a b s t r a c t

Background: Head injuries frequently occur in combat. Tactical Combat Casualty Care (TCCC) guidelines recom- mend pre-hospital use of ketamine for analgesia. Yet the use of this medication in patients with head injuries re- mains controversial, particularly among pediatric patients. We compare survival to hospital discharge rates among pediatric head injury subjects who received prehospital ketamine versus those who did not.

Methods: We queried the Department of Defense Trauma Registry (DODTR) for all pediatric (b18 years of age) subjects from January 2007 to January 2016. We performed a sub-analysis of subjects with an abbre- viated injury severity score for the head of 3 (serious) or higher and at least one documented Glasgow Coma Score <=13.

Results: Of the 3439 pediatric patients within our dataset, 555 subjects met inclusion criteria for head injury - 36 (6.5%) received prehospital ketamine versus 519 (93.5%) who did not. There was no significant differ- ence noted between groups regarding median age (10 versus 8, p = 0.259), percent male gender (72.2% versus 76.3%, p = 0.579), mechanism of injury (p = 0.143), median composite injury scores (22 versus 20, p = 0.082), median ventilator-free days (28 versus 27, p = 0.068), median ICU-free days (27.5 versus

27, p = 0.767), median hospital days (3.5 versus 4, p = 0.876) or survival to discharge (66.7% versus

70.7%, p = 0.607).

Conclusions: Within this data set, we were unable to detect any differences in mortality among pediatric head trauma subjects administered ketamine compared to subjects not receiving this medication in the prehospital setting.

Introduction

Background

Head injuries occurred frequently during the recent conflicts in Iraq and Afghanistan in both adults and children, primarily from improvised Explosive devices. By 2007 as many as 320,000 returning U.S. service members experienced a probable Traumatic brain injury [1]. Data on head injury rates for the local population, to include pediatric patients, are unavailable but are likely to be similarly high.

Ketamine is a drug commonly used for induction during intubation, procedural sedation, and analgesia. Tactical Combat Casualty Care (TCCC) guidelines recommend prehospital administration of ketamine

* Corresponding author at: Department of Emergency Medicine, Madigan Army Medical Center, 9040 Jackson Ave., Tacoma, WA 98431, United States of America.

E-mail address: [email protected] (G.J. Hill).

for casualties that have moderate to severe pain. Providers can further combine ketamine with other agents for synergistic effects [2-4]. Keta- mine provides hemodynamic and respiratory stability unlike opioids, making it an ideal agent for prehospital pain control among trauma pa- tients [5-7]. Providers can administer ketamine via intravenous, intra- muscular, intraosseous, or intranasal routes thereby offering multiple options during prehospital trauma care.

Despite its widespread use, controversy still exists regarding the safety of ketamine in the setting of head trauma due to potential effects on intracranial pressure [8,9]. Previous studies suggest that ketamine use in patients with head injuries may not have deleterious ef- fects and may even be neuroprotective [9-13]. Recently, the American College of Emergency Physicians removed head trauma from their clin- ical practice guidelines as a relative contraindication to the use of keta- mine [14]. Despite this change, there is little evidence available to determine whether ketamine administration is safe in pediatric patients that have sustained head injuries [10,15].

https://doi.org/10.1016/j.ajem.2018.10.046 0735-6757/

Goal of this investigation

We seek to determine if an association exists between prehospital administration of ketamine to pediatric trauma subjects with head inju- ries and increased mortality.

Methods

Data acquisition

We identified subjects as part of a study evaluating prehospital and emergency department (ED) Life-saving interventions for pediatric trauma patients [16,17]. The US Army Institute of Surgical Research reg- ulatory office reviewed protocol H-16-014 and determined it was ex- empt from Institutional Review Board oversight. We obtained only de- identified data.

Subjects and setting

We queried the Department of Defense Trauma Registry (DODTR) for all pediatric encounters from January 2007 and January 2016. We in- cluded subjects with missing data if there was a documented age or es- timated age within the records. The research database contained all available information for both prehospital and fixed-facility based care. This was a retrospective review of prospectively collected data within the registry.

Department of Defense Trauma Registry (DODTR) description

The DODTR, formerly known as the Joint Theater Trauma Registry (JTTR), is the data repository for DoD trauma-related injuries [18,19]. The Joint Trauma system (JTS) manages this system. The DODTR in- cludes documentation regarding demographics, injury-producing inci- dents, diagnoses, treatments, and outcomes of injuries sustained by US/non-US military and US/non-US civilian personnel in wartime and peacetime from the point of injury to final disposition. The most re- cently updated data dictionary for the DODTR is readily available [20]. subject enrollment in the DODTR occurs if he or she undergoes admis- sion to a Role 3 (fixed-facility) or forward surgical team (FST) with an injury diagnosis using the International Classification of Disease 9th Edi- tion (ICD-9) between 800 and 959.9, near-drowning/drowning with as- sociated injury (ICD-9994.1) or inhalational injury (ICD-9987.9), and trauma occurring within 72 h from presentation. The DODTR considers the prehospital environment to comprise any location prior to reaching a FST or a combat support hospital (CSH, role 3) to include the Role 1 (point of injury, casualty collection point, battalion aid station) and Role 2 (temporary limited-capability forward-positioned hospital inside the combat zone without surgical support).

Identification of subjects

We searched for all subjects with an Abbreviated Injury Score by body region (AISBR) of 3 or greater for the head region (AISBR1) and at least one ED Glasgow coma score of 13 or less. When more than one GCS was available we used the lowest value documented. We then searched for all prehospital subjects for at least one docu- mented ketamine administration. The JTS uses AIS 2005 with Update 2008 Coding Standard 2. The majority of JTS coders are Certified AIS Coding Specialists (CAISS). All coders receive an orientation and regu- larly occurring quality assurance measures are implemented.

severe head injury subgroup analysi”>Data analysis

We performed all statistical analysis using Microsoft Excel (version 16 Redmond, Washington) and JMP Statistical Discovery from SAS (ver- sion 13, Cary, NC). We compared study variables using a student t-test

for continuous variables, Wilcoxon Rank Sum test for ordinal variables, and chi-squared test for nominal variables. For regression analyses with a binary outcome we performed a binary logistic regression. We re- ported the following: categorical variables as numbers and percentages, ordinal variables reported as medians with interquartile ranges, and continuous variables as means with standard deviations. We performed multiple subgroup analyses as described and stratified age-based anal- yses based on Centers for Disease Control (CDC) age groupings: b1, 1-4, 5-9, 10-14, 15-17 [16,17,21]. We defined a severe head injury as a GCS of 8 or less [22].

Results

From January 2007 through January 2016 there were 42,790 en- counters in the DODTR. Of those, 3439 (8.0%) were pediatric by either documented or estimated age. Of the 3439, we identified 555 subjects that had an AISBR1 (head) score of >=3 and at least one GCS <= 13.

Overall cohort analysis

Of the 555 subjects available for comparison, there were 36 (6.5%) that received prehospital ketamine versus 519 (93.5%) that did not. There were no significant differences noted between the baseline pa- tient demographics of the groups with regards to age, gender, mecha- nism of injury, or remaining AIS scores. We also found no significant differences when looking at outcome data in terms of ICU-free and ventilator-free days, hospital days or survival to hospital discharge sta- tus. We did note a significantly lower median GCS score upon arrival to the emergency department in the ketamine group (median 3, IQR 3-3 versus median 3, IQR 3-8, p = 0.016). A higher proportion of sub- jects in the ketamine group sustained injuries in Afghanistan as com- pared to subjects that did not receive ketamine (OEF 100.0% versus 75.1%, p = 0.003). There was also a trend towards median higher com- posite injury severity scores in the ketamine group (ISS, median 22, IQR 16.32.25 versus 20, 14-26, p = 0.082, Table 1). We did not find any sig- nificant differences in the rates of tympanic membrane rupture, Facial fractures, intracranial hemorrhage or Diffuse axonal injury between the two groups. However, we did note a trend towards higher rates of skull Penetrating injuries in the ketamine group (50.0% versus 35.5%, p= 0.079, Table 2).

Age subgroup analysis

When stratified by age categories, we did not find any significant dif- ferences in ventilator days, ICU days, hospital days or survival to hospital discharge for any of the age groups. There were no subjects in the b1- year age group that received ketamine. There was a trend towards a shorter hospital course in the ketamine group (median days 1, IQR 0-5 versus 5, IQR 2-8, p = 0.073) for subjects in the 15-17 years age

group (Table 3).

Intubated prehospital subgroup analysis

Among subjects who underwent prehospital intubation, we did not find any significant difference with regards to baseline characteristics of the cohort to include age, gender, lowest recorded GCS, or mechanism of injury. We also did not find any significant difference when looking at the clinical course in terms of ventilator-free days, ICU-free days, hos- pital days or survival to hospital discharge among patients receiving prehospital ketamine as compared to patients not receiving prehospital ketamine (Table 4).

Severe head injury subgroup analysis

In subjects with a lowest recorded GCS of 3-8, we also did not find any significant differences with the regards to the basic characteristics

Table 1

Comparisons of head injured subjects based on administration of prehospital ketamine versus no ketamine.

		Ketamine (n = 36)	No ketamine (n = 519)	p-Value
Demographics	Age (median, IQR)	10 (6.25-13)	8 (5-12)	0.259
	Male	72.2% (26)	76.3% (396)	0.579
	Lowest total GCS	3 (3-3)	3 (3-8)	0.016
Country where injury occurred	Iraq	0% (0)	24.9% (129)	0.003
	Afghanistan	100% (36)	75.1% (390)
Mechanism of injury	Explosive	55.6% (20)	44.1% (229)	0.143
	GSW	27.8% (10)	20.2% (105)
	MVC	8.3% (3)	17.9% (93)
Injury severity scores	Other Composite ISS	8.3% (3) 22 (16-32.25)	17.7% (92) 20 (14-26)	0.082
	AISBR2	0 (0-2)	0 (0-2)	0.280
	AISBR3	0 (0-2)	0 (0-0)	0.224
	AISBR4	0 (0-0)	0 (0-0)	0.553
	AISBR5	0 (0-1.5)	0 (0-2)	0.985
	AISBR6	0 (0-1)	1 (0-1)	0.257
Outcome data	30-day ventilator-free days	28 (26-29)	27 (25-29)	0.068
	30-day ICU-free days	27.5 (20.5-29)	27 (25-29)	0.767
	Hospital days	3.5 (1-14.25)	4 (1-8)	0.876
	Discharge alive	66.7% (24)	70.7% (367)	0.607

GCS = Glasgow Coma Scale; GSW = gunshot wound; MVC = motor vehicle collision; ISS = injury severity score; AISBR = abbreviated injury score by body region; AISBR2 = face; AISBR3

= thorax; AISBR4 = abdomen; AISBR5 = extremity; AISBR6 = external (including superficial wounds from all the body regions, burns); ICU = intensive care unit; IQR = interquartile range.

of the cohorts when looking at median age, gender, or mechanism of in- jury. Furthermore, we did not find a significant difference when exam- ining the clinical course with respect to ventilator-free days, ICU-free days, hospital days or survival to hospital discharge among patients re- ceiving prehospital ketamine as compared to patients not receiving prehospital ketamine (Table 5).

Discussion

Our study found no evidence of harm following the prehospital ad- ministration of ketamine to pediatric patients who sustained head trauma in Iraq or Afghanistan and underwent admission to US or coali- tion medical facilities. We were also unable to detect a difference in out- come when performing subgroup analyses based on age, patients intubated in the prehospital setting, or those with Severe head injuries. While we found significantly lower GCS scores in the group receiving ketamine, we did not detect a mortality difference.

These findings suggest that it may be possible to extrapolate TCCC recommendations for Ketamine usage to the pediatric population with head injuries. This could give Prehospital providers an additional indica- tion for a medication which they already carry and with which they are familiar. Current TCCC guidelines apply only to the adult combatant population and make no pediatric-specific recommendations [23]. They caution against the use of ketamine only in the case of severe TBI

to its use is obstructive hydrocephalus [24]. However, the evidence spe- cifically examining the pediatric population remains limited. Our study adds to this small but growing literature, demonstrating the safety of ketamine in pediatric patients who have sustained head injuries [10,15]. Of note, we found no pediatric patients in the registry that sustained head injuries in Iraq and subsequently received ketamine and a low rate of usage overall in this population. There are several possible explana- tions for this finding. Most likely, its related to limitations on access and use within that theater with generally low use all around by the ma- jority of forces [25]. Conversely, documentation omissions may be con-

tributory [26].

There are several limitations to the study. We are only able to query the registry for information entered into it and cannot determine how many records are incomplete or how many data items are missing. Pre- vious studies demonstrate poor prehospital documentation [26,27]. While we found significantly lower GCS scores in the ketamine group, pre-administration scores were not available per the registry these score measurements occurred after the patients received ketamine as these were scores upon arrival in the emergency department. Therefore, we are unable to say if the lower GCS scores were due to medication ef- fect or the characteristics of the cohort. Our investigation is also

Table 3

Comparison of outcome data by age grouping.

in which the casualty cannot communicate pain due to a concern that it may worsen this condition.

The literature increasingly suggests that the use of ketamine in adult patients that have suffered head injuries is not harmful and may poten- tially be beneficial [9-13]. There are no reports of patients with normal flow of cerebrospinal fluid having resultant harm from the administra- tion of ketamine and some authors posit that the only contraindication

Table 2

Comparisons of select injuries.

1-4 years

(n = 102)

5-9 years

(n = 207)

10-14 years

Ketamine No p-Value ketamine

30-day ventilator-free days 26 (23-28) 28 (25-29) 0.103

30-day ICU-free days 26 (20-28) 27 (24-29) 0.404

Hospital days 6 (1-24) 3 (1-8) 0.379

Discharge alive 71.4% (5) 64.2% (61) 0.700

30-day ventilator-free days 27 (23-29.25) 28 (27-29) 0.330

30-day ICU-free days 26 (17.75-29) 27 (25-28) 0.619

Hospital days 5.5 (1-18.25) 4 (2-9) 0.751

Discharge alive 60.0% (6) 77.7% (153) 0.197

30-day ventilator-free days 28 (24.5-28.5) 28 (26-29) 0.312

	Ketamine	No ketamine	p-Value	(n = 185)	30-day ICU-free days Hospital days	28 (16.75-29) 2.5 (1-14.25)	27 (25-29) 4 (1-8)	0.821 0.969
TM rupture	8.3% (3)	3.7% (19)	0.165		Discharge alive	78.6% (11)	66.1% (113)	0.339
Facial fracture	80.6% (29)	79.2% (411)	0.845	15-17 years	30-day ventilator-free days	29 (25.5-29.5)	28 (26-29)	0.837
Skull penetration	50.0% (18)	35.5% (184)	0.079	(n = 52)	30-day ICU-free days	29 (26-30)	28 (23-29)	0.187
Intracranial hemorrhage	69.4% (25)	70.3% (365)	0.911		Hospital days	1 (0-5)	5 (2-8)	0.073
Diffuse axonal injury	2.8% (1)	1.2% (6)	0.399		Discharge alive	40.0% (2)	72.3% (34)	0.136

TM = tympanic membrane. No subjects in the b1 year group received ketamine and were excluded from this table.

Table 4

Comparison of outcome data in subjects intubated prehospital.

		Ketamine (n = 21)	No ketamine (n = 98)	p-Value
Demographics	Age	10	9.5 (5-12)	0.334
		(7.5-14)
	Male	76.2% (16)	72.5% (71)	0.726
	Lowest total GCS	3 (3-3)	3 (3-3)	0.310
Mechanism of	Explosive	47.6% (10)	42.9% (42)	0.760

Conclusions

Within this data set, we were unable to detect any differences in mortality among pediatric head trauma subjects administered ketamine compared to subjects not receiving this medication in the prehospital setting. While further research is necessary, this study adds to the grow- ing body of evidence suggesting that ketamine use in the setting of a head injury is likely safe in both children and adults. These findings may ultimately have important implications for the practice patterns

injury	GSW	28.6% (6)	24.5% (24)	of military and civilian providers alike.
	MVC	9.5% (2)	19.4% (19)

Other 14.3% (3) 13.3% (13)

Outcome data 30-day ventilator-free 27 28 (26-29) 0.398

days (24.5-29)

Conflicts

30-day ICU-free days 27

(17.5-29)

28 (25-29) 0.353

We have no conflicts to report.

Hospital days 3 (1-13.5) 3 (1-7) 0.975

Discharge alive 57.1% (12) 63.3% (62) 0.600

observational in nature therefore we can only demonstrate correlation and not causation between prehospital ketamine administration and survival to discharge. Also, encounter inclusion within the DODTR re- quires subject arrival to an FST or fixed-facility alive or with on-going in- terventions so we are unable to characterize subjects that died on the battlefield. An additional limitation is that we do not have sufficient data to determine the impact of intervention upon transport times or the tactical situation. Furthermore, we do not have data on functional outcomes or data on the neurological status upon discharge. There were only 39 records in the registry for pediatric patients that sustained head injuries and received prehospital ketamine therefore these had to be compared with a much larger number of patients that did not receive ketamine. While usually not feasible in the Prehospital combat setting, a controlled study would yield more robust data. While we used mortality as the overall study outcome, we are unable to assess differences in functional status at discharge. Similarly, we are unable to assess for Physiologic effects such as intracranial pressure. A final limitation is that we included data even if it was incomplete in the registry [27].

Further study of pediatric patients with head injuries will help con- firm this versatile medication’s safety profile in this population. Re- search should include both hospital-based and prehospital studies. Such studies could give deployed military medical providers or those working in austere settings an additional pharmaceutical option when caring for injured children.

Table 5

Comparison of outcome data in severe head injury (GCS 3-8).

		Ketamine (n = 34)	No ketamine (n = 313)	p-Value
Demographics	Age	9.5	8 (5-12)	0.467
		(5.75-12.25)
	Male	73.% (25)	75.4%	0.806
			(313)
Mechanism of	Explosive	52.9% (18)	44.1%	0.235
injury			(183)

GSW 29.4% (10) 21.2% (88)

MVC 8.8% (3) 17.8% (74)

Other 8.8% (3) 16.9% (70)

Funding

We received no funding for this study.

Acknowledgements

We would like to thank the Joint Trauma System Data Analysis Branch for their efforts with data acquisition.

Disclaimer

Opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Air Force, the Department of the Army, or the Department of Defense.

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