ACID-BASE

Metabolic or Respiratory problem?

Metabolic problems involve change in serum bicarb or anion gap

Respiratory problems involve change in PCO2

Diagnostic approach to metabolic pH abnormalities

Determine the anion gap
If AG is normal, look at bicarb
1. Bicarb<22: Pure NAGMA
2. Bicarb>28: Pure metabolic alkalosis
3. Bicarb 22-28: Normal pH status
If HIGH anion gap, determine the delta-delta
- Delta anion gap = (Anion Gap) – 10. This is roughly the degree of elevation of the anion gap.
- Delta bicarbonate = 24 – bicarbonate. This is roughly the degree of reduction of the serum bicarbonate.
  - If ΔAG ~ ΔBicarb--> Pure AGMA
  - If ΔAG > ΔBicarb--> AGMA + metabolic alkalosis
  - If ΔAG < ΔBicarb--> Combined AGMA + NAGMA

Metabolic Acidosis

High Anion Gap (AGMA)

Anion Gap (AG) = Na – Bicarb – Chloride

Normal is 4-12mM

Anion Gap Calculator

Anion Gap

Compare the AG to baseline (i.e. patients with chronic renal failure may have chronically elevated anion gap)
No need to correct for albumin

Causes of AGMA

Ketoacidosis: DKA, alcoholic ketoacidosis, starvation ketoacidosis
Uremic acidosis: when GFR<30
Lactic acidosis
- Inadequate oxygen delivery: shock, ischemia, muscle hyperactivity (seizure), extreme anemia
- Adequate oxygen delivery: liver failure, malignancy, thiamine deficiency, exogenous epinephrine/albuterol, endogenous epinephrine (shock), lactic alkalosis, severe DKA
Medications: NSAIDs, epinephrine, albuterol, metformin, linezolid, HIV drugs, propofol, propylene glycol intoxication (usually due to high IV doses of lorazepam, diazepam, nitro, esmolol, phenytoin), nitroprusside, valproate/topiramate
Poisoning: Acetaminophen, alcohols (ethylene glycol, methanol, ethanol), cyanide, carbon monoxide, salicylate, cocaine/amphetamines, iron
Others: Hyperphosphatemia, metabolic alkalosis, D-hyperlactatemia (rare, due to bacterial fermenation follow small bowel resection)

Evaluate cause of AGMA

Check CBC: Elevated WBC count of increase neutrophil/lymphocyte ratio may represent systemic illness/ sepsis
Repeat electrolytes including Ca/Mg/Phos
Check LFT's: liver disease may cause elevated lactate levels
Lactate level
Beta-hydroxybutyrate level (more accurate than urinary ketones)
Evaluate for poisonings- salicylates, acetaminophen, carbon monoxide, toxic alcohols
Consider differential diagnosis (above), review medications
Calculate Delta-Delta

Delta-Delta

Exam

Look for signs of shock (tachycardia, low urine output, hypotension, confusion) and signs of ischemia (abdominal pain, cold limbs)

Treatment of AGMA

Treat identifiable causes
Empiric IV thiamine 200mg IV q12h: thiamine deficiency much more common than we think and impossible to accurately test for
Bicarbonate: really only useful in uremic AGMA, not helpful in lactic acidosis, DKA regardless of pH
Dialysis: For patients with acidosis + renal failure especially if volume overloaded
- Indicated if pH <7.15 despite treatment or in specific intoxications (metformin, ethylene glycol, methanol, salicylate)

BEWARE, AG isn't reliable in detecting mild degrees of lactic acidosis (lactate of 2-4mM). Normal anion gap has a wide range, so someone with a baseline anion gap that is low (~4mM) can develop a lactic acidosis yet have a normal AG

How does ABG/VBG help?

Provides info about respiratory pH abnormalities. Answers 2 main questions

Is there adequate respiratory compensation?--> Metabolic alkalosis may be compensated for by mild hypoventilation & metabolic acidosis may be compensated for by hyperventilation
Is there a primary respiratory disorder? / Is this pH abnormality due to a secondary compensatory response to a respiratory abnormality?
- Metabolic acidosis could be due to a chronic respiratory alkalosis (extremely rare unless patient is mismanaged on a mechanical vent)
- Metabolic alkalosis could be due to a chronic respiratory acidosis (common in hypercapnic patients, esp. in COPD, obesity hypoventilation syndrome, chronic opioids)

Winters' Formula Calculator

Winters' Formula

To determine other forms of compensation, it is not necessary to remember all of the different formulas and to instead just use a cheat sheet:

Cheat sheet for metabolic and respiratory compensation

Normal Anion Gap Metabolic Acidosis (NAGMA)

Patient with normal anion gap with metabolic acidosis + Bicarb < 22
Patient with anion gap metabolic acidosis, but the decrease in bicarb > elevation in anion gap (combined AGMA+NAGMA)

Causes of NAGMA

Normal saline infusion
Resolving DKA
GI bicarb losses: Diarrhea, fistula, pancreatic/biliary drainage
Renal insufficiency if GFR btwn 20-50
Exogenous acids: TPN, calcium chloride
Chronic hyperventilation (very rare)
RTA

Workup for NAGMA

Cause is usually obvious based on history and medications
Look at potassium level, can be early clue
- High/normal potassium--> NS infusion, TPN, RTA type-4, chronic renal insufficiency
- Low potassium: GI losses, RTA-type1/2
Check electrolytes (including Ca/Mg/Phos)
Check UA
Check urine chemistries
- Urine: pH, sodium, potassium, glucose, urea, osmolarity
Calculate urine osmolar gap to diagnose type 1 or type 4 RTA--> indirect measurement of ammonium (acid) excretion by kidney
- Osmolar Gap = Urine osmolarity – 2(sodium + potassium) – Glucose(in mg/dL)/18 – Urea(in mg/dL)/28
  - Osmolar gap >150 mOsm: appropriate ammonium excretion (excluding RTA type I or IV)
  - Osmolar gap <150 mOsm: inadequate ammonium excretion (suggests RTA type I or IV)
  - Type II RTA may secrete normal amounts of ammonium (and thus their urine osmolar gap may be appropriately elevated)

Urine Osmolar Gap Calculator

Urine Osmolar Gap

RTA Class

Type-4 RTA

Caused by impaired renin secretion (diabetes, htn, glomerulonephritis, NSAIDs, beta blockers)
Caused by impaired aldosterone production (adrenal insufficiency, critical illness, heparin, ACEI/ARBs, renin inhibitors)
Caused by kidney being refractory to aldosterone (SLE, amyloid, obstructive uropathy, K+ sparing diuretics etc.)

Treatment of NAGMA

Treat underlying cause (medication, give fludrocortisone if type-4 RTA)
It is controversial whether NAGMA requires treatment, some rationale to treat include: hyperchloremic acidosis can injure kidneys/cause systemic inflammation, acidosis increases work of breathing (by compensatory respiratory alkalosis), acidosis increases insulin resistance
2 indications for treatment: Bicarb < 18, OR patient is at increased risk of harm from acidosis (AKI, DKA)
NAGMA represents an imbalance between sodium chloride and sodium bicarb, so treatment involves adding sodium bicarb and removing sodium bicarb. Treatment however depends on volume status. The optimal treatment will simultaneously address the NAGMA, the volume status, and the sodium concentration.
- Hypovolemia –> Add sodium bicarbonate.
- Euvolemia –> Add sodium bicarbonate and remove sodium chloride simultaneously. The goal here is to replace bicarbonate with chloride, without shifting the volume status.
- Hypervolemia –> Remove sodium chloride via diuresis.
If repleting bicarb, calculate the patient's bicarbonate deficit

Bicarbonate Deficit Calculator

Reduced anion gap

MOST COMMONLY just a lab error due to hypernatremia, hyperlipidemia
- 1st step is to recheck it
Some other causes can be increased levels of cations (hyperkalemia, hypercalcemia), lithium toxicity, multiple myeloma

Metabolic Alkalosis

Symptoms: seizures (typically at Bicarb>50), delirium, arrhythmia, hypocalcemia (high pH causes calcium to bind albumin), hypoventilation (respiratory compensation)
Causes
- Compensation for chronic respiratory acidosis- COPD, obesity hypoventilation, respiratory muscle weakness
- Chloride- depletion metabolic alkalosis- vomiting, NG suction, chloride-wasting diarrhea (laxative abuse), diuresis, renal hypoperfusion + exogenous alkali (i.e. patient with CHF takes a lot of TUMS)
- Non-chloride depletion metabolic alkalosis- thiazide/loop diuretics, hypomagnesemia/hypokalemia, hypoaldosteronism, renal insufficiency + exogenous alkali (i.e. patient with kidney failure takes a lot of TUMS)

Workup for Metabolic Alkalosis

History, physical: Usually reveals the cause.
- If hypovolemic based on history/ bedisde echo--> chloride deficiency
- Hypertension suggest excess aldosterone
- Chronicity (i.e. chronic metabolic alkalosis suggest chronic compensation for COPD)
Labs, including Ca/Mg/Phos, ABG/VBG to evaluate if it's compensatory metabolic alkalosis
Urine potassium and urine chloride levels
- Urine potassium <20-30 mM: hypokalemia may be contributory
- Urine chloride concentration is the most important:
  - Chloride <10-30 mM: suggests saline responsive.
  - Chloride >10-30 mM: suggests saline unresponsive.
  - Chloride between 10-30 mM: gray area
Evaluate RAAS (usually unnecessary). May consider if patient has persistent alkalosis with high urine chloride and is refractory to NS infusion or if other signs of excess RAAS (hypertension, hyperkalemia)
- Measure serum renin and aldosterone levels
  - ↓ renin & ↑ aldosterone: Primary hyperaldosteronism (aldosterone-secreting adenoma, bilateral adrenal hyperplasia).
  - ↑ renin & ↑ high aldosterone: Secondary hyperaldosteronism (renin-secreting tumor, renal artery stenosis).
  - ↓ renin & ↓ aldosterone: State of apparent mineralocorticoid excess (Cushing syndrome, exogenous mineralocorticoid, licorice ingestion).

When NOT to treat a metabolic alkalosis?

Compensatory metabolic alkalosis due to respiratory acidosis: Do not treat, their compensatory mechanism is beneficial, metabolic alkalosis allows them to have a normal pH despite hypoventilation

When TO treat a metabolic alkalosis?

Usually the goal is to treat the underlying cause (i.e. patient is hypovolemic, give them fluids). Treatment may be indicated in following circumstances:
- Alkalosis is severe/symptomatic
- Process causing alkalosis isn't easily reversed (most commonly patient being diuresed develops contraction alkalosis but needs to keep being diuresed)

Treatment for Metabolic Alkalosis

Give potassium chloride target K>4.5: Hypokalemia maintains alkalosis
Give magnesium: hypomagnesemia contributes to alkalosis and makes it harder to tx the hypokalemia
Give normal saline if hypovolemic: if urine chloride < 10-30 then they are saline responsive. Acidotic NS preferred over LR
Give diuretics (ACETAZOLAMIDE) if hypervolemic: Acetozolamide will cause bicarb excretion (ensure to monitor potassium, can make hypokalemic which worsens the alkalosis).
- Spironolactone is 2nd line, but can take 24-48h to work
Hold/ decrease the dose of alkalosis-inducing diuretics (furosemide): If euvolemic you can discontinue, if still volume overloaded can give furosemide + acetazolamide
Give a PPI if ongoing vomiting/ NG suction: loss of gastric acid will cause metabolic alkalosis, PPI neutralizes the pH preventing loss of acid
Dialysis: rarely needed in metabolic alkalosis unless profound electrolyte abnormalities
IV HCl: last resort if all else fails (and pH >7.55 or bicarb> 38). Must be given via central line

Primary Respiratory Pathologies

Respiratory Acidosis

Symptoms

Delirium, somnolence, coma, tremor, asterixis, headache (upon wakening in nocturnal hypoventilation)
If chronic, patient's adapt and may present with only somnolence

Lab diagnosis- based on ABG/VBG

PaCO2 > 45
Primary hypercapnia: isn't a compensatory response to metabolic alkalosis
- Look at baseline bicarbonate level. In chronic hypercapnia, there will be a greater degree of compensatory metabolic alkalosis

Causes of hypercapnia

Won't breathe: medications like opioids, benzos, alcohol, brainstem dysfunction (trauma, stroke, tumor), hypothyroid
Can't breathe: spinal cord problem (C3-C5 injury), MS/transverse myeleitis, tumor, neuromuscular disorders (GBS, ALS, MG etc.), restricted lung inflation (abdominal compartment syndrome, obesity hypoventilation, pleural effusion, kyphosis etc.), upper airway problem (angioedema, foreign body etc.), lower airway problem (COPD/asthma)
Breathing isn't working: alveolar disease (pneumonia, ARDS, ILD) or vascular disease (PE)

Evaluation

Physical exam: if low RR think opioids/ CNS issue, if not distressed then think chronic problem or neuro issue, neurologic exam to look at brainstem/spinal cord issue, auscultate to look for signs of bronchospasm, stridor, air movement
Labs: electrolytes (including Ca/Mg/Phos), TSH, CBC (polycythemia= chronic hypoxia), CK (to look for myopathies, hypothyroid), look at pH/bicarbonate
Imaging: CXR, MRI of brain spine if suspicious for neurologic problem, CT neck/lungs, CTA

Consequences of hypercapnia

Generally tolerated well, chronic COPD patients live many years with high CO2 and the hypercapnia itself is not harmful
Permissive hypercapnia: allow CO2 to increase on vent to avoid barotrauma
Potential risks: dyspnea with agitation (bucking the ventilator), sedation (CO2 narcosis), pulmonary vasoconstriction (can be bad in patient with pulmonary htn), increased ICP (vasodilate cerebral arteries)

Treatment- No universal approach, causes vary. If patient is chronically hypercapnic, goal is to return to baseline

Hypercapnia due to opioid intoxication may involve naloxone
Hypercapnia due to neuromuscular weakness may often be improved with noninvasive ventilation
Hypercapnia due to asthma or COPD requires specific treatment pathways
Mild-moderate hypercapnia in an intubated patient may often be monitored without intervention (permissive hypercapnia).

Respiratory Alkalosis

Hypocapnia is by far the most common acid-base disorder in sick patients

Diagnosis- based on ABG/VBG

pCO2 < 35mm

Symptoms

Anxiety, delirium, seizure, sx of hypocalcemia (since alkalemia reduces ionized calcium levels) such as paresthesias/cramps, arrhythmia

Causes

Nearly any pulmonary disease: pneumonia, asthma, pulmonary embolism, pneumothorax, mechanical ventilation
Neurologic: pain, anxiety, meningitis/encephalitis, trauma, stroke
Medications: salicylates, topiramate, caffeine, nicotine, beta-agonists, progesterone
Endocrine: thyrotoxicosis, pregnancy
Cirrhosis
Sepsis (early sign that can precede hypoxemia/ hypotension)

Workup

Cause is often evident from history and physical, if unclear some of the following may be considered:
- Salicylate level, TSH, LFT's, beta-HCG, PE eval (D-dimer, CTA), sepsis eval, neuroimaging

Consequences of hypocapnia

Cerebral vasoconstriction which causes hypoperfusion
Suppression of respiratory drive, bronchoconstriction
Can cause a lactic alkalosis

Treatment

Treat the identifiable etiology, often involves properly treating pain and ensuring sedation if appropriate
If ventilated: reduce the TV or RR