Introduction
Survival after cardiac arrest remains low worldwide, averaging ≤6% for out-of-hospital [
1,
2] and 18% for in-hospital arrest [
1‐
3]. Even after return of spontaneous circulation (ROSC) the overall prognosis is poor. The National Registry of Cardiopulmonary Resuscitation (NRCPR) reported in 2006 that among 19,819 adults who regained ROSC, in-hospital mortality was 67% [
4]. One important contributor to the low survival rates after ROSC is post-cardiac arrest myocardial dysfunction that is well described in both animal and human studies [
5‐
9]. Mild hypothermia is the only therapy applied in the post-cardiac arrest setting that has been shown to significantly improve survival rates [
10,
11]. Therefore, international guidelines recommend the induction of therapeutic hypothermia (32–34°C for 12–24 h) in all comatose survivors of cardiac arrest [
12,
13]. Several techniques are available to easily and safely induce therapeutic hypothermia [
10,
12,
14,
15]. By reducing oxygen consumption and numerous deleterious biochemical and physical mechanisms that lead to reperfusion cell damage hypothermia reduces brain injury and improves neurologic recovery [
10,
15]. Moreover, in several animal species [
16‐
19] and nonfailing human myocardium [
16] hypothermia has been shown to directly increase cardiac contractility. Contradictory, it has been reported that hypothermia could decrease cardiac output and increase the requirement of inotropics [
15,
20].
In the present study, we systematically analyzed hemodynamic parameters of cardiac arrest survivors during the hypothermia period. Mechanistically, we investigated the effects of hypothermia on contractility and Ca2+ handling in isolated ventricular muscle strips from explanted failing human hearts in vitro.
Discussion
The present study demonstrates that mild hypothermia improves hemodynamics in cardiac arrest survivors. In isolated failing human myocardium hypothermia significantly increases contractility. Positive inotropic response to hypothermia is accompanied by moderately increased SR Ca2+ content but can be elicited even when the SR Ca2+ storage function is blocked. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca2+ sensitivity of the myofilaments as the main mechanism for inotropy.
Hypothermic inotropism has been shown previously in several animal studies [
16‐
19]. In 1897, Langendorff [
18] was the first to describe a relation between temperature and myocardial function. Moreover, hypothermia has been shown to increase contractility in nonfailing human myocardium [
16]. However, in the failing human heart, Ca
2+ cycling, contractile function and their response to external interventions are significantly altered compared to nonfailing hearts [
27,
30,
31]. Intriguingly, we now demonstrate that mild hypothermia improves contractility also in failing human myocardium. Furthermore, in cardiac arrest survivors presenting with impaired LV function, induction of therapeutic hypothermia was associated with significantly reduced epinephrine requirement indicating hemodynamic stabilization. Since the arterial pH increased from 7.30 (arrival ICU) to 7.39 (34°C), it cannot be excluded that the pH shift contributes to the reduced epinephrine requirement. However, a pH of 7.30 indicates a very mild acidosis and by reducing the body temperature from 34 to 33°C the pH is not affected whereas the epinephrine dose could be further reduced from 4.6 to 2.8 μg/min.
In the study of Bernard et al. [
15] the cardiac index (CI) decreased in hypothermia versus normothermia treated cardiac arrest patients. However, systemic vascular resistance (SVR) was significantly increased in these patients, which might explain the reduced cardiac output. In pigs mild hypothermia increased CI without significantly affecting SVR [
16]. Higher incidence of required epinephrine infusions in the study of Bernard et al. [
15] includes the rewarming period and does therefore not argue against our results.
To elucidate the subcellular effects of mild hypothermia, we performed RCC measurements in muscle strips from failing human myocardium. In contrast to previous data from pig myocardium [
16], mild hypothermia moderately increased RCC amplitudes indicating that SR Ca
2+ content may be increased. One could speculate that increased SR Ca
2+ load may be associated with subsequent enhanced SR Ca
2+ release. However, the inotropic response to hypothermia was still observed after complete blockade of SR function with ryanodine. This finding is in line with experimental data from Shattock and Bers [
17], indicating that mechanisms, other than those involving the SR, contribute to the hypothermia-induced inotropism. One possibility is increased Ca
2+ sensitivity. In the present study, hypothermia prolonged both contraction and relaxation times, indicating increased Ca
2+ responsiveness of the myofilaments as an important underlying mechanism of positive inotropism [
32]. Increased Ca
2+ sensitivity might result from hypothermia-induced alkalosis [
33,
34] or slowed cross-bridge cycling rate [
35].
While systolic performance is clearly improved at all temperature steps investigated, increasing myofilament Ca
2+ sensitivity might induce diastolic dysfunction [
36]. In the present study, we observed an increase in diastolic force at 27°C particularly when SR function was inhibited by ryanodine, indicating that pronounced hypothermia might impair diastolic function. This has important implications for the treatment of successfully resuscitated patients, since diastolic dysfunction is a common phenomenon after ROSC [
37‐
40]. However, in the temperature range recommended for therapeutic hypothermia in cardiac arrest patients (32–34°C) [
12,
13], we did not observe any relevant changes in diastolic function. Furthermore, our clinical data demonstrate that hypothermia significantly reduces HR, an intervention that usually improves LV filling [
41]. However, since optimal cooling temperature is still under investigation, it should be considered that temperatures below the current recommendations might induce or worsen diastolic heart failure.
Post-cardiac arrest myocardial dysfunction is responsive to inotropic drugs [
39,
42]. In swine, dobutamine infusions of 5–10 μg(kg min) substantially improve systolic and diastolic function after cardiac arrest [
39]. However, cAMP dependent inotropes such as β-adreno-agonists or phosphodiesterase III inhibitors, increase myocardial oxygen consumption, can exacerbate or induce ischemia in patients with coronary artery disease, can exert direct cardiac toxicity and have consistently been proven to increase mortality in chronic heart failure [
43‐
45]. As discussed above, hypothermia most likely acts by sensitizing the myofilaments for Ca
2+. In contrast to cAMP elevating inotropes, hypothermia prolongs contraction and relaxation times, acts partially independently of SR function and significantly reduces HR. Therefore, it may favorably impact myocardial energetics relative to traditional inotropic therapies. Animal studies have shown that in myocardial infarction hypothermia decreases oxygen consumption and infarct size [
46,
47]. Preliminary data indicate that mild hypothermia might represent an attractive approach to increase contractility not only after cardiac arrest but also in other patients with cardiogenic shock [
48].
Our clinical data demonstrate that hypothermia significantly reduces HR. In this context, it is important to note that the force-frequency relation is inversed during hypothermia. Lewis et al. [
49] have nicely shown that higher HRs result in reduced contractility at colder temperatures. Therefore, lower HRs are beneficial during hypothermia.
This study has some limitations. Due to the hemodynamic stabilization during hypothermia induction, invasive hemodynamic measurements by pulmonary catheter were not performed routinely. Therefore, invasive hemodynamic data cannot be provided.
There was no normothermia control group of resuscitated patients with which to compare changes in hemodynamic parameters. Since post-cardiac arrest myocardial dysfunction is a potentially reversible phenomenon [
6,
7,
50], we cannot completely exclude that hemodynamic stabilization might occur independently of hypothermia induction. However, Bernard et al. [
15] described no increase of CI values in the normothermia group during the first 6 h after admission to the ICU. Moreover, it has been reported that CI values reach their nadir at 8 h after resuscitation [
6]. In contrast, we observed a significant reduction in epinephrine requirement within 6 h, indicating an accelerated improvement of hemodynamics by induction of hypothermia. Furthermore, our in vitro experiments were performed in a control-matched setting, demonstrating that hypothermia instantly increases contractility in one and the same failing myocardial muscle strip.
During the re-warming period, the catecholamine doses were not changed significantly. However, the re-warming period could not be compared with the cooling induction for several reasons: (1) as mentioned above, post-cardiac arrest myocardial dysfunction reaches its nadir 8 h after ROSC. Contractility is known to recover after 24 h [
6]. Therefore, it is not surprising that the requirement for epinephrine and dobutamine did not rise again. (2) As recommended [
12], hypothermia was induced as rapid as possible, whereas re-warming was performed very slowly (0.2°C/h). A body temperature of 36.5°C was reached after 18.7 h (almost 3 times slower than cooling induction). This is a long time for compensatory mechanisms. (3) Induction and maintenance of therapeutic hypothermia were performed under constantly deep sedation. During the re-warming period sedation was stopped after reaching 35°C. Increasing vigilance will likely interfere with the need for catecholamines. (4) Normothermia was reached approximately 48 h after ROSC. At this time point many of the ventilated cardiac arrest patients are affected by infections and sepsis that will influence the hemodynamic situation.
Hemodynamic instability as part of the post-cardiac arrest syndrome is not only caused by myocardial dysfunction, but also a severe systemic ischemia/reperfusion response, having many characteristics in common with sepsis, i.e. systemic inflammation, endothelial activation, impaired vasoregulation and intravascular volume depletion [
12,
51‐
54]. In the present study, we demonstrate that mild hypothermia increases contractility in failing human myocardium. This effect most likely contributes to the early hemodynamic stabilization we observed in cardiac arrest survivors treated with hypothermia. However, since hypothermia has been reported to increase SVR [
15], this might also help to stabilize the hemodynamic situation in the post-cardiac arrest syndrome. In our study population the application rate of the vasopressor norepinephrine was slightly but not significantly increased during hypothermia induction and re-warming.
In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors, which might contribute to improved survival rates in these patients. As one possible mechanism we demonstrate that hypothermia increases contractility in the failing human myocardium most likely by increasing Ca2+ sensitivity. Further studies are required to evaluate hypothermia as inotropic intervention in patients with cardiogenic shock.