Molina, D Kimberley MD; McCutcheon, J R. BS; Rulon, Jennifer J. MD
The Uniform Determination of Death Act of 1980 was intended to define the death of a person based upon neurologic criteria. However, it does not define the criteria, thereby leaving hospitals and clinicians to define their own protocols and policies. Powner et al1 found that there are many differences in medical practice concerning the definition of brain death. The majority of hospitals use a combination of clinical examinations, electroencephalograms, and cerebral blood flow studies, with or without repeat exams and confirmatory testing. However, the majority of hospitals also have exclusion criteria for the determination of brain death including hypothermia and the presence of drugs that depress the CNS. Wijdicks2 agrees that hypothermia and drug intoxication can both mimic brain death and should be excluded before a brain death pronouncement being made. Therefore, the determination of brain death, or cardiac death, should not be made if there is a concurrent intoxication with pentobarbital, a drug commonly used in head trauma patients.
Pentobarbital is a short-acting barbiturate (half-life, 15–50 hours) which is metabolized by the liver and cleared by the kidneys. It is often used in cases of head trauma or cerebral anoxia as it not only induces coma but it can reduce intracranial pressure and improve cerebral perfusion.3 In cases of brain injury, pentobarbital is usually maintained at a concentration of 25 to 40 mg/L (usual therapeutic, 1.2–4.7 mg/L), which overlaps with the fatal range for this drug (10–51 mg/L).3 Effects of pentobarbital include cerebral depression (including coma), decreased respiratory drive resulting in hypoventilation and apnea, bradycardia, hypotension, areflexia, and EEG flattening, all of which are potentially reversible with removal of the drug. Thus, it is easy to see how a brain death examination performed on a patient who is intoxicated with pentobarbital would not be valid; however, it should be noted that pentobarbital intoxication does not affect cerebral blood flow studies.
Summary of Cases
A 19-year-old man was involved in a motor vehicle collision and sustained severe closed head injuries, including cortical contusions of the brain, subarachnoid hemorrhage, diffuse axonal injury, and basilar skull fractures. On his third hospital day, he was placed in a pentobarbital coma to treat elevated intracranial pressures. On his sixth hospital day, the pentobarbital drip was discontinued and a brain flow study was positive for perfusion to the brain. The pentobarbital drip remained off and on the ninth hospital day, a second blood flow study was reportedly positive for blood flow to the brain but a clinical examination was consistent with brain death. He was taken off the ventilator and died.
His postmortem femoral blood pentobarbital concentration was 29.1 mg/L. The cause of death was determined to be craniocerebral injuries and the manner of death was ruled as accident. This was the first case our office had seen in which a significantly high level of pentobarbital was present in the postmortem blood sample and a comment was made in the conclusion of the report alluding to its presence.
A 32-year-old man was involved in a motor vehicle collision, sustaining multiple severe injuries, including a skull fracture, subarachnoid hemorrhage, cortical contusions of the brain, rib fractures, pelvic fractures, vertebral fractures, a splenic laceration, and long bone fractures. He was placed in a pentobarbital coma on the third hospital day to treat elevated intracranial pressures. On the fifth hospital day, a perfusion brain scan showed the presence of blood perfusion to the brain. On the eighth hospital day, the family decided to withdraw care due to the extremely poor prognosis and continued deterioration. They consented to live organ recovery. The patient was then transferred to the transplant service, still on the pentobarbital drip. On the ninth hospital day, the patient was taken to the operating room, removed from life support, declared “heart dead,” and his kidneys were recovered.
A postmortem femoral pentobarbital concentration was 31.5 mg/L. The cause of death was determined to be multiple blunt force injuries and pentobarbital toxicity. The manner of death was ruled unclassified.
A 15-year-old girl was involved in a motor vehicle collision and sustained multiple injuries including diffuse axonal injury, a fracture of the first cervical vertebra, a traumatic aortic pseudoaneurysm, pulmonary contusions, multiple rib fractures, right scapular fracture, bilateral lacerations of the kidneys, pelvic fractures, and a liver laceration. On her third hospital day, she was placed in a pentobarbital coma to treat increased intracranial pressures. She coded on her sixth hospital day, was successfully resuscitated and the pentobarbital drip was discontinued at this time. She remained off pentobarbital for 72 hours. A clinical brain death examination was then performed, she was declared brain dead, and care was withdrawn.
The postmortem femoral blood pentobarbital blood was 41.8 mg/L. The cause of death was determined to be multiple injuries and pentobarbital toxicity. The manner of death was ruled unclassified.
The 3 cases outlined above illustrate different scenarios in which a clinical determination of death was performed in the presence of significant concentrations of pentobarbital. In the first case, the pentobarbital drip had been discontinued for 72 hours, the patient had documented blood flow to the brain and a clinical examination formed the basis of the determination of brain death. In the second case, the individual had documented blood flow to the brain, and was declared “heart dead” in the operating room by the transplant service. In the third case, the pentobarbital drip had been discontinued for 72 hours, no brain flow studies were performed, and a clinical examination formed the basis of the determination of brain death. In all 3 cases, postmortem toxicology showed that they were all still heavily sedated thereby invalidating any clinical determination of death. Whether these patients were truly brain dead or not is not known.
Death is defined by the Uniform Determination of Death Act as “… either irreversible cessation of circulatory and respiratory functions, or irreversible cessation of all functions of the entire brain, including the brain stem, is dead.”1,2 The first part of the definition, which is often referred to as cardiac death, seems straight forward. A person who no longer has a heart beat, a pulse, or respirations is dead. The second part of the definition can be more difficult. In fact, how brain death is to be determined is not directly defined by the Act, only that “A determination of death must be made in accordance with accepted medical standards.” No standardized brain death protocol exists in the United States,1 though there are many commonalities in how hospitals and clinicians determine brain death.
Brain death is usually determined by a combination of factors including clinical examinations and confirmatory testing. Clinical criteria for brain death include: absent response to pain, absent motor responses, absent cranial response (corneal reflex, gag reflex, papillary response), and absence of respiratory drive (measured at PaCO2 >60 mm Hg).1,2 Confirmatory testing can include electroencephalography, cerebral blood flow studies or angiography, transcranial Doppler, and CT or MRI or nuclear imaging.1,2
Most hospitals also include exclusionary criteria for determining brain death, which usually take account of the presence of intoxicating drugs. However, even with these exclusionary criteria, most clinicians do not use drug level analysis to ascertain whether or not intoxicating drugs are present. In the case of pentobarbital, most brain death protocols call for cessation of the drug for a set period of time, usually 72 hours, before examination. Unfortunately, as cases 1 and 3 illustrate, waiting a set amount of time before the examination may not ensure that the drug has been removed from the system before evaluation as drug clearance may also have been affected by the injuries sustained. There are many variables to consider when analyzing the half-life and elimination of a drug. Factors include: volume of distribution which can be influenced by age, body mass, and pathologic fluid accumulations (ie, ascites, pleural effusions, anasarca); organ failure, including cardiac, renal, and hepatic; and the presence of other drugs.4 Cardiac failure can lead to decreased perfusion of the liver and kidneys, further limiting clearance.
Thus, individuals who have sustained massive trauma most likely will not clear drugs at the same rate as a healthy individual. In case 3, there were both liver and kidney injury present, and even after the 72-hour waiting period, the pentobarbital was present at an elevated concentration. In case 1, there were no other injuries except head injuries; however, head injury can also lead to cardiovascular collapse, which may affect drug elimination. Few studies have addressed the issue of pentobarbital elimination after trauma and most have small sample sizes (<10). Bayliff et al5 and Wermeling et al6 found that overall pentobarbital clearance was not affected by head injury; however, Wermeling et al did find “wide interpatient variability” with clearance rates ranging from 0.42 to 1.17 mL/min/kg. Bayliff et al5 had clearance rates which ranged from 1.2 to 3.1 L/kg. Schaible et al found that hypothermia may decrease the clearance of pentobarbital7 and Kozlowski et al8 showed that, in rabbits, hypotension induced by pentobarbital may also decrease the pentobarbital clearance rate.
Conducting a brain death examination while the patient is intoxicated with pentobarbital can lead to potentially disastrous complications, the least of which is the potential for litigation against the hospital or physician. The decision to withdraw care is often emotional and confusing for families. They may not fully understand the concept of “brain death” and its determination and the question of pentobarbital intoxication will only compound the situation. Families may experience guilt, feeling that they allowed their loved one to die when they may have been able to survive. They may express anger at the physicians for allowing the family to withdraw care when their loved one may not have been brain dead. The issues may be further compounded if, as in case 2, the patient is an organ donor and organs are harvested potentially from a nonbrain dead patient, in which case not only would the physicians caring for the individual be involved, but the transplant team as well.
Many patients who sustained head injuries and are placed in pentobarbital comas are victims of, or are involved in, a criminal activity resulting in death. Medicolegal autopsies are therefore performed to determine the exact cause and manner of death for possible future prosecution. Often, in such cases, toxicological analysis is performed on the antemortem blood samples to determine whether the decedent was intoxicated at the time of the trauma. However, if the postmortem sample is not analyzed as well, the issue of whether or not a medication was still present at the time of brain death examination may never be revealed. In fact, when the clinicians were first approached regarding the cases presented, and when this report was submitted to the clinical literature, the authors met with great skepticism that this was not actually occurring. It can be hypothesized that the reason this is not seen in more jurisdictions, and, in fact, was not seen at the BCMEO until recently, is because Medical Examiners were not looking for it.
It is important that medical examiners are aware of this potential situation and that toxicology testing is performed on both the ante- and postmortem blood samples. Should a medical examiner jurisdiction identify this situation in their area, it is imperative that they alert the clinicians responsible so that corrective action can be undertaken. The clinicians should be educated that, to avoid the issue of whether or not the pentobarbital would effect a brain (or cardiac) death examination, utilizing cerebral blood flow analyses to determine brain death would be preferable. If there is an absence of cerebral blood flow then the presence of pentobarbital is irrelevant. However, in the presence of documented cerebral blood flow, serial pentobarbital levels would be prudent to verify that the drug has been eliminated from the system before conducting the brain death examination, since simply waiting for clearance to occur within a predetermined time period does not seem to be reliable. Alternatively, serial blood flow studies may be useful if cessation of cerebral blood flow is anticipated. It is up to the forensic pathologist to lead the way for the clinicians regarding this issue and to make certain that brain death is being appropriately determined.
© 2009 Lippincott Williams & Wilkins, Inc.