Sequential episodes of ethylene glycol poisoning in the same person

Abstract

Ethylene glycol is a common alcohol found in many household products such as household hard surface cleaner, paints, varnish, auto glass cleaner and antifreeze. While extremely toxic and often fatal on ingestion, few cases with early presentation by the patient have resulted in death; thus, rapid diagnosis is paramount to effectively treating ethylene glycol poisoning. In this study, we compare two sequential cases of ethylene glycol poisoning in a single individual, which resulted in strikingly different outcomes.

Background

Poisoning with ethylene glycol, while rare, can be life threatening and the clinical outcome is highly dependent on time. Elapsed time between presentation and antidote administration is critical to patient survival; thus, rapid identification and decision making by the clinician is crucial to successfully managing ethylene glycol poisoning. Often, the clinician is required to make decisions based on clinical suspicion with limited laboratory data and without knowing definitive serum drug levels. We are presenting a case report on lethal ethylene glycol poisoning, this is the highest recorded level of ethylene glycol. Patient presented two times with ethylene glycol poisoning and each time each had different outcome.

Case presentation

First admission

A 67-year-old man with significant medical history of ethanol and benzodiazepine overdose was brought to the emergency department immediately after being found unresponsive at home. On arrival, he was inebriated and lethargic, but as his mentation rapidly deteriorated he became comatose (GCS 3) and hypotensive. On examination, he presented with a blood pressure (BP) of 133/65 mm Hg, pulse 100 beats per minute (bpm), temperature 34.5°C and respiratory rate (RR) 20/min. Endotracheal intubation was performed and fluid resuscitation was started. Findings from a CT brain scan were unremarkable. Initial laboratory data showed hypernatremia (Na⁺ 158 mEq/L), high anion gap acidosis (anion gap 32 mEq/L) and lactic acidosis (lactic acid 8.9 mEq/L). The volatile screen results were negative for methanol, acetone and isopropyl alcohol, but positive for ethanol, with serum ethanol levels of 53 mg/dL. Plasma osmolarity was 652 mOsm/kg and the calculated osmolal gap 271 mOsm/kg. Osmolar gap (OG) calculation was corrected for the presence of ethanol. An arterial blood gas test suggested high anion gap metabolic acidosis (pH 7.29).

In view of suspected toxic alcohol poisoning, the patient was treated with fomepizole at a loading dose of 15 mg/kg (860 mg in total) and haemodialysis. After 6 hours, the dosage of fomepizole was adjusted to 10 mg/kg and subsequently administered every 4 hours. In addition, thiamine at 100 mg every 8 hours and pyridoxine at 50 mg every 6 hours were given. After 8 hours of hemodialysis with an Optiflux 180 NR dialyzer (urea clearance 277 mL/min at blood flow rate 350 mL/min and dialysate flow rate 700 mL/min), his mentation improved and the anion gap and OG gradually closed. On the third day of hospitalisation, he was extubated. On day 6, ethylene glycol levels reached <10 mOsm/kg (baseline) from an initial level of 13 000.04 mg/dL, and fomepizole was discontinued. Later, the patient admitted that he had attempted to end his life by drinking 250 mL of antifreeze because he was unable to control his alcohol addiction. Psychiatric consultation was done and he was discharged home with advice to follow-up at de-addiction clinic.

Second admission

One month later, the patient was found by a motel manager with a note saying please do not resuscitate. It was unclear how long he had been unconscious. Emergency medical services were called and on arrival, the patient was in cardiopulmonary arrest and underwent cardiopulmonary resuscitation, defibrillation and transthoracic pacing. On examination, he was unresponsive, intubated and his glasgow coma scale score was 3. He was found to have a BP of 85/43 mm Hg, pulse 100 bpm, temperature 30.5°C and RR 24/min. Rhythmic eye movement, head jerking and occasional jerking of the left hand were noted and worsened with stimulation. The patient arrived at hospital with pH 7.1, and was subsequently found to have hypothermia, bradycardia and shock. Initially, ethanol was undetected in the patient’s bloodstream; volatile screen was negative. His lactic acid level was 15 mEq/L, plasma osmolality was 466 mOsm/kg and the OG was 125 mOsm/kg. Microscopic urine analysis showed several White blood cells (WBCs) and needle-shaped crystals.

Investigations

A report on the investigation is shown in table 1.

Table 1.

Investigation reports

Investigations	First admission	Second admission
WBC (4.00–10.80 109/L)	2.27	30.98
RBC (4.50–5.25 1012/L)	4.39	4.20
HGB (14.0–16.8 g/dL)	15.4	13.9
HCT (40.0%–48.4%)	45.5	50.8
BUN (6–20 mg/dL)	10	22
CR (0.6–1.2 mg/dL)	1.0	2.2
Na+ (135–146 mEq/L)	158	162
K+ (3.5–5.1 mEq/L)	5.0	5.4
Cl- (98–107 mEq/L)	103	116
Anion gap (7–15 mEq/L)	32	10.4
Calcium (8.4–10.2 mEq/dL)	9.5	116
Lactic acid (0.4–2.5 mEq/L)	8.9	15.0
Serum osmolarity (278–305 mOsm/kg)	652	466
Blood gas investigation
pH (7.350–7.450)	7.29	7.10
pCO2(35.0–45.0 mm Hg)	20.6	26.5
Bicarbonate (21.0–29.0 mEq/L)	10.1	8.0
Base deficit (0–2.0 mEq/L)	14	20.4
Osmolar gap (<10 mOsm/kg)	271	125
Ethylene glycol and glycolic acid level
Ethylene glycol (<10.0 mcg/mL) day 1	13 000.4	385
Ethylene glycol (<10.0 mcg/mL) day 2	2765.0	17
Ethylene glycol (<10.0 mcg/mL) day 4	Not done	8
Ethylene glycol (<10.0 mcg/mL) day 6	<10	Not done
Glycolic acid level (13.8–38.0 mEq/L) day 1	Not done	238.6
Glycolic acid level (13.8–38.0 mEq/L) day 2	Not done	8.8
Glycolic acid level (13.8–38.0 mEq/L) day 4	Not done	Neg
Volatile fluid investigation
Methanol (Neg)	Neg	Neg
Ethanol (Neg)	53 mg/dL	Neg
Acetone (Neg)	Neg	Neg
Isopropanol (Neg)	Neg	Neg
Urine toxicology screen
Amphetamines	Neg	Neg
Barbiturates	Neg	Neg
Benzodiazepines	Neg	Neg
Cannabinoids	Neg	Neg
Cocaine metabolite	Neg	Neg
Morphine/codeine	Neg	Neg
Methadone	Neg	Neg

BUN, Blood urea nitrogen; CR, Creatinine; HCT, Haematocrit; HGB, Hemoglobin; RBS, Random blood sugar; WBC, White blood count. 

Differential diagnosis

1. Ethanol poisoning

2. Methanol poisoning

3. Isopropyl alcohol poisoning

Treatment

Fluids, vasopressor, fomepizole and sodium bicarbonate were immediately administered, and haemodialysis was started. In addition, thiamine (100 mg) and pyridoxine (50 mg) were prescribed for 6 and 8 hours, respectively. Intermittent haemodialysis was continued for 14 hours using an Optiflux 200 with a blood flow rate of 450 mL/min and dialysate flow rate of 800 mL/min. After 8 hours of haemodialysis, the patient was still anuric and facing severe critical illness. Venovenous haemodiafiltration was started; however, despite aggressive treatment, his clinical condition continued to deteriorate leading to multiple organ dysfunction.

Outcome and follow-up

His initial ethylene glycol level was 385 mg/dL. Although ethylene alcohol and glycolic acid levels returned to baseline levels, there were no signs of neurological improvement and the patient died on the fourth day of hospitalisation.

Discussion

In the USA, ethylene glycol poisoning causes dozens of deaths annually. The direct source of ingestion by the patient can be as an ethanol substitute, accidental or the desire to inflict self-harm. Between January 2006 and December 2013, data collected by the American Association of Poison Control Centers reported approximately 45 000 cases of ethylene glycol exposure and 154 of those resulted in death.¹ Clinical evolution of ethylene glycol poisoning can be divided into three stages, although in reality these overlap: stage 1 occurs within 12 hours and affects the central nervous system with symptoms predominantly relating to the gastrointestinal system; stage 2 (12–24 hours) leads to cardiopulmonary symptoms including tachypnea (which may represent a respiratory compensation to the metabolic acidosis), tachycardia, hypotension, non-cardiogenic pulmonary oedema, congestive heart failure and shock; finally, stage 3 (24–72 hours) can result in acute renal failure due to the toxic effects of ethylene glycol metabolites (glycolate, oxalate and glyoxylate) on the kidney.²

Absorption of ethylene glycol occurs rapidly after oral ingestion and after 1 to 2 hours, peak serum alcohol concentrations are reached. Elimination of ethylene glycol from the blood serum follows first-order kinetics without treatment, with an estimated half-life between 3 and 9 hours.^{3 4} Ethylene glycol metabolite such as glycolate can interfere in the actual estimation of lactate, In the context of severe ethylene glycol poisoning, lactate level may be falsely elevated, but this spurious result can be indicative of glycolic acid accumulation. On the other hand, a true elevation of lactate can also be observed. Thereby while interpreting the results these factors should be adequately considered. The first step of metabolic conversion of ethylene glycol to toxic metabolites is mediated by the enzyme alcohol dehydrogenase. Ethanol is a competitive inhibitor of alcohol dehydrogenase. Importantly, the onset of ethylene glycol toxicity is delayed when co-ingested with ethanol. This is caused by inhibition of hepatic oxidation by an alcohol dehydrogenase antagonist, rendering elimination almost completely renal and resulting in a minimum half of 14 hours for a normally functioning kidney.^{3 5} Thus, the possibility of simultaneous consumption should always be assessed, as can be the case with alcoholics that ingest in any form.

Typically after ethylene glycol ingestion, the anion gap is normal but the OG is high. As ethylene glycol is metabolised, accumulation of toxic acids leads to an increase in anion gap accompanied by a decreasing osmolal gap. Increase in the anion gap is directly correlated to the accumulation of toxic acid metabolites.^{6 7} Thus, ethylene glycol toxicity should be considered in patients presenting with both a high OG and high anion gap metabolic acidosis. Unfortunately, tests that measure serum ethylene glycol levels are required for a definitive diagnosis and are not always readily available on site.^{8 9} These tests are generally performed off-site in reference laboratories that do not return results within a clinically relevant time scale. The volatile screen can provide a useful indication of whether ethylene glycol poisoning is the cause of symptoms; however, it is important to approach results with caution. The osmal gap can provides crucial real-time information, at low cost, and is widely available. It is a good indicator of whether the patient has been exposed to methanol, ethylene glycol or isopropyl alcohol where significant ethanol ingestion has been excluded.^{10 11} Ethanol can contribute to the osmal gap, and must always be measured and accounted for in the osmal gap calculation.

Common modalities for managing ethylene glycol poisoning include a combination the following: correcting systemic acidosis via sodium bicarbonate administration; inhibiting the alcohol dehydrogenase enzyme with fomepizole; performing dialysis; and administering co-factors. Fomepezole has been used successfully for many years; however, doses should be administered at least every 4 hours if haemodialysis is simultaneously performed, as it is dialysable. In cases where there is evidence of end organ failure, high anion gap metabolic acidosis regardless of drug level or presence of elevated serum levels of ethylene glycol (more than 50 mg/dL), the patient should be started on haemodialysis to rapidly remove toxic metabolites and alcohols from the system.^{10 11} If ingestion is uncertain, there are no precise thresholds for determining when haemodialysis should be performed; however, an arterial or venous blood gas test can be a crucial triage tool in such circumstances.

In both admissions, the patient in this study presented with symptoms characteristic of ethylene glycol intoxication. Importantly, initial laboratory findings were significantly different between admissions, due to the pharmacokinetics of ethylene glycol and the variation in lapsed time between ingestion and arriving at hospital. Whereas notable lactic acidosis presented during readmission, only mild lactic acidosis was observed during the first incident, which may have been due to the earlier presentation to hospital and accompanying ingestion of ethanol. The presence of ethanol in the first, but not the second admissions may account, in part, for the better clinical outcome of this poisoning episode.

In this case, an extraordinary amount of ethylene glycol was consumed, with initial serum level of 13 000 mcg/dL nearly 12 times higher than any previously reported case.¹² The level was confirmed by additional tests and remarkably, the patient was successfully treated despite such high levels of ethylene glycol. During second admission, the initial clinical and laboratory data suggested late presentation, with an unknown downtime. The patient underwent severe metabolic derangements in part due to ethylene glycol toxicity, shock and multi-organ failure. He had presented with several predictors for poor outcome, including a critically low initial pH and he was comatose on arrival. Moreover, there was likely a prolonged time lapse between ingestion and treatment, although the exact time was undetermined. In a retrospective study, Lung et al observed that patients presenting with comatose or seizures were those who had renal insufficiency. When compared with survivors who recovered without complications, they initially had a lower mean arterial pH (7.03 vs 7.27) and higher initial serum creatinine (1.7 vs 1.1).¹³ According to Coulter et al, higher OG and anion gap have also been associated with higher risk of death.¹⁴

The case presented in this article illustrates the spectrum of clinical presentations of ethylene glycol poisoning and how outcomes can be drastically different. Although the first presentation displayed very high serum osmolality and OG, the acidosis was relatively mild and renal function was essentially normal. Early administration of the antidote along with haemodialysis and supportive care resulted in improvement of symptoms. In contrast, the second presentation featured severe metabolic acidosis with renal insufficiency and despite administration of the antidote, haemodialysis and maximal supportive care, the patient expired. Poisoning with ethylene glycol, while rare, can be life threatening and the clinical outcome is highly dependent on time. Elapsed time between presentation and antidote administration is critical to patient survival; thus, rapid identification and decision making by the clinician is crucial to successfully managing ethylene glycol poisoning. Often, the clinician is required to make decisions based on clinical suspicion with limited laboratory data and without knowing definitive serum drug levels. Finally, it is necessary for clinicians to attain a clear understanding of the metabolic activation of alcohols and their toxic metabolites and the indications for treatment with antidotes, with or without haemodialysis. We report for the first time in this case, the lethality of ethylene glycol toxicity at different point of time in same patient.

Learning points.

• Poisoning with ethylene glycol, while rare, can be life threatening and the clinical outcome is highly dependent on time.

• Elapsed time between presentation and antidote administration is critical to patient survival; thus, rapid identification and decision making by the clinician is crucial to successfully managing ethylene glycol poisoning.

• The clinician is required to make decisions based on clinical suspicion with limited laboratory data and without knowing definitive serum drug levels.