Massive Ethylene Glycol Poisoning Triggers Osmotic Demyelination Syndrome

The Journal of Emergency Medicine, Vol. 46, No. 3, pp. e69–e74, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2013.08.068

Selected Topics: Toxicology

MASSIVE ETHYLENE GLYCOL POISONING TRIGGERS OSMOTIC DEMYELINATION SYNDROME Azeemuddin Ahmed, MD, MBA,* Paul A. Tschetter, MD,* Matthew D. Krasowski, MD, PHD,† and Amy Engelman, DO* *Department of Emergency Medicine, and †Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa Reprint Address: Azeemuddin Ahmed, MD, MBA, Department of Emergency Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, 1008 RCP, Iowa City, IA 52242

, Abstract—Background: Ethylene glycol is a toxic organic solvent implicated in thousands of accidental and intentional poisonings each year. Osmotic demyelination syndrome (ODS) is traditionally known as a complication of the rapid correction of hyponatremia. Objective: Our aim was to describe how patients with ethylene glycol toxicity may be at risk for developing ODS in the absence of hyponatremia. Case Report: A 64-year old female patient was comatose upon presentation and laboratory results revealed an anion gap of 39, a plasma sodium of 150 mEq/L, a plasma potassium of 3.5 mEq/L, an osmolal gap of 218, an arterial blood gas pH of 7.02, whole blood lactate of 32 mEq/L, no measurable blood ethanol, and a plasma ethylene glycol concentration of 1055.5 mg/dL. The patient was treated for ethylene glycol poisoning with fomepizole and hemodialysis. Despite having elevated serum sodium levels, the patient’s hospital course was complicated by ODS. Conclusions: Rapid changes in serum osmolality from ethylene glycol toxicity or its subsequent treatment can cause ODS independent of serum sodium levels. Ó 2014 Elsevier Inc.

exposure ethylene glycol events were reported by the American Association of Poison Control Centers, with 528 exposures in patients 5 years of age or younger, 145 exposures in patient ages 6 12, and 5027 exposures in patients older than 12 years of age (1). Much of the danger of ethylene glycol ingestion results from metabolism to toxic compounds. Ethylene glycol is metabolized by a series of steps to glycolic acid and oxalic acid, the latter of which has the potential to cause severe renal injury by crystallization of oxalate. Ethylene glycol ingestion can also cause increased blood lactate concentration secondary to conversion of nicotinamide adenine dinucleotide (NAD+) to NADH during the enzymatic steps involved in ethylene glycol metabolism. The increased NADH/NAD+ ratio promotes pyruvate conversion to lactate resulting in lactic acidosis (2 5). After ethylene glycol ingestion, patients often present with an altered mental state that is difficult to distinguish from other toxic ingestions or a variety of other medical conditions. Clinicians must rely on laboratory data to make a diagnosis of ethylene glycol poisoning and to determine a treatment plan that will prevent end organ damage. With aggressive treatment, patient survival has been reported for ingestions of up to 3 L of ethylene glycol (6). If diagnosed early enough, ethylene glycol poisoning can usually be treated effectively by administration of either ethanol or fomepizole, both of which inhibit the rate-limiting first step in the metabolism of

, Keywords—ethylene glycol; fomepizole; renal dialysis; acidosis; lactic; calcium oxalate; osmotic demyelination syndrome; extra pontine myelinolysis

INTRODUCTION Ethylene glycol is a toxic organic solvent commonly found in automobile antifreeze. In 2010, 5725 single-

RECEIVED: 27 February 2013; FINAL SUBMISSION RECEIVED: 2 June 2013; ACCEPTED: 15 August 2013 e69

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ethylene glycol and prevent the formation of toxic metabolites. Massive ethylene glycol ingestions or ingestions that present late (with conversion to metabolites already assumed to have occurred) generally require hemodialysis to clear ethylene glycol and the toxic metabolites. Osmotic demyelination syndrome (ODS) was first described as central pontine myelinolysis (CPM) by Adams in 1959, as his initial paper demonstrated four patients with characteristic myelin loss specifically confined to the central pons (7). He noted this phenomenon in patients with chronic alcohol abuse and malnutrition and, by the mid 1970s, several papers associated CPM with rapid correction of hyponatremia (8,9). Recently, the term ODS was introduced as an umbrella term to describe both extra pontine and central pontine myelinolysis, as the literature is now describing demyelination outside of the pons associated with a wide variety of medical conditions. In this case report, we describe a massive ethylene glycol poisoning that was recognized and treated appropriately with fomepizole and hemodialysis, but the patient’s subsequent clinical recovery was complicated by ODS. CASE REPORT A 64-year old female with medical history including hypertension and hypothyroidism was transported to the emergency department (ED) after her daughter found her prone in the bathroom incontinent of stool, having difficulty speaking, and with altered mental status. At the scene, paramedics found her responsive only to pain, with mumbling speech and no purposeful movements. There was no evidence of external trauma and no open bottles or pill containers were noted. Finger-stick glucose did not demonstrate hypoglycemia and naloxone given per protocol did not change her clinical status. On presentation to the hospital, her vital signs were temperature 36.1 C, blood pressure 101/50 mm Hg, heart rate 81 beats/min, respiratory rate 20 breaths/min, O2 saturation 96% on 15 L via face mask, and Glascow Coma Scale score of 7. An endotracheal intubation was performed. Her screening physical examination before intubation showed no major abnormalities aside from her depressed neurological status. An electrocardiogram showed a sinus rhythm with a rate of 71, a PR interval of 140 ms (120 200 ms), normal QRS width, and a QTc of 499 ms with nonspecific ST-T wave abnormalities in the inferior and lateral leads. A chest x-ray showed the endotracheal tube to be in the proper position without evidence of pneumothorax, infiltrates, or abnormal pulmonary vasculature. A computed tomography of the head was negative for intracranial hemorrhage. An arterial blood gas revealed: pH of 7.02 (reference range 7.35–7.45), a pCO2 of 30 mm Hg (reference range 35 45 mm Hg), a pO2 of 317 mm Hg (refer-

ence range 80 90 mm Hg), a base excess of 23 mEq/L (reference range 2 to 2 mEq/L), and a bicarbonate of 7 mEq/L (reference range 22 26 mEq/L) on 100% FiO2. The basic electrolyte panel revealed: sodium 150 mEq/L (reference range 135 145 mEq/L), potassium 3.5 mEq/L (reference range 3.5–5.0 mEq/L), chloride 107 mEq/L (reference range 95 107 mEq/L), bicarbonate 5 mEq/L (reference range 24 32 mEq/L), blood urea nitrogen 27 mg/dL (reference range 10 20 mg/dL), creatinine 2.3 mg/dL (reference range 0.6–1.2 mg/dL), and glucose 120 mg/dL (reference range, 70 140 mg/ dL for random level). The anion gap was 39 (reference range < 17), whole blood lactate concentration was 32.0 mEq/L (reference range 0.5–2.2 mEq/L), blood ethanol level was <10 mg/dL, and plasma osmolality was elevated at 536 mOsm/kg (reference range 275 295 mOsm/kg), with an osmolal gap of 218 mOsm/kg (reference range < 16 mOsm/kg). A urine drug screen was negative, salicylate levels were < 2.5 mg/dL, and acetaminophen levels were < 1.1 mg/mL. Urine microscopy showed no evidence of infection or abnormal casts. Based on the patient’s neurological status, significantly elevated lactate levels, a marked osmolal gap, and a negative ethanol test result, an ingestion of a toxic alcohol (e.g., methanol, ethylene glycol, isopropyl alcohol) was suspected. A toxic alcohols panel was ordered and empiric fomepizole therapy was initiated. The patient was then transferred to the medical intensive care unit (MICU) in critical condition and a nephrologist was consulted. Plasma ethylene glycol concentration was determined to be 1055.5 mg/dL using the gold standard method of gas chromatography with flame ionization detection, using a method described previously (10). Gas chromatography analysis did not reveal the presence of acetone, ethanol, isopropanol, methanol, or propylene glycol (lower limit of detection for all five analytes of 10 mg/dL). The patient received fomepizole 750 mg i.v. every 12 h with the intermittent hemodialysis, as well as thiamine 100 mg i.v. every 6 h for cofactor therapy (11). Table 1 outlines the overall course of treatment and the ethylene glycol levels after each dialysis run. The patient’s mental status marginally improved despite normalization of the acidosis and osmolal gap, and removal of the ethylene glycol (Table 2). She was extubated on hospital day 3, but demonstrated periods of alternating agitation and somnolence. She demonstrated hyper-reflexia with diffuse bilateral weakness. On hospital day 6, the patient underwent an electroencephalogram (EEG) and magnetic resonance imaging (MRI). The EEG was normal, however, the MRI (Figure 1A C) demonstrated multiple areas of abnormal T2 prolongation involving the thalami, posterior hippocampi bilaterally, and central pons, without association of restricted diffusion abnormality. These findings were consistent with

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she had made a full cognitive, neurologic, and physiologic recovery.

Table 1. Timeline of Patient Treatment for Ethylene Glycol Poisoning Date

Time

Treatment

10/7

7:30 PM 7:45 PM

Patient arrives in the emergency department Intubated for Glasgow Coma Scale score of 7; laboratory tests, chest x-ray, and ECG ordered ABG = pH 7.02, pCO2 30 mm Hg, pO2 317 mm Hg, bicarbonate 7 mEq/L, lactate 32 mEq/L Chemistry panel = CO2 5%, BUN 27 mg/dL, Cr 2.3 mg/dL Urinalysis = no calcium oxalate crystals Ethanol volatile panel ordered Ethanol level = 0, osmolal gap = 218 mOsm/kg Pathology resident contacted to initiate toxic alcohols testing, fomepizole ordered, MICU contacted for admission Transported to MICU with fomepizole being initiated ABG = pH 6.91, PCO2 16 mm Hg, PO2 203 mm Hg, bicarbonate 3 mEq/L, lactate 32 mEq/L Nephrologist performs consultation Ethylene glycol level = 1055.5 mg/dL Left femoral dialysis catheter placed HD #1 ordered for 4 h, ethylene glycol level drops to 338 mg/dL HD #2 ordered for 4 h, ethylene glycol level drops to 44.6 mg/dL HD #3 ordered for 3 h Transferred to medical psychiatry unit Discharged from the hospital with full clinical recovery

DISCUSSION

8:00 PM 8:35 PM 8:45 PM 9:15 PM 10:00 PM 10:15 PM 10:45 PM 11:10 PM 10/8

12:14 AM 12:56 AM 1:35 AM 2:00 AM 1:40 PM

10/9 10/13 11/6

5:30 PM

In this case, the patient’s symptoms and initial test results suggested an unknown toxic alcohol poisoning, and empiric treatment was started in the ED. The diagnosis was confirmed by gas chromatography (gold standard analytical method) analysis showing high levels of ethylene glycol and also by the later discovery of an empty antifreeze bottle in the patient’s garage with a fresh ring of fluid around the bottle base. The patient had the second highest ethylene glycol plasma concentration and second highest osmolal gap seen in our institution, as determined from a retrospective analysis covering January 1996 to September 2010 and a total of 20,669 evaluations of the institutional toxic alcohol panel protocol. The only patient with higher ethylene glycol plasma concentration (a 49-year-old male with plasma ethylene glycol concentration of 1282 mg/dL) did not survive (10). Patients with ethylene glycol poisoning may present with a wide array of neurological symptoms, ranging from mild confusion to coma, and may progress to cardiac dysfunction, respiratory failure, and renal failure. The American Academy of Clinical Toxicology recommends that fomepizole be given in the following cases: for ethylene glycol levels > 20 mg/dL or if there is a documented history of ingestion of a toxic amount of ethylene glycol and a serum osmolal gap > 10 mOsm/L, or a history or strong clinical suspicion of ethylene glycol ingestion and two of the following abnormalities: arterial pH < 7.3, serum bicarbonate < 20 mEq/L, osmolal gap > 10 mOsm/L, and the presence of oxalate crystals (3,6,12). The choice of fomepizole or hemodialysis, alone or in combination, for managing ethylene glycol poisoning will depend on the clinical context (6,12 15). Emergent hemodialysis is indicated when rapid lowering of ethylene

ABG = arterial blood gas; BUN = blood urea nitrogen; Cr = creatinine; ECG = electrocardiogram; HD = hemodialysis; MICU = medical intensive care unit.

subacute ODS, given the patient’s history. No further acute medical interventions were performed. With supportive care, her neurological condition resolved over several additional days in the MICU and she was transferred to the medical/psychiatric unit for treatment of depression. At the time of hospital discharge, Table 2. Laboratory Values Date

Time

10/7

19:40 20:53 21:20 00:45 04:30 09:10 12:17 18:03 20:07 00:22 04:23 04:03

10/8

10/9 10/10

Sodium (mEq/L)

Potassium (mEq/L)

BUN (mg/dL)

Glucose (mg/dL)

151

5.0

28

120

1055

146

3.6

15

185

338

143

3.1

3

134

143 144

3.7 3.9

8 6

BUN = blood urea nitrogen.

Ethylene Glycol (mg/dL)

44.6

Calculated Serum Osmolality (mOsm/kg) 318

307.6 294.5

Lactate (mEq/L) 32 32 32 32 28 24 20 4.1 3.5 1.8 1.6

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Figure 1. Radiologist findings. There are multiple areas of abnormal T2 prolongation involving the (A) thalami, (B) posterior hippocampi bilaterally, and (C) central pons, without association of restricted diffusion abnormality. These findings are consistent with subacute state of osmotic demyelination syndrome given patient’s history. Extensively scattered foci of the T2 hyperintensity throughout the white matter most likely represent small vessel ischemic changes. The ventricles and cisterns are symmetric. No mass effect identified. The vascular flow voids are unremarkable. The orbits, paranasal sinuses, and mastoid air cells are unremarkable. Final impression: subacute stage of pontine and extrapontine myelinolysis (involving the bilateral thalami and posterior hippocampi) consistent with osmotic demyelination syndrome and small vessel ischemic changes.

glycol levels is needed in the setting of severe metabolic acidosis that is unresponsive to standard therapy, or in the presence of renal failure with accompanying ethylene glycol levels >50 mg/dL or serum glycolic acid levels >8 10 mmol/L (3,4,12,16,17). However, a recent case report described a patient with ethylene glycol levels up to 706 mg/dL who was successfully treated with fomepizole alone; however, that particular patient presented early in the course of illness, had an ethanol co-ingestion, and did not harbor a metabolic acidosis or renal injury (6). Finally, in late presenters with metabolic acidosis and acute kidney injury but negligible ethylene glycol levels, hemodialysis alone is sufficient. Patients similar to our patient with high ethylene glycol levels and severe physiologic derangements that include significant metabolic acidosis and renal injury often require a combination of fomepizole and hemodialysis (4). The classic pathophysiology of ODS centers around the shrinkage of oligondendrocytes and associated demyelination brought on by a rapid increase in serum osmolality due to aggressive correction of hyponatremia. This process was described in chronic hyponatremia patients who had adapted to a lower intracellular osmolality, and did not tolerate rapid increases in sodium concentration (18). Integral in this adaptive process to low intracellular osmolality are molecules called idiogenic osmolytes (e.g., taurine, glycine, glutamine, sorbitol, and inositol). They are produced by cells to balance the intracellular tonicity with extracellular tonicity without having to

import in sodium and chloride from the extracellular space (as sodium and chloride can be disruptive to intracellular enzymes). Cells will shift idiogenic osmolytes and potassium from the intracellular space to the extracellular space as part of their adaptation to low serum osmolality as they work to reduce their intracellular volume. This process takes approximately 48 h to achieve equilibrium (19). The hypertonic stress caused by upward shifts in serum osmolality occur too quickly for the idiogenic osmolytes to react and shift back into the intracellular space. The glial cells shrink and can cause damage to the nerve axons, induction of apoptosis, and disruption of tight junctions in the cells (20,21). As the blood brain barrier is damaged, inflammatory components like complement and cytokines are allowed to damage the glial cells, leading to demyelination (20 22). Certain areas of the brain like the pons might be more vulnerable to osmotic demyelination because they have delayed recovery of the loss of the idiogenic osmolytes that occur with chronic hyponatremia (23). There is increasing evidence that ODS can be caused a ‘‘relative hypertonic insult,’’ which has been described as rapid development of severe serum hyperosmolality in the absence of preceding hyponatremia. McKee et al. described 10 out of 139 (7%) severely burned patients found to have ODS on autopsy compared with 10 out of 3528 (0.28%) patients in the general autopsy population. The burn patients had experienced a prolonged episode of

Ethylene Glycol Case Report

severe hyperosmolality without any episodes of hyponatremia during their clinical course (24). In addition, other case studies in the literature describe hypernatremic patients who developed ODS to include azotemic patients, hyperemesis gravidarum patients, dehydrated patients, and patients on hunger strikes. The literature also reports that ODS can develop due to the rapid correction of relative hyperosmolarity (25,26). Although Burns et al. focused on the relative hypertonic insult of hyperosmolar hyperglycemia as their main culprit, they also hypothesized that the ODS that occurred in their patient could have been due to rapid correction of the glucose (25). Guerrero et al. described a patient with a hyperosmolar hyperglycemic state with normal sodium levels who developed left-sided weakness and altered sensorium with anion gap normalization eventually attributed to ODS (27). It was thought that patient’s ODS was caused by either the acute hyperosmolar state itself or the correction of the condition. Finally, Khositseth et al. presented a case report of a patient with moderate dehydration and normal sodium that became quadriparetic, hypotonic, lost deep tendon reflexes, and developed cranial nerve dysfunction after hydration. The initial sodium level started at 141 mEq/L and dropped to 130 mEq/L within 8 h and then rebounded to 137 mEq/L within the next 16 h with the respective calculated serum osmolality being 301 mOsm/L, 277 mOsm/L, and 287 mOsm/L. Their conclusion was that a fluctuation in the serum sodium levels and serum osmolality precipitated the development of ODS in their patient (28). The ODS associated with rapid hyponatremia correction requires a sequence of events that include forces that swell brain cells (seen with the hyponatremia), then forces that shrink them (cellular adaptation), followed by forces that shrink them more (rapidly correcting hyponatremia without sufficient time for the various idiogenic osmolytes to re-accumulate) (19). The pathophysiology of ODS in the setting of hypernatremia is not yet known, and the myelinolysis seems to be related to the hypertonic challenge imposed by the relative hypernatremia. It is possible that the ODS associated with hypernatremia may be due to fluctuations in serum osmolality during the course of illness and treatment (29). Patients can display a wide constellation of physical examination findings in the context of ODS, including ataxia, dysarthria, dysphagia, behavioral disturbances, quadriparesis, lethargy, and coma (30). From a radiographic standpoint, the lesions of CPM occur as trident-shaped symmetric hypointense lesions on T1 and corresponding hyperintense lesions on T2-weighted images located in the brain stem. Extrapontine lesions are located mainly in the internal capsule, basal ganglia, cerebellum, and cerebrum. Other items on the differential diagnosis associ-

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ated with these types of radiographic findings include pontine ischemia or infarction, neoplasm, Wilson’s disease or hypertensive encephalopathy (31). Correlating the radiologic findings with the clinical findings can be challenging, as the patient’s imaging can look much worse then the clinical examination and vice versa. This phenomenon is true for patients with chronic hyponatremia as well as patients who suffered an acute hypertonic insult. Several explanations are offered for this dissociation, including the time interval between clinical findings and development of radiographic findings, high sensitivity of today’s imaging modalities, and abnormal radiographic findings persisting after patient improvement (31). Our patient faced both a relative hypertonic insult due to the actual ethylene glycol ingestion and then a relatively rapid correction of her serum hyperosmolality. Her initial sodium level and calculated osmolality were 151 mEq/L and 318 mOsm/kg, respectively, and there was an expected decrease as the patient was treated for her toxic alcohol ingestion (Table 2). She displayed decreased responsiveness and then periods of agitation, hyper-reflexia, and diffuse bilateral weakness and was found to have MRI brain lesions consistent with ODS. With time and supportive care, the patient’s symptoms improved and she was discharged home from the hospital with a normal neurological examination. CONCLUSIONS This case report describes a massive ethylene glycol ingestion treated appropriately with fomepizole and hemodialysis. The patient’s eventual full recovery was complicated by the development of ODS, which had been previously seen in hyperosmolar hyperglycemic states, rapid dialysis of elevated blood urea nitrogen, and patients status post liver transplantation in the absence of hyponatremia (25,26,32). To our knowledge, this is the first description of the development of ODS in the context of ethylene glycol toxicity. REFERENCES 1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila) 2009;47:911–1084. 2. Davis DP, Bramwell KJ, Hamilton RS, Williams SR. Ethylene glycol poisoning: case report of a record-high level and a review. J Emerg Med 1997;15:653–67. 3. Henderson WR, Brubacher J. Methanol and ethylene glycol poisoning: a case study and review of current literature. CJEM 2002;4:34–40. 4. Scalley RD, Ferguson DR, Piccaro JC, Smart ML, Archie TE. Treatment of ethylene glycol poisoning. Am Fam Physician 2002;66: 807–12.

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