What is the cause of QTc prolongation in patients with alcohol withdrawal syndromes?

We have read with interest the paper of Cuculi et al. in a recent issue of the Swiss Medical Weekly [1]. Clearly, one plausible explanation for the high mortality of patients with alcohol withdrawal syndromes may be the occurrence of malignant cardiac arrhythmias. Prolonged QT interval is considered as one marker for such life threatening rhythm disturbances and indeed, in the studied group of Cuculi et al. 18 patients had a normal QTc interval (<440 ms in males, <460 ms in females) and 31 patients had a prolonged interval. Patients with prolonged QTc were older (51.3 ± 10.7 yrs vs. 43.8 ± 7.7 yrs), and presented more delirium tremens and seizures (n = 20 vs. n = 13 and n = 11 vs. n = 5). Other reported clinical and laboratory parameters did not differ substantially. The mean QTc in the study group was 458 ± 42 ms, but the difference in means between subgroups with and without QT prolongation was not reported. We suppose, that the two subgroups differed significantly with regard of QT interval duration, otherwise the distinction of these groups would make no sense. The minor difference in age could not account for significant QT differences [2], so the authors were probably correct when they suggested that the number of patients with “central nervous stress possibly explained the large proportion of patients with a prolonged QT interval” in their study. However, this explanation is uncertain. The utility of any “universal” formulas for QT rate adjustment have been severely criticised. A major methodological problem with the study of Cuculi et al. is their use of the Bazett formula, which greatly over-adjusts QT interval at high heart rates and under-adjusts it at low heart rates. Any comparison of Bazett-corrected QT values can only be justified at equal (or near equal) heart rates [3] but the authors did not report on heart rate data! We assume, that morbidity in the subgroup with QT prolongation was more severe as suggested by the higher number of seizures and delirium. Indeed, such conditions may have resulted in higher heart rates. The application of “study specific” QT interval correction [4] would have been suitable in the study of Cuculi et al. in order avoid the methodological problem inherent in the use of Bazett’s method and to evaluate the association between “central nervous system stress” and QT interval prolongation. We also suggest that in their response (if applicable) the authors report the means and standard deviations for the various ECG measure for their subgroups.