Article, Emergency Medicine

Changes in blood pressure and heart rate during sedation with ketamine in the pediatric ED

a b s t r a c t

Background: Ketamine is commonly used in the emergency department for short, painful procedures. We describe changes in Blood pressure and heart rate (HR) during procedural sedation with ketamine, as these changes have not been well described in children.

Methods: We performed a secondary analysis of a prospective, observational study involving children aged 8 to 18 years who receivED procedural sedation with ketamine in a pediatric emergency department. Serial vital signs and sedation scores were recorded from baseline until recovery from ketamine procedural sedation. Time of orthopedic manipulation was also recorded. Linear mixed-effect models were used to evaluate changes in systolic BP (SBP), Diastolic BP (DBP), and HR using 3 sedation strata: presedation (baseline), sedated (ketamine administered and patient deeply sedated), and recovery (ketamine administered with patient minimally sedated), controlling for age and weight.

Results: Sixty children were enrolled; 10 were excluded due to missing manipulation time. A total of 394 observations were recorded. Mean sedated SBP, DBP, and HR were 8 mm Hg, 4 mm Hg, and 13 beats/min higher than presedation SBP (P b .001), DBP (P b .01), and HR (P b .001), respectively. Mean sedated SBP and DBP were 3 and 4 mm Hg higher than SBP (P = .006) and DBP (P b .01) during recovery. Manipulation increased mean SBP by 5 mm Hg (P b .001), mean DBP by 7 mm Hg (P b .001), and mean HR by 1 beat/min (P = .35).

Conclusions: Ketamine administered during procedural sedation for painful procedures causes a statistically significant but modest increase in SBP, DBP, and HR. Orthopedic manipulation further increases BP.

(C) 2016

Introduction

Background

Ketamine is a commonly used anesthetic for short, painful procedures in the emergency department (ED) setting. Since its introduction in the 1960s, ketamine has become a staple in this setting due to its characteristic combination of analgesia, amnesia, and sedation that create a form of dissociative anesthesia with a positive and predictable safety profile [1]. The mechanism of ketamine’s stimulation of the cardiovascular system has been studied in various animal models. Ketamine is postu- lated to directly stimulate receptors in the sympathetic nervous system and prevent reuptake of catecholamines [2]. Although the mechanism

? Funding and support: This is a secondary analysis of a project that received $5128 from a Pediatric Intradepartmental Small Grant Committee at the University of Louisville. The grant funded a biostatician (Lorenz) for this analysis.

?? Meetings: Presented at the Pediatric Academic Societies Conference, Vancouver, BC,

Canada, in May 2014.

* Corresponding author at: University of Louisville, 571 S. Floyd St, Ste. 300, Louisville, KY 40202. Tel.: +1 502 629 7212; fax: +1 502 629 5991.

E-mail address: [email protected] (A.C. Patterson).

of action of ketamine continues to be clarified, the clinical effects on the cardiovascular system include increased blood pressure, heart rate, and cardiac output. Ketamine has been shown to affect the cardiovascu- lar system in the ED setting, causing documented increases in both heart rate and blood pressure [3-5]. To our knowledge, no studies have reported these changes in the pediatric ED setting using current practice guidelines.

Importance

There is inconclusive evidence that the sympathomimetic effects of ketamine on Blood pressure and heart rate cause adverse effects on pe- diatric patients with cardiac or renal disease. Whether ketamine results in clinically significant increases in blood pressure and heart rate in a patient suitable for procedural sedation in the pediatric ED is unknown.

Goal of this investigation

The goal of this study was to describe the effect of intravenous ketamine on systolic and diastolic blood pressures and heart rate during

http://dx.doi.org/10.1016/j.ajem.2016.10.019

0735-6757/(C) 2016

A.C. Patterson et al. / American Journal of Emergency Medicine 35 (2017) 322325 323

procedural sedation for Orthopedic reduction in the pediatric ED. We aimed to describe the changes in blood pressures and heart rate from before ketamine administration, at the time of its sedative effect, after painful orthopedic manipulation, and during recovery from sedation.

Materials and methods

Study design and setting

This was a secondary analysis of a prospective, observational study conducted at a university affiliated, tertiary care pediatric hospital ED designed to evaluate the effects of ketamine on Intraocular pressure in children during procedural sedation [6]. Both the prospective study and this analysis were approved by the institutional review board of the University of Louisville.

Selection of participants

In the primary study, written informed parental consent and child assent were obtained from all participating patients before enrollment. Patients were selected using a convenience sample of children aged 8 to 18 years who underwent procedural sedation with Ketamine dosed at the discretion of the attending ED physician.

Study protocol

Each sedation was supervised by an attending pediatric emergency medicine using protocols previously described [6]. Baseline vital signs, including heart rate and systolic and diastolic blood pressures, were obtained before the start of procedural sedation. After administration of intravenous ketamine, systolic and diastolic blood pressures and heart rate were recorded immediately, after 2 minutes, then every 5 minutes. Sedation scores were also recorded at each time interval, based on a modified University of Michigan Sedation Score [7]. Recording continued until recovery to a sedation score of 0 or 1 or to a maximum time of 30 minutes after the initial dose. The time of onset of orthopedic manipulation, or when pressure was applied for fracture or dislocation reduction, was also recorded.

Blood pressures were recorded using nonInvasive blood pressure monitoring during sedations. Welch Allyn Flexiport Disposable blood pressure cuffs were sized for each participant, with size approximating one-third the length of the patient’s proximal upper extremity. The cuff was placed on the right arm, unless the patient’s injury necessitated use of the left arm.

Outcome measures

The primary outcome measures were mean changes in systolic and diastolic blood pressures and heart rate after administration of intrave- nous ketamine for procedural sedation. Secondary outcome measures included mean change in systolic and diastolic blood pressures and heart rate after orthopedic manipulation, as well as after recovery from dissociative sedation.

Primary data analysis

We analyzed systolic and diastolic blood pressures and heart rates using linear mixed-effects models. The primary fixed effect was seda- tion status, classified into 3 strata: presedation, sedated, and recovery. The presedation period encompassed baseline vital signs obtained be- fore ketamine administration. The sedation stratum was considered the period when ketamine was active, as manifested by a sedation score of 4 or greater. Recovery represented the period after ketamine administration when it is no longer producing dissociative sedation for the patient (sedation score b4). Manipulation was included in the mixed-effects model as a 2-level fixed factor (manipulated, not

manipulated), and age and weight as continuous fixed effects. The model intercepts were considered as random effects grouped at the patient level.

Marginal mean differences in systolic and diastolic blood pressures and heart rates among sedation statUS time points and associated 95% confidence intervals and hypothesis tests were generated via linear con- trasts applied to the fitted mixed-effects models. Hypothesis tests from such contrasts are essentially t tests comparing mean blood pressures and heart rates at sedation time points, adjusted for both age and weight. Similar comparisons of manipulated and nonmanipulated pressures and rates were also conducted. All analyses were conducted in the open-source R software environment (R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/).

Results

Characteristics of study subjects

Sixty patients were enrolled in the primary study from June 2011 to September 2012. Each patient required procedural sedation for ortho- pedic reduction in the ED. For the secondary analysis, 10 subjects were excluded due to the lack of recorded time of orthopedic manipula- tion. Patient characteristics and presedation medications are reported in Table 1. Among participants, mean age was 11 years; 82% were male. In total, there were 394 observations of blood pressure and heart rate from 50 participants. Separating these by sedation strata, there were 50 presedation observations, none of which involved manipulation. There were 237 observations taken while sedated with 70 involving manipu- lation. There were 96 observations during recovery from ketamine, with 13 involving manipulation (Figure).

Main results

The average (SD) systolic blood pressure before sedation was 130

(16) with a range from 91 to 161 mm Hg, and the average (SD) diastolic blood pressure before sedation was 75 (14) with a range from 47 to 128 mm Hg. The average (SD) heart rate was 92 (17) with a range from 61 to 137 beats/min. Table 2 demonstrates mean changes in blood pressure and heart rate by sedation strata and with orthopedic manipula- tion. Elevated blood pressure, defined as exceeding age-associated thresholds for systolic or diastolic blood pressures, was found in 37 of

Table 1

Patient characteristics

Patients (n = 50)

Age (y) 11.3 (+-2.62)

Weight (kg) 50.5 (+-21.2)

Initial pain score, 1-10 6.7 (+-2.3)

Sex

Male 41 (82%)

Female 9 (18%)

Race

White 37 (74%)

Black 9 (18%)

Other 4 (8%)

Ketamine administration

Initial dose (mg/kg), median 1.39 (1,1.49)

Cumulative dose (mg/kg), median 1.47 (1.25,1.67) Presedation medications

Ondansetron 32 (64%)

Opioids 37 (74%)

Intravenous morphine Intravenous fentanyl Enteral oxycodone

Benzodiazepines 2 (4%)

Diazepam 1 (2%)

Midazolam 1 (2%)

Data are presented as n (%) for categorical variables or mean (SD) for continuous variables, except for times which are presented as median (interquartile range).

324 A.C. Patterson et al. / American Journal of Emergency Medicine 35 (2017) 322325

Figure. Marginal means with interquartile ranges for blood pressures and heart rates.

the 50 participants before sedation with ketamine. In observations that did not involve manipulation, mean increases were mild but statistically significant between the 3 group comparisons (sedated compared with presedation, sedated compared with recovery, and recovery compared with presedation). Similarly, for diastolic blood pressures, mean changes were significant in 2 group comparisons (sedated compared with presedation and sedated compared with recovery). There was no signifi- cant difference comparing recovery to presedation mean diastolic blood pressures (P = .8). Mean heart rates were significantly elevated during sedation and recovery relative to presedation (P b .001), but recovery and sedation mean heart rates were not significantly different (P =

.11). Manipulation caused a significant increase in mean systolic blood pressure of 5 mm Hg (P b .001), a significant increase in mean diastolic blood pressure of 7 mm Hg (P b .001), and a nonsignificant increase of 1 beat/min (P = .35) in heart rate.

Limitations

Our study had several important limitations. We enrolled a conve- nience sample of patients from a busy ED. No patients with cardiac dis- ease or severe systemic disease (American Society of Anesthesiologists physical status classification of 3 or higher) were involved in our study. No patient in the study had a known history of hypertension, although having a baseline blood pressure above normal due to a painful injury may have dampened the effect of ketamine on blood pressure. In addition, 74% received an opioid for pain management, creating another variable for the possible reduction of increase of the observed change in blood pressure. Although 2 patients did received a benzodiazepine before sedation, the majority did not, in keeping with published recommendations [1].

During procedural sedation in the ED, blood pressures were obtain- ed via noninvasive monitoring. Although invasive monitoring may be more accurate for determining blood pressures, this approach was not feasible for our study. Although we did not record cuff size used during

data collection, protocols for sizing and placement of the blood pressure cuffs were in place and followed in presedation preparation.

Discussion

We show that intravenous ketamine administration to children un- dergoing sedation for orthopedic manipulation causes a statistically sig- nificant, though modest, increase in blood pressures and heart rate and that manipulation causes further modest increases blood pressure. Common practice over the initial decades of using ketamine for proce- dural sedation for short, painful procedures has been to coadminister midazolam with ketamine, with the goal of reducing unpleasant emer- gence reactions while providing adequate pain control and sedation [1]. More recently, it has been shown that use of ketamine alone produces similar sedation without an increase in emergence reactions compared with the combined use of ketamine and midazolam [8]. Where Parker et al [3] document less than 10 mm Hg change in systolic blood pressure, less than 5 mm Hg change in diastolic blood pressure, and less than 15 beats/min change in heart rate for procedural sedation with ketamine and midazolam pretreatment, our study also supports a mild increase in blood pressure and heart rate, without attenuation from benzodiazepines.

Ketamine for procedural sedation in the adult ED also shows a positive side-effect profile similar to that seen in the pediatric setting, with the difference being a higher incidence of undesirable emergence reactions [9]. In a study of 92 adult patients who received intravenous ketamine as the sole agent for procedural sedation, no serious adverse effects were noted, although the most common adverse effect was recovery agitation. Of note, systolic blood pressure increased by a mean of 25.4 mm Hg in this study population, and heart rate increased by a mean of 30.2 beats/min [5]. Our findings suggest that when com- pared with an adult population requiring procedural sedation, ketamine use in a typical pediatric procedural sedation results in an even milder increase in blood pressure and heart rate.

Table 2

Changes in mean blood pressures and heart rates

Systolic blood pressure (mm Hg)

Diastolic blood pressure (mm Hg)

Heart rate (beats/min)

Sedated, presedation 8 (5 to 11) (P b .001) 4 (1 to 7) (P = .003) 13 (11 to 16) (P b .001)

Sedated, recovery 3 (1 to 5) (P = .006) 4 (2 to 7) (P b .001) 2 (0 to 4) (P = .11)

Recovery, presedation 5 (2 to 8) (P = .002) 0 (-3 to 3) (P = .80) 12 (9 to 15) (P b .001)

Orthopedic manipulation 5 (3 to 7) (P b .001) 7 (5 to 9) (P b .001) 1 (-1 to 3) (P = .35) Values are mean change (95% confidence interval) (P value).

A.C. Patterson et al. / American Journal of Emergency Medicine 35 (2017) 322325 325

When intravenous access is available, preference is for intravenous administration for ease of repeated dosing to prolong sedation, as need- ed [1]. The intramuscular route is a safe alternative for administration and can be especially useful when intravenous access cannot be obtain- ed [10]. When compared with intravenous administration, the total dose needed for dissociative sedation by the intramuscular route is greater, with associated longer times to peak concentration and longer duration of dissociation [1]. Petrack et al [4] noted systolic blood pres- sure changes of 12 +- 13, diastolic blood pressure changes of 7 +- 12, and heart rate changes of 24 +- 14 with the use of intramuscular keta- mine in the pediatric ED. Our data corroborate these findings. Although there may be differences in dosing, bioavailability, and pharmacokinet- ics between the 2 routes of administration, ketamine use via either route produces only a mild increase in blood pressure and heart rate.

Orthopedic manipulation was noted to cause a statistically signifi- cant increase in blood pressures, though no significant increase in heart rate. Although the goal of the procedural sedation with ketamine is dissociation before and during the painful procedure, there are in- stances when the dissociation fails and additional ketamine doses are required. Therefore, these blood pressure changes could be influenced by perceived pain from manipulation, especially if the manipulation is time prolonged.

One relative contraindication for the use of ketamine in procedural sedation in the ED is cardiac disease, including known hypertension, due to concern for the sympathomimetic effects that can increase blood pressure [1]. Our study supports the known phenomenon that blood pressure and heart rate are increased after administration of keta- mine. However, although the vital sign changes are statistically signifi- cant, they do not correlate with clinical significance, and no adverse

effects were noted in our population due to the sympathomimetic effects of ketamine. Thus, the modest vital sign increases that were observed can inform the ED provider when considering this relative contraindication that potentially restricts ketamine’s use in the pediatric ED.

References

  1. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med 2011;57(5):449-61.
  2. Bergman SA. Ketamine: review of its pharmacology and its use in pediatric anesthe- sia. Anesth Prog 1999;46(1):10-20.
  3. Parker RI, Mahan RA, Giugliano D, Parker MM. Efficacy and safety of intravenous midazolam and ketamine as sedation for therapeutic and Diagnostic procedures in children. Pediatrics 1997;99(3):427-31.
  4. Petrack EM, Marx CM, Wright MS. Intramuscular ketamine is superior to meperi- dine, promethazine, and chlorpromazine for pediatric emergency department seda- tion. Arch Pediatr Adolesc Med 1996;150(7):676-81.
  5. Newton A, Fitton L. Intravenous ketamine for adult procedural sedation in the emer- gency department: a prospective cohort study. Emerg Med J 2008;25(8):498-501.
  6. Wadia S, Bhola R, Lorenz D, Padmanabhan P, Gross J, Stevenson M. Ketamine and intraocular pressure in children. Ann Emerg Med 2014;64(4):385-8 [e381].
  7. Malviya S, Voepel-Lewis T, Tait AR. A comparison of observational and objective measures to differentiate depth of sedation in children from birth to 18 years of age. Anesth Analg 2006;102(2):389-94.
  8. Wathen JE, Roback MG, Mackenzie T, Bothner JP. 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):579-88.
  9. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural seda- tion in adults. Am J Emerg Med 2008;26(9):985-1028.
  10. Green SM, Rothrock SG, Lynch EL, Ho M, Harris T, Hestdalen R, et al. Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases. Ann Emerg Med 1998;31(6):688-97.

Leave a Reply

Your email address will not be published. Required fields are marked *