Reply to Drs Rady and Verheijde.

We thank Drs Rady and Verheijde for their comments on our case reports. Their letter raises a number of questions regarding the accuracy of brain death determination. In response, it is important to put these questions into context. Some apply to the role of therapeutic hypothermia and extracorporeal membrane oxygenation (ECMO). However, several others question the criteria promulgated by the American Academy of Neurology (AAN) and are considerably beyond the scope of our report. Drs Rady and Verheijde point out that therapeutic hypothermia has “unpredictable effects on the pharmacokinetics and pharmacodynamics of drugs acting on central gamma aminobutyric acid (GABA) receptors…” that might result in a falsely positive determination of brain death. They suggest that substantially more time should elapse after rewarming before clinical testing is performed to determine brain death. We agree that research is required to elucidate what impact therapeutic hypothermia might have on the optimum time to apply the criteria currently used to declare brain death. However, this matter is by no means clear-cut. Even before the widespread application of therapeutic hypothermia, the AAN stated the following: “There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly.”1Wijdicks E.F. Varelas P.N. Gronseth G.S. et al.Evidence-based guideline update: Determining brain death in adults: Report of the quality standards Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1911-1918Crossref PubMed Scopus (686) Google Scholar Drs Rady and Verheijde rightly emphasize that clinicians must “exercise caution when making life-ending decisions.” However, it is also important to use appropriate judgment based on the clinical circumstances of each case, which we believe we did in the 2 cases in our report. It also must be understood that there are substantial risks in continuing ECMO support for many more hours, including the constant threat of line infection, coagulopathy, and thrombotic complications. If, as Drs Rady and Verheijde imply, nonpulsatile cerebral flow during ECMO provides suboptimal perfusion to the damaged brain, a paradox is created whereby the more time that is spent on ECMO the less the likelihood of subsequent recovery. In the healthy brain, at least, there is considerable evidence that cerebral autoregulation remains intact during nonpulsatile device flow.2Bellapart J. Chan G.S. Tzeng Y.C. et al.The effect of ventricular assist devices on cerebral blood flow and blood pressure fractality.Physiol Meas. 2011; 32: 1361-1372Crossref PubMed Scopus (4) Google Scholar, 3Potapov E.V. Loebe M. Nasseri B.A. et al.Pulsatile flow in patients with a novel nonpulsatile implantable ventricular assist device.Circulation. 2000; 102: III183-III187Crossref PubMed Google Scholar, 4Zimpfer D. Wieselthaler G. Czerny M. et al.Neurocognitive function in patients with ventricular assist devices: A comparison of pulsatile and continuous blood flow devices.ASAIO J. 2006; 52: 24-27Crossref PubMed Scopus (58) Google Scholar Until definitive data are available regarding the effect of ECMO on the established criteria for brain death, we believe that it is prudent to continue to use the current AAN guidelines.1Wijdicks E.F. Varelas P.N. Gronseth G.S. et al.Evidence-based guideline update: Determining brain death in adults: Report of the quality standards Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1911-1918Crossref PubMed Scopus (686) Google Scholar Drs Rady and Verheijde further raise concern about performing an apnea test with a patient on ECMO, which is the key element of our report. They suggest that induced hypercapnia might adversely affect cerebral perfusion and thereby worsen pre-existing neurologic injury. We know of no evidence that this is the case, but if it is then this concern is a generic one that is applicable to any patient any time an apnea test is performed to confirm brain death. The purpose of our report was to describe how the physiologic consequences of an apnea test could be duplicated in a patient on ECMO, not whether such a test is appropriate or not. They also express concern that a falsely positive apnea test might occur soon after rewarming to normothermia, but the articles that they cite5Samaniego E.A. Mlynash M. Caulfield A.F. et al.Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia.Neurocrit Care. 2011; 15: 113-119Crossref PubMed Scopus (221) Google Scholar, 6Samaniego E.A. Persoon S. Wijman C.A. Prognosis after cardiac arrest and hypothermia: A new paradigm.Curr Neurol Neurosci. 2011; 11: 111-119Crossref PubMed Scopus (58) Google Scholar describe the possible confounding effect of hypothermia and rewarming on the neurologic examination, not the apnea test itself. Several of the concerns expressed by Drs Rady and Verheijde question the scientific validity of the AAN brain death criteria, some of which are based on insufficient or conflicting data (evidence level “U”). Again, these are generic concerns that our case reports cannot possibly address. It should be noted that these criteria were established by the AAN 17 years ago and have been applied to roughly 200,000 patients declared brain-dead in the United States based on a predicted number of potential donors of 10,500 to 13,000 per year.7Sheehy E. Conrad S.L. Brigham L.E. et al.Estimating the number of potential organ donors in the United States.N Engl J Med. 2003; 349: 667-674Crossref PubMed Scopus (375) Google Scholar By 2009, only 12 cases of “reversible brain death” had been reported, of which only 4 occurred in adults. In 3 of the 4 cases, there is no documentation of an apnea test, and in the fourth case the apnea test was performed for 1 minute. At that time, the AAN Quality Standards Subcommittee concluded the following: “In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 AAN practice parameter.”1Wijdicks E.F. Varelas P.N. Gronseth G.S. et al.Evidence-based guideline update: Determining brain death in adults: Report of the quality standards Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1911-1918Crossref PubMed Scopus (686) Google Scholar In 2011, there was a report of “reversible brain death” using the original AAN criteria (2 brain death examinations 6 hours apart) after rewarming from therapeutic hypothermia.8Webb A.C. Samuels O.B. Reversible brain death after cardiopulmonary arrest and induced hypothermia.Crit Care Med. 2011; 39: 1538-1542Crossref PubMed Scopus (82) Google Scholar In the operating room in preparation for organ donation 24 hours after brain death pronouncement, the patient was noted to have regained corneal and cough reflexes and spontaneous respiration. Organ donation was aborted, and the patient was returned to the intensive care unit. Two days later, the patient lost the remaining brainstem function and was disconnected from the ventilator after a nuclear cerebral blood flow study confirmed the absence of cerebral blood flow. On the face of it, this case suggests that reversibility occurred because the brain death examination was performed too soon after rewarming. However, close review of the report reveals that the patient was noted to have an intact cough and gag reflex and spontaneous respiration during rewarming. Over the next 24 hours, he lost all this activity, and that is when the first brain death examination was performed. This pattern is the opposite to what would occur with delayed recovery after rewarming. In conclusion, we share the uncertainty expressed by Drs Rady and Verheijde regarding the optimal delay in performing brain death examination after therapeutic hypothermia. Based on the current paucity of scientific data, the most reasonable recommendation seems to be that of Wijdicks et al1Wijdicks E.F. Varelas P.N. Gronseth G.S. et al.Evidence-based guideline update: Determining brain death in adults: Report of the quality standards Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1911-1918Crossref PubMed Scopus (686) Google Scholar to “reset the clock” and wait 24 hours after rewarming before the first brain death examination. Despite the considerable challenges involved, we hope that careful prospective studies will ultimately elucidate a definitive answer. However, at the time our patients were evaluated, we were faced with the dilemma of whether a diagnosis of brain death could be established in our patients on ECMO using the AAN criteria and in accordance with our hospital policies and procedures. We believe our method of performing an apnea test on ECMO meets these criteria. Determining Brain Death After Therapeutic Hypothermia on Nonpulsatile Continuous-Flow Mechanical Circulatory Support DevicesJournal of Cardiothoracic and Vascular AnesthesiaVol. 27Issue 2PreviewGoswami et al1 described 2 cases of determining brain death (BD) after therapeutic hypothermia (TH) in patients supported on nonpulsatile continuous-flow (NPCF) systemic circulation and extracorporal membrane oxygenation. We comment on TH, sedatives, and NPCF as confounders for reversible inhibition of the central nervous system (CNS) and BD findings. Full-Text PDF