James A. Russell
James A. Russell, MD, FRCPC
Division of Critical Care Medicine
The two major current themes of my research are (1) the genetics of the systemic inflammatory response syndrome (SIRS) and sepsis and (2) randomized controlled trials in the critically ill.
- Genomics of Critical Care and Sepsis
We are doing studies in the critically ill of SNP’s and haplotypes of key coagulation, inflammatory and innate immunity genes. We focused initially on refining the clinical phenotypes of organ dysfunction in the critically ill. We are doing gene association studies of candidate genes in: (1) critically ill ICU patients who have SIRS, sepsis, and septic shock and (2) cardiovascular surgery patients.
I have been Co-investigator of a CIHR gene environment grant to study haplotypes of susceptibility genes in cardiac, pulmonary and vascular disease ($2,756,473 over 5 years). I have had peer-review grant funded studies of the association of genotype with phenotype in SIRS in the critically ill, SIRS after cardiopulmonary bypass (Co- PI of a grant from CIHR), in ARDS (grants from BC Lung Association and Providence Health Care) and in acute lung injury (funded by NIH SCCOR/University of Washington contract).
Our main findings to date are focused on key coagulation, innate immunity and inflammatory genes. We have found significant relationships of genetic markers (specific haplotypes and single nucleotide polymorphisms (SNPs)) of protein C, IL-6, IL-10 and fibrinogen with increased risk of death (protein C: peer-reviewed references # 122 & 133. IL-6: reference # 108; IL-10: reference # 112; fibrinogen reference: # 124). In contrast, genetic variants of key innate immune genes CD14, MBL, TLR-2 and TLR-1 are associated with increased risk of severe infections (sepsis) (CD14, MBL, TLR-2: reference # 110; TLR-1 reference # 135).
- Clinical Trials in the Critically Il
I have an active clinical trials program in critical care. I have previously shown that therapies such as prostaglandin E1 increase oxygen delivery but do not decrease mortality in ARDS and that sodium bicarbonate (compared to hypertonic saline) does not improve oxygen delivery in critically ill patients who have lactic acidosis. We have led clinical trials of vasopressin in septic shock, ibuprofen in sepsis (NIH grant-funded), antioxidants in ARDS and in sepsis, interleukin-1 receptor antagonist in sepsis, endotracheal tobramycin in pneumonia, anti-tumor necrosis factor in sepsis, interleukin-10 in ARDS, tissue factor pathway inhibitor, and activated protein C in sepsis.
We have published literature reviews, retrospective, prospective and animal model studies of vasopressin for septic shock. I have been Principal Investigator of a CIHR-funded multicentre, randomized controlled trial of vasopressin vs. norepinephrine in septic shock (VASST) published in the New England Journal of Medicine (Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D for the VASST investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358: 877 – 887). Mortality rates were similar in the vasopressin and norepinephrine groups at 28 days (35.4% and 39.3% respectively, P=0.26), and at 90 days (43.9% and 49.6% respectively, P=0.11). Serious adverse event rates were similar in both treatment groups. In the prospectively defined stratum of less severe septic shock, mortality was lower in the vasopressin group at 28 days (26.5% vs. 35.7%, P=0.05; absolute difference 9.2%, 95% confidence interval, -0.1 to 18.5) and at 90 days (35.8% vs. 46.1%, P=0.04; absolute difference 10.4%, 95% confidence interval, 0.4 to 18.5). Our conclusions are that low dose vasopressin in addition to conventional catecholamines appears comparable in efficacy and safety to norepinephrine in septic shock. Low dose vasopressin may be more effective than norepinephrine alone in less severe septic shock. The VASST study is cited in the 2008 international sepsis treatment guidelines.
I also have had a research contract as the only Canadian centre in the NIH/NHLBI - funded clinical network for the treatment of ARDS (ARDSnet). We participated in a clinical trial of the pulmonary artery catheter and liberal vs. conservative fluid regimens in acute lung injury (references # 120, 121).
The clinical research success in sepsis is recognized in an invited review in the New England Journal of Medicine (Russell JA. Management of sepsis. N Engl J Med 2006; 355 (16): 699 – 713.)