Ignacio Cortínez Anesthesiology Department School of Medicine, Pontificia Universidad Católica de Chile

Transcription

1 Recommended doses of Levobupivacaine for TAP Blocks: Development of a pharmacokinetic model and estimation of the risk of symptoms of local anesthetic systemic toxicity Ignacio Cortínez Anesthesiology Department School of Medicine, Pontificia Universidad Católica de Chile

2 Pain as a disease Postoperative Pain Management, Regional blocks and local anesthetic toxicity How we have applied pharmacometrics to guide Local Anesthetics dose selection in transversus abdominal plane (TAP) blocks

3 Pain The French physician, Dr. Albert Schweitzer, proclaimed in 1931 that, Pain is a more terrible lord of mankind than even death itself. Pain affects more people than diabetes, heart disease and cancer combined. Is the most common cause of long-term disability and a major contributor to health care costs.

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5 PATHOPHYSIOLOGY OF POSTOPERATIVE PAIN Surgical incision is a traumatic event triggering profound sympathetic and inflammatory responses. The inflammatory response activates peripheral nociceptors that transmit nociceptive signals centrally amplifying the inflammatory process. 10% of patients develop chronic pain after surgery

6 Postoperative Pain Treatment There are different methods to treat post-surgical pain including Systemic analgesic options (e.g. opioids, non-steroidal anti-inflammatory agents) Regional analgesic options (e.g. local anesthetics)

7 Regional Blocks Are highly effectively methods to block sympathetic and inflammatory responses from surgery Can help to reduce the risk of chronic pain after surgery Risks Nerve injury Bleeding Local anesthetic toxicity Surg Clin North Am. 2015

8 Local Anesthetics Toxicity Occur on the order of 1:1000 blocks Result from: Direct injection of drug into the vascular space symptoms then occur within a few minutes Absorption from tissue depot symptoms delayed by many minutes, or even hours Dose LA used Site of injection Patient factors Epinephrine

9 TAP BLOCK transversus abdominis plane (tap)block Ultrasound view

10 TAP BLOCK transversus abdominis plane (tap)block Ultrasound view

11 TAP Blocks and Toxicity. Requires a large volume of local anesthetic solution Current recommended doses for levobupivacaine of 3 mg/kg with epinephrine or 2.5 mg/kg without epinephrine are not supported by any formal PK analysis.

12 TAP Blocks and Toxicity. High plasma levels of LA and systemic toxicity cases have been reported using standard doses of ropivacaine and levobupivacaine. Griffiths JD. Br J of Anaesth Torup H. Eur J Anaesthesiol Weiss E. RAPM 2014

13 We perform a study to characterize levobupivacaine absorption pharmacokinetics, with and without epinephrine, and estimate the risk of toxicity, based on a previously reported toxic threshold. Eur J Clin Pharmacol Jul 14

14 Toxic thresholds animals studies

15 14 healthy subjects intravenous infusion until the appearance of early symptoms of CNS toxicity Cmax was 2.62 mcg/ml

16 Methods 11 healthy male volunteers in a 2- periods crossover study. Unilateral TAP block with 20 ml of 0.25% levobupivacaine with or without epinephrine (5 µg/ml). Serial levobupivacaine venous plasma concentrations were measured at 2, 5, 10, 30, 45, 60, and 90 minutes after completing the blockades using high-performance liquid chromatography.

17 Methods One anesthesiologist experienced in the technique performed all of the TAP blocks under ultrasound (US) guidance A second anesthesiologist evaluated and approved the US images before administration of the mixture

18 PK Analysis We used a 1-compartment first order input and elimination model to fit the data in NONMEM Parameters were scaled to weight using allometric relationships. Pi = P TVSt W i 70 PWR The PWR exponent was 3/4 for CL, 1 for V, and 1/4 for T abs

19 PK Analysis The analysis of covariates included the use of epinephrine in TAB and Bioavailability. The quality of fit was judged using NONMEM s objective function value (OFV), and visual predictive checks (VPC) plots.

20 Results The one-compartment first-order input and elimination model adequately fit the levobupivacaine data The effect of epinephrine on T abs (OFV ) and on bioavailability (OFV ) were included.

21 PK parameter estimates Estimate Bootstrap 95%CI PPV (%) Estimate Vd (L/70 kg) CL (L/min/70 kg) Tabs (min/70 kg) Without epinephrine With epinephrine F Without epinephrine 1 FIX With epinephrine Additive residual Error (mcg/ml) Proportional Residual Error (%)

22 Quality of fit (VPC) With epi Without epi

23 Simulated Cmax (1000) for standard levobupivacaine doses The red dashed line is the mean C max The black line is the 99 th percentile of the C max distribution The dashed blue line represents the toxic concetration value of 2.62 µg ml -1

24 Simulation Doses $SIMULATION SUBPROBLEMS=1000 With Epinephrine (5mcg/ml) 1.5 mg/kg. 2.0 mg/kg. 2.5 mg/kg. 3.0 mg/kg. 3.5 mg/kg. Without Epinephrine 1.5 mg/kg. 2.0 mg/kg. 2.5 mg/kg. 3.0 mg/kg. 3.5 mg/kg. Risk of LAST (Cmax > 2.62 mcg/ml)* *Bardsley H, Br J Clin Pharmacol. 1998

25 Simulation Dose (mg*kg -1 ) With epinephrine Without epinephrine 1.5 0% (0%-3%) 0.1% (0%-40%) 2.0 0% (0%-23%) 1.1% (0.1%-70%) 2.5 0% (0%-53%) 5.5% (1%-87%) % (0%-78%) 13.3% (2.5%-95%) % (0%-90%) 27.2% (5.7%-98%) Risk estimation (%) considers the mean estimated levobupivacaine concentration (2.62 mg ml 1) at which LAST sympoms occurred and the interindividual reported variability in the reported Cmax values (range mg ml 1).

26 Conclusion This study adds new information to guide levobupivacaine dose selection in TAP blocks. Our results strongly support the addition of epinephrine to levobupivacaine solution in bilateral TAP blocks.

27 Thank you for your attention