Although it is generally believed that ketamine does not substantially reduce IOP in monkeys,11-13
previous studies had often shown a tendency toward IOP reduction in the drug-free eye of ketamine-anesthetized monkeys during one-day experiments.18,19
In the present study, monkeys in protocol 1, which did not receive fluid supplements at any time, had significant reductions in IOP during ketamine anesthesia on 3 consecutive experimentation days (). The IOP declines tended to increase in magnitude on each subsequent day of ketamine anesthesia, indicating that they are not likely attributable to diurnal IOP fluctuations. However, monkeys in protocol 2, which did not receive any fluid supplements during days 1 to 4, only showed small IOP reductions on days 2 to 4 (). Causes for the difference between protocol 1 and protocol 2 are not clear. Although the two protocols were conducted by two different investigators, during which two different tear film indicators were used (fluorescein in protocol 1 and creamer in protocol 2), the IOP reductions were based on IOP changes from baselines within each protocol. Therefore, possible variances between investigators and/or between tear film indicators16
are probably not relevant to the results.
In order to obtain good IOP measurements, some monkeys require more ketamine than others or a given monkey may need different doses of ketamine on different occasions. In the current experiments, the ketamine dose per body weight per day was significantly higher in protocol 1 than in protocol 2 on days 2 and 3; the average ketamine dose per monkey per day was also significantly greater in the former than in the latter (). Therefore, the higher dosage of ketamine used in protocol 1 may have contributed to the substantial IOP reductions.
Although it is unknown how ketamine directly affects IOP, several indirect mechanisms might be involved in the IOP reduction during the daily-prolonged ketamine anesthesia. First, ketamine may decrease IOP by inducing muscle relaxation. Secondly, ketamine may dampen the animal's appetite and decrease their food and water intakes, and in turn induce weight loss and/or systemic dehydration. The latter may induce IOP reductions. In the present study, a slight and insignificant weight loss was observed in monkeys of protocols 2 and 3 that were weighed everyday during the study (data not shown), indicating that ketamine might dampen the animal's appetite. Although the weight loss was not significantly related to the change in baseline IOP, the systemic dehydration may not be excluded from the factors inducing IOP reduction during consecutive experimentation days (see below). Since different monkeys may respond to ketamine differently, changes in IOP after ketamine may be different in different groups of animals. For example, some monkeys may exhibit complete and stable muscle relaxation after ketamine (e.g., the monkeys in protocol 1), and others may not. The lack of muscle relaxation may not be improved by additional doses of ketamine in some monkeys. It is possible that IOP could be lower in monkeys exhibiting complete muscle relaxation compared to those that do not. Additionally, differences between monkeys in appetite after ketamine and/or eating or drinking habits overnight following the experiment may contribute to differences in weight loss and/or dehydration, and perhaps different IOP reductions. Nevertheless, although the magnitudes of IOP reductions are different between protocol 1 and protocol 2, both protocols show that anesthesia with ketamine on consecutive experimentation days does reduce IOP.
To determine if systemic dehydration was the cause of the IOP reductions, protocol 3 was conducted, during which subcutaneous fluid supplements were administered at the end of each 6-hrs of tonometry on days 1 - 4. Unlike in protocols 1 and 2, in which significant IOP declines began on day 2, the significant IOP decline was delayed until day 4 in protocol 3. This suggests that the subcutaneous fluid supplementation might have delayed the IOP reduction in protocol 3 (Figures -). Additionally, the constant intravenous fluid infusion on day 5 in protocols 2 and 3 either prevented or attenuated the IOP decline (Figures and ), indicating that systemic dehydration may be involved in the IOP reduction before day 5 in these protocols. Since the ketamine dose used on day 5 in protocol 3 was doubled compared to that in protocol 2 (), the incomplete reversal of the IOP reduction during the intravenous fluid infusion on day 5 in protocol 3 suggests that high doses of ketamine may reduce IOP in monkeys by mechanisms other than dehydration during daily-prolonged anesthesia.
During IOP experiments on days 2 to 4 in protocols 2 and 3, MAP was not significantly altered and was unrelated to IOP. This is not contradictory to the hypothesis that the ketamine-induced IOP reduction may be due to systemic dehydration, because systemic dehydration may not necessarily decrease MAP.20
However, since MAP was not measured in protocol 1 in which the magnitudes of IOP reductions were substantial, further studies are needed to clarify this issue.
It is worth noting that monkeys in protocol 4, which received similar ketamine doses to those in protocol 1, did not show any IOP reduction on any day (). This suggests that a daily bolus subcutaneous fluid supplementation plus one-day of recovery between experimentation days, as conducted in protocol 4, may prevent IOP reductions during long-term IOP experiments in ketamine-anesthetized monkeys. This should be taken into account when designing protocols for long-term IOP experiments in monkeys under ketamine anesthesia. However, systemic dehydration after ketamine is not the only factor inducing IOP reduction, and other ketamine-relevant factors should also be considered when designing protocols. As described above, different responses to ketamine between monkeys and in the same monkey on different occasions are also important factors affecting IOP. Additionally, since previous studies of conscious monkeys have shown IOP reduction in the drug-free eye on some occasions,21,22
possible ketamine-irrelevant factors may also be involved. To minimize confounding factors (ketamine-relevant or not) in IOP studies with ketamine-anesthetized monkeys, it is very important to compare IOPs between opposite eyes of the same monkey on the same occasion.