Drug-related deaths and toxicology

Sebastian Lucas

MoJ Coroner Stats 2022

Contents

• WHEN do you take toxicology samples?

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• WHAT is the range of possible tests?
• TOXICOLOGY LABORATORIES – protocols and costs

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• WHAT samples do you take?

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• HOW do you interpret the results? – you will learn from experience

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• WHAT drug-specific pathologies are there – gross and histology?

Obligatory tox sampling

• Hangings and other suicides
• Epilepsy / SUDEP - AEDs
• RTCs
• Known history of drug +/- alcohol abuse
• Deceased’s abode has alcohol, syringes, needles, drug saches etc
• Pre-death behaviour suspicious of drug toxicity

• Deceased found dead and no gross pathology evident
• Can be stored for later use
• Type 1 & 2 diabetes
• Needle marks and injection sinuses on skin

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Optional sampling

• Suspected medical drug toxicity in hospital
• Opioids

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• Warfarin?
• Cannot do INR on autopsy blood
• Warfarin level useful?

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• When the relatives pressure the coroner to do tox studies

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• Sudden unexpected deaths at home
• Witnessed < 1 hour from symptoms
• Unwitnessed <24 hours

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• In all such deaths?
• Acute anaphylaxis, mast cell tryptase
• Blood cultures
• Carboxyhaemoglobin
• Cyanide and H₂S
• See later talk on Ancillary tests

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CJA 2009. Discontinuance of investigation

• A major positive change from previous legislation
• All or nothing from the time of physical autopsy
• All = commitment to an inquest
• The investigation stops if the autopsy provides a natural cause of death
• From the gross examination alone;
• Or with histology/toxicology investigations.
• So there is no inquest
• Permits an incremental approach to autopsy investigation
• Hold samples in reserve – can be discarded later
• Pursue the easy/obvious possible causes of death first
• Hold off toxicology analysis as appropriate, may not be needed

Found in the colo-rectum – cocaine packets

Toxic drugs

• Medical vs illicit/illegal = difficult as much available on internet

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• Purely medicinal fatalities
• Accidental or suicidal
• Insulin – difficult to prove
• Metformin
• Painkiller opioids
• Warfarin

• Opioid = acts on opioid receptor in the brain
• Reduces cardiac and respiratory function

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• Opiate = derived from the opium plant

Recent retrospective list of fatal drugs

• [alcohol]
• Cocaine
• Opioids – heroin, morphine, tramadol, codeine, methadone, buprenorphine, pethidine, fentanyl, oxycodone, isotonitazene, tapendatol
• New psychoactive synthetic substances
• New psychotropic SSRI medications (depression, schizophrenia)
• Increased risk of VTE
• Pregabalin
• MDMA, ecstasy
• GHB – gamma hydroxybutyrate
• Amphetamine and crystal meth
• Barbiturates
• Cannabis & cannabinoids (fatal ever??)
• Benzodiazepines (ditto?)
• Nitrous oxide (N₂O) inhalation
• Multi-drug toxicity eg cocaine + morphine + methadone + alcohol + pregabalin

What to sample?

• Femoral vein blood
• Not heart/lung/central – unless ilio-femoral samples are not obtainable

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• Urine

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• Vitreous humour
• The only useful body fluid for glucose

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• Stomach contents – labs rarely analyse unless specifically requested

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• Liver – when decomposed – gives qualitative not quantitative data

Drug-related morbid anatomy

• None to see – gross or histology

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• Pathology of drug-intake process – skin, needles, nasal septum

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• Organ direct toxicity

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• Indirect effects of drug-taking

The examination

Skin injection �site

Higher power + polarised light

Iron granules = traumatic haemorrhage

Bi-refringent material = injected = chronic

Injection marks

• Easy
• Difficult
• Strange sites
• Old vs new
• Problems
• Parents cannot accept he/she injected
• So must be a third-party intervention

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• Chronic injection phenomena

Sinuses = chronicity

Skin injection sites

• Only ~75% identifiable
• How hard does one examine?

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• Alternative routes of drug intake
• Smoking
• Snorting
• Inhalation
• By mouth
• Through skin - eg fentanyl, buprenorphine

Late IVDU venous & lymphatic obstruction

Pathology of drug abuse

• COMPLICATIONS of drug usage

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• Infective endocarditis
• Injection abscess
• Mycotic aneurysm
• Lung disease

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• Long term

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• Malnutrition & wasting
• HCV, HBV, HIV infections etc
• Tuberculosis
• Amyloidosis
• Kidney FSGS

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1a…………………………….

1b. Chronic drug injection habit

Case

• F 31
• Chronic IVDU
• Injected into groin vessel in street
• Abrupt haemorrhage from groin site

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• In hospital, tranfused
• Repeat haemorrhage
• Exsanguinated

Femoral artery mycotic aneurysm

Mycotic aneurysm

Staphylococcus

IVDU – tilting disc MVR 8 weeks previous.�Staph septic endocarditis

Toxicology labs��Get to know your local & referral laboratories’ staff - what they can and cannot do re analyses��Tests change, new substances, new technical possibilities�Coroners have contracts with specific tox labs – local or distant�

Practical considerations

• What can be done?
• The limits are your knowledge & experience of pathology

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• What actually can be done within the ‘usual system’?
• Are all labs equally capable and comprehensive? NO

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• Need agreement from coroner?
• Yes – costs & delays to arriving at the MCCD

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• How to interpret the results?
• Who presents the data at inquest? You or a specialist (eg) toxicologist?

Half a page for a morphine

toxicity death

Six pages to tell

me of a fentanyl

toxicity death

Costs of ‘toxicology’ tests and what you get back

• ….there is sensitivity over costs, it is a very competitive market. Costs vary widely.
• the cheapest are analyses carried out in clinical chemistry labs, where they don’t have to cover the full cost and rely on immunoassay, to the most expensive (private) labs who have to make a profit.

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• Cost for a complete screen plus alcohol can vary from £120 to £1,000+.

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• In general you get what you pay for
• ….also important is the quality of the result and having someone on hand to interpret if needed.

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What I want

• Presence or absence of a drug
• The number (concentration) values of the drugs requested
• +/- acetone
• The known lethal ranges for blood levels
• From published case reports
• The therapeutic ranges of medical drugs
• eg for anti-epileptic drugs
• How long the samples are retained (eg 3-6 months)
• Possible further analyses

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• A contact phone number (email) for a lead scientist to discuss a case

Why do people die from drug toxicity?

• Central cardio-respiratory failure
• Action at brain level
• Heroin, methadone, alcohol binge

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• Chronic kidney & liver damage

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• Acute haemorrhage from blood vessel
• Stroke – brain haemorrhage

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• Pneumonia - delayed aspiration pneumonia

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• Cardiac failure – arrhythmia
• cocaine

Aspiration pneumonia – acute lung injury, DAD

Aspiration – visible food material in bronchus

Some specific & non-specific organ toxic damage lesions

Specific

• Ethylene glycol
• Excitatory drugs:
• MDMA
• Amphetamine
• Cocaine
• [alcohol – liver]

Non-specific

• Cannabis and inhaled drug lung damage
• Cerebral haemorrhage
• Drug-related hypertensive spike
• Injected foreign circulating material

Kidney Case

• F 33 with chronic mental health problems
• Previous suicide attempt
• Found dead at home
• Bottles about including anti-freeze

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• Autopsy
• Nothing grossly abnormal to see

Kidney failure - ?acute tubular necrosis

Oxalate crystals+++

Case

• Blood

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• Ethylene glycol 231mg/L
• Nil else significant

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• Timing of death
• Cardio-respiratory failure
• 24-48 hours from intake

Cocaine

Heart lesions – covered in the Large Heart talk

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CNS haemorrhage

Crack cocaine lung path = cannabis pathology

Cocaine – intracerebral haemorrhage

Cocaine intracerebral haemorrhage and ‘vasculitis’ [?]

Cannabis lung

General drug inhalation-related lung

Make sure your microscope polariser system works!

MDMA (ecstasy)

Infarction of pituitary & quads muscle necrosis

Amphetamine liver centriacinar necrosis

Indirect consequences of drug abuse

Perforated nasal septum - cocaine

Autopsy procedure:

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ALWAYS

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Look for skin injection

marks and sinuses

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Always probe the

nasal septum

Cocaine + alcohol + hot bath = fatal burns

Case – chronic IVDU �

• Admitted to STH
• Left lower lobe pneumonia
• ? Secondary to septic emboli

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• Renal failure ?Acute
• Creatinine ~600
• Nephrotic proteinuria: >10g/24hr

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• Renal biopsy = better preserved pathology than the autopsy kidney

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Case

Case - Congo red

EM

IHC amyloid A = chronic inflammation

Injection abscesses

• IV drug users
• +/- HIV infection
• Diabetics
• Regular medical injectors
• Contaminated needles
• Contaminated injection media
• Xylocaine solutions

Injection abscesses

• Staphs & streps
• Mycobacteria
• M.fortuitum
• M.chelonei
• M.abscessus
• Clostridium sp
• C.perfringens
• C.novyi
• C.tetani & C.botulinum

Chronic injection abscesses

Mycobacterial injection abscesses

Clostridium perfringens

Routine evaluation:

Gram

Grocott silver stain

Ziehl-Neelsen

‘Miliary’ lung nodules in IVDU

Lung arteries

It gets to the liver too – hepatic node in IVDU

Chronic IVDU lung

• Injected material
• Granulomas

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• Local thrombosis and organisation

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• Pulmonary hypertension
• Cor pulmonale

WE NEVER STOP LEARNING��Case. Male Asian 53 years

• T2 diabetes, on metformin.
• Body weight in July & November 2021 the same: BMI = 18.5

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• July 2021 diabetes screen:
• HBA1c = 6.4% [normal <5.9]
• IFCC standardised 46mmol/mol [normal <41]
• Renal function: eGFR 56ml/min

Case – scenario of death

• Unwell on 17^th Nov 2021, vomiting
• Found dead in his room the next day, by family

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• No alcohol around
• No recreational drugs around

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• Vaccinated – booster - against COVID-19 on 17^th Nov.

Autopsy

Pathology

• Grossly ‘negative’ autopsy

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• Histology:
• Kidney – severe DM glomerular disease + arteriosclerosis
• = renal failure

Body fluid analysis

• No ethanol
• Vitreous glucose = 3.1mmol/L
• Blood:
• Acetone 8mg/dL
• Beta OH butyrate 651ug/ml

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• Standard drug screen - negative

Cause of death = ketoacidosis (KA): why?

Usual causes

• Mild T2DM
• Alcohol
• Starvation
• Hypothermia
• Febrile illnesses
• Drugs and toxins

Dr Rebecca Andrews – tox scientist

• ? Ingested: methyl alcohol, ethylene glycol, isopropyl alcohol, acetone – excluded
• ?hypothermia

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• Family: his room was heated.
• They think he died of COVID-19 vaccine reaction

Stuck

• COVID-19 vaccine reaction of KAS reported rarely only in T1DM

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• Did he convert from T2 to T1 DM between July to November?
• Difficulty interpreting vitreous glucose levels.
• Probably not

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• Call Dr Stephen Morley at Leicester Forensic Toxicology Services
• Ex-diabetes clinician
• Very helpful in previous drug/toxin complex cases

Metformin toxicity?

• Can cause metabolic acidosis
• Mixed type: lactic- and keto-acidosis
• Especially in patients with renal failure
• 2010: eGFR >90, creatinine 80
• 2021: eGFR 56, creatinine 118

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• Not part of standard drug screen at Imperial College

• Additional test:

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• Blood metformin
• 71µg/ml
• Therapeutic range 1-4
• Toxic range >45

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3 scenarios of death now [Feb 2022]

• 1. metformin toxicity from accidental overdosage

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• 2. metformin toxicity from intentional overdosage

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• 3. inadvertent metformin toxicity from normal dosage but in the context of diabetic renal failure

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• WHAT DID THE CORONER DO NEXT?

Obtain expert opinion

PF: barrister, healthcare liability, medicines regulatory law

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Brief: address family’s Concerns – that COVID-19 Pfizer vaccination played a role in the death

Outcomes

PF opinion

• Agrees with me
• Metformin the most likely cause of KA and death
• Vaccine had no role
• Much safety information etc
• KAS very rare complication

Family response

• Not happy
• Inconsistencies of GP and other records concerning dosage
• Querying possible hypothermia issue

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• “From the face of his report, there still remain unanswered questions and the family strongly feels that it lacks in its investigation and research from an expert point of view”

Summary

• Have a low threshold for suspecting drug-related death

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• Take full body fluid samples
• Can be reserved against future analysis
• When taking tox samples, ALWAYS take histology
• Standard 5 major organ set

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• Get to know your tox lab and its scientists
• Read their reports critically
• Look up new drugs’ information on the internet
• Ask them questions and seek assistance in difficult cases

Bizarre finale

Hypoglycaemia death scenarios – type 1 DM

• Too much insulin

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• Overdose
• Accidental
• Intentional – suicide
• Homicide

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• Body fluids:
• Vitreous glucose = zero
• Blood level - useless

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• Measure insulin in blood & vitreous?
• What do the numbers mean?
• Useful: identification of non-human insulin has forensic utility

35 years female; husband has T1 DM

• Rows with husband
• Checked into local hotel
• Found dead in bed
• Numerous insulin syringes around
• Some injection marks in buttocks
• No other pathology

• CNS – red neurone change (tbd)
• Vitreous glucose <0.2mmol/L
• Blood insulin 11pmol/L
• C-peptide <94pmol/L

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• Conclusion
• Suicide by injecting husband’s insulin medication