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Dead in Bed Syndrome in Young Diabetic Patients Oddmund Sovik, MD, DRMEDSCI, Hranfnkell Thordarsen ,MD From the Department of Pediatrics and Medicine, University Hospital, Bergen, Norway Address correspondence and reprint requests to Oddmund Sovik, MD, Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway. E-mail: oddmund.sovik@bkb.haukeland.no Sovik O, Thordarson H, Diabetes Care 1999 Mar;22 Suppl 2:B40-2 Abstract: The so-called dead-in-bed syndrome refers to sudden death in young diabetic patients without any history of long-term complications. Autopsy is usually negative. The present report summarizes frequency data on this condition from studies in the U.K and the Scandinavian countries. It appears that such deaths occur in 6% of all deaths in diabetic patients below age 40 years. The frequency may also be expressed ass 2 - 6 events per 100,000 patient-years. [sic – the article says 10,000 patient-years; the author confirms that the abstract is wrong.] The causes are by definition unknown, but a plausible theory is a death in hypoglycemia [insulin reaction/insulin shock- ed], since history of nocturnal hypoglycemia [insulin reaction/insulin shock- ed] is noted in most cases. While waiting for the clarification of the underlying pathophysiology, one should attempt to identify patients who are at particular risk of hypoglycemia [insulin reaction/insulin shock- ed] and advocate caution in efforts to normalize blood glucose and HbA1c in these cases. Diabetes Care 22 (Suppl. 2):B40-B42, 1999. During the years 1988 – 1990, we observed in Bergen, Norway, four cases of unexpected deaths in young Type 1 diabetic patients. (1) The patients were found dead in an undisturbed bed, after having been observed in apparently good health the day before. No cause of death was established and autopsy was not informative. Tattersall and Gill (2) observed 22 similar case in patients in Great Britain during 1989. The British patients were 12-43 years old; most o them had gone to bed in apparently good health and were found dead in the morning . Of the 22 patients, 19 were sleeping alone at the time of death and 20 were found lying in an undisturbed bed. Most had uncomplicated diabetes and in none were anatomical lesions found at autopsy. The authors suggested a "syndrome" of dead in bed in diabetic patients. The purpose of this article is to summarize and review some of the available information on this type of death, with particular attention to causal factors, frequency, time trends, therapeutic consequences, and preventive measures. DEAD- IN- BED SYNDROME: THE CONCEPT -- To clarify what type of problems we are dealing with, it may be useful to look at a case history from our original publication (1). A male triplet had IDDM since age 14. He was physically and mentally normal, and there was no history of drug or alcohol abuse. He had a prolonged remission phase of 10 months, and was well organized in his diabetes self-management. There were moderate hypoglycemic episodes, mainly related to physical activity. At age 16.5 years he was transferred to multiple insulin injections with NovoPen, using Actrapid four times daily before meals, and Protophane at bedtime. The daily insulin requirement was low (0.5 U/kg). His HbA1c was 7.0%. Six months later he was found dead in his bed in the morning. He had played basketball the evening before, and went to bed in apparently excellent condition. The autopsy was negative, except for a minor lesion of the tongue. This case history presents typical features of what may be called "dead-in-bed syndrome." We are dealing with young people, with no history of diabetic complications, and in particular no autonomic dysfunction. They re found in an undisturbed bed, which seems to exclude death during a convulsive attack. Autopsy (usually without neuropathological studies) is negative. Obviously, we are not dealing with a syndrome in the strict sense of the term. We are faced with a type of death in diabetic patients that remains unexplained after routine pathological examinations, and which may or may not have a single underlying cause. MAGNITUDE OF THE PROBLEM – In the U.K., 22 cases of dead-in-bed syndrome were reported in a single year. (2) The cases were anecdotal and reported to the British Diabetic Association by physicians, relatives, and friends. Thus, the study was not population based, and it was not possible to evaluate the findings in a broader context of diabetes mortality. After the initial report from Norway, a nationwide study was set up in this country for the 10-year-period 1981-1990. (3) During these years, a total of 240 deaths from all causes were ascertained in diabetic patients 0 - 39 years of age. Sixteen cases (6.7%) fulfilled the criteria of dead- in- bed syndrome. The Norwegian data may be compared with those of Tunbridge (4), who studied factors contributing to death in 448 diabetic patients who died in the U.K. in 1976. Seven of the deaths corresponded to the dead-in-bed category, and these deaths occurred in the group of 149 patients < 40 years of age (Table 1). From the Norwegian and British data, it appears that the dead- in- bed syndrome amounts to 5 - 6% of all death in diabetic patients under the age of 40. In a Swedish population-based cohort of 4,919 childhood-onset type 1 cases, 33 patients died before the age of 28.5 years (5). Nine of these patients were found in bed, having been seen apparently healthy 1 – 2 days before death. There were no signs of alcohol or other intoxication, and autopsies were normal except for signs of cerebral hemorrhages in one case and bite marks in the mouth of another case. If the case with cerebral hemorrhages is excluded, we are left with eight cases who fulfill the criteria of dead in bed. This amounts to 24% of all deaths (Table 1). A Danish study covering the 7-year period 1982 –1988 ascertained 226 cases of sudden deaths in insulin-treated patients 0 – 50 years of age (6). Of these cases, 51 (23%) were found dead in bed in the morning. In comparing the data (Table 1), it should be noted, however, that the Danish study has a different denominator, namely "sudden deaths," and not all deaths in the diabetic patients. Also, in the Danish study, the age range is different (0 – 50 years). In a Swedish cohort of 2,000 diabetic patients, there were 18 deaths by follow-up (7). No case of dead- in- bed syndrome was found in this small group of deaths. Nor was this type of death reported in another young cohort with low numbers of deaths (8). Reported data may also be expressed as number of deaths (events) per 10,000 patient-years (Table 2). Again, data from different studies may not be easily compared, due to varying study design. One may, however, be dealing with 2 – 6 events per 10,000 patient years. [sic – the abstract says 100,000 patient-years; the author confirms that the abstract is wrong by a full order of magnitude.] This may be considered a small problem, but it is the circumstances of such deaths, rather than the numbers, which is a matter of concern. Table 1 – Frequencies of dead- in- bed syndrome in the U.K. and Scandinavian countries
Table 2 – Frequencies of dead in bed syndrome in Scandinavian countries
CAUSAL FACTORS – Discussing the causes of a condition that by definition is unexplained is necessarily a speculative exercise. The most plausible hypothesis is, however, that hypoglycemia [insulin reaction/insulin shock- ed], in one way or another, plays a role. hypoglycemia [insulin reaction/insulin shock- ed] could be particularly deleterious is associated with insufficient hormonal counter-regulation. A history of nocturnal hypoglycemia [insulin reaction/insulin shock- ed] was noted in 14 of the British cases reported (2). In our own study (3), frequent episodes of hypoglycemia [insulin reaction/insulin shock- ed] were noted in 12 cases, with nocturnal episodes in 10 of those. The problem with hypoglycemia [insulin reaction/insulin shock- ed] as a causal factor is that there are cases of hypoglycemic brain damage and death with a clinical course completely different from those with dead- in- bed syndrome. Thus, in our own material (3), eight patients were brought unconscious to the hospital with hypoglycemia [insulin reaction/insulin shock- ed] and never regained consciousness. Another problem pertains to the fact that nocturnal hypoglycemia [insulin reaction/insulin shock- ed] is a common phenomenon in type 1 diabetes, but a lethal outcome is extremely rare. In the search for pathophysiological mechanisms in the dead-in-bed syndrome of diabetic patients, there may be important lessons to learn from other disorders, particular in evaluation of cerebral versus cardiac factors. Sudden death is thus associated with physical exercise (9) and epilepsy (10), but existing data from those conditions are not helpful in explaining the dead- in- bed syndrome. Concerning a cardiac event, sudden death has been associated with QT-prolongation and ventricular arrhythmia (11). A modest QT-prolongation was found in a third of diabetic patients with definite autonomic neuropathy, but in none with normal or borderline autonomic function (12). It has been speculated that patients with similar pen injectors for short-acting premeal bolus injection and bedtime intermediate insulin might use the wrong pen injector at bedtime and go to sleep without realizing their mistake, and therefore be at risk of severe nocturnal hypoglycemia [insulin reaction/insulin shock- ed] (13). So far there are no data to support this notion. TIME TRENDS -- In the Norwegian study, 12 of the 16 deaths occurred in the years 1988, 1989, and 1990. There were significantly more cases of dead- in- bed syndrome in 1986 – 1990 than in the previous 5 year period (P<0.0003). By contrast, the Danish study revealed no increase during the years 1982 – 1988 (6). In Norway, the increased occurrence of dead- in- bed syndrome coincided with three major shifts in insulin treatment, namely the introduction of human insulin, insulin 100 U/ml, and common use of multiple daily injections. Concerning insulin 100 U/ml, it is not likely that the increased strength of insulin should lead to accidents 2 years after the transition period (1987). The human insulin controversy, with its confusing and conflicting literature, will not be reviewed here. There is no convincing scientific evidence in favor of the contention that human insulin leads to loss of hypoglycemia [insulin reaction/insulin shock- ed] warning symptoms (14,15). What remains as an important point of discussion, however, is the shifting therapeutic trend during the 1980s toward a common use of treatment regimens with multiple daily doses of rapid-acting insulin. It is now well established that efforts to normalize blood glucose and decrease HbA1c carry an increased risk of hypoglycemia [insulin reaction/insulin shock- ed], often during the night. In the Diabetes Control and Complications Trial, intensive therapy was associated with a threefold increase in the risk of severe hypoglycemia [insulin reaction/insulin shock- ed] (16), and severe hypoglycemia [insulin reaction/insulin shock- ed] occurred more often during sleep (17). The risk of hypoglycemia [insulin reaction/insulin shock- ed] associated with intensive treatment may be even greater in routine clinical settings, with less-motivated patients and less resources for supervision and follow-up. PRACTICAL CONSEQUENCES AND PREVENTIVE MEASURES – A common question asked by adolescents with recent-onset type 1 diabetes is the following: Could I die if my blood sugar falls during the night? Several years ago, most diabetologists would say definitely no. With present day knowledge, we are not so sure. In fact, it has become very difficult to talk with young diabetic patients about this question. Without concealing the facts, one should probably shift focus to preventive measures. Patients with frequent hypoglycemic reactions, with or without nocturnal hypoglycemic, need extensive education and instruction. One should be cautious in recommending near-normal blood glucose and HbA1c in these patients, particularly if they sleep alone. In physically active patients, one should focus on the problem of postexercise hypoglycemia [insulin reaction/insulin shock- ed]. SUMMARY AND CONCLUSIONS – The dead- in- bed syndrome refers to unexpected deaths in young diabetic patients without any history of complications. The patients die in their sleep and are found in an undisturbed bed, apparently excluding a convulsive attack. Autopsy is typically negative. The causes are by definition unknown, but the most plausible theory is a death in hypoglycemia [insulin reaction/insulin shock- ed]. The deaths may be related to the more intensive insulin regimens introduced during the 1980s. Fortunately, these tragedies are not very common, occurring in about 6% of all deaths in diabetic patients < 40 years of age. While we are waiting for clarification of the underlying pathophysiology, one should attempt to identify patients who are particular risk of hypoglycemia [insulin reaction/insulin shock- ed] and advocate caution in efforts to normalize blood glucose and HbA1c levels in these cases. Acknowledgements: Our studies of mortality in young diabetic patients are supported by the Norwegian Directory of Health. References
Diabetes Care 1999 Mar 22 Suppl 2:B40-2 |