Effects of mild hypothermia on hemodynamics in cardiac arrest survivors and isolated failing human myocardium

Abstract

Post-cardiac arrest myocardial dysfunction is a common phenomenon after return of spontaneous circulation (ROSC) and contributes to hemodynamic instability and low survival rates after cardiac arrest. Mild hypothermia for 24 h after ROSC has been shown to significantly improve neurologic recovery and survival rates. In the present study we investigate the influence of therapeutic hypothermia on hemodynamic parameters in resuscitated patients and on contractility in failing human myocardium. We analyzed hemodynamic data from 200 cardiac arrest survivors during the hypothermia period. The initial LVEF was 32.6 +/- 1.2% indicating a significantly impaired LV function. During hypothermia induction, the infusion rate of epinephrine could be significantly reduced from 9.1 +/- 1.3 microg/min [arrival intensive care unit (ICU) 35.4 degrees C] to 4.6 +/- 1.0 microg/min (34 degrees C) and 2.8 +/- 0.5 microg/min (33 degrees C). The dobutamine and norepinephrine application rates were not changed significantly. The mean arterial blood pressure remained stable. The mean heart rate significantly decreased from 91.8 +/- 1.7 bpm (arrival ICU) to 77.3 +/- 1.5 bpm (34 degrees C) and 70.3 +/- 1.4 bpm (33 degrees C). In vitro we investigated the effect of hypothermia on isolated ventricular muscle strips from explanted failing human hearts. With decreasing temperature, the contractility increased to a maximum of 168 +/- 23% at 27 degrees C (n = 16, P < 0.05). Positive inotropic response to hypothermia was accompanied by moderately increased rapid cooling contractures as a measure of sarcoplasmic reticulum (SR) Ca(2+) content, but can be elicited even when the SR Ca(2+) release is blocked in the presence of ryanodine. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca(2+) sensitivity as the main mechanism responsible for inotropy. In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors which might contribute to improved survival rates in these patients. Mechanistically, we demonstrate that hypothermia improves contractility in failing human myocardium most likely by increasing Ca(2+)-sensitivity.

Fig. 1

Hemodynamic support by catecholamines during induction of therapeutic hypothermia (on arrival at the intensive care unit (ICU), at 34 and 33°C body temperature) and during the re-warming period (after 24 h at 33°C and after reaching 36.5°C): a infusion rate of epinephrine. *P < 0.05 versus arrival ICU. b Infusion rate of norepinephrine. c Infusion rate of dobutamine

Fig. 2

Hemodynamic parameters during induction of therapeutic hypothermia (on arrival at the intensive care unit (ICU), at 34 and 33°C body temperature) and re-warming (after 24 h at 33°C and after reaching 36.5°C). a MAP mean arterial blood pressure. *P < 0.05 versus arrival ICU, 34 and 33°C. b HR heart rate. *P < 0.05 versus arrival ICU, ^† P < 0.05 versus 34°C, ^# P < 0.05 versus 34, 33 and 33°C (24 h)

Fig. 3

Effect of hypothermia on contractility and Ca²⁺ handling in isolated muscle strips from failing human myocardium. a Change in force of contraction during stepwise cooling from 37 to 27°C. Stimulation frequency: 1 Hz. Average values from 16 muscle strips given in percent of the control value at 37°C. *P < 0.05 versus control (37°C). b Influence of temperature on rapid cooling contractures (RCC). Changes in the amplitude of RCCs upon cooling are given in percent of the control value at 37°C. Average values from 16 muscle strips. *P < 0.05 versus control (37°C). c Effect of ryanodine on systolic and diastolic force during mild hypothermia. Average values from 13 muscle strips. *P < 0.05 versus control (37°C). d Correlation of change in force of contraction during hypothermia with and without ryanodine. 27°C values were excluded since diastolic force increased excessively at 27°C. Scatter plot with linear regression analysis and 95% confidence interval. r = 0.75, r ² = 0.57

Fig. 4

Influence of hypothermia on contraction and relaxation kinetics. Average values from 13 muscle strips with and 16 muscle strips without ryanodine (Rya). Stimulation frequency: 1 Hz. *P < 0.05 versus control (37°C). ^# P < 0.05 with ryanodine versus without ryanodine (37°C). a Time to peak tension (TTP), b total twitch time (TTT), c time to 50% relaxation (RT 50), d time to 90% relaxation (RT 90)