Ambulatory surgery comprises 70% of all surgical procedures performed in the USA and up to 65% in Europe . Patients undergoing surgical procedures on an ambulatory basis are at particular risk from residual effects of agents administered perioperatively. Our previous studies demonstrated that changes in visual evoked potentials  and electroretinogram (ERG)  are consistently present in the early post-operative period in patients who have undergone nitrous oxide (N2O)/sevoflurane anaesthesia. These abnormalities persist beyond the time at which standard clinical discharge criteria have been met. These effects indicate that a disturbance of the visual pathway exists temporarily following N2O/sevoflurane general anaesthesia. To date, the clinical significance of these previously described abnormalities is unknown. Retinal abnormalities identifiable by ERG may signify diminished visual function such as contrast sensitivity . This has important safety implications, as some patients resume routine daily activity shortly after discharge.
The objectives of this study were (a) to further characterize the postoperative ERG changes following sevoflurane anaesthesia and (b) to determine the association between these and concurrent contrast sensitivity.
With institutional ethical approval, and having obtained written informed consent from each, 10 ASA I patients undergoing non-neurological, elective surgical procedures of approximately 1 h duration were studied. Patients with decreased visual acuity or 'colour blinding' were excluded from the study.
Patients received no pre-anaesthetic medication. Each patient's right pupil was dilated approximately 20 min before the first preoperative measurement (with topical cyclopentolate hydrochloride 1% and phenylephrine 10%) and its diameter measured using a pupillometer (Essilor Digital Crp, Créteil, France). With standard monitoring in place (pulse oximetry, ERG, capnography, non-invasive blood pressure and inspired and end-tidal (ET) partial pressure of sevoflurane, N2O and oxygen (Datex AS/3® monitor; Datex Corp., Helsinki, Finland), induction of anaesthesia was performed by administering sevoflurane 8% initially in 100% oxygen, and maintained by clinically indicated concentrations of sevoflurane in a 33% oxygen/66% N2O mixture. Intraoperative analgesia was provided by administering diclofenac 100 mg per rectum and a local/regional block with weight appropriate dose of bupivacaine 0.5%. All patients were breathing spontaneously through a laryngeal mask airway.
All patients had a pattern and a full-field flash ERG recorded preoperatively and on two occasions postoperatively (i.e. as soon as possible after discharge from the recovery room, designated as T1 and approximately 2 h after emergence from anaesthesia, T2). ERG were performed in accordance with the guidelines of the ERG Standardization Committee of the International Society for Clinical Electrophysiology of Vision [5,6].
Pattern ERG were recorded from the undilated left eye of each patient using a disposable carbon fibre corneal electrode (Oxford Instruments, Surrey, UK), a self-stick reference disc electrode placed on the forehead and a ground electrode placed on the earlobe. The cornea was anaesthetized with topical proxymetacaine hydrochloride 1%. The skin was cleaned with alcohol and a water soluble conducting electroencephalogram (EEG) paste (Ten 20®; D.O. Weaver and Co., FL, USA) was used to achieve an impedance of <3 kΩ. With correction for vision in place, black and white pattern change stimulation was used at a reversal rate of 8s−1 (4 Hz).
The same carbon fibre corneal electrode was applied to the right eye. The skin was prepared in the same way to achieve an impedance of <5 kΩ. Full-field (Ganzfeld) stimulation was used. Signals were amplified, filtered, on-line averaged, saved on disc and displayed using the Nicolet Bravo® ERG equipment (Nicolet Biomedical Inc, MD, USA). Reference point selection was automated and checked by an investigator unaware of the time of recording. The Nicolet Bravo EP 3.2 software package was subsequently used to measure the following.
In the pattern ERG, P50 latency (ms) was measured from the onset of flash to the first positive peak; P50 amplitude (μV) was measured from the trough of N35 to the peak of P50 and N95 amplitude (μV) from the peak of P50 to the trough of N95 (Fig. 1).
In the photopic ERG, the latencies (ms) of the a- and b-waves were measured from the onset of the flash to the trough and peak, respectively. The A-B amplitude (μV) of the photopic ERG was measured from the trough of the a-wave to the peak of the b-wave. In the case of the oscillatory potentials, the interval from the onset of flash to first and second peak was measured (first and second oscillatory potential latency, respectively). The oscillatory potential amplitude was measured from the respective peak to the following trough, o1 and o2, respectively (Fig. 1).
A Snellen vision test and contrast sensitivity test using the Cambridge Low Contrast Gratings was performed on the undilated left eye of each patient prior to each ERG measurement . Patients also completed visual analogue scales (VASs) for sedation, anxiety and pain at the same time points .
The time of the earliest Aldrete recovery score (≥9) allowing potential discharge from the recovery room was noted [9,10]. This did not always coincide with actual discharge time. Time when Post Anaesthesia Discharge Score (PADS ≥ 9) would have allowed discharge home was also recorded [11,12].
Data were analysed using paired, one-tailed t-tests and χ2 or Fisher's exact tests as appropriate. Correlation between non-parametric variables was sought using Pearson's correlation test. P < 0.05 was considered significant.
Ten male ASA I patients aged 26.9 (range 21-44) yr were studied. All patients underwent minor limb surgery (eight finger reconstructions, one hand and one forearm laceration). The duration of anaesthesia was 62.1 (range 42-90) min; ET carbondioxide partial pressure and sevoflurane concentration immediately prior to removal of the laryngeal mask airway were 5 (±0.6)kPa and 0.26 (±0.06)%, respectively. Postoperatively, patients met the discharge criteria from the recovery room (Aldrete score ≥ 9) at 9 (±3.1) min after emergence from anaesthesia, and the post-anaesthesia discharge criteria (PADS ≥ 9) at 16.5 (±6.3) min (Table 1). The first postoperative ERG measurement was performed as soon as possible after this, at 29 (±5) min after emergence from anaesthesia (T1). The second postoperative ERG measurement was performed at 2 h after emergence from anaesthesia (T2). The pupil sizes were similar (8.6 ± 0.5, 8.5 ± 0.6 and 8.7 ± 0.4 mm) before each of the ERG measurement, respectively.
On the full-field photopic ERG, b-wave latency was greater at each postoperative time point (31.6 ± 1.1 and 30.8 ± 1.1 ms) compared to preoperatively (30.1 ± 1.1 ms, P < 0.001 and P = 0.03, respectively), although a tendency to revert to baseline values was noted at T2 (P < 0.001 compared to T1). The A-B amplitude of the photopic ERG was similar throughout the study period (Fig. 2).
Similarly, the latency of the second oscillatory potential increased at T1 compared with pre-anaesthetic values (23.1 ± 3.1 vs. 22.4 ± 3.3 ms, P = 0.01) and returned to baseline by T2. Oscillatory potential amplitudes were similar at all time points (Fig. 3).
On the pattern ERG, P50 latency was increased at T2 compared to baseline (81.5 ± 17.9 vs. 51.15 ± 22.6 ms, P = 0.004). P50 amplitude values were similar throughout the study period. N95 amplitude values were less at time T2 compared to preanaesthetic values (2.6 ± 0.5 vs. 3.3 ± 0.4 μV, P = 0.003) (Fig. 4).
Contrast sensitivity was less at T2 compared to baseline values (349 ± 153 vs. 404 ± 140, P = 0.048). There is significant positive correlation between contrast sensitivity and N95 amplitude (r = 0.99, t = 19.8 and P < 0.005) and negative correlation between contrast sensitivity and b-wave latency (r = −0.55, t = −1.86 and P < 0.05) (Fig. 5).
Figure 6 shows the VAS scores for sedation, anxiety and pain. Patients felt drowsy at time points T1 compared to the pre-anaesthetic scores. (62.5 ± 20 vs. 5.3 ± 10 mm, P < 0.001). The degree of sedation reverted to normal at time point T2 (9.3 ± 13 mm, P = 0.19 and P < 0.001 compared to pre-anaesthetic values and T1, respectively). Anxiety and pain scores were similar throughout the study period. In all cases pain VAS scores were less than 35 at time point T2, allowing for potential home discharge.
The most important finding of this study is that following N2O/sevoflurane anaesthesia, patients demonstrate decreased contrast sensitivity for at least 2 h. The magnitude of this deficit correlates with decreased N95 amplitude and prolonged b-wave latency indicating that it results from transient abnormalities of the distal visual pathway. Thus, we have demonstrated that disturbances of the visual pathway persist following sevoflurane anaesthesia after home discharge criteria had been met. It is likely that (a) these effects are due to residual sevoflurane effects and (b) have implicit functional significance.
The ERG provides information about the function of specific retinal layers . The a-wave is generated in the photoreceptor layer; the b-wave originates in the inner nuclear layer and glial cells. Thus, the b-wave depends on the a-wave, and a defective photoreceptor layer would result in loss of both a- and b-waves. Conversely, lesions of the neuronal layer have no influence on the a-wave. Similar photopic ERG changes have been described in our previous study: b-wave latency was greater at each postoperative time point (30.5 ± 0.9 and 30 ± 1.3 ms) compared to preoperatively (29.2 ± 0.8 ms, P < 0.001 and P = 0.04, respectively) .
Oscillatory potentials of the ERG consist of several rapid, low-amplitude potentials originating from depolarizing amacrine cells. Oscillatory potentials are used as a selective probe of neural circuits in the proximal retina and are sensitive to anoxia and drug effects [13,14]. Volatile anaesthetics (methoxyflurane, halothane and enflurane), at ET concentrations in excess of 0.8 minimum alveolar concentration, increased the latency of oscillatory potentials . In the current study, the latency of the second oscillatory potential was prolonged postoperatively, similarly to our previous study  and as expected from previous intraoperative measurements .
The ganglion layer is not examined by full-field flash but by pattern ERG. Pattern ERG is very sensitive to disease processes affecting the inner retinal (ganglion cell) layers such as glaucoma or optic nerve disease when the pattern ERG amplitude is diminished . Evidence exists from intraretinal recordings with penetrating microelectrodes in animals (cat) [17,18] and from studies on normal human being subjects  that the positive wave derives from more distal layers of the retina, while the negative wave originates in the proximal (inner) retinal layer. Furthermore, it has been demonstrated that the positive component of the pattern ERG is not specific to changes in retinal distribution of contrast whereas the negative wave shows significant spatial tuning across temporal frequency . As a result, the positive and negative waves have been referred to as the 'luminance' and 'contrast' components of the pattern ERG. Mild to moderate abnormalities of the ganglion cell activity will be first reflected in the negative contrast component upon central retinal stimulation . In our study, postoperative changes described in pattern ERG prove that ganglion cells are affected by N2O/sevoflurane anaesthesia. It is likely that inner layers (N95 changes) are affected more than the middle layers (P50).
It has been suggested that amacrine cells would specifically modulate bipolar cell output onto ganglion cells through GABAc and GABAa receptors . This may be important for the receptive field properties of ganglion cells, as, e.g. their centre-surround organization that contributes to contrast sensitivity of the retina .
The Cambridge Low Contrast Gratings is a simple two alternative forced-choice test. It provides a rapid, reliable estimate of detectability of gratings with just one intermediate spatial frequency namely 4 cycles/degree, the frequency at which sensitivity of the visual system is near its maximum. Forced-choice procedures are generally regarded as the best means of obtaining criterion-free (constant criterion) estimates of threshold in sensory systems with excellent long-term stability. The advantage is that the patient's judgement is not absolute but comparative and patients need not interpret what is meant by threshold sensitivity. This maximizes detectability of small contrast sensitivity deficits by minimizing sample variance and maximizing the likelihood that measured changes in an individual patient's contrast sensitivity over time reflect changes in vision and not simply fluctuations in the patient's criterion for judging threshold [22,23]. The Cambridge Low Contrast Gratings are designed to detect subtle changes in patients with normal visual acuity (determined using a Snellen chart). Contrast sensitivity in patients with normal letter acuity is relatively unaffected in the higher spatial frequency range. Despite normal letter acuity and normal contrast sensitivity at high spatial frequencies, sensitivity may nevertheless be reduced at spatial frequencies close to 4 cycles/degree, e.g. retinal and optic nerve diseases including diabetes, glaucoma and demyelination. It is uncommon for sensitivity loss to occur selectively over a limited range of spatial frequencies. Diffuse loss is the most consistent pattern but with greatest loss for spatial frequencies near 4 cycles/degree [24,25].
A limitation of this study is the relatively small number of patients studied. The application of 'within patient' comparisons and the use of a standardized anaesthetic technique decreased the number of confounding factors which could have influenced our results.
One or more elements of the anaesthetic technique probably account for the changes described. It is very likely that sevoflurane represents the main causative factor of the drugs administered. N2O caused less change in b-wave parameters compared to nitrogen added to halothane/oxygen in spontaneously breathing rats . The effects of both diclofenac and bupivacaine on the visual pathway cannot be excluded but have no known actions likely to influence the ERG patterns.
ERG changes were consistent and demonstrated little intra- or inter-patient variation. The tendency for the b-wave and the second oscillatory potential latency to revert towards pre-anaesthetic values over time indicates that these transient effects were reversible, characteristic of a drug effect (as effect site drug concentration decreases over time). Further characterization of the phenomena described needs to be addressed in the future, such as comparison with other volatile and intravenous agents, dose dependence, etc.
In conclusion, we have demonstrated that postoperative ERG abnormalities are consistently present in patients following N2O/sevoflurane anaesthesia for at least 2 h postoperatively and are detectable after standard clinical discharge criteria have been met. We determined for the first time the clinical significance of these reversible effects in the clinical setting. They are associated with decreased contrast sensitivity. Abnormal contrast sensitivity following anaesthesia has obvious safety implications, for instance the additional danger of driving under low visibility conditions.
1. Troy AM, Cunnigham AJ. Ambulatory surgery: an overview. Curr Opin Anaesthesiol
2. Iohom G, Collins I, Murphy D, et al.
Postoperative changes in visual evoked potentials and cognitive function tests following sevoflurane anaesthesia
. Br J Anaesth
3. Iohom G, Whyte A, Flynn T, O'Connor G, Shorten G. Postoperative changes in full field electroretinogram following sevoflurane anaesthesia
. Eur J Anaesthesiol
4. Enz R, Cutting GR. Molecular composition of GABAC
receptors. Vision Res
5. Marmor MF, Arden GB, Nilsson SE, Zrenner E. Standard for clinical electroretinography. Arch Ophthalmol
6. Marmor MF, Zrenner E. Standard for clinical electroretinography (1999 update). International Society for Clinical Electrophysiology of Vision. Doc Ophthalmol
7. Della Sala S, Somazzi L, Wilkins AJ. Rapid technique for detecting 'blurred vision' in diseases of primary visual pathways. Lancet
8. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol
9. Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg
10. Aldrete JA. The postanesthesia recovery score revisited. J Clin Anesth
11. Chung F. Recovery pattern and home-readiness after ambulatory surgery. Anesth Analg
12. Marshall S, Chung F. Assessment of 'home readiness': discharge criteria and postdischarge complications. Curr Opin Anaesthesiol
13. Karwosky C. Introduction to the origins of electroretinographic components. In: Hackenlively JR, Arden GB, eds. Principle and Practice of Clinical Electrophysiology of Vision.
St Louis, USA: Mosby-Year Book, 1991: 87-91.
14. Ikeda H. Clinical electroretinography. In: Halliday AM, ed. Evoked Potentials in Clinical Testing.
London, UK: Churchill Livingstone, 1982: 121-148.
15. Tashiro C, Murashini R, Gomyo I, Mashimo T, Tomi K, Yoshiya I. Electroretinogram as a possible monitor of anesthetic depth. Graefes Arch Clin Exp Ophthalmol
16. O'Donoghue E, Arden GB, O'Sullivan F, et al.
The pattern electroretinogram in glaucoma and ocular hypertension. Br J Ophthalmol
17. Sieving PA, Steinberg RH. Contribution from proximal retina to intraretinal pattern ERG: the M-wave. Invest Ophthalmol Vis Sci
18. Sieving PA, Steinberg RH. Proximal retinal contribution to the intraretinal 8-Hz pattern ERG of cat. J Neurophysiol
19. Berninger T, Schuurmans RP. Spatial tuning of the pattern ERG across temporal frequency. Doc Ophthalmol
20. Schuurmans RP, Berninger T. Luminance and contrast responses recorded in man and cat. Doc Ophthalmol
21. Wellis PD, Werblin FS. Dopamine modulates GABAc receptors mediating inhibition of calcium entry onto transmitter release from bipolar cell terminals in tiger salamanders. J Neurosci
22. Vaegan, Halliday BL. A forced-choice test improves clinical contrast sensitivity testing. Br J Ophthalmol
23. Higgins KE, Jaffe MJ, Coletta NJ, Caruso RC, de Monasterio FM. Spatial contrast sensitivity. Importance of controlling the patient's visibility criterion. Arch Ophthalmol
24. Wilkins AJ, Della Sala S, Somazzi L, Nimmo-Smith I. Age-related norms for the Cambridge Low Contrast Gratings, including details concerning their design and use. Clin Vision Sci
25. Della Sala S, Bertoni G, Somazzi L, Stubbe F, Wilkins AJ. Impaired contrast sensitivity in diabetic patients with and without retinopathy: a new technique for rapid assessment. Br J Ophthalmol
26. Wasserschaff M, Schmidt JG. Electroretinographic responses to the addition of nitrous oxide to halothane in rats. Doc Ophthalmol