Article, Toxicology

Intralipid emulsion treatment as an antidote in lipophilic drug intoxications

a b s t r a c t

Intravenous lipid emulsion (ILE) is a lifesaving treatment of lipophilic drug intoxications. Not only does ILE have demonstrable efficacy as an antidote to Local anesthetic toxicity, it is also effective in lipophilic drug intoxications. Our case series involved 10 patients with ingestion of different types of lipophilic drugs. Intravenous lipid emulsion treatment improved Glasgow Coma Scale or blood pressure and pulse rate or both according to the drug type. Complications were observed in 2 patients (minimal change pancreatitis and probable ILE treatment- related fat infiltration in lungs).

In our case series, ILE was used for different lipophilic drug intoxications to improve cardiovascular and neurologic symptoms. According to the results, it was found that ILE treatment is a lifesaving agent in lipophilic drug intoxications and it can be used in unconscious patients who have cardiac and/or neurologic symptoms but no history of a specific drug ingestion.

(C) 2014

Introduction

Intravenous lipid emulsion (ILE) is a lifesaving treatment of lipophilic drug intoxications. The history of ILE treatment is not so far. The first report of the successful use of lipid emulsion to counteract a drug toxidrome was in 1962, whereby researchers demonstrated an enhanced recovery from barbiturate-induced neurologic depression in rats.

Not only does ILE have demonstrable efficacy as an antidote to local anesthetic toxicity, its spectrum of use now clearly lies beyond this to encompass the treatment of other lipid-soluble drug toxidromes [1].

Methods

We present a case series involving 10 patients admitted to our emergency department (ED) with different lipophilic drug intoxica- tions and administered ILE treatment during a 6-month period. All patients were administered ILE as an antidote in the treatment of drug intoxication. In our ED, the patient-focused data were recorded in a central computerized database. The medical records consist of history,

? Meetings: First International Critical Care and Emergency Medicine Congress, Istanbul, Turkey; November 6-8, 2013 (as a poster presentation).

?? Conflict of interest: None.

? Financial support received: None.

* Corresponding author. Department of Emergency Medicine, Umraniye Training and Research Hospital, Istanbul, Turkey. Tel.: +90 216 632 1818-(1426), +90 533 495

7520 (Mobile).

E-mail address: [email protected] (S. Eren Cevik).

vital signs, physical examination; laboratory tests; medical treatment; and follow-up information. Each patient’s record was retrieved from the database and carefully abstracted by one of the authors to a datasheet which was designed for this study. The variables were defined as patient’s blood pressure, pulse rate, Glasgow Coma Scale (GCS), the time between initial ILE infusion and improvement of signs and symptoms, laboratory tests, and observed complications. Retrieved medical records included all of the information that was determined as variables. An increase of 2 points or more in GCS was admitted as an improvement. On the other hand, a systolic blood pressure level higher than 90 mm Hg or a diastolic blood pressure level higher than 60 mm Hg was admitted as an improvement in blood pressure; pulse rate between 60 and 100 beats/min or, if tachycardic, a decrease of 20% or above in pulse rate was determined as an improvement in pulse rate. In addition, a troponin level higher than 0.02 ng/mL was admitted as an elevation according to the threshold of laboratory kits.

The aim to review this case series is to denominate the effectiveness and complications of ILE treatment as an antidote in lipophilic drug intoxications other than local anesthetics.

Case report

Case 1

A 51-year-old woman with altered mental status presented to ED. At the time of arrival, her GCS score was 10 (E3V2M5), blood pressure was 110/72 mm Hg, and pulse rate was 82 beats/min. Her pupils were

http://dx.doi.org/10.1016/j.ajem.2014.05.019

0735-6757/(C) 2014

isocoric, and there was eye divergence (simultaneous outward movement of both eyes, away from each other). Results from electrocardiogram (ECG), the other system examinations, and blood tests were normal. From the records and the history examination, it was learned that she ingested 925 mg (a potentially toxic dose, which is N 5 mg/kg [2]) amitriptyline. Because of the fact that control blood pressure was 90/60 mm Hg, the administration of an ILE was considered. Intravenous lipid emulsion was administered at a dose of100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 4300 mL). An hour after the initial ILE dose, her GCS score was 14 (E4V4M6), divergence regressed, and blood pressure improved to normal ranges.

Case 2

A 24-year-old, unconscious woman was admitted to the ED. After history examination, it was learned that she took a total amount of 875 mg (N 5 mg/kg) amitriptyline. Her GCS score was 7 (E1V1M5). Her blood pressure was 147/91 mm Hg, and pulse rate was 143 beats/min. Her pupils were isocoric, and there was eye divergence (Fig. 1). Electrocardiogram revealed sinus tachycardia. Results from other system examinations and blood tests were normal. Intravenous lipid emulsion treatment was started at a dose of 100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3400 mL). After 45 minutes, pulse rate regressed to 101 beats/min. Glasgow Coma Scale score improved to 9 (E2V2M5). Divergence also regressed.

Case 3

A 32-year-old woman took 475 mg (a potentially toxic dose which is N 450 mg [3]) metoprolol succinat as a suicide attempt an hour before she was admitted to our ED. Her GCS score was 15 (E4V5M6). Her blood pressure was 95/65 mm Hg, and pulse rate was 52 beats/ min. Electrocardiogram revealed Sinus bradycardia. Intravenous lipid emulsion treatment was started at a dose of 100 mL bolus and

0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3100 mL). Her bradycardia and her blood pressure increased in 2 hours after the ILE treatment. Her urine color was red, but it was not because of hematuria (Fig. 2). However, on the follow-up, she had no pathological signs and symptoms and she was discharged after 24 hours of hospitalization and psychiatry consultation. Four days after the administration of the drugs, she was again admitted to the ED with an abdominal pain reverberating to her back. In her blood tests, pathological results were as follows: white blood cells, 32.300 K/uL; amylase, 249 U/L; and lipase, 438 U/L. In addition, urine test revealed a urinary system infection. According to these results, she was hospitalized with the diagnosis of minimal change pancreatitis. On the second day of the hospitalization, these blood values regressed.

Fig. 1. Eye divergence before ILE treatment in case 2.

Fig. 2. Urine color change after ILE treatment in case 3.

Case 4

A 32-year-old woman had taken an unknown amount of fluoxetine hydrochloride, alprazolam, and nifedipine tablets. Her GCS score was 8 (E4V5M6). Her blood pressure was 70/50mm Hg, and pulse rate was 48 beats/min. Electrocardiogram revealed sinus bradycardia. She was administered 0.2 mg flumazenil, and her GCS score improved to 11. Because of hypotension and bradycardia, ILE treatment was started at a dose of 100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3700 mL). However, 2 hours after initiating ILE, her blood pressure and pulse rate were 105/70 mm Hg and 85 beats/min, respectively, and her level of consciousness did not change. After the effect of flumazenil decreased, her GCS score again regressed to 8. After the administration of ILE, flumazenil administration was repeated; however, the same result with the Initial administration was not achieved. It was considered to be due to the effect of ILE on flumazenil, which is a weak lipophilic base. Her urine color was red (same as case 3). Because of the fact that her GCS score did not change, she was transported to an intensive care unit (ICU). Two days after the ILE treatment, anterior-posterior chest radiography revealed diffuse infil- tration (Fig. 3a), and there was ground-glass opacity probably related to ILE treatment in the thorax computed tomography (Fig. 4a-d). She was having coughing and chest pain. Her oxygen saturation was 97% in room air, and a result from the respiratory system examination result was normal. On the third day of the ILE treatment, chest radiography signs regressed significantly (Fig. 3b).

Case 5

A 28-year-old man had taken a total amount of 2400 mg (which is greater than the maximum daily dose of 800 mg) quetiapine an hour before he was admitted to ED. His GCS score was 13 (E3V5M5). His blood pressure was 95/50 mm Hg, and pulse rate was 144 beats/min. Electrocardiogram revealed sinus tachycardia. Intravenous Lipid emulsion therapy was initiated at a dose of 100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3580 mL). Two hours after the ILE treatment, hypotension and tachycardia regressed and GCS score improved to 15 (E4V5M6).

Case 6

A 18-year-old woman with a history of epilepsy had taken an unknown amount of lamotrigine 100 mg tablets and sertraline 50 mg tablets an hour before she was admitted to the ED. Her GCS score was 12 (E4V2M5). She was agitated, disoriented, and noncooperated. Her vital signs and ECG findings were normal. In neurologic examination, there was vertical nystagmus and myoclonia. Intravenous lipid emulsion therapy was initiated at a dose of 100 mL bolus and

0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3100 mL). In the

first hour of ILE infusion, she started to answer the questions with

Fig. 3. a, Anterior-posterior chest radiography image 2 days after the ILE treatment, in case 4. b, Control anterior-posterior chest radiography 2 days after the first radiography.

disfasia, and in the sixth hour, GCS score was 15 and her speech was minimal dysarthric.

Case 7

A 17-year-old man with a history of bonsai use was admitted to ED. His GCS score was 9 (E2V2M5). His blood pressure was 90/50 mm Hg, and pulse rate was 120 beats/min. Electrocardiogram revealed tachycardia. Her pupils were miotic. Intravenous lipid emulsion treatment was started due to hypotension and tachycardia at a dose of 100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 4000 mL). Two hours after the treatment, his blood pressure

and pulse rate increased to normal levels, and his GCS score improved to 14.

Case 8

A 24-year-old confused, disoriented woman was admitted to our ED with amitriptyline intoxication an hour after taking the drugs. From the history, it was learned that she had taken 520 mg (N 5 mg/kg) amitriptyline. Her GCS score was 12 (E2V5M5). Her blood pressure was 80/60 mm Hg, pulse rate was 125 beats/min, and temperature was

38.5?C. Her pupils were mydriatic, and Pupillary light reflex was bilateral (+). Her speech was dysarthric. Electrocardiogram revealed

Fig. 4. a-d, Thorax computed tomographic images of fat infiltration in case 4, 2 days after the ILE treatment.

sinus tachycardia. Intravenous lipid emulsion treatment was started at a dose of 100 mL bolus and 0.5 mL kg-1 min-1 infusion for 2 hours (total dose of 3400 mL). An hour after the beginning of the ILE treatment, her blood pressure started to increase (120/75mm Hg), and pulse rate started to decrease (88 beats/min). Five hours later, her GCS score was 14.

Case 9

An 18-year-old woman was admitted to ED. Her GCS score was 8 (E4V2M4). Her blood pressure was 50/30 mm Hg, pulse rate was 188 beats/min, and temperature was 38.0?C. Her pupils were bilateral mydriatic. She was agitated. Electrocardiogram revealed sinus tachycardia. In neurologic examination, there was dyskinesia. In blood gases, pH was 6.8 mL/dL and 60 mEq bolus sodium bicarbonate was administered. Intravenous lipid emulsion treatment was started on the 15th minute of her arrival to ED, due to suspicion of drug intoxication, at a dose of 100 mL bolus and 0.25 mL kg-1 min-1 infusion. However, we were not able to get a drug ingestion history from the family. Twenty minutes after the initiation of ILE, her mydriasis regressed; blood pressure increased to 90/60 and 120/70 mm Hg, respectively; and pulse rate also decreased to a value of 144 beats/min. Control pH in the blood gases was 7.01 mL/dL. Thirty minutes after the arrival, she had respiratory depression. She was intubated with propofol and rocuronium. After the intubation, gastric lavage and activated charcoal were applied. After the transport to ICU, empty amitriptyline and ?-lipoic acid boxes were found by the family at home. In the ICU, dopamine and sodium bicarbonate infusion was started. Because of hypotension, noradrenaline was started, and due to metabolic acidosis, sodium bicarbonate infusion was continued. For the reason that ILE treatment was not continued in the ICU, the patient was administered only total of 500 mL ILE in ED. During follow-up, troponin I increased to 9.24 ng/mL on the first day and greater than 50.000 ng/mL on the second day. On the second day of the ingestion, cardiac arrest occurred. She did not answer cardiopul- monary resuscitation, and she was admitted as exitus.

Case 10

A 23-year-old woman with an unknown amount of amitriptyline intoxication was admitted to the ED. Her GCS score was 8 (E2V1M5). Her blood pressure was 160/95 mm Hg, and pulse rate was 109 beats/min. Her pupils were isochoric, and there was eye divergence. Electrocardio- gram revealed sinus tachycardia. Intravenous lipid emulsion treatment was initiated at a dose of 100 mL bolus and 0.25 mL kg-1 min-1 infusion for 2 hours (total dose of 1750 mL). An hour after starting ILE therapy, GCS score improved to 13 (E3V4M5). During follow-up, creatine kinase-MB (CKMB) mass and troponin I values elevated to 4.2 ng/mL (reference value, b 3.4 ng/mL) and 1.63 ng/mL (reference value, b 0.012 ng/mL), respectively. On the fourth day of the hospitalization, CKMB mass was 2.6 ng/mL and troponin I was 0.67 ng/mL.

Discussion

Intravenous lipid emulsion is used traditionally for parenteral nutrition treatment. However, recently, it is known as a new lifesaving treatment of lipophilic drug intoxications. The first clinical study with ILE treatment of systemic toxicity from local anesthetics was reported by Rosenblatt in 2006 [4,5]. After the reports in local anesthetic toxicity, ILE treatment was used in other lipophilic drug intoxications in animal models. Recent reported cases of successful resuscitation indicate the efficacy of ILE treatment in a wide spectrum of drug intoxications such as ?-blockers, Calcium-channel blockers, parasiti- cides, herbicides, and several varieties of psychotropic agents [6]. Our case series involved 5 patients with ingestion of amitriptyline, 1 patient with metoprolol ingestion, 1 patient with nifedipine ingestion, 1 patient

with lamotrigine and sertraline ingestion, 1 patient with quetiapine ingestion as a suicide attempt, and also a patient with smoking bonsai. For different types of toxications, different outcomes were attained (Table).

In 1998, Weinberg [7] presented the “lipid sink” phenomenon,

which is the most widely accepted mechanism of action for ILE treatment. Intravenous lipid emulsion forms a lipid phase, and then a toxic drug passes from tissue to the aqueous plasma phase afterward to the lipid phase. When free drug diffuses into the lipid compart- ment, this creates a concentration gradient that removes drug from the tissues into the plasma. This reduction in tissue drug concentra- tion would then lead to reduced toxicity [8]. Supporting this hypothesis, ILE can also reverse neurologic signs and symptoms of lipophilic drug intoxications, including seizures and altered mental status, and the efficacy is not limited to cardiovascular system [5]. In our case series, according to the drug, not only blood pressure and pulse rate but also GCS score were improved after the ILE treatment. Sepehrian [9] also reported that in lipophilic non-local anesthetic drug intoxications ILE can increase GCS score. On the other hand, in a study using rabbits (Kazemi et al) [10], ILE actually increased the depth of anesthesia when infused immediately after the lipophilic barbiturate thiopental. The finding of Kazemi et al suggest that in some situations, ILE can behave as a “lipid subway” transporting drug into critical tissues instead of as a lipid sink into which toxic concentrations of drug can be made to “disappear” [8].

As another mechanism, ILE has been shown to open Voltage-gated calcium channels, increasing passage through them, which would lead to increased contractility in cardiac myocyttes. It is possible that the hemodynamic effects of ILE are partially due to its direct positive inotropic effect [8].

At toxic amitriptyline levels, membrane-bound sodium channels in conductive tissues such as nerve cells and cardiac sodium channels are blocked, resulting in neurotoxicity and cardiotoxicity. Sudden deterioration and tachyarrhythmias are common, with torsades des pointes occurring less frequently [8]. In our case series, in amitriptyline intoxications, patients’ rhythms on ECG were sinus tachycardia. The blood pH affects the dissociation of weak bases as amitriptyline. In acidotic conditions (pH b 7.35), weak bases are ionized to a higher degree, and as a result, their Lipid solubility and capacity to pass through lipid bilayers decrease. Prompt correction of acidosis is the main component of the treatment of amitriptyline intoxication. In amitriptyline intoxications, certain mechanism by which increasing pH ameliorates toxicity is unclear [8]. In case 9, blood pressure and pulse rate were improved; however, the GCS score of the patient was not improved and she was intubated because of unconsciousness. Her blood pH was 6.8 mL/dL at the arrival. In this case, it was considered that acidotic pH or the lipid subway phenomenon can be the reason for the ineffectiveness of ILE infusion. Litonius [8] reported that there was no significant difference between the lipid group and the control group in amitriptyline toxicity in pigs, with lipid infusion. However, he also mentioned that there is a significant difference between species in the efficacy of the lipid treatment, and no single animal model sufficiently reflects human physiology.

Recommended protocol is 1.5 mL/kg, or 100 mL 20% lipid bolus,

with subsequent 0.25 to 0.5 mL kg-1 min-1 infusion [11]. There is not a consensus about the infusion dose and time. In our case series, ILE was initiated as 100 mL bolus to all patients, afterward infusion for 2 hours at dose 0.5 mL kg-1 min-1 in 8 patients and 0.25 mL kg-1 min-1 in 2 patients. For the reason that different physicians treated each patient and physicians’ recent experiences in complications of ILE increased, applied infusion doses of ILE treatment were also in different values.

Adverse reactions reported in the literature are limitations in blood tests, Allergic reactions, and fat overload syndrome, inducing hepatosplenomegaly, jaundice, seizures, fat embolism, and

Table

Outcomes for ILE treatment of lipophilic drug toxications

Case

Drug

ILE dose (for 2 h),

Improvement in

GCS (before/after ILE)

Improvement in BP

Improvement in PR

Time between starting ILE and

Troponin elevation

specific complications related to ILE

Result

mL kg-1 min-1

initial improvement

of signs and symptoms

1

Amitriptyline

0.5

+ (10/14)

+

1 h

Discharged

2

Amitriptyline

0.5

+ (7/9)

+

45 min

Discharged

3

Metoprolol

0.5

+

+

2 h

+ Hyperamylasemia

Discharged

and urine color change

4

Nifedipine,

0.5

+

+

2 h

+ ILE-related infiltration

Discharged

fluoxetine,

in lungs and urine

alprazolam

color change

5

Quetiapine

0.5

+ (13/15)

+

+

2 h

Discharged

6

Lamotrigine,

0.5

+ (12/14)

1 h

Discharged

sertraline

7

Bonsai

0.5

+ (12/15)

+

+

2 h

Discharged

8

Amitriptyline

0.5

+ (12/14)

+

+

1 h

Discharged

9

Amitriptyline

0.25

+

+

20 min

+

Exitus

10

Amitriptyline

0.25

+ (8/13)

1 h

+

Discharged

BP: blood pressure; PR: pulse rate.

coagulopathies [12]. Previous studies have shown that large volumes of high concentration of lipid infusion during parenteral nutrition have resulted in pulmonary complications. On the other hand, studies in rodents have shown reduced resistance to bacterial pathogens with parenteral lipid administration. Also, there are case reports detailing the occurrence of asymptomatic hyperamylasemia after ILE use; nevertheless, most authors have not reported any adverse events associated with lipid therapy. The Association of Anaesthetists of Great Britain and Ireland recommends the monitoring of the patient and biochemical markers for the development of pancreatitis posttreatment with intravenous lipids. However, ILE can cause analytical interference, with various tests including hematologic and biochemistry assays; the extent of the interference depends on the test and analyzer used [1]. This is the most frequent complication encountered and makes the patient’s follow-up difficult. Thus, ideally, samples should be taken prior to intravenous lipid therapy, and for those taken after, they should be fully discussed with the pathology laboratory [1] (a specific filter can be used). In our case series, all patients’ laboratory tests interfered because of the lipemia within periods of 6 to 20 hours.

Our case series involved 2 patients with specific complications after the ILE treatment. In one patient, amylase and lipase values were increased and she was hospitalized with the diagnosis of minimal change pancreatitis. If there are risk factors for hypertriglyceridemia or if the rate of the ILE infusion exceeds the capacity of lipoprotein lipase to eliminate triglycerides, then hypertriglyceridemia may be formed by ILE treatment and it may cause pancreatitis [13]. In our case, on the second day of the hospitalization, the amylase and lipase values regressed. In the other patient, probable ILE treatment-related fat infiltration occurred in lungs and subsequent day fat infiltration image in the chest radiography also regressed (Fig. 3b). Pulmonary effects of ILE are thought to be due to hyperlipidemia. According to the rate, triglyceride concentrations increase with even a single dose of ILE treatment. It is known that ILE has an effect on PaO2, and this effect is explained by ventilation/perfusion inequalities, which result from prostaglandins generated from low-chain triglycerides containing ILEs. In a study, pulmonary effects were decreased by slowing the infusion rate [13]. In our case series, according to the protocol, ILE was infused fast; therefore, it may be the reason pulmonary adverse effects occurred. It was considered that with starting ILE infusion at lower doses (0.25 mL kg-1 min-1), a number of complications related to ILE treatment may decrease.

In addition, in 2 patients who had taken different drugs, the urine was reddish (Fig. 2). It was considered as a side effect of the ILE treatment. However, such a urine reaction is not mentioned in the

literature as a side effect. Levine et al [14] reported that 6 patients experienced ILE-related complications in a group of 9 patients receiving ILE treatment. laboratory interference was observed in 4 patients, pancreatitis developed in 2 patients, and adult respiratory distress syndrome developed in 3 patients.

In our case series, in 2 patients who had taken amitriptyline, there was divergence. After the ILE treatment, divergence regressed. In another 2 patients, Troponin I levels were increased, probably related to the drugs ingested, and 1 of these 2 patients who admitted with amitriptyline intoxication was exitus. This patient’s blood pressure and pulse rates were improved after the ILE treatment in the ED; however, ILE treatment was not continued after the admission to the ICU. It was considered as one of the reasons of the deterioration of the patient’s state. The other reasons considered were acidotic blood pH and lipid subway phenomenon.

Two patients presented with multiple drug intoxication. One of them had taken an unknown amount of fluoxetine hydrochloride, alprazolam, and nifedipine tablets. In this patient, it was considered that the neurologic findings were the result of fluoxetine hydrochloride and alprazolam, and there was no improvement in GCS score because ILE was not effective on these drugs. However, cardiac symptoms due to nifedipine regressed because nifedipine is a lipophilic drug. In the other patient with lamotrigine and sertraline intoxication, myoclonia was considered the result of lamotrigine; however, changes in the consciousness were considered the effect of both lamotrigine and sertraline. Both drugs were lipophilic, and the patient benefited from ILE treatment (myoclonia regressed and consciousness improved). In addition, because maximum plasma concentration of lamotrigine occurs from 1.4 to 4.8 hours and that of sertraline occurs from 4.5 to 8.4 hours [15], ILE treatment was initiated before the full toxic effects of lamotrigine and sertraline appeared.

The American College of Medical Toxicology Position Statement on use of ILE rests the decision to initiate Lipid resuscitation therapy solely on the discretion of the treating physician; however, they consider it a reasonable treatment option in cases where serious hemodynamic or other instability from a xenobiotic with a high degree of lipid solubility exists, even if the patient is not in cardiac arrest [16]. In our case series, ILE treatment was initiated in the early period after the arrival of the patient to the ED. For the reason that complications were related to ILE, it was considered that ILE infusion dose can be initiated at 0.25 mL kg-1 min-1, and depending on the patient’s response, infusion dose can be increased to 0.5 mL kg-1 min-1 for persistent Cardiovascular collapse. However, in patients with severe toxicity or cardiac arrest, initial infusion dose can be set at

0.5 mL kg-1 min-1 according to a risk-benefit analysis. In addition,

because there are no human studies with comparison of conventional therapies and ILE treatment, both treatment modalities should be performed at the same time in lipophilic drug intoxications.

In our case series, ILE was used for different lipophilic drug intoxications to improve cardiovascular and neurologic symptoms. Satisfactory results were achieved (Table). According to these results, it was found that ILE treatment is a lifesaving agent in lipophilic drug intoxications and can be used in unconscious patients who have cardiac and/or neurologic symptoms, but no history of a specific drug ingestion.

Acknowledgments

I would like to express my great appreciation to Emine Gaffari, Ozlem Tosun Giritli, and Seckin Bahar Sezgin for sharing the data of their patients.

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