Iatrogenic and Poison-Derived Acid Base Disorders

Systemic toxins are a common cause of serious and sometimes fatal acid-base disturbances. Toxin-induced acid-base disorders occur through a variety of distinct metabolic pathways. Individual toxins also exert their effects at different stages during a poisoning. Some of these mechanisms include organic acid production through metabolic pathways, the direct addition of exogenous ions, mitochondrial dysfunction, direct impairment of renal function, impaired oxygen delivery, tissue hypoperfusion, and altered ventilation. In a patient who is critically ill, these toxin-induced disturbances may be compounded by non–toxin-related sources of acid-base disequilibrium (i.e., hyperchloremia, chronic renal failure). These compounding circumstances make the management of the critically ill poisoned patient challenging. Nephrologists and intensivists must be aware of the toxin and non–toxin-induced causes of acid-base disequilibrium and be familiar with the mechanisms and treatments of each.

The differential diagnosis of iatrogenic and toxin-induced acid-base disturbances is extensive. There have been many xenobiotics, pharmaceuticals, chemicals, and other substances implicated in acid-base disturbances. In this chapter, we discuss the most frequently encountered poison-derived and most widely recognized iatrogenic acid-base disorders. This chapter follows a “physiologic disturbances type” format, discussing broad acid-base categories, within which different and common iatrogenic and poison-derived toxins are highlighted.

The issue of toxin-induced respiratory acid-base disturbances, although interesting, pales in comparison to the metabolic issues surrounding poisonings and usually is related to hyper- or hypoventilation. The vast majority of toxin-related respiratory acidosis is secondary to substances that cause respiratory depression either centrally or via respiratory muscle dysfunction (i.e., opiates). The opposite is also true in that most poison-related respiratory alkalosis is related to respiratory stimulants (i.e., salicylates, methylxanthines, and nicotine) or is compensatory in nature. These respiratory acid-base changes are mentioned briefly in the general context of the following substances and their relationship to the overall metabolic picture.

Specific Disturbances

Metabolic acidosis is encountered commonly in the setting of systemic poisoning associated with many toxicants. Metabolic acidosis arises as a result of acid overload either by endogenous (lactate production) or exogenous (glycol-dependent drugs) accumulation of acids in the body, resulting in an overwhelming acid-base disturbance. Toxicants can cause metabolic acidosis via numerous mechanisms and may present as three distinct types based on the anion gap. The first and foremost type includes poisons that cause a high anion gap metabolic acidosis. Iatrogenic toxins that are included in the discussion are the most well known, frequently discussed, and may require emergent intervention. These are followed by the most common and well-known poison-derived toxins causing metabolic acidosis. Some of the most common toxins causing metabolic disturbances are reviewed in Table 71.1 .

TABLE 71.1

Mnemonic for Common Poison- and Iatrogenic-Derived Acid-Base Disturbances Causing Anion Gap Metabolic Acidosis

C	Carbon monoxide, cyanide
A	Aminoglycosides
T	Theophylline (β-agonists)
M	Methanol
U	Uremia
D	Diabetic, alcohol, starvation ketoacidosis
P	Paracetamol (APAP), phenformin, propofol, propylene glycol
I	Iron, isoniazid
L	Lactic acidosis, lithium
E	Ethanol, ethylene glycol
S	Salicylate

High Anion Gap Metabolic Acidosis

Propofol

Propofol is a short-acting, intravenously administered sedative commonly given in the intensive care unit. One of the rare complications of intravenous (IV) administration of propofol, particularly in high doses (>4 mg/kg/hr) and long-term (>48 hours) use is propofol infusion syndrome (PRIS). PRIS results in severe lactic acidosis, rhabdomyolysis, renal failure, and cardiac dysfunction. This is thought to be secondary to a combination of increased metabolic demand in critical illness ( priming factor) coupled with catecholamine use, reduced glycogen reserve, and impaired fatty acid oxidation ( triggering factors). The pathophysiology of PRIS is not very well understood, but one of the hypotheses surrounding PRIS relates to the inhibitory process propofol may have on fatty acid oxidation, leading to impaired energy production in a catabolic state such as critical illness. This results in an inadequate energy production state, prompting anaerobic respiration, leading to peripheral muscle necrosis and lactic acid production.

PRIS ultimately results in severe myocardial and cardiovascular collapse as a result of excess serum fatty acids coupled with propofol's ability to antagonize β- and calcium receptors. The risk of PRIS can be minimized by (1) using the lowest possible dose of propofol for the shortest duration, (2) early and adequate carbohydrate intake in patients on propofol infusion to prevent energy production by way of fatty acid metabolism, and (3) early recognition of early signs of PRIS, including unexplained metabolic acidosis, hypertriglyceridemia, as well as elevated creatinine kinase and myoglobin levels. Once PRIS is suspected, propofol infusion should be stopped and an alternative sedative agent should be used. Cardiovascular support and hemodialysis are paramount in helping decrease the levels of circulating metabolic acids.

Metformin

Metformin is an oral hyperglycemic agent in the biguanide class. Metformin acts by increasing peripheral glucose uptake by increasing the capacity of insulin to bind to its receptors and increasing the synthesis of glucose transporter. Metformin also inhibits gluconeogenesis, by way of non-competitively inhibiting the enzyme mitochondrial glycerophosphate dehydrogenase, resulting in a reduced conversion of lactate to glucose, ultimately resulting in metformin induced lactic acidosis. This occurs as a result of decreased conversion of pyruvate to glucose in the liver via inhibition of pyruvate carboxylase, responsible for the first step of gluconeogenesis. As a result of this inhibition, pyruvate is diverted into lactic acid formation, responsible for the anion gap metabolic acidosis. The lactic acidosis that forms as a result of metformin poisoning is different than the lactic acidosis that is well known in critical care. Lactic acidosis occurs as a result of hypoxia and hypoperfusion (type A) or elimination, clearance, liver dysfunction without clinical evidence of hypoxemia, or hypoperfusion (type B). Type B is associated with metformin poisoning resulting in gluconeogenesis inhibition and impairment of lactate metabolism. The most common factors that predispose a patient to metformin-induced lactic acidosis are renal insufficiency, drug-drug interaction, and liver injury.

Severe lactic acidosis associated with metformin is rare but can be serious and possibly fatal. It is characterized by generalized symptoms such as nausea, vomiting, abdominal pain, and malaise. Maintaining a high index of suspicion is of utmost importance. These patients may progress to a critically ill state with hypotension, altered mental status, respiratory failure, and hypothermia, which may mimic septic shock. These patients need aggressive symptomatic and supportive care with fluid resuscitation and vasopressor use. Hemodialysis with a bicarbonate buffer may provide some benefit to patients with severe metabolic acidosis.

Propylene Glycol

Propylene glycol (PG) is a water-soluble alcohol that serves as a solvent in a variety of intravenously administered drugs in the intensive care unit and the general medicine ward. It is similar chemically and physiologically to ethylene glycol, albeit less toxic. Most commonly used drugs administered intravenously containing varying amounts of PG are found in benzodiazepines (lorazepam and diazepam), esmolol, and nitroglycerin infusions as well as in phenobarbital and phenytoin ( Fig. 71.1 ). PG is added to drug formulation to improve solubility of hydrophobic compounds. Toxicity associated with PG results as PG is metabolized by alcohol and aldehyde dehydrogenase in the liver to lactic and pyruvic acids, which can lead to varying degrees and severity of anion gap metabolic acidosis and hepatic dysfunction. PG is also eliminated in the urine unchanged, which can exacerbate toxicity in patients with acute kidney injury owing to accumulation of the compound.

Studies have shown that PG toxicity is likely to occur at doses exceeding 25 mg/dL. However, measurements of serum concentration of PG are difficult to obtain, and serum testing turnaround times are slow. One reasonable approach to monitoring for PG toxicity is calculating for an increase in osmolar gap. Increasing osmolar gap (>10 mOsm/kg) has been shown to correlate well with the likelihood of PG toxicity. Treatment for PG toxicity includes removal of the offending infusion and inclusion of cardiovascular support and hemodialysis. Given the pharmacokinetics of PG, particularly its metabolism by alcohol and aldehyde dehydrogenase to pyruvate and lactate, current evidence suggests the use of fomepizole as an inhibitor in PG toxicity.

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