This case describes an adverse event following chocolate ingestion and THC intoxication and the use of ILE therapy. After considering potential causes for the clinical deterioration, the authors suspect that development of ARDS secondary to ILE infusion resulted in acute decline of the patient. Diagnosis was based on the exclusion of other risk factors that have the potential of inducing acute lung injury.

Tetrahydrocannabinol is highly lipophilic (partition coefficient (P) value >6,000) and is distributed in adipose tissue, liver, lungs and spleen after absorption from the gastrointestinal tract. THC is slowly redistributed into plasma before excretion in feces and urine (21, 22). The lipophilicity provides a theoretical justification for use of ILE in treatment of THC toxicosis. In this case, initial improvement was noted in mentation when the patient became more responsive, but the patient subsequently developed severe respiratory distress. Criteria implicating ARDS as the cause of respiratory distress in this patient include the acute onset of clinical signs, known risk factor (ILE infusion), proteinaceous fluid in conducting airways and neutrophilic inflammation in pulmonary parenchyma. Although not traditionally considered a component of the definition of VetALI/VetARDS the finding of an edema fluid-to-plasma protein ratio ≥0.65 (TP edema fluid 5.4 g/dL and plasma protein 7.1 g/dL, ratio 0.76) makes cardiogenic pulmonary edema less likely and may indicate increased alveolar capillary membrane permeability (23, 24).

ILE infusions are used as an antidote for non-local anesthetic agents (1, 2, 20, 25). Though theoretical, there are two proposed mechanisms of ILE's antidotal properties. In the lipid sink theory the offending agent is partitioned into the intravascular lipid phase, resulting in compartmentalization of highly soluble agents, removing lipid soluble toxins from their sites of action and allowing metabolism and excretion (2, 3, 20). Furthermore, this partition results in a concentration gradient exerting a pull of the agent from tissues into the vascular compartment, accelerating removal from the interstitial space (20). An alternative theory addresses previously observed improved cardiac performance after infusion of ILE and suggests that an increase in fatty acids provides an energy source for cardiac myocytes, improving cardiac myocyte survival and counteracting cardio-toxic effects of LAST that may include inhibition of fatty acid transport into mitochondria (2, 3, 17, 20). Thus, ILE infusions may provide a benefit in toxicosis with lipophilic agents and in agents that impair mitochondrial metabolism (25).

Reports of ILE treatment in non-LAST in veterinary medicine have documented favorable outcomes in treatment of calcium channel blocker, bromethalin, avermectin parasiticides, baclofen, bupropion, loperamide, permethrin (cats), and sertraline toxicities (6, 11, 13–17, 20, 21, 26). The reported adverse events in these cases are limited to extravasation and increased toxin levels (11, 14). Case reports are available for use of ILE therapy for non-LAST in people in toxicosis resulting from tricyclic-antidepressant, calcium channel blocker, parasiticides, herbicides, and other psychotropic agents, though controlled studies are lacking (2, 20).

Unfortunately, when ILE is used as a treatment it can be difficult to delineate a complication of therapy vs. a complication from underlying intoxication, which should be considered in the case described here. Deleterious pulmonary effects documented in human medicine and animal studies are predominantly thought to include deposition of lipid in the vasculature and reticuloendothelial system and an increase in fatty acids providing a substrate for pro-inflammatory prostaglandin pathways, which leads to changes in the vascular tone and disruption of alveolar capillary membranes (13, 17, 27). These effects were not noted in clinical studies with baseline healthy lungs but were limited to critically ill or septic animal models (27, 28). There is evidence to suggest that the incidence of ARDS secondary to ILE infusion may be associated with CRI rate and total dose (13). Furthermore, lipid droplets larger than 1 μm in size have the potential to cause obstruction of microcirculation after phagocytosis by the reticuloendothelial system, initiating an inflammatory response (25).

The goal of ILE infusion in toxicosis it to achieve a sustained lipemic plasma phase without inducing fat overload, however, there are established infusion protocols only for LAST in people (29). No standardized or optimal dosing protocol has been studied for treatment of non-LAST (17, 20). Current recommended protocol for LAST, which is commonly used in other toxicities, is an initial bolus of 1.5 mL/kg 20% intralipid solution over 1 min followed by a CRI of 0.25–0.5 mL/kg/min until circulatory stability is achieved (17, 20, 29). Variations of this protocol have been used in veterinary case reports. While doses vary, they all use a 20% intralipid loading bolus followed by a CRI, with monitoring of serum for development of gross lipemia. The lack of clinical studies in veterinary medicine, emphasizes the importance of a careful risk-benefit assessment before instituting therapy and diligent pharmacovigilance in reporting of adverse events.

There are reports implicating ARDS as a potential adverse event associated with ILE infusions in people, however most of the patients were critically ill, making it hard to discern whether ARDS resulted from ILE infusion or was a result of underlying illness (12, 27, 30). The authors do not believe that this patient had an additional condition predisposing to the development of ARDS, though this cannot be entirely ruled out. Respiratory changes noted in prior adverse event reports include an increase in mean pulmonary arterial pressure, increased venous admixture, decreased PaO₂:FiO₂ (ratio of arterial oxygen partial pressure to fractional inspired oxygen) and an increased Aa-gradient (Alveolar-arterial oxygen concentration gradient) (27, 30). These changes resolved in one study after discontinuation of ILE therapy (27). Unfortunately, this data was not obtained for the patient in this study, however close temporal relation to ILE infusion makes it highly likely that the observed deterioration was related to this intervention. Post mortem findings were suggestive of ARDS as the cause of respiratory compromise.

Extrapolation from TPN cases suggests that adverse effects could occur with use of ILE in the treatment of toxicities. Potential for significant adverse effects seems to be associated with higher doses and more rapid infusion rates (13). The authors believe there may be a significant publication bias relating to adverse events associated with use of ILE therapy as an antidote. Literature in veterinary medicine is limited to case reports, resulting in a tendency to only report successful outcomes and an absence of reporting of unfavorable outcomes.

The primary limitation of this case report is common to all descriptive studies: causal inference is not possible from uncontrolled observations. Thus, it cannot be excluded that ARDS was secondary to THC or chocolate intoxication, or an adverse drug reaction to other treatments administered (i.e., maropitant). A literature search using the search engines Google Scholar, PubMed and Microsoft Academic was performed using keywords and MeSH terms including chocolate, theobromine, methylxanthines, maropitant, ARDS, respiratory, edema, dog, canine, veterinary, THC, tetrahydrocannabinol, respiratory distress, and pulmonary complications did not reveal any previous reports indicating a similar causality.

Airway complications secondary to THC inhalation (not ingestion) in people have been reported in conjunction with tainted cigarettes or chronic exposure (31, 32). To the authors knowledge, there are no reports of similar respiratory complications in dogs secondary to chocolate intoxication or maropitant use. The pulmonary effects of intravenous theophylline and a methyxanthine derivative (S9795) in dogs were decreased arterial partial pressure of oxygen without change in lung mechanics and decreased compliance, respectively (33). Thus, the potential for methylxanthine induced changes in lung function cannot be completely excluded. It is the authors' opinion that the lack of other clinical signs indicating methylxanthine intoxication makes this possibility less likely.

Although a cardiologist did not evaluate this patient for underlying cardiac disease, history, physical examination and bedside ultrasound were not consistent with underlying structural heart disease nor volume overload. In addition, total fluid rate (352 mL, 5.8 mL/kg/h) of crystalloids or total fluid load including ILE (409 mL, 6.6 mL/kg/h) respectively, was appropriate and not likely to result in fluid overload.

The causality of ILE infusion and development of ARDS cannot be proven in this case, however, temporal association and biological plausibility should bring into question the use of ILE as a treatment in benign intoxications. To the authors' knowledge, this is the first report of a case of suspected ARDS secondary to ILE infusion in veterinary medicine. Prospective, controlled studies are lacking and are needed to more accurately assess risks of this therapy option. Until this time, treatment decisions may need to be reserved for life-threatening intoxications with lipid-soluble agents, after exhaustion of traditional established therapeutic protocols. Client education poses an important aspect in veterinary medicine and should precede the use of ILE therapy as an antidote for toxicosis in all instances. Current ILE administration guidelines are extrapolated from human medicine protocols and are predominantly empiric. Controlled studies in animals may assist in determination of safe and effective dosage recommendations, duration of therapy and threshold for potential complications but are challenging to accomplish. Furthermore, patients treated with ILE should be very closely monitored for development of complications.