Final Diagnosis -- Acute Combined Drug Overdose of Ethanol, Acetaminophen, Imipramine, Desipramine, Oxycodone and Diphenhydramine

WHAT IS YOUR DIAGNOSIS? :

This case illustrates an instance of death in a 49 year old white female as a result of Acute Combined Drug Overdose of Ethanol, Acetaminophen, Imipramine, Desipramine, Oxycodone, and Diphenhydramine. The manner of death is a suicide.

DISCUSSION:

This case illustrates a typical scenario of a multi-drug induced (poly-pharmacy) suicide in a white woman and brings to discussion several specific aspects of forensic toxicology. It also highlights the importance of clinical laboratory tests in the determination of cause and manner of death, especially in overdose related accidental and suicidal deaths. The discussion covers the epidemiological aspects related to this case and emphasizes the differences in tissue sample requirements and analyses between a clinical and a forensic toxicology laboratory. Special attention is given to analysis and implication of acute alcohol intoxication, as the most prevalent substance in accidental or suicidal deaths.

1. EPIDEMIOLOGY OF SUICIDE IN ALLEGHENY COUNTY:

Suicide constitutes a major public health issue in the United States and remains in the top ten leading causes of death accounting for over 30, 000 deaths annually. The incidence of suicides in Allegheny County reflects the national U.S. incidence at approximately 10 - 12 suicides per 100, 000 population, annually. While suicide attempts are more prevalent among women, completed suicides are more prevalent among men since women adopt less violent mechanisms of suicide. Women are more likely to commit suicide by drug overdose, while men are more likely to commit suicide by firearms. Between 1990 and 1999, a total of 1447 suicides were identified in Allegheny County with a male: female ratio of 4:1. Ages of suicide victims ranged from 13 to 94 years old. The age group with the highest rates of suicide was the 31 - 40 age group, which represented approximately 25% of all suicides. 90% of suicide victims were white and 9% were black. A suicide note was located in 29% (n=419) of the suicide cases. An analysis by race showed that 30% of whites, 18% of blacks and 22% of Asians left a suicide note.

The white male represents the single group with the highest rates of suicide and the black female represents the single group with the lowest rates of suicide. While black men are less likely to commit suicide than white men, there has been a recent epidemiological trend that is indicating an increasing numbers of suicides among teenage black men. The reason for this trend is not known.

2. TOXICOLOGY OF DRUG OVERDOSES:

At the Allegheny County Coroner's Office there are in-house algorithms for comprehensive qualitative screening and quantitative confirmatory analyses of every case. The specific screening and confirmatory protocols that will be applied to a case are determined by the prevailing forensic scenario of the case. The protocol that was adopted for this case was based on the outcome of the scene investigation including the categories of drugs that were recovered from the scene. If other drugs were discovered at the scene, some other screening analyses may have been adopted to match the findings of the scene investigation. The ten most common categories of drugs (lethal and non-lethal) that were identified by post-mortem toxicological analysis of body fluids among the 1447 suicide victims in Allegheny County were Ethanol (38%), Benzodiazepines (13%), Tricyclic Andidepressants (11%), Opioid derivative (9%), Non-steroidal Anti-inflammatory Drugs (8%), Cocaine (4%), Antiepileptics 3%), Cardiotropics (3%), Antipsychotics (3%) and Antihistamines (2%). Drug overdose suicide deaths represented 11% (n=163) of the 1447 suicide cases. The ten most frequent drugs involved in suicides by lethal drug overdose in Allegheny County are shown in Table 3.

The most common lethal substance detected in the 163 drug-related suicides was ethanol, which was present in 17.8% (n=29) of the cases. The second and third most common drugs detected were acetaminophen (Tylenol) and Amitriptyline, which were present in 16.6% and 12.3% of the lethal drug overdoses respectively. Lethal levels of ethanol, acetaminophen, Amitriptyline, Doxepin and Alprazolam represent 66.9% of the 163 lethal drug overdoses. Among the ten most common overdose drugs, all act as depressants on the central nervous system, with the exception of acetaminophen, a non-steroidal anti-inflammatory agent.

Tricyclic antidepressants (TCA) are the number one cause of fatality from drug ingestion in the United States. Approximately 500,000 cases of TCA toxicity per year are reported in the US and fatality occurs in approximately 70% of patients attempting suicide with TCAs before reaching a healthcare facility. Only 2-3% of TCA overdoses that reach a health care facility result in death. Mild to moderate poisoning usually occurs when more than 10 mg/kg of tricyclics is ingested. Such patients may present with dilated pupils, dry mouth, drowsiness, sinus tachycardia, urinary retention, increased tendon reflexes, and extensor plantar responses. Severe poisoning usually occurs when more than 15 - 20 mg/kg is ingested. These patients often present with coma and cardiac arrhythmias. Death from cardiac arrest may also occur. Symptoms usually appear within 30 to 60 minutes of ingestion, and reach their peak intensity within 4 to 12 hours. Significant postmortem redistribution can occur with all tricyclics.

Acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning in the United States. It is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world and is contained in more than 100 products. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults, although the at-risk dose may be lower in persons with alcoholism and other susceptible individuals. The toxic effects of acetaminophen are often seen 2-4 days after ingestion and blood levels may not be extremely high at time of death.

3. POSTMORTEM REDISTRIBUTION OF DRUGS:

Femoral blood is widely accepted as the most reliable postmortem specimen for drug analysis in forensic toxicology. There is considerable evidence that the drug concentrations in peripheral blood samples are closer to the antemortem level than the concentration in cardiac blood. In special cases where the diagnosis of overdose is to be used as judicial evidence, a single sample of blood may prove insufficient. In such cases, analyses of several samples of blood and tissue will increase the possibility of reaching a correct conclusion, but reference values on drug concentrations in tissues are often missing. The data suggests that there is a post-mortem diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs, into the blood with resultant artefactual elevation of drug levels in blood. Highest drug levels were found in central vessels such as pulmonary artery and vein, and lowest levels were found in peripheral vessels such as subclavian and femoral veins.

4. ALCOHOL INTOXICATION RELATED DEATHS

Alcohol is implicated in 200,000 deaths each year and the following represents important instances were alcohol has been implicated:

  1. 50% of deaths by motor vehicles and fires are alcohol related
  2. 67% of murders are alcohol related
  3. 33% of suicides are alcohol related
  4. 67% of all incidents of domestic violence are alcohol related
  5. 33% of all cases of child abuse are alcohol related

Once ingested, alcohol (ethanol) is absorbed into the blood system and further distributed into the tissues. The concentration of alcohol in blood and tissue depends on the amount of total body water, since alcohol is soluble in water. Therefore, the weight of an individual is important in the analytical process of alcohol intoxication. Once ingested, alcohol is absorbed mainly in the small intestine, and to some extent, in the stomach as well as the colon. A delay in stomach emptying will delay the absorption of the majority of alcohol into the patient's system through the small intestine. The liver is the major organ to metabolize and eliminate alcohol. The metabolism of alcohol is a linear function of time, and it can be affected by increasing the concentration of alcohol in the blood. The mean rate of alcohol elimination is about 100 mg/kg/hr. It is well accepted that the time from the last drink to maximal concentration in blood usually ranges from 30 to 90 minutes. This information is important in assessing whether an event such as accident, murder, suicide, etc occurred while the individual had reached the peak level of blood alcohol content, and was on the rising limb of the curve, or whether the individual was on the down slope of the curve after having reached the peak blood alcohol concentration.

Alcohol contents of body fluids are of major importance in the forensic toxicologist's analysis in the criminal arena and commonly in the worker's compensation arena. The interpretation of the analytical results obtained from autopsy material has difficulties as a result of lack of homogeneity of blood samples, microbial alcohol production post mortem, alcohol diffusion from gastric residue and contaminated airways, and the lack of or unreliability of information on the clinical condition of the person immediately prior to death. At the same time, post mortem analysis allows the ability to measure other body fluids for alcohol content, which are usually not accessible otherwise. Nevertheless, interpretation of post mortem alcohol must take into the account the totality of the available information. A single autopsy blood alcohol level is uninterpretable without concurrent vitreous humour and urine alcohol levels, as well as information gleaned from the scene of the accident. Human plasma contains approximately 10-15% more water than whole blood. Therefore, it can be expected that the plasma alcohol content is approximately 10-15% higher than the corresponding whole blood concentrations. These facts must be taken into account when analyzing post mortem and comparing to pre-mortem hospital samples of serum or plasma analysis of alcohol.

The forensic toxicology evaluation of alcohol abuse effects requires blood alcohol samples. When blood samples are analyzed for forensic purposes, civil or criminal, a standard procedure is to make duplicate determinations. The concentration of blood alcohol should be reported with the confidence limits such as 95% or 99%. Therefore, it is imperative that in clinical chemical laboratories, the calibration of standards test by biological specimens along with the unknowns be done and kept on record for forensic evidence. The analysis done by clinical lab (such as a hospital lab) and a certified forensic lab are different. Forensic laboratories receive samples of whole blood which are commonly hemolyzed, and often contain clots, where clinical laboratories receive plasma or serum. The content of water in these specimens is not the same, and the results of analyzing alcohol at the clinical laboratory should not be used for forensic analysis without an appropriate correction for the difference between whole blood and plasma or serum.

Analysis of vitreous humour is useful to corroborate the post mortem blood alcohol and assist in assessing and extrapolating to anti-mortem intoxication from post mortem alcohol production. Vitreous alcohol can also serve as an alternative sample if a satisfactory post mortem blood sample is unavailable or contaminated. In most cases the specimen is easily obtained, and can be sampled without a full autopsy. Vitreous alcohol is also important, because studies have shown post mortem putrefaction does not contribute to the alcohol levels measured in the vitreous. Blood has lower water content than vitreous so the expectation is that the blood vitreous alcohol ratio will be less than 1. In cases where the ratio of blood to vitreous humour alcohol concentration exceeds 1, the most likely explanation is that death occurred before diffusion equilibrium had been obtained, and this observation may be of forensic significance.

Bladder urine alcohol does not necessarily reflect the blood alcohol concentration existing at the time of death. The use of urine alcohol collected post mortem is not practical for forensic purposes.

Decomposition influences postmortem concentration of alcohol , due to endogenous postmortem production. Alcohol concentrations can reach 1500 mg per liter within a few days, and physical disruption of the body can enhance post-mortem alcohol production. Post-mortem urine and vitreous fluid, however, are largely free of this effect. Blood alcohol (ethanol) concentrations in decomposed bodies can mean drinking during life and/or endogenous production after death. The correct interpretation is important in medico-legal cases.

BONUS: A SHORT REVIEW OF TECHNIQUES USED IN THE TOXICOLOGY LAB

There are several methods to detect drugs in the urine. The most frequent one is an enzyme immunoassay (EIA), or radioimmunoassay (RIA), and florescence polarization immunoassay (FPIA). There are additional more sophisticated methodologies which are performed on extract of urine which are performed using thin layer chromatography (TLC), gas chromatography (GC) high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GS/MS). The only accepted procedures based on the definition of the National Institute of Drug Abuse (NIDA), and the Department of Defense (DOD), are immunoassays followed by gas chromatography/mass spectrometry confirmation. The confirmation utilizing gas chromatography/mass spectrometry is required since the methodology of immunoassay can give false positive results due to cross reactivity. This is due to the fact that this methodology cannot specifically identify the drug, but rather the antibodies recognize substances which may have the same structure chemically, or immunologically or enzymologically, other than the drug of interest. Immunoassays for amphetamines will show reactivity with drugs structurally related to amphetamines, such over-the-counter sympatomedicoamines, phenylpropanolamine and ephedrine, over-the-counter legal medications used for nasal congestion, cold and appetite suppressant. Confirmation therefore is a must utilizing gas chromatography/mass spectrometry. The use of gas chromatography/mass spectrometry provides an extremely high index of reliability when properly preformed and applied.

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Contributed by DN Ionescu, MD, JK Janssen, MS, BI Omalu, MD, MPH



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