0000542-200802000-00005

� EDITORIAL VIEWS

Anesthesiology 2008; 108:181–2 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Full Disclosure

Not Just of Conflict, but Also of Data

THE events of the past 2 yr since the initial controversialpublication by Mangano et al.1 regarding the effect ofaprotinin on renal failure and mortality have been ofgreat interest to the anesthesiology community. In thisissue of ANESTHESIOLOGY, Dietrich et al.2 test the hypothe-sis that any potential nephrotoxic effect of aprotinin(Bayer Healthcare Inc., Toronto, Ontario, Canada) is dosedependent. This hypothesis is rooted in the original arti-cle by Mangano et al., where they reported an increasein risk of the composite renal outcome from 7% to 18%(P � 0.001) comparing low- and high-dose aprotinin.Dietrich et al. were unable to replicate this finding ineither univariate or multivariate analysis (odds ratio,0.98; 95% confidence interval, 0.90–1.07) in an ade-quately powered and statistically robust study, for iden-tical renal outcome measures to those used by Manganoet al. Importantly, three reality checks of the results arereassuring: the overall incidence of the composite out-come in aprotinin-treated patients (8.2%) is similar tothat reported by Mangano et al. (8%); the multivariablemodel reported by Dietrich et al. contains clinicallysensible variables that are in overall concordance withthose reported by Mangano et al.; and finally, analysis ofeach of the effects of aprotinin dose on each of the

individual components of the composite renal outcomevariable shows a lack of effect of aprotinin.

No matter which side of the debate one takes, there islittle doubt that much of the discussion has been fed bylack of information. The report by Mangano et al. wasquestioned for its lack of detail and conflict with priorpublications from the Multicenter Study of PerioperativeIschemia group.3 The furor was further fueled by anotable lapse in judgment by Bayer, when at the US Foodand Drug Administration (FDA) public meeting on apro-tinin on September 21, 2006, Bayer officials failed todisclose preliminary findings of a large observationalcohort being examined by faculty of the Harvard Schoolof Public Health (Boston, Massachusetts), at Bayer’s re-quest, that supported the findings of Mangano et al.*These preliminary findings were later repudiated.†‡

So, we are left with a conundrum. Why do two studies,performed by respected and statistically savvy researchersusing similar surgical populations, show diametrically op-posing results? Subtle but important differences in studydesign and definitions may contribute to this discrepancy.Alternatively, access to the raw data in both data sets couldallow a more complete analysis and perhaps allow one toresolve the discrepancy. One merely has to look at the Website of the National Center for Biotechnology Information§to grasp the ready availability and power of such informa-tion. The penultimate example of the disbursement ofinformation is seen at the National Institutes of HealthDatabase of Genotype and Phenotype,� where the com-plete genotyping of more than 32,000 individuals is avail-able to accredited researchers. Secure methods for datadeposition and distribution that “demonstrate a new com-mitment to shared scientific knowledge that should facili-tate rapid advances” are logistically feasible and impera-tive.4 Quite simply, it is time that journals encourage thepublic availability of source data as a prerequisite for pub-lishing human drug studies.

It is also time that this obligation be extended to thedrug approval process and the data provided by pharma-ceutical companies to the FDA. The FDA does not re-quire full disclosure of all information that comprises aNew Drug Application. It is time that data from everypatient reported to the FDA for a New Drug Applicationshould be made available to the research community.Arguments against such action that invoke proprietaryinformation and patient confidentiality can be counteredby review of which data should be released and by thebenefit of such release to the public. In the heyday ofsupport of faster drug approval seen in the early 1990s,Congress passed the Prescription Drug User Fee Act to

This Editorial View accompanies the following article:Dietrich W, Busley R, Boulesteix A-L: Effects of aprotinindosage on renal function: An analysis of 8,548 cardiac surgicalpatients treated with different dosages of aprotinin. ANESTHE-SIOLOGY 2008; 108:189–98.

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Accepted for publication October 26, 2007. Support was provided solely frominstitutional and/or departmental sources. The author was previously a memberof the Multicenter Study of Perioperative Ischemia and is mentoring a FellowRecipient of a Bayer Award for Blood Conservation Research. The author has alsoreceived research funding from Bayer Diagnostics, now Siemens Diagnostics,Tarrytown, New York.

* Zuckerman Spaeder LLP: Report on Trasylol for Bayer Corporation andBayer AG, 2007. Available at: http://www.bayerhealthcare.com/html/pdf/070816_Bayer_Report.pdf. Accessed October 1, 2007.

† i3 Drug Safety: Final Report: Risks of Renal Failure and Death following Useof Aprotinin or Aminocaproic Acid during CABG Surgery. Part A. Report onComputerized Inpatient Data from the Premier Perspective Comparative Data-base. Waltham, Massachusetts, 2007. Available at: http://www.trasylol.com/Trasylol_09_12_07_AddendumA.pdf and http://www.trasylol.com/Trasylol_09_12_07_AddendumA-2.pdf. Accessed October 1, 2007.

‡ FDA Advisory Committee Briefing Document: Joint Meeting of the Cardio-vascular and Renal Drugs Advisory Committee and the Drug Safety and RiskManagement Advisory Committee. September 12, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4316b1-01-FDA.pdf. AccessedOctober 1, 2007.

§ National Center for Biotechnology Information. Available at: http://www.ncbi.nlm.nih.gov/. Accessed October 1, 2007.

� National Institutes of Health Database of Genotype and Phenotype. Availableat: http://www.ncbi.nlm.nih.gov/sites/entrez?db�gap. Accessed October 1,2007.

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streamline drug approval by increasing FDA fees col-lected from drug companies. During this process, Con-gress barred the FDA from applying user fees to supportefforts in postapproval drug safety monitoring—a pro-found error that was not reversed until 2002. Since then,withdrawal of previously approved drugs, notably valde-coxib, nefazodone, and rofecoxib, and “black box”warnings for rosiglitizone, celecoxib, depot medroxy-progesterone, warfarin, omalizumab, and aprotinin havetypified the FDA’s improved ability to perform postap-proval monitoring of drug safety. Importantly, some ofthese events would not have occurred without sentinelfindings of dedicated researchers working outside theFDA process. The FDA’s improved ability is strengthenedby the congressionally requested report of the Instituteof Medicine calling for increased regulatory power, fund-ing, and independence of the FDA.5 Implementation ofsome of the recommendations are present in the reap-proval of Prescription Drug User Fee Act (S.1082) thatpassed the House and Senate on September 21, 2007,

further enhancing the FDA’s regulatory powers. How-ever, it is time that such powers invoke increased respon-sibility and effort, including public availability of raw data.

Simon C. Body, M.B., Ch.B., M.P.H., Department of Anesthesiology,Perioperative and Pain Medicine, Harvard Medical School, Brigham andWomen’s Hospital, Boston, Massachusetts. [email protected]

References

1. Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin incardiac surgery. N Engl J Med 2006; 354:353–65

2. Dietrich W, Busley R, Boulesteix A-L: Effects of aprotinin dosage on renalfunction: An analysis of 8,548 cardiac surgical patients treated with differentdosages of aprotinin. ANESTHESIOLOGY 2008; 108:189–98

3. Body SC, Mazer CD: Pro: Aprotinin has a good efficacy and safety profilerelative to other alternatives for prevention of bleeding in cardiac surgery. AnesthAnalg 2006; 103:1354–9

4. Manolio TA, Rodriguez LL, Brooks L, Abecasis G, Ballinger D, Daly M,Donnelly P, Faraone SV, Frazer K, Gabriel S, Gejman P, Guttmacher A, Harris EL,Insel T, Kelsoe JR, Lander E, McCowin N, Mailman MD, Nabel E, Ostell J, Pugh E,Sherry S, Sullivan PF, Thompson JF, Warram J, Wholley D, Milos PM, Collins FS:New models of collaboration in genome-wide association studies: The GeneticAssociation Information Network. Nat Genet 2007; 39:1045–51

5. Institutes of Medicine: The Future of Drug Safety: Promoting and Protectingthe Health of the Public, September 9, 2006. Washington, DC, National Acade-mies Press, 2006


Mito-controversies

Mitochondrial Permeability Transition Pore and MyocardialReperfusion Injury

POSTCONDITIONING, repetitive ischemia applied be-fore reperfusion, protects against ischemia–reperfusioninjury.1 Of the therapies proposed for protecting isch-emic myocardium, postconditioning offers a significantclinical advantage; it obviates predicting when someonewill have an ischemic attack. As such, mechanisms in-volved in postconditioning are of significant interest. Inthis issue of ANESTHESIOLOGY, Jang et al.2 demonstrate thatischemic postconditioning in the heart involves activa-tion of �-opioid receptors. Morphine, a mixed opioidagonist, produced postconditioning that was abolishedby a �-opioid receptor antagonist or pharmacologicopening (via atractyloside) of the mitochondrial perme-

ability transition pore (mPTP). The authors showed thatmorphine exposure in isolated cardiac myocytes pro-duced nitric oxide and attenuated hydrogen peroxideoxidant stress–induced loss of the mitochondrial mem-brane potential (��m). The attenuation of ��m producedby morphine was sensitive to �-opioid antagonism, a non-selective nitric oxide synthase inhibitor and an inhibitor ofprotein kinase G. The authors concluded that (1) postcon-ditioning protects the heart by targeting the mPTP viaactivation of �-opioid receptors and (2) the ability of �opioids to activate the nitric oxide–cyclic guanosine mono-phosphate–protein kinase G pathway may account for theeffect of postconditioning on the mPTP. The authors are tobe complimented for their original work regarding a rolefor �-opioid signaling on the mPTP.

Mitochondria, a source of cellular adenosine triphos-phate, are increasingly being implicated in cell survival anddeath signaling. mPTP opening leads to an increase inmitochondrial membrane permeability to small moleculesand plays an integral role in regulating cytoprotection. ThemPTP, a putative high conductance channel on the innermitochondrial membrane, is thought to be the final endeffector in cardiac myocyte protection and therefore animportant therapeutic target for cardiac protective strate-gies.3,4 The molecular composition of the mPTP is contro-versial. The pore putatively is composed of the adenine

This Editorial View accompanies the following article: Jang Y,Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z: Postconditioningprevents reperfusion injury by activating �-opioid receptors.ANESTHESIOLOGY 2008; 108:243–50.

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Accepted for publication November 2, 2007. The authors are not supportedby, nor maintain any financial interest in, any commercial activity that may beassociated with the topic of this article. Supported by American Heart Associa-tion Scientist Development Grant No. 060039N (to Dr. Patel) and American HeartAssociation Scientist Beginning Grant-in-Aid No. 0765076Y (to Dr. Tsutsumi),Dallas, Texas; a Merit Award (to Dr. Roth) from the Department of VeteransAffairs, Washington, D.C.; and grant No. HL081400 (to Dr. Roth) from theNational Institutes of Health, Bethesda, Maryland.

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nucleotide translocase on the inner mitochondrial mem-brane, voltage-dependent anion channel on the outer mem-brane, and cyclophilin D in the mitochondrial matrix.These components exist as individual entities that assembleinto a complex in response to stress to form the mPTP.3 Abenzodiazepine receptor, hexokinase, and creatine kinasealso have been proposed as regulators of the pore. The roleof adenine nucleotide translocase and voltage-dependentanion channel in forming the pore recently has been ques-tioned. The adenine nucleotide translocase may act as aregulator of the mPTP pore, but not as a pore-forming unitof the complex.5 In addition, voltage-dependent anionchannel knockout mice (voltage-dependent anion channels1, 2, 3, 1/3, and 1/2/3) show stress-induced mPTP openingindistinguishable from wild-type mitochondria, questioningwhether the voltage-dependent anion channel is an essen-tial component of the pore.6 Cyclophilin D seems to be theonly essential component of the mPTP described thus far.7

The authors treat the mPTP as one entity, not a multipro-tein complex. It is unclear whether cardiac protectiveagents work to inhibit the opening of a preformed mPTPcomplex, inhibit a particular subunit of the complex, orinhibit the assembly or organization of the complex. Re-cent work showed that increased phosphorylation of gly-cogen synthase kinase-3� in a model of protection reducesthe affinity of the adenine nucleotide translocase for cyclo-philin D, suggesting that assembly of the complex is tar-geted by protective signals to limit mPTP opening.8

A limitation of the current study deals with the indirectmeans by which mPTP opening was assessed. Tetram-ethylrhodamine ethyl ester, a dye used to measure ��m,was used to infer mPTP opening. Although the literaturelargely agrees that mPTP opening can be inferred by lossof ��m, they are not one in the same. A loss in ��m canbe caused by factors other than mPTP opening (e.g.,increased adenosine triphosphate demand). To circum-vent this limitation, calcein acetoxymethylester–loadedcells in the presence of Co2� can be used.9 Calcein isloaded into cells and taken up by mitochondria. Residualcalcein is quenched by Co2�. If a stress is induced toopen the mPTP, calcein is released and fluorescence islost; this is reversed by addition of cyclosporine A. Dualloading of cells with tetramethylrhodamine ethyl esterand calcein can measure both ��m and mPTP openingsimultaneously.10 In the whole heart, mPTP opening canbe assessed by a method devised by Halestrap et al.11,12 inwhich radioactive 2-deoxyglucose (3H-DOG) is loaded intocells and accumulates as a phosphate. Functioning mito-chondria exclude the 3H-DOG, and opening of the mPTPallows accumulation of 3H-DOG in mitochondria, whichcan be assessed by isolating mitochondria in the presenceof EGTA to trap mitochondrial 3H-DOG during isolation.

The authors also used atractyloside, a pharmacologicmPTP opener, to block ischemic and opioid postcondition-ing, leading to the conclusion that opioids impact mPTPopening to affect postconditioning. Because mPTP opening

is proposed to be an end effector of protection, interven-tions that open the mPTP pharmacologically would beexpected to abrogate cardiac protection induced by anyform of preconditioning or postconditioning (i.e., ischemicor pharmacologic). Atractyloside would not implicate a rolefor protective agents in the modulation of mPTP. Therefore,use of atractyloside does not address the role of mPTP inprotection, but shows that mPTP opening is responsible fortissue injury. In addition, it has been reported that atractylo-side not only opens mPTP but also inhibits adenosine diphos-phate transport by inhibition of adenine nucleotide translo-case,13 therefore limiting oxidative phosphorylation. As such,it would be difficult to differentiate the effects of atractylosideon mPTP opening versus loss of energy production as caus-ative factors in attenuated protection. Therefore, to assesswhether protective agents use mPTP as a downstream mech-anism, future studies should directly test whether these agentsimpact mPTP opening in response to stress.

The role of nitric oxide and/or reactive oxygen species inpostconditioning events is intriguing, especially with re-spect to their impact on the mPTP. We and others haveshown a role for reactive oxygen species in triggeringpostconditioning induced by ischemia, isoflurane, and the�-opioid agonist SNC-121.14,15 There is evidence that reac-tive oxygen species may impact downstream mediators ofprotection (e.g., mitochondrial adenosine triphosphate–sensitive potassium channels)16; however, the nature of thereactive species generated and the role in inducing protec-tion is under debate. During severe ischemia–reperfusioninjury, overproduction of reactive oxygen species and mi-tochondrial Ca2� overload produce mPTP opening, ��m

depolarization, inhibition of adenosine triphosphate pro-duction, mitochondrial swelling, additional reactive oxy-gen species production, and further Ca2� accumulation, allof which initiate mitochondrial dysfunction. However, re-active oxygen species at low concentrations can initiatesignaling cascades that preserve mitochondrial integrityand myocardium during ischemia and reperfusion. Thefinding by Jang et al.2 that morphine generates nitric oxideand that changes in ��m are sensitive to nitric oxidesynthase inhibition may provide a potential mechanism ofaction for opioids in ischemic postconditioning and impli-cate nitric oxide as the triggering reactive species. Lowlevels of endogenous nitric oxide and low concentrationsof nitric oxide donors (�1 �M) protect mitochondria viasuppression of mPTP opening, whereas high concentra-tions of nitric oxide (�5 �M) can produce mPTP openingand cytochrome c release.17 The fact that nitric oxide couldbe detected by fluorescence microscopy (a relatively insen-sitive technique) begs the question: Was this a small orlarge concentration of nitric oxide, and what does it meanto downstream protection? The dilemma seems to be thatif a reactive species is easily detectable, the level likely ishigh and potentially injurious, whereas if it is low, it may bea beneficial trigger to cytoprotective signaling but evadedetection.

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The current study by Jang et al.2 has focused wel-comed attention on a possible role for �-opioids in themodulation of the mPTP. Future studies will need tofocus on the effects of modulators of preconditioningand postconditioning directly on the mPTP at the cellu-lar and molecular levels. Resolution of these mito-con-troversies will add important information to our under-standing of anesthetics as cytoprotective drugs andpotential therapeutics for ischemia–reperfusion injury.

Hemal H. Patel, Ph.D.,* Yasuo M. Tsutsumi, M.D., Ph.D.,*David M. Roth, Ph.D., M.D.† *Department of Anesthesiology,University of California, San Diego, California. [email protected].†Department of Anesthesiology, University of California, San Diego,and Veterans Affairs San Diego Healthcare System, San Diego, California.

References

1. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J: Inhibition of myocardial injury by ischemic postconditioning duringreperfusion: Comparison with ischemic preconditioning. Am J Physiol Heart CircPhysiol 2003; 285:H579–88

2. Jang Y, Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z: Postconditioningprevents reperfusion injury by activating �-opioid receptors. ANESTHESIOLOGY 2008;108:243–50

3. Javadov S, Karmazyn M: Mitochondrial permeability transition pore openingas an endpoint to initiate cell death and as a putative target for cardioprotection.Cell Physiol Biochem 2007; 20:1–22

4. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD,Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ: Glycogen synthase kinase-3�mediates convergence of protection signaling to inhibit the mitochondrial per-meability transition pore. J Clin Invest 2004; 113:1535–49

5. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregorGR, Wallace DC: The ADP/ATP translocator is not essential for the mitochondrialpermeability transition pore. Nature 2004; 427:461–5

6. Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD: Voltage-depen-dent anion channels are dispensable for mitochondrial-dependent cell death. NatCell Biol 2007; 9:550–5

7. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA,Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD: Loss ofcyclophilin D reveals a critical role for mitochondrial permeability transition incell death. Nature 2005; 434:658–62

8. Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K, Ohori K, HottaH, Terashima Y, Shimamoto K: Modulation of the mitochondrial permeabilitytransition pore complex in GSK-3�-mediated myocardial protection. J Mol CellCardiol 2007; 43:564–70

9. Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, Di Lisa F:Transient and long-lasting openings of the mitochondrial permeability transitionpore can be monitored directly in intact cells by changes in mitochondrialcalcein fluorescence. Biophys J 1999; 76:725–34

10. Nieminen AL, Saylor AK, Tesfai SA, Herman B, Lemasters JJ: Contributionof the mitochondrial permeability transition to lethal injury after exposure ofhepatocytes to t-butylhydroperoxide. Biochem J 1995; 307(pt 1):99–106

11. Griffiths EJ, Halestrap AP: Mitochondrial non-specific pores remain closedduring cardiac ischaemia, but open upon reperfusion. Biochem J 1995; 307(pt1):93–8

12. Halestrap AP, Clarke SJ, Javadov SA: Mitochondrial permeability transitionpore opening during myocardial reperfusion: A target for cardioprotection.Cardiovasc Res 2004; 61:372–85

13. Gateau-Roesch O, Argaud L, Ovize M: Mitochondrial permeability transi-tion pore and postconditioning. Cardiovasc Res 2006; 70:264–73

14. Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D,Losano G, Pagliaro P: Post-conditioning induced cardioprotection requires sig-naling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K�

channel and protein kinase C activation. Basic Res Cardiol 2006; 101:180–915. Tsutsumi YM, Yokoyama T, Horikawa Y, Roth DM, Patel HH: Reactive

oxygen species trigger ischemic and pharmacological postconditioning: In vivoand in vitro characterization. Life Sci 2007; 81:1223–7

16. Jiang MT, Nakae Y, Ljubkovic M, Kwok WM, Stowe DF, Bosnjak ZJ:Isoflurane activates human cardiac mitochondrial adenosine triphosphate-sensitive K� channels reconstituted in lipid bilayers. Anesth Analg 2007;105:926–32

17. Brookes PS, Salinas EP, Darley-Usmar K, Eiserich JP, Freeman BA, Darley-Usmar VM, Anderson PG: Concentration-dependent effects of nitric oxide onmitochondrial permeability transition and cytochrome c release. J Biol Chem2000; 275:20474–9


Continuous Spinal Analgesia for Labor and Delivery

A Born-again Technique?

This editorial accompanies the article selected for thismonth’s ANESTHESIOLOGY CME Program. After reading thearticle and editorial, go to http://www.asahq.org/journal-cme to take the test and apply for Category 1 credit. Com-plete instructions may be found in the CME section at theback of this issue.

ALTHOUGH continuous spinal anesthesia (CSA) can betraced back to a 1907 publication in which Dean1 leftthe needle in place to titrate anesthesia, it was rarelyused before the 1940s, when Lemmon2 popularized thetechnique with the development of indwelling 17- and18-gauge malleable German silver needles. In 1944,Hinebaugh and Lang3 applied this technique to the par-turient, achieving pain relief in 48 of 50 patients. Toovercome the obvious limitations in patient positioningand the substantial problems with needle dislodgement,Tuohy4 modified the technique, substituting a ureteralcatheter passed through a 15-gauge needle. Althoughwell received, the high incidence of post–dural punctureheadache (PDPH) continued to temper enthusiasm. Ac-cordingly, the most significant advancement in CSA dur-ing the past half-century has been the incremental reduc-tion in catheter/needle diameter. Most recently, in thelate 1980s, three manufacturers introduced 27- to 32-gauge “microcatheters” capable of passage through stan-

This Editorial View accompanies the following article: ArkooshVA, Palmer CM, Yun, EM, Sharma SK, Bates JN, Wissler RN,Buxbaum JL, Nogami WM, Gracely EJ: A randomized, double-masked, multicenter comparison of the safety of continuousintrathecal labor analgesia using a 28-gauge catheter versuscontinuous epidural labor analgesia. ANESTHESIOLOGY 2008;108:286–98.

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Accepted for publication October 30, 2007. The authors are not supported by,nor maintain any financial interest in, any commercial activity that may beassociated with the topic of this article.

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dard 22- to 26-gauge needles. Experience with thesedevices was just gaining momentum in obstetrics whenthe occurrence of neural injuries led to their withdrawalfrom the US market.5,6 As evolving research identifiedanesthetic toxicity as the cause of injury,7,8 interest inmicrocatheters was rekindled. In 1996, seeking regula-tory approval for their reintroduction, Arkoosh et al.organized a multicenter study comparing the safety andefficacy of a 28-gauge spinal catheter with a standardepidural for labor analgesia, a rather challenging under-taking in light of the previous injuries associated withmicrocatheters. The long-awaited results of this evalua-tion are now reported in this issue of ANESTHESIOLOGY.9

The primary focus of the study was to investigate theincidence of neurologic sequelae. However, as the au-thors appropriately note, the study was powered toestablish that the incidence of persistent or permanentdeficit is less than 1% at the 95% confidence level. Al-though clearly insufficient to establish adequate safety, itwas deemed sufficient to support premarket approval,with a slow introduction of the device, coupled withextensive postmarket surveillance.

Although there were no permanent neurologic defi-cits, minor or transient changes did occur, the signifi-cance of which is unclear. Two patients (one in eachgroup) developed an abnormal gait believed to be sec-ondary to postoperative pain. Fifteen patients receivingspinal anesthesia were noted to have mild changes frombaseline. In 11 of these cases, changes were restricted todeep tendon reflexes, one of which was attributed topreeclampsia. Only one patient had findings significantenough to warrant neurologic consultation, and thesewere considered consistent with nerve compression fromthe fetal head. Reports of postpartum weakness or loss ofsensation occurred equivalently in 4% and 6% of the spinaland epidural groups, further underscoring the difficultiesinterpreting detailed sequential neurologic assessments inthe obstetric population, given the unstable physiologycompounded by the often underestimated potential forneurologic sequelae from the birthing process.

Patients receiving CSA had a higher incidence of PDPH(9% vs. 4%), although this did not achieve statistical signif-icance. However, this lack of significance likely reflects thestudy’s limited power, and the higher than expected rate ofPDPH associated with the epidural procedure. It thus re-mains to be seen whether this is the true incidence and, ifso, whether modifications in design or technique (e.g.,leaving the catheter in place for a longer period) mightreduce this to a more acceptable rate. One of the importanttarget populations for CSA, morbidly obese parturients, isthought to have a lower incidence of PDPH, so at least inthis application, PDPH may be less problematic. Similarly,PDPH poses less of a barrier to the use of these devices inthe general surgical population.

As catheter diameter decreases, so does tensile strength.The force required for withdrawal decreases as well, but

unfortunately, not to the extent that tensile strength dimin-ishes. Consequently, catheter breakage has been an impor-tant consideration since the introduction of these devicesinto clinical practice. Care in their removal is mandatory,but there are also material modifications that can poten-tially reduce risk.

In terms of efficacy, CSA performed well against theepidural technique, resulting in more immediate paincontrol and greater satisfaction at 24 h. These findingsare more impressive when one considers that the epi-dural technique might have had an unfair advantage.Years had passed since the clinical use of microcath-eters, which had been limited to start, while the expe-rience during this study was diluted among 17 investiga-tors at seven institutions, and the device itself requiredmodification after initiation of the study. The tightlycontrolled protocol mandated a single drug for spinalinfusion, in contrast to the epidural’s combination ther-apy. In addition, there was limited previous experiencewith CSA for labor on which to base the treatmentalgorithm, contrasting sharply with the epidural tech-nique that has been fine-tuned over decades. Conversely,while CSA had faster onset and produced greater earlysatisfaction, equivalent results are likely achievable withthe combined spinal–epidural technique.

There are several potential advantages of CSA that arenot evident in this study. Dosage is minimized, eliminat-ing concern for systemic toxicity or fetal exposure, evenwith a misplaced catheter. In contrast, the epidural dos-ing carries significant risk of systemic toxicity with in-travascular injection, while intrathecal misplacementcan result in complete spinal block and neural injuryfrom anesthetic neurotoxicity. In contrast to identifica-tion of the epidural space, spinal placement is facilitatedby the well-defined endpoint, permitting use in patientswith altered or abnormal neuraxial anatomy, and CSAhas an additional potential advantage in patients with acurrent or previously failed, one-sided or patchy epiduralblock. CSA has also been used successfully in a numberof patients with significant comorbidities who might nothave tolerated the hemodynamic changes associated withthe less controllable lumbar epidural anesthesia. Becauseof the more rapid onset with spinal administration, transi-tion to surgical anesthesia can be achieved more readily,potentially circumventing the need for general anesthesia.One of the difficult problems in obstetric anesthesia is whatto do after a failed attempt to convert from labor epiduralanalgesia to surgical anesthesia. In this setting, spinal anes-thesia is somewhat unpredictable and carries an increasedrisk of high or total block. The availability of CSA can be awelcome option in this not-uncommon situation. Finally, ofcourse, CSA is the clear answer for the anxious Oral Boardscandidate when faced with the semimythical case of themorbidly obese, severely preeclamptic, asthmatic parturi-ent with the class 4 airway presenting for urgent cesareandelivery.

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With respect to CSA, size does matter, particularlywith regard to regulatory restrictions, because practitio-ners currently remain at liberty to use large-bore cathe-ters for this purpose.6 Indeed, many resort to this tech-nique after inadvertent dural puncture during attemptedepidural placement. More fundamentally, there are im-portant differences in subarachnoid distribution be-tween injections made through large- and small-borecatheters,10 although these result from differences inflow rate, which will be blurred with drugs administeredby slow infusion.

Because of the substantial challenges and obstacles inconducting a study of this nature, the current data arelikely the best that will be collected anytime soon, whichis unfortunate given the numerous questions that re-main. Among the most critical, identification of the op-timal combination of analgesic/anesthetic agents and theoptimal method of delivery has yet to be determined. Itis well established that slow infusion potentiates re-stricted distribution,10 and a reduction in required dos-age, improved analgesia, and reduced risk of anestheticneurotoxicity might be achievable if an anesthetic isadministered by repetitive bolus injection. However, theextent to which this can be realized with these high-resistance catheters also remains a question.

In their 1944 report of CSA for labor and delivery,Hinebaugh and Lang3 concluded: “While no serious com-plications occurred in this series, further trial is neces-

sary to evaluate its future place in obstetrical anesthesia.”These words are perhaps as relevant now as they were60 years ago.

Kenneth Drasner, M.D.,* Richard Smiley, M.D., Ph.D.†*Department of Anesthesia, University of California, San Francisco,California. [email protected]. †Columbia University, ColumbiaUniversity Medical Center, New York, New York.

References

1. Dean HP: Discussion of the relative value of inhalation and injection meth-ods of inducing anesthesia. BMJ 1907; 5:869–77

2. Lemmon WT: A method for continuous spinal anesthesia. Ann Surg 1940;111:141–4

3. Hinebaugh MC, Lang WR: Continuous spinal anesthesia for labor anddelivery. Ann Surg 1944; 120:143–51

4. Tuohy EB: Continuous spinal anesthesia: Its usefulness and technique in-volved. ANESTHESIOLOGY 1944; 5:142–8

5. Rigler M, Drasner K, Krejcie T, Yelich S, Scholnick F, DeFontes J, Bohner D:Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 1991;72:275–81

6. US Food and Drug Administration: FDA Safety Alert: Cauda Equina Syn-drome Associated with Use of Small-bore Catheters in Continuous Spinal Anes-thesia. May 29, 1992

7. Lambert L, Lambert D, Strichartz G: Irreversible conduction block in iso-lated nerve by high concentrations of local anesthetics. ANESTHESIOLOGY 1994;80:1082–93

8. Drasner K, Sakura S, Chan V, Bollen A, Ciriales R: Persistent sacral sensorydeficit induced by intrathecal local anesthetic infusion in the rat. ANESTHESIOLOGY

1994; 80:847–529. Arkoosh VA, Palmer CM, Yun EM, Sharma SK, Bates JN, Wissler RN,

Buxbaum JL, Nogami WM, Gracely EJ: A randomized, double-masked, multi-center comparison of the safety of continuous intrathecal labor analgesia using a28-gauge catheter versus continuous epidural labor analgesia. ANESTHESIOLOGY

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model of the subarachnoid space. ANESTHESIOLOGY 1991; 75:684–92


Ultrasound-guided Regional Anesthesia and thePrevention of Neurologic Injury

Fact or Fiction?

PERIOPERATIVE nerve injuries have long been recog-nized as potentially devastating complications of re-gional anesthesia. A recent review of the published lit-erature estimates that neurologic complications mayoccur in up to 3% of patients undergoing peripheral

nerve blockade and in 0.4% of patients after neuraxialtechniques.1 Fortunately, the number of these complica-tions progressing to severe or disabling injury is ex-tremely low. In fact, it has been estimated that 1 in14,000 patients will develop a severe neurologic injuryafter spinal or epidural anesthesia.2 Despite these en-couraging results, the potential for devastating sequelaewill always be a concern for both patients and providers.In this issue of ANESTHESIOLOGY, Koff et al.3 further accen-tuate these concerns by presenting a case of severebrachial plexopathy after an ultrasound-guided inter-scalene block in a patient with multiple sclerosis (MS).The case is unique in that it highlights several importantfactors that should be considered by clinicians whenevaluating patients and assessing the risk of regionalanesthetic techniques. Important considerations in-clude identifying potential contributors to periopera-tive nerve injury, understanding the importance of

This article is featured in “This Month in Anesthesiology.”Please see this issue of ANESTHESIOLOGY, page 5A.�

This Editorial View accompanies the following article: KoffMD, Cohen JA, McIntyre JJ, Carr, CF, Sites BD: Severe brachialplexopathy after an ultrasound-guided single injection nerveblock for total shoulder arthroplasty in a patient with multiplesclerosis. ANESTHESIOLOGY 2008; 108:325–8.

�

Accepted for publication November 5, 2007. The author is not supported by,nor maintains any financial interest in, any commercial activity that may beassociated with the topic of this article.

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preexisting neurologic deficits, and recognizing thelimitations of ultrasound-guided technology in pre-venting neurologic injury.

Perioperative nerve injury is a complex phenomenonthat can be caused by a multitude of clinical factors.Patient, surgical, and anesthetic risk factors have all beenidentified as potential contributors to postoperative neu-rologic dysfunction. The case presented by Koff et al.likely represents a clinical scenario in which severalpatient, surgical, and anesthetic variables contributed toan adverse neurologic event. It is unlikely that a singleidentifiable agent was the definitive cause of injury. Infact, a review of the American Society of Anesthesiolo-gists Closed Claims database suggests that despite inten-sive medicolegal investigation, the cause of postopera-tive neurologic injuries is rarely identified.4

Patient Risk Factors

Patient risk factors most commonly associated withperioperative nerve injury include male sex, increasingage, extremes of body habitus, and preexisting diabetesmellitus.5 However, it has been suggested that patientswith preexisting neurologic deficits may be at increasedrisk as well. The patient presented in the case report byKoff et al. was an elderly man with preexisting MS. Thepresence of chronic, underlying neural compromise sec-ondary to mechanical, ischemic, toxic, metabolic, or inthis case demyelinating conditions may theoreticallyplace these patients at increased risk of further neuro-logic injury.6,7 As described by Koff et al., the “double-crush” phenomenon suggests that patients with preex-isting neural compromise may be more susceptible toinjury at another site when exposed to a secondaryinjury.7 Secondary injuries may include a variety of con-comitant patient, surgical, or anesthetic risk factors.

Many clinicians are unaware that subclinical neuralcompromise may be present within the peripheral ner-vous system of patients with MS.8,9 In fact, subclinicalsensorimotor deficits have been identified in 45%9 to74%8 of MS patients, with up to 43% having abnormali-ties in more than one peripheral nerve distribution. Thisoften ignored or poorly recognized phenomenon hasbeen appropriately highlighted by Koff et al. The authorsemphasize the need for clinicians to consider these andother factors when evaluating MS patients for peripheralnerve blockade. Unfortunately, neural compromise maybe present within the peripheral nervous system in theabsence of clinical signs or symptoms and does not seemto be correlated with patient age, disease onset, or pro-gression of the disease course. This lack of clinical cor-relation presents a unique challenge to anesthesia pro-viders when evaluating MS patients for peripheralregional techniques.

Surgical Risk Factors

Surgical risk factors associated with perioperativenerve injury include direct intraoperative trauma orstretch, vascular compromise, perioperative infection orinflammation, hematoma formation, tourniquet isch-emia, or improperly applied immobilizers or casts. Sur-gical variables may be the primary etiology of postoper-ative neurologic deficits in up to 88% of cases.10 One ofthe most important surgical risk factors may be thesurgical procedure itself. Koff et al. briefly alluded to thefact that the surgical procedure may have been a con-tributing factor in the development of the patient’s se-vere brachial plexopathy. Total shoulder arthroplastymay be associated with postoperative neurologic deficitsin up to 4.3% of cases—regardless of anesthetic tech-nique—with the majority of injuries being localized tothe upper trunks of the brachial plexus.11

Anesthetic Risk Factors

Regional anesthetic factors that may contribute di-rectly or indirectly to perioperative nerve injury includeneedle- or catheter-induced mechanical trauma, isch-emic nerve injury secondary to vasoconstrictors or neu-ral edema, and chemical injury from direct local anes-thetic neurotoxicity.12 Several authors have investigatedthe role of mechanical trauma, including the role ofneedle gauge, type, and bevel configuration on periph-eral nerve injury. The disruption of perineural tissuearound nerve fascicles compromises the blood–nervebarrier and results in the herniation of endoneurial con-tents (i.e., myelinated nerve fibers) into the perineuralspace. However, needle-to-nerve contact by itself—inthe absence of local anesthetic injection—rarely pro-duces clinical or functional abnormalities. Rather, it isthe combined effect of needle penetration and injec-tion of local anesthetic into the neural fascicle thatcauses axonal degeneration and subsequent neuro-logic injury.12

Limitations of Ultrasound-guided RegionalAnesthesia

Finally, the ability of ultrasound-guided regional anes-thesia to become the “holy grail” of regional anesthe-sia—providing neural blockade with rapid onset, longduration, and improved success, without complica-tions—has recently been discussed.13 Although manyadvocates of ultrasound theorize that direct visualizationof neural targets and needle advancement may decreasethe frequency (and severity) of neurologic injury, pre-liminary results do not support the hypothesis that ultra-sound guidance decreases the risk of neurologic compli-cations.13 This should not be surprising if we consider

187EDITORIAL VIEWS



the risk factors associated with neurologic injury and theability (or lack thereof) of ultrasound in preventing theserisk factors from making a clinical impact. For example,clearly the use of ultrasound guidance will have noimpact on patient risk factors associated with nerveinjury. The patient described by Koff et al. will have theassociated risk factors of male sex, increasing age, and apreexisting neurologic deficit regardless of anesthetictechnique. Similarly, the use of ultrasound guidance willhave no effect on surgical factors. Patients undergoingtotal shoulder arthroplasty will still be at risk of intraop-erative trauma or stretch to the brachial plexus, hema-toma formation, and perioperative inflammation. How-ever, it is not unreasonable to presume that ultrasoundmay have a positive impact on anesthetic risk factors—albeit small. Of the anesthetic risk factors involved inperioperative nerve injury (mechanical trauma, neuralischemia, and local anesthetic toxicity), ultrasound guid-ance may be able to modify one, or at most two contrib-uting factors, namely, mechanical trauma and local an-esthetic neurotoxicity.

The ability of ultrasound guidance to avoid needle-to-nerve contact and mechanical trauma is an appealingassumption. However, is this assumption a true reflec-tion of clinical practice? For example, the ability tovisualize both the needle tip and relevant neural targetsat all times is extremely difficult. In fact, data from Koffet al.’s own institution suggests that failure to maintainneedle visualization during advancement may occur inup to 43% of novices (�10 ultrasound-guided blocks)and 10% of experienced providers (�60 ultrasound-guided blocks) performing ultrasound-guided tech-niques.14 This is not a criticism, but rather a reflection ofthe difficultly associated with maintaining needle align-ment within the narrow plane (1 mm) of the ultrasoundbeam. Finally, preliminary evidence is beginning to sug-gest that ultrasound-guided technology may allow re-gional techniques to be performed with lower volumesof local anesthetic while maintaining similar degrees ofblock efficacy. This benefit may theoretically influencerisk factors of neural injury associated with direct localanesthetic neurotoxicity. However, definitive data arecurrently lacking on these assumptions as well.

In summary, the case report by Koff et al. highlightsseveral important points. First, clinicians must identifyall potential risk factors associated with perioperative

nerve injury prior to performing regional techniques.This includes recognizing that patients with preexistingneurologic deficits may be particularly susceptible tosecondary injuries. Second, consider whether the per-ceived benefits of regional anesthesia justify the poten-tial for added risk (mechanical trauma, neural ischemia,local anesthetic toxicity). If so, consider modifying youranesthetic technique to minimize the impact of addi-tional risk factors. Modifications may include reducinglocal anesthetic concentrations, eliminating epinephrineadditives, or proceeding with general anesthesia. Finally,recognize the limitations of ultrasound-guided technol-ogy in reducing the risks associated with neurologiccomplications. Failure to appreciate the limitations ofultrasound may breed complacency and create an illu-sion of safety—factors that may increase the risk ofnerve injury and adverse patient outcomes.

James R. Hebl, M.D., Department of Anesthesiology, Mayo Clinic,Rochester, Minnesota. [email protected]

References

1. Brull R, McCartney CJ, Chan VW, El-Beheiry H: Neurological complicationsafter regional anesthesia: Contemporary estimates of risk. Anesth Analg 2007;104:965–74

2. Moen V, Dahlgren N, Irestedt L: Severe neurological complications aftercentral neuraxial blockades in Sweden 1990–1999. ANESTHESIOLOGY 2004; 101:950–9

3. Koff MD, Cohen JA, McIntyre JJ, Carr CF, Sites BD: Severe brachial plex-opathy after an ultrasound-guided single injection nerve block for total shoulderarthroplasty in a patient with multiple sclerosis. ANESTHESIOLOGY 2008; 108:325–8

4. Cheney FW, Domino KB, Caplan RA, Posner KL: Nerve injury associatedwith anesthesia: A closed claims analysis. ANESTHESIOLOGY 1999; 90:1062–9

5. Warner MA, Warner ME, Martin JT: Ulnar neuropathy: Incidence, outcome,and risk factors in sedated or anesthetized patients. ANESTHESIOLOGY 1994; 81:1332–40

6. Urban MK, Urquhart B: Evaluation of brachial plexus anesthesia for upperextremity surgery. Reg Anesth 1994; 19:175–82

7. Upton AR, McComas AJ: The double crush in nerve entrapment syndromes.Lancet 1973; 2:359–62

8. Pogorzelski R, Baniukiewicz E, Drozdowski W: Subclinical lesions of pe-ripheral nervous system in multiple sclerosis patients [in Polish]. Neurol Neuro-chir Pol 2004; 38:257–64

9. Sarova-Pinhas I, Achiron A, Gilad R, Lampl Y: Peripheral neuropathy inmultiple sclerosis: A clinical and electrophysiologic study. Acta Neurol Scand1995; 91:234–8

10. Horlocker TT, Kufner RP, Bishop AT, Maxson PM, Schroeder DR: The riskof persistent paresthesia is not increased with repeated axillary block. AnesthAnalg 1999; 88:382–7

11. Lynch NM, Cofield RH, Silbert PL, Hermann RC: Neurologic complicationsafter total shoulder arthroplasty. J Shoulder Elbow Surg 1996; 5:53–61

12. Neal JM, Hebl JR, Gerancher JC, Hogan QH: Brachial plexus anesthesia:Essentials of our current understanding. Reg Anesth Pain Med 2002; 27:402–28

13. Horlocker TT, Wedel DJ: Ultrasound-guided regional anesthesia: In searchof the holy grail. Anesth Analg 2007; 104:1009–11

14. Sites BD, Spence BC, Gallagher JD, Wiley CW, Bertrand ML, Blike GT:Characterizing novice behavior associated with learning ultrasound-guided pe-ripheral regional anesthesia. Reg Anesth Pain Med 2007; 32:107–15

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