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Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure
American Journal of Emergency Medicine (2012) 30, 1215–1218
www.elsevier.com/locate/ajem
Brief Report
Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure☆ Patrick C. Drayna MD a,⁎, Cristina Estrada MD a , Wenli Wang MS b , Benjamin R. Saville PhD b , Donald H. Arnold MD, MPH a a
Pediatric Emergency Medicine, Vanderbilt Children's Hospital, Nashville, TN 37232-9001, USA Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232-2158, USA
b
Received 26 April 2011; revised 31 May 2011; accepted 1 June 2011
Abstract Background: Ketamine is widely used for procedural sedation, but there is limited knowledge on whether ketamine use is associated with elevated intraocular pressure (IOP). Objective: The aim of this study was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation. Methods: We prospectively enrolled children without ocular abnormalities undergoing procedural sedation that included ketamine for nonperiorbital injuries. We measured IOP for each eye before and at 1, 3, 5, 15, and 30 minutes after initial intravenous ketamine administration. We performed BlandAltman plots to determine if IOP measurements in both eyes were in agreement. Linear regression was used to model the mean IOP of both eyes as a function of time, dose, and age, with a robust sandwich estimator to account for repeated measures. Results: Among 25 participants, median (interquartile range) age was 11 (9-12) years, and 18 (72%) were male. Median ketamine dose was 1.88 mg/kg (interquartile range, 1.43-2.03 mg/kg; range 0.96-4 mg/kg). Bland-Altman plots demonstrated a mean difference of IOP between eyes near zero at all time points. The largest predicted difference from baseline IOP occurred at 15 minutes, with an estimated change of 1.09 mm Hg (95% confidence interval, −0.37 to 2.55). The association between ketamine dose and mean IOP was not statistically significant or clinically meaningful (P = .90; estimated slope, 0.119 [95% confidence interval, −1.71 to 1.95]). There were no clinically meaningful levels of increased measured average IOP reached at any time point. Conclusions: At dosages of 4 mg/kg or less, there are not clinically meaningful associations of ketamine with elevation of IOP. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ☆
Funding sources: Vanderbilt Institute for Clinical and Translational Research grant support (1 UL1 RR024975 from NCRR/NIH). ⁎ Corresponding author. Division of Pediatric Emergency Medicine, 2200 Children's Way, Vanderbilt Children's Hospital, Nashville, TN 37232-9001, USA. E-mail addresses: [email protected], [email protected] (P.C. Drayna). 0735-6757/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2011.06.001
Children frequently present to the emergency department with fractures, lacerations, or other injuries that require evaluation and interventions that are both painful and frightening. Since its introduction in the late 1960s, ketamine has become a widely used and effective agent for pediatric
1216 procedural sedation because it provides amnesia, analgesia, anxiolysis, and sedation without respiratory depression or hypotension. Based on reports in the literature from the 1960s to 1970s, there has been concern that ketamine may elevate intraocular pressure (IOP). These reports had several limitations and reached conflicting conclusions as to whether there is an association of ketamine use with increased IOP. Normal IOP is approximately 12 to 20 mm Hg, with diurnal variations from 5 to 25 mm Hg based on large population studies [1-3]. Although there is excellent agreement regarding the normal range for mean IOP, determining the lower and particularly the upper limits of “normal” is much more difficult because the distribution tends to be right-skewed. Ocular hypertension, which we take as a our definition of clinical meaningful elevation of IOP, has been most commonly defined as sustained elevation in IOP at or above 22 mm Hg [4-6]. Overall, a review of the literature provides conflicting and limited descriptions of the effect ketamine on IOP. However, it has become a widely accepted practice to avoid using ketamine for procedural sedation of all patients with suspected eye injuries. Because of this concern, emergency medicine providers frequently choose other agents for sedation that may expose patients to other adverse effects (eg, myocardial and respiratory depression). Our objective was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation.
2. Methods We enrolled a prospective convenience sample of patients who underwent procedural sedation that included ketamine for nonperiorbital injuries in our pediatric emergency department. Eligible patients were 7 to 17 years of age, and exclusion criteria were American Society of Anesthesiologists (ASA) class 3 or 4, prior eye surgery, ocular abnormality, or periorbital injury. Two investigators were trained to use a Tonopen XL applanation tonometer (Medtronic Solan, Jacksonville, F) by an ophthalmologist before the study initiation. After proparacaine anesthetic eye drops, IOP was measured for each eye using the Tonopen, and the average value for both eyes was calculated before and at 1, 3, 5, 15, and 30 minutes after the first dose of intravenous ketamine. We recorded the total doses of ketamine, and other medications were administered. We performed Bland-Altman plots to assess whether measurements of IOP in both eyes were in agreement. Histograms of the mean IOP by time point indicated that the normality assumptions of linear regression were satisfied. A linear regression model was used to assess the time trend of mean IOP, adjusting for dose and age. This model incorporated a linear spline function on time to allow a
P.C. Drayna et al. nonlinear relationship between time and mean IOP. The covariance variance matrix of the model was adjusted by Huber robust sandwich estimator to account for correlated observations. All analyses were performed by the statistical software R 2.10.0 (http://www.r-project.org). This study protocol (no. 031054) was reviewed and approved by the Vanderbilt University Human Protection Program. Study data were collected and managed using REDCap electronic data capture tools hosted at Vanderbilt University Medical Center [7].
3. Results Patient characteristics are presented in Table 1. Bland-Altman plots demonstrated a high level of agreement of IOP measurements performed in each eye at all time points. After adjusting for age, sex, and dose, there were no statistically significant changes of mean IOP between baseline and any of the time points (overall test, P = .15; Table 2). The largest change from baseline was observed at 15 minutes, with an estimated difference of 1.09 mm Hg (95% confidence interval [CI], −0.37 to 2.55). The upper bound of the 95% CI (2.55 mm Hg) is very small from a clinical perspective, suggesting that there are no clinically meaningful changes in mean IOP across time. In addition, the association between ketamine dose and mean IOP was not statistically significant (P = .90), with an estimated slope of 0.119 (95% CI, −1.714 to 1.951) for a 1-unit increase in dose,
Table 1 Characteristics of 25 study participants without orbital or periorbital disease or injury who received ketamine sedation Range a
Age (y) Male Total ketamine dose (mg/kg) a Other medications given Glycopyrrolate Median glycopyrrolate dose (mg/kg) Ondansetron Median ondansetron dose (mg/kg) Midazolam Median midazolam dose (mg/kg) Procedure Fracture reduction Abscess incision and drainage Laceration repair Foreign body removal Hip arthrocentesis a
Values are median (IQR).
11 (9-12) 7-16 18/25 (72%) 1.88 (1.43-2.03) 0.96-4.00 11/25 (40%) 0.002 25/25 (100%) 0.10 19/25 (76%) 0.03 11/25 (40%) 17/25 (68%) 3/25 (12%) 2/25 (8%) 2/25 (8%) 1/25 (4%)
0.0010.005 0.05-0.11 0.01-0.05
Ketamine sedation and intraocular pressure Table 2
1217
Model-based predicted IOP change (Δ) after administration of IV ketamine at dosages of 4 mg/kg or less
Time (min)
Predicted mean IOP a (mm Hg)
95% CI
Predicted mean ΔIOP a (mm Hg)
95% CI
0 1 3 5 15 30
14.66 14.84 15.18 15.46 15.75 14.14
12.46-16.86 12.65-17.04 12.95-17.42 13.14-17.78 13.23-18.28 11.75-16.54
– 0.181 0.521 0.799 1.092 −0.519
– −0.03 −0.08 −0.13 −0.37 −1.70
to 0.39 to 1.12 to 1.73 to 2.55 to 0.66
IV indicates intravenous. a Linear regression model with restricted cubic spline function; mean ketamine dose, 1.88 mg/kg; mean age, 11 years; and Huber robust sandwich estimator for repeated-measures analysis.
which, in clinical terms, means a greatest plausible 1.951-mm Hg change in IOP for every 1-mg/kg unit increase in ketamine dose. The upper bound of this interval (1.951) is too small to be clinically relevant, suggesting that dose has no clinically meaningful association with mean IOP. There were no clinically meaningful levels (≥22 mm Hg) of measured average IOP reached at any time point (Fig. 1). Five patients had sustained decreases of average IOP at all time points during the 30-minute study period, and 3 other patients had decreases of average IOP at 4 of the 5 time points. In addition, we observed that in 8 of the 11 patients who needed additional doses of ketamine, the mean IOP decreased at the next IOP measurement. Three of the 25 patients had an isolated elevation of an IOP of 22 mm Hg or greater at a single time point. One of these 3 patients was redosed with ketamine with a subsequent decrease in IOP, and the other 2 patients were given single-dose ketamine. One of the 25 patients had an elevation of an IOP of 22 mm Hg or greater at 2 consecutive time points. It was noted that this patient had a baseline average IOP of 18 mm Hg, was given single initial dose of ketamine 1.5 mg/kg for closed
Fig. 1 Average values of IOP for both eyes as a function of time from the initial ketamine administration (n = 25). Boxes comprise interquartile range (IQR) with median lines across boxes. Fences are 1.5 value of IQR beyond IQR bounds.
reduction of a distal radius fracture, and reached an IOP of 23 and 25 mm Hg at 5 and 15 minutes, respectively.
4. Discussion The results of this investigation suggest that at dosages of 4 mg/kg or less, there are no clinically meaningful associations of ketamine with IOP. The known pharmacokinetics of ketamine are such that associated change of IOP would be unlikely after this interval [8]. The absence of a clinically meaningful dose-response relationship in this sample between ketamine and IOP further suggests that ketamine use is not associated with elevation in IOP. These findings question the widely held concern that ketamine increases IOP, a concern that appears to be informed by limited evidence. The initial work on ketamine and its effects on IOP was started by Corssen and Hoy [9] in 1967 and described an increase in IOP but had several limitations. The study looked at patients of different ages undergoing general anesthesia for surgical operations of various kinds. Their data included 15 pediatric cases, several of whom had incomplete data. The premedications used in the study were not standardized and included agents not generally used in the pediatric emergency department for this purpose (eg, barbiturates). The patients were studied for 3 minutes after drug administration, a time point which alone is not appropriate for the pharmacokinetics of this drug [8]. In almost half of the participants, the measurements either did not change or decreased in one or both eyes. A lesser proportion of IOP elevation was noted in pediatric cases, and these participants yielded a pooled mean increase of less than 3 mm Hg from control readings. Furthermore, pressure readings (done by Schiøtz tonometer) varied considerably between eyes, within participants, and between participants. Yoshikawa and Murai [10] assessed 15 children for a 30-minute period and reported a peak increase from baseline IOP at 15 minutes of 37% but used no premedication and a ketamine dose greater than is customary (5 mg/kg intramuscular [IM]). The recordings were done during various types of ophthalmologic surgery.
1218 Although some descriptive data were reported, there was no mention of statistical tests of inference used. Adams [11] later reported increased IOP measurements with general halothane induction followed by ketamine administration in 15 children. However, the ketamine dose was again greater than generally used (10 mg/kg IM), and 9 of the children already had known glaucoma changes. The mean IOP increased from 11 to 15.5 mm Hg at 3 to 5 minutes, and in no child did the pressure rise or stay above the normal upper limit of 22 mm Hg within the 8-minute measurement window. In contrast, Peuler et al [12] conducted a study of 20 adult patients and concluded that ketamine in clinically used doses, administered to a premedicated patient, had no significant effect on IOP. Ausinsch et al [13] studied 10 children and found no effects of ketamine on IOP despite IM doses of 8 mg/kg. More recently, 3 studies showed decreases in IOP after ketamine administration but were limited by potential confounders involving endotracheal intubation of patients, relatively low doses of ketamine given, short duration of IOP monitoring, and procedures involving the orbit with retrobulbar nerve blocks [14-16]. A more recent study looking at IOP effects of different doses of ketamine in children reported a 2-mm-Hg increase in IOP 5 minutes after receiving 6 mg/kg of ketamine IM and no change in children receiving 3 mg/kg ketamine IM [17]. However, the study included patients undergoing general anesthesia for ophthalmologic surgery. In addition, no patient's IOP exceeded 20 mm Hg. Importantly, no prior study has used a repeated-measures analysis. Five participants in our study had sustained decreases of average IOP at all time points during the 30-minute study period, and 3 other participants had decreases of average IOP at 4 of the 5 time points. Furthermore, we observed that in 8 of the 11 patients who needed additional doses of ketamine, the mean IOP decreased at the next IOP measurement. We believe that this was a result of ketamine treatment alleviating pain, agitation, and anxiety and does not support the concern that ketamine elevates IOP. Only 1 of 25 participants met a definition of clinically meaningful elevation of IOP during the study period, as defined by an IOP of 22 mm Hg or greater at two consecutive measurements. Our study has limitations. Sedation was performed for a variety of procedures, and a cohort undergoing a single type of procedure may eliminate the type of procedure as a potential confounding variable. Also, the study investigator did not participate in decisions for medication administration, and the clinical team determined whether to give glycopyrrolate and/or midazolam during the procedural sedation, as well as other analgesic medications that, when given, were given before the procedural sedation either by Emergency Medical Services (EMS) personnel and/or the clinical team. These ancillary medications may have had independent associations with IOP that are not fully adjusted for in our analyses. However, one could argue that providing anxiolysis and analgesia before the
P.C. Drayna et al. procedural sedation would, if anything, work to prevent artificial elevation of IOP due to agitation and pain. In summary, at dosages 4 mg/kg or less, there are not clinically meaningful associations of ketamine with IOP. Further study is warranted to determine if ketamine can be used safely for procedural sedation when elevated IOP or globe injury is a concern.
References [1] Stamper RL, Tanaka GH. Chapter 7 vol. 2: intraocular pressure: measurement, regulation, and flow relationships. In: Tasman W, Jaeger EA, editors. Duane's ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. [2] Leydhecker W. The intraocular pressure: clinical aspects. Ann Ophthalmol 1976; 8(4):389-92, 395-99. [3] Davanger M, Holter O. The statistical distribution of intraocular pressure in the population. Acta Ophthalmol (Copenh) 1965;43: 314-22. [4] Kim NR, Kim CY, Kim H, et al. Comparison of Goldmann applanation tonometer, noncontact tonometer, and Tonopen xl for intraocular pressure measurement in different types of glaucomatous, ocular hypertensive, and normal eyes. Curr Eye Res 2011;36(4): 295-300. [5] Henderson P, Labbe T, Kass MA. Chapter 10.9: ocular hypertension. In: Yanoff M, Duker JS, editors. Ophthalmology. 3rd ed. Mosby Elsevier; 2008. p. 1151-3. [6] Tavares IM, Medeiros FA, Weinreb RN. Inconsistency of the published definition of ocular hypertension. J Glaucoma 2006;15(6): 529-33. [7] Harris PA, Taylor R, Tgielke R, et al. Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377-81. [8] Patel PM, Patel HH, Roth DH. Chapter 19. General anesthetics and Therapeutic Gases. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. USA: McGraw-Hill; 2011. [9] Corssen G, Hoy JE. A new parenteral anesthetic CI-581: its effect on intraocular pressure. J Pediat Ophthal 1967;4:20-3. [10] Yoshikawa K, Murai Y. The effect of ketamine on intraocular pressure in children. Anesth Analg 1971;50(2):199-202. [11] Adams A. Ketamine in paediatric ophthalmic practice. Anaesthesia 1973;28:212-3. [12] Peuler M, Glass DD, Arens JF. Ketamine and intraocular pressure. Anesthesiology 1975;43(5):575-8. [13] Ausinsch B, Rayburn RL, Munson ES, et al. Ketamine and intraocular pressure in children. Anesth Analg 1976;55(6):773-5. [14] Badrinath SK, Vazeery A, McCarthy RJ, et al. The effect of different methods of inducing anesthesia on intraocular pressure. Anesthesiology 1986;65(4):431-5. [15] Cugini U, Lanzetta P, Nadbath P, et al. Sedation with ketamine during cataract surgery. J Cataract Refract Surg 1997;23(5):784-6. [16] Frey K, Sukhani R, Pawlowski J, et al. Propofol versus propofolketamine sedation for retrobulbar nerve block: comparison of sedation quality, intraocular pressure changes, and recovery profiles. Anest Analg 1999;89(2):317-21. [17] Nagdeve NG, Yaddanapudi S, Pandav SS. The effect of different doses of ketamine on intraocular pressure in anesthetized children. J Pediatr Ophthalmol Strabismus 2006;43(4):219-23.
www.elsevier.com/locate/ajem
Brief Report
Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure☆ Patrick C. Drayna MD a,⁎, Cristina Estrada MD a , Wenli Wang MS b , Benjamin R. Saville PhD b , Donald H. Arnold MD, MPH a a
Pediatric Emergency Medicine, Vanderbilt Children's Hospital, Nashville, TN 37232-9001, USA Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232-2158, USA
b
Received 26 April 2011; revised 31 May 2011; accepted 1 June 2011
Abstract Background: Ketamine is widely used for procedural sedation, but there is limited knowledge on whether ketamine use is associated with elevated intraocular pressure (IOP). Objective: The aim of this study was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation. Methods: We prospectively enrolled children without ocular abnormalities undergoing procedural sedation that included ketamine for nonperiorbital injuries. We measured IOP for each eye before and at 1, 3, 5, 15, and 30 minutes after initial intravenous ketamine administration. We performed BlandAltman plots to determine if IOP measurements in both eyes were in agreement. Linear regression was used to model the mean IOP of both eyes as a function of time, dose, and age, with a robust sandwich estimator to account for repeated measures. Results: Among 25 participants, median (interquartile range) age was 11 (9-12) years, and 18 (72%) were male. Median ketamine dose was 1.88 mg/kg (interquartile range, 1.43-2.03 mg/kg; range 0.96-4 mg/kg). Bland-Altman plots demonstrated a mean difference of IOP between eyes near zero at all time points. The largest predicted difference from baseline IOP occurred at 15 minutes, with an estimated change of 1.09 mm Hg (95% confidence interval, −0.37 to 2.55). The association between ketamine dose and mean IOP was not statistically significant or clinically meaningful (P = .90; estimated slope, 0.119 [95% confidence interval, −1.71 to 1.95]). There were no clinically meaningful levels of increased measured average IOP reached at any time point. Conclusions: At dosages of 4 mg/kg or less, there are not clinically meaningful associations of ketamine with elevation of IOP. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ☆
Funding sources: Vanderbilt Institute for Clinical and Translational Research grant support (1 UL1 RR024975 from NCRR/NIH). ⁎ Corresponding author. Division of Pediatric Emergency Medicine, 2200 Children's Way, Vanderbilt Children's Hospital, Nashville, TN 37232-9001, USA. E-mail addresses: [email protected], [email protected] (P.C. Drayna). 0735-6757/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2011.06.001
Children frequently present to the emergency department with fractures, lacerations, or other injuries that require evaluation and interventions that are both painful and frightening. Since its introduction in the late 1960s, ketamine has become a widely used and effective agent for pediatric
1216 procedural sedation because it provides amnesia, analgesia, anxiolysis, and sedation without respiratory depression or hypotension. Based on reports in the literature from the 1960s to 1970s, there has been concern that ketamine may elevate intraocular pressure (IOP). These reports had several limitations and reached conflicting conclusions as to whether there is an association of ketamine use with increased IOP. Normal IOP is approximately 12 to 20 mm Hg, with diurnal variations from 5 to 25 mm Hg based on large population studies [1-3]. Although there is excellent agreement regarding the normal range for mean IOP, determining the lower and particularly the upper limits of “normal” is much more difficult because the distribution tends to be right-skewed. Ocular hypertension, which we take as a our definition of clinical meaningful elevation of IOP, has been most commonly defined as sustained elevation in IOP at or above 22 mm Hg [4-6]. Overall, a review of the literature provides conflicting and limited descriptions of the effect ketamine on IOP. However, it has become a widely accepted practice to avoid using ketamine for procedural sedation of all patients with suspected eye injuries. Because of this concern, emergency medicine providers frequently choose other agents for sedation that may expose patients to other adverse effects (eg, myocardial and respiratory depression). Our objective was to examine whether there are clinically important elevations of IOP associated with ketamine use during pediatric procedural sedation.
2. Methods We enrolled a prospective convenience sample of patients who underwent procedural sedation that included ketamine for nonperiorbital injuries in our pediatric emergency department. Eligible patients were 7 to 17 years of age, and exclusion criteria were American Society of Anesthesiologists (ASA) class 3 or 4, prior eye surgery, ocular abnormality, or periorbital injury. Two investigators were trained to use a Tonopen XL applanation tonometer (Medtronic Solan, Jacksonville, F) by an ophthalmologist before the study initiation. After proparacaine anesthetic eye drops, IOP was measured for each eye using the Tonopen, and the average value for both eyes was calculated before and at 1, 3, 5, 15, and 30 minutes after the first dose of intravenous ketamine. We recorded the total doses of ketamine, and other medications were administered. We performed Bland-Altman plots to assess whether measurements of IOP in both eyes were in agreement. Histograms of the mean IOP by time point indicated that the normality assumptions of linear regression were satisfied. A linear regression model was used to assess the time trend of mean IOP, adjusting for dose and age. This model incorporated a linear spline function on time to allow a
P.C. Drayna et al. nonlinear relationship between time and mean IOP. The covariance variance matrix of the model was adjusted by Huber robust sandwich estimator to account for correlated observations. All analyses were performed by the statistical software R 2.10.0 (http://www.r-project.org). This study protocol (no. 031054) was reviewed and approved by the Vanderbilt University Human Protection Program. Study data were collected and managed using REDCap electronic data capture tools hosted at Vanderbilt University Medical Center [7].
3. Results Patient characteristics are presented in Table 1. Bland-Altman plots demonstrated a high level of agreement of IOP measurements performed in each eye at all time points. After adjusting for age, sex, and dose, there were no statistically significant changes of mean IOP between baseline and any of the time points (overall test, P = .15; Table 2). The largest change from baseline was observed at 15 minutes, with an estimated difference of 1.09 mm Hg (95% confidence interval [CI], −0.37 to 2.55). The upper bound of the 95% CI (2.55 mm Hg) is very small from a clinical perspective, suggesting that there are no clinically meaningful changes in mean IOP across time. In addition, the association between ketamine dose and mean IOP was not statistically significant (P = .90), with an estimated slope of 0.119 (95% CI, −1.714 to 1.951) for a 1-unit increase in dose,
Table 1 Characteristics of 25 study participants without orbital or periorbital disease or injury who received ketamine sedation Range a
Age (y) Male Total ketamine dose (mg/kg) a Other medications given Glycopyrrolate Median glycopyrrolate dose (mg/kg) Ondansetron Median ondansetron dose (mg/kg) Midazolam Median midazolam dose (mg/kg) Procedure Fracture reduction Abscess incision and drainage Laceration repair Foreign body removal Hip arthrocentesis a
Values are median (IQR).
11 (9-12) 7-16 18/25 (72%) 1.88 (1.43-2.03) 0.96-4.00 11/25 (40%) 0.002 25/25 (100%) 0.10 19/25 (76%) 0.03 11/25 (40%) 17/25 (68%) 3/25 (12%) 2/25 (8%) 2/25 (8%) 1/25 (4%)
0.0010.005 0.05-0.11 0.01-0.05
Ketamine sedation and intraocular pressure Table 2
1217
Model-based predicted IOP change (Δ) after administration of IV ketamine at dosages of 4 mg/kg or less
Time (min)
Predicted mean IOP a (mm Hg)
95% CI
Predicted mean ΔIOP a (mm Hg)
95% CI
0 1 3 5 15 30
14.66 14.84 15.18 15.46 15.75 14.14
12.46-16.86 12.65-17.04 12.95-17.42 13.14-17.78 13.23-18.28 11.75-16.54
– 0.181 0.521 0.799 1.092 −0.519
– −0.03 −0.08 −0.13 −0.37 −1.70
to 0.39 to 1.12 to 1.73 to 2.55 to 0.66
IV indicates intravenous. a Linear regression model with restricted cubic spline function; mean ketamine dose, 1.88 mg/kg; mean age, 11 years; and Huber robust sandwich estimator for repeated-measures analysis.
which, in clinical terms, means a greatest plausible 1.951-mm Hg change in IOP for every 1-mg/kg unit increase in ketamine dose. The upper bound of this interval (1.951) is too small to be clinically relevant, suggesting that dose has no clinically meaningful association with mean IOP. There were no clinically meaningful levels (≥22 mm Hg) of measured average IOP reached at any time point (Fig. 1). Five patients had sustained decreases of average IOP at all time points during the 30-minute study period, and 3 other patients had decreases of average IOP at 4 of the 5 time points. In addition, we observed that in 8 of the 11 patients who needed additional doses of ketamine, the mean IOP decreased at the next IOP measurement. Three of the 25 patients had an isolated elevation of an IOP of 22 mm Hg or greater at a single time point. One of these 3 patients was redosed with ketamine with a subsequent decrease in IOP, and the other 2 patients were given single-dose ketamine. One of the 25 patients had an elevation of an IOP of 22 mm Hg or greater at 2 consecutive time points. It was noted that this patient had a baseline average IOP of 18 mm Hg, was given single initial dose of ketamine 1.5 mg/kg for closed
Fig. 1 Average values of IOP for both eyes as a function of time from the initial ketamine administration (n = 25). Boxes comprise interquartile range (IQR) with median lines across boxes. Fences are 1.5 value of IQR beyond IQR bounds.
reduction of a distal radius fracture, and reached an IOP of 23 and 25 mm Hg at 5 and 15 minutes, respectively.
4. Discussion The results of this investigation suggest that at dosages of 4 mg/kg or less, there are no clinically meaningful associations of ketamine with IOP. The known pharmacokinetics of ketamine are such that associated change of IOP would be unlikely after this interval [8]. The absence of a clinically meaningful dose-response relationship in this sample between ketamine and IOP further suggests that ketamine use is not associated with elevation in IOP. These findings question the widely held concern that ketamine increases IOP, a concern that appears to be informed by limited evidence. The initial work on ketamine and its effects on IOP was started by Corssen and Hoy [9] in 1967 and described an increase in IOP but had several limitations. The study looked at patients of different ages undergoing general anesthesia for surgical operations of various kinds. Their data included 15 pediatric cases, several of whom had incomplete data. The premedications used in the study were not standardized and included agents not generally used in the pediatric emergency department for this purpose (eg, barbiturates). The patients were studied for 3 minutes after drug administration, a time point which alone is not appropriate for the pharmacokinetics of this drug [8]. In almost half of the participants, the measurements either did not change or decreased in one or both eyes. A lesser proportion of IOP elevation was noted in pediatric cases, and these participants yielded a pooled mean increase of less than 3 mm Hg from control readings. Furthermore, pressure readings (done by Schiøtz tonometer) varied considerably between eyes, within participants, and between participants. Yoshikawa and Murai [10] assessed 15 children for a 30-minute period and reported a peak increase from baseline IOP at 15 minutes of 37% but used no premedication and a ketamine dose greater than is customary (5 mg/kg intramuscular [IM]). The recordings were done during various types of ophthalmologic surgery.
1218 Although some descriptive data were reported, there was no mention of statistical tests of inference used. Adams [11] later reported increased IOP measurements with general halothane induction followed by ketamine administration in 15 children. However, the ketamine dose was again greater than generally used (10 mg/kg IM), and 9 of the children already had known glaucoma changes. The mean IOP increased from 11 to 15.5 mm Hg at 3 to 5 minutes, and in no child did the pressure rise or stay above the normal upper limit of 22 mm Hg within the 8-minute measurement window. In contrast, Peuler et al [12] conducted a study of 20 adult patients and concluded that ketamine in clinically used doses, administered to a premedicated patient, had no significant effect on IOP. Ausinsch et al [13] studied 10 children and found no effects of ketamine on IOP despite IM doses of 8 mg/kg. More recently, 3 studies showed decreases in IOP after ketamine administration but were limited by potential confounders involving endotracheal intubation of patients, relatively low doses of ketamine given, short duration of IOP monitoring, and procedures involving the orbit with retrobulbar nerve blocks [14-16]. A more recent study looking at IOP effects of different doses of ketamine in children reported a 2-mm-Hg increase in IOP 5 minutes after receiving 6 mg/kg of ketamine IM and no change in children receiving 3 mg/kg ketamine IM [17]. However, the study included patients undergoing general anesthesia for ophthalmologic surgery. In addition, no patient's IOP exceeded 20 mm Hg. Importantly, no prior study has used a repeated-measures analysis. Five participants in our study had sustained decreases of average IOP at all time points during the 30-minute study period, and 3 other participants had decreases of average IOP at 4 of the 5 time points. Furthermore, we observed that in 8 of the 11 patients who needed additional doses of ketamine, the mean IOP decreased at the next IOP measurement. We believe that this was a result of ketamine treatment alleviating pain, agitation, and anxiety and does not support the concern that ketamine elevates IOP. Only 1 of 25 participants met a definition of clinically meaningful elevation of IOP during the study period, as defined by an IOP of 22 mm Hg or greater at two consecutive measurements. Our study has limitations. Sedation was performed for a variety of procedures, and a cohort undergoing a single type of procedure may eliminate the type of procedure as a potential confounding variable. Also, the study investigator did not participate in decisions for medication administration, and the clinical team determined whether to give glycopyrrolate and/or midazolam during the procedural sedation, as well as other analgesic medications that, when given, were given before the procedural sedation either by Emergency Medical Services (EMS) personnel and/or the clinical team. These ancillary medications may have had independent associations with IOP that are not fully adjusted for in our analyses. However, one could argue that providing anxiolysis and analgesia before the
P.C. Drayna et al. procedural sedation would, if anything, work to prevent artificial elevation of IOP due to agitation and pain. In summary, at dosages 4 mg/kg or less, there are not clinically meaningful associations of ketamine with IOP. Further study is warranted to determine if ketamine can be used safely for procedural sedation when elevated IOP or globe injury is a concern.
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