Wednesday, May 12, 2010

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 Photoxpress_3018802journal 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.


  1. If the patients have been volume-depleted for a while, their cells have probably generated more osmoles inside to try to shift the balance of fluid from extracellular to intracellular. Upon sudden volume restoration, cells will swell until they have time to get rid of those extra osmoles. Maybe some of this morbidity/mortality associated with volume restoration is due to subacute cerebral swelling?

  2. Salt overload is common. Few realize that each liter of "normal" saline injects 20 salt tablets.

  3. YOU SAID "the major question remains:

    Why is volume overload associated with worse outcomes in AKI?"

    I offer a thought, overload squeezes the kidney, renal blood flow is slowed by squeeze, reduced renal blood flow seems a strong signal to hold on to salt and water, urine output falls, BUN rises, we say the kidney is "failing", we respond by speeding the IV?

  4. Pascale, you asked "Why is volume overload associated with worse outcomes in AKI?"
    You said, "When my own work found this association"...As you looked at FO (fluid overload) it sounds like you felt uneasy, right? For you wanted to avoid hurting patients, correct?

    You said, "Perhaps FO itself is toxic"....... I agree......You said, "Only a prospective multicenter study will answer this question." I wonder. It seems your experience with individual patients is a valid check with "reality" until multlcenter reports.

    To a child on a ventilator does a weight gain of 20 pounds help the sick child? Can we think about the illness and separately think of the weight gain. And treat them separately? Would shedding 20 pounds help ventilation?

  5. Pascale, you report, "If FO (fluid overload) was above 20% of admission body weight when CRRT began, the odds of dying during the illness were increased 6-fold".

    So.... How to recognize FO?..... Follow weight. How to treat FO? Start with chop? Chop off the salt supply? Each 1 gm of new salt added forces body to add 100 cc water to the overload?

    Separate FO from the injury, They are two problems?

  6. ARDS and saline overload
    We want to send healthy patients home.

    But unfortunately some sick have gained 20# to 40# during one week in the hospital. They are not ready to go home. To examine their problem, saline overload, I turn to a simile. Like a garden hose and soaker hose can carry water to grass, arteries and capillaries carry water to cells


    Water oozes through the walls of the soaker hose when pushed by faucet pressure and grass flourishes. So blood pushed by the heart pushes fluid through the walls of capillaries. Cells flourish. The faucet supplies water endlessly to replace water lost in the ooze. More on edema in future posts. Anybody out there?

  8. 40# OF EDEMA ? !

    Sometimes a soaker hose, forgotten overnight, leaves a pool that chokes roots. Ooze from capillaries can leave a pool of edema weighing 20# or 40# or more. Pools of that size choke cells. More coming on drowning?

  9. I have help from a grandson. Paul, would you post a comment if you read this?

  10. Pascale Lane reports 6X deaths if weight gain exceeds 20% of adm weight. And dead infants were more apt to need ventilators!!!

    Q. If you, as an adult, had 40# gain, would you have trouble breathing?

    Your answer hides two deeper questions, 1. Know of better resuscitation? 2. Know of way to early dump weight?-Which is all saline! I nope to bring in some expert testimony.

  11. My advisors hold better answers two deeper questions. I will continue with soaker hose analogy as background to deeper questions. But, I am headed to overload!

    Unlike faucet water, blood has a limited supply. The ooze of fluid out of vessels must be replaced to keep blood pressure up and vessels full. The constant ooze might otherwise empty the arteries. The body demands a return of pooled fluid to the heart--a fluid that will stay in vessels. 25% albumin is a bigger help than saline?

  12. Physiologic saline is not "toxic". It is physiological. It is a non-toxic fluid foriegn body blocking DO2 and VO2. More later.

    Comments =

  13. Bill Lyons,

    I agree that saline is not toxic, in the strict sense of the word, but as a title to her blog, Dr. Lane has chosen the word well as an attention getter for as we well know (and Dr. Lane has given evidence of in her paper) the common overuse of saline frequently brings death. Dr. Lane has raised an important topic and I appreciate your efforts in contributing to keep the topic open

  14. Bill, this is a note on how blogs work. The blog generates a message automatically (a strength of this Blogger application that I am using) that tells us ( Bill and John) on their email if someone has commented on our earlier comment. Note that there is a distinction between a "Post" and a "Comment". Anyway, Bill, thank you for making a "comment" on Dr. Lane's blog. (to make this work you have to transcribe the distortred word and check permission to send to your email.)