Lab It Up: Hyperchloremia

Hyperchloremia

Chloride >106 mEq/L

A relative excess of chloride has been linked with [1]:
- Reduced renal blood flow
- Increased interstitial renal and gastrointestinal edema
- Reduced survival in patients with acute kidney injury
- Increased morbidity and mortality in critically ill patient
Chloride is the most abundant anion in the extracellular fluid compartment.
The primary drivers of chloride homeostasis are:
- Passive equilibration with sodium
- Chloride-bicarbonate anion exchange in the kidney, such that bicarbonate excretion is exchanged for chloride resorption (and vice versa)
In general, hyperchloremia is a reflection of either hypernatremia and/or an acid-base disorder.

Causes [1]

Excessive chloride intake

Hypernatremia often concurrently exists.

IV fluid administration: Large volume of 0.9% normal saline (154 mEq/L chloride) or hypertonic saline [2]
- Saline solutions do not contain bicarbonate.
- Hyperchloremia results in metabolic acidosis, because of volume dilution and urinary loss of bicarbonate to maintain the intracellular electrochemical gradient.
Saltwater drowning (average salinity 3.5%)

Net free water loss exceeding chloride loss

Hypernatremia often concurrently exists.

Fever
Excessive perspiration
Inadequate water intake
Diarrhea
Osmotic diuresis (e.g., glucosuria, mannitol administration)
Post-obstructive diuresis
- After decompressing the bladder or ureter, significant dehydration from diuresis may occur.
Diabetes insipidus

Association with non-anion gap metabolic acidosis

As serum bicarbonate levels fall, chloride is increasingly resorbed to maintain acid-base homeostasis. The following cause bicarbonate loss:

Diarrhea
Renal tubular acidosis
Chronic kidney disease
Various medication including:
- Inhibitors of the renin-angiotensin-aldosterone system decrease renal H+ excretion [3].
  - Angiotensin-converting enzyme inhibitors (ACEIs)
  - Aldosterone receptor blockers (ARBs)
  - Renin inhibitors
- Carbonic anhydrase inhibitors (e.g., acetazolamide) blocks renal absorption of bicarbonate.
- Ammonium, arginine, or lysine hydrochloride (releases H+ which binds bicarbonate)
- Corticosteroids and NSAIDs

Pseudohyperchloremia

Salicylate toxicity [4]
- High salicylate levels can interfere with some laboratory assays using an ion-selective electrode.
Bromide or iodide toxicity [5]
- Bromide and iodide ions mimic chloride ions in some automated laboratory assays using an ion-sensitive electrode.
- Suggested when severe hyperchloremia and negative anion gap

Special Populations

Pediatrics

There are no pediatric-specific causes for hyperchloremia. Similar to the adult population, abnormally high chloride levels are an independent predictor of higher morbidity and mortality in the setting of septic shock [6].

The chloride value in hyperchloremia are slightly different than for adults [7].

Pediatric Age	Hyperchloremia definition
Premature infant	Cl >110 mEq/L
Newborn	Cl >106 mEq/L
Child	Cl >110 mEq/L

Pregnancy

There are no pregnancy-specific causes for hyperchloremia. A 2009 review suggests that the definition of hyperchloremia in first trimester should use a lower cutoff than the other two trimesters [8].

Trimester Stage	Hyperchloremia definition
First	Cl >105 mEq/L
Second	Cl >109 mEq/L
Third	Cl >109 mEq/L

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Originally published Feb 12, 2023 (updated February 13, 2023)

References

Nagami GT. Hyperchloremia – Why and how. Nefrologia. 2016;36(4):347-353. doi:10.1016/j.nefro.2016.04.001. PMID 27267918
Sharma S, Hashmi MF, Aggarwal S. Hyperchloremic Acidosis. [Updated 2022 Aug 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.
Pham AQ, Xu LH, Moe OW. Drug-Induced Metabolic Acidosis. F1000Res. 2015;4:F1000 Faculty Rev-1460. Published 2015 Dec 16. doi:10.12688/f1000research.7006.1. PMID 26918138
Buisman L, Riphagen IJ, Kwant M, Themmen MD, Bouma M, Bethlehem C. Case report: Salicylate intoxication can present with a normal anion gap metabolic acidosis depending on method used for measuring chloride. Br J Clin Pharmacol. 2022;88(11):4933-4936. doi:10.1111/bcp.15492. PMID 35971785
Munekawa C, Kawasaki T, Miyoshi T, Yamane Y, Okada H, Oyamada H. Acute Bromide Intoxication in a Patient with Preserved Renal Function. Am J Case Rep. 2020;21:e922019. Published 2020 Apr 8. doi:10.12659/AJCR.922019. PMID 32265433
Stenson EK, Cvijanovich NZ, Anas N, et al. Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock. Pediatr Crit Care Med. 2018;19(2):155-160. doi:10.1097/PCC.0000000000001401. PMID 29394222
Pagana KD, Pagana TJ, Pagana TN. Mosby’s Diagnostic and Laboratory Test Reference. 14th ed. St. Louis, MO: Elsevier; 2019.
Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009 Dec;114(6):1326-1331. doi: 10.1097/AOG.0b013e3181c2bde8. Erratum in: Obstet Gynecol. 2010 Feb;115(2 Pt 1):387. PMID: 19935037.