Brown SL, Morrison AE. Local anesthetic infusion pump systems adverse events reported to the Food and Drug Administration. Anesthesiology. y 2004;100:1035-1037. 10. Chahar P, Cummings KC. Liposomal bupivacaine: a view of a new bupivacaine formulation. J Pain Res. 2012;5:257-264. 11. Candiotti K. Liposomal bupivacaine: an innovative nonopioid local anesthetic for the management of postsurgical pain. Pharmacotherapy. 2012;32:19S-26S. 12. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing a hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54:1552-1559.

13. Smoot JD, Bergese SD, Onel E, et al. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32:69-76. 14. Minkowitz HS, Onel E, Patronella CK, Smoot JD. A two-year observational study assessing the safety of DepoFoam bupivacaine after augmentation mammoplasty. Aesthet Surg JJ. 2012;32:186-193.

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15. White PF, Schooley G, Ardeleanu M. Analgesia following a single administration of depobupivacaine intraoperatively in patients undergoing inguinal herniorraphy: preliminary doseranging studies. Presented at: Annual Meeting of the International Anesthesia Research Society; March 14-17, 2009; San Diego, CA.

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16. Langford RM, Chappell GM, Karrasch JA. A single administration of depobupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair. Presented at: 62nd Postgraduate Assembly in Anesthesiology; December 12-16, 2008; New York, NY.

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17. Bramlett KW, Jones RK, Pink M, Pink T. A single administration of depobupivacaine intraoperatively provides analgesia and reduction in use of rescue opiates compared with bupivacaine HCl in patients undergoing total knee arthroplasty [poster]. Presented at the XXXVI Biennial World Congress of the International College of Surgeons; December 3-6, 2008; Vienna, Austria.

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P OLI C Y & M A NAGEMENT

End-of-Life Wishes Often Unheeded

he known wishes of critically ill patients to not be resuscitated or placed on life support following heart failure or stoppage of breathing are frequently ignored, researchers have found. The study, presented at the 2014 annual meeting of the Society of Critical Care Medicine (abstract 720), could have implications for end-off life

care throughout the country, suggesting an urgent need for standardized protocols for documenting patients’ wishes, making them both easily accessible and legally binding. The study, which examined the outcomes of a small group at a teaching hospital in California, found that patients’ clearly stated wishes not to be resuscitated or placed on life support were not

followed in 21 of 35 cases. The most significant factors in these unwanted intubations were intervention by patients’ families to countermand their known wishes (nine cases), and an inability to locate documentation of patients’ wishes in a timely manner (eight cases). In three cases, family members or proxies who were aware of the patients’ wishes not to be resuscitated were not

Rationale, Reversal, and Recovery of Neuromuscular Blockade Part 1: Framing the Issues Case Study Harold is a 74-year-old man undergoing a video-assisted right upper lobectomy for stage I non-small cell lung cancer. Current Symptoms • Dyspnea • Coughing with hemoptysis • Chest pain Vital Signs • Height: 177.8 cm (70”) • Weight: 65 kg (143 lb) Signi¿cant Medical History • Hypertension • Chronic obstructive pulmonary disease (moderate) Current Medications • Metoprolol succinate ER 50 mg/d • Tiotropium bromide inhalation powder Laboratory Results • 2-cm lesion in right upper lobe revealed on chest computed tomography (CT) scan; malignancy con¿rmed with needle biopsy • No abnormal bronchopulmonary or mediastinal lymph nodes; brain CT, isotopic bone scan, abdominal ultrasonography negative for distant metastases • Forced expiratory volume in the ¿rst second: 43.6% of predicted value (1.44 L) • Carbon monoxide diffusing capacity: 71.7% of predicted values (20.19 mL/min/mmHg) • Cardiac ultrasonography: normal pulmonary artery pressure (22 mm Hg) At induction, Harold receives propofol 1.5 mg/kg and rocuronium 0.6 mg/kg. During the procedure, movement of the diaphragm interferes with surgery. This activity is jointly sponsored by Global Education Group and Applied Clinical Education. Supported by an educational grant from Merck.

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present at the time the decision to resuscitate was made. In the remaining case, the patient required immediate intubation before being able to discuss the decision with family members. “I’ve been working as a critical care nurse for six years, so I knew this was happening, but I was surprised at the number, and disappointed,” said Kelli Jackson, RN, of Santa Barbara Cottage Hospital, who led the study. “I had hoped we were respecting patients’ wishes.” A large part of the problem is that patients’ wishes, even when documented and legally binding, are not easily accessible. In California, for instance, a Physician Orders for LifeSustainingg Treatment (POLST) form serves both as a document of the patient’s wishes and a legal order for doctors to obey them. Unfortunately, even when hospitals employ electronic record keeping, locating a POLST or other advance directive in an emergency often is impractical. Streamlining this process is crucial to ensuring that patients’ wishes are respected at the end of life, the researchers said. “In our medical records now, it’s quite easy to see the code status. If we click into the patient’s records, the code status, if it is known, is at the top in red,” Ms. Jackson said. “And the documents are more accessible. We can click on their code status, and it will take us to the advance directive we have on file.” More importantly, Ms. Jackson emphasized, patients’ family members or proxies need to take a more active role in the decision-makingg process at an earlier stage. “The big thing that came out of this is the piece of paper is not the answer,” she said. “Whoever’s going to be at their bedside making those decisions at push time—those are the people who need to be involved in creating the POLST or creating the advance directive.” The study highlights the need for the POLST form, or something like it, to be legally binding at the national level, said Theresa Brown, RN, a Pittsburgh area nurse who contributes to the “Well” blog for The New York Times. “If you had a stronger legal base, and if the POLST form was nationally recognized as a legally valid document, that would be helpful to hospital staff because then they could work with the family about the difficulty of that person dying,” Ms. Brown said. “But it’s such a muddle now, and that’s why you get so many of these situations where someone shows up, and you don’t know what their paperwork is.” —Ajai Raj

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POL ICY & M A N A G E ME N T

Does “Safe Use” for Epidural Steroid Injections Miss the Point?

he “Safe Use Initiative” is a program from the FDA to develop consensus among practitioners on the safe use of medications. The results of the Safe Use Initiative on epidural steroid administration were presented at the 2013 annual meeting of the American Society of Anesthesiologists. But rather than developing a safer, more prudent approach, the process has been turned on its head. The result is not safe use but an excuse to continue a practice that has been documented to cause embolic phenomena and is inherently unsafe. Data presented at the meeting suggest that the incidence of embolism caused by particulate steroids is approximately one in 5,000. A small frequency—but a real number given the fact that epidural steroid injection is the most frequently performed interventional pain procedure in the United States. In contrast, dexamethasone, a nonparticulate solution, has not been associated with embolic phenomena. Reports in the literature demonstrate its therapeutic equivalence to the other epidurally administered steroids in common clinical use. Similarly, with respect to the deaths that have resulted from safe triangle transforaminal cervical injections, these have been reported with thoracic, lumbar and even caudal epidural injection of particulate steroids. While the culprit frequently has been the artery of Adamkiewicz, there is a fundamental gap in appreciation of the foramen anatomy: The safe triangle just isn’t. Although physicians attempt to avoid the nerve root by using the “safe” triangle for epidural steroid injections, encountering the radicular artery, which lies close to the spinal nerve, can occur even in the best of hands and using advanced techniques such as digital subtraction angiography. Many experts have suggested that Kambin’s triangle may be the safer approach here. Kambin’s triangle is defined as a right triangle over the dorsolateral disk. The hypotenuse is the exiting nerve root, the base (width) is the superior border of the caudal vertebra and the height is the dura/traversing nerve root. This artery can be found in any foramen and is always located in the superior and anterior aspect of the foramen—the same region in which the “safe triangle” approach calls for placement of the needle. When placed in the triangle, and even when all normal precautions are followed according to guidelines, the needle can damage or even completely sever the artery or an embolism can occur. The result can be severe complications, including paralysis, related to spinal cord see safe use page 42

ecently in my hometown of Charleston, W.Va., we had a chemical leak that contaminated our drinking water. It was a terrible time for more than 300,000 people and led to a period of distrust and confusion about what is safe how we should best care for our families. Should we consider drinking water from the tap, drilling a well, buying a water purifier or other alternative sources? I see some corollaries as we consider the safe use of steroids in the spine. The water issue for us in the beautiful mountain state is temporary, but unfortunately our time of confusion in pain treatment is constant and always tumultuous. I applaud the American Society of Anesthesiologists and other level-minded individuals for keeping calm and not contributing to fear and misinformation about the proper choice of steroids to treat chronic spinal disorders. As we move forward, we need to consider the picture as a whole and avoid tunnel vision that leads to long-term worsening of patient care. Clinicians should always keep in mind the risk for a complication with a particulate steroid. But to conclude that similar events cannot occur with local anesthetics or nonparticulate steroids is like hiding under a blanket and hoping the monster under the bed will lumber away into the night. We can agree that safety issues are always the most important things for us to consider as we take our greatest efforts to do no harm and help people who are suffering. Given an embolism rate of one in 5,000 transforaminal injections with particulate steroids, we cannot conclude that the drug was responsible for the events noted in the reports. In some settings, the events occurred secondary to local anesthetics injected into the cerebrospinal fluid causing cardiovascular collapse or from needles causing vasospasm and limiting blood flow to the spinal cord or brain. In fact, the true number may be much less, with some studies suggesting a rate of closer to one in 20,000 injections. If we further analyze these numbers, we also should consider physician training, use of fluoroscopic guidance and proper needle placement. In my career, I have been asked to review cases of death and severe complications from steroid injections, oral medications, intrathecal medications, implantable stimulation systems and minimally invasive surgeries. Although these often are in the settings of litigation defense or quality improvement see safe use page 42

CL A SSIF IE D S

The UNMC Department of Anesthesiology seeks applications for positions in a Critical Care Anesthesiology fellowship. The 12-month ACGME-approved fellowship will prepare anesthesiologists for successful clinical practice, board certification and leadership in critical care medicine. UNMC is a 624-bed Level 1 trauma center and a nationally recognized Center of Excellence in solid organ transplantation and hematologic malignancies. UNMC provides fellows with outstanding opportunities to develop expertise in all facets of critical care, including surgical, trauma/burn, cardiac surgical, cardiovascular medicine, general medicine, neurosurgical/neuroscience, extra-corporeal circulatory support and critical care ultrasonography/echocardiography. Applicants seeking a position starting July 2014 or July 2015 should contact the Program Coordinator and visit www.unmc.edu/anesthesia to download an application. Program Director: Daniel W. Johnson MD (dan.johnson@unmc.edu) Dept. of Anesthesiology, 984455 Nebraska Medical Center, Omaha, NE 68198-4455 Program Coordinator: Mary Bernhagen (mbernhagen@unmc.edu) 402-559-7370

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CONTINUED FROM PAGE 41

damage. The Safe Use Initiative does not effectively eliminate the use of this approach. The guidelines adopted by the Safe Use Initiative allow for the status quo to persist, even though the nonparticulate dexamethasone is not associated with any embolic Clifford Gevirtz, MD phenomena and animal studies attest to its safety even when injected intra-arterially. y It is this last point that is so startling. If you have an equivalent substitute with no demonstrable morbidity or mortality, what can possibly be the justification for allowing the continued use of particulates? Similarly, no one reports injuring the artery of Adamkiewicz using the translaminar approach. Is the slight benefit of using the transforaminal over the translaminar approach worth the risk for injury?

The purpose of the Safe Use Initiative is to produce the safest approach to therapy using the best evidence. The purpose of the Safe Use Initiative is to produce the safest approach to therapy using the best evidence. Here, the process has been turned on its head. The nonparticulate steroid dexamethasone has been shown to be safe and effective, and most importantly, not associated with fungal infections or embolic phenomena. Particulates and the transforaminal approach both have liabilities that can be easily avoided. If you have the opportunity to totally avoid a complication while still providing clear therapeutic benefit, then why would you as a clinician take the riskier course? The initiative did not address the compounding issue at all other than to detail the deaths so far, that is, no statement as to using only medication produced strictly under “good manufacturing” controls. It is incredibly important not to try to save a few pennies at the risk of our patients’ safety. I am sure that a tidal wave of malpractice suits awaits those clinicians who chose to save a few pennies by using the New England Compounding Center. Going forward, the best advice is to stick to large manufacturers with robust quality assurance programs. I would hope that physicians similarly concerned with these guidelines will write to Dr. Margaret Hamburg, the commissioner of the FDA (10903 New Hampshire Avenue, Silver Spring, MD 20993) to voice their concern that this process has led to an incorrect result. —Clifford Gevirtz, MD Medical Director, Somnia Pain Management, New Rochelle, NY Dr. Gevirtz is a member of the editorial board of Anesthesiology News.

SAFE USE

arterial injury and localinduced seizure can still result peer review, it is clear to me that any in patient morbidity and procedure can lead to poor outcomes death. despite great vigilance on the part of In addition to the debate on the clinician. To assume a change to use particulate versus nonparticuonly nonparticulate steroids will make a huge late steroids, we should focus impact on this issue is naive. on other important issues. The Having said that, in the cervical and thoracic recent disaster of contamispine it is in my opinion advisable to use non- nated compounded steroids particulate steroids. The reason behind this rec- causing fungal meningitis and Timothy R. Deer, MD ommendation is scientific and is based on the in some cases death must lead diameter of the feeder vessels in the cervical and us to avoid this type of practice in the future. The thoracic spine. The size of the particles in partic- need to compound steroids should be critically conulate steroids such as triamcinolone, betametha- sidered because well-established, FDA-regulated sone and methylprednisolone can be as large as or companies make these drugs in the usual fashion. In larger than the diameter of the radicular or feeder my practice we have found no need or use for these arteries. Because nonparticulate steroids do not compounded steroid agents. have the same diameter and do not aggregate in We also should focus on the recent escalation of the lumen, the chance of an embolic event may be the number of epidural steroid injections performed reduced. In the lumbar spine this anatomic argu- on patients in the past decade, based on published ment does not appear to hold true, so comments data by the American Society of Interventional Pain on that issue are presumptive and biased and not Physicians. The number has increased tremendously and we as a specialty should evaluate the proper based on scientific or clinical knowledge. We can debate the absolutes of which steroids selection of patients who undergo these techniques. to use and uphold safety as our measure, but that Procedures that are not indicated should be elimimay only be a portion of the argument to con- nated, and we should work within our societies to sider. Studies on the efficacy of particulate ver- reduce fraud and abuse as well as set standards for sus nonparticulate steroids have shown a slightly training. increased improvement Considering these imporwith particulate steroids, tant points, what can we As we move forward, we conclude to improve patient but no investigation has looked at the ability to care? need to consider the picture reduce the need for surIn the cervical and thogery, the reduction in racic spine it appears it is as a whole and avoid tunnel opioid use or the effect advisable to use nonparticvision that leads to long-term ulate steroids when doing on health care resources. If particulate steroids procedures near the spinal worsening of patient care. improve the other factors arteries. on a long-term basis, it Compounding of stemay be that the morbidroids to inject in the spine ity and mortality improvement of nonparticulate is unnecessary, as many manufacturers commonly steroids in the immediate postprocedure analy- make sterile products that are subject to all FDA sis is greatly overestimated because of the short- protocols. term effects of these drugs compared with agents Additional studies are needed to compare the such as triamcinolone. Reducing the need for opi- long-term efficacy of particulate and nonparticuoids, eliminating surgeries and improving func- late steroids when used in the spine. This information would be major improvements for individual tion will be helpful in allowing us to evaluate the patients, for society and for the socioeconomic risk–benefit ratio and may lead to changes in pracquandary that we often encounter in the delivery tice going forward. of health care. We should mandate proper training for physiIt also should be stated that we should not cians injecting the spine, including the use of fluoput all of our eggs in one basket. The notion roscopic guidance. Nonphysicians lack the training that physicians can control or completely elim- for these types of interventions and should not inate complications is simply an illusion. In the engage in these techniques. This is a patient safety past decade, I have attended and participated in issue. meetings at which experts gave the solution for To summarize, the use of non-particulate steeliminating steroid-induced catastrophes. Live roids appears to be warranted in the cervical and continuous fluoroscopy, safe triangle injection thoracic spine when doing interventions near the and the use of non-particulate steroids are a few spinal vessels. In the lumbar spine the risks appear of those “standards” that have been published low regardless of the choice of steroid. Future outin the peer-reviewed literature and discussed at comes research to determine the best care is greatly many national and international meetings. needed, and this may include alternatives to the curUnfortunately, the placement of a needle rent therapies. under continuous fluoroscopy with nonpartic—Timothy R. Deer, MD ulate steroids in the safe triangle does not comCharleston, West Virginia pletely mitigate the risk. Vasospasm, direct CONTINUED FROM PAGE 41

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MALIKAH LATMORE, MD

D. MATT LEVINE, MBCHB

Regional Anesthesia Fellow St. Luke’s-Roosevelt Hospital Center New York, New York

JEFF GADSDEN, MD, FRCPC C, FANZ ZCA Vice Chair for Clinic cal Affairs Director of Regiona al Anesthesia Residency y Program m Director St. Luke’s--Roosevellt Hospital Center New York, New York k

raditionally, the goal of peripheral

the needle are potentially hazardous

nerve blockade (PNB) has been

and can lead to histologic and clinical

to deposit local anesthetic as

nerve injury.1-4 This recognition has

close as possible to the nerve to ensure

resulted in a paradigm shift during

a successful block. It was once widely

needle placement from “as close as

taught that needle–nerve contact was

possible” to “close enough, but not too

necessary for a reliable block (eg, “no

close.”5 This article reviews the monitors

paresthesia, no anesthesia”). However,

that are currently available to provide

it has become apparent that needle

information about the relationship

puncture, intraneural injection, and

between the needle and the nerve

even simple contact of the nerve with

during nerve block procedures.

Dr. Gadsden has consulted for B.Braun Medical Inc. and received honoraria from Cadence Pharmaceuticals. Drs. Latmore and Levine report no relevant financial conflicts of interest.

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A N E ST H E S I O LO GY N E WS • M A R C H 2 0 1 4

Nerve Stimulation

Injection Pressure

Electrical stimulation has been used for decades as a method for localizing nerves during PNB. Several clinical and animal studies have demonstrated that the distance from the nerve and the intensity of motor response are poorly correlated. That is, a needle tip can be placed intraneurally yet provoke no motor response.6-8 However, data consistently show that the presence of a motor response at a very low current (such as <0.2 mA) during PNB is highly specific for intraneural needle placement and histologic injury.9-11 In other words, the absence of a motor response is not necessarily reassuring, but if a response is obtained at more than 0.2 mA, the needle likely is intraneural and should be withdrawn (Figure 1). As such, we believe the value of nerve stimulation lies less in localization and more in ensuring the absence of a motor response during PNB.

Opening pressure (OP) is the pressure in the needle–tubing–syringe system immediately before the initiation of flow. It is independent of the dimensions of the syringe or needle, and is equal from the needle tip to the plunger. Once flow begins, however, pressure at the needle tip will vary based on factors including syringe/ needle length and diameter, and compliance of the tubing. An OP greater than 20 psi during the injection of local anesthetic has been associated with intrafascicular injection and neurologic injury.2 Moreover, an inability to generate flow with a pressure of less than 15 psi was 97% sensitive for needle–nerve contact in a study of PNBs.4 As such, it is recommended that high-pressure injection be avoided. Assessing OP by “hand feel” is both subjective and unreliable.14 Two objective methods for measuring injection pressure are the “compressed air injection technique” and commercially available in-line pressure manometers (BSmart, Concert Medical; Figures 5-7).15 Injection pressure monitoring is sensitive for detecting contact between the needle and nerve, and for intrafascicular placement of the needle tip. Yet it lacks specificity, as there are many other causes of high injection pressure, such as a blocked needle.

Ultrasound The introduction of ultrasound revolutionized the practice of regional anesthesia, allowing practitioners to visualize in real time the nerve and the needle as it approaches the target, as well as the spread of local anesthetic in a space or plane adjacent to the target. Despite its potential as a visual aid, successful use of ultrasound depends largely on the skill of the practitioner. Proficiency requires training, as well as good hand–eye coordination and 3-dimensional spatial reasoning. Needle visualization is critical for safety; an inplane approach to the femoral nerve has been shown to result in less needle–nerve contact than an outof-plane approach (Figures 2 and 3).12 Observing the spread of local anesthetic during injection may help clinicians determine the proximity of the needle to the nerve. If the needle is close to the nerve, but not inside it, local anesthetic will be seen spreading around the nerve or within a sheath (Figure 4). However, intraneural injection may be visualized as swelling of the nerve itself.13

Conclusion Three objective monitors can help regional anesthesiologists avoid intraneural injection. However, none is perfect: Ultrasound depends on the ability of the user; nerve stimulation is specific but not particularly sensitive; and injection pressure monitoring is sensitive but not specific. Because of the limitations of each of these monitors, we recommend that they be used simultaneously during PNBs to provide the most comprehensive protection possible against neurologic injury (Figure 8). We feel that approach is analogous to the simultaneous use of pulse oximetry, electrocardiography, and blood pressure and other routine monitoring during the administration of general anesthesia to avoid complications.

Figure 1. The use of electrical nerve stimulation to prevent needle–nerve contact and/or intraneural injection. (A) Median nerve motor response with a “high” (0.48 mA) current intensity. (B) With the same needle position, the motor response is absent with a current intensity less than 0.2 mA, suggesting—but not proving—the needle tip is extraneural.

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Figure 2. In-plane needle insertion. The needle is directed from the lateral aspect of the transducer, in the same plane as the ultrasound beam. In the corresponding sonographic image in a phantom, the needle is seen approaching the target (*).

Figure 4. The spread of local anesthetic between the tibial (TN) and common peroneal (CPN) branches of the sciatic nerve. Note that the structure of each component nerve is intact and the outer epineurium (dotted lines) has not been violated.

Figure 3. Out-of-plane needle insertion. The needle approaches the beam at right angles. Therefore, only the small slice that crosses the beam is visible as a bright dot. (The asterisk marks the target.)

Figure 5. Compressed air injection technique. A 20-mL syringe is filled with 10 mL of injectate and 10 mL of air. According to Boyleâ&#x20AC;&#x2122;s law, a compression of the gas by half of its original volume will double the pressure in the system (ie, increase the pressure at the needle tip by 1 atmosphere, or roughly 15 psi). Maintaining the gas bubble at greater than half of its original volume should therefore prevent injection pressures of greater than 15 psi.

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References 1.

Steinfeldt T, Graf J, Schneider J, et al. Histological consequences of needle-nerve contact following nerve stimulation in a pig model. Anesthesiol Res Pract. 2011:591851.

2. Hadzic A, Dilberovic F, Shah S, et al. Combination of intraneural injection and high injection pressure leads to fascicular injury and neurologic deficits in dogs. Reg Anesth Pain Med. 2004;29(5):417-23. 3. Farber SJ, Saheb-Al-Zamani M, Zieske L, et al. Peripheral nerve injury after local anesthetic injection. Anesth Analg. 2013;117(3):731-739. 4. Gadsden JC, Choi JJ, Lin E, et al. Opening injection pressure consistently detects needle-nerve contact during ultrasound-guided interscalene brachial plexus block. Anesthesiology. 2014. [Epub ahead of print]

Figure 6. Pressure manometer showing opening pressure less than 15 psi.

5. Albrecht E, Kirkham KR, Taffé P, et al. The maximum effective needle-to-nerve distance for ultrasound-guided interscalene block: an exploratory study. Reg Anesth Pain Med. 2014;39(1):56-60. 6. Perlas A, Niazi A, McCartney C, et al. The sensitivity of motor response to nerve stimulation and paresthesia for nerve localization as evaluated by ultrasound. Reg Anesth Pain Med. 2006;31(5):445-450. 7. Robards C, Hadzic A, Somasundaram L, et al. Intraneural injection with low-current stimulation during popliteal sciatic nerve block. Anesth Analg. 2009;109(2):673-677. 8. Chan VWS, Brull R, McCartney CJL, et al. An ultrasonographic and histological study of intraneural injection and electrical stimulation in pigs. Anesth Analg. 2007;104(5):1281-1284 9. Tsai TP, Vuckovic I, Dilberovic F, et al. Intensity of the stimulating current may not be a reliable indicator of intraneural needle placement. Reg Anesth Pain Med. 2008;33(3):207-210. 10. Voelckel WG, Klima G, Krismer AC, et al. Signs of inflammation after sciatic nerve block in pigs. Anesth Analg. 2005;101(6):1844-1846. 11. Bigeleisen PE, Moayeri N, Groen GJ. Extraneural versus intraneural stimulation thresholds during ultrasound-guided supraclavicular block. Anesthesiology. 2009;110(6):1235-1243.

Figure 7. Pressure manometer showing graduated pressure thresholds of 15 to 20 psi and greater than 20 psi.

12. Ruiz A, Sala-Blanch X, Martinez-Ocón J, et al. Incidence of intraneural needle insertion in ultrasound-guided femoral nerve block: a comparison between the out-of-plane versus the in-plane approaches. Rev Esp Anestesiol Reanim. 2014;61(2):73-77. 13. Macfarlane AJR, Bhatia A, Brull R. Needle to nerve proximity: what do the animal studies tell us? Reg Anesth Pain Med. 2011;36(3):290-302. 14. Theron PS, Mackay Z, Gonzalez JG, et al. An animal model of “syringe feel” during peripheral nerve block. Reg Anesth Pain Med. 2009;34(4):330-332. 15. Tsui BCH, Knezevich MP, Pillay JJ. Reduced injection pressures using a compressed air injection technique (CAIT): an in vitro study. Reg Anesth Pain Med. 2008;33(2):168-173.

Figure 8. Complementary monitoring strategy to reduce the risk for needle-induced nerve injury during peripheral nerve blocks.

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