Introduction
Large volumes of intravenous (IV) crystalloids are frequently given for the purpose of resuscitating critically ill or postoperative patients [
1]. While there is general agreement regarding the benefits of fluid resuscitation, there is significant variation in the type and amount of fluid used, and the debate regarding the ideal resuscitation fluid is ongoing [
2]. Crystalloids most commonly used for resuscitation are 0.9 % “normal” saline, which contains supra-physiologic levels of sodium and chloride (154 mmol/L), and “balanced” crystalloids such as Ringer’s lactate, Hartmann’s, Ringer’s acetate or Plasma-Lyte
® (Baxter Healthcare, Deerfield, IL, USA), which typically have more physiological electrolyte concentrations (98–112 mmol/L chloride; 130–140 mmol/L sodium) [
1].
Recent guidelines recommend the use of balanced crystalloids for fluid resuscitation; however, these guidelines have been scrutinized because of a lack of supportive evidence from prospective randomized trials [
3,
4]. When compared to balanced crystalloids, 0.9 % saline has been extensively studied in large randomized trials in critically ill patients and remains widely used [
5‐
7]. Infusion of 0.9 % saline induces hyperchloraemia and metabolic acidosis in healthy individuals and surgical patients [
8‐
13]. Similarly, resuscitation of critically ill patients with crystalloids containing supra-physiologic chloride concentrations has been associated with higher rates of hyperchloraemia, metabolic acidosis and clinical complications versus resuscitation with balanced crystalloids [
14‐
19].
Recent studies indicate that elevated serum chloride is associated with serious clinical consequences in certain inpatient populations. Hyperchloraemia has been shown to be independently associated with increased mortality in intensive care unit (ICU) and postsurgical patients, and the amount of chloride received via IV infusion has been identified as an important and potentially modifiable cause of hyperchloraemic acidosis [
20,
21]. Fluid choice may therefore impact outcomes in patients requiring infusion of large IV fluid volumes.
While studies have examined mortality in patients receiving crystalloids with different chloride concentrations [
11,
16,
22‐
25], the relative contributions of chloride load and fluid volume to mortality risk remain unclear. The current study examined data from a large US electronic health record (EHR) database. We investigated the association between chloride load and in-hospital mortality among patients meeting systemic inflammatory response syndrome (SIRS) criteria who received IV crystalloids, with and without adjustment for the total fluid volume administered. SIRS patients represent an important population, given that they are frequently administered large volumes of chloride-containing fluids, as well as the known associations between hyperchloraemia and adverse outcomes in surgical and critically ill patients.
Methods
Design and patients
This study retrospectively analysed prospectively collected US inpatient data between 1 January 2009 and 31 March 2013, sourced from the HealthFacts
® (Cerner Corp., Kansas City, MO) EHR database and was approved by the Duke University IRB. Inclusion criteria (Supplementary Fig. 1) were prospectively defined to identify hypovolaemic patients requiring fluid resuscitation, and included age ≥18 years; presence of SIRS criteria (tachycardia [HR > 90 bpm] plus any of the following: (1) temperature >38 or <36 °C; (2) ≥20 breaths/min or PaCO
2 ≤ 32 mmHg; (3) leukocytes ≥12,000 or ≤4,000 cells/mm
3); receipt of >500 mL crystalloid resuscitation solution within 2 days of SIRS qualification (≥2 administrations >250 mL); and hospitalization ≥24 h. Tachycardia was required for inclusion because it is readily captured in the database and can be used as a clinical marker for hypovolaemia [
26]. Crystalloid resuscitation solutions included 0.9 % saline, Ringer’s lactate and other balanced crystalloids. Dextrose-containing solutions (e.g. 5 % dextrose in water) were also included in total fluid volume, but were considered maintenance fluids and did not count toward resuscitation volume inclusion requirements. Patients receiving any fluid containing hydroxyl-ethyl starch or albumin, plasma protein fraction (PPF), hypertonic saline or 0.45 % saline, or receiving >1 L total fluid on the day preceding SIRS qualification were excluded. Gelatins (Gelofusine
®, Haemaccel
®) are unavailable in the USA, and were not specified as exclusion criteria. Patients undergoing cardiac procedures (Supplementary Table 1) were excluded, as were patients with end-stage renal disease (ESRD; ICD-9 585.6), since large-volume resuscitation is infrequently used for patients with ESRD.
Data source
HealthFacts® is a de-identified, Health Insurance Portability and Accountability Act (HIPAA)-compliant, US EHR database covering 486 clinical facilities and hospital systems. The study dataset was extracted from the database such that duplicates and entries with missing/incomplete data were removed. Care was taken to avoid multiple counts of patient encounters, such that the dataset represents individual patients.
Analysis and statistics
Patient demographics and surgical procedures undergone prior to SIRS qualification and coded as primary or secondary were collected (Table
1). Primary discharge diagnoses (final, billing, discharge), the most well-populated diagnosis fields in the database, are reported. Elixhauser comorbidities were identified using Agency for Healthcare Research and Quality (ARHQ) criteria and comorbidity scores were calculated according to published methodology [
27,
28]. Baseline and peak chloride concentrations were defined as the lowest concentration on the day of SIRS qualification and highest concentration within 72 h following SIRS qualification, respectively. Change in concentration was defined as the difference between baseline and peak values.
Table 1
Summary of patient characteristics
Age |
Mean (SD) | 58.9 (18.8) |
Median (range) | 60 (18–90) |
18−50 years, n (%) | 35,635 (32.4) |
51–64 years, n (%) | 28,673 (26.1) |
≥65 years, n (%) | 45,528 (41.5) |
Gendera
|
Female, n (%) | 60,124 (54.7) |
Male, n (%) | 49,658 (45.2) |
Race |
White, n (%) | 71,880 (65.4) |
Black, n (%) | 29,143 (26.5) |
Hispanic, n (%) | 1,911 (1.7) |
Asian/Pacific, n (%) | 1,325 (1.2) |
Other, n (%) | 4,250 (3.9) |
Not specified, n (%) | 1,327 (1.2) |
Most common primary discharge diagnosesb,c
|
Pneumonia, n (%) | 10,075 (9.2) |
Septicaemia, n (%) | 7,454 (6.8) |
General symptoms, n (%) | 7,295 (6.6) |
Symptoms involving respiratory system and other chest symptoms, n (%) | 6,962 (6.3) |
Other symptoms involving abdomen and pelvis, n (%) | 5,600 (5.1) |
Patients undergoing surgical procedure prior to SIRS qualification, n (%)d
| 1,562 (1.4) |
APS |
Mean (SD) | 7 (6) |
Median (range) | 6 (0–45) |
Elixhauser comorbidity score |
Mean (SD) | 4 (7) |
Median (range) | 3 (−18 to 54) |
Total IV fluid volumes and chloride/sodium loads were examined for the day preceding SIRS qualification for inclusion/exclusion, and from the day of SIRS qualification plus 3 days (72 h) for outcome analysis. Total volumes were determined by summing volumes for all resuscitation and maintenance solutions with product size >250 mL, in order to avoid volumes commonly used for drug delivery/admixture. Volumes were determined by (1) the EHR “order volume” field, or (2) label bag volume for the National Drug Code (NDC) for the order. Total chloride load was calculated by summing the chloride content for all solutions >250 mL. Chloride load was adjusted for fluid volume received by dividing total mmol chloride by total fluid volume. We refer to this measure, expressed in mmol/L, as the “volume-adjusted chloride load.” “Volume-adjusted sodium load” was determined using the same methodology.
Patients were prospectively grouped in 10 mmol/L increments for analysis of serum chloride concentration and volume-adjusted chloride or sodium load, 100 mmol increments for analysis of chloride load, and 1,000 mL increments for analysis of fluid volume. Mortality was determined by the database discharge value of “deceased,” and rates were compared between groups using a two-proportion z test. To control for multiple comparisons, a Bonferroni correction was applied to calculated P values by multiplying by the number of pairwise comparisons. A P value <0.05 was used to define statistical significance. Regression functions and 95 % confidence intervals were weighted on the basis of the number of patients in each group, and appropriateness of fit was assessed using the coefficient of determination (R
2) and P value of the regression model.
Mortality odds ratios (ORs) associated with volume-adjusted chloride load were calculated with and without adjustment for severity of illness using the acute physiology score (APS) [
29]. ORs represent mortality odds associated with a 10 mmol/L incremental increase in volume-adjusted chloride load (for data points <105 and ≥105 mmol/L). Post hoc analysis examined ORs associated with a 1 mmol/L incremental increase in volume-adjusted chloride load for data below, within, and above the 98–110 mmol/L range, which is the normal serum chloride range reported by hospitals in the database.
Discussion
This study demonstrates an association between greater amounts of chloride received during crystalloid resuscitation and increased in-hospital mortality, even after controlling for total fluid volume received. While previous studies have compared mortality in patients receiving balanced versus unbalanced crystalloids [
11,
16,
22‐
25], this is, to our knowledge, the first study to specifically examine whether the relationship between crystalloid chloride content and mortality is attributable to the chloride load independent of fluid volume.
The observed association between greater chloride loads and increased in-hospital mortality is not entirely surprising, since the infusion of chloride-rich fluids is itself associated with hyperchloraemia [
8‐
13], which has been associated with a greater likelihood of poor patient outcomes [
20,
21]. Consistent with previous reports, this study found elevated mortality rates in patients who would generally be classified as hyperchloraemic [
20,
21]. Similarly, large changes in serum chloride concentration, suggesting a shift to a hyperchloraemic state, correlated with greater in-hospital mortality, supporting the idea that maintenance of physiologic serum chloride levels may be important. These findings contribute to the growing observational evidence of the potentially serious clinical impact of using chloride-rich crystalloids. Two recent studies using data from a large US claims database demonstrated an elevated risk of several complications in patients receiving 0.9 % saline versus a balanced crystalloid [
18,
23].
In-hospital mortality was observed to increase with greater total chloride loads. Similarly, mortality tended to increase with increased total fluid volume, consistent with findings from the FACTT (Fluid and Catheter Treatment Trial) and trials in surgical patients showing associations between fluid overload and morbidity and mortality [
31‐
33]. Our observations within defined volume strata and based on volume-adjusted total chloride loads indicate that mortality may be related to the chloride load independent of fluid volume. An exception to the trend of increasing mortality within resuscitation fluid volume strata was observed among the lowest volume group (<1,500 mL), which may reflect the low total chloride loads received by patients in this group (0–300 mmol), and further, the importance of appropriate fluid resuscitation in hyperchloraemic patients. The observed trend in patients receiving ≥1,500 mL (increasing mortality with increasing chloride load) may reflect the potential risks of resuscitation with chloride-liberal fluids. With respect to volume-adjusted chloride load, in-hospital mortality was generally low (<4 %) among patients receiving 105–145 mmol/L chloride, with the lowest mortality among patients receiving 105–115 mmol/L. Post hoc analysis found increasing mortality odds with increasing volume-adjusted chloride load >110 mmol/L, indicating potential risks associated with chloride loads exceeding normal serum concentration ranges. These observations are particularly meaningful given that balanced crystalloids with chloride concentrations in the normal physiological range are readily available, though not widely utilized among this patient population, as the large majority (>80 %) of patients primarily receive 0.9 % saline [
1,
5]. While increasing fluid volume was associated with increased mortality (Fig.
2b), controlling for total volume does not specifically control for severity of illness. We therefore examined associations between volume-adjusted chloride load and mortality by controlling for severity of illness using the APS. The lack of a meaningful effect on mortality ORs suggests that the association between volume-adjusted chloride load and mortality was not driven by severity of illness.
It is noteworthy that mortality was elevated in the small group of patients (<2.5 % of the study population) who received relatively low volume-adjusted chloride loads (<105 mmol/L). Potential explanations include the receipt of relatively large proportions of dextrose-containing maintenance fluids, which contain lower chloride concentrations, rather than active resuscitation. Particularly high-acuity patients may have died before receiving adequate resuscitation or fluid administration may have been limited because of concerns related to comorbidities such as congestive heart failure in which higher sodium loads are not tolerated and carry a high mortality rate.
Recent evidence indicates risks associated with high sodium loads and suggests that hyperchloraemic metabolic acidosis and hypernatraemia may be independent complications associated with fluid infusion [
34]. While our study found a potential association between sodium load and mortality, the ability to fully separate sodium load from volume and tonicity is limited, and this question may warrant further study. Studies examining outcomes in light of relative differences in chloride and sodium load may provide important insights.
While the reasons for the association between increased mortality and elevated chloride levels remain to be fully elucidated, important clinical consequences of hyperchloraemia are known [
10,
12,
13,
20,
21,
35]. High serum chloride concentrations following infusion of 0.9 % saline are associated with reduced renal artery flow velocity, renal cortical tissue perfusion and longer time to urination [
10,
12,
13]. Additionally, animal studies have implicated hyperchloraemia in effects on the immune system [
36,
37], altered blood oxygen binding [
38] and organ damage [
39].
In summary, this study demonstrates an association between IV chloride load and mortality in hospitalized patients with SIRS, independent of total fluid volume. Given the study’s predefined fluid inclusion criteria, our findings may not be generalizable to all SIRS patients. Still, these findings support existing published data suggesting that fluid composition and volume both have important effects on clinical outcomes. Because the study was observational, the associations are hypothesis-generating and highlight the need for randomized controlled trials powered to detect outcome differences in patients resuscitated using different crystalloids. A multicentre study comparing 0.9 % saline and a balanced crystalloid is underway [
40]. When viewed together with the existing literature, our findings may not represent evidence that high-chloride solutions are harmful “beyond a reasonable doubt” (they are observational), but the balance of probabilities appears to be shifting away from high-chloride and toward low-chloride solutions for first-line fluid resuscitation of patients with SIRS.
Acknowledgments
This study was funded by Baxter Healthcare, Deerfield, IL, USA. The authors thank David Hayashida, Eoin O’Connell and Victor Khangulov of Boston Strategic Partners for statistical support.