Annals of Medicine, 2015; 47: 238–244 © 2015 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2015.1017528
ORIGINAL ARTICLE
High risk of abnormal QT prolongation in the early morning in diabetic and non-diabetic patients with severe hypoglycemia Tetsuro Tsujimoto1,2, Ritsuko Yamamoto-Honda1,3, Hiroshi Kajio1, Miyako Kishimoto1,3, Hiroshi Noto1,3, Remi Hachiya1, Akio Kimura4, Masafumi Kakei2,5 & Mitsuhiko Noda3 1Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan,
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
2Division of General Medicine, Jichi Medical University Graduate School of Medicine, Shimotsuke, Japan, 3Department of Diabetes Research,
Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan, 4Department of Emergency Medicine and Critical Care, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan, and 5First Department of Comprehensive Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama, Japan
Background. Several studies have suggested that the occurrence of severe hypoglycemia during sleep may be more dangerous for cardiac arrhythmia than that in the day-time. Methods. We performed a retrospective study between January 2006 and March 2012 to assess electrocardiograms during severe hypoglycemia in patients with or without diabetes. Results. A total of 59,602 patients who visited the emergency room by ambulance were screened, and 287 patients with severe hypoglycemia were enrolled. The median blood glucose levels in patients with (DM, n ⴝ 192) and without diabetes (non-DM, n ⴝ 95) were 30 and 45 mg/dL, respectively. During severe hypoglycemia, the incidence of abnormal QT prolongation was significantly higher in the early morning (4–10 a.m.) than at other times (DM group, 74.3% versus 54.1%, P ⴝ 0.02; non-DM group, 78.3% versus 50.0%, P ⴝ 0.01). Multivariate logistic regression analysis identified the occurrence of severe hypoglycemia in the early morning as a strong factor for abnormal QT prolongation (DM group, odds ratio [OR] 2.80, 95% confidence interval [CI] 1.15–6.80, P ⴝ 0.02; non-DM group, OR 4.53, 95% CI 1.30–15.74, P ⴝ 0.01). Conclusions. The incidence of abnormal QT prolongation during severe hypoglycemia was significantly higher in the early morning than at all other times, independent of the cause of severe hypoglycemia. Key words: Arrhythmia, diabetes, nocturnal hypoglycemia, QT prolongation, severe hypoglycemia
Introduction Severe hypoglycemia in patients with diabetes (DM) is hazardous and can lead to seizures, coma, and irreversible brain damage (1). In addition, recent studies have revealed that severe hypoglycemia was associated with an increased risk of death and cardiovascular disease (2,3). Severe hypoglycemia leads to the activation of the sympathoadrenal system and the subsequent release of counter-regulatory hormones such as catecholamines,
Key messages • The incidence of abnormal QT prolongation during severe hypoglycemia in patients with diabetes was the highest at night-time, particularly in the early morning. • A similar fluctuation in QT prolongation in patients without diabetes suggests that the incidence of abnormal QT prolongation may be higher in the early morning than at all other times, independent of the cause of the severe hypoglycemia. • The occurrence of severe hypoglycemia in the early morning was a strong risk factor for the incidence of abnormal QT prolongation using multivariate logistic regression analysis.
glucagon, and cortisol. As a result, hypothermia, hypokalemia, and significant cardiac stress such as marked elevated blood pressure are common during severe hypoglycemia (4). Furthermore, several studies have reported that severe hypoglycemia prolongs the QT interval (4–8), which can lead to fatal arrhythmias. A recent study has also suggested that hypoglycemia experienced after a subcutaneous injection of insulin may cause QT prolongation in patients with type 1 diabetes (9). The time during sleep is the most vulnerable period partly because it may be difficult to be aware of hypoglycemia; this is because sleep blunts the counter-regulatory response (10). Therefore, a long duration of hypoglycemia may occur during sleep. Some studies have suggested that hypoglycemia during sleep or in the early morning in patients with type 1 diabetes (T1DM) may be associated with sudden cardiac death (11–13). In addition, other studies demonstrated that nocturnal hypoglycemia in patients with type 2 diabetes (T2DM) may be associated with an increased risk of cardiac arrhythmias (14). These studies suggest that the occurrence of hypoglycemia from late evening to early morning in patients with DM may be more dangerous for cardiac
Correspondence: Tetsuro Tsujimoto, MD, Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. Fax: ⫹ 81-3-3207-1038. E-mail: [email protected] (Received 17 December 2014; accepted 6 February 2015)
Abnormal QT prolongation during hypoglycemia 239
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
arrhythmia than that in the day-time. Furthermore, the increased risk of sudden cardiac death during this period may be associated with a higher incidence of abnormal QT prolongation than that occurring in the day-time. However, although the QT interval has diurnal variation in healthy subjects (15,16) and antipsychoticrelated QT prolongation more frequently occurs at night-time than in the day-time (17), it remains unknown whether the incidence of abnormal QT prolongation during severe hypoglycemia fluctuates throughout the day. Therefore, we hypothesized that the incidence of abnormal QT prolongation during severe hypoglycemia may be significantly higher in late evening and in early morning than that in the day-time. The aim of the present study was to investigate the circadian variation in abnormal QT prolongation during severe hypoglycemia in patients with DM. In addition, it was investigated whether the circadian variation in abnormal QT prolongation was similarly found in patients with and without DM.
Patients and methods Study design We conducted a retrospective study of patients who had been transported by ambulance and diagnosed as having severe hypoglycemia at the National Center for Global Health and Medicine in Tokyo, Japan, between 1 January 2006 and 31 March 2012. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves and that required the medical assistance of another person after visiting the emergency room by ambulance (1). Blood glucose levels were mainly measured at a central laboratory (81.1%, 232/286), although some were measured using a blood glucose meter (18.9%, 54/286). At least two diabetologists independently reviewed all patient data including clinical records, laboratory data, and electrocardiograms. Disagreements between the reviewers were resolved by a third diabetologist. DM was confirmed when the patient had been previously diagnosed as having DM or was being treated with antidiabetic medication. T1DM was confirmed by previous diagnosis or by the presence of antibodies to glutamic acid decarboxylase. T2DM was confirmed by a previous diagnosis or the absence of a specific cause. Other types of diabetes were excluded from the analyses. Patients with cardiopulmonary arrest upon arrival were excluded from the study. Data were analyzed using only the latest hospital visit for each individual. A day was equally divided into four periods: late evening (10 p.m. to 4 a.m.), early morning (4 a.m. to 10 a.m.), midday (10 a.m. to 4 p.m.), and early evening (4 p.m. to 10 p.m.). The first two periods were defined as night-time, and the remaining two periods were defined as day-time. The study patients were distributed according to the time of the electrocardiogram upon arrival. Electrocardiograms performed after the improvement of severe hypoglycemia were excluded from the analysis. The primary aim of this study was to assess whether the rate of abnormal QT prolongation during severe hypoglycemia differed between the nocturnal and day-time periods. The study was approved by the institutional review board of the National Center for Global Health and Medicine Hospital.
QT intervals The QT and RR intervals for patients with severe hypoglycemia upon arrival were measured using lead II with more than five consecutive beats of a 12-lead electrocardiogram. All measurements were performed by two observers who were blinded to detailed patient characteristics (18). When QT and RR were
difficult to measure using lead II, the other limb leads were used. One corrected QT interval (QTc) was calculated using Bazett’s formula: QTc ⫽ QT interval ÷ square root of the RR interval. Based on previous studies on patients with diabetes and hypoglycemia, QTc ⱖ 0.44 s was considered to be abnormally prolonged (6,19–22). For cases with atrial fibrillation, the QT intervals that followed the longest and shortest RR intervals were measured, and each was then divided by the square root of QTc of the preceding RR interval (18). The mean of these two values was used as QTc. The corrected QT interval was not calculated for patients with coupled pulses or pacemakers.
Other measurements Serum creatinine and potassium levels were measured upon arrival, and glycated hemoglobin (HbA1c) levels were measured at the nearest time within three months of arrival. Serum potassium levels of ⬍ 3.5 mEq/L were considered to be indicative of hypokalemia. The estimated glomerular filtration rate (GFR) was calculated using the following formula as recommended by the Japanese Society of Nephrology: estimated GFR (mL/min/1.73 m2) ⫽ 194 ⫻ Cre-1.094 ⫻ Age-0.287 (⫻ 0.739 if the patient was female) (23). Systolic blood pressure, diastolic blood pressure, and heart rate were measured upon arrival.
Statistical methods Patients were initially categorized into DM and non-DM groups. Data are presented as numbers (%), mean with standard deviation (SD), and median with the lower and upper ends of the interquartile range (IQR). Continuous variables were compared using t tests, Wilcoxon rank sum tests, or Kruskal–Wallis tests. Categorical variables were compared using chi-square tests or Fisher’s exact tests. Multivariate logistic regression analysis was performed to assess whether circadian variation was associated with abnormal QT prolongation. P values of ⬍ 0.05 according to a two-sided test were considered to be statistically significant for all tests. All the analyses were performed using Stata software, version 11.1 (Stata Corp, College Station, TX, USA).
Results A total of 59,602 patients that visited the emergency room by ambulance were screened, and 530 had severe hypoglycemia. Among them, 290 patients underwent electrocardiograms upon arrival. Three patients with other diabetes were excluded from subsequent analyses, and 287 patients with T1DM, T2DM, or no diabetes (non-DM) were enrolled in this study. The clinical characteristics of the study population upon arrival are presented in Table I. In the T1DM (n ⫽ 28), T2DM (n ⫽ 164), and non-DM (n ⫽ 95) groups, the median (IQR) blood glucose levels were 25 mg/dL (20–34 mg/dL), 31 mg/dL (24–38 mg/dL), and 45 mg/dL (26–64 mg/dL), respectively. The incidences of abnormal QT prolongation (QTc ⱖ 0.44 s) during severe hypoglycemia in the T1DM, T2DM, and non-DM groups were 42.9%, 60.4%, and 56.8%, respectively. Highly abnormal QT prolongation (QTc ⱖ 0.50 s) was observed in some patients with severe hypoglycemia. The circadian variations in abnormal QT prolongation in the DM and non-DM groups are shown in Figure 1A. In the DM group, incidences of abnormal QT prolongation in late evening, early morning, mid-day, and early evening were 62.5%, 74.3%, 54.4%, and 48.3%, respectively. In the non-DM group, incidences of abnormal QT prolongation in the late evening, early morning, mid-day, and early evening were 61.1%, 78.3%, 42.9%, and 50.0%, respectively. Incidences of abnormal QT prolongation in both groups were the highest in the early morning. Similarly,
240
T. Tsujimoto et al. Table I. Characteristics of the study patients. T1DM (n ⫽ 28)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Characteristics Age (years) Female History of coronary heart diseasea Hypertension Atrial fibrillation Blood glucose (mg/dL) (n ⫽ 286) HbA1c (%) (n ⫽ 82)b Duration of diabetes (years) (n ⫽ 112) Treatment for diabetes Sulfonylurea Insulin Estimated GFR (mL/min/1.73 m2) (n ⫽ 278)c Serum potassium level (mEq/L) (n ⫽ 283)d Causes of severe hypoglycemia Glucose-lowering medications Sulfonylurea Insulin Others Abnormal QT prolongation (QTc ⱖ 0.44 s)f Highly abnormal QT prolongation (QTc ⱖ 0.50s)
49 (40–59) 17.9% 0.0% 32.1% 0.0% 25 (20–34) 7.3 (6.8–7.7) 22 (16–29)
T2DM (n ⫽ 164) 76 (65–83) 36.6% 12.8% 69.5% 14.0% 31 (24–38) 6.5 (6.0–7.2) 14 (6–23)
Non-DM (n ⫽ 95) 66 (53–78) 33.7% 1.1% 17.9% 10.5% 45 (26–64) – –
0.0% 100% 80.3 (61.6–89.3) 3.4 (3.2–3.8)
51.9% 45.6% 52.8 (29.8–77.4) 3.6 (3.3–4.2)
– – 74.7 (48.8–100.1) 3.8 (3.4–4.3)
96.4% 0.0% 96.4% 3.6% 42.9% 0.0%
94.5% 48.7% 43.7% 5.5% 60.4% 15.2%
2.2%e 1.1% 1.1% 97.8% 56.8% 22.1%
Data are presented as number, %, or median (IQR). SI conversion factors: to convert blood glucose to mmol/L, multiply by 0.0555. aHistory of coronary heart disease was defined as a history of myocardial infarction and angina pectoris. bHbA1c levels were measured at the nearest time within three months of arrival. T1DM: 7.3% (6.8%–7.7%) ⫽ 56 (51–61) mmoL/moL. T2DM: 6.5% (6.0%–7.2%) ⫽ 48 (42–55) mmoL/moL. cEstimated GFR was calculated using the following formula: estimated GFR (mL/min/1.73 m2) ⫽ 194 ⫻ Cre⫺ 1.094 ⫻ Age⫺ 0.287 (⫻ 0.739 if the patient was female). dSerum potassium levels were measured upon arrival at the hospital. eOne patient attempted suicide using insulin, and one patient took a sulfonylurea incorrectly. Both patients were discharged safely from the hospital. fQTc was calculated using Bazett’s formula: QTc ⫽ QT interval ÷ square root of the RR interval. DM ⫽ diabetes; GFR ⫽ glomerular filtration rate; HbA1c ⫽ glycated hemoglobin; non-DM ⫽ no diabetes; T1DM ⫽ type 1 diabetes; T2DM ⫽ type 2 diabetes.
incidences of abnormal QT prolongation were the highest in the early morning in both the T1DM and T2DM groups (75.0% and 74.2%, respectively; Figure 1B). Blood pressure and heart rate were not significantly associated with circadian variation in the DM and non-DM groups (Figure 2). The abnormal QT prolongations at night-time and in the daytime are shown in Figure 3A. In the DM and non-DM groups, incidences of abnormal QT prolongation were significantly higher at night-time than in the day-time (DM group, 68.6% versus 51.3%, P ⫽ 0.02; non-DM group, 70.7% versus 46.3%, P ⫽ 0.01). The differences in the abnormal QT prolongation between the early morning and at all other times are shown in Figure 3B. Incidences of abnormal QT prolongation in both groups were significantly higher in the early morning than at all other times (DM group, 74.3% versus 54.1%, P ⫽ 0.02; non-DM group, 78.3% versus 50.0%, P ⫽ 0.01). When we re-analyzed the subjects of T1DM and T2DM separately, the incidences of abnormal QT prolongation in both groups tended to be higher at night-time than in the day-time (T1DM group, 58.3% versus 31.3%, P ⫽ 0.25; T2DM group, 69.8% versus 54.5%, P ⫽ 0.05) although the differences were non-significant for both groups. Similarly, incidences of abnormal QT prolongation were insignificantly higher in both the groups in the early morning than at all other times (T1DM group, 75.0% versus 37.5%, P ⫽ 0.28; T2DM group, 74.2% versus 57.1%, P ⫽ 0.10). Results of the multivariate analyses for the variation in the incidence of abnormal QT prolongation during severe hypoglycemia are presented in Tables II and III. When multivariate logistic regression analysis was performed to identify the clinical variables that were independently associated with abnormal QT prolongation in the DM group, the occurrence of severe hypogly-
cemia at night-time was the only strong factor (odds ratio [OR] 2.17; 95% confidence interval [CI] 1.14–4.11; P ⫽ 0.01) (Table II). When HbA1c levels, of which there were limited data, were included in the multivariate analysis, the occurrence of severe hypoglycemia at night-time remained the only significant factor (OR 4.89; 95% CI 1.63–14.60; P ⫽ 0.004). The association between abnormal QT prolongation and the occurrence of severe hypoglycemia in the early morning is shown in Table III. The occurrence of severe hypoglycemia in the early morning was a strong factor for abnormal QT prolongation in multivariate logistic regression analysis (OR 2.80; 95% CI 1.15–6.80; P ⫽ 0.02). Similar to that at night-time, when HbA1c levels were included in the multivariate analysis, the occurrence of severe hypoglycemia in the early morning remained the only significant factor (OR 14.71; 95% CI 1.70–127.12; P ⫽ 0.01). Multivariate logistic regression analyses revealed that abnormal QT prolongation in the non-DM group was also significantly associated with the occurrence of severe hypoglycemia at nighttime (OR 4.07; 95% CI 1.44–11.44; P ⫽ 0.008) and in the early morning (OR 4.53; 95% CI 1.30–15.74; P ⫽ 0.01). As a result, the occurrence of severe hypoglycemia at night-time or in the early morning was a significant factor for abnormal QT prolongation in the DM and non-DM groups.
Discussion This is the first study to report that the incidence of abnormal QT prolongation during severe hypoglycemia in patients with DM was the highest at night-time, particularly in the early morning. In addition, the present study revealed that the occurrence of severe hypoglycemia in the early morning was a strong risk factor for the
Abnormal QT prolongation during hypoglycemia 241
(A) 100 DM non-DM
(%)
75
50
25
0 Early morning (4 A.M. to 10 A.M.)
Midday (10 A.M. to 4 P.M.)
Early evening (4 P.M. to 10 P.M.)
(B) 100 T1DM T2DM 75
(%)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Late evening (10 P.M. to 4 A.M.)
50
25
0 Late evening Early morning Midday Early evening (10 P.M. to 4 A.M.) (4 A.M. to 10 A.M.) (10 A.M. to 4 P.M.) (4 P.M. to 10 P.M.) Figure 1. Circadian variations in rate of abnormal QT prolongation in patients with severe hypoglycemia. Rate of abnormal QT prolongation at each period in the DM and non-DM groups (A), and in the T1DM and T2DM groups (B). DM ⫽ diabetes; non-DM ⫽ no diabetes; T1DM ⫽ type 1 diabetes; T2DM ⫽ type 2 diabetes.
incidence of abnormal QT prolongation using multivariate logistic regression analysis. Moreover, a similar fluctuation in QT prolongation in patients without DM suggests that the incidence of abnormal QT prolongation in the early morning may be higher than at all other times, independent of the cause of the severe hypoglycemia. Several previous studies in populations with T1DM and T2DM demonstrated that hypoglycemia was associated with abnormal QT prolongation (7,8,24,25). In addition, recent studies suggested that abnormal QT prolongation during severe hypoglycemia was observed in ⬎ 50% of patients with T1DM and T2DM (4), and that several patients without DM had prolonged QT intervals during severe hypoglycemia (26). QT prolongation during hypoglycemia is considered to be associated with hypokalemia and significant elevation of epinephrine and norepinephrine as well as low blood glucose itself (25). QT prolongation reflects abnormal cardiac repolarization, and hypoglycemia-induced QT prolongation can lead to fatal cardiac events such as torsade de pointes (11–14). In patients with T1DM, sudden nocturnal deaths, so-called ‘dead-in-bed syndrome’ have been reported (11–13). Patients with dead-in-bed syndrome were found dead on an undisturbed bed, and autopsies revealed no major abnormalities. Tanenberg et al. (13) described a case of deadin-bed syndrome in detail; this included data from a continuous subcutaneous glucose monitoring system (CGMS) in a young patient with T1DM. The patient’s CGMS glucose levels rapidly decreased at
midnight and declined to ⬍ 50 mg/dL at approximately 2 a.m. The patient’s death presumably occurred between 5 and 8 a.m., and an autopsy performed within 8 h of his death failed to reveal any major anatomical abnormalities that could have contributed to his death. This case suggests that a hypoglycemic event that occurred between the late evening and the early morning was one of the main causes of dead-in-bed syndrome. Previous studies reported that nocturnal hypoglycemia in patients with T1DM resulted in a prolonged QT interval (8,24). However, because hypoglycemia-induced QT prolongations were also found in the day-time (5,7,25), it was unclear why the sudden death occurred during sleep and at night-time but not in the day-time. The present study revealed that the incidence of abnormal QT prolongation during severe hypoglycemia was significantly higher at night-time, particularly in the early morning, than at all other times. Therefore, this may partially explain cases of sudden cardiac death at night-time in patients with T1DM. A recent study demonstrated that nocturnal hypoglycemia was associated with an increased risk of cardiac arrhythmia in patients with T2DM and cardiovascular risk (14). Patients with T2DM in the present study had the highest incidence of abnormal QT prolongation at night-time, and particularly in the early morning. This suggests that hypoglycemia at night-time was more hazardous than in the day-time. In the present study, blood pressure and heart rate during severe hypoglycemia showed no
242
T. Tsujimoto et al.
(A)
Diabetes Systolic BP (mmHg)
200 175
168 (145-206)
Diastolic BP (mmHg)
HR (bpm) 172 (146-194)
170 (149-195)
164 (146-188)
150 125 100
80 80 (70-97) (73-91)
75
90 81 (76-97) (60-94)
88 80 (75-101) (68-98)
86 (78-100) 69 (64-92)
50 25 0 Late evening (10 P.M. to 4 A.M.)
Early morning (4 A.M. to 10 A.M.)
Early evening (4 P.M. to 10 P.M.)
Non-diabetes
(B) 200
Systolic BP (mmHg)
Diastolic BP (mmHg)
HR (bpm)
175 150 125
85 (71-96)
100 75
115 (88-146)
113 (91-135)
68 (54-81)
137 (118-158)
124 (112-150)
84 (62-105)
79 76 (59-92) (72-90)
64 (50-85)
95 (80-110) 79 (67-95)
50 25 0 Late evening Early morning Midday Early evening (10 P.M. to 4 A.M.) (4 A.M. to 10 A.M.) (10 A.M. to 4 P.M.) (4 P.M. to 10 P.M.) Figure 2. Circadian variations in blood pressure and heart rate in patients with severe hypoglycemia. Blood pressure and heart rate in the DM group (A) and non-DM group (B). Data are presented as median (IQR). The values for blood pressure and heart rate in the DM and non-DM groups did not differ significantly using Kruskal–Wallis tests. BP ⫽ blood pressure; bpm ⫽ beats per minute; HR ⫽ heart rate.
(%)
(A) fluctuation throughout the day; only the incidence of abnormal QT prolongation showed circadian variation. The association was unchanged even after adjusting for several related variables including hypokalemia and blood glucose levels. Similar observations between DM patients and non-DM patients (Tables II and III, Figures 1 and 3) suggest that the daily variation in abnormal QT prolongation during severe hypoglycemia is not associated with the cause of severe hypoglycemia and/or diabetes-related complications such as diabetic autonomic neuropathy. Previous studies revealed that the QT interval had diurnal variation in healthy subjects (15,16) and transplanted hearts exhibited no change in QT interval (27). Based on these reports, the daily variation in QT interval may be associated with circadian fluctuation in sympathetic activity and activation in the heart. In addition, sympathetic activity is relatively high in the early morning (28,29). Therefore, the relatively high incidence of abnormal QT prolongation in the early morning may result from additional stimulation of the sympathetic nervous system caused by severe hypoglycemia in these pathophysiological backgrounds. However, the detailed mechanism remains unclear, and further studies are warranted. A recent guideline updated the normal standards for thresholds of abnormal QT prolongation to the following values: women up to 0.46 s and men up to 0.45 s (30). Additional analyses using this updated definition of prolonged QT confirmed that the incidences of abnormal QT prolongation in both groups were also the highest in the early morning. Similarly, incidences of abnormal QT
Nighttime
100 90 80 70 60 50 40 30 20 10 0
P = 0.001 69.0%
P = 0.02
P = 0.002 75.9%
70.7%
DM (n = 192) Early morning All other times P = 0.02
46.3%
non-DM (n = 95)
P = 0.01 78.3%
74.3% 52.8%
P = 0.01
51.3%
49.7%
(B) 100 90 80 70 60 50 40 30 20 10 0
Daytime
68.6%
ALL (n = 287)
(%)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Midday (10 A.M. to 4 P.M.)
54.1%
50.0%
ALL DM non-DM (n = 287) (n = 192) (n = 95) Figure 3. Rate of abnormal QT prolongation at night-time and in the early morning. Rate of abnormal QT prolongation at night-time and in the daytime (A) and in the early morning and at all other times (B).
Abnormal QT prolongation during hypoglycemia 243 Table II. Multivariate analysis of the clinical variables for abnormal QT prolongation during severe hypoglycemia at night-time. Multivariate analysis (DM group) Variables Age (years) Female History of coronary heart diseasea Hypertension Blood glucose on arrival (mg/dL) Hypokalemia (⬍ 3.5 mEq/L)b Severe hypoglycemia in the night-time
Odds ratio 1.00 1.07 0.46 1.39 0.98 0.88 2.17
95% CI 0.98–1.02 0.54–2.11 0.17–1.22 0.68–2.81 0.96–1.00 0.46–1.67 1.14–4.11
P value 0.56 0.83 0.12 0.35 0.06 0.70 0.01
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Multivariate analysis (non-DM group) Odds Variables ratio 95% CI P value Age (years) 1.03 1.00–1.06 0.01 Female 0.48 0.18–1.30 0.15 Hypertension 0.83 0.24–2.89 0.78 Blood glucose on arrival (mg/dL) 0.98 0.96–1.00 0.24 1.11 0.40–3.08 0.83 Hypokalemia (⬍ 3.5 mEq/L) Severe hypoglycemia in the night-time 4.07 1.44–11.44 0.008 aCoronary heart disease was defined as myocardial infarction or angina pectoris. bSerum potassium levels were measured upon arrival at the hospital. 95% CI ⫽ 95% confidence interval.
prolongation in the DM and non-DM groups were higher in the early morning than at all other times (DM group, 45.7% versus 36.9%, P ⫽ 0.33; non-DM group, 78.3% versus 40.3%, P ⫽ 0.002). These data may partially support our results. In addition, many formulas have been proposed to adjust the QT interval (31,32), and a different QT measurement technique may influence the results. Further studies are warranted to define the best method for QT interval correction in patients with hypoglycemia. However, many studies have reported that QTc ⱖ 0.44 s, calculated using Bazett’s formula in patients with diabetes and hypoglycemia, was associated with important clinical outcomes such as mortality and diabetes-related complications (6,19–22). Therefore, we believe that the present study provides additional evidence for QT prolongation associated with hypoglycemia.
Table III. Multivariate analysis of the clinical variables for abnormal QT prolongation during severe hypoglycemia in the early morning. Multivariate analysis (DM group) Variables Age (years) Female History of coronary heart diseasea Hypertension Blood glucose on arrival (mg/dL) Hypokalemia (⬍ 3.5 mEq/L)b Severe hypoglycemia in the early morning
Odds ratio
95% CI
1.00 1.02 0.46 1.33 0.98 0.94 2.80
0.98–1.02 0.51–2.01 0.17–1.24 0.66–2.68 0.95–1.00 0.49–1.80 1.15–6.80
Odds ratio
95% CI
P value 0.64 0.95 0.12 0.42 0.06 0.86 0.02
Multivariate analysis (non-DM group) Variables
Age (years) 1.02 1.00–1.05 Female 0.55 0.20–1.47 Hypertension 0.78 0.23–2.67 Blood glucose on arrival (mg/dL) 0.98 0.96–1.00 1.19 0.43–3.25 Hypokalemia (⬍ 3.5 mEq/L) Severe hypoglycemia in the early morning 4.53 1.30–15.74 aCoronary heart disease was defined as myocardial infarction or pectoris. bSerum potassium levels were measured upon arrival at the hospital. 95% CI ⫽ 95% confidence interval.
P value 0.02 0.23 0.70 0.13 0.73 0.01 angina
Several limitations of the study must be noted. First, the present study was performed at a single national center, and data were retrospectively reviewed. Therefore, additional large-scale prospective multicenter studies are needed to confirm these results. However, no previous studies have assessed this number of electrocardiograms in patients during severe hypoglycemia; therefore, this study revealed novel findings. Second, missing electrocardiograms before and after treatment and the limited number of samples may have affected the results and statistical analyses. In addition, duration of hypoglycemia prior to hospital visiting was unknown. However, few studies have investigated the circadian variation in abnormal QT prolongation during severe hypoglycemia. We believe that the current study provides extremely important information regarding severe hypoglycemia. Finally, we could not evaluate the other changes in electrocardiograms for ST segment and T wave. In addition, patients with prehospital cardiopulmonary arrest could not be examined. Therefore, some patients with severe hypoglycemia may have died of lethal arrhythmias in a prehospital setting. In conclusion, this study revealed that the incidence of abnormal QT prolongation during severe hypoglycemia was the highest in the early morning and was significantly higher than at other times. The goals of glycemic control in patients with diabetes should be determined individually in light of not only prevention of diabetes-related complications but also of the risk of hypoglycemia targeting particularly a minimum risk of severe hypoglycemia in the early morning. The results of this study may contribute to reducing the incidence and severity of life-threatening events associated with severe hypoglycemia.
Acknowledgements T.T. conceived the study. T.T., M.Ka., and M.N. designed the protocol. T.T., R.Y.-H., H.K., M.Ki., R.H., and A.K. contributed to the data collection and preparation. T.T., R.Y.-H., M.Ki., H.N., and M.N. analyzed the data. T.T., R.Y.-H., M.Ka., and M.N. wrote the report. All authors contributed to the interpretation of the results and approved the final version of the manuscript. T.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding: This work was supported by JSPS KAKENHI [grant number 26860701]. Declaration of interest: The authors have no potential conflicts of interest relevant to this article to report.
References 1. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26:1902–12. 2. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. 3. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–18. 4. Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care. 2014;37:217–25. 5. Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes. 2003;52:1469–74. 6. Gruden G, Giunti S, Barutta F, Chaturvedi N, Witte DR, Tricarico M, et al. QTc interval prolongation is independently associated with severe
244
7.
8. 9.
10. 11. 12.
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
13. 14. 15. 16. 17.
18. 19.
20.
21.
T. Tsujimoto et al. hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care. 2012;35:125–7. Christensen TF, Tarnow L, Randlov J, Kristensen LE, Struijk JJ, Eldrup E, et al. QT interval prolongation during spontaneous episodes of hypoglycaemia in type 1 diabetes: the impact of heart rate correction. Diabetologia. 2010;53:2036–41. Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited. Diabetologia. 2009;52:42–5. Christensen TF, Cichosz SL, Tarnow L, Randlov J, Kristensen LE, Struijk JJ, et al. Hypoglycaemia and QT interval prolongation in type 1 diabetes—bridging the gap between clamp studies and spontaneous episodes. J Diabetes Complications. 2014;28:723–8. Jones TW, Porter P, Sherwin RS, Davis EA, O’Leary P, Frazer F, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998;338:1657–62. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med. 1991;8:49–58. Thordarson H, Sovik O. Dead in bed syndrome in young diabetic patients in Norway. Diabet Med. 1995;12:782–7. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 2010;16:244–8. Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes. 2014;63:1738–47. Browne KF, Prystowsky E, Heger JJ, Chilson DA, Zipes DP. Prolongation of the Q-T interval in man during sleep. Am J Cardiol. 1983;52:55–9. Bexton RS, Vallin HO, Camm AJ. Diurnal variation of the QT interval— influence of the autonomic nervous system. Br Heart J. 1986;55:253–8. Watanabe J, Suzuki Y, Fukui N, Ono S, Sugai T, Tsuneyama N, et al. Increased risk of antipsychotic-related QT prolongation during nighttime: a 24-hour holter electrocardiogram recording study. J Clin Psychopharmacol. 2012;32:18–22. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289:2120–7. Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care. 2000;23:1381–3. Veglio M, Bruno G, Borra M, Macchia G, Bargero G, D’Errico N, et al. Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort. J Intern Med. 2002;251:317–24. Giunti S, Bruno G, Lillaz E, Gruden G, Lolli V, Chaturvedi N, et al. Incidence and risk factors of prolonged QTc interval in type 1 diabetes:
22.
23. 24.
25. 26.
27. 28. 29.
30.
31. 32.
the EURODIAB Prospective Complications Study. Diabetes Care. 2007;30:2057–63. Ziegler D, Zentai CP, Perz S, Rathmann W, Haastert B, Doring A, et al. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study. Diabetes Care. 2008;31:556–61. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92. Murphy NP, Ford-Adams ME, Ong KK, Harris ND, Keane SM, Davies C, et al. Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Diabetologia. 2004;47:1940–7. Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes. 2013;62:3570–81. Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Prediction of 90-day mortality in patients without diabetes by severe hypoglycemia: blood glucose level as a novel marker of severity of underlying disease. Acta Diabetol. 2014 Sep 7. [Epub ahead of print]. Alexopoulos D, Rynkiewicz A, Yusuf S, Johnston JA, Sleight P, Yacoub MH. Diurnal variations of QT interval after cardiac transplantation. Am J Cardiol. 1988;61:482–5. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl J Med. 1991;325:986–90. Aso Y, Wakabayashi S, Nakano T, Yamamoto R, Takebayashi K, Inukai T. High serum high-sensitivity C-reactive protein concentrations are associated with relative cardiac sympathetic overactivity during the early morning period in type 2 diabetic patients with metabolic syndrome. Metabolism. 2006;55:1014–21. Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53:982–91. Ahnve S. Correction of the QT interval for heart rate: review of different formulas and the use of Bazett’s formula in myocardial infarction. Am Heart J. 1985;109:568–74. Hnatkova K, Malik M. “Optimum” formulae for heart rate correction of the QT interval. Pacing Clin Electrophysiol. 1999;22:1683–7.
ORIGINAL ARTICLE
High risk of abnormal QT prolongation in the early morning in diabetic and non-diabetic patients with severe hypoglycemia Tetsuro Tsujimoto1,2, Ritsuko Yamamoto-Honda1,3, Hiroshi Kajio1, Miyako Kishimoto1,3, Hiroshi Noto1,3, Remi Hachiya1, Akio Kimura4, Masafumi Kakei2,5 & Mitsuhiko Noda3 1Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan,
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
2Division of General Medicine, Jichi Medical University Graduate School of Medicine, Shimotsuke, Japan, 3Department of Diabetes Research,
Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan, 4Department of Emergency Medicine and Critical Care, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan, and 5First Department of Comprehensive Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama, Japan
Background. Several studies have suggested that the occurrence of severe hypoglycemia during sleep may be more dangerous for cardiac arrhythmia than that in the day-time. Methods. We performed a retrospective study between January 2006 and March 2012 to assess electrocardiograms during severe hypoglycemia in patients with or without diabetes. Results. A total of 59,602 patients who visited the emergency room by ambulance were screened, and 287 patients with severe hypoglycemia were enrolled. The median blood glucose levels in patients with (DM, n ⴝ 192) and without diabetes (non-DM, n ⴝ 95) were 30 and 45 mg/dL, respectively. During severe hypoglycemia, the incidence of abnormal QT prolongation was significantly higher in the early morning (4–10 a.m.) than at other times (DM group, 74.3% versus 54.1%, P ⴝ 0.02; non-DM group, 78.3% versus 50.0%, P ⴝ 0.01). Multivariate logistic regression analysis identified the occurrence of severe hypoglycemia in the early morning as a strong factor for abnormal QT prolongation (DM group, odds ratio [OR] 2.80, 95% confidence interval [CI] 1.15–6.80, P ⴝ 0.02; non-DM group, OR 4.53, 95% CI 1.30–15.74, P ⴝ 0.01). Conclusions. The incidence of abnormal QT prolongation during severe hypoglycemia was significantly higher in the early morning than at all other times, independent of the cause of severe hypoglycemia. Key words: Arrhythmia, diabetes, nocturnal hypoglycemia, QT prolongation, severe hypoglycemia
Introduction Severe hypoglycemia in patients with diabetes (DM) is hazardous and can lead to seizures, coma, and irreversible brain damage (1). In addition, recent studies have revealed that severe hypoglycemia was associated with an increased risk of death and cardiovascular disease (2,3). Severe hypoglycemia leads to the activation of the sympathoadrenal system and the subsequent release of counter-regulatory hormones such as catecholamines,
Key messages • The incidence of abnormal QT prolongation during severe hypoglycemia in patients with diabetes was the highest at night-time, particularly in the early morning. • A similar fluctuation in QT prolongation in patients without diabetes suggests that the incidence of abnormal QT prolongation may be higher in the early morning than at all other times, independent of the cause of the severe hypoglycemia. • The occurrence of severe hypoglycemia in the early morning was a strong risk factor for the incidence of abnormal QT prolongation using multivariate logistic regression analysis.
glucagon, and cortisol. As a result, hypothermia, hypokalemia, and significant cardiac stress such as marked elevated blood pressure are common during severe hypoglycemia (4). Furthermore, several studies have reported that severe hypoglycemia prolongs the QT interval (4–8), which can lead to fatal arrhythmias. A recent study has also suggested that hypoglycemia experienced after a subcutaneous injection of insulin may cause QT prolongation in patients with type 1 diabetes (9). The time during sleep is the most vulnerable period partly because it may be difficult to be aware of hypoglycemia; this is because sleep blunts the counter-regulatory response (10). Therefore, a long duration of hypoglycemia may occur during sleep. Some studies have suggested that hypoglycemia during sleep or in the early morning in patients with type 1 diabetes (T1DM) may be associated with sudden cardiac death (11–13). In addition, other studies demonstrated that nocturnal hypoglycemia in patients with type 2 diabetes (T2DM) may be associated with an increased risk of cardiac arrhythmias (14). These studies suggest that the occurrence of hypoglycemia from late evening to early morning in patients with DM may be more dangerous for cardiac
Correspondence: Tetsuro Tsujimoto, MD, Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. Fax: ⫹ 81-3-3207-1038. E-mail: [email protected] (Received 17 December 2014; accepted 6 February 2015)
Abnormal QT prolongation during hypoglycemia 239
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
arrhythmia than that in the day-time. Furthermore, the increased risk of sudden cardiac death during this period may be associated with a higher incidence of abnormal QT prolongation than that occurring in the day-time. However, although the QT interval has diurnal variation in healthy subjects (15,16) and antipsychoticrelated QT prolongation more frequently occurs at night-time than in the day-time (17), it remains unknown whether the incidence of abnormal QT prolongation during severe hypoglycemia fluctuates throughout the day. Therefore, we hypothesized that the incidence of abnormal QT prolongation during severe hypoglycemia may be significantly higher in late evening and in early morning than that in the day-time. The aim of the present study was to investigate the circadian variation in abnormal QT prolongation during severe hypoglycemia in patients with DM. In addition, it was investigated whether the circadian variation in abnormal QT prolongation was similarly found in patients with and without DM.
Patients and methods Study design We conducted a retrospective study of patients who had been transported by ambulance and diagnosed as having severe hypoglycemia at the National Center for Global Health and Medicine in Tokyo, Japan, between 1 January 2006 and 31 March 2012. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves and that required the medical assistance of another person after visiting the emergency room by ambulance (1). Blood glucose levels were mainly measured at a central laboratory (81.1%, 232/286), although some were measured using a blood glucose meter (18.9%, 54/286). At least two diabetologists independently reviewed all patient data including clinical records, laboratory data, and electrocardiograms. Disagreements between the reviewers were resolved by a third diabetologist. DM was confirmed when the patient had been previously diagnosed as having DM or was being treated with antidiabetic medication. T1DM was confirmed by previous diagnosis or by the presence of antibodies to glutamic acid decarboxylase. T2DM was confirmed by a previous diagnosis or the absence of a specific cause. Other types of diabetes were excluded from the analyses. Patients with cardiopulmonary arrest upon arrival were excluded from the study. Data were analyzed using only the latest hospital visit for each individual. A day was equally divided into four periods: late evening (10 p.m. to 4 a.m.), early morning (4 a.m. to 10 a.m.), midday (10 a.m. to 4 p.m.), and early evening (4 p.m. to 10 p.m.). The first two periods were defined as night-time, and the remaining two periods were defined as day-time. The study patients were distributed according to the time of the electrocardiogram upon arrival. Electrocardiograms performed after the improvement of severe hypoglycemia were excluded from the analysis. The primary aim of this study was to assess whether the rate of abnormal QT prolongation during severe hypoglycemia differed between the nocturnal and day-time periods. The study was approved by the institutional review board of the National Center for Global Health and Medicine Hospital.
QT intervals The QT and RR intervals for patients with severe hypoglycemia upon arrival were measured using lead II with more than five consecutive beats of a 12-lead electrocardiogram. All measurements were performed by two observers who were blinded to detailed patient characteristics (18). When QT and RR were
difficult to measure using lead II, the other limb leads were used. One corrected QT interval (QTc) was calculated using Bazett’s formula: QTc ⫽ QT interval ÷ square root of the RR interval. Based on previous studies on patients with diabetes and hypoglycemia, QTc ⱖ 0.44 s was considered to be abnormally prolonged (6,19–22). For cases with atrial fibrillation, the QT intervals that followed the longest and shortest RR intervals were measured, and each was then divided by the square root of QTc of the preceding RR interval (18). The mean of these two values was used as QTc. The corrected QT interval was not calculated for patients with coupled pulses or pacemakers.
Other measurements Serum creatinine and potassium levels were measured upon arrival, and glycated hemoglobin (HbA1c) levels were measured at the nearest time within three months of arrival. Serum potassium levels of ⬍ 3.5 mEq/L were considered to be indicative of hypokalemia. The estimated glomerular filtration rate (GFR) was calculated using the following formula as recommended by the Japanese Society of Nephrology: estimated GFR (mL/min/1.73 m2) ⫽ 194 ⫻ Cre-1.094 ⫻ Age-0.287 (⫻ 0.739 if the patient was female) (23). Systolic blood pressure, diastolic blood pressure, and heart rate were measured upon arrival.
Statistical methods Patients were initially categorized into DM and non-DM groups. Data are presented as numbers (%), mean with standard deviation (SD), and median with the lower and upper ends of the interquartile range (IQR). Continuous variables were compared using t tests, Wilcoxon rank sum tests, or Kruskal–Wallis tests. Categorical variables were compared using chi-square tests or Fisher’s exact tests. Multivariate logistic regression analysis was performed to assess whether circadian variation was associated with abnormal QT prolongation. P values of ⬍ 0.05 according to a two-sided test were considered to be statistically significant for all tests. All the analyses were performed using Stata software, version 11.1 (Stata Corp, College Station, TX, USA).
Results A total of 59,602 patients that visited the emergency room by ambulance were screened, and 530 had severe hypoglycemia. Among them, 290 patients underwent electrocardiograms upon arrival. Three patients with other diabetes were excluded from subsequent analyses, and 287 patients with T1DM, T2DM, or no diabetes (non-DM) were enrolled in this study. The clinical characteristics of the study population upon arrival are presented in Table I. In the T1DM (n ⫽ 28), T2DM (n ⫽ 164), and non-DM (n ⫽ 95) groups, the median (IQR) blood glucose levels were 25 mg/dL (20–34 mg/dL), 31 mg/dL (24–38 mg/dL), and 45 mg/dL (26–64 mg/dL), respectively. The incidences of abnormal QT prolongation (QTc ⱖ 0.44 s) during severe hypoglycemia in the T1DM, T2DM, and non-DM groups were 42.9%, 60.4%, and 56.8%, respectively. Highly abnormal QT prolongation (QTc ⱖ 0.50 s) was observed in some patients with severe hypoglycemia. The circadian variations in abnormal QT prolongation in the DM and non-DM groups are shown in Figure 1A. In the DM group, incidences of abnormal QT prolongation in late evening, early morning, mid-day, and early evening were 62.5%, 74.3%, 54.4%, and 48.3%, respectively. In the non-DM group, incidences of abnormal QT prolongation in the late evening, early morning, mid-day, and early evening were 61.1%, 78.3%, 42.9%, and 50.0%, respectively. Incidences of abnormal QT prolongation in both groups were the highest in the early morning. Similarly,
240
T. Tsujimoto et al. Table I. Characteristics of the study patients. T1DM (n ⫽ 28)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Characteristics Age (years) Female History of coronary heart diseasea Hypertension Atrial fibrillation Blood glucose (mg/dL) (n ⫽ 286) HbA1c (%) (n ⫽ 82)b Duration of diabetes (years) (n ⫽ 112) Treatment for diabetes Sulfonylurea Insulin Estimated GFR (mL/min/1.73 m2) (n ⫽ 278)c Serum potassium level (mEq/L) (n ⫽ 283)d Causes of severe hypoglycemia Glucose-lowering medications Sulfonylurea Insulin Others Abnormal QT prolongation (QTc ⱖ 0.44 s)f Highly abnormal QT prolongation (QTc ⱖ 0.50s)
49 (40–59) 17.9% 0.0% 32.1% 0.0% 25 (20–34) 7.3 (6.8–7.7) 22 (16–29)
T2DM (n ⫽ 164) 76 (65–83) 36.6% 12.8% 69.5% 14.0% 31 (24–38) 6.5 (6.0–7.2) 14 (6–23)
Non-DM (n ⫽ 95) 66 (53–78) 33.7% 1.1% 17.9% 10.5% 45 (26–64) – –
0.0% 100% 80.3 (61.6–89.3) 3.4 (3.2–3.8)
51.9% 45.6% 52.8 (29.8–77.4) 3.6 (3.3–4.2)
– – 74.7 (48.8–100.1) 3.8 (3.4–4.3)
96.4% 0.0% 96.4% 3.6% 42.9% 0.0%
94.5% 48.7% 43.7% 5.5% 60.4% 15.2%
2.2%e 1.1% 1.1% 97.8% 56.8% 22.1%
Data are presented as number, %, or median (IQR). SI conversion factors: to convert blood glucose to mmol/L, multiply by 0.0555. aHistory of coronary heart disease was defined as a history of myocardial infarction and angina pectoris. bHbA1c levels were measured at the nearest time within three months of arrival. T1DM: 7.3% (6.8%–7.7%) ⫽ 56 (51–61) mmoL/moL. T2DM: 6.5% (6.0%–7.2%) ⫽ 48 (42–55) mmoL/moL. cEstimated GFR was calculated using the following formula: estimated GFR (mL/min/1.73 m2) ⫽ 194 ⫻ Cre⫺ 1.094 ⫻ Age⫺ 0.287 (⫻ 0.739 if the patient was female). dSerum potassium levels were measured upon arrival at the hospital. eOne patient attempted suicide using insulin, and one patient took a sulfonylurea incorrectly. Both patients were discharged safely from the hospital. fQTc was calculated using Bazett’s formula: QTc ⫽ QT interval ÷ square root of the RR interval. DM ⫽ diabetes; GFR ⫽ glomerular filtration rate; HbA1c ⫽ glycated hemoglobin; non-DM ⫽ no diabetes; T1DM ⫽ type 1 diabetes; T2DM ⫽ type 2 diabetes.
incidences of abnormal QT prolongation were the highest in the early morning in both the T1DM and T2DM groups (75.0% and 74.2%, respectively; Figure 1B). Blood pressure and heart rate were not significantly associated with circadian variation in the DM and non-DM groups (Figure 2). The abnormal QT prolongations at night-time and in the daytime are shown in Figure 3A. In the DM and non-DM groups, incidences of abnormal QT prolongation were significantly higher at night-time than in the day-time (DM group, 68.6% versus 51.3%, P ⫽ 0.02; non-DM group, 70.7% versus 46.3%, P ⫽ 0.01). The differences in the abnormal QT prolongation between the early morning and at all other times are shown in Figure 3B. Incidences of abnormal QT prolongation in both groups were significantly higher in the early morning than at all other times (DM group, 74.3% versus 54.1%, P ⫽ 0.02; non-DM group, 78.3% versus 50.0%, P ⫽ 0.01). When we re-analyzed the subjects of T1DM and T2DM separately, the incidences of abnormal QT prolongation in both groups tended to be higher at night-time than in the day-time (T1DM group, 58.3% versus 31.3%, P ⫽ 0.25; T2DM group, 69.8% versus 54.5%, P ⫽ 0.05) although the differences were non-significant for both groups. Similarly, incidences of abnormal QT prolongation were insignificantly higher in both the groups in the early morning than at all other times (T1DM group, 75.0% versus 37.5%, P ⫽ 0.28; T2DM group, 74.2% versus 57.1%, P ⫽ 0.10). Results of the multivariate analyses for the variation in the incidence of abnormal QT prolongation during severe hypoglycemia are presented in Tables II and III. When multivariate logistic regression analysis was performed to identify the clinical variables that were independently associated with abnormal QT prolongation in the DM group, the occurrence of severe hypogly-
cemia at night-time was the only strong factor (odds ratio [OR] 2.17; 95% confidence interval [CI] 1.14–4.11; P ⫽ 0.01) (Table II). When HbA1c levels, of which there were limited data, were included in the multivariate analysis, the occurrence of severe hypoglycemia at night-time remained the only significant factor (OR 4.89; 95% CI 1.63–14.60; P ⫽ 0.004). The association between abnormal QT prolongation and the occurrence of severe hypoglycemia in the early morning is shown in Table III. The occurrence of severe hypoglycemia in the early morning was a strong factor for abnormal QT prolongation in multivariate logistic regression analysis (OR 2.80; 95% CI 1.15–6.80; P ⫽ 0.02). Similar to that at night-time, when HbA1c levels were included in the multivariate analysis, the occurrence of severe hypoglycemia in the early morning remained the only significant factor (OR 14.71; 95% CI 1.70–127.12; P ⫽ 0.01). Multivariate logistic regression analyses revealed that abnormal QT prolongation in the non-DM group was also significantly associated with the occurrence of severe hypoglycemia at nighttime (OR 4.07; 95% CI 1.44–11.44; P ⫽ 0.008) and in the early morning (OR 4.53; 95% CI 1.30–15.74; P ⫽ 0.01). As a result, the occurrence of severe hypoglycemia at night-time or in the early morning was a significant factor for abnormal QT prolongation in the DM and non-DM groups.
Discussion This is the first study to report that the incidence of abnormal QT prolongation during severe hypoglycemia in patients with DM was the highest at night-time, particularly in the early morning. In addition, the present study revealed that the occurrence of severe hypoglycemia in the early morning was a strong risk factor for the
Abnormal QT prolongation during hypoglycemia 241
(A) 100 DM non-DM
(%)
75
50
25
0 Early morning (4 A.M. to 10 A.M.)
Midday (10 A.M. to 4 P.M.)
Early evening (4 P.M. to 10 P.M.)
(B) 100 T1DM T2DM 75
(%)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Late evening (10 P.M. to 4 A.M.)
50
25
0 Late evening Early morning Midday Early evening (10 P.M. to 4 A.M.) (4 A.M. to 10 A.M.) (10 A.M. to 4 P.M.) (4 P.M. to 10 P.M.) Figure 1. Circadian variations in rate of abnormal QT prolongation in patients with severe hypoglycemia. Rate of abnormal QT prolongation at each period in the DM and non-DM groups (A), and in the T1DM and T2DM groups (B). DM ⫽ diabetes; non-DM ⫽ no diabetes; T1DM ⫽ type 1 diabetes; T2DM ⫽ type 2 diabetes.
incidence of abnormal QT prolongation using multivariate logistic regression analysis. Moreover, a similar fluctuation in QT prolongation in patients without DM suggests that the incidence of abnormal QT prolongation in the early morning may be higher than at all other times, independent of the cause of the severe hypoglycemia. Several previous studies in populations with T1DM and T2DM demonstrated that hypoglycemia was associated with abnormal QT prolongation (7,8,24,25). In addition, recent studies suggested that abnormal QT prolongation during severe hypoglycemia was observed in ⬎ 50% of patients with T1DM and T2DM (4), and that several patients without DM had prolonged QT intervals during severe hypoglycemia (26). QT prolongation during hypoglycemia is considered to be associated with hypokalemia and significant elevation of epinephrine and norepinephrine as well as low blood glucose itself (25). QT prolongation reflects abnormal cardiac repolarization, and hypoglycemia-induced QT prolongation can lead to fatal cardiac events such as torsade de pointes (11–14). In patients with T1DM, sudden nocturnal deaths, so-called ‘dead-in-bed syndrome’ have been reported (11–13). Patients with dead-in-bed syndrome were found dead on an undisturbed bed, and autopsies revealed no major abnormalities. Tanenberg et al. (13) described a case of deadin-bed syndrome in detail; this included data from a continuous subcutaneous glucose monitoring system (CGMS) in a young patient with T1DM. The patient’s CGMS glucose levels rapidly decreased at
midnight and declined to ⬍ 50 mg/dL at approximately 2 a.m. The patient’s death presumably occurred between 5 and 8 a.m., and an autopsy performed within 8 h of his death failed to reveal any major anatomical abnormalities that could have contributed to his death. This case suggests that a hypoglycemic event that occurred between the late evening and the early morning was one of the main causes of dead-in-bed syndrome. Previous studies reported that nocturnal hypoglycemia in patients with T1DM resulted in a prolonged QT interval (8,24). However, because hypoglycemia-induced QT prolongations were also found in the day-time (5,7,25), it was unclear why the sudden death occurred during sleep and at night-time but not in the day-time. The present study revealed that the incidence of abnormal QT prolongation during severe hypoglycemia was significantly higher at night-time, particularly in the early morning, than at all other times. Therefore, this may partially explain cases of sudden cardiac death at night-time in patients with T1DM. A recent study demonstrated that nocturnal hypoglycemia was associated with an increased risk of cardiac arrhythmia in patients with T2DM and cardiovascular risk (14). Patients with T2DM in the present study had the highest incidence of abnormal QT prolongation at night-time, and particularly in the early morning. This suggests that hypoglycemia at night-time was more hazardous than in the day-time. In the present study, blood pressure and heart rate during severe hypoglycemia showed no
242
T. Tsujimoto et al.
(A)
Diabetes Systolic BP (mmHg)
200 175
168 (145-206)
Diastolic BP (mmHg)
HR (bpm) 172 (146-194)
170 (149-195)
164 (146-188)
150 125 100
80 80 (70-97) (73-91)
75
90 81 (76-97) (60-94)
88 80 (75-101) (68-98)
86 (78-100) 69 (64-92)
50 25 0 Late evening (10 P.M. to 4 A.M.)
Early morning (4 A.M. to 10 A.M.)
Early evening (4 P.M. to 10 P.M.)
Non-diabetes
(B) 200
Systolic BP (mmHg)
Diastolic BP (mmHg)
HR (bpm)
175 150 125
85 (71-96)
100 75
115 (88-146)
113 (91-135)
68 (54-81)
137 (118-158)
124 (112-150)
84 (62-105)
79 76 (59-92) (72-90)
64 (50-85)
95 (80-110) 79 (67-95)
50 25 0 Late evening Early morning Midday Early evening (10 P.M. to 4 A.M.) (4 A.M. to 10 A.M.) (10 A.M. to 4 P.M.) (4 P.M. to 10 P.M.) Figure 2. Circadian variations in blood pressure and heart rate in patients with severe hypoglycemia. Blood pressure and heart rate in the DM group (A) and non-DM group (B). Data are presented as median (IQR). The values for blood pressure and heart rate in the DM and non-DM groups did not differ significantly using Kruskal–Wallis tests. BP ⫽ blood pressure; bpm ⫽ beats per minute; HR ⫽ heart rate.
(%)
(A) fluctuation throughout the day; only the incidence of abnormal QT prolongation showed circadian variation. The association was unchanged even after adjusting for several related variables including hypokalemia and blood glucose levels. Similar observations between DM patients and non-DM patients (Tables II and III, Figures 1 and 3) suggest that the daily variation in abnormal QT prolongation during severe hypoglycemia is not associated with the cause of severe hypoglycemia and/or diabetes-related complications such as diabetic autonomic neuropathy. Previous studies revealed that the QT interval had diurnal variation in healthy subjects (15,16) and transplanted hearts exhibited no change in QT interval (27). Based on these reports, the daily variation in QT interval may be associated with circadian fluctuation in sympathetic activity and activation in the heart. In addition, sympathetic activity is relatively high in the early morning (28,29). Therefore, the relatively high incidence of abnormal QT prolongation in the early morning may result from additional stimulation of the sympathetic nervous system caused by severe hypoglycemia in these pathophysiological backgrounds. However, the detailed mechanism remains unclear, and further studies are warranted. A recent guideline updated the normal standards for thresholds of abnormal QT prolongation to the following values: women up to 0.46 s and men up to 0.45 s (30). Additional analyses using this updated definition of prolonged QT confirmed that the incidences of abnormal QT prolongation in both groups were also the highest in the early morning. Similarly, incidences of abnormal QT
Nighttime
100 90 80 70 60 50 40 30 20 10 0
P = 0.001 69.0%
P = 0.02
P = 0.002 75.9%
70.7%
DM (n = 192) Early morning All other times P = 0.02
46.3%
non-DM (n = 95)
P = 0.01 78.3%
74.3% 52.8%
P = 0.01
51.3%
49.7%
(B) 100 90 80 70 60 50 40 30 20 10 0
Daytime
68.6%
ALL (n = 287)
(%)
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Midday (10 A.M. to 4 P.M.)
54.1%
50.0%
ALL DM non-DM (n = 287) (n = 192) (n = 95) Figure 3. Rate of abnormal QT prolongation at night-time and in the early morning. Rate of abnormal QT prolongation at night-time and in the daytime (A) and in the early morning and at all other times (B).
Abnormal QT prolongation during hypoglycemia 243 Table II. Multivariate analysis of the clinical variables for abnormal QT prolongation during severe hypoglycemia at night-time. Multivariate analysis (DM group) Variables Age (years) Female History of coronary heart diseasea Hypertension Blood glucose on arrival (mg/dL) Hypokalemia (⬍ 3.5 mEq/L)b Severe hypoglycemia in the night-time
Odds ratio 1.00 1.07 0.46 1.39 0.98 0.88 2.17
95% CI 0.98–1.02 0.54–2.11 0.17–1.22 0.68–2.81 0.96–1.00 0.46–1.67 1.14–4.11
P value 0.56 0.83 0.12 0.35 0.06 0.70 0.01
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Multivariate analysis (non-DM group) Odds Variables ratio 95% CI P value Age (years) 1.03 1.00–1.06 0.01 Female 0.48 0.18–1.30 0.15 Hypertension 0.83 0.24–2.89 0.78 Blood glucose on arrival (mg/dL) 0.98 0.96–1.00 0.24 1.11 0.40–3.08 0.83 Hypokalemia (⬍ 3.5 mEq/L) Severe hypoglycemia in the night-time 4.07 1.44–11.44 0.008 aCoronary heart disease was defined as myocardial infarction or angina pectoris. bSerum potassium levels were measured upon arrival at the hospital. 95% CI ⫽ 95% confidence interval.
prolongation in the DM and non-DM groups were higher in the early morning than at all other times (DM group, 45.7% versus 36.9%, P ⫽ 0.33; non-DM group, 78.3% versus 40.3%, P ⫽ 0.002). These data may partially support our results. In addition, many formulas have been proposed to adjust the QT interval (31,32), and a different QT measurement technique may influence the results. Further studies are warranted to define the best method for QT interval correction in patients with hypoglycemia. However, many studies have reported that QTc ⱖ 0.44 s, calculated using Bazett’s formula in patients with diabetes and hypoglycemia, was associated with important clinical outcomes such as mortality and diabetes-related complications (6,19–22). Therefore, we believe that the present study provides additional evidence for QT prolongation associated with hypoglycemia.
Table III. Multivariate analysis of the clinical variables for abnormal QT prolongation during severe hypoglycemia in the early morning. Multivariate analysis (DM group) Variables Age (years) Female History of coronary heart diseasea Hypertension Blood glucose on arrival (mg/dL) Hypokalemia (⬍ 3.5 mEq/L)b Severe hypoglycemia in the early morning
Odds ratio
95% CI
1.00 1.02 0.46 1.33 0.98 0.94 2.80
0.98–1.02 0.51–2.01 0.17–1.24 0.66–2.68 0.95–1.00 0.49–1.80 1.15–6.80
Odds ratio
95% CI
P value 0.64 0.95 0.12 0.42 0.06 0.86 0.02
Multivariate analysis (non-DM group) Variables
Age (years) 1.02 1.00–1.05 Female 0.55 0.20–1.47 Hypertension 0.78 0.23–2.67 Blood glucose on arrival (mg/dL) 0.98 0.96–1.00 1.19 0.43–3.25 Hypokalemia (⬍ 3.5 mEq/L) Severe hypoglycemia in the early morning 4.53 1.30–15.74 aCoronary heart disease was defined as myocardial infarction or pectoris. bSerum potassium levels were measured upon arrival at the hospital. 95% CI ⫽ 95% confidence interval.
P value 0.02 0.23 0.70 0.13 0.73 0.01 angina
Several limitations of the study must be noted. First, the present study was performed at a single national center, and data were retrospectively reviewed. Therefore, additional large-scale prospective multicenter studies are needed to confirm these results. However, no previous studies have assessed this number of electrocardiograms in patients during severe hypoglycemia; therefore, this study revealed novel findings. Second, missing electrocardiograms before and after treatment and the limited number of samples may have affected the results and statistical analyses. In addition, duration of hypoglycemia prior to hospital visiting was unknown. However, few studies have investigated the circadian variation in abnormal QT prolongation during severe hypoglycemia. We believe that the current study provides extremely important information regarding severe hypoglycemia. Finally, we could not evaluate the other changes in electrocardiograms for ST segment and T wave. In addition, patients with prehospital cardiopulmonary arrest could not be examined. Therefore, some patients with severe hypoglycemia may have died of lethal arrhythmias in a prehospital setting. In conclusion, this study revealed that the incidence of abnormal QT prolongation during severe hypoglycemia was the highest in the early morning and was significantly higher than at other times. The goals of glycemic control in patients with diabetes should be determined individually in light of not only prevention of diabetes-related complications but also of the risk of hypoglycemia targeting particularly a minimum risk of severe hypoglycemia in the early morning. The results of this study may contribute to reducing the incidence and severity of life-threatening events associated with severe hypoglycemia.
Acknowledgements T.T. conceived the study. T.T., M.Ka., and M.N. designed the protocol. T.T., R.Y.-H., H.K., M.Ki., R.H., and A.K. contributed to the data collection and preparation. T.T., R.Y.-H., M.Ki., H.N., and M.N. analyzed the data. T.T., R.Y.-H., M.Ka., and M.N. wrote the report. All authors contributed to the interpretation of the results and approved the final version of the manuscript. T.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding: This work was supported by JSPS KAKENHI [grant number 26860701]. Declaration of interest: The authors have no potential conflicts of interest relevant to this article to report.
References 1. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26:1902–12. 2. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. 3. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–18. 4. Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care. 2014;37:217–25. 5. Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes. 2003;52:1469–74. 6. Gruden G, Giunti S, Barutta F, Chaturvedi N, Witte DR, Tricarico M, et al. QTc interval prolongation is independently associated with severe
244
7.
8. 9.
10. 11. 12.
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
13. 14. 15. 16. 17.
18. 19.
20.
21.
T. Tsujimoto et al. hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care. 2012;35:125–7. Christensen TF, Tarnow L, Randlov J, Kristensen LE, Struijk JJ, Eldrup E, et al. QT interval prolongation during spontaneous episodes of hypoglycaemia in type 1 diabetes: the impact of heart rate correction. Diabetologia. 2010;53:2036–41. Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited. Diabetologia. 2009;52:42–5. Christensen TF, Cichosz SL, Tarnow L, Randlov J, Kristensen LE, Struijk JJ, et al. Hypoglycaemia and QT interval prolongation in type 1 diabetes—bridging the gap between clamp studies and spontaneous episodes. J Diabetes Complications. 2014;28:723–8. Jones TW, Porter P, Sherwin RS, Davis EA, O’Leary P, Frazer F, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998;338:1657–62. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med. 1991;8:49–58. Thordarson H, Sovik O. Dead in bed syndrome in young diabetic patients in Norway. Diabet Med. 1995;12:782–7. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 2010;16:244–8. Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes. 2014;63:1738–47. Browne KF, Prystowsky E, Heger JJ, Chilson DA, Zipes DP. Prolongation of the Q-T interval in man during sleep. Am J Cardiol. 1983;52:55–9. Bexton RS, Vallin HO, Camm AJ. Diurnal variation of the QT interval— influence of the autonomic nervous system. Br Heart J. 1986;55:253–8. Watanabe J, Suzuki Y, Fukui N, Ono S, Sugai T, Tsuneyama N, et al. Increased risk of antipsychotic-related QT prolongation during nighttime: a 24-hour holter electrocardiogram recording study. J Clin Psychopharmacol. 2012;32:18–22. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289:2120–7. Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care. 2000;23:1381–3. Veglio M, Bruno G, Borra M, Macchia G, Bargero G, D’Errico N, et al. Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort. J Intern Med. 2002;251:317–24. Giunti S, Bruno G, Lillaz E, Gruden G, Lolli V, Chaturvedi N, et al. Incidence and risk factors of prolonged QTc interval in type 1 diabetes:
22.
23. 24.
25. 26.
27. 28. 29.
30.
31. 32.
the EURODIAB Prospective Complications Study. Diabetes Care. 2007;30:2057–63. Ziegler D, Zentai CP, Perz S, Rathmann W, Haastert B, Doring A, et al. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study. Diabetes Care. 2008;31:556–61. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92. Murphy NP, Ford-Adams ME, Ong KK, Harris ND, Keane SM, Davies C, et al. Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Diabetologia. 2004;47:1940–7. Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes. 2013;62:3570–81. Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Prediction of 90-day mortality in patients without diabetes by severe hypoglycemia: blood glucose level as a novel marker of severity of underlying disease. Acta Diabetol. 2014 Sep 7. [Epub ahead of print]. Alexopoulos D, Rynkiewicz A, Yusuf S, Johnston JA, Sleight P, Yacoub MH. Diurnal variations of QT interval after cardiac transplantation. Am J Cardiol. 1988;61:482–5. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl J Med. 1991;325:986–90. Aso Y, Wakabayashi S, Nakano T, Yamamoto R, Takebayashi K, Inukai T. High serum high-sensitivity C-reactive protein concentrations are associated with relative cardiac sympathetic overactivity during the early morning period in type 2 diabetic patients with metabolic syndrome. Metabolism. 2006;55:1014–21. Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53:982–91. Ahnve S. Correction of the QT interval for heart rate: review of different formulas and the use of Bazett’s formula in myocardial infarction. Am Heart J. 1985;109:568–74. Hnatkova K, Malik M. “Optimum” formulae for heart rate correction of the QT interval. Pacing Clin Electrophysiol. 1999;22:1683–7.
