Characterizing the Relationship Between Arterial Carbon Dioxide Trajectory and Serial Brain Biomarkers with Central Nervous System Injury During Veno-Venous Extracorporeal Membrane Oxygenation: A Prospective Cohort Study.

BACKGROUND: Central nervous system (CNS) injury following initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is common. An acute decrease in partial pressure of arterial carbon dioxide (PaCO2) following VV-ECMO initiation has been suggested as an etiological factor, but the challenges of diagnosing CNS injuries has made discerning a relationship between PaCO2 and CNS injury difficult. METHODS: We conducted a prospective cohort study of adult patients undergoing VV-ECMO for acute respiratory failure. Arterial blood gas measurements were obtained prior to initiation of VV-ECMO, and at every 2-4 h for the first 24 h. Neuroimaging was conducted within the first 7-14 days in patients who were suspected of having neurological injury or unable to be examined because of sedation. We collected blood biospecimens to measure brain biomarkers [neurofilament light (NF-L); glial fibrillary acidic protein (GFAP); and phosphorylated-tau 181] in the first 7 days following initiation of VV-ECMO. We assessed the relationship between both PaCO2 over the first 24 h and brain biomarkers with CNS injury using mixed methods linear regression. Finally, we explored the effects of absolute change of PaCO2 on serum levels of neurological biomarkers by separate mixed methods linear regression for each biomarker using three PaCO2 exposures hypothesized to result in CNS injury. RESULTS: In our cohort, 12 of 59 (20%) patients had overt CNS injury identified on head computed tomography. The PaCO2 decrease with VV-ECMO initiation was steeper in patients who developed a CNS injury (- 0.32%, 95% confidence interval - 0.25 to - 0.39) compared with those without (- 0.18%, 95% confidence interval - 0.14 to - 0.21, P interaction < 0.001). The mean concentration of NF-L increased over time and was higher in those with a CNS injury (464 [739]) compared with those without (127 [257]; P = 0.001). GFAP was higher in those with a CNS injury (4278 [11,653] pg/ml) compared with those without (116 [108] pg/ml; P < 0.001). The mean NF-L, GFAP, and tau over time in patients stratified by the three thresholds of absolute change of PaCO2 showed no differences and had no significant interaction for time. CONCLUSIONS: Although rapid decreases in PaCO2 following initiation of VV-ECMO were slightly greater in patients who had CNS injuries versus those without, data overlap and absence of relationships between PaCO2 and brain biomarkers suggests other pathophysiologic variables are likely at play.

Extracorporeal life support in trauma: Indications and techniques.

BACKGROUND: Clarity about indications and techniques in extracorporeal life support (ECLS) in trauma is essential for timely and effective deployment, and to ensure good stewardship of an important resource. Extracorporeal life support deployments in a tertiary trauma center were reviewed to understand the indications, strategies, and tactics of ECLS in trauma. METHODS: The provincial trauma registry was used to identify patients who received ECLS at a Level I trauma center and ECLS organization-accredited site between January 2014 and February 2021. Charts were reviewed for indications, technical factors, and outcomes following ECLS deployment. Based on this data, consensus around indications and techniques for ECLS in trauma was reached and refined by a multidisciplinary team discussion. RESULTS: A total of 25 patients underwent ECLS as part of a comprehensive trauma resuscitation strategy. Eighteen patients underwent venovenous ECLS and seven received venoarterial ECLS. Nineteen patients survived the ECLS run, of which 15 survived to discharge. Four patients developed vascular injuries secondary to cannula insertion while four patients developed circuit clots. On multidisciplinary consensus, three broad indications for ECLS and their respective techniques were described: gas exchange for lung injury, extended damage control for severe injuries associated with the lethal triad, and circulatory support for cardiogenic shock or hypothermia. CONCLUSION: The three broad indications for ECLS in trauma (gas exchange, extended damage control and circulatory support) require specific advanced planning and standardization of corresponding techniques (cannulation, circuit configuration, anticoagulation, and duration). When appropriately and effectively integrated into the trauma response, ECLS can extend the damage control paradigm to enable the management of complex multisystem injuries. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Prognostic factors associated with favourable functional outcome among adult patients requiring extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR), has demonstrated promise in the management of refractory out-of-hospital cardiac arrest (OHCA). However, evidence from observational studies and clinical trials are conflicting and the factors influencing outcome have not been well established. METHODS: We conducted a systematic review and meta-analysis summarizing the association between pre-ECPR prognostic factors and likelihood of good functional outcome among adult patients requiring ECPR for OHCA. We searched Medline and Embase databases from inception to February 28, 2023 and screened studies with two independent reviewers. We performed meta-analyses of unadjusted and adjusted odds ratios, adjusted hazard ratios and mean differences separately. We assessed risk of bias using the QUIPS tool and certainty of evidence using the GRADE approach. FINDINGS: We included 29 observational and randomized studies involving 7,397 patients. Factors with moderate or high certainty of association with increased survival with favourable functional outcome include pre-arrest patient factors, such as younger age (odds ratio (OR) 2.13, 95% CI 1.52 to 2.99) and female sex (OR 1.37, 95% CI 1.11 to 1.70), as well as intra-arrest factors, such as shockable rhythm (OR 2.79, 95% CI 2.04 to 3.80), witnessed arrest (OR 1.68 (95% CI 1.16 to 2.42), bystander CPR (OR 1.55, 95% CI 1.19 to 2.01), return of spontaneous circulation (OR 2.81, 95% CI 2.19 to 3.61) and shorter time to cannulation (OR 1.14, 95% CI 1.17 to 1.69 per 10 minutes). INTERPRETATION: The findings of this review confirm several clinical concepts wellestablished in the cardiac arrest literature and their applicability to the patient for whom ECPR is considered - that is, the impact of pre-existing patient factors, the benefit of timely and effective CPR, as well as the prognostic importance of minimizing low-flow time. We advocate for the thoughtful consideration of these prognostic factors as part of a risk stratification framework when evaluating a patient's potential candidacy for ECPR.

Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest.

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.

Prediction of successful veno-venous extracorporeal life support liberation using the oxygen challenge test.

BACKGROUND: The oxygen challenge test (OCT) is an underutilized measure of lung recovery, easily performed prior to proceeding with a trial-off V-V ECLS as part of a weaning algorithm. Evidence-based thresholds for OCT results which support continuing with V-V ECLS weaning are lacking, making interpretation of these tests challenging in clinical practice. METHODS: We performed a retrospective review of patients commenced on V-V ECLS as a bridge-to-recovery at Vancouver General Hospital from 2015-2019. The absolute PaO2 post-OCT and change in PaO2 proportional to incremental FiO2 change on the ventilator (∆PaO2 ) were evaluated as predictive screening metrics for identifying conditions favorable for successful trial-off of V-V ECLS. RESULTS: An optimal cut-off of PaO2 ≥ 240 mm Hg post-OCT (AUC 0.77) and ∆PaO2 ≥ 250 mm Hg (AUC 0.76) was identified as a threshold for predicting successful trials-off. A total of 26 and 24 patients achieved post-OCT PaO2 and ∆PaO2 thresholds, and 100% of these patients were liberated successfully from ECLS during their admission. CONCLUSIONS: The OCT can serve as an effective screen of shunt reduction and native lung recovery which can be used alongside other measures of ventilation to assess for suitability of liberation from V-V ECLS prior to a trial-off. Achieving a PaO2 ≥ 240 mm Hg post-OCT is a strong prognostic indicator for successful liberation from V-V ECLS during ICU admission.

Association of Respiratory Parameters at Venovenous Extracorporeal Membrane Oxygenation Liberation With Duration of Mechanical Ventilation and ICU Length of Stay: A Prospective Cohort Study.

Although the criteria for initiation of venovenous extracorporeal membrane oxygenation (VV ECMO) are well defined, the criteria and timing for VV ECMO decannulation are less certain. The aim of this study was to describe the ventilation and physiologic factors at the time of VV ECMO decannulation and to determine if these factors have association with mechanical ventilation or ICU length of stay after ECMO decannulation. DESIGN: Multicenter, prospective cohort study. SETTING: Eleven ICUs in Australia. PATIENTS: Adult patients treated with VV ECMO from March 19, 2019, to September 20, 2020. INTERVENTIONS: Liberation from VV ECMO. RESULTS: Of 87 patients receiving VV ECMO, the median age was 49 years (interquartile range, 37-59 yr), 61 of 87 (70%) were male, and 52/87 (60%) had a diagnosis of acute respiratory distress syndrome. There were 24 of 87 patients (28%) who died prior to day 90. No patient required a second run of VV ECMO. In a multivariate models, a higher partial pressure of arterial carbon dioxide (p < 0.01) and respiratory rate at the time of decannulation (p = 0.01) were predictive of a longer duration of mechanical ventilation and ICU length of stay postdecannulation in survivors. Higher positive end-expiratory pressure at ECMO decannulation was associated with shorter duration of ICU length of stay post-ECMO decannulation in survivors (p = 0.01). CONCLUSIONS: A higher partial pressure of arterial carbon dioxide and higher respiratory rate at ECMO decannulation were associated with increased duration of mechanical ventilation and increased duration of ICU stay postdecannulation, and increased positive end-expiratory pressure at decannulation was associated with decreased duration of ICU stay postdecannulation. Future research should further investigate these associations to establish the optimal ventilator settings and timing of liberation from VV ECMO.

Reduced fixed dose tocilizumab 400 mg IV compared to weight-based dosing in critically ill patients with COVID-19: A before-after cohort study.

Background: Interleukin-6 inhibitors reduce mortality in severe COVID-19. British Columbia began using tocilizumab 8 mg/kg (maximum 800 mg) in January 2021 in critically ill patients with COVID-19, but due to drug shortages, decreased dosing to 400 mg IV fixed dose in April 2021. The aims of this study were twofold: to compare physiological responses and clinical outcomes of these two strategies, and examine the cost-effectiveness of treating all patients with 400 mg versus half the patients with 8 mg/kg and the other half without tocilizumab. Methods: This was a single-centre, before-after cohort study of critically ill COVID-19 patients treated with tocilizumab, and a control cohort treated with dexamethasone only. Physiological responses and clinical outcomes were compared between patients receiving both doses of tocilizumab and those receiving dexamethasone only. We built a decision tree model to examine cost-effectiveness. Findings: 152 patients were included; 40 received tocilizumab 8 mg/kg, 59 received 400 mg and 53 received dexamethasone only. Median CRP fell from 103 mg/L to 5.2 mg/L, 96 mg/L to 6.8 mg/L and from 81.3 mg/L to 48 mg/L in the 8 mg/kg, 400 mg tocilizumab, and dexamethasone only groups, respectively. 28-day mortality was 5% (n=2) vs 8% (n=5) vs 13% (n=7), with no significant difference in all pair-wise comparison. At an assumed willingness-to-pay threshold of $50,000 Canadian per life-year, utilizing 400 mg for all patients rather than 8 mg/kg for half the patients is cost-effective in 51.6% of 10,000 Monte Carlo simulations. Interpretation: Both doses of tocilizumab demonstrated comparable reduction of inflammation with similar 28-day mortality. Without consideration of equity, the net monetary benefits of providing 400 mg tocilizumab to all patients are comparable to 8 mg/kg to half the patients. In the context of ongoing drug shortages, fixed-dose 400 mg tocilizumab may be a practical, feasible and economical option. Funding: This work was supported by a gift donation from Hsu & Taylor Family to the VGH Foundation, and the Yale Bernard G. Forget Scholarship.

Quality of life and functional status of patients treated with venovenous extracorporeal membrane oxygenation at 6 months.

PURPOSE: Quality of life (QoL) outcomes of patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) have been conflicting. This study reports on QoL outcomes for a broad group of ARDS patients managed with up-to-date treatment modalities. METHODS: We prospectively recruited patients at a quaternary hospital in the United Kingdom from 2013 to 2015 who were treated with ECMO for ARDS. We evaluated their pulmonary function and QoL at 6-months after admission using three QoL instruments: EuroQoL 5D (EQ-5), HADS, and PTSS-14. RESULTS: Forty-three patients included in the analysis had near-normal pulmonary function at 6 months. HADS showed moderate-to-severe anxiety and depression in 32% and 11% of patients, respectively. PTSS-14 showed 29% had signs of post-traumatic stress disorder. EQ-5D showed that 67% of patients had difficulty returning to usual activities, 74% suffered some pain, none reported severe problems and 77% were able to return to work. No clinical or demographic variables were associated with poor 6-month QoL. CONCLUSIONS: Patients with ARDS treated with ECMO generally had good QoL outcomes, similar to outcomes reported for patients managed without ECMO. With respect to QoL, VV-EMCO represents a valid treatment modality for patients with refractory ARDS.

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

[Figure: see text].

Goal-Directed Care Using Invasive Neuromonitoring Versus Standard of Care After Cardiac Arrest: A Matched Cohort Study.

PURPOSE: Following return of spontaneous circulation after cardiac arrest, hypoxic ischemic brain injury is the primary cause of mortality and disability. Goal-directed care using invasive multimodal neuromonitoring has emerged as a possible resuscitation strategy. We evaluated whether goal-directed care was associated with improved neurologic outcome in hypoxic ischemic brain injury patients after cardiac arrest. DESIGN: Retrospective, single-center, matched observational cohort study. SETTING: Quaternary academic medical center. PATIENTS: Adult patients admitted to the ICU following return of spontaneous circulation postcardiac arrest with clinical evidence of hypoxic ischemic brain injury defined as greater than or equal to 10 minutes of cardiac arrest with an unconfounded postresuscitation Glasgow Coma Scale of less than or equal to 8. INTERVENTIONS: We compared patients who underwent goal-directed care using invasive neuromonitoring with those treated with standard of care (using both total and matched groups). MEASUREMENTS AND MAIN RESULTS: Goal-directed care patients were matched 1:1 to standard of care patients using propensity scores and exact matching. The primary outcome was a 6-month favorable neurologic outcome (Cerebral Performance Category of 1 or 2). We included 65 patients, of whom 21 received goal-directed care and 44 patients received standard of care. The median age was 50 (interquartile range, 35-61), 48 (74%) were male, and seven (11%) had shockable rhythms. Favorable neurologic outcome at 6 months was significantly greater in the goal-directed care group (n = 9/21 [43%]) compared with the matched (n = 2/21 [10%], p = 0.016) and total (n = 8/44 [18%], p = 0.034) standard of care groups. Goal-directed care group patients had higher mean arterial pressure (p < 0.001 vs total; p = 0.0060 vs matched) and lower temperature (p = 0.007 vs total; p = 0.041 vs matched). CONCLUSIONS: In this preliminary study of patients with hypoxic ischemic brain injury postcardiac arrest, goal-directed care guided by invasive neuromonitoring was associated with a 6-month favorable neurologic outcome (Cerebral Performance Category 1 or 2) versus standard of care. Significant work is required to confirm this finding in a prospectively designed study.

Quantification of Neurological Blood-Based Biomarkers in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: To provide an objective characterization of acute neurologic injury in critically ill patients with coronavirus disease 2019. DESIGN: Prospective observational study. Demographics, comorbidities, and daily clinical physiologic and laboratory data were collected. Plasma levels of neurofilament-light chain, total tau, ubiquitin carboxy-terminal hydrolase L1, and glial fibrillary acidic protein were measured. The primary neurologic outcome was delirium defined by the Intensive Care Delirium Screening Checklist (scale 1-8). Associations among plasma biomarkers, respiratory failure, and inflammation were analyzed. SETTING: Multicenter study in ICUs. PATIENTS: Critically ill patients with respiratory failure, with coronavirus disease 2019, or without (ICU control). MEASUREMENTS AND MAIN RESULTS: A total of 27 patients with coronavirus disease 2019 and 19 ICU controls were enrolled. Compared with ICU controls with pneumonia of other etiology, patients with coronavirus disease 2019 had significantly higher glial fibrillary acidic protein (272 pg/mL [150-555 pg/mL] vs 118 pg/mL [78.5-168 pg/mL]; p = 0.0009). In coronavirus disease 2019 patients, glial fibrillary acidic protein (rho = 0.5115, p = 0.0064), ubiquitin carboxy-terminal hydrolase L1 (rho = 0.4056, p = 0.0358), and neurofilament-light chain (rho = 0.6223, p = 0.0005) positively correlated with Intensive Care Delirium Screening Checklist score and were increased in patients with delirium (Intensive Care Delirium Screening Checklist ≥ 4) in the coronavirus disease 2019 group but not in ICU controls. There were no associations between the measures of respiratory function or cytokines with glial fibrillary acidic protein, total tau, ubiquitin carboxy-terminal hydrolase L1, or neurofilament-light chain levels in patients with coronavirus disease 2019. CONCLUSIONS: Plasma glial fibrillary acidic protein is two-fold higher in critically ill patients with coronavirus disease 2019 compared with ICU controls. Higher levels of glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain associate with delirium in patients with coronavirus disease 2019. Elevated plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain are independent of respiratory function and peripheral cytokines.

The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019. DESIGN: Multicenter prospective observational study. SETTING: ICU. PATIENTS: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group). INTERVENTIONS: Daily measurement of serum inflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao2/Fio2 and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao2/Fio2 (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1ß on the day of diagnosis. CONCLUSIONS: The inverse relationship between serum interleukin-6 and Pao2/Fio2 and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-ß or tumor necrosis factor-α.

The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19.

Studies on severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) suggest a protective effect of anti-A antibodies against viral cell entry that may hold relevance for SARS-CoV-2 infection. Therefore, we aimed to determine whether ABO blood groups are associated with different severities of COVID-19. We conducted a multicenter retrospective analysis and nested prospective observational substudy of critically ill patients with COVID-19. We collected data pertaining to age, sex, comorbidities, dates of symptom onset, hospital admission, intensive care unit (ICU) admission, mechanical ventilation, continuous renal replacement therapy (CRRT), standard laboratory parameters, and serum inflammatory cytokines. National (N = 398 671; P = .38) and provincial (n = 62 246; P = .60) ABO blood group distributions did not differ from our cohort (n = 95). A higher proportion of COVID-19 patients with blood group A or AB required mechanical ventilation (P = .02) and CRRT (P = .004) and had a longer ICU stay (P = .03) compared with patients with blood group O or B. Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity. Inflammatory cytokines did not differ between patients with blood group A or AB (n = 11) vs O or B (n = 14; P > .10 for all cytokines). Collectively, our data indicate that critically ill COVID-19 patients with blood group A or AB are at increased risk for requiring mechanical ventilation, CRRT, and prolonged ICU admission compared with patients with blood group O or B. Further work is needed to understand the underlying mechanisms.

Effect of Cerebral Perfusion Pressure on Acute Respiratory Distress Syndrome.

BACKGROUND: Increased cerebral perfusion pressure (CPP)>70 mmHg has been associated with acute respiratory distress syndrome (ARDS) after traumatic brain injury (TBI). Since this reported association, significant changes in ventilation strategies and fluid management have been accepted as routine critical care. Recently, individualized perfusion targets using autoregulation monitoring suggest CPP titration>70 mmHg. Given these clinical advances, the association between ARDS and increased CPP requires further delineation. OBJECTIVE: To determine the association between ARDS and increased CPP after TBI. METHODS: We conducted a single-center historical cohort study investigating the association of increased CPP and ARDS after TBI. We collected demographic data and physiologic data for CPP, intracranial pressure, mechanical ventilation, cumulative fluid balance and delta/driving pressure (ΔP). We collected outcomes measures pertaining to duration of ventilation, intensive care unit admission length, hospitalization length and 6-month neurological outcome. RESULTS: In total, 113 patients with severe TBI and multimodal neuromonitoring were included. In total, 16 patients (14%) developed ARDS according to the Berlin definition. There was no difference in the mean CPP during the first 7 days of admission between patients who developed ARDS (74 mmHg SD 18 vs. 73 mmHg SD 18, p=0.86) versus those who did not. Patients who developed ARDS had a higher ΔP (15 mmHg [5] vs. 12 mmHg [4], p=0.016) and lower lung compliance (35 ml/cmH2O [10] vs. 49 ml/cmH2O [18], p=0.024) versus those who did not. CONCLUSION: We did not observe an association between increased CPP and ARDS. Patients with ARDS had higher ΔP and lower lung compliance.