Picture 5: Correlation of the variation percentage of the Wood-Downes clinical score with the serum magnesium level at the end of the 4-hour continuous infusion of magnesium sulfate.
When comparing the serum magnesium level and a better clinical response, assessed by varying the score (p = 0.392), no correlation was observed. Using a cutoff point of serum magnesium level at 4.0, as suggested in the literature as a therapeutic mean, no significant variation was observed (p = 0.77) (Picture 5).
There were no reports of any adverse events during and after the intravenous magnesium sulfate infusion in 4 hours, researching the description of nausea, drowsiness, vision changes, muscle weakness, hypotension, respiratory distress, arrhythmia and burning sensation and redness in the application route.
The average length of stay in the pediatric emergency was 2 days. Only 2 (5%) patients required transfer to the PICU, but without the need for ventilatory support. There was no correlation between the length of stay in the pediatric emergency and the variation in the clinical score (p = 0.242). None of the patients in the study died.
Discussion:
The management of asthma in the emergency room must be fast and organized due to the reversibility possibility of the condition and the potential risk of progression to respiratory failure (3). The classic treatment includes repeated inhaled beta-adrenergics and corticosteroids. In acute and severe cases, magnesium sulfate has been used intravenously after failure to respond to initial management. Magnesium produces smooth muscle relaxation inducing bronchodilation and has a rapid peak of action, but is also rapidly eliminated by the kidney, which restricts its use. In order to prolong the effect of magnesium sulfate, maintaining a compatible therapeutic level to compensate for the rapid elimination, Irazuzta et al. suggested the continuous infusion of this medication (16,19,20).
The present study evaluated children who were admitted to the pediatric emergency room with severe acute asthma and who used a continuous infusion of magnesium sulfate for 4 hours, at a dose of 50mg/kg/hour. It was possible to observe that there was a significant clinical improvement after the end of the infusion, the serum magnesium level ranged from 3.3 to 5.6 mg/dL, very close to the levels described in the literature as therapeutic (around 4.0 mg/dL). No patient experienced adverse events (8).
The beneficial effect of magnesium sulfate on asthma is well known, but few studies have been conducted in children. In a 2016 Cochrane review, only 5 studies with a more robust methodology were identified, where the authors concluded that intravenous magnesium sulfate could reduce the need for hospital admission in patients with moderate to severe asthma, refractory to the initial treatment. In our study, a significant clinical improvement was observed after 4 hours of infusion, assessed by varying the clinical severity score and only 2 out of 40 patients did not respond to magnesium sulfate, even with an adequate serum level, requiring transfer to PICU (16).
The normal concentration of serum magnesium in humans is 1.8 to 2.3 mg / dL. It is the fourth most abundant mineral in the body, it acts as a cofactor in more than 300 enzymatic reactions, it is necessary for the synthesis of proteins, including DNA and RNA. The ideal level of serum magnesium for the treatment of wheezing exacerbations in childhood is not well established in the literature. Several studies have reported achieving therapeutic efficacy with serum concentrations between 3 and 5 mg/dL, corroborating the data found in this study in which the median serum magnesium was 4.3 (3.9-4.6) after 4 hours of infusion (13-20).
The toxicity of magnesium sulfate has already been well evidenced in obstetric and anesthetic studies, mainly associated with the treatment of eclampsia, however there is little description outside these contexts. The side effects of magnesium sulfate are known to be dose dependent. Symptoms such as nausea, flushing, drowsiness, changes in vision and muscle weakness are more common when serum magnesium concentrations exceed 9 mg/dL. On the other hand, Graft and collaborators observed that the maintenance of serum magnesium levels between 4 and 6 mg/dL are effective in avoiding clinical signs of toxicity (15). From the data found in this study, we can observe that the use of magnesium sulfate by continuous infusion in 4 hours at a dose of 50mg/kg/hour raises the serum magnesium level to therapeutic values, non-toxic however (14,15,19).
Our study has limitations because it is a case series without a control group. Associated with this, it is a review of electronic medical records, subject to some interpretation bias, mainly in the subjective data described, however we try to minimize this fact by using only one reviewer researcher. Despite these restrictions, the results obtained corroborate with the data presented in the literature so far, showing that magnesium sulfate in continuous infusion could be useful in the treatment of severe acute asthma safely. New studies, ideally multicentric, randomized and with a larger sample size, can contribute to a deeper knowledge on the subject.
Conclusion:
Based on this study, we concluded that the use of continuous intravenous magnesium sulfate at a dose of 50mg/kg/hour in 4 hours can be a satisfactory adjuvant therapy in the setting of severe acute asthma in children. Associated with the advantage of a good clinical response, magnesium sulfate was shown to be safe, maintaining a non-toxic and therapeutic serum level, with no adverse events observed.
References:
  1. Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma [cited 2016 Jun 07]. Global Strategy for Asthma Management and Prevention 2016. [Adobe Acrobat document, 151p.]. Available from: http://ginasthma.org/wp-content/).
  2. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;35: 2226-2235.
  3. Shein S, Specher H, Proença JP et al. Tratamento atual da criança com asma critica quase fatal. Ter. Bras. Ter. Int ;2016:167-178.
  4. Solé D, Rosário Filho NA, Sarinho E et al.. Prevalence of asthma and allergic diseases in adolescents: nine-year follow-up study (2003-2012). J Pediatr (Rio J). 2015; 9:30-35.
  5. Ciarallo L; Sauer A, Shannon M et al. Intravenous magnesium therapy for moderate to severe pediatric asthma: Results of a randomized, placebo-controlled trial. J Pediatrics 1996; 129:.809-814.
  6. Cairns, 1996 Cairns CB, Krafi M. Magnesium attenuates the neutrophil respiratory burst in adult asthmatic patients. Academic Emergency Medicine 1996: 3:1093-1097.
  7. Spivey, 1990 Spivey WH, Skobeloff EM, Levin RM. Effect of magnesium chloride on rabbit bronchial smooth muscle. Annals of Emergency Medicine 1990:19:1107–1112.
  8. Glover ML, Machado C, Totapally BR: Magnesium sulfate administered via continuous intravenous infusion in pediatric patients with refractory wheezing. J Crit Care 2002: 17:255–258 .
  9. Goodacre S, Cohen J, Bradburn M, et al; 3Mg Research Team: The 3Mg trial: A randomised controlled trial of intravenous or nebulised magnesium sulphate versus placebo in adults with acute severe asthma. Health Technol Assess 2014; 18:1–168 .
  10. Singhi S, Grover S, Bansal A, et al: Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for children with acute severe asthma. Acta Paediatr 2014; 103:1301–1306.
  11. Cairns, 1996 Cairns CB, Krafi M. Magnesium attenuates the neutrophil respiratory burst in adult asthmatic patients. Academic Emergency Medicine 1996;3:1093-1097.
  12. Chesley LC, Tepper I: Some effects of magnesium loading upon renal excretion of magnesium and certain other electrolytes. J Clin Invest 1958; 37:1362-1372.
  13. Rower J, Liux Y. Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma. Eur. J. Pharmacol. 2017;73:325-331.
  14. Egelund T. High-dose magnesium sulfate infusion protocol for status asthmaticus: a safety and pharmacokinetics cohort study. Intensive Care Med 2013; 39: 117-122.
  15. Graft D. Stevenson M, Berkenbosch J. Safety of prolonged magnesium sulfate infusion during treatment for severe pediatric status asthmaticus. Pediatric Pulmonology 2019; 51:1-7.
  16. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD011050).
  17. Irazuzta J. Paredes F, Pavlivich V. High-Dose Magnesium Sulfate Infusion for Severe Asthma in the Emergency Department: Efficacy Study. Pediatr Crit Care Med 2016; 17: 29-33.
  18. Torres S. Effectiveness of magnesium sulfate as initial treatment of acute severe asthma in children, conducted in a tertiary-level university hospital: a randomized, controlled trial. Arch Argent Pediatr 2012: 110; 291-296.
  19. Irazusta JE, Chiriboga N. Magnesium Sulfate infusion for acute asthma in the emergency department. J Pediatr (Rio J) 2017; 93:19-25.
  20. Pruikkonen H, Tapiainen T, Kallio M, et al. Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial. Eur Respir J 2018; 51: 1701579 [https://doi. org/10.1183/13993003.01579-2017.
  21. Wood, D. Downes J, Leckes H. A clinical scoring system for the diagnosis of respiratory failure. Preliminary report on childhood status asthmaticus. Am J Dis Child 1972; 123: 227-228.
  22. Paro, ML; Rodrigues JC. Factors predictive of the development of acute asthma attacks in children. J Bras Pneumol 2005;31: 373-381, 2005.