Introduction: The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome. Methods: Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation. Results: All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs Control: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120–360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls. Conclusions: In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.

Introduction: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). Methods: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. Results: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure (Control: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (Control: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure (Control: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival (Control: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs Control and 40 ppm). Conclusions: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR.

Mildly elevated lactate levels (i.e., 1–2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80–1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1–5.7, P = 0.027). In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

Purpose of review: The purpose of this review is to summarize recent advances about inhaled gases as novel neuroprotective agents in the postcardiac arrest period. Recent findings: Inhaled gases, as nitric oxide (NO) and molecular hydrogen (H₂), and noble gases as xenon (Xe) and argon (Ar) have shown neuroprotective properties after resuscitation. In experimental settings, the protective effect of these gases has been demonstrated in both in-vitro studies and animal models of cardiac arrest. They attenuate neuronal degeneration and improve neurological function after resuscitation acting on different pathophysiological pathways. Safety of both Xe and H₂ after cardiac arrest has been reported in phase 1 clinical trials. A randomized phase 2 clinical trial showed the neuroprotective effects of Xe, combined with targeted temperature management. Xe inhalation for 24 h after resuscitation preserves white matter integrity as measured by fractional anisotropy of diffusion tensor MRI. Summary: Inhaled gases, as Xe, Ar, NO, and H₂ have consistently shown neuroprotective effects in experimental studies. Ventilation with these gases appears to be well tolerated in pigs and in preliminary human trials. Results from phase 2 and 3 clinical trials are needed to assess their efficacy in the treatment of postcardiac arrest brain injury.