What are the causes of hyperchloremia?

Causes of Elevated Chloride (Hyperchloremia)

Primary Causes

Hyperchloremia most commonly results from excessive administration of chloride-rich intravenous fluids (particularly 0.9% normal saline), gastrointestinal bicarbonate losses, and renal tubular acidosis. 1, 2

Iatrogenic/Fluid-Related Causes

• Excessive 0.9% normal saline administration is the most common iatrogenic cause in hospitalized patients, as this solution contains supraphysiologic chloride concentrations (154 mEq/L) compared to plasma 1, 2
• Chloride-containing medication diluents contribute to cumulative chloride load, particularly in critically ill patients receiving multiple infusions 2
• Total parenteral nutrition solutions high in chloride content can cause hyperchloremia, especially when sodium is provided predominantly as sodium chloride rather than balanced with sodium acetate or lactate 3
• Cardiopulmonary bypass priming solutions using unbalanced crystalloids or colloids lead to hyperchloremic acidosis 1

Gastrointestinal Losses

• Diarrhea causes hyperchloremia through bicarbonate loss in stool, with compensatory chloride retention by the kidneys to maintain electroneutrality 1, 4
• Intestinal fistulas, drainage tubes, and ileostomies result in bicarbonate-rich fluid losses with relative chloride retention 3, 4
• These conditions represent excessive loss of sodium relative to chloride, creating a hyperchloremic state 4

Renal Causes

• Renal tubular acidosis (RTA) causes hyperchloremia through impaired renal acidification and bicarbonate wasting, with compensatory chloride reabsorption 5
  • Proximal RTA results from filtered bicarbonate loss (NaHCO3 wasting) 5
  • Distal RTA occurs from insufficient new bicarbonate generation 5
  • Both lead to reduced effective extracellular volume, increasing dietary chloride reabsorption 5
• Renal insufficiency initially presents with normal gap (hyperchloremic) acidosis before progressing to high anion gap acidosis with severe GFR reduction 5

Pathophysiologic Mechanisms

The Stewart physicochemical approach explains hyperchloremia's effect on acid-base balance: an increase in plasma chloride relative to sodium decreases the strong ion difference (SID), which directly lowers pH and bicarbonate concentration 3. This mechanism underlies hyperchloremic metabolic acidosis regardless of the primary cause 3, 4.

Special Clinical Contexts

• Diabetic ketoacidosis (DKA) treatment frequently causes hyperchloremia, with prevalence increasing from 23% at baseline to 77% after 6 hours of normal saline resuscitation 6
• Hemodialysis patients develop hyperchloremia when dialysate chloride concentrations are elevated (≥111 mEq/L), contributing to metabolic acidosis 7
• Premature infants on parenteral nutrition are particularly vulnerable to hyperchloremia when receiving high chloride loads from amino acid solutions and sodium chloride 3

Clinical Pitfalls to Avoid

• Do not assume switching from 0.9% NaCl to 0.45% NaCl resolves hyperchloremia—the latter still contains 77 mEq/L chloride, delivering supraphysiologic concentrations 1
• In DKA, hyperchloremia can mask resolution by artificially lowering measured bicarbonate; adjusted bicarbonate calculations may show 35% resolution versus only 24% by observed values at 6 hours 6
• Cumulative chloride from multiple sources (maintenance fluids, medication diluents, blood products, parenteral nutrition) often goes unrecognized until significant hyperchloremia develops 3, 2