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Focus on Anemia May Alter Transfusion Practices New York—Blood transfusions have been among the most commonly performed invasive procedures in the United States, with a significant percentage occurring perioperatively to treat anemia. Now, there is a movement within anesthesiology to change the way anemia is managed in patients undergoing elective surgery. During a session at the 2012 PostGraduate Assembly in Anesthesiology (PGA), a panel of blood conservation specialists

Doctor Group Claims Drug Purchasing Organizations Causing Chronic Shortages

rustrated with ongoing shortages of key drugs, a new grassroots group led by anesthesiologists is calling for the repeal of federal legislation that permits group purchasing organizations (GPOs) to engage in what they call collusive and anticompetitive activities. Several senior U.S. lawmakers have asked the Government Accountability Office (GAO), the investigative arm of Congress, to look into the allegations that GPOs are at least partly responsible for the nation’s drug shortages.

see transfuse page 22

see shortage page 16

Breathing for Two: a Life in Anesthesiology The following is the first in a three-part installment of excerpts from Breathing for Two, a new memoir on a career in anesthesiology, by Wolf Pascoe (a pen name). The book is available at http:// www.amazon.com/dp/1939803012 and wolfpascoe.com.

hen I was in medical school, I heard about a curious malady called Ondine’s curse. It was a breathing disorder, and the professor had casually mentioned it during a lecture on the mechanics of breathing—an afterthought, more or less.

Gustav Klimt’s Ondines

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“Who was Ondine?” someone asked. The professor didn’t know. Who coined the name? It was an anesthesiologist who had observed it in patients with injuries to the respiratory center—the part of the brain that controls breathing. “What’s the cure?” someone else said. “There isn’t one.” You hear about many disorders when you’re in medical school, of course. Some you think about a lot. Some you even begin to think you have, but usually you get over it.

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08 | COMMENTARY Meta-headache: How the Boldt scandal complicates studies of fluid treatment.

13 | Pain Medicine Inside the Comprehensive Pain Center of Sarasota.

26 | CLinical Anesthesiology Improving ICU transfer after heart surgery.

33 | Ad LIB Ancient texts trip up would-be diagnosticians.

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Lesson 303: PreAnesthetic Assessment of the Patient with Cirrhosis-Related Pulmonary Complications, see page 28.

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Heard Here First:

April 2013

The five most-viewed articles last month on AnesthesiologyNews.com 1. It’s Not How You Look: A Cautionary Tale From the Ward 2. Near-Miss Data Show Signs of Trouble Outside OR 3. In Operating Room, a Switch to Prefilled Syringes Pays Off 4. Hospital Claims a First—IV Prep and EHR Integration 5. Two’s Company, Three’s a Crowd: Company Model Deals in the Hospital Setting

The VA hospital’s regular morbidity and mortality conference, which ‘used to be about blame and shame and where did it go wrong and who is responsible,’ now focuses on a ‘systems approach to medical errors—how can we find ways to

prevent them and fix systems to work for us rather than against us.’

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T E C H N OL O G Y

Anesthesia Illustrated Tests Open-Source Education Model

n its first year, Anesthesia Illustrated, an open-source repository of anesthesia video lectures, attracted users from more than 150 countries who downloaded videos 94,213 times, according to an assessment presented at the 2013 Society for Technology in Anesthesia meeting. “This is one of our important and exciting projects,” said Larry Chu, MD,

director of the Stanford University Anesthesia Informatics and Media Lab, in Stanford, Calif., which created and funds Anesthesia Illustrated. The website—www.anesthesiaillustrated.com—includes recordings of every lecture given during an entire three-year anesthesia residency at Stanford University, originally meant to aid Stanford residents. Dr. Chu and

his colleagues decided to open the lectures to the global community without cost. “We want to remove the silos that limit the spread of knowledge between institutions, between societies and between individuals,” he told Anesthesiology News. The video collection has expanded to include lectures from the 2012

Sol Shnider meeting of the Society for Obstetric Anesthesia and Perinatology, and from faculty members at many other institutions, including the University of Colorado, Harvard University, Washington University in St. Louis, and the University of California, San Francisco. “It’s a fantastic project, it’s a great opportunity for learning,” said Doug McKendrick, MBChB, FFA, consultant anesthetist at Dr Gray’s Hospital in Elgin in the far north of Scotland. The Association of Anaesthetists of Great Britain & Ireland has a similar website, the AAGBI Video Platform (videoplatform.aagbi.org) that includes conference videos with slides, a project in which Dr. McKendrick is involved.

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“At the moment [the site] is open to visitors, but it will soon be restricted to members only. Whilst this is necessary to retain membership of the association, it will hamper global access to some valuable information. I hope that in the future organizations are able to share educational material in an opendata arrangement for global benefit,” Dr. McKendrick said. Anesthesia Illustrated will enter a web space with earlier pioneers of open-source web-based information portals like OpenAnesthesia.org, a project of the International Anesthesia Research Society. “I don’t view them as a competitor; I view them as complementary,” Dr. Chu said.

April 2013

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TE C H N OL O G Y OpenAnesthesia is a wiki that allows users to add content that then is curated by the crowd. In contrast, Anesthesia Illustrated is curated by Dr. Chu and only takes contributions from partnering academic anesthesia departments. Another distinction: OpenAnesthesia is text-based, whereas Anesthesia Illustrated is more visual. “The key word of our website is ‘illustrated,’” Dr. Chu said. “We are a visual website. We focus on multimedia, interactive online content versus just text.” The last distinction is that Anesthesia Illustrated crowd-sources feedback on their medical checklists, but not the actual lists. “We try to leverage the wisdom of the masses by having them give us comments on our work,” Dr. Chu said. “It doesn’t actually allow people to go in and add content like a wiki.” Traditional peer review “obviously has its benefits, but tends to be quite a slow process,” Dr. McKendrick said. He and his colleagues are looking at using opinion ratings, common in consumer websites, provided by anesthetists to evaluate the educational worth. However, in an open website, crowd-sourced peer review also may come from nonexperts, which might be a potential concern. Dr. McKendrick suggested that in the future, websites like Anesthesia Illustrated, Video Platform and OpenAnesthesia could be connected using cataloged metadata working in the background to focus searches in a similar fashion to Google algorithms. This is some of the work currently being considered by the new discipline of Health Web Science. “A search engine in the background could guide users to all of the best— by peer-reviewed ranking—sources of information from multiple websites around the world. This could be invaluable for learning processes in residency programs, and for [components of continuing education] such as revalidation,” Dr. McKendrick said. Moving to MOOC Plans to expand the website include developing a massive open online course, or MOOC, platform similar to Coursera. The crowd sourcing is expected to increase as the website unrolls its MOOC section. “We can have an anesthesia resident or faculty member at Stanford take a course alongside someone from Yale or Johns Hopkins, or Cambodia or Vietnam or Africa,” Dr. Chu said. “They

can all take a course together, learn together and benefit from the learning interactions that they all provide.” The online videos could upend the traditional classroom model to one in which students watch online lectures before in-person educational sessions that include small group discussion as well as interactive simulations. “Instead of having the residents come to a lecture hall turning the lights off and watching PowerPoint slides for an hour, flipping the

classroom model says: Let’s have them do some homework beforehand,” Dr. Chu said. He also imagines residents using the videos for just-in-time procedural task learning. “A resident can review a procedure by video before they then perform it themselves,” he said. The Anesthesia Informatics and Media Lab is planning to launch free medical checklists that have been shown in medical emergencies to improve adherence to treatment

protocols and improve the time it takes for doctors to intervene. “We put crowd-sourcing tools on Anesthesia Illustrated that allow any anesthesiologist to go on our website, look at our checklist, and make suggestions for improvement or make comments,” Dr. Chu said. “In a sense, it is more crowd-sourcing the wisdom of the masses to help them through a very important patient safety initiative.” —Trevor Stokes

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C OMM E NT A R Y

The Boldt Affair: A Quandary for Meta-Analysts

eta-analyses of randomized clinical trials provide the most rigorous evidence by which to judge the effectiveness and safety of therapeutic interventions. Fraudulent data pose a threat to the validity of meta-analyses and should be excluded. This might be straightforward in some cases. In June 2012, for instance, a Special Investigation Committee for the Japanese Society of Anesthesiologists announced its finding that 172 papers of Yoshitaka Fujii, MD, had been fabricated (with a subsequent report putting the number at 183). A metaanalyst would not hesitate to exclude those papers. The case of German anesthesiologist Joachim Boldt, MD, PhD, at one time a prolific and preeminent authority on the perioperative use of intravenous fluids, is more problematic, because the scope of fraud has been neither conclusively established nor fully investigated. In March 2011, 88 of his publications were retracted because Dr. Boldt allegedly failed to secure approval from an institutional review board (IRB) for his studies.1 In announcing the retractions, a consortium of journal editors stated that lack of IRB approval “does not mean that the research results per se are fraudulent.” Accordingly, Dr. Boldt’s retracted studies continued to be included in meta-analyses.2-4 Such a course is understandable, since metaanalysts are reluctant to exclude studies without sound reason. A key safeguard against bias in metaanalysis is comprehensiveness. The meta-analyst undertakes to identify and include, without exception, all trials fulfilling prespecified eligibility criteria. A Specter of Doubt Yet, Dr. Boldt’s research misconduct clearly went beyond failure to obtain IRB approval. After suspicions were raised by anomalously low variability in interleukin-6 (IL-6) measurements, one of his papers was determined to have been fabricated.5 At least 10 articles contained false data, according to the findings of an independent investigational committee for Klinikum Ludwigshafen, announced last August. The identities of the articles were not specified, however, and the final report has not been made public. The committee did reveal that records were either missing or incomplete for the large majority of studies; indeed, only 8% of study subjects could be identified. These findings suggested fabrication on a grand scale, but the committee did not state any conclusions about fabrication. In effect, they left the validity of the 88 papers in limbo. Furthermore, the committee examined only papers that Dr. Boldt published since 1999. His earlier work, comprising nearly 40% of his total clinical studies in fluid management, may never be investigated. A shadow of doubt hangs over all of Dr. Boldt’s work.5 So, with the validity of specific papers unresolved, meta-analysts face a quandary. Which, if any, of Dr. Boldt’s studies can still be taken at face value? Some meta-analysts have chosen to include his data, even if retracted for lack of IRB approval, while also presenting sensitivity analyses to determine their impact on overall results.2-4 The drawback of this approach is that it may lend credibility to spurious

data and inflate the apparently available breadth of valid evidence on a particular clinical question. Moreover, publicly available evidence beyond that released by the retracting editors and Klinikum Ludwigshafen reveals that Dr. Boldt engaged in rampant and long-standing fabrication and data manipulation. For example, two additional cardiac surgery trial reports of his described extracorporeal circuit priming with albumin.6,7 However, no albumin was used for priming at Klinikum Ludwigshafen during that time period.5 Hence, those studies presumably must have been fabricated. Six additional trials of his in cardiac and major abdominal surgery were evidently fabricated because of anomalously low IL-6 variability.8-13

Meta-analyses14,15 have cast doubt on seven more papers describing trials of hydroxyethyl starch (HES) for fluid management in sepsis and trauma.16-22 These trials showed unusually low variability in mortality.14 They also were inconsistent with studies from other investigators.15 Whereas the Boldt trials suggested a 24% relative reduction in the odds of mortality attributable to HES, 10 trials from other investigators suggested a 30% increase. The difference was statistically significant (P=0.024). Thus, Dr. Boldt’s data introduced major bias and obscured the true effect of HES on patient survival. For two of the seven papers, underlying data were available in a doctoral dissertation.23 The dissertation indicated that in the articles, a single trial was misrepresented as two separate trials, and data were altered to conceal the double publication. Furthermore, gastric intramucosal pH data were manipulated to falsely suggest the superiority of HES over albumin in restoring splanchnic perfusion in sepsis patients. Dissertations24,25 also revealed double publication and concealment involving four more papers dating as far back as 1990.26-29 In one of these papers, data were manipulated to show incorrectly that blood loss and transfusion of red blood cells and fresh frozen

plasma were significantly lower in patients receiving HES 130/0.4 (Fresenius Kabi/Hospira) than in patients receiving a competing HES product. Deciding how to handle Dr. Boldt’s data is of immediate importance. A topic closely associated with his work, the safety of HES solutions, is now in the spotlight of international attention. Dr. Boldt had been a tireless and highly visible champion of HES.30 Thanks in large part to his clinical research papers and review articles, HES 130/0.4 alone has been administered to at least 30 million patients worldwide, according to the manufacturer. New clinical trial data indicate that many of those patients suffered organ failure, bleeding complications and death as a result.31,32 Regulatory actions are currently under consideration by both the FDA (www.fda. gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ BloodProductsAdvisoryCommittee/UCM325690. pdf ) and the European Medicines Agency (www. ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Hydroxyethyl_starchcontaining_solutions/human_referral_prac_000012. jsp&mid=WC0b01ac05805c516f ). Previous metaanalyses have been instrumental in assessing HES safety, and new meta-analyses likely will contribute to the present decision-making process. The available evidence reveals a pattern of pervasive research fraud spanning 20 years. This pattern suggests that, in the absence of evidence to the contrary, all of Dr. Boldt’s data should be viewed as unreliable and excluded from meta-analyses. Such a policy of categorical exclusion has been implemented in our recent meta-analysis of postoperative bleeding in cardiac surgery patients receiving HES.33 The continuing contemporary relevance of the Boldt issue has been dramatized further by a new meta-analysis assessing outcomes after HES exposure.34 No overall effect of HES on survival could be demonstrated. However, after exclusion of the seven unretracted sepsis and trauma studies by Dr. Boldt’s group discussed above,16-22 significantly increased mortality was shown among HES recipients. Results from Dr. Boldt and his collaborators altered the fundamental conclusion of the meta-analysis, even though objective evidence has existed since a 2004 dissertation23 and a 2006 meta-analysis14 indicating that those data were not valid. According to an editorial accompanying the new meta-analysis,35 “hydroxyethyl starch continues to be available and widely used, in part because of uncertainty surrounding both the magnitude of scientific misconduct by Boldt and the influence of this misconduct on summary measures of clinical efficacy and harm.” This uncertainty will not be dispelled until the scientific validity of all Dr. Boldt’s fluid management studies has been definitively determined and publicly disclosed. The percentage of retractions for fraud is on the rise,36 and the issues raised by the Boldt affair are likely to be recurring. What lessons can be learned for the future? Determining the scientific validity of studies under suspicion should be a high priority. Patient care may depend on it.

April 2013

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COMME N TA R Y In the cases of Drs. Fujii and Boldt, the two researchers perpetrated fraud over decades and at different institutions. All institutions concerned need to participate in the investigation. The findings of the investigation should be promptly disclosed, publicly and in full. As this may not occur, editors should be willing to act on available evidence themselves. Finally, including data in a meta-analysis amounts to a vote of confidence in their validity. Meta-analysts should err on the side of caution before including suspect data.

19. Boldt J, Mueller M, Menges T, et al. Influence of different volume therapy regimens on regulators of the circulation in the critically ill. Br J Anaesth. 1996;77:480-487. 20. Boldt J, Müller M, Heesen M, et al. Influence of different volume therapies on platelet function in the critically ill. Intensive Care Med. 1996;22:1075-1081. 21. Boldt J, Müller M, Heesen M, et al. Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients. Crit Care Med. 1996;24:385-391. 22. Boldt J, Müller M, Mentges D, et al. Volume therapy in the critically ill: is there a difference? Intensive Care Med. 1998;24:28-36. 23. Papsdorf M. Auswirkungen einer Volumenersatztherapie auf Makro- und Mikrozirkulation und deren Regulatoren: Ein Vergleich von Hydroxyethylstärke und Humanalbumin beim kritisch kranken Patienten. Abteilung Anaesthesiologie, Intensivmedizin, Schmerztherapie. Gießen: JustusLiebig-Universität Gießen; 2004: 1-113.

—Mahlon M. Wilkes, PhD, and Roberta J. Navickis, PhD Drs. Wilkes and Navickis are principals and co-founders of Hygeia Associates, a biomedical consultancy specializing in evaluation, statistical analysis and publication of biomedical research data with a focus on meta-analysis. They have received unrestricted research funding from Baxter, CSL Behring and Grifols, but not for the preparation of this article.

References 1. Rasmussen LS, Yentis SM, Van Aken H, et al. Editors-in-chief statement regarding published clinical trials conducted without IRB approval by Joachim Boldt. Minerva Anestesiol. 2011;77:562-563.

24. Herold AC. Hyperosmolarer Volumenersatz in der Herzchirurgie. Abteilung für Anaesthesiologie und Operative Intensivmedizin. Gießen: Justus-Liebig-Universität Gießen; 1992: 1-101.

he Klinikum Ludwigshafen, where Joachim T Boldt, MD, PhD, worked until 2010, could not validate the findings in many of his published studies.

2. Bunn F, Trivedi D. Colloid solutions for fluid resuscitation. Cochrane Database Syst Rev. 2012;6:CD001319. 3. Gattas DJ, Dan A, Myburgh J, et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis. Anesth Analg. 2012;114:159-169. 4. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2012;6:CD000567. 5. Shafer SL. Shadow of doubt. Anesth Analg. 2011;112:498-500. 6. Boldt J, Brosch C, Ducke M, et al. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function: a comparison with human albumin. Crit Care Med. 2007;35:2740-2746. 7. Boldt J, Brosch C, Röhm K, et al. Is albumin administration in hypoalbuminemic elderly cardiac surgery patients of benefit with regard to inflammation, endothelial activation, and long-term kidney function? Anesth Analg. 2008;107:1496-1503. 8. Lang K, Suttner S, Boldt J, et al. Volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major abdominal surgery. Can J Anesth. 2003;50:1009-1016. 9. Boldt J, Ducke M, Kumle B, et al. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Med. 2004;30:416-422. 10. Boldt J, Schölhorn T, Mayer J, et al. The value of an albumin-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery. Anesth Analg. 2006;103:191-199. 11. Boldt J, Brosch C, Röhm K, et al. Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and

inflammatory response in elderly cardiac surgery patients. Br J Anaesth. 2008;100:457-464. 12. Boldt J, Suttner S, Brosch C, et al. The influence of a balanced volume replacement concept on inflammation, endothelial activation, and kidney integrity in elderly cardiac surgery patients. Intensive Care Med. 2009;35:462-470. 13. Boldt J, Mayer J, Brosch C, et al. Volume replacement with a balanced hydroxyethyl starch (HES) preparation in cardiac surgery patients. J Cardiothorac Vasc Anesth. 2010;24:399-407. 14. Ioannidis JPA, Trikalinos TA, Zintzaras E. Extreme between-study homogeneity in meta-analyses could offer useful insights. J Clin Epidemiol. 2006;59:1023-1032. 15. Zarychanski R, Turgeon AF, Fergusson DA, et al. Renal outcomes and mortality following hydroxyethyl starch resuscitation of critically ill patients: systematic review and meta-analysis of randomized trials. Open Med. 2009;3:E196-E209. 16. Boldt J, Heesen M, Welters I, et al. Does the type of volume therapy influence endothelial-related coagulation in the critically ill? Br J Anaesth. 1995;75:740-746. 17. Boldt J, Heesen M, Müller M, et al. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth Analg. 1996;83:254-261. 18. Boldt J, Heesen M, Padberg W, et al. The influence of volume therapy and pentoxifylline infusion on circulating adhesion molecules in trauma patients. Anaesthesia. 1996;51:529-535.

25. Schellhaaß A. Untersuchungen über den Einfluss von Volumenersatzmitteln auf die Blutgerinnung in der Abdominalchirurgie - Vergleich zweier kristalloider und zweier kolloidaler Volumenersatzmittel. Klinik für Anaesthesiologie und Operative Intensivmedizin des Klinikums der Stadt Ludwigshafen am Rhein. Gießen: Justus-Liebig-Universität Gießen; 2003: 1-82. 26. Boldt J, Kling D, Herold C, et al. Volume therapy with hypertonic saline hydroxyethyl starch solution in cardiac surgery. Anaesthesia. 1990;45:928-934. 27. Boldt J, Zickmann B, Thiel A, et al. Hyperosmolarer Volumenersatz in der Herzchirurgie. Anaesthesist. 1990;39:412-419. 28. Boldt J, Haisch G, Suttner S, et al. Are lactated Ringer’s solution and normal saline solution equal with regard to coagulation? Anesth Analg. 2002;94:378-384. 29. Boldt J, Haisch G, Suttner S, et al. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend®) on measures of coagulation. Br J Anaesth. 2002;89:722-728. 30. Reinhart K, Takala J. Hydroxyethyl starches: what do we still know? Anesth Analg. 2011;112:507-511. 31. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901-1911. 32. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.4 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124-134. 33. Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg. 2012;144:223-230. 34. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309:678-688. 35. Antonelli M, Sandroni C. Hydroxyethyl starch for intravenous volume replacement: more harm than benefit. JAMA. 2013;309:723-724. 36. Fang FC, Steen RG, Casadevall A. Misconduct accounts for the majority of retracted scientific publications. Proc Natl Acad Sci U S A. 2012;109:17028-17033.

Actively Engaged Patients Have Lower Health Care Costs, Better Outcomes

atients with the knowledge, skills and confidence to be actively engaged in their health care are likely to incur lower health care costs than patients without those characteristics, according to a February study in Health Affairs. An accompanying literature review by two of the same authors found a growing body of evidence that more actively engaged patients (or “activated” patients) also have better health outcomes and health care experiences. In the cost study (2013;32:216-222), the researchers examined data from 33,163 primary care patients enrolled with Fairview Health Services, a hospital system based in Minneapolis, Minn. Patient activation was measured with a scoring system consisting of 13 items such as “I know how to prevent problems with

my health” and “I am confident that I can tell a doctor my concerns, even when he or she does not ask.” The researchers found that patient activation scores from 2010 were a significant predictor of cost of care in the first half of 2011: Patients with the lowest activation level had costs 21% higher than patients with the highest activation level (P<0.05). The findings held true even after controlling for sociodemographic factors and the severity of health conditions. “The study highlights the important role that patients play in determining outcomes,” lead author Judith H. Hibbard, PhD, MPH, professor emerita in the Department of Planning, Public Policy, and Management at the University of Oregon, in Eugene, said in a statement. “We found that patients who were

more knowledgeable, skilled and confident about managing their day-to-day [treatment] … had health care costs that were substantially lower than patients who lacked this type of confidence and skill.” The literature review (2013;32:207-214), by Dr. Hibbard and Jessica Greene, PhD, MPH, the director of research at the George Washington University School of Nursing, in Washington, D.C., identified several interventions that have been shown to increase patient activation, such as tailored coaching—a strategy that helps customize support to the individual’s activation level. Efforts to expand patient activation, the authors concluded, are “a pathway toward improving outcomes.” —George Ochoa

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µ-Opioid Receptors Impaired in Fibromyalgia Patients, Study Shows Washington—Impaired functioning of the brain’s ability to process pain stimuli may negatively affect how people with fibromyalgia experience pain, according to new research. The research also shows that abnormal pain signal processing is associated with reduced opioid receptor binding, and these

findings suggest that the brain’s normal pain-inhibiting processes malfunction in fibromyalgia patients. This study is the first to demonstrate the connection between µ-opioid receptor binding and the brain’s response to the pain of fibromyalgia, said lead investigator Richard Harris, PhD, assistant

professor in the Department of Anesthesiology and research assistant professor in the Department of Internal Medicine, University of Michigan, in Ann Arbor. “In fibromyalgia patients, the main inhibitory mechanisms are not working correctly, specifically the opioid receptors within the brain,” he

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reported at the 2012 annual meeting of the American College of Rheumatology (abstract 2450). The investigators used functional magnetic resonance imaging to measure changes in blood flow in the brains of 18 female patients with fibromyalgia after they received a painful stimulus, administered to the thumb in varying intensity, and measured by the Short-Form McGill Pain Questionnaire. The researchers also measured µ-opioid receptor binding by positron emission tomography scanning. None of the patients had received opioids prior to the study, which was conducted between 2008 and 2012. The study cohort received acupuncture and placebo acupuncture for reduction of pain before and after the tests for the brain’s response to pain and the binding of µ-opioid receptors. A negative correlation was seen between the change in blood oxygenation level–dependent (BOLD) signal and the µ-opioid receptor binding in several regions of the brain involved in processing and controlling pain. These included the right posterior insula (R= –0.82; P=0.0004), left medial insula (R= –0.82; P=0.0003), left orbital frontal cortex (R= –0.75; P=0.0004) and right amygdala (R= –0.68; P=0.002). Positive correlations also were found in the right dorsolateral prefrontal cortex (R=0.66; P=0.003), posterior cingulate (R=0.62; P=0.006) and the right putamen (R=0.72; P=0.0008). “When opioid receptor binding went down, the evoked brain pain response went up in key brain regions that are involved in pain processing, such as the insula and amygdala,” Dr. Harris said. He proposed two possible explanations: either the receptors were downregulated or activating the receptors caused pain. Dr. Harris found the study results to be somewhat paradoxical. “We found that fibromyalgia patients either have too few receptors in their brains, or the receptors themselves, when they get activated, are causing pain instead of lessening pain. It is possible that opioids are not the best treatment for fibromyalgia and may even worsen symptoms,” he added. “This study may explain why patients with fibromyalgia do not respond to narcotics,” said Kathryn Dao, MD, associate director of rheumatology research at Baylor Research Institute, in Dallas. “Further studies would help define if the same aberration in the pain signaling pathway is responsible for other chronic pain conditions.” —Alice Goodman

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SCS Found Effective for Pain Originating in the Cervical Spine

ata from 38 patients in a large multicenter trial confirm that spinal cord stimulation (SCS) is effective in reducing pain in the cervical spine. The patients’ average pain-related disability was significantly diminished within three months of treatment, and the majority also reported their pain relief as being excellent or good. “This provides further supporting evidence that, similar to placing leads in the thoracic spine, the use of SCS in the cervical spine is acceptable, medically necessary and should be reimbursed in the appropriately selected and treated patient,” said study investigator Timothy Deer, MD, head of the Center for Pain Relief in Charleston, WVa. Dr. Deer presented the results at the 2012 annual meeting of the North American Neuromodulation Society (NANS; abstract 321). The observational study “represents the real-world practice and therefore is much more useful [than controlled trials] as a reference for practitioners and patients,” said Konstantin Slavin, MD, professor of neurosurgery at the University of Illinois at Chicago and secretary of NANS, who was not involved in the research. “Following publication of this study, one may expect to see an increase in the number of referrals and implants of SCS devices in the cervical region, providing hope of symptomatic relief for many chronic pain patients.” The ongoing 40-center registry study is being supported by a research grant from St. Jude Medical. Of the 600 adults in the study, 38 received SCS implants (EON Mini, St. Jude Medical) in the cervical region of the spine. Nine subjects had complex regional pain syndrome I or II; nine others had failed spine surgery syndrome; five had failed neck disk surgery syndrome; four had chronic cervical radiculopathy; two had a nonspecific diagnosis of chronic pain syndrome; and the remaining nine had other diagnoses including cervical degenerative disk disease and neuralgia. The majority of the leads (78.9%) were implanted with the tip in the spine at the level of C2 or C3. Nearly threefourths (73.7%) were percutaneous, and the rest of the leads were paddles. At the NANS meeting, Dr. Deer, president-elect of the International Neuromodulation Society, presented data from the 26 patients who completed the three-month post-implantation assessment, 21 who completed the

six-month visit, and 16 patients who completed the one-year follow-up visit. More than half (54.2%) reported pain relief at three months; this figure rose to 60.2% and 66.8% at six and 12 months, respectively. Furthermore, 61.6% of patients categorized their pain relief as good or excellent at three months, with similar results at six and 12 months. Only one person described the pain

relief as poor. The patients’ mean Pain Disability Index scores also were significantly reduced, dropping from a baseline score of 49.6 to 34.5, 33.4 and 28.4 at three, six and 12 months, respectively. Patient quality of life improved significantly at three, six and 12 months, while a large majority of subjects said they were satisfied or very satisfied with the

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

SCS device at these time points. At 12 months, 75% said they would undergo the procedure again and would recommend the procedure to other pain patients. —Rosemary Frei, MSc Drs. Deer and Slavin are consultants for St. Jude Medical.

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

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

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

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

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April 2013

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Experts: SCS Underused in Failed Back Surgery Syndrome

esearchers specializing in spinal cord stimulation (SCS) are struggling to understand why this modality is used much less than reoperation for failed back surgery syndrome (FBSS), believing SCS is more effective and far less invasive in patients with FBSS. Previous studies have shown that FBSS affects as much as 5% to 40% of those treated with

lumbosacral spine surgery. “Many spine surgeons still view SCS as a salvage operation rather than a superior alternative in select patients,” said Nandan Lad, MD, PhD, assistant professor of neurosurgery, Duke University School of Medicine, in Durham, N.C., whose team presented results of a study on SCS for FBSS at the 2012 annual meeting of the North

THROMBATE

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

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

American Neuromodulation Society. “Additional studies are needed to increase awareness and use of SCS for the treatment of chronic pain syndromes such as FBSS.” Researchers from Duke University, the University of Louisville in Kentucky and Cedars-Sinai Medical Center in Los Angeles analyzed patient records from 2000 to 2009.

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

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

Only 2.4% (394) of the 16,455 FBSS patients underwent SCS implantation. The mean patient age in the two groups was 54 years. Comorbidities were more common in the lumbar surgery patients, as reflected in their higher average Charlson Index scores (P=0.0003). A significantly higher percentage of Medicaid patients underwent SCS implantation than reoperation (19% vs. 7.5%). The complication rate during the procedure-related hospitalization was significantly lower in the SCS group—5% versus 11.7%—as were complication rates at 30 and 90 days postoperatively (6.65% vs. 14.35%, and 6.51% vs. 14.42%, respectively; P<0.0001 for all). The investigators also conducted a parallel comparison of the outcomes of 222 patients who were matched on the basis of sex and age: 111 who underwent SCS and 111 who had repeat surgery. They found that the average length of stay for the index hospitalization also was considerably shorter in the SCS patients, at four versus two days in the unmatched population, and three versus two days in the matched cohorts (P<0.0001 for both). This resulted in markedly lower index hospitalization charges in SCS patients, both in the matched and unmatched populations compared with their reoperation counterparts. However, none of the other types of charges—such as those for outpatient emergency room care or medication— was significantly lower than in the reoperation patients, whether in the matched or unmatched populations. Ashwini Sharan, MD, professor of neurosurgery at Thomas Jefferson University Hospital, in Philadelphia, called the studies “incredibly important work” because “spinal neurosurgeons and orthopedic surgeons just are not aware of SCS’s benefits.” However, he noted, the data cannot address which patients benefit from repeat spinal surgery. "You can’t assume that SCS should always be the next approach [just] because it has fewer complications,” said Dr. Sharan, who was not involved in the investigation. “In addition, it would have been nice to know which physicians were performing SCS versus the spinal surgery— how often is there bias in the practice of a physician, who does both but opts for surgery far more often?” —Rosemary Frei, MSc

08941115-BS

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Small Florida Pain Center Looms Large in Fight Against Chronic Pain

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he Comprehensive Pain Cen“We don’t tell patients, ‘OK fine, ter (CPC) of Sarasota, Fla., you’re in pain, here are the pain meds, located on the sixth floor good luck,’” said W. Bruce Benner, AP, in Waldemere Medical Plaza, is not DOM, acupuncture physician at CPC. what most patients would expect of a “We try to open patients’ eyes to trypain clinic. Instead of a sterile medi- ing anything that will help them get rid cal facility, patients walk into a spa- of their pain—physical therapy, psylike atmosphere. The walls and floors chological techniques and even acuare colored a soothing earth tone; the puncture, because these techniques lobby has a large-screen TV, displaying can have a great effect on pain. These images of serene waterfalls, mountain- techniques also have zero side effects. tops and oceans; soft music emanates That’s another of our goals—to prothroughout the facility; and the wait- duce the best results for patients with ing room is supplied with health, fit- the least side effects.” ness and nutrition magazines. CPC offers comprehensive diagCPC reflects what nostic evaluations for all Myrdalis Diaz-Ramirez, types of pain, including MD, believes good pain acute, chronic, neuromanagement is all about. pathic and cancer, as well “There is nothing in this as pain of uncertain etienvironment that adds to ology. Its broad toolbox the patient’s stress level,” contains everything from said Dr. Diaz-Ramirez, the latest pharmacologic who founded the center in treatments to advanced 2008. “We offer a multidisinterventional procedures, ciplinary approach, incor- CPC Sarasota founder and such as occipital, paraverporating the most modern medical director Myrdalis tebral and sympathetic techniques and treatments, Diaz-Ramirez, MD nerve blocks. Dr. Diazcombined with holistic or Ramirez also performs integrative medicine approaches.” minimally invasive spinal treatments, Dr. Diaz-Ramirez’s approach to such as epidural steroid and facet pain medicine formed when she was joint injections, medial branch radioa pain management fellow at Oregon frequency ablation, and implanted Health & Science University, where intrathecal pain pumps and spinal she served as liaison between the hos- cord stimulators. CPC’s behavioral pital’s pain and palliative care pro- and integrative techniques include grams. She returned to Florida after biofeedback and relaxation therapies, a local hospital asked her to set up a acupuncture and herbal medicine. pain clinic. “Then, I decided to open “We believe in whatever works to my own clinic,” she explained, “and do make a patient well,” said Dr. Benner. pain management the right way, as I “We use our entire arsenal to accomhad learned. I wanted it to be patient- plish that.” centered and producing the best The center’s team, which consists of outcomes.” five clinicians and three support staff, Dr. Diaz-Ramirez’s beliefs and prac- has extensive pain management experitices led CPC to win the American ence. For instance, its pain psychologist Pain Society Center of Excellence and mental health counselor/biofeedAward in 2011, one of only three pain back specialists have been treating pain centers in Florida to receive that honor. patients for more than 20 years. The team conducts weekly meetings The Little Clinic That Could to discuss patient cases and develop CPC is a small, 2,600-square-foot, treatment plans, and that’s where being unaffiliated clinic with big ambitions. small is an advantage, said Dr. Benner. Like much larger pain centers, CPC’s “We can communicate better and keep bilingual team works with patients, on top of patient care. If we see somefamilies and primary care physicians to thing’s not working, we can change it develop comprehensive, biopsychoso- rapidly.” Dr. Benner added, “We also cial treatment plans to relieve pain and know how each other works, and that see CPC page 14 restore functionality.

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P A I N M E DI C I NE CPC continued from page 13 means more efficient ways to treat pain. We give our patients wider access more quickly to different modalities.” CPC’s Challenges But being a small, unaffiliated clinic also presents challenges. “To be successful and competitive, especially in the private sector, we have to be very efficient and focused on what we do,” said business manager

Tomas Rodriguez, who coordinates CPC’s growth opportunities and community education initiatives. CPC has made great efforts in choosing the right staff—people who have the breadth and scope of pain medicine expertise that makes them both capable and efficient. The center also has embraced technology to make everything it does as costeffective as possible. “From the get-go, we incorporated an electronic medical records system

to save on space and personnel, and to make capturing data, such as referral patterns, demographic trends and medication prescribing, much easier,” Mr. Rodriguez said. “There is a lot of automation built into our center, especially for things we do repetitively. This has allowed us to run relatively lean, but still increase services.” In an effort to save patients money, reduce turnaround time for results and improve clinical validations, the center recently acquired technology

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to bring some testing procedures, such as urinalysis, in-house. Perhaps the biggest challenge CPC faces is operating in what may be the toughest pain medicine market in the country. According to Dr. DiazRamirez, “the pain scene here has been hijacked by drug dealers.” Florida had developed a reputation as the epicenter of the prescription drug abuse epidemic, prescribing narcotic pain medications inappropriately or for nonmedical reasons to almost anyone who can pay cash. Because of a subsequent crackdown by the state—which last year issued new regulations regarding pain clinics and prescription pain drugs and saw more than 2,000 arrests, including 34 doctors—legitimate pain centers like CPC have had to defend their reputations and be diligent in conducting business. Screening patients correctly becomes paramount, said Dr. DiazRamirez, and that’s where CPC’s experienced staff is a valuable asset. The center’s automation helps with the new pain management regulations, which require pain clinics to register with the county, penalize doctors who overprescribe painkillers, toughen reporting requirements for the statewide prescription drug monitoring database, tighten the regulations for pharmacies, and encourage drug wholesalers and pharmacists to report people trying to make questionable purchases. “With our technolog y, we are able to adhere to the new regulations quickly and efficiently,” Mr. Rodriguez said. CPC clinicians also are active in communicating to local and state officials and the public what good pain management practices should be. They often speak to various patient and professional groups around the state, and CPC puts out a quarterly newsletter, PainSmart, with staffwritten articles on treating pain. Each September, during Pain Awareness Month, the center supports the American Pain Foundation’s Action Network by conducting “lunch and learn” meetings on pain management topics.

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AnesthesiologyNews.com I 15

P a i n M e d i c i ne come to prescheduled format arrangements,” Mr. Rodriguez said. “They will graduate a particular course designed for a specific condition. “We also are opening our procedure room for fluoroscopy,” he continued. “Right now, patients have to pay more for the use of a surgery center. In order to lower costs to them, we will offer some of it here, besides our ultrasoundguided procedures and our in-house lab. “We want to develop a research function and good clinical outcomes data,

too, that validate just how our treatment methods are working,” Dr. DiazRamirez said. “We have the systems in place to keep tabs on how our patients are doing. We want them to have objective measures of what the experience here is and what we strive for. We also want to make sure we remain competitive in this market and continue to spread the word about what real pain medicine is.” Dr. Diaz-Ramirez added, “We are very grateful for the opportunity

we’ve had and are honored to have received so many accolades in such a short period of time. I love my work. Preventing pain is a very honorable duty. Our team works hard and has stayed together. For the future, we want to continue to be able to provide patient care without the pressures of large corporate medicine. It will be a challenge, but in my mind, it is the right thing to do.” —Tom McDonagh

W. Bruce Benner, AP, DOM, CPC’s acupuncture physician, applies the ancient Chinese medicine technique of acupuncture to a patient’s hand. CPC Sarasota uses holistic medicine approaches to enhance its multidisciplinary biopsychosocial treatments.

The decor in CPC Sarasota’s lobby is designed to ease pain patients’ stress as soon as they walk through the door.

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Computer technology, as seen here in the CPC Sarasota reception area, is an important part of the pain center’s success, allowing it to run “lean and mean.”

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P OL I C Y & M A NA G EMENT Shortage continued from page 1 “We are convinced that the anticompetitive contracting and pricing practices, kickbacks and selfdealing of hospital GPOs are the root cause of this public health emergency,” said anesthesiologist Robert A. Campbell, MD, co-chair of the new group, Physicians Against Drug Shortages (PADS). “We’re launching a national campaign to build public awareness of these anticompetitive practices and press Congress to halt them,” said Dr. Campbell, who also is vice president of the Pennsylvania Society of Anesthesiologists and a state delegate to the American Society of Anesthesiologists (ASA). Dr. Campbell described PADS as “a small group of physicians who met at the recent ASA meeting. After a totally unsatisfactory panel on drug shortages we chose to exchange emails and explore an economic explanation for drug shortages. Our solution will save at first $35 billion per year in health care costs. Once competitive forces are restored in the health care supply chain, even more savings will be realized.” Any attempt to link GPOs to drug shortages is an “irresponsible and dangerous distraction,” countered Curtis Rooney, president of the Healthcare Supply Chain Association (HSCA), a trade association representing 14 GPOs, including the nation’s five largest. “The true cause of drug shortages is manufacturing problems, disruptions and barriers to entry in getting new suppliers online when there is a disruption in supply. The fact is that GPOs are taking a variety of creative and innovative steps to reduce drug shortages,” Mr. Rooney told Anesthesiology News. Leveraging Purchasing Power GPOs negotiate contracts with manufacturers and vendors of pharmaceuticals and other medical products on behalf of their customers, typically hospital groups and other large health care organizations. About 72% of all hospital purchases are made through GPO contracts. GPOs leverage their collective purchasing power in order to keep costs low for their customers. Vendors pay GPOs “administrative” fees, typically based on a percentage of sales and capped by law at 3%. GPOs have been allowed to collect these fees since 1986 through a “safe harbor” provision added to the Social Security Act’s Anti-Kickback statute, which would otherwise prohibit the practice. “By exempting GPOs from criminal prosecution for taking kickbacks from vendors, [the exemption] has given rise to monumental conflicts of interest and perverse incentives that have undermined competition and innovation and inflated costs in the health care supplies, devices and generic drug marketplace—with tragic consequences,” said Phillip L. Zweig, MBA, executive director of PADS. Mr. Zweig worked for medical device companies between 1999 and 2008 but no longer has financial ties to the industry. His current work with PADS is pro bono, he said. “Our goal is to end the generic drug shortage crisis by restoring integrity and free market competition to the broken generic injectable marketplace, and indeed, to the entire U.S. health care supplies

industry,” Mr. Zweig said. “To accomplish that, we’re pushing for the repeal of the Medicare anti-kickback safe harbor provision, which created the GPO ‘pay to play’ scheme in the first place. As a result of this misguided legislation, the GPOs now exert a stranglehold on the entire hospital supplies marketplace. They’ve rigged the market. PADS intends to end their reign of terror.” PADS, Mr. Zweig added, does not want to abolish GPOs, but rather return them to the pre–safe harbor system—“which worked fine from the early 1900s to the early 1990s.” But Phil Johnson, oncology director at Premier Inc., the nation’s second largest GPO by purchasing volume, said the accusation that GPOs have eliminated free market forces is “uninformed and wrong.” “In fact, GPOs encourage the free market by competitive bidding and multiple rewards

‘We are convinced that the anticompetitive contracting and pricing practices, kickbacks and self-dealing of hospital GPOs are the root cause of this public health emergency.’ —Robert A. Campbell, MD for the best supplier performance,” Mr. Johnson told Anesthesiology News. “Consider that Premier represents approximately 2,700 hospitals and more than 90,000 non-acute sites. Our members determine the acceptable drugs or medical supplies within a therapeutic category, and Premier obtains strong contracts ensuring multiple vendors and product choices. With GPOs, the best drugs within the category, as determined by our member providers—physicians and pharmacists—develop strong contracts with competitive pricing.” However, a June 2012 report by the House Committee on Oversight and Government Reform concluded that GPOs have contributed to the current shortage of generic injectable medications because of pressures that the purchasing organizations exert on manufacturers and suppliers. “Companies that cannot produce a drug at large enough output levels to take advantage of the economies of scale—often because they lack the guaranteed source of demand that GPOs provide—will stop producing the drug or will neglect to enter the market,” the House report stated.

Congressional Probe The controversy surrounding GPOs is not new. Over the years, hospital systems have claimed that GPOs have saved them billions of dollars annually in purchasing costs (Anesthesiology News July 2009), while lawmakers and others have worried about the anticompetitive or unethical practices of GPOs. The GPO industry has adopted voluntary codes of conduct and since 2005, many companies have participated in an annual survey of their contracting practices. In November 2012, six senior members of the House of Representatives asked the GAO to investigate whether GPOs are a “driving cause” of drug shortages. The lawmakers—Democrats Edward J. Markey (Mass.), John Dingell (Mich.), Frank Pallone (N.J.), Diana DeGette (Colo.), and Henry A. Waxman and Anna G. Eschoo (Calif.)—also said that shortages of critical drugs have forced hospitals and other providers to rely on unregulated compounding pharmacies, such as the New England Compounding Center, the Framingham, Mass., firm that has been blamed for last year’s deadly outbreak of fungal meningitis and other infections caused by contaminated epidural steroid injections. “As Congress fully investigates all the causes of the tragic meningitis outbreak in an effort to protect patients in the future, we need to look at the role GPOs play in the occurrence of drug shortages that could lead to increased reliance on compounding pharmacies,” Mr. Markey said in a statement. Expert practitioners and academics concurred. “This broken generic drug market, which is the direct consequence of unethical GPO drug purchasing contracts legalized by Congress, must be fixed immediately,” said Joel B. Zivot, MD, medical director of the cardiothoracic intensive care unit at Emory University Hospital, in Atlanta, in a statement. “GPOs are a major, if not the primary, contributor to the market distortions in the health care industry in the United States,” added S. Prakash Sethi, PhD, university distinguished professor at Baruch College, in New York City. “Through exclusive contracting, which has given GPOs effective monopolistic control of this industry, they have contributed to product shortages and disincentives for legitimate producers to manufacture and stock essential drugs. At the same time, they have given rise to unscrupulous manufacturers to produce and market substandard drugs and thereby expose the patient population to serious health risks.” But Thomas G. Moore, president of Hospira Inc., blamed shortages of injectable drugs on manufacturing problems and disputes any link between drug shortages and the meningitis outbreak or between drug shortages and GPOs. “The practice of hospitals contracting with a GPO in order to aggregate their purchasing power is not a factor in drug shortages,” Mr. Moore wrote in a Nov. 19, 2012, letter to the lawmakers. “It has been Hospira’s experience that GPOs do not limit the manufacturers who can contract with the GPO, especially in the circumstance of a drug shortage.” —Ted Agres

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POL I CY & M A N A G E M E N T

IOM Report Recommends National Track-and-Trace System

ongress should authorize and fund the FDA to establish a mandatory, national track-and-trace system for pharmaceuticals, according to an Institute of Medicine (IOM) report released Feb. 13. In the meantime, the report urged the FDA to convene a working group of stakeholders to promote voluntary track and trace. This advice, labeled Recommendation 5-2, is part of Countering the Problem of Falsified and Substandard Drugs (published by the National Academies Press in Washington, D.C.), written by an IOM committee. The report concerns the global problem of illegitimate drugs, whether they are falsified or fake, carrying a false representation of identity or source, or substandard, failing to meet accepted specifications. Many recommendations in the report apply to developing countries, but some, including the track-and-trace recommendation, are of special importance to the United States. The relevance of the track-and-trace recommendation was swiftly noted by the Pharmaceutical Distribution Security Alliance (PDSA), a coalition of pharmacies, distributors, manufacturers and others committed to strengthening the nation’s

pharmaceutical distribution supply chain. “[PDSA] applauds the [IOM] for recognizing that new legislation is needed to protect all Americans from the threat of counterfeit drugs,” PDSA said in a statement. Indicators are “good” in Congress for “potential enactment into law,” Vince Ventimiglia, principal at FaegreBD Consulting, in Washington, D.C., and an advisor to PDSA, wrote in an email. “Key committee leadership and other important members of Congress in both congressional bodies have stated that supply-chain traceability legislation remains a high priority for enactment into law this year; the FDA has asked for increased authority of this nature; and Congress has spent countless hours negotiating an effective policy.” But Gillian J. Buckley, PhD, MPH, a co-editor of the IOM report, was more cautious. “Realistically, it might take Congress a while.” Voluntary Global Effort ReposiTrak, a joint venture of Leavitt Partners and Park City Group, is a track-and-trace system that aims at an even larger scale than the national

‘The world is trying to agree on standards for identification. On a global scale, they want to agree on an identifier. It’s a huge obstacle and very expensive.’ —Randy Fields, MA

scale specified by the IOM recommendation. “ReposiTrak is a track-and-trace system with which we anticipate serving the entire global food supply system, as well as supplement nutraceuticals and pharmaceuticals,” said Randy Fields, MA, chairman of the Park City Group, in Salt Lake City. “It will keep track of all documents related to safety and compliance, track and trace movement of ingredients and tell where inventory is now.” “Although we’re not in a position to talk about mandatory versus voluntary systems, the market is moving toward greater use of track and trace,” said Kristina Lunner, senior advisor at Leavitt Partners, in Washington, D.C. “The world is trying to agree on standards for identification. On a global scale, they want to agree on an identifier. It’s a huge obstacle and very expensive,” Mr. Fields said. “Our secret sauce is to track and trace without a common identifier. Our system is completely interoperable.” Another item relevant to the United States is Recommendation 5-1, which states, “State licensing boards should only license wholesalers and distributors that meet the National Association of Boards of Pharmacy [NABP] accreditation standards.” Dr. Buckley, who is study director for IOM’s Board on Global Health, explained that NABP has high standards and a process that includes criminal background checks. “Currently, three states require wholesalers to have NABP accreditation: Indiana, North Dakota and Wyoming,” Dr. Buckley said. “Any state having a low standard is a vulnerability for others.” Another part of Recommendation 5-1 is the establishment of a public database to share information on suspended and revoked wholesale licenses. Right now, according to Dr. Buckley, “if your license is revoked, you can go to another state and get a license there.” An international code of practice on the global problem of falsified and substandard medicines, as specified by Recommendation 7-1, would potentially involve the United States as well as other countries. This is the committee’s “boldest recommendation, one that reaches out to the world,” coeditor Lawrence O. Gostin, JD, professor of global health law at Georgetown University Law Center, in Washington, D.C., said at a press briefing. The recommendation states, “The code should include guidelines on surveillance, regulation, and law enforcement, empowering states and the international community to prevent and respond to drug quality problems.” “Every country has a stake in being part of that,” Dr. Buckley said. “Keeping bad medicine out of our supply is the FDA’s job.” However, “no matter how good the FDA is, in an era of global medicines, no country can totally act alone.” “These IOM reports are helpful,” said Rich McKeown, JD, Leavitt's president and CEO. “They provide useful data for dialogue and development of strategic direction.” —George Ochoa

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P OL I C Y & M A NA G EMENT

Hospitals Too Often Neglect Drug Safety Education: ISMP

ducating pharmacists, nurses and physicians in medication safety and evaluating their knowledge and skills in that area are vital if hospitals want to avoid the errors that seriously harm patients and drive up costs. All too often, however, hospitals with other pressing needs push education and staff competency assessment to the back burner. The result,

said Matthew Grissinger, RPh, director of error reporting programs at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa., is that they miss opportunities to enhance their patient safety strategies. Speaking at a recent ISMP webinar, titled “Improving Medication Safety through Staff Education and Competency Assessment,” Mr. Grissinger

described some of the problems the ISMP witnesses during hospital consult visits across the country. Competency assessments, he said, are frequently inconsistent throughout an organization. “Often,” he added, “we’ll see competency tests that are really calculation tests, and that’s it.” Mr. Grissinger said ISMP often encounters a lack of standardized

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interdisciplinary education, “meaning education is very siloed—which is kind of odd because we’re expected to work as a team in our systems.” He also noted a lack of consistent credentialing, training and certification as well as a lack of information-sharing about errors that occur, their causes and ways to prevent future ones. Supporting ISMP’s hospital-consult observations, Mr. Grissinger presented results from the group’s most recent Medication Safety Self-Assessment survey, encompassing responses from more than 1,300 organizations. The survey, which has been submitted for publication, uncovered spotty adherence to some of ISMP’s core characteristics of effective staff education and competency assessment. Overall, Mr. Grissinger said, respondents achieved an average score of only 64% on questions designed to assess whether practitioners receive sufficient orientation on medication use; undergo baseline and annual competency evaluation of knowledge and skills related to safe medication practices; and whether they receive ongoing education on medication error prevention and the safe use of high-alert drugs. Certain items produced particularly low scores. For example, in 34% of the respondents’ hospitals, new staff pharmacists undergoing orientation are not assigned to spend time in patient care units becoming familiar with drug prescribing practices, unit stock storage conditions, medication administration procedures and patient education practices. Nearly 72% of respondents noted that newly hired nurses do not spend time in the pharmacy or with clinical pharmacists during orientation. Nearly 47% of respondents said their hospitals don’t include pharmacists in medical staff orientation, and nearly 34% reported a lack of teamwork exercises. A VA Hospital That Values Education In contrast, some hospitals make it a point to build staff education and competency assessment into their daily routines. At the ISMP webinar, Alexander Reiss, MD, chief of the Hospitalist Section at the James A. Haley Veterans Hospital and Clinics in Tampa, Fla., described a safety culture at the 548-bed VA facility that emphasizes a bottom-up, interdisciplinary approach to error prevention. “We have a morning report every day,” Dr. Reiss said, “and once a week we’ll spend about

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POL I CY & M A N A G E M E N T 15 minutes on just a quick topic on patient safety or quality. It’s often entertaining and very interactive, so no one gets too bored, and they learn a little bit along the way.” The VA hospital’s regular morbidity and mortality conference, which “used to be about blame and shame and where did it go wrong and who is responsible,” now focuses on a “systems approach to medical errors—how can we find ways to prevent them and fix systems to work for us rather than against us.” Dr. Reiss said one example of the VA hospital’s interprofessional approach is its medication tracer program. He described how an interdisciplinary group of 10 to 12 students, nurses, medical residents, staff pharmacists and others regularly gathers to learn about vulnerabilities in medication use by following an actual order through the entire process, from computerized prescriber order entry to the pharmacy to administration by a nurse at the bedside. The detailed walk-through takes about an hour, he said. The group is asked to come up with solutions to the problems they spot, Dr. Reiss said. Typically, “they start with weak solutions, but eventually come up with some really strong solutions, environmental changes and infrastructure changes.” Dr. Reiss said the process is “a very effective tool—a very interprofessional way to see where the problems exist within our system that we had no idea were even there.” The safety group also schedules other interdisciplinary learning sessions, like the “environment of care” rounds, where a group visits a nursing unit room in which a patient has agreed to take part. “We just chat,” Dr. Reiss said. “We point out things in the room, and the patient invariably tells us things that we weren’t aware of or didn’t even think about. That’s probably the most eye-opening part, the interaction with the patient.” Mr. Grissinger provided webinar participants with a number of suggestions for improving their organizations’ safe medication use education programs, including using communication logs to share safety tips in patient care areas; introducing videotapes and interactive CD-ROM programs; conducting simulation exercises; and scheduling weekly safety rounds with front-line staff and management. Multiple Sites Another Challenge Kyle Hultgren, PharmD, managing director of the Center for Medication Safety Advancement at Purdue

University, in West Lafayette, Ind., noted how challenging it can be to develop medication safety “standards inside of your hospital, let alone across the entire health system.” Part of the solution, he said, “comes down to defining a standard language. A lot of people have really excellent ideas, but how do we begin to discuss medication errors and improving medication use practices if we’re all speaking a different language?” Still, making improvements “is

certainly not impossible,” he said. “One of the things that ISMP does a great job in is stressing the notion of competency.” What they and other groups are trying to accomplish, he said, “is to create effective standards of care and make sure the people” adhere to them. And assessing competencies, he added, helps to ensure that standards are followed. Good standards don’t “script patient care,” Dr. Hultgren said, but they do ensure that when “it comes time to provide

patient care, we can think at the top end of our licenses.” Dr. Hultgren also pointed out that developing medication safety standards cannot be accomplished solely through a “top-down” process. “The parameters, the guidelines and the cultural tone have to be set by the leadership,” he said, “but from the bottom-up is where the improvements start to happen. It’s really a collaborative approach across the entire spectrum.” —Bruce Buckley

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CL I N I CA L A NEST H E S I OL O G Y

Intubation Times Longer For Video Than DL in Patients With Difficult Airways But better views are a benefit Toronto—In a patient with a difficult airway, intubation using a video laryngoscope requires significantly more time than direct laryngoscopy, a study has found. The longer intubation time for the video device also increased the amount of required overall force to a level similar to direct laryngoscopy. Lead investigator Daniel Cordovani, MD, a fellow in the Department of Anesthesia at the University of Toronto Faculty of Medicine in Toronto, Canada, speculated that a longer intubation time could raise the risk for complications in patients with cardiovascular risk factors. “A prolonged laryngoscopy is probably more likely to generate a sympathetic response, which could be detrimental in patients with cardiovascular risk factors,” said Dr. Cordovani, who presented his team’s results at the 2012 annual meeting of the Society for Airway Management (abstract 6). In the study, 44 subjects had undergone elective surgery with general anesthesia between July 2011 and April 2012, and had at least one risk factor for a difficult airway, including a Mallampati score of at least 3, an inter-incisor gap of less than 3.5 cm, a thyromental distance of less than 6.5 cm, a sternomental distance of less than 12.5 cm, and reduced neck extension and flexion. The subjects were American Society of Anesthesiologists (ASA) class 1 to 3. Twenty-four patients were randomized to undergo laryngoscopies with a size 3 Macintosh blade, followed by use of a GlideScope (Verathon Medical), while the remaining patients underwent the reverse order of laryngoscopies. Patients were intubated with the second device. The investigators

used a single-lumen endotracheal tube, compared intubation times and measured peak, average and impulse forces using sensors placed along the concave surface of the laryngoscope blade. Dr. Cordovani and his team found that video laryngoscopy required a median of 30 seconds, compared with 18 seconds for direct laryngoscopy (P<0.001). In contrast, previous research in patients with normal airways found that use of a GlideScope required a median of 19 seconds, compared with 14 seconds for a Macintosh blade (Anaesthesia 2012;67:626-631). The longer time for the video device increased the amount of impulse or overall force that was required to a level comparable to direct laryngoscopy, although peak and average forces with the video laryngoscope were significantly lower (Table). The previous study in subjects with a normal airway found that video laryngoscopy required significantly less of all three forces in those patients. “It’s hard to say which of the three types of force is most important,” Dr. Cordovani told Anesthesiology News. Video laryngoscopy maintained an edge over direct in several other parameters, Dr. Cordovani noted. Specifically, only 14% of attempts with GlideScope required external laryngeal pressure, compared with 36% of those with the Macintosh. The video device also provided a superior grade view to direct laryngoscopy in 55% of patients, and the same grade view in 43% of subjects. The video device also had a 12% intubation failure rate (three of 24), compared with a 25% failure rate (five of 20) for the Macintosh, the researchers reported. Dr. Cordovani attributed the high failure rate in both groups to the

Table. Forces Applied During Video and Direct Laryngoscopya Mac (n=40)

Video (n=40)

P Value

Median peak force (range)

21 N (13-28)

17 N (9-21)

0.03

Average force (range)

11 N (7-15)

6 N (4-8)

<0.001

Impulse force (range)

175 N-sec (127-299)

206 N-sec (115-455)

0.92

N, newtons; N-sec, newton-seconds a

Force measurements were not captured in four instances because of failure of the sensors or software.

April 2013

AnesthesiologyNews.com I 21

CL I N I CA L A N E ST H E S I OL O G Y

lthough some research suggests adding thoracic epidural anesthesia (TEA) to general anesthesia may reduce the risk for some complications, a study presented at Euroanaesthesia 2012 suggested the additional anesthetic may increase some urinary problems postsurgery. During the study, Patrick Y. Wuethrich, MD, and his colleagues randomized 40 patients to receive TEAs consisting of bupivacaine 0.125% or bupivacaine 0.125% with 2 mcg/mL of fentanyl during open renal surgery through lumbotomy. Both groups experienced a significant increase in postvoid residuals—from 15 mL (range 0-95) to 200 mL (0-695; P<0.001) in the bupivacaine group, and from 20 mL (0-90) to 450 mL (70-850; P<0.001) in the bupivacaine/fentanyl group. Moreover, 12 patients were unable to void entirely after surgery. “This is a strong indication for catheterization,” Dr. Wuethrich said.

difficult nature of the patients’ airways. James DuCanto, MD, quality management officer in the Department of Anesthesiology at Aurora St. Luke’s Medical Center in Milwaukee, said the findings would not change his use of video laryngoscopy in patients with difficult airways. However, Dr. DuCanto said, “the longer apnea time with video laryngoscopy during airway management means clinicians should focus on the pre-induction preoxygenation process. Furthermore, in selected cases in which severe difficulty is anticipated, it is important to use a sedative regimen that preserves spontaneous ventilation. “With the latest generation of anesthesia machines, the anesthesiologist should utilize new ventilator modes with pressure support and PEEP [positive end-expiratory pressure],” added Dr. DuCanto, who was not involved in the latest study. “The concurrent use of nasal cannula during pre-oxygenation and during the endoscopy should be strongly considered, as suggested by physicians in emergency medicine and anesthesia.” —David Wild Drs. Cordovani and DuCanto reported no relevant conflicts of interest.

TEA Linked to Problems With Post-op Voiding The researchers did not compare the patients with those undergoing the same surgery without TEA, but patients who do not receive TEA would receive opioids, which also can inhibit proper voiding. “This study showed TEAs may increase urinary residuals, but I have not found this to be a problem in my own practice,” said Ali

Shariat, MD, assistant professor of anesthesiology at Columbia University College of Physicians and Surgeons, in New York City, who did not participate in the research. “I think this complication may be dependent on the technique and management of the epidural, the location of the placement, bolus volume and the infusion rates.”

The researchers noted that the epidural placement covered T4 to T12, “which is a large spread,” Dr. Shariat noted. That may increase the chances of affecting the spinal roots that feed the bladder. “I would say the jury is still out on this problem,” he concluded. —Alison McCook

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22 I AnesthesiologyNews.com

April 2013

C L I N I C A L A N ES T H ES I O LO G Y Table. Transfusion-Related Adverse Reactions Reported to the Transfusion Service Number of Occurrences

Reactions:Components Transfused (N=23,669,000 total components)

Total number of reactions that required any diagnostic or therapeutic intervention

60,110

1:394

Febrile, nonhemolytic transfusion reaction

28,997

1:816

Severe allergic reactions

6,555

1:3,611

Delayed serologic transfusion reaction

2,143

1:11,044

Transfusion-associated circulatory overload (TACO)

1,417

1:16,706

Transfusion-associated dyspnea

1,150

1:20,588

Hypotensive transfusion reaction

1,140

1:20,757

Delayed hemolytic reaction

819

1:28,887

Posttransfusion purpura

493

1:47,993

Transfusion-related acute lung injury (TRALI)

460

1:51,443

Acute hemolysis (due to ABO incompatibility)

1:606,978

Acute hemolysis (due to other causes)

143

1:164,936

Posttransfusion sepsis

1:738,437

Transfusion-associated graft-vs-host disease

—

Reactions that were life-threatening, requiring major medical intervention following the transfusion; eg, vasopressors, blood pressure support, intubation or transfer to the intensive care unit

169

1:139,908

Transfuse continued from page 1 within the profession said that, given the risks associated with blood transfusion, it is time for a “new paradigm.” “There is a long tradition of accepting anemia as a relatively harmless problem that can be easily corrected with transfusion,” said Aryeh Shander, MD, chief of the Departments of Anesthesiology, Critical Care Medicine, Pain Medicine and Hyperbaric Medicine at Englewood Hospital and Medical Center, in Englewood, N.J. “Transfusion for many of us is the default. That has to change.” Studies have shown that anemia in the surgical setting is associated with significant morbidity and mortality, and the PGA panelists saw a clear need to address the condition within this patient population. However, they noted, blood transfusions carry significant risks, and too often these complications are poorly understood by clinicians—and therefore improperly explained to patients. For example, according to session moderator Linda J. Shore-Lesserson, MD, professor of anesthesiology and chief of cardiothoracic anesthesiology at Montefiore Medical Center, in New York City, inflammatory events and infection are among the well-known risks associated with transfusion. But mortality, renal damage and lung dysfunction also may occur—some of which may be the result of the age of the blood being transfused, she said. Although the advent of citrate-phosphate-dextrose-adenine-1 has enabled blood banks to store red blood cells for up to 42 days, Dr. Shore-Lesserson said this “may be too long.” “There is evidence that there is a linear if not geometric increase in the levels of cell lysis and oxidative Advertisement

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Adverse Transfusion Reactions

Source: 2009 National Blood Collection and Utilization Survey Report

injury markers as you store blood for longer periods of time,” Dr. Shore-Lesserson continued. “What is the effect clinically? If there is an effect, it is going to be difficult to measure in prospective, randomized trials. And given that in our country and in our world bloodbanking procedures are really not equipped to limit the blood supply to younger units of blood, I think it’s worth taking the time to really investigate this question further. To say that you need to only transfuse units that are 14 days [old] or younger would be catastrophic [to] our blood supply and may not be worthy of the outcomes we are looking for. However, it is clear that there is morbidity associated with blood transfusion.” Although the risk for infection—including HIV and hepatitis C—associated with transfusion is well understood, the leading cause of transfusion-related mortality in the United States is transfusion-related acute lung injury (TRALI; Table). And TRALI is “underreported and underrecognized,” said Ian J. Welsby, MD, associate professor of anesthesiology and critical care at Duke University Medical Center, in Durham, N.C. Dr. Welsby told the audience at PGA that although mitigation strategies from the American Association of Blood Banks and the National Heart, Lung, and Blood Institute have reduced the incidence of TRALI since the mid-2000s, the complication—like all pulmonary infusion reactions—remains a serious problem. As a result, he said, all clinicians involved in the management of a case that involves a transfusion must report any incident of TRALI and similar complications so that the blood supplier is aware and can take precautions, such as quarantining donor sources, against future episodes.

professor of anesthesiology and health policy, management, and evaluation, at the University of Toronto, Canada, has explored a possible alternative approach: prophylactic transfusion. Dr. Karkouti and his team published a study in Anesthesiology (2012;116:613-621) that found that prophylactic transfusions of red blood cells may reduce anemia and limit the need for additional transfusions. The trial found that anemic patients—those with hemoglobin levels of 10 to 12 g/dL—undergoing cardiac surgery with cardiopulmonary bypass who received prophylactic transfusions one to two days before surgery were less likely to experience perioperative anemia and erythrocyte transfusions (P=0.0002). Dr. Shander said Dr. Karkouti’s study indicates that when it comes to anemia, clinicians are missing an “opportunity to diagnose an underlying disease that carries significant morbidity and mortality before these patients enter the surgical arena.” Studies have found that prophylactic transfusion is used in only 25% to 50% of anemic patients who “could have been treated preemptively prior to elective surgery,” Dr. Shander added. Dr. Shander is president of the Society for the Advancement of Blood Management, which is working with the American Society of Anesthesiologists to develop new criteria for the diagnosis and treatment of anemia in patients undergoing elective surgery and position anesthesiologists as the “gatekeepers” in the management of these patients. “We can debate whether or not the best approach is transfusion or treatment with erythropoiesisstimulating agents, but if the therapy is directed, correct and implemented at the right time it is the safest option for the patient,” Dr. Shander said. “Anemia is a burden that is not well defined, and part of the burden Avoiding Transfusions by … Transfusing is lack of knowledge we have. Transfusion is only one The panelists agreed that the goal for treating treatment among many available. Preoperative detecpatients undergoing elective surgery should be to pre- tion and diagnosis of anemia reduces both the risk of vent transfusion without incurring risk for anemia. transfusion as well as risks of anemia.” Another panelist, Keyvan Karkouti, MD, associate —Brian Dunleavy

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THE INDEPENDENT MONTHLY NEWSPAPER FOR ANESTHESIOLOGISTS AnesthesiologyNews.com • A p r i l 2 0 1 3 • Volume 39 Number 4

Doctor Group Claims Drug Purchasing Organizations Causing Chronic Shortages

see transfuse page 22

see shortage page 16

Gustav Klimt’s Ondines

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3M™ SpotOn™ Temperature Monitoring System from Arizant Healthcare Inc., a 3M company, see pages 24 and 34.

Arrow FlexBlock Echogenic cPNB Catheter from Teleflex, see pages 21 and 38.

NAROPIN® from Fresenius Kabi USA, LLC, see pages 22 and 25.

see breathing page 34

INSIDE

08 | COMMENTARY Meta-headache: How the Boldt scandal complicates studies of fluid treatment.

13 | PAIN MEDICINE Inside the Comprehensive Pain Center of Sarasota.

26 | CLINICAL ANESTHESIOLOGY Improving ICU transfer after heart surgery.

33 | AD LIB Ancient texts trip up would-be diagnosticians.

EDUCATIONAL REVIEW

Regional Anesthesia for Ambulatory Surgery: The Ideal Technique for a Growing Practice see insert at page 20.

CME: PREANESTHETIC ASSESSMENT

Lesson 303: PreAnesthetic Assessment of the Patient with Cirrhosis-Related Pulmonary Complications, see page 28.

24 I AnesthesiologyNews.com

April 2013

C L I N I C A L A N ES T H ES I O LO G Y

Study of Spinal Needles Points to an Edge for One in Cesareans Miami Beach, Fla.—Not all spinal needles are created equal when it comes to delivering successful pain relief in combined spinal-epidural anesthesia for cesarean delivery. Several pointed differences emerged from a randomized study comparing 26-gauge Gertie Marx spinal needles (IMD Inc.) and 25-gauge Pencan spinal needles (B. Braun Medical Inc.).

Investigators found that the Gertie Marx needles successfully punctured the dura, leading to an effective block, in 56 of 65 parturients (88%) compared with 36 of 59 (61%) of those treated using a Pencan needle. This difference was statistically significant (P<0.001). Anesthesiologist Sameet Syed, MD, of University of Medicine and

Dentistry of New Jersey-Robert Wood Johnson University Hospital, in New Brunswick, N.J., and her colleagues launched their study after experiencing some difficulty piercing the dura with 25-gauge Pencan spinal needles for combined spinal-epidural (CSE) anesthesia. “The needle was pushed back by the dura like an arm sling,” Dr. Syed said.

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“When the dura was pushed trying to pierce, it pulled the cauda equina and made patient feel like an electric shock sensation. When the dura could not be pierced, we had to abandon this technique and perform just epidural anesthesia. We looked for a better spinal needle for CSE and found that 5-inch, 26-gauge Gertie Marx needles pierced the dura easily and without paresthesia.” Dr. Syed presented her group’s findings at the 2012 fall meeting of the American Society of Regional Anesthesia and Pain Medicine (abstract 48). The researchers enrolled 124 women in the study. The mean paresthesia rating on a scale of 0 to 10 at the time of needle insertion was 1.4 for women treated with the Gertie Marx needles and 3 in the group who received epidurals with Pencan needles (P=0.02). A significantly lower percentage of women had to be switched to an epidural block in the Gertie Marx group: 12% versus 39%, respectively (P=0.001). Time to anesthesia reaching the T6 level was faster in the Gertie Marx group as well, a mean 2.6 minutes, compared with six minutes in the Pencan group. Similarly, the mean time to incision was shorter in the Gertie Marx group, 24 minutes versus 33 minutes for women in the Pencan group. These differences were statistically significant (P=0.0001 for both). All participants requested neuraxial blockade for their cesarean deliveries. Initially, clinicians used an 18-gauge Espocan epidural needle (B. Braun Medical Inc.) to locate the epidural space at the L4-L5 or L3-L4 interspace. They used a loss of resistance to air midline approach while the women were in the lateral or sitting, flexed position. The women then received an intrathecal injection of 10 mg of isobaric bupivacaine with 25 mcg of fentanyl and 100 mcg of epinephrine in the subarachnoid space through one of the spinal needles. If clinicians encountered difficulty piercing the dura with the Gertie Marx or Pencan spinal needles, they rotated the epidural needle by 45 degrees for each subsequent attempt. If this strategy still did not work, they removed the spinal needle and converted the case to an epidural block. Regardless of success of CSE, they placed a 19-gauge Arrow FlexTip Plus (Teleflex Medical) open-end tip catheter 4 cm in the epidural space for each woman. Melissa E. Bauer, DO, an obstetric

April 2013

AnesthesiologyNews.com I 25

CL I N I CA L A N E ST H E S I OL O G Y

Intracuff Monitoring Could Prevent Overinflation Injuries

ressure from overinflated endotracheal tube cuffs and supraglottic airways has been linked to significant morbidity. But to what extent is overinflation a problem and what are the potential solutions? Researchers at the University of Washington, in Seattle, assessed 290 patients to find some answers. Anesthesiologists Darwin C. Viernes, MD, and Aaron M. Joffe, DO, measured pressures in the airways of patients undergoing general anesthesia—246 with tubes and 44 patients with supraglottic airways—at their institution over a three-month period in early 2012. The intracuff pressure (ICP) readings were recorded using a Compass Lumbar Puncture (Mirador Biomedical) three-way stopcock and 10-cm arterial line-extension tubing. The investigators defined excessive ICP as greater than 30 cm H2O for endotracheal tubes and greater than 60 cm H2O for supraglottic airways. Median ICP values exceeded these cutoffs: 43 cm H2O for ETTs and 90 cm H2O for supraglottic devices. Overall, ICP exceeded the cutoff for 61% of tube measurements, according to the researchers, who presented their findings at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 578). Similarly, supraglottic pressure exceeded the cutoff 68% of the time. Of particular concern, “nearly one out of four endotracheal tubes, 23% in our study, and nearly one out of three supraglottic airways, 30%, were inflated to twice the normal recommendations,” Dr. Viernes told Anesthesiology News. “We were surprised by how frequently these very high measurements occurred.”

anesthesiologist at the University of Michigan Women’s Hospital, in Ann Arbor, called the findings “very interesting,” but noted that the two needles are similar in design. “Further studies to confirm the findings will be needed with standardization of positioning during placement and factoring in the level of training of the resident performing the procedure,” said Dr. Bauer, who was not involved with the study.

Ischemia, tissue damage and other injury to the mucosal lining of airway are possible when inflation pressure exceeds arterial perfusion pressure, he noted. Multiple reasons likely explain the overinflation of tube cuffs and supraglottic devices revealed by the study. “First and foremost, most providers do not use manometry to measure cuff

pressure. Rather, they go by the ‘feel’ of the distension of the pilot tube,” Dr. Viernes said. In other instances, anesthesia techs, operating room nursing staff or other providers are overinflating the cuffs because they are unaware of the risks associated with overinflation, he said. If overinflation is the problem, making manometry standard practice to

see cuff page 27

NAROPIN® was associated with more spontaneous vaginal deliveries and fewer instrumented deliveries than bupivacaine.1-3 A Block Well Done. An 18% higher proportion of spontaneous vaginal deliveries and a 32% lower proportion of instrumented deliveries were observed in patients who received NAROPIN vs bupivacaine (P<0.05; P<0.01).2 To learn more about the clinical beneﬁts of NAROPIN in labor and delivery, visit www.naropin-us.com.

—Damian McNamara

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.

Dr. Syed and her co-authors reported no relevant financial conflicts.

limit cuff inflation pressures could help, Dr. Viernes said. Edward Seet, MD, and his colleagues in the Department of Anesthesia at the University of Toronto, Canada, have tested that strategy. The researchers compared 100 patients with inflation pressures maintained below 44 mm Hg with 100 others who had routine care

1. NAROPIN Prescribing Information. Data on ﬁle. 2. Writer WDR, Stienstra R, Eddleston JM, et al. Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis. Br J Anaesth. 1998;81:713717. 3. Asik I, Göktug A, Gülay I, Alkis N, Uysalel A. Comparison of bupivacaine 0.2% and ropivacaine 0.2% combined with fentanyl for epidural analgesia during labour. Eur J Anaesthesiol. 2002;19:263-270. Naropin® and logo are trademarks of Fresenius Kabi USA, LLC. APP ® and are trademarks of Fresenius Kabi USA, LLC. ©2013, Fresenius Kabi USA, LLC. All Rights Reserved. 0173-NAR-05-4/11

26 I AnesthesiologyNews.com

April 2013

C L I N I C A L A N ES T H ES I O LO G Y

Handoff Checklist Smooths ICU Transfer After Heart Surgery Washington—A structured transferof-care process can prevent complications in cardiac surgical patients, researchers have found. “Complications are common in cardiac surgery patients, and many of these complications may be affected by communication during the operating roomto-ICU transition,” said Michael L. Hall, MD, a fellow in cardiac anesthesiology

at the University of California, Los Angeles, who helped conduct the study. “Monitoring and measuring these complications is critical in outcomesfocused anesthesiology research, as well as for identifying any systems issues that might affect complication rates.” Dr. Hall, then at Oregon Health & Science University, in Portland, and his colleagues introduced a comprehensive,

Naropin

(ropivacaine HCl Injection, USP)

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

multidisciplinary transfer-of-care process involving ICU nurses, operating room nurses, anesthesiologists and surgeons, critical care anesthesiologists, medical intensivists and respiratory therapists. The verbal handover was scripted in the new system, and strict rules regarding the environment in which the handover occurred were enacted.

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.

Fresenius Kabi USA, LLC

0173-NAR-05-4/11

Rev. 11/08

Patient outcomes before and after the intervention were determined using the institution’s anesthesia information management system and an ICU complication registry. “The process consists of scripted signout between team members at several points during the operation,” said Dr. Hall, who presented his findings at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 163). “Specifically, it focuses on teamwork, task allocation and leadership.”

‘Instituting a checklist gives people guidance and improves the handover process. But if people use the checklist just to check things off, it misses the point. There has to be a two-way communication where you present the information if it’s your case and you ask questions if you’re receiving the case.’ —Leif Saager, MD The investigators reviewed three years of data from the institution’s ICU complication registry (N=1,343), comparing the 18 months before implementation (n=632) of the new transfer-of-care process with 18 months after (n=711). Patient demographics were similar, except for slightly younger patients in the postintervention group: 62.3 versus 60.5 years, respectively (P=0.02), according to the researchers. The postintervention group also had a greater number of patients with ventricular assist devices (10 vs. 49; P=0.0001). Preventable complications were predefined from a list of 30 possible adverse events, and included mean arterial pressure (MAP) of less than goal or below 60 for more than an hour, line complications, drug/dosage errors, anaphylaxis/allergic reactions, capillary blood glucose of less than 60 or greater than 250 and iatrogenic pneumothoraces.

April 2013

AnesthesiologyNews.com I 27

Situation

CL I N I CAL ANEST H ES I OLO G Y Anesthesia Provider to Critical Care

Prior to leaving the OR, ask the surgeons if there are intraoperative events o r other issues they think should be communicated in the perioperative report.

Patient name, age, and operation

Background

` Airway: Difficult/Not Difficult Bypass Time:

performed

Preop diagnosis (i.e. the reason for the operation):

taper for COPD, or dialysis dependence ), family, or social issues (alcohol use

Lines: Difficult/Not Difficult

Platelets

CBC

Coags INR PTT Fib

TEE: Other (prosthesis adequate?)

Cellsaver

Cryo

fVIIa (dose)

Immunosuppressants given and immediate plan:

Epi

Norepi

Vaso

Phenylephrine

Dopa

Milrinone

or “totally dry”)

Dobutamine

Nitroglycerin

Nonhemodynamic Infusions: Insulin

Propofol/Dexmedetomidine

Others:

Pacer leads (how many, what chamber?)

Additional Care Issues (“sensitive

Mode

Output (mA)

to pressors/fluids”,”better start dialysis

Say: “This concludes report. My patient The receiving critical care provider The receiving critical care provider

Nicardipine

Nitric Oxide

Pacing: Rhythm

Visibility – regardless of the puncture angle

Last Antibiotic/Muscle Relaxant Doses

post-‐bypass period (i.e. “a lot of oozing”

Hemodynamic Infusions:

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

Post bypass rhythms and treatment (e.g.“defibrillated for VT, amio loaded but drip not started”)

Quantity and quality of bleeding during

PA Hypertension: Yes/No UOP:

TEE:Postop LV FFP

Allergies

SH/ Issues to continuity of care: (example: steroid

Clamp Time:

TEE: Preop LV PRBC

IV Fluids

Assessment

that time from ICU transport to the end of anesthesia did not change (18 minutes before vs. 19 minutes after; P=0.057). “This is important for implementing a new anesthesia-based signout,” he added. Leif Saager, MD, assistant professor of anesthesiology at Cleveland Clinic, in Ohio, acknowledged that patient handover is a hot topic in anesthesiology. “There have been a number of studies looking at handovers between paramedics and emergency room nurses, during shift changes on the ICU or the floor, and between residents during call. They’ve all demonstrated that you lose information,” Dr. Saager said. His own group has found that intraoperative handovers increase the incidence of poor patient outcomes. Although it may be a good idea for care providers to use checklists to guide handovers, Dr. Saager warned against the process becoming a task rather than a dialogue. “Instituting a checklist gives people guidance and improves the handover process,” he explained. “But if people use the checklist just to check things off, it misses the point. There has to be a two-way communication where you present the information if it’s your case and you ask questions if you’re receiving the case.”

Prior to starting report make sure the primary nurse and admitting p rovider are able to give their undivided attention. ICU team, Nursing team and anesthesia team all present and listening to report.

PMH: (diabetes, lung disease, kidney disease):

Recommendation

Team Report

SonoLong – The new revolutionary echogenic catheter kit equipped with “3D Cornerstone” reﬂectors

is now your patient.” “Are t

(PA, NP, or MD) and the receiving

Ventricular Sensitivity

right away”, “wake the patient slowly”) here any questions?”

RN say: “Our patient”.

The investigators found 364 complications during the study period, 166 before and 198 after the intervention. However, the rate of preventable complications dropped significantly, from 5.7% before to 3.1% after the intervention (P=0.019), they reported. The rate of preventable complications within 24 hours also was reduced, from 2.5% to 1.2% (P=0.0392). Length of stay in the hospital did not change after the intervention. “Anaphylaxis and MAP goals showed the greatest reduction, but MAP goal was the only one that was statistically significant on its own,” Dr. Hall said. The researchers also looked at the effect of the intervention on the workflow of anesthesiologists. They found

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

Maximum stability and improved echogenicity – through steel stylet

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

Optimal ﬂow and localization – through central opening and depth graduations

—Michael Vlessides

Cuff continued from page 25 (Anesthesiology 2010;112:652-657). A significantly lower incidence of composite pharyngolaryngeal complications emerged in the manometry group, 13.4%, compared with 45.6% for the patients who received routine care. This translates to a relative risk reduction of nearly 71% using manometry. “There is a definite relationship between the increased cuff pressure and postoperative airway morbidity,” said Lashmi Venkatraghavan, MD, a member of the study team at the University of Toronto. The airway device inflation protocol changed at the institution following the research. “Our standard

practice now is to check the inflation pressures with manometry in all patients with a laryngeal mask airway,” Dr. Venkatraghavan said. But a hurdle to overcome remains before this strategy can become widespread, Dr. Viernes said: cost. “A standard pressure manometer may cost several hundred dollars and, if an institution were to put one in every operating room, the cost would be substantial.”

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

—Damian McNamara Drs. Viernes and Venkatraghavan reported no relevant financial conflicts.

Pioneering medical technology

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Lesson 303: PreAnesthetic Assessment of the Patient With Cirrhosis-Related Pulmonary Complications WRITTEN BY:

LEARNING OBJECTIVES

Erin Brockway, MD Resident Physician Department of Anesthesiology Vanderbilt University School of Medicine Nashville, Tennessee

At the end of this activity, the participant should be able to: 1. Identify the most common etiologies for development of cirrhosis. 2. Outline the mechanisms for increased pulmonary complications associated with advanced liver disease. 3. Identify the 3 biochemical measurements used to determine the Model for End-Stage Liver Disease (MELD) score. 4. List the differential diagnosis for hypoxia in a patient with cirrhosis. 5. Tabulate the pathophysiology of hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). 6. Compare and contrast clinical features of HPS and POPH. 7. Outline diagnostic criteria for POPH. 8. List diagnostic criteria for HPS. 9. Recognize treatment options for HPS and POPH. 10. Prescribe an anesthetic plan for patients with HPS or POPH.

Andrea Westman, MD Resident Physician Department of Anesthesiology Vanderbilt University School of Medicine Nashville, Tennessee

REVIEWED BY: Amy Robertson, MD, MMHC Assistant Professor Department of Anesthesiology Vanderbilt University School of Medicine Nashville, Tennessee

DISCLOSURES The authors and reviewer have nothing to disclose. No funding was received in preparation of the manuscript.

DATE REVIEWED: March 2013

CASE HISTORY

TARGET AUDIENCE: Anesthesiologists NEEDS STATEMENT Patients with advanced liver disease frequently present for surgical procedures. Most anesthesiologists do not know the extent to which cirrhosis and liver-related pulmonary disease may contribute to morbidity and mortality during anesthesia.

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

A 57-year-old man with alcoholic cirrhosis and ongoing gross hematuria presented for transurethral resection of a bladder tumor. Past medical history was significant for hypertension, paroxysmal atrial flutter, chronic obstructive pulmonary disease (COPD), morbid obesity (body mass index 40 kg/m2), obstructive sleep apnea, and previous use of tobacco and alcohol. The patient had been diagnosed with alcoholic cirrhosis several years earlier and exhibited clinical features of portal hypertension. He had a prior hospitalization for hepatic encephalopathy and upper gastrointestinal bleed secondary to esophageal varices. The patient reported a 6-month history of worsening shortness of breath and dyspnea on exertion with severely impaired exercise tolerance. On physical examination, he was mildly dyspneic at rest. Preoperative oxygen saturation was 88% on room air. Blood pressure was 117/64 mm Hg with a heart rate of 66 beats per minute. Cardiac examination was unremarkable. Lung examination revealed expiratory wheezes.

irrhosis is the 12th leading cause of death in the United States, accounting for approximately 32,000 deaths in 2010, with a mortality rate of 10.3 per 100,000.1 Infection with the hepatitis C virus and alcoholic liver disease are the 2 most common causes of cirrhosis. However, with the increase in obesity, the diagnosis of nonalcoholic fatty liver disease also is increasing.2 Patients with cirrhosis are living longer through improved medical and surgical treatments and presenting with increased frequency for surgical interventions. Many of these patients undergo surgery during the last 2 years of life. Perioperative morbidity and mortality should be anticipated as a result of the effects of advanced liver disease on virtually all organ systems. Even patients

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 (BirkhĂ¤user, 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 March 31, 2014. (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 1, 2013 TERMINATION DATE: March 31, 2014 ACCREDITATION STATEMENT The Icahn School of Medicine at Mount Sinai is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT The Icahn School of Medicine at Mount Sinai designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. It is the policy of the Icahn School of Medicine at Mount Sinai to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

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with well-compensated cirrhosis are at greater risk for complications of surgery and exposure to anesthesia. Furthermore, underlying pulmonary disorders inherently carry an increased perioperative risk for exacerbation of lung disease, pneumonia, and respiratory failure requiring prolonged mechanical ventilation. Although liver disease may manifest itself as dysfunction in multiple organ systems, this review focuses on preanesthetic assessment of pulmonary disorders associated with chronic liver disease, with an emphasis on hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH).

Predictive Models and Perioperative Risk Historically, the Child-Turcotte-Pugh (CTP) scoring system was used to predict surgical risk in patients with liver disease. Although the CTP score is clinically useful and simple to calculate, a limitation is its subjective grading of ascites and encephalopathy. The Model for End-Stage Liver Disease (MELD) score was developed to predict 3-month postprocedure mortality in patients undergoing transjugular intrahepatic portosystemic shunt procedures (Figure 1).3 In 2002, the United Network for Organ Sharing subsequently adopted the MELD score to prioritize and fairly allocate donor organs. Using a complex logarithmic formula, the MELD score incorporates 3 objective variables: total bilirubin concentration, serum creatinine, and international normalized ratio (INR).4 The MELD score ranges from 6 to 40, with low scores reflecting early liver disease and higher scores representing severe liver disease. Table 1 compares the clinical components of CTP with MELD scores. The magnitude of perioperative risk depends on several factors including severity of hepatic decompensation and type of surgery. A study of 800 cirrhotic patients undergoing major surgery demonstrated that the MELD score correlated with both short- and long-term

mortality. Thirty-day mortality rates correlated directly with MELD score and ranged from 5.7% (MELD score <8) to more than 50% (MELD score >20).5 In addition, studies have shown that patients with cirrhosis have a greater mortality when undergoing emergency surgery compared with patients without liver disease.2 Morbidity and mortality risks are especially high in patients undergoing cardiac and open abdominal procedures including cholecystectomy, gastric resection, colectomy, and hepatic resection.6 Data suggest that patients with MELD scores below 10 can undergo elective surgery with minimal risk. However, caution should be exercised with elective surgery in patients with MELD scores between 10 and 15. In general, the risks and benefits of elective surgery in patients with MELD scores above 15 should be carefully evaluated, as perioperative morbidity and mortality are greatly increased in this population.2

Pulmonary Conditions Associated With Cirrhosis A variety of pulmonary disorders are encountered in patients with liver disease and portal hypertension (Table 2). Patients with risk factors for liver disease such as alcohol and drug use frequently have a history of tobacco use with concomitant COPD. Emphysema is seen in patients with cirrhosis secondary to Îą-1 antitrypsin deficiency.6 Liver disease can result in altered pulmonary mechanics consistent with restrictive lung disease. A decrease in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), functional residual capacity, and oxygen saturation often is seen in patients with ascites. Hypoalbuminemia from impaired hepatic synthesis of albumin and increased intraabdominal pressure due to ascites predisposes patients to pleural effusions, atelectasis, and pulmonary edema.7 Hepatic hydrothorax, defined as the presence of pleural fluid in a patient with

Clinical Features of Predictive Models Child-Turcotte-Pugh

MELD

Ascites

Bilirubin

Encephalopathy

Serum creatinine

Bilirubin

INR

Albumin INR INR, international normalized ratio; MELD, Model for EndStage Liver Disease

cirrhosis after ruling out cardiac or pulmonary etiology, is seen in approximately 6% to 10% of patients with advanced liver disease.6,8 The risk for aspiration increases when patients demonstrate signs of encephalopathy. Finally, liver disease can disrupt the proper function of intrapulmonary vascular system.

Hepatopulmonary Syndrome HPS is an intrapulmonary vascular disorder associated with liver disease and portal hypertension. The condition is defined as hypoxemia (PaO2 <70 mm Hg or alveolar-arterial [A-a] oxygen gradient >20 mm Hg) and pulmonary vascular dilation in patients with chronic liver disease or portal hypertension.9 HPS is not associated with a specific etiology of chronic liver disease or with the degree of hepatic dysfunction.7,8 The prevalence of HPS is reported as 15% to 30% in patients with cirrhosis undergoing evaluation for liver transplantation.10

Pathophysiology

1.0

0.8

Probability

Table 1. Components of the Child-Turcotte-Pugh Scoring System And Model for End-Stage Liver Disease

0.6

0.4

0.2

0 -10

MELD Score Figure 1. Relation between Model for End-Stage Liver Disease score and 3-month mortality in patients with cirrhosis. MELD, Model for End-Stage Liver Disease Reproduced with permission from reference 3.

HPS is hypoxia caused by dilation of the pulmonary capillary bed in response to vasodilatory substances. Nitric oxide (NO) appears to be the major mediator of pulmonary vasodilation.7,8,10 Pulmonary vascular dilatation leads to shunting of blood from the venous to the arterial circulation by either microscopic or macroscopic shunts. This intrapulmonary shunting ultimately results in ventilation/perfusion (V/Q) mismatch and impaired gas exchange.8 Type 1 HPS is characterized by microscopic diffuse pulmonary vascular dilatation and a decrease in alveolar transit time. The rapid flow of blood through dilated pulmonary capillaries results in failure of red cell oxygenation.9 Type 2 HPS results from macroscopic pulmonary vascular dilatation and formation of arteriovenous (AV) connections leading to discrete shunts that bypass the alveoli.11 Increasing the alveolar oxygen therefore does not improve hypoxia in patients with type 2 HPS.7,9

Clinical Presentation Most patients with HPS exhibit signs and symptoms of chronic liver disease (esophageal varices, ascites, palmar

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Table 2. Common Cirrhosis-Related Pulmonary Conditions Obstructive lung disease COPD Emphysema Restrictive lung disease Ascites Hepatic hydrothorax Pulmonary vascular disorders Hepatopulmonary syndrome Portopulmonary hypertension Parenchymal lung disease Aspiration pneumonitis Pneumonia Pulmonary edema COPD, chronic obstructive pulmonary disease

erythema, splenomegaly). Although most patients with HPS are asymptomatic or report mild dyspnea, clinical features can encompass a spectrum of findings including digital clubbing, cyanosis, and hypoxia.10 Platypnea (dyspnea induced by the upright position and relieved by recumbency) and orthodeoxia (arterial deoxygenation increased in the upright position and relieved by recumbency) are characteristic but not pathognomonic and occur in 25% of patients with HPS.7,8,10 The phenomena are explained by the worsening of diffusionâ&#x20AC;&#x201C;perfusion matching and an increase of the shunt fraction in the upright position because of increased perfusion of the lower lobes.10,12 Telangiectasia is an indicator of systemic and pulmonary vasodilation.7

Morbidity and Mortality The estimated median survival of patients with HPS without liver transplant is 2 years, but shorter for those with a PaO2 below 50 mm Hg. However, death appears to be related more to complications of liver disease or portal hypertension rather than hypoxemic respiratory failure.8

Diagnosis Pulse oximetry is an inexpensive and effective screening tool for HPS and should be performed in both the upright and supine positions. If oxygen saturation is measured only in the supine position, the sensitivity for the detection of HPS is decreased by V/Q mismatch.10 Decreased oxygen saturation on pulse oximetry should be evaluated with arterial blood gases drawn on room air in both supine and standing positions. A PaO2 of less than 80 mm Hg or A-a gradient below 15 mm Hg suggest impaired oxygenation. In patients older than age 65 years, a PaO2 of less than 70 mm Hg or A-a gradient above 20 mm Hg on room air is used as the diagnostic

threshold. An elevated A-a gradient is the most sensitive indicator of impaired oxygenation because it accounts for hyperventilation that is common in patients with liver disease. The right-to-left shunt fraction can be calculated by repeating the test on 100% oxygen.9,12 Contrast echocardiography is the most sensitive test for identifying intrapulmonary shunting. Contrast is administered in the form of agitated saline. In the presence of an intracardiac shunt, microbubbles are seen almost immediately in the left atrium after venous injection of contrast. With intrapulmonary shunting, microbubbles appear 3 or more cardiac cycles after injection, as the agitated saline must first traverse the pulmonary circulation. In general, transesophageal echocardiography is more sensitive than transthoracic echocardiography in demonstrating intrapulmonary shunting. Although contrast echocardiography is a sensitive test for intrapulmonary shunting, it lacks the ability to quantify the degree of the condition. Scans of lung perfusion using technetium-99 macroaggregated albumin (Tc-99m MAA) have proven to be beneficial in the diagnosis. 8 MAA is characteristically trapped in the pulmonary vascular bed. However, dilation of the intrapulmonary vessels seen in HPS allow albumin to pass through the lungs resulting in abnormal uptake in the kidneys and brain. The proportion of radionucleotide taken up by the kidneys and brain can be used to quantify the degree of shunting.7,12 Unlike contrast echocardiography, nuclear scanning cannot differentiate between intracardiac and intrapulmonary shunting. Pulmonary angiography is useful for identifying large AV communications that may be amenable to embolization in patients with type 2 HPS.12 However, it is seldom performed due to the invasive nature of the procedure.

Treatment Currently, no effective medical treatment exists for HPS. Supplemental oxygen is the most frequently recommended therapy. Although oxygen improves symptoms related to hypoxemia, mortality is unchanged. Ideally, HPS could be treated medically by targeting mediators of pulmonary vasodilation. Somatostatin analogs, methylene blue, cyclooxygenase inhibitors, and a diet low in L-arginine have been proposed to decrease the production or action of vasodilators. However, the evidence supporting these treatments is anecdotal.12 The only definitive treatment is surgical. In patients with type 1 HPS, hypoxia responds well to 100% oxygen and orthotopic liver transplantation (OLT) is curative with reversal of clinical features and resolution of preoperative oxygen dependency within several months. 8 Furthermore, normalization of NO levels has been documented post-OLT.10 Conversely, type 2 HPS does not respond to 100% oxygen administration and some experts consider it a contraindication to general anesthesia and transplant surgery.6

Anesthetic Considerations Although studies have found increased perioperative morbidity and mortality in patients with advanced liver disease, minimal data exist regarding the perioperative risk in patients with HPS undergoing elective surgery. Patients with HPS undergoing OLT do

Table 3. Diagnostic Criteria for Portopulmonary Hypertension Clinical findings of portal hypertension and/or liver disease Mean pulmonary artery pressure >25 mm Hg at rest or >30 mm Hg during exercise Pulmonary vascular resistance >240 dyne/s/cm-5 Pulmonary capillary wedge pressure <15 mm Hg

Table 4. Classification of POPH

mPAP (mm Hg)

Mild POPH

Moderate Severe POPH POPH

25-35

36-45

PVR (dyne/s/cm-5) 240-500 500-800

>45 >800

mPAP, mean pulmonary artery pressure; POPH; portopulmonary hypertension; PVR, pulmonary vascular resistance

experience increased morbidity and mortality in the early postoperative period before resolution of the gas exchange abnormalities.13 In cases where general anesthesia is required, clinicians should take care to avoid exacerbation of hypoxemia. Volatile anesthetics and positive pressure ventilation may worsen hypoxemia by inhibiting hypoxic pulmonary vasoconstriction and amplifying the V/Q mismatch, respectively. In order to maximize oxygenation, high concentrations of fractional inspired oxygen and supine or Trendelenburg positions should be maintained. An arterial line is useful for serial monitoring of arterial PaO2. Neuraxial and regional anesthesia should be considered as an alternative to general anesthesia in suitable candidates. However, it is imperative to evaluate coagulation, as patients with advanced liver disease have impaired synthesis of clotting factors and thrombocytopenia due to splenomegaly.

Portopulmonary Hypertension POPH is a condition of increased pulmonary vascular resistance in the setting of portal hypertension.14 In the absence of other causes for pulmonary hypertension, the diagnosis of POPH is based on a variety of criteria (Table 3).7,9,14 POPH often is characterized as mild, moderate, or severe (Table 4).7,12 When the mean pulmonary artery pressure (mPAP) exceeds 50 mm Hg, the condition becomes life-threatening and can lead to more severe hypoxemia and right ventricular failure.6 The development of POPH appears to be independent of the etiology of portal hypertension.12 The reported prevalence of POPH in patients with cirrhosis ranges between 2% and 10%.7,8

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Pathophysiology A wide spectrum of pathology related to POPH is discussed in the literature; however, the exact mechanism remains poorly understood. Vascular changes associated with POPH include intimal proliferation, medial hypertrophy of smooth muscle cells, and fibrosis within small pulmonary arteries.9 In the presence of portal hypertension, autopsy analyses also have confirmed the contribution of microscopic pulmonary artery thromboembolism and platelet aggregates to the development of POPH.15 It is suggested that vascular mediators normally metabolized by a healthy liver are shunted from abnormal mesenteric and hepatic vessels to the pulmonary arterial bed in the setting of portal hypertension. Potential humeral substances include serotonin, interleukin-1, endothelin-1, glucagon, secretin, thromboxane B2, and vasoactive intestinal peptide.7 Finally, because a minority of patients with cirrhosis develop POPH, a proliferative pulmonary vasculopathy may be the result of genetic defect. However, a specific gene has yet to be identified in this population of patients.

Clinical Presentation POPH has an insidious onset with the clinical presentation ranging from asymptomatic to multiple physical findings consistent with right ventricular failure. The most common presenting symptom is dyspnea on exertion.12 Additional nonspecific symptoms include fatigue, palpitations, syncope, or chest pain. On examination, evidence of right-sided heart failure may be detected with evidence of an accentuated pulmonary component of the second heart sound, a murmur consistent with tricuspid regurgitation, jugular venous distension, lower extremity edema, and ascites.7-9

Morbidity and Mortality No direct correlation exists between the severity of liver disease and the severity of POPH. Patients with severe POPH have a poor prognosis. The overall 3- to 5-year survival ranges from 30% to 50%, with death occurring from complications of liver disease or POPH in an equal number of cases.8

Diagnosis In addition to a detailed history and physical examination, evaluation of a patient with cirrhosis and suspected POPH should consist of an electrocardiogram (ECG) and chest radiograph. ECG findings may include right ventricular hypertrophy, right-axis deviation, and right bundle branch block. Chest radiograph demonstrates cardiomyopathy and enlarged pulmonary vasculature.7 Arterial blood gas analyses may reveal decreased PaCO2, increased A-a oxygen gradient, and mild hypoxemia.8,9 Because patients with POPH often are asymptomatic, diagnosis frequently is made during screening for liver transplantation. The recommended screening test is transthoracic echocardiography (TTE).8 TTE findings suggestive of POPH include the presence of tricuspid jet velocity, pulmonic valve insufficiency, right ventricular wall hypertrophy and/or dilation, and an increased estimated right ventricular systolic pressure.9 A diagnosis of POPH must be confirmed with right

Table 5. Comparison of HPS and POPH HPS

POPH

Clinical features

• • • •

• Variable—asymptomatic to signs/symptoms of right ventricular failure • Dyspnea on exertion most common presenting symptom

Diagnosis

• Contrast echocardiography • Pulmonary angiography • Technetium-99 macroaggregated albumin perfusion scan

• Transthoracic echocardiography for screening • Right heart catheterization for confirmation of diagnosis

Treatment

• Supplemental oxygen • OLT curative in type 1 HPS • OLT contraindicated in type 2 HPS

• Supplemental oxygen • Vasodilating medications—bosentan, sildenafil, esoprostenol • OLT for mild to moderate POPH • OLT contraindicated in severe POPH

Dyspnea Hypoxia Orthodeoxia Platypnea

HPS, hepatopulmonary syndrome; OLT, orthotopic liver transplantation; POPH, portopulmonary hypertension

heart catheterization.14 Given that echocardiography cannot estimate pulmonary vascular resistance (PVR), approximately 30% to 40% of patients with an estimated elevation of right ventricular systolic pressure have a finding of normal PVR during right heart catheterization.8 Of note, patients with liver disease have hyperdynamic circulation that leads to increased cardiac output in the setting of low systemic vascular resistance. Approximately 20% of patients with cirrhosis have an increased pulmonary artery pressure but not true POPH. The increase in pulmonary artery pressure is likely due to elevated right ventricular output across a normal PVR. Therefore, it is essential to accurately characterize hemodynamic parameters to avoid misdiagnosis.7,9 Finally, other common causes of pulmonary hypertension must be excluded. Patients with chronic liver dysfunction may have coexisting conditions that could result in pulmonary hypertension, such as left heart disease, valvular heart disease, obstructive lung disease, sleep apnea, and chronic thromboembolism.12

Treatment If hypoxemia is present, supplemental oxygen is initiated. Medication therapy in the form of vasodilators is the mainstay of treatment.7 Bosentan, a competitive antagonist of endothelin-1 at the endothelin-A and endothelin-B receptors, decreases PVR and can be administered orally.12 Sildenafil is a selective inhibitor of phosphodiesterase type 5 and enhances the vasodilatory effects of NO by preventing the degradation of cyclic guanosine monophosphate, which promotes relaxation of vascular smooth muscle and increases blood flow. Epoprostenol, a prostacyclin analog, is a potent dilator of pulmonary vasculature.8 Treatment with epoprostenol entails significant drawbacks, specifically the requirement of permanent central venous access and uninterrupted infusion of the medication.12 Mild to moderate POPH can potentially be reversed after OLT.9,12 However, most experts agree that OLT is contraindicated in patients with severe POPH due to significant perioperative morbidity and mortality.8 Severe POPH not only carries a pulmonary risk, but also can lead

to compromised perfusion of the liver graft. Congestion of the hepatic veins due to decreased right ventricular function carries a substantial risk for primary graft dysfunction.12 Table 5 provides a comparison of HPS and POPH.

Anesthetic Considerations Patients with POPH present a unique challenge for the anesthesiologist. It is important to avoid hypercapnia, hypothermia, and acidosis, as each may worsen pulmonary artery hypertension. A patient with severe POPH may require invasive cardiopulmonary monitoring with a pulmonary artery catheter or TTE. Patients receiving vasodilating agents should remain on these medications during the intraoperative course. Even a brief interruption of a vasodilatory medication (particularly epoprostenol) can result in severe rebound pulmonary hypertension.11 Neuraxial and regional anesthesia should be considered as an alternative to general anesthesia in suitable candidates.

Management of Case Presented After completion of the initial preoperative history and physical examination, further testing was ordered to determine the etiology of the patient’s hypoxia and dyspnea. ECG revealed normal sinus rhythm with left ventricular hypertrophy. Evidence of cardiomegaly was present on a chest radiograph. Pulmonary function tests revealed FEV1 of 51% predicted, FVC of 66% predicted, and an FEV1/FVC ratio of 59%. Arterial blood gas demonstrated hypoxemia, with a PaO2 of 53 mm Hg. A contrast echocardiogram was performed, which confirmed a right to left shunt with delayed appearance of bubbles in the left ventricle (4 to 5 beats after the appearance of bubbles in the right ventricle), suggesting HPS. A right heart catheterization demonstrated severe pulmonary hypertension with an elevated mPAP of 47 mm Hg. Pulmonary vascular resistance was 192 dyne/s/cm -5 and pulmonary capillary wedge pressure was elevated, at 29 mm Hg. Pulmonary angiography performed at the time of the right heart catheterization revealed dilated

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pulmonary arteries without AV malformations. Despite the presence of pulmonary hypertension in the setting of portal hypertension, the patient did not meet the criteria for POPH. Rather, the etiology of pulmonary hypertension was likely multifactorial and resulted from long-standing COPD and obstructive sleep apnea, as well as underlying left heart disease and volume overload. Based on the results of the studies, the patient’s symptoms were medically optimized under the direction of his cardiologist and pulmonologist. He was started on an inhaled long-acting anticholinergic bronchodilator and β-2 agonist with home oxygen therapy and initiation of continuous positive airway pressure. Furosemide was titrated along with the addition of spironolactone for volume overload. On the day of surgery, the patient reported less dyspnea on exertion. His lungs were clear to auscultation bilaterally and oxygen saturation was 94% on 2 L flow through a nasal cannula in the sitting position. Platelet count and INR were 125,000 and 1.3, respectively. In an effort to avoid positive pressure ventilation with

exacerbation of intrapulmonary shunting as well as increased PVR from hypoxia, hypercarbia, and acidosis, the anesthetic plan was spinal anesthesia. Intraoperative and immediate postoperative course was unremarkable. The patient was discharged home later the same day.

References

Huffmyer JL, Nemergut EC. Respiratory dysfunction and pulmonary disease in cirrhosis and other hepatic disorders. Respir Care. 2007;52(8):1030-1036.

Sawant P, Vashishtha C, Nasa M. Management of cardiopulmonary complications of cirrhosis. Int J Hepatol. 2011;2011:280569.

Ramsay MA. Portopulmonary hypertension and hepatopulmonary syndrome, and liver transplantation. Int Anesthesiol Clin. 2006;44(3):69-82.

Murphy SL XJ, Kochanek KD. Deaths: preliminary data for 2010. Natl Vital Stat Rep. 2012;60(4).

10. Machicao VI, Fallon MB. Hepatopulmonary syndrome. Semin Respir Crit Care Med. 2012;33(1):11-16.

Malik SM, Ahmad J. Preoperative risk assessment for patients with liver disease. Med Clin North Am. 2009;93(4):917-929, ix.

11. Keegan MT, Plevak DJ. Preoperative assessment of the patient with liver disease. Am J Gastroenterol. 2005;100(9):2116-2127.

Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl. 2001;7(7):567-580.

Kamath PS, Kim WR. Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797-805.

Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology. 2007;132(4):1261-1269.

Millwala F, Nguyen GC, Thuluvath PJ. Outcomes of patients with cirrhosis undergoing non-hepatic surgery: risk assessment and management. World J Gastroenterol. 2007;13(30):4056-4063.

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.

12. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363(9419):1461-1468. 13. Arguedas MR, Abrams GA, Krowka MJ, Fallon MB. Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology. 2003;37(1):192-197. 14. Sussman NL, Kochar R, Fallon MB. Pulmonary complications in cirrhosis. Curr Opin Organ Transplant. 2011;16(3):281-288. 15. Krowka MJ. Portopulmonary hypertension. Semin Respir Crit Care Med. 2012;33(1):17-25.

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 1.

The 3 biochemical measurements used to determine Model for End-Stage Liver Disease (MELD) score are_____. a. bilirubin, albumin, international normalized ratio (INR) b. bilirubin, INR, platelet count c. bilirubin, serum creatinine, INR d. albumin, serum creatinine, INR

Which of the following is FALSE regarding diagnosis of hepatopulmonary syndrome (HPS)? a. Technetium-99 macroaggregated albumin (Tc-99m MAA) lung perfusion scan can be used to differentiate intrapulmonary from intracardiac shunting. b. Pulmonary angiography is useful for identifying arteriovenous communications in type 2 HPS. c. Transesophageal echocardiogram with contrast is the most sensitive test for intrapulmonary shunt. d. Tc-99m MAA lung perfusion scan can be used to quantify the shunt fraction.

_____ is considered a curative treatment for patients with HPS. a. Supplemental oxygen b. Methylene blue c. Orthotopic liver transplant d. IV epoprostenol

Which of the following statement pertaining to perioperative risk in patients with cirrhosis is FALSE? a. Morbidity and mortality risks are especially high in patients undergoing cardiac and open abdominal procedures. b. The magnitude of perioperative risk depends on the severity of hepatic dysfunction and the type of surgery. c. A MELD score of 25 is associated with a similar perioperative mortality risk compared with a MELD score of 8. d. Patients with cirrhosis have a greater mortality when undergoing emergency surgery compared with those without liver disease.

Which of the following is not a diagnostic criterion for POPH? a. Mean pulmonary artery pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise b. Pulmonary capillary wedge pressure <15 mm Hg c. Pulmonary vascular resistance (PVR) >240 dyne/s/cm-5 d. Alveolar-arterial oxygen gradient >20 mm Hg

Severe POPH is classified as _____. a. mPAP > 45 mm Hg b. PVR 240-500 dyne/s/cm-5 c. PVR 500-800 dyne/s/cm-5 d. mPAP 25-35 mm Hg

Which of the following tests confirms the diagnosis of portopulmonary hypertension (POPH)? a. Transthoracic echocardiography b. Arterial blood gas analyses c. Right heart catheterization d. Pulmonary function testing

The most common presenting symptom of POPH is _____. a. fatigue b. dyspnea on exertion c. chest pain d. syncope

Which of the following statements pertaining to pulmonary physiology associated with chronic liver disease is TRUE? a. A decrease in FVC, FEV1, FRC, and oxygen saturation is seen in patients with ascites. b. Upright position will result in improvement of ventilation/perfusion (V/Q) mismatch in patients with HPS. c. Patients with cirrhosis are NOT at increased risk for aspiration. d. A direct correlation exists between the severity of liver disease and severity of POPH.

10. Which of the following is not an anesthetic consideration for patients with HPS or POPH? a. Neuraxial and regional anesthesia should be considered as an alternative to general anesthesia in suitable candidates. b. Epoprostenol can be stopped safely during the intraoperative period in patients with POPH. c. Positive pressure ventilation may worsen hypoxemia by amplifying the V/Q mismatch in patients with HPS. d. An increase in pulmonary artery hypertension can be seen with hypercapnia, hypothermia, and acidosis.

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Classics Blunders: Ancient Texts Hold Peril For Amateur Diagnosticians

ing, O Muse, of the rage of Achilles, of Peleus’ son, murderous, man-killer, fated to die of massive hemorrhage secondary to an acute laceration of the calcaneal tendon, indicating the likely presence of an inherited coagulopathy such as hemophilia or von Willebrand disease. (Note: The patient’s parentage—half mortal, half immortal—could have predisposed him to yet-undescribed clotting disorders.) Classicists who devote their lives to the analysis of ancient texts such as Homer’s Iliad tend to be skeptical of physician historians who examine these literary works for insight into ancient medical practices—and who, in the process, come up with post hoc diagnoses such as the mockery above. And they’re evidently right to be wary. An anesthesiologist and a pair of classicists have identified numerous errors in the methods and conclusions drawn by several medical ‘Classics like The Iliad are constantly researchers about medicine during the time of The Iliad. The research- evolving as each translator chooses ers, from Wake Forest University, in Winston-Salem, N.C., and Tem- more modern words, terms and ple University, in Philadelphia, pre- concepts based on knowledge sented their findings at the 2012 annual meeting of the Ameri- acquired since the previous can Society of Anesthesiologists (abstract 1320). translations, and this evolution Lead author and anesthesiologist Raymond C. Roy, MD, PhD, has the effect of attributing more said that five of the six articles published from 2000 to 2010 dis- understanding by the ancients cussing medical care in The Iliad fell into common traps. Mistakes than they actually had.’ included incorrect assumptions that Homer was an eyewitness —Raymond C. Roy, MD, PhD reporter of actual events and real injuries, that accurate comparisons could be made by Salazar. Our thesis was that physito modern-day medical care based on limited cians who ‘dabble’ in history, like myself, frequently descriptions, that there was a one-to-one relation- fall into traps that lead classicists to be critical of our ship between ancient Greek and modern English conclusions.” medical terms, that medical care was organized then The epic poem about gods, heroes and heroic as it is now, and that physicians provided care to wounding and death near the end of the war stems wounded heroes during the Trojan War. from an oral tradition. Estimates of when it was composed (1184-675 B.C.) and first recorded Many a Slip Between Lip and Chart (800-675 B.C.) range widely, and there are multiple Dr. Roy said his interest in the subject was stimu- versions of the work. lated by his daughter and her husband, both classiAll accounts of Homer’s life place him cencists at Temple University in Philadelphia. “We have turies after the Trojan War. However, physician engaged in some very interesting discussions over researchers have written: “We are amazed by Homthe coffee and drinks regarding ancient Greek med- er’s meticulous account of the wounds inflicted to icine and current perceptions of it,” he said. “It has combatants” and “it may therefore be inferred that been fun to have this project with my children and Homer was a witness of the war and that he even to be ‘forced’ to read The Iliad … and a monograph participated in it: he may have been one of the

people appointed to nurse wounds of the injured warriors.” Other comments revealed a lack of knowledge about the practice of medicine in the period. Those included a reference to the likelihood that anesthetic procedure was already present in ancient Greece as well as the statement: “Numerous findings indicate that Greek physicians were present on the battlefield.” Dr. Roy and his team point out that there were no field hospitals, and surgical instruments were rarely found at archeological digs of Bronze Age battles. With regard to anesthetics, salves were applied after, not during, an arrowhead extraction. Disease was left untreated because it was believed to be inflicted by the gods, and healing temples appeared after Homer. Healers took orders from heroes and could only treat non-heroes— only heroes had the status to treat other heroes. In fact, the primary function of the healers was to fight. Medical terms that appear in modern translations present added red herrings, Dr. Roy said, “Classics like The Iliad are constantly evolving as each translator chooses more modern words, terms and concepts based on knowledge acquired since the previous translations, and this evolution has the effect of attributing more understanding by the ancients than they actually had.” For example, sinews, tendons, nerves, arteries and veins have all been used in place of the ancient term neuron, he said. The authors conclude that for reasons ranging from national pride to the projecting of modern beliefs and knowledge onto the past, physicians who otherwise are rigorous in their scientific and medical endeavors tend to be naively positive in their analysis of the quality and efficacy of ancient treatments as encountered in classics. Although medical training can aid in the analysis of ancient healing practices, Dr. Roy warned, “Physicians writing historical articles about medicine in ancient times need to collaborate with classicists, archeologists and full-time historians to avoid drawing conclusions that are at odds with facts.” —Jennifer Hanawald

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AD LIB Breathing continued from page 1 Ondine’s curse is this: during sleep, the body forgets to breathe. Ondine was a water nymph who fell in love with a man. It’s dangerous business for a nymph to get involved with a mortal, for if she has a child by him she loses her immortality. This happened to Ondine, who was content with her fate until she discovered her husband sleeping with another woman. Ondine woke her unlucky spouse with her curse: You promised faithfulness with every breath. Let it be done. Should you ever fall asleep again, you shall not breathe. Was ever revenge more poetically correct? Fortunately, permanent ruin of the respiratory center is rare. I don’t have Ondine’s curse, and neither do you, probably, if you’re reading this. On the other hand, I encounter a temporary form of Ondine’s curse every day in surgery, where, as an anesthesiologist, I must routinely interrupt normal breathing in order to make surgery possible. An anesthesiologist, you might say, is the Ondine of the operating room. Let me set the scene. You’re an observer in a modern OR. Even though there are no windows, you know the sun hasn’t yet risen. A middle-aged woman lies awake on the table. A nondescript but intense man in scrubs speaks intimately into her ear. The man isn’t acting as you imagine a surgeon would—he seems oblivious to the surgical paraphernalia in the room. You see the man remove an empty syringe from an injection port and flick the intravenous line with the back of his hand. The woman’s eyes flutter and close. One hand, with which she’d been tapping a sort of rhythm on her thigh, goes limp. Her chest stops rising and falling. One moment the woman was there, and now she’s gone. You’re not sure, exactly, what has just happened. The nurses pay no attention, either to the woman Advertisement

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Henri Fantin-Latour's L'Ondine or the man. Nothing noteworthy here, they seem to say. They go about their business, talking quietly, wheeling trays around, opening packs of instruments. The man lifts a strange, plastic cone off the woman’s face—when did it get there? He pivots and retrieves a bizarre flashlight from an adjacent cart, and begins looking in the woman’s mouth. You notice the gas machine at the man’s side, a cascade of glass columns, porcelain knobs and metal conduits too complex to fathom. The machine makes a rushing sound and the woman’s chest rises and falls. The machine is breathing for her. The man tapes the woman’s eyes closed, picks up the chart, and starts writing. The woman is inert, insensible. Her transformation into surgical tissue has taken less than a minute. It took me many thousands of hours to become the man in that vignette. I’m still becoming him. It’s been said that anesthesiologists are the last clinical generalists. They need, apart from expertise in anesthesia, physiology, anatomy, and pharmacology, a working grasp of most other medical disciplines. Obstetrics, cardiology, pediatrics, radiology, neurology, pulmonology, endocrinology—the list, including the surgical specialties, goes on. All that is true, and a lot of learning it is. But that isn’t the heart of it. The warp and woof of anesthesia is something strange, an essence different from other fields of medicine, the realization of which has come to me slowly over time, obvious only in retrospect. In all other clinical specialties, surgical and medical, the doctor’s object is to prevent illness when possible; if not to prevent, then to cure; if not to cure, then to alleviate. But in anesthesia, the object is to incapacitate. Incapacitate, incapacitated. As in no thought, no awareness, no memory, no response, no movement, no breath. The anesthetist prevents no disorder, cures no affliction, and makes better no illness. His peculiar occupation is to turn a living soul into tissue. I’ve been coming to grips with this strangeness in my profession for many years. I’ve groped for metaphors to express it. My favorite is the night sea journey. It goes like this: I’m a boatman sailing across a body of water, and the patient is my sleeping passenger. It’s night. If we make it to the other side, a change in the patient, a change that involves healing, takes place. But I don’t

directly participate in that. My job is to keep the boat moving. Crossing the dark water poses many dangers: storms and headwinds, rocks and whirlpools, even dragons. When the boat leaks, I undertake repairs. When it veers off course, I must find the way again. None of this is much fun. A lot of it is harrowing. Hours of boredom, moments of panic, as they say. The boatman’s journey is a romantic metaphor I like telling. I think of myself as the custodian of that craft and its precious cargo, sustaining a ritual of healing. But uppermost in my mind is the harrowing part of being a boatman. Of all the dangers in an operating room, the most harrowing involves Ondine’s curse (I mentioned before that the anesthesiologist routinely must interrupt normal breathing). The anesthesiologist therefore routinely faces a harrowing question: what do you do with a body that can’t breathe? The strangeness an anesthetist can experience— the strangeness I experience—comes from this: from being both Ondine’s instrument and antidote; from the need both to steal breath from my patient and then to restore it. This adds a subtle wrinkle to the metaphor of the boatman: the dangers of the journey come not only from outside, but from the boatman himself. In my own case, enacting this little drama has taken a toll over time. To be sure, the journey changes the patient. But it also changes me. Breathing Lessons In the freshman year of my anesthesia residency, I was given a lesson in breathing by a patient whom I’ll call Otto. Anesthesia residencies come replete with breathing lessons, but Otto was also teaching humility that day, a subject absent from the formal anesthesia curriculum. A doctor gets humility not from curricula but from his patients. I acquired a truckload of humility the day I met Otto, and the truck has only gotten larger since. Otto was undergoing a cystoscopy, a look inside the bladder performed by passing a thin viewing scope through the urethra. There is no incision in such a procedure. Generally, you don’t need anything fancy to support a patient’s breathing while giving anesthesia during a cystoscopy. As the patient passes from wakefulness into unconsciousness you can let him continue to breathe for himself. In Otto’s case, I strapped a rubber anesthesia mask over his mouth and nose to make an airtight seal against his skin, and delivered through the mask an appropriate combination of oxygen and anesthetic gas. In principle, what I did was essentially what the Boston dentist, William Thomas Green Morton, had done during the first public demonstration of ether anesthesia in 1846. The modern anesthesia face mask is a hollow cone of rubber or plastic. It’s like the oxygen mask that drops down from above a passenger’s head on an airplane, though it’s more substantially built. The base is malleable and cushioned by a ring of air, a sort of inner tube. The mask is shaped to fit around the nose and mouth; with a bit of pressure, it seals against the see breathing page 36

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AD LIB Breathing continued from page 34 skin. The top of the mask connects to a source of anesthetic vapor and oxygen. Readers of a certain age may remember the TV series, Marcus Welby, M.D., which began each week with Dr. Welby lowering a black anesthesia mask down over the camera lens. In those days, apparently, the family doctor did everything. The anesthesia machine—the “cascade of glass columns, porcelain knobs and metal conduits” I described previously—is the gas delivery system. The machine connects to an oxygen tank and directs the flow of oxygen from the tank through a vaporizer where the oxygen mixes with anesthesia gas. The mixture passes out of the machine through plastic tubing (“anesthesia hose”) that connects to the face mask. The patient breathes the mixture. Gas leaving the anesthesia machine actually flows through the anesthesia tubing in a circle—in fact it’s called the circle system. One limb of the circle travels from the machine to the anesthesia mask, where the patient inhales it. The other limb, carrying exhaled gas, travels from the mask back to the machine, where excess carbon dioxide from the patient is filtered out. The filtered gas is mixed with fresh gas and travels back to the patient.

The same gases, minus the carbon dioxide, keep going round and round. The system is airtight, except for a pop-off valve that relieves excess pressure. Otto was a large man with a thickly muscled neck, but by extending his head I could keep his airway clear, allowing him to continue breathing while the urologist worked. Instead of using an anesthesia mask to deliver my mix of gases, I could have assured Otto’s airway by using an endotracheal tube. This is a long breathing tube (about a centimeter in diameter) inserted through the mouth all the way into the trachea. But getting an endotracheal tube in isn’t always easy, and it’s usually not necessary during a cystoscopy. Most often an anesthesia mask will do. One side effect of anesthesia is the loss of normal muscle tone. This happened to Otto. A few minutes into the case, his flaccid tongue fell back in his throat. His diaphragm continued to contract, but air couldn’t get through to the lungs—his airway was obstructed. Otto was, of course, completely unconscious at this point. Everyone loses some muscle tone during sleep— this is the cause of snoring, and of the more serious condition of sleep apnea. But the loss of tone is even greater under anesthesia, and the anesthetized patient cannot rouse herself to find a better breathing position.

I managed the problem by putting a short plastic tube called an airway into Otto’s mouth. The airway depressed the tongue and cleared a passage for air. It wasn’t as good as an endotracheal tube, which would have extended all the way into Otto’s trachea, but it seemed to do the trick. For the next ten minutes Otto was fine, but then he began to obstruct again. Now his whole mouth seemed to have relaxed backward to cover the breathing passage. Fortunately, the gas delivery system incorporates an ingenious solution to the problem—a reservoir bag. The distensible rubber bag is connected directly into the circuit and fills with the circulating gasses. A gentle squeeze of the bag adds pressure to the system. With one hand, I felt through Otto’s skin for the back end of his jawbone, reached under it and pulled upward with my ring and small fingers. This maneuver lifted the fallen mouth tissue from the back of Otto’s throat. With the remaining fingers and thumb of the same hand, I pushed the mask down hard on Otto’s face to keep the seal airtight. I kept my other hand on the anesthesia bag, squeezing it ever so slightly with every breath Otto took. This added just enough pressure to overcome the resistance and push air in. It’s the same principle see breathing page 38

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Anesthesiologist’s Manual of Surgical Procedures: Fourth Edition

Richard A. Jaffe; Stanley I. Samuels February 1, 2009 Completely updated in full color, this practical 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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Board Stiff TEE: Transesophageal Echocardiography: Expert Consult—Online and Print: Second Edition

Christopher Gallagher; John C. Sciarra; Steven Ginsberg March 29, 2013 This highly effective, enjoyable and affordable medical reference book is not only ideal for those taking the boards, it is also a great overview for anyone looking to stay up to date on this increasingly important monitoring modality.

Evidence-Based Practice of Anesthesiology: Expert Consult—Online and Print: Third Edition

Lee A. Fleisher February 27, 2013 Make informed clinical decisions with reliable, up-to-date guidance from Evidence-Based Practice of Anesthesiology! Leading authority Lee A. Fleisher, MD, expertly explores the full range of important issues in perioperative management, discussing the available options, examining the relevant research and presenting practical recommendations.

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

Admir Hadzic December 7, 2011 The second 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, the book also includes a unique atlas of ultrasound anatomy for regional anesthesia and pain medicine.

Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult—Online and Print

Hugh C. Hemmings Jr., BS, MD, PhD March 1, 2013 Better understand the complexities of pharmacology and physiology relevant to your practice with this medical reference book. Dr. Hugh Hemmings provides the clinical insights you need to effectively administer anesthesia, ensuring patient safety and the most optimal outcomes.

Sonoanatomy for Anaesthetists

Edward Lin December 10, 2012 The accuracy with which clinicians can locate nerves and blood vessels has increased greatly with the development of portable handheld ultrasound scanners, and no specialty has felt the benefit more than anesthesia. This practical atlas of ultrasound anatomy addresses the two main challenges for anyone learning ultrasound-guided techniques: Where do I place the probe? and What exactly am I looking at?

Trauma, An Issue of Anesthesiology Clinics

Yoram G. Weiss April 11, 2013 This issue of Anesthesiology Clinics covers the latest updates in trauma anesthesia written by the world-leading experts on the topic. Procedurally focused articles cover best practices in video-assisted intubation devices, coagulation and hemorrhagic shock, homeostatis control, multiple casualties, massive bleeding and more.

Ward’s Anaesthetic Equipment: Sixth Edition

Andrew J. Davey December 21, 2012 Ward’s is an invaluable resource for qualified anesthetists, as well as essential reading for those in training or approaching examinations. Trainees in intensive care medicine, anesthetic assistants and operating department practitioners also will benefit from this most trusted guide. AN0313

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AD LIB Breathing continued from page 36 used by the CPAP (continuous positive airway pressure) machine to allow the sleep apneac to get a good night’s rest. Again I was ventilating Otto, but it was hard for me to hold the jaw in position. I asked the nurse to call my attending professor, Dr. Jerome. “How much longer?” I asked the surgeon doing the case. “I’ll be done in no time. Ten minutes.” Easy for you to say, I thought. Ten minutes later Dr. Jerome arrived. He looked at me straining to keep air flowing into Otto’s lungs. “How much longer?” Dr. Jerome asked the surgeon. “Ten minutes.” “It’s not worth intubating him just for ten minutes,” Dr. Jerome said to me. “Can you hold out?” My arms were beginning to tire. An endotracheal tube would have been a godsend, but I took Dr. Jerome’s hint. “I think so,” I said. “Good lad,” said Dr. Jerome. “Call if you need me.” Intubating Otto would have involved looking into his mouth with a laryngoscope (a deluxe metal tongue blade with a built-in light bulb) and directly visualizing Otto’s vocal cords. (I’m using the word visualize here in its technical, medical sense: meaning to see.) This is called direct laryngoscopy. Once the vocal cords are in view, it’s possible to pass a semi-rigid plastic tube between the cords into the trachea. The breathing tube (endotracheal tube) secures an open passage for getting air into the lungs. Once the breathing tube is in place, it’s not necessary Advertisement

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to maneuver a patient’s jaw to keep the airway open. The tube keeps the airway open by itself—it is the airway. Some patients are easy to intubate. Some are hard. I suspected Otto was in the latter category. Half an hour later the surgeon still hadn’t finished. I didn’t feel I had the strength to keep the pressure on Otto’s jaw much longer. It seemed pointless to ask the surgeon how much more time he needed. I sent for Dr. Jerome. When he came, my arms were shaking with fatigue. Otto’s airway was barely open now. I stepped aside as Dr. Jerome took over to give me a rest. As his hand encircled the mask, he didn’t like what he felt. He said, “You’re hard pressed to bump ’em off in cysto, but I suppose it can be done.” What Dr. Jerome meant was that losing a relatively healthy patient during a minor urology procedure was a rare mishap, but one we were nearly on the verge of. He wasn’t kidding. By this time I had a very good feel for Otto’s anatomy, and I was sure that intubating him would not be easy. His neck was short and thick and his tongue large. These physical characteristics would conspire to make it difficult for me to see his vocal cords with a laryngoscope. Difficult intubation attempts often cause bleeding at the back of the mouth. If you get the breathing tube in, the bleeding isn’t dangerous. But if you don’t, the blood makes everything worse. A single drop of blood on the vocal cords can cause them to snap shut, completely obstructing the airway. We decided to avoid the intubation attempt. While the surgeon continued to work, Dr. Jerome lifted one side of Otto’s jaw and I lifted the other. Our combined force was barely enough. Finally, the surgeon finished (the initial tenminutes-to-go estimate had been off by an hour and a half ), and I turned off the anesthetic gas. Dr. Jerome and I gradually relaxed the force on the jaw. Otto’s muscle tone returned. Now that he was almost awake, he could support his own airway. I was of two minds when, exhausted and relieved, I left Otto in the recovery room. On the one hand, I knew his difficult airway was a product of his unusual anatomy. It was nobody’s

fault. I hadn’t made an error in judgment. I had done the best I could, which is to say I had muddled through with the help of Dr. Jerome. All’s well that ends well. On the other hand, what would I have done without Dr. Jerome? I had pretty much run out of options and wasn’t sure how I’d manage Otto’s airway if I ever encountered him again as a patient. The words “hard-pressed to bump ’em off in cysto” hung darkly in my mind. Prior to encountering Otto, I’d been pretty confident that I was mastering the techniques of anesthesiology. And I’d also been confident that those techniques, which had evolved over millions of anesthetics, were all I needed to keep anesthetized patients safe. Now I wasn’t quite so sure. I had a thought that was new to me. Perhaps there was an inherent risk to doing anesthesia that simply came with the territory. Perhaps the risk could not be managed away even in the best of hands. Perhaps you could do everything right and still lose a patient. This was the lesson in humility that Otto taught. The next day the surgeon called. He said, “What did you do to my patient? His jaw is killing him, and he says he’s not ever going to have surgery again if he can help it.” Dr. Jerome explained to the surgeon what had happened, and the surgeon explained to Otto, counseling him to let any future anesthesiologist know about the incident. Otto left the hospital in disgust. Other than prescribing painkillers, there was nothing to be done. The sore jaw persisted a week (as did my sore arms). I don’t know whether Otto made good on his threat to avoid surgery, but it didn’t seem a bad idea to me. At the time of this incident, it had been a century and a third since Dr. Morton’s first public anesthetic. Morton had used a clever glass vaporizer to anesthetize his patient, who breathed spontaneously through the operation. When I reflected on my experience, what I had just gone through didn’t appear to be much of an advance in technique. The method I had used now seemed crude to me, and I felt in over my head. Morton, I reckoned, had been lucky that Otto  hadn’t been his patient.

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Regional Anesthesia For Ambulatory Surgery: The Ideal Technique for a Growing Practice

SYLVIA H. WILSON, MD

MARK E. HUDSON, MD, MBA

Assistant Professor Division Chief Regional Anesthesia Pain Service Department of Anesthesia and Perioperative Medicine Medical University of South Carolina Charleston, South Carolina

Associate Professor, Department of Anesthesiology Vice Chair, Clinical Operations University of Pittsburgh School of Medicine University of Pittsburgh Physicians Department of Anesthesiology Pittsburgh, Pennsylvania

CARL REST, MD Clinical Assistant Professor Medical Director, UPMC Shadyside Ambulatory Surgery Center Pittsburgh, Pennsylvania

BEVERLY PEARCE-SMITH, MD Clinical Associate Professor University of Pittsburgh School of Medicine Associate Director Division of Acute Interventional Perioperative Pain Management UPMC-Presbyterian University Hospital Pittsburgh, Pennsylvania

JACQUES E. CHELLY, MD, PHD, MBA Professor of Anesthesiology (with Tenure) and Orthopedic Surgery Vice Chair of Clinical Research Director of the Regional and Orthopedic Fellowships Director of the Division of Acute Interventional Perioperative Pain and Regional Anesthesia Department of Anesthesiology University of Pittsburgh Medical Center Director of Acute Interventional Perioperative Pain UPMC Presbyterian-Shadyside Hospitals Pittsburgh, Pennsylvania The authors report no relevant financial conflicts of interest.

mbulatory surgery is one of the fastest growing segments of surgery,

increasing 67% between 1996 and 2006.a With the development of minimally invasive techniques and changes in reimbursement, many

surgical procedures are shifting from inpatient to ambulatory settings. Proficient ambulatory centers depend on anesthetics that provide quality anesthesia and postoperative analgesia while expediting discharge, minimizing postoperative nausea and vomiting (PONV), and preventing unplanned admission. a

Source: Ambulatory Surgery in the United States, 2006. Centers for Disease Control and Prevention

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Table. Peripheral Nerve Blocks and Associated Surgeries. Regional Technique

Surgery

Notes

Axillary approach to the brachial plexus

Surgery on the hand, forearm and distal two-thirds of the arm

Superficial and compressible location. Different from axillary nerve block.

Femoral nerve block

Knee arthroscopy ACL repair TKA (CPNB)

Increased risk for fall with quadriceps weakness. Superficial and compressible location.

Infraclavicular approach to the brachial plexus

Surgery on the hand, forearm and distal two-thirds of the arm

Deep location more difficult to visualize by ultrasound guidance.

Interscalene approach to the brachial plexus

Shoulder arthroscopy Rotator cuff repair Total shoulder arthroplasty (CPNB)

Common side effects include Horner syndrome, ipsilateral paresis of phrenic and laryngeal nerves. Ulnar sparing.

Lumbar plexus nerve block

Hip arthroscopy THA (CPNB)

Retroperitoneal hematoma is a possible complication.

PVB

Surgery on the chest or abdominal wall

Pneumothorax is a feared complication.

Saphenous nerve block

Knee arthroscopy

Less quadriceps weakness compared with femoral nerve block.

Sciatic nerve block

Lower leg and ankle surgery Combined with femoral nerve block for ACL and TKA surgery

Foot drop with high concentration blocks.

Supraclavicular approach to the brachial plexus

Surgery on the hand, forearm and distal two-thirds of the arm

Superficial location. Pneumothorax is a feared complication. Ulnar sparing reported.

Suprascapular nerve block

Shoulder surgery

Used when interscalene approach to brachial plexus contraindicated. Often combined with axillary nerve block.

TAP block

Surgery on the lower abdomen

TAP blocks have been used on the upper abdomen with a subcostal approach.

ACL, anterior cruciate ligament; CPNB, continuous peripheral nerve block; PVB, paravertebral nerve block; TAP, transversus abdominis plane; THA, total hip arthroplasty; TKA, total knee arthroplasty

Postoperative pain management represents a particular challenge in ambulatory surgery. As many as 40% of patients experience severe pain despite conventional treatment.1 Regional anesthesia (RA) has been shown to improve pain scores, decrease use of narcotics, and lower the incidence of PONV,2,3 allowing more patients to be discharged home in less time with high satisfaction.4 Consequently, RA has increased in popularity for ambulatory surgery as both the primary anesthetic and as an anesthetic adjunct to improve postoperative analgesia.

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General Principles Ambulatory surgery constitutes the ideal milieu to demonstrate the potential benefits of RA for accelerated recovery, prevention of PONV, and perioperative pain control. Although the indication for each form of nerve block depends on the type of surgery, RA may be appropriate for anesthesia, postoperative pain management, or both (Table). Two well-studied benefits of regional techniques in the ambulatory setting are less postoperative nausea due to reduced consumption of opioids and improved postoperative analgesia.3

Whether regional techniques reduce total time in the ambulatory facility is unclear. However, both peripheral and neuraxial nerve blocks have been shown to decrease time spent in the postanesthesia care unit (PACU) and use of PACU resources.3,5 Clinicians must consider several factors when choosing a specific block. These include preferences of the surgeon and patient, the duration of surgery, and the surgical and postoperative requirement for motor examination. For example, an interscalene approach to the brachial plexus is indicated for shoulder surgery because it covers the suprascapular and axillary nerves (Figure 1). However, an interscalene block would not be appropriate for hand surgery because it spares the ulnar nerve. In addition, although discharging patients with residual motor block is not a concern in the United States, doing so generally is not the standard of care in other countries, including many in Europe. All patients should have discharge instructions that include phone numbers to contact should concerns arise regarding their nerve block. Regardless of the regional technique, block location should be above the site of the tourniquet and the surgery. This may assist in causal diagnosis in cases of postoperative nerve injury. If the nerve block is performed above the tourniquet and surgical site, a conduction study may exonerate the block as the cause of injury if the conduction is altered below the site of block insertion and/or at the level of the tourniquet or incision. The location of block performance largely depends on the anesthesiologistâ&#x20AC;&#x2122;s preference and local environment. Variables include operating room (OR) turnover, available resources, and practice conditions (eg, academic vs private practice; supervised vs physician-only anesthesia). Nerve blocks often are performed before transfer to the OR in an academic or supervision practice. Conversely, private practice or high-turnover facilities may perform nerve blocks in the OR while the room is being arranged.

Neuraxial Anesthesia One of the oldest regional techniques, spinal anesthesia remains a reasonable option for urologic, gynecologic, abdominal, and lower extremity surgery. Its rapid onset, minimal expense, and easy administration are key advantages in outpatient procedures. Limitations to spinal anesthetics include pain with regression, urinary retention, and the inability to ambulate resulting from weak lower extremities. Given the accessibility of general anesthesia and peripheral nerve blocks, these limitations may be significant. Local anesthetic (LA) options for outpatient spinals include lidocaine, mepivacaine, chloroprocaine, prilocaine, and low doses of bupivacaine. Short-acting LAs may speed discharge but have some limitations. Hyperbaric lidocaine was the mainstay for shortduration spinal anesthesia for many years. Its use was

Figure 1. Performing an ultrasoundguided interscalene block. abandoned when it was associated with 4 times the rate of transient neurologic symptoms (TNS) compared with other LAs.6 Mepivacaine, an intermediate-acting LA, was thought to be a hopeful alternative to lidocaine. Its use decreased when TNS was associated with concentrated solutions,6 although some studies have not observed TNS with lower-dose mepivacaine spinals. These events led to renewed interest in chloroprocaine spinals, particularly with the availability of a preservative-free formulation. In one study examining volunteers receiving 40 mg of 2% lidocaine or chloroprocaine, sensory block and tolerance of the tourniquet were adequate for 40 minutes, but patients who received chloroprocaine were able to ambulate and void 30 minutes sooner than those given lidocaine.7 Chloroprocaine (40 mg, 2%) produced conditions similar to those seen with 7.5 mg bupivacaine, but patients receiving chloroprocaine were ready for discharge 80 minutes sooner.8 These studies, and a retrospective review,9 indicate the utility of chloroprocaine for short surgical anesthesia, but unanticipated surgical length may increase the risk for conversion to general anesthesia. Longer-acting agents, such as ropivacaine and bupivacaine, continue to provide excellent anesthesia but

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Figure 2. Ultrasound-guided interscalene block.

Figure 3. Axillary block. may delay discharge from the PACU. Decreasing the dose of these anesthetics permits expedited recovery, but at the possible expense of block efficacy.10 Adding intrathecal fentanyl and/or clonidine11,12 to low-dose bupivacaine spinals has been shown to improve block quality and success without prolonging recovery.

Peripheral Nerve Blocks ORTHOPEDIC Patients undergoing ambulatory orthopedic surgery often experience severe pain that is aggravated

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with mobilization.13 Orthopedic surgery is exceptionally suited for RA as peripheral nerve blocks allow for the surgical limb to be anesthetized without affecting other extremities. Depending on the LA used, single-injection blocks may last from 2 to 24 hours, providing surgical anesthesia, postoperative analgesia, or both. Continuous perineural catheters permit prolonged pain control. Optimal pain control improves patient satisfaction and early rehabilitation.14 Safety is always a concern when anesthetizing an extremity in outpatients. Given the sensitive structures in proximity to the brachial plexus, it was theorized that ultrasound guidance would improve safety with block placement. Although motor- and sensory-onset times are improved with ultrasound guidance, increased safety compared with nerve stimulation techniques has not been proven. Patients also will need to care for their insensate limb with discharge to home. Blockade of the brachial plexus requires arm immobilization for the duration of nerve blockade to protect the anesthetized extremity. Patients should be discharged home in a sling or other secure immobilizer and with knowledge of how to care for the insensate limb to prevent injury. Patients undergoing the anesthetization of a lower extremity should receive crutches and be taught how to use them to prevent falls.15 All patients should be given instructions, as well as the phone numbers of their clinicians, should concerns arise regarding their nerve block. The anesthesia plan for outpatient shoulder surgery commonly includes interscalene or suprascapular nerve blocks. The interscalene approach to the brachial plexus covers cervical roots 5 through 7 and often serves as both an anesthetic and analgesic block (Figure 2). Single-injection techniques may last 12 to 24 hours and decrease both pain and time to meet discharge criteria.16 However, interscalene blockade is associated with paresis of the ipsilateral phrenic and laryngeal nerves. As a result, some patients may be inappropriate candidates for this RA option. For this population, a suprascapular nerve block is superior to systemic medications and intra-articular injections but inferior to interscalene nerve blocks.17 Because the majority of the innervation to the shoulder joint arises from the suprascapular and axillary nerves, blockade of the suprascapular nerve will improve analgesia; however, patients will require additional parenteral medications. Other alternatives, such as subacromial and intra-articular LA injections, were popular in the recent past. Yet, these techniques have been nearly abandoned over concerns about the risk for chondrolysis.18 Studies have investigated the feasibility of performing shoulder arthroplasty as an outpatient procedure with ambulatory, interscalene perineural catheters.19,20 Patients in these trials were relatively healthy, motivated individuals and reported minimal pain and opioid requirements.

Supraclavicular, infraclavicular, and axillary approaches to brachial plexus blockade provide excellent anesthesia and analgesia for operations affecting the distal two-thirds of the arm, forearm, and hand. In addition to the surgical procedure, the choice of approach should be decided based on patient factors. For example, an axillary block would not be appropriate on a patient unwilling to move the arm and a supraclavicular approach would be contraindicated in a patient with contralateral recurrent laryngeal or phrenic nerve injury. Interscalene blocks do not anesthetize the nerve root supplying the ulnar nerve (C8, T1), making it an inappropriate option for these surgeries. Once feared due to the increased risk for pneumothorax, the supraclavicular approach has experienced renewed interest with the increasing use of ultrasound. The superficial location and compact arrangement of the brachial plexus in this region result in a short onset time for the block and have led many to call the supraclavicular block the â&#x20AC;&#x153;spinal of the arm.â&#x20AC;? However, ulnar nerve sparing has been reported with this procedure. The infraclavicular approach also is reliable and has an onset time comparable to that for supraclavicular blockade.21 The deeper location of the brachial plexus cords with the infraclavicular approach may make ultrasound visualization more difficult than the supraclavicular and axillary methods for practitioners less experienced with ultrasonography or in more obese patients. The axillary approach was preferred for many years given its distance from the lungs (Figure 3). It continues to be a common technique with similar onset times to supra- and infraclavicular blockade.21 Placement of an axillary block may require more time because musculocutaneous, median, radial, and ulnar nerves all must be anesthetized, and the musculocutaneous nerve in particular is usually not near the axillary artery. However, the extremely superficial location in a compressible area makes this approach particularly appealing if anticoagulation is a concern. Arthroscopic knee procedures, including repair of the anterior cruciate ligament, routinely are performed as outpatient surgeries. Compared with administration of intra-articular or IV opioids, femoral nerve blockade to anesthetize the anterior knee improves postoperative pain and early mobilization while reducing side effects from narcotics.22,23 Once the mainstay for arthroscopic analgesia, intra-articular injection is declining as a result of animal studies and case reports showing chondrotoxicity.18 Because falling is a concern in outpatients with lower extremity nerve blockade, saphenous nerve blocks have experienced increased popularity (Figure 4). Saphenous blockade improves analgesia with rest and movement after knee arthroscopy but without increased quadriceps weakness.24 Saphenous nerve blocks also often

Figure 4. Saphenous block.

Figure 5. Politeal block. are combined with a sciatic nerve block for medial leg or ankle anesthesia in surgery on the lower leg. Surgical procedures of the foot and ankle may be associated with pain that is difficult to control. Sciatic nerve blockade decreases opioid consumption and postoperative pain while improving patient satisfaction and facilitating discharge.25 Although clinicians anesthetize the sciatic nerve via several routes, the popliteal fossa is amenable to both single injections and catheter placement (Figure 5).

JOINT REPLACEMENT An estimated 3.5 million joint replacements will be performed by 2030 in the United States, representing an increase of nearly 700% over the current figure. In the past 10 years, the development of minimally

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Figure 6. Ultrasound-guided paravertebral block using a sagittal approach. invasive techniques, the creation of specific anesthesia protocols, and improved postoperative pain control with RA and multimodal analgesia have helped shorten hospital stays from 5 to 7 days to 1 to 2 days, and sameday surgery is even possible in some cases.26-28 However, many institutions have been hesitant to allow joint replacements as ambulatory procedures because of the lack of an approved billing code. Most insurers, including Medicare, require patients to spend at least 1 night in the hospital for reimbursement, and some states have created significant penalties for discharging patients before postoperative day 5. Patients considered for ambulatory total joint replacement must meet certain preoperative requirements. The hospital environment also must be suited for the procedure, and hospital staff must educate patients and families on proper preoperative surgical preparation as well as provide postoperative tools and education before surgery. Patient selection is critical. Patients should be in optimal preoperative physical condition, as myocardial infarction and pulmonary embolism are still postoperative risks. Intraoperatively, anesthesia technique is chosen based on the preferences of the surgeon, anesthesiologist, and patient. General, epidural, and spinal anesthesia have been used with success. Irrespective of the

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technique, patients must be able to recover quickly from anesthesia, remain hemodynamically and thermodynamically stable, and not experience PONV. To allow proper recovery, the duration of surgery should be relatively shortâ&#x20AC;&#x201D;less than 1 hourâ&#x20AC;&#x201D;with minimum blood loss in order to avoid postoperative transfusions. Finally, physical therapists capable of assisting in functional recovery must be well trained and available within hours following surgery. Effective postoperative pain protocols are essential to enable early mobilization. Most of these protocols are based on the use of RA techniques: continuous femoral perineural catheters, with or without a sciatic block, for total knee arthroplasty (TKA), and lumbar plexus for total hip arthroplasty.4,26,27 In all cases, preservation of motor function is essential to permit full weight-bearing physical therapy, independent ambulation with crutches or a walker, and practice walking up and down steps. Mobility is best achieved with low concentrations of LAs, without additives. For example, in patients undergoing TKA, a femoral catheter initially may be bolused with 20 mL of 0.2% ropivacaine before surgery and an infusion of 0.1% ropivacaine or 0.0625% of bupivacaine started postoperatively. A gluteal sciatic catheter also may be placed preoperatively without LA bolus to allow surgeons to diagnose any nerve injury related to surgery. Postoperatively, the catheter may be bolused (5 mL) with 0.05% ropivacaine or 0.03% bupivacaine, followed by an infusion (3-5 mL per hour). These low concentrations of LA will permit physical therapy while providing patients with adequate analgesia. Regardless which surgical, intraoperative anesthetic and postoperative analgesia technique, the same considerations required for successful ambulatory procedures are pertinent here: Avoid PONV, improve alertness, and optimize motor function. Clinician attention to these factors allows the patient undergoing ambulatory joint replacement to undergo active physical therapy within hours after surgery and facilitate recovery.

GENERAL SURGERY Pain control after general surgery can be difficult, and inadequate analgesia can result in unplanned admission. Subcutaneous infiltration of LA may ameliorate postoperative pain but is limited by a brief duration of action. Therefore, regional techniques to anesthetize the thorax and abdomen that are amenable to discharge to home have become prevalent. Breast surgery is associated with high rates of acute and chronic pain. Although paravertebral nerve blocks (PVBs) often are used to control pain following mastectomy, they also provide effective analgesia for lumpectomy, wide local excision, and breast reduction and augmentation (Figure 6). PVBs may serve as the

primary anesthetic with sedation or in conjunction with general anesthesia. They provide superior pain control to surgical LA infiltration and reduce analgesic requirements.29,30 PVBs also may inhibit the stress response to surgery. This may limit immune suppression and reduce the risk for cancer recurrence.31 However, PVBs may be complicated by pneumothoraces. Ultrasound-guided PVBs may be preferable to landmark techniques to prevent this complication, but this benefit has not been conclusively demonstrated. Although inguinal herniorrhaphy is a common outpatient procedure, more than 60% of patients rate their postoperative pain as moderate to severe.13 As with breast surgeries, PVBs can provide excellent surgical anesthesia or postoperative analgesia for umbilical and inguinal hernia repairs. PVB is associated with reductions in pain, opioid consumption, and nausea, with earlier micturition and ambulation than general anesthesia with infiltration of LA.32,33 Transversus abdominis plane (TAP) blocks are another alternative for postoperative analgesia following abdominal surgery (Figure 7).34 Insertion of LA between the internal oblique and transversus abdominis muscles results in analgesia of T10-L2 dermatomes and the ilioinguinal and iliohypogastric nerves. TAP blocks, like PVBs, provide prolonged postoperative analgesia with decreased use of parenteral analgesics,35 but they are simpler to place and are not associated with pneumothoraces.

LAPAROSCOPIC

AND

Figure 7. Transversus abdominis plane block.

MINIMALLY INVASIVE SURGERY

The growth of minimally invasive surgery has triggered a surge in the variety of ambulatory procedures. Although minimally invasive techniques are associated with less pain than open procedures, inadequate pain control remains the most common cause for postoperative admission. Laparoscopic cholecystectomies, which produce somatic incisional pain, discomfort in abdominal viscera, and referred shoulder pain, are among the more painful of such surgeries. Whereas periportal and intraperitoneal infiltration of LAs provide shortduration (2-4 hours) analgesia,36 PVBs and TAP blocks improve analgesia and decrease opiate consumption up to 24 hours postoperatively (Figure 8).37 Similar findings also have been noted in gynecologic laparoscopic surgery and urologic procedures such as lithotripsy.38,39 A subcostal TAP block may be warranted if port sites are above the umbilicus. Preoperative LA application is superior analgesia to postoperative placement in all situations.

OPHTHALMIC NERVE BLOCKS Before the 1990s, RA for ophthalmic procedures was performed mainly by the operating surgeon as retrobulbar anesthesia (RBA). Due its intraconal injection location, small volumes (2-5 mL) of LA can effectively

Figure 8. Paravertebral block.

provide the anesthesia with akinesia of the globe and extraocular muscles required for an open eye or complex ophthalmic procedure.40 RBA may be considered analogous to spinal anesthesia for the eye. Many major structures are located within the muscular conus and may be injured by inadvertent direct needle penetration. These include the optic nerve with meningeal sheaths; arteries of the orbit; and the autonomic, sensory, and motor innervation of the globe. The risk for direct needle trauma on injection is substantial and complications may include globe perforation, intra-arterial injection (seizures), and inadvertent dural sheath injection (brainstem anesthesia).41

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For less invasive and closed intraocular surgeries (ie, phacoemulsification and anterior vitrectomy), operating times are reduced and ocular manipulations limited. Although anesthesia is needed, complete akinesia may not be required.40 In these situations, peribulbar anesthesia (PBA), low-volume sub-Tenon’s anesthesia or topical anesthesia are options. PBA may be considered analogous to epidural anesthesia for the eye. A large volume (up to 12 mL) of LA is deposited outside the muscular cone and diffuses to the extraconal corpus adiposum of the orbit, including the intraconal space, and the eyelid anesthetizing the orbicularis muscle. Repeated supplementation with additional injections is common, especially if akinesia of the globe is required. Poor operating conditions and lack of block consistency are the main drawbacks to using PBA. Increased needle depth (>25 mm) effectively converts a PBA to an RBA. For a similar anatomic reason, a highly myopic eye (longer globe) is a major risk factor for inadvertent globe perforation. Axial length more than 26 mm is the classic described contraindication to PBA.40 Tenon’s capsule is a fibroelastic layer that surrounds the entire scleral portion of the globe. Sub-Tenon’s or episcleral space is a potential space into which LA solution can be introduced. Two anesthetic techniques are used at this location: blunt cannula and needle injection. Blunt cannula involves operative placement of a cannula during the ocular procedure and usually supplements RBA. Needle injection involves LA placement between the conjunctiva and globe. This enables diffuse spread of the LA around the scleral portion of the globe, achieving dense analgesia of the globe with the low volumes typically used for RBA (2-5 mL). There is a substantially high rate of minor complications with this technique compared with either RBA or PBA.41 Topical anesthesia is the use of LA eye drops placed onto the cornea. It avoids all of the potential hazards of the other needle injection eye blocks and has become very popular for phacoemulsification cataract procedures. Drawbacks include incomplete analgesia, complete motor sparing of the globe and eyelids, and increased procedural pain.

OUTPATIENT PERINEURAL CATHETERS With the trend toward performing more complex ambulatory surgical and orthopedic procedures, continuous peripheral nerve blocks (CPNBs) can be safely adapted to home use. Single-injection nerve blocks (SINBs) can provide effective post-discharge analgesia. However, dense sensory and motor blockade inherent to SINB can lead to limb neglect, pressure injuries, and falls. CPNB can provide effective prolonged analgesia by using dilute, low-volume continuous infusions,4,19,28 which can enable significant cost savings compared with hospitalization for post-procedure CPNB infusions.42

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A major impediment to initiating ambulatory CPNB infusions is the perception among anesthesiologists of a subsequent increased need for frequent patient calls, monitoring, and interventions after normal hours. On the contrary, a retrospective review of more than 600 patients with ambulatory interscalene, popliteal sciatic, and femoral perineural catheters revealed that only 4% required interventions.43 The most common call was a need for a catheter bolus of LA. Only 1% of these interventions occurred after normal duty hours and only one patient was unable to remove the indwelling catheter at home. The 2 most commonly used LAs are bupivacaine and ropivacaine. Both provide adequate analgesia and there are no reports of LA toxicity with prolonged infusions. Common infusion rates in the literature vary from 5 to 12 mL per hour with either 0.2% ropivacaine or 0.125% bupivacaine.43 Simple basal infusion rates provide significant pain relief and opioid reduction,43,25 whereas indications for the use of basal–bolus or bolusonly infusion regimens are less clear. A variety of devices are available for at-home use. Available at all price points, these range from disposable, fixed-rate elastomeric pumps to electronically programmable disposable or returnable models. Although electronic, programmable pumps are more accurate in dispensing preset hourly rates than elastomeric pumps, a significant difference in analgesia or risk for adverse events has not been found for the different devices. Reported complications associated with outpatient CPNBs are rare. Cited infection rates are less than 1%.43,44 Specific infection risk factors include catheter duration of more than 2 days, no antibiotic prophylaxis, catheter insertion site in the axilla or groin, and CPNB pump not filled under sterile conditions.44,45 One case report identified deep, severe cellulitis attributed to a CPNB filled under unsterile conditions.43 Therefore, full sterile precautions should be used when filling pumps. Catheter tunneling has not been shown to prevent infection. Neurologic complications are rare, with pressure injury the most likely etiology.7 Casts, splints, and dressings should be applied with care and checked frequently. Falls are another area of concern and occur despite instructions not to stand on the affected leg.15 LA toxicity has not been reported with low infusion rates of dilute LA.

Management of RA in Ambulatory Surgery The benefits of RA are abundant and clear, but its implementation in ambulatory settings is far from straightforward and requires both agreement and support from anesthesiologists, surgeons, and administrative staff. Acceptance by anesthesiologists unfamiliar with RA may be a challenge. They must be willing either to learn regional techniques or assist with patient care

while a colleague is placing nerve blocks. Clinicians who choose to practice RA require adequate education and ongoing training to master various techniques and associated technology. On the logistical level, anesthesiologists who perform RA must have a pager or call center to handle outpatient concerns. Surgeons must agree with the decision to use RA. They must concur with their patients receiving nerve blocks, and whatever method of RA the anesthesiologist chooses should be appropriate for both the planned surgery and postoperative care. Patient education regarding RA by the surgeon at a preoperative office visit may expedite the preoperative process on the day of surgery. Administration must provide adequate resources. Physicians placing nerve blocks may require certain institutional credentialing or certification. Nerve block equipment and supplies need to be purchased, managed, and maintained. Medical documentation for block placement requires institutional standardization to improve record keeping, coding, and billing of regional techniques. Additionally, coding and billing staff may benefit from further education to ensure appropriate charges and reimbursement. Finally, the surgical facility must be able to accommodate the placement of nerve blocks and patient recovery from the procedures. Communication with OR management is essential to optimize patient scheduling. Earlier patient arrival facilitates RA without impeding OR flow. Nurses should receive training to assist with patient preparation, recovery, and discharge instructions, and scheduling adjustments may be necessary to match patient flow. For example, early patient preparation may demand increased nurse staffing, whereas fewer nurses may be needed for recovery due to shorter stays in the PACU or bypassing of the unit entirely.5 Pharmacy should be equipped to prepare ambulatory pumps and daily medications. Also critical are emergency plans and equipment for block-specific resuscitation, such as Intralipid (Bayer Healthcare), and plans for transport to a facility with cardiopulmonary bypass capability in cases of systemic LA toxicity.

Economic Implications Favorable reimbursement strategies and opportunities to cut costs associated with ambulatory surgery have driven much of the caseload to the outpatient setting. However, economic implications for these associated procedures often are overlooked. Continuous nerve blocks can provide outstanding postoperative analgesia, yet physicians have had an economic

disincentive to provide outpatient nerve blocks since the unbundling in 2009 of perineural catheters from follow-up care. Because follow-up is precluded in the outpatient setting, this unbundling resulted in a 46% decrease in reimbursement for these procedures between 2008 and 2010. Coupled with the extra time cost associated with catheter placement, the result has been a reluctance to perform continuous nerve blocks in the outpatient setting. Although diagnostic methodology prevents hospitals from claiming additional revenue for inpatients, additional revenue for outpatients is available under the Hospital Outpatient Prospective Payment System (HOPPS) for nerve blocks and acute interventional perioperative pain techniques. Medicare uses Ambulatory Pay Classification (APC) codes to reimburse facilities for the technical component of procedures under the HOPPS. The HOPPS APC codes available for outpatients present significant reimbursement opportunities for hospitals and can add significantly to a facilityâ&#x20AC;&#x2122;s profit margin.46 These codes currently bundle the nerve block and the use of ultrasound to perform the procedure. Rate setting by the Centers for Medicare & Medicaid Services relies on accurate documentation of the effort associated with any procedural code. Therefore, although ultrasound is bundled within the APC code for outpatient nerve blocks, it is vital to continue to report the use of ultrasound to maintain appropriate reimbursement for these procedures. Furthermore, future reimbursement models using bundled payments will require accurate accounting of costs and complete documentation of resources, and physician effort.

Future Directions The FDA in 2010 approved a new formulation of bupivacaine formulation (Exparel, Pacira) for wound administration. This new formulation contains bupivacaine in a suspension of multivesicular liposomes (DepoFoam drug delivery system). Infiltration of the drug at the surgical site has been shown to provide more effective analgesia than placebo and results in measurable plasma levels of bupivacaine that persist for 96 hours. A single injection of Exparel has been reported to decrease postsurgical pain and delay the use of opioids for between 48 and 72 hours in patients undergoing bunionectomy or hemorrhoidectomy.47,48 The long-lasting effects may represent an interesting alternative to the continuous infusion into wounds of LAs. The role that this formulation can play in RA, particularly when performing peripheral nerve blocks, remains to be established.

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References 1.

Chung F, Ritchie E, Su J. Postoperative pain in ambulatory surgery. Anesth Analg. 1997;85(4):808-816.

2. Klein SM, Bergh A, Steele SM, et al. Thoracic paravertebral block for breast surgery. Anesth Analg. 2000;90(6):1402-1405. 3. Liu SS, Strodtbeck WM, Richman JM, Wu CL. A comparison of regional versus general anesthesia for ambulatory anesthesia: a meta-analysis of randomized controlled trials. Anesth Analg. 2005;101(6):1634-1642. 4. Mears DC, Mears SC, Chelly JE, et al. THA with a minimally invasive technique, multi-modal anesthesia, and home rehabilitation: factors associated with early discharge? Clin Orthop Relat Res. 2009;467(6):1412-1417. 5. Williams BA. For outpatients, does regional anesthesia truly shorten the hospital stay and how should we define postanesthesia care unit bypass eligibility? Anesthesiology. 2004;101(1):3-6. 6. Zaric D, Pace NL. Transient neurologic symptoms (TNS) following spinal anesthesia with lidocaine versus other local anesthetics. Cochrane Database Syst Rev. 2009(2):CD003006. 7. Kouri ME, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with lidocaine in volunteers. Anesth Analg. 2004;98(1):75-80. 8. Yoos JR, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with small-dose bupivacaine in volunteers. Anesth Analg. 2005;100(2):566-572. 9. Yoos JR, Kopacz DJ. Spinal 2-chloroprocaine for surgery: an initial 10 month experience. Anesth Analg. 2005;100(2):553-558. 10. Ben-David B, Levin H, Solomon E, Admoni H, Vaida S. Spinal bupivacaine in ambulatory surgery: the effect of saline dilution. Anesth Analg. 1996;83(4):716-720. 11. Ben-David B, Solomon E, Levin H, Admoni H, Goldik Z. Intrathecal fentanyl with small-dose dilute bupivacaine: better anesthesia without prolonging recovery. Anesth Analg. 1997;85(3):560-565. 12. van Tuijl I, Giezeman MJ, Braithwaite SA, Hennis PJ, Kalkman CJ, van Klei WA. Intrathecal low-dose hyperbaric bupivacaine-clonidine combination in outpatient knee arthroscopy: a randomized controlled trial. Acta Anaesthesiol Scand. 2008;52(3):343-349. 13. Rawal N, Hylander J, Nydahl PA, Olofsson I, Gupta A. Survey of postoperative analgesia following ambulatory surgery. Acta Anaesthesiol Scand. 1997;41(8):1017-1022. 14. Chelly JE, Ben-David B, Williams BA, Kentor ML. Anesthesia and postoperative analgesia: outcomes following orthopedic surgery. Orthopedics. 2003;26(8 Suppl):s865-s871. 15. Williams BA, Kentor ML, Bottegal MT. The incidence of falls at home in patients with perineural femoral catheters: a retrospective summary of a randomized clinical trial. Anesth Analg. 2007;104(4):1002. 16. Hadzic A, Williams BA, Karaca PE, et al. For outpatient rotator cuff surgery, nerve block anesthesia provides superior same-day recovery over general anesthesia. Anesthesiology. 2005;102(5):1001-1007. 17. Singelyn FJ, Lhotel L, Fabre B. Pain relief after arthroscopic shoulder surgery: a comparison of intraarticular analgesia, suprascapular nerve block, and interscalene brachial plexus block. Anesth Analg. 2004;99(2):589-592.

20. Gallay SH, Lobo JJ, Baker J, et al. Development of a regional model of care for ambulatory total shoulder arthroplasty: a pilot study. Clin Orthop Relat Res. 2008;466:563-572. 21. Tran de QH, Russo G, MuĂąoz L, Zaouter C, Finlayson RJ. A prospective, randomized comparison between ultrasound-guided supraclavicular, infraclavicular, and axillary brachial plexus blocks. Reg Anesth Pain Med. 2009;34(4):366-371. 22. Iskandar H, Benard A, Ruel-Raymond J, Cochard G, Manaud B. Femoral block provides superior analgesia compared with intra-articular ropivacaine after anterior cruciate ligament reconstruction. Reg Anesth Pain Med. 2003;28(1):29-32. 23. Dauri M, Fabbi E, Mariani P, et al. Continuous femoral nerve block provides superior analgesia compared with continuous intraarticular and wound infusion after anterior cruciate ligament reconstruction. Reg Anesth Pain Med. 2009;34(2):95-99. 24. Akkaya T, Ersan O, Ozkan D, et al. Saphenous nerve block is an effective regional technique for post-menisectomy pain. Knee Surg Sports Traumatol Arthrosc. 2008;16(9):855-858. 25. White PF, Issioui T, Skrivanek GD, Early JS, Wakefield C. The use of a continuous popliteal sciatic nerve block after surgery involving the foot and ankle: does it improve the quality of recovery? Anesth Analg. 2003;97(5):1303-1309. 26. Ilfeld BM, Gearen PF, Enneking FK, et al. Total knee arthroplasty as an overnight stay procedure using continuous femoral nerve blocks at home: a prospective feasibility study. Anesth Analg. 2006;102(1):87-90. 27. Ilfeld BM, Gearen PF, Enneking FK, et al. Total hip arthroplasty as an overnight-stay procedure using an ambulatory continuous psoas compartment nerve block. Reg Anesth Pain Med. 2006;31(2):113-118. 28. Dervin GF, Madden SM, Crawford-Newton BA, Lane AT, Evans HC. Outpatient unicompartment knee arthroplasty with indwelling femoral nerve catheter. J Arthroplasty. 2012;27(6):1159-1165. 29. Gardiner S, Rudkin G, Cooter R, Field J, Bond M. Paravertebral blockade for day-case breast augmentation: a randomized clinical trial. Anesth Analg. 2012;115(5):1053-1059. 30. Kairaluoma PM, Bachmann MS, Korpinen AK, Rosenberg PH, Pere PJ. Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy. Anesth Analg. 2004;99(6):1837-1843. 31. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha ED, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105(4):660-664. 32. Hadzic A, Kerimoglu B, Loreio D, et al. Paravertebral blocks provide superior same-day recovery over general anesthesia for patients undergoing inguinal hernia repair. Anesth Analg. 2006;102(4):1076-1081. 33. Klein SM, Pietrobon R, Nielsen KC, et al. Paravertebral somatic nerve block compared with peripheral nerve blocks for outpatient inguinal herniorrhaphy. Reg Anesth Pain Med. 2002;27(5):476-480. 34. McDonnell JG, Oâ&#x20AC;&#x2122;Donnell B, Curley G, Heffernan A, Power C, Laffey JG. The analgesic efficacy of transversus abdominis plane block after abdominal surgery: a prospective randomized controlled trial. Anesth Analg. 2007;104(1):193-197.

18. Webb ST, Ghosh S. Intra-articular bupivacaine: potentially chondrotoxic? Br J Anaesth. 2009;102(4):439-441.

35. Sahin L, Sahin M, Gul R, Saricicek V, Isikay N. Ultrasound-guided transversus abdominis plane block in children: A randomised comparison with wound infiltration. Eur J Anaesthesiol. 2013;30:1-6.

19. Ilfeld BM, Wright TW, Enneking FK, et al. Total shoulder arthroplasty as an outpatient procedure using ambulatory perineural local anesthetic infusion. Anesth Analg. 2005;101(5):1319-1322.

36. Boddy AP, Mehta S, Rhodes M. The effect of intraperitoneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis. Anesth Analg. 2006;103(3):682-688.

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37. Naja ZM, El-Rajab M, Ziade F, Al-Tannir M, Itani T. Preoperative vs. postoperative bilateral paravertebral blocks for laparoscopic cholecystectomy: a prospective randomized clinical trial. Pain Pract. 2011;11(6):509-515. 38. De Oliveira GS Jr, Fitzgerald PC, Marcus RJ, Ahmad S, McCarthy RJ. A dose-ranging study of the effect of transversus abdominis block on postoperative quality of recovery and analgesia after outpatient laparoscopy. Anesth Analg. 2011;113(5):1218-1225. 39. Jamieson BD, Mariano ER. Thoracic and lumbar paravertebral blocks for outpatient lithotripsy. J Clin Anesth. 2007;19(2):149-151. 40. Nouvellon E, Cuvillon P, Ripart J. Regional anesthesia and eye surgery. Anesthesiology. 2010;113(5):1236-1242. 41. El-Hindy N, Johnston RL, Jaycock P, et al. The cataract National Dataset Electronic Multi-centre Audit of 55,567 operations: anaesthetic techniques and complications. Eye. 2009;23(1):50-55. 42. Ilfeld BM, Mariano ER, Williams BA, et al. Hospitalization costs of total knee arthroplasty with a continuous femoral nerve block provided only in the hospital versus on an ambulatory basis: a retrospective, case-control, cost-minimization analysis. Reg Anesth Pain Med. 2007;32(1):46-54. 43. Swenson JD, Bay N, Loose E, et al. Outpatient management of continuous peripheral nerve catheters placed using ultrasound

guidance: an experience in 620 patients. Anesth Analg. 2006;103(6):1436-1443. 44. Capdevila X, Jaber S, Pesonen P, et al. Acute neck cellulitis and mediastinitis complicating a continuous interscalene block. Anesth Analg. 2008;107(4):1419-1421. 45. Capdevila X, Bringuier S, Borgeat A. Infectious risk of continuous peripheral nerve blocks. Anesthesiology. 2009;110(1):182-188. 46. Hudson ME, Chelly JE, Williams BA. Economics: projecting costs and revenue for an interventional pain service in the ambulatory setting. Int Anesthesiol Clin. 2011;49(3):68-83. 47. Golf M, Daniels SE, Onel E. A phase 3, randomized, placebocontrolled trial of DepoFoamÂŽ bupivacaine (extended-release bupivacaine local anesthetic) in bunionectomy. Adv Ther. 2011;28(9):776-788. 48. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54(12):1552-1559.

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REPORT Optimizing Patient–Ventilator Interaction: Reducing Patient–Ventilator Asynchrony Part 1 of a 2-Part Series Faculty Sanford Levine, MD

echanical ventilation as patient–ventilator asynchrony Adjunct Professor of Surgery (MV) can be a lifesaving (PVA), occurs in up to 80% of Department of Surgery and procedure for patients with mechanically ventilated patients.1 Pennsylvania Muscle Institute various forms of acute respiPVA may increase the duration of University of Pennsylvania ratory failure.1 Ideally, patient ventilation2-4 and may have deleSchool of Medicine and machine share the venterious effects including patient Philadelphia, Pennsylvania tilatory work, and ventiladiscomfort, lower rates of suctor gas delivery is a perfect cessful weaning, 2,4 increased Catherine S. Sassoon, MD match to patient demand. work of breathing (WOB), and Professor of Medicine In practice, however, the increased need for sedation, University of California, Irvine complex patient–ventilator possibly causing higher mortality Division of Pulmonary and interaction is frequently subrates.1,5 Ventilatory interventions Critical Care Medicine optimal and has been charto promote synchrony may lead VA Long Beach Healthcare System acterized as a “tug of war.” to earlier liberation, which, in Long Beach, California This mismatch between mechanically ventilated patients, a patient’s neural inspirais associated with improved clintory time and the ventilator insufflation time, known ical outcomes and future quality of life.6

Supported by

REPORT

Conventional ventilatory modes with fixed levels of assist (eg, pressure control, pressure support [PS]) cannot respond to changes in patient demand on a breath-bybreath basis and may contribute to asynchrony.7 Although conventional ventilator support is designed to provide some degree of unloading to the respiratory muscle, MV can have the opposite effect if the patient and the ventilator are at odds over conflicting goals—that is, if the respiratory workload is not being shared by the patient’s spontaneous breathing as well as the ventilator’s set parameters.8,9 Ventilator response to patient effort can be greatly influenced by ventilator variables 8 and if these variables are not in harmony, PVA can occur. There is an established association between PVA and duration of MV, although causality of this association has not been determined.2,4,10 Factors associated with PVA include weak inspiratory effort and presence of intrinsic positive end-expiratory pressure (PEEPi), which together may lead to a common major pattern of PVA known as ineffective triggering. High ventilatory demand coupled with ventilator inspiratory time that is too short may lead to double-triggering, another common PVA.4,11,12 Clinically, deeper levels of sedation are associated with ineffective triggering, which results from low maximal respiratory flow, likely due to respiratory center depression. The association between deeper level of sedation and ineffective triggering needs to remind clinicians to titrate sedation to the lowest level and shortest duration, and to discontinue as soon as possible.1,13 An early preliminary study of 30 ventilated patients with acute respiratory failure in an ICU found a 97% prevalence of PVA and established that mortality was higher in patients with an asynchrony index (AI; percentage of monitored breaths that were asynchronous) of 30% compared with those whose failed efforts threshold was lower.1,14

Prevalence, Etiology, and Common Types Of Asynchrony Asynchrony (generally understood to be characterized clinically significant by ≥10% of asynchronous breaths) is common in mechanically ventilated patients—likely more common than originally thought4,15 —and results from multifactorial etiology. Patient characteristics and ventilatory variables have been evaluated in studies with goals of reducing PVA prevalence and clinical consequences.4 PVA triggers range from abnormal pulmonary mechanics (eg, resistance, elastance, respiratory muscle capacity) or underlying disease states to iatrogenic causes (eg, clinician-adjusted ventilator settings, inaccurate measurement of respiratory mechanics).2,16,17 An array of PVA-precipitating factors may originate with the ventilator: method of inspiratory triggering, inspiratory flow delivery, level and mode of ventilator support, and applied PEEP, which increases end-expiratory lung volume and reduces air-space closure at the end of expiration.18 The

number of ventilator techniques available to clinicians adds complexity to decision making, and patient factors must influence the MV strategy. Three main types of asynchrony patterns are recognized and occur at different phases: the beginning of the breath (the triggering phase, which can be affected by the site of triggering), during the breath (flow delivery phase), or at the end of a breath (cycle or termination asynchrony).16 The type of asynchrony, nature and length of observation, and additional factors such as level of sedation influence determination of prevalence.1 Overall a wide range of prevalence has been reported, with the highest risk reserved for patients with chronic obstructive pulmonary disease (COPD).4,19 In the ICU setting, a PVA prevalence ranging from 24% to 98% has been found.4 The most common asynchrony is ineffective triggering (“missed” triggering or wasted effort), in which the patient’s inspiratory efforts fail to trigger the ventilator. Another common asynchrony is double-triggering (breath stacking), in which ventilator inspiratory time is shorter than the patient’s inspiratory time, thus the patient’s effort triggers a second ventilator cycle.4 In a 1997 weaning center study, patients who experienced apparent difficulty weaning from prolonged MV (ie, a period of weeks) were prone to ineffective triggering; 19 of 174 patients (11%) were found, on initial assessment, to have this asynchrony pattern. 2 Compared with peers in the study cohort, the patients with ineffective triggering events were older and sicker and had a higher prevalence of COPD.19,20 Ineffective triggering is common in the early course of MV, adds to the WOB, and is associated with ventilator parameters including high tidal volume (VT), high peak inspiratory pressure, high PS, and high PEEP.2,4,12,17,19 Ineffective triggering also may result from inappropriate ventilator settings (eg, insensitive trigger setting, gas delivery, delayed triggering, cycling off criterion) or the effect of imposed resistance from the artificial airway.1,3,8 Patient-related factors may cause ineffective triggering by 2 distinct pathophysiologic mechanisms: an inability to overcome the effects of PEEPi (dynamic hyperinflation), or a consequence of reduced respiratory drive associated with deeper sedation levels.1,13 Respiratory muscle weakness can play a role in ineffective triggering.1 Several studies have found that most, but not all, patients with ineffective triggering have COPD.2,19 Patients with COPD have considerable PEEPi and dynamic hyperinflation, a finding that may partly explain the disorder’s association with missed triggers. 2,19,21 Excessive VT or pressure may contribute to missed triggers in this population; air trapping or auto-PEEP (ie, gas trapped in alveoli at end expiration) also leads to missed triggers because the patient must overcome the trapped gas pressure to receive a breath.2,22 Double-triggering results from patient respiratory efforts occurring toward the end of ventilator VT delivery, with

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patient inspiratory effort leading to a second triggered breath and VT delivered before complete exhalation of the initial VT.4,23 This asynchrony can be a consequence of low VT and ventilator inspiratory time that is too short.1,11 Less frequently recognized causes are expiratory asynchrony (ie, mismatch between ending mechanical inspiration and patient expiration, a scenario often seen with pressure support ventilation [PSV]) 9 ; periodic breathing, often in the presence of high PSV settings and characterized by a pattern in which the patient drives down carbon dioxide and apnea ensues, followed by a rise of carbon dioxide that stimulates breathing 8 ; flow asynchrony in volume control ventilation (ie, patient demand for flow exceeds set flow, resulting in an increase in WOB) 9 ; and mode asynchrony, resulting from selecting an inappropriate ventilator mode.12 Studies have helped to clarify the incidence, pathophysiology, and consequences of PVA. In one of the first such studies (Thille et al, 2006), ineffective triggering and double-triggering constituted more than 98% of the asynchrony events, and 85% of the asynchronies were ineffective triggering events.4 In this prospective study of 62 ICU patients who required MV for more than 24 hours (median, 4.5 days), an AI of greater than 10% was found in 24% (n=15); the detection method was visual inspection of flow and airway pressure signals.4 This study helped to establish the association between PVA and longer duration of MV. Patients in the 10% or greater AI group had longer median duration of MV (17 vs 7 days; P=0.04) and a relatively higher risk for tracheostomy than those with AI less than 10% (n=47); mortality was similar between the 2 groups.4 The failed efforts threshold—characterized as AI or ineffective triggering index (ITI) —has clinically important implications. An ITI of 10% or greater is an independent predictor of prolonged MV and shorter ventilator-free survival.3 In a pilot study by de Wit et al, 60 patients were evaluated during the first day of MV (mean, 13 hours after intubation). Patients with an ITI of 10% or greater (n=16) had a longer MV duration (10 vs 4 days; P= 0.0004), worse 28-day ventilator-free survival (14 vs 21 days; P=0.03), and longer hospital stay (21 vs 8 days; P=0.03), and ICU stay (8 vs 4 days; P= 0.01). However, there was no increased mortality compared with patients who had an ITI less than 10%.3 The de Wit study is notable in that the asynchronies were detected earlier in the course of MV (ie, during the first 24 hours; mean, 13 hours) compared with previous studies that evaluated patient populations after at least 24 hours of MV.3 Deeper sedation affects patient–ventilator interaction, perhaps via a mechanism of lower maximal respiratory flow likely due to decreased respiratory drive, and is predictive of ineffective triggering.13 In a pilot study by de Wit et al, ineffective triggering was detected in 17 of 20 medical ICU patients and was the most frequent asynchrony (88% of all asynchronous breaths, 9%±12% of breaths).13 Patients were awake during 11 of 35 observations.13 This association

may not be fully appreciated; in practice, clinicians often administer sedation to facilitate MV or as a first-line asynchrony intervention1,24 despite the association of sedation with poor outcomes including PVA, prolonged MV duration, and mortality.5,25,26 Improved patient–ventilator synchrony may reduce the need for sedation.25,26 Noninvasive methods of detection (ie, visual inspection of flow distortion) that can identify ineffective triggering and double-triggering may partly explain their higher known prevalence relative to other patterns of asynchrony. Airflow spectral analysis has sensitivity and specificity of greater than 80% in detecting AI of greater than 10%.10 However, the number of patient-related factors and ventilation variables influencing asynchrony make the recognition of PVA complex and attendant decision making difficult.1 The ability of clinicians to recognize PVA by visual inspection of flow and ventilator pressure (Paw ) tracings is low and only moderately influenced by clinical expertise; in a recent study, ICU physicians detected less than one-third of PVAs and residents had a 16% detection rate. 27 A working knowledge of the asynchrony-associated factors may help physicians and respiratory therapists to minimize patient–ventilator mismatches (Table).4 Once PVA is detected, clinician responses—whether in the form of protocol adherence, sedation, adjustment of ventilator settings, or initiation of weaning—can influence patient outcomes. For example, patients with COPD frequently receive excessive PS, which at more than 12 cmH2O is associated with higher prevalence of asynchronies27 and tracheostomies to facilitate weaning1; however, in multicenter studies, when patients who were assumed to be difficult to wean were allowed to breathe spontaneously for 2 hours, two-thirds were found to be ready for extubation. 20,28

Clinical Challenges in Ventilation Basic mechanisms of the spontaneous and ventilatorassisted breath have been characterized. During controlled ventilation of a passive patient, the necessary pressure generated by the patient’s respiratory muscles (P mus ) is 0 and the necessary pressure is applied by the ventilator (Paw ).29 In assisted ventilator modes, both ventilator and patient provide the required pressure, which in the patient’s case can be highly variable.29,30 Thus, a change in any of the determinants in this pattern must be met by an opposite change in the other if total pressure applied to the respiratory system is to be maintained. In clinical terms, increasing ventilator PS should increase respiratory muscle unloading (decrease Pmus ), at least theoretically (ie, alleviating WOB by providing optimal PS, which in excess can result in air trapping and missed triggers). 2 However, any change in ventilator setting affects several patient mechanisms: direct effect on neural drive 31; worsening of PEEPi, which in turn raises the inspiratory threshold load of triggering the ventilator12; delayed (expiratory)

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Table. Factors To Consider in Determining How Often Patient–Ventilator Asynchrony Occurs Timing of observations Duration of observations Method of detection • Esophageal pressure • Electrical activity of the diaphragm • Waveform analysis Type of asynchrony Definition of “significant” Patient population Type of mechanical ventilation • Invasive vs noninvasive • Pressure or volume targeted • Ventilation mode (conventional vs newer modes) • Triggering method • Cycling method • Degree of ventilator support Additional factors • Sedation

trigger”).9,34 Flow triggering as a result of inspiratory muscle contraction generally is believed to entail a lower WOB, although the difference may be of little clinical relevance.8 In some cases, a mechanical breath may be triggered in the absence of inspiratory effort (auto-triggering) as a consequence of expiratory leaks, water, or noise in the circuit. This type of PVA usually occurs with low respiratory drive and when dynamic hyperinflation is absent8 and suggests a need for careful adjustment of trigger sensitivity.35 The challenges of reducing unnecessary respiratory muscle workload and improving patient comfort through optimal patient–ventilator interaction are particularly evident in the setting of COPD.19,21 In a classic representation of missed triggers in this setting, triggering may be so delayed that the ventilator cycles are almost completely out of synchronization with the patient, defeating the purpose of assisted ventilatory support.8 Ineffective efforts may occur with high PSV and during mechanical inspiration and expiration. The alteration in expiratory flow pattern associated with patient effort becomes insufficient to trigger a breath, and the inspiratory effort is ineffective.12,35 In one such case, reviewed by Kondili et al, the ventilator frequency was 12 breaths per minute compared with that of the patient, 33 inspiratory efforts min-1.8 In patients with COPD, different levels of PSV may result in ineffective triggering unless external PEEP (PEEPe) is applied; applying PEEPe at values slightly lower than PEEPi in ventilated patients with COPD has been shown to decrease ineffective triggering events and reduce WOB. 36,37 However, PEEPi can vary with each breath 38 and because there is no validated approach for determining the optimal level of PEEPe, it may be reasonable to begin at zero end-expiratory pressure and titrate PEEPe upward in 1- to 2-cmH2O increments until ineffective triggering diminishes.29

Clinician Decisions Affect Synchrony From reference 1.

cycling (DC), a secondary increase in inspiratory flow lasting 0.3 sec or more,32 and during noninvasive ventilation, a higher risk for inspiratory leaks (insufflations) at the patientmask interface and gastric air intake, thereby increasing the risk for PVA.33 Ineffective efforts are dependent on the degree of ventilator support,12 and care must be taken to avoid the complications of both insufficient and excessive support.29 Triggering refers to the mechanism by which a patient’s inspiratory effort produces a ventilator response. This is accomplished either through a decrease in ventilator circuit pressure (“pressure trigger”) or of inspiratory flow (“flow

The most common support modes for the gradual withdrawal of patients from ventilation are PSV and synchronized intermittent mandatory ventilation (SIMV). SIMV allows the patient to breathe spontaneously between ventilator-delivered breaths delivered at a low rate in synchrony with spontaneous effort performed by the patient; a gradual decrease in the rate of mechanical breaths accompanies the weaning procedure.28 Early IMV systems had several limitations, including high airway pressure resulting from breath stacking, a consequence of nonsynchronized inspiration between the patient and ventilator. SIMV requires unassisted inspiration by the patient through an endotracheal tube (ETT), a challenging scenario in a spontaneously breathing person and a serious burden in a person with lung injury.39,40 Because the level of work can remain quite high in this mode, PS is routinely provided during spontaneous breathing to alleviate WOB.12,18

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In contrast to SIMV, there is no mandatory (ventilatory) breath during PSV and patients breathe spontaneously, with each inspiration supported by a mechanically driven flow delivered at a preset amount of pressure. PSV allows for a gradual decrease in the level of assistance.41 Weaning during PSV is accomplished by gradually decreasing the perbreath pressure level until the pressure only compensates for the work imposed by the ETT and ventilator demand valve.28,40 PSV has been shown to provide significant benefit compared with SIMV and T-piece (ETT with no ventilator assistance, a method used to gauge readiness for weaning) ventilator strategies.28 The 3 modalities were compared in a randomized trial with mechanically ventilated patients in 3 ICUs (N=109) who met standard weaning criteria. When all causes for weaning failure were considered, a significantly lower number of weaning failures was found with PSV than with the 2 other modes (23% for PSV, 43% for T-piece, 42% for SIMV; P= 0.05).28 Both weaning duration and total time in ICU were shorter with the PSV group than with the SIMV or T-piece groups pooled together (5.7±3.7 vs 9.3±8.2, P<0.05; 17.5±10.2 vs 27.8±18.3, P<0.01, respectively). 28 The relative probability of a patient being weaned from the ventilator was 2.03 times higher with PSV than with SIMV over the 21-day weaning procedure.28 However, in a study by Esteban et al, two-thirds of patients assigned to either a once-daily trial or intermittent trials of spontaneous breathing through a T-piece circuit were extubated after their first trial, and allowed for faster weaning than PSV.42 Proportional-assist ventilation (PAV) has been shown to promote synchrony by providing pressure that is proportional to instantaneous flow and volume. A major obstacle to its widespread use has been the necessity for regular measurement of key parameters of respiratory system mechanics.30 However, monitoring of respiratory mechanics has not been readily available outside of research settings; measurement can be invasive or subject to misinterpretation. When such data are obtained clinically, they can result in inappropriate ventilator response and asynchrony if adjustment is not made for natural changes in breathing rhythm, respiratory drive, and mechanics.16,43 Recent technological advances have made the measurement of these respiratory mechanics much more accurate and easier to obtain. One such advance is PAV+, clinically validated software that continuously and automatically monitors resistance and elastance in real time and, using these values, adjusts flow and volume gain factors in response to the patient’s measured values.44 PAV+ has the capacity to make many adjustments per second. This allows for easier titration of ventilator support according to the patient’s own respiratory mechanics, thus potentially simplifying respiratory care.45 Because PAV has been shown to promote patient–ventilator synchrony, the ability for clinicians to apply it more readily in practice using

PAV+ technology may aid in helping mechanically ventilated patients to achieve earlier liberation. Although PAV+ is becoming more familiar to clinicians as a synchrony-promoting mode for use in weaning,32,45 PSV is a commonly used ventilatory support mode and is administered frequently in the weaning process.42 In physiologic studies, PSV has been shown to reduce the workload on respiratory muscles.28 PSV supplies a constant level of positive airway pressure during spontaneous inspiratory efforts and compared with earlier modalities, was more comfortable for patients.19,35,36 Although inspiratory time is not directly adjustable with PSV, clinicians can use rise time and expiratory sensitivity to adjust pressure-supported breaths. Compared with PSV, the newer PAV mode (ie, PAV+) is closer to physiologic respiration. It delivers assistance in direct proportion to patient effort, thus decreasing WOB and improving comfort.35,46 The array of ventilator modes can pose challenges for clinicians and outcomes can be influenced by the ventilator strategy selected.28 SIMV would be a poor choice in a patient with COPD; similarly, PSV would not be appropriate for a patient with unstable ventilatory drive. Mode asynchrony appears to be common and widely unrecognized with adaptive pressure modes that combine the attributes of volume- and pressure-regulated ventilatory modes and are characterized by an inspiratory pressure limit that varies from one breath to the next. Examples are “dual-control” modes such as AutoFlow, Pressure Regulated Volume Control (PRVC), Volume Support Ventilation (VSV), Adaptive Support Ventilation, and Volume Control+.47 In a randomized crossover study of ICU patients who required MV, Jaber et al evaluated the effect of increased ventilator demand on VSV—which is responsive to VT—by means of continually adjusting PS to achieve a preset VT. VSV resulted in decreased pressure support provided by the ventilator, which was opposite of the desired response and significantly increased WOB as compared with PSV. Investigators concluded that VSV might result in respiratory distress and asynchrony in clinical settings.48 PVA theoretically may result in inspiratory muscle injury. Inspiratory efforts are associated with diaphragm muscle fiber shortening. With ineffective efforts, inspiratory muscle contractions commonly occur during exhalation when the muscle fibers lengthen. This phenomenon is called eccentric or pliometric contractions, which have been reported to cause skeletal muscle injury.49 In addition to PVA, disuse atrophy and injury of diaphragmatic muscle fibers during controlled MV may also contribute to prolonged ventilator dependence.50 Diaphragm muscle atrophy occurs markedly at the level of slowand fast-twitch diaphragm fibers and does so rapidly—after 18 to 69 hours of diaphragm inactivity and MV, resulting in loss of strength; in specimens from brain-dead organ donors obtained prior to organ harvest (N=14), investigators found decreased cross-sectional areas of slow- and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively.51

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Conclusion Recognizing obstacles to patientâ&#x20AC;&#x201C;ventilator synchrony is necessarily complex, as is dealing with these challenges once they are detected. Insufficient ventilatory support or PVA may result in worsening of respiratory mechanics, delayed extubation, and deleterious systemic effects. The

choice of weaning mode remains a major clinical concern. Although PSV has undisputed clinical value, it is associated with relatively higher prevalence of asynchrony than PAV, which when used with PAV+ has been shown to improve PVA and reduce incidence of asynchrony.

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Kondili E, Prinianakis G, Georgopoulos D. Patient-ventilator interaction. Br J Anaesth. 2003;91(1):106-119.

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23. Pohlman M, McCallister K, Schweickert W, et al. Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury. Crit Care Med. 2008;36(11):3019-3023.

10. Navalesi P. On the imperfect synchrony between patient and ventilator. Critical Care. 2011;15(181):1-2. 11. Tokioka H, Tanaka T, Ishizu T, et al. The effect of breath termination criterion on breathing patterns and the work of breathing during pressure support ventilation. Anesth Analg. 2001;92(1):161-165. 12. Leung P, Jubran A, Tobin MJ. Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med. 1997;155(6):1940-1948. 13. de Wit M, Pedram S, Best AM, Epstein SK. Observational study of patient-ventilator asynchrony and relationship to sedation level. J Crit Care. 2009;24(1):74-80. 14. Varon J, Fromm R, Rodart J, Reinoso M. Prevalence of patient ventilator asynchrony in critically ill patients. Chest. 1994;106(2 suppl):141S-144S. 15. Vitacca M, Bianchi L, Zanotti E, et al. Assessment of physiologic variables and subjective comfort under different levels of pressure support ventilation. Chest. 2004;126(3):851-859.

16. Davies J. Advanced patient synchrony and proportional assist ventilation. Essential Practices In Respiratory Care. 2011.

17. Thille AW, Cabello B, Galia F, Lyazidi A, Brochard L. Reduction of patient-ventilator asynchrony by reducing tidal volume during pressure-support ventilation. Intensive Care Med. 2008;34(8):1477-1486. 18. Grossbach I, Chlan L, Tracy M. Overview of mechanical ventilatory support and management of patient- and ventilatorrelated responses. Crit Care Nurse. 2011;31:30-44.

24. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119-141. 25. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114(2):541-548. 26. Kress JP, Pohlman AS, Oâ&#x20AC;&#x2122;Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):14711477. 27. Colombo D, Cammarota G, Alemani M, et al. Efficacy of ventilator waveforms observation in detecting patient-ventilator asynchrony. Crit Care Med. 2011;39(11):2452-2457. 28. Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med. 1994;150(4):896-903.

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29. Jolliet P, Tassaux D. Clinical review: patient-ventilator interaction in chronic obstructive pulmonary disease. Crit Care. 2006;10(6):236.

41. Du HL, Ohtsuji M, Shigeta M, et al. Expiratory asynchrony in proportional assist ventilation. Am J Respir Crit Care Med. 2002;165(7):972-977.

30. Younes M, Webster K, Kun J, Roberts D, Masiowski B. A method for measuring passive elastance during proporational assist ventilation. Am J Respir Crit Care Med. 2001;164(1):50-60.

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32. Hosking B, Harris C, Nikoo M, Priestap F, Bosma K. The incidence of patient-ventilator asynchrony during weaning from mechanical ventilation: a comparison of proportional assist ventilation (PAV) to pressure support (PS). Presented at: 2011 International Conference of the American Thoracic Society; May 13-18, 2011; Denver, CO. 33. Crooke PS, Hotchkiss JR, Marini JJ. Linear and nonlinear mathematical models for noninvasive ventilation. Mathematical and Computer Modeling. 2002;35(11):1297-1313. 34. Yang LY, Huang YC, Macintyre NR. Patient-ventilator synchrony during pressure-targeted versus flow-targeted small tidal volume assisted ventilation. J Crit Care. 2007;22(3):252-257. 35. Thille A, Brochard L. Promoting patient-ventilator synchrony. Clin Pulm Med. 2007;14(6):350-359. 36. Nava S, Bruschi C, Rubini F, Palo A, Iotti G, Braschi A. Respiratory response and inspiratory effort during pressure support ventilation in COPD patients. Intensive Care Med. 1995;21(11):871-879. 37. Georgopoulos D, Giannouli E, Patakas D. Effects of extrinsic positive end-expiratory pressure on mechanically ventilated patients with chronic obstructive pulmonary disease and dynamic hyperinflation. Intensive Care Med. 1993;19(4):197-203. 38. Ghamloush M, O’Connor HH, White AC. Patient-ventilator interaction in the long-term acute-care hospital. Respir Care. 2011;56(2):207-213. 39. Karcz M, Vitkus A, Papadakos PJ, Schwaiberger D, Lachmann B. State-of-the-art mechanical ventilation. J Cardiothorac Vasc Anesth. 2012;26(3):486-506. 40. Brochard L, Rua F, Lorino H, Lemaire F, Harf A. Inspiratory pressure support compensates for the additional work of breathing caused by the endotracheal tube. Anesthesiology. 1991;75(5):739-745.

44. Kondili E, Prinianakis G, Alexopoulou C, Vakouti E, Klimathianaki M, Georgopoulos D. Respiratory load compensation during mechanical ventilation—proportional assist ventilation with load-adjustable gain factors versus pressure support. Intensive Care Med. 2006;32(5):692-699. 45. Xirouchaki N, Kondili E, Vaporidi K, et al. Proportional assist ventilation with load-adjustable gain factors in critically ill patients: comparison with pressure support. Intensive Care Med. 2008;34(11):2026-2034. 46. Grasso S, Puntillo F, Mascia L, et al. Compensation for increase in respiratory workload during mechanical ventilation. Pressure-support versus proportional-assist ventilation. Am J Respir Crit Care Med. 2000;161(3 Pt 1):819-826. 47. Branson RD, Chatburn RL. Should adaptive pressure control modes be utilized for virtually all patients receiving mechanical ventilation? Respir Care. 2007;52(4):478-485, discussion 485-488. 48. Jaber S, Delay JM, Matecki S, Sebbane M, Eledjam JJ, Brochard L. Volume-guaranteed pressure-support ventilation facing acute changes in ventilatory demand. Intensive Care Med. 2005;31(9):1181-1188. 49. Hunter KD, Faulkner JA. Pliometric contraction-induced injury of mouse skeletal muscle: effect of initial length. J Appl Physiol. 1997;82(1):278-283. 50. Jaber S, Petrof BJ, Jung B, et al. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med. 2011;183(3):364-371. 51. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335.

Disclosures: Drs. Levine and Sassoon reported no relevant financial disclosures. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Covidien, 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 © 2013, 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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