Journal Club: Is Saline Toxic?

Outcomes of critically ill children requiring continuous renal replacement therapy

Hayes et al. J Critical Care (2009) 24:394-400;  PMID: 19327959

What was studied?

A number of retrospective studies in children and adults (including one by someone named Lane) demonstrate that volume overload at the initiation of renal replacement therapy for acute kidney injury (AKI) increases risk of death. The study I reviewed for today’s journal club examines a single-center (Children’s Hospital of Alabama) series of pediatric AKI patients treated with continuous renal replacement therapy (CRRT) from January 2000 through September 2005. In addition to examining predictors of mortality, a variety of secondary outcomes are included in the study (duration of mechanical ventilation, length of intensive care unit stay, days of hospitalization, and time to renal recovery). The investigators predicted that greater fluid overload at the time of initiation of CRRT would produce more adverse outcomes.

How was it studied?

After appropriate human subject protection review, charts of all CRRT patients were examined for standard demographic and diagnostic information. Fluid overload (FO) was calculated from admission to the intensive care unit until CRRT initiation:

(Total Intake Liters – Total Output Liters)/Admission Weight Kilos

I have one complaint with this score; if the patient were significantly volume depleted at the time of admission, it could overestimate volume overload. Given that a true “dry weight” would not be available for most patients, this is probably the best measure they could use.

Pediatric Risk of Mortality 2 scores (PRISM) were calculated for admission and onset of CRRT. Appropriate statistical analysis is described.

What was found?

Over this almost 6 year period, 76 courses of CRRT were studied, including 42 survivors and 34 nonsurvivors. The groups were similar for age, race, and sex. PRISM scores of “sickness” were similar, as were the requirement for blood pressure support mediations and level of kidney dysfunction. The number of hospital days before starting CRRT did not differ between the groups, nor did the type or dose of CRRT. Nonsurvivors were more likely to require a ventilator at the time of CRRT initiation, have higher airway pressures 24 hours into their course of CRRT, and had greater FO before starting CRRT.

If FO was above 20% of admission body weight when CRRT began, the odds of dying during the illness were increased 6-fold (95% confidence interval 2.2-17.0, p=0.0006). Risk of mortality also increased with sepsis (odds ratio 12.9, p=0.0001) and multiple organ dysfuntion syndrome. If only the kidneys had failed, all patients survived.

So they have confirmed the prior literature; what was new? For the 42 survivors, FO above 20% associated with longer need for a ventilator (16 v. 7 days), length of intensive care unit stay (21 v. 14 days), length of hospital stay (57 v. 27 days), and time to renal recovery (26 v. 8 days).

What does this mean?

This study confirms FO as a marker of mortality in children requiring CRRT for AKI. In addition, it shows worse outcomes for children who survive their illness, with longer time on a ventilator, on dialysis, and in the hospital.

Because of the retrospective and descriptive nature of the study, the major question remains:

Why is volume overload associated with worse outcomes in AKI?

When my own work found this association in bone marrow transplant patients, we hypothesized that sicker patients received more fluid for blood pressure support; our population also required more drugs to keep blood pressure up. In this study from Alabama, drugs for blood pressure support did not differ between these groups, nor did PRISM scores to estimate the level of “sickness” of the patients.

What is the alternative to FO as a marker, an epiphenomenon? Perhaps FO itself is toxic. Extra fluid may complicate ventilation and other body systems, especially if it leads to compromised nutritional support. Would earlier intervention with CRRT (perhaps at 10% FO) lead to better outcomes? Only a prospective multicenter study will answer this question.

Take-home message

Many physicians see fluid therapy as a completely benign thing to do, with little potential for adverse outcomes. Certainly, patients should receive fluid resuscitation, as noted by the study authors:

…it is vitally important that critically ill children in shock receive adequate treatment; we do not advocate withholding fluids from children during resuscitation.

This study provides one more piece of evidence that we need multicenter studies of earlier CRRT initiation. Only then will we know if saline is the bad guy or an innocent bystander in the morbidity and mortality of the critically ill.

Image courtesy of PhotoXpress.