Chloride in Critical Illness

Reviewed and revised 21 March 2017

OVERVIEW

• Chloride is the major anion in the extracellular fluid (ECF) and is the second most important contributor to plasma tonicity
• The possibility of harm from hyperchloraemia, particularly in the context of fluid resuscitation with chloride-rich solutions such as normal saline, is an area of intense research interest
• If chloride excess is harmful it may be an important confounder in studies that suggest that positive fluid balance is harmful in ICU patients
• Some expert clinicians advocate the use of chloride-poor balanced salt solutions in preference to normal saline for fluid resuscitation, replacement and maintenance
• The major trial of buffered crystalloids versus normal saline in ICU patients, the SPLIT trial, found no difference in rates of acute kidney injury (AKI), rates of renal replacement therapy or in-hospital mortality.

PHYSIOLOGY

Daily chloride intake

• 133 to 202 mmol or 7.8 to 11.8 g/day for adult men (USA)
• 99 to 133 mmol or 5.8 to 7.8 g/day for adult women(USA)

Renal excretion is the primary means of chloride elimination

• 180 mmol/d chloride excreted (99.1% of filtered is reabsorbed)
• renal proximal tubules are the major site of reabsorption
• distal intercalated cells also involved (type A cells: proton efflux, type B cells: HCO3 efflux, chloride reabsorption)
• chloride reabsorption involves members of the solute carrier (SLC) gene families SLC26 (primarily chloride-anion exchangers) and SLC4 (primarily chloride-bicarbonate and anion exchangers and sodium-bicarbonate co-transporters)

Chloride effect on the kidneys

• The macula densa is a collection of densely packed epithelial cells at the junction of the thick ascending limb (TAL) and distal convoluted tubule (DCT)
• detection of high sodium chloride concentrations by the macula densa leads to tubuloglomerular feedback: constriction of the afferent arteriole causing a decreased glomerular filtration rate (GFR)

CAUSES OF CHLORIDE ABNORMALITIES

Hypochloraemia

• Chloride loss
  • Diuretic therapy
  • Significant gastric drainage
  • Vomiting
  • Chronic respiratory acidosis
• Water gain in excess of chloride
  • Congestive cardiac failure
  • Syndrome of inappropriate ADH secretion
  • Excessive infusion of hypotonic solutions

Hyperchloraemia

• Chloride infusion
  • Administration of chloride-rich fluids (most common and most modifiable cause)
  • Total parenteral nutrition
• Pure water loss
  • Skin losses
  • Fever
  • Hypermetabolic states
  • Renal losses
  • Central diabetes insipidus
  • Nephrogenic diabetes insipidus
• Water loss in excess of chloride loss
  • Extrarenal loss
  • Diarrhoea
  • Burns
  • Renal loss
  • Osmotic diuresis
  • Post-obstructive diuresis
  • Intrinsic renal disease
• Definite or relative increase in tubular chloride reabsorption
  • Renal tubular acidosis
  • Recovery of diabetic ketoacidosis
  • Early renal failure
  • Acetazolamide
  • Urinary diversion procedures
  • Post hypocapnia

HYPERCHLORAEMIC ACIDOSIS

• hyperchloraemia results in acidosis when there is a concomitant reduction in the SID (strong ion difference)
• If is unchanged, then hyperchloraemia will not result in an acidosis
• thus chloride must be interpreted in the context of other strong ions, especially sodium – if sodium increases to the same extent as chloride, then SID is unchanged

NORMAL SALINE

• Normal saline is the most widely used IV fluid worldwide and is the most used fluid in RCTs of critically ill patients
• 0.9 % saline is neither normal nor physiological — the concentration of chloride in 0.9 % saline is approximately 1.5 times that of normal plasma

POTENTIAL ADVERSE EFFECTS OF CHLORIDE RICH FLUIDS

From Yunos et al, 2010:

• hyperchloraemic acidosis
  • saline resuscitation in sepsis animal models found that
    1. chloride accounts for a large portion of the acid load (~40%, much higher than lactate)
    2. chloride levels correlate with hypotension, and
    3. after controlling for hypotension, greater cytokine release seen with worse hyperchloraemic acidosis
• decreased renal blood flow and GFR, decreased urine output and acute kidney injury
  • chloride infusion and hyperchloraemia associated with renal vasoconstriction and decreased GFR in animal models and human volunteers
  • additional associations found in important human trials outlined below (but not the 2015 SPLIT trial)
• abdominal discomfort and abnormal mental changes
  • found in a Ringer’s lactate vs saline infusion cross-over trial in human volunteers by Williams et al, 1999
• possible gut hypoperfusion
  • trends in animal studies; see Wilkes et al, 2001
• hypocoagulation
  • associated with HES in saline versus HES in balanced salt solutions in human volunteers and surgical patients

EVIDENCE

The potential adverse effects of saline and hyperchloraemia listed above are largely based on animal models and small studies in human volunteers. The best trial to date, the 2015 SPLIT trial, did not find harm associated with use of normal saline. Thus the evidence base is weak. Additional important human studies are outlined below.

Wilkes et al, 2001

• RCT of balanced salt solutions versus saline-based fluids in elderly surgical patients
• “use of balanced IV solutions prevented hyperchloremic metabolic acidosis and provide better gastric mucosal perfusion compared with saline-based fluids”

Shaw et al, 2012

• observational study
• “calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline”

Yunos et al, 2012

• open-label prospective before-and-after study evaluating the effect of a restricting the use of chloride-rich fluids among critically ill patients
• the chloride-restrictive strategy was associated with a decreased incidence of acute kidney injury and need for dialysis
• this study is critically flawed as the chloride-rich study was heavily confounded by the use of gelofusin, whereas no gelofusin was given to the chloride-poor arm
• the findings in this study could be due to “restricting chloride, using balanced solutions containing lactate, stopping a commercial 4% gelatin solution, using more 20% albumin and less 4% albumin, giving less sodium, delivering more potassium, or any combination of these!” to quote the authors

McCluskey et al, 2013

• retrospective cohort trial; n >20,000
• found an association between hyperchloremia and poor postoperative outcome (including mortality and renal dysfunction)

SPLIT trial, 2015

• Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand (including one cardiothoracic ICU)
• n = 2278 ICU patients requiring crystalloid fluid therapy, >99% of eligible patients included and followed up
• Patients with established AKI requiring renal replacement therapy (RRT) were excluded
• plasmalyte (a low-chloride, acetate rich, buffered crystalloid) versus normal saline (0.9% NaCl)
• primary outcome: proportion of patients with AKI at 90 days (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality
• Findings: no significant difference in primary or secondary outcomes
  • AKI:102/1067 (9.6%) plasmalyte versus 94/1025 (92%) NS (ARR 0.4% [95% CI, −2.1% to 2.9%]; RR = 1.04 [95% CI, 0.80 to 1.36]; P = .77)
  • RRT: 38/1152 (3.3%) plasmalyte  versus 38/1110 (3.4%) NS (ARR −0.1% [95% CI, −1.6% to 1.4%]; RR, = 0.96 [95% CI, 0.62 to 1.50]; P = .91)
  • Mortality in hospital: 87/1152 (7.6%) versus plasmalyte versus 95/1110 (8.6%) NS (ARR −1.0% [95% CI, −3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40)
• Conclusion: Saline use, compared to plasmalyte, did not increase the risk of AKI. No other harms were found either.
•  Criticisms and commentary:
  • can this finding be generalised to other types of buffered crystalloids?
  • are there subgroups of patients, or high risk groups, that might still benefit from avoiding chloride-rich fluids?
  • patients received about 2L of crystalloid, if a higher dose of saline was given, might this be harmful?

PLUS study…

• a proposed follow up to the SPLIT trial that will be the largest trial ever conducted in critical care medicine intended to be the definitive study of plasmalyte versus saline in the critically ill (expected 8,800 patients)
• a subgroup analysis of the SPLIT trial, not published in the original paper, found a statistically non-significant increase in mortality with saline (~19%) compared to plasmalyte (~15%) when elective surgery patients and patients discharged alive <24 hours were excluded
• primary outcome will be mortality at 90 days
• will include chloride measurements
• trial fluids will be used for both maintenance and bolus therapy, with participants anticipated to receive about 20L of the trial fluids over the course of their ICU stays

CONTROVERSIES

• How common is hyperchloraemia in the ICU?
• Is hyperchloraemia an independent predictor of death or other adverse outcomes?
• Or does hyperchloraemia only matter when associated with SID changes or acidaemia?
• Can the elimination of chloride-rich fluids lead to clinical benefits?
• Does baseline chloride matter when administering chloride-rich fluids?
• Are all buffered crystalloids equivalent in patient effects, in comparison to chloride-rich fluids?

CONCLUSION

• There remains equipoise about the relative benefits and harms of normal saline compared with balanced salt solutions, the current evidence base is weak
• Normal saline is an acceptable resuscitation fluid, however consideration may be given to limiting it’s use to < ~2L (~20-30 mL/kg) to avoid hyperchloraemic acidosis and potential complications

References and Links

Journal articles

• Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27:(2)179-88. [pubmed]
• Eisenhut M. Adverse effects of rapid isotonic saline infusion. Arch Dis Child. 2006;91:(9)797. [pubmed]
• McCluskey SA, Karkouti K, Wijeysundera D, Minkovich L, Tait G, Beattie WS. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg. 2013;117:(2)412-21. [pubmed]
• Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255:(5)821-9. [pubmed]
• Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88:(5)999-1003. [pubmed]
• Young PJ, Joannidis M. Crystalloid fluid therapy: is the balance tipping towards balanced solutions? Intensive Care Med. 2014;40:(12)1966-8. [pubmed] [free full text]
• 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;1-10. [free full text]
• Yunos NM, Bellomo R, Story D, Kellum J. Bench-to-bedside review: Chloride in critical illness. Crit Care. 2010;14(4):226. doi: 10.1186/cc9052. Epub 2010 Jul 8. Review. PubMed PMID: 20663180; PubMed Central PMCID: PMC2945073.
• Yunos N, 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):1566-1572 [pubmed] [free full text]

FOAM and web resources

• CCR Meeting 2016 — Saline or Plasmalyte: is SPLIT the Solution? by Paul Young (2016)
• Essential Critical Care — Interview with Prof John Myburgh on PLUS trial and Simon Finfer on Buffered Salt Solutions (both ANZICS CTG meeting 2017)
• Is chloride a poison? (talk by David Story at smaccGOLD, 2014)
• Resus.ME — Hyperchloraemia and mortality (2013)
• Resus.ME — What’s with all the chloride? An assault on salt (2012)
• Resus.ME — Fluids contribute to acid-base disturbance on ICU (2012)
• PulmCrit — Is correcting hyperchloremic acidosis beneficial? (2014)
• StEmlyns — SPLIT trial published. Saline or Plasmalyte on the ICU? (2015)