Sepsis is a common problem associated with an extremely high degree of morbidity and mortality. For patients with septic shock (sepsis with hypotension), mortality rates can be as high as 40%. Fluids and antibiotics are the mainstay of treatment for sepsis and septic shock. In Canada (outside Quebec), over 30,000 hospital admissions a year are due to sepsis and 1 in 18 hospital deaths involve sepsis as a contributing or underlying cause (www.statscan.gov.ca). Given the elderly are more at risk for sepsis and Canada’s aged population is growing, it is likely the incidence of sepsis and septic shock will continue to rise.
The most widely used intravenous fluid worldwide is the ill-named ‘normal saline’. Far from ‘normal’, normal saline contains a supra-physiologic sodium and chloride content. In animal models, the resultant hyperchloremia causes metabolic acidosis, acute kidney injury, delayed gastric emptying and decreased smooth muscle contractility.
Observational studies and systematic reviews consistently suggest a potential for harm associated with normal saline. Despite growing concern regarding higher chloride solutions and calls for prospective data, no RCT has yet addressed whether lower chloride solutions improve outcomes in septic shock. Although lower chloride solutions are widely available, clinical practice is unlikely to change without further robust evidence addressing this question.
FISSH Research PICO Question
In patients with septic shock, what is the impact of administering fluids with higher chloride content (normal saline & high chloride albumin) versus lower chloride content (Ringer’s lactate & low chloride albumin) on the incidence of acute kidney injury and other patient outcomes (including 30-day mortality, need for advanced life support, and ICU/hospital length of stay)?
1) To examine the effect of different fluids on the development of acute kidney injury (defined according to KDIGO guidelines) as our primary outcome.
2) To examine the effect of different fluids on other outcomes important to patients: need for advanced life support (hemodialysis, invasive mechanical ventilation, inotropes/vasopressors), ICU and hospital length of stay and 30-day mortality).
3) To examine the effect of different fluids on circulating cell-free DNA levels that correlate with prognosis in sepsis and septic shock. This nested translational biology substudy will inform the underlying biological rationale.
4) To examine, through this provincial trial, the feasibility of a future national/international trial with respect to consent rate, recruitment parameters and protocol adherence. The primary outcome of the future national/international trial will be 30-day mortality.
The FISSH trial has the potential to change the management of patients with sepsis in ICUs, operating rooms and emergency departments across Ontario. Compared to many interventions, intravenous fluids are inexpensive and their administration requires no special training or skill set; thus if lower chloride solutions prove beneficial, changing practice is relatively straightforward. The results of this RCT will also inform international clinical practice guidelines (e.g. Surviving Sepsis Campaign) that currently make no recommendation regarding the choice of fluid or crystalloid.