Vasopressin And Septic Shock Trial Research Articles

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials

In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials. We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect. A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72). Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis. US National Institutes of Health.

The Specific Organism: Not Bacterial Gram Type: Drives the Inflammatory Response in Septic Shock

Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns.

Vasopressin versus norepinephrine in septic shock: a propensity score matched efficiency retrospective cohort study in the VASST coordinating center hospital

PurposeIt is not clear whether vasopressin versus norepinephrine changed mortality in clinical practice in the Vasopressin and Septic Shock Trial (VASST) coordinating center hospital after VASST was published. We tested the hypothesis that vasopressin changed mortality compared to norepinephrine using propensity matching of vasopressin to norepinephrine-treated patients in the VASST coordinating center hospital before (SPH1) and after (SPH2) VASST was published.MethodsVasopressin-treated patients were propensity score matched to norepinephrine-treated patients based on age, APACHE II, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, infection site, and norepinephrine dose. The propensity score estimated the probability that a patient would have received vasopressin given baseline characteristics. For sensitivity analysis, we then excluded patients who had underlying severe congestive heart failure. The primary outcome was 28-day mortality.ResultsVasopressin- and norepinephrine-treated patients were similar after matching in SPH1 (pre-VASST); vasopressin-treated patients (n = 158) had a significantly higher mortality than norepinephrine-treated patients (n = 158) (60.8 vs. 46.2%, p = 0.009). In SPH2 after matching, the 28-day mortality rates were not significantly different; 31.2% and 26.9% in the vasopressin (n = 93) and norepinephrine (n = 93) groups, respectively (p = 0.518). The day 1 vasopressin dose in SPH1 vs. SPH2 was 0.036 units/min (SD 0.009) vs. 0.032 units/min (SD 0.005), p = 0.001, significantly lower in SPH2 after VASST.ConclusionsBefore VASST, vasopressin use was associated with increased mortality compared to norepinephrine in the VASST coordinating center hospital. After VASST, there was no difference in mortality between vasopressin- and norepinephrine-treated patients. This may be the first retrospective propensity-matched cohort study of a sepsis treatment in a center that had previously coordinated a large pivotal randomized controlled trial of that treatment and could be a useful approach for other sepsis therapies.Trial registrationRegistration: ISRCTN94845869

Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury.

Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived heparin-binding protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI. To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using heparin derivatives. In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without heparin derivatives and the kidneys examined for signs of inflammation. Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo. Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI.

One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response

IntroductionObesity is an increasingly common comorbidity in critically ill patients. Whether obesity alters sepsis outcome, susceptibility, treatment, and response is not completely understood.MethodsWe conducted a retrospective analysis comparing three group of septic shock patients based on the intervals of actual body mass index (BMI) in patients enrolled in the VASST (Vasopressin and Septic Shock Trial) cohort. Primary outcome measurement was 28-day mortality. We tested for differences in patterns of infection by comparing the primary site of infection and organism. We also compared the treatments (fluids and vasopressors) and inflammatory response, measuring adipose tissue-related cytokine concentrations (interleukin [IL]-6, monocyte chemotactic protein [MCP]-1, tumor necrosis factor [TNF]-α, and resistin) in plasma in a subset of 382 patients. Of the 778 patients in VASST, 730 patients who had body weight and height measurements were analyzed. Patients with BMI <25 kg/m2 (n = 276) were grouped as a reference and compared to 'overweight' (25< BMI <30 kg/m2, n = 209) and 'obese' (BMI >30 kg/m2, n = 245) patients.ResultsObese patients had the lowest 28-day mortality followed by overweight patients while patients with BMI <25 kg/m2 had the highest mortality (p = 0.02). Compared to the patients with BMI <25 kg/m2, obese and overweight patients also had a different pattern of infection with less lung (obese 35%, overweight 45%, BMI<25 kg/m2 50%, p = 0.003) and fungal infection (obese 8.2%, overweight 11%, and BMI<25 kg/m2 15.6%, p = 0.03). Per kilogram, obese and overweight patients received less fluid during the first four days (p<0.05) and received less norepinephrine (obese 0.14, overweight 0.21, BMI <25 kg/m2 0.26 µg/kg/min, p<0.0001) and vasopressin (obese 0.28, overweight 0.36, BMI <25 kg/m2 0.43 µU/kg/min, p<0.0001) on day 1 compared to patients with BMI <25 kg/m2. Obese and overweight patients also had a lower plasma IL-6 concentration at baseline (obese 106 [IQR 34-686], overweight 190 [IQR 44-2339], BMI <25 kg/m2 235 [IQR 44-1793] pg/mL, p = 0.046).ConclusionsOverall obesity was associated with improved survival in septic shock and differences in pattern of infection, fluids, and vasopressors. Importantly, the magnitude of inflammatory IL-6 response is muted in the obese.

AA genotype of IL‐8 −251A/T is associated with low PaO2/FiO2 in critically ill patients and with increased IL‐8 expression

Interleukin-8 (IL-8) is a central chemokine in acute respiratory distress syndrome (ARDS), and the IL-8 gene contains a functional single nucleotide polymorphism (SNP) -251A/T in its promoter region. We hypothesized that IL-8 -251A/T SNP is associated with PaO(2)/FiO(2) in critically ill patients. We conducted genetic-association studies in intensive care units at academic teaching centres using a derivation septic shock cohort (vasopressin and septic shock trial (VASST), n = 467) and a validation post-cardiopulmonary bypass surgery cohort (CPB, n = 739) of Caucasian patients. Patients in both cohorts were genotyped for IL-8 -251A/T. The primary outcome variable in both cohorts was the fraction of patients who had a PaO(2) /FiO(2) < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro. The frequency of the patients with PaO(2)/FiO(2) <200 was significantly greater in patients who had the AA genotype of -251A/T than in patients who had the AT or TT genotypes in both VASST (AA = 60.8% vs AT and TT = 53.8% and 48.0%, P = 0.038) and the CPB cohort (AA = 37.0% vs AT and TT = 27.0% and 26.0%, P = 0.039). Patients having the AA genotype had a higher probability to remain on mechanical ventilation (P = 0.047) in the first 14 days. Lymphoblastoid cells having the AA genotype had significantly higher IL-8 mRNA expression than cells having the AT or TT genotype (P = 0.022). Critically ill Caucasian patients who had the AA genotype of IL-8 -251A/T had an increased risk of PaO(2)/FiO(2) <200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.

Potential for overuse of corticosteroids and vasopressin in septic shock

Guidelines recommend corticosteroids and vasopressin to treat septic shock as per specifi c indications [1]. However, the results from trials evaluating both drugs confl ict. For corticosteroids, the 2002 Annane and colleagues study showed a survival benefi t for hydrocortisone/fl udro cortisone treatment in patients with an inappropriate cortisol response to a high-dose adrenocorticotropic hormone (ACTH) test [2], while the Corticosteroid Th erapy of Septic Shock (CORTICUS) trial found no diff erence in survival by patients’ response to ACTH [3]. Th e Vasopressin and Septic Shock Trial (VASST) demon strated a survival benefi t in less severe septic shock, but guidelines espouse use ‘in patients refractory to other vasopressors’ [1,4]. Clinical variability, leading to over treatment, may have negative eff ects on survival. To evaluate the impact of these evi dence limitations, we surveyed physicians in the Critical Illness Outcomes Study (CIOS). We developed a 15-item, self-administered survey to charac terize physician practice patterns for use of corticosteroids and vasopressin in septic shock. Th e survey, conducted anonymously and with implied consent, was distributed to 92 members of the CIOS listserv. Recipients were encouraged to solicit survey completion by their colleagues. CIOS is a multicenter study among 68 ICUs designed to determine whether ICU-based organi zational and structural factors are associated with patientrelated outcomes. Th e survey fulfi lled Stanford Institutional Review Board exemption guidelines. To address when clinicians would use corticosteroids, we asked partici pants to rate their agreement (fi ve-point Likert scale) for the following situations: blood pressure poorly responsive to fl uid resuscitation and vasopressor therapy; an inappropriate response to ACTH testing [2]; and a history of treatment with corticosteroids within the prior 6 months. Likert responses were evalu ated by Pearson

IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis.

IntroductionInterleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis.MethodsWe tested for the association of IL17A SNPs with susceptibility to infection and clinical outcome of severe sepsis using two cohorts of European ancestry (derivation cohort, St Paul's Hospital (SPH), n = 679; validation cohort, Vasopressin and Septic Shock Trial (VASST), n = 517). The primary outcome variable was susceptibility to Gram-positive bacterial infection. The secondary outcome variable was 28-day mortality.ResultsOf four tested IL17A tag SNPs (rs4711998, rs8193036, rs2275913, rs1974226), rs1974226 SNP was associated with altered susceptibility to Gram-positive infection in the derivation SPH cohort (corrected P = 0.014). Patients having the rs1974226 GG genotype were more susceptible to Gram-positive infection, compared to AG/AA genotype in the two cohorts of severe sepsis (SPH, P = 0.0036, odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.72; VASST, P = 0.011, OR 1.95, 95%CI 1.16-3.27) and in the subgroup having lung infection (P = 0.017, OR 1.90, 95%CI 1.12-3.21). Furthermore, the IL17A rs1974226 G allele was associated with increased 28-day mortality in two cohorts (SPH, adjusted OR 1.44, 95%CI 1.04-2.02, P = 0.029; VASST, adjusted OR 1.67, 95%CI 1.17-2.40, P = 0.0052).ConclusionsIL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.

Arginine Vasopressin for the Treatment of Septic Shock in Adults

Sepsis remains one of the leading causes of mortality in the United States. Cardiovascular compromise is one of the major contributors to the high mortality associated with sepsis. Current cardiovascular support in patients with septic shock involves fluid administration, use of catecholamines, and potentially the use of inotropes, corticosteroids, or arginine vasopressin. Vasopressin is an endogenous hormone essential for both osmotic and cardiovascular homeostasis. Various studies have suggested that exogenous administration of arginine vasopressin may be an effective adjunctive therapy to traditional catecholamines for the management of hypotension during septic shock. Of particular interest is the Vasopressin and Septic Shock Trial (VASST), which found no mortality benefit when comparing the addition of arginine vasopressin to norepinephrine versus continuous dose increases in norepinephrine alone. However, results of the a priori subgroup and post hoc analyses of this trial suggest that patients may benefit if arginine vasopressin is used in patients with less severe shock, defined as those receiving a relatively low norepinephrine-equivalent dose of 5-14 μg/minute, or in those at risk for renal failure. Current guidelines from the Surviving Sepsis Campaign recommend arginine vasopressin 0.03 unit/minute may be added to norepinephrine with the anticipation of an effect equal to higher doses of norepinephrine alone. Many practitioners continue to utilize arginine vasopressin for patients with septic shock due to its mechanisms of benefit on pathophysiologic derangements in this disease. Clinicians must be knowledgeable about the use of arginine vasopressin in septic shock, including controversial areas where guidelines do not always provide concrete recommendations.

Best vasopressor for advanced vasodilatory shock: should vasopressin be part of the mix?

Since the publication of the Surviving Sepsis Campaign guidelines, a number of additional and highly relevant studies have been published addressing the issue of vasopressor use during septic shock. While these new results are provocative, none of the studies are definitive. In sum, they suggest that maybe we should not be thinking of one vasopressor versus another in a winner-takes-all sense. Rather, we should be looking for the best balance of vasopressor agents and, further, the choice likely depends on clinical context. Clinical context may drive the choice of adrenergic agonist; for example, norepinephrine may be superior to dopamine when the potential for arrhythmias is of concern. Norepinephrine may be superior to epinephrine if elevated lactate associated with epinephrine use confounds the clinical picture. The Vasopressin and Septic Shock Trial (VASST) identified an effective dose of arginine vasopressin (AVP) when adrenergic agonist doses are low, but higher doses of AVP may be appropriate in the context of very high adrenergic agonist doses. The effect may be a direct beneficial AVP effect or indirect sparing of adrenergic agonist use. The choice to add AVP may also be influenced by the clinical context, including renal function or the concomitant use of corticosteroids. These interim conclusions, in truth, are hypotheses warranting randomized controlled trials adequately powered to test for survival differences in these severely ill patients.

β2-Adrenergic Receptor Gene Polymorphism Is Associated with Mortality in Septic Shock

The CysGlyGln haplotype of the beta(2)-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients with asthma. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown. To determine whether genetic variation of ADRB2 influences outcome in septic shock. Two cohorts of patients with septic shock were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n = 616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2; therefore, rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype. Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio, 2.23; 95% confidence interval, 1.33-3.72; P = 0.0022), and this result was replicated in VASST (adjusted hazard ratio 2.82; 95% confidence interval, 1.56-5.09; P = 0.0006). This genotypic effect was eliminated in patients treated with acute low-dose corticosteroids. In all patients, the AA genotype was associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH; P < 0.05; VASST; P < 0.05) and required a higher norepinephrine dose over Days 1 through 3 (VASST; P < 0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P < 0.05). The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

Bench-to-bedside review: Vasopressin in the management of septic shock

This review of vasopressin in septic shock differs from previous reviews by providing more information on the physiology and pathophysiology of vasopressin and vasopressin receptors, particularly because of recent interest in more specific AVPR1a agonists and new information from the Vasopressin and Septic Shock Trial (VASST), a randomized trial of vasopressin versus norepinephrine in septic shock. Relevant literature regarding vasopressin and other AVPR1a agonists was reviewed and synthesized. Vasopressin, a key stress hormone in response to hypotension, stimulates a family of receptors: AVPR1a, AVPR1b, AVPR2, oxytocin receptors and purinergic receptors. Rationales for use of vasopressin in septic shock are as follows: first, a deficiency of vasopressin in septic shock; second, low-dose vasopressin infusion improves blood pressure, decreases requirements for norepinephrine and improves renal function; and third, a recent randomized, controlled, concealed trial of vasopressin versus norepinephrine (VASST) suggests low-dose vasopressin may decrease mortality of less severe septic shock. Previous clinical studies of vasopressin in septic shock were small or not controlled. There was no difference in 28-day mortality between vasopressin-treated versus norepinephrine-treated patients (35% versus 39%, respectively) in VASST. There was potential benefit in the prospectively defined stratum of patients with less severe septic shock (5 to 14 μg/minute norepinephrine at randomization): vasopressin may have lowered mortality compared with norepinephrine (26% versus 36%, respectively, P = 0.04 within stratum). The result was robust: vasopressin also decreased mortality (compared with norepinephrine) if less severe septic shock was defined by the lowest quartile of arterial lactate or by use of one (versus more than one) vasopressor at baseline. Other investigators found greater hemodynamic effects of higher dose of vasopressin (0.06 units/minute) but also unique adverse effects (elevated liver enzymes and serum bilirubin). Use of higher dose vasopressin requires further evaluation of efficacy and safety. There are very few studies of interactions of therapies in critical care - or septic shock - and effects on mortality. Therefore, the interaction of vasopressin infusion, corticosteroid treatment and mortality of septic shock was evaluated in VASST. Low-dose vasopressin infusion plus corticosteroids significantly decreased 28-day mortality compared with corticosteroids plus norepinephrine (44% versus 35%, respectively, P = 0.03; P = 0.008 interaction statistic). Prospective randomized controlled trials would be necessary to confirm this interesting interaction. In conclusion, low-dose vasopressin may be effective in patients who have less severe septic shock already receiving norepinephrine (such as patients with modest norepinephrine infusion (5 to 15 μg/minute) or low serum lactate levels). The interaction of vasopressin infusion and corticosteroid treatment in septic shock requires further study.