Optimal dosing of intravenous ketamine for procedural sedation in children in the ED—a randomized controlled trial

    Optimal Dosing of IV Ketamine for Procedural Sedation in Children in the Emergency Department - A Randomized Controlled Trial Nirupama Kannikeswaran MD, Mary Lieh-Lai MD, Monica Malian R.Ph., Bo Wang PhD, Ahmad Farooqi MPhil, MSC, MA, Mark G. Roback MD PII: DOI: Reference:

S0735-6757(16)30011-0 doi: 10.1016/j.ajem.2016.03.064 YAJEM 55713

To appear in:

American Journal of Emergency Medicine

Received date: Revised date: Accepted date:

20 January 2016 29 March 2016 29 March 2016

Please cite this article as: Kannikeswaran Nirupama, Lieh-Lai Mary, Malian Monica, Wang Bo, Farooqi Ahmad, Roback Mark G., Optimal Dosing of IV Ketamine for Procedural Sedation in Children in the Emergency Department - A Randomized Controlled Trial, American Journal of Emergency Medicine (2016), doi: 10.1016/j.ajem.2016.03.064

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

RI P

NU

SC

Dr. Nirupama Kannikeswaran, MD Associate Professor of Pediatrics, Wayne State University School of Medicine, Carman and Ann Adams Department of Pediatrics, Division of Emergency Medicine, Children’s Hospital of Michigan, 3901, Beaubien Blvd, Detroit, MI 48201. Ph: 313-745-5260. [email protected]

T

OPTIMAL DOSING OF IV KETAMINE FOR PROCEDURAL SEDATION IN CHILDREN IN THE EMERGENCY DEPARTMENT - A RANDOMIZED CONTROLLED TRIAL

ED

MA

Dr. Mary Lieh-Lai, MD Senior Vice President, Medical Accreditation Professor of Pediatrics (Vol) Wayne State University School of Medicine Accreditation Council for Graduate Medical Education 515 N. State Street, Suite 2000 Chicago, IL 60654

CE

PT

Monica Malian R.Ph. Investigational Drug Service Coordinator Department of Pharmacy Services Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201.

AC

Dr. Bo Wang, PhD, Assistant Professor of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201. Ahmad Farooqi MPhil MSC MA Research Assistant (Biostatistician) Department of Pediatrics Wayne State University School of Medicine, Detroit, MI 48201 Dr. Mark G Roback, MD Professor of Pediatrics, Director, Division of Emergency Medicine, University of Minnesota Medical School, MMC 814, 420 Delaware St. SE, Minneapolis, MN 55455.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

RI P

NU

SC

Dr. Nirupama Kannikeswaran, MD Associate Professor of Pediatrics, Wayne State University School of Medicine, Carman and Ann Adams Department of Pediatrics, Division of Emergency Medicine, Children’s Hospital of Michigan, 3901, Beaubien Blvd, Detroit, MI 48201. Ph: 313-745-5260. [email protected]

T

CORRESPONDING AUTHOR:

MA

Key words: Procedural Sedation and Analgesia, Ketamine, Dosing, Adverse drug events, Children, Emergency Department. An abstract of this study was presented at the Pediatric Academic Societies Meeting as a poster presentation , May 2013.

PT

ED

Grant Funding: This study was supported by the "New Investigator Grant Program", Children's Research Foundation Of Michigan as well as Children's Hospital of Michigan Foundation Grant.

AC

CE

Author Contributions: NK, MLL and MGR conceived the study and designed the trial. NK obtained research funding and supervised the conduct of the trial and data collection. MM performed the study randomization, study drug preparation, verification of the study drug dose administered. BW provided statistical advice on study design , analyzed the data and drafted the statistical analysis section of the manuscript. NK drafted the manuscript, and MLL and MGR contributed substantially to its revision. All authors have reviewed the manuscript. NK takes responsibility for the paper as a whole

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

T

Optimal Dosing of Ketamine for Procedural Sedation for Children in the Emergency Department - A Randomized Controlled Trial

RI P

Abstract:

SC

Objective: To compare need for re-dosing, sedation efficacy, duration and adverse events between three commonly administered doses of parenteral ketamine in the Emergency Department (ED).

MA

NU

Methods: We conducted a prospective, double-blind, randomized controlled trial on a convenience sample of children 3-18 years who received IV ketamine for procedural sedation. Children from each age group (3-6,7-12,13-18 years) were assigned in equal numbers to 3 dosing groups (1, 1.5 and 2 mg/kg) using random permuted blocks. The primary outcome measure was need for ketamine re-dosing to ensure adequate sedation. Secondary outcome measures were sedation efficacy, sedation duration, and sedation related adverse events.

AC

CE

PT

ED

Results: 171 children were enrolled of whom 125 (1mg/kg: 50,1.5 mg/kg :35, 2mg/kg: 40)received the randomized dose and were analyzed. The need for ketamine re-dosing was higher in the 1 mg/kg group (8/50; 16.0% vs. 1/35; 2.9% vs. 2/40; 5.0%).There was no significant difference in the median Ramsay sedation scores [5.5 (IQR:4,6) vs. 6 (IQR:4,6) vs. 6 (IQR:5,6)]; FACES-R score [0 (IQR:0,4) vs. 0 (IQR:0,0) vs. 0 (IQR:0,0)], sedation duration in minutes [23 (IQR: 19,38) vs. 24.5 (IQR: 17.5, 34.5) vs. 23 (IQR:19,29)] and adverse events (10.0% vs. 14.3% vs. 10.0%) between the 3 dosing groups. Physician satisfaction was lower in the 1mg/kg group (79.6% vs. 94.1% vs. 97.3%). Conclusions: Adequate sedation was achieved with all three doses of ketamine. Higher doses did not increase the risk of adverse events or prolong sedation. Ketamine administered at 1.5 or 2.0 mg/kg IV required less re-dosing and resulted in greater physician satisfaction.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

1. INTRODUCTION:

MA

NU

SC

RI P

T

Ketamine has become one of the most commonly administered drugs for procedural sedation and analgesia for children in the Emergency Department (ED) due to its efficacy and favorable safety profile.1-7 Two clinical practice guidelines for ED ketamine use state that the minimum dose of intravenous (IV) ketamine at which the dissociative state can be reliably achieved in children is 1.5 mg/kg IV, and common loading doses are 1.5 to 2 mg/kg.8,9 Despite these recommendations, prospective, ED comparative trials have administered ketamine IV in 0.5 mg increments to a maximum of 2 mg,10 as 1 mg/kg,11-15 1.5 mg/kg,16 1-2 mg/kg17 and 2 mg/kg.18 Although previous studies using ketamine for procedural sedation and analgesia did not find a significant change in adverse event rates unless the initial IV dose exceeded 2.5 mg/kg or the total dose exceeded 5.0 mg/kg, this wide practice variation of ketamine administration may impact sedation efficacy, duration of sedation and potentially, adverse events.5,6

CE

PT

ED

A retrospective report of sedation in the ED using ketamine and midazolam found that lower doses of IV ketamine (≤ 0.75 mg/kg) may provide adequate sedation, however, no differences in sedation duration were observed and adverse events were infrequent in all doses.19 This study did not describe the infusion time of IV ketamine. Current recommendations support administration of IV ketamine over 30-60 seconds to prevent respiratory depression.9,20 Recent studies have investigated the administration of lower doses of IV ketamine (< 1 mg/kg) over much shorter time period (≤ 5 seconds) for brief procedures as well as lower initial doses of IV ketamine with subsequent "top-up" doses and have demonstrated adequate sedation with shorter sedation times. 21,22

AC

Ketamine clearance has been shown to be higher in younger children, who might therefore potentially require a higher mg/kg dose of ketamine than older children to achieve similar sedation effects.23 Despite this finding, current dosing recommendations for ketamine do not differ by age. Furthermore, ketamine pharmacokinetics studies have demonstrated that different initial doses of IV ketamine (1 mg/kg versus 1.5 mg/kg) are associated with different serum concentrations that lead to analgesic and amnestic effects of varying duration with varying arousal times.23,24 Lower doses of ketamine in older children have been evaluated. Street et al. found that a fixed-dose ketamine protocol of 50 mg, followed by 25 mg IV provided adequate sedation for 12-17 year old normal weight and overweight/obese children in the ED.25 While it is clear that a wide range of IV ketamine dosing has been reported, to our knowledge, no studies have directly compared the sedation efficacy, sedation duration and adverse events associated with the 3 most commonly administered initial IV doses of ketamine for children in the ED. A randomized controlled trial comparing three of the most commonly used ketamine dosing regimens would either support current recommendations or suggest modifications based on patient age and projected length of procedure. Most importantly, if differences in adverse events, sedation efficacy and

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT recovery times are found based on dose or age, it will help us develop strategies for providing safer, more effective ketamine sedation for children in the ED.

SC

RI P

T

The objective of our study was to compare the efficacy, duration of sedation and adverse events between the three commonly administered doses of IV ketamine (1 mg/kg, 1.5 mg/kg and 2 mg/kg) using the traditional administration method of 30-60 second infusion for procedural sedation in children in the ED. Additionally, we sought to measure the effect of age on ketamine dosing.

2. METHODS:

PT

ED

MA

NU

2.1. Study design and setting: This was a prospective, double-blind, randomized controlled trial of a convenience sample of children aged 3 to 18 years who required IV ketamine for procedural sedation and analgesia for orthopedic procedures, incision and drainage (I & D) of skin abscess and laceration repair conducted in the ED. Written informed consent was obtained from the patient’s parents or guardians. In addition, an assent was obtained from all children >7 years of age. This study was approved by the Human Investigation Committee (HIC) of our institution. The HIC requested the submission of the study protocol to the Federal Drug Administration (FDA) for review. The FDA required that we apply for an Investigational New Drug (IND) approval, which was granted (106,683). The study was registered at ClinicalTrials.gov, Identifier: NCT02519595.

CE

The study was conducted at a free-standing children’s hospital in a tertiary care pediatric ED and Level 1 trauma center with 92,000 patient visits per year, of whom approximately 1,200 children receive procedural sedation and analgesia every year.

AC

2.2. Selection of Study Participants: Children between the ages of 3 to 18 years with American Society of Anesthesiologists (ASA) classification I or II 26 who required IV ketamine for procedural sedation and analgesia for orthopedic procedures, I & D of skin abscess and laceration repair were eligible for participation in the study. We enrolled a convenience sample of eligible patients based on availability of the research assistants. Study participants were identified using the electronic medical tracking board which lists the presenting complaint and after need for procedural sedation and analgesia with IV ketamine was established with the treating physician. The following patients were excluded from the study: 1. Children with hypertension, acute glaucoma or injury to the globe, increased intracranial pressure or intracranial mass lesion, acute porphyria and major psychiatric disorder. 2. Children with a prior allergic reaction to ketamine. 3. Children who were pregnant.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

RI P

T

4. If the parent or legal guardian was not available or declined to provide informed consent for the study, or if the child declined to provide assent. 5. If the patient received intramuscular ketamine. 6. If the patient received benzodiazepines in addition to ketamine for sedation in the ED. 7. Children weighing >100 kilogram (study drug preparation was not possible using a 10-mL syringe and blinding could not be achieved). 8. Children with developmental disabilities.

SC

Patients who received opioids or other pain medication prior to procedural sedation and analgesia were eligible for inclusion in the study.

AC

CE

PT

ED

MA

NU

2.3. Interventions: Random sequence allocation was performed using a computergenerated, random number table by a pharmacist from the Investigational Drugs Section of the Pharmacy Department. The study subjects were grouped according to their age as follows (1) 3-6 years (2) 7-12 years (3) 13-18 years. Children from each age group were assigned in equal numbers to all three ketamine dosing groups (1 mg/kg, 1.5 mg/kg and 2 mg/kg) using random permuted blocks stratified by the pharmacist. The randomized study drug was stored in a dedicated automated medication dispensing system in the ED. Once an eligible patient was identified and consent was obtained, a nurse who was not involved in the care or sedation of the patient determined the appropriate age strata of the patient. The same nurse then accessed the first sequentially labeled study drug appropriate for the age strata of the patient. Each study kit included a dose calculation and preparation instructions. Once the study drug was prepared, a second nurse, who was also not involved in the care or sedation of the patient, verified the accuracy of drug dosage and calculation. The study drug was administered as a slow IV push over 30-60 seconds by the ED physician who was in charge of the clinical care of the patient. Drug waste was documented in the medication dispensing system, and the used medication vial was saved for verification of drug administration and drug dosage by the study pharmacist. All ED staff including the physician and the nurse in charge of sedation, the study research assistant, the parents/guardians and the study subjects were blinded to the randomization and the group assignments. The dosage and administration of additional doses of ketamine were left to the discretion of the ED physician in charge of the care and sedation of the patient. The research team did not participate in the clinical care and sedation of the patient. Children were monitored per ED policy for the entire duration of sedation. The study research assistant also performed a follow up phone call beginning 48 hours after discharge from the ED to obtain information on the child’s memory and recall of the procedure and any post discharge adverse events. A total of 3 attempts were made to contact the child’s parent/guardian, and if unsuccessful, were considered as lost to follow up.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

RI P

T

2.4. Methods Of Measurements: The following variables were collected prospectively by trained research assistant: demographics, procedure type, time of last solid and liquid intake, ASA classification,26 pain medication administered prior to sedation (type, dosage and timing), number and total doses of ketamine administered after the initial study dose, sedation efficacy and duration, length of procedure, adverse events related to sedation including interventions performed to address the adverse events and patient disposition.

MA

NU

SC

Patient distress was documented by the trained research assistant at the following intervals: pre-sedation (three minutes prior to study drug administration), during the procedure (after ketamine administration and prior to and after any re-dosing) and post sedation (prior to discharge) using the Ramsay Sedation Scale.27 Assessment of severity of pain on a scale of 0 (no pain) to 10 (most pain) was performed on children ≥5 years of age during the above three intervals using the Faces Pain Scale-Revised.28 Pain severity was determined by the research assistant during sedation (using facial expression of patient or if the patient did not respond, pain was scored as 0) and by self assessment by the study participants for pre- and post-sedation. In addition, sedation efficacy was assessed by the physician performing the procedure using a 3-point Likert scale (not satisfied, satisfied, or very satisfied with the sedation).

CE

2.6. Definitions:

PT

ED

2.5. Outcome Measures: The primary outcome measure for this study was the number of additional doses of ketamine administered after the study drug to achieve adequate sedation. The secondary outcome measures were (1) sedation efficacy as measured by Ramsay Sedation Scale, FACES-P scale and satisfaction scores of the physician performing the procedure, (2) sedation duration and (3) sedation-related adverse events along with interventions performed to manage the adverse events.

AC

Length and efficacy of sedation and all adverse events were defined using the standardized definitions provided by the Quebec Guidelines for ED sedation terminology and reporting of adverse events in children.29 Procedure duration was defined as the time duration from start to completion of the procedure. Length of sedation was defined as the time from the administration of study medication until the patient was ready for discharge. Readiness for discharge was assessed using standardized discharge criteria (Aldrete scoring >9)30 by the physician providing sedation, or the nurse taking care of the patient The following adverse events were recorded for the study: oxygen desaturation (pulse oximetry reading < 90%), apnea, laryngospasm, emesis, unpleasant recovery reactions or any others that were deemed by the physician taking care of the patient as an adverse event related to sedation. Interventions performed in response to adverse events such as airway maneuvers (chin lift, jaw thrust), supplemental oxygen, bag-mask ventilation were also identified and documented using standardized criteria.29 Adverse events and interventions performed were recorded by the study research assistant and the nurse

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT providing patient care using a standardized sedation monitoring sheet for every sedation performed in the ED.

T

2.7. Statistical Analysis:

MA

NU

SC

RI P

A database was created using Excel® to host all data collected for this study. Study variables were systematically coded for analysis. The research assistant performed double data entry to verify accuracy. Descriptive statistics (proportion, median ± IQR) were calculated for patient demographic variables, ketamine dosing and adverse events. The difference in variables among the three dosing groups (i.e., 1 mg/kg, 1.5 mg/kg and 2 mg/kg) and among the three age groups (i.e., 3-6, 7-12 and 13-18 years) was examined using chi-square test for categorical variables and Kruskal -Wallis test for continuous variables. Effect sizes with a 95% confidence interval were calculated to compare the difference between the dosing groups (1 mg/kg vs. 1.5 mg/kg) and (1 mg/kg vs. 2 mg/kg). Logistic regression analysis was performed to evaluate predictors associated with need for re-dosing with ketamine. Significance level was set at 0.05. All statistical analyses were performed using the SAS 9.3 statistical software package (SAS Institute Inc., Cary, NC, USA).

AC

CE

PT

ED

A previous ketamine sedation study found that about 25% of children who received 1 mg/kg IV ketamine for orthopedic fracture reduction received at least one additional dose of ketamine.13 Based on a previous study using 2 mg/kg IV of ketamine we postulated that patients who received 2 mg/kg will have a 5% chance of requiring additional doses of ketamine.18 Using a two-sided Fisher's Exact Test to determine a significant difference in proportions, we estimated that 55 patients would be needed in both the 1 mg/kg group (25% chance of re-dosing) and the 2 mg/kg group (5% chance of re-dosing) to achieve an alpha=0.05 and power=0.80 resulting in a total sample size of 165 patients (55 in each of the three dosing groups). Based on the study mentioned above,13 25% of children of median age 7.5 years received an additional dose of ketamine after an initial 1 mg/kg IV dose. Herd’s pharmacokinetic study of ketamine in children 25 found an inverse relationship between age and ketamine dosing. A conservative estimate of re-dosing in the younger age group would be 5% more than that experienced in the group with a median age of 7.5 years. We calculated sample size for the secondary outcome using a two-sided Fisher’s Exact Test to determine a significant difference in proportions to be 132 patients in both the younger group 3 to 6 years (30% chance of re dosing) and the older group 13 years and older (15% chance of re dosing) to achieve an alpha =0.05 and power=0.80. We used the sample size for the two extreme groups as the sample size for children aged 7 to 12 years resulting in a total sample size of 396 patients. During the study, it became apparent that the ED physicians did not administer the entire randomized dose to some study subjects for whom they felt that adequate sedation was achieved with less than the randomized dose. We report "per-protocol" results for those study subjects who received the randomized dose of ketamine.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

3. RESULTS:

RI P

T

A total of 1347 patients received ketamine in the ED during the study period. Of these, 1176 patients were excluded from the study (Figure 1). 171 patients were consented and enrolled in the study from August 1, 2010 to August 31, 2012 and randomized as follows: 1 mg/kg; n=58, 1.5 mg/kg; n=57, 2 mg/kg; n=56. Due to lower than expected enrollment rate, the study ended prior to achieving the targeted 396 subjects as funding for the study was no longer available.

MA

NU

SC

Forty-six (26.9%) of patients did not receive the ketamine dose to which they were randomized (Figure 1). In 2 patients, the child’s weight was incorrectly recorded which resulted in calculated dose that was below the randomized dose. Forty-four patients received less than the randomized dose (protocol violation) as the physicians discontinued the administration of ketamine when the patient achieved dissociation and did not appear to require further drug administration for sedation. These 46 study patients who did not receive the randomized dose of IV ketamine were excluded leaving 125 patients for analysis (1mg/kg: 50, 1.5mg/kg : 35, 2mg/kg : 40)

ED

Patient demographics, procedure type, ASA classification and pre-sedation pain medications for the study patients are shown in Table 1.

PT

Eleven (8.8%) children received an additional dose of ketamine in the study cohort. The need for ketamine re-dosing was higher in the 1 mg/kg group (8/50; 16.0% vs. 1/35; 2.9% vs. 2/40; 5.0%). (Table 2)

AC

CE

There was no difference in the median Ramsay sedation score [5.5 (IQR:4,6) vs. 6 (IQR:4,6) vs. 6 (IQR:5,6)], median FACES-R score [0 (IQR:0,4) vs. 0 (IQR:0,0) vs. 0 (IQR:0,0)] and median sedation duration in minutes [23 (IQR: 19,38) vs. 24.5 (IQR: 17.5, 34.5) vs. 23 (IQR:19,29)] between the three dosing groups. There was no difference in the frequency of adverse events between the three dosing groups [1 mg/kg: 10.0 %; 1.5 mg/kg: 14.3 %; 2 mg/kg: 10.0%] (Table 2). None of the patients experienced apnea or laryngospasm and none required positive pressure ventilation. The distribution of the types of adverse events among the three dosing groups is shown in Table 3. Physician satisfaction data was available in 119 (95.2%) patients. Of these, physicians reported that they were either "satisfied" or "very satisfied" in 89.1% (106/119) of the sedation. Consultant physicians were less likely to be satisfied or very satisfied with sedation in the 1 mg/kg dosing group versus the 1.5 mg/kg and 2 mg/kg dosing group. [79.6% vs. 94.1% vs. 97.3%] (Table 4). Telephone follow up was completed in 101 (80.8%) of the study patients. Approximately 13.9% of patients experienced vomiting at home (10.5% in the 1 mg/kg group, 12.5 % in the 1.5 mg/kg group and 20.0 % in the 2 mg/kg group). The majority of children (82.2%) reached for follow-up reported having no memory of the painful procedure (80.6% in the 1 mg/kg group, 92.9 % in the 1.5 mg/kg group and 93.3 % in the 2 mg/kg group). (Table 4).

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT There were no significant differences in the mean dose of ketamine administered, need for re-dosing or frequency of adverse events among the three age groups studied (Table 5).

RI P

T

Logistic regression analysis showed only the initial IV ketamine dose (1mg/kg) to be a significant predictor for need of re-dosing (Table 6). 4. DISCUSSION:

ED

MA

NU

SC

To our knowledge, this is the first prospective, double-blind, randomized control trial comparing sedation efficacy, duration and adverse events of the three most commonly administered dosing regimens of IV ketamine sedation for children in the ED. Our study demonstrates that all three dosing regimens (1 mg/kg, 1.5 mg/kg and 2 mg/kg) of IV ketamine were effective in achieving acceptable levels of sedation and analgesia. However, children in the 1 mg/kg group required re-dosing with ketamine more frequently than in the other 2 groups and physicians were less likely to be satisfied with the level of sedation achieved with the lower dose. Children in the 2 mg/kg group were significantly less likely to recall the procedure. The frequency of adverse events was low and there was no difference in frequency of adverse events detected between the three dosing regimens. The distribution of adverse events with all three dosing regimens is similar to that reported in previous studies with ketamine.5, 6

AC

CE

PT

Due to its dissociative effects, ketamine does not exhibit a dose dependent sedation continuum like other sedatives which has been stated as one of the reasons for the favorable safety profile of ketamine.9 A recent meta-analysis of predictors of airway and respiratory adverse events with ketamine determined that a single intravenous dose of ≥ 2.5 mg/kg to be an independent predictor for adverse events. This dose is higher than any of the dosing regimens used in our study.5 Previous studies have also shown no relationship between ketamine dose and incidence of laryngospasm.31 Additionally, there was no significant difference in length of sedation or time to discharge between groups. Given these reasons, there would appear to be no benefit to starting with a lower (1 mg/kg) dose of ketamine. We did not demonstrate significant differences in the total duration of sedation and recovery times between the three dosing regimens. In an attempt to decrease total time of sedation with ketamine, a recent study investigated the use of rapidly administered IV ketamine for sedation in children with forearm fractures. The authors found a dose of 0.7 to 0.8 mg/kg IV to be effective for healthy children in 3 different age groups. 21 However, the median length of procedure in these groups was 2.5 to 4 minutes. Previous studies of ketamine sedation for orthopedic reductions have found length of procedures to be 13 and over 19 minutes respectively.13,18 While rapid administration of ketamine in lower doses may result in shorter length of sedation and ultimately shorter ED lengths of stay, the majority of orthopedic reductions (the most common painful sedation-requiring ED procedure for children) require a longer duration of sedation and analgesia making this rapid-administration regimen amenable to a limited number of, very brief, procedures. Future studies comparing low-dose, rapid-administration ketamine to traditional ketamine

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT administration would clarify the impact of this administration technique on procedural sedation in the ED for children.

RI P

T

On telephone follow-up, more children in the 2 mg/kg group (93.3%) reported no memory of the painful procedure. This difference in amnesia of the painful procedure may be especially important for children with ED visits for recurrent sedation for painful procedures. The true clinical significance and impact on patient care of this finding requires further investigation of the long-term effects of ketamine sedation.

SC

5. LIMITATIONS:

ED

MA

NU

Enrollment of patients in our study was limited by the availability of research assistants and thus represents a convenience sample of eligible patients. However, we collected information from the automated medication dispenser list weekly to determine the dosing and adverse events for those patients who received IV ketamine, but who were not enrolled in the study and the findings are similar to those of our study patients. Onefourth of the study subjects did not receive the dose of ketamine to which they were randomized. ED physicians reported, after the fact, that once they determined that patients were adequately sedated, they stopped administering ketamine. This practice precluded patients from receiving the entire dose to which they had been randomized and resulted in exclusion from analysis.

AC

CE

PT

Patient enrollment took longer than was anticipated. Funding was exhausted and the study closed before we were able to enroll an adequate sample size to definitively compare sedation efficacy and dose-related adverse events by age stratification. Although no differences were detected between age groups, patient numbers were inadequate to achieve statistical significance. The need for re-dosing was based on sedation physician discretion and not on objective sedation scoring, however, this is consistent with everyday clinical practice. Due to FDA direction, children under 3 years of age were excluded from the study. Younger children have been shown to require a higher mg/kg ketamine dosing and to be at higher risk for airway and respiratory adverse events when compared to older children.5, 24 Finally, we did not randomize by type of procedure performed which could have confounded length of sedation and total dose administered by group, however, over 60% of the enrolled patients in all 3 dosing groups received sedation for orthopedic reduction. Additionally, logistic regression analysis showed only initial IV ketamine dose to be predictive for need for re-dosing. 6. CONCLUSIONS: Adequate sedation was achieved with all three doses of IV ketamine (1 mg/kg, 1.5 mg/kg, 2 mg/kg) and higher doses did not increase the risk of adverse events or prolong the duration of sedation. Since children assigned to the 1 mg/kg IV ketamine group required more frequent re-dosing and resulted in less physician satisfaction with sedation, we conclude that our study supports the current recommendation to use 1.5 or 2.0 mg/kg IV ketamine as an initial dose for procedural sedation of children in the ED. The

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT apparent benefit of greater amnesia of the painful procedure with 2.0 mg/kg over 1.5 mg/kg requires further study. LEGEND FOR FIGURE

RI P

T

Figure 1: Study Flow Diagram LEGENDS FOR TABLES:

SC

Table1 Patient Demographics

Table 2: Intention to treat and per protocol analysis for primary and secondary outcomes

NU

Table 3: Intention to treat and per protocol adverse events by ketamine dose

MA

Table 4: Intention to treat and per protocol consultant satisfaction and phone follow up data Table 5: Median Ketamine Dosing, Re-Dosing and Adverse Events by Age Groups

ACKNOWLEDGEMENT:

ED

Table 6: Logistic Regression Analysis of Predictors for need for re-dosing with ketamine

CE

REFERENCES:

PT

The authors acknowledge the work of research assistants Mariam Hussain and Birgete Webb for enrollment of study participants and the data collection.

AC

1. Bhargava R, Young KD. Procedural pain management patterns in academic pediatric emergency departments. Acad Emerg Med. 2007;14:479-482. 2. Haley-Andrews S. Ketamine-the sedative of choice in a busy pediatric emergency department. J Emerg Nurs. 2006; 32:186-188. 3. Krauss B, Green SM. Sedation and analgesia for procedures in children. N Engl J Med. 2000; 342:938-945. 4. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet. 2006;367:766-780. 5. Green SM, Roback MG, Krauss B et al. Predictors of airway and respiratory adverse events with ketamine sedation in the Emergency Department: An individual patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54:158-168. 6. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual- patient data metaanalysis of 8,282 children. Ann Emerg Med. 2009;54(2):171-80.e1-4. 7. Roback MG, Wathen JE, Bajaj L, et al. Adverse events with procedural sedation and analgesia in a pediatric emergency department: A comparison of common parenteral drugs. Aca Emerg Med. 2005;12:508-513. 8. Green SM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation in children. Ann Emerg Med. 2004;44:460-471.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC

RI P

T

9. Green SM, Roback MG, Kennedy RM et al. Clinical practice guideline for emergency department ketamine dissociative sedation in children: 2011 update. Ann Emerg Med. 2011;57:449–461. 10. Kennedy RM, Porter FL, Miller P, et al. Comparison of fentanyl/midazolam with ketamine/midazolam for pediatric orthopedic emergencies. Pediatrics 1998;102(4):956-963. 11. Acworth JP, Purdie D, Clark RC. Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation. Emerg Med J 2001; 18(1): 39–45. 12. Wathen JE, Roback MG, Mackenzie T, et al. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial. Ann Emerg Med. 2000;36(6):579-588. 13. Roback MG, Wathen JE, Mackenzie T, et al. A randomized, controlled trial of iv versus im ketamine for sedation of pediatric patients receiving emergency department orthopedic procedures. Ann Emerg Med. 2006;48:605-612. 14. Langston WT, Wathen JE, Roback MG, Bajaj L. Effect of ondansetron on the incidence of vomiting associated with ketamine sedation in children- A double-blind, randomized, placebo controlled trial. Ann Emeg Med. 2008;52:30-4. 15. Shah A, Mosdossy G, McLeod S, et al. A blinded, randomized controlled trial to evaluate ketamine-propofol versus ketamine alone for procedural sedation in children. Ann Emerg Med. 2011;57:425-433. 16. Sherwin TS, Green SM, Khan A, et al. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, doubleblind placebo-controlled trial. Ann Emerg Med. 2000;35(3):229-238. 17. Godambe SA, Elliot V, Matheny D, et al. Comparison of propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department. Pediatrics 2003;112(1):116-123. 18. McCarty EC, Mencio Ga, Walker A, et al. Ketamine sedation for the reduction of children’s fractures in the emergency department. J Bone Joint S. 2000;82-A:912917. 19. Bleiberg AH, Salvaggio CA, Roy LC et al. Low-dose ketamine: efficacy in pediatric sedation. Pediatr Emerg Care. 2007;23(3):158-62. 20. Green SM, Kuppermann N, Rothrock SG, et al. Predictors of adverse events with ketamine sedation in children. Ann Emerg Med. 2000;35:35-42. 21. Chinta SS, Schrock CR, McAllister JD, et al. Rapid administration technique of ketamine for pediatric forearm fracture reduction: A dose-finding study. Ann Emerg Med. 2015; :1-9 22. Dallimore D, Herd DW, Short T et al. Dosing ketamine for pediatric procedural sedation in the Emergency Department. Pediatr Emerg Care. 2008;24:529-533. 23. Herd D, Anderson BJ. Ketamine disposition in children presenting for procedural sedation and analgesia in a children’s emergency department. Paediatr Anaesth. 2007;17:622-9. 24. Herd DW, Anderson BJ, Keene NA et al. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36-42. 25. Street MH, Gerard JM. A fixed-dose ketamine protocol for adolescent sedations in a pediatric emergency department. J Pediatr. 2014;165:453-8.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC

RI P

T

26. American Society of Anesthesiologists. New classification of physical status. Anesthesiology.1963:24:111. 27. De Jonghe B, Cook D, Appere-DeVecchi C, et al. Using and understanding sedation scoring systems: a systematic review. Intensive Care Med. 2000;26:275-285. 28. Bieri D, Reeve RA, Champion GD et al. The Faces pain scale for the self-assessment of the severity of pain experienced by children : development initial validation, and preliminary investigation for ratio scale properties. Pain. 1990;41:139-150. 29. Bhatt M, Kennedy RM, Osmond MH, et al. Consensus Panel on Sedation Research of Pediatric Emergency Research Canada (PERC) and the Pediatric Emergency Care Applied Research Network (PECARN). Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children. Ann Emerg Med. 2009;53:426-435. 30. Aldrete JA, Kroulik D. A Postanesthetic recovery score. Anesth Analg. 1970;49:924934. 31. Green SM, Roback MG, Krauss B;Emergency Department Ketamine meta-analysis study group. Laryngospasm during emergency department ketamine sedation : a case control study. Pediatr Emerg Care.2010;26(11):798-802.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT Table 1: Patient Demographics

Female

23 (46%)

18 (51%)

13 (33%)

54 (43%)

African American

21 (42%)

27 (77%)

18 (45%)

66 (53%)

Gender

RI P

Variable

T

Male

1 mg/kg (n=50) 27 (54%)

Groups 1.5 mg/kg 2 mg/kg (n=35) (n=40) 17 (49%) 27 (68%)

Total 71 (57%)

AC

CE

PT

ED

MA

NU

SC

Caucasian 16 (32%) 5 (14%) 11 (28%) 32 (26%) Asian 1 (2%) 0 (0%) 1 (3%) 2 (2%) *Race American Indian 2 (4%) 0 (0%) 0 (0%) 2 (2%) Mixed 4 (8%) 0 (0%) 1 (3%) 5 (4%) Other 1 (2%) 0 (0%) 1 (3%) 2 (2%) Hispanic 7 (14%) 1 (3%) 6 (15%) 14 (11%) *Ethnicity Non-Hispanic 39 (78%) 31 (89%) 32 (80%) 102 (82%) I 50 (100%) 32 (91%) 37 (93%) 119 (95%) *ASA II 0 (0%) 2 (6%) 3 (8%) 5 (4%) III 0 (0%) 1(3%) 0 (0%) 1(1%) Fracture/dislocati 33 (66%) 21 (60%) 35 (88%) 89 (71%) Procedure on reduction Type Incision and 12 (24%) 11 (31%) 2 (5%) 25 (20%) drainage Laceration repair 5 (10%) 3 (9%) 3 (8%) 11 (9%) 30 (63%) 22 (67%) 27 (71%) 79 (66%) *Pre-sedation Yes (Any) Pain Opiates 17 (35%) 11 (22%) 21 (43%) 49 (73%) Medications No 18 (38%) 11 (33%) 11 (29%) 40 (34%) * Race missing in 16, Ethnicity missing in 9 and pre-sedation pain medication missing in 6 study subjects.

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

1.5 mg/kg n=35

2 mg/kg n=40

Effect Size, Effect (95%CI ) Size, 1mg/kg (95%CI vs.1.5mg/kg ) 1.5 mg/kg vs. 2 mg/kg

6 (4,6)

0 (0,4)

0 (0,0)

6 (5,6)

NU

13.14% (0.15%, 26.43%)

0 (0,1)

0 (0,0)

0 (0,0)

0 (0,3)

23 (19, 29)

0.00 (-7.00, 6.00)

0.00 (-5.00, 4.00)

-4.29 (-18.55, 9.98)

0.00 (-12.47, 12.47)

PT

CE

23 (19,38)

24.5 (17.5, 34.5)

11.00% (1.20%, 23.20%)

0 (0,0)

ED

5.5 (4,6)

AC

Ramsay Sedation Scale Score (Median, IQR) FACES P Score (Median, IQR) Sedation Duration in Minutes (Median, IQR) Overall Adverse Events (%)

2 (5%)

MA

Primary Outcome 1 Need for 8 (16%) (2.9%) Re dosing Secondary Outcomes

SC

RI P

1 mg/kg n=50

T

Table 2: Primary And Secondary Study Outcomes

5 5 4 (10.0%) (14.3%) (10.0%)

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT

Table 3: Frequency of Adverse Events by Ketamine Dose 1 mg/kg IV n = 50 1 (2.0%)

1.5 mg/kg IV n=35 2 (5.7%)

AC

CE

PT

ED

MA

NU

SC

RI P

Oxygen Desaturation 1 (2.0%) 3 (8.6%) Emesis 3 (6.0%) 0 (0%) Unpleasant Recovery Reaction 0 (0%) 0 (0%) Others * 5 (10.0%) 5 (14.3%) Any * Other adverse reaction include maculopapular rash

T

Adverse Event

Optimal Dosing of IV Ketamine For Sedation In Children

2 mg/kg IV n=40 0 (0%) 2 (5%) 1 (2.5%) 1 (2.5%) 4 (10.0%)

ACCEPTED MANUSCRIPT

Table: 4. Consultant Satisfaction And Telephone Follow Up For Ketamine Sedation

1.5 mg/kg

2 mg/kg

Effect size (95%CI) 1mg/kg vs. 1.5 mg/kg

*Consultant Satisfaction,n=119 Not satisfied 10 (20.4%)

RI P

T

1 mg/kg

2 (5.9%)

1 (2.7%)

12 (24.5%)

3 (8.8%)

6 (16.7%)

Very Satisfied

27 (55.1%)

29 (85.3%)

29 (80.6%)

NU

SC

Satisfied

29 (80.6% )

26 (92.9% )

6 (20.0% )

28 (93.3% )

ED

No Recall of Painful Procedure

MA

Telephone Phone Follow Up, n=101 Emesis 4 (10.5% ) 4 (12.5%)

AC

CE

PT

* p=0.011

Optimal Dosing of IV Ketamine For Sedation In Children

Effect size (95%CI) 1mg/kg vs. 2 mg/kg

14.53 (0.75, 28.31) 15.67 (0.31, 31.02) -30.19 (-48.51, 11.87)

17.63 (5.13, 30.13) 7.82 (9.30, 24.95) -25.45 (-44.46, 6.45)

-1.97 (-17.02, 13.08) -4.98 (-24.06, 14.19)

-9.47 (-26.80, 7.85) -17.02 (-33.22, 0.82)

ACCEPTED MANUSCRIPT Table 5: Mean Ketamine Dosing, Re-Dosing and Adverse Events by Age Groups

4 (7.5%) 0.81 ± 0.22 6 (11.3%)

T

6 (10.7%) 1.06 ± 0.67 7 (12.5%)

13-18 years n=16 6 4 6 1.50 ± 0.45

RI P

7-12 years n=53 22 13 18 1.46 ± 0.44

AC

CE

PT

ED

MA

NU

1 mg/kg Randomized 1.5 mg/kg Dose 2 mg/kg Dose Administered in mg/kg (Mean ± SD) Need for Second Dose (%) Second Dose (Mean ± SD) Adverse Events (%)

3-6 years n=56 22 18 16 1.45 ± 0.41

SC

Variable

Optimal Dosing of IV Ketamine For Sedation In Children

2 (12.5%) 1.23 ± 0.32 1 (6.3%)

ACCEPTED MANUSCRIPT

95% CI 0.14, 15.47

1.19

0.11, 13.19

1.16

0.17, 7.92

p 0.71 0.98 0.88

SC

RI P

Odds Ratio 1.47

0.95

0.3, 7.43

0.63

6.74

0.78, 57.99

0.01

0.91

0.05, 15.93

0.37

MA

1.49

0.09, 11.35

NU

0.99

AC

CE

PT

ED

Variable Age group (3-6 vs. 13-18 years) Age group (7-12 vs. 13-18 years) Procedure Type (orthopedic vs. incision drainage) Procedure Type (orthopedic vs. laceration repair) Pre-sedation pain medication (yes/no) Initial ketamine dosing (1 mg/kg vs. 1.5mg/kg) Initial ketamine dosing (2mg/kg vs. 1.5mg/kg

T

Table 6. Logistic Regression Analysis of Predictors for need for re-dosing with ketamine

Optimal Dosing of IV Ketamine For Sedation In Children

ACCEPTED MANUSCRIPT Fig. 1

T

Total patients who received ketamine during the study period 1347

RI P

Excluded: 1176 1. Ineligible Age: 407 2. No RA coverage: 334 3. Ineligible Procedure: 176 4. Co administered benzodiazepine:148. 5. No consent (declined, absence of legal guardian, non-English speaking guardian): 55 6. Multiple Study patients at same time: 10 7. Multiple exclusion reasons: 15 8. Others: 31 (weight>100kgs:11, developmentally delayed:7, procedure in OR:2, previously enrolled in study:2, no study drug:7, IM route: 2)

MA

NU

SC

1347 1347

AC

CE

PT

ED

Randomized n= 171

Allocated to 1.5 mg/kg (n=57) Did not receive 1.5mg/kg physician did not administer entire randomized dose (n=22)

Optimal Dosing of IV Ketamine For Sedation In Children

Allocated to 2 mg/kg (n=56) Did not receive 2 mg/kg physician did not administer entire randomized dose (n=16)