TY - JOUR
AU - MD, Richard J. Kagan,
AB - Abstract Substantial evidence exists in the acute, rehabilitative and outpatient settings demonstrating the presence of significant sleep pattern disturbances after burn injury. Although the etiology is multifactorial and includes environmental, injury, and treatment mediators, previous clinical studies have not analyzed the critically important relationship of various medications to sleep architecture. The purpose of this investigation was to describe the after-effect of ketamine on sleep patterns in seriously ill burn patients. Forty pediatric patients with a mean TBSA burn of 50.1 ± 2.9% (range, 22–89%) and full-thickness injury of 43.2 ± 3.6% (range, 24–89%) were enrolled in this sleep study. Twenty-three of the 40 patients received ketamine on the day of polysomnography testing. Standard polysomnographic sleep variables were measured from 10:00 pm until 7:00 am. Chi-square test and t-test were used for comparison of descriptive variables between the ketamine and nonketamine groups. A logarithmic transformation was used for analysis when necessary. Ketamine administration was associated with reduced rapid eye movement (REM) sleep when compared with patients who did not receive ketamine on the day of the sleep study (P < 0.04). Both ketamine and nonketamine groups were clearly REM deficient when compared with nonburn norms. There was no relationship between ketamine use and effect on nocturnal total sleep time, number of awakenings, or percent of time awake or in stage 1, 2, or 3 + 4 sleep. In conclusion, ketamine was associated with altered sleep architecture as evidenced by a reduction in REM sleep. This finding does not seem to be clinically significant when considering the magnitude of overall REM sleep pattern disturbance observed in both the ketamine and nonketamine groups compared with nonburn norms. Further research is required to identify potential mechanisms of disturbed sleep so that appropriate interventions can be developed. The management of pain and anxiety in patients undergoing stressful procedures is clinically challenging, particularly in the treatment of patients who have sustained thermal injuries. Ketamine has proven to be a useful drug in critical care because of its potent sedative, hypnotic, analgesic, and amnestic properties while maintaining protective airway reflexes. Thus, ketamine is often the anesthetic of choice in pediatric burn patients undergoing bedside procedures such as postoperative dressing changes, wound care, and placement of endotracheal tubes and indwelling vascular catheters.1,–10 Although ketamine has been used for surgical procedures in the pediatric burn population for nearly four decades11 with expanding popularity and indications, much remains unknown about its pharmacologic effects.12,13 We have previously demonstrated significant alterations in the quantity and quality of sleep after burn injury.14,–17 However, the effect of various medications on sleep pathology in critically ill burn patients is poorly understood. The purpose of this study was to investigate the relationship of ketamine administration to the quantity and quality of sleep in the pediatric burn patient. METHODS This protocol was approved by the University of Cincinnati Institutional Review Board. All study subjects were admitted to a private room at the Cincinnati Shriners Hospital for Children®. Study inclusion criteria required the presence of more than 20% TBSA burn, age between 3 and 18 years, and admission within 7 days of injury. Exclusion criteria consisted of suspected anoxic brain injury or head injury, preexisting neurologic or psychiatric disorder, history of preburn sleep disorder, history of preburn use of sleep medications, or expected survival of less than 72 hours. Written informed consent was obtained from all patients before enrollment in a prospective randomized crossover trial of two sleep medications which has been described previously.15 This investigation involved a subanalysis of data collected during the first week of the 2-week crossover period immediately preceding the drug intervention component of the trial. A polysomnographic instrument (Sleep Trace 2000, Palo Alto, CA) recorded skeletal muscle activity, eye movement, and brain wave activity in 30-second epochs. Sleep studies were conducted in a single occupancy intensive care unit room, with ambient temperature ranging between 26.7 and 37.8°C. Polysomnography (PSG) testing was performed from 10:00 pm until 7:00 am (PSG measurements were delayed a minimum of 24 hours in the event of a scheduled surgery). Sleep recordings were scored visually for each 30-second interval by board-registered PSG sleep technicians and then interpreted by a medical sleep specialist. The sleep technicians and physicians were blinded to experimental conditions. Scoring procedures were performed in accordance with the standardized techniques described by Rechtschaffen and Kales.18 Time in a specific sleep stage was defined by two or more consecutive epochs in that stage. Percentage of time in any one stage was defined as the number of epochs in that stage divided by the total number of epochs in either a defined stage of sleep or awake over the study period. Total sleep time was defined as the total time spent in any of the standard sleep stages (eg, stages 1, 2, 3 + 4, or rapid eye movement [REM]) during the 9-hour sleep measurement period. Awakenings were defined as the return from any sleep stage to the wake stage. The percentage of sleep time spent in individual stages for each patient's PSG recording was compared with age- and gender-specific sleep norms reported by Williams et al.19 Forty patients with a mean TBSA burn of 50.1 ± 2.9% (range, 22–89%) and full-thickness injury of 43.2 ± 3.6% (range, 24–89%) were studied. The average age of subjects was 9.4 ± 0.7 years, and they were admitted for an average of 1.1 ± 0.2 days postburn. Sixty-two percent of the sample had inhalation injury, and 67% were males. Patients received pain medication and anxiolytics per clinical protocols; however, no sleep medication was used during this investigation. All patients enrolled in the sleep study were eligible to receive ketamine administration (per medical staff) to facilitate performance of various procedures such as escharotomies, feeding tube placement, nasal intubation, and central venous access. Patients were grouped retrospectively into ketamine group (those patients treated with ketamine beginning anytime after midnight on the calendar day of PSG and extending throughout the duration of the sleep study, ending at 7:00 am the following calendar day—a total of 30 hours) and nonketamine group (those patients who did not receive ketamine on the day preceding or during PSG testing). The amount of ketamine (mg/kg) from both continuous infusions and occasional push doses and administration timing (hours before PSG) were recorded for the ketamine group. Data Analysis All data were managed and analyzed using SAS® version 9.1 (SAS Institute, Cary, NC). The individual epochs from the PSG data were entered into Excel worksheets and then converted into SAS®. Descriptive statistics consisted of means, SE, and range. Chi-square test and t-test were used for comparison of descriptive variables between the ketamine and nonketamine groups. Because it was postulated that ketamine may have a different effect on the first half of the sleep study period compared with the second half, the total sleep study of 9 hours was divided into two 4.5-hour periods for analysis of the sleep stages. A generalized mixed model was used when examining the sleep stages to incorporate these two time periods and also examine the potential interaction. If the interaction was not statistically significant, the model with only the main effects was used. A logarithmic transformation was used for analysis when necessary, including the analysis of stages 3 + 4 sleep and REM sleep. Sleep stages are reported as mean ± SE or geometric mean and 95% confidence interval where a logarithmic transformation was used for analysis. A P-value <0.05 was considered statistically significant. RESULTS Twenty-three (57.5%) of the 40 patients received ketamine before the nocturnal PSG. Percent TBSA burn, % third-degree burn, age, gender, weight, height, inhalation injury, postburn day of sleep test, length of hospital stay, and mortality were similar among groups (Table 1). The initial dose of ketamine per clinical protocol was most commonly 1.0 mg/kg and the prescribed amount was titrated upward depending on patient response. The mean dose of ketamine given was 3.5 mg/kg, ranging between 0.95 and 7.14 mg/kg. Of the 23 patients receiving ketamine, 13 patients received a single dose, 9 patients received 2 injections, and 1 patient had 3 doses administered. Table 1. Patient admission demographics, hospitalization characteristics, and survival outcome in ketamine and nonketamine patients View Large Table 1. Patient admission demographics, hospitalization characteristics, and survival outcome in ketamine and nonketamine patients View Large The burn patients examined in this study (both ketamine and nonketamine groups) demonstrated abnormal sleep architecture (% wake, stages 1, 2, 3 + 4, and REM) when compared with age- and gender-specific published normal values19 (P < 0.01; Figure 1). Ketamine was administered 13.8 ± 0.45 hours (range, 11–21 hours) before nocturnal PSG. Dividing the time frame for polysomnographic evaluation (ie, two increments of 4.5 hours) was determined to not be a factor affecting results; therefore, the total 9-hour sleep study period was used for final analysis of sleep stages. Polysomnographic results demonstrated that study participants were in a wake state approximately half of the night; however, the ketamine and nonketamine groups experienced an average of 24 awakenings during the night. Statistical testing determined that ketamine was associated with reduced REM sleep when compared with the nonketamine group (P < 0.04; Table 2). Nevertheless, both the ketamine and nonketamine groups were clearly REM deficient when compared with nonburned norms (Figure 1). There was no relationship between ketamine use and effect on nocturnal total sleep time, number of awakenings, or percentage of time awake or in stages 1, 2, or 3 + 4 sleep. Figure 1. View largeDownload slide Comparison of study polysomnography data among pediatric burn patients stratified according to ketamine administration. Normative data for age and gender matched controls is also provided.18 P values reflect differences between ketamine and nonketamine groups. Figure 1. View largeDownload slide Comparison of study polysomnography data among pediatric burn patients stratified according to ketamine administration. Normative data for age and gender matched controls is also provided.18 P values reflect differences between ketamine and nonketamine groups. Table 2. Average total study time, total sleep time, wake and sleep stages times, and number of awakenings differentiated according to treatment with ketamine View Large Table 2. Average total study time, total sleep time, wake and sleep stages times, and number of awakenings differentiated according to treatment with ketamine View Large DISCUSSION Compared with a normal population, burned patients demonstrate severely disturbed sleep as manifested by decreased total sleep time, fewer stages of 3 + 4 and REM sleep, and a predominance of light sleep with frequent awakenings.14,–17 Dyssomnia is of clinical concern because it is an added stressor and may impede recovery.20 High-quality restorative sleep, on the other hand, is associated with heightened immune functioning and tissue repair and improvements in endocrine and glycemic measures. Sleep also benefits the brain and improves attention, learning, and memory, in addition to increased pain threshold, reduced emotional stress, and enhanced quality of life. The pathophysiology underlying postburn sleep deprivation has not been fully elucidated but undoubtedly includes the inherent nature of the noisy and well-illuminated intensive care unit environment; the endogenous response to burns, concomitant pain, and psychological stress; and finally, the effect of various treatments and drugs. The relationship of medications to changes in sleep architecture in critically ill burn patients is largely unknown. Ketamine is widely used for procedural sedation in burn patients because it maintains blood pressure and respirations better than most sedative or anesthetic medications. Ketamine is classified as an N-methyl-d-aspartate receptor antagonist21 and produces a clinical state referred to as “dissociative anesthesia.”22 Because of its structural similarity to phencyclidine, ketamine has been associated with psychotropic side effects such as hallucinations, extracorporeal experiences, and nightmares in adults.23 Other adverse events include airway complications, laryngospasm, increased heart rate and blood pressure, nonpurposeful movements, nausea, and vomiting.13,24,–26 Disturbed sleep and increased night-time awakenings have also been reported after ketamine administration.24,27,–30 These undesirable reactions seem to be less common in children,31 and thus, ketamine has proven to be a safe and effective choice for pediatric sedation and anesthesia.2,3,10,25,30,–32 Furthermore, ketamine binds to sigma opioid receptors and may enhance the clinical effectiveness of opioids.4,33 There is evidence that low-dose ketamine in combination with opioids may not be associated with adverse effects and, in fact, may improve outcomes of critically ill patients.2,34 The fact that we are a pediatric facility and that our patients typically receive morphine for pain may explain our sustained success and the minimal side effects associated with low-dose ketamine administration over the past two decades. When procedural sedation is desired for an acute burn patient, ketamine can be administered once appropriate personnel and monitors are in place. Because dose-response curves to ketamine are quite variable, initial dosing is usually low (approximately 1.0 mg/kg intravenously) and then repeated with increasing doses administered as indicated by the patient's response to the medication and/or length of the procedure. If enhanced sedation is required, dosing is dictated by previous requirements, although caution must be taken because tachyphylaxis can develop rapidly and result in dose escalation. The purpose of this study was to evaluate and describe the residual effects of ketamine on nocturnal sleep and awakening patterns in critically ill children with burns. Quantitative total sleep and wake times were similar between groups. During the sleep study, patients were in a wake state (as evidenced by the predominance of alpha EEG waves) approximately half of the night. The total nocturnal sleep times of 4.5 and 3.8 hours measured in the nonketamine and ketamine groups, respectively, suggest that an inadequate quantity of sleep was experienced by all of the burned children. Unlike normal healthy individuals who derive most of their total sleep at night, burn patients nap intermittently throughout the day. Previous research in critically ill burned children using 24-hour PSG revealed an accrual of 10.5 hours of sleep during a total 24-hour period.14 However, in this study, it is unknown how much sleep occurred in the patient sample throughout the day and how that may have been altered by ketamine. The extent to which intermittent daytime naps result in restorative sleep similar to that derived during a block of sleep time at night remains to be determined. One possible explanation for the reduced quantity of nocturnal sleep time observed during this study is the associated frequency of awakenings. Although most people experience only 1 or 2 awakenings per night, both the ketamine and nonketamine groups experienced an average of 24 awakenings during the sleep study. This finding was surprising in view of earlier reports of increased awakenings in association with ketamine administration, yet both groups were found to be similar in this study. The first stages of sleep (stages 1 and 2), characterized by theta brain waves, represent the relatively “light” stages of sleep. There was no difference in stage 1 or stage 2 in this study (Table 2). Under normal conditions of health, the sleeper typically passes from the theta waves of stages 1 and 2 to the delta waves of stages 3 and 4. Delta waves are the slowest and highest amplitude brain waves. Delta sleep is regarded to be the deepest sleep whereby brain waves are least like those of the awake state. Consequently, delta sleep is the most difficult stage in which to awaken sleepers, and it is considered to be the most restorative, anabolic period. It is conceivable that maximizing stage 3 + 4 sleep could offer therapeutic benefit during burn recovery. Therefore, the determination of the effect of ketamine on deep sleep is of interest. Feinberg and Campbell assessed the acute effect of ketamine in nonburned rats. They reported increased stimulation of delta intensity and then duration 1 to 11 hours postketamine injection.27,28 Our study, on the other hand, evaluated the subacute (11–21 hours) postketamine administration response in children with burn injury. Results from our study did not reveal any statistically significant effect of ketamine on stages 3 + 4 sleep. In addition to the four basic stages of sleep (eg, stages 1, 2, and 3 + 4), another unique stage of sleep is that of REM. This stage derives its name from the frequent REMs that occur as indicated by the electrooculogram component of PSG. It is a catabolic state characterized by a sudden and dramatic loss of muscle tone, which is measured by the electromyogram. In fact, the skeletal muscles of a person during REM sleep are effectively paralyzed. This stage is also associated with unique brain wave patterns (a combination of alpha, beta, and desynchronous waves) that are similar to the wake state and it is associated with dreaming and memory consolidation. In our study, ketamine seemed to have mild residual effects on sleep architecture based on findings of reduced duration of REM sleep. Although these differences were statistically significant, the clinical significance could be considered marginal at best because both groups had negligible REM sleep. Furthermore, the REM results in the sample of burn patients (regardless of ketamine classification) were very different from normative data. These findings highlight the overall sleep response in burn patients and discount ketamine as a significant mediator of the dyssomnia commonly observed after thermal injury. This study has several limitations. The most significant is the lapse of time from ketamine administration to PSG measurements. We cannot rule out that delivery of ketamine in closer proximity to the nocturnal sleep study may have produced different results. Dosage of ketamine and other medications received on the day of PSG are also factors requiring further study. Although patients did not receive any sleep medications during the study period, both groups continued to receive sedation and pain management in accordance with routine clinical procedures. It is recognized that sedatives and opioids may have their own effects on sleep architecture. However, the administration of methadone, morphine, versed, dopamine, and insulin was evenly distributed between groups, which permitted our focus on ketamine. Finally, it is conceivable that the “no ketamine” children also received ketamine at some point before the study period, which may increase the chance of type 2 error. However, the likelihood that any lingering effects from previous ketamine administration in the nonketamine group is small given its rapid elimination (half life = 3 hours).35 CONCLUSION Sleep is commonly disturbed in patients with acute thermal injury. REM deficiency, a common finding postburn, may be exacerbated after ketamine administration. However, the observed differences after ketamine administration do little to explain the magnitude of overall REM sleep pattern disturbance after burns. Although ketamine is a useful bedside anesthetic in pediatric burn patients, it demonstrates no beneficial effect on stage 3 + 4 sleep; and ketamine was associated with a slight reduction in REM sleep. Thus, the effect of ketamine on sleep seems to be clinically insignificant given the marked sleep pathology in both the ketamine and nonketamine groups after acute burn injury. Nevertheless, clinicians should be aware that medications used in the treatment of critically ill patients may have detrimental effects on sleep physiology and patterns. Supported, in part, by a grant from Shriners Hospital for Children®, Tampa, Florida. ACKNOWLEDGMENTS We thank Glenn Warden, MD, Milton Kramer, MD, Chris Allgeier, DTR, Robert Smith, RPSGT, Roy Saylors, RPh, Mary Rieman, RN, and Vicki Trout for their invaluable assistance. REFERENCES 1. McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH The correlation between ketamine and post traumatic stress disorder in burned service members. J Trauma  2008; 64: S195– 9. Google Scholar CrossRef Search ADS PubMed  2. White MC, Karsli C Long-term use of an intravenous ketamine infusion in a child with significant burns. Pediatr Anesth  2007; 17: 1102– 4. 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Wieber J, Gugler R, Hengstmann JH, Dengler HJ Pharmacokinetics of ketamine in man. Anaesthesist  1975; 24: 6 260– 3. Google Scholar PubMed  Footnotes 2 Presented at the Annual Meeting of the American Burn Association, Boston, Massachusetts, March 9 to 12, 2010. 3 This study is a recipient of ABA Poster Award (Best in Category-Psychosocial and Second Place Overall). Copyright © 2011 by the American Burn Association
TI - The Effect of Ketamine Administration on Nocturnal Sleep Architecture
JO - Journal of Burn Care & Research
DO - 10.1097/BCR.0b013e31822ac7d1
DA - 2011-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-effect-of-ketamine-administration-on-nocturnal-sleep-architecture-PRdUNu0qQT
SP - 535
EP - 540
VL - 32
IS - 5
DP - DeepDyve
ER -