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A Novel Use of Methylene Blue in the Pediatric ICU Chrystal Rutledge, MDa, Brian Brown, PharmDb, Kimberley Benner, PharmDc, Priya Prabhakaran, MDa, Leslie Hayes, MDa

abstract Methylene blue (MB) is a medication commonly used to treat , reducing to . 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 . A 22-month-old girl with Noonan syndrome, biventricular hypertrophic cardiomyopathy, and chronic positive pressure ventilation developed shock with tachycardia, hypotension, and 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 saturation, and leukocytosis with bandemia. Treatment of severe was initiated with fluid resuscitation, inotropic support, aDepartment of Pediatrics, University of Alabama at sedation, and paralysis. She remained hypotensive despite at Birmingham, Birmingham, Alabama; bDepartment of , Children’s of Alabama, Birmingham, Alabama; 0.7 mg/kg per minute, at 20 mg/kg per minute, and vasopressin at and cMcWhorter School of Pharmacy, Samford University, 0.04 U/kg per hour. Her vasoplegic shock worsened, despite aggressive Birmingham, Alabama conventional . Intravenous MB was initiated, with a loading dose of Dr Rutledge was involved in the care of the patient 1 mg/kg followed by a continuous infusion at 0.25 mg/kg per hour. Upon detailed in the case report and drafted the initial initiation of MB, her systolic blood pressure increased by 33 points (40% manuscript; Professors Brown and Benner assisted with the dosing of methylene blue and contributed increase), and diastolic blood pressure increased by 20 points (46% increase). to the pharmacological research for the She was able to wean off all inotropes quickly after initiation of MB. MB should manuscript; Drs Prabhakaran and Hayes were be considered in the setting of refractory vasoplegic shock in the PICU. involved in the care of the patient detailed in the case report and critically reviewed the manuscript; and all authors approved the final manuscript as submitted. Septic shock is a known cause of commonly used to treat fi www.pediatrics.org/cgi/doi/10.1542/peds.2014-3722 signi cant morbidity and mortality in methemoglobinemia by reducing children, with an incidence of 0.56 DOI: 10.1542/peds.2014-3722 methemoglobin to hemoglobin. A novel cases per 1000 children and a national use of MB, as detailed in this case Accepted for publication Jun 2, 2015 mortality rate of 10.3% (6.2 per 100 report, is in the treatment of refractory Address correspondence to Chrystal Rutledge, MD, 000 population).1 The primary goals in Department of Pediatrics, University of Alabama at vasoplegia and hypotension. A number Birmingham, 1600 7th Avenue South, CPPI Suite 102, treatment of septic shock are rapid of reports have detailed the use of MB Birmingham, AL 35233. E-mail: [email protected]. restoration of hemodynamic stability for this purpose in adults,2 but there is edu and treatment of the underlying a paucity of pediatric data. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, infection. Therapy for correcting A 22-month-old girl with Noonan 1098-4275). hemodynamic instability includes syndrome, biventricular hypertrophic Copyright © 2015 by the American Academy of aggressive fluid resuscitation followed cardiomyopathy, failure to thrive, and Pediatrics by vasoactive infusions for fluid chronic respiratory failure FINANCIAL DISCLOSURE: Kim Benner has a financial refractory shock. Vasoactive agents necessitating long-term ventilation relationship with MedImmune as a member of the commonly used include dopamine, speakers’ bureau for Flumist. The other authors developed fever with uncompensated have indicated they have no financial relationships epinephrine, norepinephrine, shock after 3 days of diarrhea. Her relevant to this article to disclose. phenylephrine, and vasopressin. initial vital signs and laboratory data FUNDING: No external funding. Methylene blue (MB) is a potentially are detailed in Tables 1 and 2. She was useful adjunct in a subset of patients POTENTIAL CONFLICT OF INTEREST: The authors have ill-appearing, with warm extremities, indicated they have no potential conflicts of interest with fluid-refractory, catecholamine- bounding pulses, and flash capillary to disclose. refractory, warm shock. MB is refill (,2 seconds). Her medications at

Downloaded from www.aappublications.org/news by guest on October 1, 2021 CASE REPORT PEDIATRICS Volume 136, number 4, October 2015 TABLE 1 Initial Vital Signs hypernatremia, and azotemia. Her infectious workup was negative. She Temperature 41.2°C central venous pressure was was eventually transferred from the Heart rate 170 beats per minute measured during resuscitation and PICU to the chronic ventilator unit on Respiratory rate 61 breaths per minute was adequate at 12 to 18 mm Hg after a laptop ventilator for additional BP 59/26 mm Hg fluids. Despite an adequate central inpatient care. Oxygen saturation 100% on 55% FiO2 venous pressure she remained hypotensive, so norepinephrine was DISCUSSION this time included calcium glubionate, added for warm shock. We decreased fluconazole, lansoprazole, metabolic demand with sedation, MB is a most commonly propranolol, and verapamil. Arterial paralysis, mechanical ventilation, and recognized for its treatment of blood gas demonstrated metabolic aggressive control of fever with methemoglobinemia but has been acidosis. Electrolyte abnormalities a cooling blanket. After transient found to have diverse uses in included hypernatremia, improvement, she worsened and . More esoteric indications hypokalemia, and hyperchloremia. became refractory to 1 mg/kg per include , , Renal function demonstrated minute of norepinephrine, 0.04 U/kg hepatopulmonary syndrome, disproportionate elevation of blood per minute of vasopressin, and vasoplegic syndrome, and refractory urea nitrogen compared with 20 mg/kg per minute of dopamine. hypotension.3 MB owes this creatinine. Complete blood cell count MB was added for severe refractory extensive repertoire to its effects on revealed leukocytosis with vasoplegia and hypotension. A multiple physiologic pathways. In a significant elevation in band forms loading dose of 1 mg/kg was methemoglobinemia, MB reduces (12%). Cultures of blood, , and administered, followed by an infusion methemoglobin to hemoglobin via its trachea were obtained. A Clostridium of 0.25 mg/kg per hour 4 hours after interaction with reduced difficile culture was also obtained, the loading dose, with dramatic nicotinamide adenine dinucleotide given her history of diarrhea. Broad- improvement. Her systolic blood (NADPH).4 Additionally, it spectrum antimicrobial therapy was pressure (BP) increased by 33 mm Hg inhibits inducible nitric oxide initiated with vancomycin, (40% increase), and diastolic BP synthase (iNOS), an enzyme that is meropenem, gentamicin, and increased by 20 mm Hg (46% activated by endotoxins and micafungin. A transthoracic increase) (Fig 1). cytokines. Activation of iNOS in echocardiogram, unchanged from her After the bolus of MB, BP improved endothelial and vascular smooth baseline, showed severe biventricular significantly. Dopamine was weaned muscle results in increased hypertrophy, dynamic left ventricular off in 6 hours and norepinephrine in generation of nitric oxide (NO), fl out ow tract obstruction (peak left 14 hours. MB was infused for a total which activates guanylate cyclase to fl ventricular out ow tract gradient, of 25 hours. Although the BP was increase cyclic guanosine 52 mm Hg), normal biventricular adequate, the clinical decision was monophosphate and causes smooth systolic function (left ventricular made to discontinue MB (without muscle relaxation, vasodilatation, ejection fraction, 65.3%), and weaning) before stopping and increased vascular moderate pulmonary valve stenosis. vasopressin. Vasopressin was able to permeability.5 This is the mechanism She was initially resuscitated with be discontinued 5 hours after MB was of action of MB in reversing 100 mL/kg of fluids to restore her stopped. She was unparalyzed 1 day refractory vasoplegia in conditions depleted intravascular volume, as after MB was discontinued and that can result in exuberant suggested by preceding diarrhea, returned to her baseline. Her production of NO, such as sepsis,

TABLE 2 Initial Laboratory Data Chemistries Arterial Blood Gas Complete Blood Cell Count Sodium 167 mmol/L pH 7.26 White blood cell count 22 3 103/mL

Potassium 2.6 mmol/L pCO2 47 mm Hg Hemoglobin 11.5 g/dL 3 Chloride 128 mmol/L pO2 61 mm Hg Platelet count 73 3 10 /mL Bicarbonate 24 mmol/L Bicarbonate 21.1 mmol/L Blood urea nitrogen 96 mg/dL Mixed venous saturation 50.3% Creatinine 0.8 mg/dL 148 mg/dL Calcium 8.8 mg/dL 2.6 mg/dL Phosphorus 5.8 mg/dL

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1031 AB Before Methylene Blue After Methylene Blue Before Methylene Blue After Methylene Blue 140 80 UCL=79.22 UCL=134.31 130 _ X=122.26 70 _ 120 X=67.16 Hg)

Hg) 110 LCL=110.20 60 100 LCL=55.10 50 90

80 40 Systolic BP (mm 70 Diastolic BP (mm 30 60

50 20 61 363126211611 41 46 61 11 16 2621 31 4136 46 Time (h) Time (h)

C 25 1 0.9

20 0.8

0.7

15 0.6  g/kg/min)

 g/kg/min) 0.5

10 0.4 Methylene blue bolus dose given Dopamine ( 0.3 (1mg/kg) Methylene Blue (mg/kg/hr) Methylene Vasopressin dose (units/kg/hr) Vasopressin

5 0.2 Norepinephrine dose (

0.1

0 0 0510 1520 25 30 35 40 45 50 55 Time (h)

Dopamine (g/kg/min) Norepinephrine (g/kg/min) Vasopressin (units/kg/hr) Methylene Blue (mg/kg/hr) FIGURE 1 BP and doses of vasoactive agents before and after MB. A, Change in systolic BP before and after MB. Systolic BP increased by 33 mm Hg (40% increase; P = .000; 95% confidence interval, 27.05–40.31). B, Change in diastolic BP before and after MB. Diastolic BP increased by 20 mm Hg (46% increase; P = .000; 95% confidence interval, 15.84–23.70). C, Doses of vasoactive agents before and after MB. LCL, lower control limit; UCL, upper control limit; x, mean. systemic inflammatory response pressure while reducing Holtby13 reported a child with syndrome, or anaphylaxis. catecholamine requirements in vasoplegia who received 2 doses of patients in septic shock, but its effects MB at 2 mg/kg intravenously for MB is rapidly distributed into the on morbidity and mortality are hypotension in relation to bypass. brain, heart, lungs, liver, and kidneys. unclear.2,5,10 Dumbarton et al11 also Another study used similar doses of It rapidly enters erythrocytes and is reportedacaseofprolongedMB 1 to 2 mg/kg in neonates for sepsis quickly reduced to leucomethylene infusion for 120 hours at doses and acquired methemoglobinemia.9 blue. Its half-life has been estimated titrated from 0.12 to 0.5 mg/kg per from 30 minutes to 6.6 hours. It is Driscoll et al14 described 5 neonates hour in an adult with refractory septic eliminated in the bile, feces, and urine with refractory hypotension due to shock. Another dose finding study as leucomethylene blue.6–9 septic shock who received 1 mg/kg infused 1, 3, or 7 mg/kg over 20 intravenously infused over 1 hour Dosing guidelines for MB in minutes in adults with septic shock. and had subsequent improvement refractory hypotension in adults have Improved hemodynamics were in BP. been previously published. Paciullo reportedwithdosesaslowas1mg/kg, et al5 summarized the trials that with more adverse effects at Prasad et al15 compared evaluated MB in septic shock and higher doses.12 intermittent and continuous MB reported bolus doses of 1, 2, 3, and infusionsin11childrenfor 4 mg/kg, including 2 studies that methemoglobinemia using the same DOSING IN PEDIATRICS used infusions of 0.25 mg/kg per hour overall dose of 2 mg/kg; these up to 2 mg/kg per hour. They reported Limited literature is available for investigators found the continuous that MB administration is associated dosing of MB in children with infusion to be more effective than with increases in mean arterial refractory hypotension. Taylor and intermittent boluses.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e1032 RUTLEDGE et al Our patient received a 1-mg/kg bolus potential for MB to cause pulmonary a good option in the treatment of of undiluted MB to treat vasodilatory vasoconstriction and possibly worsen catecholamine refractory vasoplegic shock.16 Clinical improvement the patient’s respiratory condition states including septic shock. occurred after the MB bolus, and an was given much consideration before MB continuous infusion was started it was decided that the risk/benefit ∼4 hours after the bolus at a rate of ratio was favorable. ABBREVIATIONS 0.25 mg/kg per hour for a total MB is contraindicated in patients with BP: blood pressure of 25 hours. The final concentration glucose-6-phosphate dehydrogenase iNOS: inducible nitric oxide of the MB infused was 0.05%.17 MB is deficiency. NADPH is critical to the synthase stable when diluted in normal reduction of MB to leucomethylene; MB: methylene blue or 5% dextrose in water; the length of patients with glucose-6-phosphate NADPH: nicotinamide adenine stability is uncertain. dehydrogenase deficiency have low dinucleotide phosphate levels of endogenous NADPH, putting NO: nitric oxide ADVERSE EFFECTS OF METHYLENE BLUE them at a higher risk of hemolytic The most common adverse effect of .23 Because MB may alter MB administration is self-limiting cyclic guanosine monophosphate blue-green discoloring of skin or accumulation in platelet aggregation, REFERENCES urine, which our index patient there is concern about deleterious 1. Watson RS, Carcillo JA, Linde-Zwirble WT, demonstrated. Confusion, fever, effects on platelet count; however, it Clermont G, Lidicker J, Angus DC. The , , abdominal , has been postulated that this may be epidemiology of severe sepsis in , and diaphoresis have been an effect of septic shock rather than children in the United States. Am J reported.18–20 Some studies have MB treatment because at least 1 Respir Crit Care Med. 2003;167(5): noted pulmonary vasoconstriction study has shown no significant effects 695–701 and decreases in oxygenation as well on platelets.10 2. Kirov MY, Evgenov OV, Evgenov NV, et al. as cardiac arrhythmias, decreased In pediatric patients, doses .2 mg/kg Infusion of methylene blue in human cardiac output, and decreased renal have been associated with septic shock: a pilot, randomized, fl controlled study. Crit Care Med. 2001; and mesenteric blood ow. These methemoglobinemia, hemolytic 29(10):1860–1867 more serious adverse effects anemia, and hyperbilirubinemia.9 Our reportedly did not occur with doses patient received a cumulative dose 3. Ginimuge PR, Jyothi SD. Methylene blue: , 19 2 mg/kg. Also, because of the higher than that but had no such side revisited. J Anaesth Clin Pharmacol. – ability of MB to absorb light at effects. 2010;26(4):517 520 wavelengths close to the wavelengths 4. Curry S. Methemoglobinemia. Ann Emerg emitted by some oximetry devices, Med. 1982;11(4):214–221 COST case reports have highlighted 5. Paciullo CA, McMahon Horner D, Hatton a decrease in oximetry readings, As mentioned in the case narrative, KW, Flynn JD. Methylene blue for the whereas others have reported no because of profound vasoplegia, treatment of septic shock. fi 21,22 ’ signi cant changes. Our patient s continuous infusions of vasopressin, Pharmacotherapy. 2010;30(7):702–715 hemodynamics were monitored norepinephrine, and dopamine were 6. Clifton J II, Leikin JB. Methylene blue. Am throughout the infusion. Her heart administered. Overall, the daily cost J Ther. 2003;10(4):289–291 rate decreased mildly during infusion, ∼ for the MB infusion was $7 more 7. DiSanto AR, Wagner JG. an effect thought to be secondary to than the cost of vasopressin, of highly ionized improved blood pressure. Her oxygen norepinephrine, dopamine, and drugs. II. Methylene blue—absorption, saturations were followed on arterial epinephrine; however, it provided , and excretion in man and blood gases, and there was no change a decreased drip burden for the dog after oral administration. J Pharm in pulse oximetry readings during nursing staff and allowed the Sci. 1972;61(7):1086–1090 infusion. She was ventilated with discontinuation of all vasoactive 8. Peter C, Hongwan D, Küpfer A, a pressure-regulated volume drugs after 1 day. Lauterburg BH. Pharmacokinetics and control–pressure support mode. organ distribution of intravenous and There were no changes in her CONCLUSIONS oral methylene blue. Eur J Clin ventilation strategy around the time Pharmacol. 2000;56(3):247–250 of the MB infusion. Because the Through its effect on iNOS, MB has 9. Allegaert K, Miserez M, Lerut T, Naulaers patient in this case report had a potential role in reversing G, Vanhole C, Devlieger H. a history of pulmonary valve stenosis vasodilation in conditions associated Methemoglobinemia and after and was also chronically dependent with exuberant production of NO. Its enteral administration of methylene blue on mechanical ventilation, the benign side effect profile renders it in a preterm infant: relevance for

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 136, number 4, October 2015 e1033 pediatric surgeons. J Pediatr Surg. 2004; on refractory neonatal hypotension. for vasoplegic syndrome during cardiac 39(1):e35–e37 J Pediatr. 1996;129(6):904–908 . Ann Thorac Surg. 2005;79(5): 1615–1619 10. Memis D, Karamanlioglu B, Yuksel M, 15. Prasad R, Singh R, Mishra OP, Pandey M. Gemlik I, Pamukcu Z. The influence of Dapsone induced methemoglobinemia: 20. Stawicki SP, Sims C, Sarani B, Grossman methylene blue infusion on cytokine intermittent vs continuous intravenous MD, Gracias VH. Methylene blue and levels during severe sepsis. Anaesth methylene blue therapy. Indian J Pediatr. vasoplegia: who, when, and how? Mini Intensive Care. 2002;30(6):755–762 2008;75(3):245–247 Rev Med Chem. 2008;8(5):472–490 11. Dumbarton TC, Minor S, Yeung CK, Green 16. Brown G, Frankl D, Phang T. Continuous 21. McDonagh DL, McDaniel MR, Monk TG. R. Prolonged methylene blue infusion in infusion of methylene blue for septic The effect of intravenous indigo carmine refractory septic shock: a case report. shock. Postgrad Med J. 1996;72(852): on near-infrared cerebral oximetry. – Anesth Analg – Can J Anaesth. 2011;58(4):401–405 612 614 . 2007;105(3):704 706 17. Berlin G, Brodin B, Hilden JO, 22. Mittnacht AJ, Fischer GW, Reich DL. 12. Juffermans NP, Vervloet MG, Daemen- Mårtensson J. Acute dapsone Methylene blue administration is Gubbels CR, Binnekade JM, de Jong M, intoxication: a case treated with associated with decreased cerebral Groeneveld AB. A dose-finding study of continuous infusion of methylene blue, oximetry values. Anesth Analg. 2007; methylene blue to inhibit nitric oxide forced diuresis and plasma exchange. 105(2):549–550 actions in the hemodynamics of human J Toxicol Clin Toxicol. 1984–1985;22(6): septic shock. Nitric Oxide. 2010;22(4): 23. Brewer GJ. Rediscovery of the 537–548 fi 275–280 susceptibility of G6PD de cient persons 18. Levin RL, Degrange MA, Bruno GF, et al. to methemoglobinemia from oxidant 13. Taylor K, Holtby H. Methylene blue Methylene blue reduces mortality and drugs, and to hemolysis from methylene revisited: management of hypotension in morbidity in vasoplegic patients after blue. Am J Hematol. 2007;82(1):87–88 a pediatric patient with bacterial . Ann Thorac Surg. 2004; 24. Memis D, Karamanlioglu B, Yuksel M, endocarditis. J Thorac Cardiovasc Surg. – 77(2):496 499 Gemlik I, Pamukcu Z. The influence of 2005;130(2):566 19. Ozal E, Kuralay E, Yildirim V, et al. methylene blue infusion on cytokine 14. Driscoll W, Thurin S, Carrion V, Steinhorn Preoperative methylene blue levels during severe sepsis. Anaesth RH, Morin FC III. Effect of methylene blue administration in patients at high risk Intensive Care. 2002;30(6):755–762

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e1034 RUTLEDGE et al A Novel Use of Methylene Blue in the Pediatric ICU Chrystal Rutledge, Brian Brown, Kimberley Benner, Priya Prabhakaran and Leslie Hayes Pediatrics 2015;136;e1030 DOI: 10.1542/peds.2014-3722 originally published online September 7, 2015;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/136/4/e1030 References This article cites 24 articles, 1 of which you can access for free at: http://pediatrics.aappublications.org/content/136/4/e1030#BIBL Collections This article, along with others on similar topics, appears in the following collection(s): Critical Care http://www.aappublications.org/cgi/collection/critical_care_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 A Novel Use of Methylene Blue in the Pediatric ICU Chrystal Rutledge, Brian Brown, Kimberley Benner, Priya Prabhakaran and Leslie Hayes Pediatrics 2015;136;e1030 DOI: 10.1542/peds.2014-3722 originally published online September 7, 2015;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/136/4/e1030

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