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Abstract

Background:

Various physical markers have been used to predict outcome of traumatic brain injury in children. However, the utility of metabolic alterations for prognostication has been poorly described. Thus, we aim to correlate arterial blood gas markers and lactate levels with outcomes in children with moderate to severe traumatic brain injury.

Methods:

This is a retrospective cohort study that included all patients <16 years old who presented to the Emergency Department with moderate to severe traumatic brain injury (Glasgow Coma Scale ⩽13). Serial arterial blood gas results and lactate levels in the first five days of admission to a pediatric intensive care unit (PICU) were reviewed. Primary outcome was in-hospital mortality. Secondary outcomes were 28-day ventilator-free and PICU-free days. A stepwise logistic regression analysis in conjunction with receiver operating characteristic analysis were used to identify variables that were associated with in-hospital mortality. Secondary outcomes were analyzed using multiple linear regression.

Results:

Among the 43 patients analyzed, more than half of the patients (60%) had severe traumatic brain injury (Glasgow Coma Scale 8). Twenty-seven of the 43 (65%) patients underwent neurosurgical intervention and overall mortality was 9/43 (20.9%). The worst base excess and lactate levels of Day 2 of PICU stay were found to be most predictive for mortality with maximal area-under-curve (95% confidence interval) of 0.967 (0.906, 1.000). Worst lactate level on day 2 of PICU stay was also found to be associated with ventilator-free days and PICU-free days.

Conclusion:

In children with moderate to severe traumatic brain injury, base excess and lactate on Day 2 of PICU stay were predictors of mortality, duration of mechanical ventilation and length of PICU stay.

Keywords

Traumatic brain injury arterial blood gas lactate

Introduction

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in children.^1,2 The outcome of TBI depends largely on the extent and nature of the primary injury as well as the effectiveness of therapy in limiting secondary brain damage.^3,4 Management of TBI begins in the pre-hospital setting and continues at the Emergency Department (ED) and intensive care unit (ICU), focusing on adequate airway management, oxygenation and ventilation, and maintenance of arterial blood pressure to ensure an optimum cerebral perfusion pressure.^5,6

Previous research demonstrated that lower initial Glasgow Coma Scale (GCS), age younger than two years old, initial hypotension, hypoxia on admission, and features of subarachnoid hemorrhage, diffuse axonal injury and brain swelling on brain imaging are independent predictors of poor outcomes in children with TBI.^7,8 However, the utility of metabolic alterations in prognostication of pediatric TBI is not well described. One previous study found that initial mixed metabolic and respiratory acidosis was a significant predictor for mortality in children with severe TBI.⁹ Other investigators have demonstrated that initial base deficit and lactate levels were independent prognostic factors of mortality in severe pediatric trauma patients but little is known about the utility of these values in cases of pediatric TBI.^10–13

The main aim of this study is to correlate arterial blood gas (ABG) markers and lactate levels with outcomes in children with TBI. We hypothesized that hypoxia, hypocarbia, metabolic acidosis and high lactate levels are associated with increased mortality and longer duration of mechanical ventilation and pediatric intensive care unit (PICU) stay.

Methods

Study design

We conducted a retrospective study in KK Women’s and Children’s Hospital, Singapore. Our hospital is a tertiary pediatric center that has 857 inpatient beds with 24 pediatric surgical/medical high dependency beds and 16 PICU beds. The PICU is a mixed medical–surgical PICU that admits patients from pediatric medicine, pediatric surgery and surgical subspecialties including neurosurgery, cardio-thoracic surgery and orthopedic surgery. Data was collected from the National Trauma Registry and hospital medical records with admission diagnosis of head injury or TBI coded under the International Classification of Diseases. The National Trauma Registry is a nationwide database that collects all relevant data of patients with traumatic injury in Singapore. All patients <16 years of age who presented to the ED over an 11-year period 2003–2013, with moderate to severe TBI (GCS ⩽ 13), were included. Patients were excluded if they were ⩾16 years old, were transferred from other centers in which initial clinical information was not available, were drowsy from other causes (apart from head injury) or had minor head injury with initial GCS.^14–15 Our local institutional review board approved this study without the need for informed consent.

Variables

Medical records were reviewed for demographic characteristics and clinical data including serial ABG results and lactate levels in the first five days of admission to the PICU. Decision to perform ABG analyses was based on the clinical assessment of the patient and the clinical judgment of the intensive care team. The ABG markers that were examined were partial pressure of oxygen (pO₂), partial pressure of carbon dioxide (pCO₂), pH and base excess. A pO₂ <80mmHg was defined as hypoxia. Normal range of pCO₂ was defined as 35–45 mmHg. Hypocarbia was defined as pCO₂ <35mmHg. Data on pH, base excess and lactate level in the first five days of PICU stay were collected. Degree of change in base excess and lactate was also calculated based on the difference between the worst value on the day of PICU stay and the first value on admission to PICU.

Outcome measures

Our primary outcome of interest was in-hospital mortality, and secondary outcomes were 28-day ventilator-free and PICU-free days. Ventilator-free days were defined as days alive and free from mechanical ventilation up to 28 days after intubation. Patients who died before day 28 while receiving mechanical ventilation were assigned zero ventilator-free days. PICU-free days were defined as days alive and discharged from the PICU up to 28 days. Patients who died within 28 days of PICU admission were assigned zero PICU-free days. In our PICU, there is no strict protocol for extubation or transfer. Plan for extubation or transfer out of PICU is agreed upon by the primary intensive care team and the attending neurosurgeon. Patients are generally extubated when positive end expiratory pressure is 5, fraction of inspired oxygen is < 30% and they are able to tolerate spontaneous mode of ventilation for one to two hours with good respiratory effort and satisfactory ABG. We also ensure that patients demonstrate good cough or gag reflex before extubation.

Statistical methods

Data were summarized and reported in the following way: continuous variables were presented as mean±standard deviation (SD) or median (interquartile ranges (IQRs)) as appropriate for their pattern of distribution; while binary or categorical data were presented as frequencies and percentages. For each PICU day, univariate logistic regression was used to identify predictors significant at p <0.05 for inclusion in a stepwise logistic regression analysis in conjunction with receiver operating characteristic (ROC) analysis. Variables significant at p <0.10 in the stepwise regression were entered sequentially into a multivariable model to assess contribution to area under the ROC curve (AUC). All variables were regressed on ventilator-free days and PICU-free days in a multiple regression assuming a log-normal error distribution. Statistical analysis was performed using SAS version 9.4 (SAS Inc., Cary, NC, USA). All statistical tests of significance were two-tailed and p <0.05 was considered as statistically significant.

Results

Patient characteristics

Forty-three patients fulfilled our inclusion criteria (Table 1). Mean age of all the patients was 7.7±4.2 years. Road traffic accidents (22/43 (51.1%)) and falls (17/43 (39.5%)) were the most common causes of injury. Eleven (25.6%) patients had polytrauma. These polytrauma patients suffered from intra-thoracic injuries and/or long bone fractures. The intra-thoracic injuries included pneumothorax, pneumohemothorax, mediastinal hematoma and lung contusion. The types of long bone fracture included femur, tibia, fibula, pelvic and radial fractures. Twenty-six (60.5%) patients had severe TBI with GCS ⩽8. There were significantly more patients with GCS ⩽ 8 at the ED who did not survive (p=0.006). There is also a difference in mean duration of mechanical ventilation and PICU stay between GCS >8 and GCS ⩽8 at the ED (p <0.001 and p <0.001 respectively). Thirty-eight of the 43 (88.3%) patients were intubated. In our study population, 21 (48.9%) had hemodynamic instability at the ED requiring inotropes and nine (20.9%) required cardiopulmonary resuscitation. The majority (27/43 (62.8%)) of patients underwent neurosurgical intervention: 11/43 patients (25.6%) underwent craniotomy and evacuation of hematoma (two subdural hematoma, seven epidural hematoma and two mixed hematoma), and 16/43 patients (37.2%) had insertion of external ventricular drain. Two patients (4.7%) underwent cooling to 35–36°C for three and four days respectively. Twenty-three of the 43 patients (53.4%) received intracranial pressure (ICP) monitoring. The decision for ICP monitoring was based on the treating neurosurgeon and pediatric intensivist. Overall mean ICP in our cohort was 21.8±17.3 mmHg and mean cerebral perfusion pressure was 58.2±20.8 mmHg. Overall mortality was 9/43 (20.9%).

Table 1.

Baseline clinical demographics.

	All patients(N=43)	Survivors(n=34)	Non-survivors(n=9)	p-value
Age, years, mean ± SD	7.7 ± 4.2	8.1 ± 3.9	6.3 ± 5.8	0.249
Gender, n (%)
Male	26 (61)	20 (59)	6 (67)	0.669
Female	17 (39)	14 (41)	3 (33)
Mechanism of injury, n (%)
RTA	22 (51)	18 (53)	4 (44)	0.521
Fall	17 (40)	14 (33)	3 (33)
NAI	2 (5)	1 (3)	1 (11)
Others	2 (5)	1 (3)	1 (11)
Presence of polytrauma, n (%)	11 (26)	9 (26)	2 (22)	0.795
Intrathoracic injury	5	4	1
Long bone fracture	8	6	2
GCS at ED, n (%)
GCS>8	17 (40)	17 (50)	0	0.006*
GCS⩽8	26 (60)	17 (50)	9 (100)
Cardiovascular intervention at ED, n (%)
Inotrope	21 (49)	15 (44)	6 (67)	0.229
CPR	9 (21)	1 (3)	8 (89)	0.301
Intracranial pathology, n (%)
None	5 (12)	4 (12)	1 (11)	0.024
SDH	6 (14)	4 (12)	2 (22)
SAH	3 (7)	0	3 (33)
DAI	3 (7)	3 (9)	0
EDH	5 (12)	5 (15)	0
Skull fracture	7 (16)	6 (18)	1 (11)
Mixed	14 (33)	12 (35)	2 (22)
Neurosurgical intervention done, n (%)
Craniotomy and hematoma evacuation	11(26)	11 (32)	0	0.100
SDH	2	2
EDH	7	7
Mixed	2	2
EVD insertion	16 (37)	11 (32)	5 (56)
Mean ICP ± SD, mmHg	21.8 ± 17.3	16.2 ± 8.6	42.7 ± 25.7	0.085
Mean CPP ± SD, mmHg	58.2 ± 20.8	62.1 ± 13.8	44.3 ± 35.6	0.091

CPP: cerebral perfusion pressure; CPR: cardiopulmonary resuscitation; DAI: diffuse axonal injury; ED: Emergency Department; EDH: extradural hemorrhage; EVD: external ventricular drain; GCS: Glasgow Coma Score; ICP: intracranial pressure; NAI: non-accidental injury; RTA: road traffic accident; SAH: subarachnoid hemorrhage; SD: standard deviation; SDH: subdural hemorrhage; *p-value < 0.05.

Primary outcome: mortality

An initial univariate logistic regression analysis was performed to investigate worst pO₂, pCO₂, pH, base excess and lactate levels as predictors of mortality during the first five days of PICU stay. Variables exhibiting significance at p <0.05 in univariate analysis were base excess, lactate and pH. Stepwise logistic regression selected worst base excess and lactate levels on day 2 as the risk factors most prognostic of mortality (Table 2). This was confirmed by a multivariable sequential analysis that showed maximal AUC (95% confidence interval) of 0.967 (0.906, 1.000) was achieved on day 2 of PICU using worst base excess and lactate levels as predictors, with no incremental benefit from pH (Figure 1, Table 2). The linear predictor obtained from the final logistic regression model was Y = −7.6477 to 0.6929∙X₁ + 0.8563∙X₂, where X₁ = day 2 worst base excess and X₂ = day 2 worst lactate. Hence, the predicted probability of PICU mortality for a given patient can be calculated as e^Y/ (1 + e^Y) where e is the base of the natural logarithm.

Table 2.

Summary of logistic regression analyses by PICU day.

PICU day	Candidate variable	Univariate		Order stepwise selection and p-value	Multivariate sequential
PICU day	Candidate variable	p-value	AUC	Order stepwise selection and p-value	Variables	p-values	AUC
1	Base excess	0.017	0.756	(1) 0.0387	BE	0.023	0.756
	Lactate	0.041	0.750	NS	BE, lactate	0.237, 0.345	0.792
	pH	0.022	0.794	NS	BE, lactate, pH	0.505, 0.374, 0.919	0.792
2	Base excess	0.025	0.844	(1) 0.0595	BE	0.026	0.844
	Lactate	0.010	0.896	(2) 0.0644	BE, lactate^a	0.058, 0.073	0.967
	pH	0.016	0.875	NS	BE, lactate, pH	0.210, 0.075, 0.626	0.967
3	Base excess	0.035	0.795	NS	BE	0.048,	0.795
	Lactate	0.032	0.889	(1) 0.0318	BE, lactate	0.262, 0.076	0.907
	pH	0.027	0.869	NS	BE, lactate, pH	0.304, 0.114, 0.948	0.907

Predictors of PICU mortality for the final model were PICU day 2 BE and lactate.

AUC: area under the receiver operating characteristic curve; BE: base excess; NS: not selected; PICU: pediatric intensive care unit.

Figure 1.

ROC curves for comparison between base excess on day 2 and base excess and lactate on day 2.

Secondary outcomes: duration of mechanical ventilation and length of PICU stay

In our study cohort, median ventilator-free and PICU-free durations were 22.0 (IQR: 13.0–26.0) and 21.0 (IQR: 10.5–25.0) days respectively. There was no statistically significant association between worst pO₂, pCO₂, pH or base excess with duration of mechanical ventilation or PICU stay for any given day of PICU stay. When we examined the association between lactate level on day 2 of PICU stay and ventilator-free days and PICU-free days, two outliers were identified. These two patients had initial GCS of 5: one of them had diffuse axonal injury, intraventricular hemorrhage and cerebral edema; the other had extradural hemorrhage and subdural hemorrhage with mass effect and midline shift complicated by persistent intracranial hypertension resulting in prolonged ventilation and requiring tracheostomy. When the two outliers were removed, worst lactate level on day 2 of PICU stay was significantly associated with ventilator-free days (R² = 0.52, p=0.002 ) and PICU-free days (R²=0.57, p=0.001) (Figures 2 and 3).

Figure 2.

Correlation of worst lactate on day 2 of pediatric intensive care unit stay with ventilator-free days. Solid circles represent outliers.

Figure 3.

Correlation of worst lactate on day 2 of PICU stay with PICU-free days. Solid circles represent outliers.

Discussion

The findings of this retrospective study shed light on the utility of ABG markers and lactate levels in prognostication of children with moderate to severe TBI. In this study, we demonstrated that initial base excess and lactate levels reflected injury severity and predicted mortality. Initial high lactate levels were also associated with longer duration of mechanical ventilation and PICU stay.

Head trauma and risk factors of mortality following severe TBI in adults have been studied extensively but such studies in pediatric patients are less common.^14–19 A single center prospective study on 63 adults demonstrated that patients with severe head trauma showed an early trend towards hypercarbia and acidosis, and that immediate control of airway and assisted ventilation was necessary to reduce pCO₂ levels to optimal levels in patients with severe TBI.²⁰ On the other hand, a prospective, randomized controlled trial on 113 patients found that there were significantly lower numbers of patients with favorable outcome at three and six months after injury in the hyperventilated group (pCO₂ 25 ± 2mmHg) than in the control group (pCO₂ 35 ± 2mmHg), suggesting that prophylactic hyperventilation may be deleterious in severely head-injured patients.²¹ A recent review evaluating prevalence and effect of hypocarbia in the management of patients with TBI showed that hypocarbia may cause more harm than benefit.²² In a large retrospective cohort pediatric study, it was shown that the mortality-adjusted odds ratio increased with increasing episodes of severe hypocarbia (pCO₂< 30mmHg).²³ Since then, the traditional approach of reducing pCO₂ <30mmHg has been abandoned by most centers except for emergent lowering of ICP for short periods. It is now recognized that hyperventilation reduces ICP through cerebral vasoconstriction, which will result in further decrease in cerebral blood flow and worsen ischemia.^24–26 In our study cohort, we did not find a significant association in pCO₂ with mortality, duration of mechanical ventilation or length of PICU stay.

Severe TBI profoundly disturbs cerebral acid-base homeostasis and brain tissue acidosis can cause further neural death.²⁷ Secondary insult to the brain such as acidosis exacerbates cerebral edema and further increases risk of mortality and morbidity.²⁷ To date, very few data are available on the effect of arterial acid-base imbalances on clinical outcomes in TBI, even less so in cases of pediatric TBI. Adult studies have demonstrated that initial base excess and blood lactate reflected injury severity and predicted mortality in trauma patients.^19,28-35 Some retrospective and prospective studies performed in northern America and Europe consisting of 267 pediatric patients in total had demonstrated that base excess and lactate were independent prognostic factors of mortality in severe pediatric trauma patients.^10–12 A recent prospective study on 277 children with trauma (23.1% TBI) found that a lactate of over 4.7mmol/l was strongly suggestive of severe injury.¹³ However, in these studies, no separate analysis was done on those with TBI alone. Our findings in pediatric patients with moderate to severe TBI were similar to the previously published studies on pediatric trauma patients: the worse the metabolic acidosis, the higher the mortality.

A retrospective study on 81 adults with TBI found metabolic acidosis and hypoxia to be associated with longer duration of ICU and hospital stay.³⁴ A large retrospective review of 2269 adults with non-penetrating trauma (Injury Severity Score ⩾12) found a correlation between admission lactate and base excess values with length of hospital stay³⁵ while another large retrospective review of 1298 adults on a surgical ICU (1026 trauma patients) found that increased lactate levels predicted an increase in length of hospital stay regardless of the base excess levels.³⁶ One retrospective study on 65 pediatric trauma patients consisting of 33 (50.8%) patients with TBI concluded that those with severe acidosis (base excess ⩽ –5) had longer length of ICU stay but not length of hospital stay.¹¹ In our study, we found that lactate levels on day 2 of PICU stay correlated significantly with duration of mechanical ventilation and PICU stay. This finding is an interesting one as, to our knowledge, no previous study has examined lactate level with clinical outcome of duration of mechanical ventilation.

Evidence on effect of arterial pH in outcomes of TBI has been scarce and results have been conflicting. Some early animal and human studies suggested that increase in cerebral blood flow could be contributed by a drop in arterial pH.^37,38 However, other studies have reported that arterial pH had little or no effect on cerebral hemodynamics.^39–41 In our study with multivariable sequential analysis, it was found that pH had no incremental benefit as predictor for mortality. We postulate that since base excess and lactate levels contribute to acidosis, pH is not an independent prognostic factor.

Even though we have found that worse base excess and higher lactate levels are associated with poorer outcomes, it is unclear whether these factors were due to the nature of the disease or affected by factors in the post-injury phase. A subgroup analysis excluding patients with polytrauma could not be performed due to the small numbers. What this study does suggest is that early severe metabolic acidosis identifies head-injured patients with increased risk of mortality and morbidity. This may allow for appropriate counseling to caregivers.

We acknowledge that our study is limited by a small study population. Given the long span of the review, we also recognize that the absence of a uniform algorithm for TBI may have resulted in difference in management strategies even though our institution generally followed guidelines for acute medical management of severe traumatic brain injury in infants, children and adolescents.^42,43 In our study it was also not possible to delineate the exact cause of mortality, and the need for prolonged ventilator support or ICU stay. We also acknowledge the fact that measurements of blood gases may be influenced by changes in body temperature but only two patients underwent cooling. Besides, recent large studies showed no evidence for cooling.^44,45 Lastly, we did not have long-term outcomes for our cohort of survivors. Recently, the IMPACT study suggested that lower pH was associated with poorer six-month Glasgow Outcome Scale.¹⁵ In a retrospective study on 83 children with moderate to severe TBI, it was found that longer duration of ICU stay was predictive of lower nonverbal intelligence.⁴⁶ Thus, in addition to mortality and duration of mechanical ventilation and PICU stay, further studies looking at long-term functional performance should also be examined amongst the survivors of moderate to severe pediatric TBI.

Conclusion

Our study demonstrated that worse base excess and higher lactate levels on day 2 of PICU stay are potential predictors of mortality in children with moderate to severe TBI. A higher lactate level on day 2 of PICU stay is also a potential prognostic factor for duration of mechanical ventilation and length of PICU stay in this group of pediatric patients.

Footnotes

Acknowledgements

The authors thank Dr Yeo Joo Guan and Miss Jasmine Feng for their assistance in this study. Authors’ contributions: NZM carried out design of the study, collected data and drafted the manuscript. HWJ carried out the acquisition of data. JA performed the statistical analysis and drafted the manuscript. CSL, LLE and LCYD participated in design of the study and drafted the manuscript. LJH conceived the study design, coordinated the study and drafted the manuscript. All authors read and approved the final manuscript.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Correlation of arterial blood gas markers and lactate levels with outcomes in pediatric traumatic brain injury

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Study design

Variables

Outcome measures

Statistical methods

Results

Patient characteristics

Primary outcome: mortality

Secondary outcomes: duration of mechanical ventilation and length of PICU stay

Discussion

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References