Comparison of sugammadex with neostigmine plus glycopyrrolate combination as a neuromuscular block reversal drug on postoperative cognitive dysfunction in older adults undergoing hip surgeries: a randomised controlled trial

Introduction: The mental functions of perception, memory, and information processing that enable a person to learn, solve problems, and make plans for the future are together referred to as cognition. It is not the same as intellect and consists of the mental functions needed for daily life. Therefore, the impairment of these processes is cognitive dysfunction. Patients typically describe it in terms of their inability to execute basic cognitive tasks, such as moving to another room and forgetting why they moved there, or their inability to finish previously simple tasks like crossword puzzles. Postoperative cognitive dysfunction (POCD) can be understood as cognitive impairment occurring as a postoperative complication of surgery which can either be temporary or permanent. Through nicotinic acetylcholine receptors, which are involved in chemical signalling and control of awareness, memory, and learning the cholinergic system contributes significantly to the decrease of cognitive function. POCD has been linked to a central cholinergic deficit brought on by alterations in cholinergic transmission brought on by use of perioperative anticholinergic medication treatment.  Sugammadex is a novel modified gamma cyclodextrin molecule and a selective relaxant binding agent which was developed to reverse any depth of neuromuscular block caused by NMBAs like rocuronium and vecuronium. Its use has recently started in India. Because of a unique mechanism of action that is encapsulation of muscle relaxant, it is used without the concurrent administration of an anticholinergic medication, such as glycopyrrolate, because it does not work to inhibit acetylcholinesterase. This has the potential of causing early and faster recovery from anaesthesia and also can play a role in decreasing the risk of POCD in elderly patients. Though there are a few reported cases of anaphylaxis associated with sugammadex used still the incidence is very less.

Problem statement: POCD remains an unidentified problem in our health system. According to Newman S et al A meta-analysis of POCD after non cardiac surgery showed major surgery produced between 26% and 33% of cognitive dysfunction. POCD can bring about a permanent decline of cognition in geriatric patients hence there is a need to identify the risk factors and methods to decrease the incidence of POCD in elderly.

Rationale: Neostigmine plus glycopyrrolate still remains to be preferred as reversal agents of neuromuscular blocking agents aminosteroids like rocuronium and vecuronium, but because of their anticholinergic properties which may interrupt the cholinergic transmission in CNS by crossing the blood brain barrier thus increasing the risk of postoperative cognitive dysfunction, we wish to find out whether the use of sugammadex which acts via a unique mechanism by encapsulation of NMB without affecting the neuromuscular junction, can decrease the incidence of POCD. The levels of IL4 which is an anti-inflammatory marker has also been seen to increase from the use of sugammadex after surgery which can have indirect long term neuroprotective effects which can decrease POCD.

Novelty: There is only limited literature showing the neuroprotective effect of sugammadex. One recent study has shown a significant difference after use sugammadex in POCD in patients <60yrs undergoing cardiac surgery. But no study has been done focusing on elderly patients’ cognition upto 30 days postoperatively. Also, there is no literature on neuroprotective effects of sugammadex on patients undergoing hip surgeries which are prone to POCD.

Expected outcome and application: 1. We expect that sugammadex will decrease the cognitive dysfunction in elderly as compared to neostigmine + glycopyrrolate. 2. We also might be able to find out whether sugammadex causes bradycardia and hypotension within 30 mins of its administration. 3. Sugammadex may be used as NMB reversal agent in elderly patients undergoing prolonged surgeries and those with preoperative Mild Cognitive Impairment.

Research question: Does sugammadex reduce postoperative cognitive dysfunction in older adults undergoing hip surgeries as compared to neostigmine plus glycopyrrolate combination?

Research hypothesis (es): Sugammadex reduces postoperative cognitive dysfunction in older adults undergoing hip surgeries as compared to neostigmine plus glycopyrrolate combination

Aim: To compare the effect of Sugammadex with Neostigmine + glycopyrrolate on POCD in older adults undergoing hip surgeries. 10 Objectives:

Primary objective: To compare the cognitive function using Postoperative Quality of Recovery Scale (PQRS) at 30min, 12hrs, 24hrs, 72hrs, 7 th day and 30th day postoperatively from baseline values in patients receiving Sugammadex vs those receiving neostigmine plus glycopyrrolate combination.

Secondary Objectives: 1. To assess the hemodynamic adverse effects of sugammadex that is bradycardia and hypotension within 30 mins of its administration. 2.To assess the total intraoperative opioid consumption. 3. To assess the postoperative electrolytes levels within 24hrs.

Methodology: A. Study design: A randomized controlled trial.

B. Study participants: All patients posted to undergo general anaesthesia for hip surgeries at AIIMS Patna. This study will be conducted in the Department of Anaesthesiology AIIMS, Patna after obtaining Institutional and Ethics committee approval and a written informed consent.

Inclusion criteria: 1. Patients requiring general anaesthesia for hip surgery 2. ASA I, II and III 3. Age Group >60 years, belonging to either sex

Exclusion criteria:

1. Any neurological disorder affecting the patient’s ability to understand the questionnaire 2. Patients with such visual or hearing impairment that it affects the patient’s ability to read the scale or answer the questions that will be asked 3. Patients taking antidepressants and/or tranquilisers. 4. Any known allergies to drug being administered. 5. Patient refusal 13 6. BMI ≤ 18.5 or ≥ 30

Withdrawal Criteria: The patient has a right to withdraw from the study at any point of time. Other criteria for withdrawal from the study is

1. Surgical Failure 2. Extubation failure 3. Emergency complication

Number of groups to be studied, identify groups with definition: Patients will be randomly assigned to one of two groups (Group A and B) according to the computer-generated random number table. Group A will be getting 10ml of Neostigmine(0.5mg/ml) plus Glycopyrrolate(0.1mg/ml) whereas Group B will be getting 2mg/kg of Sugammadex (100mg/ml) mixed with normal saline at the end of surgery after confirmation of a train of four ratio of 0.9 or higher. Sampling: Sampling population: Patients will be initially assessed for eligibility and recruited in the preanesthetic check-up room at AIIMS Patna. Sample size calculation: From a previous study by Muedra V et al showing the recovery percentage of 42.9% in Neostigmine group as compared to 85.7% in sugammadex group in the cognitive domain of PQRS at 30th day, sample size was calculated using the online sample size calculator, statulator. Taking alpha as 0.05, power as 80%, using the difference between the two proportions and assuming a dropout rate of 20% the sample size comes out to be a minimum of 25 patients for each group. Therefore, a total sample size of 50 will be taken.

Sampling technique: Patients will be initially assessed for eligibility and recruited in the preanesthetic check-up room at AIIMS Patna. The subjects who are willing to participate in the research will be given the participant informed consent form (PICF) which they shall be requested to fill after reading. After recruitment, sampling will be done using convenience sampling.

Randomization details: Patients will be randomized and allocated using computer generated block randomization technique with blocks of 4. Concealment: Concealment will be done using sealed opaque envelope technique. The envelopes containing the random numbers of the patients will be opened by the health personnel who will not be involved in the study. The randomization number will be concealed from the patient.

Blinding: Double Blinding. Each drug will be diluted in 10 ml saline so as to appear identical. The patient will be blinded to the drug he is about to receive. The anaesthesiologist administering the reversal drug will be unaware of the reversal agent being given. The health personnel preparing the drug will be not be part of the study.

Study procedure: A detailed pre-anesthetic check-up, informed written consent will be taken. Each patient will be visited 12h (T0) before the surgery and baseline cognitive function will be assessed with Postoperative Quality of Recovery Scale (PQRS). In the operating room, standard monitoring devices will be attached (pulse oximeter, non-invasive blood pressure, ECG, temperature). Neuromuscular monitoring will also be done. The protocol followed for induction and maintenance of anaesthesia will be the same for both groups. Induction of anaesthesia will be done by administration of propofol 2 to 2.5 mg/kg IV, fentanyl 2 μg/kg IV and rocuronium 0.8 mg/kg IV. Maintenance of anaesthesia will be done using sevoflurane, O2, air and intermittent doses of rocuronium when TOF shoes >3 detectable twitches. In both groups, all patients will receive paracetamol 1 g 30 minutes prior to the end of the procedure and/or tramadol 100mg in 100 ml NS dependent upon the discretion of the anaesthetist in charge. The patients will receive post 15 operative nausea vomiting prophylaxis according to the recent PONV guidelines. At the end of surgery, sevoflurane administration will be stopped and, after reappearance of the T2 in the TOF sequence, residual neuromuscular blockade will be reversed with administration of either sugammadex (2 mg/kg) or neostigmine/glycopyrrolate (neostigmine 0.5 mg/ml combined with 0.1mg/ml glycopyrrolate). For a period of 30mins after administration of drug the heart rate and the blood pressure will be observed and recorded. The intraoperative opioid consumption will also be recorded. The pain of the patient during the hospital stay will be managed such that the patient’s NRS scale is within ≤ 3. After extubation, the patients will be transferred to the post anaesthesia care unit where their cognitive function will be reassessed using Postoperative Quality of Recovery Scale PQRS at 30min (T1) postoperatively then 24h (T2), 72h (T3) and at 7th postoperative day(T4) and postop day 30(T5) either face to face interview or via telephone assessment when the patient gets discharged. At the time of discharge the patients will be prescribed with proper analgesics so as to keep the NRS score of ≤ 3. Serum electrolytes will be measured within 24hrs to rule out any dyselectrolytemia.

a. independent variables: Age, sex, height, weight b. Outcome variables: 1. The PQRS scores at 12hrs preop, 30min, 12hrs, 24hrs, 72hrs, 7th day and 30th day postoperatively. 2. The number of patients experiencing bradycardia within 30 mins of administration. 3. the number of patients having electrolyte imbalances within 24hrs postoperatively. 4. NRS score c. Confounding and interacting variables: uncontrolled post operative pain, electrolyte imbalances Data Collection & statistical analysis plan: The data of subjects who are recruited to participate in the Research will be entered in proforma and Google forms till the patient is in the hospital and during the discharge the patient will be informed about the date of the 7 th and 30th postoperative day for telephonic assessment after proper consent and an appropriate time will be fixed. The assessment tool will be sent via WhatsApp and the data will be entered by the principal investigator in the google form after the assessment. The normally distributed continuous variables will be expressed as mean & standard deviation and data not normally distributed will be expressed as interquartile range. For continuous variables tests like unpaired t test/ Mann Whitney U test will be applied. Categorical data will be expressed as frequency and percentage and Chi square test will be applied. The data will be analysed using the latest available version of SPSS (Statistical Product and Service Solutions) software and Microsoft excel. A P value of 0.05 or less will be considered significant.

Limitations of Study: Single centre study. This study does not use the higher doses of sugammadex which are authorised to use for deep neuromuscular blockade. Many standard neurocognitive tests have not been used for cognitive assessment.

Risk: unexpected hypersensitivity to sugammadex is an inevitable risk of this study though it is very rare. If hypersensitivity occurs it will be managed as per institutional protocol.

Benefits: If found that sugammadex indeed decreases the POCD it can be used as a NMB reversal agent in patients who already have some degree of cognitive impairment.