Article

Validation of the PECARN head trauma prediction rules in Japan: A multicenter prospective study

a b s t r a c t

Background: Head trauma in children is one of the most common causes for emergency department visits. Al- though most trauma cases are minor, identifying those patients who have Clinically important traumatic brain injury (ciTBI) is challenging. The Pediatric Emergency Care Applied Research Network head trauma prediction rules identifying children who do not require cranial computed tomography (CT) were validated and are used all over the world. However, these rules have not been validated with large cohort multicenter stud- ies in Asia.

Objectives: To investigate whether the PECARN rules can be safely applied to Japanese children.

Methods: We conducted a multicenter, prospective, observational cohort study. We included children younger than 16 with minor head trauma (Glasgow Coma Scale >=14) who presented to the six participating centers within 24 h of their injuries between June 2016 and September 2017.

The primary analysis was set to calculate the negative predictive value of the patients with Very low risk by the PECARN rules, compared with a preset threshold of 99.85%.

Results: We included 6585 children of which 463 (7.0%) had head CT scans performed and 23 (0.35%) had ciTBI. There were two patients with ciTBI who were classified as very low risk. The negative predictive value, calculated as 99.96% (95%CI: 99.86-100.00; P = .019), was significantly superior compared with the preset threshold of 99.85%.

Conclusions: The PECARN head trauma prediction rules seemed to be safely applicable to Japanese children. Fur- ther studies are needed to determine safety in hospitals where physicians do not have expertise in managing children.

(C) 2019

Introduction

? PresentationsOrganization: Japanese Association for Acute Medicine.Date: November 19-21, 2018.Meeting: The 46th Annual Meeting of the Japanese Association for Acute Medicine.Location: PACIFICO YOKOHAMA.

* Corresponding author at: Critical Care Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.

E-mail addresses: [email protected] (K. Ide), [email protected] (S. Uematsu), [email protected] (Y. Hagiwara), [email protected] (K. Tetsuhara), [email protected] (M. Mikami), [email protected] (T. Kobayashi).

Head trauma in children is one of the most common causes for emergency department (ED) visits. Most head trauma incidents in chil- dren visiting the ED are minor; however, identifying those patients who have Clinically important traumatic brain injury is challenging. A Cranial computed tomography scan is the standard diagnostic test and is widely used all over the world. Although cranial CT scans are use- ful for definitive diagnosis, potential cancer risks exist associated with ionizing radiation, particularly in children, who are more radiosensitive than adults [1,2].

https://doi.org/10.1016/j.ajem.2019.158439

0735-6757/(C) 2019

Head trauma prediction rules have been derived for supporting phy- sicians to improve accuracy in decision-making and to minimize the use of potentially harmful CT scans. The Pediatric Emergency Care Applied Research Network (PECARN) developed two age-based head trauma prediction rules to identify children with very low risk of ciTBI who do not require cranial CT scans [3]. The PECARN rules were validated to have high negative predictive values in many countries [3-10] and are used all over the world; however, these rules have not been validated with large cohort multicenter studies in Asia.

CT is widely accessible in Japan, as the number of CT units per million people in Japan is the highest in the world [11]. Ozaki et al. reported that neurosurgeons examined children with minor head trauma in their fa- cility and N60% of the children with minor head trauma underwent cra- nial CT scans [12]. In Japan, children with minor head trauma are not usually examined by pediatric emergency specialists. The PECARN pre- diction rule has not been validated in an Asian pediatric population and is not commonly used by physicians in Japan. We believe that head trauma prediction rules that are validated in an Asian population might become widely used in Asia, including Japan. Our objective was to investigate whether the PECARN rules can be safely applied to chil- dren with minor head trauma in Japan.

Methods

Study design and setting

We conducted a multicenter, prospective, observational cohort study to investigate whether the PECARN rules were applicable to Japanese children with minor head trauma. This study was conducted in accordance with the amended Declaration of Helsinki. This study was approved by the institutional ethics committees at each participat- ing site with waiver of verbal consent. We included the following six sites: three freestanding children’s hospital EDs, two general hospital EDs, and one pediatric ED within a general hospital. We enrolled the pa- tients from June 2016 to September 2017.

Selection of participants

We included children younger than 16 years with minor head trauma (Glasgow Coma Scale >=14) who presented to the participat- ing EDs within 24 h of their injuries. We included children with triv- ial injury mechanisms who were excluded in the PECARN study because excluding this population might have reduced the general- izability of this study. We excluded children with penetrating trauma, known brain tumors, pre-existing neurological disorders which can complicate assessment, neuroimaging performed at an- other hospital prior to the ED consultation, Bleeding disorders, or Glasgow Coma Scale scores b14 in keeping with the PECARN study [3]. We also excluded children with suspected non-accidental trauma, severe injuries to other parts of the body, or past history of any intracranial lesions because we felt these patients were not suit- able for application of the PECARN rules.

Methods of measurement

Patients were enrolled by the treating ED physicians who col- lected clinical data before any neuroimaging was performed. ED phy- sicians who treated the enrolled children collected data regarding predictive variables on a paper-based standardized case report form. Lead site investigators at each site trained the physicians on case report form completion. ED physicians were able to obtain a head CT in accordance with their own Clinical decisions. Manage- ment, such as admission, follow-up examination the next day, or telephone follow-up, of the children was in accordance with the in- stitutional rules at each site. In addition to the data collected by the ED physicians in the ED, lead site investigators or research assistants

at each site collected the outcome data from the electronic health re- cords at least two weeks after the first examination. Any patients who had transferred or presented to other hospitals could request to review the outcome. The paper-based case report forms at each site were de-identified and sent to the data center.

Outcome measures

The main outcome, ciTBI, was defined as death, neurosurgery, intu- bation for N24 h for traumatic brain injury, or hospital admission for two nights or more associated with traumatic brain injury on CT. CT scans were independently interpreted onsite by staff radiologists, and traumatic brain injury on CT was defined by any of the following de- scriptions: intracranial hemorrhage or contusion, cerebral edema, trau- matic infarction, sigmoid sinus thrombosis, Midline shift of intracranial contents or signs of brain herniation, diastasis of the skull, pneumocephalus, or depressed Skull fracture in keeping with the PECARN study.

Statistical analysis

Statistical analyses were performed using SAS ver.9.4 (SAS Institute, Inc.). Continuous data are presented as the mean with standard devia- tion or the median with an interquartile range, and categorical data as a number or ratio with a percentage. Sensitivity, specificity, positive pre- dictive value, and negative predictive value (NPV) are described as per- centages with the 95% Clopper-Pearson exact confidence interval (CI).

We stratified the study populations into three groups at risk for ciTBI according to the PECARN rules. We classified children with one or more high-risk predictors (for b2 years old: altered mental status or palpable skull fracture; for >=2 years old: altered mental status or signs of basilar skull fracture) as high risk, children with one or more intermediate- risk predictors (for b2 years old: severe injury mechanism, loss of con- sciousness N5 s, non-frontal hematoma, and not acting normally accord- ing to parents; for >=2 years old: severe injury mechanism, any loss of consciousness, vomiting, or Severe headache) as intermediate risk, and children with none of the predictors as very low risk. The PECARN rules were considered negative when the children had no predictors and were classified as very low risk. The primary analysis was set to cal- culate the NPV of the patients with very low risk by the PECARN rules, and to compare with a preset threshold of 99.85%. The numerator of the NPV was the number of patients with very low risk by the PECARN rules and with no occurrence of ciTBI. The binomial test with a one-sided significance level of 0.025 was used to compare the NPV with the preset threshold.

We assumed the NPV of 99.98% from a previous study [3]. The threshold of NPV was set to 99.85%, which is a clinically acceptable level, that is, oversight of one to two patients per 1000 people. Based on these proportions, with the conditions of a one-sided significance level of 0.025, and a power of 0.90, the sample size estimation was 4814 patients with very low risk.

Results

Between June 2016 and September 2017, we enrolled 7163 children with minor head trauma and included 6585 children (2237 patients b2 years old; 4348 patients >=2 years old) in the present study (Fig. 1). No patients were missed after enrollment. Of the 6585 included chil- dren, 3697 (56.1%) of these patients were assessed in tertiary pediatric centers, 2288 (34.8%) in a pediatric ED in a general hospital, and 600 (9.1%) in general emergency centers. The number of the included pa- tients who were categorized as very low risk (5041) was greater than the pre-calculated sample size (4814).

The patient demographics and other characteristics are shown in Table 1. N98% of the patients showed an initial Glasgow Coma Scale score of 15 in both age groups. With regard to positive predictor

7163 enrolled patients

6585 included patients

578 patients excluded

Age 16 or more 12

Age unknown 1

GCS 13 or less 42

GCS unknown 24

Non-accidental trauma suspected 47

Presenting 24 hrs after injury 183

Neuroimaging before ED visits 21

Severe injuries to other parts 49

Penetrative injuries 4

Past history of intracranial lesions 39

bleeding disorders 31

Developmental delay 125

2237 patients <2 years old

4348 patients 2 years old

Fig. 1. Patient flow diagram. GCS, Glasgow coma scale; ED, emergency department.

variables, severe injury mechanism (359/2237, 16.0%) and non-frontal hematoma (294/2237, 13.1%) were observed mostly in the group b2 years old, and severe injury mechanism (428/4348, 9.8%) and vomiting (332/4348, 7.6%) were common in the group >=2 years old. The outcomes are shown in Table 2. CT scans were performed at a rate of 5.5% (122/2237) for children b2 years old and 7.8% (341/4348) for children >=2 years old. Traumatic brain injury on CT was seen in 0.72% (16/2237) for children b2 years old and 0.25% (11/4348) for children

>=2 years old, but none of them underwent surgery, required mechanical ventilation for N24 h, or died. A total of 0.67% (15/2237) of children b2 years old and 0.18% (8/4348) of children >=2 years old were admitted to the hospital for more than two nights and were designated as having ciTBI.

Management and incidence of ciTBI for each category are shown in Table 3. The rates of CT scans performed were lower in the group b2 years old compared to the group >=2 years old, although the incidence

of ciTBI was higher in the group b2 years old. There were two patients with ciTBI who were classified as very low risk. A one-month-old child with linear skull fracture and epidural hematoma and a three-month- old infant with subarachnoid hemorrhage were discharged home with- out any intervention after admission for a few days. We assessed the di- agnostic accuracy of the PECARN rules for predicting the presence of ciTBI in Table 4-a and 4-b. The NPV was calculated as 99.87% (95%CI: 99.54-99.98) for children b2 years old and 100% (95%CI: 99.89-100.00) for children >=2 years old. The NPV for the total popula- tion, 99.96% (95%CI: 99.86-100.00; P = .019), was significantly greater compared with the preset threshold of 99.85%.

For the sensitivity analysis, we analyzed 4365 patients, excluding those patients with trivial injury mechanisms. CT scans were performed in 9.3% (406/4365) of those patients analyzed. ciTBI was found in 0.53% (23/4365). The NPV was calculated as 99.93% (2815/2817; 95%CI: 99.74-99.99) (Table 4-b).

Table 1

Characteristics of the groups b2 years old and >=2 years old.

Table 2

Outcomes for the groups b2 years old and >=2 years old.

b2 years old (N = 2237)

>=2 years old (N = 4348)

Demographic variables

Age in months, median (IQR)

13 (7-18)

56 (37-90)

GCS = 15, n (%)

2212 (98.9)

4306 (99.0)

GCS = 14, n (%)

25 (1.1)

42 (1.0)

b2 years old (N = 2237)

>=2 years old (N = 4348)

Overall

(N = 6585)

Observation before CT scan, n (%)

295 (13.2)

399 (9.2)

694 (10.5)

CT scan performed, n (%)

122 (5.5)

341 (7.8)

463 (7.0)

Traumatic brain injury on CT, n (%)

16 (0.72)

11 (0.25)

27 (0.41)

Epidural hematoma, n (%)

8 (0.36)

7 (0.16)

15 (0.23)

Positive predictor variables

subdural hematoma, n (%)

4 (0.18)

3 (0.07)

7 (0.11)

Altered mental status, n (%)

19 (0.8)

96 (2.2)

Subarachnoid hemorrhage, n (%)

5 (0.22)

2 (0.05)

7 (0.11)

Palpable skull fracture, n (%)

8 (0.4)

Contusion, n (%)

3 (0.13)

1 (0.02)

4 (0.061)

Signs of basilar fracture, n (%)

9 (0.2)

Pneumocephalus, n (%)

0

1 (0.02)

1 (0.015)

Severe injury mechanism, n (%)

359 (16.0)

428 (9.8)

Depressed skull fracture, n (%)

1 (0.04)

2 (0.05)

3 (0.046)

Loss of consciousness, n (%)

99 (2.3)

ciTBI, n (%)

15 (0.67)

8 (0.18)

23 (0.35)

Loss of consciousness >=5 s, n (%)

22 (1.0)

Death, n (%)

0

0

0

Non-frontal hematoma, n (%)

294 (13.1)

Surgery, n (%)

0

0

0

Not acting normally (parent report), n (%)

65 (2.9)

Mechanical ventilation, n (%)

0

0

0

Vomiting, n (%)

332 (7.6)

Admission, n (%)

15 (0.67)

8 (0.18)

23 (0.35)

Severe headache, n (%)

101 (2.3)

Follow-up or CT performed, n (%)

974 (43.5)

2050 (47.1)

3024 (45.9)

IQR, interquartile range; GCS, Glasgow Coma Scale. CT, computed tomography; ciTBI, clinically important traumatic brain injury.

Table 3

Management and incidence of ciTBI in each risk category.

b2 years old (N = 2237)

>=2 years old (N = 4348)

Overall

(N = 6585)

Very low risk Observation before CT

8.7%

4.4%

5.7% (289/5041)

scan

(137/1583)

(152/3458)

CT scan performed

2.0% (31/1583)

2.2% (75/3458)

2.1% (106/5041)

ciTBI

0.13% (2/1583)

0% (0/3458)

0.04% (2/5041)

Intermediate risk Observation before CT

24.1%

27.4%

25.9%

scan (146/607)

(211/770)

(357/1377)

CT scan performed 11.5% (70/607)

23.8%

18.4%

(183/770)

(253/1377)

acceptable value (99.85%), could be acceptable for Japanese physicians who treat children with minor head trauma. Since this kind of consen- sus can differ depending on physicians, institutions, or countries, informing parents about the data from this study may help physicians consider different management strategies depending on the risk of ciTBI versus the risks associated with CT scans.

The CT rate in our study, 7.0% (463/6585), was lower than those in the PECARN study (35.3%) [3] and in the former study in our institution (13.5%) [10]. If all the children classified as intermediate or high risk had undergone CT scans, the estimated CT rate would have been 23.4% (1544/6585) in this study. However, only 18.4% (253/1377) of the chil- dren classified as intermediate risk and 53.9% (104/167) of the children classified as high risk underwent CT scans in this study. The expertise of

ciTBI 1.15% (7/607) 0.65% (5/770) 0.87% (12/1377)

High risk

treating physicians or observations before CT scans may have contrib-

uted to reducing the CT rate [13-15]. As the CT rate was only 7.0% in

Observation before CT scan

CT scan performed

44.7% (21/47)

69.2% (83/120)

62.3% (104/167)

ciTBI

12.77% (6/47)

2.50% (3/120)

5.39% (9/167)

25.5% (12/47) 30.0% (36/120) 28.7% (48/167)

our study, the PECARN rules may not have reduced unnecessary CT scans in the participating centers. As Babl et al. reported, in a setting with a low CT rate, head trauma prediction rules have limited potential to increase diagnostic accuracy and may increase the CT rate [16]. How-

CT, computed tomography; ciTBI, clinically important traumatic brain injury.

Discussion

We conducted this prospective Multicenter cohort study to evaluate the applicability of the PECARN rules for children with minor head trauma in Japan. Our study in a Japanese pediatric population showed a significantly greater NPV, 99.96%, than the preset threshold of 99.85%. The patients with ciTBI who were classified as very low risk were discharged home without any intervention after admission for a few days. The PECARN rules seemed to be safely applicable in Japanese children with minor head trauma.

Validation studies of the PECARN rules have been performed in many countries, although large multicenter studies have been per- formed only in North America and Oceania [3,9]. Our study may be the first large multicenter validation study of the PECARN rules in Asia. The NPV for ciTBI in our study was 99.96% (95%CI: 99.86-100). As the NPVs in the previous validation studies were between 99.96% and 100% [4-8,10], our results showed similar predictive accuracy in Japan. Before conducting this study, we considered the acceptable inci- dence rate of the missed ciTBI in Japan. As long as children do not die or have Neurological sequelae, we agreed that one missed ciTBI case in one thousand was acceptable, but that two missed ciTBI cases in one thou- sand seemed to be too many. Therefore, we believe that the NPV of 99.96% (95%CI: 99.86-100.00), which was greater than the preset

ever, there is a wide range of CT rates depending on the treating physi- cians or facilities in Japan. There is a greater potential reduction in CT use by application of the PECARN rules in the hospitals where the CT rate is relatively high.

Limitations

Our study has several limitations. First, we did not exclude children with the trivial injury mechanism, defined by ground-level falls or walk- ing/running into stationary objects, who were excluded in the original PECARN study [3]. Although the risk of ciTBI in the children with the trivial injury mechanism is low, we observed that ground-level falls could result in Intracranial injury. As there are many children with trau- matic brain injury due to the trivial injury mechanism seen in Japanese EDs, we believed that we should include children with the trivial injury mechanism to enhance generalizability. Second, the incidence of ciTBI in this study, 0.4% (25/6585), was lower than that in our former study, 0.8% (18/2192), for the cohort excluding non-accidental trauma pa- tients [10]. As NPV is dependent on prevalence, low incidence should call for caution in the interpretation of the results of diagnostic tests [17]. However, in this study we tried to verify the safety of the PECARN rules by comparing with the preset threshold. As the lower limit of 95%CI of the NPV in this study was greater than the preset threshold, we believe the PECARN rules were as safe as we expected. Third, only half of the patients had a CT scan performed or had any

Table 4-a

Predictive performance of the PECARN rules for all included children.

b2 years old

>=2 years old

Overall

(N = 2237)

(N = 4348)

(N = 6585)

Sensitivitya

86.67 (59.54-98.34)

100.00 (63.06-100.00)

91.3 (72.0-98.9)

Specificitya

71.15 (69.22-73.02)

79.68 (78.45-80.87)

76.8 (75.8-77.8)

Positive predictive valuea

1.99 (1.06-3.38)

0.90 (0.39-1.76)

1.36 (0.84-2.07)

Negative predictive valuea

99.87 (99.54-99.98)

100.00 (99.89-100.00)

99.96 (99.86-100.00)

a Percentage (95% confidence interval).

Table 4-b

Predictive performance of the PECARN rules for children, excluding trivial mechanism injuries.

b2 years old

>=2 years old

Overall

(N = 1648)

(N = 2717)

(N = 4365)

Sensitivitya

86.67 (59.54-98.34)

100.00 (63.06-100.00)

91.30 (71.96-98.93)

Specificitya

60.75 (58.33-63.13)

67.44 (65.64-69.21)

64.92 (63.48-66.34)

Positive predictive valuea

1.99 (1.06-3.38)

0.90 (0.39-1.76)

1.36 (0.84-2.07)

Negative predictive valuea

99.80 (99.28-99.98)

100.00 (99.80-100.00)

99.93 (99.74-99.99)

a Percentage (95% confidence interval).

kind of follow-up. Although the participating centers were core hospi- tals in each region, there may be missing hospitalizations or CT scans in other neighboring hospitals. As a completely accurate NPV can only be determined with 100% follow-up, there may be some overestima- tion. Finally, our study results may not be generalizable to all popula- tions in Japan, as the physicians in the participating centers were relatively expert in managing pediatric patients.

Conclusions

The PECARN rules seemed to be safely applicable to children with minor head trauma in Japan. Further studies are required to show safety in the hospitals where physicians do not have expertise in managing children.

Declaration of competing interest

The authors have no conflicts of interest to disclose.

Acknowledgement

The authors would like to thank physicians, nurses, and medical as- sistants in the participating centers for logistic support with patient re- cruitment and follow-up. This work was supported by the Foundation for Growth Science (26-44) and MEXT KAKENHI JP16K11436.

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