1. Description of the problem

What every clinician needs to know

Metabolic alkalosis has been defined as any condition wherein:

  • Plasma pH is above 7.45, with normal or high Pco2 and TCO2 (total CO2) greater than 32 mM.

  • Base excess (BE) is greater than 2 mM (normal range -2 to +2 mM).

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  • Strong ion difference (SID) is greater than40 mM (the exact value depends upon the instrumentation used for measurement, and the assumption that total non-volatile weak acids are normal).

Metabolic alkalosis may be due to (1) an inherited (genetic) condition (such as Gitelman’s syndrome, Bartter’s syndrome, congenital chloride-losing diarrhea, cystic fibrosis, Liddle’s syndrome, apparent mineralcorticoid excess (AME), glucocorticoid remediable hypertension [GRA], and the 11- or 17-Beta OH deficient variants of congenital adrenal hyperplasia [CAH]); (2) acquired disease (such as gastroenteritis, bulemia, anorexia, Cushing’s syndrome, nephrotic syndrome, liver disease and hyperaldosteronism), or (3) drugs, surgery, medication or other treatments (such as thiazide or loop diuretics, laxatives, licorice, fludrocortisone, milk-alkali syndrome, augmentation cystoplasty using stomach, short bowel syndrome, penicillin, blood transfusion and the use of citrate-based dialysate).

Metabolic alkalosis may (1) occur as a primary disturbance (including those noted above); (2) arise as compensation of a primary respiratory acidosis (post hypercapnea); or (3) develop in the context of a mixed acid-base disturbance.

Clinical features

Primary metabolic alkalosis is “compensated ” by hypercarbia, so that PCO2rises by 0.5-0.7 mm Hg for each 1 mM increase in plasma bicarbonate concentration. Thus, the expected (compensated) PCO2 is approximately equal to the sum of the plasma bicarbonate concentration plus 15.

As respiratory “compensation” corrects the alkalemia only in part, pulmonary underventilation together with low oxyhemoglobin dissociation (the Bohr effect) results in poor tissue oxygenation. In addition, metabolic alkalosis may also associated with ischemic cerebral or cardiac blood flow due to vasoconstriction; hypocalcemia due to avid binding of the divalent ion to albumin; and hypokalemia due to cellular shifts and urinary losses.

Key management points

Metabolic alkalosis can be categorized as “chloride responsive” or “chloride resistant.” Patients with “chloride responsive” metabolic alkalosis may be acutely ill, and show signs of intravascular volume contraction. Laboratories will generally reveal a urine chloride concentration under 20 mM, and the patient will respond to an infusion of normal saline. Patients with “chloride resistant” metabolic alkalosis may appear chronically ill. Laboratories will generally reveal a urine chloride concentration above 20 mM, and the patient will not respond to an infusion of normal saline (or will improve only transiently).

2. Emergency Management


Elicit a history of vomiting, diarrhea (or other GI loss), polyuria, muscle weakness, GI and/or GU surgery and medications. In children, a prenatal history of polyhydramnios, recurring hospitalizations for dehydration, and early onset hypertension and/or growth retardation suggest a congenital renal tubular defect. Virilization suggests an endocrinopathy. In the adolescent, weight loss, muscle atrophy, bradycardia and hypothermia suggest an eating disorder. In adults, chronic use of diuretics, antacids and laxatives are common causes of metabolic alkalosis.

Physical examination

In children, growth (height and weight) percentiles are an important first step in making the diagnosis. Patients may have evidence of intravascular volume contraction (such as dry mucous membranes and tachycardia, due to acute or chronic GI or urinary losses), eroded dental enamel (due to chronic purging), trunchal obesity (in Cushing syndrome, along with striae, acne, and “moon facies”), hypothermia and bradycardia (in anorexia), hypertension (Liddle’s syndrome, hyperaldosteronism, apparent mineralcorticoid excess [AME], glucocorticoid remediable hypertension [GRA], deoxycortisol [DOC]-driven hypertension and renal artery stenosis), anal erosions (in inflammatory bowel disease), GU anomaly (with neurogenic bladder requiring gastrocystoplasty or viralization due to excessive androgen production in congenital adrenal hyperplasia [CAH]), and poor muscle tone (due to additional electrolyte disturbances).

A blood gas, plasma chemistries and urine chloride measurement will aid in the diagnosis. Emergency management consists of providing adequate ventilation and the administration of intravenous saline to restore intravascular volume.

3. Diagnosis

Diagnostic criteria and tests

In addition to history (of excessive GI and/or urinary losses) and physical examination (especially changes in height, weight and vital signs), obtain a blood gas (including base excess), plasma chemistries and a measurement of urine chloride. The patient’s underlying disease can often be categorized according to volume status, blood pressure, urine chloride concentration and response to chloride administration. Initial investigations should always include a measurement of all plasma electrolytes (sodium, potassium, chloride, phosphorus, Mg, calcium and uric acid), BUN and plasma creatinine, and plasma albumin. In select cases, initial investigations may also include measurement of plasma renin activity and aldosterone concentration.

Volume contracted/hypotensive/low urine chloride/chloride responsive

(Suspect based upon history and clinical examination): vomiting or other GI losses, villous adenoma, eating disorders, post-diuretic, cystic fibrosis.

Additional investigations: stool culture, stool guaic, GI tract imaging (ultrasound, CT scan, endoscopy), sweat chloride test, psychological evaluation, stool chloride.

Euvolemic/normotensive/high urine chloride/chloride resistant

(Suspect based upon the age of onset, growth pattern and associated electrolyte abnormalities): Bartter’s syndrome, Gitelman’s syndrome, chronic diuretic use.

Additional investigations: urine diuretic screen, genetic testing, renal ultrasound.

Hypervolemic/hypertensive/high urine chloride/chloride resistant

(Suspect based on the blood pressure measurements):

Low renin: Liddle’s syndrome, 11- or 17- OH Beta CAH, Cushing’s syndrome, hyperaldosteronism, AME, GRA.

Additional investigations: adrenal CT scan, genetic testing, urine and blood steroid panel.

High renin: renal artery stenosis.

Additional investigations: renal angiography.


Milk-alkali syndrome.

Total parenteral nutrition.

Blood products.

Nephrotic syndrome.

Liver disease.

Normal lab values

Plasma bicarbonate greater than 32 mM.

Plasma base excess (BE) greater than 2 mM.

Strong ion difference (SID) greater than 40 mM (with normal plasma albumin and phosphorus).

The expected respiratory “compensation” for primary metabolic alkalosis may be quantified using the following formulae:

PCO2 (mmHg) = plasma bicarbonate concentration (mM) +15


PCO2 (mmHg) = 40 + 0.7 (plasma bicarbonate concentration [mM]-24)


delta PaCO2 = 0.6 x delta standard base excess (SBE)

Establishing the diagnosis

Primary metabolic alkalosis is established by an interpretation of the blood gas, while the severity is determined by the pH and base excess (BE). If the history and physical examination alone are not diagnostic, then the differential diagnosis is unraveled according to the patient’s intravascular volume status, blood pressure, urine chloride and response to the administration of chloride (as an example, by infusion of normal saline). Once the disorder is categorized according to the algorithm above, additional testing will confirm the diagnosis.

Other possible diagnoses

Volume contracted/hypotensive/low urine chloride/chloride responsive

Possible causes include gastroenteritis, inflammatory bowel disease, liver disease, bulemia, pyloric stenosis, intestinal obstruction, cystic fibrosis. In many cases, imaging of the gastrointestinal (GI) tract is indicated.

Euvolemic/normotensive/high urine chloride/chloride resistant

If a urine diuretic screen is negative, then genetic testing for Bartter’s and/or Gitelman’s syndrome may be warranted.

Hypervolemic/hypertensive/high urine chloride/chloride resistant

Measure plasma renin activity and aldosterone concentration.

If plasma renin activity and aldosterone concentration are both high, suspect renal artery stenosis and obtain a renal angiogram (conventional or CT angiogram). If plasma renin activity is low and aldosterone concentration is high, suspect primary hyperaldosteronism and obtain CT of adrenal glands.

If plasma renin activity is low and aldosterone concentration is low, and the patient does not appear Cushinoid, has a normal cortisol level, and does not consume licorice, suspect monogenic forms of hypertension (Liddle’s syndrome, apparent mineral corticoid excess (AME), glucocorticoid remediable hypertension (GRA) and variants of CAH that are associated with hypertension and virilization). Specific genetic testing (e.g. for Liddle’s syndrome) and/or biochemical testing (e.g. measurement of plasma DOC, urinary cortisol and urinary cortisone) is warranted.

4. Specific Treatment

Specific therapies

In most cases of chloride-responsive metabolic alkalosis, the administration of normal saline and KCl (to correct associated hypokalemia) will restore intravascular volume and acid-base balance. In edematous disorders, the carbonic anhydrase inhibitor acetazolamide might be useful to induce bicarbonaturia. If acetazolamide fails, the administration of HCl may be helpful in restoring acid-base balance. In some cases, proton pump inhibitors may used to decrease gastric chloride loss, thereby lowering plasma SID toward normal values. In patients with severe renal failure, hemodialysis utilizing a high-chloride containing dialysate will correct the metabolic alkalosis.

Chloride-resistant metabolic alkalosis suggests an underlying defect in steroid metabolism (over production or under-degradation of deoxycortisol [DOC], cortisol or aldosterone), the epithelial sodium channel (Liddle’s syndrome), the mineralcorticoid receptor (progesterone-exacerbated hypertension) or renal tubular transporters (Bartter’s syndrome, Gitelman’s syndrome). Chronic metabolic alkalosis accounts for less than 5% of all cases, and these disorders require specific diagnosis and treatment.

Drugs and dosages

In chloride responsive metabolic alkalosis, the chloride deficit can be calculated after euvolemia is restored using the following formula:

Cl- deficit (mM) = 0.2 x body weight (kg) x {100 – measured chloride concentration (mM)}

Although sodium and/or potassium chloride infusion are preferred in most cases, isotonic HCl (150 mM) may be administered in critically ill patients (cardiac arrhythmia, digitalis cardiotoxicity, altered mental status, hepatic encephalopathy) with pH above 7.5 through a central catheter at a rate not to exceed 25 mM/hour.

To “half-correct” the alkalosis:

HCl dose (mM) = 0.5 x body weight (kg) x {measured bicarbonate concentration (mM)-24}/2

Refractory cases

Although sodium and/or potassium chloride infusions are preferred in most cases, isotonic HCl (150 mM) may be administered in critically ill patients (cardiac arrhythmia, digitalis cardiotoxicity, altered mental status, hepatic encephalopathy) with pH above 7.5 through a central catheter at a rate not to exceed 25 mM/hour or 0.2 mM/kg/hour.

To “half-correct” the alkalosis:

HCl dose (mM) = 0.5 x body weight (kg) x {measured bicarbonate concentration (mM)-24}/2

In volume-expanded patients with normal renal function and in whom saline administration is contraindicated, acetazolamide may be used to restore normal acid-base balance. In volume-expanded patients with poor renal function, hemodialysis using a high-chloride containing dialysate may improve the metabolic alkalosis.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Patients with chloride-responsive metabolic alkalosis should respond well to initial fluid therapy. However, the overall prognosis depends upon the underlying etiology. As an example, whereas patients with simple gastroenteritis may often be discharged from the emergency department with little or no follow-up, those will villous adenomas may require surgical resection of the lesion. The rare patient with chronic chloride-resistant metabolic alkalosis often requires highly specialized evaluation and more disease-specific management.

Incorrect diagnosis

The provisional diagnosis of acute, chloride-responsive metabolic alkalosis should always be re-considered whenever the patient does not improve (the plasma pH, bicarbonate, base excess and/or SID fails to normalize) with adequate administration of chloride. Chloride-resistance suggests inadequate replacement of ongoing and potentially chronic losses of chloride in the urine, skin or stool, and warrants further diagnostic testing.

Monitoring and follow-up

Patients with metabolic alkalosis due to:

1. infectious gastroenteritis may improve with emergency management alone.

2. eating disorder, milk-alkali syndrome, or licorice ingestion may benefit from counseling.

3. total parenteral nutrition, penicillin, or citrate-containing dialysate solutions may improve with treatment of their underlying critical illness.

4. pyloric stenosis, villous adenoma, or adrenal adenoma should benefit from surgery.

5. Cushing’s syndrome, CAH, or other adrenal disorder will require a thorough evaluation and treatment by an endocrinologist.

6. monogenetic forms of hypertension or other renal tubular disorders will require a thorough evaluation and treatment by a nephrologist.


While there are several equally correct ways of explaining metabolic alkalosis, perhaps the most straightforward and easily understood has been suggested by Peter Stewart, a Canadian physiologist. In the “Stewart” approach, metabolic alkalosis is due to an increase in the strong ion difference (SID) or to a decrease in total, non-volatile weak acids (such as albumin and phosphorus).

An increase in SID (approximately equal to the difference in plasma sodium and chloride) may be caused by the provision of excess cation (along with an anion that is metabolized by the liver, as in milk-alkali syndrome, and with the administration of sodium citrate, total parenteral nutrition, and blood products), the loss of chloride anions (vomiting, diuretics), or pure water desiccation. Plasma non-volatile weak acids may be depleted in nephrotic syndrome, liver failure and capillary leak syndrome.

Volume contraction stimulates the renin-angiotensin-aldosterone axis and potentially decreases the renal clearance of excess cations, further increasing the SID and worsening the metabolic alkalosis.


Metabolic alkalosis is one of the most common electrolyte disturbances amongst hospitalized patients. Mortality rates of 45% have been reported in patients with an arterial blood pH of 7.55 and 80% when the pH was above 7.65.



Special considerations for nursing and allied health professionals.


What's the evidence?

Description of the problem

Pappano, D. “Alkalosis-induced respiratory depression from infantile hypertrophic pyloric stenosis”. Pediatr Emerg Care. vol. 27. 2011 Feb. pp. 124(An infant with metabolic alkalosis due to pyloric stenosis who presented with apnea is described.)

Jacobi, J, Schnellhardt, S, Opgenoorth, M, Amann, KU, Küttner, A. “Severe metabolic alkalosis and recurrent acute on chronic kidney injury in a patient with Crohn's disease”. BMC Nephrol. vol. 11. 2010 Apr 18. pp. 6(In this case, a high volume of gastrointestinal fluid loss resulted in severe metabolic alkalosis and acute kidney injury.)

van Beers, EJ, Stam, J, van den Bergh, WM. “Licorice consumption as a cause of posterior reversible encephalopathy syndrome: a case report”. Crit Care. vol. 15. 2011 Feb 18. pp. R64(A patient with licorice-induced hypertensive emergency associated with severe metabolic alkalosis,is presented.)

Emergency management

Laglera, S, Sánchez-Tirado, JA, Rasal, S, Martínez-Diestre, MD, Lafuente, F, Ruiz, J. “Hypertonic saline 7.5% in the treatment of severe hypochloremic metabolic alkalosis”. Rev Esp Anestesiol Reanim. vol. 49. 2002 Dec. pp. 545-9. (The investigators describe the use of hypertonic saline in a case of severe metabolic alkalosis.)

Eiro, M, Katoh, T, Watanabe, T. “Use of a proton-pump inhibitor for metabolic disturbances associated with anorexia nervosa”. N Engl J Med. vol. 346. 2002 Jan 10. pp. 140(The investigators describe their experience with lansoprazole, a proton-pump inhibitor, in the treatment of severe hypokalemic metabolic alkalosis.)

Hsu, SC, Wang, MC, Liu, HL, Tsai, MC, Huang, JJ. “Extreme metabolic alkalosis treated with normal bicarbonate hemodialysis”. Am J Kidney Dis. vol. 37. 2001 Apr. pp. E31(The investigators report on four cases of severe, life-threatening metabolic alkalosis, all of which were treated successfully with hemodialysis.)

Martin, WJ, Matzke, GR. “Treating severe metabolic alkalosis”. Clin Pharm. vol. 1. 1982 Jan-Feb. pp. 42-8. (The investigators review therapeutic options for the treatment of severe metabolic alkalosis.)


Özbay Hoşnut, F, Karadağ Öncel, E, Öncel, MY, Özcay, F. “A Turkish case of congenital chloride diarrhea with SLC26A3 gene (c.2025_2026insATC) mutation: diagnostic pitfalls”. Turk J Gastroenterol. vol. 21. 2010 Dec. pp. 443-7. (Congenital chloride diarrhea may sometimes be confused with Bartter's syndrome. The history of watery diarrhea and the finding of high stool chloride suggests the correct diagnosis and treatment [NaCl replacement].)

Simonetti, GD, Mohaupt, MG, Bianchetti, MG. “Monogenic forms of hypertension”. Eur J Pediatr. 2011 Mar 15. (A review of monogenetic forms of hypertension, many of which are accompanied by metabolic alkalosis.)

Bahia, A, Mascolo, M, Gaudiani, JL, Mehler, PS. “PseudoBartter syndrome in eating disorders”. Int J Eat Disord. 2011 Feb 22. (Bartter's syndrome may be diagnosed incorrectly in patients with eating disorders. A distinguishing feature of this form of "pseudo-Bartter's syndrome" is edema formation.)

Priou-Guesdon, M, Malinge, MC, Augusto, JF, Rodien, P, Subra, JF. “Hypochloremia and hyponatremia as the initial presentation of cystic fibrosis in three adults”. Ann Endocrinol (Paris). vol. 71. 2010 Feb. pp. 46-50. (Cystic fibrosis may be an important and often unrecognized cause of metabolic alkalosis, even in adults.)

Borazan, A, Sevindik, OG, Solmaz, D, Gulcu, A, Cavdar, C. “A rare cause of renovascular hypertension: Takayasu arteritis with only renal artery involvement”. Ren Fail. vol. 31. 2009. pp. 327-31. (The authors remind us that renal artery stenosis is yet another cause of metabolic alkalosis associated with hypertension.)

Boris, I, Medarov, MD. “Milk-Alkali Syndrome”. Mayo Clin Proc. vol. 84. 2009 March. pp. 261-7. (The authors provide a useful review, including an interesting historical perspective.)

Naesens, M, Steels, P, Verberckmoes, R, Vanrenterghen, Y, Kuypers, D. “Bartter's and Gitelman's syndromes: from gene to clinic”. Nephron Physiol. vol. 96. 2004. pp. 65-78. (The authors review the genetics and clinical manifestations of these important causes of chloride-resistant metabolic alkalosis.)

Specific treatment

Oh, YK. “Acid-base disorders in ICU patients”. Electrolyte Blood Press. vol. 8. 2010 Dec. pp. 66-71. (The author provides a simple, practical and concise guide to treating common acid-base problems that are encountered in the ICU setting.)

Tripathy, S. “Extreme metabolic alkalosis in intensive care”. Indian J Crit Care Med. vol. 13. 2009 Oct-Dec. pp. 217-20. (The author presents two complex cases of "extreme" metabolic alkalosis and discusses various diagnostic and therapeutic strategies.)

Banieghbal, B. “Rapid correction of metabolic alkalosis in hypertrophic pyloric stenosis with intravenous cimetidine: preliminary results”. Pediatr Surg Int 2009. vol. 25. Mar. pp. 269-71. (The investigator describes a novel approach to the treatment of metabolic alkalosis using cimetidine.)

Marik, PE, Kussman, BD, Lipman, J, Kraus, P. “Acetazolamide in the treatment of metabolic alkalosis in critically ill patients”. Heart Lung. vol. 20. 1991 Sep. pp. 455-9. (The investigators describe their experience using acetazolamide in the treatment of metabolic alkalosis.)

Disease monitoring and followup

Wedenoja, S, Ormälä, T, Berg, UB, Halling, SF, Jalanko, H. “The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea”. Kidney Int. vol. 74. 2008 Oct. pp. 1085-93. (These investigators followed patients with congenital chloride diarrhea and found a high incidence of chronic renal failure due to nephrocalcinosis. The investigators speculated that poor compliance with chloride supplementation contributed to chronic volume contraction and calcium precipitation.)

Puricelli, E, Bettinelli, A, Borsa, N, Sironi, F, Mattiello, C. “Italian Collaborative Group for Bartter Syndrome. Long-term follow-up of patients with Bartter syndrome type I and II”. Nephrol Dial Transplant. vol. 25. 2010 Sep. pp. 2976-81. (The investigators present the results of a collaborative study that focuses on the long-term outcome of patients with Bartter's syndrome.)


Anderson, LE, Henrich, WL. “Alkalemia-associated morbidity and mortality in medical and surgical patients”. South Med J. vol. 80. 1987. pp. 729-33. (The investigators call attention to the morbidity and mortality that may be associated with metabolic acidosis.)

Webster, NR, Kulkarni, V. “Metabolic alkalosis in the critically ill”. Crit Rev Clin Lab Sci 1999. vol. 36. Oct. pp. 497-510. (The authors remind us that metabolic alkalosis is the most common form of acid-base disorder encountered in the ICU.)


Kellum, JA. “Determinants of blood pH is health and disease”. Crit Care. vol. 4. 2000. pp. 6-14. (An excellent introduction to the "Stewart" approach to acid-base disorders.)

Kaplan, LJ, Cheung, NH, Maerz, L, Lui, F, Schuster, K. “A physicochemical approach to acid-base balance in critically ill trauma patients minimizes errors and reduces inappropriate plasma volume expansion”. J Trauma. vol. 66. 2009 Apr. pp. 1045-51. (The investigators provide data that affirms the validity of the "Stewart" approach in the ICU setting.)

Moviat, M, Pickkers, P, van der Voort, PH, van der Hoeven, JG. “Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients”. Crit Care. vol. 10. 2006 Feb. pp. R14(The investigators discuss the use of acetazolamide in the treatment of metabolic alkalosis and explain the physiological basis of this approach.)

Haskins, SC, Hopper, K, Rezende, ML. “The acid-base impact of free water removal from, and addition to, plasma”. J Lab Clin Med. vol. 147. 2006 Mar. pp. 114-20. (The investigators present data that establishes a cause and effect relationship between pure water desiccation and metabolic alkalosis.)

Funk, GC, Doberer, D, Osterreicher, C, Peck-Radosavljevic, M, Schmid, M. “Equilibrium of acidifying and alkalinizing metabolic acid-base disorders in cirrhosis”. Liver Int. vol. 25. 2005 Jun. pp. 505-12. (The investigators examine acid-base balance in cirrhotics with hypoalbuminemia.)

Jensen, FB. “Red blood cell pH, the Bohr effect, and other oxygenation-linked phenomena in blood O2 and CO2 transport”. Acta Physiol Scand. vol. 182. 2004 Nov. pp. 215-27. (The author re-examines the "Bohr" effect, whereby alkalosis increases hemoglobin oxygen affinity and thereby decreases oxygen delivery to tissues.)

Schlichtig, R, Grogono, AW, Severinghaus, JW. “Human PaCO2 and standard base excess compensation for acid-base imbalance”. Crit Care Med. vol. 26. 1998 Jul. pp. 1173-9. (The investigators quantify the respiratory "compensation" that is expected for primary metabolic acid-base disturbances.)