QTc Intervals Are Prolonged in Late Preterm and Term Neonates during Therapeutic Hypothermia but Normalize Afterwards

Abstract

Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker for pharmacovigilance during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, and Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1–7). Results: We retrieved 94 QTc intervals (during TH (n = 50, until day 3) or subsequent normothermia (n = 44, day 4–7)) in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430–678), and 410 (317–540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We highlighted a relevant non-maturational covariate (°C dependent TH) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development.

QTc Interval Reference Values and Their (Non)-Maturational Factors in Neonates and Infants: A Systematic Review

“…In the latter study, an increase of QTc time of 28 ms per decreasing degree in body temperature was observed. We must take into account that this value is much higher than reported by Horan et al [ 34 , 35 ] A possible explanation therefore is that ECMO itself affects hemodynamics resulting in a more restricted increase of 3.12 ms per degree (°C) decrease.…”

“…Because of the growing interest in mild therapeutic hypothermia as a neuroprotective strategy following moderate to severe hypoxic-ischaemic encephalopathy, research has been conducted on cardiovascular effects of therapeutic hypothermia. Horan et al [ 34 , 35 ] investigated the relationship between body temperature and QTc values in 27 neonates, divided into five groups based on the degree and duration of cooling. Mean QTc values were measured and evolved from 431 ms at 37 °C, 459 ms at 36 °C for 24 h, 445 ms when cooled to 35 °C at 24 h, 465 ms at 34 °C for 24 h and 466 ms at 34 °C for 48 h. For each degree decrease the body temperature, the QTc increased by 3.12 ms.…”

“…This includes covariates such as late cord clamping, therapeutic hypothermia, hypocalcemia, illness, non-REM sleep and prone sleeping position. Horan et al [ 34 , 35 ] measured a temperature dependent QTc time interval in 27 neonates undergoing therapeutic hypothermia while receiving extracorporeal membrane oxygenation (ECMO). A more recent meta-analysis on the effect of therapeutic hypothermia on QTc, confirmed this finding and added that these observations normalize immediately afterwards.…”

Cardiovascular Disease in Children: The Future Is Now

“…In this Special Issue, dedicated to "Cardiovascular Disease in Children", we are covering some of these aspects. From middle-term outcomes after anatomical surgery [7]; through application of percutaneous interventional techniques in rare paediatric syndromes [8]; vasovagal syncope [9]; the role of neonatal therapeutic hypothermia on QTc interval prolongation [10]; to echocardiography applications and perspectives [11,12]; inflammatory conditions such as Kawasaki disease in young infants and children [13] and multisystem inflammatory syndrome [12,14]; prevalence variations in arterial hypertension around the COVID-19 pandemic [15]; up to the exciting field of vascular health and cardiovascular biomarkers [16,17], we are inviting you on an inspiring journey.…”