Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children

Abstract

Objectives: The devastating effect of traumatic brain injury is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure due to cerebral edema. The treatment effect of cell-based therapies in the acute post-traumatic brain injury period has not been clinically studied although preclinical data demonstrate that bone marrow-derived mononuclear cell infusion down-regulates the inflammatory response. Our study evaluates whether pediatric traumatic brain injury patients receiving IV autologous bone marrow-derived mononuclear cells within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls.

Design: The study was a retrospective cohort design comparing pediatric patients in a phase I clinical trial treated with IV autologous bone marrow-derived mononuclear cells (n = 10) to a control group of age- and severity-matched children (n = 19).

Setting: The study setting was at Children's Memorial Hermann Hospital, an American College of Surgeons Level 1 Pediatric Trauma Center and teaching hospital for the University of Texas Health Science Center at Houston from 2000 to 2008.

Patients: Study patients were 5-14 years with postresuscitation Glasgow Coma Scale scores of 5-8.

Interventions: The treatment group received 6 million autologous bone marrow-derived mononuclear cells/kg body weight IV within 48 hours of injury. The control group was treated in an identical fashion, per standard of care, guided by our traumatic brain injury management protocol, derived from American Association of Neurological Surgeons guidelines.

Measurements and main results: The primary measure was the Pediatric Intensity Level of Therapy scale used to quantify treatment of elevated intracranial pressure. Secondary measures included the Pediatric Logistic Organ Dysfunction score and days of intracranial pressure monitoring as a surrogate for length of neurointensive care. A repeated-measure mixed model with marginal linear predictions identified a significant reduction in the Pediatric Intensity Level of Therapy score beginning at 24 hours posttreatment through week 1 (p < 0.05). This divergence was also reflected in the Pediatric Logistic Organ Dysfunction score following the first week. The duration of intracranial pressure monitoring was 8.2 ± 1.3 days in the treated group and 15.6 ± 3.5 days (p = 0.03) in the time-matched control group.

Conclusions: IV autologous bone marrow-derived mononuclear cell therapy is associated with lower treatment intensity required to manage intracranial pressure, associated severity of organ injury, and duration of neurointensive care following severe traumatic brain injury. This may corroborate preclinical data that autologous bone marrow-derived mononuclear cell therapy attenuates the effects of inflammation in the early post-traumatic brain injury period.

Figure 1

Pediatric Intensity Level of Therapy (PILOT) score calculated from time of admission with divergence seen following time of cell therapy (patients were treated within 48 hours of admission) with p<0.001 verses both 2006-2008 and 2000-2008 controls. Also displayed are the mean ICP monitoring days with SEM for each group and area under the curve analysis where cumulative PILOT scores in each group of patients were summed for days 3-10 and for days 11-21.

Figure 2

Maximum sodium levels were highest in the 2006-2008 control group, which was significantly higher than the 2006-2008 Phase I group (p<0.05).

Figure 3

Pediatric Level of Organ Dysfunction (PELDO) score calculated from time of admission with divergence seen after one week with the Phase I 2006-2008 group verses both 2006-2008 and 2000-2008 controls p<0.001.

Figure 4

When plotting best GCS per day, there appears to be a cell therapy related improvement in GCS scores after one week in the Phase I 2006-2008 patients compared to either control group.

Figure 5

When plotting maximum ICP per day, there appears to be a cell therapy related decrease in maximum ICP values per day beginning approximately 48 hours after treatment which can be seen when the Phase I 2006-2008 group is compared with A) all controls B) time matched controls from 2006-2008 and C) controls from 2000-2006.