Left ventricular function: time-varying elastance and left ventricular aortic coupling

Many aspects of left ventricular function are explained by considering ventricular pressure–volume characteristics. Contractility is best measured by the slope, Emax, of the end-systolic pressure–volume relationship. Ventricular systole is usefully characterized by a time-varying elastance (ΔP/ΔV). An extended area, the pressure–volume area, subtended by the ventricular pressure–volume loop (useful mechanical work) and the ESPVR (energy expended without mechanical work), is linearly related to myocardial oxygen consumption per beat. For energetically efficient systolic ejection ventricular elastance should be, and is, matched to aortic elastance. Without matching, the fraction of energy expended without mechanical work increases and energy is lost during ejection across the aortic valve. Ventricular function curves, derived from ventricular pressure–volume characteristics, interact with venous return curves to regulate cardiac output. Thus, consideration of ventricular pressure–volume relationships highlight features that allow the heart to efficiently respond to any demand for cardiac output and oxygen delivery.Other UBCReviewedFacult

Deeper understanding of mechanisms contributing to sepsis-induced myocardial dysfunction

The inflammatory response of sepsis results in organ dysfunction, including myocardial dysfunction. Myocardial dysfunction is particularly important in patients with severe septic shock who progress to a hypodynamic pre-terminal phase. Multiple aspects of this septic inflammatory response contribute to the pathogenesis of decreased ventricular contractility. Inflammatory cytokines released by inflammatory cells contribute as does nitric oxide released by vascular endothelium and by cardiomyocytes. Endotoxins and other pathogen molecules induce an intramyocardial inflammatory response by binding Toll-like receptors on cardiomyocytes that then signal via NF-κB. These processes alter cardiomyocyte depolarization and, therefore, contractility. The particular role of the cardiomyocyte sodium current has not been characterized. Now new information suggests that the septic inflammatory response impairs normal depolarization by altering the cardiomyocyte sodium current. This results in decreased ventricular contractility. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated.Other UBCReviewedFacult

Aging and the intramyocardial inflammatory response

The sepsis-induced intramyocardial inflammatory response results in decreased ventricular function and myocardial damage. Chemokines such as monocyte chemoattractant protein-1 causally contribute to retention of intramyocardial mononuclear leukocytes and subsequent ventricular dysfunction during endotoxemic shock in mice and, importantly, this effect is age dependent. It is therefore useful to consider where monocyte chemoattractant protein-1 fits in the complex pathway leading to ventricular dysfunction during sepsis, why this might be an age-dependent effect, and what this implies for care of older sepsis patients.Other UBCReviewedFacult

Metabolic changes in cardiomyocytes during sepsis

Different types of shock induce distinct metabolic changes. The myocardium at rest utilizes free fatty acids as its primary energy source, a mechanism that changes to aerobic glycolysis during sepsis and is in contrast to hemorrhagic shock. The immune system also uses this mechanism, changing its substrate utilization to activate innate and adaptive cells. Cardiomyocytes share a number of features similar to antigen-presenting cells and may use this mechanism to augment the immune response at the reversible expense of cardiac function.Critical Care Medicine, Division ofMedicine, Department ofMedicine, Faculty ofNon UBCReviewedFacult

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

Purpose: It 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. Methods: Vasopressin-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. Results: Vasopressin- 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. Conclusions: Before 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 registration Registration: ISRCTN94845869Medicine, Faculty ofOther UBCNon UBCCritical Care Medicine, Division ofMedicine, Department ofReviewedFacult

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

Introduction: Obesity is an increasingly common comorbidity in critically ill patients. Whether obesity alters sepsis outcome, susceptibility, treatment, and response is not completely understood. Methods: We 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 30 kg/m2, n = 245) patients. Results: Obese 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). Conclusions: Overall 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.Other UBCNon UBCReviewedFacult

Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice

Introduction: Arginine vasopressin is a vasoactive drug commonly used in distributive shock states including mixed shock with a cardiac component. However, the direct effect of arginine vasopressin on the function of the ischemia/reperfusion injured heart has not been clearly elucidated. Methods: We measured left ventricular ejection fraction using trans-thoracic echocardiography in C57B6 mice, both in normal controls and following ischemia/reperfusion injury induced by a one hour ligation of the left anterior descending coronary artery. Mice were treated with one of normal saline, dobutamine (8.33 μg/kg/min), or arginine vasopressin (0.00057 Units/kg/min, equivalent to 0.04 Units/min in a 70 kg human) delivered by an intraperitoneal micro-osmotic pump. Arterial blood pressure was measured using a micromanometer catheter. In addition, mortality was recorded and cardiac tissues processed for RNA and protein. Results: Baseline left ventricular ejection fraction was 65.6% (60 to 72). In normal control mice, there was no difference in left ventricular ejection fraction according to infusion group. Following ischemia/reperfusion injury, AVP treatment significantly reduced day 1 left ventricular ejection fraction 46.2% (34.4 to 52.0), both in comparison with baseline and day 1 saline treated controls 56.9% (42.4 to 60.2). There were no significant differences in preload (left ventricular end diastolic volume), afterload (blood pressure) or heart rate to account for the effect of AVP on left ventricular ejection fraction. The seven-day mortality rate was highest in the arginine vasopressin group. Following ischemia/reperfusion injury, we found no change in cardiac V1 Receptor expression but a 40% decrease in Oxytocin Receptor expression. Conclusions: Arginine vasopressin infusion significantly depressed the myocardial function in an ischemia/reperfusion model and increased mortality in comparison with both saline and dobutamine treated animals. The use of vasopressin may be contraindicated in non-vasodilatory shock states associated with significant cardiac injury.Medicine, Faculty ofReviewedFacult

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

Introduction: Interleukin 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. Methods: We 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. Results: Of 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). Conclusions: IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.Other UBCNon UBCReviewedFacult

Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients

Background: Acute kidney injury and hyperchloremia are commonly present in critically ill septic patients. Our study goal was to evaluate the association of hyperchloremia and acute kidney injury in severe sepsis and septic shock patients. Methods: In this retrospective cohort study in a provincial tertiary care hospital, adult patients with severe sepsis or septic shock and serum chloride measurements were included. Serum chloride was measured on a daily basis for 48 hours. Primary outcome was development of acute kidney injury (AKI) and association of AKI and serum chloride parameters was analyzed. Results: A total of 240 patients were included in the study, 98 patients (40.8 %) had hyperchloremia. The incidence of acute kidney injury (AKI) was significantly higher in the hyperchloremia group (85.7 % vs 47.9 %; p < 0.001). Maximal chloride concentration in the first 48 hours ([Cl-]max) was significantly associated with AKI. In multivariate analysis, [Cl-]max was independently associated with AKI [adjusted odds ratio (OR) for AKI = 1.28 (1.02–1.62); p = 0.037]. The increase in serum chloride (Δ[Cl-] = [Cl-]max – initial chloride concentration) demonstrated a dose-dependent relationship with severity of AKI. The mean Δ[Cl-] in patients without AKI was 2.1 mmol/L while in the patients with AKI stage 1, 2 and 3 the mean Δ[Cl-] was 5.1, 5.9 and 6.7 mmol/L, respectively. A moderate increase in serum chloride (Δ[Cl-] ≥ 5 mmol/L) was associated with AKI [OR = 5.70 (3.00–10.82); p < 0.001], even in patients without hyperchloremia [OR = 8.25 (3.44–19.78); p < 0.001]. Conclusions: Hyperchloremia is common in severe sepsis and septic shock and independently associated with AKI. A moderate increase in serum chloride (Δ[Cl-] ≥5 mmol/L) is associated with AKI even in patients without hyperchloremia.Other UBCNon UBCReviewedFacult

Novel polymorphism of interleukin-18 associated with greater inflammation after cardiac surgery

Introduction: Interleukin (IL)-18 is a key modulator of the cytokine response that leads to organ dysfunction and prolonged intensive care unit (ICU) stay after cardiopulmonary bypass surgery. We hypothesised that variation in the pro-inflammatory gene IL-18 is associated with adverse clinical outcome because of a more intense inflammatory response. Methods: Haplotypes of the IL-18 gene were inferred from genotypes of 23 Coriell Registry subjects. Four haplotype tag single nucleotide polymorphisms (-607 C/A, -137 G/C, 8148 C/T and 9545 T/G) identified four major haplotype clades. These polymorphisms were genotyped in 658 Caucasian patients undergoing cardiopulmonary bypass surgery. Clinical phenotypes were collected by retrospective chart review. Results: Patients homozygous for the T allele of the 9545 T/G polymorphism had an increased occurrence of prolonged ICU stay (6.8% for TT genotype versus 2.7% for GG or GT genotype; p = 0.015). Patients homozygous for the T allele also had increased occurrence of low systemic vascular resistance index (62%) compared with the GG and GT genotypes (53%; p = 0.045). Patients homozygous for the T allele had increased serum IL-18 concentrations 24 hours post-surgery (p = 0.018), increased pro-inflammatory tumour necrosis factor alpha concentrations (p = 0.014) and decreased anti-inflammatory serum IL-10 concentrations (p = 0.018) 24 hours post-surgery. Conclusions: The TT genotype of the IL-18 9545 T/G polymorphism is associated with an increased occurrence of prolonged ICU stay post-surgery and greater post-surgical inflammation. These results may be explained by greater serum IL-18, leading to greater pro-versus anti-inflammatory cytokine expression.Critical Care Medicine, Division ofMedicine, Faculty ofMedicine, Department ofReviewedFacult