Advertisement

Intensive Care Medicine

, Volume 45, Issue 2, pp 275–277 | Cite as

Is chloride worth its salt?

  • Scott L. WeissEmail author
  • Franz E. Babl
  • Stuart R. Dalziel
  • Fran Balamuth
Editorial

Intravenous infusion of salt water to restore circulating blood volume traces its origins to the 1830s cholera pandemic. In a letter to the Lancet dated June 2, 1832, Thomas Latta noted with intravenous saline (of unknown composition) “improvement in the pulse and countenance is almost simultaneous, the cadaverous expression gradually gives place to appearances of returning animation, the livid hue disappears, the warmth of the body returns” [1]. In 1896, Hartog Jakob Hamburger recognized erythrocytes did not lyse in a saline solution and concluded that “the blood of man was isotonic with a NaCl solution of 0.9%”. Although human plasma is closer to 0.6% NaCl, the use of 0.9% “normal” saline became widespread. Other crystalloid solutions with a more buffered electrolyte composition, including lactated Ringer’s, Hartmann’s, and PlasmaLyte, were also introduced into clinical practice. Despite a burgeoning literature about the risks of saline-induced hyperchloremia and acidemia compared to buffered crystalloids, 0.9% saline remains the overwhelming preference for fluid resuscitation, particularly in children [2].

In this issue of Intensive Care Medicine, Barhight and colleagues report an association of hyperchloremia (serum chloride ≥ 110 mEq/L) at admission to the pediatric intensive care unit (PICU) and an increase in chloride of ≥ 5 mEq/L (↑ Cl ≥ 5 mEq/L) on the first calendar day of PICU admission with in-hospital mortality, length of stay, and days on mechanical ventilation among a retrospective cohort of 1,935 general PICU admissions to a single center [3]. Unadjusted mortality was highest (40%) in those with both hyperchloremia and ↑ Cl ≥ 5 mEq/L, although this group was small. The authors used logistic regression to further test the association of hyperchloremia with mortality after adjusting for 19 covariates selected a priori. Although there are some methodologic concerns about the construction of the final multivariable model (e.g., overfitting, collinearity, selection and testing of potential interaction effects), ↑ Cl ≥ 5 mEq/L conferred a 2.3 (95% CI 1.03, 5.21) increased adjusted odds of death. Notably, ↑ NA ≥ 5 mEq/L was also associated with death (adjusted OR 3.53, 95% CI 1.55, 8.05), and rise in sodium appeared more closely associated with mortality than rise in chloride in an analysis stratified by volume of PICU fluid administered on the first day. Interpretation of these findings requires caution in light of potential for measurement bias, with sicker patients most likely to have serial electrolyte assessments and the possibility of unmeasured confounding. However, this study offers another piece of evidence that hyperchloremia can have real consequences for patients, including children.

Most pediatric hyperchloremia is iatrogenic, secondary to the large chloride burden—154 mEq/L—present in 0.9% saline. In addition, an increase in blood chloride has been shown to reduce renal blood flow and glomerular filtration, thereby exacerbating reabsorption of sodium and chloride by the kidney. Saline-induced hyperchloremia is also generally accompanied by a metabolic acidosis due to the dilution of plasma bicarbonate in the absence of an alternative buffer. Hyperchloremic metabolic acidosis is pro-inflammatory in cell culture experiments [4] and, although its clinical relevance is debated, has been associated with mortality. In healthy volunteers, infusion of 0.9% saline caused more abdominal discomfort, drowsiness, and impaired cognition than buffered fluids [5]. Moreover, as in the study by Barhight and colleagues, chloride load has been associated with acute kidney injury (AKI), need for renal replacement therapy, and mortality in adult and pediatric patients [6, 7].

While not yet a settled issue, there are now ample data to support the hypothesis that resuscitation with buffered fluids may improve outcomes compared to 0.9% saline (Table 1) [8, 9, 10, 11, 12, 13, 14, 15]. Although absolute benefit is likely to be small, given that millions require fluid resuscitation worldwide each year, even a high “number needed to treat” could translate to a substantial public health benefit. Recently, two large pragmatic trials totaling 29,149 adults demonstrated a small but significant reduction in adverse kidney events and death with use of buffered fluids, although these results were generally confined to patients with predicted mortality of ~ 20–50% [11, 12]. It is uncertain how generalizable these results may be, especially to the pediatric population with a lower ICU mortality. The two largest studies comparing buffered fluids and 0.9% saline in children are contradictory. We conducted a matched analysis of 4234 children with septic shock from 382 US hospitals and did not find superiority for either fluid for death, AKI, or dialysis [13]. In contrast, a propensity-matched analysis of 10,318 septic PICU patients from 43 US hospitals reported 2.1% lower mortality and 0.9% less frequent dialysis with buffered fluids [8]. Reflecting this uncertainty, pediatric sepsis guidelines have not yet prioritized any particular type of crystalloid fluid.
Table 1

Studies comparing 0.9% saline to balanced fluid resuscitation

Study

Population

Design

Sample size

Outcome

0.9% saline (%)

Balanced (%)

P Value

Yunos et al. 2012 [15]

Adult ICU

Pre/post

1533

Mortality

15

13

0.44

Raghunathan et al. 2014 [10]

Adult sepsis

Matched cohort

6730

Mortality

23

20

0.001

Yunos et al. 2012 [15]

Adult ICU

Pre/post

1533

AKI

14

8.4

< 0.001

SPLIT Trial 2015 [14]

Adult ICU

Cross-over

2092

AKI

9.2

9.6

0.77

Self et al. 2018 [11]

Adults

RCT

13,347

MAKE30

5.6

4.7

0.01

Semler et al. 2018 [12]

Adult ICU

RCT

15,802

MAKE30

15.4

14.3

0.04

Weiss et al. 2017 [13]

Pediatric sepsis

Matched cohort

4234

Mortality

7.9

7.2

0.20

Emrath et al. 2017 [8]

Pediatric sepsis/ICU

Matched cohort

10,318

Mortality

15

13

0.051

Ngo et al. 2001 [9]

Pediatric dengue fever

RCT

222

Shock recovery

93

80

0.022

ICU intensive care unit, RCT randomized controlled trial, NA not applicable, RR relative risk, CI confidence interval, AKI acute kidney injury, MAKE30 major adverse kidney events by 30 days

Should we adjust current clinical practice to minimize hyperchloremia? Unfortunately, the answer remains unclear, especially for children. Despite suggestions of benefit, there are some practical challenges to consider. Lactated Ringer’s and Hartmann’s solution are both hypotonic and have been shown to lower blood osmolality, increase brain water content, and transiently raise intracranial pressure [16]. Infants with a disproportionally large brain and patients with an injured blood–brain barrier may be at particularly high risk of cerebral edema with hypotonic buffered solutions. The presence of calcium may also lead to microvascular thromboses, and some patients with liver failure or very young age (< 6 months) may have a reduced ability to metabolize exogenous lactate. Moreover, patients randomized to receive lactated Ringer’s for dengue fever were slower to recover from shock compared to saline [9]. More recent buffered formulations of Plasma-Lyte are limited by a cost that is several times that of other crystalloids and lack data about compatibility with other intravenous medications.

We agree with Barhight and colleagues that the time has come for a comparative effectiveness trial to “address the risks [and benefits] of 0.9% sodium chloride solution versus buffered fluid resuscitation in high-risk critically ill children.” One hundred and eighty-six years since Dr. Latta’s extraordinary observation, one such trial, the Pragmatic Pediatric Trial of Balanced vs Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study, is underway (Clinicaltrials.gov NCT03340805) with plans for a larger multicenter trial to follow.

Notes

Funding

Funding was contributed by NIGMS K23GM110496 (SLW).

Compliance with ethical standards

Conflicts of interest

Dr. Weiss and Dr. Balamuth are the co-Principal Investigators for the PRoMPT BOLUS trial but have no financial conflicts of interest to report. Professors Babl and Dalziel have no conflicts of interest to report.

References

  1. 1.
    Baskett TF (2002) William O’Shaughnessy, Thomas Latta and the origins of intravenous saline. Resuscitation 55:231–234CrossRefGoogle Scholar
  2. 2.
    Long E, Babl F, Dalziel S, Dalton S, Etheridge C, Duke T, Paediatric Research in Emergency Departments International C (2015) Fluid resuscitation for paediatric sepsis: A survey of senior emergency physicians in Australia and New Zealand. Emerg Med Australas 27:245–250CrossRefGoogle Scholar
  3. 3.
    Barhight MF, Brinton J, Stidham T, Soranno DE, Faubel S, Griffin B, Goebel J, Mourani PM, Gist KM (2018) Increase in chloride from baseline is independently associated with mortality in critically ill children. Intensiv Care Med.  https://doi.org/10.1007/s00134-018-5424-1 Google Scholar
  4. 4.
    Kellum JA, Song M, Li J (2004) Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 286:R686–R692CrossRefGoogle Scholar
  5. 5.
    Chowdhury AH, Cox EF, Francis ST, Lobo DN (2012) 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. Ann Surg 256:18–24CrossRefGoogle Scholar
  6. 6.
    Sen A, Keener CM, Sileanu FE, Foldes E, Clermont G, Murugan R, Kellum JA (2017) Chloride content of fluids used for large-volume resuscitation is associated with reduced survival. Crit Care Med 45:e146–e153CrossRefGoogle Scholar
  7. 7.
    Stenson EK, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald JC, Checchia PA, Meyer K, Quasney M, Hall M, Gedeit R, Freishtat RJ, Nowak J, Raj SS, Gertz S, Grunwell JR, Wong HR (2018) Hyperchloremia is associated with complicated course and mortality in pediatric patients with septic shock. Pediatr Crit Care Med 19:155–160CrossRefGoogle Scholar
  8. 8.
    Emrath ET, Fortenberry JD, Travers C, McCracken CE, Hebbar KB (2017) Resuscitation with balanced fluids is associated with improved survival in pediatric severe sepsis. Crit Care Med 45:1177–1183CrossRefGoogle Scholar
  9. 9.
    Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, Chu VT, Nguyen TT, Simpson JA, Solomon T, White NJ, Farrar J (2001) Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 32:204–213CrossRefGoogle Scholar
  10. 10.
    Raghunathan K, Shaw A, Nathanson B, Sturmer T, Brookhart A, Stefan MS, Setoguchi S, Beadles C, Lindenauer PK (2014) Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med 42:1585–1591CrossRefGoogle Scholar
  11. 11.
    Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, Slovis CM, Lindsell CJ, Ehrenfeld JM, Siew ED, Shaw AD, Bernard GR, Rice TW, Investigators S-E (2018) Balanced Crystalloids versus saline in noncritically Ill adults. N Engl J Med 378:819–828CrossRefGoogle Scholar
  12. 12.
    Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW, Investigators S, the Pragmatic Critical Care Research G (2018) Balanced crystalloids versus saline in critically Ill adults. N Engl J Med 378:829–839CrossRefGoogle Scholar
  13. 13.
    Weiss SL, Keele L, Balamuth F, Vendetti N, Ross R, Fitzgerald JC, Gerber JS (2017) Crystalloid fluid choice and clinical outcomes in pediatric sepsis: a matched retrospective cohort study. J Pediatr 182:304–310CrossRefGoogle Scholar
  14. 14.
    Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R, Investigators S, Anzics CTG (2015) 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 314:1701–1710CrossRefGoogle Scholar
  15. 15.
    Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M (2012) Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572CrossRefGoogle Scholar
  16. 16.
    Tommasino C, Moore S, Todd MM (1988) Cerebral effects of isovolemic hemodilution with crystalloid or colloid solutions. Crit Care Med 16:862–868CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology and Critical Care, Pediatric Sepsis Program, and the Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  2. 2.Department of PediatricsUniversity of MelbourneMelbourneAustralia
  3. 3.Emergency DepartmentRoyal Children’s HospitalMelbourneAustralia
  4. 4.Emergency ResearchMurdoch Children’s Research InstituteMelbourneAustralia
  5. 5.Departments of Surgery and Pediatrics, Child and Youth HealthUniversity of AucklandAucklandNew Zealand
  6. 6.Children’s Emergency DepartmentStarship Children’s HospitalAucklandNew Zealand
  7. 7.Department of Pediatrics and Pediatric Sepsis ProgramChildren’s Hospital of Philadelphia, University of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

Personalised recommendations