Sugammadex: Use in Specific Patient Population

Sugammadex:Use in Specific Patient Population Volkan Hancı; M.D. Dokuz Eylul University İzmir, Turkey

Sugammadex • Modified gamma cyclodextrin molecule. • Unique molecular structure. • Encapsulates the neuromuscular blocker rocuronium and vecuronium. • Removing its from the muscle-nerve junction. • Selective and rapid reversal of neuromuscular blockage.

Sugammadex • More effectivethanplaceboorneostigmine • Reduced all signs of residual postoperative paralysis,and minor respiratory events • Reduced drug-related side-effects, Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007362. Anaesthesia. 2015 Dec;70(12):1441-52.

Sugammadex • Dose • 2 mg/kg, 4 mg/kg, 16 mg/kg • Drug interaction • Steroidal drugs, endogenous steroids, oestrogens • Atropine, vancomycin, gentamicin, salbutamol, aminophylline, ephedrine, phentolamine, verapamil (120–700 times lower than rocuronium) • Precipitation • Amiodarone, dobutamine, protamine Basic Clin Pharmacol Toxicol. 2013;113(4):280-5. Braz J Anesthesiol. 2013;63(1):163-4.

SugammadexSpecial Patient Population /Special Situations

Elderly • Pediatric • Obese • Obstetric • ResidualParalysis • ReinducingNeuromuscularBlockade • NeurophysiologicMonitoring • Anaphylaxis • ExperimentalStudies • Renal • Hepatic • Cardiac • Pulmonary • Neuro-muscular SpecialSitutations SpecialDiseases S p e c i a l P a t i e n t s

Elderly • Pediatric • Obese • Obstetric • ResidualParalysis • ReinducingNeuromuscularBlockade • NeurophysiologicMonitoring • Anaphylaxis • ExperimentalStudies • ResidualParalysis • ReinducingNeuromuscularBlockade • NeurophysiologicMonitoring • Anaphylaxis • ExperimentalStudies • Renal • Hepatic • Cardiac • Pulmonary • Neuro-muscular SpecialSitutations SpecialDiseases S p e c i a l P a t i e n t s

Elderly Patients • Sugammadex facilitates rapid reversal from moderate rocuronium-induced neuromuscular blockade in adults of all ages • Recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0-2.6) min (adults) to 2.9 (2.7-3.2) min • Slower circulation time Anesthesiology. 2011 Feb;114(2):318-29.

Pediatric Patients • Sugammadex rapidly and effectively reverses rocuronium-induced NMB in pediatric patients • Sugammadex provides safer extubation with a shorter recovery time than neostigmine in pediatric patients • Sugammadex can be considered as a safe agent in order to reverse neuromuscular block in pediatric patients Saudi J Anaesth. 2015 Jul-Sep;9(3):247-52. Rev Bras Anestesiol. 2014 Nov-Dec;64(6):400-5. J Res Med Sci. 2014 Aug;19(8):762-8.

Obese Patients • Sugammadex quickly and effectively reverses NMB in obese patients • Sugammadex dosing recommendations arebased on total body weight. No dose adjustments are required in the obese patient. • Morbidly obese patients can safely be decurarised from rocuronium-induced neuromuscular blockade T1-T2 with sugammadex dosed at 2 mg.kg(-1) ideal body weight + 40% • Sugammadex dose calculated according to IBW is insufficient for reversing both deep and moderate blockades in morbidly obese patients. Am J Ther. 2015 Sep 21. [Epub ahead of print] Anaesthesia. 2011 Aug;66(8):721-5 Anesthesiology. 2012 Jul;117(1):93-8

Obstetric Patients • Sugammadex use in obstetric patients has also successfully reversed NMB • The dataregarding the teratogenicity and safety of sugammadex in pregnant women are limited. • No reported teratogenicity has been found. • Rocuronium 1.2 mg/kg reversed by sugammadex appears to be effective in the obstetric population • Sugammadex could reverse rocuronium-induced neuromuscular blockade in a dose-response manner even in the patients treated with magnesium sulfate. Acta Anaesthesiol Scand. 2011 Jul;55(6):694-9. Masui. 2014 Mar;63(3):315-9.

Renal Disease • Sugammadex-NMB complex mainly excreted by the kidneys • Decreased elemination • High-flux dialysis (Large pore in dialyzing membranes) • Renal failure; • effectively and safely reversed profound rocuronium induced neuromuscular block, • but the recovery was slower than healthy patients. • rapid reversal of deep rocuronium-induced NMB • current safety experience is insufficient to support recommended use of sugammadex in this population Eur J Anaesthesiol. 2015;32(10):681-6. Br J Anaesth. 2015 May;114(5):777-84.

Hepatic Disease • No hepatic metabolism • No restriction use in patient whit liver disease or hepatic surgery • Liver transplantation • effective and safe in liver transplant recipients. • may reduce the risk of pulmonary complications • Hepatic Surgery • rapidly reverse NMB after continuous infusion of rocuronium Anaesth Pain & Intensive Care 2015;19(3) Acta Anaesthesiol Taiwan. 2014 ;52(2):54-8.

Cardiac Disease • Safe / efficacious • Not change hemodynamic parameters • Might be preferred as it provides more hemodynamic stability compared to neostigmine-atropine combination • Sugammadex can adequately restore neuromuscular function in heart failure patients under hemodynamically stable conditions. • Not prolong QT interval J Clin Anesth. 2016;28:30-5. Acta Anaesthesiol Belg. 2012;63(2):69-73. Clin Drug Investig. 2013; 33(8):545-51 Acta Cir Bras. 2014;29(12):807-11.

Cardiac Disease • Successfully used • Brugada syndrome • Wolff-Parkinson-White (WPW) Syndrome • Long QT syndrome • On the other hand, one case report accuse one of the causative agents of cardiac arrest Anaesth Intensive Care. 2013 ;41(3):434 Braz J Anesthesiol. 2013;63(1):159-60 J Med Invest. 2011 Aug;58(3-4):273-6 J ECT. 2012 Jun;28(2):e21-2 Balkan Med J. 2015;32(3):327-9 Anaesth Intensive Care. 2010;38(6):1138-9 Masui. 2015;64(6):622-7.

Pulmonary Disease • No negative effects or side effects • Pulmonary disease • Lung surgery

Neuromuscular Disease • MyastheniaGravis • Sugammadex appears to be a safe choice to avoid prolonged action of NMBA also in patients with myasthenia gravis , • MG patients -rocuronium and sugammadex • not observe any signs of postoperative residual curarization and respiratory depression.

Neuromuscular Disease • Other neuromuscular diseases, • Duchenne • Myotonic dystrophies • Transverse myelitis • Amyotrophic lateral sclerosis • Huntington disease • Spinal / Bulbar Muscular Atrophy • Strumpell-Lorrain disease / familial spastic paraplegia • NMB effectively reversed with sugammadex

Rescue of Residual Paralysis • Conventionalreversal of NMB by a cholinesterase inhibitoris incomplete, sugammadex may be administered to fully reverse • After inadequate reversal of NMB with neostigmine and glycopyrrolate, sugammadex immediately reverse the residual paralysis • Residual NMB even after reversal with anticholinesterase agents, sugammadex, a safe alternative to reverse the NMB Anesth Analg. 2007 Mar;104(3):585-6. Rev Bras Anestesiol. 2012 Jul;62(4):543-7.

Reinducing Neuromuscular Blockade AfterSugammadex Administration • After reversal by sugammadex • Immediate reestablishment of NMB with an aminosteroidal NMB agent is difficult. • Isoquinoline NMBAs (atracurium, cisatracurium and mivacurium) or succinylcholine should be use • If the aminosteroidal NMB agent use necessary • Elimination time of sugammadex should be considered. • Sugammadex undergoes renal elimination • It takes 8 hours afterinjection in individuals with normal renal function.

Neurophysiologic Monitoring • Sugammadex has been successfully used for patients requiring neurophysiologic monitoringduring brain and spinal cord surgeries • Sugammadex-induced reversal of NMB restores fullmotor function and better reflects a patient’s true baseline motor evoked potentials • Somatosensory evoked potentials are not affected by NMB. Anaesth Intensive Care. 2012;40(6):1073-4

Anaphylaxis • Severe allergic reaction after administration of sugammadex may ocur • It can be seen bi-phasic reaction • Sugammadex may potentially be a useful adjunct in the management of rocuronium-induced anaphylaxis. • Sugammadex does not modify the clinical course of a suspected hypersensitivity reaction. Can J Anaesth. 2013 Jul;60(7):733-4 Masui. 2015 Jun;64(6):619-21. J Clin Anesth. 2012 Feb;24(1):62-4. Br J Anaesth. 2011 Feb;106(2):199-201. Anaesthesia. 2015 Nov;70(11):1264-7.

Experimental Studies • Sugammadex-rocuronium complexes are cause histopathological and immunohistochemical changes in testis interstitial tissues, changes sperm density, germ cell number • 16 mg/kg sugammadex delayed verapamil cardiotoxicity • 1000mg/kg sugammadex accelerated verapamil cardiotoxicity • 16 mg/kg sugammadex delayed teophylline toxicity, andraises mean lethal dose of teophylline J Mol Histol. 2012 Apr;43(2):235-41 Basic Clin Pharmacol Toxicol. 2013 Oct;113(4):280-5. Lat. Am. J. Pharm. 33 (8): 1290-6 (2014)

Experimental Studies • Administration of sugammadex and dexmedetomidine to rabbits by intra-arterial routes caused histological arterial damage. • Sugammadex prevented postoperative intra-abdominal adhesions • Causes neuronal apoptosis in primary cultures Rev Bras Anestesiol. 2015. http://dx.doi.org/10.1016/j.bjane.2015.01.003 Kaohsiung J Med Sci. 2015 Sep;31(9):463-7. Int J Med Sci. 2013 Aug 3;10(10):1278-85.

Elderly • Pediatric • Obese • Obstetric • ResidualParalysis • ReinducingNeuromuscularBlockade • NeurophysiologicMonitoring • Anaphylaxis • ExperimentalStudies • OtherClinicalStudies • ResidualParalysis • ReinducingNeuromuscularBlockade • NeurophysiologicMonitoring • Anaphylaxis • ExperimentalStudies • OtherClinicalStudies • Renal • Hepatic • Cardiac • Pulmonary • Neuro-muscular SpecialSitutations SpecialDiseases S p e c i a l P a t i e n t s

Other Clinical Studies

Other Clinical Studies • IV dexamethasone, given after induction of anesthesia, does not substantively affect the reversal time of sugammadex • Lower end-extubation IOP levels were obtained sugammadex • Sugammadex produced limited, transient increases in aPTT and prothrombin time • but not associated with increased risk of bleeding • Pre-treatment with magnesium did not significantly affect sugammadex reversal time of moderate neuromuscular blockade induced by rocuronium. Anesth Analg. 2016 Jan 14. [Epub ahead of print] J Pak Med Assoc. 2015 Nov;65(11):1219-25. Anesthesiology. 2014 Nov;121(5):969-77.. Anaesthesia. 2015 Aug;70(8):956-61.

SugammadexSpecial Patient Population /Special Situations

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Sugammadex: Use in Specific Patient Population