The April 2012 Digital Edition of Anesthesiology News

Ple a SCA se visi , Bo t us oth at t #4 he 17

Always Available Online at AnesthesiologyNews.com

The Independent Monthly Newspaper for Anesthesiologists AnesthesiologyNews.com • A p r i l 2 0 1 2 • Volume 38 Number 4

Web Offers Painkiller Abuse for Dummies Recreational prescription drug use gets the “how-to” treatment online

T

he explosion in prescription drug abuse shows no sign of slowing down. In 2010, according to the National Institute on Drug Abuse, approximately 7 million people were using prescription drugs for nonprescription purposes—in other words, to get high. That’s roughly 2% of the U.S. population.

And they’re learning hundreds of ways to divert legitimate prescription drugs for recreational use from the same place that teenagers research their term papers and

Journals Urging More Inquiry In Fujii Case Japanese university cites lack of ethics review in scandal, but editors fear sweeping fraud

A

leading Japanese anesthesiologist has been fired by his university for ethics violations in his clinical trials, and journal editors fear that he has been publishing fraudulent data for decades.

The researcher, Yoshitaka Fujii, MD, was released from Toho University in Tokyo in late February. Announcing its decision in early March, the institution released a list of eight published articles of studies for which Dr. Fujii had failed to obtain proper ethics approval.

see abuse page 26

see Fujii page 36

Laughter, and Tears, on the Way To Safer Anesthesia (Part 3)

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doubt there are any anesthesiologists results of some lab work that had been of any degree of experience who have ordered for the patient by his cardiologist never had a critical incident. Here is just before I anesthetized him. The serum one of mine. potassium, a vital element that I was giving anesthesia for the affects the function of the heart, excision and bypass of a man’s was too low. The surgeon asked femoral artery. It was blocked by me to give the patient an approatheroma and the patient could priate dose of potassium chlonot walk more than 50 yards ride intravenously. I should have before he was stopped by pain given 30 mEq into the intrain that leg. This occurred after I venous bag and dripped it in joined Chuck in private practice. slowly. Instead I gave 300 mEq All was going smoothly when into the line. The patient’s heart the circulating nurse answered slowed and then nearly stopped. see laughter page 28 the phone and then read the Gerald Zeitlin, MD

INside 07 | COMMENTARY

22 | CLinical Anesthesiology

MOCA running amok?

Nursing success not tied to method of anesthesia.

13 | CLinical Anesthesiology Neuromuscular blockers linked to post-op breathing problems.

24 | Pain Medicine Early treatment found superior for lumbar disk hernias.

Educational Review

Cerebral Oximetry: Emerging Applications for an Established Technology, see insert at page 12.

16 |

Goal-directed Therapies for Positive Patient Outcomes: Clinical Experience With 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride for Injection

31 | CME—PreAnesthetic Assessment PreAnesthetic Assessment of the Patient Undergoing Thoracic Endovascular Aneurysm Repair: Part 1

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4 I AnesthesiologyNews.com

April 2012

Discuss these and other articles @ AnesthesiologyNews.com.

Heard Here First: We must be very anxious because the industry may no longer put its

money in our field.

They may just move away and go to other disciplines.

See article on page 20.

April 2012

To the Editor:

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

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1. Japanese PONV Researcher Probed in Sweeping Fraud Case 2. Paravertebral Blocks: The Evolution of a Standard of Care (Educational Review) 3. Hospital Closings Helping Reshape Anesthesia Job Market 4. Hospitals Feeling Pain of Sedative Shortage 5. Addressing Current Challenges In Managing Postsurgical Pain With EXPAREL®, a new DepoFoam® Formulation Of Bupivacaine (Special Report)

Register for free @ AnesthesiologyNews.com to read these and other articles.

AnesthesiologyNews.com • mcmahonmed.com

ADVISORY BOARD JEFFREY L. APFELBAUM, MD, Chicago, IL PAUL G. BARASH, MD, New Haven, CT CHRISTOPHER W. BRYAN-BROWN, MD, Bronx, NY Keith Candiotti, MD, Miami, FL Peter J. Davis, MD, Pittsburgh, PA D. John Doyle, MD, PhD, Cleveland, OH Lee A. Fleisher, MD, Philadelphia, PA ELIZABETH A.M. FROST, MD, New York, NY Clifford Gevirtz, MD, New York, NY Julian M. Goldman, MD, Boston, MA

—Matthew Wecksell, MD Dr. Wecksell is assistant professor of anesthesiology at Albert Einstein College of Medicine of Yeshiva University, in New York City.

1. Amoako D, Lavies NG. Drug syringe labelling—does complacency come with age? Anaesthesia.

2003;58:816.

Alan Kaye, PhD, MD, New Orleans, LA

ELIZABETH Zhong, Associate Copy Chief

Robert S. Lagasse, MD, New Haven, CT

Richard tuorto, Senior Group Publication Director richardt@mcmahonmed.com, (212) 957-5300, x 916

Alex Macario, MD, MBA, Stanford, CA The Independent monthly Newspaper for Anesthesiologists

wo articles on the front page of the January 2012 issue relate to a practice taught to most anesthesiology residents on their first day of training: the dispensing, premixing, repackaging and relabeling of a milligram of phenylephrine into a bag of saline (exact dilution varying by institution!) and the “discouraging” practice of then administering this medicine to multiple patients throughout the day from the same source bag.

In light of our evolving practice guidelines and best practices, perhaps it is time to retire this practice. Let’s reserve the IV infusion bags to actual infusions, which are necessarily for single-patient use. Premixed syringes are readily available, and have been shown to reduce errors associated with dilution and labeling. Furthermore, they also solve the well-documented problem that some physicians do not bother to label syringes at all.1 It is past time we took the steps to end this old practice and start our days in a much safer way.

ALIX MATHIEU, MD, MBA, MS, Cincinnati, OH Peter J. Papadakos, MD, Rochester, NY

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April 2012

AnesthesiologyNews.com I 7

COMME N TA R Y

Simulation and the MOCA (Part 1)

public in terms of recertification of physicians are being ignored.

Some form of recertification is necessary if aging physicians are to keep current with changing pracAn evidence-based look at an opinion-based problem tice. Davis showed that the ability of physicians n the 1970s and 1980s, recertification of inter- one’s practice—is a key driver of opposition to recer- to accurately assess and evaluate themselves is limnal medicine physicians by the American Board tification.8 Wendy Levinson, MD, a practicing inter- ited.16 Numerous studies have demonstrated a of Internal Medicine (ABIM) was voluntary. In nist in Toronto, Canada, and a proponent of the decline in up-to-date knowledge in older physicians 1990, the ABIM developed the Maintenance of Cer- process, recently participated in the ABIM’s mainte- and lower adherence to standards of practice comtification (MOC) program and began issuing certif- nance of certification process and found it “far more pared with their younger counterparts.11,12,15 Noricates with a 10-year duration, requiring renewal to challenging and demanding” than the requirements cini and colleagues documented a 0.5% increase in currently existing in Canada.9 Dr. Levinson reported patient mortality from acute myocardial infarction maintain certified diplomate status.

The goals of recertification are to improve the care studying for four months and worrying that she for every year since the treating physician had graduated from medical school.17 Another study found an of patients, set standards for the practice of med- would fail. association between physician age and lower perforicine and encourage life-long learning, thus reasFailure Might Not Be an Option mance.14 Therefore, with the abundant information suring patients and the public that doctors remain ... but it Is a Possibility in the literature, why does the “grandfather” status competent and are in constant pursuit of improveThe fear of failure related to recertification is not remain? ment.1 As a member of the American Board of Medical Specialties (ABMS), the American Board of without justification. Recertification clearly is a Anesthesiology (ABA) recognized the importance of high-stakes exam with potential loss of a physician’s —Tania Haddad, MD, DMD recertification and implemented the Maintenance of practice and livelihood as a consequence.8 Ramsey and colleagues demonstrated that the Dr . Haddad is an anesthesiologist at Valley Anesthesiology Certification in Anesthesiology (MOCA) exam in likelihood of passing the examination declined in Consultants, in Phoenix, Ariz.

1999.

In recent years, the increased concern of the pub- relation to the number of years since initial certifiReferences lic about the quality movement within health care cation. More than two-thirds (68%) of physicians 1.

Norcini JJ. Recertification in the United States. BMJ. 1999;319:1183-1185. has ignited a search for a way to qualify physi- who had received initial certification 15 years before cian quality ratings. In 2003, the ABIM commis- would have failed the recertification exam, accord- 2. The Gallup Organization for the American Board of Internal Medicine.

Awareness of and Attitudes Toward Board-Certification of Physicians. sioned the Gallup Organization to poll the public ing to the researchers.7 Studies of performance on Princeton, NJ: The Gallup Organization; 2003.

2 about their views on recertification of physicians. voluntary recertification exams have found a decline 3. Brennan TA, Horwitz RI, Duffy FD, Cassel CK, Goode LD, Lipner RS. The The survey revealed that consumers of health care with age or time since completion of training.10,11 role of physician specialty board certification status in the quality movehighly value recertification. Some respondents sug- Day reported that recertification exams that focus ment. JAMA. 2004;292:1038-1043. gested they would change doctors if their own phy- on the ability of the physician to update knowl- 4. Freed GL, Dunham KM, Clark SJ, Davis MM. Perspectives and prefersician’s certification had expired.3 Based on these edge place those physicians further out from trainences among the general public regarding physician selection and board certification. J Pediatr. 2010;156:841-845. results, many specialty boards have been in a con- ing at a disadvantage. This study and others suggest stant search for new methods to increase and gain that there are distinct types of knowledge: stable 5. Brown DL. Guide to maintenance of certification in anesthesiology. The American Board of Anesthesiology, Inc. the public’s confidence. A survey from the Journal knowledge, amassed at the time of primary certiof Pediatrics, which focused on physician board cer- fication, and new knowledge, consisting of rapidly 6. Wasserman SI. Maintenance of certification and maintenance of professionalism (editorial). J Allergy Clin Immunol. 2011;128:465-466. tification found that most respondents felt hospitals evolving medical and technological advances. Older and health plans should require board certification, physicians perform as well as younger physicians— 7. Ramsey PG, Carline JD, Inui TS, et al. Changes over time in the knowledge base of practicing internists. JAMA. 1991;266:1103-1107. in addition to informing the public about the board as long as questions are directed at knowledge that 4 11-14 8.

Levinson W, King TE Jr. American Board of Internal Medicine mainteIn addicertification status of their physicians. has not changed since they were trained. nance of certification program. N Engl J Med. 2011;362:948-952.

The goal of continuously improving the quality tion to the changing of the knowledge base, older 9. Levinson W. Revalidation of physicians in Canada: are we passing the of physicians has laid the foundation for changing physicians were less likely to adhere to agreed-upon test? (editorial). CMAJ. 2008;179:979-980.

MOCA requirements over time. Since its incep- standards of practice. Czaja surveyed physicians to 10. Norcini JJ, Lipner RS, Benson JA, Webster GD. An analysis of the tion 10 years ago with a closed-book cognitive skills assess adherence to guidelines for cancer screening knowledge base of practicing internists as measured by the 1980 recerexamination, the MOCA has incorporated 140 endorsed by the American Cancer Society and the tification examination. Ann Intern Med. 1985;102:385-389. additional continuing medical education credits, a National Cancer Institute, and found that physicians 11. Day SC, Norcini JJ, Webster GD, Viner ED, Chirico AM. The effect of simulator session and assessment of practice perfor- who were more than 20 years out from primary cerchanges in medical knowledge on examination performance at the time of recertification. Proc Annu Conf Res Med Educ. 1988;27:139-144. mance. The expectation of these requirements is to tification were less likely to follow recommended decrease morbidity, mortality and health care costs practices.15 The fear of failure, therefore, is com- 12. Eva KW. The aging physician: changes in cognitive processing and their impact on medical practice. Acad Med. 2002;77:S1-S6. by ensuring that physicians’ knowledge and skills are pletely rational.

5 13. Holmboe ES, Lipner R, Greiner A. Assessing quality of care: knowledge current. matters. JAMA. 2008;299:338-340.

Respect Your Elders, But Even among physicians, however, the recertiDon’t Coddle Them 14. Choudhry N, Fletcher R, Soumerai S. Systematic review between fication process is controversial. Criticisms have clinical experience and quality of health care. Ann Intern Med. emerged on several fronts, including the time and The practice of anesthesiology often is compared 2005;142:260-273. cost required to prepare for the exam, fear of fail- to aviation. As an instrument-rated commercial 15. Czaja R, McFall SL, Warnecke RB, Ford L, Kaluzny AD. Preferences of ure and consequent loss of certification, and the lack pilot, I understand the stringent requirements that community physicians for cancer screening guidelines. Ann Intern Med. of evidence supporting the individual components a general and commercial pilot must adhere to for 1994;120:602-608. of the MOCA process.6-8 Not to mention the dis- continued currency and proficiency. These require- 16. Davis DA, Taylor-Vaisey A. Translating guidelines into practice: a systematic review of theoretic concepts, practical experience, and content that the ABA does not treat all physicians ments are irrespective of experience (hours of flight research evidence in the adoption of clinical practice guidelines. CMAJ. equally, allowing certain individuals to be “grandfa- time), ratings or age. In 2007, the Federal Aviation 1997;157:408-416. thered out” of participating in the MOCA process.

Administration raised the retirement age of commercial pilots to 65 years. In the private sector, work- 17. Norcini JJ, Kimball HR, Lipner RS. Certification and specialization: do they matter in the outcome of acute myocardial infarction? Acad Med. Time ers look toward age 65 for retirement. As physicians, 2000;75:1193-1198.

The time required away from practice while pre- we are honored to be allowed to practice medicine 18. Norcini JJ, Lipner RS, Kimball HR. Certifying examination performance paring for a one-size-fits-all exam—including the without a required retirement age. However, the and patient outcomes following acute myocardial infarction. Med Educ.

2002;36:853-859. review of material that may no longer be relevant to goals proposed by the ABMS and the desires of the

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C LI N I C A L A N ESTHESI O LO GY

Pain, Agitation and Delirium Guidelines To Be Unveiled Houston—Physicians, nurses and pharmacists will soon have an updated set of guidelines to help them manage pain, agitation and delirium (PAD) in the intensive care unit. At the recent annual meeting of the Society of Critical Care Medicine (SCCM), clinicians who helped develop the guidelines provided a preview for attendees.

“We’ve been working hard for the

last six years, and it is now time to give birth to this product,” said Gil Fraser, PharmD, clinical pharmacist in critical care at Maine Medical Center, Portland.

Juliana Barr, MD, chair of the PAD Guideline Taskforce, said the methodology used to develop the 2012 guidelines is more rigorous than that used for the previous version, issued in

2002. “The recommendations in these guidelines are more patient-centered, integrated and interdisciplinary in their approach, with less emphasis on recommending specific drugs in certain clinical circumstances,” said Dr. Barr, associate professor of anesthesia at Stanford University School of Medicine, and acting medical director at the VA Palo Alto Health

Care System, in Palo Alto, Calif.

“There is a greater evidence-based emphasis on pathophysiology, risks and management of delirium and its relationship to pain, sedation and outcomes in critically ill patients.”

To update the PAD guidelines, teams of experts sorted through a database of 19,300 references and evaluated the quality of evidence available.

The recommendations, from 20 multidisciplinary expert panel voting members, come in three strengths: strong (recommend), weak (suggest) or “no recommendation,” when the data are insufficient to generate conclusions.

Quality of evidence was ranked using a grading system: high (A), moderate (B) and low/very low (C). The updated guidelines include 53 statements and recommendations, almost twice as many as the 2002 guidelines.

Kathleen Puntillo, RN, DNSc, professor emeritus and research scientist at the University of California School of Nursing in San Francisco, said one of the biggest changes in the guidelines is the strong emphasis on assessing PAD. “There was little emphasis on assessment in the 2002 guidelines,” Dr. Puntillo said. “There has been a major increase in the science of assessment-scale development that we were able to tap into.”

The new guidelines identify which tools are considered to be the most valid and reliable for assessing PAD in critically ill patients.

Routine Pain Monitoring Urged The guidelines recommend that pain be routinely monitored in all adult ICU patients using either

April 2012

AnesthesiologyNews.com I 9

CL I N I CA L A N E S TH E SIOL OG Y ‘You may disagree with some of the patient self-report or one of two pain assessment scales for patients who [new recommendations], but I hope are unable to self-report, the Behavioral Pain Scale or the Critical-Care we have minimized the wailing and Pain Observation Tool. They recommend using either the Richmond gnashing of teeth.’

Agitation-Sedation Scale (RASS) or the Sedation-Agitation Scale (SAS) —Joseph Dasta, MSc for assessing sedation. They also recommend using one of two scales for IV opioids are recommended pharmacokinetics, pharmacodynamics routinely monitoring delirium in the for treatment of non-neuropathic and side effects. Enteral gabapentin or ICU: either the Confusion Assess- pain, with the choice largely being carbamazepine, in addition to IV opiment Method for ICU or the Intensive determined by patient response, oids, is recommended for neuropathic Care Delirium Screening Checklist.

Dr. Puntillo said that recommending only these six assessment tools does not mean the other available tools are inadequate, just inadequately studied.

She added that the panel did not recommend that objective measures of brain function be used as the primary method to monitor depth of sedation in non-comatose, nonparalyzed, critically ill adult patients. Vital signs, or observational pain scales that include vital signs, should not be used alone for pain, but they can be used as a cue to begin further assessment of pain. “Hemodynamic changes are no longer thought to be valid correlates of pain nor analgesic response,” said Dr. Fraser, who also is professor of medicine, Tufts University School of Medicine, Boston.

pain. “We are offering a weak suggestion—and it is weak only because data that are specific to the ICU are pretty skimpy—with regard to acetaminophen, nonsteroidal anti-inflammatories and ketamine,” Dr. Fraser said. “Most of the evidence suggests that the use of these adjuncts can reduce the dosing requirements of the opioids or even obviate their need.”

Dr. Fraser said the recommendation to start analgesia before adding see guidelines page 14

Music Therapy, Other Non-Drug Options Cited Preemptive treatment of pain is recommended prior to removal of a chest tube and suggested for other invasive and potentially painful procedures.

“The nonpharmacologic interventions would be biofeedback, music therapy and relaxation, and the pharmacologic interventions would include opioids, but the nonopioids as well,” Dr. Fraser said.

NAROPIN® delivers a faster return of motor function than bupivacaine.1,2 A Block Well Done.

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

Using NAROPIN beyond recommended doses to increase motor block or duration of sensory block may negate its favorable cardiovascular advantages, in the event that an inadvertent intravascular injection occurs.

Like all amide-type local anesthetics, NAROPIN may be associated with adverse reactions.

In clinical trials, side effects were mild and transient and may reflect the procedures, patient health status, and/or other medications used. Adverse events reported at a rate of ≥5%: hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain.

Important Safety Information There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. NAROPIN is not approved for this use. Please see dosage and administration details in Prescribing Information at www.naropin-us.com.

Please see accompanying brief summary of Prescribing Information. www.naropin-us.com

NAROPIN is indicated for the production of regional or local anesthesia for surgery and for acute pain management.

References: 1. Beaulieu P, Babin D, Hemmerling T. The pharmacodynamics of ropivacaine and bupivacaine in combined sciatic and femoral nerve blocks for total knee arthroplasty. Anesth Analg. 2006;103:768-774. 2. Morrison LM, Emanuelsson BM, McClure JH, et al. Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth. 1994;72:164-169.

Naropin® and logo are registered trademarks of APP Pharmaceuticals, LLC. and APP ® are registered trademarks of APP Pharmaceuticals, LLC. ©2011, APP Pharmaceuticals, LLC. All Rights Reserved. 0155-NAR-05-2/11

WHY COMPROMISE?

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April 2012

C LI N I C A L A N ESTHESI O LO GY

Dex After Heart Surgery May Reduce Risk for Arrhythmias Chicago—Patients who receive dexmedetomidine after cardiac surgery are substantially less likely to develop atrial arrhythmias than those given propofol, a recent study has found.

Arrhythmias after cardiac surgery contribute to a host of adverse events, so the study, by researchers from the Cleveland Clinic’s Department of Outcomes Research, suggests that

dexmedetomidine (Precedex, Hospira) might help improve outcomes in this growing patient population.

“Postoperative atrial arrhythmias are associated with a number of complications, including hemodynamic instability, cognitive impairment, thromboembolic events, congestive heart failure, stroke and prolonged hospitalization,” said Abdulkadir Atim,

Naropin

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BRIEF SUMMARY INDICATIONS AND USAGE Naropin is indicated for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration. Acute Pain Management: epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration.

CONTRAINDICATIONS Naropin is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.

WARNINGS In performing Naropin blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of Naropin for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. Naropin should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/ circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously. Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an i.v. line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies that may arise from the block to be employed, and then only after ensuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies (See also ADVERSE REACTIONS, PRECAUTIONS, and MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2-3 minutes, extended to the T10 level in 10-13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

PRECAUTIONS: General: The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions, which contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Administration of higher than recommended doses of Naropin to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block. Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (MH). Amide-type local anesthetics are not known to trigger this reaction. However, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for MH management should be available. Epidural Anesthesia: During epidural administration, Naropin should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When clinical conditions permit, the test dose should contain an appropriate dose of epinephrine to serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart should be continuously monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a rise in systolic blood pressure. A test dose of a shortacting amide anesthetic such as lidocaine is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. Use in Brachial Plexus Block: Ropivacine plasma concentrations may approach the threshold for central nervous system toxicity after the administration of 300 mg of ropivacaine for brachial plexus block. Caution should be exercised when using the 300 mg dose. (See OVERDOSAGE.) The dose for a major nerve block must be adjusted according to the site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used. Use in Peripheral Nerve Block: Major peripheral nerve blocks may result in the administration of a large volume of local anesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations. Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.) Use in Ophthalmic Surgery: The use of Naropin in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of Naropin for such surgery is not recommended. Drug Interactions: Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (e.g., amiodarone) have not been performed, but caution is advised (see WARNINGS). Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Naropin, can interact with Naropin leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. Pregnancy Category B: There are no adequate or well-controlled studies in pregnant women of the effects of Naropin on the developing fetus. Naropin should only be used during pregnancy if the benefits outweigh the risk. Labor and Delivery: Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY and PHARMACOKINETICS). The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia with Naropin for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural anesthesia has been reported to prolong the second stage of labor by removing the patient’s reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving Naropin than in those receiving

MD, research fellow at Cleveland Clinic and a member of the study team.

“Therefore, the prevention of atrial arrhythmias is an important goal to reduce morbidity and mortality.”

Like other α2 agonists, dexmedetomidine has anti-inflammatory effects that might help reduce postoperative atrial arrhythmias, Dr. Atim said.

For their study, Dr. Atim and his

bupivacaine. Nursing Mothers: Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total Naropin dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see Precautions).

Pediatric Use: The safety and efficacy of Naropin in pediatric patients have not been established. Geriatric Use: Of the 2,978 subjects that were administered Naropin Injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older, which includes 127 patients (4%) 75 years of age and over. Naropin Injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function. (See PHARMACOKINETICS, Elimination.)

ADVERSE REACTIONS Reactions to ropivacaine are characteristic of those associated with other amidetype local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation. The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to Naropin at concentrations up to 1.0% in clinical trials. Each patient was counted once for each type of adverse event. Incidence ≥5%: For the indications of epidural administration in surgery, cesarean section, postoperative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥5% in all clinical studies (N=3988): hypotension (37.0%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8.0%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5.0%). Incidence 1-5%: Urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection. Incidence in Controlled Clinical Trials: The reported adverse events are derived from controlled clinical studies with Naropin (concentrations ranged from 0.125% to 1.0% for Naropin and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Tables 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin-treated patients in these studies. The majority of patients receiving concentrations higher than 5.0 mg/mL (0.5%) were treated with Naropin.

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

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

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

Naropin total N=1661

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

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

Bupivacaine total N=1433

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

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

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

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

Naropin total N=1661

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

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

Bupivacaine total N=1433

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

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

APP Pharmaceuticals, LLC

0155-NAR-05-2/11

Rev. 11/08

colleagues reviewed data from the Cleveland Clinic’s cardiac anesthesiology database on patients presenting at the institution between 2006 and 2010. Patients younger than 18 years, and severely ill patients, were excluded from the analysis.

The researcher compared postoperative administration of dexmedetomidine and propofol in relation to atrial arrhythmias occurring within three days of cardiac surgery. They also conducted a sensitivity analysis, considering 37 prespecified potential confounders for inclusion in a multivariable logistic model.

The researchers evaluated the electronic records of 17,776 cardiac patients, including 765 who received dexmedetomidine for postoperative sedation in the intensive care unit and 17,011 who received propofol.

The investigators found that the incidence of atrial arrhythmias was 16.3% in the patients who received dexmedetomidine and 16.2% in those given propofol. Yet after adjusting for 13 “imbalanced factors,” including alcohol abuse and preoperative Advertisement

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CL I N I CA L A N E S TH E SIOL OG Y cardiac arrhythmias, dexmedetomidine was associated with a decreased risk (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.60-0.91) for atrial arrhythmia relative to propofol (P=0.004). A stepwise sensitivity analysis yielded similar results (OR, 0.76; 95 % CI, 0.62-0.94; P=0.01), according to the researchers.

“I think this is a nice example of how important the adjustment for potential confounding factors is,” said Andrea Kurz, MD, vice-chair of the Department of Outcomes Research and professor of anesthesiology at Cleveland Clinic. “Because obviously, patients who received and did not receive dexmedetomidine in the intensive care unit might have been different in regard to confounding factors. The danger with retrospective analysis is that most of the time, the adjustment is limited due to availability of data in regard to confounding factors or due to the fact that there might be unknown confounders.”

Harriet Hopf, MD, vice-chair and professor of anesthesiology at the University of Utah, in Salt Lake City, noted that some clinicians may be concerned about a potential link between large doses of dexmedetomidine and cardiac arrest. And she questioned whether the researchers observed more cases of cardiac arrest among the patients who received the drug than among those given propofol.

Alparslan Turan, MD, associate professor of anesthesiology in the Department of Outcomes Research, said such a signal was “very difficult to pick up in a retrospective analysis. We have data on mortality from cardiac arrest, but we don’t know if it’s from dexmedetomidine or other factors. But I can tell you that there was no difference between the groups with respect to mortality.”

Dr. Atim concluded that dexmedetomidine may be preferable to propofol for sedation in cardiac surgery patients.

“Our analysis of our surgical registry indicates that dexmedetomidine use after cardiac surgery is associated with lower incidence of atrial arrhythmias,” he said. “Dexmedetomidine is a relatively new sedative agent, and our study supports the use of dexmedetomidine in patients at high risk for atrial arrhythmias after cardiac surgery.”

Dr. Hopf also questioned the vast difference in propofol and dexmedetomidine use at the institution, and how that may have affected the results of the analysis. “Was it just that dexmedetomidine got introduced later, or are patients being selected as potential candidates for dexmedetomidine?”

Here again, said Dr. Turan, the retrospective nature of the analysis likely had an effect. “Patients who are difficult to wean are more likely to be put on dexmedetomidine than propofol,” he said. “So I imagine there’s a selection bias here.”

Dr. Atim presented the findings at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 788).

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—Michael Vlessides

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New Risk Index for Miller Blade Aids Adult Intubation Chicago—Compared with the Macintosh blade, the Miller might seem like something of an understudy. After all, whereas several multivariate indices of airway risk factors exist to assist in the prediction of difficult laryngoscopy and orotracheal intubation with the Macintosh blade, the Miller has received far less attention.

But that might be changing.

Researchers at Ochsner Medical Center, in New Orleans, have developed a multivariate risk index for Miller laryngoscopy in adult elective surgery patients.

Mallampati class, thyromental distance and ability to prognath were predictors for inferior Cormack-Lehane views; modified Mallampati class

and head/neck extension predicted increased attempts at orotracheal intubation, the researchers said.

“The Miller-2 blade is used most often at our institution,” said William B. Landry, MD, staff anesthesiologist at Ochsner. “Our practitioners are highly skilled with it, so we thought our institution would be an appropriate place to conduct this study.”

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2006;131(1):190-197.

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Dr. Landry and his colleagues enrolled 978 patients over age 17 years, who were scheduled for elective surgery requiring orotracheal intubation for general anesthesia.

The researchers recorded every patient’s airway risk factors preoperatively, including modified Mallampati class, mouth opening, thyromental distance, neck extension, ability to prognath, previous history of difficult intubation, sex, weight and height.

“The anesthesia provider then recorded, during direct laryngoscopy, the Cormack-Lehane view, the number of attempts required to successfully intubate the patient, and if any subsequent or additional airway devices were needed to intubate the patient,” Dr. Landry said.

Intubation succeeded in 96.2% of the 978 patients with the Miller blade, with the remaining patients requiring alternate airway tools—including intubating catheters and video laryngoscopes—or three attempts at intubation.

Identifying risk factors for difficult intubation is a key task for the anesthesiologist, Dr. Landry said. “Inability to intubate and ventilate is probably the single most significant factor related to adverse respiratory events in general anesthesia,” he said. “A lot of times, as an anesthesiologist you can walk into an exam room, look at a patient from a distance and recognize physical characteristics right away. Some patients, though, are not that easy to identify and you do need some sort of algorithm or physical exam to determine who’s going to give you trouble.”

Robert S. Greenberg, MD, associate professor of anesthesiology and critical care medicine at The Johns Hopkins Hospital, in Baltimore, said the new study helps illustrate that even in medicine, the magician is sometimes more important than the wand.

But Dr. Greenberg noted that the Ochsner team likely has more experience using Miller blades than most anesthesiology groups, at least for adult patients. “I wonder how many other groups have such expertise and how generalizable these results are,” he added. “In fact, with the apparent pervasive use of ‘adjunctive devices’ like video laryngoscopy, I wonder if such expertise may be going the way of expert mask management, or even open-drop anesthesia.”

—Michael Vlessides

PRINTER-FRIENDLY VERSION AT ANESTHESIOLOGYNEWS.COM

Cerebral Oximetry Emerging Applications For an Established Technology ELIZABETH A.M. FROST, MD Clinical Professor, Department of Anesthesia Mount Sinai Medical Center New York, New York Dr. Frost has no relevant financial conflicts.

C

erebral oximetry has been studied for more than 30

years, and has been commercially available to clinicians for more than 2 decades.1,2 However, whereas pulse

oximetry has been a standard of care for decades, only recently

has cerebral oximetry been extensively studied and adapted to investigate changes in oxygen delivery to the brain and how the monitor may be used as a “first alert” of impending organ dysfunction.3

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Skin/Scalp/Skull Simplified scattering photon paths Laser light source Scalp detector Brain detector

Light source window

Scalp detector window

Brain detector window

Adult sensor

Skin/ Scalp Simplified scattering photon paths

Skull

BRAIN

Figure 1. The technology of cerebral oximetry allows sampling of tissue from 2 photodetectors, each with light sources penetrating to different depths to determine tissue oxygenation.

(Courtesy of G. Fischer, MD)

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Cerebral oximetry estimates the oxygenation of regional tissue by transcutaneous measurement of the cerebral cortex, an area of the brain that is particularly susceptible to changes in the demand and supply of oxygen, and which has a limited oxygen reserve.

Measurement is based on the ability of light to penetrate the skull and determine hemoglobin oxygenation according to the amount of light absorbed by hemoglobin—a process called near-infrared spectroscopy (NIRS).4 Unlike pulse oximetry (which uses a single sensor), cerebral oximetry with NIRS uses 2 photodetectors with each light source. The technology allows selective sampling of tissue beyond a specified depth beneath the skin (Figure 1). Near-field photodetection then can be subtracted from far-field detection to provide selective measurements of tissue oxygenation.

Adhesive pads applied over the frontal lobes both emit and capture reflected near-infrared light passing through the cranial bone to and from the underlying cerebral tissue.

Tissue sampling by cerebral oximetry is mainly from venous (70%-75%) rather than arterial (25%) blood and is independent of pulsatile flow (Figure 2). Monitoring is noninvasive and can provide an early warning of decreased oxygen delivery. Many cardiothoracic and vascular anesthesiologists have adopted the technique to provide continuous intraoperative insight into brain perfusion and oxygenation dynamics.

The FDA has approved four cerebral oximeters: the CerOx (Ornim; Figure 3) Equanox (Nonin; Figure 4), Fore-Sight (CASMED; Figure 5), INVOS (Covidien; Figure 6). Normal cerebral oxygen saturation (rSO2) values are available for each manufacturer’s device; for example, the INVOS 5100 specifies a normal value for an adult cardiac surgery patient of 67% (±9%). Baseline rSO2 values for bilateral room air should be established before the induction of general anesthesia or measurement by secure adherence of the pads to the skin. Values must be interpreted in the context of available clinical information because many factors alter measurements. These factors include cardiac output, blood pressure, hypo/hypercapnia, arterial pH, inspired oxygen concentration, temperature, local blood flow, hemoglobin concentration, hemorrhage, embolism, preexisting disease (particularly cerebral infarction), and change of position.

With so many variables, there is no gold standard test to unequivocally validate that cerebral oximetry reflects regional oxygenation of frontal lobe tissue.

Also, given that the technology of the several devices differs, individual validation is required. It may be reasonable to infer that invasive and direct measurement of regional tissue oxygen pressure (tiPO2) might be equivalent to rSO2, but these are not the same parameters even if some correlations may exist.

SaO2 (Arterial oxygen saturation) Normal range: 90%-100%

SctO2 (Regional tissue oxygen saturation) Arterioles, capillaries, venules Normal range: 60%-80%

Pulse Oximeter

Cerebral Oximetry

SvO2 (Venous oxygen saturation) Normal range: 50%-70%

Arteries

Veins Tissue

Figure 2. Tissue sampling by cerebral oximetry is derived from both venous and arterial blood and thus values fall between the two. (Courtesy of G. Fischer, MD) The adequacy of global oxygen delivery also depends on central venous saturation. Traditional techniques required the placement of invasive devices for central venous access. A recent study of 40 patients compared 2 noninvasive technologies for the estimation of regional venous saturation (reflectance plethysmography and NIRS), using analysis of venous blood gas as the standard.5 In the first group, a reflectance pulse oximeter probe was placed on the skin overlying the internal jugular vein. In the second group, a cerebral oximeter patch was placed on the skin overlying the internal jugular vein as well as the ipsilateral cerebral hemisphere.

Oxygen saturation estimates from both groups were compared with measured saturation from venous blood. Correlation was statistically significant for NIRS, but not for transcutaneous regional oximetry. Placement of cerebral oximetry patches directly over the internal jugular vein (as opposed to on the forehead) appeared better to approximate internal jugular venous saturation, suggesting this modality may offer clinically useful information regarding global cerebral oxygen supply and demand matching. These findings were confirmed by Marimon et al in a study of 20 pediatric patients undergoing cardiac surgery.6 Cerebral oximetry and somatic renal oxygen saturation correlated significantly with continuous oxygen saturation from a central venous catheter.

The ‘Index’ Organ In addition to providing continuous insight into regional oxygenation of the brain, cerebral oximetry may allow clinicians to use the brain as an index organ that points to the adequacy of tissue perfusion and oxygenation of other vital organs. This concept has received support from multiple clinical outcome studies.3,7,8 Data from the Society of Thoracic Surgeons (STS) National Database strongly suggest that the intraoperative use of cerebral oximetry in cardiac surgery patients frequently (23%) served as a “first-alert” indicator of an intraoperative dynamic that could lead to potential adverse clinical outcomes in both adult and pediatric patients. The STS has the world’s largest database of cardiothoracic cases, with more than 500 participating centers contributing procedural data for in excess of 3.77 million. The database now includes 7 fields related to cerebral oximetry (Table 1). Fields 1 and 2 collect right and left baseline rSO2 values before the induction of anesthesia; 3 and 4 relate to both left and right cumulative saturation values below the threshold (25% below baseline). The cumulative values are captured as the area under the curve (AUC), and include both the time spent below the lower threshold as well as the magnitude of these excursions. Thus, the units of AUC are minute • %. For example, if a patient had a

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Figure 3. CerOx (Ornim). unilateral (left-sided) oxygen desaturation of 15% below the critical lower threshold for a total of 10 minutes for the entire surgical procedure, the left-sided AUC value would be 150 minutes â&#x20AC;˘ %. Fields 5 and 6 record rSO2 values at skin closure. Field 7 asks if the use of rSO2 monitoring during the procedure was a sentinel indicator of an intraoperative event that might have led to an adverse outcome. Taken together, these data fields will provide important insight into the clinical utility of rSO2 monitoring.

The Duke Clinical Research Institute examined the STS Adult Cardiac Surgery Database cerebral oximetry parameters collected from January 2008 to December 2009, specifically looking at whether item 7 was a first alert.3 This ongoing analysis established that in 23% of procedures (8,406 of 36,548), cerebral oximetry provided the first indication of impending potential clinical problems.

Several large clinical trials of cerebral oximetry have been conducted. In a retrospective study of 2,279 cardiac surgery patients, Goldman et al assessed 2 groups of patients, 1 of which received rSO2 monitoring.9 Significant reduction of stroke (0.97% rSO2 group vs 2.5% controls; P<0.044), duration of mechanical ventilation after surgery (6.8% rSO2 vs 10.6% controls; P<0.0014) and hospital length of stay (P<0.046) were established in the monitored group. The most notable differences in outcomes were found among the patients rated New York Heart Association Class I, indicating that the benefits of monitoring extend to not only the sickest individuals.

Prospective, randomized controlled trials examining the effects of employing rSO2 monitoring in cardiac surgery patients also have been conducted. Murkin et al

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Figure 4. Equanox (Nonin). examined the results for patients in whom saturations fell below 75% of preoperative levels and were treated, and compared the outcomes with those for untreated patients.7 Untreated patients spent more time in the intensive care unit than those in the active treatment group (P=0.029), and had significantly greater morbidity and mortality (P=0.048).

Another recent study sought to predict the limits of cerebral autoregulation during cardiopulmonary bypass.10 Patients undergoing this procedure exhibit a wide range of mean arterial pressures at the lower limit of autoregulation, making standard blood pressure an unreliable means of estimating or determining this important target. Joshi et al used real-time monitoring of rSO2 on 232 patients and found that it provided more accurate information than routine blood pressure monitoring in identifying the lower limit of autoregulation.

The lower limit of autoregulation could be identified with cerebral oximetry in 219 patients. Preoperative systolic blood pressure was associated with a higher lower limit of autoregulation, but only for patients whose systolic blood pressure was 160 mm Hg or less.

Pedrini et al assessed the reliability of cerebral oximetry during carotid endarterectomy under general anesthesia.11 Their study of 473 patients (mean age, 73 years) used a cutoff of 25% or 20% below baseline for prolonged hypoperfusion. Three patients presented with transient ischemic deficits at awakening, but no cases of death or stroke were observed. Shunting was required in 41 patients; in 30 the decision was made based on initial rSO2 and in 11 after an intraoperative

Figure 6. INVOS (Covidien).

Figure 5. Fore-Sight (CASMED). decrease of rSO2. Using the AUC analysis, for a greater than 25% reduction from baseline, sensitivity was 100% and specificity was 91%.

Other studies in general surgery and geriatric patients have found similar improvement when rSO2 values that fall below 75% of baseline are aggressively treated.8 Control patients experiencing cerebral desaturation interoperatively had significantly longer stays in the postanesthesia care unit and lower scores on the Mini-Mental Status Examination at postoperative day 7 (P=0.02) than did patients treated for desaturation. A study by Tang et al of 76 patients undergoing thoracic surgery with single-lung ventilation found that early cognitive dysfunction was directly related to an intraoperative decline of rSO2.12 In fact, more than 600 peer-reviewed retrospective studies, prospective observational studies, and case reports attest to the clinical value of rSO2 monitoring in critical care and operative settings.3

Beyond the Surgical Patient Although rSO2 monitoring occurs mainly in the operating room, a 2009 study by Padmanabhan et al evaluated the utility of the technology for patients in the emergency room.13 They found poor correlation between NIRS cerebral oximetry, pulse oximetry, and capnography among 100 children aged 9 months to 18 years. Various agents were used including ketamine, fentanyl, dexmedetomidine (Precedex, Hospira), and propofol. Changes in rSO2 occurred in 2.1% of patients and were associated with changes in SpO2 23% of the

time and changes in end-tidal CO2 29% of the time, making it a more sensitive indicator of problems developing. Few hypoxic events resulted in changes in rSO2, but these episodes were not accompanied by changes in cardiorespiratory parameters. However, most of the children were otherwise healthy and deemed suitable candidates for off-site sedation. Thus, rSO2 appears to be a more sensitive measure of cerebral oxygenation than pulse oximetry, but isolated decreases in rSO2 in children may not correlate well with short- or longterm neurologic complications. More studies in this area clearly are necessary.

Other studies in children have compared tissue oximetry in somatic sites with that of the cerebral cortex.

Mittnacht summarized recent developments and available data on the use of NIRS in children at risk for low perfusion, postulating that during states of low cardiac output, cerebral blood flow, and thus cerebral NIRS, may be better preserved than in somatic tissue sites.14 Sites other than the frontal cerebral cortexâ&#x20AC;&#x201D;such as the abdomen, flank, and muscleâ&#x20AC;&#x201D;have been investigated for a possible correlation with invasive measures of systemic perfusion and oxygenation. The abdomen seems preferable to the flank; therefore, to increase the sensitivity, specificity, and positive predictive value of tissue oximetry to detect systemic hypoperfusion, multisite NIRS, such as a combination of cerebral and somatic sites, has been proposed. NIRS also has been used to assess systemic perfusion in patients undergoing first-stage palliation for hypoplastic left heart syndrome.14 Multisite measuring is in the early stages. NIRS has been shown to predict low cardiac output, with decreases in rSO2 serving as an early warning of problems developing in other organ systems.

In the field of trauma, cerebral oximetry also may have found a place. Taussky et al compared NIRS cerebral oximetry with computed tomography (CT)

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Table 1. The Society of Thoracic Surgeons (STS) National Database Fields Related to Cerebral Oximetry

Table 2. Why Cerebral Oximetry?

The brain:

Pre-induction Baseline Regional Oxygen Saturation: Left: _____ (%) Right _____ (%)

Complex and fragile system Typically demands ~15% of normal cardiac output

Cumulative Saturation Below Threshold: Left: _____ (minute %) Right _____ (minute %)

Consumes ~20% of all oxygen used by the body

Skin Closure Regional Oxygen Saturation: Left: _____ (%) Right _____ (%)

Elapsed time critical in desaturation events The need is critical:

Cerebral Oximeter Provided The First Indication: Yes No

Cerebral ischemia the leading cause of compromised neurocognitive outcomes Brain function directly affected by duration of reduced oxygenation

15

perfusion in 8 patients with brain injuries. The investigators found that mean cerebral blood flow measured

by CT perfusion was 61 mL/100 g per minute for the left side and 60 mL/100 g per minute for the right. Mean NIRS values were 75 on the right and 74 on the left. Linear regression analysis demonstrated a statistically significant probability value (P=0.0001) for cerebral blood flow when comparing NIRS frontal oximetry with CT perfusion. Other investigators have used cerebral oximetry as an additional monitor in trauma patients at the scene and during transport of 33 ambulances and 32 helicopters.16 For outdoor monitoring, adequacy of signal was approximately 50%, improving to 100% during road transport and 86% during helicopter transport.

The investigators stated that not only was cerebral oximetry possible in this setting, but that it provided clinically valuable information.

Cerebral oximetry also may be a useful technique for predicting mortality from cardiac arrest. Nasir et al evaluated the role of cerebral oximetry in predicting the return of spontaneous circulation in 19 patients who experienced cardiac arrest in the hospital.17 Those with return of circulation had an rSO2 greater than 30% for more than 50% of the time of resuscitation, whereas those who died had rSO2 values less than 30% for more than 50% of the time. Survivors also had a significantly greater change in rSO2 from baseline than did nonsurvivors (310% vs 150%, respectively; P<0.05). Table 2 summarizes how the use of cerebral oximetry represents a critical monitor of cerebral—and indeed, whole body—dysfunction.

Conclusion Evidence suggests that the brain may act as an index organ for how well the vital organs are perfused

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and oxygenated. Cerebral oximetry has the potential to provide a measurable clinical benefit beyond cardiovascular and thoracic procedures. An aging population with decreasing organ function represents an increasing part of anesthesia practice. The use of cerebral oximetry, although not yet the standard of care, also may be useful in medicolegal situations. For example, a documented decrease in rSO2 that prompted the insertion of a shunt would indicate that a subsequent neurologic deficit was probably not related to anesthetic care. This underused technology offers anesthesiologists a noninvasive tool to continuously monitor the oxygenation of cerebral tissue in virtually any general surgical patient treated either in and out of the hospital.

References 1.

Jöbsis FF. Non-invasive monitor of cerebral and myocardial oxygen sufficiency and circulatory parameters. Science.

1977;198(4323):1264-1267.

2. McCormick PW, Stewart M, Goetting MG, Balakrishnan G. Regional cerebrovascular oxygen saturation measured by optical spectroscopy in humans. Stroke. 1991:22(5):596-602.

3. Avery EG. Cerebral oximetry: a “first alert” indicator of adverse outcomes. http://www.surgicalproductsmag.com/scripts/ShowP1R ~PUBCODE~0S0~ACCT~0000100~ISSUE~1010~RELTYPE~FEA~PR ODCODE~0000~PRODLETT~HC.asp. Accessed February 14, 2012.

4. Ferari M, Mottola L, Quaresima V. Principles, techniques and limitations of near-infrared spectroscopy. Can J Appl Physiol.

2004;29(4):463-487.

5. Colquhoun DA, Tucker-Schwartz JM, Durieux ME, Thiele RH. Noninvasive estimation of jugular venous saturation: a comparison between near infrared spectroscopy and transcutaneous venous oximetry. J Clin Monit Comput. 2012 Jan 31. [Epub ahead of print]

6. Marimón GA, Dockery WK, Sheridan MJ, Agarwal S. Near-infrared spectroscopy cerebral and somatic (renal) oxygen saturation correlation to continuous venous oxygen saturation via intravenous oximetry catheter. J Crit Care. 2011 Dec 13. [Epub ahead of print]

12. Tang L, Kazan R, Taddei R, Zaouter C, Cyr S, Hemmerling TM. Reduced cerebral oxygen saturation during thoracic surgery predicts early postoperative cognitive dysfunction. Br J Anaesth.

2012; Feb 6. [Epub ahead of print]

7. Murkin JM, Adams SJ, Novick RJ, et al. Monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study. Anesth Analg. 2007;104(1):51-58.

13. Padmanabhan P, Berkenbosch JW, Lorenz D, Pierce MC. Evaluation of cerebral oxygenation during procedural sedation in children using near infrared spectroscopy. Ann Emerg Med. 2009;54(2):205-213.

8. Casati A, Fanelli G, Pietropaoli P, et al. Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia.

Anesth Analg. 2005;101(3):740-777.

9. Goldman S, Sutter F, Ferdinand F, Trace C. Optimizing intraoperative cerebral oxygen delivery using noninvasive cerebral oximetry decreases the incidence of stroke for cardiac surgery patients.

Heart Surg Forum. 2004;7(5):E376-E381.

10. Joshi B, Ono M, Brown C, et al. Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. Anesth Analg.

2012;114(3):503-510.

11. Pedrini L, Magnoni F, Sensi L, et al. Is near-infrared spectroscopy a reliable method to evaluate clamping ischemia during carotid surgery? Stroke Res Treat. 2012;2012:156975.

14. Mittnacht AJ. Near infrared spectroscopy in children at high risk of low perfusion. Curr Opin Anaesthesiol. 2010;23(3):342-347.

15. Taussky P, O’Neal B, Daugherty WP, et al. Validation of frontal near-infrared spectroscopy as noninvasive bedside monitoring for regional cerebral blood flow in brain-injured patients. Neurosurg Focus. 2012;32(2):E2.

16. Weatherall A, Skowno J, Lansdown A, Lupton T, Garner A. Feasibility of cerebral near-infrared spectroscopy monitoring in the pre-hospital environment. Acta Anaesthesiol Scand.

2012;56(2):172-177.

17. Nasir A, Shah C, Patel R, Mani A, Parnia S. A feasibility study evaluating the role of cerebral oximetry in predicting return of spontaneous circulation in cardiac arrest. Resuscitation.

2012; Feb 6. [Epub ahead of print]

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CL I N I CA L A N E S TH E SIOL OG Y

Neuromuscular Blockers Linked to Post-op Breathing Problems Chicago—Although the advent of intermediate-acting neuromuscular blocking agents has been a boon to patient care, a study by Boston researchers at has found that the use of these agents is associated with a clinically meaningful increase in adverse postoperative respiratory outcomes.

Interestingly, the use of neostigmine for neuromuscular blockade reversal also was found to be associated with an increase in the incidence of hypoxic events.

“We’ve had the intermediate-acting neuromuscular blockers for a number of years,” said Matthias Eikermann, MD, PhD, director of research in the Department of Anesthesia, Critical Care, and Pain Medicine at Massachusetts General Hospital and assistant professor of anesthesia at Harvard Medical School, both in Boston. “And there’s some information that the use of these can be associated with adverse respiratory events, because the drugs still last longer than surgery.”

‘If you give neostigmine in the absence of neuromuscular block, it decreases muscle strength.

So we speculate that this is the mechanism, and clinicians just use reversal in patients who don’t really need it.’

—Matthias Eikermann, MD, PhD To more clearly identify these effects, Dr. Eikermann and colleagues examined data from 57,100 surgical cases requiring intubation between March 2006 and September 2010; data from the intraoperative electronic record, respiratory therapy and hospital billing were reviewed. The researchers then prospectively created a list of potential variables known to contribute to adverse postoperative respiratory outcome: age, American Society of Anesthesiologists (ASA) physical status, sex, body mass index, Charlson Comorbidity Index, case duration, surgical service, emergency status, anesthetics, opioids and use of neuromuscular blockers.

“We defined two variables as

representative of adverse respiratory outcome,” Dr. Eikermann told Anesthesiology News. “These were oxygen desaturation following extubation to a level lower than 90 in the [operating room]. And of course, the more important negative outcome criterion from a health economy point of view is re-intubation and unplanned ICU admission.”

Neuromuscular blockade with vecuronium, rocuronium and cisatracurium was associated with an increased risk for hypoxic events after extubation (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.36-1.62) and an increased risk for re-intubation/ unplanned ICU admission (OR, 2.12; 95% CI, 1.71-2.63), according to the researchers. These associations were

found to be statistically significant even after controlling for age, ASA status, sex, body mass index, Charlson Comorbidity Index, case duration, emergency status and other intraoperative medications/inhalational agents.

Use of neuromuscular blockers did not independently predict mortality or length of stay in the hospital. see block page 15

14 I AnesthesiologyNews.com

April 2012

C LI N I C A L A N ESTHESI O LO GY Guidelines continued from page 9 sedation for the vast majority of patients will involve a change in practice for many. Analgesia-first sedation, he said, may not be appropriate in patients withdrawing from either drugs or substances (with the exception of opiates), drug-induced agitation or any agitation associated with a clear and reversible etiology.

Curtis Sessler, MD, professor of medicine at Virginia Commonwealth

University Health System, in Richmond, said the two major themes that changed for sedation in these guidelines are a recommendation to prioritize non-benzodiazepine agents (either propofol or dexmedetomidine [Precedex, Hospira]) over benzodiazepines (either midazolam or lorazepam) and a recommendation to maintain light sedation in patients, using structured approaches such as daily interruptions of sedation or titration of sedative therapy to maintain light levels of sedation

using either RASS or SAS scores, both shown to improve outcomes in critically ill patients.

Increased Mortality From Delirium Is a Factor Richard Riker, MD, professor of medicine at Tufts, previewed the delirium recommendations. “Ten years ago, we did not have a lot of information about the best way to approach delirium,” he said. “We now know,” he said, “that delirium is associated with

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increased mortality in ICU patients, prolonged ICU and hospital length of stay and prolonged post-ICU cognitive impairment.

“There have been a lot of great steps forward. We do not suggest that haloperidol or atypical antipsychotics be administered to prevent delirium,” said Dr. Riker. “We have no published evidence that haloperidol reduces the duration of established delirium in the ICU. We do have data that suggest that atypical antipsychotics might reduce the duration of delirium, and we do not recommend rivastigmine in ICU patients.”

The PAD guidelines recommend early mobilization of adult ICU patients whenever feasible to reduce delirium, and they do not suggest using antipsychotics in patients who are at risk for torsades de pointes.

They suggest that either propofol or dexmedetomidine, rather than benzodiazepine infusions, be used in adult ICU patients with delirium not related to withdrawal from alcohol or benzodiazepines.

Dr. Barr said the guidelines are not meant to be comprehensive. To provide a stepwise process to managing patients, however, the guideline committee is developing an ICU PAD (IPAD) Bundle Toolkit. It will include instructional videos, PowerPoint presentations for staff education, pocket cards with bundle and guideline recommendations and templates for checklists, goal sheets and protocols. “You will have many ways to apply these data to your patients,” Dr. Fraser said.

The final version of the document is currently under review by SCCM and the American Society of HealthSystem Pharmacists. It will soon be published in the journals Critical Care Medicine and the American Journal of Health-System Pharmacy. Joseph Dasta, MSc, professor emeritus at The Ohio State University College of Pharmacy, in Columbus, said he doesn’t foresee a backlash from clinicians. “You may disagree with some of the things,” he said.

“But I hope we have minimized the wailing and gnashing of teeth.”

—Kate O’Rourke The guidelines were developed with no industry funding or involvement. Dr. Sessler disclosed speaker fees from Hospira. Dr. Riker disclosed research support from AstraZeneca, Canyon, Eli Lilly, Hospira, Takeda and The Medicines Company.

Drs. Fraser and Barr have no disclosures.

Dr. Dasta disclosed he is a consultant for AcelRx Pharmaceuticals, Cadence Pharmaceuticals, Hospira and Pacira Pharmaceuticals.

Robert D. ©Francis 2007. The Doctors Company. All rights reserved.

Chief Operating Officer, The Doctors Company

www.thedoctors.com

April 2012

AnesthesiologyNews.com I 15

CL I N I CA L A N E S TH E SIOL OG Y Block continued from page 13 To counteract the negative effects of neuromuscular blockade, anesthesiologists commonly turn to two strategies: objective monitoring and reversal with neostigmine at the end of the case. “Interestingly,” Dr. Eikermann said, “only about half of our colleagues use any neuromuscular monitoring.

The second interesting observation we made in this regard is that less than two-thirds use reversal.”

Even more surprising was the fact that neither of these interventions seemed to reduce the occurrence of adverse events.

Indeed, the use of qualitative neuromuscular monitoring using a peripheral stimulator was not associated with either outcome. Furthermore, neostigmine use was independently associated with a statistically insignificant increase in the incidence of hypoxic events (OR, 1.09; 95% CI, 0.98-1.21), but did not predict re-intubation (Table).

Reversing the Wrong Patients?

Although the researchers did not expect this finding, they offered possible explanations. “With respect to monitoring, it must be that the combination of no monitoring or inconsistent monitoring and neostigmine reversal is associated with worse outcomes,” Dr. Eikermann noted. “And it has been shown by our group that if you give neostigmine in the absence of neuromuscular block, it decreases muscle strength. So we speculate that this is the mechanism, and clinicians just use reversal in patients who don’t really need it.”

Given these results, Dr. Eikermann urged his fellow anesthesiologists to incorporate neuromuscular monitoring into their care regimen. “And second,” he added, “don’t use neostigmine in patients who have already adequately recovered.”

Michael Higgins, MD, MPH, professor of anesthesiology, surgery and biomedical informatics at Vanderbilt University in Nashville, Tenn., stressed the finding that half of the anesthesiologists involved in the study did not monitor neuromuscular blockade. “If nothing else, this could be useful to highlight that if we’re not monitoring neuromuscular blockade, then why not?” he asked.

“Perhaps there’s a good reason and we need to tease that out,” he continued. “But otherwise, we probably need to harken back to some of our practices that have been recommended for a lot of good reasons.”

Table. Relationship Between Use of Neuromuscular Blockers and Adverse Events All Patients

N

Hypoxic Reintubation, Event, n (%) n (%)

Patients with NMBA

57,100

2,425 (4.25)

421 (0.74)

Patients without NMBA

25,082

846 (3.37)

114 (0.45)

Patients with neostigmine

32,018

1,579 (4.93)

307 (0.96)

Patients without neostigmine

11,656

546 (4.69)

91 (0.78)

Paitents with neuromuscular monitoring

16,008

757 (4.73)

160 (1.00)

Patients without neuromuscular monitoring

16,010

822 (5.13)

147 (0.92)

“There are other data that show that this is how clinicians behave,” Dr. Eikermann said. “And I think it’s because anesthesiologists very much trust what they see and what they feel.

And if the patient breathes normally, opens the eyes and squeezes the hands, then they think everything is fine.”

The researchers presented their findings at the ASA’s 2011 annual meeting (abstract 437).

—Michael Vlessides

NMBA, neuromuscular blocking agent

“As I drifted off to sleep, I was thinking

I was lying in the sun.”

–Cindy C.

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Goal-directed Therapies for Positive Patient Outcomes:

Clinical Experience With 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride for Injection Faculty Gerald Rosen, MD Anesthesiologist, Miami Beach Anesthesiology Associates Clinical Professor, Department of Anesthesiology University of Miami/Jackson Memorial Hospital Clinical Professor, College of Nursing & Health Sciences Florida International University Miami, Florida

Mara Zuzel Carrasquillo, BS, PharmD Clinical Pharmacist–Critical Care Specialist Medication Safety Officer Mount Sinai Medical Center Miami, Florida

TJ Gan, MD, MHS Vice Chair, Department of Anesthesiology Duke University Medical Center Durham, North Carolina

Introduction The implementation of goal-directed fluid administration, as guided by flow-based cardiac monitoring (eg, stroke volume variation or pulse pressure variation), has proven to be effective in reducing postoperative complications and hospital length of stay (LOS).1 Recent evidence demonstrates how clinicians have improved outcomes by hemodynamically optimizing patients using goal-directed fluid boluses.2 Appropriate and cost-effective volume replacement therapy is a critical factor to consider within the hospital setting. The ideal volume expander, whether crystalloid or colloid, is determined based on institution and physician preferences as there is little clinical difference between the 2 types when mortality is the outcome of interest.

Additionally, factors such as the type of fluid, the amount administered, associated comorbidities/risks, and costeffectiveness need to be considered. In particular, it is important that patients be given the correct amount of fluid in appropriate amounts at the right time in order to optimize cardiac output and tissue oxygenation (ie, using crystalloid to replace insensible perspiration and urination losses, and colloid to replace plasma losses due to fluid shifting or acute bleeding).3 Isotonic crystalloid solutions, such as normal saline (NS), Lactated Ringer’s (LR) solution, Plasma-Lyte® (Baxter), and Normosol™-R (Hospira), commonly are used for resuscitation.

These solutions do not shift oncotic pressure and therefore allow water molecules to cross the microvascular membrane freely.4 When resuscitation is the goal, these solutions contribute to intravascular volume for approximately the first hour after they are infused. After the first hour, they move rapidly to the interstitium with approximately 20% remaining in the intravascular space.5 Crystalloid solutions are important in helping to replace typical fluid losses due to perspiration and urination. In fact, in the case of severe dehydration, a crystalloid should be given first. Evidence has suggested that large volumes of crystalloid may result in worsening bowel function and prolongation of hospital LOS in patients having major intraabdominal surgery.6 Recently, Chappell and colleagues demonstrated that the perioperatively infused amount of crystalloids corresponds to perioperative weight gain, which is strongly linked to increased mortality

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ANESTHESIOLOGY NEWS • APRIL 2012

and postoperative complications.3 Finally, crystalloids may be selected more often due to the high price of colloids.

Colloid-based fluids contain larger particles and currently are available as both naturally occurring and synthetic proteins. Naturally occurring protein colloids include human serum albumin, whereas hydroxyethyl starches (HES) (eg, hetastarch and tetrastarch), dextrans, and gelatins comprise some of the synthetic colloids. In addition to their effects on oncotic pressure, colloids are larger in size, causing the replaced volume to remain in the intravascular space for a longer duration than crystalloids. Nevertheless, colloids may prove more beneficial over crystalloids as they are more resistant to crossing the microvascular membrane, thus requiring a lower volume for resuscitation.4 However, researchers found that albumin and saline showed virtually no difference in mortality among patients in the intensive care unit (ICU) at 28 days.7 Albumin has been shown to provide positive outcomes and is used often despite its high cost and, due to its frequent use, increased risk for potential shortages as a human-derived product.8 Albumin can account for a significant portion of or addition to the total pharmacy budget in certain hospitals.9 Compared with other colloid and crystalloid solutions, albumin solutions are expensive.8,9 Volume for volume, human albumin solution is more than twice as expensive as HES and significantly more expensive than crystalloid solutions, such as sodium chloride or LR.10 Naturally occurring volume expanders also have been associated with increased risk for bacterial and prion contamination, including a small risk for viral infection when compared with synthetic proteins.8 Synthetic colloids also have been associated with numerous complications, including bleeding and liver or renal impairment, depending on the size or molecular properties of the synthetic colloid.5 A synthetic colloid alternative to albumin and other HES solutions may be found in the iso-oncotic plasma volume expander 6% HES 130/0.4 in 0.9% sodium chloride for injection. HES 130/0.4, a tetrastarch, provides a lower mean molecular weight, molar substitution, and higher C2/C6 ratio than previous HES generations, hetastarch and pentastarch. HES 130/0.4 should not be used in patients with severe hypernatremia or severe hyperchloremia since the diluent solution is 0.9% sodium chloride.11 A lower molecular weight and lower molar substitution result in no significant plasma accumulation. Increased plasma accumulation has been associated with coagulation and renal dysfunction.12 HES 130/0.4 also has a higher plasma clearance and a lower elimination half-life than older HES solutions.13 These advantageous qualities of HES 130/0.4 provide clinicians with a suitable and effective fluid replacement solution for a variety of surgical procedures. Lastly, it is important to note that HES 130/0.4 should not be used in patients with oliguria or anuria not related to hypovolemia.11

Case 1: Volume During and Following Coronary Artery Bypass Surgery A retired 67-year-old man presented to his primary care physician with atypical chest pain. Electrocardiogram demonstrated a sinus rhythm rate of 83 beats per minute with a left bundle branch block. The patient subsequently underwent a thallium stress test with reversible ischemia. The transthoracic Doppler revealed a preserved ejection fraction and mild aortic insufficiency. The heart catheterization demonstrated

multiple coronary vessel disease and surgery for coronary artery bypass grafts was scheduled via sternotomy.

The patient’s cardiac risk factors included age of 55 years or greater, hypertension, non-insulin–dependent diabetes, and cigar use. The patient was taking aspirin and Plavix® (clopidogrel bisulfate), and was asked to stop 3 days before surgery. He was to continue taking metoprolol, lisinopril, and simvastatin until day of surgery. On the day of surgery, the patient arrived as an outpatient. All IV access and invasive monitors were placed with sedation (midazolam 3 mg, fentanyl 50 mcg) before entering the operating room. The arterial line was placed in the right radial artery and the pulmonary artery catheter (volumetric swan) was placed via the right internal jugular approach. Induction was performed with a narcotic technique. Induction medications included fentanyl 500 mcg, midazolam 10 mg, succinylcholine 100 mg, and pancuronium 10 mg. Maintenance of anesthesia included sevoflurane as tolerated.

After induction, arterial blood gas and activated clotting time (ACT) tests revealed an ACT of 136 seconds, a hemoglobin level of 13.2 g/dL, and a hematocrit of 42%. One liter of autologous blood was withdrawn in a citrate phosphate dextrose adenine bag to be returned after reversal of heparin upon termination of the procedure. Additionally, PlasmaLyte® was restricted to less than 1 L prior to initiation of cardiopulmonary bypass to prevent hemodilution. The cardiopulmonary bypass circuit was primed with 500 mL of a colloid, Plasma-Lyte® 500 mL, and mannitol 12.5 g.

During initiation of cardiopulmonary bypass, hemoglobin and hematocrit levels dropped to a low of 8.9 g/dL and 29%, respectively. No blood products were required during bypass.

Post-bypass HES 130/0.4 500 mL was initiated during separation of bypass to optimize the patient’s volume status.

The autologous red blood cells were transfused after heparin reversal and an additional 503 mL of cell-saver blood.

Post-transfusion, hematocrit was 33%. The patient required norepinephrine for vasopressor support at 5 mcg/minute post-transfusion along with invasive monitors, suggesting hypovolemia. An additional dose of HES 130/0.4 500 mL was given, which allowed norepinephrine to be weaned off. The final hematocrit was 31%.

The patient remained intubated and transferred to the ICU with invasive monitors, and placed on a ventilator.

Crystalloids were initiated at maintenance dose of 100 mL per hour. The patient was extubated 4 hours after arrival in the ICU with an estimated blood loss (EBL) of less than 200 mL from chest tubes. The labs prior to extubation were hemoglobin 10.5 g/dL; hematocrit 33%; platelet count 165,000; blood urea nitrogen 26 mg/dL; and serum creatinine 1.1 mg/dL. The patient was discharged from the ICU to step-down on postoperative day 2.

Case 2: Enhanced Recovery After Cystectomy The patient is a 68-year-old woman (weight, 85 kg) who has been diagnosed with bladder cancer. Her past medical history includes hypertension, diabetes, anxiety, and hypothyroidism. She has good exercise tolerance and has been able to adequately perform her day-to-day activities. She takes regular medications to control her blood pressure and diabetes, in addition to taking a thyroid hormone supplement. The patient was scheduled to have an open cystectomy.

Her perioperative management followed an established protocol aimed at enhancing postoperative recovery. The

Supported by

enhanced recovery after surgery (ERAS) regimen is a combination of perioperative interventions involving multiple specialties, including anesthesiologists, surgeons, perioperative nurses, surgical ward nurses, and physical therapists. The aim of the ERAS regimen is to standardize perioperative care, incorporating elements that have been demonstrated to attenuate the stress response, reduce complications, and shorten hospital LOS. In the anesthesia preoperative screening clinic, the patient was educated on the ERAS regimen and various recovery milestones before and after surgery. This review was reinforced with a written copy of the perioperative plan and the recovery expectations. The patient was instructed to have no oral intake from 12 AM on the day of surgery and to drink a bottle of clear Gatorade (500 mL) 2 to 3 hours before expected surgery time.

In the preoperative holding area, LR solution was infused at 3 mL/kg per hour after an IV catheter was inserted. A thoracic epidural was inserted at T9-T10 level. Following a test dose to ensure correct placement, a bolus of hydromorphone 0.7 mg was administered through the epidural.

Following induction of anesthesia, an esophageal Doppler monitor was used as a monitoring device for goal-directed fluid therapy. First, the Doppler probe was inserted into the mid-esophagus and focused to obtain an optimal signal.

A baseline stroke volume (SV; 100 mL) was recorded (Figure).

A bolus of 250 mL of HES 130/0.4 was administered and SV was reassessed 15 minutes after the colloid bolus. A rise in SV by more than 10% suggests fluid responsiveness, and a further bolus of fluid challenge was administered. Following a third bolus, the patient’s SV rise was less than 10% and patient’s hemodynamic indicators were continually monitored. An infusion pump delivering 3 mL/kg per hour of LR solution was continued to the end of surgery.

The patient received 3 additional boluses of HES 130/0.4 following a reduction in SV. In total, the patient received 1,500 mL of HES 130/0.4 and 1,200 mL of LR solution for the entire surgical case. Epidural infusion was commenced with bupivacaine 0.125% and hydromorphone 10 mcg/mL at 6 mL per hour and continued to the postoperative period.

The patient’s pain score was no greater than 3 out of 10 (visual analog scale) throughout the postoperative period.

Episodes of hypotension not associated with blood loss were treated with phenylephrine 100 mcg after ensuring fluid administration was optimized.

The surgery was uneventful. EBL totaled 550 mL. Hemoglobin level and hematocrit were 9.5 g/dL and 28%, respectively, at the end of surgery. Nasogastric tube and urinary catheter were in place at the end of surgery. Postoperative fluid management was continued with approximately 1,000 mL per 24 hours. On day 2, the patient was started on oral fluid regimen and advanced to soft diet the following day. The patient resumed normal diet on postoperative day 5. Epidural infusion was discontinued on the same day and she was administered oral hydrocodone 5 mg as needed. The patient was discharged home on postoperative day 7 without any complications.

Conclusion HES 130/0.4 has been introduced as a colloid alternative when volume expansion is required. HES 130/0.4 is a plasma volume substitute that is indicated for the treatment and prevention of hypovolemia.11 It has been studied in both operating room and ICU patient populations.14 HES 130/0.4 should not be used in patients receiving dialysis or in patients with intracranial bleeding. Additionally, caution should be observed when administering HES 130/0.4 to patients with severe liver disease or bleeding disorders.11 This drug has been used effectively in a wide variety of the patient populations, including those with cardiovascular diseases and the elderly.

HES 130/0.4 offers similar volume expanding effects as highly substituted starches, like hetastarch. The low molecular weight and low molar substitution of HES 130/0.4 result in less plasma accumulation; plasma levels return to baseline levels within 24 hours after a 500 mL infusion in healthy patients. Plasma accumulation is what has been shown to be associated with coagulation and renal dysfunction.15 HES 130/0.4 can be dosed up to 50 mL/kg/day versus other starches, such as hetastarch, that have a labeled ceiling dose

of 20 mL/kg per day. A randomized trial comparing HES 130/0.4 with albumin in children undergoing cardiac surgery revealed that the amount of blood lost was comparable between both groups and patients receiving the synthetic starch had a lower intraoperative fluid balance and were less likely to need transfusion.16 When HES was compared with human albumin for use in priming solutions for cardiopulmonary bypass in adults, no significant differences were observed between the 2 colloids in coagulation variables, postoperative blood loss, inflammatory responses, or transfusion requirements.15,17 Be aware that HES 130/0.4 is contraindicated in patients with fluid overload (eg, pulmonary edema and congestive heart failure patients).11 Furthermore, although the drug is mainly excreted renally, a study assessing its therapeutic safety in mild to severe renal impairment found that HES 130/0.4 can be administered to patients with severe renal dysfunction without the risk for accumulation if urine flow is preserved.14 Due to HES 130/0.4 being renally excreted and also being in a 0.9% sodium chloride solution, it’s important to monitor kidney function, fluid balance, and serum electrolytes. Anaphylactoid reactions can occur so it is recommended that an initial infusion of 10 to 20 mL be given slowly.11 Economically, 500 mL of HES 130/0.4 costs approximately 40% less than the same volume of albumin.18 Compared with albumin, HES 130/0.4 has an equivalent safety profile at a lower cost; making it a beneficial cost savings initiative for the pharmacy budget of any institution.17

References 1. Gan TJ, Soppit A, Maroof M, et al. Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery.

Anesthesiology. 2002;97(4):820-826.

2. Phan TD, Ismail H, Heriot AG, Ho KM. Improving perioperative outcomes: fluid optimization with the esophageal Doppler monitor, a metaanalysis and review. J Am Coll Surg. 2008; 207(6):935-941.

3. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology. 2008; 109(4):723-740.

4. Farcy DA, Peterson P, Rabinowitz D, Scalea T. Controversies in fluid resuscitation. Emerg Med Rep. 2010;31(14):1-11.

5. Van Zundet AAJ, Mythen MC, Kerkkamp HEM, Mortier EP. Volume therapy: is there a colloideal solution? Part 1. CPD Anaesthesia. 2006;8(3):131-149.

6. Nisanevich V, Felsenstein I, Almogy G, Weissman C, Einav S, Matot I. Effect of intraoperative fluid management on outcome after intraabdominal surgery. Anesthesiology. 2005;103(1):25-32.

7. Finfer S, Bellomo R, Boyce N, et al, and the SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256.

Measure SV

Continue monitoring

8. Rizoli SB. Crystalloids and colloids in trauma resuscitation: a brief overview of the current debate. J Trauma. 2003;54(5 suppl):S82-S88.

9. McClelland DB. ABC of transfusion. Human albumin solutions. BMJ. 1990;300(6716):35-37.

10. Tarín Remohí MJ, Sánchez Arcos A, Santos Ramos B, Bautista Paloma J, Guerrero Aznar MD. Costs related to inappropriate use of albumin in Spain. Ann Pharmacother. 2000;34(10):1198-1205.

250 mL VoluvenTM over 5 min

11. VoluvenTM prescribing information. www.fda.gov/downloads/ BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/NewDrugApplicationsNDAs/UCM083138.pdf. Accessed February 27, 2012.

12. Jungheinrich C, Sauermann W, Bepperling F, Vogt NH. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery: a randomised, double-blind study. Drugs R D. 2004;5(1):1-9.

Wait 15 min

13. James MF, Latoo MY, Mythen MG, et al. Plasma volume changes associated with two hydroxyethyl starch colloids following acute hypovolaemia in volunteers. Anaesthesia. 2004;59(8):738-742.

SV falls or increase <10% from baseline or target not achieved

Consider vasopressor or inotrope or more advanced monitoring

Figure. Fluid administration and hemodynamic management algorithm.

SV, stroke volume

15. Choi YS, Shim JK, Hong SW, Kim JC, Kwak YL. Comparing the effects of 5% albumin and 6% hydroxyethyl starch 130/0.4 on coagulation and inflammatory response when used as priming solutions for cardiopulmonary bypass. Minerva Anestesiol. 2010;76(8):584-591.

16. Hanart C, Khalife M, De Villé A, Otte F, De Hert S, Van der Linden P. Perioperative volume replacement in children undergoing cardiac surgery: albumin versus hydroxyethyl starch 130/0.4. Crit Care Med. 2009;37(2):696-701.

17. Ooi JS, Ramzisham AR, Zamrin MD. Is 6% hydroxyethyl starch 130/0.4 safe in coronary artery bypass graft surgery? Asian Cardiovasc Thorac Ann. 2009;17(4):368-372.

BB1169

Increase of SV >10% from baseline and clinically fluid responsive

14. Jungheinrich C, Scharpf R, Wargenau M, Bepperling F, Baron JF. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg. 2002;95(3):544-551.

18. Data on file. Hospira, Inc. IMS National Sales Perspectives™. 2010.

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Volatile Anesthetics for ICU Sedation Linked To Faster Extubation Study of patients undergoing fast-track coronary bypass Toronto—In the largest randomized study to date of sedation with volatile anesthetics, use of these agents was associated with faster extubation, and safety and efficacy during and immediately

after coronary artery bypass graft (CABG) surgery. The findings were presented at the Critical Care Canada Forum 2011 by researchers from Toronto General Hospital, in Canada.

In the study, which was not funded by the pharmaceutical industry, two groups of patients were randomized to receive propofol (n=70) or a volatile anesthetic (either

BRIEF SUMMARY CONSULT PACKAGE FOR FULL PRESCRIBING INFORMATION

VOLUVEN® (6% HYDROXYETHYL STARCH 130/0.4 IN 0.9% SODIUM CHLORIDE INJECTION) 1 INDICATIONS AND USAGE Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia.

It is not a substitute for red blood cells or coagulation factors in plasma.

4 CONTRAINDICATIONS The use of Voluven® is contraindicated in the following conditions: • known hypersensitivity to hydroxyethyl starch [see General Warnings and Precautions (5.1)] • fluid overload (hyperhydration) and especially in cases of pulmonary edema and congestive heart failure • renal failure with oliguria or anuria not related to hypovolemia • patients receiving dialysis treatment • severe hypernatremia or severe hyperchloremia • intracranial bleeding.

5 WARNINGS AND PRECAUTIONS 5.1 General Warnings and Precautions Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. [see Adverse Reactions (6)] Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction.

In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration.

Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease).

5.2 Monitoring: Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation.

5.3 Interference with Laboratory Tests Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis.

At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit.

6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows: Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)] Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches.

Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]

6.2 Adverse Reactions in Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice.

During clinical development, 471 patients were exposed to Voluven®, and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days.

In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch.

Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group.

6.3 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of Voluven® and other types of hydroxyethyl starch solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product.

Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®.

With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2).

10 OVERDOSAGE As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)] 16 HOW SUPPLIED/STORAGE AND HANDLING Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes: Polyolefin bag (freeflex®) with overwrap: 500 mL Carton of 15 x 500 mL NDC 0409-1029-01 Store at 15° to 25°C (59° to 77°F). Do not freeze.

Manufactured by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway Distributed by: Hospira, Inc. 275 North Field Drive Lake Forest, Illinois 60045 USA Made in Norway

‘The take-home message is that volatile anesthetic sedation is safe and efficacious postaortocoronary bypass.’

—Marcin Wąsowicz, MD sevoflurane or isoflurane at the discretion of the attending anesthesiologist; n=69) for anesthesia and postoperative sedation. Postoperatively, volatilebased sedation was delivered with the AnaConDa Anaesthetic Conserving Device (Sedana Medical). Analysis of the data was blinded.

Time to extubation, the primary endpoint, was based on a protocol previously adopted by the institution. The results of the study indicated that readiness for extubation and time to extubation both were significantly shorter for patients who received volatile anesthetics. The overall time at goal sedation was the same in both groups; the overall lengths of stay were similar in the intensive care unit (ICU) and hospital.

“The take-home message is that volatile anesthetic sedation is safe and efficacious post-aortocoronary bypass,” said lead researcher Marcin Wąsowicz, MD, attending anesthesiologist at Toronto General. “The study showed that the use of volatile anesthetics is feasible. However, in order to prove that there is a real benefit, there needs to be a study looking at long-term sedation.”

Christopher G. Hughes, MD, assistant professor of anesthesiology at Vanderbilt University School of

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CL I N I CA L A N E S TH E SIOL OG Y Medicine, in Nashville, Tenn., said the study had some flaws and thus was only a preliminary step toward understanding the role of volatile anesthetics in these patients. For example, he said, time to extubation was determined by clinicians who were not blinded to sedation method, thus introducing a “significant bias.”

“The small time-to-extubation difference is unlikely to be clinically significant in light of the fact that there were no reductions in either ICU or hospital length of stay,” Dr. Hughes said.

He added that “time at target sedation, delirium rates, cost and many other variables need to be examined in future studies to determine the efficacy of volatile anesthetics for ICU sedation.”

Given the cost of new equipment for delivering volatile anesthetics in the ICU, as well as a necessary change in culture, Dr. Hughes said he was unsure of the clinical significance of the current study. However, he said the work “is important for research purposes for new potential techniques.”

Dr. Wąsowicz said that use of an objective extubation protocol removed potential bias in this measure, and that volatile anesthetics are inexpensive. “The cost of many intravenous agents is much higher, including dexmedetomidine [Precedex, Hospira],” Dr. Wąsowicz said. However, he agreed “to some extent” that the lack of a shorter length of stay with volatile anesthetics is problematic. “We could switch from an ICU nurse-to-patient ratio of 1-to-1 to 1-to-2, and perhaps that would make the use of volatile anesthetics more cost-effective.”

The study, conducted between September 2009 and August 2011, was funded by the University Health Network, the University of Toronto’s Department of Anesthesia and the Canadian Anesthesiologists’ Society.

The 139 patients included in the analysis were scheduled for “fast-track” elective CABG surgery. None of the patients had significant liver or kidney dysfunction, poorly controlled diabetes or a history of malignant hyperthermia or propofol infusion syndrome; they also were not undergoing chest reopening for bleeding, and could undergo extubation within 12 hours.

Median time to extubation was 350 minutes in the propofol group and 244 minutes in the volatile anesthetic group (P<0.01). The median time at goal sedation was 80% of sedation time in both groups (P>0.05).

The average length of stay in the ICU was 1,920 minutes (32 hours) in the

propofol group and 1,870 minutes (31.2 hours) in the volatile anesthetic group. Average length of stay in the hospital was six days for both groups (P>0.05).

Intraoperatively, 33 patients in the propofol group required norepinephrine infusion compared with 17 patients in the patients given a volatile anesthetic (P=0.001). The respective numbers for vasopressin were 17 patients and three patients (P=0.02).

Postoperatively, the average troponin requirement per patient for the first 12 hours was 5.1 ng/mL in the propofol group and 5.57 ng/mL in the volatile anesthetic group (P=0.81). “Troponins are mainly related to a secondary objective, which was studying the pre- and postconditioning effects of volatile anesthetics versus propofol,” Dr. Wąsowicz said.

Technical problems developed in two cases in the volatile anesthetic

group. A leak from the vaporizer attached to the cardiopulmonarybypass machine occurred during one surgical procedure; in the second case, the monitor for measuring end-tidal volume malfunctioned. Neither patient experienced adverse effects as a result, the researchers said.

—Rosemary Frei, MSc Dr. Wąsowicz and Dr. Hughes reported no conflicts of interest.

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Gloom and Doom Swirls Around Sepsis Research

Houston—In the 1990s, two high-profile drugs for sepsis crashed and burned after promising early mortality data fizzled in later studies and the manufacturers had to halt the clinical trials. The mood among sepsis researchers was understandably gloomy, and it now appears that the storm clouds are back—not only because of the withdrawal of drotrecogin alfa (activated; Xigris, Eli Lilly) from the market in October— but also due to a flurry of more recent, disappointing results from trials of other sepsis medications.

These developments, outlined in presentations during the recent annual meeting of the Society of Critical Care Medicine (SCCM), have fueled the feeling that there are only gray clouds hovering over sepsis research.

In fact, “we must be very anxious because the industry may no longer put its money in our field. They may just move away and go to other disciplines,” said Jean-Louis Vincent, MD, PhD, head of the Department of Intensive Care at Erasme University Hospital, in Brussels, Belgium.

and Harvard Medical School, in Boston, who presented the data at SCCM. The 28-day mortality in patients receiving drotrecogin alfa (n=846) was 26.4% compared with 24.2% in the placebo arm (n=834), which was not a statistically significant difference (P=0.31). Mortality was not improved in the subset of patients with severe protein C deficiency. No increase in serious bleeding events during infusion was identified.

Compared with the patients in the original PROWESS study, patients in PROWESSSHOCK had fewer primary sites of infection in the lung (44% vs. 54%) and abdomen (3% vs. 20%), whereas more patients in PROWESS-SHOCK experienced organ failure (Table 2) and received mechanical ventilation (82% vs. 75%). Yet, regardless of differences, said Dr. Thompson, the PROWESS-SHOCK population was one in which the drug would have been expected to work.

Dr. Thompson said subgroup analyses would be published in an upcoming journal article, but there were no green shoots of hope in the dismal forest plots.

“We found no benefit in any of the prespecified subgroups,” he said.

Anatomy of a Failed Trial At the SCCM meeting, Dr. Vincent offered several possible explanations for the trial’s failure. Perhaps, he said, the original PROWESS was positive by chance and the drug never worked. Perhaps the mortality rate, which has fallen in recent years due to better care, makes detecting a difference more difficult.

Perhaps PROWESS-SHOCK suffered from the drug being available on the market for the best candidates, and the randomized patients were not good candidates for the drug. “I would vote for the third option, Table 1. PROWESS-SHOCK Patient Inclusion Criteria

Lack of PROWESS Meet at least two of the four systemic inflammatory In the beginning, the prospects for drotrecogin response syndrome criteria alfa were promising. The drug was approved in 2001 Clear evidence of infection based on results from the PROWESS (RecombiIV fluid resuscitation of ≥30 mL/kg adminnant Human Activated Protein C Worldwide Evalua- Received istered 4 h before or after initiation of vasopressor tion in Severe Sepsis) trial, which demonstrated a 6% therapy improvement in 28-day mortality for patients with Continuous requirement of at least one of four severe sepsis who received the drug (30.8% vs. 24.7%; vasopressors for at least 4 h P=0.05). Until it was withdrawn, this drug was the Hypoperfusion (renal, acidosis, hepatic) only available pharmaceutical specifically designed to Drotrecogin initiated within 24 h of shock onset treat sepsis.

PROWESS-SHOCK was launched in 2008 at the request of the European Medicines Agency (EMA). In Table 2. Comparison of Organ Failures at Baseline 2007, the EMA said the positive PROWESS results In PROWESS and PROWESS-SHOCK had not been reproduced in other studies and encourNumber of Prowessaged Eli Lilly to conduct a randomized placebo- Organ Failures Prowess, % Shock, % controlled study in patients with severe sepsis and One 2.5 25 documented organ failure to confirm that the drug’s Two 13 32 benefits outweighed the risks, the most serious being bleeding.

Three 34 26 PROWESS-SHOCK included 1,696 patients with Four 38 14 severe sepsis and septic shock (Table 1). The patient Five 13 4 population was “a subset with a strong efficacy signal in PROWESS,” said B. Taylor Thompson, MD, pro- PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in fessor of medicine at Massachusetts General Hospital Severe Sepsis

but nobody knows,” he said.

According to Dr. Thompson, the mortality rate in the placebo arm of PROWESS-SHOCK (24%) was lower than projected (32%). This is consistent with other recent randomized trials. In a study evaluating the small molecule TAK-242, the 24.2% mortality rate identified in the placebo arm was much lower than the 40% that was expected (Crit Care Med 2010;38:1685-1694). The nine-year observational ARISE (Australasian Resuscitation in Sepsis Evaluation) study identified a 21% mortality rate for patients with sepsis.

“If the attributable mortality from sepsis has been reduced, much larger sample sizes will be needed to detect potential beneficial effects of new therapies.

That is just simple math,” said Dr. Thompson. “If the lower attributable mortality from sepsis is due to early and more effective care, then the severity and/or consequences of aberrant innate immune activation, and thus the therapeutic target, will be reduced.”

Dr. Thompson presented data from 11 registries showing a benefit in mortality for the use of drotrecogin, including a U.S. registry of 1,576 patients (mortality, 47% vs. 41%) and a French registry of 1,049 patients (68% vs. 47%). Questioning whether a responsive subset of patients could have been included in the registries that were excluded in the PROWESSSHOCK trial, he said, it is possible that registries of usual-care practices include under-resuscitated patients with greater degrees of inflammation and/or organ/ endothelial injury than what was seen in PROWESSSHOCK. Another possibility is that observational studies do not adequately control for residual confounding factors. “If there is some subset out there that responds to this drug, you would think that we would have a few of [these patients] in PROWESS-SHOCK.” According to Dr. Thompson, severe sepsis and septic shock phenotypes are unreliable surrogate markers for aberrant or excessive innate immune/coagulation system activation. “We need to better understand innate immune suppression,” he said. “We need enrichment strategies like the cancer community—biomarkers and genetics—to find the responsive subsets. But I think the severe sepsis phenotype is obsolete.”

Outgoing SCCM President’s Take Judith Jacobi, PharmD, a critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis, and immediate past-president of the SCCM, said the results of PROWESS-SHOCK are “very disappointing.” She added that she will miss the drug particularly when treating patients who have sepsis-induced coagulopathy. “The mechanism of action of the activated protein C is geared toward that underlying problem of sepsis coagulopathy,” she said.

Patients with sepsis coagulopathy were included in the trial only if severe thrombocytopenia was also present, Dr. Thompson said.

Dr. Jacobi said, “I suspect that the decision [whether or not] to continue to sell this agent is a business decision by Lilly. I understand it is a difficult and expensive compound to produce, and so unless there is some orphan status, it would probably not be a good business [decision to resume

APRIL 2012

Brought to You by

REPORT IV Acetaminophen Improves Pain Management and Reduces Opioid Requirements in Surgical Patients: A Review of the Clinical Data and Case-based Presentations

A

cute pain is a common and suboptimally managed occurrence in the postoperative setting. In a survey of adults who had undergone surgical procedures in the United States, Warfield and colleagues noted that 77% reported pain after surgery, with 80% of affected individuals experiencing moderate to severe pain.1 Furthermore, postoperative pain is associated with various complications and poor

outcomes, including longer times to ambulation, longer hospital lengths of stay (LOS),2 higher rates of medical complications (eg, venous thromboembolic disease from reduced activity), and decreased patient satisfaction.3,4 Long-term complications also can arise from undertreated postoperative pain, including worse functional outcomes and a higher prevalence of chronic pain syndromes.2,4,5

Chair

Faculty

Eugene R. Viscusi, MD

Neil Singla, MD

Nasser Saad, PharmD

Associate Professor Director, Acute Pain Management Service Department of Anesthesiology Thomas Jefferson University Philadelphia, Pennsylvania

Founder and Chief Medical Officer Lotus Clinical Research Pasadena, California

Critical Care Pharmacy Manager Pharmacy Department New York Methodist Hospital Brooklyn, New York

Anthony Gonzalez, MD Chief of Surgery, Baptist Hospital of Miami Medical Director, Bariatric Surgery South Miami Hospital Assistant Professor of Surgery Florida International University College of Medicine Miami, Florida

Supported by

Jeffrey Stepanian, PA-C Senior Physician Assistant Orthopedics Evergreen Orthopedic Clinic Kirkland, Washington

REPORT

Table 1. Mean Pharmacokinetic Data After First Dose in Healthy Adults Parameter

OFIRMEV 1g (n=34)

Cmax

28.4 mcg/mL

Oral acetaminophen 1g (n=33) 15.1 mcg/mL

Tmax

0.28 h

0.72 h

t1/2

2.39 h

2.66 h

Area under the curve

47.0 mcg • h/mL

42.4 mcg • h/mL

Hepatic firstpass exposure

2

in postoperative patients. A review of the pharmacokinetics and pharmacodynamics will be followed by a discussion of data from clinical studies and case-based presentations.

IV Acetaminophen: Pharmacokinetics and Pharmacodynamics Although acetaminophen (paracetamol or N-acetyl[APAP]) produces a central analgesic effect, its precise mechanism(s) remain unknown. Postulated targets include cyclooxygenase isoenzymes, endogenous opioid or serotoninergic bulbospina pathways, and/or cannabinoid/ vanilloid tone.17 More recently, evidence suggests that acetaminophen is a TRPV-1 agonist that mediates response to pain.18 It also has an antipyretic effect, which may be mediated by inhibition of prostaglandin formation that otherwise acts to increase the temperature “set point” within the hypothalamus.19 This agent is available in oral and rectal formulations in the United States and also has been available as an IV formulation in Europe since 2002 and in the United States since 2010.

One important advantage of acetaminophen over other analgesic agents used for the treatment of postoperative pain is its safety and tolerability profile.20 In contrast to opioids, acetaminophen does not produce sedation, respiratory depression, or ileus and constipation, nor is it associated with a risk for substance abuse or misuse.16 Nonsteroidal antiinflammatory drugs (NSAIDs) also are commonly used in the postoperative setting, but can compromise renal function and increase the risk for cardiovascular events.21 Furthermore, the adverse effects of NSAIDs on mucosal integrity and platelet function are associated with an increased risk for bleeding, a complication that can be particularly problematic in the postoperative setting.22 The pharmacokinetics and pharmacodynamics of IV acetaminophen have been well characterized (Table 1).16 IV infusion of acetaminophen results in a rapid elevation in plasma concentrations and higher peak levels compared with P-aminophenol

Acetaminophen Concentration, mcg/mL

Although monotherapy with opioids has been the mainstay of treatment for postoperative pain, these agents are associated with various adverse events (AEs)—nausea and vomiting, constipation, and ileus—that can occur even at low doses of opioids and can result in significant discomfort and longer hospital LOS.6 Some of the more severe AEs include respiratory depression and sedation, both of which increase the risk for respiratory failure, aspiration, decreased mobility, and falls.6,7 Thus, opioid monotherapy is not an adequate or appropriate strategy to improve pain management in postoperative patients.

Over the past decade, multimodal analgesia has gained recognition for being an effective strategy in managing postoperative pain.8-10 Using different classes of analgesics each with different pathways and receptors, multimodal analgesia optimizes analgesic efficacy using lower doses of each of the respective agents, thus limiting the risk for dose-related AEs.10 Clinicians find this approach beneficial, particularly when using regimens that allow lower doses of opioids. Consequently, multimodal analgesia can improve recovery after surgery and ensure rehabilitation and transfer to the outpatient setting, while reducing overall costs.11,12 Agents with potency for modulating one or more discrete mechanisms of pain transmission and that have a good safety profile are favorable for multimodal analgesia.4 Additionally, analgesics that can be given intravenously can enhance bioavailability and earlier onset of analgesic effect in the immediate postoperative period, as surgical patients may experience postoperative nausea and vomiting or because the enteral route may not be an option based on the procedure.13 In fact, both parenteral opioids and major surgery have been shown to cause profound delays in gastric absorption, which have implications regarding optimal route of drug delivery during the perioperative period.14,15 IV acetaminophen (OFIRMEV™) can be integrated into a multimodal approach to optimize pain management effectively. In November 2010, the FDA approved the use of IV acetaminophen for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever.16 The following material will discuss the use of IV acetaminophen as a component of multimodal analgesia

Mean Plasma Values

25

IV acetaminophen 1,000 mg ( n=6 ) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg 2 (n=6)

20

15

10

5

0 0

No

Yes

2

Time, h

4

6

Cmax, peak concentration; t½, half-life; Tmax, maximum plasma concentration

Figure 1. Acetaminophen plasma concentration over time.

Based on reference 16.

Based on reference 23.

REPORT

Clinical Studies of IV Acetaminophen Two pivotal trials investigated the use of IV acetaminophen for the treatment of postoperative pain. In the first study, 101 patients with moderate to severe pain following orthopedic surgery were given either 1 g IV acetaminophen or placebo

at 6-hour intervals for 24 hours.24 Supplemental IV patientcontrolled analgesia (IV-PCA) morphine was available to all patients if needed. IV acetaminophen was significantly better than placebo in terms of pain relief from 15 minutes to 6 hours postoperatively, median time to morphine rescue (IV acetaminophen: 3 hours; placebo: 0.8 hours), and morphine consumption over 24 hours (38.3 vs 57. 4 mg for placebo; 33% decrease in morphine consumption with IV acetaminophen) (Figure 3).24 An expanded analysis of these study data was recently published and demonstrated that the sum of pain intensity differences over 24 hours (SPID24) using a 0- to 100-mm visual analog scale (VAS) was significantly improved with IV acetaminophen when compared with placebo.36 Rescue medication consumption, requests, and actual administration were all lower in the IV acetaminophen group when compared with placebo for each 6-hour dosing interval.36 The other pivotal trial of IV acetaminophen was a double-blind, placebo-controlled, parallel-group study in which 244 patients with moderate to severe pain after abdominal laparoscopic surgery were randomized to receive either IV acetaminophen (1,000 mg every 6 hours or 650 mg every 4 hours) or IV placebo (100 mL every 6 hours or 65 mL every 4 hours) over 24 hours.37 Results showed that the primary end point, SPID24, was statistically more favorable than placebo (-194.1 vs -45.2 mm; P<0.007),37 and the time to meaningful pain relief was significantly shorter in patients receiving IV acetaminophen 1,000 mg compared with placebo (24.9 vs 53.9 minutes, P<0.003).37 Furthermore, IV acetaminophen was associated with a longer median time to first rescue medication, a lower proportion of patients requiring rescue medications, and significantly better

IV acetaminophen 1,000 mg (n=6) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg 2 (n=6)

Acetaminophen Concentration, mcg/mL

oral acetaminophen (Figure 1),23 sustained pharmacokinetic differences from oral acetaminophen over repeated doses, with a clinical analgesic effect that occurs within 5 to 15 minutes of administration.24 The clinical analgesic effect peaks within 1 hour and lasts for approximately 4 to 6 hours.16 These characteristics are favorable when compared with either oral or rectal formulations of acetaminophen. Specifically, the mean peak concentration after infusion of IV acetaminophen is approximately 70% higher than the mean peak concentration observed at an equivalent oral dose.16 Additionally, the higher peak concentration with IV acetaminophen remains far below the concentration considered the threshold for potential hepatotoxicity (150 mcg/mL at 4 hours post-administration).25-27 The median time to reach maximum plasma concentration (Tmax) for IV acetaminophen, is 15 minutes (at the end of infusion), whereas the Tmax for oral or rectal routes of administration is 45 to 75 minutes (depending on the formulation) or 3 to 4 hours, respectively.28,29 Pharmacokinetic parameter estimates for IV acetaminophen are similar in children, adolescents, and adults, when normalized for body weight.16 IV acetaminophen is not approved for patients under the age of 2.16 Acetaminophen readily penetrates the blood–brain barrier, and its analgesic and antipyretic effects correlate well with cerebrospinal fluid (CSF) levels.23,25,30 In fact, the rapid CSF penetration, combined with the earlier and higher peak concentration observed with IV acetaminophen, may be responsible for its more rapid onset of action and peak efficacy compared with oral or rectal acetaminophen (Figure 2).23,25,31 Regardless of route of administration, acetaminophen is metabolized by the liver via 3 primary pathways: glucuronidation (85%), sulfation, and oxidation.25,32 The latter pathway metabolizes acetaminophen into the hepatotoxic compound, N-acetylP-benzoquinone imine, which is subsequently metabolized to non-hepatotoxic compounds by glutathione.33 Thus, hepatotoxicity may occur in the setting of elevated hepatic levels of acetaminophen that overcome hepatic glutathione stores.25 This mechanism of hepatotoxicity becomes especially relevant when considering that absorption of drugs via the enteral route may result in locally high drug levels in the portohepatic circulation (ie, “first-pass” effect).25 By contrast, IV infusion of drugs results in rapid elevations of plasma levels while avoiding this first-pass effect. Indeed, first-pass pharmacokinetic models have shown that the IV route of administration reduced initial hepatic acetaminophen exposure by approximately 2-fold when compared with the oral route.25,34 In adults weighing more than 50 kg, a maximum dose of 4 g per day, in repeated doses, has been shown to be safe and well tolerated.16 The American Society of Anesthesiologists (ASA) Task Force on Acute Pain Management has endorsed the use of acetaminophen as a component of multimodal analgesia for the purposes of reducing reliance on opioids.35 The availability of this agent as an IV formulation furthers the ability to deliver acetaminophen in the postoperative setting. The ASA guidelines specifically advocate the use of nonopioid analgesics administered as first-line agents around the clock and for opioids to be used as adjunctive agents.35

Mean Cerebrospinal Fluid Values

6

5

4

3

2

Acetaminophen AUC 0-6 (SD) ( mcg • h/mL) IV: 24.9 (17.4) vs PO: 14.2 (52.1); P<0.0001 vs PR: 10.3 (24.6); P<0.0001

1

0 0

2

Time, h

4

6

Figure 2. Mean (SD) CSF acetaminophen concentration-time curves after IV, PO, and PR administration of 1,000 mg (N=6).

AUC, area under the curve; CSF, cerebrospinal fluid; PO, oral; PR, rectal; SD, standard deviation Based on reference 23.

3

REPORT patient satisfaction with pain control when compared with placebo.37 Although both IV acetaminophen regimens, 1,000 mg every 6 hours or 650 mg every 4 hours, are efficacious, only the 1,000-mg dose produced a statistically significant difference in time to meaningful pain relief and total pain relief over the first dosing interval compared with placebo.37 IV acetaminophen also has been studied in other surgical populations. For example, Cakan and colleagues performed a prospective, double-blind, randomized placebo-controlled study of IV acetaminophen (1 g every 6 hours for 24 hours) in 40 patients undergoing lumbar laminectomy and discectomy.38 Pain scores at rest and on movement at multiple time points (12, 18, and 24 hours) were significantly lower with IV acetaminophen than with placebo.38 Furthermore, patients receiving IV acetaminophen had greater satisfaction with pain control (“excellent” rating: 45% vs 5%, P<0.05), lower morphine consumption at all evaluation times, and a decreased incidence of vomiting (P<0.05).38 The efficacy and safety of IV acetaminophen versus placebo has been investigated in patients following major abdominal and pelvic surgery requiring a planned admission to the intensive care unit (ICU). Memis and colleagues studied the efficacy of IV acetaminophen (1 g every 6 hours for 24 hours) or placebo (100 mL saline every 6 hours for 24 hours).39 Use of IV acetaminophen was associated with significantly lower pain scores and lower postoperative opioid consumption (61% reduction, P<0.05) and lower nausea and vomiting (P<0.05) and sedation scores (P<0.05) when compared with placebo. Patients were sent to the ICU still intubated, and those receiving IV acetaminophen demonstrated a shorter time to extubation compared with placebo (64.3 vs 204.5 minutes; P<0.05).39 In addition to these studies, IV acetaminophen has been

OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52)

60

-33%

Morphine Consumption, mg

50



40

30

-46%

20

0

Conclusion



10 17.8 mg

9.7 mg

Over 6 h P<0.01

57.4 mg

38.3 mg

Over 24 h P<0.01

Figure 3. Morphine consumption following orthopedic surgery.

PCA, patient-controlled analgesia Based on reference 24.

4

shown to exert similar benefits in the postoperative setting in adults undergoing a variety of other types of surgical procedures, including open abdominal, gynecologic, cardiac surgery, and thyroidectomy.40 Several studies have shown that these postoperative benefits also occurred in pediatric patients undergoing hernia repair, tonsillectomy, strabismus surgery, or dental procedures.41-44 Another benefit associated with the use of IV acetaminophen in the postoperative setting is its antipyretic properties. Peacock and colleagues reported that IV acetaminophen was as effective as oral acetaminophen in reducing fever.45 The significance of this effect is underscored by the fact that fever can adversely affect the patient’s metabolism and cardiovascular system, especially during the “temperature spike” phase with its shivering-induced increase in metabolic rate, norepinephrinemediated peripheral vasoconstriction, and increased arterial blood pressure.46 Additionally, antipyretic therapy may enhance patient comfort in the postoperative setting and could potentially reduce the risk for fever-associated delirium in the elderly or febrile seizures in the pediatric population.47,48 However, the role of postoperative fever or the use of antipyretics as independent predictors of outcomes has not been definitively studied in the postoperative setting.

IV acetaminophen may be preferable for some surgical patients because, unlike other analgesics, it does not affect mental status, rates of bleeding, respiratory drive, gastric mucosal integrity, or renal function.21 However, acetaminophen doses in excess of 4 g daily have been associated with hepatic injury, and therapeutic doses have been associated with injury in patients who are at an increased risk for hepatotoxicity (eg, the elderly, alcoholics, and those who have preexisting liver disease or who are severely malnourished)16 ; thus, clinicians are encouraged to follow the recommended doses based on the patient’s weight and the appropriate time intervals when administering repeat doses (Table 2).16 Clinicians should be cautious to ensure that patients are not receiving more than one form of acetaminophen at a given time as overdoses have been associated with accidental administration of multiple drugs containing acetaminophen.

In a study of 213 patients, the safety of IV acetaminophen was compared with standard of care, with results showing a numerically lower proportion of patients with elevated liver function tests in the IV acetaminophen group.49 Furthermore, in a meta-analysis of 36 studies involving the use of IV acetaminophen in the postoperative setting, there was no statistical difference in the rates of AEs, including liver function abnormalities, when comparing IV acetaminophen with placebo.50

Postoperative pain is a common problem with serious implications in terms of patient outcomes and health care costs. Opioid monotherapy is inadequate for postoperative pain management, and opioids and NSAIDs are associated with various common AEs that limit their overall utility.

IV acetaminophen has properties well suited for use within a multimodal analgesia paradigm, including delivery by a nonoral route, fast onset, proven safety, and reduction in pain and fever as demonstrated by multiple clinical studies. When used as a component of multimodal analgesia, IV acetaminophen also can improve outcomes by reducing the amount of opioids required for pain control in the postoperative setting among a wide variety of surgical patients.

REPORT Table 2 . Recommended Dosing of IV Acetaminophen Age Group

Dose Given Every 4 h

Dose Given Every 6 h

Maximum Single Dose

Maximum Total Daily Dose of Acetaminophen (Any Route)

Adults and adolescents (≥13 y) weighing ≥50 kg

650 mg

1,000 mg

1,000 mg

4,000 mg in 24 h

Adults and adolescents (≥13 y) weighing <50 kg

12.5 mg

15 mg/kg

15 mg/kg (up to 750 mg)

75 mg/kg in 24 h (up to 3,750 mg)

Children (2-12 y)

12.5 mg

15 mg/kg

15 mg/kg

75 mg/kg

Based on reference 16.

Case Study 1 A 47-year-old woman undergoing an anterior-posterior cervical spine procedure.

Eugene R. Viscusi, MD

T

he patient had a 2-month history of severe, burning neck pain radiating to her arms and numbness and weakness of the upper extremities. Magnetic resonance imaging confirmed discogenic cord impingement at C 4-5-6 levels.

She had had moderate control of her pain with oxycodone 10 mg every 4 hours over the past month. Otherwise, she was generally healthy. She required a general anesthetic with electrodiagnostic monitoring of her spinal cord and hence needed total IV anesthetic. The surgeon cautioned that NSAIDs would be contraindicated because of concerns for bone healing.

A multimodal perioperative analgesic approach was planned.

Because she used 40 to 60 mg of oxycodone per day, she was considered opioid-tolerant and special care would be taken to meet her opioid requirements and avoid opioid withdrawal.

Approximately 1 hour before induction, 1 g IV acetaminophen was administered. Her surgery concluded in approximately 5 hours. Upon arrival to the postanesthesia care unit (PACU), she was awake, responsive, and complaining of pain. Because more than 4 hours had elapsed since her last dose of IV acetaminophen, 1 g was administered and her pain improved. IV-PCA with hydromorphone was initiated in the PACU. Because she was opioid-tolerant, the patientadministered dose was set at 0.3 mg with a 6-minute lock-out.

Supplemental nursing doses were 0.6 mg as needed every 2 hours. IV acetaminophen was continued for 24 hours, 1 g every 6 hours to a maximum of 4 g every 24 hours. Oral pregabalin

150 mg was continued twice daily throughout the inpatient stay. Throughout the remainder of her operative day, she was able to titrate to comfort with supplemental IV-PCA. At 24 hours following surgery, the patient was awake, alert, comfortable, and had advanced to solid food. She described her pain as “aching now but the burning was much less than before surgery.” She said she was able to maintain reasonable comfort with her PCA but noticed improvement when IV acetaminophen was administered. She said the IV acetaminophen did not make her sleepy. She used approximately 20 mg of hydromorphone via IV-PCA over 24 hours. Oral conversion was requested with intent to discharge by postoperative day (POD) 3. She was placed on oxycodone extended release (ER) 20 mg twice daily, oxycodone immediate release (IR) 10 mg as needed every 4 to 6 hours, and IV acetaminophen was continued for an additional 24 hours. She remained comfortable throughout the next day.

On POD 3, she was discharged home on oxycodone ER 20 mg, oxycodone IR 10 mg every 4 hours as needed, pregabalin 75 mg twice daily, and oral acetaminophen 975 mg (ie, 325 g x 3) every 6 hours with follow-up in 2 weeks.

At 2 weeks, her pain was much improved and she was using her oxycodone IR 10 mg only 2 to 3 times per day. At this point, oxycodone ER and pregabalin were discontinued. She was maintained on oxycodone IR 10 mg every 4 to 6 hours as needed and acetaminophen 650 mg every 4 to 6 hours as needed.

Case Study 2 A 60-year-old woman undergoing total left knee revision.

Jeffrey Stepanian, PA-C

T

he patient presented with a history of uncomplicated left knee total joint arthroplasty 2 years prior and an 18-month complaint of severe pain in her left knee causing significant mobility issues and requiring a walker. X-rays showed a loose tibial component, with no signs of infection. She was diagnosed

with aseptic loosening and a total left knee revision was planned.

At the time of surgery, she had been taking oral oxycodone/ acetaminophen as her primary analgesic for the past 8 months, normally a total of 30 mg oxycodone and 2 g acetaminophen per day. Despite this, she complained of persisent, constant,

5

REPORT and severe pain at an 8 on a 10-point pain intensity scale. No other significant comorbidities were noted.

The patient underwent a left total knee revision under general anesthesia. A regional nerve block was not performed. Prior to the skin incision at 7:30 AM, 1,000 mg IV acetaminophen was administered simultaneously with 2 g of cefazolin.

Following the surgery, which lasted 181 minutes, the patient was taken to the PACU in stable condition. A Polar Care cryotherapy bladder was applied to the patient’s left knee.

While in the PACU, the patient complained of pain at a level of 6 to 9/10. A bolus of 100 mcg IV fentanyl was administered, but failed to be effective. The patient was then administered boluses of 0.2 mg IV hydromorphone, and she required 4 doses while in the PACU still with a pain intensity reading of 7.

The patient arrived on the orthopedic floor at 12:05 PM still complaining of significant pain. At 12:40 PM, 0.5 mg IV hydromorphone was administered with a pain intensity rating of 6/10. Almost 2 hours later, the patient was administered 15 mg IV ketoralac with no change in pain intensity. At 2:25 PM, the patient received a second dose of 1,000 mg IV acetaminophen, and at 4:45 PM, she received 10 mg oxycodone IR. The pain intensity rating was now 5/10. The patient received a second dose of 10 mg oxycodone IR at 9:15 PM, at which time the pain intensity rating was still 5/10. Cryotherapy and rehabilitation using a continuous motion machine were continued every 4 hours. IV acetaminophen was continued at a dose of 1,000 mg every 6 hours At the start of POD 1, the patient’s pain intensity rating was 5/10. The patient felt that her pain was controlled better

with IV acetaminophen than with oxycodone. She was given one last dose of IV acetaminophen at 7:15 AM, resulting in a pain intensity rating of 3/10. Cryotherapy and rehabilitation continued as before. The patient was able to ambulate 150 feet using a front-wheeled walker and ascend and descend a flight of stairs. With adequate pain control and good mobility, the patient was discharged home at 1:30 PM with oxycodone to use as needed.

At her postoperative visit a week later, she confirmed that she never needed to use the oxycodone following discharge.

She no longer required the walker and was using a cane for ambulation.

This case describes a total knee revision where the patient was opioid-tolerant, and where the IV acetaminophen contributed to good-quality analgesia and allowed for discharge on POD 1. In addition, this facility has instituted a multimodal pre-op and post-op pain protocol for primary total knee arthroplasties that consists of a preoperative joint injection of 20 cc 2% lidocaine with epinephrine, a postoperative joint injection of 60 cc 0.25% bupivacaine with 2 mg of morphine sulfate, 15 to 30 mg IV ketorolac for 4 doses (unless medically contraindicated), continuous passive motion machine, cryotherapy, and IV/oral opiates.

IV acetaminophen has now been added to the protocol commencing at time of induction and continuing every 6 hours for 24 hours. The addition of IV acetaminophen has resulted in an average hospital LOS of 1.7 days for primary total knee arthroplasties, a reduction of 0.6 days compared with the previous pain protocol.

Case Study 3 A 49-year-old woman undergoing a robotic laparoscopic sleeve gastrectomy.

Anthony Gonzalez, MD

T

he patient had a history of diabetes, hyperlipidemia, hypertension, back pain, shortness of breath with exertion, gastroesophageal reflux disease, diabetic neuropathy, chronic foot infections, and was morbidly obese with a body mass index (BMI) of 46 kg/m2 (height: 64 inches, weight: 120 kg).

She also had a past surgical history of a perforated bowel with history of exploratory laparotomy. She had failed multiple medical attempts for weight loss as prescribed by her primary care physician. These failed attempts included a grapefruit diet; low-carb diets; restricted caloric diets in combination with exercise, hypnosis, and acupuncture; and use of diet pills such as phentermine and orlistat.

She sought consultation for weight loss surgery for morbid obesity and comorbid medical problems. After a complete surgical and psychological evaluation, the patient was offered 3 procedures for consideration: adjustable gastric banding, sleeve gastrectomy, and gastric bypass. Based on her age, BMI, and comorbid medical issues, the sleeve gastrectomy was deemed the best option. After a long discussion and obtaining consent, she agreed to proceed with the bariatric procedure.

The patient underwent a robotic laparoscopic sleeve gastrectomy uneventfully. This procedure involved the creation of 5 small (5-mm) incisions and had an operative time of nearly

1 hour. In addition to preoperative antibiotic and prophylaxis for deep vein thrombosis, she was given a preoperative dose of 1 g IV acetaminophen. She was maintained without anything to eat or drink for the first 24 hours following surgery.

Postoperatively, she was prescribed IV acetaminophen 1 g every 6 hours around the clock for mild to moderate pain. She was given hydromorphone 1 to 2 mg every 3 hours as needed for severe or breakthrough pain. During the first 24 hours after surgery, the patient did not require any opioids for pain relief.

She only received IV acetaminophen during the first 24 hours.

Upon questioning by the nursing staff, she stated that the pain was well relieved and did not require additional medication.

On POD 1, now able to eat and drink, the patient was offered acetaminophen/hydrocodone elixir. She tolerated clear liquids, but did not ask for any pain medication.

The patient was discharged on POD 2 with a prescription for acetaminophen/hydrocodone elixir. At her follow-up office visit, the patient was doing well and reported no need to use the prescribed medication for pain relief. She reported excellent pain control and was “very satisfied” with the care at the hospital. She noted that the overall experience of undergoing and recovering from this surgery was much better than her previous surgical experience.

Note: The case studies presented are composite and are not intended to identify specific patients.

6

REPORT

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2. Morrison RS, Magaziner J, McLaughlin MA, et al. The impact of post-operative pain on outcomes following hip fracture. Pain. 2003;103(3):303-311.

3. Haljamäe H, Stomberg MW. Postoperative pain management—clinical practice is still not optimal. Curr Anaesth Crit Care. 2003;14:207-210.

4. Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin North Am. 2005;23(1):21-36.

5. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology. 2000;93:1123-1133.

6. Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother.

2007;41(3):400-406.

7. Pergolizzi J, Böger RHø, Budd K, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert panel with focus on six clinically most often used World Health Organization Step 3 opioids (buprenorphine, fentanyl, hydromorphone, methadone, codeine, oxycodone. Pain Pract. 2008;8(4):287-313.

8. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77(5):1048-1056.

9. Elvir-Lazo OL, White PF. Postoperative pain management after ambulatory surgery: role of multimodal analgesia. Anesthesiol Clin. 2010;28(2):217-224.

10. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5):588-593.

11. Duncan CM, Hall Long K, Warner DO, Hebl JR. The economic implications of a multimodal analgesic regimen for patients undergoing major orthopedic surgery: a comparative study of direct costs. Reg Anesth Pain Med. 2009;34(4): 301-307.

12. Duellman TJ, Gaffigan C, Milbrandt JC, Allan DG. Multi-modal, pre-emptive analgesia decreases the length of hospital stay following total joint arthroplasty.

Orthopedics. 2009;32(3):167.

13. Holmér Pettersson P, Owall A, Jakobsson. Early bioavailability of paracetemol after oral and intravenous administration. Acta Anaesthesiol Scand. 2004;48(7):867-870.

14. Petring OU, Dawson PJ, Blake DW, et al. Normal postoperative gastric emptying after orthopaedic surgery with spinal anaesthesia and i.m. ketorolac as the first postoperative analgesic. Br J Anaesth. 1995;74(3): 257-260.

15. Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Intestinal absorption in patients after cardiac surgery. Crit Care Med. 2000;28(7):2217-2223.

7

REPORT

16. OFIRMEV (acetaminophen) injection prescribing information. San Diego, CA: Cadence Pharmaceuticals, Inc.; November, 2010. http://www.ofirmev.com/ pdf/OFIRMEVPrescribingInformation.pdf. Accessed January 31, 2012.

34. Royal MA, Gosselin NH, Pan CP, Mouksassi MS, Breitmeyer JB. Route of administration significantly impacts hepatic acetaminophen exposure.

Nature. 2010;87(suppl 1):S62. Abstract POO-73.

17. Mattia A, Coluzzi F. What anesthesiologists should know about paracetamol (acetaminophen). Minerva Anestesiol. 2009;75(11):644-653.

35. American Society of Anesthesiologists. Practice Guidelines for acute pain management in the perioperative setting: an updated report by the ASA Task Force on acute pain management. Anesthesiology. 2012;116(2): 248-273.

19. Graham GG, Scott KF. Mechanism of action of paracetemol. Am J Ther.

2005;12(1):46-55.

20. Joshi GP. Multimodal analgesia techniques and postoperative rehabilitation.

Anesthesiol Clin North Am. 2005;23(1):185-202.

21. Graham GG, Graham RI, Day RO. Comparative analgesia, cardiovascular and renal effects celecoxib, rofecoxib, and acetaminophen (paracetemol).

Curr Pharm Des. 2002;8(12):1063-1075.

22. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol. 2000;40(2): 124-132.

23. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral or rectal acetaminophen. Proceedings and Abstracts of the 10th Annual American Society of Regional Anesthesia and Pain Medicine Pain Medicine Meeting and Workshops. New Orleans, Louisiana; November 17-20, 2011.

24. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, PayenChampenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102(4):822-831.

25. Jahr JS, Lee VK. Intravenous acetaminophen. Anesthesiol Clin. 2010;28(4): 619-645.

26. Gregoire N, Hovsepian L, Gualano V, Evene E, Dufour G, Gendron A. Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose. Clin Pharmacol Ther.

2007;81(3):401-405.

27. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Clinical Toxicology. 2002;40(1):3-20.

28. Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund LA. Onset of acetaminophen analgesia: comparison of oral intravenous routes after third molar surgery. Br J Anaesth. 2005;94(5): 642-648.

29. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology. 1997;87:244-252.

30. Jensen LL, Handberg G, Brosen K, Schmedes A, Ording H. Paracetamol concentrations in plasma and cerebrospinal fluid. Eur J Anaesthesiol. 2004; 21(suppl 32):193. Abstract A-785.

31. Pan CP. Breitmeyer JB, Royal MA. IV acetaminophen PK/PD correlation following total hip arthroplasty. Nature. 2010;87(suppl 1):S63. Abstract PIII-75.

32. Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults.

Clin Pharmacol Ther. 2007;81(6):840-848.

33. Manyike PT, Kharasch ED, Kalhourn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther.

2000;67(3):275-282.

36. Sinatra RS, Jahr JS, Reynolds L, et al. Intravenous Acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. 2011 Oct 19.

[Epub ahead of print] 37. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther. 2010;32(14):2348-2369.

38. Cakan T, Inan N, Culhaoglu S, Bakkal K, BaĹ&#x;ar H. Intravenous paracetamol improves the quality of postoperative analgesia but does not decrease narcotic requirements. J Neurosurg Anesthesiol. 2008;20(3):169-173.

39. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3): 458-462.

40. Macario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain.

Pain Pract. 2011;11(3):290-296.

41. Alhashemi JA, Daghistani MF. Effects of intraoperative i.v. acetaminophen vs i.m. meperidine on post-tonsillectomy pain in children. Br J Anaesth. 96(6): 790-795.

42. Murat I, Baujard C, Foussat C, et al. Tolerance and analgesic efficacy of a new i.v. paracetamol solution in children after inguinal hernia repair. Paediatr Anaesth. 2005;15(8):663-670.

43. Cok OY, Eker HE, Pelit A, et al. The effect of paracetamol on postoperative nausea and vomiting during the first 24h after strabismus surgery: a prospective, randomised, double-blind study. Eur J Anaesthesiol. 2011;28(12):836-841.

44. Alhashemi JA, Daghistani MF. Effect of intraoperative intravenous acetaminophen vs. intramuscular meperidine on pain and discharge time after paediatric dental restoration. Eur J Anaesthesiol. 2007;24(2):128-133.

45. Peacock WF, Breitmeyer JB, Pan C, Smith WB, Royal MA. A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever. Acad Emerg Med. 2011;18(4): 360-366.

46. Nakamura K. Central circuitries for body temperature regulation and fever.

Am J Physiol Regul Integr Comp Physiol. 2011;301(5):R1207-R1228.

47. Isaacs SN, Axelrod PI, Lorber B. Antipyretic orders in a university hospital.

Am J Med. 1990;88(1):31-35.

48. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Arch Intern Med. 2000;160(4):449-456.

49. Candiotti KA, Bergese SD, Viscusi ER, Singla SK, Royal MA, Singla NK. Safety of multiple-dose intravenous acetaminophen in adult inpatients.

Pain Med. 2010;11(12):1841-1848.

50. Tzortzopoulou A, McNicol ED, Cepeda MS, Francia MB, Farhat T, Schumann R. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev. 2011;(10):CD007126.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Cadence Pharmaceuticals, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Copyright Š 2012, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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18. Mallet C, Barriere DA, Ermund A, et al. TRPV1 in brain is involved in acetaminophen-induced antinociception. PLoS ONE. 2010;5(9):e12748.

April 2012

AnesthesiologyNews.com I 21

CL I N I CA L A N E S TH E SIOL OG Y

Behold the Eyes During Surgery Bruising, swelling signal high pressure

D

uring surgery, certain physical cues such as eyelid edema and bulging of the surface of the eyes may serve as a signal to anesthesiologists that a patient is experiencing a surge in intraocular pressure—and as a result may be at risk for postoperative blindness, a recent study found.

While observing physical cues and measuring intraocular pressure (IOP) in 111 patients undergoing lengthy procedures in the head-down (steep Trendelenburg) position, the researchers

observed that, once patients began experiencing ocular edema, their IOP typically had risen to 2.5 times their baseline pressure. If patients began experiencing conjunctival edema (chemosis), their IOP was most likely approximately 3.4 times higher than normal. Patients with ecchymosis—black and blue areas of the conjunctivae—were typically experiencing IOP 4.3 times higher than their baseline (Table).

Normal IOP typically ranges between 5 and 15 mm Hg. An increase

production]. If they continue to make it available on an emergency basis, I am sure there would be opportunities to use it in selected patients.” According to a representative for Lilly, the company is not pursuing any further avenues for the drug.

Conflicting Results Not all the news presented on drotrecogin at SCCM was bad. Two small studies showed positive results for the drug in bone marrow transplant patients, a group that was excluded from PROWESS because of their increased risk for bleeding (abstracts 369 and 705). In a third study—a retrospective propensitymatched, cohort study—researchers used the Cooperative Antimicrobial Therapy of Septic Shock database to investigate the real-world effectiveness of drotrecogin alfa (abstract 39). The database includes consecutive patients older than age 18 years who were admitted to 29 academic and community intensive care units between 1997 and 2007. “It is essentially a pseudo-randomization method,” said Emily Rimmer, MD, hematologist from the University of Manitoba, in Winnipeg, Canada, who presented the study.

The final study cohort included 310 patients who received drotrecogin and 630 patients who did not.

The researchers identified a 7% absolute reduction in 30-day mortality associated with the use of drotrecogin (34.5% vs. 41.5%; P=0.05). Subgroup analyses identified a significant reduction in mortality in patients in the lowest APACHE II quartile (9.5% vs. 22%; P=0.04) and consistent but nonsignificant reductions in mortality among all remaining quartiles.

“The results of our study are at odds with the recent PROWESS-SHOCK study, and we believe that our data may help to provide some insight into possible reasons for these discrepant results,” said Dr. Rimmer. “Our study suggests that the mortality rate of patients with septic shock is decreasing over time. This may be related to improvements in the supportive care of these patients, including improvements in the administration of timely antibiotics.”

Other Disappointing Agents The bad news from PROWESS-SHOCK is compounded by a flurry of disappointing results from studies assessing other agents. Herwig Gerlach, MD, PhD, director of the Department of Anesthesiology,

by a factor of 3 or 4 would bring patients up to 40 mm Hg, and put them at risk for experiencing postoperative visual loss or even complete blindness, said study author Bonnie Molloy, PhD, CRNA, of Anesthesiologists can use ocular tonometry to Bridgeport Hospital, in assess intraocular pressure during surgery.

Bridgeport, Conn. “That’s a forewarn- surgery with the patient positioned ing to the anesthesiology caregiver to head-down is no surprise; other watch closely.” research has shown the same, said see pressure page 23 The fact that IOP increases during

Critical Care and Pain Management at the Vivantes Klinkikum Neukoelln Hospital in Berlin, discussed a number of negative prospective trials and metaanalyses that evaluated immunoglobulin use in sepsis.

For this reason, the 2012 Surviving Sepsis Campaign guidelines suggest that IV immunoglobulin G not be used in adult patients with severe sepsis/septic shock.

The investigational agent talactoferrin (Agennix) is the most recent drug to flame out. Researchers were excited when a randomized Phase II trial involving 190 patients with severe sepsis showed that talactoferrin reduced 28-day all-cause mortality (26.6% vs. 14.6%; P=0.04). On Feb. 2, however, Agennix announced that the promising results did not pan out in the Phase III OASIS (Oral Talactoferrin in Severe Sepsis) trial. Preliminary data from the 930-patient trial showed 28-day mortality was higher in the talactoferrin arm than in the placebo arm.

At the SCCM meeting, Steven LaRosa, MD, director of the Division of Infectious Disease and associate professor of medicine at Texas A&M Health Science Center College of Medicine, in Temple, presented data from the ACCESS trial that evaluated the toll-like receptor 4 (TLR4) inhibitor eritoran tetrasodium. This Phase III randomized, double-blind trial compared eritoran with placebo in patients with severe sepsis. The international, multicenter trial, which analyzed data from almost 2,000 patients, found that eritoran did not improve the primary end point of all-cause mortality at day 28 or the secondary end point of mortality at one year. “There is no separation in the curves,” Dr. LaRosa said. No benefit could be identified in any subgroups.

“We are left with endotoxin being thought to be a key mediator of sepsis pathology and a drug that, at least in vitro, appears to block TLR4 signaling quite well, and yet, we have a very stone-cold negative result,” Dr. LaRosa said.

According to Dr. LaRosa, large sepsis trials are challenging for myriad reasons including patient heterogeneity, as well as sepsis involving a variety of pathogens and infection sites and widely different practice patterns. “It is hard to think that a single agent is going to behave the same in all the patients,” said Dr. LaRosa. He pointed out, however, that in the case of eritoran, they might have picked

the wrong agent or perhaps a multi-targeted attack is required. Another possible explanation is that once septic shock has begun, it is too late to intervene with a TLR4 inhibitor.

Future Outlook The wave of negative trials has fueled the gloom surrounding sepsis research. According to Dr. Vincent, little headway is being made because there are fundamental problems with the way sepsis research is being done. Trials have included a potpourri of patients— those with trauma, elective surgery, early sepsis and late sepsis. Should these patients be grouped together?

According to Dr. Vincent, biomarker analysis and genomic research are the future of sepsis clinical trials. A study published in December concluded that similarities in gene expression patterns between different injuries reveal a fundamental human response to severe inflammatory stress, with genomic signatures surprisingly far more common than different (J Exp Med 2011;208:2581-2590). “Maybe in the future, we may not target the infection so much, but rather the host immune response,” said Dr. Vincent.

Dr. Thompson pointed out that if Phase II trials with strong signals for efficacy do not predict results in Phase III trials, then all of the efficacy risk is carried over to Phase III trials. Although this is not attractive to industry, neither is the fact that positive results from a Phase III trial may not predict the success of a second Phase III trial, as in the case of PROWESS-SHOCK. A recent study in Lancet Infectious Disease concluded that investigators need a deeper understanding of the process leading to sepsis before they can design an effective suite of interventions (2012;12:89).

In the meantime, researchers will continue their efforts. Ongoing clinical trials are evaluating AZD9773 (AstraZeneca), an antibody against tumor necrosis factor, and endotoxin removal by hemoperfusion through a polymyxin B column (Spectral Diagnostics).

—Kate O’Rourke Dr. Thompson disclosed relationships with AstraZeneca, Hemodec and Lilly. Dr. LaRosa disclosed receiving investigator grants from Eisai. Dr. Vincent disclosed serving on the advisory board of 39 companies and receiving study grants from 34. Drs. Jacobi and Rimmer had no disclosures.

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April 2012

CLINICA L A NESTH E SIOL OG Y

Nursing Success Not Related To Method of Labor Analgesia Chicago—Use of epidural analgesia for women in labor does not appear to hurt their ability to successfully nurse their infants in the weeks and months after delivery, according to a recent meta-analysis.

Although the analysis, which included three studies, found no negative effect of labor epidurals on breastfeeding success, the researchers acknowledged that their review was hampered by the limited number of trials and their varying follow-up periods. Still, they said, the results should be reassuring.

“We know that breastfeeding has maternal and infant benefits, and there have been some observational data in the midwifery literature saying that epidurals may cause decreased success in breastfeeding,” said Natalie Moreland, MD, anesthesia resident at Northwestern University Feinberg School of Medicine, in Chicago, who led the study.

“This is really a controversial issue.”

Dr. Moreland and her colleagues identified published trials that compared breastfeeding outcomes in relation to the method of anesthesia. They looked specifically at epidural versus no epidural analgesia, and epidural analgesia with fentanyl and local anesthetic versus local anesthetic alone. Long-term breastfeeding was defined as a duration of six or more weeks. Patients who did not receive any analgesia, or those who received only intravenous narcotics, were combined into a no-epidural group.

As Dr. Moreland reported at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 345), three studies met the inclusion criteria.

The meta-analysis found no effect of anesthetic technique on the long-term success of breastfeeding (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.69-2.72). The study also did not show a difference in breastfeeding outcome between the epidural fentanyl and no-fentanyl groups (OR, 0.47; 95% CI, 0.085-2.62).

“In both of those analyses, we found that the 95% confidence intervals of the odds ratios crossed 1,” Dr. Moreland told Anesthesiology News. “So there was essentially no effect.”

Dr. Moreland recognized that it may be difficult to recruit patients for a randomized controlled trial comparing epidurals and no epidurals in laboring women, regardless of the outcome. “As with any study where you’re trying to

see the effect of epidural analgesia, it’s very difficult or impossible to actually randomize patients, because patients will not agree to a study in which they would not get an epidural. But I think that the question of epidural fentanyl versus no fentanyl is an interesting one that could be looked at fairly easily.”

Why epidural analgesia might affect breastfeeding success is not so clear.

“With respect to epidural fentanyl, there’s concern about systemic absorption by the mother that then crosses the placenta and goes to the baby, affecting the baby’s behavior at birth,” Dr. Moreland said. “Or it may be that the babies of women who receive epidurals are getting introduced to the bottle first, which may subsequently affect breastfeeding success. Finally, it may be that women who are more likely to refuse an epidural are also more likely to breastfeed.”

The relative dearth of data makes the question difficult to answer at this time.

“If a patient came in and was unsure about whether or not she wanted to have an epidural and asked me if it would have that kind of effect on the infant, I would say that there have been some data in the past, but very little randomized controlled data, so we really don’t know the answer to the question.”

B. Scott Segal, MD, associate professor of anesthesiology at Brigham and Women’s Hospital, in Boston, said that the study helps confirm that studies linking epidural analgesia to poor breastfeeding represent selection bias.

“Randomized trials—in addition to well-conducted and controlled retrospective cohort studies—have failed to confirm any link between epidurals and breastfeeding,” Dr. Segal said.

Dr. Segal noted that one “enormous” randomized study that the Chicago researchers did not include in their meta-analysis (Anesthesiology 2009;​ 111:​871-880), which compared almost 13,000 women receiving an epidural early in labor with those receiving it later, found a small difference in breastfeeding success favoring shorter exposure to the epidural. “It’s not clear what the mechanism of this difference is, or even if it was merely a statistical fluke,” Dr. Segal said. “But some have speculated that the cumulative exposure to opioids, such as epidural fentanyl, may be responsible.”

—Michael Vlessides

April 2012

AnesthesiologyNews.com I 23

CL I N I CA L A N E S TH E SIOL OG Y Pressure continued from page 21 Table. The Molloy/Bridgeport Anesthesia Associates Eye Observation Scale Conjunctival Baseline Probability Edema IOP (%) 0

5

14.6

0

10

33.8

0

15

78.3

0

20

100

0

25

100

1

5

100

1

10

100

1

15

100

1

20

100

1

25

100

prostate surgery at Bridgeport Hospital. Dr. Molloy and her Bridgeport colleague, Charles Watson, MD, presented their findings at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 1358). Dr. Watson is a member of the Anesthesiology News editorial board.

The prevalence of visual impairment or blindness after surgery remains to be determined. In 1999, researchers created a registry of POVL, to which clinicians have reported cases, most of

which have occurred during spine and cardiac surgeries.

In January, the POVL Study Group reported on the factors that increase the odds of developing ischemic optic neuropathy in the setting of spine surgery (Anesthesiology 2012;116:15-24).

A 2007 case report in the Journal of Neuro-Ophthalmology (27:285-287) described two patients who developed ischemic optic neuropathy after lengthy robotic prostatectomy with the patients positioned head-down.

However, how many cases have resulted from this type of surgery is unclear.

In the current study, partially funded by the American Association of Nurse Anesthetists (AANA) Foundation, Dr. Molloy and Dr. Watson used ocular tonometry to gauge pressure. The technique is not difficult to learn, she said, but it requires some training, and most anesthesiologists are not used to doing it during surgery.

—Alison McCook

Probabilities of reaching >40 mm Hg, the critical threshold for patients in the steep Trendelenburg position.

IOP, intraocular pressure

Steven Roth, MD, professor of anesthesia and critical care and director of neuroanesthesia at the University of Chicago, who did not participate in this research. It is also no surprise, Dr. Roth added, that high IOP would lead to physical cues such as those found in the current study.

What is less clear, however, is whether high IOP increases the risk for postoperative blindness. “You cannot say increased IOP will lead to ischemic optic neuropathy, a dreaded cause of postoperative visual loss,” Dr. Roth said. “There is no objective evidence to support that idea.”

To prevent patients from experiencing such a steep rise in IOP that blood vessels are compressed and can no longer perfuse the eye, Dr. Molloy recommended that anesthesiologists constantly check the physical appearance of patients’ eyes, even lifting their eyelids to examine the whites. “That is what anesthesiology caregivers don’t do—they tape the eyelids shut to protect them but rarely look at them.”

If the physical cues appear, anesthesiologists should administer eyedrops, ask surgeons to take a “rest stop” and elevate the patient’s head if the pressure does not return to normal levels, Dr. Molloy said. “Once you see chemosis, you should consider eyedrops or a rest stop where you elevate the head, for five to seven minutes,” she said.

“That’s all you need.”

Dr. Molloy began researching postoperative vision loss (POVL) in 2005, when a healthy 63-year-old man woke up blind after lengthy laparoscopic

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24 I AnesthesiologyNews.com

April 2012

P A I N M E DI C I NE

Delays in Care Blunt Recovery From Lumbar Disk Herniation Analysis finds benefit from speedy treatment

A

post-hoc analysis of data from SPORT (Spine Patient Outcomes Research Trial) showed that people with intervertebral lumbar disk herniation who had symptoms for less than six months improved more following operative or nonoperative treatment compared with

patients who had symptoms for more than six months (J Bone Joint Surg 2011;93:1906-1914).

The investigators examined 927 people who had symptoms for six months or less prior to receiving treatment for lumbar disk herniation and 265 people who received

treatment more than six months after symptoms began. At all follow-up intervals—one, two, three and four years—patients treated operatively or nonoperatively within six months of symptom onset did better than those treated later. These findings mesh with those from the initial SPORT study

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(Spine 2008;33:2789-2800).

When the four-year follow-up data were compared with the baseline values, patients in the operative treatment group who had had symptoms for six months or less experienced a greater increase in the bodily pain domain of the Short Form-36 (SF-36) (mean change, 48.3 vs. 41.9; P<0.001), a greater increase in the physical function domain of the SF-36 (mean change, 47.7 vs. 41.2; P<0.001) and a greater decrease in the Oswestry Disability Index (ODI) score (mean change, –41.1 vs. –34.6; P<0.001) than those who had had symptoms for more than six months. Higher scores on the SF-36 and lower scores on the ODI indicate less-severe symptoms.

And when four-year follow-up values were compared with baseline values, patients in the nonoperative treatment group who had had symptoms for six months or less had a greater increase in the bodily pain domain of the SF-36 (mean change, 31.8 vs. 21.4; P<0.001), a greater increase in the physical function domain of the SF-36 (mean change, 29.5 vs. 22.6; P=0.015) and a greater decrease in the ODI score (mean change, –24.9 vs. –18.5; P=0.006) than those who had had symptoms for more than six months.

The investigators also found that operative and nonoperative treatment had similar benefits and these benefits did not depend on the duration of symptoms.

Justin Smith, MD, PhD, codirector of the University of Virginia Spine Center, in Charlottesville, said that despite the limitations of the study, including the high rate of crossover in the randomized arm, the data are useful for research on treatments for the most common lumbar spinal conditions.

“The findings of this study confirm what are likely common perceptions among spine care specialists. These data should prove to be a valuable resource for surgical decision making and patient counseling,” said Dr. Smith, who was not involved in either the original SPORT study or this post-hoc analysis.

Jeffrey Rihn, MD, one of the investigators of the follow-up study, agreed that the results are clinically relevant.

“A lot of patients ask when they come into the office, ‘I’ve had symptoms for a year—can I still get better? And can

April 2012

AnesthesiologyNews.com I 25

Pa in M e d ic ine

Knowledge Gap in Pain Meds Common Among Specialists

P

ain medicine specialists may be lacking key knowledge regarding the safety and efficacy of the medications they prescribe, a recent study has found. Some experts said the results highlight the need for more specific guidelines regarding the administration of pain drugs.

‘We observed gaps in

guidelines established by the American Geriatrics Society, their knowledge of the drugs safety considerations was mixed.

“We surveyed physician members of pain medicine organizations who we considered knowledgeable in this area and we observed gaps in their knowledge on the efficacy and safety of medications prescribed for chronic pain,”

said lead investigator Honorio T. Benzon, MD, professor of anesthesiology and chief of the Division of Pain Medicine at Northwestern Feinberg School of Medicine. “Considering that most prescriptions are done by primary care physicians, educating pain medicine physicians on the pharmacologic management of pain is probably worthwhile.”

The survey, based on a 49-question questionnaire, was mailed to nearly 4,000 members of the three societies in 2010. In total, 472 members of these societies responded to the mailin survey. On the positive side, 72% of the survey respondents reported they see their patients every two to three months, and the same percentage said see survey page 27

their knowledge on the efficacy and safety of medications prescribed for chronic pain.’

—Honorio T. Benzon, MD

Less pain. Less opioids.

From the start.

OFIRMEV® provides significant pain relief*1

The study, a survey of pain medicine specialists from the American Pain Society, the American Academy of Pain Management and the American Society of Regional Anesthesia and Pain Medicine, was presented at the annual meeting of the American Society of Anesthesiologists in October.

The researchers from Northwestern University’s Feinberg School of Medicine in Chicago found that although pain medicine specialists’ prescribing patterns generally fell within the

surgery help me?’” said Dr. Rihn, assistant professor of orthopedic surgery at Thomas Jefferson University Hospital, in Philadelphia. “Based on our data, the answer is ‘yes’ to both questions.

Patients may not do as well as they would have if they had symptoms for just three months, but they can have improvement over baseline.”

Dr. Rihn admitted that because spinal surgeons performed the investigation, the results might be a little biased, but “we made sure that we did not word our interpretation of the results to push for early surgery, because the data did not support this. Patients do better with early intervention compared to late intervention, whether it’s surgical or nonsurgical.”

—Rosemary Frei, MSc Drs. Rihn and Smith reported no conflicts of interest.

• OFIRMEV 1 g (Q6h) + patient-controlled analgesia (PCA) morphine demonstrated significant pain relief vs placebo + PCA morphine (P<0.05 over 6 h)1 • OFIRMEV 1 g (Q6h) + PCA morphine showed greater reduction in pain intensity over 24 h (SPID24)† compared to placebo + PCA morphine (P<0.001)2

OFIRMEV reduces opioid consumption*1 • OFIRMEV 1 g (Q6h) + PCA morphine significantly reduced morphine consumption vs placebo + PCA morphine (–46% over 6 h, P<0.01; –33% over 24 h, P<0.01)1 • The clinical benefit of reduced opioid consumption was not demonstrated

OFIRMEV from the start • Consider administering the first dose of OFIRMEV PreOp or post-induction • Schedule OFIRMEV Q6h for first 24 h and continue as clinically warranted

Indication OFIRMEV is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever.

Important Safety Information OFIRMEV is contraindicated in patients with severe hepatic impairment, severe active liver disease or with known hypersensitivity to acetaminophen or to any of the excipients in the formulation. Acetaminophen should be used with caution in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment.

Do not exceed the maximum recommended daily dose of acetaminophen.

Administration of acetaminophen by any route in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death.

OFIRMEV should be administered only as a 15-minute intravenous infusion.

Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy.

The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients.

OFIRMEV is approved for use in patients ≥2 years of age.

The antipyretic effects of OFIRMEV may mask fever in patients treated for postsurgical pain.

To report SUSPECTED ADVERSE REACTIONS, contact Cadence Pharmaceuticals, Inc. at 1-877-647-2239 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com.

Please see Brief Summary of Prescribing Information on adjacent page or full Prescribing Information at OFIRMEV.com.

*Randomized, double-blind, placebo-controlled, single- and repeated-dose 24-h study (n=101). Patients received OFIRMEV 1 g + PCA morphine or placebo + PCA morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a 5-point verbal scale over 6 h. Morphine rescue was administered as needed. †SPID24=sum of pain intensity differences, based on VAS score, from baseline, at 0 to 24 h.

References: 1. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery.

Anesthesiology. 2005;102:822-831. 2. Data on file. Cadence Pharmaceuticals, Inc.

©2012 Cadence Pharmaceuticals, Inc. All rights reserved.

OFIRMEV and the OFIRMEV dot design are trademarks of Cadence Pharmaceuticals, Inc.

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P A I N M E DI C I NE Abuse continued from page 1

wouldn’t belive the rush smoking 5 mg.”

The above paragraph—errors and you download the latest version of all—comes directly from a discussion Angry Birds: the Internet. thread on the online forum BlueLight (www.bluelight.ru), responding to a A Proliferation of question about how to prepare fenHow-to Sites tanyl patches for smoking. Hosted by “I extracted gel from, say, 20 patches. a server in the Netherlands, BlueLight Add some distilled water & up the pH to is one of several Web sites that allow about 12. Vaccum distill off liquid and users to post all kinds of advice, quesplace a little of the powder on to foil and tions, requests and stories about drug smoke THAT. The freebase is MUCH use. (You can even follow them on better to smoke than the citrate. You Twitter at @BlueLightForum.)

There’s also Drugs-Forum.com, “an information hub of high standards and a platform where people can freely discuss recreational drugs in a mature, intelligent manner.”

On Erowid.org, users post detailed stories of their experiences with particular drugs. “If Only Reality Was This Pleasurable” is the headline for a saga about experiences with oxycodone posted by “RighteousDopeFiend.”

“It’s a really concerning problem,” said Seddon Savage, MD, medical

director of the newly opened Silver Hill Hospital Chronic Pain and Addiction Center, in New Canaan, Conn., and president of the American Pain Society. “These sites are devoted to drug users exchanging information on the newest highs and ways to alter all sorts of legitimate prescription drugs for misuse, as well as the latest illicit drugs on the street.”

Lilit Karayan, PharmD, assistant director of pharmacy at Silver Hill, said she has found sites like BlueLight to be a very useful research tool.

“Often, the first time we hear about the new ways people are abusing something is that they come in here and tell us, ‘I’m doing this, and this, and this.’

And you think, ‘How in the world are you doing that?’ Following these sites gives you insight into what’s going on out there.”

There’s a surprising amount of interest in safety on these sites as well, Dr. Savage said.

For example, the BlueLight poster sharing tips about smoking fentanyl might have learned a thing or two from “drugs_bunny” on Drugs-Forum. com, who warned others: “You won’t get high, you will just die.”

April 2012

AnesthesiologyNews.com I 27

Pa in M e d ic ine “This is a harm reduction message,” she continued, noting that her general practitioner quickly wrote her a prescription for the fentanyl because “it is still perceived as a safe drug. It is NOT if you mess with [it].”

But for every participant holding up a caution flag, there are dozens of others sharing dangerous information.

“When patients or, more often, people who’ve diverted the medications, misuse a drug to get high, they often alter the drug’s delivery system and they don’t know what they’re doing in terms of dosing,” Dr. Savage said. “On these Web sites, they try and calculate what you’ll be getting if you do this or that with a patch or a pill, but it’s very dangerous.”

A Chance for Harm Reduction, Information Gathering That’s one reason it’s not just drug users and abusers who participate in sites like BlueLight, Drugs-Forum and Erowid. Harm reduction specialists, addiction counselors, pharmacists, physicians, researchers and yes, law enforcement officials visit these sites both as open participants and silent observers. (Site participants receive

warnings in the FAQs that they could be opening themselves up to arrest if they reveal too many identifying details about their activities; many people relate their own experiences using the made-up pronoun SWIM, for “Someone Who Isn’t Me.”) Steven D. Passik, PhD, professor of psychiatry and anesthesiology at Vanderbilt Medical Center in Nashville, Tenn., said he periodically visits these sites to find out what his patients might not be telling him.

“When you’re seeing patients in the clinic, it’s not like someone is going to say to you, ‘Thanks doc, smoking that fentanyl really makes it work better!’” he said. “This is part of the problem for pain clinicians. We check our prescription monitoring programs, do our urines, do an occasional pill count and talk to patients, but most diversion is not the kind of thing you’ll elicit in self-report or that will be obvious in clinical practice. Monitoring sites like these at least gives you an idea of what’s going on out there. I try to stay on top of what’s being abused.”

Dr. Savage noted that the drug sites often have chatter about new ways of using drugs before the methods hit the mainstream news or the medical literature. “Researchers into the epidemiology of addiction and public health officials often monitor the sites as well,” he said.

In fact, said Dr. Passik, pain specialists are likely to learn a lot more about which drugs they prescribe are really being diverted and abused, and how it’s being done, from reading such forums than by scanning the headlines.

“Some report about a particular drug being used will surface somewhere and then every newspaper will pick up the same report, get a comment from local law enforcement and make it seem as if it’s an epidemic in your own backyard,” he said.

Dr. Karayan noted that pharmaceutical companies can use information gleaned from online drug forums to help them comply with their risk evaluation and mitigation strategy requirements. “A couple of years ago, Purdue Pharma went back and reformulated controlled-release oxycodone so it’s harder to abuse,” she said. “The new formulation actually turns into a gel in your nose if you try to inhale it. Similarly, if any new method of abuse gets really hyped up on these sites, that can give drug companies information about how patients are misusing their drugs, so they can devise ways around it. The first way to deal with abuse is to understand how it’s done.”

—Gina Shaw

Survey continued from page 25 they have all patients sign “narcotic contracts” when prescribing opioids.

When asked about their methadone prescribing habits, however, only 21% of the responding pain medicine specialists said they converted patients to another drug once their dose reached 100 mg, despite the risk for cardiovascular side effects; 44% said they didn’t convert patients at all unless there was “a clinically evident problem.”

And, only 43% of the respondents said they ordered a baseline electrocardiogram (ECG), 41% said they ordered extra ECGs once a patient’s methadone dose exceeded 100 mg and 34% did not order repeat ECGs. Perhaps most troubling: Even though earlier this year the FDA recommended limiting the dose of acetaminophen to 325 mg per day in combined prescription products, 42% of the survey respondents said that they prescribe a maximum

daily dose of 3,000 mg, and 75% prescribed a maximum daily dose of 2,000 mg in moderate alcohol drinkers.

While acknowledging that respondents administering more than 2,400 mg of acetaminophen daily are doing so contrary to the guidelines, Mellar P. Davis, MD, professor of medicine at the Cleveland Clinic Lerner School of Medicine and Case Western Reserve University, both in Cleveland, noted that “the methadone monitoring choices are all over the map because there is no evidence-based guidelines” for methadone patient monitoring.

“Most physicians perform monitoring based on the patient’s personal risk, such as a family history of sudden death,” Dr. Davis said.

Dr. Davis was not involved in the Northwestern study, but said the researchers’ findings indicate the need for further clarity on the administration of opioids and other pain drugs in some high-risk populations.

—Brian P. Dunleavy

www.CMEZone.com Your premier source for practical, relevant and timely continuing medical and pharmacy education

Available now on CMEZone Perspectives in Chronic Pain: Evidence Into Practice expires July 29, 2012

E-Journal Exchange: Current and Emerging Therapies in Chronic Pain expires November 16, 2012

Malignant Hyperthermia: Diagnosis, Treatment, and Prevention expires December 1, 2013

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PRN Laughter continued from page 1 The surgeon was concerned and quite verbal about his concern. I gave the correct antidote. The heart resumed its usual boring rhythm. The patient did well and went home a week later in good spirits.

Do you know the children’s nursery rhyme?

‘I know an old lady who swallowed a fly.

I don’t know why She swallowed that fly Perhaps she’ll die’

Note the poet’s use of the word ‘perhaps’. That is the key to Dr. [ Jeffrey] Cooper’s study. He asked a number of anesthesiologists at MGH, ranging from experienced faculty to new residents to talk to him, under conditions of strict confidentiality about critical incidents they had had whether or not the patient was harmed. The point of course is that even if the patient was not harmed, they might have been.

He arrived at two key conclusions. First, only 14% of 359 incidents told to Dr. Cooper were due to equipment failure, whereas nearly all the rest were due to human error. Second, the interviewees had no difficulty in talking about their own errors. The purpose of the study, as told by Dr. Cooper himself, was to collect and analyze the events and seek to find patterns. Later, he told us the ultimate purpose was to expose human error in anesthesia and its underlying causes as problems that needed to be fixed.

That should be the obvious thing to do, you will say. It was, but no one had ever done it before. As you will have read in previous chapters, all that had been done, other than John Snow and Goodman Levy’s work was to add up the numbers of people who had died or been injured permanently as a result of anesthesia, so-called mortality and morbidity studies, lots of them. All those studies showed was that some agents, particularly chloroform, were more dangerous than others, and that anesthesia given by untrained nonspecialists was a likely cause of the many deaths.

You know that in life it’s no use having regrets, but I must here confess that I’m sorry I left MGH at the end of 1968 for private practice. What happened at MGH in those next two decades was exciting and original and out of it grew the first major branch of the tree planted by Jeff Cooper. But first another anecdote—I’m sorry, but it is completely true and very important.

Late one weary afternoon in 1983 at the Union Hospital, Chuck and Michael and I were finishing our cases. Michael was worried he’d be late for his tennis foursome; Chuck wondered if he would get a

run in on Swampscott Beach before the rain began; and I was dreaming of a pre-supper nap hoping the children would not need too much homework help.

Our secretary called into the operating room to tell us she was going home but that there was a gentleman from a company called Nellcor who had a gadget to show us.

Ugh! Another gadget we did not really need.

Nevertheless, we gathered in the office and with barely a word the salesman affixed a small clip to Chuck’s finger, turned on a box of electronics and told Chuck to hold his breath as long as he could.

The number on the screen started at 97 and slowly but surely fell until it reached 82. Chuck was in very good shape. Your body continues to use 250 to 300 cubic centimeters of oxygen at rest, much more if you are active, whether or not you are breathing. If you hold your breath, that continues and the oxygen attached to your red blood cells becomes depleted. It

reminds me of the anti-American joke we told when we first saw enormous American cars in London’s West End after the war: The driver of a Hugemobile pulls into a gas station in Texas and tells the attendant, “Fill her up, please.”

He waits, with the engine idling. And waits. And waits.

The attendant reappears and says, “Sir, please turn the engine off. You’re getting ahead of me.”

“Take three deep breaths,” said the salesman. Chuck did and the number shot up to 98.

“Can we borrow it for a few days and try it out in the O.R.?” Chuck said.

“Only for 24 hours,” said the salesman. “All the other anesthesiologists are interested.”

Next morning, Chuck went to see the hospital’s administrator, Henry Moran, and more or less forced him to make out a check for $4,000 to Nellcor, the manufacturer. When the salesman returned all he got was that check. The machine stayed with us; in fact, until we were able to buy several more we used to compete for it.

“My patient is the sickest,” we would say to each other.

As I said before, until this machine came along we were guessing whether the patient’s oxygen level was adequate. In my case, 25 years of guessing. Guessing whether your patient is getting enough oxygen makes one anxious, or put another way, is stressful. After I had my first heart attack my wife used to say, “I don’t understand why you did not become a dermatologist.”

Heart trouble is largely the result of the genes you got from your parents. Stress might exacerbate it.

Paradoxically, the stress and the accompanying sense of responsibility is part of the excitement of anesthesiology. Soldiers go to war for the excitement and challenge. Many change their minds when they see

one of their buddies disemboweled.

These digressions are as worrying to me as they are boring for you, but I can think of no other way of getting you to understand what the practice of anesthesia is like as seen from the inside. In your everyday life you see chaps and chapesses and their offspring walking down High Street, painting their houses, digging their vegetable plots and climbing up the frames in the local playground. It never occurs to you to wonder if they are getting enough oxygen to do this stuff. Why? Because you know they are breathing air, which contains 21% oxygen.

On the other hand, take the chap digging up his allotment, lay him down on an operating table, give him drugs that depress his ability to breathe, allow the surgeon to open his chest and compress one of his lungs so as to get at a tumor seen on an x ray.

Now consider that you the anesthesiologist are completely in control and in charge of the atmosphere the patient is breathing. Put another way, under general anesthesia the patient breathes a completely artificial atmosphere with effects on his oxygenation that used to be unmeasurable and unpredictable.

Do you remember the word ‘preventable’ in the title of Dr. Cooper’s paper? This machine, this oximeter, gave us hope in that regard.

What was going on at MGH during those years I spent in private practice? Probably the most important was that they realized that careful monitoring of the patient’s condition was the key to safety.

They wrote and enforced standards for the minimum degree of monitoring each and every time a patient was anesthetized in one of the nine Harvard Hospitals. Coincidentally, ideas being developed by the leaders of the Massachusetts Society of Anesthesiologists and its attorney, the legislature and the insurance consortium, the Joint Underwriters Association, to improve safety were derived from these monitoring standards.

The Harvard anesthesiologists got started on their project as a result of a kick in the ankle by an executive of Harvard’s captive insurance company, the Risk Management Foundation. His name is Jim Holzer, and as Jeff Cooper wrote: “Jim asked that something proactive be done about the increasing (financial) losses from medical malpractice claims.”

One of the members of the committee then formed from the four main Harvard teaching hospitals, Dr. John Eichhorn, analyzed the malpractice data and presented it to that committee. He “came to the intuitive conclusion—the most critical feature common to the serious events was a lack of appropriate monitoring of the patient by the anesthetist.”

The standards were published in the Journal of the American Medical Association in 1986. They were specific and detailed and were mandatory at all the Harvard hospitals. The authors commented that such standards had not previously existed (for any medical specialty: author’s comment) and resistance to the standards was anticipated but not seen, which is surprising since doctors as a whole think of themselves as independent professionals and do not want to follow rules, whether written by other physicians or for example, government bureaucrats. And critically, the final published standards required the use of pulse oximetry—the device we never gave back to see laughter page 30

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Stays late.

1. Kotelko DM, Rottman RL, Wright WC, et al. Transdermal scopolamine decreases nausea and vomiting following cesarean section in patients receiving epidural morphine. Anesthesiology.

1989;71:675-678. 2. Transderm Scop® [package insert]. New Providence, NJ: Baxter Healthcare Corporation; 2006.

Indications and Important Risk Information for the Transderm Scop® patch (scopolamine 1.5 mg) Transdermal Therapeutic System

Indications The Transderm Scop® patch is indicated in adults for prevention of nausea and vomiting associated with recovery from anesthesia and surgery. The patch should be applied only to skin in the postauricular area.

Important Risk Information The Transderm Scop® patch is contraindicated in: Persons who are hypersensitive to the drug scopolamine or to other belladonna alkaloids or to any ingredient or component in the formulation or delivery system.

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Since drowsiness, disorientation and confusion may occur, patients should not drive, operate dangerous machinery, or participate in activities that require alertness. Patients should not use alcohol.

Use with caution in patients taking other drugs that can cause CNS effects, such as sedatives or tranquilizers.

Rarely, idiosyncratic reactions have occurred. The most serious that have been reported include acute toxic psychosis, confusion, agitation, rambling speech, hallucinations, paranoid behavior and delusions.

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30 I AnesthesiologyNews.com

April 2012

PRN Laughter continued from page 28

sea level where the air is significantly thinner) four years ago, I took a portathe Nellcor salesman. Anesthesiolo- ble pulse oximeter with me on account gists introduced the use of pulse oxim- of my bad heart: It only pumps out eters into clinical medicine. Nowadays, about half of the blood that it should measuring oxygen saturation with an at each heartbeat. I took it very easy oximeter has become a basic standard and felt fine. Interestingly, I previously used by the nurse who undresses you had written to three of my colleagues and checks your weight, your pulse who are experts on hearts and lungs rate and your blood pressure in your and how they work. In essence they doctor’s examination room. wrote back, “Whatever happens, do When our son Jon married Lisa on not miss your son’s wedding. If you die, top of Mount Baldy (9,300 feet above you’ll die happy.”

As an afterthought they also said, “If you feel unwell, get on the chairlift and go down to the village.”

None of them even considered oxygen or cardiopulmonary resuscitation as a precaution and no one had the gall to ask whether any of the guests had passed the Red Cross’s Basic Life Support (BLS) test!

My story is like a braided cord. Each thread has to be considered and then

carefully wound into the core.

Now we turn to Dr. Richard Ward, an anesthesiologist on the faculty of the University of Washington, Seattle, in the late 1970s. One of his residents (trainees) was Dr. Richard Solazzi, whose wife was an attorney. As you have already seen, this was a time of agonizing discussion of the damage that we anesthesiologists were inflicting on patients and the first serious attempts to ascertain its causes in detail. Although Dr. Davis of Duke University had already carried a similar but much more modest study, it was Dr. Solazzi’s wife who first instigated a large study by asking the question: Are there clues in the history of anesthetic malpractice experience that might identify repetitively seen problems that can and should be avoided?

These two doctors, with the permission of the Aetna Life and Casualty Company, the University Hospital, the Health Cooperative in Seattle and the medical examiner of King County were allowed to review all their malpractice claim files from 1971 to 1982.

They reviewed 135 cases in which general anesthesia was used. In nearly all the cases the patient suffered harm. I am not going to tell you what they found—you’ll soon see why! The important point is that the insurance company and the three other organizations actually allowed two doctors to look at their files. This is remarkable. Prior to this, bad results were kept as hidden as possible—an aspect of the practice of all of medicine going back into the Victorian era, and in the case of anesthesia, the innumerable disasters mostly but by no means exclusively resulting from chloroform use.  Gerald Zeitlin, MD, graduated from the University of Cambridge in England, in 1954.

After qualification as a physician in 1958, he became intrigued by the power of anesthesiologists in saving the lives of young patients dying of poliomyelitis. After practicing in England for six years, Dr. Zeitlin accepted a position at the Peter Bent Brigham Hospital in Boston. Dr. Zeitlin has served as president of the Massachusetts Society of Anesthesiologists, delegate to the House of Delegates of the American Society of Anesthesiologists and reviewer for the American Society of Anesthesiologists Closed Claims Project.

This article is the final installment of an excerpt from his new book, “Laughing and Crying About Anesthesia: A Memoir of Risk and Safety” (Allandale Publishers, 2011). Dr. Zeitlin will donate half the proceeds of the sales of the book, which he wrote in part “for a non-medical audience to help them understand what we do,” to the Foundation for Anesthesia Education and Research.

Baxter Healthcare Corporation | 95 Spring Street | New Providence, NJ 07974 1-800-ANA-DRUG (1-800-262-3784) | 01/12 720254| www.baxter.com

CONTINUING MEDICAL EDUCATION

APRIL 2012

PreAnesthetic Assessment of the Patient Undergoing Thoracic Endovascular Aneurysm Repair: Part 1 WRITTEN BY:

LEARNING OBJECTIVES

Jayanta Mukherji, MBBS Associate Professor, Department of Anesthesiology, Loyola University Medical Center, Maywood, Illinois

At the end of this activity the participant should be able to: 1. Outline the causes of aortic dissection and natural history of descending thoracic aneurysm.

2. Describe the criteria and technique used for performing thoracic endovascular aneurysm repair (TEVAR).

3. Prescribe the preanesthetic assessment of the patient undergoing TEVAR. 4. Evaluate the anesthetic implications for the patient undergoing endovascular graft deployment.

5. Tabulate the criteria for TEVAR. 6. List common comorbidities in vascular patients.

7. Recognize the off-label status of endovascular stents when used in the treatment of aortic dissection.

8. List the indications for stent graft placement.

9. Identify perioperative goals.

10. Describe the intraoperative use of adenosine.

Michael Trembowicz, DO Fellow in Cardiothoracic Anesthesia, Department of Anesthesiology, Loyola University Medical Center, Maywood, Illinois

REVIEWED BY: Pierre Levan, MD Professor, Department of Anesthesiology, Loyola University Medical Center, Maywood, Illinois (In Part 1 of this 2-part series, the causes of thoracic aneurysms and the noninvasive treatment by stent placement are described. In Part 2, the complications of this therapy and monitoring requirements will be outlined.)

DISCLOSURES The authors, editor, and reviewer have declared no conflict of interest related to financial disclosures, research, and written presentation of this manuscript.

PROFESSIONAL GAPS Thoracic endovascular aneurysm repair represents a technique with special considerations that may not be known by many practicing anesthesiologists. This lesson aims to explain these changes and developments.

CALL FOR WRITERS If you would like to write a CME lesson for Anesthesiology News, please send an email to Elizabeth A.M. Frost, MD, at ElzFrost@aol.com.

TARGET AUDIENCE Anesthesiologists

CASE HISTORY A 67-year-old woman presented to the emergency room with severe back pain and diaphoresis. She had a history of hypertension and coronary artery disease (CAD). Computed tomography (CT) angiogram revealed an aortic dissection involving the descending thoracic aorta distal to the left subclavian artery origin extending to the aortic bifurcation. There was a 6-cm dilatation of the proximal region of the descending thoracic aorta with evidence of extravasation. There was no disruption of blood flow to the celiac axis, superior mesenteric, and renal vessels on angiogram. Cardiac catheterization revealed nonobstructive CAD and an ejection fraction of 40%. Transthoracic echo revealed left ventricular hypertrophy with normal aortic root and ascending aorta.

On physical examination, the patient had no neurologic deficits; blood pressure (BP) was 170/110 mm Hg; heart rate was 110 beats per minute; and all peripheral pulses were palpable. She was scheduled to undergo thoracic endovascular stent placement to create a seal at the area of extravasation.

Causes of Aortic Dissection

A

ortic dissection occurs when an intimal tear develops, permitting entry of blood to a diseased media characterized by elastic degeneration and loss of smooth muscle cells. Causes include connective tissue disorders, chronic arterial hypertension in combination with atherosclerosis, decelerating injuries, blunt trauma, pregnancy, and use of tobacco and cocaine.

Descending thoracic aorta dissections that are distal to the origin of the left subclavian artery are classified as DeBakey type III or Stanford type B, and may extend to the aortic bifurcation.

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

A COURSE OF STUDY FOR AMA/PRA CATEGORY 1 CREDIT Read this article, reflect on the information presented, then go online (www.mssm.procampus.net) and complete the lesson posttest and course evaluation before December 31, 2012. (CME credit is not valid past this date.) You must achieve a score of 80% or better to earn CME credit.

TIME TO COMPLETE ACTIVITY: 2 hours RELEASE DATE: April 2012 TERMINATION DATE: April 30, 2013 ACCREDITATION STATEMENT The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT The Mount Sinai School of Medicine designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance, independence, and scientific rigor in all CMEsponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.

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CONTINUING MEDICAL EDUCATION

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

APRIL 2012

The mean growth rate for thoracic aneurysms is 0.1 cm per year, with the site of the aortic aneurysm directly correlating with rupture, dissection, and death.

Aneurysms that have reached 5 cm in diameter have a faster rate of enlargement with increased risk for rupture.

Independent risk factors for rupture of a thoracoabdominal aortic aneurysm (TAAA) include nondimensional characteristics, such as a history of tobacco use, presence of chronic obstructive pulmonary disease (COPD), advanced age, and the presence of hypertension.1 Diagnostic techniques for aortic dissections include CT, transesophageal echocardiography (TEE), magnetic resonance imaging (MRI), and aortography.

Criteria Used To Determine TEVAR Thoracic endovascular aneurysm repair (TEVAR) was initially developed for the treatment of degenerative aneurysms of the descending thoracic aorta. It has been applied to the entire spectrum of descending thoracic aortic pathology in both the elective and emergent settings.

Emergent TEVAR increasingly is being considered a potentially safer and less-invasive technique for acute surgical emergencies involving the descending thoracic aorta.

It entails a lower short-term morbidity and mortality and compares favorably with historic results for emergent open surgical procedures on the descending thoracic aorta.2 Although endovascular stent grafts commonly are used for treatment of aortic dissection in the acute or chronic phases, such use is off-label as the FDA has not yet approved any endovascular stent grafts for treatment of aortic dissections. More evidence is needed to support the use of TEVAR in type B aortic dissection. A nationwide inpatient survey showed that the safe use of the endovascular approach is increasing for older patients with more comorbidities.3 Currently, the indications for stent-graft placement include the obstruction of aortic branch arteries, descending thoracic dissection with intractable pain, extravasation of blood from the aorta (periaortic hematoma) as a sign of impending rupture, or a rapidly expanding false lumen.

If attempts at endovascular repair are unsuccessful, open surgical repair may be necessary.1

Figure 1. Thoracic aortic aneurysm repair.

Thoracic endovascular aortic repair is a minimally invasive procedure in which a stent graft is compressed on a delivery catheter, threaded through an artery in the groin, and expanded at the site of the aneurysm.

Courtesy Medtronic, Inc

Not every patient with a TAAA is considered suitable for TEVAR. Suitability depends on anatomical/pathologic characteristics of the aneurysm (Table 1). The landing zones or neck of the aneurysm is the area of normal aorta situated proximal and distal to the aneurysm. This zone provides a seal zone for the stent graft to fasten in place. When considering the endovascular management of thoracic aortic aneurysms, a proximal and distal landing zone of 2 to 2.5 cm is recommended.

The seal zone should be devoid of excessive thrombus or calcification as it may weaken endograft apposition to the aortic wall. Endograft coverage may span regions of thoracic aorta between the left common carotid artery and celiac axis. The celiac axis occasionally may be covered if necessary to achieve an adequate distal seal zone.

Table 1. Criteria for Thoracic Endovascular Aneurysm Repair Landing zone or neck of the aneurysm

A seal zone of 2-2.5 cm usually is needed for the stent graft Adequate seal zone diameter. The endografts usually are oversized by 10% to 15% Absence of excessive thrombus or calcification in seal zone Endograft coverage may span regions of thoracic aorta between the left common carotid artery and celiac axis Celiac coverage by graft is safe if the vessel is small, and the superior mesenteric artery is large with a patent gastroduodenal, which will supply the celiac distribution after celiac coverage5

Aneurysm shape

Aneurysm should be straight rather than S-shaped More flexible stent grafts are useful

For endovascular access

An adequately sized femoral or iliac access vessels (required vessel diameters of 7.6-9.2 mm)

Delivery systems

Gore TAG device ranging from 20 to 22 F Talent and TX-2 devices ranging from 22 to 25 F

Hybrid techniques, including open aortic arch and thoracoabdominal debranching procedures, have been used to allow creation of proximal and/or distal landing zones for the stent-graft seal.4

Surgical Technique for TEVAR An adequately sized femoral or iliac access vessel is necessary for endograft introduction (Figure 1). The endografts generally are introduced via the femoral vessels, although introduction via the iliac arteries may be necessary in some cases if the femoral vessels are unsuitable because of inadequate size or heavy calcification.

A stent graft is a self-expandable stent that is positioned to exclude the aneurysmal sac. The stent is a meshlike metal structure providing support to the graft. The graft is a special fabric (ie, Dacron or polytetrafluoroethylene) that is impervious to blood and covers the stent (Figure 2). The blood remaining in the aneurysm sac will clot off, sealing the sac. The stent graft used to treat aneurysms is compressed in small-diameter tubes. When released, the graft expands to its original diameter. The area where the stent graft makes contact with the normal artery is known as the landing or seal zone. The outward radial force of the stent creates a seal in this area, preventing the flow of blood outside the stent graft and into the aneurysmal sac.

After the femoral/iliac vessels are exposed, various catheters are advanced proximally to the descending thoracic aorta under fluoroscopic guidance. The contra-lateral groin is accessed for intra-arterial catheter placement. The patientâ&#x20AC;&#x2122;s respiration is suspended during digital subtraction angiography as the slightest movement may distort images. Molding of the stent graft is performed with a balloon at all the sealing zones to fix the stents in place. Digital subtraction angiogram confirms stent-graft position, verifies visceral and renal arterial flow, and authenticates that there is no filling of the aneurysm sac (Figure 3).

CONTINUING MEDICAL EDUCATION

APRIL 2012

Preanesthetic Considerations for TEVAR The goal of preoperative evaluation is to optimize the patientâ&#x20AC;&#x2122;s medical status, and plan an anesthetic technique that minimizes complications. Prior to surgery it is important to discuss with the surgeon the operative procedure, and whether evoked potential (EP) monitoring is planned.

Symptomatic patients with leaking aneurysms require urgent intervention, and there generally is little time to perform more than the most basic preoperative assessment.

Systemic hypertension contributes to expansion and rupture of TAAA. All antihypertensive medications should be continued until the time of surgery. β-blockers are used initially to reduce the shear force exerted on the dissection.

Patients undergoing TEVAR are subjected to less hemodynamic stress as the aorta is not cross-clamped, and the anesthesiologist does not have to contend with major fluid shifts and blood loss.

Pulmonary injury is an unlikely event after TEVAR, as increased fluid resuscitation, blood product transfusion, and one-lung ventilation do not complicate the procedure. Dyspnea or stridor may be signs of tracheal/bronchial compression.

A history of transient ischemic attacks, and stroke should be specifically sought preoperatively because of the potential for neurologic complications after surgery. Carotid angiography or duplex studies may be appropriate in patients with a history of strokes or severe atherosclerosis.

Baseline renal insufficiency is related to hypertension, diabetes, and atherosclerotic disease and is an independent predictor of postoperative renal failure. Angiographic contrast dye used preoperatively during CT imaging and during the intraoperative evaluation of the aneurysm often causes transient abnormalities of renal function.

Preoperatively, it is routine to discontinue antiplatelet medications and warfarin. Coagulopathy following TEVAR is uncommon but is likely to occur in the setting of hypothermia, and use of heparin

Anesthetic Considerations During Endovascular Graft Deployment Although endovascular repair is a less-invasive procedure, patients should be anesthetized with the possibility

that open surgical repair may be necessary. The risk has decreased with improvements in endovascular devices and with greater surgical experience.

Endovascular aortic repair should be classified, similar to aortic and peripheral vascular surgery, as a higher risk procedure.

Perioperative goals during TEVAR are to provide hemodynamic stability while preserving cardiac, spinal, and splanchnic flow; and maintaining intravascular volume, adequate oxygenation, and body temperature. Both general and regional techniques have been used successfully.

However, with the increasing use of neurologic monitoring and TEE for TEVAR, general anesthesia is an appropriate choice. Although epidural anesthesia can be used, it may be difficult to distinguish the effects of central neuroaxial blockade by local anesthetics from spinal cord ischemia (SCI). The use of epidural anesthesia is disadvantageous if lower extremity weakness ensues following operations involving the thoracic aorta. Neurologic examination is performed immediately upon emergence from general anesthesia. Any neurologic deficit detected should be considered to be SCI until disproved.

Figure 2. Talent Captivia system tip.

Figure 3. Talent thoracic stent-graft placement in aorta.

The Captivia Delivery System being used for accurate placement and deployment of the Thoracic Stent Graft.

The Talent Thoracic Stent Graft reduces pressure on the aneurysm and the risk for rupture.

Courtesy Medtronic, Inc

Courtesy Medtronic, Inc

33

CONTINUING MEDICAL EDUCATION

34

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

Various imaging modalities such as angiography, fluoroscopy, and TEE may be used to confirm the position of the stent. The proximal and distal ends of the endograft are then sealed to the aortic wall by endoluminal balloon inflation. The transient balloon inflation may cause a short-lived hemodynamic change that usually will not require any intervention.

Blood loss can be difficult to quantify as it often is lost around the sheaths and catheters and can be retroperitoneal in the case of injury to femoral or iliac vessels. The retroperitoneal approach is an alternative technique used in cases with failed femoral access. However, this approach results in higher risks for retroperitoneal bleeding and a

longer procedure time. Because of the difficulty associated with accurate prediction of substantial blood loss and the possible need for allogenic blood transfusion it would be appropriate to set up a cell-salvage device in a back-up mode. Following graft deployment, vasopressors and inotropes are needed to manage hemodynamic emergencies and maintain higher mean arterial pressures.6

2.

Mitchell ME, Rushton FW Jr, Boland AB, Byrd TC, Baldwin ZK. Emergency procedures on the descending thoracic aorta in the endovascular era. J Vasc Surg. 2011;54(5):1298-1302.

3.

Sachs T, Pomposelli F, Hagberg R, et al. Open and endovascular repair of type B aortic dissection in the Nationwide Inpatient Sample. J Vasc Surg. 2010;52(4):860-866.

4.

Hughes GC, Sulzer CF, McCann RL, Swaminathan M. Endovascular approaches to complex thoracic aortic disease. Semin Cardiothorac Vasc Anesth. 2008;12(4):298-319.

5.

Falkenberg M, Lönn L, Schroeder T, Delle M. TEVAR and covering the celiac artery. Is it safe or not? J Cardiovasc Surg (Torino). 2010;51(2):177-182.

6.

Vaughn SB, Lemaire SA, Collard CD. Case scenario: anesthetic considerations for thoracoabdominal aortic aneurysm repair.

Anesthesiology. 2011;115(5):1093-1102.

References 1.

Ramanath VS, Oh JK, Sundt TM 3rd, Eagle KA. Acute aortic syndromes and thoracic aortic aneurysm. Mayo Clin Proc.

2009;84(5):465-481.

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

APRIL 2012

For inquiries about course content only, send an email to ram.roth@mssm.edu.

Ram Roth, MD, is director of PreAnesthetic Assessment Online and assistant professor of anesthesiology at The Mount Sinai School of Medicine, New York, NY.

Post-Test 6.

Suitability for TEVAR depends on: a. presence of a seal zone of 1-2 cm b. absence of excessive thrombus c. predominately S-shaped aneurysm d. small iliac access vessels

7.

The stent graft is: a. a mesh-like metal structure b. impervious to blood c. self-expandable d. all of the above

8.

Differences between open aortic aneurysm repair and TEVAR technique include which of the following: a. less blood loss with TEVA, as the aorta is not cross-clamped b. greater hemodynamic instability with TEVAR as all antihypertensive agents must be stopped c. none of the above

The natural history of thoracoabdominal aortic aneurysms is_______. a. static over about 10-20 years b. about 90% are in the descending aorta c. 1 cm per year d. no relationship between site and risk for rupture

9.

Preoperative testing for patients undergoing TEVAR are least likely to include: a. CT or MR angiography b. echocardiography c. pulmonary function tests d. liver function tests as a baseline

TEVAR _______. a. is not used in the emergent situation b. applies to the entire spectrum of descending thoracic aortic pathology c. has yielded only slightly poorer results than open repair d. was developed for acute situation only

10. Adenosine: a. has no cardiac effects b. has been replaced by self-deploying stents c. increases patient movement d. is essential to allow correct stent graft deployment

1.

Anesthetic considerations for endovascular graft deployment include all of the following EXCEPT: a. The procedure may become open at any time b. The procedure is performed on vascular patients with significant comorbidities c. Vasopressors and inotropes should be immediately available for management of hemodynamic emergencies

2.

Aortic dissection is least likely to include: a. an intimal tear b. loss of smooth muscle cells c. blood in the arterial wall d. increased elasticity of the arterial wall, which allows ballooning

3.

Precipitating causes of aortic dissection include: a. chronic hypertension b. decelerating injuries c. some hereditary disorders such as Marfan’s syndrome d. all of the above

4.

5.

Spotlight On Our Very Best As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidified their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

2011

Here is a look at those recognized for their unique contributions during 2011.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

Employees were asked to select the two most outstanding members from these departments. The first winner was JOHN CABA, software developer, for his tireless devotion toward improving the company’s digital platforms.

The second winner was ROSA DIMICCO, accounting associate, for diligently ensuring that freelance writers and key opinion leaders are paid in a timely manner for their exceptional work.

JEANETTE MOONEY won the award in recognition of her creative talents as art director for Pain Medicine News, along with her superb layout designs for a host of Special Reports and custom newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

NEWSMAGAZINE EDITOR OF THE YEAR:

Each member of the sales staff seeks to improve throughout the year; however, one inevitably displays accelerated growth. DAVID NATHANSON, account manager, managed to do just that across several publications in 2011.

SETH KANDEL was voted best projects editor for his exemplary work on numerous custom media programs for medical industry clients as well as his management of the editorial in Infectious Disease Special Edition.

DONALD PIZZI, managing editor of Pain Medicine News, was recognized for the excellence of his news coverage throughout 2011. Under Don’s discerning eye, the magazine offers a comprehensive resource for clinicians involved in the management of pain.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

DAVE KAPLAN, publication director of Pharmacy Practice News, was the 2011 winner in this category. Dave has proven himself to be an innovator among his peers by championing exciting new platforms and marketing opportunities for his many clients.

Whereas the other awards are decided by a jury of one’s peers, this honor is bestowed on the one salesperson who brings in the most revenue. For a record-breaking sixth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News. Richard’s dedication to his clients’ marketing needs and intimate knowledge of their products enable him to reach the zenith of sales proficiency year after year.

PERSON OF THE YEAR

PARTNERS AWARD

PERSON OF THE YEAR 2011:

PARTNERS SPECIAL RECOGNITION AWARD 2011:

This award recognizes the cream of the crop, and MARY LOU CAMPANELLA, chief financial officer, was the 2011 Person of the Year. Mary Lou has been able to streamline the company’s finances by thwarting inefficiencies and highlighting excess expenditures. Her constant professionalism, hard work and keen eye for detail have proven to be invaluable commodities that are greatly appreciated by her peers.

The partners of McMahon Publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was URBAN S. MULVEHILL, who has provided legal services to the company since 1983. He became a partner at his law firm, O’Neill DiManno and Kelly, in 1980 after having served as a trial lawyer for several years at the U.S. Department of Justice. Urban’s relaxed demeanor and sage advice over the past three decades have been greatly appreciated.

36 I AnesthesiologyNews.com

April 2012

P OLI C Y & M A NAGEMENT Fujii continued from page 1 In a statement posted online, Masaru Kuroda, MD, PhD, dean of the Toho University Faculty of Medicine, declared that an internal investigation revealed that eight of Dr. Fujii’s papers “should be retracted since they did not conform to the global standard of ethics for clinical studies.” Dr. Kuroda also noted that those studies, and one other trial by Dr. Fujii, took place at Ushiku Aiwa General ­Hospital—“which has no relation to his research activity in Toho University.”

However, editors of several anesthesia journals believe Dr. Fujii’s misconduct goes much deeper, and could involve roughly 170 papers he had published during the past two decades.

Many of Dr. Fujii’s papers involved trials of drugs to treat postoperative nausea and vomiting (PONV), particularly the antiemetic granisetron.

The bulk of Dr. Fujii’s papers appeared in the anesthesia literature, and in particular the Canadian Journal of Anesthesia (CJA), which has at least 39 articles.

The investigation was triggered last summer when Dr. Fujii submitted a manuscript to that journal containing what appeared to be borrowed text and fabricated data.

Although the scope of the deception might prove to be shocking, it likely will come as no surprise to some in the anesthesia community. In 2000, a group of researchers led by Peter Kranke, MD, PhD, MBA, of the Department of Anaesthesia and Critical Care at University of Würzburg Hospital, in Germany, challenged the veracity of Dr. Fujii’s studies in a letter to the journal Anesthesia & Analgesia. Its title: “Reported data on granisetron and postoperative nausea and vomiting by Fujii et al. are incredibly nice!”

Dr. Kranke and his colleagues analyzed 47 of Dr. Fujii’s papers, published between 1994 and 1999, on the treatment of PONV with granisetron. “With increasing amazement, we noticed that the results reported by Fujii et al. are incredibly nice and we became skeptical when we realized that side Advertisement

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effects were almost always identical in all groups,” Dr. Kranke’s group wrote. They closed their letter with the conclusion that “there must be an underlying influence causing such incredibly nice data.”

Dr. Fujii, who at that time was affiliated with the University of Tsukuba Institute of Clinical Medicine, in Ibaraki, dismissed the implied accusation in a response that the journal published alongside Dr. Kranke’s letter. In many of his trials, he wrote, “we found that several patients who had received granisetron experienced mild headache and that an incidence of headache was approximately 10%. Consequently, an incidence of headache seems to be identical, but it was true. How much evidence is required to provide adequate proof about antiemetics’ adverse events introduced recently by several investigators?”

Christian C. Apfel, MD, PhD, an expert on PONV and a co-author of the letter by Dr. Kranke, said he has been disappointed that the anesthesiology journals did not retract any of the papers his critique cited, and that other journals continued to publish Dr. Fujii’s studies despite what he considered to be clear evidence of fabrication. “The likelihood that the data are true, as we calculated, is something like less

than seven in a billion,” said Dr. Apfel, of the University of California, San Francisco Medical Center.

In a follow-up study published in 2001 in Acta Anaesthesiologica Scandinavica (45:659-670), Drs. Apfel, Kranke and colleagues conducted a meta-analysis of Dr. Fujii’s studies of granisetron and showed that his trials demonstrated efficacy for the drug that was well outside what other groups were finding.

Although the recommended dose of granisetron is 1 mg, Dr. Fujii’s papers said that amount was ineffective. Instead, the papers said, 3 mg worked— and remarkably well. On average, Dr. Apfel said, Dr. Fujii’s studies indicated that the drug was three times as effective as any other antiemetic. “The data for effectiveness are off the charts,” he said.

However, Dr. Apfel noted, Dr. Fujii’s findings likely did not affect patient care in the United States.

“If Fujii’s data had an impact, people would have used 3 mg. But people didn’t.”

Dr. Apfel even wrote to the FDA, its Japanese counterpart and the Japanese Society of Anesthesiologists to warn them about Dr. Fujii’s results—but

Lego Hobbyist Builds Anesthesia Machine

E

ric Harshbarger might not be an anesthesiologist but he likely knows anesthesia machines more intimately than any specialist.

That’s because Mr. Harshbarger, of Auburn, Ala., has built an anesthesia machine from the ground up—with Legos.

Mr. Harshbarger, a mathematician by training, said GE Healthcare approached him in March 2011 with the idea for the project. Some six months, and more than 30,000 Lego pieces later, he unveiled the model at the 2011 annual meeting of the American Society of Anesthesiologists, in Chicago.

To accomplish the feat, Mr. Harshbarger requested—and received—a real anesthesia machine from the company, which shipped it to his home. There he built his model, from the wheels up (the core is mostly hollow, although struts support the weight, he said).

Among Mr. Harshbarger’s many other Lego opuses are a rendering of da Vinci’s Mona Lisa; a bust of talk-show host Conan O’Brien; the skylines of Fort Worth, Texas, and New York City; and, most recently, a replica of Samford Hall, a stately brick building on the campus of Auburn University.

He also is a competitive Scrabble player and puzzle master.

—AN Staff

see Fujii page 38

April 2012

AnesthesiologyNews.com I 37

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38 I AnesthesiologyNews.com

April 2012

P OLI C Y & M A NAGEMENT Fujii continued from page 36 received either no reply or a cursory acknowledgment of his concerns. The FDA could not confirm whether it had received the letter.

Ronald Miller, MD, former editor-in-chief of Anesthesia & Analgesia, said he had largely forgotten the details of the exchange of letters regarding Dr. Fujii’s studies. However, he said in an interview that his decision to print the correspondence was an effort to promote a public vetting of the competing claims. “I felt publishing those two letters might shake out whether there was any more to it,” he said.

Steven L. Shafer, MD, editor-in-chief of Anesthesia & Analgesia, which published 24 of Dr. Fujii’s papers, said the case revived in earnest last spring after the researcher submitted a manuscript to the CJA. Signs of Plagiarism Donald Miller, MD, editor-in-chief of the CJA, said he first had suspicions about Dr. Fujii’s 2011 submission when a plagiarism screening turned up the prospect of lifted text from an earlier article.

When he looked at that paper, he noticed “a similarity in the nature of experiments.”

Dr. Miller corresponded with Dr. Fujii, asking for a copy of the ethics approval form for the study.

What he received “was translated and the form did not match the experiment. The number of animals was different,” as were other details, he said. “At that point, I informed Dr. Fujii that I had substantial concerns and would be contacting his institution.”

Although the CJA has published more of Dr. Fujii’s papers than any other journal— “regrettably,” Dr. Miller said—at the moment it will not be retracting any. Retractions may come after the journal has had the opportunity to communicate with the other institutions where Dr. Fujii worked.

In the meantime, Dr. Miller said he would “definitely issue an expression of concern” for all of Dr. Fujii’s articles published in the CJA. “There’s a cloud of suspicion over everything he has published.”

Dr. Shafer said he agreed to analyze the statistics in the manuscript for the CJA, and reached the conclusion that there was “a very high probability of fraudulent data.”

The journal corresponded with Dr. Fujii, asking for a copy of the ethics approval form for the study.

What it received was inadequate, at which point the editors contacted Dr. Fujii’s clinical institution and were informed that not only were the data fabricated, but that Dr. Fujii had not obtained approval to conduct such a study. (He published a similar paper in Anesthesia & Analgesia in 2003, prior to Dr. Shafer’s arrival as editor.)

In a letter to readers that will be posted online, Dr. Shafer apologized for what he called his journal’s “inadequate response” to the 2000 letter challenging Dr. Fujii’s results. “Publication of the letter was appropriate, but the lack of institutional followup was not appropriate,” the letter stated. “It was similarly inappropriate to publish additional manuscripts by Dr. Fujii when the allegations of fraud were unresolved.”

Anesthesia & Analgesia published 11 articles by Dr. Fujii after the 2000 letter that alleged improprieties in his data, Dr. Shafer noted. Dr. Shafer said he

Legacies of Deception Scott Reuben, MD

In February 2009, anesthesiology journals announced that they would be retracting nearly 20 of Dr. Reuben’s published studies after the pain specialist acknowledged fabricating data.

The eventual toll of retractions reached 22.

Dr. Reuben was convicted of health care fraud and spent six months in federal prison.

He also was forced to pay more than $360,000 in fines to drug companies that had funded his research.

Joachim Boldt, MD, PhD

Suspicions about Dr. Boldt’s work surfaced in late 2010, when a reader questioned the validity of a figure in a recently published study in Anesthesia & Analgesia. Subsequently, it was learned that Dr. Boldt had failed to obtain proper ethics approval for dozens of studies—of which approximately 90 have been retracted so far. An investigation into whether Dr. Boldt also committed research misconduct is ongoing.

Yoshitaka Fujii, MD

Although Dr. Fujii’s former institution, Toho University, limited its statement to the researcher’s failure to obtain proper ethics approval in some trials, editors of several anesthesiology journals strongly suspect that the misconduct runs much deeper.

With some 170 published studies potentially implicated in the scandal, the number of potential retractions has a chance to nearly double Dr. Boldt’s tally.

would issue expressions of concern for all of Dr. Fuji’s papers in his journal.

“There are multiple allegations of research fraud involving Dr. Fujii, dating at least to the April 2000 Letter to the Editor in Anesthesia & Analgesia,” Dr. Shafer told Anesthesiology News. “Although Toho University does not mention fraud in their announcement of his dismissal, I have grave concerns about the possibility of manipulation or fabrication in Dr. Fujii’s published research. This will be investigated, and compromised papers in Anesthesia & Analgesia will be retracted.”

Long Odds The journal Anaesthesia, which has been looking into Dr. Fujii’s research record, has posted four articles and editorials about the case and related issues on its Web site. One in particular is remarkable for its conclusions: Written by an anesthesiologist named John Carlisle, in the United Kingdom, the article claims to have analyzed 169 randomized controlled trials that Dr. Fujii conducted between 1991 and 2011. Dr. Carlisle found that “published distributions of 28/33 variables (85%) were inconsistent with the expected distributions, such that the likelihood of their occurring ranged from 1 in 25 to less than 1 in 1 000 000 000 000 000 000 000 000 000 000 000 (1 in 1033), equivalent to P values of 0.04 to <1 × 10(33), respectively.”

Similarly, Dr. Carlisle found that in 142 human trials, the distribution of 13 continuous variables— including age, height and various drug doses—was similarly implausible, while Dr. Fujii’s studies in dogs returned equally outlying results.

Like Dr. Shafer, Steve Yentis, MD, editor-in-chief of Anaesthesia, expressed disappointment in the direction of the Toho University investigation.

“As far as the head of the hospital knows, there was only one clinical study listed by Dr. Fujii as having been conducted at the hospital–but the conclusion of the investigation was that the studies were conducted without ethics approval, not that they were fabricated,” Dr. Yentis said. “I’d have liked to have seen a statement about the investigating committee’s conclusions as to whether these studies took place at all or whether they took place but without approval.”

oho University, which fired Yoshitaka Fujii, MD, in T late February.

This case is the latest in a string of recent misconduct scandals involving anesthesiologists, in the United States and abroad. In 2009, journals were forced to retract nearly two dozen papers by Scott Reuben, MD, a Massachusetts pain specialist, who fabricated data and eventually spent six months in federal prison for health care fraud.

That was followed last year by revelations that Joachim Boldt, MD, PhD, a critical care specialist in Germany, had failed to receive ethics approval for many of his clinical trials. To date, journals have retracted nearly 90 of his papers. Dr. Boldt also may have fabricated data in at least one study, a 2010 article in Anesthesia & Analgesia. In fact, it was Dr. Shafer’s response to that paper that led to the massive retractions.

—Adam Marcus Editor’s note: A version of this article appeared previously on AnesthesiologyNews.com.

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Anesthesia Oral Board Review: Knocking Out the Boards

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Anesthesiologist’s Manual of Surgical Procedures: Fourth Edition

Richard A. Jaffe; Stanley I. Samuels Lippincott Williams & Wilkins, February 1, 2009 This practical full-color reference is a comprehensive guide to the anesthetic and perioperative management of patients during all procedures performed by general and subspecialist surgeons.

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Atlas of Image-Guided Intervention in Regional Anesthesia and Pain Medicine: Second Edition

James Rathmell Lippincott Williams & Wilkins, November 7, 2011 This atlas is a practical guide for practitioners who perform interventional procedures with radiographic guidance to alleviate acute or chronic pain.

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Basics of Anesthesia: Expert Consult—Online and Print / Sixth Edition

Ronald D. Miller; Manuel Pardo Elsevier/Saunders, June 24, 2011 Widely acknowledged as the foremost introductory text, this full-color edition has been thoroughly updated to reflect new and rapidly changing areas in anesthesia practice including new chapters on awareness under anesthesia, quality and patient safety, orthopedics, and expanded coverage of new ultrasound techniques in regional anesthesiology.

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Hadzic’s Peripheral Nerve Blocks and Anatomy for Ultrasound-Guided Regional Anesthesia

Admir Hadzic McGraw-Hill, December 7, 2011 This edition places an emphasis on clarity, standardization and safety of peripheral nerve block techniques. Featuring sections that progress from the foundations of regional anesthesia to the clinical applications of nerve blocks, this book includes tips and insider perspective from The New York School of Regional Anesthesia.

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Neville Robinson John Wiley, December 20, 2011 This book covers basic aspects of airway and fluid management and equipment, followed by common emergencies. It tackles all the common surgical specialties step by step. Practical, contemporary and frequently amusing, it provides safe and practical advice to not only help novices survive those first few months, but to enjoy them too.

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Surgical Palliative Care and Pain Management, An Issue of Anesthesiology Clinics

Geoffrey Dunn Elsevier/Saunders, March 28, 2012 This issue of Anesthesiology Clinics covers the most important advances in surgical palliative care for anesthesiology intensivists. Topics covered include palliative care of patients on high doses of narcotics, trauma in the surgical ICU and care of the family in the surgical ICU.

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Techniques in Regional Anesthesia & Pain Management

Steven Stanos Elsevier/Saunders, 2012 The concept underlying this publication is to combine the timeliness of a quarterly journal with the illustrative aspects of a procedure-oriented atlas. Exact techniques are well illustrated, giving precise drug dosages and helpful clinical pearls.

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