Sudden Unexpected Death and the Mammalian Dive Response: Catastrophic Failure of a Complex Tightly Coupled System.

In tightly coupled complex systems, when two or more factors or events interact in unanticipated ways, catastrophic failures of high-risk technical systems happen rarely, but quickly. Safety features are commonly built into complex systems to avoid disasters but are often part of the problem. The human body may be considered as a complex tightly coupled system at risk of rare catastrophic failure (sudden unexpected death, SUD) when certain factors or events interact. The mammalian dive response (MDR) is a built-in safety feature of the body that normally conserves oxygen during acute hypoxia. Activation of the MDR is the final pathway to sudden cardiac (SCD) in some cases of sudden infant death syndrome (SIDS), sudden unexpected death in epilepsy (SUDEP), and sudden cardiac death in water (SCDIW, fatal drowning). There is no single cause in any of these death scenarios, but an array of, unanticipated, often unknown, factors or events that activate or interact with the mammalian dive reflex. In any particular case, the relevant risk factors or events might include a combination of genetic, developmental, metabolic, disease, environmental, or operational influences. Determination of a single cause in any of these death scenarios is unlikely. The common thread among these seemingly different death scenarios is activation of the mammalian dive response. The human body is a complex tightly coupled system at risk of rare catastrophic failure when that "safety feature" is activated.

Unintentional drowning: Role of medicinal drugs and alcohol.

BACKGROUND: Alcohol is a well-known risk factor in unintentional drownings. Whereas psychotropic drugs, like alcohol, may cause psychomotor impairment and affect cognition, no detailed studies have focused on their association with drowning. Finland provides extensive post-mortem toxicological data for studies on drowning because of its high medico-legal autopsy rates. METHODS: Drowning cases, 2000 through 2009, for which post-mortem toxicological analysis was performed, came from the database of the Toxicological Laboratory, Department of Forensic Medicine, University of Helsinki, using the ICD-10 nature-of-injury code T75.1. The data were narrowed to unintentional drowning, using the ICD-10 external-injury codes V90, V92, and W65-74. Each drowning case had its blood alcohol concentration (BAC) and concentrations of other drugs recorded. Evaluation of the contribution of psychotropic drugs to drowning was based on their blood concentration by means of a 6-grade scale. RESULTS: Among victims ≥15 years old, unintentional drownings numbered 1697, of which, 303 (17.9%) were boating-related and 1394 (82.1%) non-boating-related. Among these, 65.0% of boating-related and 61.8% of non-boating-related victims were alcohol-positive (=BAC ≥ 50 mg/dL). The male-to-female ratio in alcohol-positive drownings was 7.3. At least one psychotropic drug appeared in 453 (26.7%) drowning cases, with some victims' bodies showing up to 7 different drugs. Overall 70 different psychotropic drugs were detectable, with 134 (7.9%) cases both alcohol-negative and psychotropic-drug-positive, of these, 59 (3.5%) were graded 4 to 6, indicating a possible to very probable contribution to drowning. Our findings suggest that psychotropic drugs may play a significant role in drowning, in up to 14.5% of cases, independently or in association with alcohol. CONCLUSIONS: Psychotropic drugs alone or in association with alcohol may be an overlooked risk factor in drowning, due to their effects on psychomotor function and cognition. Future studies should also address other mechanisms-for instance drug-induced long-QT syndrome-by which drugs may contribute to drowning.

Drug-induced long QT syndrome increases the risk of drowning.

There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation.

Citalopram-Induced Long QT Syndrome and the Mammalian Dive Reflex.

While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram. The post mortem blood level of citalopram was 1300 ng/mL. The patient was found to be an intermediate metabolizer via CYP2D6, the major pathway for metabolism of desmethylcitalopram; the level of which was also abnormally high. It is suggested that drug-induced long QT syndrome (DILQTS), caused by citalopram, combined with the mammalian dive reflex triggered malignant ventricular rhythms resulting in the patient's death. It is further suggested that, in general, the dive reflex increases the risk of fatal cardiac rhythms when the QT interval is prolonged by drugs.