Search

The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic-ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI., Author(s): Ryan L. Hoiland [sup.1] [sup.2] [sup.3] [sup.4] [sup.5], Chiara Robba [sup.6] [sup.7], David K. Menon [sup.8], Giuseppe Citerio [sup.9], Claudio Sandroni [sup.10], Mypinder S. Sekhon [sup.1] [sup.4] [sup.5] [sup.11] [...]

Aim: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. Methods: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady‐state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial‐internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). Results: The CMRO2 was altered by 0.5 mL × min−1 (95% CI: −0.6 to −0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: −13.2 to −6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo‐ and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: −15.4 to −0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: −11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. Conclusion: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production. [ABSTRACT FROM AUTHOR]

Purpose Targeted temperature management (TTM) may improve survival and functional outcome in comatose survivors of out-of-hospital cardiac arrest (OHCA), though the optimal target temperature remains unknown. We conducted a systematic review and network meta-analysis to investigate the efficacy and safety of deep hypothermia (31-32 °C), moderate hypothermia (33-34 °C), mild hypothermia (35-36 °C), and normothermia (37-37.8 °C) during TTM. Methods We searched six databases from inception to June 2021 for randomized controlled trials (RCTs) evaluating TTM in comatose OHCA survivors. Two reviewers performed screening, full text review, and extraction independently. The primary outcome of interest was survival with good functional outcome. We used GRADE to rate our certainty in estimates. Results We included 10 RCTs (4218 patients). Compared with normothermia, deep hypothermia (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.73-2.30), moderate hypothermia (OR 1.34, 95% CI 0.92-1.94) and mild hypothermia (OR 1.44, 95% CI 0.74-2.80) may have no effect on survival with good functional outcome (all low certainty). Deep hypothermia may not improve survival with good functional outcome, as compared to moderate hypothermia (OR 0.97, 95% CI 0.61-1.54, low certainty). Moderate hypothermia (OR 1.23, 95% CI 0.86-1.77) and deep hypothermia (OR 1.27, 95% CI 0.70-2.32) may have no effect on survival, as compared to normothermia. Finally, incidence of arrhythmia was higher with moderate hypothermia (OR 1.45, 95% CI 1.08-1.94) and deep hypothermia (OR 3.58, 95% CI 1.77-7.26), compared to normothermia (both high certainty). Conclusions Mild, moderate, or deep hypothermia may not improve survival or functional outcome after OHCA, as compared to normothermia. Moderate and deep hypothermia were associated with higher incidence of arrhythmia. Routine use of moderate or deep hypothermia in comatose survivors of OHCA may potentially be associated with more harm than benefit., Author(s): Shannon M. Fernando [sup.1] [sup.2], Pietro Di Santo [sup.3] [sup.4], Behnam Sadeghirad [sup.5] [sup.6], Jean-Baptiste Lascarrou [sup.7], Bram Rochwerg [sup.6] [sup.8], Rebecca Mathew [sup.1] [sup.3], Mypinder S. Sekhon [sup.9], [...]

Passive hyperthermia causes cerebral hypoperfusion primarily from heat‐induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro‐inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water‐perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet‐poor plasma via cells expressing CD62E (activated endothelial cells), CD31+/CD42b− (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan‐leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P‐values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+/CD42b− (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2/pH‐mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. Key points: The hyperthermia‐induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow.We tested the hypothesis that the respiratory‐induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow.At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross‐brain microvesicle kinetics.However, when core temperature was increased by 2°C with CO2/pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2/pH‐mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia.These new findings suggest that the heat‐induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain. [ABSTRACT FROM AUTHOR]

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro‐inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia–reperfusion. In particular, interleukin‐1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia–reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules. [ABSTRACT FROM AUTHOR]