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Home , Brain death, Death

Pronouncing brain Contemporary practice and safety of the test

Eelco F.M. Wijdicks, ABSTRACT MD, PhD Background: Little is known of hospital practice in determination, specialty involve- Alejandro A. Rabinstein, ment, and followed procedures, including the apnea test. MD Methods: We reviewed 228 patients pronounced brain dead at Mayo Clinic from 1996 to 2007. Edward M. Manno, MD We performed a detailed review of clinical determination of brain death, intensive care support, John D. Atkinson, MD apnea test procedure, and complications.

Address correspondence and Results: There were 228 patients who were pronounced brain dead, mostly after traumatic brain reprint requests to Dr. Eelco F.M. , cerebral hematoma, or aneurysmal . Brain death was declared Wijdicks, Mayo Clinic College of within 24 hours of ictus in 30% of the patients and within 3 days in 62%. All patients were using , Department of and Division of one or more vasopressors, and 61% of the patients received vasopressin for insipidus. Critical Care Neurology, 200 An apnea test could not be performed in 7% of the patients because of hemodynamic instability First Street SW, Rochester, MN 55905 or poor oxygenation at baseline. In 3% of the patients, the apnea test procedure was aborted [email protected] because of hypoxemia or hypotension. No major complications ( or pneumothorax) occurred during the apnea test. Polytrauma resulting in brain death was significantly more com- mon in patients with aborted or not attempted apnea tests than in patients with completed apnea tests (p ϭ 0.0004). During the study epoch, we found a shift toward determination of the tests by neurointensivists, pediatric neurologists, and neurosurgeons. Conclusions: Brain death declaration is frequent within the first 3 days of admission. It is usually performed in hemodynamically unstable patients requiring vasopressors and vasopressin. If pre- conditions are met, apnea testing using an -diffusion technique is safe. However, in 1 of 10 patients, an apnea test could not be completed and confirmatory tests were needed. Neurology® 2008;71:1240–1244

GLOSSARY AAN ϭ American Academy of Neurology; ICU ϭ .

No appreciable function of the brain and constitutes brain death—a credible and practically useful designation for this condition.1 The emergence of brain death in a patient with a catastrophic brain injury is uncommon, and surveys have indicated that only 5% to 10% of all comatose patients admitted to intensive care units (ICUs) become brain dead.1-3 The appearance of total flaccidity, absent cough to tracheal suctioning, at ventilator rate, sudden hypotension, invariant rate, profound diuresis in a patient with fixed pupils, and no corneal and oculovestibular are clinical indicators. The declaration of brain death is a major responsibility for , often performed by those who are staffing or consulting in ICUs. In 1995, the clinical determination of brain death was described in an evidence-based practice guideline.4 This document has been adopted by organ procurement agencies in the and elsewhere. However, since this compre- hensive guideline became known, studies have largely focused on specific neurologic manifes- tations or type of confirmatory tests.5-7 No detailed studies as yet have been published on actual hospital practice in a large number of patients pronounced brain dead. A review could identify

From the Division of Critical Care Neurology (E.F.M.W., A.A.R., E.M.M.) and Department of Neurosurgery (J.D.A.), Mayo Clinic, Rochester, MN. Disclosure: The authors report no disclosures.

1240 Copyright © 2008 by AAN Enterprises, Inc. concerns in key areas such as correctly fol- epochs (1996–1999, n ϭ 78; 2000–2003, n ϭ 78; lowed procedures, involvement, 2004–2007, n ϭ 72). and apnea testing. In this analysis, we present The cause of brain death was traumatic brain in- a single (tertiary) center experience with 228 jury (32%), intracerebral hematoma or aneurysmal subarachnoid hemorrhage (39%), anoxic injury brain death determinations. (11%), ischemic with brain swelling (8%), or miscellaneous causes (10%; brain tumor, CNS infec- METHODS Hospital policy requires contacting an organ pro- curement organization when clinical examination shows evi- tion, brain edema and fulminant hepatic failure, dence of loss of all brain function, but also when rapid acute hydrocephalus, and battering). In 13 patients progressive loss of brain function is anticipated. These contacts (6%), emergency craniotomy was performed to re- are typically initiated by ICU staff. Patients identified move a tumor or subdural or cerebellar hematoma. for this study were therefore retrieved from a database main- After admission, brain death could be declared tained by our organ procurement organization (LIFESOURCE). within 24 hours in 69 patients (30%), between 1 and In both Mayo-affiliated hospitals, the detailed guidelines of 2 days in 47 patients (21%), between 2 and 3 days in the American Academy of Neurology (AAN) are readily available 26 patients (11%), and after 3 days in 86 patients for consultations to physicians performing a brain death exami- nation and the apnea test. (38%). The study was approved by the institutional review board. At the of diagnosis of brain death, all pa- Two of the authors (E.F.M.W. and A.A.R.) reviewed full medi- tients became hypotensive and required one or more cal records of 236 patients considered brain dead from 1996 to vasopressors or inotropes. Diabetes insipidus was di- 2007. We excluded 8 patients who were referred to - agnosed in 141 patients (61%) and treated with va- SOURCE but, at the request of the family, had support with- sopressin. Hypernatremia (146–170 mmol/L) was drawn before a full neurologic assessment could be completed (4 observed in 46 patients (20%). Pulmonary injury patients within 24 hours, 4 patients within 6 days of admission). In the remaining 228 patients, demographics, cause of cata- was apparent in 51 patients (22%). It consisted of strophic injury, time from admission to brain death, specialty of pneumothorax requiring chest tubes in 23 patients, physician determining brain death, findings on neurologic ex- diffuse pulmonary edema in 20 patients, and lobar amination, and details on the apnea test were reviewed. Findings infiltrates in 8 patients. on chest x-rays were collected. Laboratory data with changes in Clinical examination and apnea test. Neurointensiv- pH, arterial PCO2, and arterial PO2 during apnea testing were obtained (in patients with two apnea tests, mostly children, we ists and neurosurgeons more commonly declared pa- entered the first apnea test values). Hypotension was defined as a tients brain death, but during the 12 years of the new blood pressure decrease to less than 90 mm Hg systolic; study, there was a notable increase in the number of hypoxemia was defined as arterial PO2 less than 60 mm Hg or a neurointensivists performing the entire procedure of pulse oximeter reading of less than 90%. Diabetes insipidus was brain death declaration (figure 1). The neurologic diagnosed as sudden polyuria with hypernatremia, decreased examination and apnea test closely followed the specific gravity, or osmolality. AAN guidelines, and documentation included exclu- According to protocol, apnea testing was performed using an oxygen-diffusion technique.4 As described before, minute venti- sion of confounders (, , lation was adjusted, and preoxygenation with 100% oxygen for acid–base disturbances, or neuromuscular junction 10 minutes preceded disconnection from the ventilator.4,8 The blockers), review of neuroimaging, and details of aim was to normalize arterial PCO2 and increase arterial PO2. The , including lack of response to apnea test was aborted when progressive hypotension or hypox- noxious stimuli documentation and absence of at emia occurred in the minutes after disconnection. Repeat blood least pupillary, cornea, oculovestibular, and cough gasses were obtained after 8 to 10 minutes of disconnection to reflexes followed by an apnea test. In four patients, document either a 20-mm Hg increase in PaCO2 from a normal baseline or a target value of at least 60 mm Hg. Statistical analy- brief flexion of arm and fingers was observed, and in sis using a two-tailed Student t test was performed to compare one patient, subtle head turning was noted, and these pre– and post–apnea test data measurements. A significant dif- were interpreted as spinal reflexes4 (confirmatory ference was determined to be present for p Ͻ 0.05. tests in these five patients showed absent intracranial blood flow or electroencephalographic silence). Ex- RESULTS Patient population. During the 12-year aminations were repeated in children after a 12- to study period, 228 patients were pronounced brain 24-hour interval as per protocol, followed by a con- dead. There were 195 and 33 children (aged firmatory test. Ͻ18 years). The age ranged from 2 months to 84 Apnea tests were initiated only after brainstem re- years (median 46 years). Seventy-six patients (33%) flexes were absent. Disconnection from the ventilator were admitted outside the Neurosciences ICU documented a normal breathing drive in 2 patients, (Trauma ICU, Coronary Care Unit, Cardiovascular but repeat apnea testing 12 hours and 3 days later ICU, Transplant Unit, and Pediatric ICU) Brain resulted in documentation of apnea. Apnea testing death determinations were consistent across 4-year was not attempted in 16 patients (7%). The reason

Neurology 71 October 14, 2008 1241 Figure 1 Number of physicians determining brain death in three time epochs Figure 2 Changes in arterial pH, PCO2, and PO2 during apnea test

Neurointensivists (NICU), staff neurosurgeon or chief resident (NEUROSURG), pediatric neu- rologist (PEDNEURO), surgical intensivist (SICU), neurology chief resident (RESNEURO).

for not proceeding with an apnea test was inability to maintain a stable blood pressure (n ϭ 6), high posi- tive end-expiratory pressure requirements (more than ϭ 15 cm H2O), or refractory hypoxemia (n 10) de- spite a pretest oxygenation trial using a fraction of inspired oxygen of 1 for 10 minutes. An apnea test was performed with placement of an endotracheal suction catheter providing 6 to 10 L of oxygen. In three instances, an bag with 100% oxygen and an open valve for 5 minutes’ duration was used, and in one patient a T piece with a continuous posi-

tive airway pressure valve of 15 cm H2O was used. An apnea test was started in 212 patients, but was aborted in 7 patients (3%) with progressive hypoten- sion or hypoxemia after disconnection from the ven- Circles are group means; error bars represent SD. All differ- Ͻ tilator. In the remaining 205 patients, arterial pH ences were statistically significant (p 0.05). (mean Ϯ SD) decreased from 7.38 Ϯ 0.07 to 7.18 Ϯ Ͻ Ϯ 0.07 (p 0.001), PaCO2 increased from 40 5to completion of the apnea test was not predicted by Ϯ Ͻ 70 9mmHg(p 0.001), and PaO2 decreased pulmonary abnormalities or chest tube placement. from 265 Ϯ 140 mm Hg to 236 Ϯ 155 mm Hg (p Ͻ in polytrauma patients was 0.05) (figure 2). In 22 of 205 patients (11%), the significantly more common in patients with aborted

pretest PaO2 was borderline and between 70 and 100 or not attempted apnea tests than in patients with mm Hg. Patients with an aborted apnea test had pre- completed tests (15/23, 65% vs 59/205, 29%; ␹2 test ϭ test PaO2 values between 70 and 100 mm Hg more 12.52, p 0.0004). often than did patients who completed the apnea Additional tests (EEG, n ϭ 15; cerebral angiogram, test, but the difference was not statistically different n ϭ 3; nuclear scan, n ϭ 2; transcranial Doppler, (28% vs 8%; Fisher exact test p ϭ 0.12). Brief hypo- n ϭ 3) were confirmatory in patients with aborted ap- tension (systolic blood pressure between 75 and 90 nea tests and in patients in whom the apnea test was mm Hg) at the end of a completed apnea test was deemed unsafe.

noted in 14 patients (7%). Hypoxemia (PaO2 be- The possibility of organ procurement was dis- tween 33 and 60 mm Hg) was documented on the cussed with family members of all patients, and eligi- posttest blood gas in 10 patients. Cardiac arrhyth- bility was determined by LIFESOURCE. The mias or cardiac arrest was not observed. None of the conversion rates were calculated as actual brain death patients developed a pneumothorax. Unsuccessful donors/all patients who were declared brain dead.

1242 Neurology 71 October 14, 2008 These conversion rates were 81% for 1996–1999, apnea test was expectedly more common in patients 67% for 2000–2003, and 70% for 2004–2007. with multitrauma prone to hemodynamic instability. Several more patients had brief hypotension or hy- DISCUSSION There were several new observations poxemia at the completion of the apnea test, but in our detailed review of a large series of brain death without noticeable clinical consequences. Most im- determinations. First, a majority of patients who suc- portantly, cardiac arrest or pneumothorax from high- cumb to brain death after being admitted to a tertiary flow oxygen insufflation was not observed in 212 center can be declared within 3 days of admission, apnea tests in our study. These findings are different and even one-third of patients can be declared on the from our earlier experience in apnea testing. In a same day. This seemingly trivial finding has impor- prior study, hypotension occurred in 24% of apnea tant practical implications for patients who may be- tests, in particular among patients without preoxy- come candidates for . If clinically genation measures.9 In our study, preoxygenation be- likely, physicians should allow patients to progress to fore the start of the apnea test resulted in marked brain death after all possible interventions have hyperoxia, and adequate oxygen administration dur- failed. A practice of early withdrawal of support in ing the procedure likely contributed to the low prev- these patients limits possibilities for donation, be- alence of complications. Pulmonary edema, cause it could only—after consent—result in contusions, or pneumothorax may hamper passive retrieval. Even when a “Donation after Cardiac transport of oxygen flow across the alveolar–arterial Death” protocol is operational, such a measure will anatomic space, but we were unable to predict the result in fewer transplantable organs per patient. In development of oxygen desaturation before the ap- our series, eight patients could perhaps have been nea test was initiated. organ donors if further time had been allowed for the Finally, hospital guidelines on brain death deter- patient to fulfill the clinical criteria of brain death. mination vary significantly among hospitals in the Second, acute hypotension and often polyuria sig- United States and countries around the world, but nal the moment of brain death. All patients devel- the clinical practice is largely unknown.10,11 This oped hypotension requiring vasopressors, and a study, for the first time, provides data on the actual majority required vasopressin for treatment of diabe- practice of declaring brain death in a tertiary institu- tes insipidus. Hypotension is therefore a defining tion. Our study noted a shift toward brain death test- characteristic of transition to brain death. The high ing by practicing physicians in the neurosciences. prevalence of diabetes insipidus is primarily related Although in principle all physicians are qualified to to increased intracranial pressure and brain tissue determine death by cardiac or neurologic criteria, shift, damaging the hypothalamic–pituitary axis. We most determinations were performed by neurolo- found hypernatremia in 40% of the patients, and gists, neurointensivists, and neurosurgeons. This therefore a considerable proportion of patients were gradual unsolicited increase can be in part attributed intravascularly volume depleted. Vasopressin and to comfort level of physicians not familiar with disor- large amounts of fluids are needed to avoid marked ders of the nervous system, a preference to concen- dehydration. trate this effort, and a preference to have these Third, we may conclude from our study that the determinations performed by physicians with clinical apnea test—to passively increase PaCO2—is a safe expertise in the neurosciences. Our study did not and simple procedure. Typically, apnea testing is per- find an appreciable increase in organ donation due to formed using the apneic oxygen-diffusion technique. increased involvement of neurointensivists. This Preoxygenation and oxygen insufflation quickly in- contradicts a prior study that noted not only im- creases PaCO2 (through ), decreases proved documentation in brain death determination plasma pH and CSF pH, and stimulates the respira- but also increased organ donation consent rates in a tory centers in the medulla oblongata. neurosciences ICU.12 As a member of the Organ Do- The apnea test is a fixture in brain death determi- nation Collaborative launched by the Department of nation, but there is a perceived concern about the Health and Human Services, Mayo Clinic Rochester safety of the procedure. For appropriate reasons, in Hospitals has a conversion rate that is higher than the 7% of the patients in our series, the examiner de- national average rate of 69% (as of September 2007). cided not to proceed with the apnea test. In 3% of The national aim of the collaborative is a conversion patients, the apnea test was aborted because of hypo- rate of 75%. It is conceivable that the efforts of organ tension or hypoxemia. This became apparent usually procurement organizations rather than physicians within minutes of commencing the test, and no fur- determine consent rates.13 ther complications occurred after the patients were We need to acknowledge limitations in our study. reconnected to the ventilator. Failure to complete the Our study was retrospective, and we may not have

Neurology 71 October 14, 2008 1243 accurately appreciated the presence of brief cardiac injury, subarachnoid hemorrhage and intracerebral hemor- or blood pressure fluctuations. None- rhage. Intensive Care Med 2006;32:217–222. theless, we had access to clinical data, including vital 4. Practice parameters for determining brain death in adults (summary statement): report of the Quality Standards signs measured with intervals no longer than 5 min- Subcommittee of the American Academy of Neurology. utes. With our case identification method, we may Neurology 1995;45:1012–1014. have excluded polytrauma patients who—if tested 5. Sasposnik G, Maurino J, Saizar R, et al. Spontaneous and systematically—could have fulfilled the criteria of movements in 107 patients with brain death brain death, but were not registered because of irre- Am J Med 2005;118:311–314. versible shock and early cardiac arrest. 6. De Freitas GR, Andre´ C. Absence of the Babinski sign in The declaration of brain death occurs under com- brain death: a prospective study of 144 cases. J Neurol plex circumstances. Patients not only require a high 2005;252:106–107. 7. Ruiz-Garcia M, Gonzalez-Astiazara´n A, Collado-Corana level of ventilatory support, but also are supported by MA, et al. Brain death in children: clinical, neurophysio- both vasopressors and vasopressin to ensure adequate logical and radioisotopic angiography findings in 125 pa- arterial pressure and renal function. Only if oxygen- tients. Childs Nerv Syst 2000;16:40–45. ation is maintained can absent breathing drive be 8. Wijdicks EFM. The diagnosis of brain death. N Engl safely assessed. Failure to complete the apnea test J Med 2001;344:1215–1221. cannot be predicted, but is uncommon when an 9. Goudreau JL, Wijdicks EFM, Emery SF. Complications oxygen-diffusion technique is used. during apnea testing in the determination of brain death: predisposing factors. Neurology 2000;10:55: Received April 23, 2008. Accepted in final form June 26, 2008. 1045–1048. 10. Greer DM, Varelas PN, Haque S, Wijdicks EFM. Vari- REFERENCES ability of brain death determination guidelines in leading 1. Senouci K, Guerrini P, Diene E, et al. A survey on patients US neurologic institutions. Neurology 2008;70:284–289. admitted in severe : implications for brain death 11. Wijdicks EFM. Brain death worldwide: accepted fact but identification and organ donation. Intensive Care Med no global consensus in diagnostic criteria. Neurology 2004;30:38–44. 2002;58:20–25. 2. Bustos JL, Surt K, Soratti C. Glasgow coma scale 7 or less 12. Helms AK, Torbey MT, Hacein-Bey L, et al. Standardized surveillance program for brain death identification in Ar- protocols increase organ and tissue donation rates in the gentina: and outcome. Transplant Proc neurocritical care unit. Neurology 2004;63:1955–1957. 2006;38:3697–3699. 13. Rodrigue JR, Cornell DL, Howard RJ. Organ donation 3. Kompagne EJO, Bakker J, Slieker FJ, et al. Organ dona- decision: comparison of donor and non donor families. tions and unused potential donations in traumatic brain Am J Transplant 2006;6:190–198.

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1244 Neurology 71 October 14, 2008