Ventilation in patients with intra-abdominal hypertension: what every critical care physician needs to know

Ventilation in patients with intra-abdominal hypertension: what every critical care physician needs to know

by Adrian Regli, Paolo Pelosi and Manu L. N. G. Malbrain  

Annals of Intensive Care:  2019 9:52

The incidence of intra-abdominal hypertension (IAH) is high and still underappreciated by critical care physicians throughout the world. One in four to one in three patients will have IAH on admission, while one out of two will develop IAH within the first week of Intensive Care Unit stay. IAH is associated with high morbidity and mortality. Although considerable progress has been made over the past decades, some important questions remain regarding the optimal ventilation management in patients with IAH. An important first step is to measure intra-abdominal pressure (IAP). If IAH (IAP > 12 mmHg) is present, medical therapies should be initiated to reduce IAP as small reductions in intra-abdominal volume can significantly reduce IAP and airway pressures. Protective lung ventilation with low tidal volumes in patients with respiratory failure and IAH is important. Abdominal-thoracic pressure transmission is around 50%. In patients with IAH, higher positive end-expiratory pressure (PEEP) levels are often required to avoid alveolar collapse but the optimal PEEP in these patients is still unknown. During recruitment manoeuvres, higher opening pressures may be required while closely monitoring oxygenation and the haemodynamic response. During lung-protective ventilation, whilst keeping driving pressures within safe limits, higher plateau pressures than normally considered might be acceptable. Monitoring of the respiratory function and adapting the ventilatory settings during anaesthesia and critical care are of great importance. This review will focus on how to deal with the respiratory derangements in critically ill patients with IAH.

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559)*

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559)*

 by Hotchkiss, Richard S.; Colston, Elizabeth; Yende, Sachin; Angus, Derek C.; Moldawer, Lyle L.; Crouser, Elliott D.; Martin, Greg S.; Coopersmith, Craig M.; Brakenridge, Scott; Mayr, Florian B.; Park, Pauline K.; Ye, June; Catlett, Ian M.; Girgis, Ihab G.; Grasela, Dennis M.

Critical Care Medicine: May 2019 - Volume 47 - Issue 5 - p 632–642

Objectives: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.

Design: Randomized, placebo-controlled, dose-escalation.

Setting: Seven U.S. hospital ICUs.

Study Population: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL. Interventions: Participants received single-dose BMS-936559 (10–900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels. 

Measurements and Main Results: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1–2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1–2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.

Conclusions: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.

Cardiovascular determinants of resuscitation from sepsis and septic shock

Cardiovascular determinants of resuscitation from sepsis and septic shock

By Fabio Guarracino, Pietro Bertini and Michael R. Pinsky  

Critical Care: 201923:118

Background: We hypothesized that the cardiovascular responses to Surviving Sepsis Guidelines (SSG)-defined resuscitation are predictable based on the cardiovascular state.

Methods: Fifty-five septic patients treated by SSG were studied before and after volume expansion (VE), and if needed norepinephrine (NE) and dobutamine. We measured mean arterial pressure (MAP), cardiac index (CI), and right atrial pressure (Pra) and calculated pulse pressure and stroke volume variation (PPV and SVV), dynamic arterial elastance (Ea_dyn), arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees), Ees/Ea (VAC), LV ejection efficiency (LVeff), mean systemic pressure analogue (Pmsa), venous return pressure gradient (Pvr), and cardiac performance (Eh), using standard formulae.

Results: All patients were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beat min⁻¹), with increased lactate levels (lactate = 5.0 ± 4.2 mmol L⁻¹) with a worsened VAC. CI was variable but > 2 L min⁻¹ M⁻² in 74%. Twenty-eight-day mortality was 48% and associated with admission lactate, blood urea nitrogen (BUN), and creatinine levels but not cardiovascular state. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Fluid administration improved Pra, Pmsa, and Pvr in all patients, whereas both HR and Ea decreased after VE, thus normalizing VAC. CI increases were proportional to baseline PPV and SVV. CI increases proportionally decreased PPV and SVV. VE increased MAP > 65 mmHg in 35/55 patients. MAP responders had higher PPV, SVV, and Ea_dyn than non-responders. NE was given to 20/55 patients in septic shock, but increased MAP > 65 mmHg in only 12. NE increased Ea, Ea_dyn, Pra, Pmsa, and VAC while decreasing HR, PPV, SVV, and LVeff. MAP responders had higher pre-NE Ees and lower VAC. Dobutamine was given to 6/8 patients who remained hypotensive following NE. It increased Ees, MAP, CI, and LVeff, while decreasing HR, Pra, and VAC. At all times and all steps of the protocol, CI changes were proportional to Pvr changes independent of treatment.

Conclusions: The cardiovascular response to SSG-based resuscitation is highly heterogeneous but predictable from pre-treatment measures of cardiovascular state.

Does Obesity Protect Against Death in Sepsis? A Retrospective Cohort Study of 55,038 Adult Patients*

Does Obesity Protect Against Death in Sepsis? A Retrospective Cohort Study of 55,038 Adult Patients*

by Pepper, Dominique J.; Demirkale, Cumhur Y.; Sun, Junfeng; Rhee, Chanu; Fram, David; Eichacker, Peter; Klompas, Michael; Suffredini, Anthony F.; Kadri, Sameer S.

Critical Care Medicine: May 2019 - Volume 47 - Issue 5 - p 643–650

Objectives: Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index at inconsistent time points, and/or use administrative data to define sepsis. To estimate the relationship between body mass index and sepsis mortality using detailed clinical data for case detection and risk adjustment. Design: Retrospective cohort analysis of a large clinical data repository.

Setting: One-hundred thirty-nine hospitals in the United States.

Patients: Adult inpatients with sepsis meeting Sepsis-3 criteria. Exposure: Body mass index in six categories: underweight (body mass index < 18.5 kg/m2), normal weight (body mass index = 18.5–24.9 kg/m2), overweight (body mass index = 25.0–29.9 kg/m2), obese class I (body mass index = 30.0–34.9 kg/m2), obese class II (body mass index = 35.0–39.9 kg/m2), and obese class III (body mass index ≥ 40 kg/m2).

 Measurements: Multivariate logistic regression with generalized estimating equations to estimate the effect of body mass index category on short-term mortality (in-hospital death or discharge to hospice) adjusting for patient, infection, and hospital-level factors. Sensitivity analyses were conducted in subgroups of age, gender, Elixhauser comorbidity index, Sequential Organ Failure Assessment quartiles, bacteremic sepsis, and ICU admission.

 Main Results: From 2009 to 2015, we identified 55,038 adults with sepsis and assessable body mass index measurements: 6% underweight, 33% normal weight, 28% overweight, and 33% obese. Crude mortality was inversely proportional to body mass index category: underweight (31%), normal weight (24%), overweight (19%), obese class I (16%), obese class II (16%), and obese class III (14%). Compared with normal weight, the adjusted odds ratio (95% CI) of mortality was 1.62 (1.50–1.74) for underweight, 0.73 (0.70–0.77) for overweight, 0.61 (0.57–0.66) for obese class I, 0.61 (0.55–0.67) for obese class II, and 0.65 (0.59–0.71) for obese class III. Results were consistent in sensitivity analyses. 

Conclusions: In adults with clinically defined sepsis, we demonstrate lower short-term mortality in patients with higher body mass indices compared with those with normal body mass indices (both unadjusted and adjusted analyses) and higher short-term mortality in those with low body mass indices. Understanding how obesity improves survival in sepsis would inform prognostic and therapeutic strategies.

How and Whom to Monitor for Seizures in an ICU: A Systematic Review and Meta-Analysis

How and Whom to Monitor for Seizures in an ICU: A Systematic Review and Meta-Analysis

by Limotai, Chusak; Ingsathit, Atiporn; Thadanipon, Kunlawat; McEvoy, Mark; Attia, John; Thakkinstian, Ammarin  

Critical Care Medicine: April 2019 - Volume 47 - Issue 4 - p e366–e373

Objectives: To pool prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, and epileptiform activity detected by different electroencephalography types in critically ills and to compare detection rates among them.

Data Sources: MEDLINE (via PubMed) and SCOPUS (via Scopus)

Study Selection: Any type of study was eligible if studies were done in adult critically ill, applied any type of electroencephalography, and reported seizure rates. Case reports and case series were excluded.

Data Extraction: Data were extracted independently by two investigators. Separated pooling of prevalence of nonconvulsive seizure/nonconvulsive status epilepticus/epileptiform activity and odds ratio of detecting outcomes among different types of electroencephalography was performed using random-effect models. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and also adhered to the Meta-analyses Of Observational Studies in Epidemiology guidelines. Quality of evidence was assessed with the Newcastle-Ottawa Quality Assessment Scale for observational studies and Cochrane methods for randomized controlled trial studies.

Data Synthesis: A total of 78 (16,707 patients) and eight studies (4,894 patients) were eligible for pooling prevalence and odds ratios. For patients with mixed cause of admission, the pooled prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, either nonconvulsive seizure or nonconvulsive status epilepticus detected by routine electroencephalography was 3.1%, 6.2%, and 6.3%, respectively. The corresponding prevalence detected by continuous electroencephalography monitoring was 17.9%, 9.1%, and 15.6%, respectively. In addition, the corresponding prevalence was high in post convulsive status epilepticus (33.5%, 20.2%, and 32.9%), CNS infection (23.9%, 18.1%, and 23.9%), and post cardiac arrest (20.0%, 17.3%, and 22.6%). The pooled conditional log odds ratios of nonconvulsive seizure/nonconvulsive status epilepticus detected by continuous electroencephalography versus routine electroencephalography from studies with paired data 2.57 (95% CI, 1.11–5.96) and pooled odds ratios from studies with independent data was 1.57 (95% CI, 1.00–2.47).

Conclusions: Prevalence of seizures detected by continuous electroencephalography was significantly higher than with routine electroencephalography. Prevalence was particularly high in post convulsive status epilepticus, CNS infection, and post cardiac arrest.

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia – results from the prospective observational PROGRESS study

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia – results from the prospective observational PROGRESS study

by Peter Ahnert, Petra Creutz, Katrin Horn, Fabian Schwarzenberger, Michael Kiehntopf, Hamid Hossain, Michael Bauer, Frank Martin Brunkhorst, Konrad Reinhart, Uwe Völker, Trinad Chakraborty, Martin Witzenrath, Markus Löffler, Norbert Suttorp and Markus Scholz

Critical Care: 201923:110

Background: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity.

Methods: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA.

Results: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA.

Conclusions: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies.

Trial registration

clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

Airway pressure release ventilation during acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials

Airway pressure release ventilation during acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials

By Andrea Carsetti, Elisa Damiani, Roberta Domizi, Claudia Scorcella, Simona Pantanetti, Stefano Falcetta, Abele Donati and Erica Adrario  

Annals of Intensive Care:  2019 9: 44

Background: Airway pressure release ventilation (APRV) has been considered a tempting mode of ventilation during acute respiratory failure within the concept of open lung ventilation. We performed a systematic review and meta-analysis to verify whether adult patients with hypoxemic respiratory failure have a higher number of ventilator-free days at day 28 when ventilated in APRV compared to conventional ventilation strategy. Secondary outcomes were difference in PaO₂/FiO₂ at day 3, ICU length of stay (LOS), ICU and hospital mortality, mean arterial pressure (MAP), risk of barotrauma and level of sedation. We searched MEDLINE, Scopus and Cochrane Central Register of Controlled Trials database until December 2018.

Results: We considered five RCTs for the analysis enrolling a total of 330 patients. For ventilatory-free day at day 28, the overall mean difference (MD) between APRV and conventional ventilation was 6.04 days (95%CI 2.12, 9.96, p = 0.003; I² = 65%, p = 0.02). Patients treated with APRV had a lower ICU LOS than patients treated with conventional ventilation (MD 3.94 days [95%CI 1.44, 6.45, p = 0.002; I² = 37%, p = 0.19]) and a lower hospital mortality (RD 0.16 [95%CI 0.02, 0.29, p = 0.03; I² = 0, p = 0.5]). PaO₂/FiO₂ at day 3 was not different between the two groups (MD 40.48 mmHg [95%CI − 25.78, 106.73, p = 0.23; I² = 92%, p < 0.001]). MAP was significantly higher during APRV (MD 5 mmHg [95%CI 1.43, 8.58, p = 0.006; I² = 0%, p = 0.92]). Then, there was no difference regarding the onset of pneumothorax under the two ventilation strategies (RR 1.94 [95%CI 0.54, 6.94, p = 0.31; I² = 0%, p = 0.74]). ICU mortality and sedation level were not included into quantitative analysis.

Conclusion: This study showed a higher number of ventilator-free days at 28 day and a lower hospital mortality in acute hypoxemic patients treated with APRV than conventional ventilation, without any negative hemodynamic impact or higher risk of barotrauma. However, these results need to be interpreted with caution because of the low-quality evidence supporting them and the moderate heterogeneity found. Other well-designed RCTs need to be conducted to confirm our findings.

Safety and efficacy of volume-based feeding in critically ill, mechanically ventilated adults using the ‘Protein & Energy Requirements Fed for Every Critically ill patient every Time’ (PERFECT) protocol: a before-and-after study

Safety and efficacy of volume-based feeding in critically ill, mechanically ventilated adults using the ‘Protein & Energy Requirements Fed for Every Critically ill patient every Time’ (PERFECT) protocol: a before-and-after study

by Sue Brierley-Hobson, Graham Clarke and Vincent O’Keeffe  

Critical Care:  2019 23:105

Background: Underfeeding in critical illness is common and associated with poor outcomes. According to large prospective hospital studies, volume-based feeding (VBF) safely and effectively improves energy and protein delivery to critically ill patients compared to traditional rate-based feeding (RBF) and might improve patient outcomes. A before-and-after study was designed to evaluate the safety, efficacy and clinical outcomes associated with VBF compared to RBF in a single intensive care unit (ICU).

Methods: The sample included consecutively admitted critically ill adults, mechanically ventilated for at least 72 h and fed enterally for a minimum of 48 h. The first cohort (n = 46) was fed using RBF, the second (n = 46) using VBF, and observed for 7 days, or until extubation or death. Statistical comparison of percentage feed volume, energy and protein delivered, plus indices of feed intolerance, were the primary outcomes of interest. Secondary observations included ventilation period, mortality, and length of ICU stay (LOICUS).

Results: Groups were comparable in baseline clinical and demographic characteristics and nutrition practices. Volume delivered to the VBF group increased significantly by 11.2% (p ≤ 0.001), energy by 13.4% (p ≤ 0.001) and protein by 8.4% (p = 0.02), compared to the RBF group. In the VBF group, patients meeting > 90% of energy requirements increased significantly from 47.8 to 84.8% (p ≤ 0.001); those meeting > 90% of protein requirements changed from 56.5 to 73.9% (p = 0.134).VBF did not increase symptoms of feed intolerance. Adjusted binomial logistic regression found each additional 1% of prescribed feed delivered decreased the odds of vomiting by 0.942 (5.8%), 95% CI [0.900–0.985], p = 0.010.No differences in mortality or LOICUS were identified. Kaplan-Meier found a significantly increased extubation rate in patients receiving > 90% of protein requirements compared to those meeting < 80%, (p = 0.006). Adjusted Cox regression found the daily probability of being extubated tripled in patients receiving > 90% of their protein needs compared to the group receiving < 80%, hazard ratio 3.473, p = 0.021, 95% CI [1.205–10.014].

Conclusion: VBF safely and effectively increased the delivery of energy and protein to critically ill patients. Increased protein delivery may improve extubation rate which has positive patient-centred and financial implications, warranting larger confirmatory trials. This investigation adds weight to the ICU literature supporting VBF, and the growing evidence which advocates for enhanced protein delivery to improve patient outcomes.

Flagellin attenuates experimental sepsis in a macrophage-dependent manner

By Xiaoliang Yang, Yibing Yin, Xingxing Yan, Zebo Yu, Yi Liu and Ju Cao

Critical Care: 2019 23:106

Background: Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis.

Methods: We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages.

Results: Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)–dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis.

Conclusions: These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.