Treatment of Lethal Caffeine Overdose with Haemodialysis: A Case Report and Review

The advent of over the counter [OTC] caffeine formulations has opened the window for potential toxicity, either by inadvertent or intentional overdosing. Caffeine consumption is widely prevalent in all races and ethnic groups, with no scientific data showing preference in any groups [3, 6].

In the United States for the year 2018 the American Association of Poison Control Centres [AAPCC] reported 1592 single exposures to caffeine-containing energy drinks. From those 6 had major outcomes defined as signs or symptoms that were life-threatening or resulted in significant residual disability or disfigurement. No deaths were reported. Most exposures from caffeinated energy drinks happened in children younger than 6 years of age. With adults 20 years and older representing the second highest number of exposures. Gender was not included in this report. Additionally, the AAPCC also reported 2849 cases of caffeine exposure from street drugs use with 21 major outcomes and 2 reported deaths [7].

As in many other substance intoxication cases, examinations start with a thorough investigation on the exposure to the substance. This can be done through questioning about prescription medications, over the counter drugs and illicit drugs. The finding of empty pill bottles by witnesses and family members in cases of suicide attempt has a big impact in determining risk of co-ingestion of other substances.

In excessive amounts patients present with a specific caffeine toxidrome [caffeinism] which involves neurological, cardiovascular, gastrointestinal, and renal. These primary toxic effects of caffeine are mediated through multiple mechanisms. Caffeine causes pleiotropic effects depending on the receptors and organs affected, producing paradoxical physiological effects. Antagonism of adenosine receptors by caffeine in the brain are linked with development of altered mentation and seizures. Hypertension is mediated by vasoconstriction though inhibition of the vasodilatory effect of the A2 receptors [11]. Although at physiological doses its inhibition of phosphodiesterase is not significant, toxicity or overdose scenarios make this relevant causing severe hypotension [12]. Caffeine also increases catecholamine levels due to antagonism of pre-synaptic A1 receptors in the sympathetic nerves and the adrenal medulla [13,14]. This adrenergic surge will have clinical consequences such as tachyarrhythmias (b1-stimulation), hypotension, hypokalaemia, leucocytosis, and hyperglycaemia from glycogenolysis (b2-stimulation) and lipolysis (b-3 stimulation). In the renal system caffeine antagonises the A1 receptors in the proximal tubules and prevents sodium reabsorption, finally resulting in increased natriuresis (15).

Lactic acidosis is caused by shock induced by hypotension and tissue hypoxia. Rhabdomyolysis has been associated with the calcium release from the sarcoplasmic reticulum of skeletal and cardiac muscle [16, 17]. The full spectrum of caffeine toxicity is summarized in Figure 3.

Fig. 3

The average cup of coffee has an estimated of 100mg of caffeine. A greater number of dietary and over the counter supplements and prescription medications also contain caffeine at different doses. Caffeine is rapidly absorbed after oral consumption with clinical effects noticed within 15 minutes and a peak plasma concentration reached after 1 hour of ingestion [18].

Caffeine generally has dose-dependent effects (table 2) and is considered safe at doses of less than 400mg/ day in healthy adults [19]. Toxicity is seen above 400mg/day with sub-lethal dose estimated to be about 7–10 mg/kg of weight in normal adults [20].

There is no agreement upon the lethal dose of caffeine, however serum concentrations above 80 mg/L are considered lethal, these levels are typically seen after ingestions exceeding 5g. A recent review showed a mean caffeine concentration of 187 ± 96 mg/L with ranges between 33–567 mg/L in patients who died from caffeine intoxication [21]. Nevertheless, there might be individuals who can have serious toxicity and lethality below this range [22,23].

Cardiovascular events are the most common cause of death in patients with caffeine intoxication. The most common mechanisms are rhythm disturbances, with ventricular fibrillation the most frequently described. Myocardial infarction caused by coronary artery vasospasm has also been proposed as one of the causes [21,24].

We did an extensive literature search and review and to date there were 21 well-documented reports of caffeine overdose in adults treated with dialysis techniques. Details pertaining to the serum caffeine levels, clinical presentation and treatment modalities were reviewed and extracted focusing on cardiovascular complications (Table 3). Studies in paediatric populations, non-human research, reviews, laboratory investigations and post-mortem analysis were excluded.

On this review we also mentioned the wide set of treatment strategies have been proposed for the acute management of caffeine intoxication. A common step is the supportive treatment with intravenous fluid resuscitation and the use of potassium chloride and sodium bicarbonate. Symptomatic treatment with benzodiazepines and propofol is a reasonable option in the acute setting where agitation and seizures arise [46].

Decontamination using activated charcoal is considered essential by some authors and should be used in patients presenting within a reasonable time frame of around 1-2 hours [17, 31, 32, 37, 41, 45].

The use of intralipid infusion has been shown to be effective used either alone or in combination with haemodialysis.

Intravenous lipid emulsion is proposed to act by removing of caffeine molecules (an amphiphilic substance) from target organs such as the heart and brain; the so-called “lipid sink.” acting by removal of caffeine molecules (amphiphilic substance) from target organs such as the heart and brain [17, 37, 41, 43].

The first case of caffeine toxicity we found in our review of the literature treated with hemoperfusion was by Zimmerman et al, in the 1980s [25]. Since then, many others have described the use of several dialysis techniques in the management of acute caffeine intoxication [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. In the reported cases the most common acid base disorder was metabolic acidosis with elevated lactic acid. Other laboratory findings included leucocytosis, hyperglycaemia, hypokalaemia, rhabdomyolysis, acute kidney injury (AKI) and elevated troponins.

Multiple arrhythmias were reported including sinus tachycardia, supraventricular tachycardia [25, 30, 39, 42, 44], bradycardia and 3^rd degree AV block [25], PVCs and bigeminy [42], ventricular tachycardia [31, 36, 37, 43, 44], Torsades des pointes [37, 41], and ventricular fibrillation [25, 26, 33, 35, 37, 41].

In the critical and acute phases of intoxication a rapid and effective therapy with intermittent haemodialysis seems effective, with dramatic changes in both clinical status of the patients and outcomes.

Due caffeine’s low molecular weight (194 g/mol), relatively small volume of distribution (0.6–0.8 L/ kg) and the low fraction bound to plasma proteins (10% to 35%) [17], it is a good candidate for extrarenal purification by conventional haemodialysis techniques. Both hemoperfusion and haemodialysis have proven to be successful, with short courses of intermittent HD almost completely reversing the cardiac and neurological signs of caffeine intoxication. Hemoperfusion has been used in the past but its use is limited by practical limitations. Use of other modalities such as continuous veno-venous hemodiafiltration (CVVHF) are adequate options for the removal of excess fluid or uremic toxins. Studies shows mixed results for the use of CVVHF for the treatment of caffeine intoxication, although it seems less effective than HD, there was insufficient data to estimate the clearance values to compare each modality [31, 35, 37].

Extra Corporeal Membrane Oxygenation (ECMO) is one of the newest tools in management of patients with severe cardiovascular and pulmonary dysfunction. The use of veno-arterial ECMO (i.e., VA-ECMO) in patients with severe drug overdose and profound cardiac toxicity has been also reported with positive results. It allows an increase in mean arterial pressure to permit the concomitant use of haemodialysis in patients with caffeine toxicity [35, 41, 44].

In the cases reviewed, most of the articles consisted of a single case of caffeine-related overdose, whereas other included 2-3 patients [32, 38]. One article described the use of haemodialysis in only one of the three cases reported [38]. The time between caffeine ingestion and the establish dialysis was reported in most of the cases. Lack of serial monitoring of caffeine levels was a common denominator in the cases we reviewed.

The current case herein presented had one of the highest reported degrees of caffeine overdose, with approximately 50000 mg of caffeine ingested (387mg/ kg). Our patient presented with progressive cardiovascular and neurological decline which could have progressed given this large dose of caffeine. A multidisciplinary team including toxicology, nephrology, and critical care physicians stabilized the patient and prevented further complications by initiating haemodialysis in a timely manner. The relatively young age of our patient and overall good health could have played one role on the positive outcome.

A wide differential, including caffeine intoxication, and a thorough toxicology work-up is mandatory for patients who present with symptoms of CNS stimulation and vomiting with or without hypokalaemia. Early identification of the typical symptoms may be of critical importance in the emergency room to prompt timely interventions that can be lifesaving in these individuals.

The lack of clinical trials on patients presenting with caffeine intoxication authors cannot recommend which of the treatment options has better outcomes. No clear strategies exist based on the dose of caffeine ingested or time of ingestion.