Contrary to our expectations, we observed increases in serum sodium in both the 0.45% and 0.9% groups, although this change was only statistically significant in the 0.9% group. Furthermore, similar proportions of individuals in both treatment arms developed hyponatremia.
After decades of using hypotonic fluids, the best choice of solution for maintenance IV fluid therapy has recently become a topic of intense debate. Six randomized trials favored isotonic over hypotonic fluids for the prevention of hyponatremia [25, 27–31]. There were two main differences between the present trial and past studies. First, the present study included a more diverse population than past trials, including both non-critically ill general medical patients and surgical patients after completion of surgery. Second, prior trials dictated both the rate and composition of fluids administered. A strength of the present study is that only fluid composition was dictated by study protocol; physicians were advised that study fluid was to be used for maintenance needs, and allowed the freedom to choose the rate of administration and any additional fluids according to their usual practice. This allowed us to isolate the impact of fluid composition on changes in serum [Na] in a 'real world' clinical setting in which physicians determined the rate of fluid administration.
Maintenance fluids are one of the three key components of an IV fluid prescription, along with deficit replacement, and replacement of ongoing losses . The goal of maintenance fluids is to maintain fluid homeostasis by replacing both insensible water losses and obligate urinary water losses. Combining theoretical considerations regarding obligate urinary water losses, empiric estimates of average daily insensible water losses, and estimates of daily electrolyte requirements, Holliday and Segar recommended hypotonic solutions (0.2% saline) for the maintenance component of the IV fluid prescription . However, their assumptions regarding obligate urinary water losses - or at least regulation of urinary water losses -may not be valid among hospitalized children.
Recommendations for replacement of a volume deficit vary. For rapid volume expansion, only isotonic fluids are considered safe and effective . Although some sources suggest that 0.45% saline can be used for slow correction of volume deficits , use of 0.45% saline in a volume depleted patient (who therefore has elevated ADH) will predictably lead to a drop in serum [Na]. Volume deficits are isotonic deficits, so should be replaced with isotonic fluid. This view is reflected in current recommendations [32, 34]. The composition of fluid used for ongoing losses depends on the type of fluid being lost.
Regardless of the recommendation to consider deficit replacement separately from maintenance fluid needs, it has been common practice to simply increase the rate of infusion of the maintenance fluid solution to "1.5 times or 2 times maintenance" in an effort to replace volume deficits that remain after bolus isotonic fluids have been given for rapid intravascular volume expansion. This practice was evident among the medical patients participating in the present study, who received study fluid at an average of 142% of the traditional maintenance rate. Our study design isolated the impact of differing maintenance fluid composition on [Na] in the context of current prescription practices.
As expected, we observed a significant increase in serum [Na] among patients in the 0.9% saline group. A smaller and slower, though not statistically significant, increase in [Na] was observed in the 0.45% saline group. This was not anticipated. Rather, we had hypothesized that patients randomized to receive hypotonic fluids would experience a drop in serum [Na]. The rationale for this hypothesis was that the patients enrolled in the study were at risk for high ADH secretion, stimulated by either volume depletion (appropriately) or the syndrome of inappropriate ADH secretion (due to pain, medications, pulmonary disease, etc.). Because free water excretion is impaired in the presence of ADH, the administration of hypotonic solutions to patients secreting ADH will inevitably lead to a fall in serum [Na] .
The fact that most children who received 0.45% saline did not experience a drop in [Na] suggests that most did not have an ongoing stimulus for ADH secretion. Adequate volume repletion with isotonic fluids prior to and during IV maintenance fluid administration likely protected patients against hyponatremia despite hypotonic maintenance fluids. Those who did experience a drop in [Na] can be assumed either to have not been adequately volume expanded (and therefore have ongoing physiologic volume-related stimulus for ADH secretion) or to have had inappropriate ADH secretion (non-physiologic, unpredictable ADH secretion). Children in the 0.9% saline group who experienced a decrease in [Na] were very likely to have had inappropriate ADH secretion; unless they developed new onset adrenal insufficiency, hypothyroidism, or renal salt wasting, inappropriate ADH secretion is the only reasonable explanation for a drop in [Na] in this group [25, 36].
The average rate of study fluid administration in both treatment groups was only slightly greater than the traditionally recommended maintenance rate. This likely also played a role in the relative stability in serum [Na]. Hypotonic fluids prescribed at high rates have been implicated in many of the reported deaths due to iatrogenic hyponatremia .
Two features of the study design may have resulted in bias toward finding no difference between treatment groups. First, the exclusion for safety reasons of children with baseline [Na] < 133 mmol/L or serious neurological disease may have eliminated those children at the highest risk for progressive hyponatremia. Second, this study focused on the first 12 hours of maintenance fluids. This was done in part for practical reasons, but also because we hypothesized that more pain and a greater degree of volume depletion would make this early period the period of highest risk for non-osmotic stimuli for ADH secretion. However, the syndrome of inappropriate ADH secretion may occur at any time, and may be more likely to occur later in the hospitalization, particularly in surgical patients [10, 27]. If the risk of inappropriately elevated ADH increases with increasing duration of hospitalization, then evaluating only the first 12 hours of IV fluids may have biased towards finding no difference between the groups.
This was a small trial. The small sample limited our ability to detect small differences between the two treatment groups. It is possible that both the observed difference between treatment groups and the change in [Na] in the 0.45% saline group would have been statistically significant with a larger sample. The relatively large proportion of patients who failed to complete the study was an additional limitation. There were some differences in the characteristics of patients who completed the study compared with those who did not. This may limit generalizability of findings.
It is also important to recognize that this study was designed to examine intermediate outcomes (rate of change in [Na], absolute change in [Na], exit [Na]) rather than a clinically important outcome (complications associated with choice of fluid). This was done for power reasons: clinical complications are rare and would require a very large sample. Complications of hyponatremia are believed to depend on both the magnitude of the serum [Na] and the rate of change; therefore, these were considered relevant outcomes. However, much larger trials, examining clinically important outcomes, are required to establish the safety of different maintenance fluids.
The most important finding of this study was that there was no decrease in [Na] in the 0.45% saline group; this can likely be attributed to judicious use of volume expansion with isotonic fluids and to the fact that, in most patients, study fluids were prescribed at rates generally not exceeding traditional maintenance rates. This result highlights the importance of considering maintenance fluids separately from deficit replacement.
It is important to recognize that there is no IV fluid strategy that will completely eliminate the risk of iatrogenic hyponatremia. Hypotonic fluids in the setting of subtle, unrecognized volume depletion will result in a drop in [Na]. In the setting of the syndrome of inappropriate ADH secretion, [Na] may fall even with isotonic fluids - although larger drops will occur with hypotonic fluids. The use of isotonic fluids may reduce the risk of important hyponatremia, but if tragic consequences of IV fluids are to be avoided, monitoring of serum [Na] is important.