Abstract
Acute alcohol (ethanol) toxicity is a definition that encompasses both the metabolic toxicity of alcohol and the association of alcohol with traumatic deaths, suicide, and criminal activities. As with any postmortem measurement, there must be control of postmortem sampling, storage of specimens, and appropriate analysis to ensure that there is not artifactual alcohol production or incorrect measurement of other postmortem alcohols. It is almost unheard of for acute alcohol toxicity to cause death secondary to metabolic effects in a naïve individual, although there has been a recent trend in social media dares that have led to deaths due to isolated episodes of extreme alcohol consumption. However, in most cases, there will be evidence for chronic alcohol misuse at the postmortem examination.
Introduction
Alcohol consumption is an accepted social norm in many societies. However, the consumption of excess alcohol has a significant association with premature mortality (1,2).
When writing a review, it is useful to be able to define what is to be reviewed. Unfortunately, there is a lack of clarity in the literature as to the concentration of alcohol that allows a death to be attributed to acute alcohol toxicity. The range in the published literature is 74–680 mg/dL, but with a woeful lack of detail in many of the case reports. The mechanism of death when attributed to acute alcohol toxicity is almost never ascertained.
Sudden death in an individual who abuses alcohol is a familiar scenario for anyone involved in medicolegal autopsy practice. These cases present a number of difficulties as the history may be lacking or minimal and an anatomical cause of death may not be readily apparent.
There has been a less familiar but worrying emergence of young people, with no history of alcohol abuse, dying from genuine acute alcohol toxicity after undertaking online stunts which involve players filming themselves downing drinks and posting the videos, daring each other to outdo the stunts with increasingly large amounts of alcohol or in dangerous situations.
As well as acute alcohol toxicity as a primary mechanism of death, there is a strong association between alcohol toxicity and deaths due to accidents, violence, and suicide. As the deaths attributable to acute alcohol toxicity almost always occur in those who have a history of alcohol dependence, there may be pathological findings in the heart, liver and brain associated with chronic alcohol misuse.
As with any drug measured at postmortem, there are significant confounding factors regarding the interpretation of the measured result. Alcohol may be both produced, with postmortem concentrations of up to approximately 200 mg/dL in some extreme cases, as well as being metabolized, making it imperative that as much information is gathered as possible about the circumstances of death.
There is a general consensus of among pathologists and toxicologists that a blood ethanol concentration of greater than 400 mg/dL can be used to ascribe acute alcohol toxicity cause of death if no other cause of death is apparent. Many of us will consider it a possibility at concentrations above 350 mg/dL. However, the published literature has figures of 225–400 mg/dL (3), 350–400 mg/dL (4), 400 mg/dL (5), >350 mg/dL (6), and, based on the pathologists conclusions, 74–680 mg/dL (with a mean of 360 mg/dL) (7). Unfortunately, all bar the last study are flawed in their reporting as they lack full details regarding the sampling site, sample type, storage of samples, and methodology. It is also unclear that all cases reported were actually due to acute alcohol toxicity rather than the alcohol being a contributory factor in the death, such as contributing to a road traffic collision.
A further complication is that death may be due to acute alcohol toxicity when other drugs which have similar or synergistic negative effects on consciousness levels or respiratory drive. Such drugs would include benzodiazepines, opioids, antiepileptics, and antipsychotics. These drugs may have been administered either therapeutically or illicitly. Even when these drugs are present at therapeutic concentrations, the blood alcohol concentration (BAC) required to cause potentially fatal acute alcohol toxicity is likely to be lower.
Discussion
Association of Acute Alcohol Toxicity to All-Cause Mortality
The literature often does not allow for differentiation of the causes of mortality beyond it relating to acute poisonings, alcohol-related disease, accidents, homicide, or suicide (6, 8–15). Acute alcohol toxicity is the most common reported mono-substance death (16–21). Death is often ascribed to respiratory depression but this may be speculative. The risk of death from respiratory depression is significantly increased when there are other central nervous system (CNS) depressants, that frequently involve benzodiazepines and opioids (5,9,22).
Acute alcohol toxicity will increase the risk of incidents. There is marked impairment of all perceptual, cognitive, and motor functions. Although there are varying legal limits for drunk driving across the world, between a third and a half of drivers killed in road traffic incidents were found to be positive for alcohol on postmortem toxicology testing (23–27). Acute alcohol toxicity has a similar prevalence in case reports of deaths from falls, fire, and drowning (10, 23, 24, 28–31). The other significant area in which acute alcohol toxicity has a significant contribution is that of positional asphyxia (32,33).
As well as accidental deaths, there is a strong association of acute alcohol toxicity and violence to third parties (34). Alcohol is detected in up to 50% of victims of violent homicides (22, 24, 35, 36). The cognitive changes of acute alcohol toxicity lead to a strong association of acute alcohol toxicity and suicide, with 40% of cases of suicide having alcohol present at postmortem examination (24,37,38).
Epidemiology of Deaths from Acute Alcohol Toxicity
The epidemiology of acute alcohol toxicity is poorly researched. The only extensive study from New South Wales found only 0.75% of cases over a decade of retrospective study had postmortem femoral blood concentrations over 300 mg/dL (39). They reported that only half of these cases were considered to be death due to acute alcohol toxicity. Of these cases, a third of cases died due to accident, suicide, or homicide. A third of the cases with concentrations of over 300 mg/dL had pathological findings sufficient to report the death as due to the chronic effects of alcohol.
Deaths from acute alcohol toxicity tend to occur in older males with often greater than a third of cases being over the age of 50 (16, 17, 20, 23, 26, 27, 39). The published data indicates death it is almost entirely in regular heavy drinkers or established alcoholics. The New South Wales study showed no variation in day or month in which death occurred.
Another interesting feature in the New South Wales study was that none of the individuals who died were in treatment programs for alcohol addiction as the time of their death (39).
Factors that Complicate Interpretation of Postmortem Alcohol Concentrations
One of the primary concerns of measuring alcohols in postmortem samples is that alcohols, including ethanol, are produced as part of the postmortem putrefactive process. As with any interpretation of postmortem drug concentrations, it has been recognized since the 1960s (40) that when interpreting postmortem alcohol concentrations the following information is essential: site and method of collection, time after death and the state of the body at the time of collection, condition of storage, use of preservatives and time from collection to analysis, and the method used for analysis.
To mitigate against postmortem redistribution, femoral vein blood sampling is recommended. This should allow standardization of results and inter-case comparison. The sampling of either cardiac or even pleural cavity blood will increase the risk of contamination of samples with alcohol that may have diffused from surrounding organs (e.g., stomach or lungs).
Analysis should ideally be performed by gas chromatography with flame ionization detection. This allows for reliable determination of ethanol even if there are other alcohols (e.g., propanol, butanol) and acetaldehyde contaminating the sample. Headspace analysis tends to be the favored sampling technique. With these techniques, intralaboratory variation is as low as 1% (41). However, even within the same laboratory, there is a larger variation in the postmortem blood alcohol concentrations between different body sites (42).
There are some case reports of unusual contaminants causing falsely high postmortem blood alcohol concentrations. Administration of intravenous fluids containing sugars such as mannitol provides a substrate for ethanol production (43). Contamination of femoral blood due to ante-mortem cleaning of a femoral wound with 70% ethanol has been reported as causing a falsely high blood alcohol at a later postmortem examination (44). Therefore, standardized techniques for collection must be followed to allow useful interpretation and to prevent false results being produced.
Metabolism of Alcohol
Death will often occur after the peak BAC has been reached. Alcohol will continue to be metabolized until the moment of death (45–47). After discontinuation of drinking until death, the BAC might decrease appreciably with reduction in heavy drinkers of 20 or 30 mg/dL per hour (48).
Sampling for Postmortem Alcohol Measurement
Use of Concurrent Specimens
Urine and vitreous samples are commonly provided alongside postmortem blood samples. The samples should be collected such as to have a final fluoride concentration of 2% w/v.
Because of variability in postmortem blood alcohol, it is recommended that supplementary samples, in particular vitreous fluid and urine, be obtained (49–51).
Ethanol is relatively stable in blood and other fluids during prolonged periods of storage at 4°C provided a fluoride preservative is present (52,53). In these two studies, when stored at 4°C after 12 months with fluoride added, the mean ethanol concentration in vitreous was 200 mg/dL compared with 121 mg/dL in specimens without fluoride. In the same studies, the concentration of ethanol in femoral blood samples with fluoride added decreased by 8% after 12 months storage at 4°C. The mean starting BAC was 175 mg/dL (range 39–360), which dropped to 161 mg/dL (range 30–340) after 12 months storage and the change was statistically highly significant (p < 0.001).
Samples should contain adequate fluoride to ensure a final concentration of 2% w/v. The fluoride ions are enzyme inhibitors that reduce the in vitro production of alcohol from the time of autopsy to time of analysis. They will have no effect on any alcohol production that may have occurred prior to sampling. It is of note that the vacuum containers produced for the collection of samples for glucose analysis contain insufficient fluoride to act as an effective preservative for postmortem work; however, these are still widely utilized.
Urine is a useful specimen as, if collected correctly, it is almost always sterile. It also, unless an individual suffers with diabetes mellitus or glycosuria (54–56), rarely contains glucose or other substrates for alcohol production. Hence, the urine results tend to be more reliable.
There has been extensive study of the quantitative relationship between urine alcohol concentration (UAC) and BAC (57). There is a shift in time curves between blood and urine (58). Hence, if there can be shown to be minimal postmortem alcohol production, it is possible to provide estimation of the status of alcohol absorption and excretion at the time of death (59,60). A urine: blood ratio less than or close to unity is indicative of incomplete absorption of alcohol. This likely indicates recent consumption. A ratio of 1.25 or more suggests that absorption and distribution of ethanol was complete by the time of death (59).
Vitreous fluid has a high water content and is remote from the gut and hence not prone to contamination, making it a useful specimen for postmortem ethanol determination. The reduction of contamination is important in cases where there may have been significant visceral disruption such as road traffic accidents where alcohol analysis is vital (61). However, vitreous may contain glucose, and this has been reported to cause falsely high ethanol results due to it acting as a substrate for postmortem ethanol production (62).
The concentration of ethanol in vitreous humour and in blood follow a similar time course with only a short lag time evident (63). As discussed above, there is adequate stability for a matter of weeks in vitreous humour if stored in a 2% w: v fluoride preservative (52,53). The blood: vitreous ethanol ratio is usually reported as being between 1.15–1.20: 1 (64–66).
Vitreous analysis for alcohol can be useful when a body has been embalmed (67). The constituents of embalming fluid are often not known at the time of the postmortem, or indeed afterwards, and often contain alcohols including methanol and ethanol. In such circumstances, it is useful to be provided with a sample of embalming fluid if this is available.
Individuals who have suffered head trauma secondary to alcohol toxicity may survive for several hours after the trauma. If there is clot formation from an intracerebral hemorrhage and hematoma formation, the hematoma ethanol may provide a more accurate measurement of the ethanol concentration at the time of the incident (68–71). However, caution when interpreting the results is required as delayed subdural hemorrhage formation would give a negative result, whilst concentrations in slowly forming hematomas in hospitalized individuals might actually be higher in the hematoma than that which would have been present at the time of injury (71). Alcohol metabolism is variable, and alcohol diffusion rates will differ depending on the size of the hematoma and anatomical location.
Pathology of Acute Alcohol Toxicity
Many individuals who die as a result of alcohol toxicity have associated alcohol dependence, which is associated with high levels of systemic disease. Hepatic disease is almost universal in individuals who abuse alcohol, most commonly severe steatosis (72–75). Steatosis can progress to cirrhosis, which can lead to portal hypertension and consequent problems such as bleeding esophageal varices (76). Sudden arrythmogenic cardiac death is postulated to occur at a higher frequency in individuals who abuse alcohol, and in a study of Coroner's autopsies in a UK city, 0.5% were deemed to have died as a result of an alcohol associated arrythmogenic death (so called sudden unexpected death in alcohol misuse, SUDAM) (77). The diagnostic requirements of SUDAM is a death in a known alcohol abuser with low or absent alcohol detectable in the blood and liver steatosis with a morphologically normal heart.
However, high blood alcohol is associated with sudden death in a majority of cases. In a review of 263 cases with a blood alcohol concentration above 300 mg/dL, Darke found that the majority of decedents had cardiac disease, most commonly cardiomegaly, and ischemic heart disease, which was diagnosed in 31% (78). There is a complex relationship between alcohol consumption and heart disease, with low and moderate levels of alcohol consumption being associated with a protective effect against myocardial infarction (79,80), although higher levels of alcohol consumption are associated with increased levels of hypertension, atherosclerosis, congestive heart failure, and stroke. Certain cardiac diseases are very specific to alcohol abuse, and include alcoholic cardiomyopathy, which is the most common cause of dilated cardiomyopathy. This is usually seen in patients who abuse alcohol. The patients often do not have liver cirrhosis and have an increased left ventricular mass. On histological examination, there is an increase in interstitial fibrosis and fatty change in myocytes, although none of these change are specific for alcoholic cardiomyopathy (81).
Alcohol abuse can cause fatal pathology within other organ systems. A frequent disease seen in alcohol abusers clinically includes alcohol-induced pancreatitis (82), which can lead to complications including death, respiratory distress syndrome, peritonitis, disseminated intravascular coagulation, and sepsis (83,84).
Alcohol abuse can lead to a range of neuropathology, with or without coexisting vitamin or nutritional deficiencies (85). Acute effects of alcohol on the CNS are mainly caused by alcohol poisoning or hepatic dysfunction leading to encephalopathy or myelopathy. Alcohol poisoning can be fatal due to hemorrhage in the ventral diencephalon, mesencephalon, basal ganglia, and severe white matter edema. Hepatic encephalopathy is a neuropsychiatric disorder that is manifested by confusion, delirium, coma, and cerebellar and cognitive impairment. Acute hepatic encephalopathy is associated with severe liver dysfunction caused by continued alcohol abuse, leading to high concentrations of serum ammonia. Postmortem studies show that in hepatic encephalopathy the principal abnormality is noninflammatory brain edema. Acute hypoxic encephalopathy is characterized by increased prominence and abundance of Alzheimers type II astrocytes in deep gray matter structures.
Heavy alcohol intake is associated with an increased risk of an intracerebral hemorrhage at a younger age, and the risk increases in a dose dependent manner (86,87). Alcohol intake can increase blood pressure, and alcohol induced transient peaks in systolic blood pressure may increase the risk of stroke (86,88). Liver disease and its effect on coagulation may also add to the risk of intracranial hemorrhage, including the risk of hemorrhagic stroke (89), and subdural hemorrhage (90).
Knowledge of the circumstances of death can be vital, and in some circumstances, scene examination by a forensic pathologist is necessary to reach an appropriate conclusion. Positional asphyxia occurs when an individual is in a position that prevents effective respiration, and these cases often lead to death. There are numerous case reports of such events occurring in intoxicated individuals (32,91,92). In a study of 30 deaths due to positional asphyxia, chronic alcoholism or acute alcohol toxicity were found to be significant risk factors in 75% of cases (93).
There is also an association of acute alcohol toxicity with gastric aspiration. In cases in which there was aspiration of gastric contents, the postmortem blood alcohol was significantly lower (326 mg/dL) than in those where there was no aspiration (382 mg/dL) (46).
Hypothermia refers to a situation where the core body temperature drops below 35°C; it is a potentially fatal condition (94). Hypothermia may occur in immersion deaths, homeless individuals, and other vulnerable individuals (95,96) who may abuse alcohol, and alcohol may significantly contribute to hypothermia (96). Alcohol is often associated with such deaths and may prevent the appearance of adaptation responses to cold (97), leading to difficulties in reaching such a diagnosis.
Conclusion
The literature reviewed does not allow pathologists to be definitive as to the concentration of alcohol that may have caused death due to acute alcohol toxicity. As with any conclusions provided at autopsy, the patient's medical history, circumstances of death, and toxicology results are required. Although acute alcohol toxicity per se may not be the cause of death, alcohol toxicity may have had a significant contribution to death through its detrimental effects on cognitive function.
Footnotes
The authors, reviewers, editors, and publication staff do not report any relevant conflicts of interest.