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

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

2 Conflict of interest None

3 Overview Local anesthetic systemic toxicity (LAST) Background Prevention & Recognition Rescue strategies Take home messages

4 Local anesthetic systemic toxicity Neurological toxicity Cardiac toxicity CNS toxicity threshold: Bupivacaine 0.3 mg/l; Ropivacaine 0.6 mg/l 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? Reg Anesth Pain Med 2004; 29:564-75

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) EJA 2014; 31:575

7 Local anesthetic systemic toxicity Time course of LAST 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 Reg Anesth Pain Med 2010;35:152-61

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 / O 2 / Air Intubated and artificially ventilated J Anesth. 2011; 25:710-5.

10 Injection rate Group 1 (n=15) Group 2 (n=15) Group 3 (n=15) Injection speed (mg/kg/min) Time (s) until MAP 50% 297* 119* 65* Total amount bupivacaine (mg/kg) 5.0* ( ) 7.8* ( ) 17.0* ( ) Bupivacaine plasma conc. (µg/l) 54* (41-102) 180* ( ) 439* ( ) 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) (30-296) 21 (10-123) * p<0.001 J Anesth. 2011; 25:710-5.

11 Injection rate Plasma-bupivacaine / bupivacaine ratio Group A: 11.2 ( ) Group B: 18.8 ( ) Group C: 25.9 ( ) Disproportionately high bupivacaine plasma concentrations with faster injection 5 of 15 piglets in slow injection rate group spontaneously recovered J Anesth. 2011; 25:710-5.

12 Injection rate FAST Disproportionately high plasma concentrations Increased mortality SLOW Increases therapeutic safety J Anesth. 2011; 25:710-5.

13 Intravascular marker Preferred marker in paediatric anaesthesia: Epinephrine ST-T-wave changes with unintentional intravascular injection of bupivacaine with epinephrine in infants Anesthesiology 1993; 79:394 T-waves controversial in the literature Caused by LA or by epinephrine? Sensitivity / reliability? Anesth Analg 2001; 93:1156

14 Intravascular marker n=15 per group 2-6 weeks of age, weighing 4-6 kg Anaesthetized with sevoflurane / O 2 / Air Intubated and artificially ventilated Br J Anaest 2010;

15 Intravascular marker Bupivacaine 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 # *p<0.001 between group 1 and 2, # p<0.001 between group 1 and 3 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 # ECG changes caused by epinephrine Br J Anaest 2010;

16 Intravascular marker Ropivacaine Pre-injection After injection of test solution RA Delta heart rate (min -1 ) Delta mean arterial pressure (mmhg) Ropivacaine Ropi + Epinephrine ECG changes caused by epinephrine Ropivacaine Ropi + Epinephrine Paediatr Anaesth 2013; 23: 144

17 Intravascular marker Children Bupivacaine 0.125% Bupivacaine 0.125% + epinephrine 5 µg/ml Epinephrine 5 µg/ml Positive intravascular test dose criteria in children: T-wave: 25% HR: 10 bpm BP syst.: 15 mmhg n =105 Age: years Test dose: 0.2 ml/kg iv BJA 2012; 108: 283

18 Intravascular marker 6/12 Combination of T-wave and HR allows detection of an epinephrine-containing test dose with a 100% reliability BJA 2012; 108: 283

19 Intravascular marker Increase in Heart rate Sevoflurane anaesthesia 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

20 Intravascular marker Increase in Heart rate Blood pressure T-wave elevation? Propofol TIVA Following intravenous injection of a bupivacaine test dose are caused by epinephrine. Add epinephrine to test dose in anaesthetized child

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 Anesth Analg 2010; 110:41

22 Intravascular marker Children Propofol/ Remifentanil TIVA Test dose: Bupivacaine 0.25% 0.1ml/kg + epinephrine 5 µg/ml Positive intravascular test dose criteria in children: T-wave: 25% HR: 10 bpm BP syst.: 15 mmhg Anesth Analg 2010; 110:41

23 Intravascular marker Increase in Heart rate Propofol TIVA Blood pressure T-wave elevation X Following intravenous injection of a bupivacaine test dose are caused by epinephrine. Add epinephrine to test dose in anaesthetized child

24 Resuscitation Ventilation Oxygenation Effective CPR Lipid Rescue TM Mechanism of action not clearly elucidated (Lipid sink/ improved oxidation of fatty acids) Other non-anaesthetic poisening

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??? lipid emulsion, epinephrine, CPR

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 / O 2 / Air Tracheally intubated and artificially ventilated Paediatr Anaesth 2011: 1103

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) 2-6 weeks of age, weighing 4-6 kg Anaesthetized with sevoflurane / O 2 / Air Tracheally intubated and artificially ventilated 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 BJA 2014; 112: 729

29 Rescue strategies Resuscitation per group Control (n=7) Lipid (n=9) Epinephrine (n=7) Lipid + epinephrine (n=10) Died Survived Effective CPR and haemodynamic support BJA 2014; 112: 729

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 2-6 weeks of age, weighing 4-6 kg Anaesthetized with sevoflurane / O 2 / Air Tracheally intubated and artificially ventilated Survival Course of haemodynamics? Paediatr Anaesth 2012: 22: 124

31 Rescue strategies Epinephrine (n=7) Lipid (n=7) Lipid + Epinephrine (n=7) Lipid+ Vasopressin (n=7) Survival ROSC due to study medication ROSC due to epinephrine rescue 10 µg/kg Paediatr Anaesth 2012: 22: 124

32 Rescue strategies Ongoing cardiovascular support (epinephrine 3mcg/kg) Epinephrine support required: Epinephrine (n=5) Lipid (n=2) Lipid + Epinephrine (n=6) Lipid+ Vasopressin (n=4) 0x x x Paediatr Anaesth 2012: 22: 124

33 First line treatment??? lipid emulsion, epinephrine, CPR 1. CPR maintain perfusion 2. Epinephrine support circulation 3. Lipid emulsion possibly influence outcome

34 Protocols LAST - Lipidrescue R

35 Protocols LAST - AAGBI

36 Summary

37 APA - SPA joint meeting Aberdeen, Scotland th May

38 Thanks to Dr Jacqueline Mauch, Luzern and copies of talk:

39

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