March 2015 by McMahon Group

The best-read anesthesiology publication in the United States

THE INDEPENDENT MONTHLY NEWSPAPER FOR ANESTHESIOLOGISTS AnesthesiologyNews.com • M a r c h 2 0 1 5 • Volume 41 Number 3

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Anesthesiologists Think They Should Be in Charge: Survey

Perioperative QTc Prolongation Linked to Administration Of General or Spinal Anesthesia

For a surgeon’s view, see p. 14.

New York—Most k anesthesiologists believe they should be in charge of key decisions in the operating room (OR) regarding resource and personnel allocation, despite a lack of training in these areas, according to a recent survey. Researchers asked attendees at the 68th New York State Society of Anesthesiologists’ (NYSSA) PostGraduate Assembly (PGA) if they thought anesthesiologists should serve as “OR directors.” Respondents were also asked whether they thought

New w Orleans—Once thought to be an isolated perioperraative phenomenon, QTc prolongation seems to be com mm mon during surgery under general and spinal—but nooot local—anesthesia, a study has found. Additionally, the relative risk for extended QTc prolongation is more than five times greater with general anesthesia than with spinal. “QTc prolongation is an indicator of abnormal ccardiac repolarization,” explained Andreas Duma, MD, one of a team of researchers at WashingM ton University of St. Louis in Missouri; Dr. Duma to is now a resident at the Medical University of is

see OR manager page 13

see QTc page 18

Coarse-Grained Simulation Model Reveals Similarities Among General Anesthetics New York—General anesthetics, despite differences among them at the molecular level, modulate ligand-gated ion channels in a highly generalized fashion. A coarse-grained simulation model of this behavior now offers valuable Thomas T. Joseph, insights into common molecular MD, PhD mechanisms of anesthetic action. Joshua Mincer, MD, PhD, assistant professor, and Thomas T. Joseph, MD, PhD, CA-2 resident and an Eliasberg Research Scholar, both from the

for iPad see page 4

Department of Anesthesiology at Mount Sinai Hospital, New York City, presented their research at the most recent Anesthesiology Residents’ Night, held at the New York Academy of Medicine. Their work won first prize and applause from Joshua Mincer, MD, PhD the anesthesiologists in attendance. Scientists recognized early on that a nonspecific mechanism of anesthetic action could account for the fact that diverse molecules see LGICs page 12

PRN

“Standing My Ground: Memoir of a Woman Physician”

POLICY & MANAGEMENT

Surgeon disagrees with anesthesiologists assuming role of perioperative director.

TECHNOLOGY

3D anatomy simulator aids identification of regional anesthesia anatomy.

PAIN MEDICINE

Managing the Difficult Pain Case: 4 Examples

EDUCATIONAL REVIEW The Role of Local Anesthetic Additives in Perineural Analgesia, see insert after page 40.

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F1RSTAnalytics: Real-Time Insight at Your Fingertips

Can You Ever Have Too Much of a Good Thing? ABCâ&#x20AC;&#x2122;s powerful, intuitive F1RSTAnalytics Key Performance Indicators (KPI) Dashboard helps you quickly understand whatâ&#x20AC;&#x2122;s going on and what you need to focus on. The KPI Dashboard is a set of measures specifically for anesthesia practices. At a glance, the dashboard tells you what you need to know, giving you insight into where you are strong â&#x2C6;&#x2019; but more importantly â&#x2C6;&#x2019; where you need to focus. It allows you to compare year-over-year performance, your payor mix and options to focus on procedures, cases and even your staff.

How Smooth is Your Revenue Cycle? The F1RSTAnalytics Accounts Receivable (AR) Dashboard is a set of measures specifically for anesthesia practices. At a glance, the AR Dashboard tells you what you need to know about where and how revenue is generated, and where you may have issues. The AR Dashboard gives you a multi-year view of your charges, payments and performance trends with in-depth visibility into various aspects of the revenue cycle. The F1RSTAnalytics Dashboards give you actionable insight, real-time. Need more data? The KPI and AR related performance reports give you the ability to drill-down into more detailed data. The F1RSTAnalytics suite of dashboards and performance reports give you the knowledge you need to operate your anesthesia practice as an effective clinical organization and successful business.

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DYLOJECT IS AN INJECTABLE NON-OPIOID ANALGESIC NOW APPROVED BY THE FDA FOR USE IN ADULTS FOR THE: › Management of mild to moderate pain. › Management of moderate to severe pain alone or in combination with opioid analgesics.

Request a Dyloject representative at dyloject.com/rep

Avaailable soon.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS › Known hypersensitivity to diclofenac.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

› History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

See full prescribing information for complete boxed warning

› Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Cardiovascular Risk › Non-steroidal anti-inﬂ ﬂammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

› Moderate to severe renal insuﬀiciency in the perioperative period and who are at risk for volume depletion. WARNINGS & PRECAUTIONS › Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke: Patients with known CV disease or risk factors for CV disease may be at greater risk. Use for the shortest possible duration.

› Dyloject is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

› Serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation, which can be fatal: Use for the shortest possible duration. Use with caution in patients with prior history of ulcer disease or GI bleeding.

Gastrointestinal Risk

› Renal papillary necrosis and other renal injury with longterm administration of NSAIDs: Use Dyloject with caution in patients at greatest risk for this reaction, including the elderly; those with impaired renal function, heart failure, or liver impairment; and those taking diuretics or ACE inhibitors.

› NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Events can occur at any time without warning symptoms. Elderly patients are at greater risk.

› Elevation of one or more liver tests and severe hepatic reactions: Discontinue Dyloject immediately if abnormal liver tests persist or worsen.

› New onset or worsening of hypertension: Monitor blood pressure closely during treatment with Dyloject. › Fluid retention and edema: Use Dyloject with caution in patients with ﬂuid retention or heart failure. › Anaphylactic reactions in patients with the aspirin triad or in patients without prior exposure to Dyloject: Discontinue Dyloject immediately if an anaphylactic reaction occurs. › Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Discontinue Dyloject if rash or other signs of local skin reaction occur. ADVERSE REACTIONS › The most common adverse reactions (>5%) in controlled clinical trials include nausea, constipation, headache, infusion site pain, dizziness, ﬂatulence, vomiting, and insomnia. Please see Brief Summary of full Prescribing Information on adjacent page.

Hospira, Inc. 275 North Field Drive Lake Forest, IL 60045 P14-0277-10.5x13-Jan., 15

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

Dyloject™ (diclofenac sodium) Injection, for intravenous use Rx Only

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)]. • Dyloject is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)]. Gastrointestinal Risk • NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)].

INDICATIONS AND USAGE

Dyloject is an NSAID indicated in adults for the management of mild to moderate pain and management of moderate to severe pain alone or in combination with opioid analgesics. 4

CONTRAINDICATIONS

Dyloject is contraindicated in patients with: • known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac [see Warnings and Precautions (5.7, 5.8)]. • a history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.13)]. • perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • moderate to severe renal insufficiency in the perioperative period and who are at risk for volume depletion [see Warnings and Precautions (5.3)]. 5

WARNINGS AND PRECAUTIONS

5.1

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)]. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and

an NSAID does increase the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. 5.2 Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Dyloject, can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. Dyloject is administered by intravenous injection and is intended for acute short term use. However, even short-term therapy is not without risk. Prescribe NSAIDs, including Dyloject, with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to treated patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most reports of spontaneous fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. 5.3

Renal Effects

Use caution when initiating treatment with Dyloject in patients with considerable dehydration. Dyloject is not recommended in patients with moderate to severe renal insufficiency and is contraindicated in patients with moderate to severe renal insufficiency in the perioperative period and who are at risk for volume depletion. Acute renal decompensation was observed in 4% out of 68 patients enrolled with renal impairment and treated with Dyloject in clinical trials in the perioperative period. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. 5.4

Hepatic Effects

Elevations of one or more liver tests may occur during therapy with Dyloject. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients in clinical trials of indications other than acute pain. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials of oral diclofenac, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In this open-label

study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Measure transaminases (ALT and AST) periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. Dyloject is not indicated for long-term treatment. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue Dyloject immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver-related event in patients treated with diclofenac, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Dyloject with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, anti-epileptics). 5.5

Hypertension

NSAIDs, including Dyloject, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including Dyloject, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. 5.6

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Use Dyloject with caution in patients with fluid retention or heart failure. 5.7

Anaphylactic Reactions

As with other NSAIDs, anaphylactic reactions may occur in patients without known prior exposure to Dyloject. Dyloject is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4)]. 5.8

Serious Skin Reactions

NSAIDs, including Dyloject, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue Dyloject at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)].

5.9

Pregnancy

Starting at 30 weeks gestation, Dyloject and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations in full prescribing information]. 5.10 Corticosteroid Treatment Dyloject cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroidresponsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. 5.11 Masking Inflammation and Fever

studies of another drug and may not reflect the rates observed in practice. During clinical development, 1,156 patients were exposed to Dyloject in multiple-dose, controlled and open-label studies. Dyloject was administered post-surgically every 6 hours for up to 5 days. The incidence rates of adverse reactions listed in the following table are derived from multicenter, controlled clinical studies in post-operative patients comparing Dyloject to placebo in patients who may have also received morphine rescue medication. Table 1: Proportion of Patients Experiencing Common Adverse Reactions in Placebo-Controlled Clinical Studies in Patients with Acute Moderate-to-Severe Postoperative Pain occurring in greater than or equal to 3% in patients treated with Dyloject* Placebo N=126

Dyloject N=187

Any Reaction

104 (83%)

146 (78%)

Nausea

50 (40%)

45 (24%)

Constipation

14 (11%)

25 (13%)

Headache

20 (16%)

19 (10%)

Infusion Site Pain

10 (8%)

19 (10%)

Dizziness

2 (2%)

15 (8%)

Flatulence

20 (16%)

15 (8%)

Vomiting

23 (18%)

12 (6%)

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

Insomnia

12 (10%)

11 (6%)

Pruritus

10 (8%)

9 (5%)

Hypotension

6 (5%)

9 (5%)

Pyrexia

13 (10%)

8 (4%)

Anemia

9 (7%)

8 (4%)

5.13 Pre-existing Asthma

Infusion Site Extravasation

1 (1%)

6 (3%)

The pharmacological activity of Dyloject in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. 5.12 Hematological Effects Anemia may occur in patients receiving NSAIDs, including Dyloject. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term treatment with NSAIDs, including diclofenac, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss. Dyloject is not indicated for long-term treatment.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, including bronchospasm, Dyloject is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma [see Contraindications (4)]. 5.14 Monitoring Because serious GI tract ulcerations and bleeding can occur without warning symptoms, monitor for signs or symptoms of GI bleeding. For patients on long-term treatment with NSAIDs, periodically check a CBC and chemistry profile, including liver function tests. Discontinue Dyloject if clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash), or abnormal liver tests persist or worsen. Dyloject is not indicated for long-term treatment. 6

ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.1)] • Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]

MedDRA Preferred Term

Body as a Whole: anaphylactic reactions, appetite changes, death Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional: hyperglycemia Nervous System: convulsions, coma, hallucinations, meningitis Respiratory System:: respiratory depression, pneumonia Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special Senses: conjunctivitis, hearing impairment Adverse reactions of special p interest Based on the analysis of the pooled data from the multi-dose, controlled clinical trials, post-operative patients treated with Dyloject had more adverse reactions related to wound healing (7.5%) compared to patients treated with placebo (4%).

* Intravenous morphine was permitted as rescue medication for pain management. Adverse reactions from clinical studies or spontaneous p reports p for other formulations of diclofenac and other NSAIDs In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/ perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting. Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse reactions reported occasionally include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope Digestive System: esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

• Renal effects [see Contraindications (4) and Warnings and Precautions (5.3)]

Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

• Hepatic effects [see Warnings and Precautions (5.4)]

Metabolic and Nutritional: weight changes

• Hypertension [see Warnings and Precautions (5.5)]

Other adverse reactions, which occur rarely are:

• Congestive heart failure and edema [see Warnings and Precautions (5.6)]

Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

• Anaphylactoid reactions [see Warnings and Precautions (5.7)]

Respiratory System: asthma, dyspnea

• Serious skin reactions [see Warnings and Precautions (5.8)]

Skin and Appendages: alopecia, photosensitivity, sweating increased

Adverse reactions from clinical studies of Dyloject y j Special Senses: blurred vision Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical

Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

Adapted from: EN-3738; Revised 12/2014 Manufactured for: Hospira, Inc., Lake Forest, IL 60045 USA

8 I AnesthesiologyNews.com

MARCH 2015

PRN Standing My Ground: Memoir of a Woman Physician

ll of Europe was ablaze when Clair M. Callan was born in 1940, as World d Dr. Callan provides insight into her War II raged. In Standing My Ground, experiences. Dr. Callan recounts how she partly cracked the glass ceiling to upper management at a time when it seemed impenetrable for women. While employed in different medical environments, she created innovative approaches to the quality of health care and improved patient safety. Standing My Groundd offers practical lessons from her life, illustrating how one can advance in a competitive environment, no matter one’s sex. What follows is an excerpt that discusses Dr. Callan’s role in the development of sevoflurane.

Standing My Ground My Ground

Memoir of a Woman Physician

The Anesthesia (Sevoflurane) Venture Clair M. Callan, MD, MBA, CPE

n the spring of 1992, things suddenly changed for me in a big way. I had been Abbott’s director of medical affairs for the Hospital Products Division for seven years. One evening I was seated at my desk, studying the latest reports on the Omniflo infusion pump, when the telephone rang. The pump was a complex, four-channel infusion apparatus recently acquired by Abbott, and there were issues that needed attention. Although I had been included peripherally in discussions regarding Sevoflurane, a new inhalation agent for anesthesia, it was not my primary responsibility. It was now about six months since I had first reviewed information on this short acting anesthesia agent and recommended that Abbott not get involved with it. The drug was far from my mind as I picked up the phone. “Get your body up to Kringel’s office now!” barked Lawrence in his clipped English voice without any preamble. He was not known for his courtesy, especially toward women. Many times he wasn’t much better with men. “We have a question to ask you,” he said, and abruptly hung up. Clearly he expected me to hop to it without question. I frowned, wondering what was up. It was not every day I was abruptly summoned to the office of Kringel, the big boss, even if it was by my little boss, to answer a question. What could be going on? Was there a crisis or something else? I quickly picked up my folder and walked up the stairs to Kringel’s corner office on the second floor. It was a sign of status to have a corner location. Nancy, Kringel’s assistant, waved me straight in to the office without chitchat. That, too, was unusual. I was used to waiting and chatting with Nancy for a few moments before being invited to enter the inner sanctum, the division president’s spacious office. I pushed open the door, and saw four people sitting around the rectangular conference table that filled much of the room. In addition to Kringel and Lawrence, there were J. Duncan McIntyre, president of Abbott’s International Division (AI), and Romeo Bachand, MD,

vice president, medical affairs, AI. Romeo was Lawrence’s equivalent in the international area. “Come in, Clair, air, and have a seat,” greeted Kringel, pointing too a chair at the end of the table. I slid into it as the others nodded in silence. “As you may have heard, we have been discussingg ways for Abbott to develop a more significant role in anesthesia ,” began Kringel. “We have a great positioon with our current pproducts, including Isofluurane and Pentothal™, but healthcare is changing. We think there is an opportunity to develop a new inhalation agent such as Sevoflurane, but we don’t have much time. We have been given the go-ahead by Burnham and Hodgson to set up a venture team to work on this project, and we would like you to head it up.” He leaned back in his chair. My head was spinning. Burnham and Hodgson were the CEO and president of the company, respectively. The project must have been considered worthy if it had already passed muster with them. But Sevoflurane? I thought it was a dud, but started reconsidering when I learned more about it. I now saw that the compound had some possibilities, but why continue? Was Abbott really willing to get involved with what could be a lot of aggravation over possible kidney damage often described by Dr. Ted Eger, a heavy hitter in anesthesia and a Sevoflurane critic. His voice in the anesthesia media was loud, persistent, and supportive of Sevoflurane’s rival, Desflurane. I knew that Desflurane was in an advanced stage of development. These were some of my thoughts whirling in my head. I was brought back to reality by the sound of Kringel’s voice. “This is a big challenge for both divisions,” he said. “Neither of us has developed a new drug like this. As you know, we are strong in generics, but a

CLAIR M. CALLAN, MD, MBA, CPE Author of Sevoﬂurane: u The Untold Story of How a Dedicated Team Brought the Mos Most Widely Used Inhalation Anesthetic to the World

proprietaary drug development program is totally new for us. Will you do this?” I looked around and saw the four men staring at me. I could feel the tension, and sensed that they were offering me a unique opportunity. If I accepted, I would be breaking new ground not only for myself but also for HPD and AI as well. But if I failed, and all thee data I knew about Sevoflurane at the time indicated that it would not be an easy success, what then? Clearly, the four wanted an answer, and they wanted it on the spot. There was no time to equivocate. I felt my heart jump to my mouth but marshaled my thoughts and found my voice. “I am surprised, but delighted,” I heard myself saying in a calm voice. “I would like to work on this, and I do think it is a great opportunity for Abbott. I will work hard to justify your confidence.” “Good. This is a great opportunity for us all,” said Kringel as the others relaxed. Some of their tension had dissipated. “We have decided to do this as a joint venture between the two divisions,” Kringel said. He was referring to HPD and AI. “This has never been done before in the history of the company, and there is some concern that the Pharmaceutical Products Division should be the group to handle it. Drug development is their bread and butter, and they are used to dealing with the challenges of new drug development with the FDA [Food and Drug Administration] and other regulatory agencies. But they don’t have a presence in anesthesia, and we both do.” Kringel leaned forward. “Let’s show them what we can do.”

MARCH 2015

AnesthesiologyNews.com I 9

PRN I described this in the book Sevoflurane: The Untold Story of How a Dedicated Team Brought the Most Widely Used Inhalation Anesthetic to the World. The book recounts the efforts that were required to turn a drug that was supposed to be dead on arrival into the most successful inhalational anesthesia ever, earning more than $1 billion a year for several years. In many ways, it is a story about overcoming adversity, and how I led the rookie team that did so. When I was appointed venture head I was given very specific goals, the antithesis of what I thought a drug investigation should be: First, I was to kill the drug as quickly and painlessly as possible because it was expected to be a lemon. (The company was playing defense. It didn’t want to waste much money on the drug, but it didn’t want another company to get its hands on it in case it proved to be a moneymaker.) Second, I was to get it all done within twenty-four months, an unheard of, unrealistic expectation for drug development. I may have been crazy to agree, but I saw it as an opportunity to show what I could do, even if the drug proved to be stillborn. The book covers a lot of challenges involved in product development and management of Sevoflurane (Sevo, for short). It describes how the inexperienced team had to learn just about everything from scratch: how to bond and how to achieve the virtually impossible performance targets set for it by upper management on an almost daily basis. It also gives insight into the pharmaceutical industry (Big Pharma) and how it works—the good, the bad, the ugly, and eventually the beautiful. It provides a window into some of the unscrupulous practices employed by individuals in Big Pharma and supposedly pristine academic drug researchers. It outlines the many political and economic hurdles that my team had to overcome. And it describes the supporting role played by Irish medicine in the gestation of this surprising drug. In fact, running the venture gave me a chance to hone all of the management skills I had acquired in my previous assignments as a community volunteer and a medical and business professional. I was keenly aware that time was passing. Although the twenty-fourmonth clock for getting the New Drug Application (NDA) submitted to the FDA would not start until all the agreements were signed and in place, I wanted to get a head start. I wanted to be in a good position after

we were given the official go-ahead. I thought about people I hoped would agree to become part of the team, either as full-time members or as volunteers from other units with expertise in key areas of the development program. I decided to use an approach we had used successfully at AMWA for strategic planning; we’d brought in a consultant to help us decide what we wanted the organization to be. I contacted the AMWA consultant, Denise Cavanaugh, explained the

project to her, and she was delighted to help. I made a list of the groups I would need, including regulatory, quality assurance, science, and toxicology, among others. I then contacted the chiefs of those units at Abbott and asked them to appoint a person to be on the Sevo team. I used that list to invite people to a strategy/ development meeting, a two-day session at Glen Rowan House, a nearby conference center; all were expected to come for both days. Sean Murphy

and Alan Westwood, in charge of new business development at HPD and AI, respectively, were also included in this meeting, which was very encouraging. Denise was a wonderful facilitator and by the end of the sessions managed to get everyone committed to being part of the exciting program. We agreed on a logo—the letters SV entwined and looking a lot like the Superman logo, quite appropriate I thought. We even received see ground page 10

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10 I AnesthesiologyNews.com

MARCH 2015

PRN GROUND

gave me something to go on when I deciding what type of studies, how specific assignments; mine was to focus on the clini- many patients, and which otheer cal development program. issues needed to be covered. It was a start of a very ambitious The Project program. Even though the venture team was still unofficial, Next on the agenda was to the project had to get started. After all, I’d been find key staff. I was lucky that assigned to it full-time and couldn’t afford to be a possible COO and a direcseen wasting any time. Although I had negotiated tor of clinical studies were that the timeframe for getting the drug submitted very interested in the prowould not start until all of the legal agreements had gram. But others were less sure. been signed, I knew that as soon as that happened I They were concerned that join-would have to be off and running quickly out of the ing the venture team would starting blocks. be a big risk; if it failed, they First, I had to see how much support I would get would be out of a job. And from the Abbott marketing team. This group, both there was no shortage of naysayy HPD and AI were the internal customers for the ers in the company who predicted project. I arranged an all day, offsite meeting with that would happen. Nevertheless, I put together a Sean Murphy and Alan Westwood. Together, we core team of people, none of whom, other than me, mapped out a very broad label claim for the drug had ever held a passport. And none of us had ever that would make it more likely that the drug would been part of an NDA program. This changed as prove profitable if it were approved. The approach time went on. Passports became essential for every CONTINUED FROM PAGE 9

may have been crazy to agree, but I saw it as an opportunity to show what I could do, even if the drug proved to be stillborn. teeam member as this would be a global development en ndeavor. Team members became a strong unified grroup, very supportive of “their” drug, and willin ng to commit an enormous amount of time to the prrogram. As I slowly found the ideal internal team membeers, I accumulated external expert advisors as weell. This was somewhat easy to do. The competition between Sevoflurane and Desflurane had gentio erated interest among experts and other clinicians. It was as if a war were being waged on the pages of peer-review w journals, including Anesthesiology, Anesthesia and Analgesia, and the British journal Anaesthesia. Dr. Burnell Brown, chief of anesthesia at the University of Arizona, was a longtime supporter of

Risk for Anesthesia Complicati In Children With Pulmonary Hyp

hildren with pulmonary hypertension (PHT) are still at a high risk for adverse events during anesthesia even when using the latest disease-modifyingg treatments, according to a new study. PHT, which affects the arteries in the lungs and right side of the heart, historically restricted children from surgery because of their shortened life expectancy and high risk for serious anesthesia-related complications, according to researchers from the Hospital for Sick Children, Toronto, Ontario, Canada. They conducted a retrospective review of 122 patients (60 male), median age 2.2 years old, with PHT to examine surgery and anesthesia risks. These patients underwent anesthesia or sedation for noncardiopulmonary bypass procedures from January 2008 to November 2012. Pediatric patients with untreated PHT have a median survival of 10 months; disease-modifyingg treatments have reduced mortality in this group by 43% in the last five years, according to the researchers. These drugs were administered in 121 of the 284 procedures; researchers collected data on the type of surgical procedure, anesthetic management, airway technique and incidence of major or

minor complications. Major complications included hypotension, hypoxia, and arrhythmia occurring during or within 24 hours of anesthesia that required resuscitation by external cardiac massage and unplanned tracheal intubation. Minor complications were defined as transient selff limitingg disturbances in arterial blood pressure, oxygenation or cardiac rhythm that required either minimal therapy or no treatment at all. Disease-modifyingg drugs lowered complication rates compared with untreated procedures (2.5% vs. 3.7% for serious complications; 4.1% vs. 8.6% overall). Complications occurred in 13 of the 136 procedures for male patients and six of the 148 procedures for females. There was no association between complications and the airway type or anesthetic drugs used. The researchers found that age was a significant factor for determining complications (P≤0.0001). When stratified for disease severity, children <5 months of age were more likely to experience severe complications compared with children >2 years of age (odds ratio [OR], 6.15; 95% confidence interval [CI], 1.23–30.7; P=0.03) and more likely to have intraoperative complications (OR, 6.05; 95% CI, 1.4-26.08;

P=0.02). Children from 6 to 24 months of age were more likely than children >2 years old to experience intraoperative complications (OR, 6.4; 95% CI, 1.8-22.6; P=0.004) but not severe complications (OR, 2.1; 95% CI, 0.4-10.8; P=0.39). They also found that patients with less severe disease had fewer complications—regardless of age—and patients with suprasystemic disease were at the greatest risk. The study authors noted that this is the largest study on infants and children with PHT to date since the

introduction of effective PHT treatments. They wrote that the number of events is a limitation to this study— there were nine serious complications and three deaths—and that collaborative studies from multiple hospitals are needed. The findings were published in Anesthesia & Analgesia (2015;120[2]: 420-426). —AN Staff Based on a press release from the International Anesthesia Research Society.

MARCH 2015

AnesthesiologyNews.com I 11

PRN Sevoflurane. His support and interest continued even while the drug had sat inactive on the shelf. In addition, some young researchers expressed interest in studying the drug more closely in the laboratory. This turned out to be crucial as their results showed the reason why Sevoflurane was not damaging to the kidney as it had been projected to do. This group of advisors became an integral part of the NDA program and went with us to the FDA when it was time to justify our data and the safe use of the drug. Everyone worked hard to ensure that the NDA package was submitted on time to the FDA. The final submission files filled a whole container truck. We relaxed a little when we waved it off. But we still had all of the international packages to submit. We were given one month to get this done, another almost impossible deadline but one that we met. Regulatory approvals started to come in from overseas, and Sevoflurane was on its way to becoming the most widely used inhalation agent in the world with no obvious safety issues. It was a very successful program achieved by a relatively naïve team who worked together as a solid unit, even with the barriers were raised to derail them. Despite that success or perhaps because of it, I became an unwitting political pawn. Sevoflurane had great success in Japan where it was produced and marketed by Maruishi. It was approved for sale the same day that Abbott’s Isoflurane, a similar inhalation drug, was approved. The latter was expected to be very successful in Japan, as it was a leading agent in the rest of the world, but because of the quick uptake of Sevoflurane by Japanese anesthetists, Isoflurane sales were way behind expectations. Pleased with the continued and expanding success of Sevoflurane, Maruishi, invited me to be the keynote speaker at a large anesthesia meeting in Japan, and I agreed. It wasn’t long before the managing director of Abbott Japan, Isidore Horowitz, was on the phone, furiously demanding that I cancel my speaking engagement. He was furious that I would even consider going to support what he considered a non-Abbott product, especially one that was having such an impact on his sales. Originally I was incensed and refused his request. I thought he had some nerve and was way out of line. But some gentle persuasion from Kris Kringel finally convinced me that this was not a good thing to do. The political repercussions would be

bad for the company, he said. There was a lesson for me here. I was not the totally independent manager I thought I was. Everyone in the company, even the CEO, had someone above us who could make us toe the line when appropriate, no matter what we thought. The goal would always be to do what was the best for the product and the company. “Standing My Ground: Memoir of a Woman Physician” is available on Amazon.com.

questions comments story ideas Contact Editor James Prudden at

jprudden@mcmahonmed.com

Interested in conducting your own research? Consider the Merck Investigator Studies Program. What is MISP? The mission statement of the Merck Investigator Studies Program (MISP) is to advance science and improve patient care by supporting, through the provision of drug/vaccine and total/partial funding, high-quality research that is initiated, designed, implemented and sponsored by external investigators. Who Can Participate? The Merck Investigator Studies Program is open to all academic and community-based physicians, anesthesiologists, surgeons, and researchers worldwide who are interested in conducting their own research. How Does the Program Work? This program consists of committees of medical and scientiﬁc staff from different therapeutic areas who meet regularly to review Merck investigator study proposals. Support and funding are provided based on the scientiﬁc merit of the proposal as well as whether it is in alignment with the published areas of interest.

How to get started: To learn more about the areas of interest for anesthesia and requirements for submission visit http://engagezone.merck.com/anesthesia.html. There are two review cycles for anesthesia submissions:

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12 I AnesthesiologyNews.com

MARCH 2015

PRN LGICs

on LGIC—i.e., a site determined by crystallographic measurements to bind could cause general anesthesia. An propofol. There is in fact evidence fidelity of the full simulation to create longer time earlier unifying theory of anesthefrom prior research that multiple difsia, called the Meyer-Overton princiferent anesthetic molecules can fit into scales, and as long as you are careful about the ple, highlighted the observation that that binding site, and so the researchers then the more lipid-soluble a molecule was, looked at a coarse-grained model conclusions you reach, you can learn new things the more potent the anesthetic effect. for xenon, which, being a noble gas, This led to the idea that anesthetics is chemically simpler than the other that you couldn’t from a full, all-out model.’ imparted their effect by dissolving in anesthetics, and found that the bindthe lipid membrane of neurons and ing site also has affinity for it, which —Thomas T. Joseph, MD, PhD interfering with their function in an is a new finding. “We believe the abilotherwise nonspecific manner. ity of such a model to produce these Although the lipid membrane pertime, which is much shorter than results is consistent with a mechanism Coarse-Grained Simulation sists in some modern theories of anesmost biological processes. In a coarse- of general anesthetic function that Drs. Joseph and Mincer created grained model, however, you trade requires minimal atomic-level selectivthesia, ion channels are now a central part of most theories. “What an ion their model by employing molecu- some of the fidelity of the full simula- ity,” Dr. Mincer said. channel does is help modulate the rel- lar dynamics, which traditionally takes tion to create longer time scales, and as Future Research ative concentrations of ions inside and into account every atom that is pres- long as you are careful about the conoutside the cell,” Dr. Joseph explained. ent in a particular system. “In this sys- clusions you reach, you can learn new The research also looked at fluc“Ion channels are in the cell membrane, tem, you have an ion channel, which things that you couldn’t from a full, tuations within the structure. “If regulating the ion concentrations on is a very large protein with multiple all-out model,” Dr. Joseph said. Both you consider what happens when either side, and since ions are charged subunits and is embedded in a lipid Drs. Joseph and Mincer used all-atom you bind a ligand to one part of the they are also regulating the electrical bilayer, which is comprised of a num- molecular dynamics in their respec- ion channel, other parts get influpotentials on either side. That is the ber of large molecules that are glom- tive dissertations (each has a PhD in enced, but they are farther away from basis through which, for example, neu- med together to form a cell membrane,” computational/theoretical biophys- the site of the binding, so you wonronal action potentials are propagated.” Dr. Joseph said. ics). Dr. Mincer has also done research der how did that information travel One could therefore theorize that disThe problem with creating a simu- in the use of coarse-grained methodol- from the binding site to the rest of rupting the function of these chan- lation that incorporates all the atoms ogy in order to create computer mod- the molecule,” Dr. Joseph said. “We nels might then disrupt brain function. in the system is that it takes a huge els that give results on a timescale large analyzed the dynamics of our coarseThe challenge, then, is to understand amount of computational power to enough to be biologically relevant. grained model to identify the residues how general anesthetics, which are get just a small amount of simulation Besides yielding to more complex in the protein that are most impormolecularly diverse, target and mod- time—often measured in nanosec- analysis, a simulation results in a tra- tant in propagating that information, ulate these ligand-gated ion channels onds. “In a given day you might pro- jectory, essentially a movie that can be and showed that there are actually (LGICs). duce 15 nanoseconds of simulation viewed onscreen. The resultant images quite a lot of them. Many of them are are faithful to reality. “It is not a car- restricted to exactly where we would toon,” explained Dr. Mincer. “Each expect them to be—within the lipid of these images is calculated based on bilayer.” Binding of propofol and the the laws of physics. So to the extent model xenon yielded similar sets of the physics approximations are right, it residues, a finding that provides addishould mimic what is actually happen- tional evidence for common molecing in vivo.” ular mechanisms of action of general anesthetics. Propofol and Xenon Drs. Joseph and Mincer will conThe researchers started with a crys- tinue their research. “We are intrigued tal structure of the Gloeobacter viola- that so many different types of moleceous LGIC, a bacterial homolog to cules actually create general anesthethe nicotinic acetylcholine receptors sia,” Dr. Mincer said. “The ability of that is considered to be a good struc- the coarse-grained model, which by tural model for human ion channels. definition simplifies certain atomicA coarse-grained model of the LGIC level interactions, to recapitulate and from the bacterium was constructed. extend results from both theory and Propofol was first studied, partly as experiment is itself a proof of concept a validation to show that the coarse- to some extent of minimal selectivity grained model devised by the research- in the interactions of anesthetic ligands ers matched up well with experimental with ion channels. Trying to further results and with earlier all-atom stud- delineate what exactly is important is ies of LGICs. “We needed to show that something we want to explore further.” there was some connection between The team envisions their work conthe two models,” Dr. Joseph explained. tributing alongside the efforts of “And it turns out that even given the researchers employing both theoretilimitations of the coarse-grained cal and experimental methodologies model, it nonetheless shows things to improve the understanding of how seen in the all-atom model.” diverse agents produce general anesthesia. So stay tuned…. The researchers found that in the Above: a still from the simulation. To view the moving simulation, visit coarse-grained model, propofol prefAnesthesiologyNews.com and search “coarse-grained.” —James Prudden erentially localized to the correct area CONTINUED FROM PAGE 1

‘In a coarse-grained model, you trade some of the

MARCH 2015

AnesthesiologyNews.com I 13

POLICY & MANAGEMENT OR MANAGER

CONTINUED FROM PAGE 1

anesthesiologists had the leadership skills, ability to gather data and knowledge of necessary interventions needed to take on the role. The survey results were posted on the last day of the PGA. More than 11% of the 3,069 attendees responded, and 94.2% said anesthesiologists should be OR directors. “The OR can either be a major source of revenue for a hospital or a major drain on its operating budget,” said lead investigator Steven Boggs, MD. “In order to maximize revenues, there needs to be a coordinated effort to increase quality and efficiency, and we believe as a profession that anesthesiologists are best suited to take a leadership role in this effort.” Dr. Boggs, OR director and chief of anesthesiology, James J. Peters VA Medical Center, New York City, acknowledged that the PGA survey enrolled a “selff selected population” that did not include the perspectives of nurses and surgeons on this issue. He and the co-authors of the study—Elizabeth A.M. Frost, MD, clinical professor of anesthesiology at Mount Sinai Hospital, New York City, and Jessica Feinleib, MD, PhD, assistant professor of anesthesiology at Yale School of Medicine, New Haven, Conn.—emphasized that they do not view the findings as a referendum on the American Society of Anesthesiologists’ Perioperative Surgical Home (PSH) model because the survey addressed a specific aspect of the potential leadership function for anesthesiologists in the OR: resource and staff management. However, they noted that their findings were particularly striking because other studies suggest recent graduates of residency programs are not adequately trained in OR financial and personnel management. “At our centers, we’ve really seen a dramatic improvement in all of the major OR productivity metrics since anesthesiology assumed the role of OR director,” said Dr. Boggs. “We’ve seen that anesthesiologists really offer the attention to detail and can handle the learning curve this shift entails. But there are fundamental questions for the profession as a whole, particularly in light of the [PSH] model. Are we preparing our young anesthesiologists to assume this leadership role?” Another issue is whether or not the other specialists working in the OR—namely the surgeons and nurses—are ready and willing to defer leadership to their colleagues in anesthesiology. According to the study

authors, surgeons in their respective centers have been “happy” to cede this management role and the additional work and responsibilities it entails to anesthesiologists—especially surgeons who handle complex surgical cases, such as orthopedic surgeons and neurosurgeons. They said anesthesiologists are logical managers of surgical cases in these settings given their extensive responsibilities in “preoperative optimization” and postoperative recovery of the patients involved.

On the other hand, anesthesiologists can still improve efficiency in the OR without being permanently assigned as an OR director, according to Frederick L. Greene, MD, FACS, clinical professor of surgery at University of North Carolina School of Medicine, Chapel Hill, and medical director of Cancer Data Registry, Levine Cancer Institute, Charlotte, N.C. Dr. Greene said his institution implemented a system that established a “surgeon of the day” to manage the

OR. In this system, a surgeon is effectively appointed OR director for a specific day and given responsibility for making OR staffing and scheduling decisions and managing efficiency. The surgeon serving in this role is not assigned surgical cases for the day. The anesthesiologist in this system coordinates the provision of anesthesia and oversees patient care in the postanesthesia care unit. —Brian Dunleavy

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There are inherent risks in all medical devices. Please refer to the product labeling for Indications, Cautions, Warnings, and Contraindications. Failure to follow the product labeling could directly impact patient safety. Physician is responsible for prescribing and administering medications per instructions provided by the drug manufacturer. Refer to www.halyardhealth.com for product safety Technical Bulletins. 1. Sherwinter DA, et al. Continuous infusion of interperitoneal bupivacaine after laparoscopic Surgery: A randomized controlled trial. Obes Surg. 2008: 18 (12): 1581-6. 2. Klein et al. Interscalene brachial plexus block with continuous catheter insertion system and a disposable infusion pump. Anesth Analg. 2000; 91:1473-8. 3. Data on File. ON-Q* Pain Relief System. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2015 HYH. All rights reserved. RX Only. MK-00754 03/2015.

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POLICY & MANAGEMENT

The ‘Perioperativists’ Are Coming! Editor’s note: Dr. Greene, clinical professor of surgery, UNC School of Medicine, Chapel Hill, North Carolina, wrote the following commentary for General Surgery News, a sister publication. He does not agree with the notion that anesthesiologists should assume a perioperative managerial role.

By Frederick L. Greene, MD

fascinating trend in medicine that has developed during the past decade or two is the expansion of certain specialties and the creation of diverse kinds of specialists in order to fill needs abandoned by other groups of physicians. “Intensivists” have proliferated as critical care medicine has become more complex and as many physicians have been encouraged to abdicate intensive care unit management to others. The concept of the “hospitalist” evolved because of the desire of many internal medicine specialists to avoid taking hospital call or making rounds in the inpatient hospital setting. Radiologists and cardiologists expanded their turf and became “interventionalists” to provide services traditionally offered by cardiac and vascular surgeons. The “laborist” appeared as obstetricians eschewed traditional call responsibility for deliveries and encouraged hospitals and obstetrical practices to hire physicians who sought hospitalbasedd and shift-basedd practices. The “surgicalist” emerged in a similar fashion as the exigencies of acutecare surgery and the presumed burden of unassigned emergency department patients changed the mindset of many surgeons regarding hospital call. These examples of “specialist” expansion and “turf creep” have generally occurred because of the perceived needs of patients and the medical community or as responses to the unwillingness of certain specialties to continue to provide traditional care. Recently, I came across a new paradigm of this phenomenon: the “perioperativist.” This new creation emanates from the anesthesiology community as an expression that the anesthesiologist is the most appropriate person to have total oversight over the preoperative, intraoperative and postoperative phases of the care of the surgical patient. I certainly recognize that the preoperative assessment is improved when coordinated with anesthesia personnel who counsel patients regarding current

medications and the potential risks of anesthesia associated with certain comorbidities. The American Society of Anesthesiology (ASA) is now advocating the concept of the “perioperativist” and the Perioperative Surgical Home (PSH; see www.asahq.org) and espouses the concept that in the name of safety, economy and overall efficiency, management of operative patients should be

coordinated in a multidisnot capable of or have abdicated their role in the manciplinary fashion and that this approach should be led agement of the perioperative by the anesthesiologist. The patient. This includes dis“perioperativist,” by definipensing information in the tion, is the anesthesiologist Frederick L. Greene, MD preoperative setting as well who will provide overall supas providing appropriate port in all phases for the surgical patient. post-anesthesiaa care and other postopIt appears that some in the anesthe- erative supervision regarding perioperasia community believe that surgeons are tive drug management, pain control and

Experience the power of predictable control 1- 4

Visit www.aboutULTIVA.com to see how Remi could work for you. *Remifentanil is commonly referred to as Remi by anesthesia providers. † Continuous infusions of Remi should be administered only by an infusion device and continuous monitoring is necessary. Interruption of infusion will result in rapid offset of effect. ‡ Within 5 to 10 minutes after discontinuation of Remi, no residual analgesic activity will be present. However, respiratory depression may occur in some patients up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Other analgesics should be administered prior to discontinuation of Remi where postoperative pain is anticipated. INDICATIONS ULTIVA® (remifentanil HCl) for Injection is indicated for intravenous administration: • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting • As an analgesic component of monitored anesthesia care in adult patients

ULTIVA is a registered trademark of Glaxo Group Limited. The Mylan logo is a registered trademark of Mylan Inc.

IMPORTANT RISK INFORMATION Continuous infusions of ULTIVA should be administered only by an infusion device. IV bolus administration of ULTIVA should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of ULTIVA should be administered over 30 to 60 seconds. Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects (within 5 to 10 min) upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia particularly where postoperative pain is anticipated. Vital signs and oxygenation must be continuously monitored during ULTIVA administration. ULTIVA produces adverse events that are characteristic of μ-opioids, such as respiratory depression, apnea, tachycardia, bradycardia, hypotension,

ULT-2014-0052

MARCH 2015

AnesthesiologyNews.com I 15

POLICY & MANAGEMENT even recommendations for postoperative activity. I certainly agree that a coordinated multidisciplinary approach for the patient undergoing an operation is both reasonable and beneficial. The PSH should be a patient-centered, physician-led, multidisciplinary team– based model of coordinated care. The preoperative, intraoperative, immediate postoperative and post-discharge care should be fully coordinated and treated as a continuum of care.

My concern, however, is that in this model, the surgeon is marginalized while the anesthesiologist assumes the role of the “perioperativist” in ensuring that all of these phases are coordinated. The president of the ASA opined that “physician anesthesiologist–led anesthesia care teams are associated with better patient outcomes, fewer complications, less pain, earlier return to functionality and home, and lower costs” (ASA website, December 2014). Our anesthesiology colleagues believe

that the best specialty and best specialist to coordinate this overarching activity is the anesthesiology-created “perioperativist.” The creation of new specialty models and physician genres has generally occurred because of abdication of certain responsibilities and traditional roles previously provided by physicians and specialties. I would certainly not want to see the role of the operating surgeon sequestered solely into the technical phase of an operation while

Remi* is a potent μ-opioid agonist with rapid analgesic onset and peak effect, and short duration of action.†1

Rapid response†1

Early post-op neurological assessment‡3,4

Rapid recovery‡1

No accumulation1

Established hemodynamic proﬁle1,2 Remi produces adverse events that are characteristic of μ-opioids, such as respiratory depression, apnea, tachycardia, bradycardia, hypotension, hypertension, and skeletal muscle (including chest wall) rigidity. Please see Indications and Important Risk Information below, and accompanying brief summary of Prescribing Information on adjacent page for all precautions, warnings, contraindications, and adverse events. hypertension, and skeletal muscle (including chest wall) rigidity. Because these effects are dose-dependent and can occur rapidly, continuous monitoring is necessary. ULTIVA should not be used as a sole agent because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. ULTIVA should be used with caution in pediatric, geriatric, and morbidly obese patients due to high variability in pharmacodynamics and dose/response. Intraoperative awareness has been reported with concomitant administration with propofol infusion ≤75 mcg/kg/min. Failure to adequately clear the IV tubing to remove residual ULTIVA has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional ﬂuids or medications through the same IV tubing.

October 2014

Due to the presence of glycine in the formulation, ULTIVA is contraindicated for epidural or intrathecal administration. ULTIVA is also contraindicated in patients with known hypersensitivity to fentanyl analogs. ULTIVA SHOULD BE USED IN A CAREFULLY MONITORED SETTING BY SPECIFICALLY TRAINED PERSONS NOT INVOLVED IN THE SURGICAL OR DIAGNOSTIC PROCEDURE. OXYGEN SATURATION IS TO BE CONTINUOUSLY MONITORED. RESUSCITATIVE AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST MUST BE READILY AVAILABLE. References: 1. ULTIVA [package insert]. Rockford, IL: Mylan Institutional LLC; 2011. 2. Twersky RS, et al. J Clin Anesth. 2001;13(6):407-416. 3. Wilhelm W, et al. Br J Anaesth. 2001;86(1):44-49. 4. Bilotta F, et al. Eur J Anaesth. 2007;24(2):122-127.

leaving the preparation, education and postoperative management of patients to the nonsurgical “perioperativist.” Although some facets of the PSH are appealing, the overall management of the surgical patient must not transition to nonsurgical specialists because of the presumption that we have undervalued or abdicated our responsibility for coordinating the care of the surgical patient. The operating surgeon should and must remain the captain of the entire ship!

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CLINICAL ANESTHESIOLOGY

Anesthesiologists Must Strive To Improve Infection Control New York—It is important for those in the anesthesiology community to work together to improve infection control practices and to prevent the occurrence of infections linked to the practice of anesthesiology. That was the message from a session (“Infection Control Issues Impacting Anesthesia Practice: What’s the Evidence?”) held at the recent

ULTIVA® for Injection

New York State Society of Anesthesiologists’ (NYSSA) 68th Annual PostGraduate Assembly (PGA) in Anesthesiology. The speakers cited an article (Anesth ( Analgg 2014 Jun 16. [Epub ahead of print]) that found a within- and between-case Enterococcus faecalis transmission rate of 11% to 23%. They also noted that some hepatitis B and C outbreaks in health

(remifentanil hydrochloride) For IV Use Only Rx only Brief Summary: The following is a brief summary only. Before prescribing, see complete ULTIVA prescribing information. CONTRAINDICATIONS Due to the presence of glycine in the formulation, ULTIVA is contraindicated for epidural or intrathecal administration. ULTIVAA is also contraindicated in patients with known hypersensitivity to fentanyl analogs. WARNINGS AND PRECAUTIONS Continuous infusions of ULTIVA should be administered only by an infusion device. IV bolus administration of ULTIVA should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of ULTIVA should be administered over 30 to 60 seconds. Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia. Injections of ULTIVA should be made into IV tubing at or close to the venous cannula. Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later point in time. Failure to adequately clear the IV tubing to remove residual ULTIVA has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing. USE OF ULTIVA IS ASSOCIATED WITH APNEA AND RESPIRATORY DEPRESSION. ULTIVA SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF ANESTHETIC DRUGS AND THE MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS, INCLUDING RESPIRATORY AND CARDIAC RESUSCITATION OF PATIENTS IN THE AGE GROUP BEING TREATED. SUCH TRAINING MUST INCLUDE THE ESTABLISHMENT AND MAINTENANCE OF A PATENT AIRWAY AND ASSISTED VENTILATION. ULTIVA SHOULD NOT BE USED IN DIAGNOSTIC OR THERAPEUTIC PROCEDURES OUTSIDE THE MONITORED ANESTHESIA CARE SETTING. PATIENTS RECEIVING MONITORED ANESTHESIA CARE SHOULD BE CONTINUOUSLY MONITORED BY PERSONS NOT INVOLVED IN THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE. OXYGEN SATURATION SHOULD BE MONITORED ON A CONTINUOUS BASIS. RESUSCITATIVE AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST MUST BE READILY AVAILABLE. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of ULTIVA V by 50% or by temporarily discontinuing the infusion. Skeletal muscle rigidity can be caused by ULTIVA and is related to the dose and speed of administration. ULTIVA may cause chest wall rigidity (inability to ventilate) after single doses of >1 mcg/kg administered over 30 to 60 seconds, or after infusion rates >0.1 mcg/kg/min. Single doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of ULTIVA. Muscle rigidity induced by ULTIVA should be managed in the context of the patient’s clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications. Muscle rigidity seen during the use of ULTIVA in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of ULTIVA. Resolution of muscle rigidity after discontinuing the infusion of ULTIVA occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered. ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. PRECAUTIONS Vital signs and oxygenation must be continually monitored during the administration of ULTIVA. General: Bradycardia has been reported with ULTIVA and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate. Hypotension has been reported with ULTIVA and is responsive to decreases in the administration of ULTIVA or to IV fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration. Intraoperative awareness has been reported in patients under 55 years of age when ULTIVA has been administered with propofol infusion rates of ≤ 75 mcg/kg/min. Rapid Offset of Action: WITHIN 5 TO 10 MINUTES AFTER THE DISCONTINUATION OF ULTIVA, NO RESIDUAL ANALGESIC ACTIVITY WILL BE PRESENT. However, respiratory depression may occur in some patients up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of ULTIVA. ULTIVA should not be used as a sole agent for induction of anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. Pediatric Use: The efficacy and safety of ULTIVA as an analgesic agent for use in the maintenance of general anesthesia in outpatient and inpatient pediatric surgery have been established in controlled clinical trials in pediatric patients from birth to 12 years. In clinical trials, the clearance rate observed in neonates was highly variable and on average was two times higher than in the young healthy adult population. While a starting infusion rate of 0.4 mcg/kg/min may be appropriate for some neonates, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required. The individual dose for each patient should be carefully titrated (see ULTIVA Prescribing Information [PI], DOSAGE AND ADMINISTRATION, Table 11). ULTIVA has not been studied in pediatric patients for use as a postoperative analgesic or as an analgesic component of monitored anesthesia care. Geriatric Use: Of the total number of subjects in clinical studies of ULTIVA, 486 were in the age range 66 to 90 years. While the effective biological half-life of remifentanil is unchanged, elderly patients have been shown to be twice as sensitive as the younger population to the pharmacodynamic effects of remifentanil. The recommended starting dose of ULTIVA should be decreased by 50% in patients over 65 years of age. Use in Morbidly Obese Patients: As for all potent opioids, caution is required with use in morbidly obese patients because of alterations in cardiovascular and respiratory physiology. Long-term Use in the ICU: No data are available on the long-term (> 16 hours) use of ULTIVA as an analgesic in ICU patients. Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with remifentanil. Remifentanil did not induce gene mutation in prokaryotic cells in vitroo and was not genotoxic in an in vivoo rat assay. No clastogenic effect was seen in hamster or mouse studies. In the in vitroo mouse lymphoma assay, mutagenicity was seen only with metabolic activation. Remifentanil has been shown to reduce fertility in male rats when tested after approximately 40 times the maximum recommended human dose (MRHD). The fertility of female rats was not affected at IV doses as high as 1 mg/kg when administered for at least 15 days before mating. Pregnancy Category C: Teratogenic effects were not observed in either rats or rabbits following administration of remifentanil at doses up to 400 times and 125 times the MRHD, respectively. Administration of radiolabeled remifentanil to pregnant rabbits

care settings over the past 15 years have been attributed to mishandling of medications, fluids, syringes, needles and cannulae by anesthesia professionals. Meanwhile, however, some published infection control recommendations, such as a provision of the US Pharmacopeia (USP) Chapter <797>, present unique challenges to anesthesia professionals.

and rats demonstrated significant placental transfer to fetal tissue. There are no adequate and well-controlled studies in pregnant women. ULTIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of remifentanil to rats throughout late gestation and lactation at IV doses up to 400 times the MRHD in terms of mg/m2 of body surface area, had no significant effect on the survival, development, or reproductive performance of the F1 generation. Animal Toxicology: Intrathecal administration of the glycine formulation without remifentanil to dogs caused agitation, pain, hind limb dysfunction, and incoordination. These effects are believed to be caused by the glycine. Glycine is a commonly used excipient in IV products and this finding has no relevance for IV administration of ULTIVA. Labor and Delivery: Respiratory depression and other opioid effects may occur in newborns whose mothers are given ULTIVA shortly before delivery. The safety of ULTIVA during labor or delivery has not been demonstrated. Placental transfer studies in rats and rabbits showed that pups are exposed to remifentanil and its metabolites. In a human clinical trial, the average maternal remifentanil concentrations were approximately twice those seen in the fetus. In some cases, however, fetal concentrations were similar to those in the mother. The umbilical arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate. Nursing Mothers: It is not known whether remifentanil is excreted in human milk. After receiving radioactive-labeled remifentanil, the radioactivity was present in the milk of lactating rats. Because fentanyl analogs are excreted in human milk, caution should be exercised when ULTIVA is administered to a nursing woman. ADVERSE EVENTS In controlled clinical trials in approximately 2770 adult patients, ULTIVA produced adverse events characteristic of μ-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipated within minutes of discontinuing or decreasing the infusion rate of ULTIVA. Table 1: Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies* at the Recommended Doses† of ULTIVA Induction/Maintenance Adverse Event Nausea Hypotension Vomiting Muscle rigidity Bradycardia Shivering Fever Dizziness Visual disturbance Headache Respiratory depression Apnea Pruritus Tachycardia Postoperative pain Hypertension Agitation Hypoxia

ULTIVA (n=921)

Alfentanil/ Fentanyl (n=466)

Postoperative Analgesia ULTIVA (n=281)

Morphine (n=98)

After Discontinuation ULTIVA (n=929)

Alfentanil/ Fentanyl (n=466)

8 (<1%) 178 (19%) 4 (<1 % ) 98 (11%)‡ 62 (7%) 3 (<1%) 1 (<1%) 0 0 0

0 30 (6%) 1 (<1%) 37 (8%) 24 (5%) 0 0 0 0 0

61 (22%) 0 22 (8%) 7 (2%) 3 (1%) 15 (5%) 2 (<1%) 1 (<1%) 0 1 (<1%)

15 (15%) 0 5 (5%) 0 3 (3%) 9 (9%) 0 0 0 1 (1%)

339 (36%) 16 (2%) 150 (16%) 2 (<1%) 11 (1%) 49 (5%) 44 (5%) 27 (3%) 24 (3%) 21 (2%)

202 (43%) 9 (2%) 91 (20%) 1 (<1%) 6 (1%) 10 (2%) 9 (2%) 9 (2%) 14 (3%) 8 (2%)

1 (<1%) 0 2 (<1%) 6 (<1%) 0 10 (1%) 2 (<1%) 0

0 1 (<1%) 0 7 (2%) 0 7 (2%) 0 0

19 (7%) 9 (3%) 7 (2%) 0 7 (2%) 5 (2%) 3 (1%) 1 (<1%)

4 (4%) 2 (2%) 1 (1%) 0 0 3 (3%) 1 (1%) 0

17 (2%) 2 (<1%) 22 (2%) 10 (1%) 4 (<1%) 12 (1%) 6 (<1%) 10 (1%)

20 (4%) 1 (<1%) 7 (2%) 8 (2%) 5 (1%) 8 (2%) 1 (<1%) 7 (2%)

*Does not include adverse events from cardiac studies or the neonatal study. See ULTIVA PI, Tables 6, 7, and 8 for cardiac information. † See ULTIVA PI, Table 10 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. Administration of ULTIVA in excess of the recommended dose (i.e., doses >1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%). ‡ Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is <1% when remifentanil is administered concurrently or after a hypnotic induction agent. In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower. DRUG ABUSE AND DEPENDENCE ULTIVA is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and has the potential for being abused. OVERDOSAGE As with all potent opioid analgesics, overdosage would be manifested by an extension of the pharmacological actions of ULTIVA. Expected signs and symptoms of overdosage include: apnea, chest-wall rigidity, seizures, hypoxemia, hypotension, and bradycardia. In case of overdosage or suspected overdosage, discontinue administration of ULTIVA, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If depressed respiration is associated with muscle rigidity, a neuromuscular blocking agent or a μ-opioid antagonist may be required to facilitate assisted or controlled respiration. Intravenous ﬂuids and vasopressors for the treatment of hypotension and other supportive measures may be employed. Glycopyrrolate or atropine may be useful for the treatment of bradycardia and/or hypotension. Intravenous administration of an opioid antagonist such as naloxone may be employed as a speciﬁc antidote to manage severe respiratory depression or muscle rigidity. Respiratory depression from overdosage with ULTIVA is not expected to last longer than the opioid antagonist, naloxone. Reversal of the opioid effects may lead to acute pain and sympathetic hyperactivity. ULTIVA is a registered trademark of Glaxo Group Limited. US Patent Nos. 5,019,583; and 5,866,591 Version C, 07/2011 Manufactured for Mylan Institutional LLC, Rockford, IL 61103 Manufactured by Hospira, Inc. Lake Forest, IL 60045

‘The long-term consequences of infections for our patients can be devastating. Sound, practical procedures must be designed to reduce their incidence and developed with the unique needs of anesthesia professionals in mind.’ —Amanda Rhee, MD

“Anesthesia professionals often react negatively to infection control policies, and many of these policies have been developed without input from anesthesia professionals,” Richard A. Beers, MD, professor of anesthesiology at State University of New York Upstate Medical University, in Syracuse, told the audience. As a result, he added, many of the policies include provisions that are “contradictory and paradoxical” to the safe and efficient delivery of anesthesia. For example, anesthesia professionals know the importance of hand hygiene; however, according to Dr. Beers, protocols that call for hand hygiene after every patient contact are impractical in the intraoperative setting because, during induction, anesthesia providers may contact the patient more than 150 times. Elliott S. Greene, MD, professor of anesthesiology, Albany Medical College, in New York, noted that the state is mulling legislation that would require pharmacists who are

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CLINICAL ANESTHESIOLOGY compounding medications to comply with the provisions of USP <797>. Nevertheless, he said there is limited evidence supporting the “immediateuse” provision of USP <797>, which is applicable to clinicians and requires a “use time” (time between preparation and use of medications and fluids) of one hour, after which disposal is required. He also noted that USP <797>, originally published in 2004, does not include reference citations. Anesthesiologists Can Do a Better Job Most infection control guidelines are strongly supported by clinical data—and there is evidence that anesthesia professionals can do a better job of following them. According to Dr. Greene, the Centers for Disease Control and Prevention (CDC) issued recommendations in 2007 for the safe use of needles, cannulae, syringes, medications and fluids, and reported on the etiology of outbreaks of blood-borne infections in health care settings. According to Dr. Greene, the CDC found that these outbreaks stemmed from: • the reuse of a syringe, cannula or needle for more than one patient; • the use of a contaminated syringe, cannula or needle to access a medication or fluid container; • the use of single-use containers for multiple patients; and/or • the preparation of medications in the same workplace where used needles, cannulae and syringes were dismantled. Multiple studies, he said, have documented these outbreaks, identified the faulty practices and discussed recommendations to eliminate unsafe practices. However, since 2001, the CDC has identified at least 49 hepatitis B, hepatitis C or bacterial outbreaks attributed to the aforementioned causes, with 26 outbreaks occurring since 2007—after the publication of its guidelines. Amanda Rhee, MD, assistant professor of anesthesiology, Icahn School of Medicine at Mount Sinai in New York City, acknowledged that “many health care professionals don’t like being asked to wash their hands.” She noted that there are creative solutions to the time constraints that potentially limit proper hand hygiene among anesthesia professionals, including the practice of “doublegloving” or the use of specially designed tools (she cited an example of a small portable device that

dispenses hand sanitizer). As Dr. Rhee told the audience at PGA, “We are different, therefore we need to address this problem differently.” Indeed, according to Dr. Rhee, hand hygiene has to be a fundamental component of any infection control program designed to reduce the incidence of surgical site infections (SSIs). At her institution, for example, researchers cultured the hands of anesthesia professionals to demonstrate the level of contaminants and “gain their buy-in”

to the program. Her team has also posted signs throughout the surgical section touting the message “foam in, foam out,” which reminds providers to wash their hands every time they enter and leave the room. Hygiene dispensers are conveniently located inside and outside the doors to every room in the section. Although he was not a speaker during the PGA lecture, Brian Currie, MD, MPH, assistant dean, clinical research, Montefiore Medical Center

and professor of clinical epidemiology and population health, Albert Einstein College of Medicine, New York City, said in an interview that he was pleased that anesthesiologists are paying greater attention to the issue of infection control, as he believes the profession, like many who work in the hospital setting, can improve in this regard. He lauded the NYSSA for including the topic on the PGA agenda; in comparison, he said infection control was only see infection page 26

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LMASUPREME.COM REFERENCES FERENCES 1. Belena J.M. et al. Journal of Clinical Anesthesia 2011; 23:456-460. | 2. Roiss M. et al. Poster presented at The American Association of Anesthesiologists Annual Meeting 15th -19th, Oct. 2011, Chicago. | 3. Sharma V. et al. BJA 2010; 105(2): 228-232. | 4. Whitacre W. et al. AANA Journal 2014; 82 (2): 101-107. | 5. Abdi W. et al. Acta Anaethesiol Scand. 2010; 54 (2): 141-146. | 6. Bernardini A. et al. Anesthesia 2009; 64: 1289-1294. | 7. Verghese C. et al. Anesthesia and Analgesia 1996; 82: 129-133. | 8. Tretiak S. Anethesiology News 2009. | 9. Viernes D. et al. Anesthesiology News 2010; 9-13. | 10. Verghese C. et al. BJA 2008; 101 (3): 405-410. | 11. Jagannathan N. et al. Pediatric Anesthesia 2012; 22:759-764. | 12. Jagannathan N. et al Anesthesia 2012; 67(2): 139-144. | 13. Ferson D. et al. Anesthesiology 2007; 107:A592.

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Postop Cognition in Elderly Improved With Dexamethasone New Orleans—One of the main adverse events faced by elderly patients undergoing surgery is postoperative cognitive dysfunction (POCD). Yet, according to researchers at the University of Sao Paulo, in Brazil, the incidence of POCD appears to be manageable with the addition of dexamethasone to a general anesthetic regimen, especially one that uses light anesthesia. As reported by Livia S. Valentin, PhD, POCD occurs most commonly in elderly patients, making it a very real issue, given the increasing frequency with which elderly patients are undergoing surgery based on current demographics. To help determine the effect of dexamethasone and depth of anesthesia on POCD after noncardiac surgery, the researchers enrolled 170 patients, aged 60 to 87 years, with American Society of Anesthesiologists performance status I-II, into the prospective, randomized double-blindd trial. The patients underwent general anesthesia that was either deep

QTc T

CONTINUED FROM PAGE 1

Vienna in Vienna, Austria. “If longer than 450 msec, it increases the risk of potentially life-threateningg arrhythmia. That brought us to the key questions in this study: Does QTc prolongation occur regularly in the intraoperative period and does the type of anesthesia influence the incidence of QTc prolongation?” To help answer those questions, Dr. Duma and his colleagues enrolled 300 patients into a prospective cohort study. QTc duration was continuously recorded by 12-lead Holter electrocardiogram from 30 minutes preoperatively to up to 60 minutes postoperatively. Additionally, QTc prolongation was compared between patients undergoing general (n=101) or spinal (n=99) anesthesia for orthopedic surgery, or local anesthesia for

or light according to the Bispectral Index (35-45 vs. 46-60, respectively). Of these, half received IV dexamethasone 8 mg and the remaining patients did not. Neuropsychological tests were administered preoperatively as well as on days 3, 7, 21, 90 and 180 after surgery; these data were then compared with normative data using Z-score analysis for POCD definition. “We observed that the group with the highest incidence of cognitive impairment was those receiving the

deep anesthesia without dexamethasone,” Dr. Valentin reported at the 2014 annual meeting of the American Society of Anesthesiologists (abstract A2045). Global cognitive function assessments performed on postoperative day 3 revealed that POCD occurred in 68.2% of patients undergoing deep anesthesia and 27.2% of those in the light-anesthesiaa group. By comparison, 25.2% of deep-anesthesia patients receiving dexamethasone, and 15.3% of those undergoing light

anesthesia and receiving dexamethasone experienced POCD (P<0.0001). “Not surprisingly, the incidence of postoperative cognitive dysfunction decreased during the evaluation period for all groups,” Dr. Valentin said. “Moreover, no patient in the dexamethasone–light anesthesia group presented with postoperative cognitive dysfunction six months after surgery [P<0.0001]. Neuropsychological testing also revealed that dexamethasone with light anesthesia was particularly effective in preserving long-term memory, attention and executive function. “We conclude that dexamethasone can reduce the incidence of postoperative cognitive dysfunction in noncardiac surgical patients undergoing general anesthesia, especially if the depth of anesthesia is light and the patients are elderly,” Dr. Valentin said. “It remains to be seen why this association exists, and further research is certainly warranted.”

biopsy (n=53) or diagnostic coronary angiography (n=47). Although the trial’s primary outcome was intraoperative QTc increase (defined as the intraoperative-to-preoperative QTc duration difference), the researchers also determined the incidence of long QTc episodes, defined as those greater than 500 msec for at least 15 minutes. “Within all cohorts, the general anesthesia cohort had the most pronounced intraoperative QTc prolongation, with a median of 33 msec [range, 22-46 msec],” Dr. Dumaa reported at the 2014 annual meeting of the American Society of Anesthesiologists (abstract A1020). “This declined postoperatively but never went back to baseline.” Significant QTc prolongation also occurred during spinal anesthesia (mean 22 msec; range, 12-29 msec). By comparison, no QTc prolongation was observed during local anesthesia: mean 4 msec during biopsy

(range, –4 to 7 msec) and 6 msec during coronary angiography (range –5 to 16 msec). The Table illustrates the median preoperative, intraoperative and postoperative QTc for the three groups. “We also performed a secondary analysis to see if those patients who had a QTc prolongation greater than 500 msec already had prolonged QTc duration at baseline,” Dr. Dumaa said. It was found that the relative incidence risk for a long QTc episode—defined as

QTc greater than 500 msec for at least 15 minutes—was 5.3 (95% confidence interval, 0.7-43) times greater with general than with spinal anesthesia. Finally, the investigators analyzed the incidence of moderate (>0 to ≤30 msec), marked (>30 to <60 msec) and substantial (≥60 msec) QTc prolongation by anesthesia type (Figure). “In the general anesthesia group, 64% had either marked or substantial QTc prolongation,” Dr. Duma said.

Table. Median Preoperative, Intraoperative and Postoperative QTc For Three Anesthesia Types Preoperative QTc, msec General

430

Intraoperative QTc, msec 464

Postoperative QTc, msec

≥60 msec 100%

80%

33%

≥0 to ≤30 msec

<0 msec

60%

40%

>30 to <60 msec

33%

38%

74%

57%

54% 62%

20% 21% 11%

10%

447 0%

Spinal

438

457

461

Local (biopsy)

421

420

421

Local (angiography)

448

454

450

General Anesthesia

Spinal Anesthesia

Local Anesthesia Biopsy

Local Anesthesia Coronary Angiography

Figure. Prevalence of moderate, marked and substantial QTc prolongation by anesthesia type.

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AnesthesiologyNews.com I 19

CLINICAL ANESTHESIOLOGY According to Roderic G. Eckenhoff, MD, the Austin Lamont Professor and vice chair for research at the Perelman School of Medicine, at the University of Pennsylvania, in Philadelphia, the rationale for dexamethasone’s ability to mitigate POCD is clear and logical. “It is known that surgery induces peripheral inflammation, and that in many patients this stimulates neuroinflammation as well, causing well-described ‘sickness behavior,’” he said. “This may be ‘early’ POCD, which resolves in most people, but could turn into ‘durable’ POCD in certain subpopulations. “But if it all starts from inflammation, then a strong anti-inflammatoryy drug like dexamethasone should block it. The Valentin study supports this idea, but extends it by also implicating anesthesia depth, which has variously been also implicated by other studies. The anesthetic itself could also be important, as some have suggested that certain drugs, such as isoflurane, are worse than others. Unfortunately, single clinical studies are rarely definitive.” Indeed, as Dr. Eckenhofff pointed out, at least two other trials of

This compared with 21% for the spinal anesthesia group, 0% for the local anesthesia biopsy group and 11% for the local anesthesia angiography group. “Nine percent of patients in the general anesthesia group even had a QTc prolongation longer than 500 msec,” Dr. Duma added. “In conclusion,” he said, “QTc prolongation is not an isolated postoperative phenomenon, but starts early during anesthesia and surgical care. Moreover, marked QTc prolongation is common under general and spinal anesthesia.” Bruce D. Spiess, MD, professor of anesthesiology and director of the Virginia Commonwealth University Reanimation Engineering Shock Center in Richmond, found the study intriguing. “Perhaps the QTc prolongation is a factor of whole-bodyy generalized inflammation rather than anesthesia,” he said. “It strikes me that short procedures and local procedures do not have the event-related QTc prolongation. Many things get ascribed to anesthesia, but perhaps they are really part of the entire process of a major operation. As a result, general and spinal anesthesia may be preferable for a surgical event that involves more inflammatory processes than just a local excision.”

dexamethasone were published in 2014, neither of which demonstrated a beneficial effect of the drug on POCD ((J Neurosurg Anesthesioll 2014; 26:220-225; Anesthesiology 2014;121: 492-500). “The bottom line,” he said, “is that sufficient evidence to change practice does not yet exist, and that more research on this important topic is needed.” —Michael Vlessides Dr. Valentin reported no financial conflicts of interest.

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CLINICAL ANESTHESIOLOGY

Multimodal Antiemesis Protocol Loses Efficacy Post-Discharge

multimodal antiemetic protocol can help to reduce postoperative nausea and vomiting (PONV) in patients undergoing Le Fort I osteotomy, but has little effect on post-discharge nausea and vomiting (PDNV), according to findings from two recent studies. As noted in the latest consensus guidelines for the management of PONV

(Anesth Analgg 2014;118:85-113), PONV is common and distressing to patients and can lead to increased medical costs and time in the postanesthesia care unit. The prevalence of PONV in the 24 hours after surgery is 44% to 68% in Le Fort I osteotomy patients compared with 8% to 30% in general surgery populations, according to researchers from the University of North Carolina at

Chapel Hill. They conducted these studies to draw attention to these patients because they are “often underappreciated as a high-riskk group.” The researchers believe that factors such as having their jaws held together by elastics, swallowing blood during and after surgery, altered diets, lengthy surgical times and deliberate hypotension may increase these patients’ risk for PONV.

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Le Fort I Osteotomy “Imagine if you have nausea, or even worse, vomiting with your teeth held together like that, there’s all sorts of issues that can occur, like bleeding, wound complications and infection,” said Jay A. Anderson, DDS, MD, associate professor, Department of Anesthesiology, School of Medicine, and Department of Oral & Maxillofacial Surgery, School of Dentistry, the University of North Carolina at Chapel Hill. “And of course, it’s very unpleasant for the patient and their family.” The first study was an institutional review board–certified prospective clinical trial to assess the effectiveness of a multimodal antiemetic protocol for reducing PONV. The trial consisted of 230 patients undergoing Le Fort I osteotomy with or without additional procedures at a single academic institution. Patients were divided into an intervention group that received the protocol (n=93) and a retrospective comparison group (n=137) managed primarily with volatile anesthetics and standard narcotics. Both groups were asked to record in a diary any incidents of PONV. The protocol was based primarily on guidelines from the Society for Ambulatory Anesthesia, and included the use of total IV anesthesia; prophylactic ondansetron, steroids and a scopolamine patch; gastric decompression at the end of surgery; opioid-sparingg analgesia; prokinetic erythromycin; and administration of fluids at a minimum of 25 mL/kg. Dr. Anderson and his colleagues asked the anesthesia team managing these patients to limit excessive use of opioids and to avoid using volatile anesthetics, nitrous oxide, morphine and codeine to minimize the potential risk for PONV. “Our protocol was, first of all, to basically eliminate anesthetic factors that we know promote nausea and vomiting,” said Dr. Anderson. Results The researchers found that the protocol significantly reduced the intervention group’s prevalence of postoperative nausea (PON) from 70% to 23% (P<0.0001) and postoperative vomiting (POV) from 30% to 10% (P=0.01)—P<0.05 was considered significant. They hypothesized that this protocol would have a similar outcome for PDNV, but were disappointed to find that it did not have a lasting effect. Patients were followed for one

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AnesthesiologyNews.com I 21

CLINICAL ANESTHESIOLOGY ‘What I see every day when I’m interviewing patients is that many of them are more concerned about nausea and vomiting afterward than almost any other factor related to their anesthesia care.’

giving five or six antiemetics is good practice.” Dr. Gan said a randomized controlled study is needed to provide better data. Dr. Anderson said he did not see any adverse effects from this combination of antiemetic drugs and that more research is needed. He said they —Jay A. Anderson, DDS, MD are currently looking to design a better He noted that using more antiemet“There is no evidence that anything multimodal analgesia regimen and to ics does not increase the efficacy of the more than three prophylactic antiemet- simplify the previous protocol. protocol and may even increase the risk ics is better than five or six,” he said. —Martin Leung for potential adverse drug interactions. “There is really no data to suggest that

week after discharge from the hospital and asked to record any incidents of PDNV. The diaries were completed by 79 patients in the intervention group (85%) and 103 in the comparison group (75%). The entries were then compared with the first week of diary entries from the initial study. The researchers found that postdischarge nausea was reported by 72% in the intervention group and 60% in the comparison group and the rates of post-discharge vomiting were 22% and 29%, respectively. Dr. Anderson said PDNV usually lasts one to two days, and the risk for readmission is rare but is a possibility. He said the biggest reason for reducing PDNV is because it is a major fear of patients and affects overall patient satisfaction and well-being. “What I see every day when I’m interviewing patients is that many of them are more concerned about nausea and vomiting afterward than almost any other factor related to their anesthesia care,” he said. “It’s a big concern for the patients, especially when you add the fact that they had an operation in their mouth and now their teeth are being held together with elastics. That becomes that much more of an anxiety-provokingg situation.” Tong Joo (TJ) Gan, MD, professor and chairman of the Department of Anesthesiology at Stony Brook University, in Stony Brook, N.Y., agreed that it is equally important to reduce PONV and PDNV to maximize patient satisfaction. However, Dr. Gan said he is not surprised by the results of this multimodal antiemetic protocol for PDNV. “Most of the antiemetics are fairly short-acting, so I’m not really surprised that in the immediate post-op period there is significant relief, but post-discharge there is no difference,” Dr. Gan said.

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TECHNOLOGY

3D Anatomy System Aids Anatomy Recognition New Orleans—Ten postgraduate year-44 (PGYY 4) anesthesia residents took part in a pilot study of a threedimensionall (3D) anatomy simulator as an aid to identifying regional anesthesia anatomy on ultrasound. By so doing, this small group of University of Pittsburgh residents got a sneak peek into the future. The residents were asked to identify 20 ultrasound-based anatomic

structures relevant to regional nerve blockade, with and without the aid of the 3D system. After being stumped nearly half of the time without the use of the 3D system, the residents were able to identify 85% of the structures with the aid of the 3D system. The 3DMAS (3-dimensional Multiview Anatomy System; Panasonic Corporation ACV Networks Company;

Osaka, Japan) uses a proprietary workstation, consisting of a hard drive, 3D monitor and 3D glasses, to display multilayered images of a dissected cadaver. The images can be rotated, magnified and dissected layer by layer. They also can be displayed in two dimensions. In 2013, Joe Resti, MD, at the time a third-year resident in the Department

Anesthesia residents use the 3DMAS as an aid to identify sonographic structures during ultrasoundguided upper extremity brachial plexus blockade.

of Anesthesia at the University of Pittsburgh Medical Center (UPMC), and two of his colleagues recruited 10 PGYY 4 anesthesia residents with prior experience conducting regional nerve blocks and instructed them on the use of the system. Following training, participants were asked to examine several ultrasound images and identify 20 interscalene, axillary, femoral and popliteal fossa structures without the aid of the 3DMAS. They were then able to use the 3DMAS to name the structures they had not recognized on ultrasound alone. In a presentation at the American Society of Anesthesiologists’ 2014 annual meeting (abstract A1040), coinvestigator Pulsar Li, DO, a thirdyear anesthesia resident at UPMC, reported that participants identified an average of 51% of the structures correctly without the use of the 3DMAS. With access to the system, they correctly named an additional 68% of the structures they were not able to initially (Table). The findings are preliminary and further research is needed to confirm the utility of the technology, Dr. Li noted. However, the results indicate the need for better approaches to teaching the anatomy of regional anesthesia, he said. “A big problem in anatomy education is that there are significant lapses in the time between the study of anatomy and the study of regional anesthesia,”

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AnesthesiologyNews.com I 23

TECHNOLOGY deceased body have become more significant for our anatomy instruction,” he explained. “This type of 3D technology is very exciting and a big step toward shortening the sono-anatomyy learning curve for regional nerve blocks,” said interventional pain expert Sukdeb Datta, MD, who is a professorial lecturer in the Department of Anesthesiology at Icahn School of Medicine at Mount Sinai, in New York City, and medical director of the Datta Endoscopic Back Surgery and

Pain Center, also in New York City. A virtual cadaver system also has the advantage of allowing users to “backk track” their dissection, said Dr. Datta, who was not involved in the research. “This type of 3D technology probably provides better depth perception than learning from embalmed cadavers, since once the layers are removed from a cadaver it is very difficult to reconstruct and return to previous layers and understand spatial relationships between anatomical structures,” he said.

Although the system has not been studied in the clinical setting, Dr. Orebaugh believes it could hold value for practicing anesthesiologists. “I think that for highly motivated clinicians who want to refresh or retain their knowledge of anatomy, this is a wonderful tool,” he said. The 3DMAS is not yet available in the United States. —David Wild Drs. Li, Orebaugh and Datta reported no relevant financial conflicts of interest.

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explained Dr. Li. “Spatial relationships can be lost, for example.” The 3DMAS offers a cadaver-based tutorial “that can be quickly utilized at any point in the education process,” he said. Dr. Li’s instructor and co-investigator,r Steven Orebaugh, MD, who is professor of anesthesiology and critical care medicine at the University of Pittsburgh, added that virtual anatomy education systems like the 3DMAS could substitute for actual cadavers in some instances. “As costs for cadavers have increased, and more and more strident regulations about access and potential infectious issues have been put into place, the practical limitations of using the

Overall (Pre and Post): % Correct

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POLICY & MANAGEMENT

The Morbidity and Mortality Conference: Its Origin and Evolution By Sandiya Bindroo, MD, MS, and Yaniv Cozacov, MD These standards of objective truth and criticism may teach him (the individual man) to try again and to think again; to challenge his own conclusions, and to use his imagination in trying to find whether and where his own conclusions are at fault. They may teach him to apply the method of trial and error in every field, and especially in science; and thus they may teach him how to learn from his mistakes, and how to search for them. These standards may help him to discover how little he knows and how much there is he does not know. They may help him to grow in knowledge, and also to realize that he is growing. They may help him to become aware of the fact that he owes his growth to other people’s criticism and that reasonableness is readiness to listen to criticism. —Karl Popper, 1978

he morbidity and mortality conference (M&MC) appears to have sprung from the efforts of physicians to improve practice through the examination of medical errors and bad outcomes. It developed as a means of quality control for medical practice, by which the profession would regulate its activities with the intention of improving overall patient care.1 The first antecedents of the M&MC are difficult to trace. The rise of a modern hospital as a center of clinical practice and education stimulated the development of systems to review, standardize and improve medical procedures. Hospital committees were established to examine adverse outcomes. These committees represent the most immediate precursors of the M&MC. The first clinical audit was undertaken by Florence Nightingale during the Crimean War of 1853-1855, in Scutari, in modern-dayy Turkey, at Medical Barracks Hospital. Nightingale was appalled by the unsanitary conditions and high mortality rates among injured or ill soldiers. She and her team of 38 nurses applied strict sanitary routines and standards

of hygiene to the hospital and equipment, and kept meticulous records of the mortality rates among the patients. After this change, the mortality rate fell from 40% to 2%. Nightingale’s methodical approach is recognized as one of the earliest programs of outcomes management.2 Historically, clinical audit was introduced by Ernest W. Hey Groves, MD, in 1908 in Great Britain and Ernest Amory Codman, MD, in 1910 in the United States. Formal collection of hospital records and statistics was advocated by Percival in his “Medical Ethics,”3 by Florence Nightingale in her “Notes on Hospitals,”4 and by Groves in an article in the British Medical Journall in 1908.5 Although they all argued that this organized approach would help the systematic improvement of hospital treatment, their pleas fell on deaf ears. In 1900, Dr. Codman conceived his “end result idea,” a vision that each hospital should analyze the results of treatment in every patient and study the long-term outcomes with a view toward improving treatment. Dr. Codman applied the methods of the natural scientist and the industrial manager to surgical practice at Massachusetts General Hospital, in Boston. He reflected a desire to improve medical practice by the examination of experience. He developed the concept of the end result card, which documented each patient’s symptoms, clinical diagnosis, treatment plan, complications, final diagnosis and annually updated outcome. Whenever perfection was not achieved, an analysis of the cause was detailed on the card, based on the taxonomy of errors he developed.6 Dr. Codman called for open acknowledgment of these “end results” to physicians and to the public, and challenged hospitals to hire clerks to record these data, to publish results and to establish efficiency committees empowered to correct errors identified by this process. Dr. Codman’s ideas elicited intense opposition from physicians, who resisted the loss of autonomy inherent in his model. In 1910, Abraham The first clinical audit was performed by Florence Nightingale. Flexner published a scathing attack on

the standard of American medical schools and hospitals,7 which led to drastic changes in these schools and stimulated the Clinical Congress of North America to announce plans for the reform of hospital care and surgical practice. Congress was influenced by Dr. Codman, who had resigned from Massachusetts General Hospital because of his dissatisfaction with the standards of surgical care.8 Dr. Codman set up his own hospital, published abstracts of all cases admitted between 1912 and 1916, and analyzed unfavorable results. He advocated critical appraisal of the care of individual cases, arguing that it would help to discover correctable deficiencies and to improve the overall quality of medical care. Dr. Codman’s views were ahead of their time.9 His zeal alarmed some doctors, and no hospital fully accepted his challenge to analyze and compare cases according to his proposals.

There were sporadic but unsuccessful attempts to promote the audit of patient care during the 1920s and 1930s. In 1935, the Philadelphia County Medical Society continued in this tradition by forming a group initially called the Anesthesia Mortality Committee, which was an early precursor of the M&MC. The American College of Surgeons (ACS) took over the work of Dr. Codman and his colleagues, and introduced a “hospital standardization program.” But this was limited to five aspects: medical staff organization; qualifications for medical staff membership; rules and policies governing professional work in the hospital; medical records; and diagnostic and therapeutic facilities. The program’s results were beneficial. Yet this program omitted the analysis of outcomes and the identification of avoidable errors, the two points about which Dr. Codman was most concerned. Dr. Codman’s ideas ultimately contributed to the standardization of hospital practices by the ACS in 1916. This has relevance even today for both the M&MC and quality assurance practices. There were sporadic but unsuccessful attempts to promote the audit of patient care during the 1920s and 1930s. In 1935, the Philadelphia County Medical Society continued in this tradition by forming a group initially called the Anesthesia Mortality Committee, which was an early precursor of the M&MC. Its objective was to facilitate discussion and to share knowledge about fatalities secondary to anesthesia, and “other interesting anesthetic situations.”10 This multi-institutional review group attempted to disseminate new information and to improve community standards of care. In 1940, the name of the organization was changed to the Anesthesia Study Commission, and its mandate was expanded to review a variety of

MARCH 2015

AnesthesiologyNews.com I 25

POLICY & MANAGEMENT topics, not limited to fatalities. It met monthly and was composed of anesthesiologists, surgeons and internists representing a variety of institutions. Its meetings were open to “all physicians, residents and interns … as well as numerous nonresident visitors.” The commission generated periodic public reports of its activities. In his 1945 review of the commission’s history and data, anesthesiologist Henry Ruth, MD, reported that at least two-thirds of fatalities reviewed were classified as preventable, and that the commission’s conclusions often differed from the causes of death included on death reports.10 The goals and format of the Anesthesia Mortality Committee have been highly influential and widely replicated. It is instructive to review the elements of this antecedent of the M&MC that remain relevant to our current conferences. Meetings were held monthly, and error was confronted directly, albeit anonymously. The style was participatory; discussion proceeded with comments from the floor. Physicians caring for the patient were not identified by name, but Dr. Ruth reports that they not infrequently chose to identify themselves during the discussion of the case. Dr. Ruth’s work stressed the instructional value of open discourse of problematic cases while protecting participants through optional participation. Nevertheless, Dr. Ruth describes tension within the Mortality Committee between its educational goals and a fear of incrimination on the part of participants. The historical tensions inherent in the roots of the M&MC remain relevant today. Over the years, the M&MC has evolved as a forum for resident education. The conference is now a required component of surgical resident training, mandated by the Accreditation Council for Graduate Medical Education.11 Although application was irregular, surgical audit was promoted internationally by 1950. In 1953, the ACS, in collaboration with the Committee on Professional Hospital Activities, initiated a research program to “develop an adequate surgical audit.” The audit system was adopted for a range of surgical specialties; continuing modifications were made; and the ability to analyze very large databases became available. A regional audit committee was first established in Yorkshire, England, in 1989.11 Despite this progress, several shortcomings of the M&MC and surgical audits were frequently noted, and this

led to a proactive approach in the form of a surgical quality improvement program. The ACS’s National Surgical Quality Improvement Program is the first validated, outcome-based, riskadjusted and peer-controlled program for the measurement and enhancement of the quality of surgical care.12 References 1. Bulstrode CJK, Russel RCG, Williams NS. Surgical audit. In: Bailey & Love’s Short Practice of Surgery. y 23rd ed. London, UK: Arnold; 2000:1307-1313.

2. Morrell C, Richard B, Shaw E, et al. Principles of Best Practices in Surgery. y NICE 2002. Scrivener R, Morrell C, Baker R, et al. Principles for Best Practice in Clinical Audit. National Institute for Clinical Excellence. Abingdon, UK: Radcliffe Medical Press; 2002. 3. Percival T. Medical Ethics. 3rd ed. Oxford, UK: John Henry Parker; 1849. 4. Nightingale F. Notes on Hospitals. 3rd ed. London, UK: Longman, Green, Longman, Roberts, and Green; 1863. 5. Groves EW. Surgical statistics: a plea for uniform registration of operation results. Br Med J. 1908;7:ii:1008-1009. 6. Reverby S. Stealing the golden eggs: Ernest Amory Codman and the science and management of medicine. Bull Hist Med. 1981;55:156-171.

7. Flexner A. Medical education in the United States and Canada. New York, NY: Carnegie Foundation; 1910. 8. Codman EA. A study in hospital efficiency: the first five years. Boston, MA: Thomas Todd Co; 1916. Available from University Microfilms, Ann Arbor, Michigan. 9. Lembcke PA. Evolution of the medical audit. JAMA. 1967;199:534-550. 10. Ruth HS. Anesthesia study commissions. JAMA. 1945;127:514-517. 11. Amanda JL, Gabbay J, McNicol MC, et al. What did audits achieve? Lessons from preliminary evaluation of a year’s medical audit. Br Med J. 1990;301:526-529. 12. Wright JE. The history of surgical audit. J Qual Clin Pract. 1995;15:81-88.

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POLICY & MANAGEMENT INFECTION

CONTINUED FROM PAGE 17

included as part of two larger sessions at the annual meeting of the American Society of Anesthesiologists. Dr. Currie acknowledged that some of the provisions of USP <797> “may be more onerous than necessary,” but given the limited locations and circumstances in which medications are prepped outside of the pharmacy, he added, it is clear that anesthesiologists as well as nurses working in these

areas need additional education in proper medication preparation and safe-handlingg techniques. “There are a lot of infection control–related issues in anesthesiology—the most glaring one being the transmission of hepatitis B and C due to improper use of syringes,” Dr. Currie said. His own hospital has incorporated the CDC’s “One & Only Campaign” protocol emphasizing “one needle, one syringe, only one time,” and built a training module off that program.

Dr. Rhee explained that the SSI control program at Icahn School of Medicine includes restrictions on traffic in and out of the operating room (OR), and instills a communications protocol with OR technicians about frequently contaminated areas, which has led to better cleaning. Other program components have been developed to improve antibiotic compliance. Thanks to these and other initiatives, her unit has seen incidence of coronary artery bypass graft SSIs reduced from 6.6% in

2011 to 2.1% as of winter 2014. “Compared with immediate physiologic changes associated with anesthesia, infection control issues are not quite so sexy,” Dr. Beers told the audience at PGA. “But the long-term consequences of infections for our patients can be devastating. Sound, practical procedures must be designed to reduce their incidence and developed with the unique needs of anesthesia professionals in mind.” —Brian Dunleavy

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1 Go to the home page. 2 Click on the “Medical Education” button. 3 The drop-down menu gives you access to free educational materials from Anesthesiology News.

MARCH 2015

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POLICY & MANAGEMENT

Study Tackles Delays in Documentation of Bedside Pain Scores here are significant lag times between when nurses assess patient pain scores at the bedside and when these scores are entered into patients’ electronic health records (EHRs), according to findings presented at the American Medical Informatics Association’s 2014 annual symposium. Researchers analyzed pain scores documented by 6,414 inpatient nurses from January 2013 to January 2014 at 10 hospitals to determine these lag times and their effect on patient care. They also emailed a link to an online survey to 5,876 nurses

and observed 25 nurses on inpatient units. The investigators received 1,769 responses; of those, 4% of these nurses reported using just their memory during the lag time rather than writing down the scores. The researchers found that the mean lag times ranged from 16 to 33 minutes, with larger hospitals and patients with lower pain scores having longer lag times. The mean delay for patients with severe pain scores was 17 minutes, compared with 48 minutes for no-pain scores. “I am not sure how we can study or measure the reliability or accuracy of the

documentation in the context of this study, but we will consider that question as we look at impact of delayed documentation in the next phase of this project,” said lead investigator Tamara Winden, MBA, a graduate research assistant at the University of Minnesota, in Minneapolis. The investigators said the most common reasons for delaying the score entries included being too busy; having conversations with the patients or their family members; grouping documentation of several patients’ pain scores to make better use of their time; and forgetting to enter the data.

Medical Education CME From the Bench to the Bedside Procedural Breakthrough Pocket Guides Special Reports

The nurses suggested ways to reduce the delay, including having lighter workloads, and using EHR alerts for pain reassessment and mobile devices in units that do not have computers in every room. “We’re interpreting the responses as indicating that the EHR systems aren’t as usable as they should be. So we need to redesign our systems or implement other systems that will help expedite pain score documentation by our clinicians,” said Ms. Winden. —Rosemary Frei, MSc Ms. Winden reported no relevant conflict of interest.

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POLICY & MANAGEMENT

RAND Corporation: Biosimilars Could Save Billions

he introduction of biosimilar versions of complex biologic drugs in the United States could cut spending on biologics by an estimated $44 billion over the next decade, according to a new analysis from RAND Corporation. The calculations were based on several variables, including future use of biosimilars and the effect of increased

competition and acceptance of the drugs by physicians, patients and payors. Experience with the drug class in the European Union, where biosimilars have been available for a decade, was also considered, as were U.S. sales figures for more than 100 biologics, including all blockbuster biologics with sales of more than $1 billion annually.

In total, the drugs had sales of $66.3 billion in 2013 across all distribution channels. Assuming that biosimilars will penetrate 60% of the market, the researchers estimated that savings with biosimilars would be $44.2 billion over 10 years or about 4% of the total sales for biologics over that period. “However, the magnitude of savings will depend on a number of factors,

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including forthcoming decisions from the FDA,” said Andrew Mulcahy, the report’s lead author and a policy researcher at RAND, a nonprofit research organization. That’s why the researchers cited a range of potential savings, he noted—from a low of $13 billion to a high of $66 billion. Sandoz, a Novartis company, supported the analysis. In July, the FDA accepted the company’s biologics license application for filgrastim, which was filed under the agency’s new biosimilar pathway. The reference product, Neupogen (Amgen), is a human granulocyte colony-stimulating factor indicated to reduce infection manifested by febrile neutropenia in certain cancer patients. Not ‘Generics’ Biosimilars are highly similar versions of branded biologic “reference” products. Because of that similarity, many people will think of biosimilars as “generic” fomulations, but the FDA’s Leah Christl, PhD, said in an interview that the term is incorrect. “Unlike generic drugs, whose structure can usually be completely defined and entirely reproduced, biologic products are typically more complex,” said Dr. Christl, associate director for therapeutic biologics at the FDA’s Office of New Drugs. “Biosimilars and interchangeable biological products are unlikely to be shown to be structurally identical to a previously licensed biologic product.” Draft materials released by the FDA underscore that point, making it clear that not all biosimilars will be deemed interchangeable with their reference products. In addition, nearly all biosimilars will require at least one head-tohead clinical trial to confirm similarity to the original biologic, a more stringent process than required for standard generics. This confirmation is not required in the European Union. A Huge Market As the U.S. approval pathway for biosimilars continues to play out, one factor remains clear: the huge size of the pharmaceutical market that will be affected when biosimilars are finally passed. In 2011, eight of the top 20 drugs in this country in terms of sales were biologics, and the annual spending on the class has increased three times faster than for other prescription medications, according to the latest industry figures. —Marie Rosenthal

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PAIN MEDICINE

Managing the Difficult Pain Case: 4 Examples

abdominal paresthesias upon initial stimulation. The stylet was replaced with a more rigid one, and the leads 1. Spinal Cord Stimulation for Treatment of Chronic Low were then redirected even more lateral left of midline. The patient stated Back Pain in a Patient With Severe Dextroscoliosis he had excellent paresthesias coverage over the painful region of his low Sanjay S. Sastry, MD Kristina Berger, MD Jorge Mirabelli, MD back after subsequent stimulation. VAS was 1-2/10 during stimulation. It Director of Pain Management Lake Mary Family Practice Assistant Director was noted that his physiologic midline Coastal Pain Center Lake Mary, Florida Department of Neurology stimulation was different from his anaSouth Daytona, Florida Coastal Neurology tomic midline. South Daytona, Florida The patient returned for a followThe authors report no relevant financial conflicts of interest. up visit 3 days later and stated that he he patient was a 59-year-old antibiotics. The patient also received An imaginary 10-cm line was drawn had nearly 100% pain relief with the man who reported experiencing sedation with oral diazepam 10 mg 40 from the midline of the T12-L1 region. trial SCS. His need for pain medicapersistent low back pain (LBP) minutes before the procedure. He was The line was angled 30 degrees from tion also decreased during the trial for the past 10 years—mainly on the then placed in the prone position and midline of where L2 should have been period. He said he was content with right side of his body. the low back region was prepped on a (Figure 2). Once the epidural space was his ability to walk for extended periHe described the pain as a continu- sterile field using Betadine. accessed at the T12-L1 region using an ods without pain. The patient had The placement of a spinal cord stimu- intralaminar technique (Figure 3), the a permanent spinal cord stimulator ous, spasmodic, and throbbing dull ache that was present throughout the day lator in patients with fairly normal anat- curvature of the spine from the scolio- implant 5 weeks later and is still curand would become worse at night. The omy may be challenging under normal sis was severe enough to produce a chal- rently enjoying pain relief. pain was aggravated by walking, work- circumstances. A patient with aberrant lenge to driving the leads superiorly Conclusion ing, and exercise, and relieved with sleep, spinal anatomy, as with dextroscoliosis, into the midline region to the T8-9 rest, and medication. He said the pain may present extraordinary challenges. region (Figure 4). This patient was an ideal candidate would start in the low back region, radi- Access into the epidural space for this The leads were driven as to fol- for an SCS trial. The severity of abnorate down to the buttocks, and then to patient was difficult because normal ver- low the curvature of the spine as close mal curvatures of his spine might overthe lateral aspect of the thigh into the tebral landmarks were not present for a to midline as possible. The patient whelm and intimidate some physicians posterior aspect of the calf region, caus- paramedian technique. complained of right-sided anterior into not considering a trial spinal cord stimulator, but patience and knowling “sciatica or an electric shock–like feeling.” He also complained of interedge of the spinal anatomy were essenmittent bouts of paresthesias and numbtial in this case. Stimulation of the dorsal column ness in the legs and feet region. There were no complaints of any tract at the physiologic midline of this weakness, nor were there any bowel or patient ensured paresthesias over the bladder problems. Visual analog scale painful areas of the low back and lower extremities. Driving the leads, either (VAS) score for the patient was usually 6-7/10 on a daily basis. He had mulby double rotation of the needle or increasing the curve of the stylet, aided tiple spinal nerve blocks that did not in proper lead placement. Patients with yield pain relief. He then underwent lumbar spine surgery with a L4-5 lamivarious degrees of scoliosis deserve consideration for SCS as a valid therapeunectomy with fusion in February 2013 (Figure 1). The surgery provided pain tic option for chronic pain syndromes relief for 2 to 3 months, but eventually just as much as patients with normal spinal anatomy. led to increased pain compared with Figure 2. Ideal placement of leads before the surgery. The patient “wanted Figure 1. Origin of patient’s pain per patient’s pain syndrome. his life back” and was seeking continu- from post–lumbar laminectomy Selected Reading ous pain relief when walking and doing syndrome, L5–S1 region. Atullah J, Armah FA, Wong D, et al. Pain Physician. other physical activities. 2008;11(4):555-559. We discussed the option of a fluoBoswell MV, Trescot AM, Datta S, et al. Pain Physician. roscopically assisted trial placement of 2007;10(1):7-111. a percutaneous spinal cord stimulator Cameron T. J Neurosurg. 2004;100(3):254-267. using dual electrode leads. Fairbank JC, Couper J, Davies JB. Physiotherapy. y Spinal cord stimulation (SCS) is an 1980;66(8):271-273. excellent therapy for patients with lumFairbank JC, Pynsent PB. Spine (Phila Pa 1976). 2000; bar radiculopathy and axial LBP with 25(22):2940-2952. post–lumbar laminectomy syndrome, McLeod A, Roche A, Fennelly M. Can J Anaesth. also known as failed back surgery syn2005;52(7):717-720. drome. SCS is an option for patients North RB, Kidd D, Shipley J, et al. Neurosurgery. y who wish not to have another lumbar 2007;61(2):361-368. spine surgery. Taylor RS. J Pain Symptom Manage. 2006;31(4):S13-S19. The patient was eager for the procedure to be scheduled. The informed Taylor RS, Van Buyten JP, Buchser E. Spine (Phila Pa 1976). 2005;30(1):152-160. Figure 4. Point of entry into the consent was signed inside the proce- Figure 3. Abnormal curvature epidural space for advancement of Turner JA, Loeser JD, Deyo RA, et al. Pain. dure room on the day of surgery. He of patient’s spine from severe 2004;108(1-2):137-147. was given an IV with preoperative scoliosis. leads, L1-2 region.

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PAIN MEDICINE 2. Efficacy of Percutaneous Cordotomy for Refractory Cancer-Related Pain Anish Doshi, MD

J. Adam Dailey, MD

Thomas Chai, MD

methadone. However, all of these regimens provided minimal relief of pain. Pain Medicine Fellow Pain Medicine Fellow Clinical Assistant Professor Given the refractory nature of the Department of Pain Medicine Department of Pain Medicine Department of Pain Medicine patient’s pain and poor prognosis of The University of Texas MD Anderson The University of Texas MD Anderson The University of Texas MD Anderson his disease, a percutaneous cordotomy Cancer Center Cancer Center Cancer Center procedure was conducted for pain conHouston, Texas Houston, Texas Houston, Texas trol optimization (Figure). The procedure successfully eliminated the The authors report no relevant financial conflicts of interest. patient’s left-sided hip pain and signifdequate pain management will develop opioid tolerance or continue successful use of a cordotomy in a patient icantly improved his overall quality of continues to be a challenging to have refractory and unrelenting pain with persistent pain from metastatic can- life during hospice care. dilemma faced by many physi- despite the use of procedural interven- cer, and who was ascending the recomDiscussion cians caring for patients with cancer- tions and adjuvant medications. mended analgesic ladder. Two studies examined the effiA cordotomy under computed tomogrelated illnesses. Case Presentation According to the World Health Orga- raphy (CT) guidance, which involves cacy of percutaneous cordotomy for nization (WHO), a 3-step analgesic contralateral radiofrequency ablation The patient is a 56-year-old man refractory cancer pain. Kanpolat et al ladder—an oral administration of nono- of the spinothalamic tract at C1 and diagnosed with metastatic lung can- selected 193 patients who underwent pioids first, then mild opioids as needed, C2, could be a potentially remarkable cer who underwent a right lobectomy. CT-guided percutaneous cordotomy and finally strong opioids until the solution. There are conflicting reports His cancer metastasized to his left for cancer pain. Patients in this study patient is free of pain—is currently the regarding the efficacy and timing of a proximal femur, for which he had sur- reported 100% pain relief postoperaguiding principle for treating pain in can- cordotomy in the cancer patient popula- gical resection and radiation therapy. tively and their performance improvecer patients.1 However, many patients tion. Our case presentation illustrates the Despite these palliative efforts, he con- ment nearly doubled.2 The incidence tinued to have severe persistent pain of temporary motor dysfunction and in his left pelvic region, described as a ataxia was minimal (2.4%) and there constant throbbing sensation, with an were no permanent neurologic injuintensity of 10/10 on the visual ana- ries.2 Given that long-term efficacy log scale. The pain also significantly was not analyzed, Raslan’s study conaffected his functional status. ducted a 6-month follow-up on 41 The pain persisted for the next 2 years, patients who had undergone percutaand he was treated with an escalation neous cordotomy for the treatment of of medications that included celecoxib, cancer-related pain.3 He found that gabapentin, pregabalin, hydrocodone, 32% had no pain and 48% had parpropoxyphene, morphine sulfate, oxy- tial satisfactory pain relief at 6 months Figure. CT-guided percutaneous cordotomy for refractory pain. morphone, hydromorphone, transder- postoperatively.3 CT, computed tomography mal and transmucosal fentanyl, and see case 2 page 32

3. Successful Treatment of a Brachial Plexus Injury With Spinal Cord Stimulation Timothy R. Deer, MD, DABPM, FIPP

Jason E. Pope, MD, DABPM, FIPP

normal routine. In 2012, while trimming a tree and being suspended nearly President, The Center for Pain Relief, Inc. Medical Director, Center for Pain Relief 80 ft above the ground, he fell. FortuClinical Professor of Anesthesiology Teays Valley, West Virginia nately, a tree limb broke his fall durWest Virginia University School of Director of Implantable Technologies ing his descent. He initially suffered a Medicine and Intrathecal Therapy weak, painful, and tingling right arm, Morgantown, West Virginia Center for Pain Relief along with a laceration to the forehead Charleston, West Virginia and a bruised right thigh. He had no Dr. Deer is a consultant for Axonics, Bioness, Flowonix, Jazz Pharmaceuticals, Medtronic, Nevro, Spinal obvious broken bones, and felt that he Modulation, St. Jude Medical, and Vertos. Dr. Pope is a consultant for Flowonix, Jazz Pharmaceuticals, would be better by the next morning. Mallinckrodt, Medtronic, Spinal Modulation, and St. Jude Medical. When he awoke the next day, he began rachial plexopathy is a painful settings, spinal cord stimulation (SCS) to experience what he later reported as and life-alteringg condition that has had mixed results in the treatment his right upper extremity being “asleep.” occurs after disease or trauma to of this disorder. We present an example He also noted that he could move his the axillary region. Individuals with this of successful treatment and a potential fourth and fifth digits, but otherwise disorder often have comorbidities of model for future treatment of this seri- had no arm muscle strength. Later depression, disability, and social distress. ous and painful condition. that night, his pain became severe and Treatment has included physical medhe was taken to the local hospital. At Patient History icine, anticonvulsants, opioids, nerve admission, he was diagnosed with a blocks, surgery, and alternative mediThe patient is a 44-year-old man brachial plexus injury and referred to a cine options. Despite these therapies, who owned a small farm and per- neurologist and a physiatrist. Over the many patients have intractable pain and formed the daily maintenance and next 24 months, he was administered greatly reduced quality of life. In many labor of his property as part of his muscle injections, epidural injections,

and axillary nerve blocks with steroid. None of these interventions resulted in sustainable pain relief, and eventually he was placed on long-actingg morphine at a dose of 300 mg per day, gabapentin 2,400 mg per day, and alprazolam 0.5 mg 3 times daily. Despite this aggressive (and questionable) drug cocktail, he still rated his pain at 10/10 on the Numeric Rating Scale (NRS) at most times, and he sought a second opinion. Twenty-six months after his accident, he was referred to our practice for an evaluation regarding his eligibility for an intrathecal pump. An evaluation of this patient found that his pain was burning and shooting in nature; he had limited movement in his shoulder but no movement in his arm or hand; and he was distraught by his lack of recovery. Despite his severe disability, he was still trying to operate his farming business.

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AnesthesiologyNews.com I 3 1

PAIN MEDICINE Clinical Course Despite the referral for an intrathecal drug delivery system, we felt this patient would be appropriate for SCS system trial. A magnetic resonance imaging scan (MRI) was obtained of the cervical spine to ensure there was no evidence of contraindications to lead placement. The MRI showed mild degenerative disk disease, mild spondylosis, and no evidence of cord impingement or narrowing. The patient was given the option of an SCS trial and was informed about its risks. He was found to be a good candidate psychologically, and had no medical contraindications. The patient was given the option of commercially available devices, had no imminent needs for MRI, and chose to proceed. SCS Trial: The patient was prepped and positioned in the normal fashion. He was given minimal sedation and remained conversant during the entire procedure. Needle entry (Coude, Epimed International) was at T2-3 based on a left paramedian approach. The initial octipolar lead (Octrode, St. Jude Medical) was placed just off the midline to the right side and confirmed on fluoroscopic views (Figure). Hand-held programming gave excellent coverage of his arm, hand and anterior shoulder, and the patient was pleased with the paresthesia. The leads were secured and a 7-dayy trial was undertaken. The patient experienced 75% to 80% pain reduction and improvement in his

pain toleration during manual labor on his farm. His medications were stable during the SCS trial. On the day of removal, the patient asked that the lead not be removed, but to maintain safety the leads were discontinued and a permanent device was requested. Three weeks later, a permanent device was placed, mimicking the permanent device with only a few modifications, based on patient feedback. The leads were secured with mechanical locking anchors, and an upgradable, rechargeable generator was placed (ProtĂŠgĂŠ, St. Jude Medical). The patient did well postoperatively and was discharged home the next morning. Follow-up: At 6 months, the patient is doing very well. He was able to wean off morphine, alprazolam, and gabapentin. His current medications include ibuprofen and tramadol, both as needed. Current goals are to improve his overall health. He is interested in future neuromodulation motor studies to try to improve his functioning. Future Options and Discussion This case represents a successful outcome in a complicated patient. Successful treatment with SCS to manage brachial plexopathies is not guaranteed. The use of opioids in this type of patient is often unsuccessful. The addition of the lateral lead was critical in achieving a positive outcome. Future options in the United States, in these complicated patients, include experimental therapies such as burst waveforms, high-frequencyy stimulation at 10 kHz, and dorsal root ganglion SCS. We are hopeful that having devices that allow for different modes of treatment will reduce failures. Future research in the brain, spine, and externally may lead to improvement in motor function disorders. The horizon for success in neuromodulation therapies is bright, and patients will benefit greatly going forward.

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Selected Reading Chien G, Heninger J, Candido K. Cervical spinal cord stimulation for neuropathic pain after brachial plexus avulsion injury: case report. J Pain. 2013;suppl:S64. De Ridder D, Plazier M, Kamerling N, et al. Burst spinal cord stimulation for limb and back pain. World Neurosurg. 2013 Jan 12. pii: S1878-8750(13)00101-0. doi: 10.1016/j.wneu.2013.01.040. [Epub ahead of print]

Figure. Anterior-posterior (A) and lateral (B) radiograph of the lead placement.

Liem L, Russo M, Huygen FJ, et al. A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. Neuromodulation. 2013 May 13. doi: 10.1111/ner.12072. [Epub ahead of print] Van Buyten JP, Al-Kaisy A, Smet I, et al High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study. Neuromodulation. 2013;16(1):59-65; discussion 65-66.

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PAIN MEDICINE 4. Intrathecal Ziconotide in the Treatment of Failed Back Surgery Syndrome Jason E. Pope, MD, DABPM, FIPP

Timothy R. Deer, MD, DABPM, FIPP

Medical Director Center for Pain Relief Teays Valley, West Virginia Director of Impla ntable Technologies and Intrathecal Therapy Center for Pain Relief Charleston, West Virginia

President, Center for Pain Relief, Inc. Clinical Professor of Anesthesiology West Virginia University School of Medicine Morgantown, West Virginia

Case Report A 63-year-oldd man with a 7-yearr history of back and leg pain presented to our office. He had a L5-S1 fusion approximately 5 years before and continued to experience both axial back and unilateral, left-sided, L5 radicular pain extending to the distal extremity, similar to his complaint before surgery. His pain was predicatively made worse by sitting and standing. He recently returned to his surgeon and was told he was not an operative candidate. A recent magnetic resonance imaging scan demonstrated previous L5-S1 surgery, with continued narrowing along the left L5-S1, neuroforaminal narrowing, and lateral recess stenosis with scarring along the left S1. At presentation, he was taking OxyContin

CASE 2

CONTINUED FROM PAGE 30

Conclusion Although the WHO guidelines provide a clear pharmacotherapeutic approach to the treatment of cancer pain, it lacks potentially life-altering procedural interventions. Although cordotomy has been shown to be both efficacious and safe, indications for its clinical use remain undefined. Based on the benefit provided to terminally ill cancer patients, a cordotomy could potentially be used in the treatment of other chronic pain etiologies that are refractory to current standards of care. Prospective controlled studies are required to evaluate the effectiveness of short- and

Postsynaptic nerve

Opioid receptor Calcium N-type calcium channel

Neurotransmitter

Dr. Pope is a consultant for Flowonix, Jazz Pharmaceuticals, Mallinckrodt, Medtronic, Spinal Modulation, and St. Jude Medical. Dr. Deer is a consultant for Axonics, Bioness, Flowonix, Jazz Pharmaceuticals, Medtronic, Nevro, Spinal Modulation, St. Jude Medical, and Vertos.

ntrathecal drug delivery is an important option in the pain treatment algorithm. The use of intrathecal agents to treat chronic pain requires a commitment to patient safety, efficacy, and long-term outcomes. The possible medication options include opioids and nonopioid agents. This case illustrates the use of ziconotide (Prialt, Jazz Pharmaceuticals) to treat a patient with severe pain secondary to failed back surgery syndrome.

Pain signal

ER (Purdue Pharma) 40 mg 3 times daily and oxycodone 15 mg 3 times daily as needed. He was also taking gabapentin 900 mg 3 times daily; physical therapy had not been effective. The patient had received L5 and S1 transforaminal epidural steroid injection with transient relief of 80%, lasting only 10 days. After discussions regarding advanced pain care therapies, the patient was given a trial of spinal cord stimulation (SCS), and despite appropriate paresthesia coverage, he obtained approximately 20% pain reduction in his leg, with poor coverage in his back. He then wanted to consider intrathecal therapy and was trialed with ziconotide, using a bolus, dualtrialingg strategy at L1-2. He obtained 80% and 90% pain relief for 10 and 8 consecutive hours, respectively, after trials of 2 and 4 mcg. He underwent intrathecal drug delivery device placement, employing a nocturnal flexx dosingg strategy of 2.2003 mcg per day with dosing at 11 pm, with a concentration of 5 mcg/cc (Figure 1). The patient remained stable on this regimen at 9 months. During his treatment course, the patient changed his oral opioid medications to acetaminophen/oxycodone 10/325 mg 3 times daily for bilateral knee pain, and required no additional long-term effects of this relatively novel procedural intervention.4 References 1. World Health Organization. Cancer pain relief: with a guide to opioid availability. Second edition. 1996. http://whqlibdoc.who.int/publications/9241544821.pdf. Accessed November 6, 2014. 2. Kanpolat Y, Ugur HC, Ayten M, et al. Computed tomography-guided percutaneous cordotomy for intractable pain in malignancy. Neurosurgery. y 2009;64(3 suppl):ons187-ons194. 3. Raslan AM. Percutaneous computed tomography-guided radiofrequency ablation of upper spinal cord pain pathways for cancer-related pain. Neurosurgery. y 2008;62(3 suppl 1):226-234. 4. Viswanathan A, Bruera E. Cordotomy for treatment of cancer-related pain: patient selection and intervention timing. Neurosurg Focus. 2013;35(3):E6.

Prialt

Figure 1. Anterior-posterior radiograph of the intrathecal drug delivery system medications for spinal-induced pain complaints. He was scheduled for a bilateral total knee replacement with postoperative plans to wean him from all controlled-substance drugs. Discussion Ziconotide is a non-narcotic, nonopioid medication with a mechanism of action of presynaptic N-type calcium channel blockade at the dorsal horn of the spinal cord (Figure 2).1 Ziconotide is the only FDA-approved nonopioid medication to treat chronic pain by intrathecal infusion.2 It was listed as a tier 1 treatment for both nociceptive and neuropathic pain at the 2012 Polyanalgesic Consensus Conference.3 Pharmacokinetics suggest that the linear pharmacokinetics4-6 may encourage bolus trials4,7 and more flex dosing compared with continuous long-term infusion. Importantly, this case shows that patients traditionally considered candidates for SCS might also be candidates for ziconotide intrathecal therapy. Rauck et al studied this patient population in a placebo-controlled trial, and demonstrated a clear reduction in visual analog scale of pain intensity scores and opioid consumption.8 Our center has performed bolus trials in a dual-controlledd fashion to determine efficacy and side effects, and to mitigate the placebo effect. When treatment was successful with at least 80% pain relief for 6 consecutive hours for both trials, we proceeded to implant. These successfully trialed patients were followed consecutively and were treated with intrathecal, nocturnal flex dosing, similar to the patient represented in this case report; at 6 months, 70% of the patients were maintained on ziconotide monotherapy, with an average numeric rating scale reduction in pain of 7.3, and an average reduction in morphine equivalents of 91.5%. These results are

Îą2Î´-1 subunit

Presynaptic nerve

Figure 2. Mechanism of action of ziconotide.2 awaiting publication. Although these outcomes are compelling, additional higher-powered studies need to be performed. Conclusions Ziconotide was once traditionally thought of as a treatment for neuropathic pain, and as evidence and recent insights suggest, it is also very effective in treating nociceptive pain. Ziconotide is effective in a very challenging patient group, including those with a history of failed back surgery syndrome. Many dosing and trialing strategies exist, and further pharmacokinetic and dosing studies may improve patient tolerability. References 1. McGivern JG. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007;3(1):69-85. 2. Prialt Intrathecal Infusion (Ziconotide). Prescribing information. Palo Alto, CA: Jazz Pharmaceuticals; 2013. 3. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: Recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464. 4. Pope JE, Deer TR. Ziconotide: a clinical update and pharmacologic review. Expert Opin Pharmacother. 2013;14(7):957-966. 5. Yaksh TL, De Kater A, Dean R, et al. Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog. Neuromodulation. 2012;15(6):508-519. 6. Wermeling DP. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy. 2005;25(8):1084-1094. 7. Mohammed SI, Eldabe S, Simpson KH, et al. Bolus intrathecal injection of ziconotide (Prialt) to evaluate the option of continuous administration via an implanted intrathecal drug delivery system: a pilot study. Neuromodulation. 2013;16(6):576-581. 8. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006;31(5):393-406.

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COMMENTARY

‘The Ocean’s Waters Are Never Still’ By Marc A. Neff, MD

went back into the hospital. I got didn’t. The beautiful sunsets I had you can hear the leaves rustling in into my car, and as I was driving off, witnessed, and the terrible storms I the background from a gentle breeze. had an opportunity to walk out I thought about the analogy further. had survived. The pirate ships I had That’s not reality. Reality is the ocean: teeming with life and advenof the hospital recently with one I thought about the shipyard where warded off. of the future chief residents. He I was built. The initial journey until And then I realized that I had to ture and challenge and danger and is a young, talented individual who is I, myself, lost sight of the land. The share this analogy. To help teach the unknown just over the horizon. very pensive and observant. He com- other ships I had passed on my jour- some other sailors and captains out mented on his recent observation ney across the sea. The different har- there, that the journey of life isn’t Dr. Neff is director, Bariatric Surgery Program, that the only constant in medicine is bors in which I docked; the ones I about finding the tranquil lake where Kennedy University Hospital, Cherry Hill, N.J. change. I asked him to explain. After a few minutes, I understood his perspective. He remarked that there are changes in medical billing, changes in upcoming ICD [International Classification of Diseases]-10, changes in resident work hours, changes in quality measures, changes in insurance company contracts, changes in SCIP [Surgical Care Improvement Project] protocols, changes in surgical techniques and, finally, changes in medications prescribed. He said that after four years of being a surgical resident, Part 1: the only part of the “being a surgeon” Framing the Issues equation he understood was the variEarn 1.0 AMA PRA Category 1 Credit™ ability. He wondered what was in or 1.0 AANA Credit store for him and his family over the Expiration Date: September 30, 2015 next 30 years of his surgical career. Jon Gould, MD My response was, “the ocean’s Chief, Division of General Surgery waters are never still.” He looked at Alonzo P. Walker Chair in Surgery me questioningly, and so I went on Associate Professor of Surgery Medical College of Wisconsin to explain. “Pretend you are a ship’s Senior Medical Director of Clinical Affairs Froedtert Hospital captain manning your ship, sailing Part 2: Milwaukee, Wisconsin across the Atlantic Ocean, traveling Ongoing Challenges Glenn S. Murphy, MD from America to Europe. You can’t Clinical Professor, Anesthesiology and Opportunities expect the voyage to be calm. There University of Chicago Pritzker School of Medicine Director Cardiac Anesthesia and Clinical Research will be peaks and valleys, swells and Earn 1.0 AMA PRA Category 1 Credit™ NorthShore University HealthSystem or 1.0 AANA Credit troughs. There will be waves that will Evanston, Illinois try to capsize your vessel. There also Expiration Date: October 1, 2015 will be helicopters that come drop Sorin J. Brull, MD off much-needed supplies. There will Professor of Anesthesiology Mayo Clinic College of Medicine be strange sightings, maybe even a Jacksonville, Florida sea monster or two. You might have Part 3: Claude Meistelman, MD to fend off an attack from pirates or Medical Director, Manager A Multidisciplinary a rogue submarine that shoots a torNew Medical Center Nancy, France pedo your way. But you will make Approach to Optimizing your journey across the mighty ocean. It won’t be easy, but you’ve been 6DIHW\ DQG (I¿ FLHQF\ trained to make it across. Earn 1.0 AMA PRA Category 1 Credit™ or 1.0 AANA Credit “You will, after a time, get your ‘sea Expiration Date: October 1, 2015 legs.’ The minor waves won’t even Jon Gould, MD Jan Paul Mulier, catch your attention after a while.” I These activities are Chief, Division of General Surgery MD, PhD further commented that someone jointly provided by Alonzo P. Walker Chair in Surgery Bariatric Anesthesiologist Global Education Group and should have told him this in high Professor of Surgery St. Jan’s Hospital Medical College of Wisconsin Applied Clinical Education. school, college or medical school. It Bruges, Belgium Senior Medical Director of Clinical Affairs Supported by an educational took me several years as an attending Froedtert Hospital grant from Merck. Milwaukee, Wisconsin surgeon to learn it, but life isn’t about Tricia Meyer, PharmD, MS, FASHP looking for the “still waters”; it is Departments of Pharmacy and Anesthesiology about learning to navigate the stormy Scott and White Memorial Hospital sea and make it across. “You have the Texas A&M University System HSC College of Medicine talents and the training to be the capTemple, Texas tain of this ship and you won’t sink.” We smiled at each other, and he

Rationale, Reversal, and Recovery of Neuromuscular Blockade

Access these se e activities at www.cmezone.com

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PAIN MEDICINE

Study Finds Low Complication For TFESI and ILESI in Lumbosa And Cervicothoracic Regions

ransforaminal and interlaminar epidural steroid injections (TFESI and ILESI, respectively) have minimal immediate and delayed complication rates when performed using evidence-based guidelines, according to an analysis of 16,638 such procedures performed at several centers in the United States. A presentation at the International Spine Intervention Society’s 2014 annual scientific meeting indicated that less than 0.1% of the procedures resulted in a transfer to an emergency department (ED) or aborting the procedure. “With a good track record of safety for both TFESI and ILESI—with no major complications and only relatively

‘With a good track record of safety for both TFESI and ILESI, the technique a physician uses should rely on existing efficacy and effectiveness data, which overwhelmingly favor transforaminal epidurals for the treatment of radicular pain.’ —Christine El-Yahchouchi, MD

rare minor ones—the technique a phy- overwhelmingly favor transforaminal sician uses should rely on existing effi- epidurals for the treatment of radicular cacy and effectiveness data, which pain,” said lead author Christine

El-Yahchouchi, MD, an interventional pain physician at the American University of Beirut, in Lebanon. However, Mehul Desai, MD, MPH, who h was not involved i l d in i the h study, d noted that it’s important to take the results with a dose of skepticism. “They did a nice job overall. I think it’s vital to look at this kind of information. But there are multiple cautions,” see epidural page 37

Test Predicts Poor Candidates for Cervical Facet Joint Block

atients who have negative results on a manual spine examination (MSE) or palpation for segmental tenderness (PST) are not good candidates for cervical facet joint blocks, according to a study presented at the International Spine Intervention Society’s 2014 annual scientific meeting. Lead author Geoff Schneider, PT, PhD, and three other physiotherapists completed a standardized testing protocol on 125 patients with neck pain. The physicians then performed medial branch blocks of the dorsal ramus and/or third occipital nerve on all the patients using 0.5 mL of either bupivacaine or lidocaine under fluoroscopic guidance. Of the patients, 42% had positive responses to the blocks. Statistical analyses showed that a negative result on the MSE or PST had high sensitivity and moderate specificity, as well as a low negative likelihood ratio for predicting which patients would fail a cervical facet joint block. “Based on these results, if you know the patient is negative on either of these, you should not refer [him or her] for cervical facet joint blocks,” said Dr. Schneider, a postdoctoral fellow and clinical specialist in musculoskeletal physiotherapy, University of Alberta, in Edmonton, Canada. He

Table. Comparative Efficacy of Neurologic Examinations Test

Sensitivity, % (95% CI)

Specificity, % (95% CI)

Positive Likelihood Ratio (95% CI)

Negative Likelihood Ratio (95% CI)

MSE

92 (88-97)

71 (63-79)

3.17 (2.22-4.64)

0.11 (0.04-0.28)

PST

94 (90-98)

73 (65-80)

3.48 (2.35-5.03)

0.08 (0.03-0.24)

MSE + PST

92 (88-97)

75 (68-83)

3.74 (2.49-5.63)

0.10 (0.04-0.26)

CI, confidence interval; MSE, manu manual ual spine p examination;; PST, palpation p p for segmental g tenderness

added the findings have yet to be validated independently by other groups. Binit Shah, MD, a pain physician and psychiatrist in private practice in Columbus, Ohio, who was not involved in the study, said the research “does a tremendous service in trying to guide interventionalists.” However, Dr. Shah h noted that in the United States, physiotherapists do not often assess patients before injections are given. Therefore, the methods used in the study would need to be adapted or taught to physicians for them to be used stateside. He also said 0.5-mL doses of anesthetic are “excessive” for cervical spine procedures and the excess could “diffuse away from the nerve to anesthetize adjacent structures and decrease the diagnostic accuracy.” Dr. Schneider said every patient in the study received postinjection

imaging to determine whether there was any radiate spread of the medication and contrast material, and none was found. Patients in the study with persistent neck pain were aged 18 to 65 years. They were assessed and underwent the comparative medial branch blocks, as the reference standard for the diagnosis of facet joint pain, at the Advanced Spinal Care Centre (EFW Radiology), in Calgary, Canada, between October 2011 and December 2012. To standardize the examinations, the physiotherapists were trained for one hour and received a training manual on the details of the clinical tests: cervical range of motion, MSE, PST and extension-rotation test. The average baseline age for the study group was 49 years. The patients had neck pain for an average of 1.5 years and

74 of them had Neck Disability Index scores greater than 15. The participants had an average score of 13 on the Pain Catastrophizing Scale, a selff assessment tool composed of 13 questions with a maximum pain score of 52. Among the positive responders, 14 were positive at C2-3, 12 at C3-4, four at C4-5, 21 at C5-6, and 11 at C6-7. Ten were positive at both C2-3 and C3-4. The results of the statistical analyses indicated that MSE and PST, alone or in combination, yielded high sensitivity, moderate specificity and low negative likelihood ratio (Table). The findings were published in the Archives of Physical Medicine and Rehabilitation (2014;95:1695-1701). —Rosemary Frei, MSc Drs. Schneider and Shah reported no relevant conflicts of interest.

McMahon Group Acknowledges Exemplary Staff Every year the entire McMahon Group staff takes a moment to review the past year and celebrate the achievements of its various departments and the company overall. McMahon Group’s print and digital properties enjoyed signiﬁcant successes during 2014, often ft advancing d i in i both b th readership d hi andd reevenues.

2014

The following employees were singled ouut as exemplary at this year’s annual celebration. We thank them, and we thank our readerrs for their continued enthusiasm for our medical journalism, which has made many of our publications the best read in their specialty.

SUPPORT/ART/PRODUCTION/IT/FINANCE

This award is for a commingled groupp of several vital departments within the company, without any onee of which the company would not thrive, and as such there are two recipients of this award. MARTIN BARBIERI is the production manager for several of the company’s newsmagazines—a coomplicated task, which he accomplishes seamlessly month after month.

KWA ANGHEE CHUNG is senior lead developer in the IT Department, havinng input in all things digital, including our various websites, internnal content management systems, and apps, to name a few.

EDITOR OF THE YEAR

SALES ACHIEVEMENT AWARD tor among the publication,

copy and projects editorial staffs. KEVIN HORTY Y won for his editorial dirrection of General Surgery News, the best-read publication in general surgery. His contributions have included an important effort to enhance our Web-based video offerings.

MATTTHEW SPOTO is senior account manager for Gastrroenterology & Endoscopy News, the best-read publication in gastroenterology. This award celebrates creative thinking to enhance sales and customer service.

SALESPERSON OF THE YEAR

THE MCMAHON GROUP PARTNERS’ AWARD

RICHARD TUORTO, the senior groupp publication director for Anesthesiology News and Pain Mediicine News, both of which are the best-read publications in their fiields, earned this award for the ninth year in a row for generatinng the most revenue in the calendar year.

ROSA ANNE MCMAHON is a partner and co-founder of the comppany and the wife of CEO Ray McMahon. For many years she was personally involved in financial oversight, but nowadays she continues to do what she has done expertly from the very beginning: supporting the CEO and family members working at the company!

THE MCMAHON GROUP PERSON OF THE YEAR RICHARD TUORTO, this year’s Salesperson of the Year, was voted Person of the Year by McMahon Group employees for his longstanding excellence in both sales and publication management.

CLASSIFIEDS ANESTHESIOLOGY NEWS • MARCH 2015

CHAIR AND CHIEF OF THE DEPARTMENT OF ANESTHESIA WORLD AIRWAY MANAGEMENT MEETING

We expect our candidate to be a leader with clinical experience and strong management skills. Depending on academic credenƟals, the candidate will receive his/her academic appointment as Associate or Full Professor from Rowan University. The candidate will provide leadership in educaƟon, research and clinical service. The chairperson will implement strategic plans of the Hospital, CMSRU and MD Anderson Cancer Center at Cooper. He/she should be able to work in a team and have good communicaƟon skills to bring together mulƟdisciplinary service lines, support our rapidly growing surgery services, and foster operaƟonal OR eĸciency. Cooper University Hospital is located approximately three miles from Center City Philadelphia. CUH is a Level I trauma center and a 600 bed terƟary care academic medical center. The Cooper campus includes the new state-of-the-art MD Anderson Cancer Center at Cooper with rapidly expanding oncologic and tumor surgery services.

BOOK NOW FOR THE

WORLD’S LARGEST AIRWAY MEETING

DUBLIN, IRELAND

Cooper Medical School of Rowan University (CMSRU) and Cooper University Hospital (CUH) are seeking an excepƟonal physician to serve as Chair and Chief of the Department of Anesthesia which currently has 34 anesthesiologists, 47 CRNAs, and 13 anesthesia residents and fellows . An acƟve research program is in place.

The department administers anesthesia services in 18 operaƟng rooms with a planned expansion to 23 ORs this year to support rapidly growing surgery services in the main OR with 20000 cases per year. It provides anesthesia in Voorhees Cooper Surgery Center and Mt Laurel Cooper DigesƟve Health InsƟtute. Please send your personal statement and CV in electronic form to:

Roland SchwaƌƟng, M.D. Chairman, Department of Pathology and Chair of the Search commiƩee SchwaƌƟng-Roland@CooperHealth.edu Cooper University Hospital is an AA/EO Employer.

UF ANESTHESIOLOGY ASCENT Are you seeking collegial partners and a supporƟve work environment in an academic seƫng? To T accommodate expansive growth in perioperaƟve, ICU, and pain services, the University Of Florida Department of Anesthesiology seeks 15 commiƩed physician faculty members for tenure and non-tenure track Assistant / Associate / Full Professor ranks to teach and pracƟce at UF Health Shands Hospital, Shands Children’s Hospital, and Shands Cancer Hospital at the University of Florida, a terƟary care teaching facility located in Gainesville, FL (including, terƟary care / Level I Trauma Center / High risk Ob / Comprehensive Stroke Center / Level 4 NICU / Congenital Heart Center / Solid Organ TransplantaƟon / Cancer Center). These posiƟons require skills in clinical care, ABA cerƟĮcaƟon/eligibility, y and credenƟals to obtain a State of Florida physician’s license. Abundant opportuniƟes exist to develop independent and collaboraƟve research as well as innovaƟve educaƟon models. Base salary is negoƟable commensurate with experience and educaƟon. AddiƟonal variable compen sation is available. Department anesthesiologists pracƟce at UF Health hospitals in Gainesville, FL at the University of Florida alongside 62 / University employment beneĮts include 403(b) plan, 457 plan, faculty anesthesiologists, 78 residents, 17 fellows, and 57 CRNA/AAs. individual and family health insurance, professional disability insurance, Baby Gator childcare, domesƟc partner beneĮts, sovereign immunity malpracƟce status, and others. Gainesville is a vibrant, sun drenched, university city with a low cost of living, Division I NCAA sports, and no state income tax. Salary: Commensurate with educaƟon and experience Minimum Requirements: M.D. or equivalent, credenƟals to obtain a State of Florida physician’s license Criminal background and post oīer health assessment required. Interested applicants must apply through gatorjobs at ŚƩp://jobs.uŇ.edu/posƟngs/60184. Please aƩach curriculum vitae and leƩer of interest. The Universi r ty t of Fl F orida is an equal opportunity insƟtuƟon dedicated to building a broadly l diverse r and inclusive fa f culty and staī aī.

CLASSIFIEDS

ANESTHESIOLOGY NEWS • MARCH 2015

Large, stable, and growing Chicago-area prĂĐƟce is seeking BC/BE anesthesiologists. PosiƟons are available for general pƌĂĐƟĐe, pain and cardiac. CompeƟƟve salary with opportunity for rapid advancement to $350,000 plus. BeneĮts package including 401(k) with match, health and disability insurance, CME allowance, and full malpƌĂĐƟĐe insurance coverage including tail. ͻ Leadership track opportuniƟes leading to addiƟonal compensĂƟon. ͻ Nurturing work environment with mixture of personal cases and care team model. ͻ 6 weeks paid vacĂƟon. ͻ ͻ ͻ

Interested candidates should send inquires to KaƟe Enright at kenright@conƟnentalanesthesia.com. Mailing address: 1301 West 22nd Street, Suite 610, Oakbrook, IL 60523; telephone: 847.772.2293

Cardiothoracic Anesthesiologist

University Hospitals Case Medical Center in Cleveland, OH is seeking a full-Ɵme board eligible/cerƟĮed anesthesiologist who has completed a one year cardiothoracic anesthesia fellowship. NBE Advanced PerioperaƟve TEE Testamur status is necessary if you are not a Diplomate of the NBE. We are strongly encouraging applicaƟons from individuals who will signiĮcantly contribute to the growing academic core of a mid-sized academic anesthesia pracƟce. Our pracƟce involves providing anesthesia for thoracic, coronary, valve, major aorƟc, heart/lung transplant, ventricular assist device implantaƟon surgeries and electrophysiology/catheterizaƟon laboratory based procedures. Provision of some main operaƟng room anesthesia care is expected. MoƟvaƟon to teach residents, medical, nursing and anesthesia assistant students is a requirement. Faculty appointment at Case Western Reserve University School of Medicine will be commensurate with one’s academic record. University Hospitals is an equal opportunity employer. Interested applicants should send a cover lĞƩer along with their curriculum vitae to edwin.avery@uhhospitals.org.

ACADEMIC PEDIATRIC ANESTHESIOLOGIST - COLUMBIA, MO. The University of Missouri (UM) Department of Anesthesiology and PerioperaƟve Medicine is seeking a fellowship-trained pediatric anesthesiologist. Successful candidates will be ABA cerƟĮed or eligible. Academic rank and pay is based upon qualiĮcaƟons in either a tenure or non-tenure track. An interest in teaching is essenƟal; research experience is desirable. The pracƟce is based at the UM Women’s & Children’s Hospital where all pediatric surgical subspecialƟes are represented except solid organ transplant and cardiac surgery. The department supports pediatric emergency services, criƟcal care transport, a PICU and a NICU. Three pediatric anesthesiologists currently share clinical responsibiliƟes and home call for all high risk pediatric cases. During regular duty hours, they provide care for adult paƟents on occasion. UM oīers a generous compensaƟon and beneĮt package. Columbia is a vibrant university community of over 100,000 with a low cost of living. It has been cited by Money Magazine as the 13th most highly educated municipality in the US and by Outside Magazine as one of the 10 Best US communiƟes. For addiƟonal informaƟon about the posiƟon, please contact: B. Craig Weldon, MD at weldonb@health.missouri.edu An Equal Opportunity/Access/AĸrmaƟve AcƟon/Pro Disabled & Veteran Employer To request ADA accommodaƟons, please call Human Resource Services at 573-882-7976.

PAIN MEDICINE

headache

Drs. Desai and El-Yahchouchi reported no relevant conflicts of interest.

ILESI, interlaminar epidural steroid injections; TFESI, transforaminal epidural steroid injections

ILESI, Cervicothoracic (%)

delayed complications and a possibility Table. Complications Recorded From Lumbosacral and of false negatives and errant data entry. Cervicothoracic ILESI and TFESI Delayed complications were defined as the next business day at the RIC and the University of Pennsylvania, and two weeks for Mayo Clinic. The investigators reviewed patients’ electronic medical records to verify the type of complications reported in the database. There were 14,960 procedures performed in the lumbosacral area (1,412 ILESI and 13,548 TFESI). The remainType of Complication ing 1,678 were cervicothoracic (270 ILESI and 1,408 TFESI) procedures. Immediate There were no cases of infection, neurologic deficit or hemorrhage. Less than Vasovagal reaction 3 (0.2) 189 (1.4) 5 (1.9) 0.1% of cases resulted in ED transfer or Vasovagal abort 0 34 (0.03) 0 Aborted procedures 5 (0.4) 103 (0.8) 2 (0.7) a visit to the ED within 48 hours. Dural puncture 4 (0.3) 6 (<0.1) 0 The other main complications, all of which were considered by the investiDelayed gators to be minor, are summarized in the Table. Increased pain 36 (2.5) 364 (2.7) 7 (2.6) —Rosemary Frei, MSc Cerebrospinal fluid leak/spinal 1 (<0.1) 5 (<0.1) 0 TFESI, Lumbosacral (%)

Dr. Desai, director, Spine, Pain Medicine & Research, Metro Orthopedics & Sports Therapy, in Washington, D.C., said in an interview. “The investigators have a bias in favor of TFESI because that’s the preponderance of the procedures they do. And also, they can’t make an efficacy claim based on these data because that’s not what the data addressed.” The review included 1,402 ILESIs and 9,963 TFESIs performed between 2006 and 2013 at the Department of Radiology, Mayo Clinic, in Rochester, Minn.; 280 ILESIs and 4,507 TFESIs performed between 2004 and 2009 at the Rehabilitation Institute of Chicago (RIC), Northwestern Memorial Hospital; and no ILESIs and 486 TFESIs performed between September 2009 and July 2010 at the Department of Physical Medicine and Rehabilitation, Penn Spine Center, University of Pennsylvania, in Philadelphia. The investigators noted that there was an incomplete follow-up of

TFESI, Cervicothoracic (%)

CONTINUED FROM PAGE 34

ILESI, Lumbosacral (%)

EPIDURAL

11 (0.8) 2 (0.1) 17 (1.2) 0

26 (1.8) 0

38 I AnesthesiologyNews.com

MARCH 2015

POLICY & MANAGEMENT

ISMP Urges Move Away From Voluntary Drug Error Reporting

safety expert at the Institute for Safe Medication Practices (ISMP) is urging institutions to look beyond voluntary error reporting when assessing medication safety risk. During a recent webinar, Susan Paparella, MSN, RN, vice president of the ISMP, said voluntary reports only represent the tip of the medication error iceberg. “Voluntary reporting yields important qualitative information, but it should serve as a stepping stone from which institutions can ask more questions, gather more useful information and perform more thorough risk assessments,” Ms. Paparellaa said. Many organizations use voluntary reporting as their primary source of information on medication errors and risk, even though data indicate that as few as 1.5% of all adverse events are reported through this method, she said ((Ann Intern Med 1993;119:370-376). Since the Institute of Medicine published its seminal report, “To Err is Human” (http://goo.gl/I2sGpj) in 1999, strides have been made toward mitigating risk, Ms. Paparellaa noted. However, there are still too many errors and “there’s still a lot we don’t know about how to design safe medication use processes,” she said. “That’s why prospective techniques are needed.” Selff Assessments in Bite-Sized Pieces. A good place for organizations to begin examining their own processes before an error occurs is by conducting one of several selff assessments available online, Ms. Paparellaa suggested ( Table 1). With roughly 300 items, the ISMP’s own tool may feel like a daunting project, but Ms. Paparellaa said it can be completed in segments. Those results can spur more rigorous evaluations, she said. “What we’ve heard from organizations is that gathering teams to discuss the selff assessment results, either in part or in whole, can help really important information emerge,” Ms. Paparellaa noted. Electronic Systems a Data Trove. In addition to the insights gleaned from selff assessments, organizations can identify errors and error-prone processes by looking at data collected in electronic health records (EHRs), computerized prescriber order entry (CPOE) systems and newer devices, some of which offer data reporting functions, Ms. Paparellaa said. For example, CPOEs and EHRs can be queried to list alerts that have come up when entering medication orders, or instances of medications discontinued soon after ordering. Additionally, trigger tools can indicate use of rescue medications, orders for STAT laboratory tests or acute changes in patient care, she explained. “These are important clues that are often overlooked and can tell us about missed doses or prescribing errors,” Ms. Paparellaa noted. “But many organizations are not yet taking advantage of these sources.” James Hoffman, PharmD, MS, a medication outcomes and safety officer and an associate member of the Pharmaceutical Sciences Department at St. Jude Children’s Research Hospital in Memphis, Tenn., agreed that proliferating use of automated systems in the medication use process is a potential boon to error prevention initiatives. He said the question remains as to how these new technologies should be optimally leveraged. “There are apps, trigger tools, IV workflow products and barcode management software that all

Table 1. Self-Assessment Tools Available Online Assessment Tool

URL

ISMP Medication Safety Self-Assessments

ismp.org/selfassessments/default.asp

American Hospital Association Leadership Assessment for Patient Safety

aha.org/aha/content/2002/pdf/conwaytool.pdf

Agency for Healthcare Research and Quality Hospital Patient Survey on Safety Culture

ahrq.gov/qual/patientsafetyculture

Tubing Misconnections Self-Assessment for Healthcare Facilities

ismp.org/selfassessments/tubingmisconnections/default.asp

International Medication Safety Self-Assessment for Oncology

mssa.ismp-canada.org/oncology

Opioid Knowledge Self-Assessment

patientsafetyauthority.org/educationaltools/patientsafetytools/ opioids/documents/assessment.pdf

Table 2. External Sources of Risk Identification Category

Source

URL

Error reporting programs

The Joint Commission “Sentinel Event Alerts”

jointcommission.org/sentinel_event.aspx

Pennsylvania Patient Safety Reporting System

papsrs.state.pa.us/PSA

Professional publications

ISMP publications (ismp.org); ISMP Quarterly Action Agendas

ismp.org/newsletters/acutecare/ actionagendas.aspx

Discussion boards

Medication Safety Officers Society listserve

medsafetyofficer.org/forums/ msos-discussion-board

provide data that need to somehow be mined to identify events,” said Dr. Hoffman, who recently presented a study examining whether rapid changes in dosing and drug discontinuations can be used as surrogate markers of drug errors at the American Medical Informatics Association’s 2014 Annual Symposium, held in Washington, D.C. “My hope is that vendors will include more capabilities to identify errors as part of their products.” Engage With Staff. A lower-tech way of gathering information on errors or error-prone processes is to speak with staff, Ms. Paparellaa said. “Who knows better than front-line workers where the existing hazards are?” she pointed out. Safety briefs, shift changes, staff meetings or walkarounds are all opportunities to engage with staff and to find out whether there are elements of the medication use process that are challenging, Ms. Paparellaa explained. “Ask about mistakes or near-mistakes they have made, or workarounds they have developed.” While pharmacists tend to think of order reviews and related interventions as “part of their job,” Ms. Paparellaa said data from these reviews and interventions can be collected and used to inform the risk evaluation process. Whether they are collected electronically or manually, the data can identify order sets that need to be modified or prescribers who “may not be appreciating the therapeutic nuances of certain medications,” she said. In the outpatient setting, conducting random audits and comparing will-calll orders with medication labels can uncover errors in labeling and packaging, as well as other points of vulnerability in the pharmacy workflow, Ms. Paparellaa added. Don’t Wait for an Error To Happen! Organizations need to consider errors that have not occurred internally when they decide what processes to scrutinize, Ms. Paparellaa said. It’s thus helpful to carefully

review information on errors that have occurred at other institutions (Table 2). Dr. Hoffman agreed, cautioning against a belief “that error can never happen here.” Organizations, he noted, “need to embrace the idea of making improvements in their own processes based on reports of errors at other [facilities],” he said. “Be proactive, and don’t wait for things to happen at your hospital or health system.” Do a Deep Dive. After error-prone processes are identified, they should be closely examined, Ms. Paparellaa said. One methodology she said is particularly effective is the failure mode and effects analysis (FMEA). FMEA helps organizations identify ways by which a process might fail, factors that might cause it to fail, the potential consequences of failure and ways to improve the safety of the process, Ms. Paparellaa explained. FMEA tools are available through organizations such as The Institute for Healthcare Improvement (http://app.ihi.org/ Workspace/tools/fmea). “FMEA takes time to learn, but it can be really helpful in guiding you to the right questions to ask about a process, and it can identify most of the safety gaps in a process,” she said. Because it is a time-consumingg method, Ms. Paparella suggested prioritizing high-alert medications for FMEA evaluations. She also suggested narrowing the focus of an analysis to look at subprocesses in the use of a medication. Such an approach, she noted, will increase the likelihood that an analysis will produce results. “You can end up getting bound up with the complexity of bigger processes,” she said. “So, looking at subprocesses will likely get you more actionable results.” —David Wild Ms. Paparella and Dr. Hoffman reported no relevant financial conflicts of interest.

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The Role Anesthet In Perine JAIME L. BARATTA, MD Clinical Assistant Professor Director of Regional Anesthesia Director, Regional Anesthesia and Acute Pain Medicine Fellowship Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania

ngoing evidence continues to support the finding that postoperative pain remains the greatest concern for patients presenting for surgery.1 In fact, recent surveys demonstrate that patients continue to suffer moderate to

severe pain postoperatively.2,3

Additionally, patient satisfaction is becoming an increasingly important aspect of health care reimbursements reported via the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, since the Affordable Care Act established reimbursements based on HCAHPS scores. Pain after orthopedic surgery may be severe; when uncontrolled, it is the most common reason for readmission after ambulatory orthopedic surgery.4 Although perineural analgesia is widely considered the gold standard for postoperative pain control for a wide variety of ambulatory orthopedic procedures, a single-injection nerve block with bupivacaine or ropivacaine lasts less than 24 hours. Compared with a single-injection nerve block, continuous peripheral nerve blockade (CPNB) resulted in lower pain scores up to 48 hours postoperatively, decreased opioid use, decreased nausea, and improved patient satisfaction scores.5 However, CPNB is more costly and takes more time to place compared with a single-injection nerve block, and instituting an ambulatory regional analgesia program requires a dedicated team with 24-hour availability to attend to patient questions and follow-ups. CPNB is also not foolproof and is subject to catheter

dislodgement, migration, failure, and leakage. Thus, an ambulatory regional analgesia program is not optimal for each patient or each department of anesthesiology. In this review, I address options for providing the most optimal analgesia for patients undergoing ambulatory orthopedic procedures and the role local anesthetic additives play in perineural analgesia.

Clonidine Clonidine is an α2-adrenergic agonist that has been widely used as an analgesic adjuvant for more than 20 years.6 Clonidine has high lipid solubility allowing easy passage across the blood–brain barrier and interaction at spinal and supraspinal sites. Epidural and intrathecal clonidine produce analgesia when used as a single agent.7 Hence, there is a long track record of safety when clonidine is applied to neuronal tissue. Clonidine also has been added to local anesthetics for peripheral blocks. However, the exact mechanism of its perineural action is unclear; possible explanations include axonal or bloodstream transport to the spinal cord, vasoconstriction, direct action on nerve conduction, or a synergistic effect with local anesthetics. Animal studies have shown clonidine to have a direct effect on nerve impulse conduction,

A N E ST H E S I O LO GY N E WS • M A R C H 2 0 1 5

with increased inhibition of A and even more so of C fibers when combined with local anesthetics.8,9 Still, the exact mechanism of clonidine when administered perineurally is largely unknown and likely a complex and compound interaction of both direct and indirect effects. What is the effect of clonidine clinically when combined with local anesthetics in perineural analgesia? Numerous studies over 20 years have examined the effect of clonidine in peripheral nerve blockade, but the results remain controversial. In a systematic, qualitative review, McCartney et al identified 27 studies that included 1,385 patients in which clonidine was used as a local anesthetic additive, using doses ranging from 30 to 300 mcg, with 15 supportive results and 12 failing to show benefit.6 The literature appears to support clonidine as an adjunct in upper extremity blockade, but few studies were performed involving lower extremity blockade. The most benefit in prolongation of the sensory block occurred when clonidine was combined with intermediate-acting local anesthetics such as mepivacaine and lidocaine.6,10-13 When comparing the systemic and perineural effects of clonidine as an adjunct to local anesthetic, the literature was again inconclusive.6 However, side effects such as hypotension and sedation appear to be limited up to doses of 150 mcg.6 A separate review of the literature concluded that perineural clonidine prolonged sensory and motor blockade by about 2 hours for both intermediate- and longacting local anesthetics, thus making prolongation less significant for long-acting local anesthetics.14 This review found an increased risk for hypotension, fainting, and sedation with perineural clonidine as well. Thus, based on the currently available literature, clonidine on its own may not be an effective local anesthetic adjunct to prolong perineural analgesia.

Dexmedetomidine Dexmedetomidine (Precedex, Hospira) also is an α2 agonist with selectivity 8 times greater than clonidine. Its mechanism of action is likely multifactorial when administered perineurally. Dexmedetomidine decreases the release of norepinephrine and causes inhibition of nerve fiber action potentials; centrally, it inhibits substance P in the nociceptive pathway at the dorsal root and activates α2 adrenoreceptors in the locus coeruleus. As with clonidine, animal studies have shown dexmedetomidine causes a prolonged duration of analgesia by blockade of hyperpolarization-activated cation currents.15 Interestingly, when examining perineural inflammation in rat sciatic nerves, the addition of dexmedetomidine attenuated perineural inflammation when compared with bupivacaine alone.16 Few studies have examined the effect of dexmedetomidine as a local anesthetic adjunct for perineural analgesia. A review by Abdallah et al, which included 4 studies investigating perineural dexmedetomidine, found that unlike clonidine, dexmedetomidine prolonged the duration of long-acting local anesthetics when used in brachial plexus blocks; however, both sensory and motor

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blockade were prolonged, which may not be a desirable effect. Additionally, although sensory blockade was prolonged, it did not reach statistical significance.17 Interestingly, in a smaller study comparing both systemic and perineural dexmedetomidine in combination with ropivacaine in ultrasound-guided ulnar block in healthy volunteers, a profound prolongation of both sensory and motor blockade of approximately 60% occurred in the perineural group, whereas the systemic group showed only a 10% prolongation.18 Dexmedetomidine as a local anesthetic adjunct produced a reversible bradycardia but did not increase the incidence of hypotension or cause any other clinically relevant adverse effect in the limited studies available.17 Although dexmedetomidine appears to prolong both sensory and motor blockade when used as a local anesthetic additive to peripheral nerve blocks, more studies are needed to support its general use as a perineural adjunct.

Buprenorphine Buprenorphine is a partial μ-opioid agonist and κ and δ antagonist, and is 25 to 50 times more potent than morphine. As in the case of the additives already discussed, buprenorphine’s mechanism of action in the periphery is controversial, and possibly due to peripheral receptor sites, systemic interaction, or enhancement of local anesthetics. Candido et al completed several interesting studies involving buprenorphine as a perineural adjunct. They found that the addition of 0.3 mg buprenorphine to a mixture of mepivacaine and tetracaine produced a 3-fold increase in the duration of brachial plexus blockade. Interestingly, a majority of patients in the additive group had complete analgesia and decreased opioid use persisting 30 hours beyond the duration provided by local anesthetic alone (ie, 6 hours).19 In a follow-up study, Candido et al produced similar results in axillary brachial plexus blockade, showing a 3-fold increase in duration of analgesia with the addition of perineural buprenorphine and a 2-fold increase when compared with patients given systemic buprenorphine injection in combination with the local anesthetic–only block. Of note, the systemic buprenorphine group in combination with peripheral blockade had a 2-fold increase in analgesia compared with the local anesthetic block.20 The incidence of side effects was comparable for all 3 groups (local anesthetic alone, perineural buprenorphine adjunct, and systemic buprenorphine adjunct). However, when used in lower extremity blockade in combination with bupivacaine, both the perineural and systemic buprenorphine groups had improved analgesia compared with bupivacaine alone but without significant differences between the 2 buprenorphine groups.21 Increased nausea and vomiting occurred in both the perineural and systemic buprenorphine groups when compared with bupivacaine alone.21 In the limited studies available, buprenorphine appeared to be effective as a local anesthetic additive

with acceptable side effects; however, more clinical trials are needed to definitively show benefit and address any possible risks associated with its use.

Dexamethasone Although dexamethasone’s exact mechanism of action on the peripheral nerve is unknown, it is thought to be mediated by decreasing the release of inflammatory mediators and reducing ectopic neuronal discharge of nociceptive C fibers.22 Numerous recent studies have focused on the efficacy of dexamethasone as a local anesthetic adjunct and it has gained significant popularity in recent years. Movafegh et al described a greater than 2-fold increase in duration of both sensory and motor blockade when dexamethasone 8 mg was combined with lidocaine for axillary block.23 Cummings et al showed that dexamethasone 8 mg in combination with ropivacaine prolonged analgesia following interscalene block in 218 patients, from 11.8 to 22.2 hours, whereas the addition of bupivacaine improved duration from 14.8 to 22.4 hours.24 Of note, no adverse effects were noted at 14 days and there was no difference in duration between nerve stimulation or an ultrasound-guidance technique.24 Interestingly, Desmet et al suggested that dexamethasone prolonged duration of analgesia independent of administration while demonstrating decreased analgesic need at 48 hours, improved pain scores, and decreased sleep disturbance with both systemic and peripheral dexamethasone adjuncts to interscalene block when compared with ropivacaine alone in 150 patients.25 Rahangdale et al documented similar results and comparable analgesia when administering perineural versus systemic dexamethasone in sciatic nerve blocks for ankle surgery.26 A recent meta-analysis examined 9 studies with 801 patients, 393 of whom received perineural dexamethasone in doses ranging from 4 to 10 mg. Analgesia was prolonged from 730 to 1,306 minutes when used in conjunction with long-acting local anesthetics and 168 to 343 minutes when combined with intermediate-acting local anesthetics. However, motor block was prolonged as well, from 664 to 1,102 minutes, when dexamethasone was added to the nerve block.22 This may be undesirable in some cases if physical therapy is needed in the early postoperative period. Furthermore, consideration must be given in the ambulatory setting to the risk for falls with such a prolonged motor blockade.

Are Local Anesthetic Additives Safe? From the limited data that exist, local anesthetic additives appear to be safe, but due to the small number of studies with a minimal number of patients, it is difficult to make a definitive claim regarding their safety, so use in this setting is still considered off-label (Table). It is known that repeated intrathecal injections of betamethasone did not produce spinal neurotoxicity and locally applied corticosteroids have shown no long-term effect on structure, electrical properties, or function of peripheral nerves.27,28

In models of central nervous system ischemia, α−2 adrenoceptor agonists are neuroprotective, whereas clonidine was shown to decrease the response to nerve injury in animal models.15 As nerve injury is rare and likely secondary to needle trauma, no clinical trial has reported neurotoxicity; given the small sample size, it would require roughly 16,000 patients to show a doubling of the baseline complication rate of 0.4%.22 In animal models, Williams et al showed that ropivacaine was neurotoxic to sensory neurons, whereas high concentrations of adjuvants alone, including buprenorphine, clonidine, and dexamethasone, were significantly less toxic. Additionally, buprenorphine and clonidine appear safe at estimated clinical concentrations when used in combination with ropivacaine, whereas dexamethasone may have a dose–related neurotoxicity, suggesting the lowest possible dose (1-2 mg per nerve block) should be used.29 A recent study by Williams et al demonstrated that clonidine, buprenorphine, and dexamethasone combined with either bupivacaine or midazolam produced reversible nerve blockade and no long-term deficits in rat sciatic nerves.30

Liposomal Bupivacaine Liposomal bupivacaine (Exparel, Pacira Pharmaceuticals) is an extended-release formulation of bupivacaine that is designed to allow drug diffusion to occur for up

Table. Key Points Use of clonidine, dexamethasone, buprenorphine, and dexmedetomidine perineurally is off-label. Clonidine in doses up to 150 mcg has limited side effects and prolongs analgesia with intermediateacting local anesthetics most effectively. Dexmedetomidine prolongs both sensory and motor blockade with potential side effect of reversible bradycardia and no hypotension, but limited studies exist to support routine use. Buprenorphine 0.3 mg prolonged analgesia most effectively in brachial plexus blockade but demonstrated equivocal analgesia as well as side effects to systemic buprenorphine in lower extremity blockade. Dexamethasone 4 to 8 mg prolonged both sensory and motor blockade; however, 2 studies demonstrated equivocal analgesic prolongation with systemic and perineural use. Too few studies exist to definitively determine safety, although no clinical studies resulted in clinically relevant nerve injury. Animal studies do not demonstrate neurotoxicity when low clinical doses are used in combination with ropivacaine, but dexamethasone demonstrated dose-related neurotoxicity. Limit dexamethasone dose to 1 to 2 mg per peripheral nerve block.

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to 72 hours after administration. A single injection of Exparel in patients undergoing bunionectomy or hemorrhoidectomy has been reported to decrease postsurgical pain and delay opioid use for 48 to 72 hours.31,32 Currently, the FDA has approved Exparel only for surgical site infiltration; however, at press time the manufacturer is awaiting a response from the FDA on its application for a new indication for use in peripheral nerve blockade. A small study in healthy volunteers by Ilfeld et al suggested that Exparel administered via femoral block results in partial sensory and motor block of more than 24 hours for doses greater than 40 mg without significant adverse effects.33 However, there is little published information regarding the use of Exparel in perineural blockade for postoperative analgesia, and clinical studies must be completed to determine its efficacy.

Conclusion The results are promising for local anesthetic additives to serve as inexpensive and effective extensions of peripheral blockade and as alternatives to CPNB when their utility is limited by technical challenges, incapability of placement, or limited personnel for management of ambulatory catheters at oneâ&#x20AC;&#x2122;s institution. There are limited clinical studies with small patient cohorts in the literature regarding perineural additives. The use of all the additives discussed continues to be off-label, which does not preclude their use in clinical practice if based on sound clinical judgment and scientific rationale. Epinephrine is an approved local anesthetic additive, although it has failed to prolong analgesia for long-acting local anesthetics in perineural blockade,34 and recent concerns about its effects on local vasoconstriction of the neural vascular supply, as well as advancements in ultrasound, have diminished its use in this setting.35

Given the off-label use of the additives discussed, more clinical studies of perineural additives must be done to establish efficacy, duration, safety, and side effects. It is also necessary to further determine how these medications compare both perineurally and systemically when administered with a local anesthetic block. When using adjuncts, it is imperative to use a preservative-free formulation as well as the lowest effective dose to reduce the risk for neurotoxicity and unwanted side effects. At our institution, we frequently use dexamethasone as a perineural adjunct resulting in block prolongation (sensory and motor) to greater than 24 hours when combined with ropivacaine; however, we do not exceed 1 to 2 mg per nerve block and have found no clinically significant adverse events with its use. Although no studies have shown a clinically relevant increase in blood glucose after the perineural use of dexamethasone, we avoid its use in patients with diabetes. Additionally, we use caution in administering local anesthetic additives perineurally in the setting of preexisting neuropathy. Ultimately, the decision whether to use a local anesthetic additive such as dexamethasone must be based on risk and benefit and should be determined by each clinician in the setting of each individual patient. In the future, Exparel may prove superior to the local anesthetic additives discussed; however, until more clinical trials determine its utility, consideration of the off-label use of local anesthetic additives discussed may prove effective in prolonging regional analgesia, decreasing opioid requirements, and improving patient satisfaction. Another consideration is the concept of multimodal perineural analgesia, which is the use of medications such as clonidine, buprenorphine, and dexamethasone with or without dilute local anesthetic to provide postoperative analgesia while limiting motor blockade.36

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