SCCM Resource Library-01-CSF Sur1 Is Associated With ICP and Outcome After Pediatric TBI: An Exploratory Study in Cool Kids

Video Transcription

Hello everyone, thanks so much for coming today. My name is Ben Zussman, I'm a fourth year medical student at the University of Pittsburgh  School of Medicine in Pittsburgh, Pennsylvania. Today I'm delighted to share with you guys the results of an exploratory study that we  carried out looking at the association between CSF levels of the self-familiar rear receptor 1 protein with intracranial pressure and functional outcomes after severe pediatric TBI.  Before I begin, I have no conflicts of interest to disclose myself, but my mentor Dr. Ujira Jha is a paid consultant for Biogen, which is currently sponsoring a study looking at  the efficacy of SIR1 inhibition with the drug Glyburide in TBI. To give some background information, although severe TBI constitutes a relatively small  proportion of all pediatric TBI, it causes a disproportionate share of morbidity and mortality, and it's one of the leading causes of death in patients under the age of 18.  In spite of this, no randomized placebo-controlled trial has demonstrated the efficacy of a novel  therapy when that therapy was compared to established guideline-directed care alone. This is a pretty clear unmet need in this very ill patient population.  The self-familiar rear receptor 1, or SIR1 protein, is a component of many ATP-sensitive heteroameric cation channels.  Over the last decade, the SIR1-trypin-4 nonspecific cation channel in particular has attracted  much attention for moderating injury in multiple acute neurological diseases, including TBI. Previously, we found that SIR1 protein was elevated in the CSF of adult TBI patients  but was undetectable in the CSF of non-head-injured controls.  SIR1 levels in the CSF were also temporarily associated with the development of intracranial hypertension and cerebral edema after TBI.  In addition, there is mounting evidence, both preclinical and clinical, that inhibition of the SIR1 channel may prevent the formation of cerebral edema, reduce traumatic contusion  expansion, and provide neuroprotection after TBI. Following the results of an earlier phase 2 trial, the ASTRAL trial of SIR1 inhibition  with the antidiabetic drug Glyburide is currently ongoing in adult contusional TBI patients.  Unfortunately, the role of SIR1 in pediatric TBI remains entirely unexplored to this point. Thus, we set out to test the following hypotheses.  One, SIR1 is elevated in the CSF of pediatric severe TBI patients relative to age-appropriate controls.  Two, increased SIR1 levels in the CSF are associated with increased intracranial pressure in the acute phase following injury.  And three, increased SIR1 levels in the CSF are associated with worse functional outcome over the first year after injury.  In order to test these hypotheses, we performed an exploratory analysis of the patients enrolled in the COOLKIDS trial of therapeutic hypothermia and severe pediatric TBI.  COOLKIDS was a multicenter randomized controlled trial of 48 to 72 hours of therapeutic hypothermia  that enrolled patients from 2007 to 2011, which was ultimately terminated early due to futility.  For this analysis, we included all patients enrolled into the COOLKIDS trial from our institution who had at least one sample of CSF available for study.  All CSF was obtained from an external ventricular drain as part of clinical standard of care for TBI patients.  This resulted in 54 CSF samples across 16 patients, 8 patients from each interventional arm. All CSF was obtained from seven pediatric control patients via clinically indicated  lumbar puncture. Each of these CSF samples had zero white blood cells and zero red blood cells and was obtained from a patient who had no history of traumatic head injury.  Only one sample was obtained from each of these patients. CSF levels of SIR1 protein were subsequently quantified using the commercially available  ELISA kit, and any sample with an undetectable level of SIR1 was assumed to have a level of zero nanograms per milliliter.  The mean CSF SIR1 level across samples is then calculated for each patient. Our study subsequently looked at three primary outcomes, one for each of our hypotheses.  First we compared the proportion of TBI patients with any CSF sample of detectable SIR1 with the proportion of control patients with a sample of detectable SIR1.  Then we tested for an association between mean CSF SIR1 and hourly intracranial pressure measurements taken over the first seven days from injury as measured by EVD.  This was done using random coefficient models. Finally, we tested for an association between mean CSF SIR1 and the Glasgow outcome scale  extended pediatric version over the first year from injury. The pediatric version of the GOSC scale differs from the adult version in that higher scores  indicate more severe disability. A score of one represents no disability and a score of eight represents death. These analyses were also performed using random coefficient models.  Moving into our results, the table shown here presents the age, sex, admission GCS, mechanism of injury, and interventional arm of the patients included in our analysis.  It also shows the mean and peak CSF SIR1 levels for each patient, the mean intracranial pressure, and the 12-month GOSC pediatric score for each of these patients.  As you can see, patient ages range from approximately 10 months to almost 15 years old with similar numbers of male and female patients.  Those patients were toward the more mild end of the severe TBI spectrum by GCS score with a median GCS of seven.  Similarly, mean ICP for most of these patients was below 10, relatively low, and only one patient passed away by 12 months.  In terms of SIR1 quantification, we detected SIR1 in 14 out of 54 CSF samples from TBI patients, but none of the seven samples from pediatric controls.  Of the 16 patients, nine had detectable SIR1 in the CSF compared to none of the controls.  This was a difference that was statistically significant, suggesting that, at least variably, CSF SIR1 is elevated in TBI patients relative to controls.  Looking for an association between CSF SIR1 and other measured demographic variables, we found no association between CSF SIR1 in patient age, sex, or interventional arm.  There was, however, an association between CSF SIR1 and GCS. Patients admitted with lower GCS scores tended to have higher SIR1 levels than CSF.  Looking for an association between SIR1 and ICP, we performed multiple random coefficient models.  At the top is a univariable model followed by a model adjusted for age, sex, and GCS. Both found similar results with similar beta coefficients.  Increased CSF SIR1 was associated with increased ICP. Below is a random coefficient model that included SIR1 and hypothermia, finding that  both variables were independently associated with ICP, with the results in opposite directions.  While hypothermia was associated with decreased ICP, increased SIR1 was associated with increased ICP.  Finally, on the right is a figure presenting an analysis where patients were dichotomized  into those nine patients where SIR1 was detected in at least one CSF sample and the seven patients where SIR1 was never detected.  While ICP measurements between groups were similar early on, after approximately the first day, the patients with undetectable SIR1 had consistently lower ICP measurements  than those with detectable SIR1. We then looked for an association between mean SIR1 levels and functional outcomes.  Much like with ICP, mean SIR1 was associated with higher or worse GOSC pediatric scores in both the univariable model and the model adjusted for age, sex, and admission GCS.  Again, higher mean SIR1 remained associated with worse outcome after adjusting for hypothermia. The hypothermia itself was not associated with outcome in this model.  After dichotomization, patients with detectable SIR1 had consistently higher GOSC scores or worse functional outcomes than patients with undetectable SIR1, and this remained true  throughout the first year after injury. In summary, in this study, we found that SIR1 is undetectable in the CSF of non-head-injured  pediatric patients, but variably elevated after TBI. Interestingly, this was different from our findings in adult TBI patients, where all  the injured patients had elevated SIR1, and the average levels of SIR1 were almost five-fold higher than what we saw here.  The reason for these differences is unclear, but they could be related to age-related differences  in SIR1 expression, differences in injury severity between groups, or differences in CSF sample processing and storage.  We demonstrated that increased SIR1 in the CSF following TBI is associated with increased intracranial pressure, particularly following the first 24 hours from injury, and is also  associated with worse functional outcome for the first year after injury. And finally, our finding that SIR1 did not differ between interventional arms, and that  both SIR1 and hypothermia were independently associated with ICP, raises the possibility  that these may be independent processes, and that they could possibly be separate therapeutic targets. However, our study is certainly not without limitations.  First, apparently, this was an exploratory study limited by a very small sample size, though our results were robust in multiple forms of analysis and were strengthened by  collection in the context of an RCT. Additionally, we were unable to obtain CT imaging for 13 of 16 TBI patients, despite  our repeated best efforts, and so we did not include imaging data in the analysis. This may be especially important, as SIR1 is currently being studied specifically in  contusional TBI in adults. Finally, we were limited by relatively low ICP values in this sample.  This may further limit the generalizability of our results, though likely it would be expected to bias them towards the null, given the direction of our associations.  In conclusion, increased CSF SIR1 may be associated with increased ICP and worse functional outcomes  after severe pediatric TBI, while it's undetectable in the CSF of pediatric controls. This may make it potentially useful as a biomarker, and is certainly worth studying further in  this context. Additionally, given the ready availability of the sulfameliuria medications and the serious  unmet need for therapeutic options in pediatric TBI patients, pharmacologic inhibition of  the SIR1 channel may be a promising therapy for this patient population and warrants investigation.  I would like to thank you for listening to my presentation, and would also like to thank my mentors and collaborators, some of whom are shown here.  I would especially like to thank Dr. Ruchira Jha for her dedicated mentorship over the last several years, and Dr. Patrick Kohanek for his patience in teaching me just a small  amount of his vast knowledge about pediatric TBI.  I'd also like to thank the investigators and staff of the COOLKIDS trial. And finally, I'd like to thank SCCM for the opportunity to present this work and for the  Bronze Medal Award. Thank you again, and I hope that you enjoy the rest of the conference. I'm happy to take any questions.

Video Summary

In this presentation, Ben Zussman, a fourth-year medical student, discusses a study that explores the relationship between the SIR1 protein and pediatric traumatic brain injury (TBI). The study analyzed cerebrospinal fluid (CSF) samples from pediatric TBI patients and controls to determine if SIR1 levels were associated with intracranial pressure and functional outcomes. The study found that SIR1 levels were elevated in the CSF of TBI patients compared to controls. Additionally, increased SIR1 levels were associated with increased intracranial pressure and worse functional outcomes. The study suggests that SIR1 could serve as a potential biomarker and target for therapeutic intervention in pediatric TBI.

Asset Subtitle

Pediatrics, Neuroscience, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Benjamin Zus

Introduction/Hypothesis: Sulfonylurea Receptor 1 (Sur1) is a key contributor to cerebral edema. Sur1 inhibition is protective in multiple preclinical models of acute brain injury. In adult traumatic brain injury (TBI), Sur1 expression has been associated with cerebral edema, intracranial hypertension and contusion expansion. A phase 2 clinical trial of a Sur1 antagonist, in adult TBI patients is ongoing. Sur1 in pediatric TBI, however, remains unexplored despite a high risk of cerebral edema and unfavorable outcome.

Methods: Cerebrospinal Fluid (CSF) from 16 pediatric severe TBI patients enrolled in the Cool Kids trial and 7 non-brain injured pediatric controls was evaluated for Sur1 expression using commercially available ELISAs. CSF samples from multiple time points (up to 5) per TBI patient were tested. Linear mixed models tested for an association between mean CSF Sur1 and intracranial pressure (ICP) over the first 7 days after injury and 1-year GOS-E Peds.

Results: Median age in TBI was 132.6 months (range 9.7-176.1 months). 61% of patients were male. Median initial Glasgow coma scale (GCS) score was 7 (range 4-8). 50% of patients were randomized to hypothermia. CSF Sur1 was undetectable in all controls, but elevated in 9/16 (56.25%) TBI patients. Mean CSF Sur1 was not associated with age, sex, or hypothermia. Each 1-point increase in GCS was associated with a 1.88 ng/mL decrease in CSF Sur-1. A 1 ng/mL increase in CSF Sur-1 was associated with a 0.73 mmHg increase in ICP over 7 days (p=0.004) and with a 0.24 point increase in GOSE-Peds score over the first year after injury (p=0.004). These associations remained significant after adjusting for age, sex, hypothermia, or admission GCS individually or altogether however univariable analyses results are presented given the small sample size and risk of model overfitting with inclusion of covariates.

Conclusions: In this exploratory study, Sur1 was undetectable in controls, and variably elevated in severe TBI. This is different than adults, where although Sur1 undetectable in controls, it was consistently elevated in all severe TBI patients. Furthermore, in children, mean CSF Sur-1 was associated with both ICP and functional outcome. Targeting Sur-1 may be a viable therapeutic target in a subset of pediatric TBI patients. Further study in pediatric TBI is warranted.

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Neuroscience

Knowledge Level Advanced

Membership Level Select

Tag Traumatic Brain Injury TBI

Year 2021

Keywords

SIR1 protein

pediatric traumatic brain injury

cerebrospinal fluid

intracranial pressure

functional outcomes

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