Cognitive function recovery rate in early postoperative period: comparison of propofol, sevoflurane and isoflurane anesthesia

Introduction : There is no simple answer to the question as to when the brain function is back to normal after anaesthesia. Research done so far has identi ﬁ ed different factors in ﬂ uencing the rate of cognitive function recovery and type of anaesthetic as one of those factors. Methods : This study encountered 90 patients hospitalized in neurosurgical department of University Clinical Centre Tuzla in period from October 2011 to may 2012 year. Aim of the study was to compare in ﬂ uence of three different anesthetics (propofol, iso ﬂ urane and sevo ﬂ urane) on recovery rate of cognitive performance 1, 5 and 10 minutes following extubation. Assessment of cognitive functions was preformed using the short Orientation-Memory-Concentration (OMC) Test. All patients included in the study underwent lumbar microdiscectomy surgery and were allocated to one of three groups: propofol, sevo ﬂ urane and iso ﬂ urane. Results : Trough comparison of OMC test values there is obvious superiority in recovery of cognitive functions between propofol group and inhaled anesthetic group, after 1 minute (p = 0.008) and after 5 minutes (p =0.009). Comparison of propofol and iso ﬂ urane anesthesia shows signi ﬁ cantly faster recovery of cognitive performance in propofol group (after 1 minute p = 0.002, 5 minutes p = 0.004, 10 minutes p = 0.038). Faster recovery of cognitive function is present in sevo ﬂ urane compared to iso ﬂ urane group only 1 minute after extubation p = 0.049. Conclusions : Fastest recovery of cognitive performance appears after propofol anesthesia, than follows sevo ﬂ urane based anesthesia and after that iso ﬂ urane anesthesia.


INTRODUCTION
General anesthesia encompasses amnesia, hypnosis (defi ned as a lack of perceptive awareness to nonnoxious stimuli), analgesia, immobility, and blunting of autonomic refl exes. Th ese eff ects are induced by specifi c interactions of general anesthetics on discrete neuronal loci (1). For a long time it has been believed that anesthetic eff ects do not outlast their pharmacological action, and that the target organ is restored to its pre-anesthetic state with the elimination of anesthetic agent (2). Brain function changes during and in the immediate period after general anesthesia, which is characterized with depressed consciousness, impaired attention, memory, and prolonged reaction time (1). Cognition is defi ned as the mental processes of perception, memory, and information processing, which allows the individual to acquire knowledge, solve problems, and plan for the future (2). Postoperative disturbance in cognition, or as often been referred to as postoperative cognitive dysfunction (POCD) is a term used variably and it is useful to make a distinction between three types of cognitive deterioration after surgery. POCD needs to be distinguished from postoperative delirium, which is transitory and intermittent disturbance of consciousness that usually occurs shortly after surgery, and short-term cognitive disturbance that may be apparent in early postoperative course. Short-term cognitive impairment occurs relatively frequently and may be due to a combination of factors, including surgery and anesthetic agents and it lasts several days after surgery (1,3). While POCD is deterioration of intellectual function presenting as impaired memory or concentration, long-term complication of surgery and anesthesia related with changes in cognitive performance, both are usually assessed trough various neuropsychological tests (3)(4)(5). Propofol is the most frequently used IV anesthetic today, it is short acting intravenous anesth etic used as an induction agent, for sedation and maintenance of anesthesia. Propofol hypnotic activity is mostly mediated through enhancing γ-aminobutyric acid (GABA) induced chloride current through its binding to the β-subunit of GABA A receptor (6). Propofol is rapidly metabolized mostly in the liver however since its clearance exceeds hepatic blood fl ow, extrahepatic metabolism is suggested, its metabolites are considered inactive (1). Half-life of propofol after initial dose is 2 to 8 minutes (7), and even after prolonged infusions, propofol provides rapid recovery (1). Volatile anesthetics are relatively inexpensive drugs, easily administered via inhalation, readily titrated, and have a high safety ratio. Depth of anesthesia can be quickly adjusted in a predictable way while monitoring tissue levels via end-tidal concentrations, in addition inhaled anesthetic cause relaxation of skeletal muscle (8). Sevofl urane (1-trifl uoromethyl-2,2,2-trifl uoroethyl monofl uoromethyl ether) was synthesized in the 1970s, but its introduction into clinical practice was delayed, due to the occurrence of toxicity in experimental animals, it was fi rst used in 1981 (1). Sevofl urane is relatively insoluble in blood and has a low blood-gas partition coeffi cient (0.65); it is slightly more soluble than nitrous oxide and desfl urane. Since its tissue-blood partition coeffi cients are also low, induction and recovery from anaesthesia are extremely rapid, and the level of anaesthesia is easily controlled (9). Isofl urane, (1-chloro-2,2,2-trifl uoroethyl difl uoromethyl ether) was synthesized by R.C. Terrell during the 1960s, and is now widely used as an inhalational agent, it is a clear, non-fl ammable liquid at room temperature and has a high degree of pungency. Th ere has been a period of controversy concerning the use of isofl urane in patients with coronary disease because of the possibility for coronary steel eff ect arising from the potent eff ects of isofl urane on coronary vasodilatation (8,9). All potent inhaled anesthetic cause dose dependant decrease in cerebral metabolic rate, paralleling changes in electro encephalography (EEG). Duration of recovery of cognition after anesthesia is variable and depends on many factors such as type of surgery, type of anesthesia, duration of surgery, respiratory complications, and second operation as well as patient related factors (1). Aim of this study is to obtain adequate insight in cognitive performance recovery rate in early postoperative period after use of diff erent anesthetic for maintaining anesthesia.

METHODS
We conducted a prospective study with 90 patients hospitalized in neurosurgical department of University Clinical Centre Tuzla in period from October 2011 to May 2012. Aim of the study was to compare infl uence of three diff erent anesthetics (propofol, isofl urane and sevofl urane) on recovery rate of postoperative cognitive disorders in early postoperative period. All patients included in the study underwent lumbar microdiscectomy surgery due to herniated lumbar disc, and were assessed as ASA I (American Society of Anesthesiologists) physical status. Written consent was obtained from all the patients included in the study. Patients were randomly allocated to one of three groups and received designated anaesthetics, each group consisting of thirty patients: Group 1 -propofol maintained anesthesia; Group 2 -sevofl urane maintained anesthesia; Group 3: isofl urane maintained anesthesia. Balanced anesthesia was used in all three groups. Patients where premedicated using either diazepam 5 mg or midazolam 2.5 mg and fentanyl 0.10 mg. Following induction with propofol 1.5 to 2.5 mg/ kg, tracheal intubation was facilitated with atracurium, which was also used in maintaining muscular relaxation in a doze 0.3-0.6 mg. Anesthesia was maintained using nitrous oxide (N 2 O) and oxygen (O 2 ) in ratio 60:40 in all three groups and in group 1 with continuous propofol infusion 8 to 10 mg/kg/h. In group 2 to N 2 O: O 2 mixture, 1. 0 volume % of sevofl urane was added for maintaining anesthesia and in group 3, 1.0 volume % of isofl urane. In all three groups analgesia was provided with fentanyl boluses ranging form 0.05 to 0.10 mg per dose. Assessment of cognitive functions was preformed 1, 5 and 10 minutes following extubation, using the short Orientation-Memory-Concentration (OMC) Test or Short Blessed Test (Appendix 1) (10). Th is test addresses cognitive performance in the areas of orientation, memory, and concentration. It is been used in quick evaluation of cognitive functions, and it is sensitive and reliable in detecting early cognitive impairments. OMC test possesses good metric characteristics and it is perceptive to global as well as cognitive defi cits of left-brain hemisphere. Short OMC test consists of six questions and it is a part of larger test known as Blessed Information-Memory Concentration (BIMC) test, consisting of 26 questions (10).

Statistical analysis
Results are displayed in numeric-percentual form, as well as mean value with standard deviation (SD). Signifi cance was evaluated using Chi square test and Student test, and correlation between gender and cognitive disorder caused by specifi c anesthetic was estimated using Pearson's Test. Regression analysis was used to identify factors infl uencing recovery of cognitive functions. Statistical analysis was performed with a confi dence interval of 95% and value of p <0.05 was considered statistically signifi cant.

RESULTS
Th e study is conducted in University Clinical Centre Tuzla, it included 90 patients randomly allocated in three groups each group consisting of 30 patients. Average age of patients in all three groups was 45.47 (SD ± 8. 03 years), average age in group 1 was 45.48 years (SD ± 7.98), in group 2 it was 46.23 years (SD ± 8.63) and in group 3 patients' average age was 45.37 years (SD ± 7.94). Out of 90 patients included in the study, 58 were men (64.44%) and 32 (35.56 %) were women. In-group 1 there were 21 (70 %) men and 9 (30 %) women, in group 2 out of 30 patients 20 (66.7 %) were men and 10 (33.3 %) were women and group 3 consisted of 17 (56.7 %) men and 13 (43.3 %) women. Demographic (age, gender) characteristics, body mass index (BMI), smokers-non/smokers, duration of anesthesia is shown in (Table 1), gender distribution of patients shown in (Figure 1).   (Table 1), there was no statistical significance in age distribution of the patients (p = 0.79), there was also no statistical signifi cance between the groups concerning gender allocation (p = 0.53). In group 1 there was 11 (36.6%) smokers, in group 2 there was 9 (30 %) and in group 3, 10 (33.3 %) patients were smokers. No statistical signifi cance between the observed groups in correlation to smoking was noticed (p = 0.75). BMI was in group 1 24.6 (± 4.66), in group 2 23.06 (± 3.27) and in group 3, 24.5 (± 3.65), there was also no signifi cance concerning BMI between the groups (p = 0.83). Average duration o anesthesia in group 1 was 96.67 minutes (SD ± 18.68), in group 2 average length of anesthesia was 99 minutes (SD ± 21) and in group 3 it was 96.37 minutes (SD ± 19.79). Th ere was no statistical signifi cance between the groups concerning length of anesthesia (p = 0.85). Infl uence of specifi c anesthetic on cognitive functions recuperation was evaluated based on the values obtained performing OMC test. As seen in (Table  2), trough comparison of OMC test values there is obvious correlation and statistical signifi cance present regarding recovery of cognitive functions depending on the type of anesthetic used. Th is statistical signifi cance is present in evaluation of cognitive function recovery between propofol group and inhaled anesthetic group, after 1 minute (p=0.008) and after 5 minutes (p =0.009), after 10 minutes there was no signifi cant diff erence (p=0.006). By comparing intravenous anesthesia with propofol to inhaled anesthesia with sevofl urane no statistically signifi cant diff erence was found (OMC score after 1 minute p=0.251, OMC score after 5 minutes p = 0.190 and OMC score after 10 minutes p=0.066) ( Table 3).
Comparison of propofol and isofl urane anesthesia shows signifi cant diff erence in recovery of cognitive functions between groups. Cognitive recovery was signifi cantly quicker in propofol group expressed by     OMC score and after one minute p = 0.002, after 5 minutes p=0.004 and after 10 minutes p=0.038 as shown in (Table 4). As seen from (Table 5) statically signifi cant difference exists between sevofl urane and isofl urane group, indicating faster recovery of cognitive function in sevofl urane group only 1 minute after extubation p=0.049.
Based on values of OMC test preformed 1, 5 and 10 minutes after extubation it is clearly visible that the fastest recovery of cognitive function appears after propofol anesthesia, than follows sevofl urane based anesthesia and after that isofl urane anesthesia, where cognitive performance recuperation is the slowest (Figure 2).

DISCUSSION
Despite technological development in fi eld of surgery and anesthesiology during the last decades, postoperative cognitive dysfunction is still relatively frequent complication in surgical patients. After surgery, elderly patients in particular often display evidence of a temporary state of cognitive function deterioration. Anesthetics administered as part of a surgical procedure may alter the patient's behavioural state by infl uencing brain activity (11). Brain is the target organ for anesthetics and their eff ects on brain activity are often present after ending of the surgical procedure and awakening of the patient. Available literature off ers no defi nite conclusion on possible diff erences between anesthetics and their infl uence on cognitive functions and duration of cognitive impairment.
International study on cognitive dysfunctions examined infl uence of age on POCD; results of this study have shown higher incidence of POCD in patients age 60 to 81 years (average age 68 years) up to 26% compared to patients age 40 to 60 years (average age 51 years) where cognitive dysfunction was found in 19% of patients examined (10). Average age of patients included in our study was 45.47 years (SD ± 8.03) and age range in all three groups was approximately same, age did not signifi cantly infl uenced recovery rate of cognitive function. Out of 90 patients included in the study, 64.44 % were men and 35.56 % were women, there was no statistically signifi cant diff erence between the groups in correlation to gender. Use of inhaled anesthesia is widespread, frequently used inhaled anesthetics are sevofl urane, isofl urane and desfl urane usually in combination with N 2 O, only several studies examined infl uence of these anesthetics on cognitive functions (13). Isofl urane is present in anaesthesiological practice for a long time and there are various studies that explored eff ects of isofl urane on cognitive performance in postoperative period. Study conducted by Tsai et al. in year 1992, explored infl uence of isofl urane and desfl urane on cognitive dysfunction in patients undergoing elective orthopaedic surgery and found desfl urane to be superior to isofl urane regarding cognitive recovery (14). Th ese results were also confi rmed in studies conducted by Dupont et al. and Loscar et al. in patients who underwent elective thoracic surgery (15,16). Sevofl urane is most common inhaled anesthetic in current anaesthesiological practice. In the study conducted by Schwender et alt. cognitive and psychomotor performance recovery was quicker and more complete after sevofl urane compared to isofl urane anesthesia (17,18). Superiority of sevofl urane compared to isofl urane anesthesia in cognitive performance recovery was proven in analysis done by El-Dawlatly (19). Our results show sevofl urane to be superior to isofl urane when cognitive performance recovery was concerned.
Recovery of cognitive functions in our study was superior in propofol group compared to inhaled anesthesia with sevofl urane and isofl urane, determined with OMC test, measured in the fi rst and fi fth minute. Larsen et alt. conducted a study on accuracy of the answers concerning orientation, short term memory and concentration. Results of this study showed that 30 minutes after anesthesia administration, patients in the remifentanil-propofol and in the desfl urane groups gave signifi cantly more correct responses in the Trieger Dot Test and Digit Substitution Test (DSST) compared with sevofl urane (18). Th ere are other fi ndings such as these of Magni et alt. who proved in there study that total intravenous anesthesia with propofol/remifentanil shows no patient benefi t over sevofl urane/fentanyl-based anesthesia in terms of recovery and cognitive functions (20). It is generally assumed that general anesthesia is completely reversible state, but this cannot be proved, Jevtovic-Todorovic et alt. found histological changes in the brain of animals exposed to isofl urane, N2 O, ketamine and midazolam (21). All the patients included in the study were discharged form the hospital in due time, with out verifi ed permanent cognitive disorders. Th ere is no simple answer to the question as to when brain function is beck to normal after anesthesia, research done so far has identifi ed diff erent factors infl uencing rate of cognitive function recovery, and type of anesthetic is confi rmed to be signifi cant factor by several studies conducted so far.

CONCLUSIONS
Th is study confi rmed faster recovery of cognitive performance following propofol anesthesia compared to anesthesia with sevofl urane and isofl urane, after fi rst and fi fth minute after extubation. Th ough OMC score was lower in propofol group, ten minutes post extubation, compared to inhale anesthetic group, still statistical signifi cance was not found. When compared propofol and sevofl urane anesthesia, OMC scores were lower in propofol group, but with out statistical signifi cance. It was established that the recovery of cognitive performance was superior after propofol anesthesia compared to isofl urane, and statistical signifi cance was observed at all three times measured. Sevofl urane anesthesia shoved faster recovery of cognitive functions compared to isofl urane anesthesia after fi rst and fi fth minute post extubation. Fastest recovery of cognitive performance appears after propofol anesthesia, than follows sevofl urane based anesthesia and after that isofl urane anesthesia.