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Ethylene Glycol and Propylene Glycol Toxicity
What Are the Stages of Ethylene Glycol Intoxication?

Course: WB 1103
CE Original Date: October 3, 2007
CE Renewal Date: October 3, 2010
CE Expiration Date: October 3, 2012
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Learning Objectives

Upon completion of this section, you should be able to

  • explain the mechanism of ethylene glycol toxicity and
  • describe the three stages of ethylene glycol toxicity.

Introduction

Ethylene glycol itself is toxic, but its harmful effects mainly result from the accumulation of its more toxic metabolites.

Ethylene glycol is a central nervous system (CNS) depressant that can produce acute effects similar to those of ethanol. These CNS effects predominate during the first hours after exposure.

Mechanism of Toxicity

The main toxicity results from hepatic metabolism of ethylene glycol to glycoaldehyde, glycolate, glyoxylate, and oxalate. These metabolites inhibit

  • oxidative phosphorylation and cellular respiration
  • glucose and serotonin metabolism
  • protein synthesis
  • DNA replication
  • ribosomal RNA formation

The accumulation of organic acid metabolites, especially glycolic acid, results in anion gap metabolic acidosis which affects many cellular functions.

Stages of Ethylene Glycol Intoxication

Severe ethylene glycol poisoning may go through three stages: CNS depression, cardiopulmonary toxicity, and renal toxicity (Table 1) (Friedman, Greenberg et al. 1962). However, signs and symptoms in an individual patient might not be separated so cleanly and could have much overlap.

Stage 1 (CNS depression phase)

CNS depression begins soon after exposure, lasting for up to 12 hours after ingestion. This depression appears similar to ethanol intoxication, but without the characteristic odor of alcohol. Initially, the inebriation, euphoria, slurred speech, sleepiness, and so forth are due to the unmetabolized ethylene glycol.

After the glycoaldehyde forms (at 4-12 hours) and metabolic acidosis begins, CNS depression—if it is a serious intoxication—can lead to the following effects:

  • seizures
  • coma
  • cerebral edema (in some cases)
  • gastrointestinal irritation (nausea and vomiting)

An osmolal gap, without metabolic acidosis, or an anion gap may be seen before significant metabolism of ethylene glycol occurs. As ethylene glycol is metabolized, the osmolal gap, if present, will decrease and an anion gap metabolic acidosis evolves. Patients who present late may have renal failure with normal osmolal and anion gaps and no acidosis or measurable ethylene glycol levels (Ford M 1991).

Signs of metabolic acidosis due to the metabolites may become apparent late in stage 1.

Stage 2 (Cardiopulmonary toxicity phase)

The following cardiorespiratory symptoms may appear 12-24 hours after ingestion

  • tachycardia,
  • tachypnea, and
  • hypertension or hypotension.

The following conditions may develop in this stage

  • pulmonary edema,
  • pneumonitis,
  • congestive cardiac failure, and
  • shock.

Formation of oxalic acid may lead to deposition of calcium oxalate crystals in

  • the meninges,
  • blood vessel walls,
  • lung, and
  • myocardium.

These deposits can cause tissue injury. They also may lead to hypocalcemia secondary to calcium oxalate precipitation. Most deaths from ethylene glycol poisoning occur during stage 2.

Stage 3 (Renal toxicity phase)

Kidney damage usually develops 24-72 hours after exposure. Acidosis and acute renal failure may result from deposition of calcium oxalate crystals in the kidneys.

The following conditions characterize the third phase

  • flank pain,
  • costovertebral angle tenderness, and
  • oliguric renal failure.

Prolonged, rarely permanent, kidney failure is distinguished by

  • proteinuria,
  • hematuria,
  • crystalluria, and
  • increased serum BUN and creatinine.

Calcium oxalate crystals may appear in the urine as early as stage 1, but absence of these crystals does not rule out the diagnosis of ethylene glycol poisoning.

Table 1. Clinical course in acute ethylene glycol intoxication.
Stage Onset after ingestion Primary systems affected Signs and symptoms
1 30 minutes to 12 hours Central nervous system Inebriation, euphoria, ataxia, slurred speech, drowsiness, irritation, restlessness, and disorientation
    Gastrointestinal Nausea and vomiting
    Metabolic Elevated osmolal gap
2 12 to 24 hours Cardiovascular Mild hypertension, tachycardia, and shock
    Pulmonary Tachypnea, adult respiratory distress syndrome, pulmonary edema, and pneumonitis
    Metabolic Metabolic acidosis with elevated anion gap and decreased osmolal gap, possible tetany from hypocalcemia, and hyperventilation
3 24 to 72 hours Renal Flank pain, costovertebral angle tenderness, oliguric renal failure, hyperkalemia, and hypocalcemia
    Metabolic May have normal anion and osmolal gaps.

Key Points

  • Unmetabolized ethylene glycol contributes to CNS depression.
  • Delayed clinical toxicity results from conversion of ethylene glycol to metabolites of greater toxicity.

   

Progress Check

7. Which of the following cellular biochemical reactions can be inhibited by acid and aldehyde metabolites of ethylene glycol?

A. oxidative phosphorylation and cellular respiration
B. protein synthesis
C. DNA replication
D. All of the above.

Answer:

To review relevant content, see Mechanism of Toxicity in this section.

8. Tachypnea generally appears in which of the following stages:

A. stage 1 (0.5 – 12 hr)
B. stage 2 (12 – 24 hr)
C. stage 3 (24 – 72 hr)
D. stages 2 and 3 ( 12 – 72 hr).

Answer:

To review relevant content, see Table 1 in this section.

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