This study identifies and characterises the unfortunate occurrence of sudden unexplained deaths (SUDs), including dead-in-bed syndrome, in two related cohorts in Southwestern Pennsylvania, one hospital-based and one population-based, of individuals diagnosed with Type 1 diabetes between 1965 and 1979. SUDs and DIB deaths accounted for 7.8% and 2.8% of all deaths so far classified, respectively, in this cohort. Individuals meeting dead-in-bed criteria had a higher HbA1c and daily insulin dose, and lower BMI compared to similar Type 1 DM individuals.
Two-thirds of the SUDs did not have an autopsy, and an underlying cause of death could not be determined by the MCC for nearly one-third of the SUDs, despite interviews with next-of-kin and hospital or autopsy records, when appropriate. Without (and sometimes even with) autopsies, post-mortem diagnoses are highly speculative and often inaccurate or non-specific (e.g., 32% of these SUDs listed diabetes mellitus or sudden death as the only cause of death on the death certificate).
Although the contribution of SUDs (and DIB syndrome) to early mortality in Type 1 DM is not insignificant (5–10% of all Type 1 DM deaths),[8
] it has been unclear whether SUDs occur more frequently in Type 1 DM than in the similarly-aged general population. compares data from a review of the literature on the incidence density of sudden deaths, SUDs, and DIB syndrome. The incidence densities found in the present study are quite comparable to the range reported in a recent review of DIB syndrome in Type 1 DM.[8
] However, compared to incidence densities for all sudden deaths or for SUDs alone in the young (age<50) general population, SUDs appear to occur up to 10 times more often in Type 1 DM.
These results confirm findings from previous studies showing that SUDs and dead-in-bed syndrome tend to occur more in males (Thordarson et al[5
]: 10 M, 6 F, Tu et al[6
]: 8 M, 2 F). While one U.K. report (n
=128 deaths) on Type 1 DM children aged 1–19, reported more female DIB deaths (7 F, 2 M),[9
] they also reported that a significant proportion of deaths overall occurred in young males with poorly controlled diabetes who died at home (often of hypo- or hyperglycaemia).
Potential mechanisms for DIB syndrome in Type 1 DM include both nocturnal hypoglycaemia and undiagnosed cardiac autonomic neuropathy (AN).[10
] A plausible theory for the etiology of DIB syndrome has been proposed and developed over the last decade.[10
] Although nocturnal hypoglycaemia rarely itself results in sudden death,[11
] those at risk of DIB syndrome may have reduced parasympathetic activity (and, thus, relative sympathetic predominance), due to both long-standing diabetes and early stages of cardiac AN,[10
] which leads to ventricular arrhythmias.[15
] Also, both AN and severe hypoglycaemia have also been associated with abnormal cardiac repolarisation, as evidenced by prolonged corrected QT (QTc) intervals.[14
] However, none of the 3 DIB or 5 other SUDs in our subgroup analysis had any clinical evidence of prolonged QTc interval in any EDC exam visits. Nonetheless, this does not preclude the possibility that severe nocturnal hypoglycaemia might have caused acute QT prolongation, as has been demonstrated recently.[24
Nocturnal hypoglycaemia has a higher propensity to persist for hours due to long-standing diabetes causing “hypoglycaemia-associated autonomic failure” (HAAF), where the body produces an inadequate response of glucagon and adrenaline when it senses hypoglycaemia. Woodward et al. very recently showed that nocturnal hypoglycaemia (<3.5 mmol/l) is still very common in individuals with long-standing Type 1 DM,[25
] where nearly 50% experienced nocturnal hypoglycaemia, a rate which has not dramatically changed in over 20 years despite the current wide usage of long-acting insulin analogs.[26
] A 2009 case report describes a 23-yr old man with recurrent severe hypoglycaemia placed on continuous glucose monitoring (CGM) and then found dead in an undisturbed bed the next day.[27
] The CGM revealed glucose levels below 1.7 mmol/L around the time of his death with only minimal counterregulatory response.
The findings in this study are preliminary as several limitations exist. Nearly 25% of all deaths have yet to be classified by the MCC. However, of the deaths not yet classified, at present only three deaths potentially meet SUD criteria. As the number of SUDs might increase slightly, the SUD incidence density reported herein might be underestimated. Also, this report is primarily descriptive in nature, because clinical and diabetes complication data were not available for the majority of the study population, since the Allegheny County cohort has only been contacted three times since the cohort was developed (late 1970s), primarily to determine population-based mortality rates. Few associations reach statistical significance; however, there is limited sample size. Generalising these finding to other Type 1 DM populations should be done with caution.
In conclusion, these results suggest patterns predictive of sudden unexplained deaths and dead-in-bed syndrome in Type 1 diabetes. However, since SUD and DIB comprise a limited proportion of all Type 1 DM deaths, large epidemiologic studies combining data from multiple centers or studies are necessary to determine predictors and work to prevent these devastating deaths in Type 1 diabetes.