This is a single center, double blind, randomized controlled study to demonstrate the
effectiveness of continuous, intravenous administration of magnesium sulfate as compared
to placebo in decreasing pain in critically injured patients.
Study Hypothesis The primary hypothesis is that continuous infusion magnesium sulfate
will significantly decrease opioid requirements and pain scores in critically ill
patients.
Background Magnesium is one of the most abundant cations in the human body. The
physiologically active form of magnesium, ionized magnesium, is involved in hundreds of
enzyme reactions that are important for homeostasis, action potentials, and membrane
stability, among others.[Seo, et al] Hypomagnesemia is one of the most common electrolyte
disturbances in the hospitalized patient, especially in the critically ill population.
Studies have established that low magnesium levels increase mortality and morbidity in
the critically ill patient,[Upala, et al] and thus magnesium is often repleted with
intermittent infusion. Outside of its role in enzyme reactions, magnesium was discovered
to have analgesic effects approximately twenty years ago.[Albrecht, et al] It appears to
potentiate morphine analgesia, attenuate morphine tolerance, and suppress neuropathic
pain.[Albrecht, et al] At a mechanistic level, these effects are thought to be secondary
to magnesium regulating calcium influx into cells and antagonizing NMDA receptors in the
central nervous system.
Magnesium has long been utilized in prevention and management of preeclampsia and
eclampsia. A typical dosing regimen in this setting involves a 4 g loading dose of
magnesium sulfate, followed by a magnesium infusion of 1-2 g/hr. When compared to
eclampsia regimens, studies investigating the role of magnesium sulfate in multimodal
surgical pain management consistently use lower doses. Even with this dosing, multiple
trials have shown reduced postoperative pain and analgesic requirements.[Albrecht, et al,
Sousa, et al, Hwang, et al, Shariat, et al] In one example, Shariat Moharari and others
used a regimen of 40 mg/kg magnesium bolus followed by 10 mg/kg/hr infusion in
perioperative gastrointestinal surgery patients, without adverse effects.[Shariat, et al]
Normal reference range for serum magnesium has been defined as approximately 0.7-1 mmol/L
(1.5-2 mEq/L or 1.7-2.4 mg/dL).[Williamson, et al] Tramer et al. reported that a 3 g
bolus dose of magnesium sulfate followed with 0.5 g/hr infusion for 20 hours resulted in
an increase from baseline serum magnesium of approximately 0.6 mmol/L. Despite the higher
post-treatment serum magnesium levels in the treatment group, no difference in safety
outcomes was noted in comparison to the control group receiving 0.9% sodium
chloride.[Tramer,et al] Similarly, Ozcan et al. found that 30 mg/kg bolus dose of
magnesium sulfate followed by infusion of 10 mg/Kg/hr for 48 hours resulted in an
increased serum magnesium level from baseline by approximately 0.7 mmol/L. The noted
increase in serum magnesium level in this study also did not translate into any
difference in safety endpoints between the intervention group and control group receiving
0.9% sodium chloride.[Ozcan, et al] Initial signs of magnesium toxicity following
administration of magnesium sulfate have been reported to occur at serum magnesium levels
greater than 3.5-5 mmol/L.[Lu, et al, Jahnen-Dechent, et al]
Despite the successful use of magnesium in perioperative pain management, it has yet to
be applied in patient populations outside of the operating room. Given the need for
adequate pain control among critically ill patients with traumatic injuries, the use of
magnesium for pain management may assist in decreasing opioid requirements and provide
another non-opioid adjunct for pain control.
Methods:
All trauma patients admitted to an adult ICU are screened during the first 24 hours after
admission. If they meet criteria for admission to the study, an informed consent will be
obtained. Patients meeting eligibility will be randomized by the Investigational Drug
Service in a computer-generated, blinded block, 1:1 ratio to treatment with either
magnesium sulfate (diluted appropriately in normal saline per standard procedures) or
placebo (normal saline)."
Opioid administration will be recorded per usual nursing protocol in the electronic
medial record. Heart rate, mean arterial pressure (MAP), respiratory rate, and RASS will
be recorded at least every two hours per unit protocol.
A study worksheet will be posted at bedside for consistent collection of pain scores and
CAM. Pain will be assessed per unit protocol using the numeric rating scale, with zero
representing no pain and ten representing the worst pain imaginable.
The EMR will be reviewed; opioid administration, pain scores, and vital signs will be
transferred to a separate data sheet through REDCap (Research Electronic Data Capture)
software.
The primary outcome measure will be the total opioid requirement during the 24 hours of
magnesium infusion. We performed this power analysis based on a recent retrospective
cohort study performed at our institution.[Hamrick, et al] We estimate that the 24 hour
OME requirement will decrease from 70 mg in the control group to 50 mg in the treatment
group, with a standard deviation of 50 mg in each group, leading to an effect size of
0.4. Using the statistical program G*Power 3.0.1 with an effect size of 0.4, alpha of
0.05, power of 0.8, and equal allocation ratios, a sample size of 78 patients per group
would be required.
Data will be assessed for normality by assessing distribution skewness and kurtosis.
Depending on these results, t-tests or Wilcoxon rank-sum tests for two groups will be
used to assess the primary outcome of total opioid dose. Other data, including pain
scores, that is collected repeatedly will be analyzed with two-way repeated measures
analysis of variance, with subsequent pair-wise comparison for any significant findings.
Statistical significance will be set at a P value of less than 0.05. We will use SAS to
perform the statistical analysis.