Tacon on Lipid Rescue Therapy
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Transcript of Tacon on Lipid Rescue Therapy
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 …