Demographic and surgical variables were similar between groups. The mean dose of anesthetic medications was higher in the control group; the difference was significant for midazolam, whereas a trend was observed for fentanyl (Table 1).
Before surgery, similar SD in the results of the SPMSQ were reported for the control and ketamine groups (1.9, SD = 1.6, and 2.1, SD = 2.0, respectively) (t = −0.60, df = 63, P = 0.54). Table 2 shows the change in the score of errors in the SPMSQ between baseline and postoperative evaluations (compared with the analysis of covariance model). Significant changes over time were observed only in the ketamine group, in which patients had fewer errors in the postoperative SPMSQ compared with the baseline evaluation.
According to the scoring scale, in the preoperative assessment, 68.8% (n = 22) of patients in the control group and 66.7% (n = 22) in the ketamine group performed within the normal range, whereas the remaining patients performed within the mild/moderately impaired range (χ2 = 0.03, df = 1, P = 0.85). After surgery, an increased number of patients in the ketamine group performed within the normal range (n = 28, 84.8%; P = 0.03), whereas the percentage of patients in the control group with a normal cognitive performance remained almost unchanged (n = 24, 75%; P = 0.62).
Hemodynamic Measurements, Oxygen Saturation, Sedation, Intraocular Pressure, and Analgesia
Significant decreases over time were observed independently in both groups in hemodynamic variables and respiratory rate (P < 0.001), whereas oxygen saturation and sedation level increased (P < 0.001). No significant changes over time × group were observed in these variables in the general linear model (Table 3). Similarly, the control and the ketamine groups showed similar changes in intraocular pressure between the preoperative (15.9, SD = 2.8 vs 14.4, SD = 3.6 mm Hg, respectively) and the postoperative evaluation (15.0, SD = 3.0 vs 13.2, SD = 3.4 mm Hg, respectively; Ftime × group = 0.20, P = 0.65).
Conversely, significant changes were observed in analgesia, which was evaluated using a numerical verbal scale, followed by a Likert scale for statistical analysis. After anesthesia, 75% (n = 24) of patients in the control group reported mild/moderate pain, compared with 56.2% (18) of patients in the ketamine group (χ2 = 4.8, df = 3, P = 0.18). After surgery, a significantly smaller proportion of patients reported mild/moderate pain in both groups, although it was less in ketamine group patients (n = 3, 9.1% vs n = 17, 51.3% of the control group; χ2= 18.5, df = 3, P < 0.001).
In this study, we found statistical differences between the errors committed in the postoperative SPMSQ compared with the baseline evaluation. Previous studies concerning the effect of ketamine on POCD focused on complex surgery involving different levels of anesthesia; the subject of these studies were intracellular signaling26 and neurologic effects related to attention, working, and semantic memory,27 but the effect of ketamine on common conditions of geriatric patients, including comorbid conditions and minor surgeries, has not been well studied. More studies should be conducted on ophthalmic surgery, because common age-related eye diseases such as cataracts, as well as age-related macular degeneration, have been proposed to be associated with the changes in cognition,28 with aging as a major preoperative risk factor.
Some studies suggest that the NMDA receptor has a direct role in short-term and recognition memory29 through anti-inflammatory mechanisms,30 whereas other reports assign the effect to increased cerebral blood flow31 or to the binding of the drug to NMDA receptors. This binding reduces neuronal apoptosis by suppressing the expression of the factor kβ2 involved in transcription of genes that codify proinflammatory cytokines,32 such as tumor necrosis factor α and interleukins 6 and 8.33 Consequently, ketamine attenuates the systemic inflammatory response to tissue injury and maintains cerebral perfusion pressure by activating the sympathetic nervous system.34
In the control group, the number of baseline errors recorded in the SPMSQ was 1.91, whereas the number was 1.73 after surgery. In the ketamine group, the number of baseline errors was 2.18, which decreased to 1.18 after surgery. Given the nature of the questions, it is difficult to know with precision if the difference reported really had anything to do with the effect of ketamine on cognitive changes or if it was a difference in learning, but this issue can be answered by comparing the cognitive performance between groups.
Our aim was to detect minor changes in cognitive performance; this is why the baseline evaluation of cognitive function was compared with another evaluation immediately after surgery. By performing the study in this way, we sought to avoid confusion that could be introduced by a postoperative evaluation after a longer period of time.
Unlike other studies, we included patients with mild depression (without treatment), which means that cognitive deterioration could be caused by this depression (an etiologic factor) or by the eye illness (a prodromal clinical manifestation).35 The former possibility should be explored in future studies.36
As in other studies, ketamine reduced the required dose of opioids,37 which suggests the importance of new research on the relationship between pain and cognitive performance. There is a possible relationship between the cognitive distortion and the degree of pain experienced in the past38; to our knowledge, this approach is absent in the literature.
We found that, with the dose used in our study, ketamine did not increase intraocular pressure. Because patients received a retrobulbar block, neither blepharospasm nor nystagmus was observed in eyes before or after surgery. This could be associated with the dose used, regional anesthesia, and the degree of comfort provided by sedative agents, particularly ketamine, which is known as a sedative agent in ophthalmic surgery.39,40
Furthermore, patients in the ketamine group required a significantly lower average dose of midazolam. There was a difference in the use of fentanyl, but no significant difference between groups with respect to the sedation required according to the Ramsey scale. This might be explained by the scale used and/or the interobserver variations.
Ketamine was administered throughout the surgical procedure; therefore, the need for midazolam/fentanyl was reduced with potential benefits. It is possible to assume that the evaluation performed in the immediate postoperative period considered only the immediate effects of the administered drugs. Because patients not receiving ketamine received larger amounts of midazolam, it is not possible to exclude that the difference was because of the effect of the drug. However, we do not think it very probable that the statistically significant difference was produced by the effect of midazolam because of the minimally different doses between groups, which does not represent a clinical difference of interest with respect to patients’ cognitive function or sedation.
Because of the design of this study, we can provide no evidence of pathophysiologic mechanisms and the neuroprotective effect on POCD attributable to ketamine. Because POCD may last longer than the immediate postoperative periods, further studies should be done to evaluate cognitive performance at least 24 hours after surgery using various validated tests.41
The use of only 1 questionnaire has limited benefits, and further research using other instruments is needed. However, our study showed that 0.3 mg/kg ketamine may be useful for inducing better cognitive performance after ophthalmic surgery in elderly patients, enhancing the effect of analgesics with safety improvements in hemodynamics, oxygen saturation, and intraocular pressure. However, these results need to be replicated in future studies.
Name: Dulce M. Rascón-Martínez, MD, MSc.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Dulce M. Rascón-Martínez has seen the original study data and approved the final manuscript.
Name: Ana Fresán-Orellana, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Ana Fresán-Orellana has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: María E. Ocharán-Hernández, PhD.
Contribution: This author helped design the study and write the manuscript.
Attestation: María E. Ocharán has seen the original study data and approved the final manuscript.
Name: Jorge H. Genis-Zarate, MD.
Contribution: This author helped conduct the study, performed cognitive evaluations, and helped with the cognitive aspects of the manuscript.
Attestation: Jorge H. Genis-Zarate approved the final manuscript and is the author responsible for archiving the study files.
Name: Antonio Castellanos-Olivares, MD, MSc.
Contribution: This author helped conduct the study.
Attestation: Antonio Castellanos-Olivares has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Jianren Mao, MD, PhD.
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© 2016 International Anesthesia Research Society
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