Comparative evaluation of the effects of propofol and sevoflurane on cognitive function and memory in patients undergoing laparoscopic cholecystectomy: A randomised prospective study.

BACKGROUND AND AIMS: General anaesthesia (GA) may cause post-operative impairment of cognition and memory. This is of importance where time to discharge after anaesthesia is short as after laparoscopic cholecystectomy. This study was conducted to compare the effects of propofol and sevoflurane on cognitive function in the post-operative period.
METHODS: After approval of the Ethical Committee, 80 female patients posted for laparoscopic cholecystectomy to be performed under GA were randomly divided into two groups. Propofol was used in Group P and sevoflurane in Group S. Data analysis was done with California verbal learning test (CVLT), digit span test (DST), Rivermead behavioural memory test (RBMT), mini mental state examination (MMSE) score, and semantic memory tests. Aldrete recovery scoring system and visual analogue scale for pain were assessed post-operatively. The level of statistical significance was set at P < 0.05.
RESULTS: There was no significant difference in demographic and haemodynamic data. Cognition and explicit memory were affected more in the propofol group in the immediate post-operative period. With majority of tests, such as semantic memory test, MMSE score, DST and RBMT, the difference was insignificant at 2 and 4 h post-operatively. But CVLT values were found to be statistically significant between groups even at 4 h.
CONCLUSION: Propofol was associated with significant impact on cognitive functions in comparison to sevoflurane in the immediate post-operative period. Sevoflurane anaesthesia might be a better option in day care surgeries.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

General anaesthesia (GA) clearly affects brain function in the post-operative period. Impairment of attention, memory, reaction time, and depressed level of consciousness are often reported.[1] Delayed functional recovery as a consequence of cognitive dysfunction would lead to prolonged hospital stay in patients undergoing GA. This is of great importance where time to discharge after anaesthesia is short as after laparoscopic cholecystectomy. Daycare surgeries are becoming more and more popular to cater to the needs of patients with tight work schedules and delayed recovery due to cognitive dysfunction is definitely not warranted. When providing GA, the goal is to achieve optimal surgical conditions while ensuring an early recovery. The causes of prolonged recovery of cognition and memory after anaesthesia and surgery are multifactorial. Various studies have implicated agents such as propofol and sevoflurane in the development of post-operative cognitive dysfunction (POCD).[23] Agents such as propofol, sevoflurane, nitrous oxide (N2 O), midazolam, and fentanyl act on various types of receptors in the brain and these in turn may lead to POCD.[45] Sevoflurane and propofol are two most commonly used anaesthetic agents in day care cases. The present study was an attempt to compare the effects of sevoflurane with that of propofol in patients undergoing laparoscopic cholecystectomy under GA as regards POCD in the immediate post-operative period (up to 4 h after surgery).

METHODS

This double-blinded randomised comparative study was conducted from November, 2012 to November, 2013 after obtaining approval of the Ethical Committee of the Institution. A total of 80 female patients posted for elective laparoscopic cholecystectomy to be performed under GA were included, after informed consent and divided into two groups of 40 patients each with the help of a computer generated randomisation list. The primary endpoint was to compare early post-operative cognitive functions between the two groups. Haemodynamic events, post-operative recovery and pain were also evaluated. A previous study by Flouda et al.[2] found that explicit memory score correlating to bispectral index (BIS®) 61-80 was 0.066 ± 0.089 and 0.004 ± 0.015 for anaesthetic agents propofol and sevoflurane, respectively. Assuming the same, at 2-sided type 1 error of 0.05 and power of 90%, a sample size of 32 per group was required to detect a significant difference. But we decided to take 40 patients per group for the study to account for drop outs. The principal investigator enrolled the patients and an anaesthesiologist not related to the study finally assigned the patients to the respective groups. Pre- and post-operative data were collected by a blinded observer who would not administer anaesthesia to the study subjects. Propofol was used in Group P and sevoflurane in Group S. All patients underwent a thorough pre-anaesthetic check-up. Inclusion criteria comprised female sex, American Society of Anaesthesiologists (ASA) I physical status, age group between 18 and 60 years, education till high school and pre-operative mini mental state examination (MMSE) score >23. Exclusion criteria included male patients, age >60 years or <18 years, ASA Grade-II or higher, allergy to the drugs to be used, patients receiving treatment with anti-anxiety drugs, anticonvulsants and antipsychotics, patients with known psychiatric illness, drug or alcohol abuse, patients having chronic pain syndrome, Alzheimer's disease or presenile dementia, pregnant and lactating women, history of jaundice in the past, patient refusal, patient's education level below high school and pre-operative MMSE score <23. All patients were kept nil orally from 8 h before surgery and pre-medicated with tablet alprazolam 0.25 mg and tablet ranitidine 150 mg orally on the night before surgery and 1 h prior to surgery. Pre-operative data were collected 1 h prior to surgery. In the operation theatre, baseline haemodynamic parameters (heart rate [HR], electrocardiography [ECG], non-invasive blood pressure [NIBP], pulse rate and pulse oximetry [SpO2 ]) were recorded in all patients. After securing the intravenous (IV) line, injection fentanyl 2 μg/kg IV, injection glycopyrrolate 5 μg/kg IV and injection ondansetron 4 mg IV were administered to the patients.

In Group P, anaesthesia was induced with injection propofol 2 mg/kg IV slowly till surgical plane of anaesthesia was achieved (BIS® value at 40-60). Injection vecuronium 0.1 mg/kg was administered and trachea was intubated with an appropriate sized cuffed endotracheal tube. Maintenance of anaesthesia was done using oxygen: N2 O at the ratio of 33:67, propofol infusion at the rate of 100–300 μg/kg so as to maintain BIS® value between 40 and 60 and vecuronium (0.01 mg/kg) supplements. Continuous intra-operative monitoring for ECG, HR, NIBP, BIS®, SpO2, and end-tidal CO2 was performed.

In Group S, anaesthesia was induced with inhalation of O2 and sevoflurane (5%) till BIS® value of 40-60 was reached and maintenance of anaesthesia was with oxygen: N2 O (33:67), sevoflurane and vecuronium (0.01 mg/kg) supplements. Rest of the procedure was kept uniformly same as in Group P. Anaesthesia was maintained at a BIS® level of 40-60 by adjustment of flow of propofol or minimum alveolar concentration of sevoflurane. Injection paracetamol 15 mg/kg IV was administered to all the patients intra-operatively. Neuromuscular blockade was reversed with injection neostigmine 0.05 mg/kg and injection glycopyrrolate 0.01 mg/kg.

Data collection and analysis were done as per following tests both pre-operatively (1 h prior) and post-operatively (at 5 min; 1, 2 and 4 h): (1) California verbal learning test (CVLT)[6] – Patients were asked to remember the names of five fruits so as to check verbal memory. (2) Digit span test (DST)[7] – Patients were asked to repeat four, five or six digit numbers to assess numerical memory. (3) Rivermead behavioural memory test (RBMT)[8] – Patients were shown a picture of an animal pre-operatively and asked to identify this animal post-operatively and also asked if the location of the animal was same so as to check the recall of day to day items by picture recognition. (4) RBMT[8] was used to check the semantic memory through recall of date of birth post-operatively. (5) Patients were asked to recall the names of the anaesthesiologist and the surgeon post-operatively. (6) MMSE[9] score – evaluated prior to surgery in order to know if there was any pre-existing cognitive dysfunction. Same was evaluated after reversal of anaesthesia.

Recovery from anaesthesia was determined by Aldrete recovery scoring system.[10] Post-operative pain was assessed by visual analogue scale (VAS) score up to 4 h post-operatively.[11]

Software used for statistical analysis was the SPSS version 18.0 (2009). The level of statistical significance was set at P < 0.05 for all tests. For each participant, we calculated the proportion of correct responses given post-operatively. Based on these results, we estimated the mean responses in each of the questions for propofol and sevoflurane groups separately. Normality and equal variance t-tests were used for quantitative variables. Two-tailed t-tests were performed to check the calculated memory scores and to analyse different hemodynamic data for both the groups. For nominal data, the Chi-square test was applied. Correlation coefficients of Pearson (for normally distributed variables) were used to test possible correlations between memory and quantitative variables (age, duration of anaesthesia/surgery).

RESULT

Demographic data were comparable between the two groups of 40 patients each [Table 1]. The mean duration of anaesthesia/surgery was 64.75 ± 12.65 min and 64 ± 12.20 min for Groups S and P, respectively (P = 0.788). There was no statistical significance between the two groups (P = 0.090) when the haemodynamic variables were compared. BIS values were maintained between 40 and 60 throughout anaesthesia in both groups (P > 0.05). Difference in Aldrete recovery score at 5 min post-reversal was found statistically significant (P < 0.05) whereas there was no significant difference (P = 0.077) at 1, 2 and 4 h [Figure 1]. Difference in the pain score of the patients in both groups as observed post-operatively by the visual analogue score (VAS) was not found to be significant (P > 0.05).

Table 1

Demographic data of the patients in group S and P

Figure 1

Aldrete recovery score of patients in Group S and P

Cognitive functions and memory assessed by various tests and questionnaires after reversal of anaesthesia at 5 min, 1, 2 and 4 h post-operatively showed following results: MMSE [Figure 2]; pre-operative MMSE score in all patients of both the groups was >23. The difference between the groups was statistically significant (P < 0.05) at 5 min, 1 and 2 h post-operatively (at 4 h post-operatively, P = 0.314). CVLT [Figure 3]; the difference between the groups was found to be statistically significant (P < 0.05) at all times up to 4 h. DST; the difference between the groups was statistically significant (P < 0.05) at 5 min, 1 and 2 h post-operatively but not at 4 h. RBMT; in Group S, all patients identified the animal post-operatively at all times. In Group P, however, 9 and 5 patients did not identify the animal at 5 min and 1 h respectively (P < 0.05). After 2 and 4 h post-operatively, there was no significant difference (P = 0.134). When asked whether the animal shown pre-operatively was at the same location or not, the difference between the groups was significant only at 5 min post-operatively (P < 0.05). 1, 2 and 4 h post-operatively, the association was not statistically significant (P = 0.152).

Figure 2

Mini mental state examination pre- and post-operatively in Groups S and P

Figure 3

Number of fruits that patient can remember post-operatively in Groups S and P

In regard to recall of anaesthesiologist's name, difference between the groups was found to be statistically significant (P < 0.05). Recall of surgeon's name; the difference was statistically significant (P < 0.05) again [Figure 4]. In Group S, 37 patients remembered their DOB after 5 min and all patients remembered it at 1, 2 and 4 h post-operatively; whereas in Group P only 17 and 26 patients remembered their DOB after 5 min and 1h respectively (P < 0.05). At 2 and 4 h post-operatively, the difference ceased to be statistically significant.

Figure 4

No of patients who remembered the name of the surgeon in Groups S and P

DISCUSSION

Post-operative cognitive dysfunction is characterised by impairment of memory and cognitive function, reduced ability to concentrate and deterioration in emotional or social behaviour. The term cognition comes from the Latin verb congnosco (con ‘with’ + gnosco ‘know’).[112] Three types of cognitive deterioration after surgery are delirium, short-term cognitive disturbance and true POCD which is a subtle deterioration in cognitive function lasting for weeks, months or longer.[1] It has been subjected to extensive research. Apart from anaesthetic agents, various other suspected factors are glucocorticoid levels, pre-existing cognitive impairment, neuroinflammation, age, brain hypoperfusion, hypoxia, and genetic aspects.[131415] One study by Terri[16] however, offered firm evidence that commonly used inhaled anaesthetic agents do not increase the incidence of cognitive problems such as delirium in the early post-operative period. Anaesthetic drugs may act by causing long-term receptor changes, apoptosis, changes in cholinergic binding and gene expression.[1718] The incidence of POCD which is reported in various studies involving the same form of surgery and anaesthesia varies immensely. This may be due, in part, to methodological issues as well as to individual patient differences. Large differences are apparent in available literature such as the choice of test batteries (too easy or too difficult tests), the interval between sessions, the time of post-operative assessments, the endpoints to be analysed, statistical methods, change of test personnel, suitability of normative population and period of follow-up and attrition.[192021] In the present study, short-term POCD is evaluated. Traditionally, intelligence tests or tests developed for clinical neuropsychology have been used mostly in the geriatric age group. Post-operative delirium in elderly is one of the most under-diagnosed clinical entities in anaesthesiology practice, which enhances the morbidity and mortality on this subset of the population.[22] We could find a few such studies with younger patients undergoing anaesthesia, comparing these drugs. Similar studies[22324] have showed that sevoflurane affects the implicit memory and cognition of adequately anaesthetised subjects less than propofol. There was no benefit of using total IV anaesthesia with propofol and opioid over the conventional balanced volatile technique in terms of recovery and cognitive functions.[25] Emergence and return of cognitive function were significantly faster after propofol compared with sevoflurane when assessed 60 min post-operatively in another study.[326] Thus, the inferences of different studies have been different. In our study, propofol has been shown to affect explicit memory and other cognitive functions more in the immediate post-operative period. Sevoflurane, an inhalational anaesthetic of the ethereal origin with low solubility in blood and body tissue is characterised by rapid induction and recovery and has been found to have less cognitive impairment than propofol.[23] Sevoflurane with a blood gas partition coefficient of 0.65 might, therefore, be a better drug as far as short-term preservation of cognitive functions are concerned and hence a better option in day care surgeries.

The limitation of this study was that it was not possible for us to follow-up the patients beyond 4 h post-operatively. A short-term comparison between the two groups was therefore planned.

CONCLUSION

Propofol was found to have a significant impact on cognitive functions and memory in comparison to sevoflurane in the immediate post-operative period of up to 1 h. At 2 and 4 h post-operatively, the values were not significantly different for many of the variables except for verbal memory which was affected in the propofol group even at 4 h. Therefore, sevoflurane anaesthesia might be a better option in day care surgeries where patients have to be discharged early.