Acid-Base Disorders

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

MethanolHemodialysisEthylene glycol (EG)Diethylene glycol (DEG)Propylene glycol (PG)Isopropyl alcoholSalicylate intoxication

In Chaps. 5 and 6, lactic acidosis and ketoacidosis were discussed. These acidoses are characterized by high anion gap (AG). Other causes of high AG metabolic acidosis include ingestion of alcohols, glycols, salicylates, acetaminophen (paracetamol), toluene, and paraldehyde. This chapter focuses on the following toxins that cause acid-base disorders:

1.

Methanol
2.

Ethylene glycol
3.

Diethylene glycol
4.

Propylene glycol
5.

Isopropyl alcohol
6.

Salicylates
7.

Acetaminophen (5-Oxoproline or pyroglutamic acid)
8.

Toluene
9.

Paraldehyde

General Considerations

Ingestion of alcohols, such as ethanol, methanol, ethylene glycol, and diethylene glycol, or administration of propylene glycol generates not only hyperosmolality but also metabolic acidosis with high AG. Whenever ingestion of these toxins is suspected, it is important to measure and calculate serum osmolality to identify osmolal gap.

Osmolal gap is defined as the difference between the measured and calculated serum osmolality. Generally, the measured osmolality is 10 mOsm higher than the calculated osmolality. Values >10 mOsm represent the presence of an osmolal gap.

Note that in one study, the osmolal gap in healthy volunteers varied from −14 to 10 mOsm, suggesting that >10 is found to be abnormal. Elevated osmolal gap suggests the presence of osmotically active substances that are measured, but not included in the calculation of osmolality. Lactate, keto acids, and salicylate intoxication also cause high osmolal gap. Traditionally, the presence of an osmolal gap and an elevated anion gap is considered to represent the ingestion of toxic alcohols such as methanol, ethylene glycol, and others (Table 7.1).

Table 7.1

Contribution of some toxic substances to serum osmolality

Substance (100 mg/dL)	Molecular weight	mOsm/kg H₂O
Methanol	32	31
Ethylene glycol	62	16
Diethylene glycol	106	9.4
Propylene glycol	76	13
Isopropanol	60	17
Salicylate	180	6
Acetone	58	17
Paraldehyde	132	8

In a suspected case of toxic alcohol ingestion, one can estimate its blood levels by using the following formula:

$\mathrm{Blood}\ \mathrm{level}\ \left(\mathrm{mg}/\mathrm{dL}\right)=\frac{\mathrm{Osmolal}\kern0.5em \mathrm{gap}\times \mathrm{Molecular}\kern0.5em \mathrm{wt}\kern0.5em \mathrm{of}\kern0.5em \mathrm{alcohol}}{10}$

However, the use of this formula may not be necessary, as the levels of many alcohols are available through the clinical laboratory.

The first step in the metabolism of all toxic alcohols is catalyzed by the enzyme alcohol dehydrogenase (ADH), which is the most critical step in metabolism. Administration of an antidote to inhibit the enzyme ADH prevents the toxic metabolites of the parent alcohol. Metabolism of ethanol was discussed in Chap. 6. Table 7.2 shows metabolic end products that cause toxicity.

Table 7.2

Toxic metabolites of alcohols and acetylsalicylate (aspirin)

Substance	Toxic metabolite (s)	Comment
Methanol	Formic acid	Blindness and mortality high, if not recognized and treated early
Ethylene glycol	Glycolic acid, oxalic acid	Acute kidney injury, ↓ cardiac contractility, mortality high, if not treated early
Diethylene glycol	2-hydroxyethoxyacetic acid	Acute kidney injury, neurotoxicity, GI toxicity, high mortality, if not recognized
Propylene glycol	Lactic acid	Hospital-acquired lactic acidosis, minimal clinical manifestations
Isopropyl alcohol	Acetone	No acidosis, acetone breath, low mortality
Acetylsalicylic acid (aspirin)	Salicylic acid	Respiratory alkalosis and metabolic acidosis in adults, metabolic acidosis in children

Management of toxic alcohol ingestion includes (1) gastric lavage, (2) ethanol, (3) antidote to inhibit the enzyme ADH, and (4) renal replacement therapies. Details of these therapeutic modalities will be presented later in the chapter.

Let us discuss each one of these toxins and others in detail.

Methyl Alcohol (Methanol)

Common names: methyl alcohol, wood alcohol, wood spirit, and carbinol
Sources: antifreeze, additive to gasoline and diesel oil, windshield wiper fluid (most common abuse in the USA), dyes, varnishes, and cheap alcohols
Lethal dose is 30 mL of absolute methanol
Easily absorbed from the gastrointestinal (GI) tract. Other less routes of exposure are inhalation and skin absorption
Half-life of methanol in low dose is 14–24 h, and in higher doses the half-life is prolonged to 24–30 h

Metabolism

As shown in Fig. 7.1, methanol is metabolized to formaldehyde by the enzyme ADH, which is then converted to formic acid (formate) by aldehyde dehydrogenase (ALDH). Both enzymes require the reduction of NAD⁺ to NADH +H⁺; thus the ratio of NADH +H⁺/NAD⁺ is increased. The increase in this ratio converts pyruvate to lactate. When folinic acid (folate) is given, formic acid is rapidly converted to CO₂ and water. Methanol is not itself toxic, but its metabolites, formaldehyde and formic acid, are extremely toxic.

../images/480755_1_En_7_Chapter/480755_1_En_7_Fig1_HTML.png — Fig. 7.1

Metabolism of methanol. ADH alcohol dehydrogenase, ALDH aldehyde dehydrogenase

Clinical Manifestations

Mostly due to formic acid (formate)

Signs and symptoms of methanol intoxication are related to central nervous and GI systems:
- Lethargy, headache, confusion, and vertigo are common.
- Eye pain, blurred vision, photophobia, and blindness are common at presentation in 50% of patients.
- Hyperemia of optic disc, fixed and dilated pupils, and papilledema are the ophthalmoscopic findings, which are related to formaldehyde.
- Nausea, vomiting, pancreatitis, and abdominal pain are common GI complaints.
Coingestion of ethanol delays the manifestations of methanol intoxication.

Diagnosis

The following labs and clinical suspicion are important in making the diagnosis of methanol intoxication.

Serum electrolytes, BUN, creatinine, glucose, serum osmolality, serum Ca²⁺, Mg²⁺, ethanol, ethylene glycol, and ketone levels, urine microscopy, and ABG
Visual impairment, high osmolal gap, and high AG metabolic acidosis should alert the physician of methanol intoxication and warrant immediate treatment to prevent blindness. High AG is contributed by formic acid, lactic acid, and keto acids.

Treatment

The criteria for the initiation of therapy in patients with known or suspected methanol poisoning are:

Plasma methanol level of ≥ 20 mg/dL

or
Documented recent history of toxic amounts of methanol ingestion and an osmolal gap >10 mOsm/L

or
Suspected methanol ingestion and at least two of the following criteria:
- Arterial pH < 7.30
- Serum [HCO₃ ⁻] < 20 mEq/L
- Serum osmolal gap > 10 mOsm/kg H₂O
Immediate supportive care includes:
1. 1.
  
  Hydration with normal saline and glucose for hypoglycemia
2. 2.
  
  Intravenous NaHCO₃ to maintain blood pH > 7.2
3. 3.
  
  Intravenous folinic acid (1 mg/kg) one dose and then folate supplementation to accelerate formate metabolism to CO₂ and water by tetrahydrofolate synthetase. This may benefit some alcoholics with folate deficiency
4. 4.
  The American Academy of Clinical Toxicology recommendations are:
  
  Fomepizole (4-methylpyrazole), the drug of choice in the USA.
  
  Ethanol, if fomepizole not available.
  
  Fomepizole is a competitive inhibitor of ADH, and the recommended dosages are as follows:
  
  Without dialysis
  
  Loading dose: 15 mg/kg
  
  Maintenance dose: 10 mg/kg Q12 h for four doses
  
  After 48 h or four doses, 15 mg/kg Q12 h until methanol levels are < 20 mg/dL
  
  With dialysis
  
  Same doses as above except that the drug is given 6 h after the first dose and then Q4 h thereafter

Ethanol is a substrate for ADH, and its administration decreases the metabolism of methanol. It has 10–20 times greater affinity for ADH than other alcohols. Ethanol at a serum concentration of 100 mg/dL inhibits completely the enzyme ADH. The recommended dosage is as follows:

Dose	Absolute alcohol	10% i.v. solution
Loading	600 mg/kg	7.6 mL/kg
Maintenance (nondrinker)	66 mg/kg/h	0.83 mL/kg/h
Maintenance (drinker)	154 mg/kg/h	1.96 mL/kg/h
Maintenance during dialysis (nondrinker)	169 mg/kg/h	2.13 mL/kg/h
Maintenance during dialysis (drinkers)	257 mg/kg/h	3.26 mL/kg/h

Hemodialysis

With the introduction of fomepizole, routine use of hemodialysis has diminished, and it has become an adjunctive therapy. However, hemodialysis is indicated in the following situations:

1.

Ethanol-treated patient with methanol level >50 mg/dL
2.

Renal dysfunction
3.

Visual impairment
4.
Severe acidemia
- It is important to understand the advantages and disadvantages of each of these treatment modalities for judicious use in the management of methanol poisoning (Table 7.3).
- Severe acidemia has a prognostic significance. Serum [HCO₃ ⁻] <20 mEq/L carries 10% mortality, whereas [HCO₃ ⁻] <10 mEq/L has the mortality of 50%. Therefore, maintenance of arterial pH >7.2 is important.
- It should be noted that intermittent hemodialysis is the modality of choice for methanol poisoning and continuous renal replacement therapies are acceptable alternatives if the patient cannot tolerate hemodialysis or it is not available
  
  1.
  
  Methanol clearance is more (an average of 208 mL/min) with hemodialysis comrade to an average of 36.7 mL/min with continuous renal replacement therapy (Roberts DM, Yates C, Megarbane B, et al. Crit Care Med 2015; 43:461–47).

Table 7.3

Advantages and disadvantages of antidotes and dialysis

Treatment modality	Advantages	Disadvantages
Fomepizole	High affinity for alcohol dehydrogenase (ADH). Plasma concentration of 0.8 μg/mL inhibits ADH activity	Not immediately available in all clinical facilities
	Effective at low serum concentrations	Expensive ($ 4000–5000)
	Few adverse effects other than slight increases in AST/ALT	Approved only for methanol and ethylene glycol poisoning
	Admission to intensive care units is not always necessary	No oral form available
	No effect on serum osmolal gap
Ethanol	Easily available	Lower affinity for ADH than fomepizole
	Inexpensive	ICU monitoring required
	Can be given i.v. or orally	Maintenance of 100 mg/dL necessary to inhibit ADH
		Ethanol intoxication in some patients
		↑ Serum osmolal gap
Dialysis	Highly efficient to remove both primary alcohol and its metabolites	Invasive
	Improves renal function	Expensive
	Improves acidemia with HCO₃ ⁻ dialysis bath	Unavailability in many countries
	Decreases hospital stay
	Rapid improvement in signs and symptoms of methanol poisoning

Ethylene Glycol (EG)

Colorless, odorless, and sweet-tasting alcohol.
Sources: antifreeze, deicers, and many industrial products.
EG intoxication is more common than methanol intoxication.
Oral ingestion of EG is the most common route of EG intoxication.
EG is metabolized to glycolic and oxalic acids (Fig. 7.2).
Glycolic acid is the major cause of high AG acidosis.
Oxalic acid is the major cause of AKI, myocardial, neurologic, and pulmonary dysfunction due to deposition of calcium oxalate in these organ systems.
Lethal dose of EG is 1.4 mL/kg.