DEFINITIONS

Acid

An acid is a substance that can release a hydrogen ion (H⁺)
In water, an acid dissociates reversibly into a H⁺ and its conjugate base (written as A^-): HA ⇌ H⁺ + A^-
The more an acid is present in the dissociated form at equilibrium (H⁺ + A^-), the stronger the acid

Base

A base is a substance that can accept a hydrogen ion (H⁺)
In the formula HA ⇌ H⁺ + A^-, A^- is a base because it can accept H⁺

Buffer

A buffer is a chemical that minimizes the change in pH when an acid or base is added to a solution
The main buffer in the human body is carbonic acid (H₂CO₃)
Carbonic acid buffers blood through the following reaction:

H⁺ + HCO₃^- ⇌ H₂CO₃ ⇌ H₂O + CO₂

Anions and cations

Anions are atoms or groups of atoms that carry a negative charge. The main anions in human blood are chloride (Cl^-) and bicarbonate (HCO₃^-).
Cations are atoms or groups of atoms that carry a positive charge. The main cation in human blood is sodium (Na⁺).
In blood, the concentration of cations and anions must always balance in order to maintain electroneutrality
See electrolytes for more

pH is a measure of free hydrogen ions (H⁺) in a solution
pH is calculated in the following manner: pH = log₁₀(1/[H⁺])
Because pH is inversely related to H⁺, it decreases as the concentration of H⁺ increases
The pH of blood is measured on an arterial blood gas
The normal pH of arterial blood is 7.35 - 7.45

PaCO₂ (pCO₂, PCO₂)

PaCO₂ is the partial pressure of CO₂ in arterial blood
Partial pressure is defined as the amount of pressure an individual gas contributes to the overall pressure of a mixture of gases
In arterial blood, CO₂ normally exerts a partial pressure of 38 - 42 mmHg
The PaCO₂ in arterial blood is identical to the PaCO₂ in alveolar air
PaCO₂ is measured in an arterial blood gas
The normal PaCO₂ in arterial blood is 38 - 42 mmHg

PaO₂ (pO₂, PO₂)

PaO₂ is the partial pressure of oxygen in arterial blood
Partial pressure is defined as the amount of pressure an individual gas contributes to the overall pressure of a mixture of gases
PaO₂ is measured in an arterial blood gas
The normal PaO₂ of arterial blood is 75 - 100 mmHg

Bicarbonate (HCO₃^-) (arterial)

HCO₃^- is the concentration of arterial bicarbonate. Because HCO₃^- has a negative charge, it is an anion.
The carbon dioxide value reported on a venous blood draw is also equivalent to the bicarbonate concentration (see carbon dioxide below)
HCO₃^- is measured indirectly on an arterial blood gas
The normal concentration of bicarbonate is 22 - 26 mEq/L (mmol/L)

Carbon dioxide (CO₂) (venous)

Carbon dioxide is the amount of dissolved carbon dioxide in venous blood
Carbon dioxide dissolved in venous blood is almost entirely in the form of bicarbonate (H₂O + CO₂ ⇌ H₂CO₃ ⇌ H⁺ + HCO₃^-). Because of this, the carbon dioxide value is considered equivalent to the venous bicarbonate (HCO₃^-) value.
Carbon dioxide (CO₂) is reported on a standard basic metabolic profile
The normal value for carbon dioxide is 18 - 30 mEq/L

NORMAL ACID-BASE PHYSIOLOGY

Overview

Macronutrient metabolism typically generates a net gain of acid
Carbohydrates and fats are oxidized to CO₂ and H₂O. The CO₂ immediately reacts with H₂O in the blood to produce H⁺ and HCO₃^- via the following reaction: H₂O + CO₂ ⇌ H₂CO₃ ⇌ H⁺ + HCO₃^-. In a normal adult, food metabolism produces 300 liters of CO₂ a day.
Proteins are metabolized to strong acids (e.g. H₂SO₄, HCl, H₃PO₄)
In order to maintain a normal pH, the body must buffer and eliminate the CO₂ and strong acids that are produced
CO₂ is typically eliminated through the lungs at the same rate that it is produced
The kidneys help remove strong acids by excreting H⁺, and they generate new HCO₃^- to replace HCO₃^- lost through buffering
NOTE: Other chemicals buffers exist (e.g. proteins, phosphate, hemoglobin, bone minerals, etc.), but carbonic acid (H₂CO₃) is the most important one for maintaining blood pH [5]

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Illustration of normal acid-base physiology

THE ANION GAP

Overview

The anion gap, an important component of acid-base disorders, is calculated with the following formula:

Anion gap = Na⁺ - (Cl^- + HCO₃^-), where HCO₃^- is represented by the venous carbon dioxide
A normal anion gap is 6 - 12 mEq/L

The sum of all anions and cations in plasma must be equal at all times in order to maintain electroneutrality. If there is an increase in cations, a compensatory increase in anions must occur and vice versa.
Sodium (Na⁺) is the main extracellular cation, and chloride (Cl^-) and bicarbonate (HCO₃^-) are the main extracellular anions
Under normal conditions, there is a difference of about 12 mEq/L between sodium and the sum of chloride and bicarbonate (Na⁺ - [Cl^- + HCO₃^-] = 12 mEq/L)
The difference between the main cation (Na⁺) and the main anions (Cl^-, HCO₃^-) represents the "anion gap." The anion gap contains a mixture of other anions that, when added to Cl^- and HCO₃^-, achieve electroneutrality with Na⁺.
The primary anion in the anion gap is albumin, which accounts for almost 75%. If hypoalbuminemia is present, the estimated anion gap will not represent the clinically relevant increase in anions, and a correction must be made to the anion gap. For every 1-gram decrease in the albumin concentration from 4 grams/dl, 2.5 mEq/L should be added to the anion gap.

Corrected anion gap (hypoalbuminemia) = (4 - serum albumin concentration) X 2.5 + calculated anion gap [1,2,5]

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Illustration of the normal anion gap, including formulas, sodium, chloride, bicarbonate, and other anions

ACUTE AND CHRONIC COMPENSATION

Overview

The lungs and the kidneys are the two organs that regulate blood pH
The lungs can raise pH by blowing off more CO₂, and they can lower pH by decreasing ventilation and retaining CO₂
The kidneys can raise pH by increasing the production of HCO₃^- and excreting acid, and they can lower pH by eliminating HCO₃^- and retaining acid
If the primary acid-base disorder is from a respiratory cause, the kidneys will compensate (renal compensation). If the primary disorder is from a metabolic cause, the lungs will compensate (respiratory compensation).
Respiratory compensation can begin within minutes and becomes maximal in 12 - 24 hours. Renal compensation has an acute and chronic phase, where the effect is smaller at first before reaching a peak in 2 - 5 days.
The table below describes the general compensatory effects of each system

Reference [2,5]
ACID-BASE DISORDER COMPENSATION
Metabolic acidosis Respiratory compensation (decrease in PaCO₂): Compensated PaCO₂ is decreased by 1.3 mmHg for each 1 mEq/L decrease in HCO₃^- Begins within minutes and is maximal at 12 - 24 hours
Metabolic alkalosis Respiratory compensation (increase in PaCO₂): Compensated PaCO₂ is increased by 0.7 mmHg for each 1 mEq/L increase in HCO₃^- Begins within minutes and is maximal at 12 - 24 hours
Respiratory acidosis Renal compensation (increase in HCO₃^-): Acute: Compensated HCO₃^- is increased by 1 mEq/L for each PaCO₂ increase of 10 mmHg above 40 mmHg Chronic (full compensation occurs in 2 - 5 days): Compensated HCO₃^- is increased by 4 - 5 mEq/L for each PaCO₂ increase of 10 mmHg above 40 mmHg
Respiratory alkalosis Renal compensation (decrease in HCO₃^-): Acute: Compensated HCO₃^- is decreased by 2 mEq/L for each PaCO₂ decrease of 10 mmHg below 40 mmHg Chronic (full compensation occurs in 2 - 5 days): Compensated HCO₃^- is decreased by 4 - 5 mEq/L for each PaCO₂ decrease of 10 mmHg below 40 mmHg

ALVEOLAR-ARTERIAL OXYGEN GRADIENT (A-a gradient)

Overview

Under normal conditions, the partial pressure of O₂ in alveolar air (PAO₂) is equal to the partial pressure of O₂ in alveolar capillary blood (PaO₂)
As blood leaves the alveolar capillaries and enters the systemic arterial circulation, a slight decrease in PaO₂ occurs. The drop is referred to as the alveolar-arterial gradient (A-a gradient).
The A-a gradient increases as the fraction of inspired oxygen increases and as people age. When breathing room air at sea level, the normal A-a gradient is ≤ 10 mmHg in young people and ≤ 20 mmHg in elderly people. It can also be estimated with the following formula:

A-a gradient = 2.5 + 0.21 X age in years

PaO₂ is measured directly on an arterial blood gas. PAO₂ is estimated with the following equation:

PAO₂ = FiO₂(PB - PH₂O) - (PaCO₂/RQ)

Where:
FiO₂ = fraction of inspired oxygen
PB = barometric pressure, which is 760 mmHg at sea level
PH₂O = partial pressure of water vapor, usually 45 mmHg
PaCO₂ = partial pressure of CO₂ in the alveoli, which is obtained from an ABG
RQ = respiratory quotient, which is the ratio of CO₂ production and O₂ consumption from a patient's diet, usually assumed to be 0.82

The A-a gradient is reported on an arterial blood gas, and it can be help determine the cause of certain respiratory conditions [2,5,10]

Reference [2,5]
ALVEOLAR-ARTERIAL GRADIENT UNDER CERTAIN CONDITIONS
Condition	A-a gradient	Cause/Comment
Diffusion impairment	Increase	Occurs when there is impairment of oxygen diffusing across alveolar-capillary membrane Causes include pulmonary edema, pulmonary fibrosis
Ventilation-perfusion mismatch	Increase	Occurs when areas of the lung do not receive normal ventilation and/or normal perfusion Causes include pulmonary embolism, airway obstruction, and pneumonia
Physiologic shunt	Increase	Occurs when blood is shunted from the venous circulation to the arterial circulation Causes include cardiac right-to-left shunt, alveolar shunt, etc.
Generalized hypoventilation	Normal	Occurs when there is a decrease in overall respiration Causes include emphysema, head injury, drug overdose, comatose patient
Reduced oxygen content of blood	Normal	Occurs when the oxygen-carrying capacity of the blood is reduced Causes include anemia and carbon monoxide poisoning

RESPIRATORY ALKALOSIS

Overview

Respiratory alkalosis occurs when the lungs blow off excessive CO₂

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Illustration of respiratory alkalosis, including causes, laboratory and blood gas findings, and renal compensation

RESPIRATORY ACIDOSIS

Overview

Respiratory acidosis occurs when the lungs retain CO₂

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Illustration of respiratory acidosis, including causes, laboratory and blood gas findings, and renal and pulmonary compensation

METABOLIC ALKALOSIS

Overview

Metabolic alkalosis occurs when there is an increase in HCO₃^-, which is typically caused by one or more of the following: chloride loss/malabsorption, increased mineralocorticoid activity, and low potassium.
The most common cause of metabolic alkalosis is vomiting and dehydration, where loss of gastric H⁺ and Cl^- in emesis raises plasma HCO₃^-. Concomitant dehydration and potassium depletion promote renal HCO₃^- retention, further exacerbating the alkalosis.

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Illustration of metabolic alkalosis, including causes, laboratory and blood gas findings, Bartter syndrome, Gitelman syndrome, and renal pathology

METABOLIC ACIDOSIS

Overview

Metabolic acidosis occurs when the blood either gains acid (high anion gap) or loses bicarbonate (normal anion gap). The anion gap is important in determining the cause of acidosis and is reviewed here - anion gap.

High anion gap metabolic acidosis

High anion gap metabolic acidosis occurs when an acid is added to the blood from an additional source
Two common causes of high anion gap metabolic acidosis are diabetic ketoacidosis and lactic acidosis
In diabetic ketoacidosis, a lack of insulin causes the liver to excrete ketone bodies (β-hydroxybutyric acid, acetoacetate), which are used by cells as fuel and add H⁺ to the blood
In lactic acidosis, hypoxia induces anaerobic metabolism, which produces lactate and H⁺

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Illustration of high anion gap metabolic acidosis, including causes, laboratory and blood gas findings, and renal and pulmonary compensation

Normal anion gap metabolic acidosis

Normal anion gap metabolic acidosis occurs when HCO₃^- is lost. To compensate for the lost anion (HCO₃^-), Cl^- levels rise to maintain electroneutrality. Because the additional Cl^- is included in the anion gap calculation (Na⁺ - [Cl^- + HCO₃^-]), the anion gap does not change.
Two causes of normal anion gap metabolic acidosis are diarrhea (intestinal loss of HCO₃^-) and renal tubular acidosis (renal loss of HCO₃^-)

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Illustration of normal anion gap metabolic acidosis, including causes, laboratory and blood gas findings, and renal and pulmonary compensation

PRACTICAL APPROACH TO ACID-BASE DISORDERS

Overview

Acid-base disorders may occur as singular disorders, singular disorders with compensation, or a combination of disorders (mixed acid-base disorders). Given these complexities, they can be intimidating for many providers.
A practical approach to diagnosing acid-base disorders is presented below. This approach is primarily derived from "A practical approach to acid-base disorders" by Haber et al. (Reference 1).

Reference [1,2]
Practical approach to acid-base disorders
Step 1 - obtain appropriate lab values In order to assess acid-base disorders, the following lab values are necessary: Arterial blood gas (ABG) - pH value, PaCO₂, PaO₂, HCO₃^- Comprehensive metabolic profile - Sodium (Na⁺), Chloride (Cl^-), Carbon dioxide (CO₂), Albumin
Step 2 - determine if the primary disorder is an acidosis or alkalosis pH < 7.35 - primary disorder is an acidosis pH > 7.45 - primary disorder is an alkalosis
Step 3 - determine the source of the primary disorder Acidosis (pH < 7.35) If the PaCO₂ is > 42 mmHg, then the primary disorder is a respiratory acidosis If the HCO₃^- is < 22 mEq/L, then the primary disorder is a metabolic acidosis Alkalosis (pH > 7.45) If the PaCO₂ is < 38 mmHg, then the primary disorder is a respiratory alkalosis If the HCO₃^- is > 26 mEq/L, then the primary disorder is a metabolic alkalosis Compensation - respiratory/metabolic compensation may or may not be present depending on the length of the disorder. See compensation above for more.
Step 4 - calculate the anion gap Anion gap Anion gap = Na⁺ - (Cl^- + HCO₃^-) where HCO₃^- is represented by venous carbon dioxide If serum albumin is < 4 grams/dl, then the anion gap should be corrected: Corrected anion gap (hypoalbuminemia) = (4 - serum albumin concentration) X 2.5 + calculated anion gap See anion gap for a review of the anion gap If the anion gap is ≥ 20, then a metabolic acidosis is either the primary or coprimary disorder regardless of the bicarbonate or pH value The reasoning behind this is that the body will not generate an anion gap ≥ 20 even in the face of chronic alkalosis If the primary disorder is a metabolic acidosis: Anion gap > 12 mEq/L - high anion gap metabolic acidosis is present (see high anion gap metabolic acidosis) Anion gap ≤ 12 mEq/L - normal anion gap metabolic acidosis is present (see normal anion gap metabolic acidosis) NOTE: Normal range may vary by lab
Step 5 - look for a mixed acid-base disorder Calculate the excess anion gap and add it to the bicarbonate value: Excess anion gap (EAG) = Calculated anion gap - 12 Bicarbonate value = venous carbon dioxide measurement If EAG + bicarbonate > normal serum bicarbonate (30 mEq/L) then extra bicarbonate has been added to the serum and a metabolic alkalosis is also present If EAG + bicarbonate < normal serum bicarbonate (23 mEq/L) then a normal anion gap metabolic acidosis is also present

Examples presented in reference 1 (Haber):

Patient #1

Lab values: pH 7.5, PaCO₂ 20 mmHg, HCO₃^- 15 mEq/L, Na⁺ 140, Cl^- 103
Step 2 - pH > 7.45 so primary disorder is alkalosis
Step 3 - PaCO₂ is < 38 mmHg so the source of the primary disorder is respiratory alkalosis
Step 4 - Anion gap = 140 - (103 + 15) = 22. Because the anion gap is ≥ 20, metabolic acidosis is a coprimary disorder.
Step 5 - EAG = 22 - 12 = 10; EAG + bicarbonate = 10 + 15 = 25. No other acid-base disorder is present.
Conclusion:

Disorders: respiratory alkalosis and metabolic acidosis
Setting: Aspirin overdose. Salicylates stimulate respiratory drive leading to respiratory alkalosis. They also cause a high anion gap metabolic acidosis because they inhibit cellular metabolism which leads to the formation of ketoacids and lactic acid.

Patient #2

Lab values: pH 7.4, PaCO₂ 40 mmHg, HCO₃^- 24 mEq/L, Na⁺ 145, Cl^- 100
Step 2 - no apparent acid-base disorder based on pH alone
Step 3 - no apparent disorder identified
Step 4 - Anion gap = 145 - (100 + 24) = 21. Because the anion gap is ≥ 20, metabolic acidosis is a coprimary disorder.
Step 5 - EAG = 21 - 12 = 9; EAG + bicarbonate = 9 + 24 = 33. Because EAG + bicarbonate is > 30, a metabolic alkalosis is present
Conclusion:

Disorders: metabolic acidosis and metabolic alkalosis
Setting: Patient with chronic renal failure (metabolic acidosis) who began vomiting (metabolic alkalosis) from uremia

Patient #3

Lab values: pH 7.5, PaCO₂ 20 mmHg, HCO₃^- 15 mEq/L, Na⁺ 145, Cl^- 100
Step 2 - pH > 7.45 so primary disorder is alkalosis
Step 3 - PaCO₂ is < 38 mmHg so the source of the primary disorder is respiratory alkalosis
Step 4 - Anion gap = 145 - (100 + 15) = 30. Because the anion gap is ≥ 20, metabolic acidosis is a coprimary disorder.
Step 5 - EAG = 30 - 12 = 18; EAG + bicarbonate = 18 + 15 = 33. Because EAG + bicarbonate is > 30, a metabolic alkalosis is present
Conclusion:

Disorders: respiratory alkalosis and metabolic acidosis and metabolic alkalosis
Setting: Patient with history of vomiting (metabolic alkalosis), alcoholic ketoacidosis (metabolic acidosis), and pneumonia (respiratory alkalosis)

Patient #4

Lab values: pH 7.1, PaCO₂ 50 mmHg, HCO₃^- 15 mEq/L, Na⁺ 145, Cl^- 100
Step 2 - pH < 7.35 so primary disorder is acidosis
Step 3 - PaCO₂ is > 42 mmHg so the source of the primary disorder is respiratory acidosis
Step 4 - Anion gap = 145 - (100 + 15) = 30. Because the anion gap is ≥ 20, metabolic acidosis is a coprimary disorder.
Step 5 - EAG = 30 - 12 = 18; EAG + bicarbonate = 18 + 15 = 33. Because EAG + bicarbonate is > 30, a metabolic alkalosis is present
Conclusion:

Disorders: respiratory acidosis and metabolic acidosis and metabolic alkalosis
Setting: Obtunded patient (respiratory acidosis) with history of vomiting (metabolic alkalosis) and diabetic ketoacidosis (metabolic acidosis)

Patient #5

Lab values: pH 7.15, PaCO₂ 15 mmHg, HCO₃^- 5 mEq/L, Na⁺ 140, Cl^- 110
Step 2 - pH < 7.35 so primary disorder is acidosis
Step 3 - HCO₃^- is < 22 mEq/L so the source of the primary disorder is metabolic acidosis
Step 4 - Anion gap = 140 - (110 + 5) = 25. Because the anion gap is ≥ 20, metabolic acidosis is a coprimary disorder.
Step 5 - EAG = 25 - 12 = 13; EAG + bicarbonate = 13 + 5 = 18. Because EAG + bicarbonate is < 23, a normal anion gap acidosis is present
Conclusion:

Disorders: high anion gap metabolic acidosis and normal anion gap metabolic acidosis
Setting: Diabetic ketoacidosis (high anion gap acidosis) during the recovery phase when kidneys fail to regenerate HCO_3^- from ketoacids lost in the urine (normal anion gap metabolic acidosis)

ALTITUDE SICKNESS (ACUTE MOUNTAIN SICKNESS)

Overview

As elevation rises above sea level, the pressure of oxygen in the air decreases. For example, at the top of Mount Everest, oxygen pressure is < 30% of that at sea level. When a person ascends rapidly, the amount of oxygen in inspired air decreases, and the body reacts by increasing the rate and depth of inspiration. This can lead to hyperventilation, which causes the arterial PaCO₂ to fall and respiratory alkalosis to develop. Respiratory alkalosis inhibits ventilation and hypoxia occurs.
People who rapidly ascend from near sea level to ≥ 3000 meters are at risk of developing altitude sickness, a syndrome caused by hypoxia and respiratory alkalosis. Symptoms of altitude sickness usually occur within 2 - 3 hours of ascent and resolve after 2 - 3 days. [6,7,8]

Altitude sickness symptoms include the following:

Headache
Lightheadedness
Fatigue
Insomnia
Nausea/decreased appetite

Carbonic anhydrase and acetazolamide

Carbonic anhydrase is an enzyme found throughout the body. It is particularly important in the kidneys, where it helps regulate renal bicarbonate (HCO₃^-) reabsorption. Carbonic anhydrase promotes HCO₃^- retention and H⁺ excretion in renal tubular cells by catalyzing the conversion of CO₂ and H₂O to H₂CO₃ (see illustration below). Carbonic anhydrase inhibitors block this reaction, causing renal HCO₃^- loss and acidosis.
Acetazolamide (Diamox®) is the main carbonic anhydrase inhibitor available in the U.S. A handful of other medications (e.g. topiramate, zonisamide) also have mild inhibitory activity.
Carbonic anhydrase inhibitors have been used to treat the following conditions:

Glaucoma - carbonic anhydrase inhibitors decrease the secretion of aqueous humor and lower intraocular pressure
Idiopathic intracranial hypertension (pseudotumor cerebri) - carbonic anhydrase inhibitors are believed to decrease the production of cerebrospinal fluid (CSF)
Altitude sickness

Illustration of carbonic anhydrase activity in the renal tubule

Acetazolamide to prevent altitude sickness

Acetazolamide promotes renal HCO₃^- excretion, which counteracts the respiratory alkalosis that occurs in altitude sickness. As PaCO₂ rises, ventilation is stimulated, and oxygenation improves. Other effects that may help alleviate symptoms include diuresis and decreased CSF production.
Prescribing information for acetazolamide is provided below. Two studies that compared acetazolamide to placebo for the prevention of altitude sickness are also reviewed (see studies). [6,7,8]

Reference [6,7,8,9]
Acetazolamide for prevention of altitude sickness
Dosage forms Standard-release tablet 125 and 250 mg tablet Cost for 30 tablets is < $50 Extended-release capsule (Diamox Sequels®) 500 mg capsule Cost for 30 capsules is $50 - $100
Dosing Standard-release tablet 500 - 1000 mg/day given in two to three divided doses In studies, the lowest effective dose has been shown to be 125 mg twice a day In circumstances of rapid ascent, such as in rescue or military operations, the higher dose level of 1000 mg is recommended It is preferable to initiate dosing 24 to 48 hours before ascent and to continue for 48 hours while at high altitude, or longer as necessary to control symptoms Extended-release capsule 500 mg once or twice daily In circumstances of rapid ascent, such as in rescue or military operations, the higher dose level of 1000 mg is recommended It is preferable to initiate dosing 24 to 48 hours before ascent and to continue for 48 hours while at high altitude, or longer as necessary to control symptoms
Contraindications / precautions Sulfonamide allergy - acetazolamide is a sulfonamide derivative Hyponatremia - may worsen Hypokalemia - may worsen Significant kidney disease - may worsen acidosis Metabolic acidosis - may worsen Cirrhosis - may exacerbate hepatic encephalopathy
Common side effects Paresthesia (numbness and tingling) of the fingers and toes - up to 90% Increased urination - up to 55% Nausea and tiredness - up to 20% Taste perversion, especially carbonated beverages - up to 14%

Acetazolamide vs Placebo to Prevent Altitude Sickness in Healthy Adults [NEJM Evidence]

The trial enrolled 345 healthy adults living not higher than 800 meters above sea level

Main inclusion criteria

Age 40 - 75 years
Living below 800 m above sea level

Main exclusion criteria

Any active respiratory or cardiovascular disease
Current heavy smoker
Regular alcohol use

Baseline characteristics

Average age 53 years
Female sex - 69%
Average FEV₁ % predicted - 101%
Average pulse oximetry - 96%

Randomized treatment groups

Group 1 (170 patients): Placebo
Group 2 (175 patients): Acetazolamide 125 mg in the AM and 250 mg in the PM starting 24 hours before and during the stay at 3100 meters
Patients were evaluated at 760 meters before traveling for 3 - 5 hours by minibus to a high-altitude clinic at 3100 meters, where they stayed for 2 days and nights

Primary outcome: Incidence of acute mountain sickness defined by a LLS score ≥ 3 including headache (LLS 1993 version; the scale of self-assessed symptoms ranges from 0 to 15 points, indicating absent to severe)

Results

Outcome	Placebo	Acetazolamide	Comparisons
Duration: 2 days
Primary outcome	32%	22%	p=0.035
Primary outcome (men)	14%	11%	p=0.77
Primary outcome (women)	39%	27%	p=0.035
Severe hypoxemia (pulse ox < 80% for > 30 min)	31%	7%	N/A
Paresthesias	42%	59%	N/A

Findings: In this trial of healthy individuals, 54 of 170 (32%) receiving placebo and 38 of 175 (22%) receiving acetazolamide experienced acute mountain sickness (hazard ratio, 0.48; 95% CI, 0.29 to 0.80; chi-square statistic P=0.035). The NNT to prevent one case of AMS was 10 (95% CI, 5 to 141). No serious adverse events occurred in this trial.

Acetazolamide vs Placebo to Prevent Altitude Sickness in Adults with COPD [NEJM Evidence]

The trial enrolled 176 adults with COPD living not higher than 800 meters above sea level

Main inclusion criteria

Age 18 - 75 years
Living below 800 m above sea level
COPD according to GOLD criteria
Pulse oximetry ≥ 92%
PaCO₂ < 45 mmHg

Main exclusion criteria

COPD exacerbation within 3 months
Uncontrolled cardiovascular disease
Current heavy smoker

Baseline characteristics

Average age 57 years
Male sex - 66%
Average FEV₁ % predicted - 63%
Average pulse oximetry - 95%
GOLD stage: II - 84% | III - 16%

Randomized treatment groups

Group 1 (90 patients): Placebo
Group 2 (86 patients): Acetazolamide 125 mg in the AM and 250 mg in the PM starting 24 hours before and during the stay at 3100 meters
Patients were evaluated at 760 meters before traveling for 3 - 5 hours by minibus to a high-altitude clinic at 3100 meters, where they stayed for 2 days and nights

Primary outcome: Incidence of altitude-related adverse health effects (ARAHE), defined as one or more of the following: (1) acute mountain sickness, (2) severe hypoxemia (mean SpO2 of < 80% for > 30 minutes or < 75% for > 15 minutes), (3) symptomatic cardiovascular disease requiring intervention or treatment, (4) study withdrawal upon request by the patient or the independent physician

Results

Outcome	Placebo	Acetazolamide	Comparisons
Duration: 2 days
Primary outcome	76%	49%	p<0.001
Primary outcome (men)	69%	47%	p=0.015
Primary outcome (women)	89%	52%	p=0.002
Severe hypoxemia (pulse ox < 80% for > 30 min)	44%	16%	N/A
Acute mountain sickness	28%	27%	N/A
Paresthesias	21%	28%	N/A

Findings: In this trial of patients with COPD, 68 of 90 (76%) receiving placebo and 42 of 86 (49%) receiving acetazolamide experienced ARAHE (hazard ratio, 0.54; 95% confidence interval [CI], 0.37 to 0.79; P<0.001). The number needed to treat (NNT) to prevent one case of ARAHE was 4 (95% CI, 3 to 8). No serious adverse events occurred in this trial.

BIBLIOGRAPHY

1 - PMID 1843849 - Practical approach to acid-base disorders, West J Med, (1991) Haber et al.
2 - PMID 25295502 - NEJM acid-base review
3 - PMID 9708770 - Lancet review
4 - PMID 9794863 - ABG review
5 - Medical Physiology, First edition, 1995. Rhoades and Tanner. ISBN 0-316-74228-7
6 - PMID 15545679 - ACP mountain sickness review
7 - PMID 23758234 - NEJM Mountain sickness review
8 - PMID 12801752 - Lancet mountain sickness review
9 - Acetazolamide PI
10 - PMID 29489223 - Sharma S, Hashmi MF, Burns B. Alveolar Gas Equation. 2022 Aug 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.

ACID-BASE DISORDERS

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