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Abstract

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Conclusion
  6. Source of funding
  7. Conflict of Interest Statement
  8. References

Abstract:  Intravenous fat emulsion (IFE) is emerging as a novel antidote in clinical toxicology. Its current usage is extending beyond local anaesthetic toxicity into management of severe toxicity from some lipophilic drugs. We present a 51-year-old woman with severe bupropion toxicity whose haemodynamic status transiently improved after IFE. Serum analysis demonstrated an increase in serum concentration of hydroxybupropion, an active metabolite of bupropion, after IFE administration, lending support to one of the proposed mechanisms of IFE. A 51-year-old woman presented to the emergency department with generalised tonic-clonic convulsions lasting approximately 30 sec., and a wide complex rhythm on her ECG that was suggestive of myocardial sodium channel blockade. Despite sodium bicarbonate therapy, the patient developed profound hypotension refractory to high-dose norepinephrine. IFE was administered with haemodynamic improvement over the course of 30 min., followed by a significant decrease in norepinephrine requirement. The patient had an episode of ventricular tachycardia 24 hr after presentation, and received a second infusion of IFE. Analysis of serum for a panel of myocardial sodium channel blocking drugs revealed that significant bupropion ingestion had occurred. Bupropion poisoning may produce life-threatening clinical effects, and IFE may be considered in cases of severe haemodynamic instability. Further studies would be instrumental in determining the optimal clinical situations for utilisation of IFE.

Poisoned patients with severe haemodynamic compromise present a unique challenge to clinicians. Unlike sepsis or cardiogenic shock, the haemodynamic compromise in poisoned patients can generally reverse if the offending drug is removed from the target organ. Intravenous fat emulsion (IFE) is a relatively novel antidote that is well studied in animal models but only has anecdotal support in human poisoning [1,2]. Although the currently proposed mechanisms of action (lipid sink, improved cellular metabolism and modulation of ion channels) all have experimental support [3], the exact therapeutic mechanism remains unknown. By acting as a lipid sink, IFE may remove a portion of the lipophilic drug from the target receptor and sequester it in the lipid phase of the blood. A previous case report chronicled haemodynamic and neurological recovery in a 17-year-old girl after administration of IFE in the setting of prolonged cardiac arrest from bupropion and lamotrigine toxicity [4]. Serum bupropion concentration increased markedly after IFE administration, presumably from redistribution from affected tissue into the lipid, lending support to the ‘lipid sink’ hypothesis. We report a 51-year-old woman who developed severe haemodynamic compromise after an ingestion of bupropion and received IFE with clinical improvement.

Case Report

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Conclusion
  6. Source of funding
  7. Conflict of Interest Statement
  8. References

A 51-year-old woman with a history of depression was brought to the hospital after two tonic-clonic convulsions at home. The husband reported that an undetermined number of diphenhydramine tablets were missing. During transportation by EMS, the cardiac rhythm was reported as ventricular tachycardia, which was successfully cardioverted to sinus tachycardia. A capillary glucose concentration was 140 mg/dL.

In the ED, her vital signs were as follows: BP, 144/95 mmHg; HR, 130/min.; RR, 16/min.; T, 38.5°C; SpO2, 100% on 15 L of oxygen. Her physical examination was significant for lethargy with withdrawal of all extremities to painful stimuli, sluggish 4 mm pupils, moist mucous membranes, normal bowel sounds and a non-distended bladder. Her initial ECG (fig. 1) demonstrated a widened QRS complex, which narrowed with intravenous administration of hypertonic sodium bicarbonate (fig. 2) as a bolus of 1.5 mEq/kg (100 mEq total). Another intravenous bolus of 100 mEq of sodium bicarbonate was administered with subsequent transition to a sodium bicarbonate infusion.

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Figure 1.  Initial ECG of the patient.

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Figure 2.  ECG of the patient after sodium bicarbonate administration.

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Within 2 hr of arrival to the ED, the patient’s haemodynamic and mental status began to deteriorate. She was intubated for increasing lethargy. The QRS complex widened despite sodium bicarbonate therapy and systolic BP fell to 80 mmHg. Hypotension persisted despite 3 g of 10% calcium gluconate, 5 mg of intravenous glucagon and 3 L of normal saline. Dopamine infusion was initiated, subsequently changed to norepinephrine and increased to 25 μg/min. with persistent hypotension. Given the severe haemodynamic compromise and presumed presence of diphenhydramine (which is lipophilic), IFE was recommended. The patient received a 1.5 mL/kg bolus of 20% soybean-based IFE for 1 min., followed by a repeat bolus of 1.5 mL/kg 5 min. later, and a 1 hr infusion at 0.25 mL/kg/min. (http://www.lipidrescue.org). Her haemodynamic status markedly improved within 30 min. (table 1). BP increased from 73/55 to 120/74 mmHg. The patient sustained two seizures without further haemodynamic compromise. Norepinephrine infusion was weaned to 2 μg/min. within 16 hr of IFE infusion. The patient’s ICU course was complicated by a sustained unstable ventricular tachycardia necessitating cardioversion and, subsequently, persistent hypotension necessitating one more bolus dose of intravenous lipid emulsion in addition to vasopressor and anti-dysrhythmic agents. The patient sustained cardiogenic shock with subsequent systolic dysfunction and estimated ejection fraction (EF) of 20–25%. She subsequently developed aspiration pneumonia, diffuse colitis (with mesenteric fatty infiltration) diagnosed by computed tomography (CT), sepsis with transient thrombocytopenia, gastrointestinal bleeding necessitating blood transfusion, transient hepatic failure and acute renal failure because of acute tubular necrosis (ATN) requiring haemodialysis.

Table 1.    Haemodynamic parameters and pharmacological interventions.
DateTimeBP mmHgIFEEventsPharmacological interventions
Day 114:3095/61  Norepinephrine: 15 μg/min.
14:4580/55  Norepinephrine: 17 μg/min.
15:0082/541.5 mL/kg IV bolus 0.25 mL/kg infusion (start) Norepinephrine: 20 μg/min.
15:1573/550.25 mL/kg infusion Norepinephrine: 30 μg/min.
15:30120/740.25 mL/kg infusion Norepinephrine: 30 μg/min.
15:45136/730.25 mL/kg infusion Norepinephrine: 25 μg/min.
16:00117/740.25 mL/kg infusion (stop) Norepinephrine: 25 μg/min.
16:2599/43 2 seizuresNorepinephrine: 25 μg/min.
     
Day 202:00139/93  Norepinephrine: 13.4 μg/min.
04:00100/72  Norepinephrine: 7.4 μg/min.
07:00120/73  Norepinephrine: 2 μg/min.
08:0077/54  Norepinephrine: 3.5 μg/min. Sodium bicarbonate:15 mEq/hr
08:2444/21 Ventricular tachycardia200 J electrical shock Norepinephrine: 30 μg/min. Sodium bicarbonate: 15 mEq/hr
08:25191/119 Sinus rhythm PVCsNorepinephrine: 25 μg/min. Sodium bicarbonate: 15 mEq/hr
11:00137/89 Sinus rhythmNorepinephrine: 10 μg/min. Sodium bicarbonate: 15 mEq/hr
14:00114/65  Norepinephrine: 5 μg/min. Sodium bicarbonate: 15 mEq/hr Vasopressin: 0.05 units/min.
16:0575/39 Ventricular tachycardiaNorepinephrine: 30 μg/min. Sodium bicarbonate: 15 mEq/hr
16:1944/32  Norepinephrine: 30 μg/min. Dopamine: 10 μg/kg/min. Lidocaine: 2 mg/min. Sodium bicarbonate: 15 mEq/hr
16:2893/43  Norepinephrine: 30 μg/min. Dopamine: 10 μg/kg/min. Lidocaine: 3 mg/min. Sodium bicarbonate: 15 mEq/hr
17:15 1.5 mL/kg IV bolus Norepinephrine: 30 μg/min. Lidocaine: 3 mg/min. Sodium bicarbonate: 15 mEq/hr
17:5090/50  Norepinephrine: 30 μg/min. Lidocaine: 3 mg/min. Sodium bicarbonate: 22.5 mEq/hr
22:15127/69  Norepinephrine: 30 μg/min. Dopamine: 10 μg/kg/min. Lidocaine: 3 mg/min. Sodium bicarbonate: 22.5 mEq/hr

The patient’s initial serum diphenhydramine concentration prior to IFE administration was therapeutic, making it challenging to account for prolonged QRS duration and such severe systemic toxicity. In search of a causative drug, a panel of myocardial sodium channel blocking drugs was tested including the following: cyclic antidepressant panel, venlafaxine, propoxyphene and bupropion. Only bupropion and hydroxybupropion concentrations were markedly elevated upon presentation (table 2). At the start of IFE therapy, the serum bupropion concentration was undetectable; however, its active metabolite hydroxybupropion was elevated. Furthermore, the serum hydroxybupropion concentration increased after administration of IFE.

Table 2.    Serum bupropion and hydroxybupropion concentrations.
Time and eventsSerum bupropion concentration (ng/mL)Serum hydroxybupropion1 concentration (ng/mL)
  1. IFE, intravenous fat emulsion.

  2. 1Clinical relevance of hydroxybupropion concentrations has not been established.

04:55 ED presentation5401100
12:05 3 hr prior to IFE0990
20:00 4 hr after IFE01200

Gradually, the patient’s mental status improved. Her cardiac function, haematological parameters and liver function normalised. With haemodynamic improvement, QRS complex narrowed and remained narrow throughout the remainder of hospitalisation. She spent 17 days in the MICU and was discharged home on hospital day 26, after an extensive psychiatric evaluation. She required outpatient haemodialysis for 9 days after hospital discharge, with subsequent normalisation of renal function.

Discussion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Conclusion
  6. Source of funding
  7. Conflict of Interest Statement
  8. References

The utilisation of IFE in a clinical setting has extended beyond bupivacaine toxicity to lipophilic drugs such as calcium channel blockers, β-adrenergic antagonists and cyclic antidepressants [1]. Bupropion is a lipophilic unicyclic antidepressant that blocks reuptake of dopamine, serotonin and norepinephrine. Bupropion’s myocardial sodium channel blocking properties have the potential to cause severe haemodynamic compromise and death [4]. In this case, comprehensive toxicological testing only demonstrated a small amount of diphenhydramine along with the bupropion. Although an additive or synergistic effect of these two drugs cannot be excluded, we believe that the severe cardiovascular compromise likely resulted from the bupropion ingestion. Furthermore, the data suggest that the patient’s haemodynamic compromise was likely mediated by the lipophilic bupropion metabolite of hydroxybupropion, given the absence of the parent drug during severe clinical toxicity. Although the QRS complex narrowed initially in response to hypertonic sodium bicarbonate, haemodynamic compromise failed with standard measures such as continuous bicarbonate administration, calcium, glucagon and vasopressors. The dramatic improvement after administration of IFE is consistent with a previously reported case [4]. More importantly, we demonstrated that the serum concentration of hydroxybupropion increased after administration of IFE. The persistent elevation of serum hydroxybupropion concentration four hours after lipid therapy may be a result of redistribution of hydroxybupropion from target organs into the serum. This provides further support for the ‘lipid sink theory.’ As the serum bupropion concentration was undetectable at that time, the rise in serum hydroxybupropion concentration was unlikely to result from ongoing absorption or metabolism. Another plausible hypothesis involves an increase in tissue perfusion and subsequent release of the drug into circulation. A pharmacokinetic study of clomipramine concentrations in rabbits with clomipramine-induced hypotension demonstrated that a rapid increase in blood pressure after IFE is associated with increased serum concentration and decreased volume of distribution of clomipramine [5]. Unfortunately, this case does not provide data to determine whether other beneficial effects of lipid may have occurred. Further studies will be instrumental in evaluating the contribution of circulation and lipid-based drug sequestration to toxicokinetics of various lipophilic drugs.

The reasons for ventricular tachycardia responsive to cardioversion 24 hr after IFE administration are not well understood. Possibilities include delayed gastrointestinal absorption of the drug, incomplete sequestration of hydroxybupropion and/or release of sequestered hydroxybupropion into the circulation. Furthermore, subsequent intravenous bolus of IFE did not improve the patient’s haemodynamic status. Drug-induced widened QRS complex would not likely respond to cardioversion. Other possibilities include Torsades de Pointes or irritable myocardium in the setting of critical illness. Further investigation of these concepts is beyond the scope of this case report.

Adverse effects from IFE are rare in the setting of lipid rescue therapy in acute treatment of lipophilic drug toxicity [2]. In the setting of protracted administration, IFE has been associated with impaired pulmonary function in patients with acute respiratory distress syndrome (ARDS) [6] and has been implicated in fat overload syndrome marked by hyperlipidaemia, fever, fat infiltration, jaundice, hepatomegaly, splenomegaly, anaemia, coagulation disturbances, leukopenia, thrombocytopenia, seizures and coma, attributed to sludging and inadequate clearance of lipids [7]. Additionally, intravascular deposition of lipid was reported in the central nervous system of two children with seizures who were treated with IFE as part of parenteral nutrition [8]. However, we believe that the seizures in this patient were not related to IFE. Although this patient had two seizures after IFE therapy, the hydroxybupropion metabolite is epileptogenic. Also, the children reported were given much larger doses of IFE than are used in Lipid Rescue therapy. We should consider the possibility of enhanced hydroxybupropion delivery to the CNS via the fat emulsion vehicle. It is possible that the seizures stemmed from the deposition of lipid into cerebral vessels, but it is not likely given return to normal mental status after extubation. The patient described here was critically ill after the initial haemodynamic compromise and the subsequent cardiac arrest. Although she had some features of the fat overload syndrome including mesenteric and fatty liver infiltration, hepatotoxicity and thrombocytopenia in addition to ARDS, it is challenging to unify all her complications under a single cause other than prolonged cardiac dysfunction.

Conclusion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Conclusion
  6. Source of funding
  7. Conflict of Interest Statement
  8. References

Intravenous fat emulsion may be life saving in a patient with exposure to potentially lethal amount of a lipophilic drug with evidence of haemodynamic compensation. Lipid therapy in the setting of life-threatening bupropion toxicity was followed by a marked haemodynamic improvement and ability to decrease vasopressor requirement. Furthermore, data presented in this case report suggest that hydroxybupropion, the active metabolite of bupropion, played an important role in cardiac toxicity and redistributed into the plasma from tissues after lipid infusion. Perhaps, removal of a limited amount of toxin away from the target organ into the lipid phase may help alleviate toxicity and improve the chance of survival. Further studies are needed to elucidate and validate mechanisms of action, appropriate dosage, indications and toxicity profile of IFE.

References

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. Conclusion
  6. Source of funding
  7. Conflict of Interest Statement
  8. References