Abstract
Background. Daily and globally, millions of adult hospitalized patients are exposed to maintenance i.v. fluid solutions supported by limited scientific evidence. In particular, it remains unclear whether fluid tonicity contributes to the recently established detrimental effects of fluid, sodium, and chloride overload.
Methods. This crossover study consisted of two 48 h study periods, during which 12 fasting healthy adults were treated with a frequently prescribed solution (NaCl 0.9% in glucose 5% supplemented by 40 mmol litre−1 of potassium chloride) and a premixed hypotonic fluid (NaCl 0.32% in glucose 5% containing 26 mmol litre−1 of potassium) at a daily rate of 25 ml kg−1 of body weight. The primary end point was cumulative urine volume; fluid balance was thus calculated. We also explored the physiological mechanisms behind our findings and assessed electrolyte concentrations.
Results. After 48 h, 595 ml (95% CI: 454–735) less urine was voided with isotonic fluids than hypotonic fluids (P<0.001), or 803 ml (95% CI: 692–915) after excluding an outlier with ‘exaggerated natriuresis of hypertension’. The isotonic treatment was characterized by a significant decrease in aldosterone (P<0.001). Sodium concentrations were higher in the isotonic arm (P<0.001), but all measurements remained within the normal range. Potassium concentrations did not differ between the two solutions (P=0.45). Chloride concentrations were higher with the isotonic treatment (P<0.001), even causing hyperchloraemia.
Conclusions. Even at maintenance rate, isotonic solutions caused lower urine output, characterized by decreased aldosterone concentrations indicating (unintentional) volume expansion, than hypotonic solutions and were associated with hyperchloraemia. Despite their lower sodium and potassium content, hypotonic fluids were not associated with hyponatraemia or hypokalaemia.
Clinical trial registration. ClinicalTrials.gov (NCT02822898) and EudraCT (2016-001846-24).
Editor’s key points
The physiological response to i.v. fluid therapy composition (tonicity, electrolytes, osmoles) and volume will determine risk of fluid overload.
Daily administration of several litres of commonly used i.v. crystalloid fluids will lead to electrolyte–salt overload in surgical patients.
This study found that an isotonic crystalloid fluid was associated with less urine output when compared with a hypotonic fluid.
More care should be used when prescribing perioperative fluid therapy; this is crucially important when larger volumes are administered over more than 24 h.
Maintenance i.v. fluid solutions are prescribed to cover the daily need for water and electrolytes in patients who are unable to ingest food or fluids. Ideally, they also contain dextrose or glucose to prevent starvation ketosis while awaiting full (par)enteral nutrition. Although maintenance fluids are used daily in hospitals worldwide, the scientific evidence guiding clinical practice is strikingly limited. Current guidelines are based on older dietary reference values, which by their very nature concern only oral intake.1–3 Our understanding of the human organism’s response to the tonicity of correctly dosed i.v. maintenance fluids remains an educated guess based on older physiological experiments.4 Previous studies showed that a large volume of isotonic fluid administered rapidly is excreted more slowly than an equal amount of a hypotonic solution.5–7 However, it remains unclear whether the tonicity of maintenance fluids could be a separate contributor to fluid overload and altered electrolyte concentrations. The scarce data on prescription practices demonstrate the frequent use of isotonic solutions, ignoring available guidelines.8
Important paediatric research emphasized the protective effect of isotonic maintenance solutions against hyponatraemia-induced morbidity compared with hypotonic solutions prescribed using the classical Holliday and Segar formula.9–12 Yet this use of isotonic fluids remains contested, even among paediatricians, some of whom have called for improved awareness of inappropriate (and appropriate, i.e. hypovolaemia-induced) secretion of antidiuretic hormone (ADH) instead of redundantly salt loading a large number of children.13,14 Furthermore, the design of the abovementioned trials, all of which focused on the occurrence of hyponatraemia, provided no insights into the deleterious potential of salt-rich solutions. Even more controversially, some authors recently suggested extrapolating the routine use of isotonic maintenance fluids to the adult setting.15 Not only are the symptoms of potential hyponatraemia less dramatic in this population but also the detrimental effects of fluid and salt overload are well known in the care of surgical and critically ill adult patients.16–19
We designed this study to test the hypothesis that isotonic fluids, even at maintenance rate, lead to lower urine output than their hypotonic counterparts. As a secondary end point, we explored possible physiological explanations by studying key players in volume regulation and osmoregulation. Furthermore, we aimed to investigate the impact of maintenance fluids on the serum concentration of various electrolytes, sodium, potassium, chloride, calcium, and phosphate. In many hospitals, it is routine practice to add hypertonic potassium chloride to maintenance fluids manually, although this is regarded as a high-risk medication.20 Premixed solutions have a better safety profile, but most commercially available solutions contain potassium in lower-than-recommended doses. Strong ion difference, a marker of fluid-induced metabolic acidosis, was also assessed.
Methods
We conducted a single-blind crossover study in 12 healthy volunteers at the Antwerp University Hospital, Belgium. In order to be eligible for the study, participants had to be between 18 and 70 yr of age, with a BMI of between 17 and 45 kg m−2 and an estimated glomerular filtration rate of >60 (ml−1 min−1 (1.73 m)−2.21 Exclusion criteria were acute medical illness in the 3 weeks before any of the study periods, the use of medication interfering with urine output, pregnancy, medical history of cardiac failure, malnourishment, diabetes mellitus, urological disease preventing complete emptying of the bladder, or any medical or non-medical issue preventing complaint-free fasting for 48 h. The study was approved by the hospital’s Institutional Review Board (reference number 16/15/175) and the relevant national authority, the Federal Agency for Medicines and Health Products, Belgium (EudraCT 2016-001846-24). Participants were recruited through advertising in the investigators’ institution. After selection, they received an information brochure and signed an informed consent form. The trial was registered at ClinicalTrials.gov (NCT02822898).
The study consisted of two study periods of 48 h, one for each maintenance solution. In order to ensure a balance in treatment sequence, subjects were matched by sex and BMI, after which each matched pair was allocated to the two treatment sequences as a block. To avoid any carryover effects, the two periods were separated by a 2 week washout period. The study was conducted in July and August 2016 in an air-conditioned facility to ensure a stable room temperature (∼20 °C). Subjects were admitted at 08.00 h after a normal night’s rest, having refrained from caffeinated drinks for at least 16 h and from any oral intake for at least 8 h before admission. Having asked the subjects to empty their bladders, we began infusion of the study fluid using an electronic infusion pump with an auditory alarm to detect obstruction. We blinded subjects to the treatment by concealing the fluids with opaque covers. To correct for insensible losses during the night, subjects were given identical breakfasts shortly after admission, during which they drank a fluid volume five times their infusion rate (see below). From then on, they refrained from any oral intake for the rest of the study period. The infusion ran until the first urination after 48 h of fluid administration. Each study period was permanently medically supervised by a trained intensivist.
The study fluids were administered at 25 ml kg−1 of body weight per day. When a subject’s BMI was between 25 and 30 kg m−2, we used the ideal body weight calculated using the formula of Devine.22 If the BMI was >30 kg m−2, the adjusted body weight was calculated by increasing the ideal body weight by 25% of the difference between the actual and ideal body weights. The isotonic solution was NaCl 0.9% in glucose 5% with an added 40 mmol of potassium chloride 7.45% (osmolarity 614 mOsm litre−1; tonicity 373 mOsm litre−1), so that a fluid volume of 25 ml kg−1 per day would represent a daily potassium dose of 1 mmol kg−1 of body weight. Notably, the addition of potassium chloride essentially renders this solution hypertonic, although potassium has a negligible effect on tonicity after administration. As for the hypotonic solution, we used a commercially available premixed solution (Glucion 5%®; Baxter Healthcare, Deerfield, IL, USA) containing sodium (54 mmol litre−1), potassium (26 mmol litre−1), chloride (55 mmol litre−1), phosphate (6.2 mmol litre−1), magnesium (2.6 mmol litre−1), and lactate (25 mmol litre−1; osmolarity 447 mOsm litre−1; tonicity 169 mOsm litre−1).
The primary end point was cumulative urine volume over the course of 48 h; fluid balance was thus calculated. Subjects emptied their bladders as the need arose, day or night. The exact urinary volume was determined by dividing its weight by its point-of-care-assessed density. Secondary end points were markers of volume regulation (the mineralocorticoid hormone aldosterone, urinary sodium, and serum albumin concentration) and osmoregulation (serum and urine osmolality, serum ADH, and thirst), and the serum concentration of clinically important electrolytes: sodium, potassium (especially as the hypotonic fluid contained a lower-than-guideline-recommended dose), chloride, phosphate, and calcium. Strong ion difference was also assessed.23 Clinical parameters were collected mainly for safety reasons and body weight as a back-up primary end point. In summary, the following variables were assessed. Each urine void was sampled for measurement of urinary osmolality, sodium, potassium, and chloride. At baseline (t0) and every 12 h (t12, t24, t36, and t48), we assessed body weight, blood pressure, heart rate, and a thirst score on a scale from 0 to 5. At t0, t24, and t48, blood was obtained for serum sodium, potassium, chloride, osmolality, magnesium, calcium, phosphate, albumin, ADH, and aldosterone, with additional assessments of sodium, chloride, and potassium at t12 and t36. Strong ion difference was calculated as: Strong ion difference = [Na+]+[K+]+[Ca2+]+[Mg++]−[Cl−].23 The technicalities and normal ranges of the laboratory analyses are reported in the Supplementary material (Table S1). The subjects’ usual dietary salt intake was approximated by assessing urinary sodium output by means of a 24 h urine collection 3–4 weeks after completion of the study.
Statistical analyses were performed using Stata 14 (StataCorp LP, College Station, TX, USA). Based on the literature, we assumed mean urinary outputs of 1250 ml for hypotonic solutions and 1050 ml for isotonic solutions during the trial period, both with an sd of 200 ml and an intrapatient correlation of 0.5.6 Using simulation (10 000 trials), we estimated that a sample size of 10 would give the study a power of 80% to detect a 200 ml difference in urine output between infusions with a two-sided α set at 5%. We included two extra subjects to compensate for unexpected dropouts. An anova of the area under the urinary output curve showed no sequence or period effects, so these were excluded from any further analysis. Absence of a carryover effect was assumed. Next, a random effects model was fitted for the primary end point, cumulative urine volume over the course of 48 h, with treatment, time, and their interaction as fixed effects and time as a random slope for each subject. Adjustment for body weight type (actual, ideal, adjusted) was evaluated using likelihood ratio tests and omitted in the absence of model improvement. The same procedure was followed for fluid balance and the more generalizable fluid balance per kilogram of actual body weight. Effect size was evaluated at t48. The difference in laboratory and clinical values (e.g. thirst score) between the two solutions was assessed with a random intercept model using treatment as fixed effect, the baseline value as a covariate, and all subsequent values as outcome. We fitted per-treatment mixed models using time (categorical) as a fixed effect and subject as a random effect to assess the difference in serum values since t0 within each treatment arm. Dunnett-adjusted P-values were used to correct for multiple testing. Statistical significance was set at a P-value of <0.05 (two-sided) for all tests. The results are reported with their 95% confidence intervals (CIs).
Results
The subjects’ characteristics and details of their fluid therapy are presented in Table 1. The effect of treatment on cumulative urine volume and fluid balance is shown in Fig. 1. In the isotonic treatment arm, the cumulative urine output at t48 (3060 ml; 95% CI: 2474–3647) was significantly lower than in the hypotonic treatment arm (3655 ml; 95% CI: 3069–4242; P<0.001); we observed a mean difference of 595 ml (95% CI: 454–735). This finding was reflected in the fluid balance, which was estimated to be 590 ml (95% CI: 450–729) or 8.9 ml kg−1 of actual body weight (95% CI: 7.2–10.5) higher at t48 with isotonic treatment (P<0.001). The raw data (black lines) revealed a clear outlier (§) characterized by an exceptionally large diuresis and a negative fluid balance in the isotonic arm. It is likely that this subject developed the exaggerated natriuresis sometimes seen in mild essential hypertension after the administration of saline.24,25 After omitting this subject from the subsequent sensitivity analysis, the difference in predicted urine output between the two solutions increased to 803 ml (95% CI: 692–915) and the difference in fluid balance to 794 ml (95% CI: 681–906) or 10.8 ml kg−1 (95% CI: 9.3–12.4).
Cumulative urine volume (primary end point) and fluid balance over the course of each study period. Black lines are individual observations per subject. Coloured lines are the marginal means estimated using the mixed effects model; the shaded areas represent 95% confidence intervals. Dashed lines are predicted values at 48 h (t48). §Outlier with exaggerated natriuresis; see text for details. The positive fluid balance at t0 is attributable to oral fluid intake (see Table 1).
Characteristics of the study population at the start of the first study period (n=12; 50% female) and the fluids administered during the two study periods
| Subject characteristics | Mean (sd) | Range | |||
|---|---|---|---|---|---|
| Age (yr) | 35 (10) | 18–56 | |||
| Body weight (kg) | 84 (31) | 52–142 | |||
| Height (cm) | 173 (12) | 154–191 | |||
| BMI (kg m−2) | 27 (8) | 19–45 | |||
| Systolic blood pressure (mm Hg) | 132 (17) | 98–160 | |||
| Estimated glomerular filtration rate21 (ml min−1 (1.73 m)−2) | 110 (13) | 91–130 | |||
| Dietary sodium intake (mmol day−1); 24 h urine collection | 133 (61) | 53–249 | |||
| Oral fluid intake at start of study period (ml) | 364 (85) | 245–521 | |||
| Infusion rate during first study period (ml h−1) | 73 (17) | 49–102 | |||
| Fluid therapy characteristics per day | Isotonic period | Hypotonic period | |||
| Mean (sd) | Mean (sd) | ||||
| Administered volume (ml day−1) | 1731 (410) | 1732 (411) | |||
| Administered sodium (mmol day−1) | 267 (63) | 94 (22) | |||
| Administered chloride (mmol day−1) | 323 (77) | 95 (23) | |||
| Administered potassium (mmol day−1) | 67 (16) | 45 (11) | |||
| Subject characteristics | Mean (sd) | Range | |||
|---|---|---|---|---|---|
| Age (yr) | 35 (10) | 18–56 | |||
| Body weight (kg) | 84 (31) | 52–142 | |||
| Height (cm) | 173 (12) | 154–191 | |||
| BMI (kg m−2) | 27 (8) | 19–45 | |||
| Systolic blood pressure (mm Hg) | 132 (17) | 98–160 | |||
| Estimated glomerular filtration rate21 (ml min−1 (1.73 m)−2) | 110 (13) | 91–130 | |||
| Dietary sodium intake (mmol day−1); 24 h urine collection | 133 (61) | 53–249 | |||
| Oral fluid intake at start of study period (ml) | 364 (85) | 245–521 | |||
| Infusion rate during first study period (ml h−1) | 73 (17) | 49–102 | |||
| Fluid therapy characteristics per day | Isotonic period | Hypotonic period | |||
| Mean (sd) | Mean (sd) | ||||
| Administered volume (ml day−1) | 1731 (410) | 1732 (411) | |||
| Administered sodium (mmol day−1) | 267 (63) | 94 (22) | |||
| Administered chloride (mmol day−1) | 323 (77) | 95 (23) | |||
| Administered potassium (mmol day−1) | 67 (16) | 45 (11) | |||
Characteristics of the study population at the start of the first study period (n=12; 50% female) and the fluids administered during the two study periods
| Subject characteristics | Mean (sd) | Range | |||
|---|---|---|---|---|---|
| Age (yr) | 35 (10) | 18–56 | |||
| Body weight (kg) | 84 (31) | 52–142 | |||
| Height (cm) | 173 (12) | 154–191 | |||
| BMI (kg m−2) | 27 (8) | 19–45 | |||
| Systolic blood pressure (mm Hg) | 132 (17) | 98–160 | |||
| Estimated glomerular filtration rate21 (ml min−1 (1.73 m)−2) | 110 (13) | 91–130 | |||
| Dietary sodium intake (mmol day−1); 24 h urine collection | 133 (61) | 53–249 | |||
| Oral fluid intake at start of study period (ml) | 364 (85) | 245–521 | |||
| Infusion rate during first study period (ml h−1) | 73 (17) | 49–102 | |||
| Fluid therapy characteristics per day | Isotonic period | Hypotonic period | |||
| Mean (sd) | Mean (sd) | ||||
| Administered volume (ml day−1) | 1731 (410) | 1732 (411) | |||
| Administered sodium (mmol day−1) | 267 (63) | 94 (22) | |||
| Administered chloride (mmol day−1) | 323 (77) | 95 (23) | |||
| Administered potassium (mmol day−1) | 67 (16) | 45 (11) | |||
| Subject characteristics | Mean (sd) | Range | |||
|---|---|---|---|---|---|
| Age (yr) | 35 (10) | 18–56 | |||
| Body weight (kg) | 84 (31) | 52–142 | |||
| Height (cm) | 173 (12) | 154–191 | |||
| BMI (kg m−2) | 27 (8) | 19–45 | |||
| Systolic blood pressure (mm Hg) | 132 (17) | 98–160 | |||
| Estimated glomerular filtration rate21 (ml min−1 (1.73 m)−2) | 110 (13) | 91–130 | |||
| Dietary sodium intake (mmol day−1); 24 h urine collection | 133 (61) | 53–249 | |||
| Oral fluid intake at start of study period (ml) | 364 (85) | 245–521 | |||
| Infusion rate during first study period (ml h−1) | 73 (17) | 49–102 | |||
| Fluid therapy characteristics per day | Isotonic period | Hypotonic period | |||
| Mean (sd) | Mean (sd) | ||||
| Administered volume (ml day−1) | 1731 (410) | 1732 (411) | |||
| Administered sodium (mmol day−1) | 267 (63) | 94 (22) | |||
| Administered chloride (mmol day−1) | 323 (77) | 95 (23) | |||
| Administered potassium (mmol day−1) | 67 (16) | 45 (11) | |||
On a physiological level, we made separate assessments of the processes responsible for regulating effective circulating volume (Fig. 2) and osmolality (Fig. 3). Figure 2 clearly shows that aldosterone concentrations were significantly lower (P<0.001) with isotonic treatment, as further illustrated by significantly higher concentrations of urine sodium (P<0.001) and osmolality (P=0.01). Serum albumin, which has been used as an experimental marker of plasma expansion, was lower with isotonic fluids (P=0.01).26 Serum osmolality (P=0.67) and ADH (P=0.22) did not differ significantly between and within solutions (Fig. 3). Thirst score, although increasing with both treatments, was not different between the two solutions (P=0.69).
Physiological factors involved in the regulation of effective circulating volume. In-graph P-values are for the difference between the two fluids. #Significantly different from t0 on a fluid-specific level (P<0.05). Coloured lines indicate the median value at t0 for each fluid. For representational purposes, urinary sodium and osmolality are the raw data shown as fractional polynomial prediction plots; shaded areas represent 95% confidence intervals.
Physiological factors involved in osmoregulation. In-graph P-values are for difference between fluids. #Significantly different from t0 on a fluid-specific level (P<0.05). Coloured lines indicate median value at t0 for each fluid.
The impact of each solution on the serum concentration of the various electrolytes is summarized in Fig. 4. No hyponatraemia or hypernatraemia (<135 or >145 mmol litre−1) was observed during the study. Serum sodium concentrations were significantly higher with the isotonic treatment than the hypotonic treatment (1.2 mmol litre−1; 95% CI: 0.7–1.7; P<0.001), but no significant change from baseline values was observed with either solution. Serum potassium concentrations did not differ significantly between the two solutions (P=0.45). One episode of hyperkalaemia (>5 mmol litre−1) was encountered with each of the treatments. Chloride concentrations were significantly higher with isotonic treatment than with hypotonic treatment (1.7 mmol litre−1; 95% CI: 1.2–2.2; P<0.001); the increase in the isotonic arm was significantly different from baseline at t12, t24, and t48, where six of 48 assessments after t0 (13%) exceeded the normal range. Strong ion differences were significantly lower with isotonic treatment (0.9 mEq litre−1; 95% CI: 0.2–1.6; P=0.01) and changed from baseline. For the hypotonic treatment, phosphate (P<0.001) and calcium (P=0.01) concentrations were significantly higher, although their serum concentrations largely remained within the normal range.
Serum concentration of various electrolytes and strong ion difference (SID) over the course of both study periods. In-graph P-values are for the difference between the two fluids. #Significantly different from t0 on a fluid-specific level (P<0.05). Black dashed lines represent the normal range of the electrolytes. Coloured lines indicate the median value at t0 for each fluid.
Discussion
Despite our growing awareness of the detrimental effects of perioperative volume, salt, and chloride overload, fluid research has focused almost exclusively on the resuscitation setting. Surprisingly, given their widespread use, this appears to be the first study to assess the effect of the tonicity of commonly prescribed maintenance solutions. This important characteristic of i.v. fluids is determined by the number of solutes to which cell membranes are impermeable. Despite contributing to the in vitro osmolality of a fluid, glucose crosses cell membranes rapidly after i.v. administration. As a result, only dissolved electrolytes contribute to the tonicity of a solution and exert an osmotic pressure gradient. Previous studies demonstrating the clinical impact of salt-poor perioperative maintenance therapy invariably involved the restriction of fluid volume, thereby precluding conclusions about the specific role of fluid tonicity.16,17 Although guidelines recommend a hypotonic maintenance strategy, the scarce observational data demonstrate that this advice is frequently ignored.8 We compared a premixed hypotonic fluid with a solution containing NaCl 0.9% in glucose 5% to which 40 mmol of potassium chloride was added manually to supply the subjects with the recommended amount potassium of 1 mmol kg−1 of body weight per day.1 Although conveniently termed isotonic, it should be acknowledged that this widespread practice essentially renders this solution hypertonic.
Our study not only showed that urine output was significantly lower after 2 days of isotonic vs hypotonic maintenance therapy, but also that the observed effect was remarkably substantial; isotonic retention exceeded 10 ml kg−1 of body weight. Previous evidence of the morbidity associated with a weight gain of 3 kg during a typical perioperative period underscores the importance of this finding.16 The stable fluid balance we observed in the absence of increased aldosterone suggests that both the fluid volume and its sodium content are appropriate during hypotonic treatment. As we followed our subjects for only 2 days, however, it is unclear at what point a new steady state (characterized by renewed correspondence between intake and renal sodium excretion) would be reached. Based on previous dietary experiments, we can assume that fluid retention would persist for 3–5 days.4 Even then, the contracted fluid gain would be maintained until several days after the cessation of the increased sodium administration.4
We explored several markers of volume regulation and osmoregulation, the two main adaptive physiological mechanisms that are potentially responsible for the observed findings. Osmoregulation did not appear to play a major role because serum osmolality, serum ADH, and thirst were not influenced by the type of the infusion fluid. On the contrary, the observed fluid retention with isotonic treatment could be explained by the reduction in aldosterone concentration, which acts as a marker of expanded effective circulating volume.4 This was further illustrated by the enhanced urinary sodium excretion and hinted at by the lower albumin concentrations in this treatment arm. We firmly believe that volume expansion is not the purpose of a routine maintenance prescription. Although it is usually the result of ADH secretion, the increase in urine osmolality can also be explained by isotonic plasma expansion without exceeding the osmoreceptor threshold. It is the consequence of compensatory water reabsorption at the level of the collecting tubule of the nephron after the reduced reabsorption of glomerular filtrate in the proximal tubule.27 Likewise, decreased proximal tubular reabsorption is the most plausible explanation for the lower serum calcium concentrations during isotonic treatment.4
Despite the large difference in the sodium content of the two solutions, no abnormal sodium concentrations were encountered, and no significant variation from baseline value was observed. Of course, the incidence of inappropriate or appropriate ADH secretion is virtually non-existent in healthy subjects, and our finding does not contradict recent findings on paediatric maintenance prescription.9,10 However, as these studies considered the incidence of hyponatraemia in isolation, their conclusions might overlook the potentially important detrimental effects of salt-rich solutions. Our data indicate that these solutions could expose patients to unintended plasma expansion and fluid retention, even at maintenance rate; the consequences of this fact require further examination. Current guidelines recommend the administration of 1 mmol of potassium per kilogram of body weight, but the 26 mmol litre−1 content in the hypotonic solution was sufficient to keep serum potassium concentrations unchanged from baseline and well within the normal range. The two episodes of hyperkalaemia recorded in a total of 120 measurements are likely to have been coincidental, especially as they were encountered in both treatment arms.
Chloride was the only electrolyte affected substantially by the isotonic solution, even frequently causing hyperchloraemia and a decreased strong ion difference, an established cause of metabolic acidosis.28 It is common practice to add potassium manually in the form of concentrated potassium chloride to infusion fluids. In our study, this resulted in the administration of a remarkable 323 (77) mmol of chloride per day with the isotonic treatment [vs 95 (20) mmol using the hypotonic fluid]. The potential importance of these findings is illustrated by a recent study demonstrating the association between a chloride-rich fluid strategy and a higher incidence of acute kidney injury in critically ill patients.29 Recently, a large chloride load was also shown to be associated with an unfavourable impact on various renal parameters in healthy volunteers.30,31 It is plausible that the ill-considered prescription of maintenance solutions is responsible for a substantial portion of iatrogenic chloride load, perhaps more so than resuscitation fluids, which are better researched but used for shorter periods.
Our study had certain limitations. First, to be able to measure the effect size as precisely as possible, we designed the study as a crossover experiment including only healthy volunteers rather than patients. Although we attempted to counteract this issue by selecting broad inclusion criteria, mimicking real life as closely as possible, the applicability of our findings to certain patients is unclear. In particular, the management of maintenance fluids in patients who are already fluid expanded or have renal failure requires exploration. The role of essential hypertension also remains unclear, as exaggerated natriuresis was clearly present in one of our subjects who had not previously been diagnosed with hypertension.25 The extent and incidence of this phenomenon is unknown. Nonetheless, we believe our findings could easily be extrapolated to the majority of hospitalized patients in view of the 48 h fasting setting that resembles the clinical use of maintenance therapy. Finally, it is difficult to assess the definitive clinical impact of our findings, because the exact mechanisms behind the deleterious effect of fluid and salt overload require elucidation in many patient populations, including the critically ill. Only a set of well-designed clinical trials, performed in different subgroups, will be able to clarify this issue.
Conclusions
At the guideline-recommended dose, isotonic vs hypotonic maintenance solutions caused the retention of a potentially clinically relevant amount of fluid, characterized by decreased serum aldosterone concentrations that indicate volume expansion, which is not the intent of maintenance fluid therapy. In the absence of appropriate or inappropriate secretion of ADH, the hypotonic solution did not cause sodium abnormalities and, despite its lower potassium content of 26 mmol litre−1, serum potassium concentrations remained well within normal limits. The use of NaCl 0.9% supplemented by hypertonic potassium chloride caused a substantial chloride load and hyperchloraemia. In view of the widespread use of maintenance fluids, trials with carefully chosen end points are needed to address their safety in different clinical settings.
Authors’ contributions
Study design: N.V.R., T.V.d.W., T.D.W., A.V.C., K.D., W.V., P.J., M.M.
Drafting the protocol: N.V.R., T.V.d.W., PJ.
Advice on the statistical analysis: E.R., T.V.d.W.
Advice on the physiological explanation behind the findings: T.D.W., A.V.C., W.V.
First draft of the manuscript. N.V.R.
Study coordinator and guarantor: N.V.R.
All authors have read and approved the final draft. All authors had full access to all of the data.
Supplementary material
Supplementary material is available at British Journal of Anaesthesia online.
Acknowledgements
We are indebted to Petra Vertongen for essential logistical support before, during, and after the two extremely intense study periods and to our subjects for their endurance. We also wish to thank our laboratory staff, Nina Jansoone, Gwladys Verstraete, Jan Van Den Bossche, and Laurence Roosens, for their expert handling of countless serum and urine samples.
Declaration of interest
N.V.R. has received speaker’s fees from Baxter Belgium and resided in a medical advisory board organized by Baxter Healthcare, USA. M.M. reports speaker’s fees from Maquet (Getinge Group) and is member of the medical advisory board. N.V.R. and M.M. are co-chairmen of the International Fluid Academy, a not-for-profit organization promoting education on fluid management and haemodynamic monitoring that received sponsoring from the industry. The other authors declare no conflicts of interest.
Funding
Baxter Belgium SPRL; Department of Intensive Care Medicine of the Antwerp University Hospital, Belgium; International Fluid Academy (www.fluidacademy.org; educational grant to cover open access publication costs for this article).
Comments
We read with interest the comments by Leroy et al. and Moritz et al., mainly focusing on the occurrence of hyponatremia after the use of hypotonic maintenance solutions, an association extensively demonstrated in paediatric populations. First and foremost, we set out to investigate whether, how and how much fluid retention could be induced by isotonic compared to hypotonic maintenance fluid therapy[1]. All prior studies focused almost exclusively on the occurrence of hyponatraemia, thereby systematically neglecting this potential side effect. Although the clinical impact remains to be judged in dedicated trials, fluid retention of the size we observed in our experiment will not be regarded as trivial by most physicians dealing with postoperative or critical care[2-5]. The effect size after being exposed to salt-rich solutions for more than 48 hours, as frequently encountered in clinical practice, can be expected to be even more substantial. There is no reason to suppose that our findings on fluid retention would be different in a situation of non-osmotic stimulation of antidiuretic hormone (ADH).
We fully acknowledge that iatrogenic hyponatraemia is an important phenomenon, at least when viewed in the right perspective. The largest of the mentioned trials, of which we do not seek to minimize the findings, reported a significant difference in symptomatic hyponatraemia: it was encountered in 0.3% of cases when using isotonic maintenance solutions, compared to 2% under hypotonic treatment[6]. The question that needs to be answered urgently is whether it is clinically acceptable to induce unnecessary salt and fluid overload in the vast majority of patients (98.3%, using the same data) to protect the remaining 1.7% from harm. This is especially true when putting non-osmotic ADH-stimulation and subsequent hyponatraemia in perioperative or critical care into their right context by regarding them as markers of an underlying problem rather than an issue with the fluid itself. This is illustrated by the fact that hyponatremia was repeatedly found to be associated with worse outcomes, while symptoms of fluid-induced hyponatraemia are rarely encountered, especially in adults. Also in this debate, association seems to have been confused with causality. Regular assessments of serum and urine sodium are key to identify patients at risk and protect them from harm by treating the underlying problem. Together with others, we believe the most important cause of non-osmotic stimulation of antidiuretic hormone is hypovolemia, occurring sometimes very subtly and thus remaining frequently undetected[7]. This situation prompts treatment with isotonic resuscitation fluids before even considering the administration of maintenance fluids.
One of the other concerns raised is the challenge imposed by the injudicious extrapolation of findings in healthy individuals to the clinical setting, thereby overlooking the issue of non-osmotic stimuli of ADH-production. In our view, our study setting resembles at least part of the stress level of certain clinical situations in which maintenance fluids are prescribed. Being a study subject in an elaborate 48-hour, intensively supervised experiment, spending a total of four sleep-deprived nights in a research facility with noisy volumetric pumps and bothersome infusion catheters in both arms, experiencing hunger, thirst and weight loss, being venepunctured and weighed every few hours, all the while having to precisely collect every drop of urine, is not what many would regard as a normal, unstressful situation. Nevertheless, we agree with this limitation of our study and therefore designed the double blind randomized controlled TOPMAST-trial (clinicaltrials.gov identifier NCT03080831) to assess not only fluid balance, but also the occurrence of electrolyte disorders due to maintenance fluids in a setting of major surgery in adult patients. Currently, half of the subjects are recruited and the first results are to be expected in the beginning of 2018.
Regarding our choice of study solutions, Drs. Leroy and Hoorn consider NaCl 0.9% with an added 40 mmol litre-1 of potassium as inferior and advocate the use of balanced solutions because of their lower chloride content. Common examples of such fluids are Hartmann solution (chloride 111 mmol/L), Ringer's acetate (112 mmol/L) and PlasmaLyte® (98 mmol/L). It should be considered that, besides commonly not containing glucose or dextrose, not one of these solutions contains more than 4-5 mmol litre-1 of potassium. This is far less than recommended by guidelines and necessary to protect patients from hypokalaemia. To prevent or treat this important electrolyte disorder, most clinicians will choose to administer extra potassium chloride, thereby renouncing the advantages of these low-chloride solutions. Our hypotonic comparator combines the advantages of a low chloride content (55 mmol/L), while supplementing enough potassium and still being a balanced solution due to its strong ion difference of around 30 mEq litre -1. Drs. Moritz and Ayus hint at the safety of isotonic fluids used in the SPLIT-trial[8]. We would like to point out that only fluids for resuscitation were evaluated in this study, while the prescription of maintenance fluids remained at the discretion of the treating clinicians. This was reflected in the overall very low volumes of the study solutions (median 2000 mL during the whole ICU stay). In these amounts, it is unlikely that the slightly different chloride content would have caused a detectable difference in harm, especially since over two litres of isotonic fluids were already administered prior to enrolment. The clinical importance of chloride loading and/or hyperchloraemia remains a matter of debate, but it should be unwise to minimize the abundant recent safety signals[9-11].
Niels Van Regenmortel
Philippe Jorens
On behalf of all the co-authors
1. Van Regenmortel N, De Weerdt T, Van Craenenbroeck AH, et al. Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers. Br J Anaesth 2017; 118(6): 892-900.
2. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002; 359(9320): 1812-8.
3. Murphy CV, Schramm GE, Doherty JA, et al. The importance of fluid management in acute lung injury secondary to septic shock. Chest 2009; 136(1): 102-9.
4. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care 2014; 4: 21.
5. Vaara ST, Korhonen AM, Kaukonen KM, et al. Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study. Crit Care 2012; 16(5): R197.
6. McNab S, Duke T, South M, et al. 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet 2015; 385(9974): 1190-7.
7. Holliday MA, Ray PE, Friedman AL. Fluid therapy for children: facts, fashions and questions. Arch Dis Child 2007; 92(6): 546-50.
8. Young P, Bailey M, Beasley R, et al. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA 2015; 314(16): 1701-10.
9. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308(15): 1566-72.
10. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Annals of surgery 2012; 256(1): 18-24.
11. Van Regenmortel N, Verbrugghe W, Van den Wyngaert T, Jorens PG. Impact of chloride and strong ion difference on ICU and hospital mortality in a mixed intensive care population. Ann Intensive Care 2016; 6(1): 91.
Van Regenmortel et al[6] conducted and prospective study in 12 healthy adult volunteers comparing an isotonic solution to a hypotonic solution to assess if isotonic fluids were associated with complications in comparison to hypotonic fluids. They concluded that hypotonic fluids could be used safely as it was not associated with hyponatremia and that their results could be extrapolated to most hospitalized patients. This is not a valid conclusion, as they studied healthy volunteers who did not have stimuli for AVP production. Their results can’t be generalized to acutely-ill patients. Any fluid would be expected to be safe when used at maintenance rates in healthy individuals. They can’t conclude from this study that hypotonic fluids are safe to be used in acutely ill hospitalized patients, when all data suggests otherwise.
Hyponatremia is extremely prevalent in hospitalized patients and is associated with increased mortality.[7, 8] It has been long known that acutely-ill patients have stimuli for AVP which lead to hyponatremia, and this is particularly so in post-operative patients.[9, 10] The primary factor leading to hyponatremia is the use of hypotonic fluids. There are over 20 prospective pediatric trial in almost 3000 patients which have consistently demonstrated that isotonic fluids significantly decrease the incidence of hyponatremia in comparison to hyponatremic fluids without any apparent harm.[11, 12] A recent study of post-operative adults demonstrated that the incidence of hyponatremia could be decreased from 51% to 16% by using an isotonic solution in favor of hypotonic solution.[13] In the recently published SPLIT trial, over 2000 adults in the intensive care unit received isotonic fluids and there was no evidence that this approach was unsafe.[14]
Regenmortel at al suggested that isotonic fluids were associated with decreased urine output and a higher chloride concentration. Both the fluid retention and change in chloride were of no clinical significance though, and are not a sufficient justification to use a hypotonic fluid which is known to produce harm in acutely ill patients. Hypotonic fluids can’t be recommended in acutely ill adults due to significantly increased risk of producing hyponatremia, and this is particularly so in the post-operative patient who are at the highest risk for hyponatremia.
1. Moritz, M.L. and J.C. Ayus, Maintenance Intravenous Fluids in Acutely Ill Patients. N Engl J Med, 2015. 373(14): p. 1350-60.
2. Moritz, M.L. and J.C. Ayus, Prevention of hospital-acquired hyponatremia: a case for using isotonic saline. Pediatrics, 2003. 111(2): p. 227-30.
3. Moritz, M.L. and J. Carlos Ayus, Hospital-acquired hyponatremia--why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol, 2007. 3(7): p. 374-82.
4. Arieff, A.I., J.C. Ayus, and C.L. Fraser, Hyponatraemia and death or permanent brain damage in healthy children. BMJ, 1992. 304(6836): p. 1218-22.
5. Ayus, J.C., J.M. Wheeler, and A.I. Arieff, Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med, 1992. 117(11): p. 891-7.
6. Van Regenmortel, N., et al., Effect of isotonic versus hypotonic maintenance fluid therapy on urine output, fluid balance, and electrolyte homeostasis: a crossover study in fasting adult volunteers. Br J Anaesth, 2017. 118(6): p. 892-900.
7. Holland-Bill, L., et al., Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients. Eur J Endocrinol, 2015. 173(1): p. 71-81.
8. Wald, R., et al., Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med, 2010. 170(3): p. 294-302.
9. Anderson, R.J., et al., Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med, 1985. 102(2): p. 164-8.
10. Chung, H.M., et al., Postoperative hyponatremia. A prospective study. Arch Intern Med, 1986. 146(2): p. 333-6.
11. McNab, S., et al., Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. Cochrane Database Syst Rev, 2014. 12: p. CD009457.
12. McNab, S., et al., 140 mmol/L of sodium versus 77 mmol/L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-blind trial. Lancet, 2015. 385(9974): p. 1190-7.
13. Okada, M., et al., Comparison of the incidences of hyponatremia in adult postoperative critically ill patients receiving intravenous maintenance fluids with 140 mmol/L or 35 mmol/L of sodium: retrospective before/after observational study. J Anesth, 2017.
14. Young, P., et al., Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA, 2015. 314(16): p. 1701-10.
1 Department of Paediatrics, Division of Paediatric Critical Care, Maastricht University Medical Centre, Maastricht, The Netherlands ([email protected])
2 Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Centre, Rotterdam, The Netherlands
Editor - Sick patients who are unable to ingest oral fluids usually receive intravenous maintenance fluid therapy (IVMFT). IVMFT’s main goal is to temporarily meet the body’s water, electrolyte and glucose needs, pending a more sustainable (par)enteral solution for feeding and hydration. Despite its routine application, IVMFT is still often based on dogmatic principles rather than high quality empirical research.(1) Furthermore, macro- and micronutrient deficiencies, fluid overload, hyperchloraemic acidosis and hyponatraemia have all been repeatedly reported as potentially detrimental complications. Fortunately, well-designed high quality studies performed over the last decade have substantially improved our insights in what is safe and effective IVMFT. Recently, Van Regenmortel and colleagues contributed additional data to this growing body of evidence by comparing the effects of isotonic and hypotonic IVMFT in healthy adult volunteers.(2) They conclude that a hypotonic IVMFT (NaCl 0.32%) increased diuresis and resulted in significantly less intravascular fluid retention compared to isotonic IVMFT (NaCl 0.9%). In line with a previous report by this group, the authors argue that IVMFT should be hypotonic in order to avoid fluid overload.(3)
We fully concur that fluid overload can negatively impact on outcomes and should be avoided at all times. The study findings are, however, in strong contradiction with the rapidly growing evidence that favours the use of isotonic balanced solutions for IVMFT in sick patients.(4) A closer look at the study by Van Regenmortel et al. illustrates why its external validity to draw meaningful conclusions on IVMFT in sick patients is limited.
The study findings are not a surprise. Basic physiological principles explain that the distribution volume of isotonic fluids is limited to the extracellular fluid compartment (ECF) (which includes the intravascular space), whereas hypotonic solutions will diffuse over the extracellular and intracellular compartments.(5) In addition, any hypotonic infusion in healthy humans will lead to a minimal decrease of plasma osmolality. This change, sensed by hypothalamic osmoreceptors, switches off antidiuretic hormone (ADH) release and hence decreases water reabsorption in the renal collecting ducts. As a consequence free water excretion will increase and osmotic homeostasis is maintained. This explains the absence of hyponatraemia, as this would only occur if maximal free water excretion capacity is overwhelmed or in the presence of so-called non-osmotic stimuli for ADH. The fact that the authors still detected ADH levels does not exclude the above mechanism, because ADH assays are not very sensitive for low concentrations.(6)
In sick patients, however, free water excretion is frequently impaired due to non-osmotic stimuli for ADH secretion. Decreased circulating volume (even subclinical), pain, nausea, anxiety, stress, certain drugs and inflammation have all been shown to trigger ADH release and to overrule the ‘normal’ osmoregulation.(7), (8) Such non-osmotic ADH release is a common response to sickness and is highly prevalent in hospitalized patients. In this setting hypotonic infusions can cause hyponatraemia due to the retention of water in the ECF. This acute drop in ECF osmolality can cause potentially life-threatening cerebral oedema, mainly in sick children.(9-11) Furthermore, hyponatraemia is increasingly recognized as an independent risk factor for adverse outcomes.(12)
An additional issue with the study by Van Regenmortel et al. is the use of NaCl 0.9% as the isotonic infusion. The high chloride load predictably caused a hyperchloraemic acidosis. Hyperchloraemic acidosis is increasingly recognized as a factor that impairs microcirculation and kidney function.(13), (14) Therefore it cannot be excluded that a decrease in microvascular renal circulation partially explains the lower urine production in the group that received NaCl 0.9%. Time has come to agree that NaCl 0.9% is not ‘a physiological solution’ or ‘normal saline’, but rather ‘an abnormal acidogenic solution’ that in no way deserves the epithet ‘physiological’. Fortunately hyperchloraemic acidosis can be prevented by the use of more balanced isotonic solutions.(15)
In conclusion, we believe that this study compared two inferior solutions in a non-representative (i.e. healthy) group of study participants lacking the non-osmotic ADH triggers that many of our sick patients have. This study provides no evidence whatsoever to favour the use of hypotonic solutions for IVFMT in sick patients. In our opinion, the evidence-lacking part of this debate is no longer about the optimal fluid composition but rather the amount of fluid that we calculate as normal daily intake. The latter is, unfortunately, still mainly based on dogmas and traditions.(1)
Declaration of Interest
None declared
References:
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