Stroke in critically ill patients with respiratory failure due to COVID-19: Disparities between low-middle and high-income countries.

PURPOSE: We aimed to compare the incidence of stroke in low-and middle-income countries (LMICs) versus high-income countries (HICs) in critically ill patients with COVID-19 and its impact on in-hospital mortality. METHODS: International observational study conducted in 43 countries. Stroke and mortality incidence rates and rate ratios (IRR) were calculated per admitted days using Poisson regression. Inverse probability weighting (IPW) was used to address the HICs vs. LMICs imbalance for confounders. RESULTS: 23,738 patients [20,511(86.4 %) HICs vs. 3,227(13.6 %) LMICs] were included. The incidence stroke/1000 admitted-days was 35.7 (95 %CI = 28.4-44.9) LMICs and 17.6 (95 %CI = 15.8-19.7) HICs; ischemic 9.47 (95 %CI = 6.57-13.7) LMICs, 1.97 (95 %CI = 1.53, 2.55) HICs; hemorrhagic, 7.18 (95 %CI = 4.73-10.9) LMICs, and 2.52 (95 %CI = 2.00-3.16) HICs; unspecified stroke type 11.6 (95 %CI = 7.75-17.3) LMICs, 8.99 (95 %CI = 7.70-10.5) HICs. In regression with IPW, LMICs vs. HICs had IRR = 1.78 (95 %CI = 1.31-2.42, p < 0.001). Patients from LMICs were more likely to die than those from HICs [43.6% vs 29.2 %; Relative Risk (RR) = 2.59 (95 %CI = 2.29-2.93), p < 0.001)]. Patients with stroke were more likely to die than those without stroke [RR = 1.43 (95 %CI = 1.19-1.72), p < 0.001)]. CONCLUSIONS: Stroke incidence was low in HICs and LMICs although the stroke risk was higher in LMICs. Both LMIC status and stroke increased the risk of death. Improving early diagnosis of stroke and redistribution of healthcare resources should be a priority. TRIAL REGISTRATION: ACTRN12620000421932 registered on 30/03/2020.

Current trends and latest developments in echocardiographic assessment of right ventricular function: load dependency perspective.

Right ventricle (RV) failure is a common complication of many cardiopulmonary diseases. Since it has a significant adverse impact on prognosis, precise determination of RV function is crucial to guide clinical management. However, accurate assessment of RV function remains challenging owing to the difficulties in acquiring its intricate pathophysiology and imaging its complex anatomical structure. In addition, there is historical attention focused exclusively on the left ventricle assessment, which has led to overshadowing and delayed development of RV evaluation. Echocardiography is the first-line and non-invasive bedside clinical tool for assessing RV function. Tricuspid annular plane systolic excursion (TAPSE), RV systolic tissue Doppler velocity of the tricuspid annulus (RV S'), and RV fractional area change (RV FAC) are conventional standard indices routinely used for RV function assessment, but accuracy has been subject to several limitations, such as load-dependency, angle-dependency, and localized regional assessment. Particularly, load dependency is a vexing issue, as the failing RV is always in a complex loading condition, which alters the values of echocardiographic parameters and confuses clinicians. Recently, novel echocardiographic methods for improved RV assessment have been developed. Specifically, "strain", "RV-pulmonary arterial (PA) coupling", and "RV myocardial work" are newly applied methods for RV function assessment, a few of which are designed to surmount the load dependency by taking into account the afterload on RV. In this narrative review, we summarize the latest data on these novel RV echocardiographic parameters and highlight their strengths and limitations. Since load independency is one of the primary advantages of these, we particularly emphasize this aspect.

Echocardiographic surrogate of left ventricular stroke work in a model of brain stem death donors.

BACKGROUND: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS: In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS: PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

The Impact of Acute Exercise on Hemostasis and Angiogenesis Mediators in Patients With Continuous-Flow Left Ventricular Assist Devices: A Prospective Observational Pilot Study.

Impaired primary hemostasis and dysregulated angiogenesis, known as a two-hit hypothesis, are associated with gastrointestinal (GI) bleeding in patients with continuous-flow left ventricular assist devices (CF-LVADs). Exercise is known to influence hemostasis and angiogenesis in healthy individuals; however, little is known about the effect in patients with CF-LVADs. The objective of this prospective observational study was to determine whether acute exercise modulates two-hit hypothesis mediators associated with GI bleeding in patients with a CF-LVAD. Twenty-two patients with CF-LVADs performed acute exercise either on a cycle ergometer for approximately 10 minutes or on a treadmill for 30 minutes. Blood samples were taken pre- and post-exercise to analyze hemostatic and angiogenic biomarkers. Acute exercise resulted in an increased platelet count (p < 0.00001) and platelet function (induced by adenosine diphosphate, p = 0.0087; TRAP-6, p = 0.0005; ristocetin, p = 0.0009). Additionally, high-molecular-weight vWF multimers (p < 0.00001), vWF collagen-binding activity (p = 0.0012), factor VIII (p = 0.034), angiopoietin-1 (p = 0.0026), and vascular endothelial growth factor (p = 0.0041) all increased after acute exercise. This pilot work demonstrates that acute exercise modulated two-hit hypothesis mediators associated with GI bleeding in patients with CF-LVADs.

A novel echocardiographic parameter considering left ventricular afterload during V-A ECMO support.

BACKGROUND: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO. METHODS: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively. RESULTS: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558). CONCLUSIONS: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO.

Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue therapy in patients with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19. While bleeding and thrombosis complicate ECMO, these events may also occur secondary to COVID-19. Data regarding bleeding and thrombotic events in COVID-19 patients on ECMO are sparse. METHODS: Using the COVID-19 Critical Care Consortium database, we conducted a retrospective analysis on adult patients with severe COVID-19 requiring ECMO, including centers globally from 01/2020 to 06/2022, to determine the risk of ICU mortality associated with the occurrence of bleeding and clotting disorders. RESULTS: Among 1,248 COVID-19 patients receiving ECMO support in the registry, coagulation complications were reported in 469 cases (38%), among whom 252 (54%) experienced hemorrhagic complications, 165 (35%) thrombotic complications, and 52 (11%) both. The hazard ratio (HR) for Intensive Care Unit mortality was higher in those with hemorrhagic-only complications than those with neither complication (adjusted HR = 1.60, 95% CI 1.28-1.99, p < 0.001). Death was reported in 617 of the 1248 (49.4%) with multiorgan failure (n = 257 of 617 [42%]), followed by respiratory failure (n = 130 of 617 [21%]) and septic shock [n = 55 of 617 (8.9%)] the leading causes. CONCLUSIONS: Coagulation disorders are frequent in COVID-19 ARDS patients receiving ECMO. Bleeding events contribute substantially to mortality in this cohort. However, this risk may be lower than previously reported in single-nation studies or early case reports. Trial registration ACTRN12620000421932 ( https://covid19.cochrane.org/studies/crs-13513201 ).

Early myocardial injury in children on doxorubicin for cancer chemotherapy: a cross-sectional study in a tertiary referral centre in Kenya.

INTRODUCTION: Use of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death. OBJECTIVE: To investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy. METHODS: Design: A cross-sectional study. SETTING AND SUBJECTS: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH). INTERVENTIONS AND OUTCOMES: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO. RESULTS: One hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18-97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23-7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury. CONCLUSION: When compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.

Comparative analysis of novel esophageal pressure monitoring catheters versus commercially available alternatives in a biomechanical model of the thoracic cavity.

Transpulmonary pressure can be estimated using esophageal balloon (EB) catheters, which come in a variety of manufacturing configurations. We assessed the performance of novel polyurethane EB designs, Aspisafe NG and NG+, against existing alternatives. We created a biomechanical model of the chest cavity using a plastic chamber and an ex-vivo porcine esophagus. The chamber was pressurized (- 20 and + 20 cmH2O) to simulate pleural pressures. We conducted tests with various EB inflation volumes and measured transesophageal pressure (TEP). TEP measurement was defined as accurate when the difference between pressure within the EB and chamber was 0 ± 1 cmH2O. We computed the minimal (Vaccuracy-min) and maximal (Vaccuracy-max) EB inflation volumes of accuracy. Inflation volumes were further validated using a surrogate method derived by the clinically validated positive pressure occlusion test (PPOT). When the esophageal balloons were filled with inflation volumes within the range provided by the manufacturers, the accuracy of TEP measurements was marginal. Our tests found median Vaccuracy-min across EB of 0.00-0.50 mL (p = 0.130), whereas Vaccuracy-max ranged 0.50-2.25 mL (p = 0.002). Post PPOT validation, median TEP was - 0.4 cmH2O (- 1.5 to 0.3) (p < 0.001 among catheters). The Aspisafe NG and NG+ were accurate in 81.7% and 77.8% of the measurements, respectively. We characterized two new EBs, which demonstrated good benchtop accuracy in TEP measurements. However, accuracy was notably influenced by the precise selection of EB inflation volumes.

Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after coronavirus disease 2019 hospitalization: an international multi-centre prospective observational study.

Although it is known that coronavirus disease 2019 can present with a range of neurological manifestations and in-hospital complications, sparse data exist on whether these initial neurological symptoms of coronavirus disease 2019 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; PANSC) and whether female versus male sex impacts symptom resolution. In this international, multi-centre, prospective, observational study across 407 sites from 15 countries (30 January 2020 to 30 April 2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time. PANSC symptoms included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia and muscle ache/joint pain, on which information was collected at index hospitalization and during follow-up assessments. The analysis considered a time to the resolution of individual and all neurological symptoms. The resulting times were modelled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. The model results were summarized as cumulative probability functions and age-adjusted and sex-adjusted median times to resolution. We included 6862 hospitalized adults with coronavirus disease 2019, who had follow-up assessments. The median age of the participants was 57 years (39.2% females). Males and females had similar baseline characteristics, except that more males (versus females) were admitted to the intensive care unit (30.5 versus 20.3%) and received mechanical ventilation (17.2 versus 11.8%). Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median = 102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. The reported prevalence in females was generally higher (versus males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, although fatigue, altered consciousness and myalgia remained unresolved in >10% of the cohort. Females had a longer time to the resolution (5.2 versus 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom. In the multivariable analysis, males were associated with a shorter time to the resolution of symptoms (hazard ratio = 1.53; 95% confidence interval = 1.39-1.69). Intensive care unit admission was associated with a longer time to the resolution of symptoms (hazard ratio = 0.68; 95% confidence interval = 0.60-0.77). Post-discharge stroke was uncommon (0.3% in females and 0.5% in males). Despite the methodological challenges involved in the collection of survey data, this international multi-centre prospective cohort study demonstrated that PANSC following index hospitalization was high. Symptom prevalence was higher and took longer to resolve in females than in males. This supported the fact that while males were sicker during acute illness, females were disproportionately affected by PANSC.

Variability of oxygen requirements in critically ill COVID-19 patients.

Background: The global scarcity of medical oxygen has proven to be catastrophic during the surges in COVID-19 cases over the past two years, with the heaviest burden felt in low- and middle-income countries. Despite its criticality, data and analyses of oxygen consumption, even for typical clinical cases, are missing. Consequently, planning oxygen needs, particularly with variable surges in COVID-19 cases, has presented a substantial challenge to policymakers and hospital decision-makers. Methods: We performed a sub-analysis of the COVID-19 Critical Care Consortium database assessing the oxygen consumption requirements of COVID-19 patients admitted to intensive care units between February 2020 and October 2021. We calculated descriptive statistics for oxygen flow-rates, stratified by oxygen supplementation method, and developed a multi-state model for estimating the frequency, therapy duration, probability of transition, and number of oxygen therapy modes per patient. Results: Overall, 12 429 patients from 35 countries received oxygen support on at least one day of their hospitalisation. Of the patients with measurable flow rates, 6142 received invasive mechanical ventilation, 838 received high-flow nasal oxygen, and 257 received both modalities. The median flow rate for mechanical ventilation was 3.2 L per minute (interquartile range (IQR) = 2.0-4.9), with a median duration of 12 days (IQR = 6-24), while the median flow rate for high-flow nasal cannula was 40 L per minute (IQR = 15-55), with a median duration of three days (IQR = 2-6). Conclusions: Oxygen consumption among critical COVID-19 patients varies by mode of delivery (invasive ventilation vs high-flow nasal cannula), across patients, and over treatment duration. Therefore, it is essential that health facilities routinely monitor oxygen utilization to better inform oxygen delivery system design and regular supply planning. Registration: ClinicalTrials.gov: CTG2021-01 ACTRN12620000421932.

An appraisal of lung computer tomography in very early anti-inflammatory treatment of two different ovine ARDS phenotypes.

Mortality and morbidity of Acute Respiratory Distress Syndrome (ARDS) are largely unaltered. A possible new approach to treatment of ARDS is offered by the discovery of inflammatory subphenotypes. In an ovine model of ARDS phenotypes, matching key features of the human subphenotypes, we provide an imaging characterization using computer tomography (CT). Nine animals were randomized into (a) OA (oleic acid, hypoinflammatory; n = 5) and (b) OA-LPS (oleic acid and lipopolysaccharides, hyperinflammatory; n = 4). 48 h after ARDS induction and anti-inflammatory treatment, CT scans were performed at high (H) and then low (L) airway pressure. After CT, the animals were euthanized and lung tissue was collected. OA-LPS showed a higher air fraction and OA a higher tissue fraction, resulting in more normally aerated lungs in OA-LPS in contrast to more non-aerated lung in OA. The change in lung and air volume between H and L was more accentuated in OA-LPS, indicating a higher recruitment potential. Strain was higher in OA, indicating a higher level of lung damage, while the amount of lung edema and histological lung injury were largely comparable. Anti-inflammatory treatment might be beneficial in terms of overall ventilated lung portion and recruitment potential, especially in the OA-LPS group.

Effects of transfusing older red blood cells and platelets on obstetric patient outcomes: A retrospective cohort study.

OBJECTIVE: To investigate associations between transfusion of blood products close to the end of shelf-life and clinical outcomes in obstetric inpatients. METHODS: Mortality and morbidity were compared in patients transfused exclusively with red blood cells (RBC) stored for less than 21 days (fresh) versus RBC stored for 35 days or longer (old), and platelets (PLT) stored for 3 days or fewer (fresh) versus 4 days or longer (old) in Queensland, Australia from 2007 to 2013. Multivariable models were used to examine associations between these groups of blood products and clinical end points. RESULTS: There were 3371 patients who received RBC and 280 patients who received PLT of the eligible storage durations. Patients transfused with old RBC received fewer transfusions (2.7 ± 1.8 vs. 2.3 ± 1.0 units; P < 0.001). However, a higher rate of single-unit transfusions was also seen in those patients who exclusively received old RBC (252 [9.3%] vs. 92 [13.7%]; P = 0.003). Comparison of fresh vs. old blood products revealed no differences in the quantities of transfused RBC (9.5 ± 5.9 vs. 9.1 ± 5.2 units; P = 0.680) or PLT (1.5 ± 0.8 vs. 1.4 ± 1.1 units; P = 0.301) as well as the length of hospital stay for RBC (3 [2-5] vs. 3 [2-5] days; P = 0.124) or PLT (5 [4-8] vs. 6 [4-9] days; P = 0.120). CONCLUSION: Transfusing exclusively older RBC or PLT was not associated with increased morbidity or mortality.

A novel speckle-tracking echocardiography parameter assessing left ventricular afterload.

BACKGROUND: Left ventricular stroke work index (LVSWI) and afterload-related cardiac performance (ACP) consider left ventricular (LV) afterload and could be better prognosticators in septic cardiomyopathy. However, their invasive nature prevents their routine clinical applications. This study aimed to investigate (1) whether a proposed speckle-tracking echocardiography parameter, Pressure-Strain Product (PSP), can non-invasively predict catheter-based LVSWI, ACP and serum lactate in an ovine model of septic cardiomyopathy; and (2) whether PSP can distinguish the sub-phenotypes of acute respiratory distress syndrome (ARDS) with or without sepsis-like conditions. METHODS: Sixteen sheep with ARDS were randomly assigned to either (1) sepsis-like (n = 8) or (2) non-sepsis-like (n = 8) group. Each ARDS and sepsis-like condition was induced by intravenous infusion of oleic acid and lipopolysaccharide, respectively. Pulmonary artery catheter-based LVSWI (the product of stroke work index, mean arterial pressure and .0136), ACP (the percentage of cardiac output measured to cardiac output predicted as normal) and serum lactate were measured simultaneously with transthoracic echocardiography. Two PSP indices were calculated by multiplying the mean arterial blood pressure and either global circumferential strain (PSPcirc) or radial strain (PSPrad). RESULTS: PSPcirc showed a significant correlation with LVSWI (r2 = .66, p < .001) and ACP (r2 = .82, p < .001) in the sepsis-like group. Although PSP could not distinguish subphenotypes, PSPcirc predicted LVSWI (AUC .86) and ACP (AUC .88), and PSPrad predicted serum lactate (AUC .75) better than LV ejection fraction, global circumferential and radial strain. CONCLUSIONS: A novel PSP has the potential to non-invasively predict catheter-based LVSWI and ACP, and was associated with serum lactate in septic cardiomyopathy.

Race and ethnicity in the COVID-19 Critical Care Consortium: demographics, treatments, and outcomes, an international observational registry study.

BACKGROUND: Improving access to healthcare for ethnic minorities is a public health priority in many countries, yet little is known about how to incorporate information on race, ethnicity, and related social determinants of health into large international studies. Most studies of differences in treatments and outcomes of COVID-19 associated with race and ethnicity are from single cities or countries. METHODS: We present the breadth of race and ethnicity reported for patients in the COVID-19 Critical Care Consortium, an international observational cohort study from 380 sites across 32 countries. Patients from the United States, Australia, and South Africa were the focus of an analysis of treatments and in-hospital mortality stratified by race and ethnicity. Inclusion criteria were admission to intensive care for acute COVID-19 between January 14th, 2020, and February 15, 2022. Measurements included demographics, comorbidities, disease severity scores, treatments for organ failure, and in-hospital mortality. RESULTS: Seven thousand three hundred ninety-four adults met the inclusion criteria. There was a wide variety of race and ethnicity designations. In the US, American Indian or Alaska Natives frequently received dialysis and mechanical ventilation and had the highest mortality. In Australia, organ failure scores were highest for Aboriginal/First Nations persons. The South Africa cohort ethnicities were predominantly Black African (50%) and Coloured* (28%). All patients in the South Africa cohort required mechanical ventilation. Mortality was highest for South Africa (68%), lowest for Australia (15%), and 30% in the US. CONCLUSIONS: Disease severity was higher for Indigenous ethnicity groups in the US and Australia than for other ethnicities. Race and ethnicity groups with longstanding healthcare disparities were found to have high acuity from COVID-19 and high mortality. Because there is no global system of race and ethnicity classification, researchers designing case report forms for international studies should consider including related information, such as socioeconomic status or migration background. *Note: "Coloured" is an official, contemporary government census category of South Africa and is a term of self-identification of race and ethnicity of many citizens of South Africa.

Resuscitation-associated endotheliopathy (RAsE): a conceptual framework based on a systematic review and meta-analysis.

INTRODUCTION: Shock-induced endotheliopathy (SHINE), defined as a profound sympathoadrenal hyperactivation in shock states leading to endothelial activation, glycocalyx damage, and eventual compromise of end-organ perfusion, was first described in 2017. The aggressive resuscitation therapies utilised in treating shock states could potentially lead to further worsening endothelial activation and end-organ dysfunction. OBJECTIVE: This study aimed to systematically review the literature on resuscitation-associated and resuscitation-induced endotheliopathy. METHODS: A predetermined structured search of literature published over an 11-year and 6-month period (1 January 2011 to 31 July 2023) was performed in two indexed databases (PubMed/MEDLINE and Embase) per PRISMA guidelines. Inclusion was restricted to original studies published in English (or with English translation) reporting on endothelial dysfunction in critically ill human subjects undergoing resuscitation interventions. Reviews or studies conducted in animals were excluded. Qualitative synthesis of studies meeting the inclusion criteria was performed. Studies reporting comparable biomarkers of endothelial dysfunction post-resuscitation were included in the quantitative meta-analysis. RESULTS: Thirty-two studies met the inclusion criteria and were included in the final qualitative synthesis. Most of these studies (47%) reported on a combination of mediators released from endothelial cells and biomarkers of glycocalyx breakdown, while only 22% reported on microvascular flow changes. Only ten individual studies were included in the quantitative meta-analysis based on the comparability of the parameters assessed. Eight studies measured syndecan-1, with a heterogeneity index, I2 = 75.85% (pooled effect size, mean = 0.27; 95% CI - 0.07 to 0.60; p = 0.12). Thrombomodulin was measured in four comparable studies (I2 = 78.93%; mean = 0.41; 95% CI - 0.10 to 0.92; p = 0.12). Three studies measured E-selectin (I2 = 50.29%; mean = - 0.15; 95% CI - 0.64 to 0.33; p = 0.53), and only two were comparable for the microvascular flow index, MFI (I2 = 0%; mean = - 0.80; 95% CI - 1.35 to - 0.26; p < 0.01). CONCLUSION: Resuscitation-associated endotheliopathy (RAsE) refers to worsening endothelial dysfunction resulting from acute resuscitative therapies administered in shock states. In the included studies, syndecan-1 had the highest frequency of assessment in the post-resuscitation period, and changes in concentrations showed a statistically significant effect of the resuscitation. There are inadequate data available in this area, and further research and standardisation of the ideal assessment and panel of biomarkers are urgently needed.

Application of anti-inflammatory treatment in two different ovine Acute Respiratory Distress Syndrome injury models: a preclinical randomized intervention study.

Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO2/FiO2 ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO2/FiO2 ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.

Characteristics and outcomes of patients with severe COVID-19 in Indonesia: Lessons from the first wave.

BACKGROUND: Indonesia's national response to COVID-19 evolved rapidly throughout 2020. Understanding pandemic response and outcomes is crucial for better mitigation strategies ahead. This study describes the characteristics and outcomes of patients admitted to ICU during the early stages of the pandemic. METHODS: This is a multi-centre prospective observational study including patients from twelve collaborating hospitals in Indonesia. All patients were clinically suspected or laboratory-confirmed COVID-19 cases admitted to ICU between January 2020 and March 2021. The primary outcome was monthly ICU mortality. Descriptive statistics of patient characteristics and treatment were generated as secondary outcomes. RESULTS: From 559 subjects, the overall mortality was 68% and decreased over the study period, while the mortality of patients that received mechanical ventilation was 92%, consistently high over the study period. Fatal cases showed 2- and 4-day delays from symptoms onset to hospital admissions and ICU admissions, respectively. Evidence-backed approaches which could influence patient outcome, such as extracorporeal membrane oxygenation, prone positioning, renal replacement therapy, and neuromuscular blockade were scarcely administered. CONCLUSIONS: The mortality rate of COVID-19 patients in Indonesia was extremely high during the first major outbreak of disease, particularly in those mechanically ventilated. Delayed admission and unavailability of evidence-based approaches due to high burden on health facility during COVID-19 crisis could be addressed by efficient public health measures and enhancing health infrastructure to improve the future pandemic response.

The effects of nitric oxide on coagulation and inflammation in ex vivo models of extracorporeal membrane oxygenation and cardiopulmonary bypass.

BACKGROUND: Extracorporeal life support (ECLS) has extensive applications in managing patients with acute cardiac and pulmonary failure. Two primary modalities of ECLS, cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), include several similarities in their composition, complications, and patient outcomes. Both CPB and ECMO pose a high risk of thrombus formation and platelet activation due to the large surface area of the devices and bleeding due to system anticoagulation. Therefore, novel methods of anticoagulation are needed to reduce the morbidity and mortality associated with extracorporeal support. Nitric oxide (NO) has potent antiplatelet properties and presents a promising alternative or addition to anticoagulation with heparin during extracorporeal support. METHODS: We developed two ex vivo models of CPB and ECMO to investigate NO effects on anticoagulation and inflammation in these systems. RESULTS: Sole addition of NO as an anticoagulant was not successful in preventing thrombus formation in the ex vivo setups, therefore a combination of low-level heparin with NO was used. Antiplatelet effects were observed in the ex vivo ECMO model when NO was delivered at 80 ppm. Platelet count was preserved after 480 min when NO was delivered at 30 ppm. CONCLUSION: Combined delivery of NO and heparin did not improve haemocompatibility in either ex vivo model of CPB and ECMO. Anti-inflammatory effects of NO in ECMO systems have to be evaluated further.

Current animal models of extracorporeal cardiopulmonary resuscitation: A scoping review.

Aim: Animal models of Extracorporeal Cardiopulmonary Resuscitation (ECPR) focusing on neurological outcomes are required to further the development of this potentially life-saving technology. The aim of this review is to summarize current animal models of ECPR. Methods: A comprehensive database search of PubMed, EMBASE, and Web of Science was undertaken. Full-text publications describing animal models of ECPR between January 1, 2000, and June 30, 2022, were identified and included in the review. Data describing the conduct of the animal models of ECPR, measured variables, and outcomes were extracted according to pre-defined definitions. Results: The search strategy yielded 805 unique reports of which 37 studies were included in the final analysis. Most studies (95%) described using a pig model of ECPR with the remainder (5%) describing a rat model. The most common method for induction of cardiac arrest was a fatal ventricular arrhythmia through electrical stimulation (70%). 10 studies reported neurological assessment of animals using physical examination, serum biomarkers, or electrophysiological findings, however, only two studies described a multimodal assessment. No studies reported the use of brain imaging as part of the neurological assessment. Return of spontaneous circulation was the most reported primary outcome, and no studies described the neurological status of the animal as the primary outcome. Conclusion: Current animal models of ECPR do not describe clinically relevant neurological outcomes after cardiac arrest. Further work is needed to develop models that more accurately mimic clinical scenarios and can test innovations that can be translated to the application of ECPR in clinical medicine.