Cyclosporine for Reperfusion Injury After Cardiac Arrest: Too Little Too Late?

Conductingarigorousout-of-hospital studyonpatients incardiac arrest is a daunting task. It requires training all members of the emergencymedical system, randomization in the field (most commonly via a central physician-dispatcher), obtaining an exception to the typical requirement of informed consent, and rapidly administering a study drug in the fieldviaan intravenouscatheter thatmustbeplaced inapulseless patient. All of thismust occur in the chaotic andemotionally charged setting of a cardiac arrest, where every second counts with a dying patient, often in the presence of distraught familymembers and other bystanders. The interventionmust not delay or interferewith the standard care thepatient must receive, including high-quality cardiopulmonary resuscitation, defibrillation, obtaining and transmitting important information about the event and prior medical conditions,documentingall careadministeredandevents that take place, communicationwith the receivinghospital, andpreparation for transport. These are critically ill cardiac arrest patients in whom less than 2% survive to hospital discharge so the search for a more effective therapy is compelling. There ismuch to admire in theArgaud et al article “Effect of Cyclosporine in Nonshockable Out-of-Hospital Cardiac Arrest: TheCYRUSRandomizedClinical Trial”1 in this issue of JAMACardiology. The investigators are tobe congratulatedon conducting a rigorous randomized clinical trial that was robustlynegative.They foundnoeffectonthepreventionofmultiple organ failure at 24 hours in nonshockable out-ofhospital cardiac arrest patients who were resuscitated and quickly given 2.5 mg/kg of intravenous cyclosporine A in an effort to prevent reperfusion injury-mediatedmultiple organ dysfunction. It is truly impressive that the investigators achieved an average time interval from the arrival of the advancedcardiac life support teamto intravenous studydrugadministration of a mere 8 minutes. However, the kinetics of reperfusion injury biology suggest that even this brief delay may be significant, especially when added to other delays in treatment, like the aggregate time fromhemodynamiccollapse toadvancedcardiac life support team arrival (totaling about 19 additionalminutes in this study). Thus, patients received the study drug an average of 27 minutes after collapse, which the authors cite as the most likely reason for their negative findings. While that may well be true, it is hard to imagine that this can be substantially improved with our current level of emergency medical system capabilities. Numerous lessons from the laboratory highlight that even a very brief delay in cyclosporine A treatment after return of circulation will cause a total loss of cyclosporine A protection in the setting of cardiac arrest–mediated reperfusion injury. Huang et al2 demonstrated highly protective effects of cyclosporine A in a rat model of cardiac arrest when given immediately on resuscitation, but these protective effects were completely absent after a mere 3-minute delay in administration after restoration of circulation. In addition to thepossibility thatdelay to treatmentmight explain the negative findings, selection of a low dose of cyclosporineAmayhavecontributedaswell. Themajorityof animal studiesofcyclosporineAuseddosagesof 10mg/kg,4 times theamountadministered in this study.2Adose-responsestudy in a piglet model of cardiac arrest concluded that the dose of cyclosporineArequired forprotectionwas 10mg/kg toachieve optimal benefit.3 Theauthorsof the current studycited2prior human studies for their selection of 2.5 mg/kg dosage. One positive study thatwas quite small had 28 controls and 30patients treated with cyclosporine A4 and the other was a positive cyclosporineApretreatment studyduringaorticvalve surgery in which 10 minutes of circulating drug was allowed to elapsebefore reperfusionwasperformed.5 Ina third recenthuman trial of cyclosporine A after ST-segment elevation myocardial infarction/percutaneous coronary intervention, adose of only 2.5 mg/kg was also administered; it was negative as well.6 The low dose of cyclosporine A administered in the current study is as likely to contribute to the negative findings as the delay in treatment (as impressively brief as it was). Cyclosporine A is a rather largemolecule (C62H111N11O12) and its circulatory and diffusion-mediated journey from the vascular space to interstitial fluid, to intracellular compartment, to the mitochondrial permeability transitionpore (MPTP) in theneurons of the brain, is expected to take some time. Collectively, the human data on cyclosporine A support the idea that the number of cyclosporine Amolecules in a dose of 2.5mg/kg is simplynot timelyor sufficient toprovide the target tissues the dose of cyclosporine A needed for protection. The approach used in this and most other recent studies of agents to reduce reperfusion injury and improve outcome incardiacarrest raisesanother importantquestionbeyonddose and time to administration: Is administering a single therapeuticagent in thesettingofcardiacarrest inanattempt to treat reperfusion injury theoptimalapproach?Thehopethatasingle agentdirectedat a singlemolecular pathwaymight correct the greatmanymetabolic derangements that occur during reperfusion injurymaybewishful thinking.Perhaps themanynegative studies we have now amassed suggest that such an approach is oversimplified given the complexity of the disease. Consider 2 other complex pathologies with which we currently treatwithmore thanoneagent, and inmost casesmany agents: cancer andhuman immunodeficiency virus. For both conditions, we typically use multiple drugs targeted at Related article page 557 Research Original Investigation Cyclosporine in Nonshockable Out-of-Hospital Cardiac Arrest