A middle aged man presented after having taken a mixed antihypertensive overdose of ramipril, amlodipine and bendroflumethiazide. He had refractory hypotension despite fluids, noradrenaline, adrenaline vasopressin and calcium infusions.  After discussion with toxicologists he was given 20% intralipid as per the AAGBI guidelines for LA toxicity. There was an immediate but transient improvement in his BP with two bolus doses of intralipid. Over the subwequent hours and days, he stabilised and weaned off his vasopressor support. There was no long-lasting organ dysfunction.

What is the evidence for the use of intralipid in the management for antihypertensive overdose?

Sam Clark

20% Intralipid (ILE) is a long chain triglyceride soybean emulsion that is employed in parenteral nutrition. In 1998, a chance finding by Weinberg and colleagues demonstrated that the toxicity of bupivacaine could be attenuated with administration of ILE in a rat model (1). Further animal studies in isolate rat hearts (2) and in intact canines (3) confirmed this effect in animal models, with an editorial published at the time asking the pertinent question: is ILE the “silver bullet” in the management of local anaesthetic toxicity (4). This laboratory research was followed up by a seminal case report by Rosenbatt et al., who reported the successful resuscitation of a middle-aged man that had suffered cardiac arrest post mepivacaine and bupivacaine administration during a brachial plexus block (5). Initial attempts at resuscitation had included advanced life support, defibrillation, amiodarone, and multiple doses of ionotropes and vasopressors. Despite current best practice for the time, there was no return of spontaneous circulation, therefore the authors decided to administer a 100ml bolus of ILE, leading to a rapid improvement in haemodynamic status. The patient was discharged from hospital neurologically intact, with no reported cardiovascular sequelae. Further cases reports (6) followed that demonstrated similarly positive results leading to the AAGBI to include the use of ILE in its guidelines on the management of Local Anaesthetic toxicity (7).

Initial theories, discussed below, that explained the mechanism of action of ILE led to it being employed for various other lipophilic drug overdoses, with varying degrees of success. In 2007, ILE was successfully used in the resuscitation of a 17-year old girl, who arrest post an overwhelming bupropion and lamotrigine overdose, was unresponsive to all therapy until 100mls of ILE administration 70 minutes later. Again ILE administration produced an almost immediate improvement in cardiovascular status, with the patient surviving to discharge (8). Since 2007 and the publications of these impressive responsive to ILE, clinicians have utilized ILE in a variety of lipophilic drug overdoses with varying success: antipsychotics (haloperidol, quetiapine, olanzapine & sertraline), beta-blockers (atenolol & nevibolol), tricyclics (imipramine, dosulepin, & amitriptyline) and Calcium channel blockers (verapamil, diltiazem & amlodipine)

There have been a number of theoretical explanations of the benefits of ILE administration. The initial mechanism proposed by Weinberg et al (1) is that ILE acts as a “lipid sink” for free circulation cardio toxic lipophilic drugs including local anaesthetics, binding them in an newly created intravascular lipid compartment and pulling the toxic away from their effect site. Along with the case reports discussed above, there is evidence from pre-clinical animal models for not only bupivacaine, but also other lipophilic drugs including Calcium channel blockers (6). Two studies, one in humans and the second in rats demonstrated that free verapamil concentrations reduced after ILE with improved haemodynamic status in both species (8,9). A systematic review of the management of calcium channel blocker overdose concluded that there was evidence in animal models that ILE reduced verapamil toxicity in animals after IV verapamil, but not oral administration (10). One potential reason for this latter finding has been used as evidence for the lipid sink theory: binding and therefore effective removal of the toxin form the intravascular compartment changes the pharmacokinetics and may change the gradient from the intraluminal part of the gastrointestinal tract to the blood stream favouring further absorption of the offending toxin (4,6). It is, therefore, reasonable to suggest that the timing of ILE in relation to the timing of oral overdose is vital prior to its use.
In the case of both amlodipine and ramipril overdoses possibly the most relevant beyond the “lipid sink” theory are increase in fatty acid uptake into mitochrondria and the promotion of calcium entry into cells via voltage gated calcium channels. The evidence underpinning these theories is limited, however, there is suggestion from the literature from rat models that the levels of lipid in the circulation are inadequate to significantly alter free bupivacaine levels (11) and direct cardiotonic effects on hearts both in vivo and vitro (13, 14). There is, however, currently no evidence directly relating these theories to either ACE inhibitors or calcium channel blockers of any type and though potentially interesting both clinically and academically, requires further research prior integration to day-to-day medical practice.

There have been a number of case reports involving cardiologically targeted calcium channel blockers, mostly verapamil, as discussed earlier, however, there is only one case report in the literature describing ILE for an amlodipine overdose (12). West et al reported a case of 71-year old lady, who took 135mg of amlodipine leading to cardiopulmonary and renal compromise. ILE was commenced 12.5 hours post ingestion and continued for 2 hours exceeding the standard maximum dose. Similar to the case presented above, there was a mild improvement in haemodynamics though short lived and no evidence of haemodynamic compromised induced by administration of ILE however, ILE appears to have interfered with the measurement of a number of blood parameters for up to 24 hours post infusion including full blood count, sodium levels and oxygenation. Care was withdrawn 48 hours after initial treatment.

Conclusions:

As with many rescue therapies, the evidence underlying the use of ILE for lipid soluble overdose is based solely on animal models, case reports and case series. The evidence for its use in amlodipine overdose or polypharmacy overdose including amlodipine is limited to one case report and extrapolation from other agents. It is essential to remember that there are considerable limitations to extrapolating such data in the clinical setting, given the inherent biases including potential under –reporting of fatal cases, the difficulty in establishing a casual relationship between ILE and any clinical improvement and decreased reporting of cases with either positive or negative outcomes as ILE becomes more common place. The second of these biases is particularly relevant to the case presented: there was a successful outcome, however, many treatments were instigated almost concurrently due to the critical nature of the clinical situation and the observed improvements in clinical parameters were not spectacular, it is difficult to conclude that ILE many a significant difference to the clinical outcome.

This leaves clinicians with a dilemma, however, one possible solution is that we should consider a few factors prior to the administration of ILE outside Bupivacaine overdose: is its use biologically plausible given the suggested mechanisms of action; are other treatments likely to be effective without ILE; are the consequences of ILE administration e.g. limitation blood monitoring post administration likely to severe impact on care; finally, if managing an oral overdose, is there a risk of exacerbating the clinical situation.

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References:

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