Is Sugammadex the right choice for reversal? YES NO

Transcription

1 Is Sugammadex the right choice for reversal? YES NO

2 Residual Neuromuscular Blockade (rnmb) rnmb after GA using nondepolarizing NMBA s has pathophysiological, clinical, and economic consequences. Significant number of patients with muscle relaxation sustain residual curarization causing muscle weakness, oxygen desaturation, pulmonary collapse, and acute respiratory failure that may lead to severe permanent brain damage or death. Despite extensive documentation of such residual paralysis in the literature, awareness of its clinical consequences remains surprisingly limited, and the use of NMBDs, neuromuscular monitoring, and reversal agents are dictated more by tradition/local practices than by evidence-based medicine. Up to 64% incidence of rnmb occurs in recovery room. Murphy GS et al. Anesth Analg. 2008; 107: Berg H et al. Acta Anaesthesiol Scand. 1997; 41: Eikermann M. Anesthesiology. 2003; 98:

3 Post-Operative Outcomes Associated with Residual Block (RECITE-U.S. Leif Saager, M.D., Tricia Meyer, PharmD, Harold S. Minkowitz, M.D., Scott B. Groudine, M.D., Beverly K. Philip, M.D., Pedro P. Tanaka, M.D., Ph.D., Tong J. Gan, M.D., YiliamRodriguez-Blanco, M.D., Roy G. Soto, M.D., Eric M. Maiese, Ph.D. Multi site (10) study conducted Aug 2012-April subjects across 10 hospitals Adult patients undergoing elective open or laparoscopic abdominal surgery lasting 4 hours Received at least one dose of a non-depolarizing NMBA 255 subjects had valid TOF measurements at TE Ave. age-52yrs. NMB was reversed with neostigmine in 99% of patients and PNS was used in 68% of patients Overall incidence of rnmb at tracheal extubation was 65% Scientific Poster Session ASA Annual Meeting A4127

4 Residual Neuromuscular Blockade Defining Residual NMB Most clinical trials examining postoperative residual paralysis now use a train-of-four (TOF) ratio <0.9 to define incomplete neuromuscular recovery TOF ratio >0.9 indicates sufficient recovery of neuromuscular transmission for awakening the patient and ensuring safe tracheal extubation Murphy G, Brull S. Anesth Analg. 2010; 111:120-8.

5 Factors Affecting Reversal of the NMBA Intensity/Dose of block - the more intense block, longer recovery; the degree and rate of recovery depend on dose Choice of NMBA - recovery of intermediate-acting agents is more rapid than longacting agents following same dose of anticholinesterase Age - residual weakness in recovery is found less in children than in adults Drug interactions - drugs that potentiate blockade can slow reversal Renal failure - duration of action of neostigmine and edrophonium is increased in renal failure

6 Residual Neuromuscular Blockade How Do You Monitor for Residual NMB? Clinical Signs and Symptoms (unreliable) Head or leg lift x 5 seconds, hand grip, tongue depressor, smile, speak, swallow Train-of-four (qualitative) (unreliable) Visual, tactile assessment of train-of-four nerve stimulation for equal movement/strength or for double burst or tetanic stimulation x 5 seconds Train-of-four (quantitative) (more reliable) Electromyography, acceleromyography, kinemyography, phonomyography, mechanomyography (gold standard)

7 Residual Neuromuscular Blockade Clinical Signs Qualitative TOF Quantitative TOF ratio Head lift x 5 sec TOF ratio = Ability to swallow TOF ratio = Eye opening / ability to speak / tongue thrust TOF ratio <0.45 Clench teeth TOF ratio = Abnormal vision TOF ratio < Hz tetanic stimulation TOF ratio 0.3 Fade on TOF TOF ratio Fade with double burst TOF ratio Most clinical trials 100 examining Hz tetanic postoperative stimulation residual x 5 paralysis TOF ratio now 0.85 use (AMG a TOF -ratio unreliable); <0.9 to define incomplete neuromuscular recovery; ensures safe tracheal extubation. AMG=acceleromyography, sec TOF ratio 0.47 (MMG) MMG=mechanomyography Murphy G, Brull S. Anesth Analg. 2010; 111:120-8.

8 Residual Neuromuscular Blockade ADVERSE EFFECTS (TOF ratio 0.7 to <0.9) VOLUNTEER STUDIES Impairment of pharyngeal coordination and force of contraction, swallowing, upper airway dilator muscle function, hypoxic ventilatory drive Reduced upper esophageal sphincter tone, upper airway volumes, inspiratory air flow Increased risk of aspiration Visual disturbances, facial weakness, difficulty speaking and drinking SURGICAL PATIENT STUDIES Increased risk of hypoxemia, upper airway obstruction, critical respiratory events in PACU, atelectasis, pneumonia Prolonged PACU stay Prolonged postoperative ventilatory weaning and increased intubation times in cardiac surgical patients Profound muscle weakness Murphy G, Brull S. Anesth Analg. 2010; 111:120-8.

9 FDA-approved NMBA Reversal Agents Drug Anticholinesterases Dose mg/kg Time to peak (min) Duration of antagonism (min) Excretion Edrophonium % renal 30% hepatic Neostigmine up to 5 mg Gamma-Cyclodextrins Sugammadex % renal 50% hepatic 2 3 -?? 1.5 NMBAs reversed rocuronium, vecuronium, pancuronium, cisatracurium, atracurium rocuronium, vecuronium, pancuronium, cisatracurium, atracurium 100% renal rocuronium (best), vecuronium 16 pyridostigmine not clinically used for NMBA reversal because of variability in duration of antagonism from min.

10 Factors that Increase the Risk of Residual NMB No quantitative monitoring -Clinical signs of reversal unreliable Inadequate use of monitors Inadequate monitors Improper dosing / choice of NMBAs Improper use of reversal agents Patient factors: hypothermia, metabolic acidosis, hypercarbia, hypoxia, renal or hepatic disease Use of certain antibiotics (colistin/polymyxin E, aminoglycosides, tetracyclines, clindamycin)

11 Residual Neuromuscular Blockade Axon terminal Action potential ACh=acetylcholine AChE=acetylcholinesterase AChR=acetylcholine receptor Voltage-gated Ca++ channel opens NMBA ACh AChR Na+ NMBA Action potential muscle contraction /File:The_Muscle_Contraction_Process.png

12 Anticholinesterases (edrophonium, neostigmine) Inhibit acetylcholine breakdown to increase concentration of acetylcholine at neuromuscular junction (NMJ) Axon terminal AChR NMBA Acetylcholine (ACh) Exert potent parasympathomimetic activity ( HR, peristalsis, secretions, bronchospasm, N/V Require co-administration anticholinergic (glycopyrrolate or atropine) to block muscarinic/cardiovascular SE s The_Muscle_Contraction_Process.png#/ media/file:the_muscle_contraction_process.png

13 Sugammadex Mechanism of Action Forms a complex with the steroidal NMBAs (rocuronium & vecuronium) and inactivates NMBA by encapsulating (chelating) the free molecule to form a stable complex Affinity: rocuronium > vecuronium >>> pancuronium Axon terminal AChR Does not bind non-steroidal NMBAs (cisatracurium, atracurium) rocuronium sugammadex File:The_Muscle_Contraction_Process.png

14 Sugammadex (Su refers to sugar and gammadex refers to ۷-cyclodextrin) Gamma-cyclodextrin - (made up of a ring of 8 sugars to which negatively charged side chains are added to accommodate the rocuronium molecule) Novel selective relaxant binding drug (SRBA) Directly removes the NMBA from the neuromuscular junction ( chemical encapsulation ) Specific affinity(tight affinity, 1:1) for steroidal relaxants in the order [rocuronium > vecuronium >> pancuronium] Trials found that sugammadex can antagonize any level of neuromuscular blockade, including the profound blockade induced by rocuronium Does not bind to any known receptor Does not bind NMBA that do not have steroid nucleus Reports of recurarization have been published; risk of under dosing is incomplete reversal Side effects; possibility of drug hypersensitivity to include anaphylaxis (rare)/delayed FDA approval; bleeding Sugammadex is approved in U.S.

15 Structure

16 2 Molecules

17 Complex Formation of Sugammadex and Rocuronium rocuronium Sugammadex

18 Sugammadex Information Given intravenously as a single bolus injection, given over 10 sec. into existing IV line (ensure line is flushed between administration of sugammadex & other drugs) Approved & available in 75+ markets Safety/Effectiveness not established in <17 yrs; not recommended in severe renal impairment; not approved for reversal in ICU do not use for reversal induced by steroidal NMBA s other than rocuronium, vecuronium; no data in pregnant women nor in breast fed infants Advise females using hormonal contraceptives to use additional non-hormonal contraceptive for 7 days Recovery may be delayed in patients on toremifene One case of accidental overdose with 40 mg/kg BRIDION was reported without significant effects. Protect from light& when not protected, vial should be used within 5 days Physical incompatible with verapamil, ondansetron and ranitidine Common adverse reactions: vomiting (11-15%), pain at injection site (48-52%), nausea (26%), hypotension (5-13%), and headache (10%)

19 Pharmacodynamics Rocuronium or vecuronium-induced NMB, sugammadex rapidly removes free rocuronium or vecuronium molecules from the plasma Creates a concentration gradient favoring movement of the remaining rocuronium or vecuronium molecules from the neuromuscular junction back into the plasma, where they are encapsulated Capable of reversing any depth of neuromuscular blockade (profound or shallow) induced by rocuronium or vecuronium to a train-of-four (TOF) ratio of at least 0.9 within 3 min Results in an increase in the total plasma concentration of rocuronium or vecuronium (both free and bound) Shields M, Giovannelli M, Mirakhur RK, Moppett I, Adams J, Hermens Y. Org (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium-induced neuromuscular block. Br. J. Anaesth.96(1),36-43 (2006). Sorgenfrei IF, Norrild K, Larsen PB et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology104(4), (2006). Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth. Analg.104(3), (2007

20 Sugammadex Dosing for Rocuronium TOF = 2 twitches 2 mg/kg IV median time to TOF ratio 0.9 = 2 minutes 140 mg for 70 kg patient -> one 200 mg vial ~ $84.56* Post-tetanic count = 1-2 twitches 4 mg/kg IV - median time to TOF ratio 0.9 = 3 minutes Reversal 3 minutes after administration of 1.2 mg/kg rocuronium 16 mg/kg median time to TOF ratio 0.9 = 1.5 min 1120 mg for 70 kg patient -> six 200 mg vials = $506.35* Quicker than spontaneous recovery with succinylcholine May be useful for can t ventilate, can t intubate scenario *Chambers D, et al. Brit J Anaesth. 2010;105:568.

21 Role of sugammadex in accelerating postoperative discharge: A meta-analysis Systematic review and meta-analysis-518 patients/6 studies Suga associated significantly faster discharge from the OR to the PACU (mean difference [MD]=22.14min, 95% CI (14.62, 29.67), P<0.0001, I2=0%) & from the PACU to the surgical ward (MD=16.95min, 95% CI (0.23, 33.67), P=0.0469, I2=98.4%) Discharge-readiness was shorter for suga than neo from the OR to the PACU (MD=5.58min, 95% CI (3.03, 8.14), P , I2=0%) Discharge-readiness was similar in both groups from the PACU to ward Results of meta-analysis; suga accelerates postoperative discharge of patients after general anesthesia compared with neo J Clin Anesth Jun;39: doi: /j.jclinane Epub 2017 Mar 23.

22 Sugammadex Cochrane Review 18 Randomized controlled trials (RCT)(n = 1321 patients) 7 trials published as full-text papers, and 11 trials as abstracts. All had adequate methods of randomization and allocation concealment. Results - compared with placebo or neostigmine, sugammadex can more rapidly reverse rocuronium-induced NMB regardless of the depth of the block (trials are limited on vecuronium and pancuronium) Serious adverse events occurred in <1% of all patients who received the medication. There was no significant difference between sugammadex and placebo in terms of the prevalence of drug-related adverse events, and no significant difference was found between sugammadex and neostigmine for adverse events. Abrishami A et al. Cochrane Database Syst Rev Oct 7;(4):CD

23 The comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A Cochrane systematic review with meta-analysis and trial sequential analysis Compared efficacy & safety suga vs. neostig in reversing NM blockade 41 studies with 4206 participants Outcomes: (1) recovery time from 2 nd twitch to TOF ratio >0.9, (2) recovery time from post tetanic count 1-5 to TOF ratio >0.9,(3) SAE s Results for (1) Suga 2mg/kg =2 min. vs neostig 0.05mg/kg =12.9 min (2) Suga 4mg/kg =2.9 min vs neostig 0.07mg/kg= 48.8min (3) Fewer composite AE s in suga group Anaesthesia Dec 27. doi: /anae [Epub ahead of print]

24 Effects of sugammadex on incidence of post op residual neuromuscular blockade: randomized controlled study Adults (154) undergoing abdominal surgery with rocuronium were randomized to sugammadex 2 or 4mg/kg or neo/glyco 0% of sugammadex and 43.4% of neo/glyco had TOF Watch of rnmb at PACU admission Conclusion: eliminated rnmb in PACU and shortened time from start of admin to time pt. was ready for d/c from OR Brueckmann et al. BJA.2015; 115 (5):743 Merck funded

25 Use of Sugammadex in Patients with Obesity: A pooled analysis Package insert for sugammadex-use actual body weight (mg/kg) 27 trials pooled analysis with 267 pts BMI > 30kg/m 2 Primary efficacy variable was time of dose to recovery of TOF >0.9 No clinically relevant correlation was observed between BMI and recovery time

26 Financials Drug Strength Form Size GPO Cost/each WAC cost/each Sugammadex 100mg/ml SDV 2ml $$$ 1/2 $$$1/2 Sugammadex 100mg/ml SDV 5ml $$$$$$ 1/2 $$$$$1/2 Neostigmine (generic) 1mg/ml MDV 10ml $ $$ Neostigmine (Bloxiverz) 1mg/ml MDV 10ml $ $$ Glycopyrrolate 0.2mg/ml SDV 1ml 1/5 $ 1/5 $ Glycopyrrolate 0.2mg/ml SDV 2ml ½ $ ½ $ Glycopyrrolate 0.2mg/ml MDV 5ml $ $

27 RX REPORT CARD Category Grade Comments Efficacy A Has shown quicker response Value/Cost C <$100-but could be strain on budget Outcomes C Need more studies to prove early D/C Solution to real issue B Evaluate your post op care Special Populations A+ Neuro, Obese, Geriatric patients Side effects C Hypersensitivity concerns Patient Safety A Residual paralysis complications Drug interactions A Minimal Promotes use of monitor A Conclusive diagnosis of residual NMB Dosing B Wt based, 2 dosing levels Co-admin 2 nd agent A None Unique action A yes

28 Other New Agents in the Field of Neuromuscular Blocking Drugs and Antagonists Drug Structure Target Mechanism Dose response Sugammadex Cyclodextrin Steroidal compounds Calabadion Cysteine Comparison of reversal agents that act directly on NMB drug molecules Acyclic cucurbituril Amino acid with thiol side chain All NMBD s Novel isoquinoliniums Envelops NMBD Binds to quaternary amines Adducts to fumarate moiety Increasing dose for early reversal Stage Approved EU, Japan; US --- Not approved Reversal at any time with same dose Not approved Heerdt P et al. Curr Opin Anesthesiol. 2015; 28: Haerter F et al. Anesthesiology Sep 29. [Epub ahead of print].

29 Potential Agents: Calabadion 2 and CW002 Calabadion: broad spectrum reversal agent; rapidly reversed deep rocuronium, vecuronium and cisatracurium induced blockade in vitro/animal models CW002: intermediate duration, nondepolarizing, cysteine-inactivated neuromuscular blocking drug Can be reversed with cysteine injection Heerdt P et al. Curr Opin Anesthesiol. 2015; 28: Haerter F et al. Anesthesiology Sep 29. [Epub ahead of print].