Plasma dynamics of neutrophil extracellular traps and cell-free DNA in septic and non-septic vasoplegic shock: a prospective comparative observational cohort study.

BACKGROUND: The association between neutrophil extracellular traps (NETs) and the requirement for vasopressor and inotropic support in vasoplegic shock is unclear. This study aimed to investigate the dynamics of plasma levels of NETs and cell-free DNA (cfDNA) up to 48 hours after the admission to the intensive care unit (ICU) for management of vasoplegic shock of infectious (SEPSIS) or non-infectious (following cardiac surgery, CARDIAC) origin. METHODS: Prospective, observational study of NETs and cfDNA plasma levels at 0H (admission) and then at 12H, 24H and 48H in SEPSIS and CARDIAC patients. The Vasopressor Inotropic Score (VIS), the Sequential Organ Failure Assessment (SOFA) score and time spent with invasive ventilation, in ICU and in hospital were recorded. Associations between NETs/cfDNA and VIS and SOFA were analysed by Spearman's correlation (rho), and between NETs/cfDNA and ventilation/ICU/hospitalisation times by generalised linear regression. RESULTS: Both NETs and cfDNA remained elevated over 48 hours in SEPSIS (n = 46) and CARDIAC (n = 30) patients, with time weighted average concentrations greatest in SEPSIS (NETs median difference 0.06 [0.02-0.11], p = 0.005; cfDNA median difference 0.48 [0.20-1.02], p < 0.001). The VIS correlated to NETs (rho = 0.3-0.60 in SEPSIS, p < 0.01, rho = 0.36-0.57 in CARDIAC, p ≤ 0.01) and cfDNA (rho = 0.40-0.56 in SEPSIS, p < 0.01, rho = 0.38-0.47 in CARDIAC, p < 0.05). NETs correlated with SOFA. Neither NETs nor cfDNA were independently associated with ventilator/ICU/hospitalisation times. CONCLUSION: Plasma levels of NETs and cfDNA correlated with the dose of vasopressors and inotropes administered over 48 hours in patients with vasoplegic shock from sepsis or following cardiac surgery. NETs levels also correlated with organ dysfunction. These findings suggest that similar mechanisms involving release of NETs are involved in the pathophysiology of vasoplegic shock irrespective of an infectious or non-infectious etiology.

The impact of frailty and rapid response team activation on patients admitted to the intensive care unit: A case-control matched, observational, single-centre cohort study.

BACKGROUND: Frailty is a multi-dimensional syndrome associated with mortality and adverse outcomes in patients admitted to the intensive care unit (ICU). Further investigation is warranted to explore the interplay among factors such as frailty, clinical deterioration triggering a medical emergency team (MET) review, and outcomes following admission to the ICU. METHODS: Single-centre, retrospective observational case-control study of adult patients (>18 years) admitted to a medical-surgical ICU with (cases) or without (controls) a preceding MET review between 4 h and 14 days prior. Matching was performed for age, ICU admission diagnosis, Acute Physiology and Chronic Health Evaluation III (APACHE III) score and the 8-point Clinical Frailty Scale (CFS). Cox proportional hazard regression modelling was performed to determine associations with 30-day mortality after admission to ICU. RESULTS: A total of 2314 matched admissions were analysed. Compared to non-frail patients (CFS 1-4), mortality was higher in all frail patients (CFS 5-8), at 31% vs. 13%, and in frail patients admitted after MET review at 33%. After adjusting for age, APACHE, antecedent MET review and CFS in the Cox regression, mortality hazard ratio increased by 26% per CFS point and by 3% per APACHE III point, while a MET review was not an independent predictor. Limitations of medical treatment occurred in 30% of frail patients, either with or without a MET antecedent, and this was five times higher compared to non-frail patients. CONCLUSION: Frail patients admitted to ICU have a high short-term mortality. An antecedent MET event was associated with increased mortality but did not independently predict short-term survival when adjusting for confounding factors. The intrinsic significance of frailty should be primarily considered during MET review of frail patients. This study suggests that routine frailty assessment of hospitalised patients would be helpful to set goals of care when admission to ICU could be considered.

Volume responsiveness revisited: an observational multicenter study of continuous versus binary outcomes combining echocardiography and venous return physiology.

Echocardiography can assess cardiac preload when fluid administration is used to treat acute circulatory failure. Changes in stroke volume (SV) are inherently a continuous phenomenon relating to the pressure gradient for venous return (VRdP). However, most clinical studies have applied a binary definition based on a fractional change in SV. This study tested the hypothesis that calculating the analog mean systemic filling pressure (Pmsa) and VRdP would enhance echocardiography to describe SV responses to a preload challenge. We investigated 540 (379 males) patients during a standardized passive leg raising (PLR) maneuver. Patients were further categorized by the presence of impaired right ventricular function (impRV) or increased intra-abdominal hypertension (IAH). Multivariable linear regression identified VRdP (partial r = -0.26, P < 0.001), ventilatory-induced variations in superior vena cava diameter (partial r = 0.43, P < 0.001), and left ventricular outflow tract maximum-Doppler velocity (partial r = 0.13, P < 0.001) as independent variables associated with SV changes. The model explained 38% (P < 0.001) of the SV change in the whole cohort and 64% (P < 0.001) when excluding patients with impRV or IAH. The correlation between Pmsa or VRdP and SV changes lost statistical significance with increasing impRV or IAH. A binary definition of volume responsiveness (>10% increase in SV) generated an area under the curve of 0.79 (P < 0.001) in logistic regression but failed to identify Pmsa or VRdP as independent variables and overlooked the confounding influence of impRV and IAH. In conclusion, venous return physiology may enhance echocardiographic assessments of volume responsiveness, which should be based on continuous changes in stroke volume.NEW & NOTEWORTHY The analog mean systemic filling pressure and the pressure gradient for venous return combined with echocardiography predict continuous changes in stroke volume following a passive leg raising maneuver. The confounding effects of impaired right ventricular function and increased intra-abdominal pressure can be identified. Using a binary cutoff for the fractional change in stroke volume, common in previous clinical research, fails to identify the importance of variables relevant to venous return physiology and confounding conditions.

Capnodynamic monitoring of lung volume and blood flow in response to increased positive end-expiratory pressure in moderate to severe COVID-19 pneumonia: an observational study.

BACKGROUND: The optimal level of positive end-expiratory pressure (PEEP) during mechanical ventilation for COVID-19 pneumonia remains debated and should ideally be guided by responses in both lung volume and perfusion. Capnodynamic monitoring allows both end-expiratory lung volume ([Formula: see text]) and effective pulmonary blood flow (EPBF) to be determined at the bedside with ongoing ventilation. METHODS: Patients with COVID-19-related moderate to severe respiratory failure underwent capnodynamic monitoring of [Formula: see text] and EPBF during a step increase in PEEP by 50% above the baseline (PEEPlow to PEEPhigh). The primary outcome was a > 20 mm Hg increase in arterial oxygen tension to inspired fraction of oxygen (P/F) ratio to define responders versus non-responders. Secondary outcomes included changes in physiological dead space and correlations with independently determined recruited lung volume and the recruitment-to-inflation ratio at an instantaneous, single breath decrease in PEEP. Mixed factor ANOVA for group mean differences and correlations by Pearson's correlation coefficient are reported including their 95% confidence intervals. RESULTS: Of 27 patients studied, 15 responders increased the P/F ratio by 55 [24-86] mm Hg compared to 12 non-responders (p < 0.01) as PEEPlow (11 ± 2.7 cm H2O) was increased to PEEPhigh (18 ± 3.0 cm H2O). The [Formula: see text] was 461 [82-839] ml less in responders at PEEPlow (p = 0.02) but not statistically different between groups at PEEPhigh. Responders increased both [Formula: see text] and EPBF at PEEPhigh (r = 0.56 [0.18-0.83], p = 0.03). In contrast, non-responders demonstrated a negative correlation (r = - 0.65 [- 0.12 to - 0.89], p = 0.02) with increased lung volume associated with decreased pulmonary perfusion. Decreased (- 0.06 [- 0.02 to - 0.09] %, p < 0.01) dead space was observed in responders. The change in [Formula: see text] correlated with both the recruited lung volume (r = 0.85 [0.69-0.93], p < 0.01) and the recruitment-to-inflation ratio (r = 0.87 [0.74-0.94], p < 0.01). CONCLUSIONS: In mechanically ventilated patients with moderate to severe COVID-19 respiratory failure, improved oxygenation in response to increased PEEP was associated with increased end-expiratory lung volume and pulmonary perfusion. The change in end-expiratory lung volume was positively correlated with the lung volume recruited and the recruitment-to-inflation ratio. This study demonstrates the feasibility of capnodynamic monitoring to assess physiological responses to PEEP at the bedside to facilitate an individualised setting of PEEP. TRIAL REGISTRATION: NCT05082168 (18th October 2021).

Interpreting the results of clinical trials, embracing uncertainty: A Bayesian approach.

Most clinical trials use null hypothesis significance testing with frequentist statistical inference to report P values and confidence intervals for effect estimates. This method leads to a dichotomisation of results as 'significant' or 'non-significant'. A more nuanced interpretation may often be considered and in particular when the majority of the confidence interval for the effect estimate suggests benefit or harm. In contrast to the frequentist dichotomised approach based on a P value, the application of Bayesian statistics allocates credibility to a continuous spectrum of possibilities and for this reason a Bayesian approach to inference is often warranted as it will incorporate uncertainty when updating our current belief with information from a new trial. The use of Bayesian statistics is introduced in this paper for a hypothetical sepsis trial with worked examples in the R language for Statistical Computing environment and the open-source statistical software JASP. It is hoped that this general introduction to Bayesian inference stimulates some interest and confidence among clinicians to consider applying these methods to the interpretation of new evidence for interventions relevant to anaesthesia and intensive care medicine.

Volume status and volume responsiveness in postoperative cardiac surgical patients: An observational, multicentre cohort study.

BACKGROUND: The best strategy to identify patients in whom fluid loading increases cardiac output (CO) following cardiac surgery remains debated. This study examined the utility of a calculated mean systemic filling pressure analogue (Pmsa ) and derived variables to explain the response to a fluid bolus. METHODS: The Pmsa was calculated using retrospective, observational cohort data in the early postoperative period between admission to the intensive care unit and extubation within 6 hours. The venous return pressure gradient (VRdP) was calculated as Pmsa  - central venous pressure. Concurrent changes induced by a fluid bolus in the ratio of the VRdP over Pmsa , the volume efficiency (Evol ), were studied to assess fluid responsiveness. Changes between Pmsa and derived variables and CO were analysed by Wilcoxon rank-sum test, hierarchial clustering and multiple linear regression. RESULTS: Data were analysed for 235 patients who received 489 fluid boluses. The Pmsa increased with consecutive fluid boluses (median difference [range] 1.3 [0.5-2.4] mm Hg, P = .03) with a corresponding increase in VRdP (median difference 0.4 [0.2-0.6] mm Hg, P = .04). Hierarchical cluster analysis only identified Evol and the change in CO within one cluster. The multiple linear regression between Pmsa and its derived variables and the change in CO (overall r2  = .48, P < .001) demonstrated the best partial regression between the continuous change in CO and the concurrent Evol (r = .55, P < .001). CONCLUSION: The mean systemic filling Pmsa enabled a comprehensive interpretation of fluid responsiveness with volume efficiency useful to explain the change in CO as a continuous phenomenon.

Associations between mean systemic filling pressure and acute kidney injury: An observational cohort study following cardiac surgery.

BACKGROUND: Venous congestion has been implied in cardiac surgery-associated acute kidney injury (CSA-AKI). The mean systemic filling pressure may provide a physiologically more accurate estimate of renal venous pressure and renal perfusion pressure but its association with CSA-AKI has not been reported. METHODS: Patients admitted to ICU following cardiac surgery without pre-operative renal dysfunction were included with monitoring of mean arterial pressure (MAP) and central venous pressure (CVP) and cardiac output (CO) to calculate the mean systemic filling pressure analogue (Pmsa ). The AKI-KDIGO guidelines were used to define CSA-AKI. Logistic regression models including CO, heart rate, MAP, CVP and Pmsa were used to ascertain the association with CSA-AKI and reported by odds ratio (OR) with 95% confidence interval (95%CI) and area under the curve (AUROC). RESULTS: One hundred and thirty patients (out of 221 screened) were included of whom 66 (51%) developed CSA-AKI. Patients with CSA-AKI were older, with greater weight and increased stay in ICU while the proportion of comorbidities, type of surgical procedures, APACHE III scores and fluid volumes administered were similar to patients without AKI. The Pmsa , but not CVP, was associated with CSA-AKI (OR 1.2 95%CI [1.16-1.25]). Renal perfusion pressure was associated with CSA-AKI estimated as MAP-Pmsa (OR 0.81 [0.76-0.86]) and MAP-CVP (OR 0.89 [0.85-0.93]) with the former generating a higher AUROC (median difference 0.10 [0.07-0.12], P < .001) in the regression model. CONCLUSIONS: The Pmsa in post-operative cardiac surgery patients was associated with the development of CSA-AKI also when incorporated into estimates of renal perfusion pressure.

Comparison of echocardiographic and invasive measures of volaemia and cardiac performance in critically ill patients.

Echocardiographic measurements are used in critical care to evaluate volume status and cardiac performance. Mean systemic filling pressure and global heart efficiency measures intravascular volume and global heart function. This prospective study conducted in fifty haemodynamically stabilized, mechanically ventilated patients investigated relationships between static echocardiographic variables and estimates of global heart efficiency and mean systemic filling pressure. Results of univariate analysis demonstrated weak correlations between left ventricular end-diastolic volume index (r = 0.27, p = 0.04), right atrial volume index (rho = 0.31, p = 0.03) and analogue mean systemic filling pressure; moderate correlations between left ventricular ejection fraction (r = 0.31, p = 0.03), left ventricular global longitudinal strain (r = 0.36, p = 0.04), tricuspid annular plane systolic excursion (rho = 0.37, p = 0.01) and global heart efficiency. No significant correlations were demonstrated by multiple regression. Mean systemic filling pressure calculated with cardiac output measured by echocardiography demonstrated good agreement and correlation with invasive techniques (bias 0.52 ± 1.7 mmHg, limits of agreement -2.9 to 3.9 mmHg, r = 0.9, p < 0.001). Static echocardiographic variables did not reliably reflect the volume state as defined by estimates of mean systemic filling pressure. The agreement between static echocardiographic variables of cardiac performance and global heart efficiency lacked robustness. Echocardiographic measurements of cardiac output can be reliably used in calculation of mean systemic filling pressure.

Assessment of volume status and volume responsiveness in the ICU: Protocol for an observational, multicentre cohort study.

BACKGROUND: Expansion of the intravascular compartment is common to treat haemodynamic instability in ICU patients. The most useful and accurate variables to guide and evaluate a fluid challenge remain debated and incompletely investigated resulting in significant variability in practice. The analogue mean systemic pressure has been reported as a measure of the intravascular volume state. METHODS: This is a protocol and statistical analysis plan for a review of the application of an analogue of the mean systemic pressure and the use of derived variables to assess the volume state and volume responsiveness. A pulmonary artery catheter was used in 286 postoperative cardiac surgical patients to monitor cardiac output before and after a fluid bolus in addition to arterial and central venous pressures. With otherwise similar monitoring, echocardiography was used in 540 general ICU patients to determine cardiac outputs and indices related to intravascular filling. The responses to a fluid bolus or the passive leg raising manoeuvre will be investigated using continuous and dichotomous definitions of volume responsiveness. The results will be stratified according to the method of monitoring cardiac output. CONCLUSIONS: This study investigating 2 cohorts that encompass a wide variety of reasons for haemodynamic instability will illustrate the applicability of the analogue mean systemic pressure and derived variables to assess the volume state and responsiveness. The results may guide the rationale and design of interventional studies.

Delayed medical emergency team calls and associated outcomes.

OBJECTIVE: To determine whether there was an association between delayed medical emergency team calls and mortality after a medical emergency team review. DESIGN: This was a prospective observational study. SETTING: A university-affiliated tertiary referral hospital in Porto Alegre, Brazil. PATIENTS: All patients were reviewed by the medical emergency team from July 2008 to December 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,481 calls for 1,148 patients. Delayed medical emergency team calls occurred for 246 patients (21.4%). The criterion associated with delay was typically the same criterion for the subsequent medical emergency team call. Physicians had a greater prevalence of delayed medical emergency team calls (110 of 246 [44.7%]) than timely medical emergency team calls (267 of 902 [29.6%]; p < 0.001). The mortality at 30 days after medical emergency team review was higher among patients with delayed medical emergency team activation (152 [61.8%]) than patients receiving timely medical emergency team activation (378 [41.9%]; p < 0.001). In a multivariate analysis, delayed medical emergency team calls remained significantly associated with higher mortality. CONCLUSIONS: Delayed medical emergency team calls are common and are independently associated with higher mortality. This result reaffirms the concept and need for a rapid response system.

Clinical characteristics and evolution of non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis.

OBJECTIVE: To investigate the characteristics of and risk factors for mortality among non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis. METHODS: This was a two-year, retrospective cohort study of patients with an in-hospital diagnosis of tuberculosis. The predictive factors for mortality were evaluated. RESULTS: During the study period, 337 hospitalized patients were diagnosed with tuberculosis, and 61 of those patients presented with immunosuppression that was unrelated to HIV infection. Extrapulmonary tuberculosis was found in 47.5% of cases. In the latter group, the in-hospital mortality rate was 21.3%, and the mortality rate after discharge was 18.8%. One-year survival was significantly higher among the immunocompetent patients than among the HIV patients (p = 0.008) and the non-HIV-infected immunocompromised patients (p = 0.015), although there was no such difference between the two latter groups (p = 0.848). Among the non-HIV-infected immunocompromised patients, the only factor statistically associated with mortality was the need for mechanical ventilation. Among the patients over 60 years of age, fibrosis/atelectasis on chest X-rays and dyspnea were more common, whereas fever and consolidations were less common. Fever was also less common among the patients with neoplasms. The time from admission to the initiation of treatment was significant longer in patients over 60 years of age, as well as in those with diabetes and those with end-stage renal disease. Weight loss was least common in patients with diabetes and in those using corticosteroids. CONCLUSIONS: The lower prevalence of classic symptoms, the occurrence of extrapulmonary tuberculosis, the delayed initiation of treatment, and the high mortality rate reflect the diagnostic and therapeutic challenges of tuberculosis in non-HIV-infected immunocompromised patients.

Características clínicas e evolução de pacientes imunocomprometidos não HIV com diagnóstico intra-hospitalar de tuberculose / Clinical characteristics and evolution of non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis

OBJETIVO: Investigar as características de pacientes imunocomprometidos não HIV com diagnóstico intra-hospitalar de tuberculose e determinar os fatores de risco para mortalidade. MÉTODOS: Durante um período de dois anos, foi realizado um estudo de coorte retrospectivo que incluiu os pacientes com diagnóstico de tuberculose após a internação. Os fatores preditores de mortalidade foram coletados. RESULTADOS: Durante o período do estudo, 337 pacientes foram internados e diagnosticados com TB, e desses, 61 apresentavam imunossupressão não decorrente da infecção pelo HIV. A tuberculose extrapulmonar estava presente em 47,5 por cento dos casos. Nesse grupo, a taxa de mortalidade intra-hospitalar foi de 21,3 por cento, e a mortalidade após a alta foi de 18,8 por cento. Os pacientes imunocompetentes tiveram sobrevida em um ano maior que os pacientes com HIV (p = 0,008) e que os imunocomprometidos não HIV (p = 0,015), mas não houve diferença na sobrevida entre esses dois últimos grupos (p = 0,848). Entre os pacientes imunocomprometidos não HIV, o único fator estatisticamente associado à mortalidade foi a necessidade de ventilação mecânica. Entre os maiores de 60 anos, dispneia e presença de fibrose/atelectasias na radiografia de tórax foram mais comuns, enquanto febre e consolidações foram menos frequentes nesse grupo. A febre também foi um sintoma encontrado menos comumente nos pacientes com neoplasias. O tempo até o início do tratamento foi significativamente maior nos pacientes maiores de 60 anos, nos diabéticos e nos pacientes renais crônicos. Nos pacientes diabéticos e naqueles usuários de corticosteroides, o emagrecimento foi um sintoma menos frequentemente relatado. CONCLUSÕES: A menor prevalência de sintomas clássicos, a ocorrência de tuberculose extrapulmonar, o atraso no início do tratamento e a alta taxa de mortalidade refletem o desafio diagnóstico e terapêutico da tuberculose em pacientes imunocomprometidos não HIV.

OBJECTIVE: To investigate the characteristics of and risk factors for mortality among non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis. METHODS: This was a two-year, retrospective cohort study of patients with an in-hospital diagnosis of tuberculosis. The predictive factors for mortality were evaluated. RESULTS: During the study period, 337 hospitalized patients were diagnosed with tuberculosis, and 61 of those patients presented with immunosuppression that was unrelated to HIV infection. Extrapulmonary tuberculosis was found in 47.5 percent of cases. In the latter group, the in-hospital mortality rate was 21.3 percent, and the mortality rate after discharge was 18.8 percent. One-year survival was significantly higher among the immunocompetent patients than among the HIV patients (p = 0.008) and the non-HIV-infected immunocompromised patients (p = 0.015), although there was no such difference between the two latter groups (p = 0.848). Among the non-HIV-infected immunocompromised patients, the only factor statistically associated with mortality was the need for mechanical ventilation. Among the patients over 60 years of age, fibrosis/atelectasis on chest X-rays and dyspnea were more common, whereas fever and consolidations were less common. Fever was also less common among the patients with neoplasms. The time from admission to the initiation of treatment was significant longer in patients over 60 years of age, as well as in those with diabetes and those with end-stage renal disease. Weight loss was least common in patients with diabetes and in those using corticosteroids. CONCLUSIONS: The lower prevalence of classic symptoms, the occurrence of extrapulmonary tuberculosis, the delayed initiation of treatment, and the high mortality rate reflect the diagnostic and therapeutic challenges of tuberculosis in non-HIV-infected immunocompromised patients.

Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study.

BACKGROUND: To describe the characteristics of patients with tuberculosis (TB) requiring intensive care and to identify the factors that predicts in-hospital mortality in a city of a developing country with intermediate-to-high TB endemicity. METHODS: We conducted a retrospective, cohort study, between November 2005 and November 2007. The patients with TB requiring intensive care were included. Predictors of mortality were assessed. The primary outcome was the in-hospital mortality. RESULTS: During the study period, 67 patients with TB required intensive care. Of them, 62 (92.5%) had acute respiratory failure and required mechanical ventilation. Forty-four (65.7%) patients died. Coinfection with human immunodeficiency virus was present in 46 (68.7%) patients. Early intensive care unit admission and ventilator-associated pneumonia were independently associated with the in-hospital mortality. CONCLUSIONS: In this study we found a high mortality rate in TB patients requiring intensive care, especially in those with an early ICU admission.

Factors associated with mortality in hospitalized patients with newly diagnosed tuberculosis.

The purpose of this study was to identify clinical and epidemiological factors associated with death in patients with an in-hospital diagnosis of tuberculosis (TB), in a city with a high prevalence of TB and human immunodeficiency virus (HIV) infection. The study was a retrospective, cohort study conducted at a general, tertiary-care, university-affiliated hospital. Patients who began treatment for TB after hospitalization were included. Predictors of mortality were assessed. The primary outcomes were the in-hospital mortality and the mortality after discharge. We evaluated the medical records of 311 patients with TB. The overall mortality rate of all study participants was 99/311 (31.8%). The mortality rates during hospitalization and after discharge were 50/311 (16.1%) and 49/261 (18.8%), respectively. Mechanical ventilation, consolidation in chest X-ray, and negative sputum smear were predictors of in-hospital death in multivariate analysis. Independent predictors of mortality after discharge in multivariate analysis included total duration of hospitalization and being a current smoker. We found a high overall mortality rate for patients hospitalized with TB in a region with a high prevalence of TB and HIV. The risk of mortality once patients with TB are hospitalized is unlikely to be explained only by the HIV epidemic.