Impact of therapeutic hypothermia on bleeding events in adult patients treated with extracorporeal life support peri-cardiac arrest.

PURPOSE: Whether therapeutic hypothermia (TH) adds to the risk of bleeding in patients on extracorporeal life support (ECLS) peri-cardiac arrest remains unknown. MATERIAL AND METHODS: Single center retrospective study on patients receiving veno-arterial ECLS peri-cardiac arrest ± TH at 32-34 °C (January 2009-December 2015). PRIMARY OUTCOME: major bleeding (including intracerebral hemorrhage, ICH) < 72 h of cardiac arrest. Logistic regression and marginal structural models were used to analyze associations with major bleeding. RESULTS: Of 66 patients receiving ECLS, 36 were treated with TH. Major bleeding occurred in 14 patients (39%) treated with ECLS+TH and in 17 patients (57%) with ECLS alone. ICH was reported in 3 (8%) and one patient (3%), respectively. There was no difference in mortality, but lung injury occurred more often in ECLS+TH. A platelet count <60 × 109/L but not TH was associated with major bleeding (including ICH). The estimated causal risk ratio of TH on the occurrence of major bleeding (including ICH) at 72 h post cardiac arrest was 0.95 (95%CI 0.62-1.45). CONCLUSIONS: Bleeding complications were common in our study. However, TH (32-34 °C) was not associated with an increased risk of major bleeding in patients on ECLS peri-cardiac arrest.

Feasibility, safety, and resource utilisation of active mobilisation of patients on extracorporeal life support: a prospective observational study.

BACKGROUND: There is scarce evidence on the feasibility, safety and resource utilisation of active mobilisation in critically ill patients on extracorporeal life support (ECLS). METHODS: This prospective observational single-centre study included all consecutive critically ill patients on ECLS admitted to an academic centre in Germany over a time period of one year. The level of mobilisation was categorised according to the ICU Mobility Scale (IMS). Primary outcome was complications during mobilisation. RESULTS: During the study period, active mobilisation with an activity level on the IMS of ≥ 3 was performed at least on one occasion in 43 out of 115 patients (37.4%). A total of 332 mobilisations with IMS ≥ 3 were performed during 1242 ECLS days (26.7%). ECLS configurations applied were va-ECMO (n = 63), vv-ECMO (n = 26), vv-ECCO2R (n = 12), av-ECCO2R (n = 10), and RVAD (n = 4). Femoral cannulation had been in place in 108 patients (93.9%). The median duration of all mobilisation activities with IMS ≥ 3 was 130 min (IQR 44-215). All mobilisations were undertaken by a multi-professional ECLS team with a median number of 3 team members involved (IQR 3-4). Bleeding from cannulation site requiring transfusion and/or surgery occurred in 6.9% of actively mobilised patients and in 15.3% of non-mobilised patients. During one mobilisation episode, accidental femoral cannula displacement occurred with immediate and effective recannulation. Sedation was the major reason for non-mobilisation. CONCLUSIONS: Active mobilisation (IMS ≥ 3) of ECLS patients undertaken by an experienced multi-professional team was feasible, and complications were infrequent and managed successfully. Larger prospective multicentre studies are needed to further evaluate early goal directed sedation and mobilisation bundles in patients on ECLS.

Reduced pulmonary inflammatory response during cardiopulmonary bypass: effects of combined pulmonary perfusion and carbon monoxide inhalation.

OBJECTIVE: Pulmonary inflammation induced by cardiopulmonary bypass (CPB) is one of the main causes for lung injury after cardiac surgery. Pulmonary perfusions as well as carbon monoxide (CO) inhalation are known to reduce the inflammatory reaction of the lung. We hypothesized that a combination of pulmonary perfusion and carbon monoxide inhalation leads to an even stronger reduction of the lung inflammation. METHODS: Pigs (n=7 per experimental group) were randomized to sham operation (SHAM), conventional CPB (CPB), inhalation of CO (CPB+CO, 250 ppm), pulmonary perfusion (CPB+PP) or pulmonary perfusion plus inhalation of CO (CPB+PP+CO). Various cytokine levels (TNF-alpha, IL-1, IL-6, and IL-10) and caspase-3 activity were measured using enzyme-linked immunosorbent assay (ELISA). Transcription factor activity was analyzed via electrophoretic mobility shift assay (EMSA). Blood gases and hemodynamics were measured continuously. A p value <0.05 assessed by Holm-Sidak method was considered statistically significant. RESULTS: Hemodynamic parameters and blood gas analysis showed no significant differences between the groups. While IL-1 protein expression was comparable between the groups, TNF-alpha (478+/-58 vs 869+/-95 pg/ml; p<0.001) and IL-6 protein levels in the lung (256+/-82 vs 936+/-76 pg/ml; p<0.001) showed a significant inhibition in the CPB+PP+CO group at 120 min post-bypass time compared to the CPB group. The cytokine levels were comparable to the CPB+PP and CPB+CO group. IL-10 protein expression (325+/-47 vs 65+/-27 pg/ml; p<0.05) was significantly higher in the CO-treated compared to CPB+PP and CPB-treated animals at 120 min post-bypass. Activation of the transcription factors NF-kappaB and AP-1 showed a CO-mediated induction compared to the CPB or CPB+PP group. Caspase-3 activity revealed a CO-dependent, significant inhibition in CO and CPB+PP+CO-treated animals compared to CPB animals (p<0.05). CONCLUSION: The combination of pulmonary perfusion and inhalative carbon monoxide inhibits CPB-mediated pulmonary inflammation as well as pulmonary apoptosis stronger than pulmonary perfusion or carbon monoxide alone.

Pulsatile pulmonary perfusion during cardiopulmonary bypass reduces the pulmonary inflammatory response.

BACKGROUND: Pulmonary dysfunction presumably linked to an inflammatory response is frequent after cardiac operations using cardiopulmonary bypass (CPB) and pulmonary hypoperfusion. We previously demonstrated that active perfusion of the lungs during CPB reduces ischemic lung injury. We now hypothesized that avoiding ischemia of the lungs during CPB by active pulmonary perfusion would decrease pulmonary inflammatory response. METHODS: Pigs were randomized to a control group with CPB for 120 minutes, followed by 120 minutes of postbypass reperfusion, or to the study groups where animals underwent active pulmonary perfusion with pulsatile or nonpulsatile perfusion during CPB (n = 7 in each group). Activation of transcription factor activity (nuclear factor [NF]-kappaB and activating protein [AP]-1) was determined by electrophoretic mobility shift assay. Levels of proinflammatory protein expression (interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-alpha) were quantified by enzyme-linked immunoabsorbent assay. Caspase-3 activity was measured using a fluorogenic assay. RESULTS: The activation of transcription factor AP-1 and NF-kappaB was reduced in the pulsatile pulmonary perfusion group. The caspase-3 activity and the expression of IL-1, IL-6, and TNF-alpha revealed a significant decrease in the pulsatile and nonpulsatile pulmonary perfusion groups. Animals of the pulsatile pulmonary perfusion group showed significantly reduced IL-6 expression and caspase-3 activity compared with the nonpulsatile pulmonary perfusion group. CONCLUSIONS: Active pulmonary perfusion reduces the inflammatory response and apoptosis in the lungs observed during conventional CPB. This effect is greatest when pulmonary perfusion is performed with pulsatility. The reduction in cytokine expression by pulsatile pulmonary perfusion might be mediated by AP-1 and NF-kappaB.

Carbon monoxide inhalation reduces pulmonary inflammatory response during cardiopulmonary bypass in pigs.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with pulmonary inflammation and dysfunction. This may lead to acute lung injury and acute respiratory distress syndrome with increased morbidity and mortality. The authors hypothesized that inhaled carbon monoxide before initiation of CPB would reduce inflammatory response in the lungs. METHODS: In a porcine model, a beating-heart CPB was used. The animals were either randomized to a control group, to standard CPB, or to CPB plus carbon monoxide. In the latter group, lungs were ventilated with 250 ppm inhaled carbon monoxide in addition to standard ventilation before CPB. Lung tissue samples were obtained at various time points, and pulmonary cytokine levels were determined. RESULTS: Hemodynamic parameters were largely unaffected by CPB or carbon monoxide inhalation. There were no significant differences in cytokine expression in mononuclear cells between the groups throughout the experimental time course. Compared with standard CPB animals, carbon monoxide significantly suppresses tumor necrosis factor-alpha and interleukin-1beta levels (P < 0.05) and induced the antiinflammatory cytokine interleukin 10 (P < 0.001). Carbon monoxide inhalation modulates effector caspase activity in lung tissue during CPB. CONCLUSIONS: The results demonstrate that inhaled carbon monoxide significantly reduces CPB-induced inflammation via suppression of tumor necrosis factor alpha, and interleukin-1beta expression and elevation of interleukin 10. Apoptosis induced by CPB was associated with caspase-3 activation and was significantly attenuated by carbon monoxide treatment. Based on the observations of this study, inhaled carbon monoxide could represent a potential new therapeutic modality for counteracting CPB-induced lung injury.