The use of therapeutic magnesium for neuroprotection during global cerebral ischemia associated with cardiac arrest and cardiac bypass surgery in adults: a systematic review protocol

Abstract

Review objective The objective of this review is to present the best currently available evidence in relation to the neuroprotective effectiveness of magnesium during a period of global cerebral ischemia in adults with cardiac arrest or undergoing cardiac bypass surgery. Background Global cerebral ischemia may result from several causes, including the cessation of organized myocardial activity in conditions such as cardiac arrest or cardiac bypass surgery. Hemodynamic collapse results in ischemia of the brain tissue.1,2 In an ischemic environment, neurological cellular functions begin to fail within minutes, resulting in irreversible pathological damage due to a number of biochemical processes.3 Cardiac arrest Survival outcomes post cardiac arrest (CA) are generally very poor.1 For out of hospital CA, survival (up to 28 days) for bystander witnessed CA is 10.6%4 and for Emergency Medical Service (EMS) witnessed out of hospital, CA around 33%.4 This data is limited to shockable rhythms only, including ventricular fibrillation (VF) or ventricular tachycardia (VT). Survival rates for in hospital CA are slightly higher where survival rate to hospital discharge increases from up to 14% to 32%, depending on initial rhythm.5,6 Patients may survive CA due to resuscitation and life support practices; however post cardiac arrest syndrome,7 including extensive cerebral damage, frequently prevents full neurological recovery.2,8 Current estimations suggest only 3% to 7% of CA survivors return to their pre cardiac arrest level of neurological functioning.8 Post cardiac arrest syndrome is the pathology, which follows reperfusion after whole body ischemia.2 The four key components include: post arrest brain injury, post arrest myocardial dysfunction, systemic ischemia and reperfusion response.2 Precipitating pathology contributes significantly to high morbidity and mortality rates in patients with return of spontaneous circulation.2,7 Cerebral dysfunction occurs due to a combination of anoxic cerebral conditions and reperfusion injury.2 ore than 50% of CA survivors sustain some degree of permanent cerebral injury.8,9 The resulting cerebral deficits range from memory loss and severe depression to brain death and cerebral necrosis, causing significant reduction of quality of life.8 The magnitude of cerebral damage post CA is measured by several methods including the cerebral performance category, Glasgow coma score, Karnofsky performance status,6 brain stem reflexes,10 neurological imaging and motor neuron assessments.1,10 Overall, the advances in life support practices have had little effect on the survival outcome of CA since cardio-pulmonary resuscitation was introduced in the 1960s.1,6 There is some evidence that hemodynamic optimization, oxygenation and ventilation, circulatory support, management of acute coronary syndrome and treatment of the reversible causes (including metabolic control) can reduce post CA neurological injury. Currently, the International Liaison Committee on Resuscitation recommends therapeutic hypothermia post cardiac arrest for neuroprotection. However, to date, there have been few pharmacological measures introduced which elicit neuroprotection. Improved survival outcomes and preserved neurological functioning may be achievable with a neuroprotective agent such as magnesium.11 Cardiac bypass surgery Cardiac bypass surgery is often performed to increase quality of life, however for patients with cognitive decline and neurologic dysfunction post-surgery, quality of life rapidly decreases.12 Neurologic dysfunction is a major cause of mortality and morbidity post cardiac surgery, when associated with prolonged hospital stay and decreased independent living.10 Dysfunction is apparent in 50% to 80% of cardiac surgery patients at hospital discharge, 20% to 50% at six weeks and 10% to 30% at six months post operatively.10 The mechanisms for neurologic dysfunction are similar to CA where global cerebral ischemia occurs due to decreased perfusion.10,12 Additional contributing factors include genetic predisposition, transcerebral platelet activation, cerebral embolism, cell salvage, systemic inflammatory responses, hemodilution, variation in blood glucose and control of body temperature.10 Neurological deficits are similar to those seen in patients who suffer CA, including altered neurocognitive state and behavioral abnormalities.10 Magnesium for neuroprotection The properties of magnesium suggest that it has the potential to be an ideal neuroprotective therapy during global cerebral ischemia, based on its cellular actions and membrane stabilization properties.13 Magnesium is the fourth most abundant cation in the body and is fundamental for essential bodily functions.3 Normal homeostatic balance of magnesium is achieved through utilizing feedback systems involving intestinal absorption, renal excretion and bone metabolism.14 Intracellular magnesium concentrations correlate to the rate of protein synthesis, as magnesium is a fundamental cofactor for intracellular enzymes during cellular metabolism.14 Cerebral magnesium is predominantly found bound with adenosine triphosphate, thus suggesting magnesium plays a central role in cellular energy metabolism, the formation of cellular growth and regulation.15 The neuroprotective mechanisms of magnesium on neurons and glia have been investigated since the 1980s.16 It is associated with several physiological processes relevant to cerebral ischemia.17 These include: vasodilatory regulation of cerebral blood flow,18 inhibition of presynaptic excitotoxic neurotransmitters such as glutamate, and anti-apopogenic modulation of growth factors.17 Magnesium provides non-competitive inhibition at post-synaptic glutamate N-methyl-D-aspartate (NMDA) coupled calcium receptors, thereby inhibiting the release of calcium into neuronal cells.13,18 Increased intracellular magnesium also provides antagonist actions at voltage gated channels preventing entry of ions up regulated during ischemia including calcium, sodium and potassium.13,17 Free magnesium has been shown to diminish during acute and chronic cerebral pathologies.19 Ischemia causes glutamate excitotoxicity, resulting in excess calcium and sodium influx via ligand-gated channels causing alterations to the intracellular ionic environment. The neurochemical consequences result in oxygen free radical generation, membrane lipid breakdown, proteolysis, up regulation of specific genes, apoptosis, neuroinflammation and necrosis.20,21 These processes present clinically as possible neurological dysfunction and neurocognitive decline.10 Cerebrospinal concentrations of magnesium are generally higher at 1.1mmol/l compared to plasma serum concentrations at 0.8 mmol/l.17 Animal models demonstrate cortical extracellular concentrations of magnesium are higher than cerebrospinal fluid, indicating active transport across the blood brain barrier (BBB).14 It is unclear whether magnesium travels across the BBB via the paracellular or transcellular route.14 Both intramuscular and intravenous administration of magnesium can increase cerebrospinal fluid concentrations by 20% to 25%, indicating the possibility of clinically effective therapy.22 Current clinical applications The clinical application of antenatal magnesium for neuroprotection of preterm infants has been reported to show beneficial neurological outcomes.23,24 Currently, due to the lack of comparative trials, there is no consensus as to the regimen of choice for the use magnesium in terms of dose and duration.23 Women with pre-eclampsia and eclampsia are at a high risk of developing seizures, which result in adverse outcomes for both mother and fetus.24 Magnesium is currently an anticonvulsant treatment used to reduce seizures, improve maternal and infant outcome and reduce mortality.25 Other current clinical applications of magnesium include unstable angina,26 acute severe asthma,27 traumatic brain injury28,29 sub-arachnoid hemorrhage28,29 and focal ischemia.28,29 Magnesium is also used for several cardiac dysrhythmias, including torsade de points and ventricular tachycardia.30 The neuroprotective effects of magnesium are still debated and further research is required. Variations in dosage, time of administration and combination with other therapies contribute to the varying results of clinical trials.18 The therapeutic dose of magnesium administered for neuroprotection during global cerebral ischemia may be in the range of two to six grams.3,6,30,31 Adverse reactions from high doses are few, however may include cardiovascular effects such as systemic vasodilatation and sinoatrial node blockade.6 A preliminary search of the Cochrane Library, PubMed and CINHAL has revealed that there are currently no other systematic reviews published that exclusively investigate the neuroprotective properties of magnesium during global cerebral ischemia associated with cardiac arrest and cardiac bypass surgery in humans. This review aims to address the lack of existing evidence by providing neuroprotective recommendations specifically for global cerebral ischemia to improve clinical outcomes for these patients. Inclusion criteria Types of participants This review will consider adults above 18 years of age. Studies of patients with existing neurological deficits or under the age of 18 will be excluded from the review. Types of intervention(s) The intervention of interest is magnesium in doses of at least two grams compared to placebo administered to adult patients within 24 hours of cardiac arrest or coronary bypass surgery. Types of outcomes The outcome of interest is neurological recovery post-cardiac arrest or coronary bypass surgery as measured by objective scales, such as, but not limited to: cerebral performance category, brain stem reflex, Glasgow Coma Score and independent living or dependent living status. Types of studies This review will consider both experimental study designs including randomized controlled trials, non-randomized controlled trials, and quasi-experimental. In the absence of such studies, this review will also include analytical epidemiological studies including, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies. Descriptive studies including case series, case reports and descriptive cross sectional studies will be considered in the absence of analytical epidemiological studies. Search strategy The search strategy aims to find both published and unpublished studies. The Joanna Briggs Institute (JBI) three step search strategy will be utilized in this review. An initial limited search of PubMed and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe each article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. The clinical implications of magnesium therapy have been investigated since the early 1980's. Studies published between January 1, 1980 and August 1, 2014 will be considered for inclusion in this review. PRISMA flowchart for reporting number of records identified, screened and included will be used. The databases to be searched include: PubMed, EMBASE, CINAHL & Cochrane Central Register of Controlled Trials (CENTRAL) The search for unpublished studies will include: Australian Clinical Trials Register (www.australianclinicaltrials.gov.u), Australian and New Zealand Clinical Trials Register (www.anzctr.org.au), Clinical Trials (https://clinicaltrials.gov/), European Clinical Trials Register (www.controlledtrials.com) and ISRCTN Registry (http://www.isrctn.com/) Initial keywords to be used will be: Neuroprotection, magnesium, cardiac arrest and cardiac bypass surgery Assessment of methodological quality Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Data collection Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Double data extraction will be undertaken to ensure the accuracy and reliability of the data. Where the required data is not available from the included studies, the authors will be contacted requesting the primary data. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data), weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square and I2 and explored using subgroup analyses (on studies where the intervention is implemented in the same way) based on the different study designs included in this review. Where clinical and methodological heterogeneity is not evident, all studies will be combined in meta-analysis. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Conflicts of interest The authors have no conflicts of interest. Acknowledgements This review is completed as part of the Master of Clinical Science academic program, at the Joanna Briggs Institute, Faculty of Health Sciences, University of Adelaide. Rochelle Kurmis (Secondary Reviewer) Burns Unit, Royal Adelaide Hospital