RESUSCITATIVE FLUIDS IN SEPSIS AND SEPTIC SHOCK: A SYSTEMATIC REVIEW, NETWORK META-ANALYSIS AND PILOT STUDY PROTOCOL

Abstract

This thesis consists of two related studies presented as three separate manuscripts (all three have been published in peer-reviewed journals) and a study protocol that has been submitted for peer-reviewed funding. The over-arching theme of this thesis was to better characterize the efficacy of different intravenous fluids used for the resuscitation of intensive care unit (ICU) patients with severe sepsis or septic shock.

We performed an extensive search including multiple databases which found 20 randomized controlled trials (RCTs) that examined the effects of different intravenous fluids used in septic patients and met our a priori inclusion and exclusion criteria. In the first manuscript, we described in detail the composition of the 19 unique fluid products that were used in the various studies. This description included the fluid type, trade name, osmolality, tonicity, electrolyte content, molecular composition, pH, and manufacturer. We reviewed manufacturer’s websites, product monographs, and emailed industry representatives or study authors for more information regarding the fluids as required. The results of this study and systematic review led us to the second and third manuscripts which reported on a Bayesian network meta-analysis (NMA) of all fluid type comparisons.

Despite multiple well-done RCTs, comparative data regarding the clinical effect of different resuscitative fluids when used for sepsis was incomplete. Most RCTs used 0.9% saline (normal saline) as control fluid and very few studies compared colloids directly. The advantage of using an NMA model in this setting was the ability to include indirect data into the overall point estimates. Data was abstracted from the 14 studies which focused on adult ICU patients and analyzed examining the outcomes of mortality (manuscript #2) and the use of renal replacement therapy (RRT) (manuscript #3). Certainty of evidence was evaluated for both outcomes using the GRADE approach.

Results of the analysis clearly document the harm of starch-based fluids when used in septic patients. Albumin containing fluids and crystalloids (such as normal saline and Ringer’s Lactate) are better options. Lower chloride solutions, such as Ringer’s Lactate, showed a signal towards decreased mortality and a decreased use of renal replacement therapy when compared to higher chloride fluids, such as normal saline, however this was based on indirect data, not statistically significant, and warrants direct comparison trials.

The final component of this thesis is a pilot study protocol for a study assessing the feasibility of a larger RCT examining the effect of low chloride versus high chloride fluids for resuscitation in patients with sepsis and septic shock. This protocol has been submitted as part of a peer-reviewed grant with the hopes of addressing this clinically important and timely question.