Post-operative cognitive dysfunction (POCD) is a serious condition associated with substantial long-term mortality.1 The incidence of POCD varies from 7 to 60% after different types of surgery.1–8 This wide variation in the incidence of POCD could be the result of variation in the definition of and diagnostic criteria for POCD as well as the tests used to determine this condition. However, the literature addresses predominantly cardiac surgery or other major surgery, including hip fracture surgery and vascular surgery.2 The incidence of POCD after minor surgery has not been evaluated to any great extent. Most of these studies lack power and some have problems with study design.2 Furthermore, the effects of different anaesthetic agents and different dosages on POCD have not been elucidated. Other potential pathogenic factors such as the degree of tissue trauma and neurone inflammation are not fully understood.2 Risk factors known to be associated with POCD include age, sex, level of education, type of surgery, concomitant disease and degree of pre-operative cognitive dysfunction.1,6,8 One challenge in POCD studies is to evaluate whether the effect seen is due to exposure to the anaesthetic agents per se or to the inevitable trauma of surgery on cognitive function.8
Anaesthesiologists usually rely on somatic signs such as motor response changes in respiratory patterns, and autonomic signs such as tachycardia, hyperventilation, sweating and lacrimation to administer the appropriate doses or concentrations of anaesthetic agents. However, these clinical signs are not reliable measures of consciousness and may lead to overdosage or underdosage.9,10 Monitoring the depth of anaesthesia using digital processing of the EEG makes it possible to prevent overdosing, thus reducing anaesthetic requirements.11–16 To our knowledge, no study has evaluated the influence of AEP-guided anaesthesia on POCD.
The aim of this study was to evaluate the influence of AEP-guided anaesthesia on requirements for anaesthetic drugs and the influence on cognitive decline after minor surgery without substantial tissue damage.
Permission was obtained from the Ethics Committee of Uppsala University hospital (Ethical Committee Nr. 2004:M-267, 27 September 2004, President E Lempert), Uppsala, Sweden, prior to the start of the study. Written informed consent was obtained from 450 adult patients with the American Society of Anesthesiologists (ASA) 1–4 status, aged 18–92 years, scheduled to undergo anterior or posterior segment ophthalmic surgery between January 2005 and April 2008. Exclusion criteria included pregnancy, inability to fulfil investigational procedures due to mental disabilities, hearing impairment or any form of substance abuse. Patients operated on out-of-hours and those who could not fulfil the perioperative protocol were also excluded.
A selected group of anaesthesiologists or nurse anaesthetists, specially trained in guiding anaesthesia depth using auditory evoked potentials (AEPs), performed the anaesthesia. The post-operative personnel were blinded to group assignment, and all data were processed independently of group allocation and blinded to the investigator until the study was completed.
An independent person not involved in the study performed the computerised randomisation procedure (Fig. 1), assigning each patient a specific study number and group allocation, which were then enclosed in envelopes and sealed. Patients were assigned randomly to one of two groups.
In AEP group (group A), anaesthesia was guided by AEP. The A-line AutoRegressive (ARX) index (AAI) version 1.6 was calculated from the mid-latency auditory evoked potential (MLAEP) using the A-line monitor (Danmeter A/S, Odense, Denmark)13,14 and AAI maintained between 15 and 25.14
In the control group (group C), anaesthesia was guided by clinical signs of depth of anaesthesia, including blood pressure (BP), pulse rate, pupil reaction, sweating and lacrimation at the discretion of the attending anaesthesiologist or nurse anaesthetist. AAI was recorded in all patients in the control group, but the AAI value was blinded to the attending anaesthetist. After surgery, the data were transferred to storage media for later analysis of AAI.
Baseline characteristics and clinical data were recorded before surgery. Pre-operative BP and heart rate were recorded and a 12-lead ECG was obtained. Baseline BPs were recorded on two occasions: on the day before and 2 h before surgery.
All patients were premedicated with oral midazolam 0.1 mg kg−1 and oral paracetamol 1 g approximately 20 min before surgery. Induction of general anaesthesia was performed by administering fentanyl 1.5 μg kg−1 and propofol 1 mg kg−1, and additional propofol 0.3 mg kg−1 was given if necessary to maintain adequate anaesthetic depth as guided by AEP or clinical signs in group A and C, respectively. Intubation was facilitated by non-depolarising muscle relaxation using atracurium 0.3 mg kg−1. Anaesthesia was maintained with nitrous oxide and desflurane in oxygen. Before the start of surgery, all patients received sub-Tenon's block with 2 ml bupivacaine 0.5% (10 mg).17 Glucose 10% with electrolytes was administered at a rate of 1 ml kg−1 h−1 during surgery. Following induction, Ringer's acetate solution was given at a rate of 10 ml kg−1 h−1 for the first 20 min to avoid hypotension. Thirty minutes before extubation, droperidol 10 μg kg−1 was given to all patients as an antiemetic.
Hypotension was defined as a decrease in mean arterial pressure (MAP) of 20% or more below pre-operative baseline MAP.18,19 Similarly, hypertension was defined as an increase in MAP of 20% or more above pre-operative baseline values.20 Hypotension was treated primarily with volume substitution using Ringer's acetate 5 ml kg−1. Persistent hypotension lasting more than 5 min was treated with ephedrine 5 mg intravenously, and hypotension persisting after an additional 2.5 min was treated with phenylephrine up to a maximum of three boluses of 0.1 mg each. If hypotension persisted after three doses, the patient was excluded from the study (n = 1). Hypertension was treated with an additional bolus of fentanyl 25 μg. Persistent hypertension (>5 min) was treated with a second injection of fentanyl 25 μg and the concentration of desflurane was increased. If hypertension persisted after these procedures, the patient was excluded from the study (n = 0).
The AAI from the MLAEP was calculated using the A-line monitor.13,14 AAI values range from 0 to 60, where 60 indicates an awake patient. MLAEP was elicited with a bilateral click stimulus of 32-dB intensity and 2-ms duration. Three silver/silver chloride electrodes (A-line AEP electrodes; Danmeter A/S) were positioned at mid-forehead (+), left or right forehead (reference electrode) and left or right mastoid (–).13,14 Extraction of the MLAEP was achieved using a short moving-time average technique together with an ARX evolution model. These calculations of the AAI have been described in detail elsewhere.14
Analysis of intra-operative BP variation was based on differences between the intra-operative MAP and pre-operative MAP monitored by automatic BP measurement every 5 min (Drager Infinity; Dräger Medical, Lubeck, Germany). During anaesthesia, the patients were monitored with a 5-lead ECG and ST-T, J segment analysis. The monitor automatically checked for the references. Transcutaneous oxygen saturation, and end-tidal concentrations of CO2, desflurane, nitrous oxide and oxygen, were recorded at 5-min intervals during anaesthesia, together with neuromuscular transmission using the Drager Infinity Monitor.
Post-operatively, physiological variables (BP, pulse and oxygen saturation) were measured every 15 min during the first 90–120 min. Supplemental oxygen at 2 l min−1 was administered via a nasal cannula in all patients during the first 30 min, or longer if required. If oxygen saturation decreased below 94% without oxygen, the patient received oxygen 2 l min−1 for another 30 min. Alertness was evaluated with the Aldrete score during the first 60 min post-operatively.21,22 An Aldrete score below 8 was regarded as inadequate post-operative wakefulness.22 Post-operative nausea and vomiting (PONV) was treated with ondansetron (4 mg) or betamethasone (4 mg). Post-operative pain was treated by using ketobemidone and paracetamol on demand when visual analogue scale (VAS) pain score was more than 3.
Evaluation of cognitive dysfunction
The mini-mental test (MMT)23–26 and the Cognitive Failure Questionnaire (CFQ)27,28 were used pre-operatively and post-operatively to evaluate cognitive status.
MMT score questions and maximum points achievable are as follows:
- ‘What is the year? Season? Date? Day of the week? Month?’ (5 points)
- ‘Where are we now: State? County? Town/city? Hospital? Floor?’ (5 points)
- The examiner names three unrelated objects clearly and slowly, then asks the patient to name all three of them. The patient's response is used for scoring. The examiner repeats them until the patient learns all of them, if possible. Number of trials: ___________ (3 points)
- ‘ I would like you to count backward from 100 by sevens.’ (93, 86, 79, 72, 65, …). Stop after five answers. (5 points) Alternative: ‘Spell WORLD backwards.’ (D-L-R-O-W) (5 points)
- ‘Earlier I told you the names of three things. Can you tell me what those were?’ (3 points)
- Show the patient two simple objects, such as a wristwatch and a pencil, and ask the patient to name them (2 points)
- ‘Repeat the phrase: ‘No ifs, ands, or buts.” (1 point)
- ‘Take the paper in your right hand, fold it in half, and put it on the floor.’ (The examiner gives the patient a piece of blank paper.) (3 points)
- ‘Please read this and do what it says.’ (Written instruction is ‘Close your eyes.’) (1 point)
- ‘Make up and write a sentence about anything.’ (This sentence must contain a noun and a verb.) (1 point)
- ‘Please copy this picture.’ (The examiner gives the patient a blank piece of paper and asks him/her to draw the symbol below. All 10 angles must be present and two must intersect.) (1 point)
(Questions 2, 6, 8, 9, 11 were excluded in the telephone test. Cut-off point was reduced by two points)
CFQ questions are as follows:
- Do you find you forget why you went from one part of the house to the other?
- Do you have trouble making up your mind?
- Do you find you forget appointments?
- Do you find you forget peoples' names?
- Do you bump into people?
ADL question is as follows:
Do you feel the same as you did before your operation or do you have any new complaints that have not been mentioned?
These tests (MMT, CFQ and ADL) assess orientation, registration, attention and calculation, recall, language and activities of daily living (ADL). Baseline results were obtained pre-operatively on the day before, or on the morning of, surgery. The cognitive tests were performed on four occasions. Tests were undertaken on the day before, or the day of, surgery, and on the day after surgery (first post-operative day) when the patient was fully awake. Patients were contacted by telephone after 1 week and 1 month and assessed using a modified MMT; the visual parts of the test were excluded, but all other cognitive items were included (MMT nine items; CFQ five items). A MMT value below 2523–25 was regarded as POCD at day 1 and a value below 16 was regarded as POCD at 1 week and 1 month.
The number of patients who were to be recruited into the study was based on an assumed POCD incidence of 20%.2 An estimated reduction in POCD of 10% (relative reduction 50%) with an α error of 0.05 and β error of 0.8 required 450 patients. Data were compared using the Mann–Whitney U-test for non-parametric data and Student's t-test for parametric values. Categorical data were analysed using Fisher's exact test and confirmed by a Wilcoxon rank-sum test. Multivariate analyses (logistic regression analyses) were performed to analyse risk factors associated with POCD. A Pearson's χ2 test was performed to compare proportions. The Bonferroni correction test was performed for multiple comparison correction. All values are presented as median and range or mean ± SD, according to the variability of the sample.
Of the 500 patients assessed to be eligible for the study, nine did not consent, 40 did not meet the inclusion criteria and one was excluded due to protocol violations. Hence, 450 patients were randomised into one of the two groups. These groups were comparable in respect of age, weight, ASA class and sex (Table 1).
No significant differences in characteristics or baseline variables were found between the groups, and no adverse haemodynamic events occurred during induction in either group.
Durations of anaesthesia and surgery were similar in the two groups. Apart from a minor, but statistically significant difference in systolic BP during surgery (109.3 ± 11.1 vs. 107.1 ± 11.7 mmHg, P = 0.035), the AEP group and the control group did not differ significantly in respect of haemodynamic variables. The dose of propofol for induction of anaesthesia was significantly lower in group A than in group C. Similarly, the mean end-tidal concentration of desflurane during surgery was significantly lower in group A than in group C (Table 2). The AAI values differed significantly between the groups: group A 18 (11–21) and group C 12 (10–19; P < 0.0001, Fig. 2). The number of patients who required fluids and vasopressors was significantly greater in group C than in group A [n = 65 (28%) vs. n = 36 (16%); P < 0.01]. The total volume of fluids and the total dose of vasopressors administered were larger in group C than in group A (Table 2).
POCD as assessed by the MMT was significantly more prominent in group C on the first post-operative day; 16 patients in group C had MMT scores below 25 compared to two patients in group A (P < 0.002). No patient had a MMT score lower than 16 at 1 week or 1 month, indicating no differences in cognitive function between the groups. The odds ratio for developing signs of early (day 1) POCD was 3.4 [confidence interval (CI) 1.3–9.0] in group C vs. group A. In group C, early (first 60 min) post-operative recovery after anaesthesia as assessed by the Aldrete score was significantly worse on all assessments during the first hour (Table 3). No patient had died when a 1-year follow-up was conducted.
The main findings of our study were that patients anaesthetised using AEP-guided anaesthesia had a higher BP, less need for fluids and vasopressors, lower consumption of anaesthetic agents and a lower risk of early post-operative cognitive decline. Taken together, these findings could imply that cognitive function may be affected by the quantity of anaesthetics administered and is not related to low BP, provided that this is treated correctly.
The term POCD has been generally accepted to identify patients who complain of memory and thought process impairment in the post-operative period, which persists over a period of time. POCD should not be confused with delirium, which is a transient and fluctuating disturbance of consciousness that tends to occur shortly after surgery.6 Although the diagnosis of POCD is clinical, a number of tests can aid in its diagnosis. However, the precise tests that should be used to confirm the diagnosis of POCD are unclear and several tests have been described and used in the literature.2 POCD is a well known problem following both regional and general anaesthesia and appears to affect the elderly more frequently than the young with an incidence of about 23% at 1 week in patients 60–69 years old undergoing non-cardiac surgery.6 Our patients underwent minor surgery and there was a cognitive decline in 4% of patients at day 1 but none after 1 week or 1 month, showing that early post-operative cognitive decline improves after the first day to pre-operative levels at 1 week. The low incidence (4%) of cognitive decline in our patients might be explained by the presence of several known protective factors: surgery with minor tissue trauma, a low median age of 60 years, lack of post-operative opioid use and short hospital stay.8 However, we did find a difference between the groups in that patients who had AEP-guided anaesthesia had significantly less cognitive decline at 24 h compared to control patients.
The practice of anaesthesia is generally based on combining different intravenous and inhaled anaesthetic agents with different pharmacological actions to induce unconsciousness and analgesia, block motor responses and suppress autonomic activity. To achieve this, anaesthesiologists rely upon somatic signs (e.g. change in motor responses in the respiratory pattern) and autonomic signs (e.g. tachycardia, hyperventilation, sweating and lacrimation) to administer appropriate doses and concentrations of anaesthetic agents.9 However, the use of these clinical signs may lead to either overdosage or underdosage of anaesthetic drugs. Therefore, these clinical signs are not reliable measures of the state of consciousness in anaesthetised patients.9,10 Recart et al.12 compared AEP monitoring with bispectral index (BIS) monitoring on several outcome measures and did not find any significant differences between the two cerebral monitoring techniques. It has been suggested that cerebral function monitoring allows drug delivery to be optimised to the individual needs of each patient, thus reducing the risk of overdosing or underdosing.12,15 A recent Cochrane review showed that BIS-guided anaesthesia reduced the requirements for propofol by 1.3 μg kg−1 h−1 and volatile anaesthetic agents (desflurane, sevoflurane, isoflurane) by 0.17 minimal alveolar concentration (MAC) equivalents, leading to reduced recovery times.16 Consistent with that conclusion, we found that AEP-guided anaesthesia resulted in reduced doses of anaesthetic agents.
Although the role of cerebral function monitoring in POCD has not been studied extensively, the results of our study demonstrate that patients who had AEP monitoring had better cognitive function on the first post-operative day. However, the influence of anaesthesia depth on POCD is controversial. One study has shown deep anaesthesia to preserve cognitive function post-operatively.11 In that study, patients with low BIS values showed improved cognitive function 4–6 weeks post-operatively. However, cognitive function was measured using a more sensitive instrument (process speed index).11 As referred to earlier, major surgery is associated with greater incidences of POCD, which could be due to the effects of the trauma per se, and not anaesthetic factors. Our model of minimal surgical trauma in patients undergoing ophthalmic surgery may separate the influences of anaesthesia and surgery on POCD. The short-lasting cognitive decline may be consistent with a residual effect of anaesthetic drugs on cerebral function, but this cannot be confirmed in any way by our results.
The greater the anaesthetic concentration, the greater appears to be the cognitive decline during the first 24 h because AEP-guided anaesthesia resulted in a lower incidence of cognitive impairment compared to clinically guided anaesthesia. In contrast to previous studies, we found a very short-lasting POCD, which is somewhat more difficult to explain. To evaluate POCD, we used the MMT, a simple cognitive test, modified (follow-up at 1 week, 1 month) for telephone evaluation, and the CFQ, a subjective overall test evaluating well being, also modified to evaluate patients by telephone. We excluded the visual part of MMT, and the CFQ test battery was reduced to five items because, for practical reasons, it was not feasible to make more extensive evaluation at 1 week and 1 month by telephone. These modifications might have influenced the results, making the tests less sensitive. Subjectively, none of the patients had any complaints of limitations in ADL functions at 1 week or 1 month after the anaesthetic (see section ‘evaluation of cognitive dysfunction’).
Finally, the role of hypotension during anaesthesia needs to be addressed in relation to cognitive impairment. There are very few studies on this topic and, therefore, the discussion remains largely theoretical. It could be argued that sustained periods of hypotension during anaesthesia could lead to decreased cerebral perfusion and consequently cognitive decline. Most anaesthetic drugs, including propofol and inhalational agents result in hypotension, which can either be accepted or treated. Common methods for treatment of hypotension include the use of vasopressors or fluids (or both). We found that patients monitored using AEP had lower requirements for both fluids and vasopressors, which is probably due to the haemodynamic stability resulting from lower anaesthetic drug requirement, thereby avoiding unnecessarily deep anaesthesia. As the BP was similar in both groups of patients, transient hypotension during greater depths of anaesthesia cannot explain the cognitive decline found in this study in patients monitored clinically rather than using AEP.
One major limitation of our study relates to the tests used to detect POCD. Although the MMT and CFQ tests have been used extensively to detect cognitive impairment, it is currently recommended that a battery of tests should be used, some of which are more sensitive than others in detecting POCD. At the time of planning this study (2004), there were no such recommendations. We used these tests because they are simple and easy to perform in a clinical setting with an aged population undergoing eye surgery. Many of the more sophisticated tests suffer from the fact that they require clear vision in order to be completed, which was not applicable to our patients. Another limitation of this study is that the MMT test performed at 1 week via a telephone interview with the patient was a modification of the original test and excluded the visual parts of the test. Thus, it is possible that we may have missed visual aspects of cognition and thereby made the test less sensitive at 1 week and 1 month. However, as our patients underwent ambulatory surgery and were recruited from a large area, it was not possible for them to return to the hospital for more elaborate testing.
In conclusion, our results indicate that AEP monitoring allows dose reduction of anaesthetic agents, leading to better cardiovascular stability and less early POCD. Cognitive decline following minor ophthalmic surgery is short-lived. Long-term sequelae might be confined to more subtle changes that are demonstrated only by more sensitive tests.
The authors would like to thank the nurses in the ophthalmic ward and the anaesthesiologists and nurse anaesthetists of the Department of Anaesthesiology for their dedicated support for this project. This study received funding from Danmeter-Denmark for AEP 2 silver electrodes. The sponsor did not participate in generation of hypothesis, data collection, analysis or writing of the article. The study was sponsored by the scientific committee of Örebro county council.
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