Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

BACKGROUND: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. METHODS/EXAMPLES: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. CONCLUSION: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

Effect of low-to-moderate hyperoxia on lung injury in preclinical animal models: a systematic review and meta-analysis.

BACKGROUND: Extensive animal investigation informed clinical practice regarding the harmful effects of high fractional inspired oxygen concentrations (FiO2s > 0.60). Since questions persist whether lower but still supraphysiologic FiO2 ≤ 0.60 and > 0.21 (FiO2 ≤ 0.60/ > 0.21) are also harmful with inflammatory lung injury in patients, we performed a systematic review examining this question in animal models. METHODS: Studies retrieved from systematic literature searches of three databases, that compared the effects of exposure to FiO2 ≤ 0.60/ > 0.21 vs. FiO2 = 0.21 for ≥ 24 h in adult in vivo animal models including an inflammatory challenge or not were analyzed. Survival, body weight and/or lung injury measures were included in meta-analysis if reported in ≥ 3 studies. RESULTS: More than 600 retrieved reports investigated only FiO2s > 0.60 and were not analyzed. Ten studies with an inflammatory challenge (6 infectious and 4 noninfectious) and 14 studies without, investigated FiO2s ≤ 0.60/ > 0.21 and were analyzed separately. In seven studies with an inflammatory challenge, compared to FiO2 = 0.21, FiO2 ≤ 0.60/ > 0.21 had consistent effects across animal types on the overall odds ratio of survival (95%CI) that was on the side of harm but not significant [0.68 (0.38,1.23), p = 0.21; I2 = 0%, p = 0.57]. However, oxygen exposure times were only 1d in 4 studies and 2-4d in another. In a trend approaching significance, FiO2 ≤ 0.60/ > 0.21 with an inflammatory challenge consistently increased the standardized mean difference (95%CI) (SMD) in lung weights [0.47 (- 0.07,1.00), p = 0.09; I2 = 0%, p = 0.50; n = 4 studies] but had inconsistent effects on lung lavage protein concentrations (n = 3), lung pathology scores (n = 4) and/or arterial oxygenation (n = 4) (I2 ≥ 43%, p ≤ 0.17). Studies without an inflammatory challenge had consistent effects on lung lavage protein concentration (n = 3) SMDs on the side of being increased that was not significant [0.43 (- 0.23,1.09), p = 0.20; I2 = 0%, p = 0.40] but had inconsistent effects on body and lung weights (n = 6 and 8 studies, respectively) (I2 ≥ 71%, p < 0.01). Quality of evidence for studies was weak. INTERPRETATION: Limited animal studies have investigated FiO2 ≤ 0.60/ > 0.21 with clinically relevant models and endpoints but suggest even these lower FiO2s may be injurious. Given the influence animal studies examining FiO2 > 0.60 have had on clinical practice, additional ones investigating FiO2 ≤ 0.60/ > 0.21 appear warranted, particularly in pneumonia models.

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model.

Introduction: Because prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). Methods: In Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production. Results: Study 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. Discussion: In Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

Comprehensive adjusted outcome data are needed to assess the impact of immune checkpoint inhibitors in cancer patients with COVID-19: Results of a systematic review and meta-analysis.

BACKGROUND: Determining how prior immune checkpoint inhibitor (ICI) therapy influences outcomes in cancer patients presenting with COVID-19 is essential for patient management but must account for confounding variables. METHODS: We performed a systematic review and meta-analysis of studies reporting adjusted effects of ICIs on survival, severe events, or hospitalisation in cancer patients with COVID-19 based on variables including age, gender, diabetes mellitus, hypertension (HTN), chronic obstructive pulmonary disease, and other comorbidities. When adjusted effects were unavailable, unadjusted data were analysed. RESULTS: Of 42 observational studies (38 retrospective), 7 reported adjusted outcomes for ICIs and 2 provided sufficient individual patient data to calculate adjusted outcomes. In eight studies, adjusted outcomes were based on ≤7 variables. Over all studies, only one included >100 ICI patients while 26 included <10. ICIs did not alter the odds ratio (95%CI) (OR) of death significantly (random effects model), across adjusted (n = 8) [1.31 (0.58-2.95) p = 0.46; I2  = 42%, p = 0.10], unadjusted (n = 30) [1.06 (0.85-1.32) p = 0.58; I2  = 0%, p = 0.76] or combined [1.09 (0.88;1.36) p = 0.41; I2  = 0%, p = 0.5)] studies. Similarly, ICIs did not alter severe events significantly across adjusted (n = 5) [1.20 (0.30-4.74) p = 0.73; I2  = 52%, p = 0.08], unadjusted (n = 19) [(1.23 (0.87-1.75) p = 0.23; I2  = 16%, p = 0.26] or combined [1.26 (0.90-1.77) p = 0.16; I2  = 25%, p = 0.14] studies. Two studies provided adjusted hospitalisation data and when combined with 13 unadjusted studies, ICIs did not alter hospitalisation significantly [1.19 (0.85-1.68) p = 029; I2  = 5%, p = 0.40]. Results of sensitivity analyses examining ICI effects based on 5 variables were inconclusive. Certainty of evidence was very low. CONCLUSIONS: Across studies with adjusted and unadjusted results, ICIs did not alter outcomes significantly. But studies with comprehensive adjusted outcome data controlling for confounding variables are necessary to determine whether ICIs impact COVID-19 outcomes in cancer patients.

Modeling current practices in critical care comparative effectiveness research.

Objective: To determine whether contemporaneous practices are adequately represented in recent critical care comparative effectiveness research studies. Design: All critical care comparative effectiveness research trials published in the New England Journal of Medicine from April 2019 to March 2020 were identified. To examine studies published in other high impact medical journals during the same period, such trials were subsequently also identified in the Journal of the American Medical Association and The Lancet. All cited sources were reviewed, and the medical literature was searched to find studies describing contemporary practices. Then, the designated control group or the comparable therapies studied were examined to determine if they represented contemporaneous critical care practices as described in the medical literature. Results: Twenty-five of 332 randomised clinical trials published in these three journals during this 1-year period described critical care comparative effectiveness research that met our inclusion criteria. Seventeen characterised current practices before enrolment (using surveys, observational studies and guidelines) and then incorporated current practices into one or more study arm. In the other eight, usual care arms appeared insufficient. Four of these trials randomly assigned patients to one of two fixed approaches at either end of a range of usually titrated care. However, due to randomisation, different subgroups within each arm received care that was inappropriate for their specific clinical conditions. In the other four of these trials, common practices influencing treatment choice were not reflected in the trial design, despite a prior effort to characterise usual care. Conclusion: One-third of critical care comparative effectiveness research trials published in widely read medical journals during a recent year did not include a designated control arm or comparable therapies representative of contemporary practices. Failure to incorporate contemporary practices into critical care comparative effectiveness trials appears to be a widespread design weakness.

Anti-PD-L1 Therapy Does Not Improve Survival in a Murine Model of Lethal Staphylococcus aureus Pneumonia.

BACKGROUND: Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia. METHODS: Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (HD)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production. RESULTS: LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance. CONCLUSIONS: Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.

A Review of the Efficacy of FDA-Approved B. anthracis Anti-Toxin Agents When Combined with Antibiotic or Hemodynamic Support in Infection- or Toxin-Challenged Preclinical Models.

Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.

Bacillus anthracis edema toxin inhibits hypoxic pulmonary vasoconstriction via edema factor and cAMP-mediated mechanisms in isolated perfused rat lungs.

Bacillus anthracis edema toxin (ET) inhibited lethal toxin-stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared with diluent, ET perfusion reduced maximal Ppa increases (mean ± SE percentage of maximal Ppa increase with baseline hypoxia) during 6-min hypoxic periods (FIO2 = 0%) at 120 min (16 ± 6% vs. 51 ± 6%, P = 0.004) and 180 min (11.4% vs. 55 ± 6%, P = 0.01). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production, respectively. In lungs perfused with ET following baseline measures, compared with placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180 min (56 ± 6% vs. 10 ± 4% and 72 ± 12% vs. 12 ± 3%, respectively, P ≤ 0.01) as did adefovir (84 ± 10% vs. 16.8% and 123 ± 21% vs. 26 ± 11%, respectively, P ≤ 0.01). Compared with diluent, lung perfusion with ET for 180 min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1) (21.12 ± 2.96 vs. 3.00 ± 0.76 × 108 cmH2O/M, P < 0.0001) and U46619, a thromboxane A2 analogue (7.15 ± 1.01 vs. 3.74 ± 0.31 × 107 cmH2O/M, P = 0.05) added to perfusate. In lungs isolated from rats after 15 h of in vivo infusions with either diluent, ET alone, or ET with PA-mAb, compared with diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone (P ≤ 0.004) but not with ET and PA-mAb together (P ≥ 0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection.NEW & NOTEWORTHY The most important findings here are edema toxin's potent adenyl cyclase activity can interfere with hypoxic pulmonary vasoconstriction, an action that could worsen hypoxemia during invasive anthrax infection with lung involvement. These findings, coupled with other studies showing that lethal toxin can disrupt pulmonary vascular integrity, indicate that both toxins can contribute to pulmonary pathophysiology during infection. In combination, these investigations provide a further basis for the use of antitoxin therapies in patients with worsening invasive anthrax disease.

Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

BACKGROUND: Lethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related. METHODS: At 6 h before and the start of 24 h anthrax PGN infusions, rats (n = 198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 µg/kg), non-selective and selective anti-inflammatory agents, respectively. RESULTS: Compared to controls, hydrocortisone 125 and 12.5 mg/kg each decreased 7-day lethality (p ≤ 0.004). Hydrocortisone 125 mg/kg decreased IL-1ß, IL-6, TNFα, MCP, MIP-1α, MIP-2, RANTES and nitric oxide (NO) blood levels at 4 and 24 h after starting PGN (except MCP at 24 h). Each decrease was significant at 4 h (except MIP-1α that was significant at 24 h) (p ≤ 0.05). Similarly, hydrocortisone 12.5 mg/kg decreased each measure at 4, 24 and 48 h (except TNFα at 24 h and MIP-1α at 24 and 48 h and NO at 48 h). Decreases were significant for IL-6 and NO at 4 h and RANTES at 48 h (p ≤ 0.05). Hydrocortisone 1.25 mg/kg had non-significant effects. Each TNFsr dose decreased lethality but non-significantly. However, when doses were analyzed together, TNFsr decreased lethality in a potential trend (p = 0.16) and IL-6 and NO significantly at 4 h (p = 0.05). CONCLUSIONS: Peptidoglycan-stimulated host inflammation may contribute to B. anthracis lethality.

Inhibitory Immune Checkpoint Molecule Expression in Clinical Sepsis Studies: A Systematic Review.

OBJECTIVES: Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis. DATA SOURCES: PubMed, EMBASE, Scopus, Web of Science, inception through October 2019. STUDY SELECTION: Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors. DATA EXTRACTION: Two investigators extracted data and evaluated study quality. DATA SYNTHESIS: Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly (p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression. CONCLUSIONS: Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.

Comparative effectiveness research in critically ill patients: risks associated with mischaracterising usual care.

Comparative effectiveness research can help guide the use of common, routine medical practices. However, to be safe and informative, such trials must include at least one treatment arm that accurately portrays current practices. While comparative effectiveness research is widely perceived as safe and to involve no or only minimal risks, these assumptions may not hold true if unrecognised deviations from usual care exist in one or more study arms. For critically ill subjects in particular, such practice deviations may increase the risk of death or injury and undermine safety monitoring. Furthermore, unrecognised unusual care seems likely to corrupt informed consent documents, with underappreciated risks shrouded under the reassuring "comparative effectiveness" research label. At present, oversight measures are inadequate to ensure that research subjects enrolled in comparative effectiveness trials are actually receiving usual and not unusual care. Oversight by governmental and non-governmental entities with appropriate expertise, empowered to ensure that current clinical practice has been properly represented, could help prevent occurrences in clinical trials of unusual care masquerading as usual care.

The Effects of Obesity on Outcome in Preclinical Animal Models of Infection and Sepsis: A Systematic Review and Meta-Analysis.

Background: Clinical studies suggest obesity paradoxically increases survival during bacterial infection and sepsis but decreases it with influenza, but these studies are observational. By contrast, animal studies of obesity in infection can prospectively compare obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis. Methods: Databases were searched for studies comparing survival in obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis. Methods. Databases were searched for studies comparing survival in obese versus nonobese animals following bacteria, lipopolysaccharide, or influenza virus challenges. Results: Twenty-one studies (761 obese and 603 control animals) met the inclusion criteria. Obesity reduced survival in 19 studies (11 significantly) and the odds ratio (95% CI) of survival (0.21(0.13, 0.35); I 2 = 64%, p < 0.01p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 64%, p < 0.01p < 0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I 2 = 31%, p=0.20 and n = 5, 0.22(0.13, 0.36); I 2 = 0%, p=0.59, respectively), (2) not significantly with cecal ligation and puncture (n = 4, 0.72(0.08, 6.23); I 2 = 75%, p < 0.01), and (3) significantly with influenza but with high heterogeneity (n = 6, 0.12(0.04, 0.34); I 2 = 73%, p < 0.01). Obesity's survival effects did not differ significantly comparing the four challenge types (p=0.49). Animal models did not include antimicrobials or glycemic control and study quality was low. Conclusions: Preclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity's impact on survival during severe infection.

Driving blind: instituting SEP-1 without high quality outcomes data.

In 2015, the Centers for Medicare and Medicaid Services (CMS) instituted an all-or-none sepsis performance measure bundle (SEP-1) to promote high-quality, cost-effective care. Systematic reviews demonstrated only low-quality evidence supporting most of SEP-1's interventions. CMS has removed some but not all of these unproven components. The current SEP-1 version requires patients with suspected sepsis have a lactate level, blood cultures, broad-spectrum antibiotics and, if hypotensive, a fixed 30 mL/kg fluid infusion within 3 hours, and a repeat lactate if initially elevated within 6 hours. Experts have continued to raise concerns that SEP-1 remains overly prescriptive, lacks a sound scientific basis and presents risks (overuse of antibiotics and inappropriate fluids not titrated to need). To incentivize compliance with SEP-1, CMS now publicly publishes how often hospitals complete all interventions in individual patients. However, compliance measured across hospitals (5 studies, 48-2,851 hospitals) or patients (three studies, 110-851 patients) has been low (approximately 50%) which is not surprising given SEP-1's lack of scientific basis. The largest observational study (1,738 patients) reporting survival rates employing SEP-1 found they were not significantly improved with the measure (P=0.53) as did the next largest study (851 patients, adjusted survival odds ratio 1.36, 95% CI, 0.85 to 2.18). Two smaller observational studies (158 and 450 patients) reported SEP-1 improved unadjusted survival (P≤0.05) but were confounded either by baseline imbalances or by simultaneous introduction of a code sepsis protocol to improve compliance. Regardless, retrospective studies have well known biases related to non-randomized designs, uncontrolled data collection and failure to adjust for unrecognized influential variables. Such low-quality science should not be the basis for a national mandate compelling care for a rapidly lethal disease with a high mortality rate. Instead, SEP-1 should be based on high quality reproducible evidence from randomized controlled trials (RCT) demonstrating its benefit and thereby safety. Otherwise we risk not only doing harm but standardizing it.

Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis.

BACKGROUND: Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. RESULTS: Nineteen experiments from 11 studies (n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity (I2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3-4 days after CLP. In these six experiments (n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I2 = 0%, p = 0.99]. In the three experiments (n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. CONCLUSIONS: Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.

Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1).

OBJECTIVE: To address three controversial components in the Centers for Medicare and Medicaid Service's sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. DATA SOURCES: PubMed, Embase, ClinicalTrials.gov through March 15, 2018. STUDY SELECTION: Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. DATA EXTRACTION: Two investigators (D.J.P., P.Q.E.). DATA SYNTHESIS: Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697-12,486 patients per study) (1.20 [1.11-1.30]; I = 0%) and six medium-sized studies (167-1,029) (2.03 [1.52-2.71]; I = 8%) but not the six smallest (64-137) (1.25 [0.42-3.66]; I = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5-2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. CONCLUSIONS: Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.

Bacillus anthracis lethal toxin, but not edema toxin, increases pulmonary artery pressure and permeability in isolated perfused rat lungs.

Although lethal toxin (LT) and edema toxin (ET) contribute to lethality during Bacillus anthracis infection, whether they increase vascular permeability and the extravascular fluid accumulation characterizing this infection is unclear. We employed an isolated perfused Sprague-Dawley rat lung model to investigate LT and ET effects on pulmonary vascular permeability. Lungs (n ≥ 6 per experimental group) were isolated, ventilated, suspended from a force transducer, and perfused. Lung weight and pulmonary artery (Ppa) and left atrial pressures were measured over 4 h, after which pulmonary capillary filtration coefficients (Kf.c) and lung wet-to-dry weight ratios (W/D) were determined. When compared with controls, LT increased Ppa over 4 h and Kf.c and W/D at 4 h (P < 0.0001). ET decreased Ppa in a significant trend (P = 0.09) but did not significantly alter Kf.c or W/D (P ≥ 0.29). Edema toxin actually blocked LT increases in Ppa but not LT increases in Kf.c and W/D. When Ppa was maintained at control levels, LT still increased Kf.c and W/D (P ≤ 0.004). Increasing the dose of each toxin five times significantly increased and a toxin-directed monoclonal antibody decreased the effects of each toxin (P ≤ 0.05). Two rho-kinase inhibitors (GSK269962 and Y27632) decreased LT increases in Ppa (P ≤ 0.02) but actually increased Kf.c and W/D in LT and control lungs (P ≤ 0.05). A vascular endothelial growth factor receptor inhibitor (ZM323881) had no significant effect (P ≥ 0.63) with LT. Thus, LT but not ET can increase pulmonary vascular permeability independent of increased Ppa and could contribute to pulmonary fluid accumulation during anthrax infection. However, pulmonary vascular dilation with ET could disrupt protective hypoxic vasoconstriction. NEW & NOTEWORTHY The most important findings from the present study are that Bacillus anthracis lethal toxin increases pulmonary artery pressure and pulmonary permeability independently in the isolated rat lung, whereas edema toxin decreases the former and does not increase permeability. Each effect could be a basis for organ dysfunction in patients with this lethal infection. These findings further support the need for adjunctive therapies that limit the effects of both toxins during infection.