Metabolic Alkalosis

Overview

Definition

Metabolic alkalosis is the process that results in the loss of hydrogen ions (H⁺) or the gain of HCO₃^–. In primary metabolic alkalosis, arterial blood gas will show:

• pH > 7.4 
• Partial pressure of CO₂ (PCO₂) > 40 mm Hg 
• HCO₃^– > 28 mEq/L

Epidemiology

• The most common acid-base disturbance in hospitalized patients
• Incidence: varies, depending on etiology
• Mortality: 
  • 45% when pH > 7.55
  • 80% when pH > 7.65

Etiology

• Vomiting and/or nasogastric suctioning
• Ingestion of non-absorbable antacids
• Mineralocorticoid excess:
  • Primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism
  • Cushing’s syndrome
• Loop or thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics
• Bartter and Gitelman syndromes
• ↓ Effective arterial blood volume (prerenal states):
  • Renal artery stenosis Renal artery stenosis Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis

Acid-base Review

Acid-base disorders are classified according to the primary disturbance (respiratory or metabolic) and the presence or absence of compensation.

Identifying the primary disturbance

Consider pH, PCO₂, and HCO₃^– to determine the primary disturbance. 

• Normal values:
  • pH: 7.35–7.45
  • PCO₂: 35–45 mm Hg
  • HCO₃^–: 22–28 mEq/L
• Difference between “-emia” and “-osis”:
  • The suffix “-emia” refers to “in the blood”:
    • Acidemia: more H⁺ in the blood = pH < 7.35
    • Alkalemia: more hydroxide ions (OH^–) in the blood = pH > 7.45 
  • The suffix “-osis” refers to a process:
    • Acidosis and alkalosis refer to the processes that cause acidemia and alkalemia, respectively. 
    • Blood pH may be normal in acidosis and alkalosis.
• Primary (uncompensated) respiratory disorders: 
  • Disorders caused by abnormalities in PCO₂
  • Both pH and PCO₂ are abnormal, in opposite directions 
  • Primary respiratory acidosis: pH < 7.35 and PCO₂ > 45
  • Primary respiratory alkalosis: pH > 7.45 and PCO₂ < 35
• Primary (uncompensated) metabolic disorders: 
  • Disorders caused by abnormalities in HCO₃^– 
  • Both pH and PCO₂ are abnormal, in the same direction. 
  • Primary uncompensated metabolic acidosis:
    • pH < 7.35 and PCO₂ < 40 
    • Think: “So the acidosis is not due to ↑ CO₂; it must be due to ↓ serum HCO₃^–”→ metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • Confirm by looking at HCO₃^–: will be low (< 22 mEq/L)
  • Primary uncompensated metabolic alkalosis: 
    • pH > 7.45 and PCO₂ > 40
    • Think: “So the alkalosis is not due to ↓ CO₂; it must be due to ↑ serum HCO₃^–” → metabolic alkalosis
    • Confirm by looking at HCO₃^–: will be high (> 28 mEq/L)
• Simple disorders:
  • The presence of any 1 of the above disorders with appropriate compensation
  • Respiratory disorders are compensated by renal mechanisms.
  • Metabolic disorders are compensated by respiratory mechanisms.
• Mixed disorders: presence of 2 primary disorders

Compensation

When a patient develops acidosis or alkalosis, the body will try to compensate. Oftentimes, compensation will result in normal pH.

• In primary metabolic acid-base disorders, the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs may try to compensate in an attempt to normalize the pH.
  • Lungs respond to metabolic acidosis by ↑ ventilation
  • Lungs respond to metabolic alkalosis by ↓ ventilation
• Interpreting serum HCO₃^– levels:
  • Normal range: 22–28 mEq/L
  • ↑ HCO₃^– is due to either:
    • Metabolic alkalosis, or
    • Compensated chronic respiratory acidosis Respiratory acidosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. In the setting of hypoventilation, this acid load is not adequately blown off, and respiratory acidosis occurs. Renal compensation occurs after 3-5 days, as the kidneys attempt to increase the serum bicarbonate levels. Respiratory Acidosis
  • ↓ HCO₃^– is due to either:
    • Metabolic acidosis, or
    • Compensated chronic respiratory alkalosis Respiratory alkalosis The respiratory system is responsible for eliminating the volatile acid carbon dioxide (CO2), which is produced via aerobic metabolism. When hypoventilation occurs, excess carbon dioxide is blown off and respiratory alkalosis develops. The kidneys respond by decreasing serum bicarbonate (HCO3-) through increased HCO3- excretion or decreased excretion of H+. Respiratory Alkalosis

Clinical Presentation, Diagnosis, and Management

Clinical presentation

The clinical presentation is dependent on the underlying etiology. Symptoms may include:

• Vomiting
• BP abnormalities:
  • Hypertension (primary mineralocorticoid excess)
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension (↓ effective circulating volume)
• Hypokalemia
• Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia:
  • Tetany
  • Chvostek sign: contraction of facial muscles when the facial nerve is tapped
  • Trousseau sign: carpopedal spasm with inflation of the BP cuff
  • Changes in mental status/ seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
• Findings consistent with a prerenal state: 
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure: 
    • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea on exertion
    • ↑ Jugular venous distension
    • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema (e.g., crackles on lung exam)
    • Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis:
    • Jaundice
    • Ascites
    • Hepatomegaly with/without splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Telangiectasias

Diagnosis

The etiology of metabolic alkalosis is usually ascertainable from the history alone. Urine Cl^– can be helpful in cases in which the patient is reluctant to provide a full history (e.g., self-induced vomiting in eating disorders) or for less common etiologies (e.g., Conn, Bartter, and Gitelman syndromes).

Urine chloride:

• Urine Cl^– < 20 mEq/L: body Cl^– is also depleted, typically in volume depletion:
  • Vomiting
  • Nasogastric suction
• Urine Cl^– > 20 mEq/L: Body Cl^– level is normal, typically in patients with volume expansion:
  • Mineralocorticoid excess:
    • Cushing’s syndrome (hypercortisolism)
    • Conn syndrome (primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism)
    • Licorice ingestion (glycyrrhizic acid)
    • Liddle syndrome Liddle syndrome Liddle syndrome, a type of pseudohyperaldosteronism, is a rare cause of secondary hypertension. Liddle syndrome results from autosomal dominant gain-of-function mutations in the genes that encode the epithelial sodium channel (ENaC) subunits, also known as the "collecting tubule sodium channel" or "amiloride-sensitive sodium channel." The activity of ENAC is increased, leading to sodium and water retention. Liddle Syndrome
    • Bartter and Gitelman syndromes
  • Severe hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia (K⁺ < 2)

Other tests:

• Basic metabolic panel (BMP): 
  • Allows assessment of HCO₃^–
  • Important for managing electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, especially K⁺
• Arterial blood gas
• Testing relevant to the suspected underlying etiology

Management

Treatment is aimed at the underlying etiology.

• Attempt to improve renal HCO₃^– excretion to resolve alkalosis:
  • In patients without edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (true volume depletion): volume repletion with isotonic saline
  • In patients with ↓ effective circulating volume (e.g., heart failure):
    • Potassium chloride
    • K⁺-sparing diuretics (e.g., amiloride)
    • Avoid isotonic saline as it will worsen symptoms without improving alkalosis.
• Correct electrolyte abnormalities, especially:
  • K⁺
  • Cl^–
  • Na⁺ (through fluid management)
• Consider dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis in patients with CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease.

Clinical Relevance

• Primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism: an increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Classically, hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism presents with hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, and metabolic alkalosis. Patients with hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension who are either treatment resistant and/or associated with hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia should be screened for hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism by assessing plasma aldosterone concentration and plasma renin activity. The diagnosis of primary hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism requires confirmatory tests and an abdominal CT scan. Management involves the use of aldosterone receptor antagonists and surgical excision of any aldosterone-secreting tumors.
• Cushing’s syndrome: a disorder characterized by features resulting from chronic exposure to excess glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids. The condition may be exogenous due to chronic glucocorticoid intake, or endogenous due to the increased adrenal secretion of cortisol or increased production of adrenocorticotropic hormone (ACTH) from the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland or ectopic sources. Typical clinical features include central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, thin and bruisable skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, abdominal striae, secondary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hyperglycemia, and proximal muscle weakness. The initial diagnostic approach is to establish hypercortisolism via urinary and salivary cortisol tests along with a low-dose dexamethasone suppression test. 
• Calcium-alkali syndrome: previously known as milk-alkali syndrome. Calcium-alkali syndrome leads to hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia, metabolic alkalosis, and AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury due to the excessive ingestion of a source of calcium and alkali, which is usually calcium carbonate. Treatment involves stopping the supplements and giving loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics to alleviate hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia.
• Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure: the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. In congestive heart failure, the cardiac output is reduced, which decreases blood flow to the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys. In several patients, congestive heart failure can lead to metabolic alkalosis. Echocardiography can confirm the diagnosis and provide information about the EF. Treatment is directed at the removal of excess fluid and decreasing oxygen demand of the heart. Prognosis depends on the underlying cause, compliance with medical therapy, and the presence of comorbidities.