19 Nov 2024
Costel Zagan examines a case of toxin ingestion in a terrier and the use of intravenous lipid emulsion.
Costel Zagan
Job Title
Image © Darya / Adobe Stock (generated with AI)
Toxin ingestion is a common reason for presenting a dog or a cat to a veterinary clinic in the UK.
The pathophysiology, clinical signs and treatment for toxicoses depend on the organ(s) affected. Mainly, the treatment consists of decontamination/clearance and supportive care.
Encephalopathy refers to a disease or damage to the brain that alters its normal function or structure. The clinical signs vary from one patient to another and include a change in mental state, lethargy, reduced ability to swallow, tremors, collapse, seizures and death1.
Numerous potential causes for encephalopathy exist, including infectious, toxic, metabolic, vascular, anoxic, traumatic, and secondary to severe systemic inflammation. The pathophysiology and treatment for encephalopathy depend on the underlying cause.
Intravenous lipid emulsion (ILE) has been used for the treatment of multiple types of lipophilic toxicoses, such as organophosphates, psychotropic drugs, local anaesthetics and NSAIDs1.
This case report describes the successful use of ILE to treat acute encephalopathy and gastrointestinal signs secondary to hyperammonaemia thought to be associated with sodium valproate ingestion.
A five year old neutered female Airedale terrier weighing 14.1kg was presented to the emergency service of a referral clinic two hours after sodium valproate 500mg ingestion with a maximum ingested dose of 14 tablets (equivalent to 496mg/kg). The owner left the house for approximately 30 minutes, and when they returned, they found valproic acid tablets on the floor inside the house and 14 tablets were missing. Between 10 and 20 minutes later, the dog developed diarrhoea, teeth chattering, vomiting and lethargy.
Previously, the dog had a history of chronic and intermittent protein-losing enteropathy (PLE), diagnosed one year before presentation, with intestinal biopsies taken endoscopically. The dog was managed with long-term prednisone by the same practice, with the last unremarkable re-examination two days before this incident.
On presentation, the dog was tetraparetic, had dull mentation, reduced pupillary light reflexes bilaterally at the direct and consensual examination, and was hypersalivating. Heart rate was mildly increased at 140 beats per minute, and blood pressure was 156/103, with a mean of 127mmHg on an oscillometric device. Femoral pulses were weak and synchronous with the heart rate. Mucous membranes were pale pink and mildly tacky, with a capillary refill time of two seconds. Modified Glasgow Coma Scale (MGCS) was 15 (reference interval [RI]: 3-18).
Within 30 minutes of arrival, the dog collapsed and was only responsive to noxious stimuli, with semi-comatose mentation and deterioration to an MGCS of 8. Oxygen saturation (SpO2) was 100%, and respiratory rate was 32 beats per minute, with no respiratory effort. The electrocardiogram showed sinus rhythm with occasional ventricular premature complexes. Peripheral lymph nodes were considered normal. Abdominal palpation was unremarkable. Rectal temperature was 38°C.
Within the first hour of hospitalisation, a complete neurological examination was performed, which was normal, excepting the aforementioned abnormalities. Haematology showed no significant changes: mild neutrophilia (13.8×109/L; RI: 3.50×109/L to 12.00×109/L).
The blood serum did not look grossly lipaemic after the centrifugation. Biochemistry and electrolytes documented a mild increase in gamma-glutamyl transferase activity (28U/L; RI: 1U/L to 14U/L), moderate hypophosphataemia (0.41mmol/L; RI: 0.8mmol/L to 1.85mmol/L), marked hyperglycaemia (18.3mmol/L; RI: 3.3mmol/L to 7.1mmol/L), mild hypokalaemia (3.52mmol/L; RI: 3.66mmol/L to 4.72mmol/L). The rest of the markers were within the normal limits.
Ammonia (NH3), measured within the first hour of presentation according to the guidelines, was markedly increased (more than 500ug/dL; RI: 11.00ug/dL to 54.00ug/dL). Pre-prandial bile acids were within normal limits (3.7umol/L; RI: 0.00umol/L to 10.00umol/L).
Post-prandial bile acids (24 hours later, when mentation was appropriate) were normal (5.6umol/L; RI: 0.00umol/L to 10.00umol/L). Prothrombin time and activated partial thromboplastin time were within the reference range (PT: 15.2s; RI: 14.0s to 20s; aPTT: 109.2; RI: 94 to 123). Lactate was markedly increased (12.6mmol/L; RI: 0.43mmol/L to 2.10mmol/L). Urinalysis (free catch sample) showed a urine-specific gravity of 1.010 (RI: 1.030 to 1.040), pH of 8 (RI: 6 to 7.5), and the rest unremarkable. Diagnostic imaging findings (thoracic and abdominal x-rays and abdominal ultrasound scan) were unremarkable.
Initial treatment included 4 boluses of 15ml/kg and 1 bolus of 10ml/kg to a total of 70ml/kg of isotonic crystalloids, followed by a maintenance rate of 2ml/kg/h. Maropitant was added to stop the vomiting at 1mg/kg IV every 24 hours. The dog was fluid responsive, so the heart rate dropped down to 84 beats per minute, and the blood pressure was 132/90 with a mean of 106mmHg; however, the mentation remained dull.
Soon after the fluid resuscitation, ILE therapy was started (1.5ml/kg IV as a bolus, then 0.25ml/kg/min IV as a CRI over 2.5 hours). Other medications followed shortly after: metoclopramide (2mg/kg/24h CRI) and ondansetron (0.5mg/kg IV every 12 hours) for the anti-emetic effect to reduce the risk of an aspiration event, given the patient’s comatose state.
One hour post-ILE, the dog’s mentation gradually started to improve. Six hours later, ammonia, blood glucose, potassium and lactate normalised (ammonia 36ug/dL; RI 11ug/dL to 54ug/dL; blood glucose 4.1mmol/L; RI: 3.3mmol/L to 7.1mmol/L; potassium 4.39mmol/L; RI: 3.66mmol/L to 4.72mmol/L; lactate 1.6mmol/L; RI: 0.43mmol/L to 2.10mmol/L).
At this point, lactulose (1ml/kg by mouth every 8 hours, after gag reflex and mentation were appropriate) was instituted, as the recommended duration of administration of ILE was overpassed.
Serial MGCS revealed neurologic improvement from a score of 8 to 17 in only 6 hours. After 12 hours, the neurologic examination was unremarkable, and heart rate and oscillometric blood pressure were normal. At 36 hours after presentation, oral prednisolone was restarted at 1.5mg/kg by mouth every 24 hours, and the rest of the medications were discontinued. Subsequent urinalysis results were all within normal limits.
The dog was discharged 48 hours after admission with oral prednisone (1.5mg/kg every 24 hours) and B9 and B12 complex (1 capsule by mouth every 24 hours) for the chronic PLE. At the time of discharge, no concerns existed and the ammonia level was 23ug/dL. One month after discharge, the owner reported no concerns.
This case report describes the successful medical management of an Airedale terrier that presented with clinical signs consistent with hyperammonaemia, shortly after sodium valproate ingestion.
Hyperammonaemia represents an increased level of ammonia in the blood and, in some cases, this can be lethal due to the neurotoxic effect of ammonia, a nitrogen-containing compound. The most common reasons for this include congenital or acquired portosystemic shunt, overproduction of ammonia by the colon and small intestine, or defective detoxification, such as in the case of liver dysfunction2,3. Other possible causes for hyperammonemia are as follows: urea cycle defects, urinary tract obstruction concurrent with urease-producing bacteria infection, and L-asparaginase therapy3.
Protein exists in the body in a balance between its formation and its breakdown, known as anabolism and catabolism, respectively. The excess of protein in the body comes from an increased intake. Excess protein is broken down into amino acids in the gastrointestinal tract, which are further broken down, releasing nitrogen that circulates in the body as ammonia. Ammonia is then carried to the liver by the portal vein, where it is converted into urea via the urea cycle and excreted in the urine2.
The ammonia measurement process is often challenging. The patient must be fasted 12 hours prior to blood sample collection, and the sample must be collected in a chilled ethylenediaminetetraacetic acid tube. Following this, the blood sample needs to be separated within the next 20 to 30 minutes in a cooled centrifuge, and the ammonia should be measured within another 20 to 30 minutes, too3.
Potential causes for false positive results include haemolysis, collection errors, ammonia or cigarette smoke in the air, saliva or sweat interacting with the sample, valproic acid use, asparaginase, narcotics, hyperalimentation, high protein meals, gastrointestinal bleeding, strenuous exercise, hypokalaemia and alkalosis3.
In this case, the increased protein intake was ruled out, as the dog was on a balanced diet. Defective detoxification or hepatopathies were also considered unlikely, based on the biochemistry, clotting times, and bile acid stimulation test results, respectively. Further diagnostics failed to identify a metabolic cause for the marked increase in ammonia; infection, urinary tract obstruction, dehydration, or other pathologic processes were considered unlikely and ruled out by investigations.
Most clinical signs in hyperammonaemia are neurological and include (but are not limited to) lethargy, aimless wandering, circling, head pressing, blindness, stupor, seizures and coma1.
Sodium valproate is a second-line to fourth-line anticonvulsant drug used as adjunctive treatment in some dogs, and acts as a mood-stabilising drug in humans. The recommended dose is 60mg/kg by mouth every 8 hours. Sodium valproate raises the gamma-aminobutyric acid (GABA) levels in the brain, which stops voltage-gated ion channels from working and inhibits histone deacetylases.
Sodium valproate is converted to valproic acid in the acidic gastric environment, where it is rapidly absorbed from the gastrointestinal tract. The valproic acid inhibits GABA transferase and succinic aldehyde dehydrogenase, which leads to increased levels of GABA in the central nervous system4-6.
“[The] contemporaneous improvement in clinical signs with the administration of ILE supports further investigations into the use of this drug to treat hyperammonaemia.”
The presented dog showed encephalopathic signs (teeth chattering, depressed mentation), prompting to look for an association between the sodium valproate ingestion and these signs. The history, clinical signs and the investigation results strengthened the presumed diagnosis.
The sodium valproate elimination half-life ranges from 1.5 to 2.8 hours in dogs3. Emesis was not induced due to the rapid metabolism of sodium valproate and the altered mentation. For the same reason, activated charcoal was not administered, either.
The changes in the haematology were consistent with a stress leukogram. The electrolyte disturbances were suspected to be consecutive to diarrhoea, being normal in the subsequent analyses, after supportive care. The marked hyperglycaemia was thought to be stress-related, being within the normal limits afterward. The initially marked hyperlactataemia was interpreted as secondary to hypoperfusion due to the hypovolaemic shock caused by vomiting, as it was normal in the next tests.
The dog’s owner was not aware of any other medication taken by the dog, so the use of reversal agents was not warranted.
ILE provides fatty acids needed by human and animal organisms, helps the intermediary metabolism, and buffers the harmful effects of lipid-soluble substances by sequestering them in the plasma compartment7. At the same time, ILE also has immunosuppressive effects, can increase pro-inflammatory cytokines and affects pulmonary function5.
One study8 assessed the mechanism of action of ILE in depth and the findings were consistent with two modes of action:
In this case, it was theorised that, as a lipid-soluble molecule, ILE would effectively sequester ammonia in the plasma compartment, thereby increasing excretion and reducing systemic effects.
ILE therapy was initiated after documenting severe hyperammonaemia (more than 500ug/dL). Both mechanisms were considered possible, as ILE was enhancing the inotropism to excrete the toxin; the provided fatty acids were a source of energy for the organism to continue with the disposal process, and they also provided cell support and helped in buffering the foreign substance.
Perfusion parameters were normalised by fluid resuscitation; however, mentation was still affected. Initiation of ILE 20% coincided with a rapid improvement in encephalopathic signs. The dog recovered to being neurologically normal within 24 hours.
Initially, the lipid emulsion was used in regional lipophilic local anaesthetic drug reactions, but more recently has been used off-label for organophosphate, psychotropic drug and NSAID intoxication1.
At the time of writing, no established guidelines exist, but the recommended protocol for dogs is as follows: a bolus of ILE 20%, 1.5ml/kg to 4ml/kg (equivalent to 0.3g/kg to 0.8g/kg) IV, over 1 minute, followed by a CRI of 0.25ml/kg/min (equivalent to 0.05g/kg/min) over 30 to 60 minutes. If this dosing is not efficient, additional boluses can be administered to a maximum of 7ml/kg (or 1.4g/kg). Some clinicians have reported successful treatment using ILE boluses of 1.5ml/kg every 4 to 6 hours over the initial 24 hours4.
The infusion rate needs to be titrated to the individual’s response. This recommendation is extrapolated from human medicine, and the used dose should not exceed 8ml/kg/day. However, this dose has been exceeded by the Pet Poison Helpline without ill effects; therefore, the dogs and cats might have different tolerance levels, but no evidence for this exists.
If the outlined dose is not effective, consider additional doses of 1.5ml/kg IV over 30 minutes every 4 to 6 hours for 24 to 36 hours until clinical signs resolve (based on clinical judgement), or maintaining a CRI of 0.5ml/kg/hour until clinical signs resolve5. It is recommended to only use the ILE for local anaesthetic toxicosis after the standard resuscitation protocols have been unsuccessful. In case of cardiac arrest, the bolus could be repeated.
During cardio-pulmonary-cerebral resuscitation, ILE administration should not be interrupted. If the patient still does not respond to resuscitation, the bolus can be repeated twice after five minutes each time. The CRI rate can be increased to 0.5ml/kg/min if progressive hypotension appears4.
Studies from human medicine indicate that the ILE has been successfully used in hyperammonaemia in neonates, but also in infants and children with in-born metabolic diseases (that is, in whom urea cycle defect seemed possible or was suspected)2.
In the field of veterinary medicine, the use of ILE in local anaesthetic and non-local anaesthetic drug-related toxicoses has been investigated in experimental studies and case reports4. Another study also assessed the successful use of ILE in a dog showing hepatic encephalopathy signs after suspected naproxen ingestion, which proved to have a portosystemic shunt1.
Based on the evidence, presentation and outcome in this case, the contemporaneous improvement in clinical signs with the administration of ILE supports further investigations into the use of this drug to treat hyperammonaemia.
