Ketamine has increasingly become an important part of the multimodal approach in pain treatment. Its analgesic effects have been evaluated in different types of pain, such as cancer, neuropathic, and postoperative acute pain,1 but have not been fully assessed in the intraoperative period as a stand-alone drug. Although there has been significant focus on neurophysiologic techniques to ensure unconsciousness and amnesia, identifying the neural signatures of effective analgesia has received less attention,2 and so has the development of monitoring devices for nociception.
Recently, the appraisal of intraoperative nociception has gained acceptance through the assessment of the autonomic nervous system response to noxious stimuli. Examples of used surrogates include the heart rate variability, heartbeat intervals, plethysmographic pulse wave amplitude, skin conductance, and pupillary response.
To evaluate the analgesic effect of ketamine intraoperatively, we measured pupillary reflex dilation (PRD), which is very sensitive to detect noxious stimuli.3 Ketamine is known to alter pupillary reflexes,4 but to our knowledge, only its effect on the pupillary light reflex (PLR) has been studied.
We report the case of a woman undergoing general anesthesia with ketamine only where the different pupillary reflexes were measured in an attempt to assess the analgesic effect of ketamine.
Written consent was obtained from the patient to publish this report.
The patient was a 53-year-old woman with an advanced oropharyngeal carcinoma (T4b) scheduled for a revision of an infected gastrostomy. She was undergoing palliative radiotherapy and chemotherapy and had a profound state of cachexia weighing 35 kg (body mass index of 12 kg/m2). She had previous surgical interventions, but none of the anesthetic procedures involved tracheal intubation because of concerns regarding airway management. She had a Mallampati score of 4, a thyromental distance of 3 cm, very limited neck extension, an upper lip bite test classified as II, and a very friable tumor.
On arrival at the operating room, standard monitoring (including body temperature) was applied. The patient’s vital signs were blood pressure 135/80 mm Hg, heart rate 75 beats/min, and peripheral oxygen saturation (SpO2) 98% without supplemental oxygen. Premedication consisted of 50 μg intravenous (IV) fentanyl for pain and anxiolysis 30 minutes before induction of anesthesia. Out of concern for possible airway problems, we decided to maintain the patient’s spontaneous respiration by providing general anesthesia with ketamine exclusively. The advantages and risks of the technique were explained to the patient.
A portable infrared pupillometer (AlgiScan, IDMed, France) was used to provide an objective measure of pupil size and pupillary reflexes (Table). A light-emitting diode of infrared light is directed toward the eye, a sensor detects the reflected infrared light from the iris, and then it calculates the area and the diameter of the pupil. Application of visible light or a noxious stimulus elicits the PLR and the PRD. PLR is the change in pupil size that occurs after a light stimulus, and PRD is the change that occurs after a noxious stimulus.5 Measuring PRD is useful because its depression in response to a standardized noxious stimulus will predict nonmovement to a surgical stimulus.6 Variables of these 2 reflexes such as latency of onset, the maximum amplitude of the reflex, duration of the reflex, and constriction and dilation velocities can also be analyzed.5,7
The PRD can be assessed by the pupillary pain index (PPI), which measures the changes in pupillary dilation in response to a continuously increasing electric stimulus discharge, and then classifies the response from 1 (when pupillary dilation is <5% despite 60 mA tetanic stimulation) to 10 (when pupillary dilation rises above 13% with just 10 mA).8 Using PPI instead of fixed tetanic stimulus of 60 mA avoids unnecessary high stimulation. In this case, the electrodes were placed over the left ulnar nerve.
A baseline measurement of PLR was taken. Pupil size was 3.0 mm and it constricted by 37%. The estimated effect site concentration of fentanyl9 was 0.3 ng/mL at the time of this measurement and declined across the following measurements.
Anesthesia was induced with an IV bolus of 1.5 mg/kg of racemic ketamine, which was enough to reach loss of consciousness (Table). There was a transient increase in blood pressure (from 146/86 to 178/95 mm Hg) and heart rate (from 72 to 86 beats/min). Oxygen saturation continued at 99% with supplemental oxygen at 3 L/min through a nasal cannula. The PLR decreased to a constriction of 8%, a velocity of 0.66 mm/s, and a latency of 144 milliseconds (Table). The PPI was of 6/10 (Table), dilating 28% from the baseline in response to the 50 mA tetanic stimulation.
Because of the large reflex dilation, an additional IV bolus of 1 mg/kg ketamine was administered. The PPI became 2/10 (Table), dilating 6% in response to the 60 mA tetanic stimulation and the PLR decreased to 7% constriction. After this bolus, the blood pressure was 166/87 mm Hg, heart rate 81 beats/min, and oxygen saturation 98%. At this point, the incision was made in the absence of reflex movement and significant hemodynamic changes (blood pressure 162/83 mm Hg and heart rate 83 beats/min).
The surgery lasted 30 minutes and proceeded uneventfully, with the patient breathing spontaneously throughout the procedure. Two additional IV boluses of 0.5 mg/kg ketamine were administered (Table). Postoperative analgesia consisted of acetaminophen 600 mg IV.
After surgery, the patient was monitored in the postanesthetic care unit and 1 mg of IV midazolam was administered. The patient fully recovered and 120 minutes later was discharged to the infirmary.
We here report a ketamine-induced decrease in the PRD that appeared to be dose related. Ketamine has been shown to decrease the PLR,4 but its effect on the PRD has never been demonstrated.
Pupillary reflexes are useful to predict the response to a surgical stimulus,5 because there are similarities between the movement reflex and reflex dilation of the pupil during anesthesia.5 Both reflexes are subcortically mediated, initiated by nociceptors, and suppressed by opioids6; they are also useful for titration of depth of anesthesia.10,11 In addition, the PRD can be used to guide analgesia in anesthetized patients.3,12 The amplitude of the pupillary dilation reflex evoked by standard noxious stimuli allows for individual assessment of the nociception/antinociception balance because the reflex amplitude changes in a predictable way with the application of the nociceptive stimulus and with the administration of analgesics.12 However, these studies are based on the analgesic effect of opioids13 and do not describe the effect of other analgesics, such as ketamine.
Our measurements showed a decrease in both pupillary reflexes in response to ketamine administration. This could be due to the effects of ketamine on the N- methyl-D-aspartate (NMDA) receptors involved in the pupillary reflex,4 or on the NMDA receptors involved in the nociceptive and inflammatory pain transmission.1 After the second bolus of ketamine, the decrease in PRD was larger than that of the PLR, showing a slight difference in the behavior of the 2 reflexes in the presence of ketamine. This suggests that even though ketamine decreases both reflexes, it is possible to differentiate the NMDA antagonism of the pain transmission from the NMDA receptors involved in the generation of the pupillary reflexes.
The doses of ketamine used are in accordance with what is routinely recommended for general anesthesia.11 The novelty of this case is in the measurement of the pupillary reflexes with increasing concentrations of ketamine. Besides the advantages in titrating analgesia using PRD,14 we consider there is also a potential benefit of measuring PLR to supplement the information acquired from depth of anesthesia monitors,10,11 which can provide inaccurate readings when ketamine is being used.15
Regardless of the limitations of this case report, it opens the discussion of the ketamine effects on the PRD, which should be further evaluated in a clinical study. The absence of movement or hemodynamic changes with the tetanic stimulation as well as skin incision, and the decrease of PRD with increasing concentrations of ketamine, suggests that PRD might have some predictive value for the analgesic effect of ketamine.
Name: Sérgio Vide, MD.
Contribution: This author helped conceive and design the manuscript, acquire and interpret the data, and draft and revise the manuscript.
Name: Catarina M. Costa, MD.
Contribution: This author helped conceive and design the manuscript, acquire and interpret the data, and revise the manuscript.
Name: Pedro L. Gambus, MD, PhD.
Contribution: This author helped interpret the data and revise the manuscript.
Name: Pedro P. Amorim, MD.
Contribution: This author helped interpret the data and revise the manuscript.
This manuscript was handled by: Hans-Joachim Priebe, MD, FRCA, FCAI.
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