Utility of QT interval corrected by Rautaharju method to predict drug-induced torsade de pointes

Introduction: New QT correction formulae derived from large populations are available such as Rautaharju’s [QTcRTH?=?QT * (120?+?HR)/180] and Dmitrienko’s [QTcDMT?=?QT/RR^0.413]. These formulae were derived from 57,595 and 13,039 cases, respectively. Recently, a study has shown that they did not experience errors across a wide range of heart rates compared to others.

Objectives: (1) To determine the best cut-off value of QTcRTH and QTcDMT as a predictor of torsade de pointes (TdP) and (2) to compare the sensitivity and specificity using the cut-off value of QTcRTH with those of the QTcBazett (QTcBZT), QTcFridericia (QTcFRD), and QT nomogram.

Methods: Data were derived from two data sets. All cases aged over 18 years with an exposure to QT-prolonging drugs. Group-1, all cases developed TdP. Data in Group-1 were obtained from systematic review of reported cases from Medline since its establishment until 10 December 2015. Group-2 is composed of those who overdosed on QT prolonging drugs but did not develop TdP. This data set was previously extracted from a chart review of three medical centers from January 2008 to December 2010. Data from both groups were used to calculate QTcRTH and QTcDMT. The cut-off values from QTcRTH and QTcDMT that provided the best sensitivity and specificity to predict TdP were then selected. The same method was applied to find those values from QTcBZT, QTcFRD, and QT nomogram. The receiver operating characteristic curve (ROC) was applied where appropriate.

Results: Group-1, 230 cases of drug-induced TdP were included from the systematic review of Medline. Group-2 (control group), which did not develop TdP, consisted of 292 cases. After applying all of the correction methods to the two datasets, the best cut-off values that provided the best accuracy (Ac) with the best sensitivity (Sn) and specificity (Sp) for each formula were as follows: QTcRTH at 477 milliseconds (ms), Ac?=?89.08%, Sn?=?91.30% (95%CI?=?86.89–94.61), Sp?=?87.33%(95%CI?=?82.96–90.92); QTcDMT at 475?ms, Ac?=?88.31%, Sn?=91.30% (95%CI?=?86.89–94.61), Sp?=?85.96%(95%CI?=?81.44–89.73); QTcBZT at 490?ms, Ac?=?86.97%, Sn?=?88.26% (95%CI?=?83.38–92.12), Sp?=?85.96% (95%CI?=?81.44–89.73); QTcFRD at 473?ms, Ac?=?88.89%, Sn?=?89.13% (95%CI?=?84.37–92.84), Sp =88.70% (95%CI?=?84.50–92.09). We found a significant difference (p-value?=?0.0020) between area under the ROC of the QTcRTH (0.9433) and QTcBZT (0.9225) but not QTcFRD (0.9338). The Ac, Sn, and Sp of the QT nomogram were 89.08%, 91.30% (95%CI?=?86.89–94.61), and 87.33% (95%CI?=?82.96–90.92), respectively, and they were all equal to those of QTcRTH.

Conclusion: Rautaharju method not only produced minimal errors for QT interval correction but also at QTcRTH 477?ms, it could predict TdP as accurately as QT nomogram and was better than the QTcBZT.     

Diospyros rhodocalyx (Tako-Na), a Thai folk medicine,associated with hypokalemia and generalized muscle weakness: a case series

Introduction: Diospyros rhodocalyx (Tako-Na) is a Thai folk medicine purported to promote longevity, treat impotence, etc. We present patients with hypokalemia, weakness and hypertension after consuming Tako-Na tea.

Case series: Case 1: A 61-year-old man was brought in nine hours after drinking 400–500?mL of Tako-Na tea. One handful of Tako-Na bark was boiled in water to make tea. He had vomiting and watery diarrhea six hours after drinking it. He took no medications and had no history of hypertension. The only remarkable vital sign was BP 167/90?mmHg. Physical examination revealed generalized muscle weakness. Laboratory findings were potassium 2.7?mmol/L, bicarbonate 24?mmol/L, and transtubular potassium gradient (TTKG) 5.6. He was discharged the next day with a BP 140/90?mmHg and potassium 4.2?mmol/L. Case 2: A 78-year-old man, a friend of case 1, also drank Tako-Na tea from the same pot at the same time as case 1. He also had vomiting and diarrhea six hours later. He took no medications despite past history of hypertension (baseline SBP 140–160). Initial BP was 230/70?mmHg. He also had muscle weakness. Laboratory findings were potassium 3.3?mmol/L, bicarbonate 24?mmol/L, TTKG 7.37 and normal thyroid function. He was also discharged the next day with a BP 148/70?mmHg and potassium 4.2?mmol/L. Case 3–7: These were patients reported to a poison center and their potassium concentrations were 1.4, 1.4, 3.3, 1.3 and 1.2?mmol/L, respectively. Three of them were intubated and case 3 died.

Conclusions: Tako-Na contains betulin, betulinic acid, taraxerone, lupeol, and lupenone. Their structures are similar to glycyrrhetic acid, the active metabolite of glycyrrhizic acid found in licorice which is well known to cause pseudoaldosteronism. Glycyrrhetic acid is potent in inhibiting 11-beta-hydroxysteroid dehydrogenase, and causes pseudoaldosteronism. We hypothesize that the compounds in Tako-Na act in the same way as glycyrrhetic acid in producing pseudoaldosteronism.