Clinical trial NCT02414880: Sugammadex Versus Neostigmine in Patients With Liver Cirrhosis Undergoing Liver Resection
Official title: Sugammadex Versus Neostigmine for Antagonism of Rocuronium-induced Neuromuscular Blockade in Patients With Liver Cirrhosis Undergoing Liver Resection: A Controlled Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cirrhosis and Chronic Liver Disease
Keywords: Sugammadex
Neostigmine
Rocuronium
Cirrhosis
Liver resection
Neuromuscular
Lead sponsor: Cairo University
Sponsor class: OTHER
Collaborators: name: National Liver Institute, Egypt
First posted: 2015-04-13
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes that substantially affects drug pharmacokinetics. Rocuronium onset time is longer and recovery time from it is prolonged in cirrhotic patients than in those with normal liver function.

This randomized controlled study is designed to compare the pharmacodynamic profiles of sugammadex and neostigmine when used for the antagonism of moderate degree of rocuronium-induced neuromuscular block in cirrhotic patients undergoing liver resection and in patients with preoperative normal liver functions undergoing liver resection.

Detailed description: Liver resection is a lengthy operation that has major effects on patient hemodynamics and perioperative liver functions. These effects are more obvious in patients with liver cirrhosis. Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes that substantially affects drug pharmacokinetics.

Rocuronium is an intermediate acting steroidal non-depolarizing neuromuscular blocker that is mostly metabolized by the liver. Its onset time is longer in cirrhotic patients than in those with normal liver function. This can be explained by an increase in the volume in which it initially distributes. Although elimination kinetics are unchanged in patients with cirrhosis, Rocuronium recovery time is prolonged in cirrhotic patients.

To speed up the process of antagonism of residual neuromuscular blockade, inhibitors of acetyl cholinesterases such as Neostigmine are usually administered only when there is evidence of spontaneous recovery of neuromuscular function. Too early administration of Neostigmine is not effective and may produce serious side-effects from accumulation of Acetylcholine in other organs, especially the brain and heart.

Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding agent. It forms very tight, stable complexes in a 1:1 ratio with Rocuronium. The inactive Sugammadex-Rocuronium complex undergoes renal elimination. Sugammadex has no effect on acetyl cholinesterases or on any receptor system in the body, eliminating the need for anticholinergic drugs. Sugammadex can antagonize any level of neuromuscular blockade, including the profound blockade induced by Rocuronium.

The use of Sugammadex in different patient populations including end-stage renal failure is associated with consistent, complete and rapid recovery of neuromuscular functions. It is of clinical relevance to note that in the presence of Sugammadex, the hepatic biotransformation and final clearance of Rocuronium via biliary excretion is changed to a completely different (liver-independent) renal pathway. A recent report described the successful use of Sugammadex to antagonize prolonged deep rocuronium-induced neuromuscular block in patients with normal liver functions undergoing liver resection. Furthermore, the successful use of Sugammadex to antagonize Rocuronium neuromuscular block was also reported in a case series of three patients with liver dysfunction.

To the best of our knowledge, there are no controlled randomized studies evaluating the use of Sugammadex to antagonize residual Rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing open surgical liver resection. This randomized controlled study is designed to compare the pharmacodynamic profiles of Sugammadex and Neostigmine when used for the antagonism of moderate degree of Rocuronium-induced neuromuscular block in cirrhotic patients undergoing liver resection and in patients with preoperative normal liver functions undergoing liver resection.

Eligibility criteria: Inclusion Criteria:

* American Society of Anesthesiologists physical status (ASA) class I for patients with preoperative normal liver function test (two groups) and I-III for patients with liver cirrhosis (two groups).
* For the two "Liver Cirrhosis" groups: Patients with liver Cirrhosis with Child classification "A" and a Model for End-Stage Liver Disease (MELD) score \<10 undergoing Liver resection surgeries.
* For the two "Normal Liver" groups: Patients with normal preoperative liver functions undergoing Liver resection surgeries.

Exclusion Criteria:

* Co-existing neuromuscular disease.
* Body mass index more than 35 kg/m-2.
* Renal impairment.
* Medications known to affect neuromuscular transmission (e.g. Aminoglycoside antibiotics or Magnesium Sulphate).
* Bleeding tendency.
* Intra-operative adverse events (e.g. massive bleeding or hypothermia).

Primary outcomes:
measure: The time from reversal to Train-of-four (TOF) ratio of 0.9
timeFrame: 15 min
Secondary outcomes:
measure: The time from reversal to Train-of-four (TOF) ratio of 1
timeFrame: 30 min
measure: Length of stay in the post-anesthesia care unit (PACU)
timeFrame: 4 hours
measure: Time from last Rocuronium dose to Train-of-four (TOF) ratio of 0.9
timeFrame: 1 hour
measure: Duration of action of the initial intubating dose of Rocuronium
timeFrame: 45 min
measure: Incidence of postoperative re-curarization
timeFrame: 4 hours
measure: Total dose of Rocuronium
timeFrame: 24 hours
measure: Duration of anesthesia
timeFrame: 24 hours
Other outcomes:
Locations:
city: Garden City
country: Egypt
facility: National Liver institute
state: Cairo
Study officials:
affiliation: Cairo University
name: Mohamed Abdulatif Mohamed, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schaller SJ, Fink H. Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evid. 2013;8:57-67. doi: 10.2147/CE.S35675. Epub 2013 Sep 25.
citation: Edginton AN, Willmann S. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet. 2008;47(11):743-52. doi: 10.2165/00003088-200847110-00005.
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citation: Nonaka T, Fujimoto M, Nishi M, Yamamoto T. [The effect of rocuronium and sugammadex in hepatic tumor patients without preoperative hepatic impairment]. Masui. 2013 Mar;62(3):304-8. Japanese.
citation: Batistaki C, Matsota P, Kalimeris K, Brountzos E, Kostopanagiotou G. Sugammadex antagonising rocuronium in three patients with liver dysfunction undergoing transjugular intrahepatic portosystemic shunt. Anaesth Intensive Care. 2012 May;40(3):556-7. No abstract available.
citation: Blobner M, Eriksson LI, Scholz J, Motsch J, Della Rocca G, Prins ME. Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol. 2010 Oct;27(10):874-81. doi: 10.1097/EJA.0b013e32833d56b7.
citation: Illman HL, Laurila P, Antila H, Meretoja OA, Alahuhta S, Olkkola KT. The duration of residual neuromuscular block after administration of neostigmine or sugammadex at two visible twitches during train-of-four monitoring. Anesth Analg. 2011 Jan;112(1):63-8. doi: 10.1213/ANE.0b013e3181fdf889. Epub 2010 Oct 26.