Question

An 8 year old boy was admitted to the emergency room with severe breathing problems. He had previously been playing at a friends house and developed nausea, vomiting and respiratory difficulty several hours after returning home.

The following lab data were obtained upon admission:

Sodium: 143 mmol/L

Potassium: 3.6 mmol/L

Chloride: 96 mmol/L

Bicarbonate: 10 mmol/L

pCO2: 25 mmHg

BUN: 31 mg/dL

Glucose: 82 mg/dL

pH: 7.22

Measured Osmolality: 292 mOsm/kg

Additional laboratory testing revealed the following data:

Drug screen = negative

Salicylate level = 82 mg/dL

Ethanol was not measured and assumed to be 0 since there was no indication that the child was intoxicated. Using a Done nomogram, the salicylate level plotted against the time of ingestion, indicated the child had a toxic drug level.

QUESTION: Explain the mechanism of the salicylate toxicity that would account for these lab data.

Answer 1

Salicylates are commonly available agents found in hundreds of over-the-counter medications and in numerous prescription drugs, making salicylate toxicity an important cause of morbidity and mortality specially in children.

After ingestion, acetylsalicylic acid is rapidly converted to salicylic acid, its active moiety of salicylates. Salicylic acid is readily absorbed in the stomach and small bowel. At therapeutic doses, salicylic acid is metabolized by the liver and eliminated in 2-3 hours. Acute ingestion of > 150 mg/kg can cause severe toxicity. Salicylate poisoning is manifested clinically by disturbances of several organ systems, including the central nervous system (CNS) and the cardiovascular, pulmonary, hepatic, renal, and metabolic systems.

Salicylic acid (HS) is a weak acid. The direct presence of acetyl salicylic acid or salicylate molecules probably contributes little to the acidotic state.

After entering in body salicylates break down into as-

HS ‐ --------à H+ + sal-

Uncharged molecules (HS) can also easily move across cell membrane, including the blood‐brain barrier and the epithelium of the renal tubule.

Absorption is more in acidic environment like as in the stomach, so more of the drug will be absorbed compared in stomach than tissues at a higher pH. Salicylates are also easily absorbed in the unionized form from the small intestine. After absorption salicylates are conjugated with glycine in the liver. A small amount of salicylates is excreted unchanged in the urine.

Dehydration, hyperthermia, and chronic ingestion increase salicylate toxicity because they result in greater distribution of salicylate to tissues. Excretion of salicylates increases when urine pH increases.

Salicylate toxicity initially creates a pure respiratory alkalosis because of direct stimulatory effects of increased salicylates in blood on the respiratory centres of medulla. Patients may hyperventilate with a normal respiratory rate by increasing tidal volume which is often unrecognized in young children. It results in decreased PCO2. Carbon dioxide is acidic in nature and decreased carbon dioxide level due to hyperventilation result in increased blood pH and slightly decreased levels of HCO3. So the result is primary respiratory alkalosis and compensatory alkaluria. Potassium and sodium bicarbonate are excreted in the urine. This phase may last as long as 12 hours. Later paradoxical aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys, may begin within hours and may last 12–24 hours.

Increased but imperceptible respiratory water loss due to hyperventilation lead to dehydration and increased serum osmolality.

Salicylates simultaneously and independently cause primary metabolic acidosis also by impairing cellular respiration in mitochondria. They do so by uncoupling oxidative phosphorylation. Inhibition of Kerb’s cycle, means the body is unable to produce ATP by oxidative respiration, leading to anaerobic respiration with consequent reduced ATP production and accumulation of lactic acid and ketone bodies. Interference with oxidative phosphorylation also causes glycogen depletion, gluconeogenesis, and catabolism of proteins and free fatty acids. The end result is central nervous system hypoglycaemia (because it depends only on glucose for energy) relative to serum glucose levels. Progressive acidosis leads to altered mental status, confusion and agitation.

Eventually, as the salicylates disappear from the blood, enter the cells, and interferes with mitochondrial functioning metabolic acidosis becomes the primary acid-base abnormality along with hypokalaemia and dehydration. This phase may begin 4–6 hours after ingestion in a young infant or 24 hours or more after ingestion in an adolescent or adult

The inefficiency of anaerobic metabolism results in less energy being used to create ATP and release of the energy created during the metabolism of glucose in the electron transport chain as heat, so salicylate poisoned patients may become febrile.

Later as the ability to compensate for the acidosis is overwhelmed, pH drops; lactic acid accumulates and serum bicarbonates are consumed.

Lactic acid is later converted to ketones by liver, so salicylate poisoning causes ketosis even when systemic hypoglycaemia is absent. At this stage of salicylate poisoning patient demonstrates pH <7.4, low CO2 and low bicarbonates and are dangerously unstable, likely to decompensate hemodynamically and will begin to demonstrate other symptoms of end‐organ injury.

Salicylate level should be interpreted in the context of acuity of exposure, clinical condition and serum pH. Done nomogram does not predict severity of intoxication.

If salicylates poisoning is suspected, serum salicylate level, urine pH, ABGs, serum electrolytes, serum creatinine, plasma glucose, and BUN are measured. Usually, ABGs show primary respiratory alkalosis during the first few hours after ingestion; later, they show compensated metabolic acidosis or mixed metabolic acidosis/respiratory alkalosis. Eventually, usually as salicylate levels decrease, poorly compensated or uncompensated metabolic acidosis is the primary finding. If respiratory failure occurs, ABGs suggest combined metabolic and respiratory acidosis,

Significant salicylate toxicity is suggested by serum levels of salicylates much higher than therapeutic (therapeutic range, 10 to 20 mg/dL), particularly 6 h after ingestion (when absorption is usually almost complete), and by acidemia plus ABG results compatible with salicylate poisoning.

Plasma glucose levels may be normal, low, or high. Serial salicylate levels help determine whether absorption is continuing; ABGs and serum electrolytes should always be determined simultaneously.