In theory, stupor and coma can be caused by an almost overwhelmingly vast spectrum of medical and surgical causes. In practice though, the majority of cases encountered in the emergency department are due to either trauma, cerebrovascular disease, central nervous system (CNS) infections, metabolic derangements, alcohol intoxication, or poisonings or drug overdoses. If available, a history from the family or friends of the patient may go a long way in narrowing down the possibilities; the value of a careful examination cannot be underemphasized either. Furthermore, the observations of the paramedical team involved in the on-site resuscitation and transportation of the patient may also yield vital clues. In this specific case, our diagnostic process is considerably aided by the presence of mydriasis, dry skin and mucous membranes, and tachycardia; these features hint at anticholinergic toxicity, directing our attention towards a poisoning or overdose. Potential candidate drugs include tricyclic antidepressants (TCA), atropine, antihistamines (such as diphenhydramine), and certain antipsychotics and antispasmodics; unfortunately, without a proper history, it is almost impossible to clinically differentiate between these agents. Given the presence of tachycardia and an irregular pulse, an ECG might provide some further clues; in this patient, the presence of right-axis deviation (RAD) could be considered a pointer towards TCA poisoning, although this is by no means definite. A toxicology screen is a good follow-up investigation; this is found to be positive for TCAs, allowing us to arrive at a diagnosis. Note that it is essential to exclude other substances as well, as co-ingestions are common. It is also prudent to definitively rule out the other common causes of coma; in this respect, there are no features suggestive of trauma, while the absence of meningism and focal neurological signs, and the normal CT scan of the brain argue against CNS infections and cerebrovascular accidents. Furthermore, the normal random capillary glucose, serum electrolytes, and renal and liver functions essentially exclude metabolic derangements. An arterial blood gas (ABG) assay should also be obtained, so as to guide the further management. While this is currently within normal parameters, the low normal bicarbonate (HCO3) levels might herald an impending acidosis. Individuals with TCA poisoning are at high risk of developing dysrhythmias; ECG monitoring is mandatory, and should be continued until the ECG has been normal for 24 to 48 hours. While alkalinisation with sodium bicarbonate (NaHCO3) may be considered for the treatment of QRS prolongation (>100ms) or other arrhythmias, the occasional premature ventricular complexes seen in this patient do not warrant immediate therapy. Note also that intubation is only mandatory in individuals with a Glasgow Coma Score (GCS) of 8 or less, although it can be considered in persons who have a higher score, but suffer from airway compromise, hypoventilation, or refractory seizures; it is certainly not indicated in this specific case. Furthermore, gastric lavage should only be attempted if the patient presents within the first hour following ingestion; in this patient's case, as the time of ingestion is unknown, this technique is thus best avoided.
Tricyclic Antidepressants (TCA) are among the most frequently ingested substances in self poisonings, along with Acetaminophen (Paracetamol), Benzodiazepines, and Alcohol. They are second only to analgesics as a cause of fatal drug overdose. In particular, most TCAs have a narrow therapeutic index; ingestion of over 10 mg/kg is likely to produce toxicity while over 30 mg/kg is considered a potentially lethal dose, although the exact response varies between individuals. These agents are rapidly absorbed from the gastrointestinal (GI) tract, and are highly protein bound, with a large volume of distribution, resulting in a long half life that generally exceeds 24 hours. Following metabolism in the liver, the metabolites (some of which also have pharmacological activity), are conjugated and excreted by the kidneys. Note that in cases of overdose, the above pharmacokinetics are altered; gastrointestinal absorption may be delayed because of inhibition of gastric emptying, and significant enterohepatic recirculation prolongs the final elimination. Furthermore, acidosis (which is a common accompaniment) reduces the binding of TCAs to proteins, resulting in increased unbound levels. The clinical manifestations of TCA overdose are directly related to their effects on the autonomic system, cardiovascular system (CVS) and the central nervous system (CNS). The autonomic manifestations are due to the anticholinergic activity of these agents; these include mydriasis, dry mucous membranes and skin, brisk reflexes, urinary retention, and impaired sweating. Less often, marked gastric stasis and ileus may occur. Coma and seizures are the commonest CNS symptoms, while the commonest CVS manifestation is sinus tachycardia, secondary to inhibition of norepinephrine reuptake, and the anticholinergic action of TCAs. However, the most important cardiovascular effect is the slowing of cardiac depolarization by inhibition of sodium currents; this results in prolongation of the QRS complex, and the PR and QT intervals, predisposing to cardiac arrhythmias. The aforementioned inhibition of sodium flux into the myocardial cells can be severe enough that cardiac contractility is reduced, resulting in hypotension. Note that most patients with TCA overdose will generally exhibit clinical effects within one hour of ingestion, with major complications almost always becoming apparent by six hours post-ingestion; individuals who do not develop signs of toxicity by this time can be safely discharged. Unfortunately, TCA overdose is often extremely tricky to detect, especially in the absence of clues in the history; in particular, the clinical findings can be mimicked by certain other medications, or masked by the co-ingestions. In such patients, ECGs are helpful in determining the presence of toxicity; common findings include QRS, QT, and PR prolongation, and right axis deviation. QRS prolongation is the most important prognostic factor, with durations >100 ms being associated with an increased risk of seizures, and >160 ms with a high risk for malignant arrhythmias. Prolongation of the QT interval (> 430 ms) and an R/S ratio >0.7 in lead aVR are also useful in identifying patients at high risk for cardiac complications. Urine drug screens for TCAs are available in many hospitals, and can help rapidly confirm the diagnosis. Estimation of plasma TCA concentrations is not widely available, and has little clinical value, as levels do not correlate well with severity of toxicity, and are a poor predictor of clinical outcome. Arterial blood gas assays are also an essential part of the workup, with acidosis being the most frequent abnormal finding; this is often mixed, with both respiratory depression and myocardial impairment and/or hypotension resulting in reduced tissue perfusion and production of lactate. A significant number of patients are also hypokalemic; in a case series, almost 10% of patients were found to have levels <3.0 mEq/L. The initial management of a patient with suspected TCA overdose involves assessing and securing the airway, breathing and circulation (ABCs). Individuals with a GCS ≤8 should undergo rapid sequence induction at the earliest opportunity to protect the airway; certain patients with higher scores may also need intubation, particularly if airway compromise, hypoventilation, or refractory seizures are present. Note that there is no clinical evidence for the benefit of gastric lavage; however, this may be considered in potentially life-threatening overdoses, if it can be delivered within 1 hour of ingestion, and the airway is protected. Activated charcoal is less invasive and may be a preferable alternative in conscious patients; however, this should be balanced against the potential for pulmonary aspiration. In individuals with features of cardiovascular toxicity, sodium bicarbonate (NaHCO3) is the first line agent; this is believed to act via both systemic alkalinisation (which increases plasma protein binding of TCAs, thus decreasing levels of the pharmacologically active unbound fraction), and hypertonic sodium loading. Current guidelines recommend that NaHCO3 should be administered to all patients with cardiac arrhythmias, QRS prolongation >120 ms, or hypotension, even in the absence of acidosis. The target is alkalinisation to a serum pH of 7.45 to 7.55. Note that administration of NaHCO3 can result in hypokalemia; thus, serum potassium levels should be regularly monitored, and potassium supplementation commenced as necessary. If hypotension is present, a bolus of intravenous fluids is the first-line therapy; vasopressors should be considered in refractory cases. Where life-threatening hypotension or arrhythmias unresponsive to other measures occur, intravenous glucagon can be considered; magnesium sulphate is a treatment of last resort. Note that antiarrhythmic drugs should be avoided if possible; in particular class 1a and class 1c drugs may potentially exacerbate the cardiotoxic effects of TCAs. Furthermore, where patients have a cardiac arrest after ingestion of TCAs, recovery is possible even after prolonged resuscitation. Patients have recovered after three and five hours of external cardiac massage. Seizures are usually self limiting, but where treatment is considered necessary benzodiazepines are the drugs of choice. Note also that all patients who have signs of severe toxicity should receive meticulous supportive care in an intensive care setting. In general, most severe clinical effects typically resolve over a 24 to 48 hour period. Cardiac monitoring should be continued until the ECG has been normal for 12 to 24 hours. Furthermore, where the overdose has been intentional in nature, psychiatric assessment should be arranged following recovery.