Abstract
An 18-month-old dog was presented to the emergency department with a marked discrepancy in lactate measurements obtained on different analyzers (lactate gap), an elevated anion gap, and a renal azotemia, which raised concern for ethylene glycol intoxication. The dog was treated with intermittent hemodialysis until the lactate gap was normal.
Key clinical message:
It is hypothesized that the lactate gap can be used by veterinary clinicians as both a diagnostic tool and a therapeutic tool to determine when intermittent hemodialysis treatment can be stopped.
RÉSUMÉ
Intoxication à l’éthylène glycol : utilisation de l’écart lactate pour le diagnostic et la détermination de la durée du traitement par hémodialyse intermittente
Un chien de 18 mois a été présenté aux urgences vétérinaires avec une discordance marquée entre les mesures de lactate obtenues sur différents analyseurs (écart lactate), un écart anionique élevé et une azotémie rénale, faisant suspecter une intoxication à l’éthylène glycol. Le chien a été traité par hémodialyse intermittente jusqu’à normalisation de l’écart lactate.
Message clinique clé :
Il est suggéré que l’écart lactate peut être utilisé par les vétérinaires comme outil diagnostique et thérapeutique pour déterminer le moment opportun pour interrompre un traitement par hémodialyse intermittente.
(Traduit par Dr Serge Messier)
Ethylene glycol is a toxicant encountered in veterinary medicine, with a well-documented poor prognosis if ingested. Intoxication poses both diagnostic and therapeutic challenges. Rates of mortality in cats and dogs are high, at 96 to 100% and 59 to 70%, respectively (1,2). Lethal doses of ethylene glycol in dogs and cats were reported to be 6.6 mL/kg and 1.5 mL/kg respectively (3,4). Ethylene glycol should be a top differential diagnosis for any dog presented with metabolic acidosis, a high anion gap, and an increased osmolar gap with clinical signs suggestive of ethylene glycol toxicity (5). Ethylene glycol is rapidly absorbed from the gastrointestinal tract and metabolized by the liver (6). Hemodialysis is the treatment of choice in cases where suspected amounts of ethylene glycol have already been metabolized (7).
In human medicine, the “lactate gap” is a diagnostic tool that is extremely useful for increasing the suspicion for ethylene glycol ingestion/toxicosis (8,9). The lactate gap is observed when the measured lactate is compared between analyzers with different measurement methodology. Spurious hyperlactatemia can occur with point-of-care (POC) analyzers that use the L-lactate oxidase pathway, due to cross-reactivity with glycolate, a metabolite of ethylene glycol (10). In particular, most POC whole-blood analyzers that use L-lactate oxidase cross-react with glycolate or glyoxylate, breakdown products from ethylene glycol. This is due to a similarity in chemical structure. In contrast, several laboratory serum analyzers, which are used for routine analysis of venous blood samples, have less cross-reactivity and show minimal lactate elevation (11,12). However, to the authors’ knowledge, lactate gap has not been used as a therapeutic tool in veterinary medicine. In the case reported herein, the lactate gap was used as an adjunctive diagnostic test, to determine the length of intermittent hemodialysis (IHD) treatment required to remove the metabolites of ethylene glycol from a dog presented with acute ethylene glycol toxicity.
CASE DESCRIPTION
An 18-month-old spayed female golden retriever dog was referred to the emergency department for treatment of suspected ethylene glycol intoxication. The dog had been presented that morning to another emergency department, where a baseline diagnostic workup was carried out. The owners reported possible access to unattended vehicles (possible ethylene glycol exposure) 1 to 2 d before presentation. Clinical signs included lethargy, protracted vomiting, and abnormal vocalization. Vital parameters were within normal limits but mentation was described as dull.
A blood gas analysis (ABL90 Flex Blood Gas Analyzer; Radiometer Medical, Copenhagen, Denmark) completed on presentation revealed an increased anion gap of 30 mEq/L [reference interval (RI): 8 to 16 mEq/L] and a lactate value of 31 mmol/L (RI: 0 to 2 mmol/L). A handheld lactometer (Nova Biomedical Corporation Lactate Plus Meter; Nova Biomedical, Waltham, Massachusetts, USA) revealed a lactate value of 1.1 mmol/L (RI: 0.3 to 2.5 mmol/L). Initial complete blood (cell) count (True North Veterinary Diagnostics, Langley, British Columbia) revealed a leukocytosis characterized by a neutrophilia (15.44 × 109/L, RI: 3.62 to 12.3 × 109/L).
Serum biochemistry revealed azotemia (BUN: 13.78 mmol/L, RI: 3.210 to 10.35 mmol/L; creatinine: 164 μmol/L, RI: 35 to 124 μmol/L) and a mildly decreased ionized calcium (1.12 mmol/L). Urinalysis revealed urine specific gravity of 1.009, supportive of a renal azotemia, 4 + hematuria, proteinuria (5 g/L), glucosuria (4.1 mmol/L), and crystalluria. The crystals were identified as calcium oxalate monohydrate in moderate quantity. Serum was tested with a Kacey Ethylene Glycol Test Strips (Kacey, Asheville, North Carolina, USA) and the result was 0, indicating that there was no detectable level of ethylene glycol in the sample (< 20 mg/dL) (5). Abdominal radiographs were obtained due to the presenting complaint of vomiting and images were interpreted by a Board-certified radiologist. Radiographs revealed nonobstructive stippled, mineralized gastric material, thought to be either a portion of the dog’s normal diet or foreign material. The appearance of the small intestines was suggestive of ileus likely associated with enteritis.
The dog was admitted for supportive treatments and monitoring. Intravenous (IV) fluid therapy (Plasma-Lyte; Baxter Healthcare, Deerfield, Illinois, USA) was administered at a maintenance rate + 5% dehydration: 66 mL/h. Medications included maropitant (1 mg/kg, IV) and ampicillin (30 mg/kg, IV, q8h). During the examination, the dog became obtunded and a POC ultrasound examination revealed a medullary rim sign in both kidneys. A repeat blood gas analysis showed a persistently elevated lactate concentration compared with a handheld lactometer (29 versus 1.8 mmol/L) (ABL90 Flex Blood Gas Analyzer; Radiometer Medical, and Nova Biomedical Corporation Lactate Plus Meter; Nova Biomedical). This persistent lactate gap, in combination with the dog’s progressive clinical signs and clinicopathologic findings, including an azotemia, decreased ionized calcium, and calcium oxalate monohydrate crystalluria, raised concern for an acute kidney injury (AKI) secondary to ethylene glycol intoxication.
A pet poison toxicology service was contacted and advised that, given the time frame of suspected ingestion and the presence of a negative Kacey test (Kacey), the parent compound had been metabolized. As such, ethanol or fomepizole were not indicated. A poor prognosis was reported as an azotemia had already occurred (13).
The dog was then transferred to the authors’ institution for management of suspected ethylene glycol toxicity. The dog appeared nauseous on presentation but its condition was otherwise unchanged. On admission, a repeat blood gas analysis (ABL90 Flex Blood Gas Analyzer; Radiometer Medical) revealed a high anion gap metabolic acidosis, (pH: 7.247, RI: 7.320 to 7.430; pCO2: 21.1 mmHg, RI: 37 to 45 mmHg; AG: 34.3 mmol/L, RI: 8.0 to 16.0 mmol/L; HCO3: 9.2 mmol/L, RI: 18 to 26 mmol/L; BE: 18.1 mmol/L, RI: −4 to −1 mmol/L). Initial results (ABL90 Flex Blood Gas Analyzer; Radiometer Medical) indicated the lactate concentration was above detectable limits (30 mmol/L). Two hours later, the lactate was measurable at 29 mmol/L (RI: 0 to 2 mmol/L). The lactate concentration was 2.1 mmol/L (RI: 0.3 to 25 mmol/L) measured concurrently on a handheld lactometer (Nova Biomedical Corporation Lactate Plus Meter; Nova Biomedical). The calculated lactate gap was 26.9 mmol/L.
The following treatments were initiated on arrival at the referral hospital: IV fluid therapy (Isolyte; B. Braun Medical, Mississauga, Ontario) (60 mL/h), ethanol 40% (120 mL IV bolus administered over 1 h), maropitant (1 mg/kg, IV, q24), metoclopramide (0.3 mg/kg, SC, followed by 0.08 mg/kg per hour continuous-rate infusion, ondansetron (0.5 mg/kg, IV, once).
Intermittent hemodialysis was recommended due to concern for suspected persistent ethylene glycol metabolites, given the markedly increased lactate gap. A 12-French, 25-centimeter, double lumen hemodialysis catheter (MILA International, Florence, Kentucky, USA) was placed in the right jugular vein, under sedation, using a modified Seldinger technique. The dialysis prescription is detailed in Table 1.
TABLE 1.
Dialysis prescription.
| Parameter | Value |
|---|---|
| Modality | Intermittent hemodialysis |
| Dialyzer/kidney | Polyflux 6H (Baxter) |
| Tubing | Pediatric |
| Priming | Lactated Ringer’s solution |
| Heparin prime | 2500 IU |
| Target time vs actual time | 240 min vs 277 min |
| Target ultrafiltration vs actual ultrafiltration | 400 mL vs 450 mL |
| Target Qb vs actual Qb | 208 mL/min vs 251 mL/min |
| Target Qp vs actual Qp | 51.2 L vs 69.7 L |
Qb — Extracorporeal blood flow; Qp — Total blood processed.
A 90% urea reduction ratio was planned that corresponded to 2 L/kg blood processed (51.2 L) and a target time of 4 h. The dialysate components were as follows: bicarbonate (BiCart; Vantive, Mississauga, Ontario) (28 mmol/L), potassium (3 mmol/L), phosphorus (59 mL) fleet enema (Fleet Company, Lynchburg, Virginia, USA) added to 4 L of acid concentrate, and ethanol 40% (120 mL) were added to the dialysate. A high-flux dialyzer (Polyflux 6H; Baxter Healthcare) was used with pediatric tubing and a goal of zero net ultrafiltration. A gradual decrease of the lactate gap was expected as the IHD removed the ethylene glycol metabolites. The time frame of therapy was 277 min, the extracorporeal blood flow was 251 mL/min, and total blood processed was 69.7 L. Table 2 details the change in lactate gap and total blood processed with increasing treatment time.
TABLE 2.
Lactate gap and total blood processed at different time intervals.
| Time (min) | Lactate gap (mmol/L) | Qp (L) |
|---|---|---|
| 0 | 27 | 0 |
| 60 | 17 | 14 |
| 115 | 6.8 | 27 |
| 205 | 1.4 | 50 |
| 240 | 0.6 | 60 |
| 277 | 0 | 69.7 |
Qp — Total blood processed.
During the treatment, the dog’s vital parameters remained stable. It was maintained on Isolyte (B. Braun Medical) at a rate of 140 mL/h. Anticoagulation was achieved with an unfractionated heparin continuous-rate infusion and monitored with an activated clotting time machine (ACT II; Medtronic, Minneapolis, Minnesota, USA). The dog received intermittent boluses of butorphanol (0.2 mg/kg, IV) to maintain mild sedation during the procedure. During treatment, both the blood gas analyzer (ABL90 Flex Blood Gas Analyzer; Radiometer Medical) and lactometer (Nova Biomedical Corporation Lactate Plus Meter; Nova Biomedical) were used to measure lactate until the lactate gap had returned to the expected range for a patient with no ethylene glycol metabolites. Lactate concentrations measured with the blood gas analyzer gradually decreased over time, whereas lactate concentrations measured with the lactometer remained low (Figure 1).
FIGURE 1.
Comparison between lactate measurements on ABL90 Flex Blood Gas Analyzer (Radiometer Medical) (ABL Lactate) and Nova Biomedical Corporation Lactate Plus Meter (Nova Biomedical) (Lactometer).
Bloodwork done on admission revealed an azotemia (BUN: 26 mmol/L, RI: 2.7 to 9.8 mmol/L; creatinine: 349 μmol/L, RI: 46 to 131 μmol/L) (True North Veterinary Diagnostics, Langley, British Columbia) that had progressed since the initial bloodwork done by the referring veterinarian (BUN: 13.78 mmol/L, RI: 3.210 to 10.35 mmol/L; creatinine: 164 μmol/L, RI: 35 to 124 μmol/L).
Although we proceeded with IHD until the lactate gap had returned to normal without reoccurrence of a lactate gap, the dog progressed to oliguric renal failure 2 d following IHD. The dog received a furosemide bolus (3 mg/kg, IV) but the urine output did not improve and the azotemia worsened (BUN: 28 mmol/L, RI: 2.7 to 9.8 mmol/L; creatinine: 531 μmol/L, RI: 46 to 131 μmol/L). Due to the poor prognosis, the owners elected to proceed with humane euthanasia.
DISCUSSION
Ethylene glycol toxicosis is encountered infrequently and has a high mortality rate in dogs and cats, especially when treatment is delayed (1,2). In this case, the prognosis upon presentation to the referral center was poor regardless of treatment, due to the already established AKI (12).
Ethylene glycol is rapidly absorbed from the gastrointestinal tract, where it is subsequently metabolized by the liver (Figure 2). The first step is conversion to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde is then converted to glycolic acid by aldehyde dehydrogenase. Finally, glycolic acid is converted to glyoxylic acid and oxalic acid. An AKI is induced by metabolites of ethylene glycol, especially oxalic acid. This metabolite induces necrosis of proximal tubular epithelium and deposition of calcium oxalate crystals within the tubular lumen (5). Metabolism of ethylene glycol produces a lactic acidosis from the conversion of pyruvate, in the presence of increased nicotinamide adenine dinucleotide hydride, to lactate. However, serum lactate concentrations, particularly those assessed using lactate dehydrogenase methods, are typically much lower compared to those generated by analyzers using lactate oxidase-based methods to measure lactate. This results in a lactate gap derived by the 2 different methodologies.
FIGURE 2.
Metabolism of ethylene glycol.
NAD — Nicotinamide adenine dinucleotide; NADH — Nicotinamide adenine dinucleotide hydride.
The lactate gap has been used in human medicine, to aid in the diagnosis of ethylene glycol toxicosis and the management of patients following this diagnosis (8). The present case demonstrated that an increased lactate gap could be calculated when comparing lactate results from 2 different analyzers. The first POC analyzer used was the ABL90 Flex Blood Gas Analyzer (Radiometer Medical), which uses the L-lactate oxidase pathway to quantify lactate concentrations. This analyzer uses L-lactate oxidase to catalyze the reaction between lactate and oxygen, resulting in pyruvate and hydrogen peroxide. The machine then measures the levels of hydrogen peroxide by amperometric measurement, which is proportional to the quantity of lactate in the blood (14). It was reported that analyzers using this method of analysis can cross-react with glycolate, a metabolite of ethylene glycol (10), thus causing the erroneous and massively increased lactate measurements. Other analyzers, such as the handheld lactometer Nova Biomedical Corporation Lactate Plus Meter (Nova Biomedical), also use the L-lactate oxidase enzyme, catalyzing the conversion of L-lactate to pyruvate and hydrogen peroxide and providing an amperometric reading. However, this analyzer was shown to have minimal cross-reaction with glycolic acid, and comparison of these divergent results has been reported in dogs (14). The reason for the lack of cross reactivity with the Nova Biomedical Corporation Lactate Plus Meter is not entirely understood; however, a proposed mechanism is a difference in enzymatic substrate specificity, depending on its bacterial source organism (14,15).
This reported lactate gap has served as a helpful tool in the diagnosis of ethylene glycol toxicity; however, its use as a method to guide therapy has not been reported in veterinary literature. There is no established concentration for which we would consider the lactate gap to be elevated, despite the obvious elevation noted in the present case. For a sample of 10 dogs at the authors’ institution that had not been exposed to ethylene glycol, lactate concentrations were obtained using 2 analyzers (ABL90 Flex Blood Gas Analyzer and Nova Biomedical Corporation Lactate Plus Meter) to determine the lactate gap. The maximum lactate gap observed was 0.5 mmol/L (Table 3). Although a larger sample size would be necessary to determine a reference interval for the lactate gap, the markedly increased lactate gap in this dog supported a diagnosis of ethylene glycol toxicosis.
TABLE 3.
Comparison of lactate concentrations using Nova Biomedical Corporation Lactate Plus Meter and ABL90 Flex Blood Gas Analyzer.
| Canine patients without exposure to ethylene glycol | Lactate concentration (mmol/L) using Nova Biomedical Corporation Lactate Plus Meter (Nova Biomedical) | Lactate concentration (mmol/L) using ABL90 Flex Blood Gas Analyzer (Radiometer Medical) |
|---|---|---|
| 1 | 0.9 | 0.9 |
| 2 | 0.9 | 0.9 |
| 3 | 2.0 | 2.1 |
| 4 | 1.5 | 1.6 |
| 5 | 1.8 | 2.1 |
| 6 | 1.4 | 1.3 |
| 7 | 0.9 | 0.8 |
| 8 | 1.7 | 2.2 |
| 9 | 1.0 | 1.0 |
| 10 | 1.6 | 1.3 |
Hemodialysis for treatment of ethylene glycol can be done early in the course of disease, to remove the ethylene glycol and its metabolites before development of an AKI, or after an AKI has developed (5). With early recognition of erroneous lactate measurements or a known ingestion of ethylene glycol, hemodialysis can be initiated and the lactate gap can be used to determine the time point at which the metabolites of ethylene glycol have been removed from circulation. To maximize the success of therapy, administration of either fomepizole or ethanol before referral to a tertiary facility with capacity for hemodialysis or on presentation before hemodialysis is still recommended. For the dog in this report, the lactate gap decreased with increasing length of hemodialysis time. This was an important finding, as there was a discrepancy in the initial targeted time of dialysis (240 min) and the actual time that dialysis was conducted (277 min). The remaining lactate gap (0.6 mmol/L) once the target time of 240 min was reached meant that dialysis was continued for an additional 37 min. The lactate gap decreased gradually as the dialysis time increased (Figure 1). It was only when the lactometer measurement matched the ABL90 Flex Blood Gas Analyzer measurement that discontinuing dialysis was deemed appropriate. Resolution of the lactate gap indicated presumptive successful removal of the ethylene glycol metabolites. We hypothesized that the lactate gap could be used to monitor for the presence of ethylene glycol metabolites, to guide length and timing of hemodialysis therapy.
As in the present case, direct quantification of ethylene glycol and its metabolites is not readily available in most veterinary hospitals. Since measurement of ethylene glycol and associated metabolites is not often possible, it is challenging to determine timing and length of therapeutic intervention. Without a method for monitoring these cases, premature discontinuation of therapy could risk continued toxicity. A case report by Manini et al documented good correlation between serum glycolate and falsely elevated serum lactate concentrations in humans, both of which resolved following hemodialysis. Thus, it may be reasonable to use the lactate gap as a surrogate measurement for glycolate concentration (16).
To the authors’ knowledge, this is the first report of the lactate gap being used to guide IHD therapy in veterinary medicine. Further clinical investigations are warranted to assess its wider diagnostic utility. Although the dog did not survive, this case demonstrated the lactate gap as a useful surrogate monitoring tool to ensure removal of ethylene glycol metabolites via IHD therapy.
This case also demonstrated the well-documented unfavorable outcome in animals with advanced ethylene glycol toxicity that are unable to receive expeditious treatment. It serves as a reminder that suspected “spurious” hyperlactatemia that is inappropriate to the hemodynamic status of the case should be corroborated with a second measurement modality (7–9,14). If a lactate gap is observed, then the level of suspicion for toxin ingestion should increase. Earlier diagnosis of ethylene glycol toxicity enables more rapid and aggressive therapeutic intervention. For cases in which an increased lactate gap has developed, hemodialysis is recommended over conventional competitive inhibition therapy with ethanol or fomepizole, as this indicates the metabolism of ethylene glycol by alcohol dehydrogenase has already occurred (9). CVJ
Footnotes
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