- 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
- 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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- 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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- 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
ACID-BASE DISORDER COMPENSATION | |
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Metabolic acidosis
Respiratory compensation (decrease in PaCO2):
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Metabolic alkalosis
Respiratory compensation (increase in PaCO2):
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Respiratory acidosis
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Respiratory alkalosis
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- 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]
ALVEOLAR-ARTERIAL GRADIENT UNDER CERTAIN CONDITIONS | ||
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Condition | A-a gradient | Cause/Comment |
Diffusion impairment | Increase |
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Ventilation-perfusion mismatch | Increase |
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Physiologic shunt | Increase |
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Generalized hypoventilation | Normal |
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Reduced oxygen content of blood | Normal |
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- RESPIRATORY ALKALOSIS
- Overview
- Respiratory alkalosis occurs when the lungs blow off excessive CO2
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- RESPIRATORY ACIDOSIS
- Overview
- Respiratory acidosis occurs when the lungs retain CO2
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- 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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- 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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- 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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- 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).
Practical approach to acid-base disorders |
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Step 1 - obtain appropriate lab values
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Step 2 - determine if the primary disorder is an acidosis or alkalosis
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Step 3 - determine the source of the primary disorder
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Step 4 - calculate the anion gap
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Step 5 - look for a mixed acid-base disorder
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- 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 HCO3- 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

- 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]
Acetazolamide for prevention of altitude sickness |
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Dosage forms
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Dosing
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Contraindications / precautions
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Common side effects
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- 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
Duration: 2 days | |||
Outcome | Placebo | Acetazolamide | Comparisons |
---|---|---|---|
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.
- 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
Duration: 2 days | |||
Outcome | Placebo | Acetazolamide | Comparisons |
---|---|---|---|
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–.