ACADEMIC EMERGENCY MEDICINE 2012; 19:1145–1150 © 2012 by the Society for Academic Emergency Medicine
Objectives: Ketamine is one of the most commonly used procedural sedation and analgesia (PSA) agents in pediatric emergency departments (PEDs). It is considered a very safe and reliable agent, with limited respiratory suppression, hemodynamic effects, and adverse outcomes. However, physicians are often reluctant to use ketamine for patients with eye injuries due to a concern that ketamine might increase intraocular pressure (IOP). The objective was to measure IOP in previously healthy children receiving ketamine for PSA for a reason other than eye injury.
Methods: This was a prospective noninferiority study of patients seen in an academic tertiary care children’s hospital emergency department (ED) who required ketamine for PSA. The authors measured IOP in the right eye as soon as possible after ketamine had been administered and then at 2.5, 5, and 10 minutes after ketamine had been administered.
Results: Eighty patients were enrolled (28 between 1 and 5 years of age, 26 between 6 and 10 years, 26 between 11 and 15 years); 49 (61%) were male. Procedures requiring PSA included fracture/dislocation reduction (63%), abscess incision and drainage (16%), laceration repair (11%), dental abscess incision and drainage (6%), and other (4%). The mean total ketamine dosage was 1.6 mg/kg (95% confidence interval [CI] = 1.4 to 1.7). The mean initial IOP was 17.5 mm Hg (95% CI = 16.4 to 18.6 mm Hg) and at 2.5 minutes was 18.9 mm Hg (95% CI = 17.9 to 19.9 mm Hg). The mean difference was 1.4 mm Hg (95% CI = 0.4 to 2.4 mm Hg). Using a noninferiority margin of 2.6 mm Hg (15%), noninferiority (no significant elevation in IOP) was demonstrated with 95% confidence between the first and second readings.
Conclusions: Ketamine does not significantly increase IOP in pediatric patients without eye injuries receiving typical PSA dosages in the PED. Further study should assess its safety in patients with ocular injury.
Objetivos: La ketamina es uno de los agentes más frecuentemente utilizados en el procedimiento de sedación y analgesia (PSA) en los servicios de urgencias pediátricos (SUP). Se considera un agente muy seguro y fiable, con limitados efectos hemodinámicos, depresión respiratoria y efectos adversos. Sin embargo, los médicos a menudo son reacios a usar la ketamina en los pacientes con daño ocular debido a la preocupación de que la ketamina pueda incrementar la presión intraocular (PIO). El objetivo fue medir la PIO en niños sanos previamente a la administración de ketamina parael PSA por otra razón distinta al daño ocular.
Métodos: Estudio prospectivo de no inferioridad en pacientes atendidos en un SU de un hospital infantil terciario y universitario que requirieron ketamina para PSA. Se midió la PIO en el ojo derecho tan pronto como fue posible tras la administración de ketamina, y posteriormente a los 2 minutos y medio, 5 minutos y 10 minutos tras la administración de ketamina.
Resultados: Se incluyeron ochenta pacientes (28 entre 1 y 5 años, 26 entre 6 y 10 años, 26 entre 11 y 15 años). La media de edad fue de 7,7 años y 49 (61%) fueron varones. Los procedimientos que requirieron PSA incluyeron la reducción de fractura/luxación (63%), la incisión y drenaje de absceso (16%), la sutura de herida (11%), la incisión y drenaje de absceso dental (6%) y otros (4%). La dosis media total de ketamina fue 1,6 mg/kg (IC 95% = 1,4 a 1,7). La media de PIO inicial fue 17,5 mm Hg (IC 95% = 16,4 a 18,6 mm Hg), y a los 2 minutos y medio fue de 18,9 mm Hg (IC 95% = 17,9 a 19,9 mm Hg). La media de la diferencia fue de 1,4 mm Hg (IC 95% = 0,4 a 2,4 mm Hg). Usando un margen de no inferioridad de 2,6 mm Hg (15%), se demostró la no inferioridad (no elevación significativa de la PIO) entre la primera y la segunda lectura con un intervalo de confianza del 95%.
Conclusiones: La ketamina no incrementa de forma significativa la PIO en los pacientes pediátricos sin lesiones oculares tras recibir las dosis habituales de PSA en los SUP. Futuros estudios deberían valorar su seguridad en los pacientes con lesión ocular.
Population-based studies suggest that the mean intraocular pressure (IOP) is approximately 15 mm Hg, with 97% of the population having a pressure less than 24 mm Hg.1 The criteria used to define intraocular hypertension vary between different studies, although in the majority of studies the upper limit of normal lies between 22 and 26 mm Hg.2 There is some suggestion that age affects IOP measurements.3
The concern that ketamine might increase IOP stems from animal studies,4–7 human studies using multiple anesthetics concurrently,8 and studies using much larger dosages of ketamine9 than one would typically use for procedural sedation and analgesia (PSA). However, other studies report no significant increase.10,11 Blumberg et al.12 concluded that ketamine might have advantages over gas anesthetics for obtaining IOP measurements in children as ketamine neither increased nor decreased IOP from baseline measurements. Our objective was to measure IOP in previously healthy pediatric patients receiving ketamine PSA in the pediatric emergency department (PED) to evaluate if ketamine may be considered as a PSA agent for patients with eye injuries.
We performed a prospective noninferiority study measuring IOP in pediatric patients receiving ketamine PSA for a complaint other than an eye injury (e.g., fracture or dislocation reduction, laceration repair, abscess incision and drainage) in an urban tertiary care PED. This study was approved by the institutional review board. Written informed consent was obtained from the parent or guardian of all patients enrolled in the study; written assent was obtained from all patients 7 years of age and older. An Investigational New Drug (IND) application was approved to use proparacaine hydrochloride ophthalmic solution 0.5% drops as it is not approved by the U.S. Food and Drug Administration for use in children (IND No. 107557).
Study Setting and Population
Study subjects were recruited from patients between 1 and 15 years of age who had an American Society of Anesthesiologists physical status classification of 1/1E or 2/2E. After the parent or guardian consented to ketamine PSA, each was approached to participate in the study. To control for potential IOP differences by age, subjects were recruited in the following age blocks: 1 to 5, 6 to 10, and 11 to 15 years.
Patients were excluded from the study if they had a history of glaucoma or any other eye condition. Patients with a latex allergy were excluded, as the cover tips for the tonometer contain latex. Patients with an allergy to ester-type local anesthetics such as benzocaine, butacaine, tetracaine, or proparacaine were excluded as we used proparacaine hydrochloride ophthalmic solution 0.5%.
After patient enrollment, one to two drops of the local anesthetic proparacaine ophthalmic solution were placed in the right eye immediately prior to PSA. IOP was measured with the Tono-Pen XL (Reichert Technologies, Buffalo, NY), an accurate handheld applanation tonometer,13,14 in the right eye as soon as possible after ketamine had been administered and then at 2.5, 5, and 10 minutes after initial ketamine administration. IOP was measured by pediatric emergency medicine attending physicians and fellows who were trained on the Tono-Pen XL by a pediatric ophthalmologist. Tono-Pen readings were considered acceptable if the reliability measure was 5 or 10% (i.e., the standard deviation of the measurements was 10% or less of the measurement). The same physician obtained all measurements for a given patient. The ketamine was administered intravenously (IV) by the treating attending physician, who was not the same physician measuring IOP. The dosage and timing of the ketamine administration, as well as all the administration of other medications, were left to the treating physician’s discretion.
Demographic and clinical variables, including age, sex, weight, procedure performed, other medications given, and total dosage of ketamine administered, were recorded onto a standardized data collection sheet. Pulse and blood pressure were recorded at the same intervals as the IOP measurements by research associates.
The primary outcome measure was the mean difference in IOP between the initial and 2.5-minute measurements with a noninferiority margin of 15%. The secondary outcome measure was the change in IOP over the 10-minute study period.
The Kruskal-Wallis test was used to compare total dosages of ketamine between the three age groups as the distribution was nonparametric. The mean difference with 95% confidence intervals (CIs) of the initial IOP and the 2.5-minute IOP measurement were used to evaluate noninferiority. Linear regression was performed to analyze the dose–response relationship between total ketamine dosage and IOP at 10 minutes controlling for baseline IOP measurements. Repeated-measures analysis of variance (ANOVA) was performed to analyze IOP trends during the study period controlling for age and initial heart rate as a proxy for discomfort. Sample size calculations were performed a priori with a power of 0.9 and α = 0.05. Using a noninferiority design with a clinically significant margin of noninferiority of 15% between the initial and 2.5-minute measurements, 26 patients would be required for each of the three age groups (1 to 5, 6 to 10, 11 to 15 years) for a total study population of 78. The noninferiority margin of 15% was chosen by a pediatric ophthalmologist (RE) as a clinically relevant difference. Data were analyzed using SAS 9.2 (SAS Institute Inc., Cary, NC).
Eighty patients were enrolled between February 2010 and May 2011: 28 between 1 and 5 years of age, 26 between 6 and 10 years, and 26 between 11 and 15 years; 49 (61%) were male (Table 1). The most commonly performed procedure during the study was fracture/dislocation reduction, although abscess incision and drainage and laceration repair were more common in the youngest age group. Other procedures included gynecologic exam and oral foreign body removal (Table 1). The mean total ketamine dosage administered IV was 1.6 mg/kg (95% CI = 1.4 to 1.7). The dosage did not differ based on the age of the patient (p = 0.44). Other medications received by patients during their PED course included glycopyrolate, midazolam, and ondansetron. Glycopyrolate was the most commonly used other medication (11%), primarily in the youngest age group. Other less frequently administered medications included methylene blue and lidocaine cream (Table 1).
|Variable||Overall (n = 80)||1–5 yr (n = 28)||6–10 yr (n = 26)||11–15 yr (n = 26)|
|Male, n (%)||49 (61)||16 (57)||15 (58)||18 (69)|
|Procedures, n (%)|
|Fracture/dislocation reduction||50 (63)||5 (18)||21 (80)||24 (92)|
|Abscess incision and drainage||13 (16)||10 (36)||2 (8)||1 (4)|
|Laceration repair||9 (11)||7 (25)||2 (8)||0|
|Dental abscess incision and drainage/tooth extraction||5 (6)||5 (18)||0||0|
|Other||3 (4)||1 (3)||1 (4)||1 (4)|
|Mean total dosage of ketamine, mg/kg (95% CI)||1.6 (1.4–1.7)||1.6 (1.4–1.8)||1.7 (1.3–2.0)||1.4 (1.2–1.6)|
|Other medications, n (%)|
|Glycopyrolate||9 (11)||8 (29)||0||1 (4)|
|Midazolam||1 (1)||0||1 (4)||0|
|Ondansetron||1 (1)||0||1 (4)||0|
|Other||2 (3)||0||2 (8)||0|
The mean initial IOP was 17.5 mm Hg (95% CI = 16.4 to 18.6 mm Hg), and at 2.5 minutes was 18.9 mm Hg (95% CI = 17.9 to 19.9 mm Hg). The mean difference was 1.4 mm Hg (95% CI = 0.4 to 2.4 mm Hg). Using a noninferiority margin of 2.6 mm Hg (15%), noninferiority (no significant elevation in IOP) was demonstrated with 95% confidence between the first and second readings. The mean difference between initial and 2.5 minutes for the 1- to 5-year-old group was 1.4 mm Hg (95% CI = −0.4 to 3.3 mm Hg), for the 6- to 10-year-old group was 2.0 (95% CI = 0.7 to 3.3 mm Hg), and for 11- to 15-year-old group was 0.7 (95% CI = −1.5 to 3.0). Patient-level analysis was included in by-subject plots for the three different age groups (Figures 1–3). There was no evidence of a dose–response relationship between IOP at 10 minutes and total ketamine dosage in mg/kg controlling for the baseline IOP measurement (p = 0.15). There was a statistical difference in IOP over the 10-minute study period controlling for age and initial heart rate using repeated measures ANOVA (p < 0.01; Table 2).
|Age Group (yr)||Initial IOP (95% CI)||2.5-minute IOP (95% CI)||5-minute IOP (95% CI)||10-minute IOP (95% CI)|
|1–5||19.1 (16.9–21.4)||20.5 (18.4–22.7)||20.6 (18.2–22.9)||18.6 (16.5–20.7)|
|6–10||16.5 (14.7–18.3)||18.5 (16.9–20.1)||18.7 (16.5–20.9)||17.6 (15.9–19.3)|
|11–15||16.8 (14.9–18.6)||17.5 (16.2–18.8)||18.2 (16.7–19.6)||17.5 (16.3–18.8)|
We found that ketamine did not significantly increase IOP in pediatric patients undergoing PSA. Although we saw a statistically significant trend in IOP during the study period, we do not believe that this finding is clinically significant given the small changes seen in IOP (<2.5 mm Hg). Small, transient elevations in IOP in this range are not even considered clinically significant for patients with glaucoma, as diurnal fluctuations of IOP to this degree are anticipated.15,16 These findings are important because ketamine has not been traditionally used in the PED for PSA for ophthalmic exams in pediatric patients with eye injuries due to concerns that ketamine might increase IOP. The strengths of our study include stratification by age to ensure the inclusion of younger children, a noninferiority design with sample size calculations, and dosage of ketamine typical for PSA usage in the PED (i.e., 1–2 mg/kg IV). In addition, we saw no evidence of a dose–response relationship between ketamine dosage and IOP.
Our study agrees with a recently published manuscript that there are no clinically meaningful associations of ketamine with IOP at typical PSA dosages.17 Although Drayna et al.17 found no statistically significant changes of mean IOP between baseline and any time point during their study period, there were only 25 patients enrolled in their study. In our study of 80 patients, we found a statistically significant difference that a smaller study would be unlikely to observe due to sample size considerations. One of the advantages of repeated-measures ANOVA analysis is its power to detect statistically significant differences. To date, our study is the largest examining the relationship between IOP and ketamine in pediatric patients.
Previous studies that showed a relationship between IOP and ketamine used intramuscular (IM) ketamine in the operating room (OR) in larger dosages (e.g., 5–10 mg/kg) than one would typically use for PSA.8,9,12 The typical range for IM dosing of ketamine for PSA is 2 to 4 mg/kg. The standard initial dose of IV ketamine for PSA is 1 mg/kg and usually no more than 2 mg/kg total IV dosage is required. In addition, these studies included patients who were scheduled for ophthalmic procedures, suggesting the presence of some type of prior ocular pathology.8,9,12 These studies performed in the OR are also confounded by the administration of different medications such as atropine, pentobarbital, meperidine, methohexital, and inhaled anesthetics.8,9,12 Physicians should use caution when extrapolating data from different patient care settings, including different types of patients and different dosages of medications, to their patients and practice location.
We specifically included pediatric patients in the age group of 1 to 5 years as there is a paucity of data regarding the relationship between IOP and ketamine in this age range. The youngest patient enrolled in the study by Drayna et al. was 7 years of age.17 Nagdeve et al.8 studied patients in the 1- to 6-year-old age group, but their study was performed in the OR after receiving halothane for induction. Inhaled anesthetics have been shown to reduce IOP so their results are not generalizable to patients receiving PSA in the pediatric ED.12 We thought it was important to include this age group as they are the pediatric patients most likely to require PSA for thorough ophthalmic exams. Reassuringly, the IOP in this age group did not show a clinically meaningful change.
Limitations to our study included that IOP measurements were obtained by multiple providers who were unfamiliar with the Tono-Pen XL prior to the study, likely resulting in greater variability in the measurements than would be expected if there were fewer observers. Our study may be underpowered, as our sample size calculations assumed less variability in the measurement of IOP. We measured IOP as soon as possible after ketamine administration, which was most difficult in the younger patients. Therefore, the initial IOP measurement may have included some effect of the ketamine, resulting in an underestimation of the true difference between the initial and 2.5-minute measurements. We were not able to measure IOP continuously, so could have potentially missed clinically important spikes in IOP between measurements. We measured IOP in patients without eye injuries so cannot comment on ketamine’s effect on IOP in the presence of an eye injury. Potential confounders included other medications administered during the study period such as glycopyrolate and midazolam. We also did not control for the type of procedure performed, which may have confounded the relationship between ketamine and IOP due to the varying levels of discomfort with different procedures.
Ketamine does not significantly increase intraocular pressure in pediatric patients without eye injuries receiving typical procedural sedation and analgesia dosages in the pediatric ED. Further study should assess its safety in patients with ocular injury.
The authors thank Drs. Ryan Caltagirone, Julia Fuzak, Joseph Grubenhoff, Amanda Greene, Sam Wang, and Keith Weisz for their help measuring IOP in study patients. They also thank their research associates, Sarah Baumbach, Korie Burroughs, and Kendra Kocher, for patient enrollment and data collection.