aka Toxicology Conundrum 037
A 50 year-old man presented to the emergency department confused and ataxic with slurred speech. He was mildly tremulous, sweating and mildly tachycardic and hypertensive. Although he appeared drunk, his breath alcohol test was negative. He had no known comorbidities and did not take any regular medications.
His fingerprick blood glucose reading was 1.6 mmol/L.
Q1. Is the presentation in keeping with hypoglycemia?
He has a combination of autonomic symptoms (e.g. sweating, tachycardia, tremor) and neuroglycopenic symptoms (e.g. confusion, ataxia, dysarthria). Hypoglycemia accounts for over 5% of emergency presentations of ‘altered mental state’.
- Hypoglycemia can cause focal neurological signs — don’t miss hypoglycemia masquerading as stroke!
- The ‘drunk’ patient may be hypoglycemic — even when they are actually intoxicated with alcohol…
Q2. What is Whipple’s triad?
Whipple’s triad confirms the diagnosis of clinically significant hypoglycemia. It consists of:
- the presence of symptoms consistent with hypoglycemia
- a low serum glucose level
- resolution of the symptoms and signs of hypoglycemia with the administration of glucose
Q3. What are the causes of hypoglycemia?
The vast majority of ED hypoglycemia presentations involve patients with diabetes that are taking insulin or oral hypoglycemic drugs. Factors that contribute to hypoglycemia include missed meals, incorrect medication dosage or administration, intercurrent illnesses, alcohol consumption, increased exercise and deteriorating renal function.
However, there are other causes of fasting hypoglycemia — which my old Oxford Handbook explains as:
- Exogenous drugs — insulin, oral hypoglycemics, quinine, chloroquine, beta-blocker overdose, valproate overdose, salicylate overdose, pentamidine.
- Pituitary insufficiency
- Liver disease — hepatocellular cancer, hepatitis and rare genetic defects.
- Addison’s disease
- Islet cell tumours — insulinomas;
Immune hypoglycemia — e.g. anti-insulin receptor antibodies in Hodgkin’s disease or anti-insulin antibodies that release insulin when insulin levels are relatively low;
Infection — e.g. severe sepsis, malaria
- Non-pancreatic neoplasms — fibromas, sarcomas, mesotheliomas, and small cell carcinomas that produce IGF-2; extensive metastases that overwhelm the body’s ability to produce glucose;
Nesidioblastosis or Noninsulinoma pancreatogenous hypoglycemia (NIPH) syndrome — islet cell hyperplasia, which can be congenital or acquired, e.g. post-gastric surgery
- Starvation and malnutrition
- Hypothyroidism (myxoedema coma)
Post-prandial hypoglycemia can also occur due to a rapid surge of insulin (‘late dumping’) following rapid entry of food into the small intestine. This may occur after gastric surgery, for instance.
Finally, remember to consider pseudohypoglycemia — leukocytosis, thrombocytosis, or erythrocytosis can cause excess consumption of glucose in the collection vial while the sample awaits testing.
Q4. What is the emergency treatment of hypoglycemia?
In the awake, cooperative patient appropriate initial management may be as simple as:
- oral intake of simple carbohydrates (e.g. a sugary drink, jam, sugar lumps , barley sugars, etc) followed by a sandwich or biscuits.
In the uncooperative or unconscious patient, parenteral therapy is needed:
- 50 mL 50% glucose (or 5 mL/kg of 10% glucose in small children) —
flush with saline as it is hypertonic and can cause phlebitis.
- glucagon 1mg IM/SC or IV —
this may be administered by family members or by paramedics at the scene when IV access is difficult. It is inappropriate in settings where liver glycogen stores are depleted (e.g. liver failure or chronic alcoholism).
Full neurological recovery is usually rapid, and is expected within about 20 minutes – otherwise suspect a complication (e.g. stroke) or an alternative coexisting diagnosis.
Start an octreotide infusion in the case of sulfonylurea poisoning.
Q5. What is the role of thiamine in the treatment of hypoglycemia?
It is traditionally advocated that thiamine 100mg IV be given prior to administering a bolus of glucose to the patient with altered mental status. This comes from the concern that Wernicke’s encephalopathy may be precipitated or exacerbated by the glucose load in the absence of thiamine administration.
“Thiamine is a cofactor for several essential enzymes in the Krebs cycle and the pentose phosphate pathway, including α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and transketolase. Because thiamine-dependent enzymes play an important role in cerebral energy use, deficiency may initiate tissue injury by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover.”
— Donino et al, 2007.
The concern is that an excessive carbohydrate load will lead to the build up of toxic metabolites when the activity of these enzymes is reduced because of thiamine deficiency. However, there appears to be no instances of a single bolus of glucose precipitating Wernicke’s encephalopathy, although prolonged carbohydrate administration (e.g. from total parenteral nutrition) without thiamine supplementation certainly can.
The bottom line is:
Never delay the correction of hypoglycemia because of an irrational desire to administer thiamine first.
By all means give thiamine (and magnesium, another cofactor, while you’re at it) — especially to the alcoholic or malnourished patient — it is safe and is an effective treatment for Wernicke’s encephalopathy.
Q6. What investigations are required in the patient presenting with hypoglycemia?
In the otherwise well patient with diabetes who simply missed a meal, it might be that no further investigations are needed. Investigations should be appropriate to the clinical situation and aim to identify the causes and complications of the hypoglycemic episode.
Useful investigations may include:
- glucose, insulin, beta-hydroxybutyrate, C-peptide
- high/normal insulin with no excess ketones is consistent with insulinoma, sulfonylureas, insulin administration and insulin autoantibodies. C-peptide is absent if exogenous insulin is administered.
- low insulin with no excess ketones is consistent with anti-insulin receptor antibodies and non-pancreatic neoplasms.
- low insulin with high ketones is consistent with ethanol-induced hypoglycemia, pituitary and adrenal failure.
- Consider other causes, such as:
- septic screen, thick and thin films for malaria, or malaria antigen tests.
- LFTs and INR (liver disease)
- UEC, 24h creatininee clearance, renal imaging (renal failure)
- Endocrine tests:
- cortisol (adrenal insufficiency)
- GH response to hypoglycemia stimulation test, synACTHen test (pituitary failure)
- TFTs (hypothyroidism)
- monitored prolonged fasting for recurrent hypoglycemia (especially if investigations were not obtained on the presenting episode of hypoglycemia)
- tests for insulinomas — absence of C-peptide suppression following insulin administration, pancreatic arterial calcium-stimulation and vein sampling.
- autoantibodies — anti-insulin receptor and anti-insulin antibodies
- tumour imaging (e.g. MRI)
- drug levels if occult drug administration is suspected (e.g. sulfonylureas).
Unusual causes of hypoglycemia may not be suspected at thetime of initial presentation — if feasible, try to save 20 mL of blood in serum tubes for later analysis prior to correcting the initial episode of hypoglycemia (but do not unduly delay treatment!).
Following the initial management of his hypoglycemia, the patient became more lucid. He said he began to feel unwell after taking some cialis that had been bought in Vietnam.
Q7. Does cialis cause hypoglycemia?
Cialis is the trade-name for tadalafil. It is a cyclic GMP-phosphodiesterase 5 inhibitor used for erectile dysfunction. It’s main adverse effects include priapism, hypotension and the exacerbation of symptoms in those predisposed to ischemia.
It does not cause hypoglycemia.
Q8. What is the likely explanation?
The ‘cialis’ may have been a counterfeit drug. This can be determined by laboratory analysis of the remaining tablets.
In the case report by Chaubey et al, 2010, on which this scenario is based, the tablets and the packaging were clearly different from that of genuine cialis as marketed by Eli Lily. Laboratory tests showed that the tablets actually contained the sulfonylurea oral hypoglycemic agent glibenclamide.
According to WHO estimates up to 1% of drugs in the industrialised world are counterfeit. Globally it is an even bigger problem — up to 10% of drugs worldwide are thought to be counterfeit. This is a particular hazard for those who purchase medications from overseas using the Internet.
Q9. No sulfonylurea drugs were detected when the patient’s blood was tested. How can this be explained in light of Q7?
The glibenclamide may have been undetectable for the following reasons:
- the laboratory test may not have been sensitive enough. Checking with the lab to confirm the sensitivity of drug screens, particularly in forensic cases, is important.
- the hypoglycemic effects of sulfonylureas may persist after the elimination of the drug from the circulation.
- if the possibility of sulphonylurea toxicity was not initially suspected, the test may have been performed at the time of the hypoglycemic episode. The blood sample may have been sent some time after the initial presentation.
Indeed, a notorious murder case in New Zealand (described by Manning et al, 2003 and Marks and Richmond, 2008 — read their fascinating papers if you get a chance) saw South African psychiatrist Colin Bouwer convicted of murdering his wife despite negative sulfonylurea drug tests on her initial presentation to hospital. The toxicological tests performed at the victim’s autopsy told a different story…
Beware of “tox screens” they need careful interpretation!
- Chaubey SK, Sangla KS, Suthaharan EN, & Tan YM (2010). Severe hypoglycaemia associated with ingesting counterfeit medication. Medical Journal of Australia, 192 (12), 716-7 PMID: 20565353
- Donnino MW, Vega J, Miller J, Walsh M. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007 Dec;50(6):715-21. Epub 2007 Aug 3. Review. PMID: 17681641
- Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am. 2006 Dec;35(4):753-66, viii-ix. Review. PMID: 17127144
- Hack JB, Hoffman RS. Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom. JAMA. 1998 Feb 25;279(8):583-4. PMID: 9486750
- Manning PJ, Espiner EA, Yoon K, Drury PL, Holdaway IM, Bowers A. An unusual cause of hyperinsulinaemic hypoglycaemia syndrome. Diabet Med. 2003 Sep;20(9):772-6. PMID: 12925060
- Marks V, Richmond C. Colin Bouwer: professor of psychiatry and murderer. J RSoc Med. 2008 Aug;101(8):400-8. PMID: 18687863
- WHO. Counterfeit medicines.