Q J Med 2002; 95: 431-437
© 2002 Association of Physicians
Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) ingestion
From the 1 Respiratory Unit, Ninewells Hospital, Dundee, 2 Medical Toxicology Unit, Guy's Hospital, London, 3 Broomfield Hospital, Chelmsford, UK, 4 The Cloisters, Cherrybrook, Sydney NSW 2126, Australia, and 5 Academic Department of Accident & Emergency Medicine, Imperial College, St Mary's Hospital, London, UK
Received 2 November 2002 and in revised form 21 February 2002
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Summary |
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Background: Life-threatening and fatal hyponatraemic complications following ecstasy use have previously been documented.
Aim: To define clinical features of hyponatraemia following the ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’).
Design: Retrospective case series.
Methods: All enquiries to the London centre of the National Poisons Information Service (NPIS) between December 1993 and March 1996 were screened for cases of MDMA use associated with hyponatraemia (serum sodium <130 mmol/l). History of fluid consumption, presenting features and subsequent clinical course were recorded.
Results: Seventeen patients, aged 15–26 years, were identified. Serum sodium levels ranged between 107 mmol/l and 128 mmol/l. In six patients, biochemical results were consistent with inappropriate secretion of antidiuretic hormone (SIADH). Analytical confirmation of MDMA ingestion was obtained in 10 patients. Ten patients were known to have ingested a large amount of non-alcoholic or alcoholic fluid. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed in 11 patients by seizures. Drowsiness, a mute state and disorientation were observed for up to 3 days. Two patients died; 14 made a complete recovery.
Discussion: MDMA can cause life-threatening hyponatraemic encephalopathy when accompanied by excessive fluid ingestion. The mechanism involves inappropriate secretion of antidiuretic hormone.
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Introduction |
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During the 1990s, MDMA (‘ecstasy’) gained widespread popularity as a dance drug. Cases of hyperthermia began to be reported,1–6 and, subsequently, hyponatraemia emerged as another acute complication.7–14 Excessive fluid intake and inappropriate ADH secretion have been implicated in the emergence of this distinct clinical syndrome.7 We carried out a study at the London centre of the NPIS, screening all telephone enquiries for cases of MDMA-associated hyponatraemia, and report 17 patients who presented with hyponatraemia, two of whom died.
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Methods |
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All documented telephone enquiries to the London centre of NPIS between December 1993 and November 1995 were screened by a professional information officer for cases where MDMA use was complicated by hyponatraemia (serum sodium concentration <130 mmol/l). Clinical details and blood and urine biochemistry results were requested from the hospital concerned. Furthermore, between December 1995 and March 1996, management advice was given for acute cases by NPIS medical staff and, where possible, serial measurements of plasma and urine osmolality and serum sodium levels were requested. Blood and urine samples were obtained for toxicological analysis at our laboratory. A further fatal case is included where our advice was sought. This case has since been reported.12
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Results |
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Of a mean 13762 enquiries per month to the NPIS, 135 telephone calls per month concerned ‘ecstasy’ (1.0%). Over the 28-month study period, 17 cases of MDMA-associated hyponatraemia were identified (0.4% of all enquiries about ‘ecstasy’): seven male and 10 female, aged 15–26 years. History of MDMA ingestion and concomitant fluid consumption, presenting features and subsequent clinical course of the 15 patients who recovered are summarized in Table 1
. Analytical confirmation of MDMA ingestion was obtained in eight cases. Eight patients were known to have ingested a large amount of non-alcoholic or alcoholic fluid; in five patients, the history of fluid ingestion was not available. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed by drowsiness, agitation and in 10 patients, seizures. Clinical findings did not necessarily reflect the magnitude of the hyponatraemia. Drowsiness, a mute state and disorientation were observed for up to 3 days. In six patients the blood and urine biochemistry were consistent with a diagnosis of SIADH, as evidenced by the presence of hyponatraemia, low serum osmolality and inappropriately concentrated urine.
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Table 2
shows the sequence of events in the two fatal cases. Symptoms of hyponatraemic cerebral oedema occurred within 5 h of ingestion of one ‘ecstasy’ tablet. In both cases an excessive amount of fluid had been drunk.
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Discussion |
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Acute complications following MDMA use may be under-reported, but are relatively uncommon.15 A pattern of fatal and near-fatal hyperthermic collapse with disseminated intravascular coagulation, rhabdomyolysis and acute renal failure1–6 is now well-documented. Hyponatraemia has more recently been added to the list of complications. It appears to be a result of water consumption in excess of the body's requirements, compounded by failure of the renal response to water loading. Although unusual, it is important to recognize this distinct clinical entity as early as possible. Further fluid consumption to counteract evolving symptoms, or intravenous fluid administration could have fatal consequences. The clinical differentiation from hyperthermic collapse is important and should be straightforward; however, the management is very different in each case.
All of the patients developed symptoms within 12 h of drug ingestion. The observed neurological dysfunction was probably caused by a rapid fall in serum osmolar pressure, leading to intracellular movement of water, and subsequently to cerebral oedema. Early clinical features of hyponatraemic encephalopathy are well described and include headache, nausea, vomiting and weakness, progressing to confusion, hallucinations, reduced conscious level and seizures. Previously published cases of ‘ecstasy’-associated hyponatraemia8–10 reported clinical features of stupor, mutism and seizures occurring within 8–21 h of drug ingestion, followed by spontaneous recovery. In severe cases, cerebral oedema, tentorial herniation, respiratory arrest and cerebral hypoxia can ensue16 as post-mortem findings confirmed in two patients of our series, and in four previously reported fatal hyponatraemic cases.13,14,17,18
The hyponatraemia appears to involve inappropriate secretion of antidiuretic hormone. In one case of severe MDMA-associated hyponatraemic encephalopathy, plasma arginine vasopressin was found to be inappropriately raised at 9 h post ingestion.1 A recent report demonstrated that a rapid rise in arginine vasopressin concentrations followed administration of MDMA in eight normally hydrated healthy male volunteers.19 The syndrome of inappropriate secretion of antidiuretic hormone (SIADH), first described by Bartter and Schwartz,20 may occur post-operatively,14 as a feature of a concurrent medical condition or following the administration of psychotropic drugs.21 However, in these cases it tends to develop gradually as a result of normal fluid intake with inhibition of the urinary response by excessive ADH production. The mechanism by which MDMA causes SIADH remains to be established. Animal experiments have shown that vasopressin secretion is regulated by serotoninergic pathways.22,23 It seems possible that MDMA, an indirect serotonin agonist, augments ADH release from the neurohypophysis. Acute stress and excessive visual and auditory stimuli might also contribute to exaggerated ADH secretion.24 Nicotine, a known ADH-releasing agent, could add to the deleterious water-conserving effects.21 We do not know whether the cases in this series had been smoking.
The acute onset of symptoms in ‘ecstasy’-associated cases can be explained by excessive intake of fluid over a short space of time rapidly leading to symptomatic hyponatraemia. In contrast, if hyponatraemia develops slowly, patients often remain asymptomatic.21 Recovery appears to be uneventful if fluid intake is discontinued in time; the recovery is consistent with the elimination of MDMA and its metabolite MDA over 24–48 h.
MDMA users were initially advised in underground magazines and in the lay press to ‘drink plenty of fluids’. This harm limitation message was aimed at preventing hyperthermic collapse, since adequate hydration is essential for thermoregulation in situations of prolonged heavy exertion. However, the advice did not specify that a high fluid intake could be detrimental in the absence of prolonged exertion. This was subsequently rectified, particularly after the publicity attaching to the fatal cases.
The management of acute hyponatraemia remains controversial.25 Fluid restriction to <1 l/day is usually sufficient. The use of intravenous mannitol or loop diuretics may be considered if there is evidence of cerebral oedema. While Arieff16 favoured rapid correction of post-operative hyponatraemia with hypertonic saline, this did not appear necessary in most of the 15 non-fatal cases of this series, who were managed conservatively with fluid restriction only. Three patients received frusemide, and mannitol was used in two. Whether early, pre-hospital administration of hypertonic saline could have altered the outcome in the two fatal cases is speculative. In a retrospective study, Sarnaik et al. found the treatment of hyponatraemic seizures in children with a 3% saline solution to be safe and effective.26 However, once respiratory arrest due to cerebral oedema has occurred, the likelihood of recovery is extremely remote.
The hyperthermic and hyponatraemic complications of MDMA use appear to be largely avoidable. Although the safest counsel is not to take the drug, the advice regarding fluid ingestion given to intending MDMA users should be carefully worded and take into account the circumstances under which ‘ecstasy’ is taken, i.e. level of physical exertion (dance) and environmental temperature (indoor club vs. outdoor event). ‘Ecstasy’ users who experience marked or unusual symptoms should seek urgent medical assessment.
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Notes |
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Address correspondence to Professor J.A. Henry, Academic Department of Accident & Emergency Medicine, Imperial College, St Mary's Hospital, London W2 1NY. e-mail: j.a.henry{at}ic.ac.uk
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References |
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