Effect of intraoperative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.136908
Source of Support: None, Conflict of Interest: None
Background: Cognitive dysfunction after subarachnoid hemorrhage (SAH) has been attributable to presence of subarachnoid blood, hydrocephalus (HCP), cerebral edema, vasospasm, and temporary clipping of intracranial aneurysm. Provision of neuroprotection during temporary clipping may improve postoperative cognition in such patients. Materials and Methods: Good-grade aneurysmal SAH patients undergoing temporary clipping during surgery were allocated either to group C (control) or group P (propofol). Patients in group P received propofol in titrated doses to attain a burst suppression ratio of 75 ± 5% on bispectral index (BIS) monitor. The cognitive function as assessed by Hindi-language modification of mini-mental state examination (HMSE) score was evaluated preoperatively, 24 h after surgery, and at discharge from hospital. A score of ≤23 was indicative of cognitive dysfunction. Perioperative complications, duration of intensive care unit (ICU) and hospital stay, and outcome at discharge were noted. Results: A total of 66 patients (32 and 34 in group C and P respectively) were included in the study. 97% of the patients had anterior circulation aneurysms. At 24 h after surgery, eight and 12 patients in group C and P respectively; and at discharge, five patients in each group had cognitive dysfunction. In both groups, the trend showed a decline in cognition at 24 h followed by improvement at discharge. Glasgow outcome score in both the groups was comparable (P > 0.05). Intraoperative brain bulge, postoperative vasospasm, and cerebral infarction were found to be independent risk factors for cognitive dysfunction. Conclusions: Pharmacologic neuroprotection with propofol at the time of temporary clipping during surgery for aneurysmal SAH did not offer any advantage as far as preservation of cognition is concerned.
Keywords: Intracranial aneurysmal surgery, neuroprotection, postoperative cognition, propofol temporary clipping
The management of subarachnoid hemorrhage (SAH) witnessed remarkable changes during past few decades; however, it still remains a major cause of morbidity and mortality. The patients with good neurological outcome continue to suffer from high degree of neurobehavioural deficits. , Often these patients are not able to resume their routine activities and thus, the quality of life is compromised. Neuropsychological examination may help evaluating the outcome of these patients in a comprehensive manner. Various neuropsychological test batteries are used for assessment of cognition. The mini-mental state examination (MMSE) is a screening test used for cognitive dysfunction. It has been modified and translated into Hindi mental state examination (HMSE) with a score ranging from 0-30; a value of less than or equal to 23 is considered as impaired cognition. HMSE is more apt for usage in Indian population. ,
The neurocognitive dysfunction after SAH has been attributed to multiple factors like exposure of brain to subarachnoid blood, associated hydrocephalus (HCP), global cerebral edema, vasospasm or to temporary clip application during the surgery. Technique of temporary clipping though indispensible, involves the risk of focal cerebral ischemia, which may lead to neurological deficit or neurocognitive impairment in the postoperative period. ,
Provision of neuroprotection with barbiturates, etomidate, mannitol, isoflurane, propofol, and mild hypothermia during temporary clipping has been studied by various authors. ,, Although animal experiments have emphasized the usefulness of these agents, human studies yielded conflicting results. Neuroprotection with propofol has been attributed to its ability of reducing cerebral metabolism, potentiation of gamma-amino butyric acid (GABA) activity, free radical scavenging, antioxidant properties, reduced eosinophilic, and apoptotic injury.
Bispectral index (BIS) is an electroencephalogram (EEG) based monitor which provide burst suppression ratio (BSR), a value of 71% commensurate with minimal cerebral metabolic rate of oxygen (CMRO 2 ). , The rationale is to minimize the CMRO 2 with pharmacological agents, so that the brain sustains the focal ischemia induced during temporary clipping. No improvement in short- or long-term neurologic outcome observed with use of either thiopental or etomidate during temporary clipping.  Our literature search did not reveal any study evaluating the effect of propofol for neuroprotection on postoperative cognitive function. Therefore, this study was carried out with the aim to evaluate the effect of intra-operative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery .
After approval from the Institutional Ethics Committee, written informed consent for participation in the study was obtained from all patients. The study population comprised of patients with SAH who underwent intracranial aneurysm clipping at our centre over a period of 2 years. Patients with Hunt and Hess grade (H and H)  more than II, those who did not require temporary clipping, Glasgow Coma Scale (GCS) <15, those with history of any psychiatric illness, alcoholics, and drug abusers were excluded from the study.
Prior to surgery, all relevant details regarding history and clinical examination were noted including the SAH grades (H and H grade  and Fisher grade  ). The baseline neuropsychological examination with the help of HMSE was performed. All patients received intramuscular glycopyrrolate 0.2 mg, 30 min before induction of anesthesia. In the operation theatre, routine monitors such as electrocardiography (ECG), pulse oximetry (SpO 2 ) and noninvasive blood pressure were attached. After intravenous (IV) access was secured, the radial artery was cannulated under local anesthetic infiltration for continuous blood pressure monitoring. A BIS sensor was placed on the forehead on the side opposite to the planned craniotomy. Anesthesia was induced with fentany l 2 μg/kg and propofol 2 mg/kg. Muscle relaxation was achieved with vecuronium 0.1 mg/kg. Lignocaine 1.5 mg/kg was administered IV to suppress the pressor responses of laryngoscopy and tracheal intubation. All the patients were mechanically ventilated to maintain an end-tidal CO 2 of 30 + 2 mmHg. Anesthesia was maintained with 60% nitrous oxide in oxygen and isoflurane to maintain a BIS value of 40-60. Fentanyl and vecuronium were supplemented as needed, at the discretion of the attending anesthesiologist. Nasopharyngeal temperature probe was inserted and normothermia (36-37 o C) was maintained with the use of convective air warmers and warm IV fluids. Central venous catheterization was done in all the patients and a central venous pressure (CVP) of 6-8 mmHg was maintained with fluid infusions. A 20% deviation of mean arterial pressure (MAP) on either side of the baseline was treated whenever deemed necessary. Mannitol 20% (1 g/kg) was infused over 20-30 min before dural opening.
Once the decision to place temporary clip was taken the patients were randomly allocated to either group "C" (control) or group "P" (propofol) according to a computer-generated randomization chart. Patients in group P received propofol 1.5 mg/kg bolus followed by 100-200 μg/kg/min titrated to attain BSR of 75 + 5%. The propofol infusion was stopped when temporary clip was removed and the total amount of propofol used was noted. The patients of group C (control) did not receive propofol and BIS was kept between 40-60. Frequency and duration of temporary clip application, BSR, MAP and temperature were recorded during the temporary clipping. Phenylephrine 50-100 μg was administered to maintain MAP 10-20% above baseline during this period. Once the aneurysm was clipped, central venous pressure (CVP) was maintained between 10-12 mmHg while MAP at 10-20% above baseline by administration of IV fluids and dopamine. Intra-operative complications like brain bulge, cardiac arrhythmias, or aneurysm rupture were noted. Time to eye opening, obeying verbal commands (time taken from cessation of anesthetic agent to spontaneous eye opening or obeying verbal commands, respectively), and time of extubation (time from cessation of anesthetic agent to extubation) were recorded. Immediate postoperative complications such as shivering, restlessness, headache, convulsions, nausea, and vomiting were recorded. All the patients were shifted to intensive care unit (ICU) for further management. Post-operative complications like cerebral vasospasm, rebleeding, meningitis, and HCP were noted. The postoperative cognitive functions were evaluated at 24 h after the surgery. Duration of ICU and hospital stay, Glasgow Outcome Scale (GOS) and cognitive function at discharge were also recorded.
Statistical analysis was done using software SPSS-15. Data were expressed as mean ± standard deviation (SD) or number (percentage). Student's t-test or Mann Whitney test was applied to compare continuous variables. Qualitative data were analyzed using Chi-Square test or Fisher's exact test. The change in cognition scores over period of time was assessed by repeated measures one way analysis of variance (ANOVA) followed by post-hoc comparison by Bonferroni method. Univariate analysis for factors causing cognitive dysfunction was performed by applying Chi-square/Fisher's exact test, wherever applicable. Multivariate analysis by logistic regression by stepwise forward method was done for overall sample. Besides this, the data was presented as odds ratio (95% CI). A P value less than 0.05 was considered significant.
A total of 66 patients (30 male and 36 female) were included in this study out of which 32 and 34 patients were randomized to groups C and P, respectively. Mean age, gender, weight, associated co-morbid conditions, and ECG changes were comparable in between the two groups [Table 1]. The number of patients belonging to different SAH grades was comparable [Figure 1] and [Figure 2]. The average number of days from ictus to surgery was 16.3 and 13.6 days in group C and P respectively. Initial computed tomographic (CT) scan of the head revealed presence of HCP in five patients in group C and eight patients in group P. At admission, in group C, one patient had left frontal cerebral infarct and another patient in group P had right posterior-frontal infarct. Majority of the patients were operated for anterior circulation aneurysm (97%). Multiple aneurysms were present in 10 patients. The distribution of various aneurysms at different locations was comparable in both the groups [Figure 3]a and b. Preoperative cognitive dysfunction (HMSE score ≤23) was seen in three patients in group C and two patients in group P. The mean HMSE score was 27.7 ± 2.4 and 27.6 ± 2.7 in groups C and P, respectively.
Intraoperative tight brain was observed in 10 patients, five in each group [Table 2]. One patient required additional dose of mannitol, whereas others improved with bolus dose of propofol and hyperventilation. Mean duration and frequency of temporary clipping was comparable in both the groups. Target burst suppression of 77.5% was achieved in all the patients in group P at the time of temporary clip application. The aneurysm was ruptured intraoperatively in 31.3% and 5.9% patients in group C and P, respectively (P < 0.01). During temporary clipping, the core temperature was comparable in both groups. Phenylephrine was required in all the patients in propofol group, at the time of burst suppression. Intraoperative blood loss and duration of surgery were comparable in between the two groups [Table 3]. After reversal of residual neuromuscular blockade two patients in group C and five in group P remained drowsy; hence, trachea was not extubated. The mean time for eye opening and obeying to verbal commands was similar in the two groups [Table 3].
Two patients in group C could not undergo cognition assessment at 24 h as they remained intubated. Eight and 12 patients in group C and P had HMSE score ≤23. Mean HMSE score at 24 h was 24.7 ± 3.6 and 25.2 ± 3.1 in group C and P respectively.
In the ICU, all patients received triple-H therapy and nimodipine during the postoperative period. The patients, who developed a new neurologic deficit, underwent Transcranial Doppler (TCD) ultrasonography for the assessment of cerebral vasospasm. Cerebral vasospasm was seen in eight and nine patients in group C and P respectively. Development of new infarct was seen in 4 patients in each group. In group C, the temporary clipping time in these four patients was 5 min 3 sec, 12 min 27 sec, 40 min, and 77 min respectively. Vasospasm was observed, postoperatively, in first three patients. The patients, who developed postoperative cerebral infarct in the group P, had temporary clipping time 7 min 50 sec, 6 min 52 sec, 5 min 56 sec, and 23 min 45 sec, respectively. All these patients developed postoperative cerebral vasospasm. Decompressive craniectomy was performed in two patients from each group, for reducing raised intracranial pressure.
Postoperatively, two patients in group C developed hemiparesis, one patient developed lower limb weakness and one patient died. In group P, one patient developed right upper limb weakness another patient developed paraparesis and three patients suffered hemiparesis. The duration of ICU and hospital stay [Table 4] and GOS at discharge [Figure 4] were comparable between the two groups.
Cognition assessment at discharge could not be undertaken in two patients, in each group. Five patients in each group had HMSE scores ≤23 [Figure 5]. Change in HMSE scores over time was significantly different between the two groups. In group C, there was a significant decrease in HMSE scores from 27.7 to 24.7 at 24 h (P = 0.00) followed by an increase at the time of discharge (26.50, P = 0.01). A similar trend of HMSE scores in relation to time was seen in group P. Mean HMSE scores decreased at 24 h after surgery from 27.59-25.22 (P = 0.00) and then improved to 26.47 (P = 0.01) at the time of discharge.
Univariate analysis suggested that the intraoperative brain bulge, postoperative vasospasm and cerebral infarct were associated with cognitive dysfunction at discharge. These three factors were confirmed to be independent risk factors for cognitive dysfunction, on multivariate analysis.
Cognitive function of patient determines the social integration and ability to regain the day to day activities. This measures the outcome of patient in real sense.
Results of various studies have been conflicting regarding the relation of site and cognitive impairment. Stenhouse et al.,  found that 56% of the patients who underwent surgical repair of ruptured anterior communicating (Acom) artery aneurysm had evidence of greater degree of intellectual and memory deterioration and a poor performance on conceptual learning. However, several other authors found no significant effect of aneurysm location on neuropsychological outcome. ,, Acom artery aneurysm comprised 60.6% in our study. 53.9% of patients with Acom artery aneurysm had cognitive dysfunction which was comparable with the results of Stenhouse and colleagues. 
Akyuz et al.,  studied the effect of temporary clipping on frontal lobe functions in patients with ruptured Acom artery aneurysm. At 2 years, patients who did not undergo temporary clipping during surgery, had normal executive functions as healthy control subjects, whereas, those who underwent temporary clipping (mean duration 8.2 ± 2.9 min) continued to have significant impairment. There are conflicting views on safe limits of temporary clip application. Ogilvy and co-workers  studied a series of SAH patients undergoing aneurysm clipping and found that intra-operative aneurysm rupture and duration of temporary clip application more than 20 min was associated with development of infarct and thus poor outcome. Lavine and colleagues suggested that 10 min is a general guideline for safe temporary arterial occlusion in the middle cerebral artery.  Goldmann and associates claimed that 5 min of reperfusion after 10 min of ischemia can reduce the infarct volume than continuous cerebral ischemia.  In the present study, 50% of the patients with cognitive dysfunction at discharge had application of temporary clip for more than 10 min. However, this was found to be statistically insignificant.
It has been found that IV brain protection has a significant advantage of reducing the incidence of postoperative infarction in aneurysmal patients.  However, Hindman et al., did not find any beneficial effect with either mild hypothermia or thiopentone/etomidate during temporary clip application.  In the present study, the average duration of temporary clip application was comparable between the two groups (11.9 vs 9.9 min) and a comparable incidence of postoperative cerebral infarction was observed. There are few concerns that neurologic injuries or recovery after an insult may evolve over time. Therefore, short-lasting interventions intended to minimize the adverse effect may not have a long-term benefit.
Intra-operative aneurysm rupture adversely affects the outcome of intracranial aneurysm surgery.  In the present study, during dissection, rupture of aneurysm occurred in 31.3% and 5.9% patients in group C and P, respectively (P = 0.00). This difference may be attributed to better brain condition provided by the propofol in group P. However, neurological outcome was good (GOS = 5) in majority (75%) of these patients which is consistent with the results of the study by Sandalcioglu et al. 
It has been found by Cheng et al., observed one or more impaired cognitive function in 70.3% of aneurysmal SAH patients, during preoperative period.  Incidence of cognitive dysfunction, however, in good H and H grade patients, at the time of admission has not been studied extensively. We observed preoperative cognitive dysfunction in five (7.6%) patients; two had HCP on admission, and two with Fisher grade 3/4. At the time of discharge, all these patients had HMSE score more than ≥23 except for one patient in group C, who was tracheostomized and could not undergo neuropsychological testing and another patient in group P, in which it remained below cutoff (<23).
At 24 h (postoperative), 26.6% and 35.3% patients in group C and P, respectively had HMSE score of ≤23. Amongst these, five (62.5%) patients in group C and four (33.3%) patients in group P had temporary clipping time more than 10 min (mean 17.4 min). At the time of discharge, cognitive dysfunction was observed in 16.7% and 15.7% of patients in group C and P respectively.
The mean cognition score at the time of admission was 27.7 and 27.6 in the two groups. At 24 h, there was significant decline in cognitive function (24.7 and 25.2) in both the groups. This decline may be attributed to the effect of surgery, pain, sleep deprivation, anxiety, residual effects of anesthetics, cerebral vasospasm, HCP, and several unknown factors. , At the time of discharge, a significant improvement was seen in cognition probably due to the interplay of several factors such as resolution of headache, clearance of blood in contact with cortical surface of brain, resolving HCP, and vasospasm. However, exact mechanism responsible for this change is not known. Moreover, subtle dysfunction in cognition may persist for several months, which requires a battery of neuropsychological tests with long-term follow-up.
Multivariate analysis revealed three major contributory factors for postoperative cognition dysfunction to be intraoperative tight brain, postoperative cerebral vasospasm and infarct which was present in 40%, 90%, and 40% cases, respectively. Global cerebral edema has been described as a predictor of cognitive dysfunction.  Tight brain may require further retraction of brain to for better surgical exposure. This may result in neuronal injury and edema leading to postoperative cognitive dysfunction. Patients in both the groups in this study had comparable incidence of occurrence intraoperative tight brain. Stenhouse et al., reported that postoperative vasospasm was a significant predictor of residual cognitive impairment at variable periods of follow-up, others did not find any association between vasospasm and cognitive function. ,, Cerebral infarction is a well-known predictor of cognitive dysfunction  which was also observed in this study.
Based on the current study results, to achieve an alpha (α) of 0.05 and a beta (β) power of 0.8, at least 300 patients were required, in each group. Therefore, this study is limited by a very small sample size. The selection of good-grade aneurysmal patients was deemed necessary to obtain neuropsychological test data, which might not have been possible in poor-grade patients. Usage of less elaborative cognitive test may have missed subtle cognitive dysfunction. Moreover, long-term follow up for cognitive dysfunction could not be done as patients are referred from remote and distant places.
Pharmacologic neuroprotection with propofol during temporary clipping in patients undergoing intracranial aneurysm surgery following SAH did not offer any advantage as far as preservation of cognitive function is concerned. The perioperative complications were comparable between the two groups except for the intraoperative aneurysm rupture which occurred more in patients of control group. This may be attributed to better brain condition in the propofol group. However, intraoperative tight brain, postoperative cerebral vasospasm and infarct were found to be independent risk factors for cognitive dysfunction at the time of discharge.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]