Hypothermia and Postconditioning after Cardiopulmonary Resuscitation Reduce Cardiac Dysfunction by Modulating Inflammation, Apoptosis and Remodeling

Meybohm, Patrick; Gruenewald, Matthias; Albrecht, Martín; Zacharowski, Kai; Lucius, Ralph; Zitta, Karina; Koch, Alexander; Tran, Nguyen; Scholz, Jens; Bein, Berthold

doi:10.1371/journal.pone.0007588

Cited by 69 publications

(46 citation statements)

References 38 publications

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“…In an experimental model of acute myocardial ischemia and subsequent CPR and hypothermia, cooling reduced myocardial damage and dysfunction via a reduced rate of apoptosis and pro-inflammatory cytokine expression (33). Elevated cytokine levels were reported in patients after CA under hypothermia (34,35), whereas the level of TTM seems to have no effect on systemic inflammatory cytokine responses (36).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic hypothermia impacts leukocyte kinetics after cardiac arrest

Dufner

André

Stiepak³

et al. 2016

Cardiovasc. Diagn. Ther.

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Background: Patients admitted to the hospital after primarily successful cardiopulmonary resuscitation (CPR) are at a very high risk for neurologic deficits and death. Targeted temperature management (TTM) for mild therapeutic hypothermia has been shown to improve survival compared to standard treatment.Acute cardiovascular events, such as myocardial infarction (MI), are a major cause for cardiac arrest (CA) in patients who undergo CPR. Recent findings have demonstrated the importance and impact of the leukocyte response following acute MI.Methods: In this retrospective, single center study we enrolled 169 patients with CA due to non-traumatic causes and primarily successful CPR. A total of 111 subjects (66%) underwent TTM aiming for a target temperature of 32-34 ℃.Results: Analysis of 30 day follow up showed a significantly improved survival of all patients who received TTM compared to patients without hypothermia (P=0.0001). Furthermore TTM was an independent variable of good neurological outcome after 6 months (P=0.0030). Therapeutic hypothermia was found to be beneficial independent of differences in age and sex between both groups. While a higher rate of pneumonia was observed with TTM, this diagnosis had no additional impact on survival or neurological outcome. The beneficial effect on mortality remained significant in patients with the diagnosis of an acute cardiac event (P=0.0145). Next, we evaluated the kinetics of leukocytes in this group over the course of 7 days after CA.At presentation, patients showed a mean level of 16.5±6.7 of leukocytes per microliter. While this level stayed stable in the group of patients without hypothermia, patients who received TTM showed a significant decline of leukocyte levels resulting in significantly lower numbers of leukocytes on days 3 and 5 after CPR. Interestingly, these differences in leukocyte counts remained beyond the time period of TTM while C-reactive protein (CRP) levels were suppressed only during ongoing cooling, but differences between the groups were diminished after TTM was terminated (from day 3 on, P>0.2). Finally, patients who received TTM and showed a leukocyte count of less than 12.7/μL on day 3 had an improved survival (P=0.0214) and neurological outcome (P=0.0049) compared to patients above that level.Conclusions: Our data underline the beneficial effects of TTM and demonstrate an impact of hypothermia on leukocyte counts after CA.

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Section: Discussionmentioning

confidence: 99%

Therapeutic hypothermia impacts leukocyte kinetics after cardiac arrest

Dufner

André

Stiepak³

et al. 2016

Cardiovasc. Diagn. Ther.

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“…HT in post-resuscitation circulatory shock. Animal data have suggested a beneficial effect of HT in cardiogenic shock mediated through modulations in inflammation, apoptosis, and remodeling (67,68). In humans, although post-resuscitation shock is a relatively frequent complication of cardiac arrest (66), such patients have been excluded from RCTs, and the results of observational studies have been hampered by variations used to define "shock" and lack of report on outcomes in this subset of patients (Table 2).…”

Section: Ht and Cardiac Arrestmentioning

confidence: 99%

Hypothermia Therapy

Delhaye

Mahmoudi

Waksman

2012

Journal of the American College of Cardiology

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Due to its protective effect on the brain and the myocardium, hypothermia therapy (HT) has been extensively studied in cardiac arrest patients with coma as well as in patients presenting with acute myocardial infarction (MI). In the setting of cardiac arrest, randomized studies have shown that HT decreases mortality and improves neurological outcomes. Subsequent guidelines have therefore recommended cooling (32°C to 34°C) for 12 to 24 h in unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest due to ventricular fibrillation. Observational studies have also confirmed the feasibility of this therapy in clinical practice and support its early application in patients with nonventricular fibrillation cardiac arrest and in post-resuscitation circulatory shock. In patients with acute MI, available clinical evidence does not yet support HT as the standard of care, because no study to date has shown a clear net benefit in such a cohort. After a brief review of the mechanisms of action for HT, we provide a review of the clinical evidence, cooling techniques, and potential adverse effects associated with HT in the setting of post-cardiac arrest patient and acute MI.

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“…Zymography was performed as described previously (22). Briefly, 1 μL of the respective serum (T0 and T2 from RIPC patients [n = 6] as well as T0 and T2 from control patients without RIPC [n = 6]) was loaded and separated on 7% SDS polyacrylamide gels (containing 1 mg/mL gelatin) under nonreducing conditions.…”

Section: Gelatin Zymographymentioning

confidence: 99%

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

Zitta

Meybohm

Bein

et al. 2011

Mol Med

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Remote ischemic preconditioning (RIPC) can be induced by transient occlusion of blood flow to a limb with a blood pressure cuff and exerts multiorgan protection from ischemia/reperfusion injury. Ischemia/reperfusion injury in the intestinal tract leads to intestinal barrier dysfunction and can result in multiple organ failure. Here we used an intestinal cell line (CaCo-2) to evaluate the effects of RIPC-conditioned patient sera on hypoxia-induced cell damage in vitro and to identify serum factors that mediate RIPC effects. Patient sera (n = 10) derived before RIPC (T0), directly after RIPC (T1) and 1 h after RIPC (T2) were added to the culture medium at the onset of hypoxia until 48 h after hypoxia. Reverse transcription-polymerase chain reaction, lactate dehydrogenase (LDH) assays, caspase-3/7 assays, silver staining, gelatin zymography and Western blotting were performed. Hypoxia led to morphological signs of cell damage and increased the release of LDH in cultures containing sera T0 (P < 0.01) and T1 (P < 0.05), but not sera T2, which reduced the hypoxia-mediated LDH release compared with sera T0 (P < 0.05). Gelatin zymography revealed a significant reduction of activities of the matrixmetalloproteinase (MMP)-2 and MMP-9 in the protective sera T2 compared with the nonprotective sera T0 (MMP-2: P < 0.01; MMP-9: P < 0.05). Addition of human recombinant MMP-2 and MMP-9 to MMP-deficient culture media increased the sensitivity of CaCo-2 cells to hypoxia-induced cell damage (P < 0.05), but did not result in a reduced phosphorylation of prosurvival kinases p42/44 and protein kinase B (Akt) or increased activity of caspase-3/7. Our results suggest MMP-2 and MMP-9 as currently unknown humoral factors that may be involved in RIPC-mediated cytoprotection in the intestine.

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Hypothermia and Postconditioning after Cardiopulmonary Resuscitation Reduce Cardiac Dysfunction by Modulating Inflammation, Apoptosis and Remodeling

Cited by 69 publications

References 38 publications

Therapeutic hypothermia impacts leukocyte kinetics after cardiac arrest

Therapeutic hypothermia impacts leukocyte kinetics after cardiac arrest

Hypothermia Therapy

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

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