Randomised trial of epinephrine dose and flush volume in term newborn lambs

Abstract

ObjectivesNeonatal resuscitation guidelines recommend 0.5–1 mL saline flush following 0.01–0.03 mg/kg of epinephrine via low umbilical venous catheter for persistent bradycardia despite effective positive pressure ventilation (PPV) and chest compressions (CC). We evaluated the effects of 1 mL vs 3 mL/kg flush volumes and 0.01 vs 0.03 mg/kg doses on return of spontaneous circulation (ROSC) and epinephrine pharmacokinetics in lambs with cardiac arrest.DesignForty term lambs in cardiac arrest were randomised to receive 0.01 or 0.03 mg/kg epinephrine followed by 1 mL or 3 mL/kg flush after effective PPV and CC. Epinephrine (with 1 mL flush) was repeated every 3 min until ROSC or until 20 min. Haemodynamics, blood gases and plasma epinephrine concentrations were monitored.ResultsTen lambs had ROSC before epinephrine administration and 2 died during instrumentation. Among 28 lambs that received epinephrine, 2/6 in 0.01 mg/kg-1 mL flush, 3/6 in 0.01 mg/kg-3 mL/kg flush, 5/7 in 0.03 mg/kg-1 mL flush and 9/9 in 0.03 mg/kg-3 mL/kg flush achieved ROSC (p=0.02). ROSC was five times faster with 0.03 mg/kg epinephrine compared with 0.01 mg/kg (adjusted HR (95% CI) 5.08 (1.7 to 15.25)) and three times faster with 3 mL/kg flush compared with 1 mL flush (3.5 (1.27 to 9.71)). Plasma epinephrine concentrations were higher with 0.01 mg/kg-3 mL/kg flush (adjusted geometric mean ratio 6.0 (1.4 to 25.7)), 0.03 mg/kg-1 mL flush (11.3 (2.1 to 60.3)) and 0.03 mg/kg-3 mL/kg flush (11.0 (2.2 to 55.3)) compared with 0.01 mg/kg-1 mL flush.Conclusions0.03 mg/kg epinephrine dose with 3 mL/kg flush volume is associated with the highest ROSC rate, increases peak plasma epinephrine concentrations and hastens time to ROSC. Clinical trials evaluating optimal epinephrine dose and flush volume are warranted.

Effect of a Larger Flush Volume on Bioavailability and Efficacy of Umbilical Venous Epinephrine during Neonatal Resuscitation in Ovine Asphyxial Arrest

“…In one lamb that did not achieve ROSC with the first dose, a subsequent dose of epinephrine 0.03 mg/kg with 1-mL flush led to ROSC. A graphic summary combining results from the current paper and our previous publication [12] of 3 doses of flush (1-mL, 2.5-mL, and 10-mL) is shown in Figure 2.…”

“…Adequately powered clinical trials are warranted to study the effect of a larger flush volume following UVC epinephrine on survival and long-term cardiovascular and neurodevelopmental outcomes. [12] comparing 1-mL, 2.5-mL, and 3 mL/kg (~10 mL) flush in term lambs with asphyxial arrest induced by umbilical cord occlusion. In lambs receiving 10-mL flush, only the first dose of epinephrine was associated with high volume flush.…”

“…The experiments were performed in compliance with animal ethical guidelines (the ARRIVE guidelines) [11]. Time-dated healthy pregnant ewes from May Family Enterprises (Buffalo Mills, PA, USA) and Van Laningham Farms (Arbuckle, CA, USA) were fasted overnight and underwent cesarean section after endotracheal intubation under general anesthesia with IV diazepam and ketamine, and inhaled 2% isoflurane, as previously described [12,13].…”

“…Probability of <5% was used for statistical significance. Some of the data included in this manuscript were previously published [9,12].…”

“…We have previously compared the effect of flush volumes of 1-mL and~10-mL after low UVC epinephrine in a term ovine model of perinatal cardiac arrest [12]. Larger flush volume of~10-mL resulted in quicker ROSC when compared to 1-mL flush after the first epinephrine dose.…”