Invasive brain tissue oxygen and intracranial pressure (ICP) monitoring versus ICP-only monitoring in pediatric severe traumatic brain injury

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  • 1 Division of Neurosurgery, Children’s Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
  • | 2 Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Pennsylvania;
  • | 3 Department of Chemistry, Union College, Schenectady, New York;
  • | 4 Department of Physical Medicine and Rehabilitation and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
  • | 5 Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and
  • | 6 Department of Radiology and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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OBJECTIVE

Severe traumatic brain injury (TBI) is a leading cause of disability and death in the pediatric population. While intracranial pressure (ICP) monitoring is the gold standard in acute neurocritical care following pediatric severe TBI, brain tissue oxygen tension (PbtO2) monitoring may also help limit secondary brain injury and improve outcomes. The authors hypothesized that pediatric patients with severe TBI and ICP + PbtO2 monitoring and treatment would have better outcomes than those who underwent ICP-only monitoring and treatment.

METHODS

Patients ≤ 18 years of age with severe TBI who received ICP ± PbtO2 monitoring at a quaternary children’s hospital between 1998 and 2021 were retrospectively reviewed. The relationships between conventional measurements of TBI were evaluated, i.e., ICP, cerebral perfusion pressure (CPP), and PbtO2. Differences were analyzed between patients with ICP + PbtO2 versus ICP-only monitoring on hospital and pediatric intensive care unit (PICU) length of stay (LOS), length of intubation, Pediatric Intensity Level of Therapy scale score, and functional outcome using the Glasgow Outcome Score–Extended (GOS-E) scale at 6 months postinjury.

RESULTS

Forty-nine patients, including 19 with ICP + PbtO2 and 30 with ICP only, were analyzed. There was a weak negative association between ICP and PbtO2 (β = −0.04). Conversely, there was a strong positive correlation between CPP ≥ 40 mm Hg and PbtO2 ≥ 15 and ≥ 20 mm Hg (β = 0.30 and β = 0.29, p < 0.001, respectively). An increased number of events of cerebral PbtO2 < 15 mm Hg or < 20 mm Hg were associated with longer hospital (p = 0.01 and p = 0.022, respectively) and PICU (p = 0.015 and p = 0.007, respectively) LOS, increased duration of mechanical ventilation (p = 0.015 when PbtO2 < 15 mm Hg), and an unfavorable 6-month GOS-E score (p = 0.045 and p = 0.022, respectively). An increased number of intracranial hypertension episodes (ICP ≥ 20 mm Hg) were associated with longer hospital (p = 0.007) and PICU (p < 0.001) LOS and longer duration of mechanical ventilation (p < 0.001). Lower minimum hourly and average daily ICP values predicted favorable GOS-E scores (p < 0.001 for both). Patients with ICP + PbtO2 monitoring experienced longer PICU LOS (p = 0.018) compared to patients with ICP-only monitoring, with no significant GOS-E score difference between groups (p = 0.733).

CONCLUSIONS

An increased number of cerebral hypoxic episodes and an increased number of intracranial hypertension episodes resulted in longer hospital LOS and longer duration of mechanical ventilator support. An increased number of cerebral hypoxic episodes also correlated with less favorable functional outcomes. In contrast, lower minimum hourly and average daily ICP values, but not the number of intracranial hypertension episodes, were associated with more favorable functional outcomes. There was a weak correlation between ICP and PbtO2, supporting the importance of multimodal invasive neuromonitoring in pediatric severe TBI.

ABBREVIATIONS

BOOST-II = Brain Tissue Oxygen Monitoring and Management in Severe Traumatic Brain Injury; CPP = cerebral perfusion pressure; FiO2 = fraction of inspired oxygen; GCS = Glasgow Coma Scale; GOS-E = Glasgow Outcome Score–Extended; ICP = intracranial pressure; LOS = length of stay; MAP = mean arterial pressure; PbtO2 = brain tissue oxygen tension; PEEP = positive end-expiratory pressure; PICU = pediatric intensive care unit; PILOT = Pediatric Intensity Level of Therapy; TBI = traumatic brain injury.

OBJECTIVE

Severe traumatic brain injury (TBI) is a leading cause of disability and death in the pediatric population. While intracranial pressure (ICP) monitoring is the gold standard in acute neurocritical care following pediatric severe TBI, brain tissue oxygen tension (PbtO2) monitoring may also help limit secondary brain injury and improve outcomes. The authors hypothesized that pediatric patients with severe TBI and ICP + PbtO2 monitoring and treatment would have better outcomes than those who underwent ICP-only monitoring and treatment.

METHODS

Patients ≤ 18 years of age with severe TBI who received ICP ± PbtO2 monitoring at a quaternary children’s hospital between 1998 and 2021 were retrospectively reviewed. The relationships between conventional measurements of TBI were evaluated, i.e., ICP, cerebral perfusion pressure (CPP), and PbtO2. Differences were analyzed between patients with ICP + PbtO2 versus ICP-only monitoring on hospital and pediatric intensive care unit (PICU) length of stay (LOS), length of intubation, Pediatric Intensity Level of Therapy scale score, and functional outcome using the Glasgow Outcome Score–Extended (GOS-E) scale at 6 months postinjury.

RESULTS

Forty-nine patients, including 19 with ICP + PbtO2 and 30 with ICP only, were analyzed. There was a weak negative association between ICP and PbtO2 (β = −0.04). Conversely, there was a strong positive correlation between CPP ≥ 40 mm Hg and PbtO2 ≥ 15 and ≥ 20 mm Hg (β = 0.30 and β = 0.29, p < 0.001, respectively). An increased number of events of cerebral PbtO2 < 15 mm Hg or < 20 mm Hg were associated with longer hospital (p = 0.01 and p = 0.022, respectively) and PICU (p = 0.015 and p = 0.007, respectively) LOS, increased duration of mechanical ventilation (p = 0.015 when PbtO2 < 15 mm Hg), and an unfavorable 6-month GOS-E score (p = 0.045 and p = 0.022, respectively). An increased number of intracranial hypertension episodes (ICP ≥ 20 mm Hg) were associated with longer hospital (p = 0.007) and PICU (p < 0.001) LOS and longer duration of mechanical ventilation (p < 0.001). Lower minimum hourly and average daily ICP values predicted favorable GOS-E scores (p < 0.001 for both). Patients with ICP + PbtO2 monitoring experienced longer PICU LOS (p = 0.018) compared to patients with ICP-only monitoring, with no significant GOS-E score difference between groups (p = 0.733).

CONCLUSIONS

An increased number of cerebral hypoxic episodes and an increased number of intracranial hypertension episodes resulted in longer hospital LOS and longer duration of mechanical ventilator support. An increased number of cerebral hypoxic episodes also correlated with less favorable functional outcomes. In contrast, lower minimum hourly and average daily ICP values, but not the number of intracranial hypertension episodes, were associated with more favorable functional outcomes. There was a weak correlation between ICP and PbtO2, supporting the importance of multimodal invasive neuromonitoring in pediatric severe TBI.

In Brief

There are limited data on brain tissue oxygen tension (PbtO2) monitoring and management in pediatric severe traumatic brain injury. This retrospective, single-institution study compares functional outcomes between patients who received intracranial pressure (ICP)–only versus ICP + PbtO2 monitoring. The findings reveal that ICP and PbtO2 are weakly correlated and independently affect functional outcomes, supporting the use of both invasive neuromonitoring techniques.

Traumatic brain injury (TBI) is a leading cause of morbidity and death in the worldwide pediatric population.1 More than 600,000 children require medical attention due to TBI each year in the United States.2 Patients with severe TBI are especially at risk for developing intracranial hypertension. Prior studies have shown that treating elevated intracranial pressure (ICP) is associated with improved outcomes, making invasive ICP monitoring and ICP-guided therapy a standard of care in adult and pediatric populations with severe TBI.38 Despite this standard, cerebral ischemia as determined by low brain oxygen values may still occur despite ICP-directed treatment.913

Because brain hypoxia may have a more direct impact on tissue viability compared to intracranial hypertension, brain tissue oxygen tension (PbtO2) monitoring has been introduced and evaluated as an additional form of patient-specific therapy, primarily in the adult population with severe TBI. The Brain Tissue Oxygen Monitoring and Management in Severe Traumatic Brain Injury (BOOST-II) randomized control trial, in addition to other studies, has examined primarily adult patients with severe TBI using ICP and PbtO2 monitoring and revealed improved outcomes and reduced mortality rates.1418 The current BOOST-III trial enrolls patients 14 years of age and older (ClinicalTrials.gov identifier: NCT03754114). Similar randomized controlled trials evaluating the addition of PbtO2 on patient outcomes have not been conducted in the pediatric TBI population. Most pediatric studies have evaluated the safety of PbtO2 monitoring and the relationship between PbtO2 and conventional parameters, such as ICP and cerebral perfusion pressure (CPP).1922 One of the goals of the Approaches and Decisions for Acute Pediatric TBI (ADAPT) trial, a multinational cohort study of 1000 children with severe TBI, was to evaluate the efficacy of PbtO2 monitoring.23 Almost all of the studies that have been conducted in the pediatric population have found that direct brain oxygen monitoring in children was a safe and useful adjunct to ICP monitoring, as PbtO2 values revealed additional information about the viability of brain tissue.1922,24,25 Single-institution studies have also shown that reduced PbtO2 was strongly associated with poorer functional and neuropsychological outcomes after pediatric severe TBI.21,26,27

Given the inconsistent use of PbtO2 monitoring across institutions, there is a need to better understand the risks and benefits of PbtO2 monitoring in the treatment of pediatric severe TBI.2830 The primary objective of the current study was to analyze two cohorts of a pediatric severe TBI population at a single quaternary children’s hospital, one group with invasive ICP + PbtO2 monitoring and treatment and the other with invasive ICP-only monitoring and treatment, to evaluate whether there was a difference in outcome at 6 months postinjury using the Glasgow Outcome Scale–Extended (GOS-E).31 Our secondary objective was to analyze whether cerebral hypoxic episodes and intracranial hypertension episodes correlated with this GOS-E outcome. The third objective was to determine if there were differences between these two groups in hospital length of stay (LOS), pediatric intensive care unit (PICU) LOS, duration of mechanical ventilation (intubation), and extent of ICP-directed therapy, as calculated by the Pediatric Intensity Level of Therapy (PILOT) scale score.32 Our main hypothesis was that the cohort of pediatric patients who received ICP + PbtO2 monitoring and treatment would have more favorable GOS-E scores. Our secondary hypothesis was that lower overall PbtO2 levels, increased number of cerebral hypoxic episodes, higher overall ICP values, and increased number of intracranial hypertension episodes would correlate with less favorable outcomes. Our third hypothesis was that those who received ICP + PbtO2 monitoring and treatment would have a decreased hospital and PICU LOS, decreased duration of mechanical ventilation, and decreased extent of ICP-directed therapy compared to patients who received ICP-only monitoring and treatment.

Methods

Patient Population

Pediatric patients were retrospectively reviewed in a single-center quaternary pediatric hospital between 1998 and 2021. Inclusion criteria included age ≤ 18 years, accidental severe TBI with Glasgow Coma Scale (GCS) score ≤ 8, and the presence of a Camino intraparenchymal ICP monitoring device (Camino, Integra NeuroSciences) and/or a Licox PbtO2 dual-lumen monitoring system (Integra NeuroSciences). Exclusion criteria included penetrating or abusive head trauma, fixed and dilated pupils upon admission, and cardiac arrest before or during the hospital admission. The IRB of Children’s Hospital of Philadelphia approved the study.

Management of Pediatric Severe TBI

Initial neurocritical care management included placing the patient supine with the head of the bed elevated at 30° and providing adequate oxygenation from intubation and mechanical ventilation with a goal of normocarbia. An intracranial hypertension episode was defined as sustained ICP ≥ 20 mm Hg for ≥ 5 minutes. To achieve an ICP goal < 20 mm Hg, patients received sedation and/or analgesia medications, hyperosmolar therapy, and a neuromuscular blockade as needed. Phenylephrine, epinephrine, and dopamine were used as needed to increase mean arterial pressure (MAP) to maintain minimum age–dependent CPP at 40–65 mm Hg. Decompressive hemicraniectomy was considered for refractory elevated ICP despite maximal medical management. PILOT scores were calculated to assess the extent of therapeutic intensity required for ICP management. Our treatment protocol was consistent with the "Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents."7,33

For patients with PbtO2 monitoring, the PbtO2 goal was ≥ 15 mm Hg based on a small number of pediatric TBI studies and a larger number of adult TBI studies that demonstrated unfavorable outcomes with lower PbtO2.10,17,21,22,29 PbtO2 < 15 mm Hg was treated with an initial increase in fraction of inspired oxygen (FiO2) and other maneuvers to promote oxygen delivery, such as an increase in positive end-expiratory pressure (PEEP), intravenous isotonic fluid bolus or vasopressor support to augment CPP, packed red blood cell transfusion for anemia, and increases in arterial CO2, with adjustments of mechanical ventilator support as long as there was no intracranial hypertension. Mechanisms to decrease metabolic demand for oxygen consumption, such as sedation, analgesia, neuromuscular blockade, or seizure treatment and prophylaxis, were also used to increase PbtO2.

Of note, many of the treatments used to decrease ICP are also indicated in the setting of low PbtO2, such as sedation, analgesia, and neuromuscular blockade. Thus, in the scenario with high ICP and low PbtO2, the same therapies helped improve both measures. In situations of ICP and PbtO2 discordance (i.e., high ICP and high PbtO2 or low ICP and low PbtO2), treatments were provided to either lower the ICP or increase the PbtO2, while monitoring and addressing changes in the other modality if they arose. In one case, a 15-year-old female presenting with loss of consciousness after a motor vehicle accident initially experienced increased ICP in the range of 30–40 mm Hg, which prompted clinicians to focus their treatment on sedation, analgesia, neuromuscular blockade, and hyperosmolar therapy to reduce the elevated ICP. Even during episodes when ICP was refractory to medical management, PbtO2 values remained within the appropriate range. This metric and the patient’s stable imaging findings over time provided objective evidence for the clinicians to appropriately discontinue hyperosmolar therapy with hypertonic saline due to severe hypernatremia, knowing there were no signs of cerebral ischemia. The patient’s ICP eventually normalized. In another case, an 8-year-old male presenting after a pedestrian versus motor vehicle collision initially had low PbtO2 and normal ICP. Thus, treatment centered on increasing cerebral oxygenation. While the patient was on mechanical ventilator support, FiO2 was increased and packed red blood cells were administered to increase oxygen-carrying capacity and delivery. However, the ICP eventually increased into the range of 40–50 mm Hg. Hypertonic saline, sedation, analgesia, a neuromuscular blockade, and pentobarbital were administered to help decrease ICP. Because of the continued poor PbtO2, FiO2 was kept at a higher percentage of 55% with an increase in PEEP on mechanical ventilator support. An epinephrine infusion was needed to maintain adequate MAP and CPP due to the increase in ICP. This increase in CPP improved PbtO2 and eventually decreased ICP.

Our institution has a protocol for pediatric severe TBI, including the recommendation to place an invasive monitor for GCS scores ≤ 8. Children were selected to receive dual ICP + PbtO2 monitoring versus ICP-only monitoring based on pediatric neurosurgeon familiarity with the PbtO2 monitoring device. Increased injury severity was not an indication for PbtO2 monitoring. Prior to 2005, PbtO2 monitoring was not available at this institution; therefore, pediatric patients admitted prior to this time frame would have only ICP data.

Data Variables

Hourly ICP, CPP, and PbtO2 were analyzed to calculate the minimum hourly and average hourly values over a 24-hour period, which is equivalent to weighted average daily values. To account for some missing data and be inclusive of all patients’ average daily measurements, we used weighted mean values. The number of intracranial hypertension episodes (ICP ≥ 20 mm Hg, > 25 mm Hg, and > 30 mm Hg lasting for ≥ 5 minutes), the number of episodes of low CPP < 40 mm Hg, and the number of brain hypoxic episodes (PbtO2 < 15 mm Hg and < 20 mm Hg) were calculated. The first 2 hours of ICP, CPP, and PbtO2 recordings were excluded from analysis, due to potential inaccuracy innate to initial probe placement. A Marshall score, which categorizes brain injury by severity based on the admission CT scan, was analyzed by a pediatric neuroradiologist (S.S.) who was blinded to patient history and outcomes.34

Outcome Variables

The Glasgow Outcome Score–Extended (GOS-E), which categorizes patient outcome after TBI according to level of function, was calculated by a blinded pediatric rehabilitation physician (C.T.K.) at 6 months posthospital admission.31 This scale ranges in score from 1 to 8, in which 1 represents death and 8 indicates normal or near-normal function without disabling deficits. GOS-E scores of 7–8 were categorized as favorable outcomes and scores of 1–6 as unfavorable. We also calculated hospital and PICU LOS, duration of mechanical ventilation, and PILOT scores, a measure of the use of ICP-directed therapies, for the first 6 days after TBI.32

Statistical Analysis

In the group that received both ICP + PbtO2 monitoring, a partial Spearman’s correlation with sex and age adjustment was used to analyze the relationship between PbtO2 and clinical outcomes. Longitudinally, average daily PbtO2 change over time was assessed by a linear mixed-effects model with subject-specific random intercepts and random slopes. The relationship between physiological variables of ICP + PbtO2 was analyzed using linear regression. To compare outcomes between the ICP-only group and the ICP + PbtO2 group, a Student t-test, Wilcoxon rank-sum test, or Fisher’s exact test was used. ICP was analyzed in relation to outcomes using partial Pearson’s correlation with sex and age adjustment. The weighted daily ICP and/or PbtO2 mean is calculated by multiplying the weight (the ratio of the number of measurement hours in 1 day to the total number of measurement hours over all study days) associated with the daily ICP and/or PbtO2 arithmetic mean and then summing all the products together.

Results

Patient Characteristics

ICP ± PbtO2 measurements were recorded in a total of 73 pediatric patients, using either invasive fiber-optic ICP ± PbtO2 probes or external ventricular devices. Of these 73 patients, 62 received invasive intraparenchymal ICP ± PbtO2 monitors, as opposed to external ventricular drains. From these 62 patients, 13 were excluded based on their mechanism of trauma (such as gunshot wound or abusive head trauma) or cardiac arrest before or during treatment. As a result, 49 of these patients were included in this study (Table 1). Thirty patients with a mean age of 7.4 years were analyzed in the ICP-only group. Nineteen patients with a mean age of 12.2 years were analyzed in the ICP + PbtO2 group.

TABLE 1.

Patient demographic, invasive monitoring, and imaging findings

CharacteristicICP + PbtO2 Group, n = 19ICP-Only Group, n = 30p Value
Demographic variables
 Sex, n (%)
  Male15 (78.95)24 (80.00)
  Female4 (21.05)6 (20.00)1.000
 Mean age at PICU admission (SD), yrs12.21 (4.81)7.37 (4.73)<0.001
 Mean body weight (SD), kg45.24 (20.47)28.82 (20.03)0.006
 Race, n (%)
  White8 (42.11)14 (46.67)
  Asian2 (10.53)1 (3.33)
  Black6 (31.58)8 (26.67)
  Other3 (15.79)7 (23.33)0.713
Clinical/CT variables at baseline
 Median GCS score (IQR)3 (3–3)3 (3–3)0.457
 CT categorization, n (%)
  Subdural2 (10.53)7 (23.33)
  Intraparenchymal11 (57.89)8 (26.67)
  Subdural + intraparenchymal1 (5.26)7 (23.33)
  Subdural + epidural + intraparenchymal2 (10.53)0 (0.00)
  All other combinations3 (15.79)8 (26.67)0.041
 Mean duration of monitoring (SD), days8.16 (3.59)7.80 (2.83)0.698
 Mean PbtO2 measurements over course (SD), mm Hg
  Minimum hourly PbtO212.41 (6.28)
  Average daily PbtO2*23.20 (8.33)
  No. of episodes PbtO2 <158.84 (21.98)
  No. of episodes PbtO2 <2015.42 (23.94)
 Mean ICP measurements over course (SD), mm Hg
  Minimum hourly ICP5.37 (3.64)7.63 (10.35)0.360
  Average daily ICP*13.35 (4.54)18.79 (14.77)0.120
  No. of episodes of ICP >2018.21 (37.9)15.07 (20.17)0.705
 Mean CPP measurements over course (SD), mm Hg
  Minimum hourly CPP46.96 (9.64)40.18 (15.17)0.083
  Average daily CPP*68.24 (8.13)64.11 (14.78)0.265
  No. of episodes of CPP <400.63 (1.5)5.4 (15.15)0.173
 Surgery, n (%)
  No surgery12 (63.16)26 (86.67)
  EVD2 (10.53)1 (3.33)
  DHC2 (10.53)2 (6.67)
  DHC & hematoma evacuation2 (10.53)1 (3.33)
  EVD, DHC, & hematoma evacuation1 (5.26)0 (0.00)0.332

DHC = decompressive hemicraniectomy; EVD = external ventricular drain.

Boldface type indicates statistical significance.

Weighted mean values.

There were no significant differences in ICP or CPP measurements between the two groups, with an average daily value of 18.79 mm Hg in the ICP-only group and ICP of 13.35 mm Hg in the ICP + PbtO2 group (Table 1). The average daily PbtO2 was 23.2 mm Hg, with an average of 8.84 hypoxic episodes for PbtO2 < 15 mm Hg and 15.42 episodes for PbtO2 < 20 mm Hg (Table 1). There was a weak negative correlation between average daily and hourly ICP and PbtO2 (Fig. 1) without adjusting for covariates. Conversely, there was a strong positive correlation between CPP ≥ 40 mm Hg and PbtO2 ≥ 15 and ≥ 20 mm Hg (β = 0.30 and β = 0.29, p < 0.001, respectively; Fig. 2).

FIG. 1.
FIG. 1.

Correlation between average daily (A; β = −0.03, p = 0.847) and hourly (B; β = −0.04, p < 0.001) ICP and PbtO2. *Weighted daily ICP/PbtO2 means. Figure is available in color online only.

FIG. 2.
FIG. 2.

Correlation between CPP and PbtO2 ≥ 15 mm Hg (A) and CPP and PbtO2 ≥ 20 mm Hg (B). Figure is available in color online only.

Correlation Between ICP and Outcomes

Higher minimum hourly (r = −0.52, p < 0.001) and higher average daily ICP values (r = −0.61, p < 0.001) were significantly correlated with less favorable GOS-E scores (Fig. 3). Minimum hourly ICP values and average daily ICP values did not show strong or significant relationships to hospital or PICU LOS or duration of mechanical ventilation. However, increased episodes of intracranial hypertension (ICP ≥ 20 mm Hg) were associated with increased LOS in the hospital (r = 0.39, p = 0.007) and PICU (r = 0.49, p < 0.001) and increased duration of mechanical ventilation (r = 0.57, p < 0.001). Increased episodes of intracranial hypertension (ICP > 25 mm Hg) were correlated with increased LOS in the PICU (r = 0.36, p = 0.012) and increased duration of mechanical ventilation (r = 0.42, p = 0.003). There was an association between higher minimum hourly (r = 0.3, p = 0.044) and average daily (r = 0.34, p = 0.019) ICP and higher average PILOT scores, but a lack of association between the number of intracranial hypertension episodes ≥ 20 mm Hg and PILOT scores (Fig. 3).

FIG. 3.
FIG. 3.

Correlation between ICP and clinical outcomes. Direction of ellipse, color, and circle shape indicate magnitude and direction of correlation. Direction of ellipse to the left or right indicates a negative or positive correlation, respectively. The darker the blue or orange color indicates an increased negative or positive correlation, respectively. The rounder the shape of the circle, the weaker the correlation; the more elliptical the shape, the stronger the correlation. The average daily ICP means are weighted. *p < 0.05, **p < 0.01, ***p < 0.001. Figure is available in color online only.

Correlation Between PbtO2 and Outcomes

In the cohort that received ICP + PbtO2 monitoring, more cerebral hypoxic episodes (< 15 mm Hg) were associated with more unfavorable GOS-E scores (ρ = −0.49, p = 0.045) as well as increased hospital LOS (ρ = 0.61, p = 0.01), PICU LOS (ρ = 0.58, p = 0.015), and duration of mechanical ventilation (ρ = 0.58, p = 0.015; Fig. 4). This was also true for number of PbtO2 episodes < 20 mm Hg, except that the duration of mechanical ventilation was positively correlated but not statistically significant (ρ = 0.46, p = 0.063). The number of PbtO2 episodes < 20 mm Hg was strongly correlated with more unfavorable GOS-E (ρ = −0.55, p = 0.022). More cerebral hypoxic episodes (PbtO2 < 15 mm Hg and < 20 mm Hg) were significantly associated with increased PILOT scores (ρ = 0.63, p = 0.006, and ρ = 0.5, p = 0.041, respectively; Fig. 4).

FIG. 4.
FIG. 4.

Correlation between PbtO2 and clinical outcomes. Direction of ellipse, color, and circle shape indicate magnitude and direction of correlation. Direction of ellipse to the left or right indicates a negative or positive correlation, respectively. The darker the blue or orange color indicates an increased negative or positive correlation, respectively. The rounder the shape of the circle, the weaker the correlation; the more elliptical the shape, the stronger the correlation. The average daily PbtO2 means are weighted. *p < 0.05, **p < 0.01, ***p < 0.001. Figure is available in color online only.

While the children with favorable GOS-E scores had higher daily PbtO2 values, the average daily PbtO2 did not differ significantly between patients with favorable outcomes (GOS-E scores 7–8) and unfavorable outcomes (GOS-E scores 1–6) during the first 6 days of admission (p = 0.949; Fig. 5).

FIG. 5.
FIG. 5.

Graph of average daily PbtO2 (mm Hg) change over time grouped by outcome. Figure is available in color online only.

Difference in Outcomes Between the ICP + PbtO2 and ICP-Only Groups

Long-term outcome as reflected by GOS-E score at 6 months, PILOT score, Marshall score, hospital LOS, duration of mechanical ventilation, discharge location, and mortality did not differ significantly between the two groups (Table 2, Fig. 6). Mean LOS in the PICU was longer in the ICP + PbtO2 group compared to the ICP-only group, but after adjusting for age and sex, this difference became insignificant (Table 2, Fig. 6).

TABLE 2.

Patient characteristics by clinical outcomes

Clinical OutcomeICP + PbtO2 Group, n = 19ICP-Only Group, n = 30p ValueAdjusted p Value*
Median GOS-E score (IQR)8 (6–8)8 (5.25–8.00)0.7330.623
Average PILOT score (SD)9.72 (2.02)10.15 (3.31)0.6090.685
Median Marshall score (IQR)3 (2.5–4.5)3 (2.00–4.25)0.6140.588
Mean hospital LOS (SD), hrs632.47 (392.65)466.48 (274.27)0.0840.354
Mean PICU LOS (SD), hrs401.17 (238.24)258.85 (181.3)0.0180.112
Mean hrs of mechanical ventilation (SD)234.52 (153.23)170.25 (120.29)0.1020.238
Deceased, n (%)
 No19 (100.00)27 (90.00)
 Yes0 (0.00)3 (10.00)0.4170.996
Discharge location, n (%)
 Expired0 (0.00)3 (10.00)
 Home5 (26.32)5 (16.67)
 Inpatient rehab facility13 (68.42)21 (70.00)
 Other1 (5.26)1 (3.33)0.468

Boldface type indicates statistical significance.

Adjusted by sex and age.

FIG. 6.
FIG. 6.

Box-and-whisker plots showing clinical outcome comparisons between ICP-only and ICP + PbtO2 groups. Red dots represent means. Figure is available in color online only.

ICP and PbtO2 Burden

Supplemental Fig. 1 shows the correlations between PbtO2 and clinical outcomes, independent of elevated ICP. The cumulative and daily ICP burdens in both the ICP-only and ICP + PbtO2 groups were calculated for ICP ≥ 20 mm Hg (representing elevated ICP), PbtO2 < 15 mm Hg, and PbtO2 < 20 mm Hg (representing low PbtO2; Supplemental Figs. 2–7). The cumulative and daily hypoxic burdens of PbtO2 < 15 mm Hg and < 20 mm Hg while ICP remained ≥ 20 mm Hg were also calculated (Supplemental Figs. 8–11).

Discussion

Our study evaluated outcomes in pediatric patients with severe TBI who received directed therapy of ICP + PbtO2 compared to those who received directed therapy of ICP only. The additional analyses specific to ICP + PbtO2 measurements allowed us to evaluate the role of cerebral oxygen levels influencing treatment course and outcomes. We found that an increased number of cerebral hypoxic episodes were associated with less favorable functional outcomes (i.e., lower GOS-E scores). An increased number of cerebral hypoxic episodes also resulted in longer hospital and PICU LOS and longer durations of mechanical ventilator support. Regarding ICP, we found that higher minimum hourly ICP and average daily ICP measurements were strongly correlated with less favorable functional outcomes. These results are consistent with the literature on pediatric severe TBI, which indicates that lower average ICP measurements and reduced intracranial hypertensive episodes correlate with improved functional outcomes and reduced mortality rates.3540 While we did not notice an improvement in functional outcome in patients who received PbtO2 in addition to ICP monitoring and treatment, the lack of a strong correlation between ICP and PbtO2 values supports the importance of multimodal invasive neuromonitoring in pediatric severe TBI.

The weak correlation between the measurement modalities indicates that ICP and PbtO2 measurements may not be related to the same injury processes occurring within the pediatric brain. The independent analyses of ICP and PbtO2 with functional outcomes support this conclusion, as the number of episodes of low PbtO2, versus the minimum hourly or average daily PbtO2, correlates most strongly with GOS-E scores. However, in terms of ICP measurements, minimum hourly and average daily values, rather than the number of intracranial hypertensive episodes, correlate most strongly with GOS-E scores. ICP and PbtO2 might reflect brain injury (ischemia vs hyperemia) occurring at different timescales or with differing severity. Our study shows that both low PbtO2 and high ICP are correlated with worse GOS-E scores; therefore, we believe it is valuable to monitor and treat both modalities.

In the pediatric TBI literature, outcomes that are important markers of patient safety, such as hospital and PICU LOS and duration of mechanical ventilation, have been less studied compared with mortality, discharge location, or GOS-E score. In our study, we discovered that more episodes of intracranial hypertension were associated with increased LOS in the hospital and PICU and increased duration of mechanical ventilation. In a study using the National Trauma Data Bank, the authors evaluated more than 3000 pediatric patients with TBI and found that patients who received ICP monitoring and ICP-directed therapy experienced increased hospital and PICU LOS as well as duration of mechanical ventilation compared to patients who did not receive ICP monitoring.41 Although the authors evaluated the correlation between safety outcomes and the presence of ICP monitoring, as opposed to actual ICP measurements, their findings suggest that increased monitoring predicts worse safety outcomes. However, ICP monitoring was also associated with a reduction in mortality for patients with the most severe injury (i.e., GCS score of 3).41 In another single-institution, severe pediatric TBI study, ICP monitoring was not associated with a significant increase in average hospital LOS and duration of mechanical ventilation, but fewer intracranial hypertension episodes were associated with decreased mortality.42 Similarly, a study of severe TBI in adults found no significant association between ICP monitoring and intensive care unit LOS.43 In our institution, none of the patients with invasive neuromonitoring developed clinically significant or operative intracranial hemorrhage or infection.

In our study, an increased number of low PbtO2 events were associated with longer hospital and PICU LOS and longer duration of mechanical ventilation. These patients may have experienced increased duration of intubation because FiO2 and PEEP titrations were specific care treatments used to increase PbtO2. Interestingly, patients with lower PbtO2 values received more ICP-intensive therapy, as demonstrated by the higher average PILOT scores. This result may reflect the PbtO2 treatment protocol, which includes many of the therapies used to treat high ICP, such as sedation, analgesia, and neuromuscular blockade. While there was a weak correlation between ICP and PbtO2 in this study, the increase in PILOT scores with cerebral hypoxic episodes may also suggest that cerebral hypoxic episodes foster ICP elevation in a subset of patients and subsequently require more intensive ICP-directed therapy. Within the ICP + PbtO2 group, an increased number of cerebral hypoxic episodes were also associated with more unfavorable GOS-E scores, consistent with our hypothesis. One single-institution study of pediatric severe TBI found a positive yet insignificant correlation between daily mean PbtO2 values and GOS-E scores.21 Other pediatric studies have demonstrated significant correlations between PbtO2 measurements and functional outcomes.24,2628

The correlation between ICP and PbtO2 was small, revealing that increased ICP did not always correspond to decreased PbtO2. Conversely, during periods of normal ICP, PbtO2 could be lower than normal. This finding differs from our initial pilot study of only 6 children, which found that PbtO2 was significantly higher at an ICP < 20 mm Hg compared with an ICP ≥ 20 mm Hg.22 However, our present study is consistent with findings from more recent multimodal neuromonitoring studies, which suggest that even though PbtO2 may be negatively correlated with lower ICP, the association is weak because episodes of low PbtO2 may occur during periods of normal ICP.2022,25,44 At the same time, we found that as CPP increases (CPP ≥ 40 mm Hg), PbtO2 also increases for thresholds of both ≥ 15 mm Hg and ≥ 20 mm Hg. These findings reiterate the importance of multimodality neuromonitoring to inform treatment.19,20,45

When evaluating differences between the ICP + PbtO2 versus the ICP-only group, we found that our primary outcome of GOS-E scores at 6 months did not differ significantly between groups. PICU LOS was significantly higher in the ICP + PbtO2 compared to the ICP-only group. While not statistically significant, hospital LOS and length of mechanical ventilation were also longer in the ICP + PbtO2 group. Although these correlations became insignificant after controlling for age and sex, these trends aligned with a recent study in the adult severe TBI population that found significantly increased ICU LOS and duration of mechanical ventilation in patients receiving ICP + PbtO2 monitoring, compared to patients receiving only ICP monitoring.14 Despite the increased LOS and mechanical ventilation period, which could be due to adverse effects from the treatments for cerebral hypoxia, the ICP + PbtO2 group demonstrated lower mortality than the ICP-only group.14 In a phase 2 safety and feasibility BOOST-II trial for adult severe TBI, a reduction in cerebral hypoxia time and a trend toward lower mortality and improved GOS-E outcome at 6 months were demonstrated in the ICP + PbtO2 treatment group compared with the ICP-only treatment group.18 The ongoing BOOST-III adult study is a multi-institutional randomized clinical trial to determine the comparative effectiveness of guided treatment with ICP + PbtO2 versus that with only ICP (ClinicalTrials.gov identifier: NCT03754114). Collectively, these studies demonstrate that further adult and pediatric TBI studies on the safety and efficacy of PbtO2 monitoring and treatment are warranted.

Our study has several limitations. Our analysis is retrospective in nature and is a single-institution study with a small sample size. Our data are also limited by hourly collection of data, because this is a retrospective study and continuous data were not available for all modalities. In the future, our PICU will have a more continuous and rigorous data-capturing capability that will provide more granular analysis of PbtO2 and other clinical physiological variables. Despite the limitations of our study, our results highlight the importance of weighing the risks and benefits when introducing invasive multimodality neuromonitoring in pediatric patients with severe TBI.

To our knowledge, this is the first study that has examined the difference in safety and functional outcomes between invasive ICP + PbtO2 versus ICP-only groups in the severe pediatric TBI population in a single institution. These outcomes are especially important to consider in the pediatric population, as longer LOS may impact absences from school and family life, which may influence children’s social, emotional, and cognitive development. Our pediatric study is also unique as it analyzes multiple aspects of PbtO2 data in relation to functional outcomes to help guide clinicians’ interpretation of data and management decisions. It is valuable for clinicians to note that the number of low PbtO2 episodes is more significantly correlated with poorer outcomes than average daily PbtO2. In addition, the number of low PbtO2 episodes, more so than the minimum hourly or average daily PbtO2 values, indicates greater complexity of care in terms of longer hospital and PICU LOS, duration of mechanical ventilation, and increased PILOT score.

While we observed significant correlations between PbtO2, ICP, and CPP values and functional outcomes, we did not observe an improvement in the primary functional outcome of GOS-E score with the addition of PbtO2 compared to ICP-only monitoring and treatment. Although the GOS-E score was higher in the ICP + PbtO2 group than in the ICP-only group, the small size of each group may have prevented this difference from being statistically significant, although clearly further studies with a larger pediatric population need to be conducted. The BOOST-II adult study that demonstrated an improved trend in morbidity and mortality was a higher-powered, multi-institutional study with a much larger sample size.18 In addition, many adult studies measure outcome by examining mortality rate or discharge location.14,16,18 These outcomes were not as apparent in our study: for example, there were only 3 deaths and only 2 patients were discharged to another institution. Another difference between our results and findings compared to the adult population is the inherent difference in children recovery patterns. Nonetheless, our study has demonstrated that ICP or cerebral brain tissue oxygen levels can independently influence outcome.

Conclusions

We demonstrated that ICP and PbtO2 are weakly correlated to one another, while ICP or PbtO2 independently affected functional outcome, supporting the use of both invasive neuromonitoring techniques to complement each other and help guide therapy in the pediatric severe TBI population. Future research with larger, multicenter studies may seek to understand whether certain subpopulations, based on the type of injury and/or age, would benefit more from PbtO2 monitoring and treatment.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Lang, Huh. Acquisition of data: Lang, Zhang, Gajjar, Sotardi. Analysis and interpretation of data: Lang, Kumar, Zhao, Zhang, Sotardi, Huh. Drafting the article: Lang, Kumar, Zhao, Zhang, Huh. Critically revising the article: all authors. Reviewed submitted version of manuscript: Lang, Kumar, Zhao, Tucker, Storm, Heuer, Kim, Yuan, Sotardi, Kilbaugh, Huh. Approved the final version of the manuscript on behalf of all authors: Lang. Statistical analysis: Lang, Zhao, Huh. Administrative/technical/material support: Lang, Huh. Study supervision: Lang, Huh.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

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Supplementary Materials

Images from Oushy et al. (pp 195–202).

  • View in gallery

    Correlation between average daily (A; β = −0.03, p = 0.847) and hourly (B; β = −0.04, p < 0.001) ICP and PbtO2. *Weighted daily ICP/PbtO2 means. Figure is available in color online only.

  • View in gallery

    Correlation between CPP and PbtO2 ≥ 15 mm Hg (A) and CPP and PbtO2 ≥ 20 mm Hg (B). Figure is available in color online only.

  • View in gallery

    Correlation between ICP and clinical outcomes. Direction of ellipse, color, and circle shape indicate magnitude and direction of correlation. Direction of ellipse to the left or right indicates a negative or positive correlation, respectively. The darker the blue or orange color indicates an increased negative or positive correlation, respectively. The rounder the shape of the circle, the weaker the correlation; the more elliptical the shape, the stronger the correlation. The average daily ICP means are weighted. *p < 0.05, **p < 0.01, ***p < 0.001. Figure is available in color online only.

  • View in gallery

    Correlation between PbtO2 and clinical outcomes. Direction of ellipse, color, and circle shape indicate magnitude and direction of correlation. Direction of ellipse to the left or right indicates a negative or positive correlation, respectively. The darker the blue or orange color indicates an increased negative or positive correlation, respectively. The rounder the shape of the circle, the weaker the correlation; the more elliptical the shape, the stronger the correlation. The average daily PbtO2 means are weighted. *p < 0.05, **p < 0.01, ***p < 0.001. Figure is available in color online only.

  • View in gallery

    Graph of average daily PbtO2 (mm Hg) change over time grouped by outcome. Figure is available in color online only.

  • View in gallery

    Box-and-whisker plots showing clinical outcome comparisons between ICP-only and ICP + PbtO2 groups. Red dots represent means. Figure is available in color online only.

  • 1

    Dewan MC, Mummareddy N, Wellons JC III, Bonfield CM. Epidemiology of global pediatric traumatic brain injury: qualitative review. World Neurosurg. 2016;91:497509.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Faul M, Xu L, Marlena M. Wald, Victor G. Coronado. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. Centers for Disease Control and Prevention,. National Center for Injury Prevention and Control;2010.

    • Search Google Scholar
    • Export Citation
  • 3

    Alali AS, Gomez D, Sathya C, et al. Intracranial pressure monitoring among children with severe traumatic brain injury. J Neurosurg Pediatr. 2015;16(5):523532.

  • 4

    Carney N, Totten AM, O’Reilly C, et al. Guidelines for the management of severe traumatic brain injury,. fourth edition. Neurosurgery. 2017;80(1):615.

  • 5

    Cremer OL, van Dijk GW, van Wensen E, et al. Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med. 2005;33(10):22072213.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Farahvar A, Gerber LM, Chiu YL, Carney N, Härtl R, Ghajar J. Increased mortality in patients with severe traumatic brain injury treated without intracranial pressure monitoring. J Neurosurg. 2012;117(4):729734.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kochanek PM, Tasker RC, Carney N, et al. Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: update of the Brain Trauma Foundation Guidelines. Pediatr Crit Care Med. 2019;20(3 suppl 1):S1S82.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Saul TG, Ducker TB. Effect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury. J Neurosurg. 1982;56(4):498503.

  • 9

    Bohman LE, Heuer GG, Macyszyn L, et al. Medical management of compromised brain oxygen in patients with severe traumatic brain injury. Neurocrit Care. 2011;14(3):361369.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    van den Brink WA, van Santbrink H, Steyerberg EW, et al. Brain oxygen tension in severe head injury. Neurosurgery. 2000;46(4):868878.

  • 11

    Oddo M, Levine JM, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011;69(5):10371045.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Hlatky R, Valadka AB, Robertson CS. Intracranial hypertension and cerebral ischemia after severe traumatic brain injury. Neurosurg Focus. 2003;14(4):e2.

  • 13

    Le Roux PD, Jardine DS, Kanev PM, Loeser JD. Pediatric intracranial pressure monitoring in hypoxic and nonhypoxic brain injury. Childs Nerv Syst. 1991;7(1):3439.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Hoffman H, Abi-Aad K, Bunch KM, Beutler T, Otite FO, Chin LS. Outcomes associated with brain tissue oxygen monitoring in patients with severe traumatic brain injury undergoing intracranial pressure monitoring. J Neurosurg. 20121;135(6):17991806.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Patchana T, Wiginton J IV, Brazdzionis J, et al. Increased brain tissue oxygen monitoring threshold to improve hospital course in traumatic brain injury patients. Cureus. 2020;12(2):e7115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Stiefel MF, Spiotta A, Gracias VH, et al. Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg. 2005;103(5):805811.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Valadka AB, Gopinath SP, Contant CF, Uzura M, Robertson CS. Relationship of brain tissue PO2 to outcome after severe head injury. Crit Care Med. 1998;26(9):15761581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Okonkwo DO, Shutter LA, Moore C, et al. Brain Tissue Oxygen Monitoring and Management in Severe Traumatic Brain Injury (BOOST-II): a phase II randomized trial. Crit Care Med. 2017;45(11):19071914.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Young AMH, Guilfoyle MR, Donnelly J, et al. Multimodality neuromonitoring in severe pediatric traumatic brain injury. Pediatr Res. 2018;83(1-1):4149.

  • 20

    Appavu B, Burrows BT, Nickoles T, et al. Implementation of multimodality neurologic monitoring reporting in pediatric traumatic brain injury management. Neurocrit Care. 2021;35(1):315.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Stippler M, Ortiz V, Adelson PD, et al. Brain tissue oxygen monitoring after severe traumatic brain injury in children: relationship to outcome and association with other clinical parameters. J Neurosurg Pediatr. 2012;10(5):383391.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Stiefel MF, Udoetuk JD, Storm PB, et al. Brain tissue oxygen monitoring in pediatric patients with severe traumatic brain injury. J Neurosurg. 2006;105(4 suppl):281286.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Bell MJ, Adelson PD, Wisniewski SR. Challenges and opportunities for pediatric severe TBI-review of the evidence and exploring a way forward. Childs Nerv Syst. 2017;33(10):16631667.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Narotam PK, Burjonrappa SC, Raynor SC, Rao M, Taylon C. Cerebral oxygenation in major pediatric trauma: its relevance to trauma severity and outcome. J Pediatr Surg. 2006;41(3):505513.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Figaji AA, Zwane E, Thompson C, et al. Brain tissue oxygen tension monitoring in pediatric severe traumatic brain injury. Part 2: Relationship with clinical, physiological, and treatment factors. Childs Nerv Syst. 2009;25(10):13351343.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

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