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Hyperchloremia in the Neurocritically Ill Patient

By Currents Editor posted 06-28-2018 15:58

By Caroline Der Nigoghossan, PharmD, BCCCP, and Shivani Ghoshal, MD (pictured)

NCS_201806_Hyperchloremia_headshot.jpgIntravenous crystalloid administration is one of the most common interventions performed in critically ill patients. However, during the last decade, a growing body of literature suggests potential harm with 0.9 percent sodium chloride (also known as normal saline) and its associated hyperchloremia, most notably in the critically ill.

In actuality, the adjective “normal” is a misnomer; 0.9 percent sodium chloride solution contains a supraphysiologic chloride concentration of 154 mEq/L – 40-60 percent higher than normal human plasma levels. Hyperchloremia itself may lead to nonanion gap metabolic acidosis and has been associated with renal dysfunction, among other complications. On the other hand, balanced crystalloids contain organic anions such as acetate and lactate, which are then metabolized to bicarbonate and electrolyte concentrations similar to human plasma. Clinicians may be reluctant to use some of the balanced crystalloids in patients with hyperkalemia, hypercalcemia, hyponatremia, hyperlactatemia and cerebral edema.

The majority of studies comparing 0.9 percent sodium chloride to balanced crystalloids (Table 1) thus far have been conducted in general critical ill populations and large studies including neurocritically ill patients are lacking. In 2012, Yunos et al. studied the association of chloride-restrictive versus chloride-liberal intravenous fluid administration with acute kidney injury (AKI) in a mixed-bed intensive care unit (ICU). The group found that a chloride-restrictive strategy among their critically ill patients was associated with a significant decrease in both the incidence of AKI as well as the use of renal replacement therapy (RRT).1 Subsequent large retrospective analyses have also found association between higher chloride loads and in-hospital mortality in patients with systemic inflammatory response syndrome and septic shock, even after controlling for received volume and other confounding variables.2,3 The much-awaited double-blind, cluster-randomized, double-crossover 2015 SPLIT feasibility trial did not show reduced incidence of kidney injury in critically ill patients receiving buffered crystalloid versus 0.9 percent sodium chloride. Both groups showed a low utilization of RRT and low mortality. The study was limited by unreported serum chloride levels, relatively low volumes of administered fluids and low patient acuity, making it poorly generalizable. The majority of patients were admitted following elective surgery, with a mean APACHE II score of 14 and a median two liters of fluid administered in both groups.4

The most recent Isotonic Solutions and Major Adverse Renal Events Trial (SMART) published by Semler et al. at Vanderbilt, is the largest trial to date comparing the use of balanced crystalloids (Lactated Ringer’s or Plasma-Lyte A) versus 0.9 percent sodium chloride in the critically ill. Five intensive care units were randomized to a sequence of alternating crystalloid group on a monthly basis. Relative contraindications to balanced crystalloids included hyperkalemia and brain injury and decision to use saline instead was left to the clinician’s preference. Fewer patients in the balanced crystalloids group had a plasma chloride > 110 mEq/L (24.5 percent versus 35.6 percent, p<0.001). The primary endpoint was a composite of major adverse kidney events
within 30 days: new renal replacement therapy, persistent renal dysfunction (defined as an increase of the serum creatinine by ≥ 200 percent from baseline), and death from any cause. The composite endpoint occurred less in the balanced-crystalloids group, a difference that was mirrored in the subgroup analysis of neurologic ICU patients. Although the effect size was low, the widespread use of crystalloids renders this difference clinically significant. These results were inconsistent among patients with traumatic brain injury; however, clinicians had the option of administering 0.9 percent sodium chloride for these patients regardless of group assignment, making conclusions difficult to be drawn for this patient population.5

Hyperchloremia is often seen as a necessary evil in management of the neurocritically ill, where hypertonic saline is a mainstay treatment for increased intracranial pressure (ICP). Two recent studies, summarized in Table 1, have evaluated the impact of hyperchloremia in neurocritically ill patients. The first, by Riha et al., evaluated the impact of hyperchloremia (chloride ≥ 115 mEq/L) in a multicenter retrospective propensity-matched cohort study of intracerebral hemorrhage (ICH) patients with continuous infusion of 3 percent hypertonic saline. Patients exhibiting hyperchloremia were associated with a higher incidence of inhospital mortality, though patients in the hyperchloremia group had lower baseline Glascow Coma Scale score, higher ICH score, and required more mechanical ventilation and cerebrospinal fluid diversion.

After adjusting for differences between both groups by propensity score matching, in-hospital mortality and AKI still occurred more frequently in the hyperchloremia group.6 Another retrospective analysis from Sadan et al. evaluated AKI prevalence in patients with subarachnoid hemorrhage. Patients with AKI were found to have higher Hunt and Hess scores, longer duration of mechanical ventilation and ICU length of stay compared to patients without AKI. Additionally, these patients received more hypertonic saline (3 percent or 23.4 percent NaCl) treatment, had higher mean serum creatinine, chloride and sodium concentrations during their ICU stay. The authors identified male gender, hypertension, abnormal admission creatinine, mean serum chloride concentration and hypertonic saline therapy as predictors of AKI development.7 In both studies, patients in the AKI group were sicker and older, and it is difficult to determine if the mortality difference between both groups was a result of hyperchloremia, a higher incidence of AKI, or a higher severity of illness in the hyperchloremic patients.

Despite study limitations in the literature evaluating the impact of hyperchloremia in neurocritically ill patients, the available data in the critically ill suggests that hyperchloremia should not be disregarded in patient care. Growing evidence prompts clinicians to develop new strategies to reduce chloride accumulation in patients with ICP crises. An alternative strategy includes the use of mixed sodium acetate/sodium chloride solutions for both crisis and continuous infusion therapies. Further research is similarly needed to evaluate the role of isotonic balanced crystalloids containing physiologic sodium concentration (e.g. Plasma-Lyte) for fluid resuscitation in neurocritically ill patients.

Table 1: Summary of major trials evaluating the use of crystalloids and/or hyperchloremia in critically ill patients.


Patient Population

Study Design

Study Groups

Major Outcomes

Yunos et al

JAMA 20121



Multidisciplinary ICU



 diagnosis (8%)

Prospective, open label, sequential period pilot study

CL (0.9% NaCl, 4% gelatin, 4% albumin)



CR (Hartmann solution, PL-148, chloride-poor 20% albumin)


Kidney injury and failure*:

CL 14% vs. CR 8.4%

(p <0.001)



CL 10% vs. CR 6.3% (p=0.005)


ICU mortality:

CL 9% vs. CR 8% (p=0.42)

Young et al

JAMA 20154


Postsurgical (72%)


Neurological operative admission (3%)


Traumatic brain injury (3%)


Double-blind, cluster randomized, double-crossover

0.9% NaCl






Kidney injury or failure*:

0.9% NaCl 9.2% vs. PL-148 9.6% (p=0.77)



0.9% NaCl 3.3% vs. PL-148 3.4% (p=0.91)


ICU mortality:

0.9% NaCl 6.6% vs. PL-148 7.2% (p=0.62)

Semler et al

N Engl J Med5 2018


Five ICUs (medical, cardiac, neurologic, trauma, surgical)


Neuroscience ICU



Traumatic brain injury (9%)




Pragmatic, unblended, cluster randomized, multiple crossover trial

0.9% NaCl



BC: PL-A or LR


^Major adverse kidney event within 30 days:

All cohort: 0.9% NaCl 15.4% vs. BC 14.3% (p=0.04)


Neuroscience ICU: 0.9%NaCl 10.2% vs. BC 8.1% (p=0.04)


TBI: 0.9% NaCl 14% vs. BC 15% (p=0.58)



0.9% NaCl 2.9% vs. BC 2.5% (p=0.08)


ICU mortality:

0.9% NaCl 7.3% vs. BC 6.6% (p=0.08)

Riha et al

Crit Care Med6 2017


Neurosciences ICUs


Intracerebral hemorrhage receiving continuous 3% hypertonic saline


Multicenter, retrospective, propensity-matched cohort






+AKI in propensity-matched cohort:

Hyperchloremia 34% vs. nonhyperchloremia 14%



In-hospital mortality in propensity-matched cohort:

Hyperchloremia 34% vs. nonhyperchloremia 14%



Logistic regression analysis:

Hyperchloremia predicts in-hospital mortality

(OR 4.4; 95% CI, 1.4-13.5)

Sadan et al

Crit Care Med7 2017


Subarachnoid hemorrhage

Retrospective analysis






In-hospital mortality:

AKI 28.3% vs. no AKI 6.1% (p<0.001)


Logistic regression analysis to evaluate for risks for AKI:

10 mEq/L increase in mean serum chloride (OR 7.39; 95% CI, 3.44-18.23)

CL: chloride liberal fluids; CR: chloride restricted fluids; PL-148: Plasma-Lyte 148; 0.9% NaCl: 0.9% sodium chloride; PL-A: Plasma-Lyte A; LR: Lactated Ringer’s solution; BC: balanced crystalloids; TBI: traumatic brain injury

*Per RIFLE criteria; ^Composite of death from any cause, new renal replacement therapy or renal dysfunction,+per AKIN criteria, #per KDIGO criteria


1. Yunos NMM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566-72.
2. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med 2014;42:1585-91.
3. Shaw AD, Raghunathan K, Peyerl FW, et al. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Med 2014;40:1897-905.
4. 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. JAMA 2015;314:1701-10.
5. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829-39.
6. Riha HM, Erdman MJ, Vandigo JE, et al. Impact of moderate hyperchloremia on clinical outcomes in intracerebral hemorrhage patients treated With continuous infusion hypertonic saline: A pilot study. Crit Care Med 2017; 45:e947-53.
7. Sadan O, Singbartl K, Kandiah PA, et al. Hyperchloremia is associated with acute kidney injury in patients with subarachnoid hemorrhage. Crit Care Med 2017;45:1382-8.

#LeadingInsights #Pharmacy #CarolineDerNigoghossan #ShivaniGorshal #June2018 ​​​​​
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