Local Anaesthetic Systemic Toxicity. Dr Thomas Engelhardt, MD, PhD, FRCA Royal Aberdeen Children s Hospital, Scotland

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Dr Thomas Engelhardt, MD, PhD, FRCA Royal Aberdeen Children‘s Hospital,

Scotland

Local Anaesthetic

Systemic Toxicity

(2)

Conflict of interest

(3)

Overview

Local anesthetic systemic toxicity (LAST)

•  Background

•  Prevention & Recognition

•  Rescue strategies

(4)

Local anesthetic systemic toxicity

Neurological toxicity Cardiac toxicity

Br J Anaesth. 1997; 78:507-14

(5)

Local anesthetic systemic toxicity

Mechanisms of LAST

Inadvertent intravascular injection

Rapid absorption into circulation

Co-morbidity: renal, hepatic, cardiac disease, end-stage pregnancy Individual disposition, extremes of age

•  ?

(6)

Local anesthetic systemic toxicity

Time course of LAST

•  Instant – IV injection (few circulation times, CVS collapse) •  Instant – arterial injection (seizures, no CVS collapse)

•  Delayed – excessive plasma concentrations (< 30min)

(7)

Local anesthetic systemic toxicity

EJA 2014; 31:575

(8)

Prevention

•  Administer lowest effective dose (I;C) •  Ultrasound guidance (II;C)

•  Aspirate needle/catheter before/during injection (I;C) •  Use slow injection rate (I;C)

•  Use of an intravascular marker (II;B)

No single technique can prevent LAST

(9)

Injection rate

Animal studies – piglets

•  Bupivacaine iv until MAP was reduced by 50%

•  1 mg/kg/min (Group 1)

•  4 mg/kg/min (Group 2) •  16 mg/kg/min (Group 3)

Outcome measures

•  Total amount of bupivacaine

Bupivacaine plasma concentration

Spontaneous course of haemodynamics?

n=15 per group

•  2-6 weeks of age, weighing 4-6 kg •  Anaesthetized with sevoflurane / O₂ / Air •  Intubated and artificially ventilated

(10)

Injection rate

Group 1 (n=15) Group 2 (n=15) Group 3 (n=15) Injection speed (mg/kg/min) 1 4 16 Time (s) until MAP 50% 297* 119* 65*

Total amount bupivacaine (mg/kg) 5.0* (3.1-24.4) 7.8* (5.5-12.9) 17.0* (12.0-20.0) Bupivacaine plasma conc. (µg/L) 54* (41-102) 180* (103-686) 439* (245-693) Bupivacaine plasma conc : amount 11 (3-22) 21 (14-61) 26 (16-41) Survival (yes/no) 5 / 10 0 / 15 0 / 15

Time until circulatory arrest (s) 78-∞ 120 (30-296) 21 (10-123)

* p<0.001

(11)

Plasma-bupivacaine / bupivacaine ratio

Group A: 11.2 (2.9 - 22.2) Group B: 18.8 (12.3 - 60.9) Group C: 25.9 (16.2 - 41.2)

Injection rate

5 of 15 piglets in slow injection rate group spontaneously recovered Disproportionately high bupivacaine plasma concentrations with faster injection

(12)

Injection rate

FAST

Disproportionately high plasma concentrations

Increased mortality

SLOW

Increases therapeutic safety

(13)

Intravascular marker

•  Preferred marker in paediatric anaesthesia: Epinephrine

•  ST-T-wave changes with unintentional intravascular injection of bupivacaine with epinephrine in infants

•  T-waves controversial in the literature •  Caused by LA or by epinephrine ? •  Sensitivity / reliability ?

Anesthesiology 1993; 79:394

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Intravascular marker

Br J Anaest 2010;104 94-7 n=15 per group

•  2-6 weeks of age, weighing 4-6 kg •  Anaesthetized with sevoflurane / O₂ / Air •  Intubated and artificially ventilated

(15)

Intravascular marker

Test dose 0.2 ml/kg Bupivacaine Bupi + Epi Epinephrine

ΔHR (bpm) -7 (-18-12) 89 (27-116)* 86 (73-127) #

ΔHR (%) -5.4 (-13-9) 74 (17-101)* 74 (42-123) #

T-elevation (yes/no) 1/14 14/1* 14/1#

Test dose 0.4 ml/kg Bupivacaine Bupi + Epi Epinephrine

ΔHR (bpm) -8 (-16-0) 100 (60-132)* 102 (83-140) #

ΔHR (%) -7 (-13-0) 87 (42-112)* 78 (55-117) #

T-elevation (yes/no) 4/11 15/0* 15/0 #

*p<0.001 between group 1 and 2, #_{p<0.001 between group 1 and 3}

ECG changes caused by epinephrine

Br J Anaest 2010;104 94-7

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-40 -20 0 20 40 60 80 100 120 140

Delta heart rate (min-1₎

-20 0 20 40 60 80 100

Delta mean arterial pressure (mmHg)

Ropivacaine Ropi + Epinephrine

Pre-injection After injection of test solution RA Paediatr Anaesth 2013; 23: 144 Ropivacaine

Intravascular marker

ECG changes caused by epinephrine

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Intravascular marker

Children •  Bupivacaine 0.125% •  Bupivacaine 0.125% + epinephrine 5 µg/ml •  Epinephrine 5 µg/ml n =105 Age: 0.2-16 years Test dose: 0.2 ml/kg iv Positive intravascular

test dose criteria in children:

T-wave: ≥ 25% HR: ≥ 10 bpm BP syst.: ≥ 15 mmHg

(18)

Combination of T-wave and HR allows detection of an epinephrine-containing test dose with a 100% reliability

Intravascular marker

6/12

(19)

Intravascular marker

Increase in

•  Heart rate

•  Blood pressure •  T-wave elevation

Following intravenous injection of a bupivacaine test dose are caused by epinephrine.

Add epinephrine to test dose in anaesthetized child

Sevoflurane anaesthesia

(20)

Intravascular marker

Increase in

Add epinephrine to test dose in anaesthetized child

? Propofol TIVA

(21)

Intravascular marker

Children

•  Propofol/ Remifentanil TIVA

•  Test dose: Bupivacaine 0.25% 0.1ml/kg + epinephrine 5 µg/ml _{n =17}

Age: 11/12 -11 years ASA-PS: 1/2

(22)

Intravascular marker

Children

•  Propofol/ Remifentanil TIVA

•  Test dose: Bupivacaine 0.25% 0.1ml/kg + epinephrine 5 µg/ml

Anesth Analg 2010; 110:41

Positive intravascular

test dose criteria in children:

T-wave: ≥ 25% HR: ≥ 10 bpm BP syst.: ≥ 15 mmHg

(23)

Intravascular marker

Increase in

Add epinephrine to test dose in anaesthetized child

Propofol TIVA

(24)

Resuscitation

Ventilation Oxygenation Effective CPR

Lipid Rescue

TM

Mechanism of action not clearly elucidated

(Lipid sink/ improved oxidation of fatty acids)

(25)

Lipid Rescue

TM

Case reports with encouraging results Risks

Fat embolism? Pancreatitis? Overestimation as „magic bullet“

Losing sight of standard resuscitation therapy

First line treatment

(26)

Animal studies – piglets (7 per group)

•  Bupivacaine iv (1mg/kg/min) until MAP was reduced by 50%

•  Epinephrine 3mcg/kg (Group 1) •  Intralipid 20% 2ml/kg (Group 2) •  Intralipid 20% 4ml/kg (Group 3) Outcome measures •  Survival •  Course of haemodynamics?

•  2-6 weeks of age, weighing 4-6 kg •  Anaesthetized with sevoflurane / O₂ / Air •  Tracheally intubated and artificially

ventilated

(27)

Rescue strategies

Group 1: Epinephrine 3 µg/kg Group 2: Intralipid®_{20% 2 ml/kg} Group 3: Intralipid®_{20% 4 ml/kg} No chest compressions.. Paediatr Anaesth 2011: 1103

(28)

Animal studies – piglets (33 total)

•  Bupivacaine iv (8.3mg/kg/min) until MAP was reduced by 50%

•  Control (Group 1)

•  Intralipid 20% 4ml/kg plus infusion (0.25ml/kg/min) (Group 2) •  Epinephrine 10mcg/kg every 3 min (Group 3)

•  Intralipid 20% plus Epinephrine (Group 4)

Outcome measures •  Survival

•  Duration of CPR to achieve ROSC

ventilated

(29)

Rescue strategies

Effective CPR and haemodynamic support

Control (n=7) Lipid (n=9) Epinephrine (n=7) Lipid + epinephrine (n=10)

Resuscitation per group

Died 6 2 1 0

Survived 1 7 6 10

(30)

Animal studies – piglets (7 per group)

•  Bupivacaine iv (1mg/kg/min) until circulatory arrest

•  CPR +100% oxygen

•  Epinephrine 10mcg/kg (Group 1)

•  Intralipid 20% 4ml/kg (Group 2)

•  Epinephrine + Intralipid 20% (Group 3) •  Vasopressin 2IU + Intralipid 20% (Group 4)

Outcome measures •  Survival

•  Course of haemodynamics?

ventilated

(31)

Rescue strategies

Epinephrine (n=7) Lipid (n=7) Lipid + Epinephrine (n=7) Lipid+ Vasopressin (n=7) Survival 5 2 6 4

ROSC due to study

medication 5 0 6 0

ROSC due to epinephrine

rescue 10 µg/kg 0 2 0 4

(32)

Epinephrine support required:

Rescue strategies

Epinephrine (n=5) Lipid (n=2) Lipid + Epinephrine (n=6) Lipid+ Vasopressin (n=4) 0x 2 1 6 3 1x 2 - - - 2x 1 1 - 1

Ongoing cardiovascular support (epinephrine 3mcg/kg)

(33)

First line treatment

??? lipid emulsion, epinephrine, CPR

1.  CPR – maintain perfusion

2.  Epinephrine – support circulation

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APA - SPA joint meeting

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Thanks to

Email and copies of talk: [email protected] [email protected]

Dr Jacqueline Mauch, Luzern

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Local Anaesthetic Systemic Toxicity. Dr Thomas Engelhardt, MD, PhD, FRCA Royal Aberdeen Children s Hospital, Scotland