Randomized control trial of intravenous acetaminophen for reduction of intrapartum maternal fever

Abstract

BACKGROUND: Intravenous acetaminophen reaches a higher mean peak plasma concentration than oral acetaminophen in a shorter period of time. The favorable pharmacokinetics of intravenous acetaminophen may be beneficial for treating intrapartum maternal fever. OBJECTIVE: The primary objective was to compare intravenous and oral acetaminophen in time to defervescence (temperature <38 C). The secondary objective was to compare intravenous and oral acetaminophen in the percentage of participants being afebrile and percent reduction in maternal temperature 30 minutes after administration of first dose. Other outcomes evaluated were histopathological placental findings; neonatal outcomes; oxidative stress; and levels of RANTES, interferon-d, interleukin 1b, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and tumor necrosis factor-a in maternal and neonatal blood. STUDY DESIGN: This was a randomized, comparator-controlled, double-dummy, double-blind clinical trial. At the onset of intrapartum fever !38 C, patients !36 weeks' gestation were either randomized to the control or experimental study arm. Patients in the control arm received 1000 mg of oral acetaminophen capsules and an intravenous placebo resembling intravenous acetaminophen. Patients randomized to the experimental arm received 1000 mg of intravenous acetaminophen and oral placebo capsules resembling acetaminophen. Maternal temperatures and fetal heart rates were recorded at consecutive intervals following administration of the first dose of acetaminophen. Maternal blood, collected at the onset of fever and after delivery, and neonatal cord blood collected at delivery were evaluated for oxidative stress (glutathione levels), levels of RANTES and cytokines (interferon-d, interleukin 1b, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and tumor necrosis factor-a). Placentas were collected for pathologic review. A P value of <.05 was considered statically significant. RESULTS: A total of 121 patients (55 in the intravenous and 66 in the oral group) were recruited from December 1, 2016, to February 28, 2018. Patient demographics and intrapartum factors were similar between both arms. The intravenous group showed a mean time of 54.86 minutes (95% confidence interval, 20.57e39.43) to defervescence vs 52.58 minutes (95% confidence interval, 16.58e43.42) in the oral group (P¼.71). In addition, intravenous and oral acetaminophen showed similar results in percentage of patients being afebrile and percent reduction in maternal temperature 30 minutes after administration of the first dose. Histopathological findings, neonatal outcomes, oxidative stress markers, and RANTES and cytokine levels were not statistically significant between intravenous and oral acetaminophen groups. CONCLUSION: Intravenous acetaminophen did not demonstrate a higher efficacy than oral acetaminophen in treating intrapartum maternal fever. Select patients may benefit from intravenous acetaminophen for treatment o...

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

“…These data were included as LLOQ/2 in this analysis. It has to be noted that in the study by Mehraban et al ( 18 ), maternal concentrations were not measured.…”

“…Few measured concentrations in the study by Mehraban et al ( 18 ) fell below the lower limit of quantification (LLOQ). These data were included as LLOQ/2 in this analysis.…”

“…Note that the structure of the PBPK model was not changed in this study and is thus consistent with the structure of the PBPK model reported in our previous publication ( 13 ). Thereafter, fetal pharmacokinetics were predicted in the umbilical vein compartment of the PBPK model and predictions were evaluated with clinical data from Nitsche et al ( 17 ) and Mehraban et al ( 18 ).…”

“…Additional concentration data in the umbilical cord were obtained from the study by Mehraban et al ( 18 ). From the 121 patients with intrapartum fever of whom blood samples were collected in this study, we included the 45 patients who received a single oral dose of 1,000 mg acetaminophen.…”

“…Several parameters of the in silico cotyledon perfusion model relevant to maternal-fetal drug transfer were then optimized using previously published data for acetaminophen. The optimization results were then transferred into the PBPK model and the predicted pharmacokinetics in the umbilical vein at delivery were re-evaluate using the pooled data of Nitsche et al ( 17 ) and Mehraban et al ( 18 ).…”