Esmolol and its Anesthetic Implications

Jonathan Sawers, BSN, SRNA York College of Pennsylvania / Wellspan Health NAP

2 Harless et al. (2015)

3

Addiction

Opioid Side Effects

Objectives

• Discuss the research and evidence on esmolol’s use as

an adjunct to anesthesia

• Describe the proposed physiology and pharmacology of

how esmolol may reduce anesthetic and analgesic

requirements in patients undergoing general anesthesia.

• Identify patient population and procedure types in

which esmolol may be useful as an adjunct.

• Determine appropriate methods of administering esmolol and address economic considerations.

4

Pharmacology • Ultra-short acting cardioselective β1-receptor antagonist

o 34 times higher affinity for β1 then β2-receptor

• Loading Dose – 0.5 - 1 mg/kg

• Infusion Rate – 50 - 300mcg/kg/min

• Rapid onset and short duration o Peak hemodynamic effects 6-10 min

o Distribution half life – 2 minutes

o Elimination half life – 9 minutes

o 55% Protein bound

• Hydrolyzed by esterases within the cytosol of RBCs

• Renal excretion of inactive metabolite (1/1500th potency)

5

Pharmacology • (Classic) Clinical Indications

o Supraventricular Tachycardia (Slows AV Node Conduction)

o Torsade de pointes control in patients with prolonged QTc intervals

o Medical treatment of Aortic Aneurysm or Dissection

o Hypertensive emergency

o Blunt stress response to laryngoscopy & intubation

o Intraoperative and postoperative tachycardia and hypertension

• Contraindications o Heart block

o Heart Failure

o WPW

o Severe pulmonary disease (COPD, asthma)

o Bradycardia and hypotension not caused by RVR

o Pheochromocytoma in absence of alpha-blockade

6

Multimodal Analgesia

7

Propofol Anesthesia • Propofol Induction

o 25% reduction in dose required for loss of response to command

(Wilson et al. 2004)

• Maintenance of anesthesia o 26% reduction in propofol concentration to prevent movement in

propofol / nitrous oxide / morphine based anesthesia

(Johansen et al. 1998)

8

• Some authors attribute this to the

reduction in cardiac output,

redistribution rate, and reduced

hepatic clearance of

concurrently administered

anesthetics and analgesics.

β-Blocker Effects on Pharmacokinetics

• Arm-To-Brain Circulation Time

• Cardiac output inversely related to arterial plasma

concentration

• Reduced rate of redistribution

• Reduced hepatic clearance

9

10

MAC Requirements

11 Chia et al. (2004)

Anesthesia

• Induction: Thiopental, fentanyl, succinylcholine

• Maintenance: Isoflurane, fentanyl, atracurium

Intervention vs. Placebo - double blinded

• Esmolol 0.5 mg/kg Before Induction

• Esmolol 50 mcg/kg/min

12 Chia et al. (2004)

13 Chia et al. (2004)

14 Collard et al. (2007)

Esmolol in Absence of Opioids

Esmolol

• Esmolol 1 mg/kg

with induction

• Esmolol gtt 5-15

mcg/kg/min

titrated to keep HR

within 20% of base

15

Remifentanil

• Remi 1 mcg/kg

with induction

• Remi gtt 0.1 – 0.5

mcg/kg/min

titrated to keep HR

within 20% of base

Control

• Fentanyl 1 mcg/kg

with induction

• Fentanyl boluses

50mcg to keep HR

within 20% of base

Desflurane Requirements

• Titrated to keep BP within 20% of baseline and BIS < 60.

• 4 – 8% to maintain a MAC between 0.7 and 1.2

Control 0.93 ± 0.4

Remifentanil 0.89 ± 0.3

Esmolol 0.95 ± 0.4

Collard et al. (2007)

16

Demographics were similar between

groups

All patients received multimodal

analgesia and PONV prophylaxis o Acetaminophen 1.3g PR

o Ketorolac 30 mg

o Bupivacaine 0.25%/epi injected at incision sites

o Dexamethasone 8 mg IV

o Droperidol 0.625 mg

Esmolol in Absence of Opioids

Collard et al. (2007)

17

Esmolol in Absence of Opioids

Collard et al. (2007)

18

Discharge and POD #1

Collard et al. (2007)

Beta-adrenergic antagonists during general anesthesia reduced postoperative pain systematic review and meta-analysis of RCTs

19 Härkänen et al. (2015)

Physiology and Pharmacology

Theories Behind the Mechanism of Action

1. Reduced redistribution rate and hepatic blood

flow resulting in the slowed extraction of drugs

2. Improved intraoperative hemodynamics resulting

in reduced opioid administration – attenuation of

opioid induced hyperalgesia (OIH) and tolerance

3. Non-β1-receptor mediated increase in inhibitory

signals in the substantia gelatinosa

4. Blockade of voltage gated Na+ Channel

5. Reduced catecholamine induced inflammation

and sensitization of nociceptors

21

22

• 25 Rats divided into three groups

• (n = 9) Saline treated • (n = 7) Esmolol low – 150 mg/kg bolus followed by 40 mg/kg/hr • (n = 9) Esmolol high – 600 mg/kg bolus followed by 150 mg/kg/hr

• Formalin 5% was injected into rats’ hind paw to induce pain

• Measurements of paw lifting occurred in 5 minute intervals over 35 minutes

Davidson et al (2001)

23

Antinociception Properties of Esmolol

Saline Esmolol Low Esmolol High

Saline Esmolol Low Esmolol High

Saline Esmolol Low Esmolol High

Davidson et al (2001)

Theories Behind the Mechanism of Action

1. Reduced redistribution rate and hepatic blood

flow resulting in the slowed extraction of drugs

2. Improved intraoperative hemodynamics resulting

in reduced opioid administration – attenuation of

opioid induced hyperalgesia (OIH) and tolerance

3. Non-β1-receptor mediated increase in inhibitory

signals in the substantia gelatinosa

4. Blockade of voltage gated Na+ Channel

5. Reduced catecholamine induced inflammation

and sensitization of nociceptors

24

Opioid Induced Hyperalgesia (OIH)

and Opioid Tolerance • Pneumoperitoneum causes the

release of catecholamines and hormones such as NE, epi, renin, and ADH.

• Opioids inhibit the hypothalamic sympatho-adrenal response to pain

• Opioids do not, however, prevent local NE release in response to pneumoperitoneum

• Beta-blockers reduce intra-operative opioid requirements by improving autonomic stability

• Could we be blunting this physiologic response with adrenergic antagonists rather then opioids?

25 Myre et al (2003)

26

Conclusion: These data suggest that esmolol modulates inhibitory transmitter release in the Sp5c through a mechanism involving Ca2+ -entry but in a β1 -adrenoceptor-independent manner. The present results suggest that the facilitation of inhibitory transmitter release in the central nociceptive network underlies, at least in part, the antinociceptive effect of esmolol.

Yasui et al. (2011)

Esm

olo

l v

s. C

on

tro

l

27 Yasui et al. (2011)

Esmolol + or –β-agonist

28 Yasui et al. (2011)

29

Conclusion: Esmolol, but not landiolol, may have useful effects against pain related to TTX-r Na+ channel activity.

Tanahashi (2009)

30

β2

β1

Li et al. (2013) Bruehl (2010)

Reduced Peripheral Inflammation

C-Reactive Protein Interleukin-6 (a known pain trigger) Cell mediated immunity inhibition

31 Kim et al. (2013) Kim et al. (2015)

32

Median Survival None 34 mo β1-selective 38 mo

Non-selective 90 mo

Watkins et al (2015)

n. = 1425

33 Powe & Entschladen. (2011)

34 Gottschalk et al. (2010)

Regional Anesthesia

Celecoxib

Indomethacin

Normal core temp

Βeta-Blockers

Βeta-Blockers

Βeta-Blockers

Indomethacin

Celecoxib

Anesthesia Intervention

35

Current Clinical Pharmacology

Anaesthesia in Cancer Surgery: Can it Affect Cancer Survival? (2016)

“The tantalizing possibility that anaesthetic care of the surgical oncology patient might affect long term oncologic outcome remains unproven speculation, awaiting prospective human study.”

Ben-David (2016)

36

PeriOperative ISchemic Evaluation Trial

However, there were more deaths in the metoprolol group than in the placebo group (120 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03 - 1.74; p=0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26-3.74; p=0.0053).

POISE Study Group (2008)

37 Yu et al. (2011)

Meta analysis of 67 articles evaluating esmolol infusion

• Increased incidence of unplanned hypotension that

occurred in a dose dependent manner.

• Reduced risk when given as an infusion

• Reduced risk of myocardial ischemia when titrated to

hemodynamic end points

• Very few studies address safety in higher risk patients

(ASA III and IV)

• More studies need to be performed to investigate

safety of esmolol

38

Safety Concerns

Yu et al. (2011)

Pharmacoeconomics

39

Zofran 4mg vial

• $0.56

Fentanyl 100mcg

• $1.92

Ketamine 500mg/10cc

• $4.28

Scopolamine 1 patch

• $21.40

Ofirmev 1000mg

• $42.48

Precedex 200mcg/2ml vial

• $47.52

Remifentanil 1mg vial

• $67.48

Esmolol 100mg/10cc

• $17.26

Bolus 0.5 mg/kg Infusion 5 - 15 mcg/kg/min Vial 100 mg / 10cc Weight 70 kg Bolus 35 mg Infusion 21 - 63 mg/hr Duration 1 - 3 hours Plan on 2nd Vial for: Patients > 90 - 100 kg or Surgeries > 2 - 3 hours

Based on AWP on 03/06/16 from http://online.lexi.com/action/home

40 Chou et al. (2016)

41

In Conclusion . . .

Anesthesia

References

42

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Questions?

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