Health Professionals

Statement of Grover M. Hutchins, M.D. "Review and Analysis of 276 Adverse Event Reports in FDA Docket."

Introduction

1. I am a Professor of Pathology at The Johns Hopkins University School of Medicine and a member of the Active Staff of The Johns Hopkins Hospital. I also have appointments as a visiting pathologist at The Bayview Medical Center and the Baltimore VA Medical Center. I received the degree of bachelor of arts in 1957 and a doctorate in medicine in 1961, both from The Johns Hopkins University. From 1961 until 1965 I trained in anatomic pathology at The Johns Hopkins Hospital. I then spent one year in a fellowship in experimental pathology at the Scripps Clinic and Research Foundation in La Jolla, California. Subsequently, I returned to Baltimore and have been on the staffs of The Johns Hopkins Medical Institutions since. I became board certified in anatomic pathology in 1972, and in pediatric pathology in 1990. My publications, grant support, and extramural activities are detailed in my curriculum vitae, a copy of which is attached.
2. My professional activities have been related to anatomic pathology with a major emphasis on hospital-based autopsy pathology. Within the field of autopsy pathology I have had special interest in cardiovascular, pulmonary, and pediatric diseases. My work, exclusive of a minor component of administrative activities, has long been approximately equally divided among closely interrelated service, research, and teaching activities.
3. I have been asked to review certain adverse event reports (AERs) developed by the Food and Drug Administration (FDA) where there was concern that the consumption of ephedrine alkaloids may have played a causative role in the adverse event. In particular, I was asked to examine those cases where a death had occurred.

Methods

1. In conducting my review of the AERs reporting a death, I have looked for the most likely cause or a likely differential diagnosis of the cause of the individualís event. I have used my training and experience in correlating clinical and pathologic information derived from autopsies to these AERs to develop opinions on causation.
2. In examining the likelihood of any causative role of ephedrine alkaloids in the events, I have considered the group as a whole for a likely and consistent pathogenetic process that could account for the events. There are a number of conditions where exposure to an environmental or chemical agent may lead to well-characterized pathologies. A few examples of such agents include: asbestos, silica, coal dust, tobacco smoke, ethyl alcohol, non-steroidal anti-inflammatory drugs, and fenfluramine. Observation of the pathologic changes characteristic of the substance, even without knowledge of a history of exposure, is usually sufficient for an experienced pathologist to at least suggest that exposure to the agent had occurred. Thus, in my review of the AERs, I was seeking evidence for the existence of a similar coherent pathogenetic explanation for the events.
3. I have reviewed 22 AERs involving a death. The following is a short summary and a statement of my opinion about each case.

A 38-year-old male who had taken Ripped Fuel for about one year at the recommended dosage had a sudden collapse after jogging and could not be resuscitated. Autopsy showed an enlarged heart with two-vessel coronary artery disease. Toxicology on postmortem blood showed an ephedrine level of 0.11 micrograms per milliliter.

More probably than not, death was due to an arrhythmia arising from coronary artery disease in an individual recently engaged in exercise. This was also the interpretation of the pathologist performing the autopsy. The likelihood that ephedrine would have been a contributing factor in the death is remote given the history of regular and appropriate usage and the blood level found.

12506

A 32-year-old woman, who may have taken Escalation, was found unresponsive at home, and declared DOA at a local facility. Autopsy showed an enlarged heart with the typical findings of asymmetrical hypertrophy, also known as idiopathic hypertrophic subaortic stenosis (IHSS). Toxicology on postmortem blood was negative.

Death in this case is due to IHSS, a well-known cause of sudden unexpected deaths. There is no basis to invoke a role for ephedrine in the death given the absence of both a history of ingestion and toxicologic evidence of its presence in the body.

12594

A 5-day-old female was the product of a pregnancy during which the mother had taken Ripped Fuel. The baby was born at 34-weeks gestation by precipitous delivery following 36 hours of ruptured membranes. Birth weight was 2,090 grams and Apgars 8 at one minute and 9 at five minutes. The baby developed necrotizing enterocolitis (NEC), demonstrated at operation to involve all of the small intestine except the proximal 16 centimeters of jejunum and the large bowel down to the level of the distal sigmoid colon. The child was deemed inoperable and allowed to die. No autopsy was performed. There are no toxicology studies.

The pathogenesis of NEC is poorly understood. A body of opinion holds that exposure of the intestinal tract of premature infants to bacteria or other infectious agents may be a major causative factor. The prematurity of this infant and the prolonged rupture of membranes would be consistent with these factors being the cause of the NEC. It is highly unlikely that ephedrine, even if present, would have played any role in this infantís NEC.

12720

A 22-year-old male had consumed Ripped Fuel, reportedly for the last time about two months prior to his death. As a student he was in training for an athletic event and needed to make a certain weight through rapid reduction in his body weight. To that end, he engaged in alternating periods of exercise and exposure to a sauna while dressed in a rubber suit and sweat suit. He was observed to develop a state of alternating periods of reduced consciousness. A pulse was initially present but was then lost, and despite resuscitation attempts, he died. Shortly before death, a rectal temperature of 108ƒF was noted. Death investigation showed rectal temperature to be 107ƒF one hour after death. Autopsy showed no gross abnormalities. Blood toxicology showed "2. Less than 0.01 mcg Ephedrine & Pseudoephedrine/ml ‚ if any." Curiously, this result is interpreted on the report as showing that these agents may have contributed to ". . . the cardiac events of this death. . . ."

My opinion is that this young man died of hyperthermia in the context of an attempt to achieve rapid weight loss, an opinion that is the same as that of the pathologist who performed the autopsy. It seems inconceivable that an agent taken many weeks prior to death and not detectable by toxicologic analysis could have been a contributing cause of death.

12722

This 21-year-old male had consumed Thermogenics plus and Prochrome II. Under circumstances similar to those of AER 12720, he was attempting to reduce his body weight from 170 or 174 pounds to 163 pounds in an approximately four-day period using an exercise bicycle and sauna and a reduced intake of food and fluids. He became unresponsive. He was initially breathing and had a pulse but rapidly progressed to arrest and could not be resuscitated. Body temperature was not measured. Autopsy examination showed no abnormal gross findings. Postmortem toxicology demonstrated values consistent with dehydration, rhabdomyolysis, and hyperkalemia. Ephedrine and pseudoephedrine were detected in a postmortem bile sample but not in postmortem blood.

More probably than not, death in this case was caused by dehydration and rhabdomyolysis with hyperkalemia, an opinion consistent with that of the pathologist who performed the autopsy. There is no reason to believe that ephedrine was a contributing factor to the death given its absence from the postmortem blood.

12843

A 15-year-old female, who may have taken Ripped Fuel, had sudden collapse during an athletic event and was pulseless and apneic. She was resuscitated but remained comatose and died three days later. An autopsy was performed, and it was determined that she had a congenital malformation of the heart, anomalous origin of the left coronary artery from the pulmonary trunk. This had led to extensive ischemic injuries of varying ages in the distribution of the left coronary artery. Also, changes due to chronic ischemia were found in the still viable myocytes in that distribution.

The malformation present in this heart arose during embryonic development and led to a state of ischemic caridomyopathy as a result of the altered blood flow pattern in the left ventricular myocardium. The condition is well-known to present for the first time as sudden cardiac death. There is no reason to believe that ephedrine was a contributing cause of death in this case, especially given the absence of evidence that the agent had been taken. Curiously, in the AER, most diagnostic statements about the specific cardiac malformation present in this case have been purged.

12871

A 46-year-old man, who may have taken products containing ma huang and guarana, had the sudden onset of a massive left hemisphere cerebral infarct while talking on the telephone. Investigative studies were interpreted as showing complete occlusion of the left internal carotid artery at its origin. He became brain dead and an organ harvest was conducted four days after the event. A segment of the left carotid artery was submitted for examination and showed only minimal atherosclerosis. Plasma toxicology was negative for ephedrine and pseudoephedrine.

Death was due to a massive cerebral infarct caused by occlusion of the left internal carotid artery. It was not determined if the occlusion was caused by thrombosis, thromboembolism, or dissection of the artery. There is no basis for considering ephedrine to have been a contributing cause of death.

13021

A 43-year-old man had taken Ripped Fuel for several months and was thought to have followed the recommendations for its use. His father died of a myocardial infarct at age 50. The decedent had an elevated cholesterol. For one month prior to death he had chest pain after eating. On the day of death, he collapsed and could not be resuscitated.

More probably than not, given the family history, elevated cholesterol, and chest pains, he died of an arrhythmia induced by morphologic changes in a coronary artery atherosclerotic plaque. There is nothing to indicate that ephedrine was a contributing factor in his sudden unexpected death.

13096

A 37-year-old woman had taken Metabolife for a short period prior to her event. She had also used fenfluramine and phentermine for over a year, stopping a year prior to her death. The day prior to death she complained of sharp pains in her abdomen, which apparently went away. On the day of death she went to the bathroom and was discovered some time later on the floor in arrest and could not be resuscitated. An autopsy was performed, including toxicology, which failed to show any abnormality that would account for the death.

The pathologist who performed the autopsy ascribed the intervening cause of death to profound hypokalemia based on analysis of a blood specimen obtained 30 minutes after she had been pronounced dead. Such a determination is unreliable. In my opinion, the cause of death remains undetermined.

13127

This 37-year-old female who was six feet two inches tall, and may have had bipolar disorder, had a sudden death. It was determined that she had purchased multiple over-the-counter medications, but the extent of her ingestion of these materials was unknown. An autopsy was performed with examination of the heart by a consultant who found it to weigh 590 grams, and to have typical, marked, pathologic changes of floppy mitral valve.

Death in this case is entirely attributable to an arrhythmia arising in a heart with floppy mitral valve, a condition well-known to be associated with sudden unexpected death. There is no information that suggests that the over-the-counter products present in the home contributed to her death.

13380

This 26-year-old man had taken Ultimate Orange. About ten minutes into his workout in a gymnasium he had a seizure. Over the course of time he became unresponsive and, upon medical investigations was found to have subarachnoid and interventricular hemorrhage believed to have arisen from rupture of an intracerebral aneurysm. He died and no autopsy was performed.

Based on the available information, it is more likely than not that death was caused by rupture of an aneurysm in the cerebral circulation. There is nothing to suggest that any dietary supplement contributed to his death.

12859

A 34-year-old man on active duty in the military underwent a three-week regimen of weight loss during which he took eight different dietary supplements. Three days prior to his fitness run, he stopped eating. During his two mile run he collapsed and was found to be in sinus tachycardia and severely dehydrated. Over subsequent days he manifested renal failure; gluteal, thigh and leg compartment syndrome; and multiorgan failure as a result of rhabdomyolysis. Death occurred six days after his collapse. No autopsy was performed.

The fatal rhabdomyolysis in this case is entirely explained by heavy physical exertion in a state of fasting and dehydration.

13032

A 32-year-old man who had reportedly taken St. Johnís Wort for several months was found dead in the morning. An autopsy was apparently performed since it is stated that there was no trace of a malignant melanoma noted two years before.

Information on this case is extremely limited, and it is classified as an unexplained death.

13634

This 49-year-old male was said to have a history of "congenital cardiomyopathy." Metabolife may have been taken the day of or the day prior to death. An autopsy may have been performed, but the findings are not provided.

More likely than not, based on the scant information available, death was caused by cardiomyopathy.

13706

A 41-year-old female who had been taking Metabolife for two or three weeks had a sudden collapse and could not be resuscitated. Autopsy demonstrated an approximately 1,000 milliliter hemopericardium which had originated from a rupture of a markedly dilated aorta.

The cause of death in this case is the aortic dissection. That the ruptured aorta was markedly dilated is indicative of a long-standing process, more likely than not a form of the genetically determined connective tissue disorders that account for a large proportion of the aortic dissections that occur in younger individuals without other predisposing causes of dissection.

13762

A 37-year-old female with a past history of hypertension, for which she was under treatment, developed an intracranial hemorrhage during a workout which led to her death. She may have taken Thermadrene. No autopsy was performed.

Fatal intracerebral hemorrhages are associated with systemic hypertension.

13802

A 59-year-old woman had a poorly characterized illness of a few days duration involving chest pain, coughing, and dizziness. She then collapsed and died. She had taken small quantities of Metabolife, but none for the week prior to death. Apparently no autopsy was performed.

The decedent had been ill for a time prior to death, but the exact cause of death is uncertain. Leading possibilities would be cardiac or pulmonary process.

13806

This 37-year-old man collapsed unexpectedly and was found at autopsy to have a significant obstructive lesion of his left anterior descending coronary artery. An autopsy was performed but the details are not available. He had taken Metabolife for about two weeks prior to death.

From the available information, it is more likely than not that the death is entirely explained by coronary artery atherosclerosis.

13901

A 42-year-old female had had "flu-like" symptoms for three days prior to a sudden collapse with respiratory distress. She was said to have taken Herbalife Thermojetics. Autopsy demonstrated the presence of acute myocarditis. Postmortem toxicology found phenylpropanolamine but no ephedrine.

It seems more probable than not that the cause of death in this case is an arrhythmia arising from the myocarditis that was found at autopsy. As in most cases of myocarditis, the cause of the myocardial inflammation in this individual remains unknown.

13906

This 26-year-old man had taken Ripped Fuel for about two weeks prior to death. His death occurred from an acute dissection of the aorta following episodes of chest pain several days before. Of particular note, there was a history of several other family members who had had aortic dissections.

As in AER 13706, the cause of death is aortic dissection more probably than, than not secondary to a genetic abnormality of the structural tissues of the aorta.

13914

A 21-year-old man had taken two capsules of Hydroxycut prior to a physical agility run during a training exercise. During the course of the run he collapsed and could not be resuscitated. Autopsy demonstrated focal myocarditis. Toxicology on urine and blood showed ephedrine in low therapeutic ranges.

More probably than not the death of this individual was the result of an arrthymia triggered by the myocarditis in the setting of physical exertion.

13993

This 59-year-old female with a history of hypertension and possible exposure to Metabolife developed a headache which progressed to a seizure and coma. She was said to have a "stroke" prior to her death. An autopsy was apparently not performed and there was no mention of toxicology studies.

In the absence of medical records it is difficult to be certain, but it would seem probable that the "stroke" was an intracerebral hemorrhage in light of her history of hypertension.

1. The 22 AERs reviewed and briefly described above do not show any consistency of clinical or pathologic features nor do they show that exposure to ephedrine was a more likely than not contributing or causative factor in the deaths.

Four deaths are entirely attributable to a structural abnormality of the heart that had arisen during the formation of the heart. These cases are 12506 with IHSS, 12853 with anomalous origin of the left coronary artery from the pulmonary trunk, and 13127 with floppy mitral valve. Case 13634, described as having "congenital cardiomyopathy," is included here, as well.

Three deaths were the consequence of attempts at rapid weight loss by fasting and exercise. In 12720, death was caused by hyperthermia; in 12722, by hyperkalemia arising from rhabdomyolysis; and 12859, by rhabdomyolysis during exertion.

Three deaths were more probably than not the result of coronary artery atherosclerosis. These are 12485, a death after jogging; 13021, a man with risk factors and premortem symptoms consistent with ischemic heart disease; and 13806, a man found to have severe left anterior descending coronary artery obstruction at autopsy.

Two deaths occurred in individuals found to have myocarditis at autopsy. In 13901, there was acute myocarditis, and in 13914, a death during exercise, focal myocarditis was demonstrated.

Two deaths were caused by dissections of the aorta. In 13706, the aorta was dilated, and in 13906, there was a familial history of aortic dissections.

Four deaths are the result of cerebral vascular disease. In 12871, the cause of the internal carotid occlusion remains unknown. In 13380, the intracranial hemorrhage more likely than not arose from a ruptured aneurysm. In 13762 and 13993, the explanation of death is hypertensive intracranial hemorrhage.

Two miscellaneous events include 12506, with death of a 5-day-old infant from necrotizing enterocolitis, a disorder of uncertain etiology, and 13802, a female dying after a short course of a flu-like illness, possibly related to pulmonary or cardiac disease.

Two cases, 13032 and 13096, have no explanation for the death.

The 22 AERs reviewed and briefly described above that involved a death do not show any consistency of clinical or pathologic features nor do they show that exposure to ephedrine alkaloids was a more likely than not contributing or causative factor in the death.

It is only in the last two unexplained events from the total of 22 events reviewed that the use of ephedrine alkaloids could be a speculative explanation for the adverse event. It should be noted that the occurrence of two unexplained deaths from a total of 22 unexpected deaths is consistent with general experience in death investigation.

Grover M. Hutchins, M.D.

September 22, 2000

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