CONTENTS
diagnosis of metabolic acid-base disorders
- Diagnostic approach to metabolic pH abnormalities
- Respiratory pH analysis & how much will it help us?
- Other approaches to pH analysis
- Single-digit bicarbonate
anion gap (AG)
elevated lactate (hyperlactatemia)
Metabolic disorders involve a primary change in the serum bicarbonate and/or anion gap. This should be analyzed any time electrolytes are measured.
[1] determination of the anion gap to evaluate for anion gap metabolic acidosis (AGMA)
- Anion gap should be evaluated on every electrolyte panel. Ideally the computer will do this automatically; otherwise, it should be calculated.
- Anion gap is calculated as (Na – Cl – Bicarb). Nothing fancy, no corrections for anything (glucose, albumin, potassium, etc.).
- Elevated anion gap is concerning, because many causes of this are immediately life-threatening. (Unlike, for example, non-anion-gap metabolic acidosis – where most causes are not life threats).
[2] if the anion gap is normal, just look at the bicarbonate
- Bicarbonate <22 mM with a normal anion gap indicates a pure non-anion-gap metabolic acidosis (NAGMA).
- Bicarbonate >28 mM with a normal anion gap indicates a pure metabolic alkalosis.
- A bicarbonate of 22-28 mm with a normal anion gap indicates a normal metabolic pH status.
[3] if the anion gap is elevated, determine the “delta delta”
- What are these?
- 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.
- Comparing these values can help determine if there is an additional process, in combination with the anion gap metabolic acidosis. Specifically:
- (1) If delta anion gap is roughly equal to the delta bicarbonate, then no other process is present. This is about what we would expect for an isolated, pure anion gap metabolic acidosis.
- (2) If the delta anion gap is much higher than the delta bicarbonate, then a second process is present which is increasing the bicarbonate level. This reveals a combination of an anion gap metabolic acidosis plus a metabolic alkalosis.
- (3) If the delta anion gap is much lower than the delta bicarbonate, then this reveals a second process which is decreasing the bicarbonate. This indicates a combined anion gap metabolic acidosis plus a non-anion-gap metabolic acidosis.
An ABG/VBG will provide information about respiratory pH abnormalities. Although this is traditionally considered a mandatory component of pH analysis, the amount of useful information provided by this analysis is variable. Blood gas analysis can answer essentially two questions:
[#1] is there adequate respiratory compensation?
- Patients with metabolic pH abnormalities should “normally” be expected to develop respiratory compensation, as shown in the left side of the table below:
- Metabolic alkalosis may be compensated for by mild hypoventilation (secondary respiratory acidosis)
- Metabolic acidosis may be compensated for by hyperventilation (secondary respiratory alkalosis)
- By determining whether the patient is obeying these rules, we could theoretically determine whether their ventilation is intact (or whether it is proportionally inadequate or excessive).
- In practice, ventilation in critically ill patients is generally influenced by numerous factors (e.g. anxiety, opioids, mechanical ventilation settings). Compensation equations are historically based on fairly stable patients without multiple active problems. It's unclear how well these equations function in the context of modern critically ill patients, who frequently have numerous active medical problems.
- Overall, it's murky how information about respiratory compensation should affect our management of critically ill patients. Specifically, decisions regarding intubation or selection of respiratory support devices are generally made on the basis of clinical assessment and diagnosis (not blood gas values).
[#2] is there a primary respiratory disorder?
- If we detect a metabolic pH abnormality, there is a possibility that it represents a secondary compensatory response to a respiratory abnormality (the right side of the chart above). Specifically:
- (a) Metabolic acidosis could be due to a chronic respiratory alkalosis
- (b) Metabolic alkalosis could be due to a chronic respiratory acidosis
- Sorting this out is important, because it leads to an entirely different diagnosis and management.
- From a practical standpoint:
- (a) Metabolic acidosis due to chronic respiratory alkalosis is extremely rare (unless a patient is being mismanaged on mechanical ventilation). This is a bit of a zebra.
- (b) Metabolic alkalosis due to chronic respiratory acidosis is common in patients with hypercapnia of any etiology (most commonly COPD, obesity hypoventilation syndrome, or possibly chronic opioid use). This can generally be diagnosed based on a compatible clinical history, as well as review of archival labs (which show a chronic metabolic alkalosis).
so, what does the blood gas analysis really add to a clinically relevant analysis of pH?
- Blood gas analysis usually won't have a major effect on our diagnosis and management of the patient (assuming that we have fully evaluated the electrolyte panel and performed a thoughtful history and physical examination).
- Occasionally, blood gas analysis may reveal a chronic respiratory acidosis as the cause of a metabolic alkalosis (2b) – but in most cases this would already have been suspected on the basis of clinical history and/or prior laboratory studies.
- So, in sum, blood gas analysis isn't mandatory when analyzing a patient's acid-base status. It may be obtained on a selective basis, rather than broadly being ordered for any patient with a pH abnormality. This is preferable for the following reasons:
- (1) Acid-base abnormalities are extremely common among critically ill patients (present in perhaps a majority of patients). If we take the attitude that any acid-base abnormality mandates a blood gas analysis, then we are going to be subjecting our patients to lots of blood gas analyses (at considerable pain and expense).
- (2) Treatment decisions can often be made directly on the basis of the electrolytes (metabolic acid-base analysis). This allows for the streamlining of clinical management (without a delay for blood gas analysis).
- French guidelines do recommend measurement of arterial blood gas in every patient with decreased plasma bicarbonate level. However, they cite no high-quality evidence to support this recommendation. (31418093)
- There are numerous approaches to pH analysis, most of which are much more complex (e.g. Stewart's Acid-Base approaches). However, different strategies of analysis will generally yield the same conclusions.
- Choice of various models remains controversial. There's no solid evidence that one model is clinically superior to the other. (22976522) Most comparisons of various models are theoretical rather than actually field-tested.
- iPhone apps based on Stewart Acid-Base analysis may provide misleading information.(27925790)
- Any approach which you understand and apply in a consistent fashion is great. The above approach is easy to perform and widely used by clinicians (which may facilitate communication with colleagues). However, if you already have a method that you are using, there is no reason to switch.
- The main problem occurs when people fail to apply any pH analysis at all (for example, failing to note that the anion gap is elevated).
Some etiologies of serum bicarbonate <10 that deserve consideration include the following list. (36796238) However, this list is not intended to replace a comprehensive evaluation of all possible etiologies.
- Liver failure.
- Post cardiac arrest.
- Severe ketoacidosis:
- Diabetic ketoacidosis.
- Alcoholic ketoacidosis.
- Toxicological etiologies:
- Toxic alcohol ingestion.
- Metformin poisoning.
- Salicylate intoxication.
- Cyanide toxicity. (36796238)
introduction to the anion gap
basic calculation & interpretation of the anion gap
- Anion Gap (AG) = Na – Bicarb – Chloride
- A normal anion gap is roughly 4-12 mM.
- Historically, the normal range of anion gap was often quoted as being higher (e.g. up to ~16 mM). However, with newer electrolyte analyzers, the upper limit of normal has decreased to ~11-12 mM. (24766940)
- Normal ranges may vary somewhat between hospital laboratories.
- Comparison with a baseline anion gap is helpful, if that is available. For example:
- [1] Patients with chronic renal insufficiency may often have a chronically elevated anion gap. If their anion gap is at its chronic level, this is reassuring.
- [2] If the anion gap is rapidly elevating over time, this is worrisome and requires aggressive investigation.
you don't need to correct for albumin 🌊
- Albumin is a negatively charged protein, which will theoretically tend to increase the anion gap.
- Most literature and textbooks on acid-base status recommend correction of anion gap for the albumin. However, my experience is that clinicians actually don't do this in real life (because measurement of the albumin is often unavailable).
- Correcting the anion gap for albumin makes theoretical sense, but it is supported by no clinical evidence.
- Correcting for albumin shifts the anion gap upwards by ~4 mM. Thus, a higher cutoff value must be needed for the detection of an anion-gap metabolic acidosis if correction is made for albumin.
- Using an un-corrected anion gap with a cutoff value of >10 mM has the same performance for detecting anion gap metabolic acidosis as using a corrected anion gap with a higher cutoff value of ~14 mM. (16858097, 18431828, 19087326) Different cutoffs may affect sensitivity and specificity, but the overall performance of the test is unchanged (i.e. same area under the Receiver Operator Curve). So correcting for the albumin is an extra step which provides no improved clinical utility to this test.
- If you feel compelled to correct the anion gap for albumin that's fine, but you need to use a higher cutoff value.
performance of anion gap in detecting lactic acidosis
- Anion gap is not reliable for detecting mild degrees of lactic acidosis (e.g. lactate of 2-4 mM). This is because a normal anion gap spans a range of ~10 mM. If the patient begins with a baseline anion gap at the lower limit of normal (e.g. 4 mM), they could easily develop a substantial lactic acidosis while still having an anion gap within the normal range.(17699401)
- Studies vary in the precise sensitivity and specificity of anion gap for lactate detection (and this will likely vary between laboratories as well). One study found that an anion gap >10 mM could detect a lactate level >2.5 mM with a sensitivity of 63% and specificity of 65%.(19087326)
- If there is a specific concern regarding whether the patient might have lactic acidosis, the best strategy is to check lactate directly. An anion gap cannot be relied upon to exclude elevated lactate. However, an anion gap remains a useful surveillance test for the detection of marked lactic acidosis.
causes of high anion gap
ketoacidosis
- Diabetic ketoacidosis (DKA).
- Alcoholic ketoacidosis (AKA).
- Starvation ketoacidosis.
uremic acidosis
- Occurs when GFR <20-30 ml/min.
- Uncomplicated uremia rarely causes bicarbonate to fall below ~12-15 mM or anion gap to increase over >20 mM (if these are found, look for an alternative or additional disease process).
hyperlactatemia
- Causes are listed below: ⚡️
medication/substance related
- Inhalants (i.e., carbon monoxide, cyanide, toluene).
- Iron.
- Isoniazid.
- NSAIDs.
- Salicylates.
- Sympathomimetics.
- Toxic alcohols (methanol, ethylene glycol, diethylene glycol, propylene glycol).
- High-dose penicillins.
- Colchicine.
- 5-oxoproline aka pyroglutamic acidosis (therapeutic acetaminophen use). (35461626) Usually occurs in women who are ill and malnourished, causing depletion of glutathione and cysteine. Discontinuation of acetaminophen usually leads to rapid resolution. (34400023)
other causes of high AG
- Hyperphosphatemia.
- Metabolic alkalosis (increases the negative charge on albumin).
- D-hyperlactatemia (Due to small intestinal resection or malabsorption that causes carbohydrate to be delivered to the colon and fermented by gut bacteria. Note that laboratory tests for “lactate” will not detect D-lactate. D-hyperlactatemia may cause neurological symptoms including confusion, ataxia, incontinence, and nystagmus.) (34400023)
evaluation of high anion gap
basic, usual evaluation
- Repeat lab draw with simultaneous measurement of:
- [1] Electrolytes.
- [2] Lactate level.
- [3] Beta-hydroxybutyrate.
- Repeat electrolytes is useful to exclude laboratory error or random variation.
- Simultaneously obtaining all of these tests facilitates rapid and definitive management.
other tests that could be considered
- Poisoned patient: evaluate for salicylates, acetaminophen, carbon monoxide, and toxic alcohols.
clinical management of high anion gap
The treatment of elevated anion gap depends on its cause. While evaluation is underway, the following management steps may be considered:
bicarbonate
- Uremic AGMA:
- Traditionally, bicarbonate has been used to support the pH in efforts to stave off dialysis.
- The BICAR-ICU trial supported the concept of using bicarbonate in uremic metabolic acidosis (with a goal of reducing the requirement for dialysis).
- Other causes of AGMA (e.g. hyperlactatemia or diabetic ketoacidosis)
- Bicarbonate has no evidence-based role here (regardless of pH).
hemodialysis
- May be indicated in patients with metabolic acidosis and renal failure (especially in the presence of volume overload, which precludes the use of IV bicarbonate).
- The exact point at which dialysis is beneficial is controversial (i.e. early dialysis vs. late dialysis).
- According to French guidelines, refractory acidemia (e.g. pH < 7.15 despite conservative measures) might be an indication for dialysis.(31418093) However, the overall clinical picture may be more illuminative than any specific cutoff value.
- Earlier dialysis may be indicated for specific intoxications (e.g. metformin, ethylene glycol, methanol, or salicylate).
compensatory hyperventilation
- For intubated patients with mechanical ventilation, it may be reasonable to target a lower pCO2 target than usual.
- The goal here is to mimic the normal physiology of compensatory respiratory alkalosis (a responsibility which the clinician has taken over from the patient's medulla).
- The extent of hyperventilation will depend on balancing various physiologic derangements:
- In patients with ARDS or obstructive lung disease, achieving a low pCO2 may be impossible or dangerous.
- In patients with severe metabolic acidosis and hemodynamic instability, there may be a greater incentive to improve the pH by decreasing the pCO2. Alternatively, if the acidosis is well tolerated clinically then there is less imperative to adjust the ventilator.
low anion gap
Low AG might be regarded as an anion gap ≦3 mM. (37783490)
causes of low AG:
- Laboratory error:
- Possibly most common cause.
- May occur in:
- (1) Severe hypernatremia.
- (2) Pseudohyponatremia (e.g., 2/2 hyperlipidemia).
- (3) Drawing upstream of an IV infusion.
- Increased levels of cations:
- Hyperkalemia.
- Hypercalcemia.
- Hypermagnesemia (MgCl2 or MgBicarb >> MgSO4).
- Elevated levels of immunoglobulins:
- Multiple myeloma.
- Polyclonal gammopathy (variable effects).
- Pseudohyperchloremia: Falsely elevated chloride level may occur due to:
- Other drugs:
- Polymyxin B.
- Administration of ammonium chloride.
- Lithium overdose/poisoning.
- Low albumin level (only mild effect on anion gap).
initial considerations
- Consider the above differential diagnosis, within the patient's clinical context.
- Compare electrolytes to recent/baseline values:
- Is low AG chronic? (may suggest chronic disorder such as elevated immunoglobulins)
- Rapid shifts in sodium/chloride levels may suggest an incorrect laboratory draw.
- Is chloride level extremely high? Consider pseudohyperchloremia.
- Is the sodium low? Consider pseudohyponatremia.
laboratory investigation panel
- Initial investigation might include:
- Electrolytes (repeat).
- Calcium, magnesium.
- Salicylate level.
- Lithium level (if lithium intoxication is possible).
- Albumin level.
- Point-of-care electrolyte panel (may rapidly reveal pseudohyponatremia).
- May also consider:
- SPEP (serum protein electrophoresis).
- Serum osmolality (for evaluation of pseudohyponatremia).
rising AG (delta AG) in a hospitalized patient
- Hospitalized patients will often have daily electrolytes, which allows for trending of the anion gap over time.
- A rapidly rising anion gap may be an early reflection of ketoacidosis or lactic acidosis (even if the absolute value of the anion gap remains within the range of normal). The range of normal values is often broad (e.g., 5-14 mM), so if the patient has a low baseline anion gap then a substantial lactic acidosis could develop without pushing the anion gap above the normal range.
what constitutes a significant rise in anion gap?
- This is unclear.
- Some studies indirectly suggest that changes of ≧5 or ≧8 are clinically significant. (35568886, 23190721)
- Additional features may factor into whether to investigate further:
- Other soft signs of instability.
- If the current anion gap reflects a departure from the patient's prior anion gap trends.
causes of rapidly rising anion gap in a hospitalized patient
- This has a relatively narrow differential diagnosis:
- [1] Lab artefact / incorrect electrolyte measurement.
- [2] Lactic acidosis.
- [3] Ketoacidosis (e.g., starvation or diabetic ketoacidosis).
- Most other causes of elevated anion gap either cause slower shifts (e.g., uremia) or are unlikely to occur in the hospital (e.g., overdose).
investigation of a rapidly rising anion gap
- Obtain repeat labs with simultaneous measurement of electrolytes, lactate, and beta-hydroxybutyrate level.
- (Further discussion of the evaluation of elevated anion gap: ⚡️)
definition of elevated lactate
- A normal lactate level is ~0.5-2 mM.
- >2 mM is elevated.
- >4 mM is increasingly worrisome for an occult shock state or serious illness (yet the differential diagnosis is broad, as explored below).
causes of increased lactate production
- Increased glycolysis and pyruvate production:
- IV glucose administration.
- Beta-2 agonist activity (this also inhibits pyruvate formation from lactate).
- Metabolic or respiratory alkalosis (increases phosphofructokinase). Clinically, this very rare entity may be referred to as “lactic alkalosis.”
- Increase in NADH/NAD+ ratio (i.e., NAD+ deficiency):
- Mitochondrial dysfunction due to hypoxemia.
- Mitochondrial dysfunction for any other reason (e.g., medications).
- Low insulin levels or insulin resistance (e.g., ketoacidotic states).
causes of hyperlactatemia
type A: generalized or regional tissue hypoxia
- Shock of any etiology, including: 📖
- Septic shock.
- Cardiogenic shock.
- Obstructive shock (e.g., pulmonary embolism).
- Hypovolemic shock.
- (Note: this is an oversimplification, in most cases systemic oxygen delivery is actually preserved. Discussed further here).
- Regional hypoperfusion:
- Ischemic limb.
- Mesenteric ischemia.
- Muscle hyperactivity:
- Generalized seizure.
- Extreme exertion.
- Extreme anemia (e.g., <4 g/dL). (Reddi 2020)
- Systemic hypoxemia.
type B1: systemic diseases
- Liver failure.
- Malignancy (usually leukemia/lymphoma).
- Thiamine deficiency (e.g. due to persistent critical illness, poor nutritional status, or gastric bypass surgery).
- Lactic alkalosis.
type B2: drugs
- Beta-agonist excess:
- Albuterol.
- Terbutaline.
- Epinephrine.
- Linezolid.
- Metformin. 📖
- Nucleoside reverse-transcriptase inhibitors (e.g., used for treatment of HCV or HIV).
- Propofol (propofol infusion syndrome).
- Propylene glycol intoxication:
- Lorazepam, diazepam.
- Nitroglycerine.
- Esmolol.
- Phenytoin.
- Trimethoprim-sulfamethoxazole.
- Nitroprusside (due to cyanide accumulation).
- Oxaliplatin. (36558947, 31361914)
type B2: toxins
- Acetaminophen poisoning (massive) 📖
- Alcohols:
- Carbon monoxide.
- Cyanide.
- Salicylate.
- Sympathomimetics (cocaine, amphetamine, cathinones).
- Toluene.
- Iron.
type B3: inherited
- MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).
evaluation of hyperlactatemia to determine cause
[1] review medications
- Potentially problematic medications are listed above.
- Any medication which could be causing acidosis should be stopped immediately (especially: propofol, nitroprusside, or metformin).
- One potential exception here is hyperlactatemia due to epinephrine. This is not necessarily harmful, in fact some evidence suggests that it may be beneficial. (20016405) Unless the lactate elevation due to epinephrine is substantial (e.g. >10 mM), it may be best to continue epinephrine regardless of an elevated lactate level.
[2] examine patient with focus on features of shock
- Signs of shock? 📖 (tachycardia, low urine output, hypotension, confusion, impaired skin perfusion).
- If there are signs of shock, then resuscitation should begin immediately without delay.
- When in doubt, assume that the hyperlactatemia is real.
- POCUS: Evaluate for unusual types of shock (e.g., massive pulmonary embolism, tamponade).
- Signs of focal ischemia? (abdominal pain or cold limb).
[3] send a lab panel
- Repeat lactate level and electrolytes (if there is any doubt about the validity of these labs).
- Note: Occasionally, elevated lactate measurement may result from lab measurement upstream from an infusion of lactated ringers!
- Venous lactate is fine for clinical use. (Technically, arterial lactate is the reference standard. However, venous values are extremely close and clinical decisions should not be made on the basis of small differences in lactate anyway.)
- Complete blood count (if not recently available):
- Elevated white blood cell count or neutrophil/lymphocyte ratio may reflect systemic illness, such as sepsis.
- Severe anemia can increase lactate (but it needs to be extreme).
- Liver function tests (hepatic insufficiency may directly cause or amplify lactate levels).
- Sepsis evaluation: If sepsis is a consideration, consider obtaining:
- Blood cultures.
- Imaging studies (e.g., chest radiograph +/- CT scans).
- Procalcitonin and/or C-reactive protein levels.
- (Further discussion of the approach to sepsis: 📖)
- Poisoned patient: consider evaluation for
- Acetaminophen.
- Carbon monoxide.
- Salicylates.
- Toxic alcohols.
treatment of hyperlactatemia
- Treat any identifiable causes of hyperlactatemia.
- Review the medication list and discontinue potentially causative medications.
- Empiric IV thiamine repletion, if deficiency is possible:
- Thiamine deficiency may be more common than generally believed, particularly among critically ill patients who have been in the ICU for several days.
- It's impossible to test for thiamine deficiency. When in doubt, just give empiric IV thiamine.
- Insulin for insulin-deficient states:
- Insulin increases the activity of PDC (pyruvate dehydrogenase complex), so theoretically it may decrease lactate levels.
- Insulin administration might be considered for patients with hyperglycemia and borderline ketoacidosis. (Reddi 2020)
- Diuresis or exogenous alkali administration:
- Dialysis is generally ineffective for management of hyperlactatemia (En vivo, lactic acid is very rapidly being produced and metabolized. Dialysis isn't able to remove lactate rapidly enough to affect this balance). However, dialysis may be considered as a temporizing measures in patients with profound acidemia.
- There is no evidence-based role for bicarbonate in the treatment of elevated lactate level.
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- The anion gap should be calculated whenever evaluating any set of chemistries (if your computer system doesn't do this for you automatically).
- An anion gap elevation in a critically ill patient should be considered to likely represent lactic acidosis and a life-threatening process, until proven otherwise.
- Elevated anion gap should be regarded as reflecting a life-threatening abnormality until proven otherwise. In an ill patient, seriously consider whether elevated anion gap may reflect hyperlactatemia and consider initiating the evaluation for hyperlactatemia (even before the lactate level returns).
- When facing an elevated lactate of unclear etiology, consider empiric IV thiamine. Thiamine deficiency is common in critical illness, and thiamine administration is entirely safe.
- Don't panic in response to an elevated lactate value following a generalized seizure. This is generally benign and should clear within about an hour – follow closely to ensure that the patient is improving.
- Don't assume that lactic acidosis indicates the presence of septic shock. Lactic acidosis has an extensive differential diagnosis which includes dozens of disorders (including every type of shock).
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References
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