ACID-BASE DISORDERS

















Illustration of normal acid-base physiology


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



  • 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




  • 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



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


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



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




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



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



  • 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:
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





Illustration of carbonic anhydrase activity in the renal tubule

  • 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

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.
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

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.