Evaluation and Management of the Hypochloremic Patient

Subnormal serum chloride concentrations (i.e., [Cl]) are often noted in patients with changes in total body water content and are therefore associated with proportional decreases in serum sodium (Na⁺) values.¹ These animals will have a “corrected” chloride that falls within the reference range for this electrolyte (where [Na] is the sodium concentration):

Corrected [Cl] = Normal [Na]/Patient [Na] × Patient [Cl]

Normal [Na] = Midpoint of the reference interval

Specific evaluation of chloride status is unnecessary in these patients, and reasons for a change in serum [Na] should be investigated instead. However, a subnormal corrected Cl^– has significant diagnostic and therapeutic implications and merits specific consideration.²

Disorders of [Cl] are routinely associated with acid–base derangements.³ The evaluation of a hypochloremic patient may therefore require blood gas analysis and concurrent evaluation of urine pH. Some laboratories report serum total carbon dioxide (TCO₂) concentrations as part of a standard biochemical profile; this provides an approximation of serum bicarbonate (HCO₃^–) levels. A change in bicarbonate concentration (i.e., [HCO₃]) alerts us to a disturbance in acid–base status but does not inform us about the cause, and an increase in [HCO₃] is consistent with an underlying metabolic alkalosis or the compensatory response to a respiratory acidosis.

Chloride handling by the kidney is a complex process, and chloride may be either excreted or reabsorbed in the collecting duct in response to homeostatic needs.⁴ A net chloride loss or gain in this region of the kidney is influenced primarily by the patient’s volume status and aldosterone concentrations and/or the need for HCO₃^– generation or secretion. Noniatrogenic hypochloremia can therefore usually be attributed to the loss of chloride-rich fluid or the presence of respiratory acidosis.

Initial Patient Assessment

If hypochloremia is noted on a serum biochemical profile, the corrected chloride should be calculated (FIGURE 1). If this is normal, the animal has a sodium/water imbalance that merits attention. If the corrected [Cl] is below the reference range, reasons for true hypochloremia should be considered. Current medical regimens should be investigated, and agents known to cause hypochloremia (e.g., furosemide, thiazide diuretics) should be evaluated.

If the patient has a recent history of vomiting or gastroesophageal reflux, the possibility of a gastric outflow or other gastrointestinal (GI) obstruction should be immediately investigated. A high TCO₂ and concurrent aciduria strongly support this differential diagnosis. Abdominal radiographs may be sufficient to indicate an obstructive foreign body, but transabdominal ultrasonography should be considered if plain films are unrewarding. A barium series should be considered if ultrasonography is not readily available, although barium aspiration associated with ongoing reflux or vomiting is a concern.

As a general rule, patients with hypercapnia and hypochloremia secondary to a respiratory acidosis are easily recognized clinically by changes in ventilatory patterns, an abnormal thoracic auscultation, a history of exercise intolerance, or a cough. Blood gas analysis is necessary to confirm carbon dioxide (CO₂) retention and guide further diagnostics, such as airway imaging and sampling the lower respiratory tract for cytology and culture.

Case Scenario

History

A 7-year-old spayed female miniature schnauzer weighing 8.5 kg was presented for acute onset of vomiting. The owner reported that the dog had vomited repeatedly for the previous 48 hours and was unable to keep down any food. The owners had withheld food for the past 14 hours, although the dog appeared hungry. She was still drinking water but intermittently vomited that too. There are 2 dogs in the house, and both had gotten into the trash a few hours before this dog first vomited. The owners were unsure of what either pet may have consumed but reported that the garbage contained a substantial quantity of discarded food. This patient has a history of acute pancreatitis (2 years prior) that necessitated several days of hospitalization for treatment. The dog is currently managed with a therapeutic low-fat diet and had been doing well for the previous 18 months.

Physical Examination

The patient was friendly but quiet. She was assessed at 5% dehydrated but was not painful on abdominal palpation. Vital signs and temperature were normal.

Initial Diagnostics

The complete blood count, serum biochemical profile, and urinalysis results are detailed in TABLES 1–3. The results from a SNAP cPL test were abnormal.

Comments

Corrected [Cl] = Normal [Na]/Patient [Na] × Patient [Cl]

Corrected [Cl] = 143/138 × 98

Corrected [Cl] = 101.6 mmol/L

This patient’s corrected [Cl] is significantly below the reference range for this electrolyte (107 to 116 mmol/L) and indicates a chloride loss that is independent of changes in total body water and sodium content. In addition, the TCO₂ is increased, and in a eupneic patient, it is appropriate to assume that this reflects a metabolic alkalosis rather than a respiratory acidosis. The combination of substantial hypochloremia and metabolic alkalosis in a vomiting patient is indicative of a substantial loss of acid and would not be expected in a patient with acute pancreatitis. The dog’s urine pH is low, consistent with paradoxical aciduria secondary to hypochloremia. These findings are highly suggestive of GI obstruction.

The SNAP cPL is a highly sensitive test for pancreatic inflammation, and an abnormal result approximates a quantified canine pancreatic lipase immunoreactivity >200 µg/L. The threshold for establishing a diagnosis of pancreatitis is 400 µg/L, with values between 200 and 400 µg/L regarded as equivocal. An abnormal SNAP cPL is therefore not adequate to establish a diagnosis of acute pancreatitis, and additional possibilities for the clinical signs should be considered.

Additional Diagnostics

Abdominal radiographs (FIGURE 2) revealed some material within the stomach; its appearance was consistent with normal ingesta, but the possibility of foreign material could not be excluded. In light of the fact that the dog had not eaten in more than 12 hours, these findings supported the concern for a gastric outflow obstruction. There was no evidence of intestinal obstruction, peritoneal effusion, or other intra-abdominal pathology.

A venous blood gas analysis revealed a pH of 7.49, which was indicative of a metabolic alkalosis.

Next Steps

Abdominal ultrasonography was considered, as this could provide more information about the gastric contents and the condition of the pancreas. However, the additional cost for this diagnostic was problematic for the owner, so the decision was made to do a diagnostic/therapeutic gastroscopy.

Treatment Plan

Sodium chloride (NaCl) 0.9% with 30 mEq/L of potassium chloride (KCl) was initiated at 7 mL/kg/hr. Within 2 hours, the dog was anesthetized for gastroscopy, during which time she was administered lactated Ringer’s solution at the aforementioned rate. Clumps of plastic foreign material were noted within the stomach, including a piece that was traversing and occluding the pylorus (FIGURE 3). The debris was successfully removed with the endoscope, and the dog recovered uneventfully.

NaCl 0.9% with 30 mEq/L KCl was restarted and administered at 5.3 mL/kg/hr overnight. The dog did well overnight and ate 2 small meals of a low-fat canned food with enthusiasm. The following morning, she was euhydrated and appeared comfortable. Serum chloride, sodium, and potassium were within reference ranges on a point-of-care testing device. The patient was discharged later that day.

Causes of Hypochloremia

Drug Induced

Loop (e.g., furosemide) and thiazide (e.g., hydrochlorothiazide) diuretics directly promote the renal loss of chloride in the loop of Henle or the distal convoluted tubule, respectively. As net chloride loss is disproportionate sodium loss, patients may become progressively hypochloremic.^5,6 Glucocorticoids are also associated with hypochloremia, although the magnitude of this change is usually modest.⁷ The inappropriate administration of sodium bicarbonate will also induce hypochloremia, due to changes in acid–base status (see Acid–Base Related).

Chloride Loss

The most common cause of chloride loss in excess of sodium is through vomiting secondary to GI obstruction, as substantial amounts of gastric acid (i.e., hydrogen chloride [HCl]) can be lost from the body. As chloride loss is accompanied by proton loss, an upper GI obstruction should be the primary consideration for a patient with metabolic alkalosis and hypochloremia. It is noteworthy that metabolic alkalosis is significantly less common than metabolic acidosis in dogs and cats and should always merit particular attention.⁸ Until recently, it was assumed that finding hypochloremia with metabolic alkalosis in a vomiting patient was essentially pathognomonic for a gastric outflow obstruction. However, these findings are also reported in patients with more distal obstructive disorders and clinicians should interpret this laboratory pattern with caution. This may be explained by transient lodgment of foreign material at the gastric outflow tract or may instead reflect marked alterations in the bowel’s secretory capacities secondary to obstruction.⁹ However, in the authors’ opinion, it is not expected to see a hypochloremic metabolic alkalosis in patients with vomiting due to extragastrointestinal conditions such as pancreatitis or renal failure. These individuals are more likely to be acidotic due to volume depletion and have a TCO₂ or HCO₃^– within or below the reference range.

Patients with GI obstruction will also experience volume contraction and subsequent release of aldosterone from the adrenal cortices. This hormone will cause avid reclamation of sodium from filtrate in the distal convoluted tubules; sodium is pulled back into the extracellular fluid in exchange for hydrogen ions and potassium. However, this loss of hydrogen (H⁺) is particularly impactful in patients with metabolic alkalosis, as the inability to reclaim protons exacerbates this condition. In addition, excretion of surplus HCO₃^– is hindered by low [Cl] in the filtrate, as these ions are usually exchanged for each other. Consequently, urine pH will fall below 7 despite a progressive metabolic alkalosis. This phenomenon is termed “paradoxical aciduria” and is routinely noted in patients with hypochloremia secondary to GI obstruction. These individuals are additionally vulnerable to significant hypokalemia, as potassium (K⁺) moves into cells in exchange for protons in an effort to mitigate alkalosis. In addition, an increase in the pH of the extracellular fluid exacerbates renal potassium loss by stimulation of renal sodium transporters.¹⁰

A similar phenomenon may occur in patients undergoing repeated gastric suction due to reflux, gastroparesis, or ileus. Clinicians should carefully monitor [Cl] and acid–base status under these circumstances.¹¹

Acid–Base Related

HCO₃^– and Cl^– are the primary anions in the extracellular fluid compartment and play a key role in the maintenance of electroneutrality. As acid–base changes impact [HCO₃], it is expected to see a compensatory shift in [Cl] to maintain a normal anion gap:

Anion gap = Patient [Na⁺ + K⁺] – Patient [Cl^– + HCO₃^–]

Dog: 12 to 24 mEq/L

Cat: 13 to 27 mEq/L¹²

Respiratory acidosis: Patients that hypoventilate or have compromised pulmonary gaseous exchange will retain CO₂; this results in an increase in H⁺ and a respiratory acidosis. In essence, the carbonic acid dissociation equation shifts to the right:

H₂O and CO₂  →  H₂CO₃  →  H⁺ and HCO₃^–

H₂CO₃ = Carbonic acid

A detailed description of renal responses to chronic hypercapnia (i.e., increased levels of CO₂ in the blood) is beyond the scope of this article, but essentially, proton excretion into the tubular lumen is facilitated by the generation of ammonia from glutamine within tubular cells; this is combined with protons and chloride and is excreted as ammonium chloride. This process results in chloride loss across the kidneys and promotes hypochloremia.^13,14 Causes for chronic hypercapnia include chronic obstructive pulmonary disease; pleural space disease, in which tidal volume is decreased but dead space remains constant; and any process resulting in a ventilation–perfusion mismatch.¹⁵

Consequences of Hypochloremia

Hypochloremia does not appear to have any specific metabolic consequences and does not usually require direct intervention. However, a retrospective study in critically ill human patients demonstrated an association between hypochloremia and a poorer outcome.¹⁶ Another study had similar findings but also reported that patients in which [Cl] increased by as little as 1 mEq/L had decreased mortality rates.¹⁷ However, concurrent hypokalemia can be refractory to treatment in patients with hypochloremic metabolic acidosis, due to ongoing movement of potassium into cells and sustained kaliuresis. Therefore, it is important to monitor potassium concentration (i.e., [K]) and promptly address the chloride and acid–base disorder.

Treatment of Hypochloremia

Iatrogenic hypochloremia due to drug administration is managed by alterations to the patient’s treatment plan and is expected to improve rapidly. A decrease in [Cl] secondary to repeated gastric decompression may require adjustments to the patient’s fluid therapy plan, along with the administration of acid-suppressing agents, such as proton pump inhibitors.

Hypochloremia and metabolic alkalosis secondary to GI obstruction should be initially addressed with a high chloride replacement fluid. NaCl 0.9% has the highest [Cl] of all the replacement fluids, at 154 mmol/L, and has the added advantage of being an acidifying product. Prompt intervention to address the GI obstruction is also indicated. Serum [K] is often subnormal in these patients; hypokalemia should be addressed appropriately and rechecked within several hours.

Hypochloremia secondary to CO₂ retention will depend on the underlying cause(s). Concurrent hypoxemia is likely and should be addressed with oxygen supplementation.