Ketamine is a noncompetitive N-methyl-d-aspartate receptor antagonists traditionally used as a safe anesthetic and sedative in the clinical practice. In addition to its anesthetic effects, ketamine possesses analgesic, anti-inflammatory, and antidepressant activities. Currently, ketamine is used not only for anesthetic purposes but also for treating patients with intractable pain such as those with complex regional pain syndrome (CRPS) and refractory depression.
Three expert societies—the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists—recommend an intravenous dose of ketamine of 0.5–2 mg/kg/h for chronic pain, with higher doses providing more benefit. Transient cardiorespiratory and neuropsychiatric adverse events have been observed in patients who receive a subanesthetic dose of ketamine infusion therapy. The coadministration of benzodiazepines to mitigate psychomimetic symptoms may increase the risk of respiratory depression during ketamine infusion. Therefore, it is becoming increasingly important to monitor the depth of sedation and to prepare for adverse events.
Bolus administration of ketamine significantly increases bispectral index (BIS) values compared with continuous infusion of ketamine when using BIS to monitor the depth of anesthesia. The index values from processed electroencephalographic (EEG) monitoring remain constant during the continuous infusion of ketamine. As the depth of sedation progresses, respiratory and cardiovascular adverse effects are more likely to occur. Hence, it is important to carefully monitor the depth of sedation. The BIS and patient state index (PSI) devices are widely used in our institution. There is a paucity of studies comparing PSI and BIS in CRPS patients undergoing ketamine infusion therapy.
Eight CRPS patients who underwent ketamine infusion therapy between February and April, 2018, were included in this case series. The data collection was approved by the local institutional review board (HPIRB 2022-09-020). The patients’ demographic and clinical details are shown in Table 1. Intravenous glycopyrrolate 0.2 mg and palonosetron 0.075 mg were administered to the patients before starting ketamine infusion in the operating room. The total dose of ketamine was 500–750 mg during approximately 2 h (112 ± 10.5 min). The values of PSI and BIS, blood pressure, heart rate, respiratory rate, end-tidal carbon dioxide, and oxygen saturation were recorded. When the artifact was greater than 50%, the PSI and BIS values were not recorded. Intravenous midazolam 5 mg was administered to four patients (50%) when agitation or movement was not controlled by verbal instructions from the clinicians. We recorded the time for achieving a Ramsay sedation score (RSS) of −4 (deep sedation). Deep sedation was achieved in five patients (62%) 20 min after the start of ketamine infusion.
The comparison of BIS and PSI values is shown in Table 2. PSI values were higher than BIS values at 30, 40, 50, and 60 min after the start of ketamine infusion. Hypertension and hypotension were defined as an increase and decrease of more than 20% from the baseline systolic blood pressure, respectively. Tachycardia was also defined as an increase of more than 20% from the baseline heart rate. Intravenous labetalol 5 mg or nicardipine 0.5 mg was administered to the patients at the discretion of the clinicians. Supportive care such as nasal airway insertion or oxygen supply was performed when oxygen saturation decreased below 94%.
Hypertension occurred in three patients, hypotension in one patient, and tachycardia in six patients. Oxygen desaturation was observed in two patients because of obstructive sleep apnea syndrome and narrow jaw. Oxygen desaturation was treated with supportive care.
In this case series, BIS and PSI values were compared with eight CRPS patients receiving ketamine infusion therapy. The PSI values remained in the 80s, but BIS values showed more variation. The BIS index was lower than the PSI index from 30 min to 60 min after the start of ketamine infusion.
Each processed EEG monitor provides index values through its algorithm. For example, the BIS utilizes an algorithm based on power spectral analysis, bispectral analysis, and burst suppression, whereas the PSI is calculated by a four-channel EEG with an algorithm that introduces high heterogeneity of variance. Even with the same depth of sedation using the same sedatives, the displayed index values of processed EEG monitors are different. For example, the PSI values were lower than the BIS values by ~10–15 points at high propofol concentrations. In another study, a calculated cut-off PSI value of 58 was found to be lower than a calculated cut-off BIS value of 67. Although PSI was launched on the market after BIS, its effectiveness has been proven in several anesthetic agents.[6,8,9]
CRPS is a chronic neurological condition with an unclear etiology characterized by autonomic, motor, and sensory disturbances. The postulated mechanisms for the pathophysiology of CRPS include central sensitization, alterations in the innervation of the affected limb, sympathoafferent coupling, inflammatory changes, cortical plasticity, and contribution of genetic and emotional factors. Because of its unique mechanisms and potential to blunt central sensitization, ketamine may theoretically prevent the development of chronic postsurgical pain. In a randomized controlled trial comparing prolonged low-dose ketamine infusion with placebo, a significant decrease in pain scores persisted for up to 12 weeks in the ketamine group (P < 0.001). Another double-blind, randomized, placebo-controlled trial using repeated prolonged low-dose ketamine infusions (0.35 mg/kg/h for 4 h during 10 days) demonstrated varying degrees of pain relief. However, there is little consensus on the best way to administer ketamine for CRPS.
Subanesthetic doses of ketamine are favorable because of its short half-life and low risk of clinically significant respiratory depression. At low doses, ketamine produces a dissociative state characterized by hallucinations, altered sensory perception, and analgesia, whereas at higher doses, it induces a state of unconsciousness appropriate for general anesthesia. The ideal dose of subanesthetic ketamine is 0.1–0.3 mg/kg as a bolus and 0.1–0.3 mg/kg/h as an infusion. When low-dose ketamine is infused, the index of EEG does not increase differently from bolus injection probably because the serum concentration does not change significantly. Stubhaug et al. studied a low-dose ketamine protocol consisting of an initial bolus of 0.5 mg/kg followed by a 72-h continuous infusion (first 24 h at 2 µg/kg/min followed by 48 h at 1 µg/kg/min) and measured serum concentrations of ketamine and norketamine at 1, 24, and 72 h. Their results suggest that after 72 h, the serum concentrations of ketamine are still below those observed at 1 h following a 0.5 mg/kg bolus. Further, an intravenous induction dose (1–2 mg/kg) of ketamine causes a rapid loss of consciousness that typically lasts for approximately 10 min. Akeju et al. found that ketamine anesthesia-induced unconsciousness was associated with coherent theta oscillations. EEG patterns, such as gamma bursts (consisting of gamma oscillations alternating with slow oscillations), were observed.
Ketamine is highly lipid soluble and has a large volume of distribution. The context-sensitive half-time of ketamine is similar to that of propofol. The concentration of ketamine and inactive norketamine rapidly declines upon the termination of ketamine infusion. Procedural sedation is frequently performed in spontaneously breathing patients, but hypnotics and opioids decrease respiratory drive and put the upper airways at the risk of collapse. The cardiorespiratory and neuropsychiatric adverse events are mostly transient, but particular attention should be paid to airway obstruction when coadministered with midazolam to reduce psychomimetic effects. Nausea, vomiting, and psychomimetic symptoms (nystagmus and double vision) occur more frequently in ketamine infusion patients. The administration of ketamine has been associated with hypersalivation, and hence we pretreated our patients with an anticholinergic agent. In addition, ketamine is a scheduled agent with abuse potential, making its long-term use challenging and mandating further research.
Although the BIS and PSI values did not match during ketamine infusion, this case series could help clinicians determine an appropriate course of action and give each patient the best safe sedation of ketamine. Clinicians have to look at the clinical symptoms as well. Further prospective studies are needed to assess the ability of PSI and BIS to determine the depth of sedation in ketamine infusion therapy.
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