Hypothermia Decreases Cerebrospinal Fluid Asymmetric Dimethylarginine Levels in Children With Traumatic Brain Injury

Abstract

Objectives Pathological increases in asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, have been implicated in endothelial dysfunction and vascular diseases. Reduced NO early after traumatic brain injury (TBI) may contribute to hypoperfusion. Currently, methods to quantify ADMA in the cerebrospinal fluid (CSF) have not been fully explored. We aimed to develop and validate a method to determine ADMA in the CSF of a pediatric TBI population and to use this method to assess the effects of (i) TBI and (ii) therapeutic hypothermia (TH) on this mediator. Design, Setting, Patients An ancillary study to a prospective, phase II randomized clinical trial (RCT) of early hypothermia in a tertiary care pediatric intensive care unit for children with TBI admitted to Children's Hospital of Pittsburgh. Interventions None Measurements and Main Results A UPLC-MS/MS method was developed and validated to quantitate ADMA. A total of 56 samples collected over 3 days starting with injury onset were analyzed from the CSF of consented therapeutic hypothermia (n=9) and normothermia (n=10) children. Children undergoing diagnostic lumbar puncture (n=5) were controls. ADMA was present at a quantifiable level in all samples. Mean ADMA levels were significantly increased in normothermic TBI children compared to control (0.19± 0.08 μmol/L and 0.11± 0.02μmol/L respectively, p=0.01), and hypothermic children had significantly reduced mean ADMA levels (0.11 ± 0.05 μmol/L) vs. normothermic (p=0.03) measured on day 3. Patient demographics including age, gender, and NO levels (measured as nitrite and nitrate using liquid chromatography coupled with Griess reaction) did not significantly differ between normothermia and hypothermia groups. Also, NO levels did not correlate with ADMA concentrations. Conclusions ADMA levels were significantly increased in the CSF of TBI children. Early hypothermia attenuated this increase. The implications of attenuated ADMA on NOS activity and regional cerebral blood flow after TBI by TH deserve future attention.

Endogenous Nitric-Oxide Synthase Inhibitor ADMA after Acute Brain Injury

“…Similarly increased ADMA levels accompanied by decreased NO levels in CSF and NOS inhibition have been demonstrated in cases of brain injury caused by aneurysmal subarachnoid hemorrhage [ 27 , 28 ]. Furthermore, Thampatty et al reported elevated CSF ADMA level within 3 days after TBI in children [ 29 ]. The delayed detection of elevated ADMA levels in CSF and serum parallels the timescale for apoptosis and neuronal cell-death as well as the time-course of blood brain-barrier breakdown after TBI [ 17 , 30 ].…”

Neurotrauma and Repair Research: Traumatic Brain Injury (TBI) and its Treatments

“…Recent work found that children treated with hypothermia after TBI had reduced CSF levels of dimethylarginine. 8 Dimethylarginine is a nitric oxide synthase inhibitor, blocking production of the potent vasodilator nitric oxide. Thus, hypothermia acutely permits vasodilation and increased perfusion to cerebral tissues which may mitigate secondary damage of TBI.…”