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Illustrative Cases

Epinephrine at 25°C Core Body Temperature and During Rewarming

Case Report of Successful Infant Resuscitation After Cold Water Submersion

Mann, Christian MD; Baer, Walter MD; Riedel, Thomas MD, PD

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doi: 10.1097/PEC.0000000000001766
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A 13-month-old white girl with an uneventful medical history was in her stroller in the mountains of eastern Switzerland when it rolled over the edge of a 2-m sidewall, bumped down into a fast-running stream (temperature, 8°C), and was promptly carried out of sight. The accident occurred at 11:24 a.m., defined as time zero (T0); subsequent timepoints are expressed as T followed by the number of minutes postsubmersion.

The local Emergency Medical Communication Centre was alerted at T10. The medical dispatcher alerted the helicopter crew, based at a flight distance of 35 km, at T14 and the ground-based ambulance team and local police at T16.

Anticipating that the stream was flowing fast enough to have carried the toddler a considerable distance, the flight crew saved valuable minutes by beginning their search downstream, tracking upwards until spotting her bright blue jacket in the water 700 m from the point of accidental entry. Because they could not land in the deep and narrow gorge, they radioed directions to the ambulance and police car, which arrived at T29.

The police found the infant submerged face down in the countercurrent behind a large rock. They pulled her out at T32 and carried her up to the ambulance where cardiopulmonary resuscitation (CPR) was started at T35.

Primary survey revealed absent vital signs, Glasgow coma scale score of 3, mouth full of water, no breathing movements, no brachial pulse, dilated pupils (6 mm) nonreactive to light, multiple skull hematomas, laceration above left ear, no obvious limb injuries, core (esophageal) temperature of 25.0°C, by definition stage 3 hypothermia.

Cardiopulmonary resuscitation was started at a 15:2 compressions-to-breaths ratio and 120 per minute compression rate, with bag-mask ventilation, repeated suction to clear copious water from the mouth, and placement of an extrication collar (Stifneck, Laerdal Medical AS, Stavanger, Norway). Electrocardiographic monitoring (Propaq MD, ZOLL Medical, Cologne, Germany) showed pulseless electrical activity (PEA) with broad deformed ventricular complexes at a rate of 40 per minute.

Cardiopulmonary resuscitation was maintained in the ambulance to the helicopter landing site 300 m in distance. The helicopter crew performed orotracheal intubation (internal diameter, 4.0; cuffed tube). Volume-controlled ventilation (expiratory tidal volume, 100 mL [10 mL/kg]) was set at 25 per minute (inspiratory pressures were not recorded). Manual chest compressions were continued. End-tidal CO2 was 36 mm Hg; pulse oximetry showed no consistent reading.

Given PEA, and despite a core body temperature of 25°C, 2 doses of epinephrine (10 μg/kg) were administered via intraosseous line at T48, followed over the next 30 minutes by a normal saline bolus of 200 mL (20 mL/kg) via free drip.

During helicopter transport, chest compressions were maintained and external rewarming was performed with 2 heat packs either side of the infant on the stretcher. After landing, the child was brought to the emergency room located in the intensive care unit at T71. At a rectal temperature of 25.4°C, external rewarming was continued with a warming blanket (Bair Hugger, 3 M, Minn). The electrocardiogram still showed broad deformed ventricular complexes. Brachial and femoral pulses were absent.

Over the next 50 minutes, 12 doses of epinephrine (10 μg/kg, intraosseous) were given at 4-minute intervals, plus 3 doses of sodium bicarbonate (2 mmol/kg; as a bolus after the second and fourth dose of epinephrine, followed by another dose infused over 2 hours). No further fluid bolus was given. Epinephrine infusion (0.1 μg/kg/min) was started via a femoral vein at T116 (Table 1). Blood gases were measured in the first 2 samples drawn in the emergency department at T142 and T165 (Table 2).

Timelines and Epinephrine Doses During Resuscitation Until Return of Spontaneous Circulation
Capillary and Venous Blood Gas Results From the First 2 Samples Drawn in the Emergency Department at T142 and T165 After CPR for 107 and 130 Minutes

Return of spontaneous circulation (ROSC) was finally recorded at T191, after 2.5 hours of CPR, at a rectal temperature of 29.5°C. The first post-ROSC blood pressure reading was 83/53 mm Hg (mean, 58 mm Hg).

In the intensive care unit, the temperature target was set at deep normothermia (36.0°C–37.0°C) for 48 hours. Active rewarming was slowed down as soon as 33.0°C was reached. The first temperature in normothermia was at T600 (T10 hours). Epinephrine infusion was withdrawn at T660 (T11 hours). Peak high-sensitivity cardiac troponin T at T12 hours was 0.857 μg/L (normal, <0.014 μg/L).

Chest x-ray at T4 hours (T243) showed aspiration and pulmonary edema. Acute respiratory distress syndrome was diagnosed 7 hours later. Highest ventilation settings were as follows: peak inspiratory pressure, 34 cm H2O; positive end-expiratory pressure, 14 cm H2O; f 50/min; inspiratory time, 0.7 seconds. Inverse ratio ventilation was administered for the edema. Mechanical ventilation was stopped on day 8.

Neurologic outcome at 6 weeks was normal except for slight truncal hypotonia. Subsequent milestones included walking at 20 months and first words at 24 months. At age of 6 years, the parents reported regular kindergarten attendance, good fine motor skills, and 2-wheel bicycle riding.


Submersion and drowning are major causes of accidental death in children.1 However, hypothermia may be protective, especially if it develops quickly, before ischemia onset.2,3 Specific management issues include cardiac dysfunction that may result not only from hypothermia2,4 but also from hypoxia and acidosis and require pharmacologic support.1 European resuscitation guidelines (and former American guidelines) advocate withholding intravenous drugs at core body temperatures below 30°C, in particular epinephrine given its proarrhythmogenic side effect.5,6

Once the patient has been rewarmed to 30°C, the guidelines advise doubling the drug dosing intervals compared with normothermia. Only as normothermia is approached (≥35°C) should standard drug protocols apply.5–7 However, American Heart Association resuscitation guidelines since 2010 note inconsistencies between this advice and certain animal data and clinical case reports.8,9 In practice, up to two thirds of hypothermic patients (47%–66%) receive inotropic agents to improve cardiac output.10,11

There is as yet no hard evidence from prospective clinical or experimental studies either for or against the use of epinephrine for pediatric advanced life support in severe hypothermia and/or during rewarming. Furthermore, the guidelines do not consider pediatric and adult patients separately, despite the apparently differing temperature thresholds for hypothermic arrhythmias in children and adults.12

In normothermia, timely epinephrine administration in the first minutes of adult out-of-hospital cardiac arrest is associated with favorable neurologic outcome.8,13,14 However, a randomized controlled trial in over 8000 adults found increased post–out-of-hospital cardiac arrest survival in the epinephrine group to be offset by poorer neurologic outcome.15

In hypothermic animal models, epinephrine increases ROSC rates while increasing coronary perfusion pressures.16,17 Low doses raised heart rate and cardiac output in a rat model of hypothermia and rewarming.18 The main benefit of epinephrine can be expected in the rewarming phase when hypotonia is a major problem and excitation-contraction coupling in cardiomyocytes is impaired.19 However, overall, the animal data remain inconclusive.18,20–22

The one area in which the animal evidence appears consistent is dosing: rewarming studies comparing boluses of 45 versus 200 μg/kg in pigs21 and infusions of 0.125 versus 1.25 μg/min in rats (converting to 0.45 and 4.5 μg/kg/min in body weight-based units22) concur in finding significantly fewer negative effects with lower doses. Hypothermia alters dose-dependent physiologic responses, narrowing the therapeutic window downwards, with high-dose epinephrine markedly elevating cardiac afterload while leaving inotropy unchanged.22

In our case, it may have been important for successful outcome that epinephrine not only was used early, in 25°C hypothermia, but also, after 12 standard doses during the first 24 cycles of CPR in the hospital, was maintained at low dose during the entire active external rewarming phase.

Both the ambulance and emergency department teams administered epinephrine in full awareness of its potential for inducing ventricular fibrillation. It would have been withheld immediately at the first sign of tachycardia. Pulseless electrical activity was recorded in the field and repeatedly thereafter during rewarming until ROSC.

We recognize 2 limitations to our report. The first is that we cannot clearly separate the cardiovascular effect of epinephrine in hypothermia from its effect on cardiac posthypoxia-ischemia because we do not know to what extent aspiration and submersion hypoxemia preceded hypothermia. The second is that we cannot differentiate the effect of epinephrine given in the first 1.5 hours of CPR from its effect on myocardial and vasoregulatory dysfunction in the subsequent ongoing rewarming phase.


Our report contributes to the ongoing debate in pediatric advanced life support for hypothermic circulatory arrest below 30°C over whether to withhold epinephrine or to trial repeated doses in the presence of PEA or asystole.7,8 Given the array of life support and postresuscitation interventions, we cannot tell from this single case if epinephrine was responsible for the good neurologic outcome. However, there is a pathophysiologic case to be made for the benefits of epinephrine in severe hypothermia and especially during rewarming. The continuing insufficiency of evidence for or against the use of epinephrine in children rescued from accidental hypothermia only underlines the urgent need for further animal studies and human data, for example, from pediatric case series.


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submersion; accidental hypothermia; epinephrine; pulseless electrical activity; resuscitation guideline

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.