Under the Microscope: Too Much Drug Will Kill You With No Doubt


In most countries, especially those with advanced economies and relatively sophisticated medical services, poisoning with medicinal compounds is common. In many such counties, poisoning with therapeutic substances exceeds deaths from other types of toxic agents, especially in suicidal and accidental poisoning. This is explained by the ease of access of such substances, whether they are obtainable from a doctor on prescription or on demand across the counter of a pharmacy. Where state- sponsored health services exist, the cost to the recipient may be minimal or absent and this ease of access contributes to opportunities for self-poisoning, whether it be deliberate self-destruction, suicidal gestures or accidental ingestion - the latter especially in children. Unfortunately, overprescribing or the supply of too great a quantity of drugs at one time allows excessive stocks of drugs to be easily available to the public. Though only a minority of victims of medicinal poison- ing fail to recover, there are still an appreciable number of deaths. These come to the attention of the investigative authorities and hence to pathologists. The autopsy investigation of a fatality from a therapeutic substance can be difficult, for a number of reasons:

-          The nature of the substance may be uncertain or unknown.

-          There may be more than one such substance involved.

-          There may be a delay between ingestion and death sufficient to allow blood, urine and tissue concentrations to decline below fatal, toxic or even therapeutic levels.

-          Analysis may be difficult to arrange because of lack of facilities.

-          Information about fatal levels may be unobtainable.

-          Most medicinal poisons leave virtually no characteristic features at autopsy, so diagnosis depends upon laboratory findings.

-          Post-mortem changes may make analysis difficult, inaccurate or impossible.

-          Where death is delayed after taking the substance, none may be recoverable from the stomach (which has emptied) or even from the intestine.

-          The original substance may be rapidly metabolized into one or more breakdown products, adding to difficulties in identification and interpretation.

 

The lack of characteristic autopsy appearances is often very frustrating for the pathologist. Unless there is an indicative or suggestive history as to which drug was taken - a matter for the investigators in respect of circumstances and recovery of containers - then an autopsy may have to be performed 'blind'. Where no significant morphological lesions can be discovered, then a full toxicology screen must be considered, which in some jurisdictions may be difficult or impossible to obtain, or be extremely expensive. The majority of modern medicinal substances are, by design, bland and non-irritant to the tissues and gastro- intestinal tract. Most of those met with in forensic practice are taken orally and, though the active constituents may be potent in their pharmacological effect on target organs and tissues, the medicine will cause no erosion or damage to the alimentary tract. Thus little or no physical evidence can be obtained from a gross or even microscopic examination of the gastrointestinal tract or other organs. Much of the physical bulk of modern tablets or capsules is merely the vehicle for introducing the active component into the body and is thus unlikely to have any adverse effect. When a medicinal compound causes death, the mode of death is most often some form of cardiorespiratory failure, often secondary to depressive effects on the central nervous system. This mode of death causes only non-specific changes discernible at autopsy, which are usually of no use in indicating the basic reason for the death. Acute congestive cardiac failure, pulmonary oedema, sometimes cerebral oedema, generalized organ congestion, scattered petechiae on serous membranes - none of these is of any real use to the pathologist, who has to rely on the results of toxicological analysis for a definitive answer. The toxicology laboratory conducts the technical assays, and produces qualitative and quantitative results. The toxicologist analyst interprets those results to the pathologist, by providing an indication of the therapeutic, toxic and fatal ranges of concentrations in various body fluids and tissues, and by pointing out problems such as decline from post- ingestion survival, conversion to metabolites and many others. The pathologist then collates this information with his own knowledge of the history and autopsy findings to offer the best interpretation of the investigation for judicial authorities. Most problems arise either because the information about the medicine (especially if it is newly developed or where its toxicity is low) is incomplete in terms of toxic blood and tissue levels - because post-ingestion survival has allowed the originally lethal levels to have subsided to therapeutic or even lower limits. What is offered in the remainder of this chapter is a digest of information about such potentially lethal levels, culled from a variety of sources. The ranges are often wide as most of the data are of necessity derived anecdotally, and the problems of uncertainty of dosage, variation in post- ingestion survivals and wide individual biological variation make it impossible to lay down strict thresholds between therapeutic, toxic and fatal concentrations. Wherever possible, the advice of the analytical toxicologist should be taken about each case - but where this is impracticable, then the following data and similar material, which is constantly being updated in forensic and toxicological publications, may be of assistance. The choice of substances is arbitrary, but represents the most common medicines seen in suicidal and accidental poisoning.

Aspirin is the most widely used therapeutic drug, being analgesic, antipyretic and anti-inflammatory. It was formerly very common as an agent of self-poisoning, both accidental in children and suicidal in adults. In Britain in the last two decades, its use as a self-poisoning agent has declined remarkably, so that fatalities are now rarely seen. The therapeutic dose is usually 325-975.mg, that is, 1-3 tablets. Rarely, persons with an aspirin hypersensitivity may become ill or even die after therapeutic doses, suffering urticaria, angioneurotic oedema, hypotension, vasomotor disturbances and laryngeal and glottal oedema.

Patients on long-term salicylate therapy for arthritic or rheumatic diseases may take 3-5 g/day and slowly reach blood concentrations which would be in the lethal range if caused by acute overdoses. Those on 3gIday have blood levels varying between 44 and 330 mg/l. Apart from deaths caused by hypersensitivity, death in an adult is unlikely with the ingestion of fewer than about 50 tablets, that is, about 16g. The blood concentration - (measured as total salicylate), from a medicinal dose of 975 mg, ranges from about 30 to 100 mg/l (with a mean of 77) 2 hours after ingestion. There is a rapid fall to around 25 mg/l some 8 hours later. At autopsy, aspirin is one of the few medicines that may cause some gross abnormalities, though they are not particularly specific. Externally there is nothing to see, unless vomiting has taken place, when dark or even red, bloody gastric contents may be expelled. Rarely, there may be some haemorrhagic manifestations in the form of skin petechiae.

Post-mortem toxicology requires the usual samples of blood, urine, stomach contents and liver. The mass of aspirin in the stomach may remain for several days in life, forming a partly insoluble concretion that may retard the absorption of the drug. This is why it is always worth washing out the stomach of a live victim, as a large proportion of the aspirin may be removed before it can cause systemic effects. With the advent of soluble aspirin or effervescent preparations, this aspect is lost as no such insoluble bolus forms. At autopsy, part of such a mass can be sent for analysis, whilst quick 'spot' tests can be carried out on another part. Such quick chemical confirmation may be performed in the autopsy room itself, by using a 10 per cent solution of ferric chloride. If a small quantity is added to a urine sample or to the surface of the tablet mass, an immediate purple-blue colour suggests aspirin. This is by no means specific, but is merely suggestive. If negative, however, then aspirin can be virtually discounted. These are only rapid screening methods and by no means replace proper laboratory analysis. Toxic blood levels (measured as total salicylate) begin at about 300-500 mg/l, though both death and survival are consistent with far higher or lower levels. Blood concentrations in fatal cases may range from about 60 to 7300 mg/l, some authorities suggesting that 500mgll is an average minimum level. The liver concentration in fatalities varies from 2.5 to 1000 mg/kg and urine salicylate from 20 to 1350 mg/l, emphasizing the wide levels that are compatible with life. Salicylate has a rather slow clearance rate from the blood, the half-life being up to a day in some massive overdoses. Aspirin poisoning is dangerous in that sudden cardiac arrest can occur in the absence of any toxic symptoms. This accounts for the deaths that take place after patients have been discharged fit from the emergency departments of hospitals. They may have seemed quite well and symptom free, but suffer a fatal collapse up to a day or so later. Fatal cardiac arrhythmias can supervene without warning and make it advisable, where possible', to admit patients with aspirin overdoses for observation for a day or so.

The tricyclic antidepressants are frequently involved in self-poisoning, partly associated with the type of patient for whom they are prescribed. Amitriptyline, dothiepin, doxepin and trimipramine have additional sedative properties. Those with little or no sedating action include protriptyline, nortriptyline, imipramine, clomipramine, iprindole, loperamide, desipramine and butriptyline. Tetracyclic antidepressants include maprotiline and mianserin. Other types include the monoamine oxidase inhibitors, which are well known to have dangers related to the concurrent ingestion of other drugs and foods, especially those with sympathomimetic action and tyramine content, such as rich cheese, yeast extracts, red wine and beans. Dangerous hypertension may ensue with the risk of cerebrovascular haemorrhage. Drugs of this class include phenoxypropazine, tranylcypromine, isocarboxazid and phenelzine. These widely used drugs are employed for their sedative and tranquillizing effects. A large number of both 1,4- and 1,5-benzodiazepines are available, divided into short-acting, intermediate-acting and long-acting compounds. Long-acting benzodiazepines include: flurazeparn, nitrazepam, diazepam, ketazalam, chlordiazepoxide, clobazam, chlorazepate, medazepam and alprazolarn. Intermediate- acting benzodiazapines include: loprazolam, lormetazepam, ternazepam, flunitrazeparn, lorazepam, bromazepam and oxazepam. A shortacting benzodiazepine is triazolam. This group of tranquillizer drugs includes: haloperidol (butyrophenone), chlormethiazole, chlorpromazine, fluphenazine, diphenylbutylpiperidine, promazine, trifluoperazine and prochlorperazine. The autopsy appearances are non-specific and toxicology may resolve any diagnostic problems if the death has occurred fairly soon after ingestion - which may often not be the case, when history and ante-mortern investigations can provide the only answer.

The massive problem posed by therapeutic administration of barbiturates until about 20 years ago has largely abated in countries with a responsible medical profession, which voluntarily refrained from the prescription of these drugs except where specifically indicated. Their use as sleeping tablets and general soporific sedative agents led to widespread abuse, so that at one time they were easily the most common agent of drug addiction. The development of non-barbiturate hypnotics, such as the benzodiazepines, helped to remove the need for the older and more lethal compounds. Unfortunately, barbiturates are still widely available on the illicit market, either alone or in combination with other substances such as amphetamines. Much lower blood levels will be found in fatal poisonings in the short-acting group as death may occur more quickly from the usual mode of action, a central depression of the respiratory centres.

At autopsy, the signs are of general cardiorespiratory failure, with often a cyanotic, congestive appearance. Though non-specific, probably the congested lungs in acute barbiturate poisoning are more intense than in any other condition. These organs may be almost black and the whole venous system is engorged with dark, deoxygenated blood. There may be 'barbiturate blisters' on dependent parts of the skin surface, especially buttocks, backs of thighs, calves and forearms, though as discussed in the chapter on carbon monoxide poisoning, these blisters are common to all states of deep coma. Internally there may be local signs of erosion from the drug itself. The gastric mucosa may be badly damaged from the alkaline attack of drugs such as sodium amytal which, being the sodium salt of a weak organic acid, hydrolyses in the stomach. The fundus may be thickened, granular and haemorrhagic. The cardia and lower oesophagus may be eroded from reflux and, if the victim regurgitates, then black, altered blood may appear at the nose and mouth. The capsules of certain barbiturates also leave characteristic traces in the mouth, oesophagus and stomach. The colour varies with the manufacturer, but the turquoise- blue of sodium amytal capsules may stain the stomach contents and even be visible through the wall of the intestine when the abdomen is opened. Other pigmented gelatine capsules can be red, yellow or blue.

Fatal insulin toxicity may be accidental, suicidal or homicidal. The accidental fatalities are usually examples of medical error, mostly from misreading the label on the box or ampoule. Insulin is, of course, inactive orally and has to be given by injection to perform its hypoglycaemic effect. At autopsy, where either from the circumstances or the finding of needle marks, insulin is a possibility, peripheral blood samples and skin and underlying tissue from the injection site should be carefully preserved, together with control skin from another site. The fine needles usually used by diabetics may leave virtually no mark on the skin.

Attempting to prove insulin-induced hypoglycaemia by measuring glucose levels in human post-mortem fluids is impracticable, due to the unreliability of such estimations after death. Very low vitreous humour glucose levels may strongly suggest hypoglycaemia, but are not absolutely acceptable.

 

Acknowledgements:

www.aived.nl    AIVD – @Erik Akerboom ©

www.politie.nl  Politiekorpschef  @Janny Knol©

www.politie.nl WEB Politie - @Henk van Essen©

 

Bibliography:

 

1.    Criminal Investigations – Crime Scene Investigation.2000

 

2.    Forensic Science.2006

 

3.    Techniques of Crime Scene Investigation.2012

 

4.    Forensics Pathology.2001

 

5.    Pathology.2005

 

6.    Forensic DNA Technology (Lewis Publishers,New York, 1991).

 

7.    The Examination and Typing of Bloodstains in the Crime Laboratory (U.S. Department of Justice, Washington, D.C., 1971).

 

8.    „A Short History of the Polymerase Chain Reaction". PCR Protocols. Methods in Molecular Biology.

 

9.    Molecular Cloning: A Laboratory Manual (3rd ed.). Cold Spring Harbor,N.Y.: Cold Spring Harbor Laboratory Press.2001

 

10.   "Antibodies as Thermolabile Switches: High Temperature Triggering for the Polymerase Chain Reaction". Bio/Technology.1994

 

11.   Forensic Science Handbook, vol. III (Regents/Prentice Hall, Englewood Cliffs, NJ, 1993).

 

12.   "Thermostable DNA Polymerases for a Wide Spectrum of Applications: Comparison of a Robust Hybrid TopoTaq to other enzymes". In Kieleczawa J. DNA Sequencing II: Optimizing Preparation and Cleanup. Jones and Bartlett. 2006

 

13.   Nielsen B, et al., Acute and adaptive responses in humans to exercise in a warm, humid environment, Eur J Physiol 1997

 

14.   Molnar GW, Survival of hypothermia by men immersed in the ocean. JAMA 1946

 

15.   Paton BC, Accidental hypothermia. Pharmacol Ther 1983

 

16.   Simpson K, Exposure to cold-starvation and neglect, in Simpson K (Ed): Modem Trends in Forensic Medicine. St Louis, MO, Mosby Co, 1953.

 

17.   Fitzgerald FT, Hypoglycemia and accidental hypothermia in an alcoholic population. West J Med 1980

 

18.   Stoner HB et al., Metabolic aspects of hypothermia in the elderly. Clin Sci 1980

 

19.   MacGregor DC et al., The effects of ether, ethanol, propanol and butanol on tolerance to deep hypothermia. Dis Chest 1966

 

20.   Cooper KE, Hunter AR, and Keatinge WR, Accidental hypothermia. Int Anesthesia Clin 1964

 

21.   Keatinge WR. The effects of subcutaneous fat and of previous exposure to cold on the body temperature, peripheral blood flow and metabolic rate of men in cold water. J Physiol 1960

 

22.   Sloan REG and Keatinge WR, Cooling rates of young people swimming in cold water. J Appl Physiol 1973

 

23.   Keatinge WR, Role of cold and immersion accidents. In Adam JM (Ed) Hypothermia – Ashore and Afloat. 1981, Chapter 4, Aberdeen Univ. Press, GB.

 

24.   Keatinge WR and Evans M, The respiratory and cardiovascular responses to immersion in cold and warm water. QJ Exp Physiol 1961

 

25.   Keatinge WR and Nadel JA, Immediate respiratory response to sudden cooling of the skin. J Appl Physiol 1965

 

26.   Golden F. St C. and Hurvey GR, The “After Drop” and death after rescue from immersion in cold water. In Adam JM (Ed). Hypothermia – Ashore and Afloat, Chapter 5, Aberdeen Univ. Press, GB 1981.

 

27.   Burton AC and Bazett HC, Study of average temperature of tissue, of exchange of heat and vasomotor responses in man by means of bath coloremeter. Am J Physiol 1936

 

28.   Adam JM, Cold Weather: Its characteristics, dangers and assessment, In Adam JM (Ed).Hypothermia – Ashore and Afloat, Aberdeen Univ. Press, GB1981.

 

29.   Modell JH and Davis JH, Electrolyte changes in human drowning victims.Anesthesiology 1969

 

30.   Bolte RG, et al., The use of extracorporeal rewarming in a child submerged for 66 minutes. JAMA 1988

 

31.   Ornato JP, The resuscitation of near-drowning victims. JAMA 1986

 

 

 

32.   Conn AW and Barker CA: Fresh water drowning and near-drowning — An update.1984;

 

33.   Reh H, On the early postmortem course of “washerwoman’s skin at the fingertips.” Z Rechtsmed 1984;

 

34.   Gonzales TA, Vance M, Helpern M, Legal Medicine and Toxicology. New York, Appleton-Century Co, 1937.

 

35.   Peabody AJ, Diatoms and drowning – A review, Med Sci Law 1980

 

36.   Foged N, Diatoms and drowning — Once more.Forens Sci Int 1983

 

37.   "Microscale chaotic advection enables robust convective DNA replication.". Analytical Chemistry. 2013

 

38.   Sourcebook in Forensic Serology, Immunology, and Biochemistry (U.S. Department of Justice, National Institute of Justice, Washington, D.C.,1983).

 

39.   C. A. Villee et al., Biology (Saunders College Publishing, Philadelphia, 2nd ed.,1989).

 

40.   Molecular Biology of the Gene (Benjamin/Cummings Publishing Company, Menlo Park, CA, 4th ed., 1987).

 

41.   Molecular Evolutionary Genetics (Plenum Press, New York,1985).

 

42.   Human Physiology. An Integrate. 2016

 

43.   Dumas JL and Walker N, Bilateral scapular fractures secondary to electrical shock. Arch. Orthopaed & Trauma Surg, 1992; 111(5)

 

44.   Stueland DT, et al., Bilateral humeral fractures from electrically induced muscular spasm. J. of Emerg. Med. 1989

 

45.   Shaheen MA and Sabet NA, Bilateral simultaneous fracture of the femoral neck following electrical shock. Injury. 1984

 

46.   Rajam KH, et al., Fracture of vertebral bodies caused by accidental electric shock. J. Indian Med Assoc. 1976

 

47.   Wright RK, Broisz HG, and Shuman M, The investigation of electrical injuries and deaths. Presented at the meeting of the American Academy of Forensic Science, Reno, NV, February 2000

Komentarze

Popularne posty z tego bloga

Dark Side: Some Kind of Justice From Behind The Grave

Methodology in Language Learning: The Ehrman & Leaver Construct

Under the Microscope: The Formation of Adipocere