The MA method showed modest increase in QTcB and no increase in QTcF during hypoglycemia, while the SI method showed considerable prolongation of both QTcB and QTcF. Comparing the two methods directly showed that SI underestimated the QT interval at baseline and overestimated it at hypoglycemia compared to MA.
The use of the SI method for measuring the end of the T wave is known to be sensitive to changes in T wave amplitude, although the method was originally meant for cases with partial T-U fusion [11
]. In particular a flattened T wave will cause an overestimation of the QT interval with the SI method when compared to the MA method (). Since there exists no gold standard of measuring the QT interval, neither of the measurement techniques can from this study be judged more correctly than the other. However, the discrepancy between the two methods illustrates that comparing studies of hypoglycemia using different QT measurement methods may be problematic. Also, it is apparent from the results that the SI method produces significantly longer QT intervals than the MA method which could indicate a higher probability of false positives with the SI method. An approach which could eliminate the bias associated with measuring the QT interval is to use alternative T wave morphology variables. Xue and Reddy [17
] used principal component analysis of the T wave and showed that this approach had superior reproducibility than several QT measurement methods. Alternative T wave morphology parameters might therefore be better at characterizing changes in repolarization during hypoglycemia.
Figure 2 Measurements of the T wave offset from ECG lead II using the semiautomatic slope-intersect method (SI) and manual annotation (MA) method. The two ECGs are from t0 (left side) and at thypo (right side) at the same episode. At t0 the SI method underestimates (more ...)
A pathologically prolonged QTc interval is usually defined as >450
ms for men and >470
ms for women [18
]. In the present study, mean QTc did not exceed these thresholds with any of the methods. This could indicate that prolongation of the QTc cannot in itself explain the mechanism implicated in the dead-in-bed syndrome.
The differences between QTcB and QTcF in this study were larger at hypoglycemia than at baseline. It is known that Bazett's formula tends to overcorrect the QTc at higher heart rates [10
]. In this study we observed a significant increase in heart rate during hypoglycemia which may have contributed to an overcorrection by Bazett's formula compared to Fridericia's formula. Similar findings of differing results using the two correction formulas have been reported [6
] although they in other cases produce similar results [19
One of the main limitations of the study is the absence of a control group. Without a control group it is less clear if the observed QT prolongation is caused by hypoglycemia per se. Indeed, insulin could act as a confounding variable as it has been shown to cause moderate QT interval prolongation [20
]. To account for the effect of insulin, we measured the ECG variables of interest 15 minutes after insulin injection where the subjects were still normoglycemic. We anticipated that this measurement would quantify the effect of hyperinsulinemia alone. The results show that the change in ECG variables 15 minutes after insulin injection is comparable to the change at hypoglycemia. This could indicate that the observed changes during hypoglycemia may not be caused by hypoglycemia per se but rather by hyperinsulinaemia. We acknowledge that the small number of subjects in the study limits its generalisability to the general population, although measurements on each subject were repeated to reduce intrasubject variation. Additionally, the use of only one ECG lead for QT measurement may have introduced some variation in the measurements, which could have been mitigated by the use of several leads.
The results of this study are in agreement with previous studies of experimentally induced hypoglycemia using the MA method [4
] although some studies also report a QTc prolongation [5
]. Studies using the SI method consistently find significantly prolonged QTc during hypoglycemia [2
]. We found no difference in the observed variables between HI and Iasp which is in line with previous findings [12
]. Ireland and colleagues [11
] compared the SI and MA methods and concluded that the SI method was preferred over the MA method because of a lower inter observer difference despite an overestimation of the QT interval at hypoglycemia. We cannot infer on inter-observer differences from our study but our results confirm that the SI method overestimates the QT interval during hypoglycemia.