Combined Use of Low-dose Sugammadex Plus Neostigmine Administered for Reversal of Rocuronium

Background Neuromuscular paralysis is a frequent requirement to facilitate airway management and surgery. Patients receiving neuromuscular blocking agents (NMBAs) are at risk of residual neuromuscular blockade (RNMB) that can lead to postoperative cardio-pulmonary complications, and may increase postoperative morbidity and mortality.1-2 NMBAs can be antagonized with the cholinesterase inhibitor neostigmine; however, this agent has several undesirable side effects because of its parasympathetic stimulation.3 Thus, muscarinic receptor antagonists, such as atropine, are used along with cholinesterase inhibitors; however, these drugs also have their own set of adverse effects. Despite its relatively slow onset of action and inability to antagonize profound blockade, neostigmine is still used frequently for reversal of rocuronium-induced neuromuscular blockade because of its low cost. Sugammadex is a selective relaxant biding agent, developed to encapsulate the steroidal NMBAs, and proved to be extremely effective for the reversal of either shallow (dose of 2 mg/kg), deep (dose of 4 mg/kg), or even profound (dose of 16 mg/kg) neuromuscular blockade. However, routine use of sugammadex is limited by its relatively high cost compared with neostigmine.

The purpose of the study is to investigate drug costs and adverse effects of low-dose neostigmine (0.025 mg/kg) plus low-dose sugammadex (1 mg/kg) for reversal of rocuronium-induced neuromuscular block, and compare efficacy of antagonism and costs of this combination therapy with the current standard therapies: full-dose sugammadex (2 mg/kg) and full-dose neostigmine (0.05 mg/kg) plus atropine.

Randomization and blinding On randomization, each patient will be allocated by a unique identifying number into study groups "A", "B", or "C". The allocation of a patient to the specific group will be only known by the research assistant. The participating anaesthetists as well as the research staff who collect patient data will remain blinded until after the completion of the study.

For reversal of rocuronium neuromuscular- block we used:

• Group A - Sugammadex (Bridion®) 2 mg/kg,
• Group B - Neostigmine (Miostin®; Stigmosan®) 0.05 mg/kg and atropine 1 mg/ dose.
• Group C - Neostigmine (Miostin®; Stigmosan®) 0.025 mg/kg and atropine 0.5 mg/dose followed within 3 min by Sugammadex 1 mg/kg.

Monitoring the neuromuscular blockade After induction of anesthesia and before administration of rocuronium, monitoring of neuromuscular blockade at the adductor pollicis muscle is initiated using acceleromyography (TOF-Watch SX, Organon, Dublin, Ireland). After degreasing the skin, two surface electrodes are placed above the ulnar nerve near the wrist. After induction of general anesthesia, 50-Hz tetanic stimulation is applied for 5 sec and followed after 1 min by train-of-four (TOF) stimulation every 15 sec. If the response to TOF is stable, calibration and supramaximal stimulation are ensured by built-in calibration function (CAL2). After at least 2 min of a stable baseline documentation of the response to TOF, rocuronium is administered.

At the end of surgery, inhalational agent (sevoflurane) will be discontinued. Once the end-tidal concentration of sevoflurane reaches 0.4-0.6%, the previously randomized reversal study drug will be administrated at shallow neuromuscular block (TOF count of 2). The primary efficacy variable is the incidence of residual neuromuscular block (defined as TOFR \<0.90) measured at least 15 min. after the administration of the reversal agent. In case of residual block, a rescue dose of 2 mg/kg sugammadex will be administrated before tracheal extubation. Extubation is performed once patient is deemed fully recovered (TOFR = 1.0)