Treatment of Severe Sepsis: Where Next? Current and Future Treatment Approaches After the Introduction of Drotrecogin Alfa

Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed

Design Considerations for Factorial Adaptive Multi-Arm Multi-Stage (FAST) Clinical Trials

Multi-Arm, Multi-Stage (MAMS) clinical trial designs allow for multiple therapies to be compared across a spectrum of clinical trial phases. MAMS designs can be categorized into several overarching design groups, including adaptive designs (AD) and multi-arm (MA) designs. Factorial clinical trials designs represent an additional group of designs which can provide increased efficiency relative to fixed, traditional designs. In this work, we explore design choices associated with Factorial Adaptive Multi-Arm Multi-Stage (FAST) designs, which represent the combination of factorial and MAMS designs. This category of trial can potentially offer benefits similar to both MAMS and factorial designs. This work is motivated by a proposed clinical trial under development

Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

INTRODUCTION: The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis. METHODS: Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions. RESULTS: Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness. CONCLUSIONS: In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Vascular pedicle width in acute lung injury: correlation with intravascular pressures and ability to discriminate fluid status

Abstract Introduction Conservative fluid management in patients with acute lung injury (ALI) increases time alive and free from mechanical ventilation. Vascular pedicle width (VPW) is a non-invasive measurement of intravascular volume status. The VPW was studied in ALI patients to determine the correlation between VPW and intravascular pressure measurements and whether VPW could predict fluid status. Methods This retrospective cohort study involved 152 patients with ALI enrolled in the Fluid and Catheter Treatment Trial (FACTT) from five NHLBI ARDS (Acute Respiratory Distress Syndrome) Network sites. VPW and central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) from the first four study days were correlated. The relationships between VPW, positive end-expiratory pressure (PEEP), cumulative fluid balance, and PAOP were also evaluated. Receiver operator characteristic (ROC) curves were used to determine the ability of VPW to detect PAOP <8 mmHg and PAOP ≥18 mm Hg. Results A total of 71 and 152 patients provided 118 and 276 paired VPW/PAOP and VPW/CVP measurements, respectively. VPW correlated with PAOP (r = 0.41; P < 0.001) and less well with CVP (r = 0.21; P = 0.001). In linear regression, VPW correlated with PAOP 1.5-fold better than cumulative fluid balance and 2.5-fold better than PEEP. VPW discriminated achievement of PAOP <8 mm Hg (AUC = 0.73; P = 0.04) with VPW ≤67 mm demonstrating 71% sensitivity (95% CI 30 to 95%) and 68% specificity (95% CI 59 to 75%). For discriminating a hydrostatic component of the edema (that is, PAOP ≥18 mm Hg), VPW ≥72 mm demonstrated 61.4% sensitivity (95% CI 47 to 74%) and 61% specificity (49 to 71%) (area under the curve (AUC) 0.69; P = 0.001). Conclusions VPW correlates with PAOP better than CVP in patients with ALI. Due to its only moderate sensitivity and specificity, the ability of VPW to discriminate fluid status in patients with acute lung injury is limited and should only be considered when intravascular pressures are unavailable

Balanced Crystalloids versus Saline in Critically Ill Adults — A Systematic Review with Meta-Analysis

BACKGROUND: The comparative efficacy and safety of balanced crystalloid solutions and saline for fluid therapy in critically ill adults remain uncertain. METHODS: We systematically reviewed randomized clinical trials (RCTs) comparing the use of balanced crystalloids with saline in critically ill adults. The primary outcome was 90-day mortality after pooling data from low-risk-of-bias trials using a random-effects model. We also performed a Bayesian meta-analysis to describe the primary treatment effect in probability terms. Secondary outcomes included the incidence of acute kidney injury (AKI), new treatment with renal replacement therapy (RRT), and ventilator-free and vasopressor-free days to day 28. RESULTS: We identified 13 RCTs, comprising 35,884 participants. From six trials (34,450 participants) with a low risk of bias, the risk ratio (RR) for 90-day mortality with balanced crystalloids versus saline was 0.96 (95% confidence interval [CI], 0.91 to 1.01; I2 = 12.1%); using vague priors, the posterior probability that balanced crystalloids reduce mortality was 89.5%. The RRs of developing AKI and of being treated with RRT with balanced crystalloids versus saline were 0.96 (95% CI, 0.89 to 1.02) and 0.95 (95% CI, 0.81 to 1.11), respectively. Ventilator-free days (mean difference, 0.18 days; 95% CI, −0.45 to 0.81) and vasopressor-free days (mean difference, 0.19 days; 95% CI, −0.14 to 0.51) were similar between groups. CONCLUSIONS: The estimated effect of using balanced crystalloids versus saline in critically ill adults ranges from a 9% relative reduction to a 1% relative increase in the risk of death, with a high probability that the average effect of using balanced crystalloids is to reduce mortality

Non-disclosure of HIV testing history in population-based surveys: implications for estimating a UNAIDS 90-90-90 target

Background: HIV/AIDS programmes and organisations around the world use routinely updated estimates of the UNAIDS 90-90-90 targets to track progress and prioritise further programme implementation. Any bias in these estimates has the potential to mislead organisations on where gaps exist in HIV testing and treatment programmes. Objective: To measure the extent of undisclosed HIV testing history and its impact on estimating the proportion of people living with HIV (PLHIV) who know their HIV status (the ‘first 90’ of the UNAIDS 90-90-90 targets). Methods: We conducted a retrospective cohort study using population-based HIV serological surveillance conducted between 2010 and 2016 and linked, directly observed HIV testing records in Kisesa, Tanzania. Generalised estimating equations logistic regression models were used to detect associations with non-disclosure of HIV testing history adjusting for demographic, behavioural, and clinical characteristics. We compared estimates of the ‘first 90’ using self-reported survey data only and augmented estimates using information from linked records to quantify the absolute and relative impact of undisclosed HIV testing history. Results: Numbers of participants in each of the survey rounds ranged from 7171 to 7981 with an average HIV prevalence of 6.9%. Up to 33% of those who tested HIV-positive and 34% of those who tested HIV-negative did not disclose their HIV testing history. The proportion of PLHIV who reported knowing their status increased from 34% in 2010 to 65% in 2016. Augmented estimates including information from directly observed testing history resulted in an absolute impact of 6.7 percentage points and relative impact of 12.4%. Conclusions: In this population, self-reported testing history in population-based HIV serological surveys under-estimated the percentage of HIV positives that are diagnosed by a relative factor of 12%. Research should be employed in other surveillance systems that benefit from linked data to investigate how bias may vary across settings