Fat Chance … or Passing Fad?:

Lipid Rescue Therapy

Cath Tacon

Suicide Attempt1: 17 yo, 55kg ♀

PMHx: bipolar and ADHD Meds: mixed salts of amphetamine,

bupropion, lamotrigine Missing pills: 7.95g bupropion, 4g lamotrigine

ED 6hrs after ingestion: BP 123/77, HR 116bpm, Sats 100% 15LNRBM, RR 14 GCS 6 (withdrawal) CXR - NAD

1Sirianni et al, Ann Emerg Med. 2008

Initial ECG

Sirianni et al, Ann Emerg Med. 2008

Initial ECG: Na channel blockade

Sirianni et al, Ann Emerg Med. 2008

ED to ICU

Supportive therapy x 3hrs (NPA, NRBM, IVF) Some eye opening

Transferred to ICU – 10 hours post ingestion Tonic-clonic seizure then PEA VT VF Initial 18 minutes:

ETT Defibrillated x 11 1mg adrenaline x 6 300mg amiodarone 1g MgS04

No ROSC

NaHCO3 50mEq/L

ROSC within 2 minutes BP 84/55, HR 97bpm

Sirianni et al, Ann Emerg Med. 2008

ROSC x 17 minutes … Further PEA Further interventions:

Transcutaneous pacing (unsuccessful) 1mg adrenaline x 12 50mEq NaHCO3 x 2 1g CaCl Continuous infusion high-dose adrenaline +

noradrenaline ABG at 10 minutes:

pH 7.252, pCO2 46.6mmHg, pO2 48.1mmHg, HCO3 20.1mEq/L

No sustained ROSC 200mL bright red blood ETT

52 minutes into 2nd period of ACLS: 100mL bolus 20% lipid emulsion (Intralipid) 1 minute later: sustained palpable pulse

Sirianni et al, Ann Emerg Med. 2008

So …

Were lipids the cure …?

How it Started 16 yo 60kg patient1 - 22mg s/c bupivacaine

(0.37mg/kg < 2mg/kg) Ventricular dysrythmias and hypotension Subsequently discovered to have severe systemic

carnitine deficiency

? Hypothesis that bupivacaine inhibited a carnitine-dependent step in fatty-acid metabolism Subsequently confirmed to inhibit mitochondrial

carnitine exchange inhibition of fatty acid oxidation

1Weinberg et al. J Clin Anesth. 1997.

Intravenous Lipid Emulsion Animal studies:

Examined use of intravenous lipid emulsion (ILE) in bupivacaine cardiotoxicity

Pre-treatment with ILE protected from lethal effects of systemic bupivacaine

Further studies showed that ILE given during resuscitation (ie post-treatment with LA) improved outcomes from bupivacaine-induced asystole

Local Anaesthetic Systemic Toxicity (LAST) in Humans Rosenblatt et al, 20061:

1st case report of ILE treating local anaesthetic systemic toxicity (LAST)

58 yo ♂ bupivacaine/mepivacaine brachial plexus block for arthroscopic rotator cuff repair Seizures followed by VT/asystole unsuccessful

resuscitation x 20 minutes; planned for cardiopulmonary bypass

Trial of 100mL 20% intralipid ROSC Intralipid continued at 0.5mL/kg/min x 2hours then

discontinued Extubated without neurological sequelae

1Rosenblatt et al. Anesthesiology 2006.

1st guidelines for use of ILE in local-anaesthetic induced cardiac arrest published in 2007

Mechanism: ‘Lipid Sink’ Phenomenon

Lipid emulsion infusion expanded lipid phase

Lipophilic substances (eg LA) are drawn into ‘lipid sink’ concentration gradient develops between tissue and blood

Drives toxic drug from tissue aqueous plasma phase lipid phase

‘Lipid Sink’ – Evidence?

Indirect: Lipids can reverse both neurological and cardiac toxicity of LA Has been reported to reverse toxicity in a range of drugs lacking

a common mechanism, site of action, chemical structure or clinical effect only common factor of high lipid solubility

Animal studies: Shown lower tissue phase of drugs post lipid emulsion solutions

But … Healthy volunteers given small dose of bupivacaine – no

difference in free bupivacaine concentration post lipid infusion

Alternate Mechanisms: Metabolism

Fatty acids = heart’s preferred energy substrate for oxidative phosphorylation under normal aerobic conditions:

LA block fatty acid transport and oxidation ↓ATP production

Lipid emulsion therapy theoretically increases intracellular fatty acid concentration

ILE may also directly increase intramyocyte Ca++ levels +ve inotropic effect

Are all Lipids Equal?

Different ILE preparations have varying fatty acid composition

Intralipid: Soy-based, long-chain fatty acid emulsion Used in most studies Theoretical advantage in binding capacity

Other preparations with medium chain fatty acids: In at least 2 case reports Yet to have head-to-head studies for clinical efficacy

Safety and Side Effects

Theoretical risks: Infections, thrombophlebitis with peripheral

administration, fat emboli, allergic reactions, drug interactions…

Reported adverse effects: Interference with laboratory studies due to lipaemia

Several hours only

Hyperlipidaemia-induced pancreatitis ARDS

Probably multi-factorial

Use in Other non-LA Toxicological Emergencies

1st case report in 2008: Bupropion and lamotrigine overdose

Since then case reports of use in: Ca++ channel blockers (verapamil, diltiazem, amlodipine) B-blockers (propanolol, atenolol) TCAs (imipramine, amitriptyline, doxepin, dothiepin) Anti-psychotics (quetiapine, haloperidol, lamotrigine, olanzapine) Anti-depressants (sertraline, venlafaxine) Glyphosate herbicide Ivermectin (in a Border Collie and miniature Shetland Pony)

Ca-channel Blockers

Verapamil, nifedipine, diltiazem all lipophilic Experimental evidence:

Verapamil in rats: prolonged survival Verapamil in dogs: prolonged survival Nifedipine in rats: no benefit

Clinical Experience: Several peer reviewed case reports

Maybe …

B-blockers

Propanolol more lipophilic than metoprolol Experimental evidence:

Propanolol: no evidence of benefit (MAP or survival time) Metoprolol: no evidence of benefit (MAP)

Case Reports: 2 peer-reviewed case reports

Propanolol and propanolol + EtOH

Abstracts Atenolol

Jury still out

TCAs

Lipophilic Experimental evidence:

Rabbits: faster haemodynamic recovery Rats: no benefit

Clinical evidence: Several case-reports

Varying results, haemodynamic improvement in some, not all

Recommendations?

Established role in local anaesthetic toxicity with cardiovascular collapse 20% lipid emulsion 1.5ml/kg over 1 minute

(100mL in 70kg) Infusion at 15ml/kg/hr

(1L/hr in 70kg) Maximum cumulative dose = 12mL/kg

(840ml in 70kg) Cease when cardiovascularly stable or maximum

dose given

Recommendations?

Other lipophilic drug toxicities with haemodynamic instability despite standard therapy?

Consider Intravenous Lipid Emulsion

But maybe it’s just a fat chance …