Methylene blue (MB) is a medication commonly used to treat methemoglobinemia, reducing methemoglobin to hemoglobin. A novel use of MB, as detailed here, is in the treatment of refractory hypotension. A number of reports have detailed use of MB for this purpose in adults, but few data in pediatrics. A 22-month-old girl with Noonan syndrome, biventricular hypertrophic cardiomyopathy, and chronic positive pressure ventilation developed shock with tachycardia, hypotension, and fever after 3 days of diarrhea. She was critically ill, with warm extremities, bounding pulses, and brisk capillary refill. Laboratory tests revealed metabolic acidosis, low mixed venous oxygen saturation, and leukocytosis with bandemia. Treatment of severe septic shock was initiated with fluid resuscitation, inotropic support, sedation, and paralysis. She remained hypotensive despite norepinephrine at 0.7 μg/kg per minute, dopamine at 20 μg/kg per minute, and vasopressin at 0.04 U/kg per hour. Her vasoplegic shock worsened, despite aggressive conventional therapy. Intravenous MB was initiated, with a loading dose of 1 mg/kg followed by a continuous infusion at 0.25 mg/kg per hour. Upon initiation of MB, her systolic blood pressure increased by 33 points (40% increase), and diastolic blood pressure increased by 20 points (46% increase). She was able to wean off all inotropes quickly after initiation of MB. MB should be considered in the setting of refractory vasoplegic shock in the PICU.
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October 2015
Case Report|
October 01 2015
A Novel Use of Methylene Blue in the Pediatric ICU
Chrystal Rutledge, MD;
aDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
Address correspondence to Chrystal Rutledge, MD, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, CPPI Suite 102, Birmingham, AL 35233. E-mail: crutledge@peds.uab.edu
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Brian Brown, PharmD;
Brian Brown, PharmD
bDepartment of Pharmacy, Children’s of Alabama, Birmingham, Alabama; and
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Kimberley Benner, PharmD;
Kimberley Benner, PharmD
cMcWhorter School of Pharmacy, Samford University, Birmingham, Alabama
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Priya Prabhakaran, MD;
Priya Prabhakaran, MD
aDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
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Leslie Hayes, MD
Leslie Hayes, MD
aDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama;
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Address correspondence to Chrystal Rutledge, MD, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, CPPI Suite 102, Birmingham, AL 35233. E-mail: crutledge@peds.uab.edu
FINANCIAL DISCLOSURE: Kim Benner has a financial relationship with MedImmune as a member of the speakers’ bureau for Flumist. The other authors have indicated they have no financial relationships relevant to this article to disclose.
Pediatrics (2015) 136 (4): e1030–e1034.
Article history
Accepted:
June 02 2015
Citation
Chrystal Rutledge, Brian Brown, Kimberley Benner, Priya Prabhakaran, Leslie Hayes; A Novel Use of Methylene Blue in the Pediatric ICU. Pediatrics October 2015; 136 (4): e1030–e1034. 10.1542/peds.2014-3722
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Comments
Methylene blue in pediatric intensive care
To the Editor
The Rutledge and colleagues' excellent presentation, including the case report and excellent literature review, will be a capital reference about methylene blue (MB) to treat distributive circulatory shock in children [1]. Because we believe that MB is a lifesaving drug, we do not resist, even on a repeated way, in reinforce this faith. The MB use in children has two main concerns: pulmonary hypertension and the controversial use in acute respiratory distress syndrome (ARDS). These aspects have not been systematically studied. Few studies have reported MB to increase pulmonary artery pressures and vascular resistance. However, these elevations in pulmonary vascular indices were noted to be clinically and statistically insignificant [2]. Our institution has a solid experience with MB to treat cardiac surgery- related vasoplegic syndrome (VS) [3-4]. Some observations in adults would apply to children: 1) The use of MB did not cause endothelial dysfunction; 2) The MB effect appears in cases with NO up-regulation; 3) MB is not a vasoconstrictor itself: by blocking off the cGMP pathway, it releases the cAMP pathway, facilitating the epinephrine's vasoconstrictor effect through this "crosstalk" mechanism; 5) The most used dosage is 2 mg/kg as IV bolus, followed by the same continuous hourly infusion, because the plasma concentrations strongly decay in the first 40 minutes. Many times the hemodynamic and metabolic effects of MB were not observed because there is a potential "window of opportunity" for its effectiveness. A possible explanation was given based on Fernandes' academic thesis using a mouse sepsis model, which evidenced 3 eight-hour windows of guanylate cyclase (GC) activity [5]. In the first 8 hours, there was increased nitric oxide synthase (NOS) activity and GC upregulation. In the next 8 hours, there was a lack of GC expression and downregulation of NOS. In the third 8-hour window, there was an upregulation of GC and NOS. Therefore, there are 2 opposing situations when using MB: (1) The use of MB as rescue therapy, and (2) the use of MB as an early adjuvant drug (first window). MB use as a final rescue therapeutic option is against the concepts we mentioned above. A late MB use may result in lack of effect (second window) or at too late effect (third window), when the circulatory shock is metabolically irreversible. Therefore, it is more reasonable to consider MB use not as a late rescue treatment, but rather as an early adjuvant drug to be used early (first window). Surely, these concepts would also be useful for the neonatal and pediatric areas, where there have been some reports. Mortality in sepsis is still high worldwide. Neonates and children with distributive shock are especially susceptible to the undesirable side effects of high-dose catecholamine infusions, and could be greatly benefitted from early MB infusion. If there is a cheap, available, safe and effective adjuvant drug, why not use it?
References 1. Rutledge C, Brown B, Benner K, Prabhakaran P, Hayes L. A Novel Use o Methylene Blue in the Pediatric ICU. Pediatrics. 2015 Oct;136(4):e1030-4. doi: 10.1542/peds.2014-3722. Epub 2015 Sep 7. PubMed PMID: 26347436. 2. Raikhelkar JK, Milla F, Darrow B, Scurlock C. Adjuvant therapy with methylene blue in the treatment of right ventricular failure after pulmonary embolectomy. Heart Lung Circ. 2011 Apr;20(4):234-6. doi: 10.1016/j.hlc.2010.08.018. Epub 2010 Oct 16. PubMed PMID: 20952252. 3. Evora PR, Ribeiro PJ, Vicente WV, Reis CL, Rodrigues AJ, Menardi AC, Alves Junior L, Evora PM, Bassetto S. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc. 2009 Jul-Sep;24(3):279- 88. Review. PubMed PMID: 20011872. 4. Evora PR, Alves Junior L, Ferreira CA, Menardi AC, Bassetto S, Rodrigues AJ, Scorzoni Filho A, Vicente WV. Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised. PMC4389523. 5. Fernandes D, da Silva-Santos JE, Duma D, Villela CG, Barja-Fidalgo C, Assreuy J. Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity. Mol;Pharmacol. 2006 Mar;69(3):983-90. Epub 2005 Dec 2. PubMed PMID: 16326931
Conflict of Interest:
None declared