Loop diuretics in adult intensive care patients with fluid overload: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

Abstract

Background: Fluid overload is a risk factor for organ dysfunction and death in intensive care unit (ICU) patients, but no guidelines exist for its management. We systematically reviewed benefits and harms of a single loop diuretic, the predominant treatment used for fluid overload in these patients.

Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis (TSA) of a single loop diuretic vs. other interventions reported in randomised clinical trials, adhering to our published protocol, the Cochrane Handbook, and PRISMA statement. We assessed the risks of bias with the ROB2-tool and certainty of evidence with GRADE. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020184799).

Results: We included 10 trials (804 participants), all at overall high risk of bias. For loop diuretics vs. placebo/no intervention, we found no difference in all-cause mortality (relative risk (RR) 0.72, 95% confidence interval (CI) 0.49-1.06; 4 trials; 359 participants; I² = 0%; TSA-adjusted CI 0.15-3.48; very low certainty of evidence). Fewer serious adverse events were registered in the group treated with loop diuretics (RR 0.81, 95% CI 0.66-0.99; 6 trials; 476 participants; I² = 0%; very low certainty of evidence), though contested by TSA (TSA-adjusted CI 0.55-1.20).

Conclusions: The evidence is very uncertain about the effect of loop diuretics on mortality and serious adverse events in adult ICU patients with fluid overload. Loop diuretics may reduce the occurrence of these outcomes, but large randomised placebo-controlled trials at low risk of bias are needed.

Keywords: Critical care; Diuretics; Fluid accumulation; Fluid overload; Furosemide; Loop diuretics; Systematic review.

Fig. 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart

Fig. 2

Meta-analysis and TSA for all-cause mortality for loop diuretics vs. placebo/no intervention. a Meta-analysis. b TSA. The diversity adjusted required information size (DARIS) was calculated according to a mortality proportion in the control group (CEP) of 27%; risk ratio reduction (RRR) of 20% in the experimental intervention group; alpha of 1.7%; a beta of 10% (90% power); and diversity 0%. The DARIS was 3132 participants. The cumulative Z-curve (blue line) did not cross the trial sequential boundaries for benefit or harm or the inner-wedge futility line (red outward sloping red lines) nor the DARIS. The light blue dotted lines show naïve conventional boundaries (alpha 5%)

Fig. 3

Meta-analysis and TSA on highest event rate of SAEs for loop diuretics vs. placebo/no intervention. a Meta-analysis. b TSA. The diversity adjusted required information size (DARIS) was calculated according to the proportion of SAEs in the control group (CEP) of 47%; risk ratio reduction (RRR) of 20% in the experimental intervention group; alpha of 1.7%; a beta of 10% (90% power); and diversity 0%. The DARIS was 1372 participants. The cumulative Z-curve (blue line) did not cross the trial sequential boundaries for benefit or harm or the inner-wedge futility line (red outward sloping red lines) nor the DARIS. The light blue dotted lines show naïve conventional boundaries (alpha 5%)