Background:  Our current intravenous fluid (IVF) orders for pediatric patients follow an equation first published in 1957 (Holliday and Segar).  Electrolyte composition of IVF are based on average sodium content in low solute infant formula, with the untested assumption that oral requirements translate to a safe and appropriate IV solution.

 

Over time, case reports of iatrogenic hyponatremia in pediatric patients have been described, some leading to permanent neurologic impairment or death.  The hyponatremia is attributed to the use of hypotonic IVF such as 0.45 NS and 0.2NS.  The mechanisms are not fully elucidated, but likely are related to the temporarily high arginine vasopressin (AVP) levels seen in children hospitalized with many common disorders (asthma, infection, post-op, dehydration, etc), and an impaired clearance of electrolyte-free water.   Proponents of the status quo cite concerns about isotonic fluids leading to hypernatremia, hypertension, interstitial fluid overload and tissue damage from extravasation.

 

In 2007, the National Patient Safety Agency in the UK warned against the use of hypotonic IVF fluids in children, followed by similar warnings by the Institute for Safe Medication Practices in Canada in 2008 and the United States in 2009, yet many hospitals continue to use hypotonic IVF for their pediatric patients.

 

Article #1:

Montanana PA, Alapont M, Ocon AP et al. The Use of Isotonic Fluid as Maintenance Therapy Prevents Iatrogenic Hyponatremia in Pediatrics: A Randomized, Controlled Open Study,Pediatr Crit Care Med 2008;9:589 –597. 

 

In this non-blinded RCT, 128 PICU patients received either isotonic IVF (NaCl = 140 mEq/L) or hypotonic IVF (NaCl < 100 mEq/L).  Patients were followed for 24 hours, with electrolytes, glucose and BP measured at 0, 6, and 24 hours.  Baseline Na levels were similar in the two groups.  The primary outcome was hyponatremia (Na < 135) at 6 and 24 hours.   All eligible patients consented to be in the study (whoah, what’s going on with informed consent in Spain…and Australia in article 3-also 100% compliance!).   They did lose a number of patients, mostly because IVF were no longer required, but 8 patients discontinued the study due to hyponatremia.  At 24 hours, 20.6% of the hypotonic IVF group were hyponatremic, compared to 5.1% in the isotonic IVF group:  NNH (number needed to harm) with hypotonic fluids = 7.  There was no significant difference in adverse events or hypernatremia between the 2 groups.

Statistics Rant:  this study included a Bayesian analysis, which is worth a comment.   In a nutshell, there are two types of probability:  Bayesian and Frequency.  Frequentists rely on objective probabilities defined through well defined random experiments….think p values.  Bayesians interpret probability using their degree of belief in a hypothesis.  It’s more of a “how do we feel” about the statistics, rather than an arbitrary “p < 0.05 = truth”.   Many current journals are getting away from p values entirely.  A large effect size, combined with prior knowledge about the topic, can be more persuasive than a statistically significant p value in isolation.  Bayesians are all about pre-test and post-test probability; how does additional new information change your view of the likelihood of an event?

 

Discussion:  McKean brought up the excellent point that the study is not blinded, and therefore open to confounders.  It would also be preferable to use clinical, or patient oriented outcomes, rather than surrogate markers like sodium level, but clinical complications are going to be rare in this situation.  Although the number of patients with moderate or severe hyponatremia was low, they were all in the hypotonic fluid group and this is potentially more clinically relevant.

 

 

Article #2:

Choong K, Arora S, Cheng J et al. Hypotonic Versus Isotonic Maintenance Fluids After Surgery for Children: A Randomized Controlled Trial. Pediatrics 2011:128;857-864.

 

In this blinded study 258 post-op kids either received hypotonic (0.45NS) or isotonic (0.9NS) IVF for 48 hours.  Baseline characteristics in the two groups were similar.  Primary outcome was acute hyponatremia, defined as Na < /= 134.   Secondary outcomes included severe hyponatremia (Na < /= 129 or symptomatic), hypernatremia (Na >/= 146), and adverse events attributable to fluid choice or sodium level.   The risk of hyponatremia was significantly greater in the hypotonic group (40.8% vs 22.7 %; RR: 1.82 [95%CI:1.21-2.74]).  Eight patients in the hypotonic group developed severe hyponatremia as compared with 1 patient in the isotonic group.  In Harwood’s view, this is a study of 9 kids with severe hyponatremia (the most clinically concerning patients), and all but one received hypotonic fluids.  The risk of hypernatremia was not significantly different between the two groups, nor was the rate of adverse events.   NNT with isotonic IVF to prevent one case of hyponatremia = 6.

 

Discussion:   As Jess mentioned, there was a safety officer who alerted physicians if predetermined Na levels were met.  If electrolyte values were persistently abnormal, physicians could change the study solution to an open label IVF.   More patients in the hypotonic group were changed to open label IVF, with hyponatremia being the most commonly stated reason for the change.  This methodology likely decreased the rate of harmful outcomes and diluted the magnitude of the primary outcome (anticipate more harm and even more significance in the outcomes if the above safety choices hadn’t been made).

 

 

 

Article #3:

Neville KA, Verge CF, Rosenberg AR et al. Isotonic is Better than Hypotonic Saline for Intravenous Rehydration of Children with Gastroenteritis: a Prospective Randomised Study.Arch Dis Child 2006;91:226–232. 

 

The final study evaluated dehydrated children diagnosed with acute gastroenteritis.  In this study, a total of 102 children with acute gastroenteritis (AGE) received either D2.5 0.9NS or D2.5 0.45NS for 4 hours, with electrolytes measured in both blood and urine at 0 and 4 hours.  Results were analyzed according to whether patients started the study with a normal Na or if they began hyponatremic (Na < 135).  Physicians chose between two different rehydration rate protocols.  Patients were similar at baseline except for a higher rate of baseline hyponatremia in the isotonic fluid group.  The primary outcome was the change in serum sodium at 4 hours.  Thirty-six percent of the children were hyponatremic at the start of the study, and these patients were more likely to have been ill longer than patients with baseline normal serum sodiums.   The IV infusion rate did not affect the change in serum sodium, which is important as proponents of hypotonic fluids have argued that the rate rather than the type of IVF determines the risk of hyponatremia.  At 4 hours, in the hypotonic fluid group patients initially hyponatremic did not demonstrate a significant change in serum sodium, but patients initially normonatremic had a small drop in serum sodium.  In the isotonic group, at 4 hours those initially hyponatremic had a small increase in serum sodium, while those initially normonatremic had overall unchanged serum sodiums.  In other words, isotonic fluids appeared to prevent hyponatremia and did not cause any cases of hypernatremia.

Discussion:  Beau pointed out that this is a non-blinded study, but it did look at a “hard” outcome, serum sodium, that shouldn’t have been affected by blinding.  He also mentioned that the study did not address complications, length of stay, etc, and did not specify prior interventions such as anti-emetic administration.   As Jim Maletich discussed, this really was only a four-hour study, although for the subset of patients followed longer, the few cases of hyponatremia identified were all in the hypotonic fluid group.  Urine biochemical analysis reiterated Harwood’s point:  kids can handle sodium, but they aren’t good at handling (excreting) free water. 

 

Bottom line consensus from the group:  it’s time to change our practice.  Except for rare situations when children present with profound hypo or hypernatremia (for example patient with DI), the IVF of choice is 0.9NS, usually with KCl and dextrose added after any necessary initial resuscitation boluses have been given.  It’s the medically appropriate choice, should be financially equivalent to current practice, and makes our lives easier (bonus!).    Our pediatric colleague Patty, who managed to sit through 2 journal clubs on this topic in one day, voiced similar conclusions from the Department of Pediatrics discussion.

There’s always a caveat…

There is a potential concern for the induction of metabolic acidosis when administering IVF with equal chloride and sodium ion concentrations.   As Harwood pointed out, none of the three studies evaluated chloride or pH.   LR contains less chloride than NS, but is still hypotonic.  Future studies.