Ketamine may be related to reduced ejection fraction in children during the procedural sedation

Abstract

Objective:

Ketamine is a dissociative anesthetic agent with sympathomimetic effects used commonly for procedural sedation in emergency department. The present study aimed to reveal the effect of ketamine on myocardium by measuring ejection fraction (EF).

Methods:

Patients less than 9 years old undergoing procedural sedation with ketamine secondary to minor trauma composed the study population by convenience sampling. Study patients received ketamine at a dose of 1.5 mg/kg. A cardiologist performed the measurements of cardiac contractility pre-ketamine and 10 min after the ketamine administration.

Results:

A total of 22 patients were enrolled into the study. Patient recruitment has been ceased after the 22nd patient because of the thought that more patients would not provide additional information. The study subjects had a mean age of 3.5 ± 2.2 years and 14 (64%) of them were male. EF reduced in 14 (63.6%) patients (mean: 5.6 ± 3.1; median: 5; interquartile range (IQR): 3.75–7; minimum–maximum (min–max): 1–14). Systolic blood pressures reduced in 10 of 14 patients with decreased EF and increased in 8 of 10 patients without decreased EF. The changes in systolic blood pressure in patients with decreased EF (n = 14) were as follows: −7.6 ± 10.9; median: −7.5; IQR: −16.5 to 1.75; and min–max: −30 to 9. There were two patients with elevated high-sensitive troponin.

Conclusion:

Ketamine may reduce EF and systolic blood pressure in children less than 9 years old undergoing procedural sedation.

Introduction

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist thought to be providing anesthesia, amnesia, and analgesia but commonly used for procedural sedation particularly in emergency departments. The American College of Emergency Physicians has offered ketamine as level A recommendation for children undergoing procedural sedation and analgesia. ¹ Ketamine is accepted to be a relatively safe agent with no hemodynamical compromise through sympathomimetic effects by inhibiting catecholamine uptake resulting with an increase in heart rate, blood pressure, and cardiac output. ² Meanwhile, ketamine has recently gaining a wide range of indications such as an analgesic or an induction agent for the intubation of critically ill patients. ^{3 –5}

However, an experimental swine model and a small human study showed an approximately 6% decrease in ejection fraction (EF) after ketamine administration. ^6,7 Although, the sympathomimetic effects of ketamine is well known, there is not so much information regarding the direct effects of ketamine on myocardium. The present study aimed to reveal the effects of intravenous ketamine on myocardium by measuring the pre- and post-ketamine EF and fractional shortening.

Material and methods

Study setting

This observational study was conducted in an emergency department of a tertiary care hospital by an annual census of 70,000 patients between March 2015 and May 2015. The local ethics committee approved the study.

Patient selection

Patients aged less than 9 years old undergoing procedural sedation by ketamine administration secondary to minor trauma composed the study population. Because children aged over 9 years usually do not need sedation for minor procedures, patients aged less than 9 years were selected as the target population. Nine years as the age cutoff was selected because the patients aged over 9 years and where the parents of the child denied to give inform consent were excluded from the study.

Patients eligible for the study were enrolled with a convenience sampling during the day time of the week because of the availability of the cardiologist responsible from performing the echocardiography.

Interventions

The study patients received ketamine at a dose of 1.5 mg/kg via intravenous route. Additional doses were administered if there was insufficient sedation.

Vital signs of the patients were monitored and recorded during the procedure. The total dose of ketamine administered to the patients was also recorded.

Besides the echocardiographic measurements, high-sensitive troponin (hsTn) levels of study patients were also measured before and 3 h after the ketamine administration. hsTn levels were measured by Roche Cobas 8000/e602 (Indianapolis, Indiana, USA) device with a less than 10% coefficient of variation at the 99 percentile upper limit of reference limit of the reference population. The normal limits for hsTn were 0–14 pg/mL.

Echocardiographic measurements, which defined in detail below, were performed by an associate professor of pediatric cardiology just before and 10 min after the ketamine administration.

Echocardiographic measurements

Echocardiographic analysis was performed using a GE Vivid-I portable cardiac ultrasound machine (General electric, Fairfield, Connecticut, USA) with an 1.5–3.6 MHz sector array transducer as a per standard imaging technique recommended by the American Society of Echocardiography. The results were calculated as mean values of three consecutive heart beats. Measurements were determined using the M-mode method at the parasternal long axis position near papillary muscle level: the left ventricular end-diastolic diameter (LVEdD), the interventricular septum end-diastolic thickness, and the left ventricular posterior wall end-diastolic thickness were measured, and EF and fractional shortening (FS) were calculated. EF was calculated by subtracting stroke volume (end-diastolic volume to end-systolic volume) from end-diastolic volume. The normal value of EF is over 60%. FS is a method of computing not volume but distance and calculated by (LVEdD − LVESD/LVEdD) × 100. The normal value of FS is higher than 28%.

Primary outcome

The primary outcome of the study was the changes in EF and FS of study patients. Changes in vital signs, systolic blood pressure, blood pressure and heart rate, hsTn, and adverse effects were also recorded.

Statistical analysis

Study data were analyzed in SPSS 18.0. Numeric variables were presented as mean ± standard deviation and median (interquartile range (IQR) and (min–max)), frequent variables as rates.

Results

A total of 22 patients were enrolled into the study. Patient recruitment has been ceased after the 22nd patient because more patients would not provide additional information. The study subjects had a mean age of 3.5 ± 2.2 years and 64% (n = 14) of them were male. Twelve patients (54.5%) had a skin incision on the face or scalp and 10 patients (45.5%) on the hand. The mean weight of the study patients was 17.6 ± 6.5 kg and the mean ketamine dose administered was 30.5 ± 10.1 mg.

EF reduced in 14 (63.6%) patients (mean: 5.6 ± 3.1; median: 5; IQR: 3.75–7; min–max: 1–14). Systolic blood pressures reduced in 10 of 14 patients with decreased EF and increased in 8 of 10 patients without decreased EF vice versa. The changes of systolic blood pressure in patients with decreased EF (n = 14) were as follows: −7.6 ± 10.9; median: −7.5; IQR: −16.5 to –1.75; min–max: −30 to –9. The mean change for diastolic blood pressure was −4 ± 5.9 (median: −3.5;, IQR:−9 to −0.259) and 8 ± 7 (median: 9.5; IQR: 5–12) for pulse rate in patients with reduced EF. Table 1 displays the changes in EF, FS, and vital signs for each study patient.

Table 1.

Changes in EF, FS, and vital signs for each study patient.^a

Patient	EF (%)	Fractional shortening (%)	Systolic blood pressure (mmHg)	Diastolic blood pressure (mmHg)	Pulse rate per minute
1	3	1	6	3	−4
2	0	−1	11	9	12
3b	−1	0	−3	6	5
4b	−4	−3	−4	−15	11
5b	−7	−5	−16	−4	11
6	1	0	6	−3	−13
7	1	0	5	7	9
8	1	1	−7	5	−8
9b	−4	−6	−8	−2	13
10b	−14	−5	−30	−9	22
11	4	2	16	6	−20
12b	−3	−2	6	2	−4
13	2	1	9	7	−2
14b	−7	−5	−20	−8	12
15b	−3	−1	9	4	−6
16b	−4	−2	4	−3	10
17b	−5	−4	−9	−1	9
18	5	2	21	7	−9
19b	−5	−3	−7	−2	7
20b	−7	−5	−11	−5	5
21b	−7	−8	1	−11	9
22b	−8	−5	−18	−9	12

EF: ejection fraction; FS: fractional shortening.

^aPositive numbers presents increases and negatives present decline after ketamine administration.

^bPatients with decreased EF after ketamine administration.

FS also reduced in 14 patients (mean: 3.9 ± 2; median: 4.5; IQR: 2–5; min–max: −1 to 8). There were two patients with elevated hsTn. hsTn levels of these two patients at the time of pre-ketamine, 3, 5, and 24 h after the ketamine administration were as follows: 6, 54, 21, 7, and 7 ng/L and 3, 18, 7, and 3 ng/L, respectively.

The 10th study patient who had a reduction of 14% in EF resulted with a 30-mm Hg decrease in systolic blood pressure. This oxygen saturation of this patient also fell to 93% but not lower than this value. The control echocardiography of this patient performed 24 h later revealed a normal EF (60%). Minor adverse effects occurred in four patients to ketamine. Three patients had tremor during the procedure and one patient vomited after the procedure.

Discussion

Ketamine is a popular drug used mainly for procedural sedation and accepted as a safe drug with no hemodynamic compromise because of its sympathomimetic effects. Ketamine also has been gaining a wider range of indications in adults such as an analgesic or an induction agent for the intubation of critically ill patients. However, the present study showed that ketamine may be related to the reduction of EF and systolic blood pressure in children aged less than 9 years besides its sympathomimetic effects.

A general agreement that ketamine leads increases in blood pressure and heart rate secondary to the inhibition of reuptake of catecholamine. However, there are some in vitro studies that ketamine may have detrimental effects on myocardium demonstrated by decline in EF and troponin elevations. ^6,8

Wessler et al. trialed the effect of ketamine on EF on a swine model. ⁶ They reported the post-ketamine EF as 41 ± 6.5% which dropped from a baseline value of 47 ± 3.2% after 5 min of ketamine administration with a dose of 12 mg/kg via intramuscular route with no statistical and clinical change in the heart rate. A small study by Jakobsen et al. reported a fall of approximately 6% in EF (52.5% vs. 46.9%) in 11 patients after a ketamine administration of 0.5 mg/kg despite the significant increase in systolic and diastolic blood pressures and heart rate. ⁷ Christ et al. also reported a decreased cardiac index secondary to ketamine in patients with heart failure despite the increase in mean arterial pressure and systemic vascular resistance. ⁹

One of the main finding of this study is the confirmation of the findings of a recent study that ketamine may be related to minor hsTn elevations. ⁹ Elevation of hsTn and return to the normal limits are also similar to the study by Serinken et al. A detailed description on the dynamics of hsTn elevation in children secondary to ketamine and related medical literature could be achieved by the aforementioned article. ¹⁰

Reduction in EF led to a decrease in systolic blood pressure in most of the patients but this is not true for the heart rate, because the heart rate increased in most of the patients with reduced EF. Decreases in blood pressure related with reduced EF arises a question that whether ketamine could be safely used in patients with limited reserves.

The findings of this study does not mean that ketamine reduces EF in all patients. On the contrary, EF improved in seven patients within a range of 1–5%. Ketamine should still be accepted as a safe drug in children with no comorbidities or congenital diseases for procedural sedation. However, the trend to use the ketamine in adult patients for various indications has been rising. Because it has been accepted to have positive hemodynamic effects, ketamine has been offered as a choice as a sedative or induction agent of critically ill patients. However, the present study showed that ketamine may be related to remarkable declines in EF and systolic blood pressure that should not be ignored. But we still do not know which patients are candidates for the depressive effects of ketamine on myocardium. This should be an issue of the future studies.

Limitations

The present study has several limitations. The study has small sample size but the high rate of patients with reduced EF may be an indicator on the issue and conduction of further studies. Furthermore, the present study only enrolled the patients aged less than 9 years. The findings of the study should not be applied to the whole population. The external validity of the study for the other populations should also be tested. EF of patients was not evaluated after the study ended whether they have returned to normal limits.

Conclusion

Ketamine may reduce EF and systolic blood pressure in children aged less than 9 years undergoing procedural sedation. However, patients with the potential to be suffered from the depressive effect of ketamine on myocardium should be an issue of further studies.