Pilot Study To Determine The Hemodynamic Safety and Feasibility of Magnesium Sulfate Infusion In Children With Severe Traumatic Brain Injury.

JoAnne Natale, E. MD, PhD; Anne-Marie Guerguerian, MD; Jill G. Joseph, MD, PhD; Robert McCarter, ScD; Cheng Shao, MS; Beth Slomine, PhD; James Christensen, MD; Michael V. Johnston, MD; Donald H. Shaffner, MD

Disclosures

Pediatr Crit Care Med. 2007;8(1):1-9. 

In This Article

Abstract and Introduction

Abstract

Objective: Magnesium sulfate is neuroprotective in preclinical models, but there are limited safety data regarding its clinical use for pediatric traumatic brain injury. We conducted a pilot study in children with severe traumatic brain injury to a) examine if magnesium sulfate decreases mean arterial pressure, decreases cerebral perfusion pressure, increases intracranial pressure, or adversely effects cardiac conduction; and b) determine the feasibility of a multiple-center trial of magnesium sulfate.
Design: Double-blinded, placebo-controlled, randomized pilot trial with repeated measurement of hemodynamic variables.
Setting: Two pediatric trauma centers.
Patients: Six children (3 months to 18 yrs) with severe traumatic brain injury.
Interventions: Magnesium sulfate (50 mg/kg) bolus followed by (8.3 mg/kg/hr) infusion for 24 hr vs. equivolume placebo.
Measurements and Main Results: We screened 96 patients with severe traumatic brain injury during 24 months; 20 were eligible for enrollment, six provided informed consent, four received magnesium sulfate, and two received placebo. Before and after study drug infusion, we repeatedly measured blood ionized magnesium concentration, mean arterial pressure, cerebral perfusion pressure, intracranial pressure, heart rate, and corrected QT interval. Mean age (7.9 yrs), mean highest Glasgow Coma Scale score (6), gender (33% boys), inflicted injury rate (17%), and case mortality rate (17%) did not differ between those enrolled and those not enrolled. Compared with baseline, magnesium sulfate did not change cerebral perfusion pressure, intracranial pressure, heart rate, or corrected QT interval. Mean arterial pressure was unchanged until the late phase of magnesium sulfate infusion, when mean arterial pressure rose (82 ± 5 vs. 93 ± 6 mm Hg, p < .05). Sixty-four percent of corrected QT interval determinations obtained in the first 6 days after injury exceeded 440 msecs; 12% were >600 msecs.
Conclusions: In children with severe traumatic brain injury, magnesium sulfate administration did not decrease mean arterial pressure or cerebral perfusion pressure or adversely effect cardiac conduction. Our data suggest that enrollment of brain-injured children in a therapeutic trial remains challenging. These results provide information important for clinical trials of magnesium sulfate in children with severe traumatic brain injury.

Introduction

Traumatic brain injury (TBI) requiring hospital admission occurs in approximately 37,000 children aged 0-14 yrs annually in the United States[1] and carries the potential for resultant long-term impairment of physical, cognitive, and psychosocial function.[2,3] Clinical trials testing strategies to improve recovery after TBI have failed to demonstrate significant improvement in outcome.[4]

As suggested by an expert committee,[4] we evaluated the attributes of candidate therapeutic agents before selecting magnesium sulfate (MgSO4) to consider as a therapy for TBI in children. MgSO4 is an attractive neuroprotective pharmacotherapy because it targets several pathophysiologic mechanisms that produce secondary injury after TBI. Specifically, MgSO4 a) blocks N-methyl-d-aspartate receptor-gated calcium channels;[5] b) decreases pathologic cerebral vasoconstriction leading to improved cerebral blood flow (CBF) to salvageable regions in the injured brain;[6] c) restores alterations in the cerebral cellular environment, including a decrease in extracellular magnesium, which may reduce the risk for early and potentially late posttraumatic seizures;[7] and d) attenuates production of reactive oxygen species, thereby reducing oxidative stress.[8,9]

Preclinical studies provide the biological rationale for magnesium as a neuroprotective agent. Specifically, a decline in intracellular magnesium is associated with worse neurologic outcome after experimental TBI in rats.[10] Magnesium administration after experimental TBI produces attenuation of the proapoptotic protein p53, reduction in postinjury edema formation, and improvement in motor, cognitive, and psychological recovery.[11,12,13,14]

Human studies treating neurologic injury with MgSO4 are both limited and inconclusive, with data only now emerging from randomized trials in adults,[15,16,17,18] although the major trial examining effects on posttraumatic neurologic recovery has not yet been published (ClinicalTrials.gov Identifier: NCT00004730). In the environment of stroke and subarachnoid hemorrhage in older adults, early administration of MgSO4 provided no clear, statistically significant benefit in the overall sample, although specific subgroups (e.g., those with lacunar infarcts), demonstrated a favorable response.[15,17,18] Based on emerging evidence, future trials will be required to define neuroprotective effects of MgSO4 across a broader age range.

The wealth of clinical experience with MgSO4 for other indications, encouraging preclinical and clinical data, and the relative safety of this agent make magnesium an attractive therapy to investigate for pediatric brain injury. However, the potential benefits must be balanced with the risks associated with systemic administration of MgSO4 in the setting of severe acute TBI. Specifically, magnesium's vasodilatory activity could potentially adversely affect systemic hemodynamics, leading to reduced cerebral perfusion. Furthermore, MgSO4 could produce excessive cerebral vasodilation, with subsequent increases in intracranial blood volume and increased intracranial pressure (ICP) in the patient with decreased intracranial compliance. Therefore, before MgSO4 can be evaluated in a pediatric TBI clinical trial, more information regarding its hemodynamic effects in this patient population is required.

We report data from a pilot study designed to assess the hemodynamic effects of MgSO4 administration in children with severe TBI. In addition, we sought data on recruitment and retention in this patient population for whom obtaining informed consent may be especially challenging.[19] Together, this information can contribute to decision making about the advisability of a larger clinical trial of MgSO4 for pediatric TBI.

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