Methylene Blue for Refractory Shock in Pediatric Patients

Kristin Bohannon
PGY1 Pediatric Focus Pharmacy Resident
Seton Healthcare Family
Kbohannon@seton.org
October 28, 2016
Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

Objectives:
• Review the pathophysiology of distributive shock
Methylene Blue for Refractory • Describe the rationale for using methylene blue in shock
Shock in Pediatric Patients patients
• Evaluate the literature available utilizing methylene blue in
Kristin Bohannon, Pharm.D.
PGY1 Pediatric Focused Pharmacy Resident
shock patients
Seton Healthcare Family • Discuss the potential place in therapy for methylene blue

©2015 Seton 1 ©2015 Seton 2

Patient Case Patient Case

• MJ is a 13 yo female who is afebrile with a HR 120, RR 28, BP • 12 hours later Current vitals:
79/50, MAP 58. Upon physical exam, her extremities remain – MAP 57 mmHg despite Temp HR RR BP MAP
adequate fluids and 98.8 122 39 83/44 57
warm and her capillary refill is >3 seconds. Physician vasopressors °C beats/min breaths/min mmHg mmHg
diagnoses her with distributive shock.
• Current Medications:
– Norepinephrine 1 mcg/kg/min
• Which therapy would not be used in a patient with – Vasopressin 0.04 units/kg/min
distributive shock? – Epinephrine 0.5 mcg/kg/min

A. Fluid bolus – Hydrocortisone 2 mg/kg x1, 1

B. Norepinephrine mg/kg Q8H
C. Epinephrine
D. Methylene Blue
E. None of the above

©2015 Seton 3 https://canaanhesterman.files.wordpress.com/2011/08/img_3916.jpg ©2015 Seton 4

Background:
Shock and MB

©2015 Seton 5 ©2015 Seton 6

Bohannon 1
Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

Epidemiology Types of Shock

• Mortality rate for adults with vasoplegia estimated up to 50%

• Mortality rate for adults with septic shock 30-50% Hypovolemic Distributive Cardiogenic Obstructive

• Septic shock in pediatric patients •Sepsis

•Anaphylaxis
– Consistently among top 10 causes of mortality in children •Drug ingestion
•Vasoplegia
– Mortality rate 14-24%

– Healthcare costs of $1.9 billion annually in the U.S.

Hosseinian L, et al. Anesth Analg. 2016.

Fitzgerald JC, at al. Pediatr Crit Care Med. 2016. ©2015 Seton 7 Sinniah D. IeJSME. 2012 ©2015 Seton 8
Hartman ME, et al. Pediatr Crit Care Med. 2013.

Shock spiral Distributive Shock Effects

Shock

Systemic vascular resistance

- Vasoplegia
Myocardial Tissue
- 3rd space fluid dysfunction hypoperfusion
extravasation
Cardiac output

- Release of vasodilators
- Systemic inflammation

©2015 Seton 9 ©2015 Seton 10

Stages of Shock Distributive Shock Treatment Options

Compensated
Early shock
Tachycardia, tachypnea, capillary refill <3 Fluid boluses Norepinephrine Epinephrine
seconds

Uncompensated
Tachycardia, tachypnea, hypotension,
Vasopressin Dopamine Corticosteroids
Late shock
capillary refill >4 seconds

Irreversible Phenylephrine Albumin

Complete failure of compensatory
Death in presence of resuscitation
mechanisms

Sinniah D. IeJSME. 2012 ©2015 Seton 11 ©2015 Seton 12

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Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

Methylene Blue Mechanism of MB in Shock

FDA indication • Drug-induced methemoglobinemia See Appendix B

Dosing for • 1 – 2 mg/kg

methemoglobinemia • May repeat every 30 – 60 minutes
Adverse events • Skin discoloration MB
• Hypertension
• Tachycardia
• Urine/fecal discoloration
• Hyperbilirubinemia ↑Ca2+ 
• Infusion site reaction vasoconstriction
• Skew pulse oximetry measurements
Contraindications • Hypersensitivity to methylene blue or any component
• G6PD deficiency
Cost • $75.00 for one 2mg/kg dose for a 25 kg patient

Methylene Blue injection [package insert]. Akorn, Inc. 2011. ©2015 Seton 13 Jang et al. J Med Toxicol. 2013. ©2015 Seton 1414

NO during shock
- Decreases responsiveness to
vasopressors
- Alters distribution of blood flow
- Increases capillary leak
- Multiple organ dysfunction
Methylene Blue in the Literature

- Increases oxygen delivery to

ischemic tissue
- Increases macrophage activity
- Reduces platelet aggregation
- Augments free radical scavenger
capabilities

Paciullo CA, et al. Pharmacotherapy. 2010. ©2015 Seton 15 ©2015 Seton 16

MB Randomized Trials
Randomized, Citation Population Intervention Results
Controlled • Adult trials
Trials Kirov MY, et al. Crit • n=20 • 2 mg/kg MB over • ↑ MAP
Care Med. 2001. • Septic shock 15 minutes • ↓ vasopressor
• 0.25 -2 mg/kg/hr use
MB for 4 hours • No change in
oxygen delivery,
Body of Observational SV, or CI
Studies • Adult studies
• n=30 • 0.5 mg/kg/hr MB • ↑ MAP
Literature Memis D, et al.
Anaesth Intensive • Severe sepsis for 6 hours • No change in
Care. 2002. cytokine levels
• No change in
clinical outcomes
Case • Adult reports Levin RL, et al. Ann • n=56 • 1.5 mg/kg over • ↓ mortality
Series/Reports Thorac Surg. 2004. • Vasoplegic 60 minutes • ↓ time of
• Pediatric reports syndrome vasoplegia
MB=methylene blue; MAP=mean arterial pressure; SV=stroke volume; CI=cardiac index

Kirov MY, et al. Crit Care Med. 2001.

©2015 Seton 17 Memis D, et al. Anaesth Intensive Care. 2002. ©2015 Seton 18
Levin RL, et al. Ann Thorac Surg. 2004.

Bohannon 3
Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

Kirov, 2001 – Study Overview Kirov, 2001 – Population

• Evaluate the effects of continuous infusion of MB on
Objective hemodynamics and organ function in septic shock Inclusion Exclusion
• Severe sepsis or septic shock • < 18 years old
Design • Prospective, randomized, controlled, open-label pilot study • Mechanical ventilation • Pregnant
• Pulmonary artery catheters • Receiving corticosteroid,
• 1:1 randomization (n=20) for MB or isotonic saline
• Bolus 2 mg/kg over 15 minutes
in place immunosuppressant, or
Methods • Continuous infusion 0.25 mg/kg/hr, 0.5 mg/kg/hr, 1 mg/kg/hr, chemotherapy
2 mg/kg/hr each for a one hour period

• Hemodynamics and organ function assessed over 24 hours

Endpoint • Survival rate at 28 days

MB=methylene blue

Kirov MY, et al. Crit Care Med. 2001. ©2015 Seton 19 Kirov MY, et al. Crit Care Med. 2001. ©2015 Seton 20

Kirov, 2001 – Results Kirov, 2001 – Conclusions

Outcome Methylene Blue Isotonic Saline P
Inotropic and vasopressor Decreased requirement: Author’s conclusion Presenter’s conclusion
support
- Norepinephrine - 87% <0.05 • Administration of MB: • Small sample size
- Epinephrine - 81% <0.05 • ↑ cardiovascular function • Promising role for MB as
- Dopamine - 40% <0.05
• ↓ requirement for adjuvant therapy for septic
MAP at 24 hours, mmHg - 86.6 ± 15.3 - 69.9 ± 18.4 0.04
adrenergic support shock as it ↓ need for
Clinical characteristics
- Duration septic shock - 58.9 ± 36.7 - 66.3 ± 44.3 0.73 • Maintains oxygen delivery vasopressors
- Duration vasopressor - 71.4 ±34.2 - 93.3 ± 49.7 0.54 and consumption • Only minor adverse
support, h reactions seen
• Has relatively small risk of
- Duration ventilation, h - 84.4 ± 43.9 - 75.1 ± 57.1 0.72
- Resolution of shock - n=7 - n=3 0.07 toxicity
- Survivors at day 28 - n=5 - n=3 0.65
MAP=mean arterial pressure
p<0.05 is significant MB=methylene blue

Kirov MY, et al. Crit Care Med. 2001. ©2015 Seton 21 Kirov MY, et al. Crit Care Med. 2001. ©2015 Seton 22

Memis, 2002 – Study Overview Memis, 2002 – Population

• To assess the effect of methylene blue infusion on plasma Inclusion Exclusion
Objective levels of cytokines in severe sepsis
• Bacteriologically-documented • <18 years
infection with at least two • Pregnant
• Prospective, randomized, double-blind, placebo-controlled sepsis criteria
Design study • Receiving corticosteroids,
• One of the following immunosuppressants, or
conditions: chemotherapy
• Computer-steered permuted block design (n=30) • Hypocapemia • Known irreversible underlying
Methods • 0.5 mg/kg/hr x 6 hours MB or isotonic saline
• Oliguria disease
• Lactic acidosis
• Cytokine levels at 48 hours • Thrombocytopenia
Endpoint • Hemodynamics and organ function over 48 hours • Recent change in mental
MB=methylene blue
status

Memis D, et al. Anaesth Intensive Care. 2002. ©2015 Seton 23 Memis D, et al. Anaesth Intensive Care. 2002. ©2015 Seton 24

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Methylene Blue for Refractory Shock in 10/28/2016
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Memis, 2002 – Results Memis, 2002 – Conclusions

Author’s conclusion Presenter’s conclusion
Outcome Methylene Blue Isotonic Saline p
MAP • No difference in cytokine • Small sample size
- End of MB infusion, mmHg - 85±14 - 74±10.3 <0.001 levels
- 48 hrs later, mmHg - 75±12.5 - 74±14.8 >0.05
• No loading dose
• Transient increase in MAP
Cytokine levels >0.05 • Low dose of MB used
• No difference in survival
Mechanical ventilation duration, h 7±2 8±3 >0.05
outcome • Only minor adverse reaction
Mortality rate, % 26.6 26.6 >0.05 seen
MAP=mean arterial pressure; MB = methylene blue
p<0.05 is significant

MAP=mean arterial pressure; MB=methylene blue

Memis D, et al. Anaesth Intensive Care. 2002. ©2015 Seton 25 Memis D, et al. Anaesth Intensive Care. 2002. ©2015 Seton 26

Levin, 2004 – Study Overview Levin, 2004 – Population

• To analyze the incidence of postoperative vasoplegic
Objective syndrome, to consider its prognosis, and to evaluate the effect Inclusion Exclusion
of methylene blue on mortality
• Patients having cardiac • Off-pump coronary artery
surgery bypass surgery
Design • Prospective, randomized, placebo-controlled trial
• Vasoplegic syndrome • Bacterial endocarditis
• Aortic dissection
• 1:1 randomization (n=56) to MB or placebo
Methods • MB 1.5 mg/kg over 60 minutes • Urgent or emergent
procedures
• Morbidity
Endpoint • Mortality

MB=methylene blue

Levin RL, et al. Ann Thorac Surg. 2004. ©2015 Seton 27 Levin RL, et al. Ann Thorac Surg. 2004. ©2015 Seton 28

Levin, 2004 – Results Levin, 2004 – Conclusions

Outcome Methylene Blue (n=28) Placebo (n=28) p Author’s conclusion Presenter’s conclusion
Mortality, % (n) 0 (0) 21.4 (6) 0.01
Duration of vasoplegia >48 0 (0) 28.6 (8) 0.002 • Placebo group • Largest randomized trial to
hours, % (n)
• Worse evolution date
Renal failure, % (n) 0 (0) 14.3 (4) 0.05 • No definition of when
• More sepsis
Respiratory failure, % (n) 0 (0) 14.3 (4) 0.05 morbidity outcomes were
• Higher mortality assessed
Supraventricular arrhythmia, 7.1 (2) 28.6 (8) 0.03
% (n) • No significant adverse • Significant mortality benefit
Sepsis, % (n) 0 (0) 25 (7) 0.005 effects • No discussion on
Multi-organ dysfunction, % (n) 0 (0) 25 (7) 0.005 hemodynamic variables or
on weaning vasopressors

Levin RL, et al. Ann Thorac Surg. 2004. ©2015 Seton 29 Levin RL, et al. Ann Thorac Surg. 2004. ©2015 Seton 30

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Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

MB Adult Observational Studies

Randomized, Citation Population Intervention Results Key Points
Controlled • Adult trials
Trials Daemen- • n=9 • 2 mg/kg over • ↑ MAP • Transient
Gubbels CR, et • At least one 20 minutes • ↑ CI increase in
al. Crit Care vasopressor hemodynamics
Med. 1995.
Preiser JC, et • n=14 • 2 mg/kg over • ↑ MAP • Reproducible
Body of Observational
• Adult studies
al. Crit Care • At least one 15 minutes • ↑ SVR response to MB
Studies Med. 1995. vasopressor • 2nd dose given • CO and oxygen bolus
Literature at 90 minutes delivery did not
in 6 patients change
Andresen M, • n=10 • 1 mg/kg over • ↑ MAP • MB initiated
et al. J Crit • At least two 15 minutes • ↑ SVR after 1 hour of
Care. 1998. vasopressors • CO and oxygen vasopressors
Case • Adult reports delivery did not
Series/Reports change
• Pediatric reports
MAP=mean arterial pressure; CI=cardiac index; SVR=systemic vascular resistance; CO=cardiac output

Daemen-Gubbels CR, et al. Crit Care Med. 1995.

©2015 Seton 31 Preiser JC, et al. Crit Care Med. 1995. ©2015 Seton 32
Andresen M, et al. J Crit Care. 1998

MB Adult Observational Studies MB Adult Observational Studies

Citation Population Intervention Results Key Points
Citation Population Intervention Results Key Points
Gachot B, et al. • n=6 • 3 mg/kg • ↑ MAP • Larger dose and
Intensivve Care • At least one over 10 • ↑ PVR decreased Park et al. • n=20 • 1 mg/kg MB • ↑ MAP • No change in
Med. 1995. vasopressor minutes • CI and oxygen infusion time  Korean J • At least one over 15 • ↑ SVR cytokine levels
delivery did not ↑ PVR and Intern Med. vasopressor minutes • No change in or NO
change ↓ PaO2:FiO2 2005. CO production
Weingartner • n=10 • 4 mg/kg • ↑ MAP • Larger dose  Heemskerk S, • n=9 • 1 mg/kg/hr • ↑ MAP • ↑ kidney
R, et al. Braz J • At least one over 60 • ↑ SVR ↑pulmonary et al. Intensive • At least one for 4 hours • ↑ CrCl function
Med Biol Res. vasopressor minutes • No change CI or pressure Care Med. vasopressor • ↓kidney
1999. oxygen delivery 2008. injury markers
Donati A, et al. • n=15 • 3 mg/kg • ↑ MAP • Larger dose  MAP=mean arterial pressure; SVR=systemic vascular resistance; CO=cardiac output; NO=nitric oxide;
Crit Care Med. • At least one over 10 • ↑ SVR ↑pulmonary CrCl=creatinine clearance
2002. vasopressor minutes • ↑ PVR pressure
• No change in CO
MAP=mean arterial pressure; PVR=pulmonary vascular resistance; CI=cardiac index; PaO 2:FiO2=ratio of partial
pressure arterial oxygen and fraction of inspired oxygen; SVR=systemic vascular resistance; CO=cardiac output

Gachot B, et al. Intensivve Care Med. 1995. Park et al. Korean J Intern Med. 2005.
Donati A, et al. Crit Care Med. 2002. ©2015 Seton 33 Heemskerk S, et al. Intensive Care Med. 2008. ©2015 Seton 34
Weingartner R, et al. Braz J Med Biol Res. 1999.

Juffermans, 2010 – Dose-Finding Study

Randomized,
Objective • To evaluate dose-dependency of MB in septic shock Controlled • Adult trials
Trials
• n=15 adults
Methods • 1 mg/kg (n=4), 3 mg/kg (n=6), 7 mg/kg (n=5) over 20
minutes

• MAP/CO
Body of Observational
Endpoints Studies • Adult studies
• Splanchnic blood flow Literature
• Increase in dose 
Results • ↑ positive effects
• ↓ splanchnic blood flow
Case
Conclusion • 1-3 mg/kg dose provides benefit while minimizing side Series/Reports • Pediatric reports
effects

MB=methylene blue; MAP=mean arterial pressure; CO=cardiac output

Juffermans NP, et al. Nitric Oxide. 2010. ©2015 Seton 35 ©2015 Seton 36

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Methylene Blue for Refractory Shock in 10/28/2016
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Driscoll, 1996 – Study Overview Driscoll, 1996 – Neonatal Study

• To evaluate the use of MB in neonates with septic shock Patient Characteristics and Outcomes
Objective refractory to conventional therapy
1 2 3 4 5
40 weeks, 24 weeks, 2
Patient 23 weeks, 3
Patient 24 weeks, 30 weeks,
3.61 kg 0.573 kg 0.525 kg 0.574 kg 1.339 kg
Design • Observational study 24 weeks, 23 weeks,
573 gm MB
525post
gm MB post
MB post MB post colloids,
MB post crystalloid,
colloids, colloids and crystalloids,
colloids, colloid,
MB postand
crystalloids, inotropic hydrocortisone,
crystalloids,
MB post inotropic
crystalloid,
• n=5 inotropic agents
Methods • 1 mg/kg MB over 60 minutes agents, and
andcolloids,
inotropic
agents
crystalloids,
colloid,
agentsand
inotropic agents
and inotropic
agents
hydrocortisone and inotropic 2ndnddose MB 6 2nd dose MB 5
agents 2 dose
hours MB16st
after st
hours after 1
hours after 1st 2nd dose MB 12
• MAP hours after 1st
Discharged Discharged
Endpoint • Heart rate Discharged
home DOL 7
Discharged
home
home at
at 55
Discharged
home
home at 44
Patient Patient
• Blood gas months
months months
months passed away passed away
MB=methylene blue; MAP=mean arterial pressure MB=methylene blue; DOL=day of life

Driscoll W, et al. J Pediatr. 1996. ©2015 Seton 37 Driscoll W, et al. J Pediatr. 1996. ©2015 Seton 38

Driscoll, 1996 – Results Driscoll, 1996 – Conclusions

See Appendix C
Author’s Conclusion Presenter’s Conclusion
• ↑ BP • Diverse group of neonates
• ↑ HR in 4/5 neonates • Small sample size
• No change in oxygen • ↑ MAP
requirement or blood gases
• ↓ need for vasopressors
• Need for larger, randomized
controlled trial

BP=blood pressure; HR=heart rate; MAP=mean arterial pressure

Driscoll W, et al. J Pediatr. 1996. ©2015 Seton 39 Driscoll W, et al. J Pediatr. 1996. ©2015 Seton 40

Pediatric Case Reports Taylor, 2005 – The Patient

Study Population Intervention Results
Taylor K, et al. J 10 yo with • 2 mg/kg LD • Vasopressors
•
Thorac Cardiovasc
Surg. 2005.
endocarditis
• Refractory
1 mg/kg/hr discontinued within 2
days of MB
10 yr old endocarditis mitral valve operation
hypotension
Flynn BC, et al. J 14 yo with bilateral • 1.5 mg/kg over 10 • Vasopressors weaned Prior to surgery Post surgery
Cardiothorac Vasc lung transplant minutes or discontinued
Anesth. 2009. • Vasoplegia within 10 minutes of • Dopamine 10 mcg/kg/min • Epinephrine 0.05 to 0.1
MB • Epinephrine 0.5 mcg/kg/min mcg/kg/min
Bhalla T et al. World 5 yo with heart • 1 mg/kg over 5 • ↑ MAP • Methylene Blue 2 mg/kg load • Norepinephrine 0.1 mcg/kg/min
J Pediatr Congenit transplant minutes • Vasopressors weaned
Heart Surg. 2011. • Vasoplegia within 12 hrs • Methylene Blue 1 mg/kg/hr • Vasopressin 0.0001 to 0.0003
units/kg/min
Rutledge C, et al. 22 mo with • 1 mg/kg LD • ↑ SBP 33%
Pediatrics. 2015. cardiomyopathy • 0.25 mg/kg/hr • ↑ DBP 46% • Milrinone 0.33 mcg/kg/min
• Refractory • Drips discontinued • Methylene Blue 1 mg/kg/hr
vasoplegia and within 5 hrs of MB
hypotension discontinuation
yo=year old; LD=loading dose; MB=methylene blue; MAP=mean arterial pressure; mo=month old;
SBP=systolic blood pressure; DBP = diastolic blood pressure

Rutledge C, et al. Pediatrics. 2015.

Taylor K, et al. J Thorac Cardiovasc Surg. 2005. ©2015 Seton 41 ©2015 Seton 42
Flynn, et al. J Cardiothorac Vasc Anesth. 2009.

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Methylene Blue for Refractory Shock in 10/28/2016
Pediatric Patients

Taylor, 2005 – Case Report Flynn, 2009 – The Patient

• 2 mg/kg MB load
Intervention • 1 mg/kg/hr for an unknown duration Phenylephrine
0.75 mcg/kg/min
• Epinephrine and norepinephrine discontinued POD 1
Vasopressin Epinephrine
Result • Vasopressin discontinued POD 2
• Milrinone discontinued POD 8 0.002 units/kg/min 0.03 mcg/kg/min

Side Effects • None reported

14 yr old
• Vasopressors discontinued within 2 days and inotrope Norepinephrine bilateral Inhaled nitric oxide
Key Point discontinued day 8 0.5 mcg/kg/min lung 20 ppm
• Post-operative course benign transplant
MB = methylene blue; POD=postoperative day

Taylor K, et al. J Thorac Cardiovasc Surg. 2005. ©2015 Seton 43 Flynn BC, et al. J Cardiothorac Vasc Anesth. 2009. ©2015 Seton 44

Flynn, 2009 – Case Report Bhalla, 2011 – The Patient

Intervention • 1.5 mg/kg MB over 10 minutes
Epinephrine
Milrinone 0.222 mcg/kg/min Vasopressin
• ↓ vasopressor drip rate before MB infusion ended
• NE off; phenylephrine off; Epi ↓ by half; 0.75 mcg/kg/min 0.002 units/kg/min
Results vasopressin ↓ by a factor of 6
• No change in CVP
Dobutamine Norepinephrine
15 mcg/kg/min 8 mcg/kg/min
Side Effects • None reported

5 yr old
• MB aided in quick reversal of vasodilatory shock Dopamine post Fluid
Key Point • No deleterious effects noted 17 mcg/kg/min cardiac boluses
• Can be used concomitantly with NO transplant
MB =methylene blue; NE=norepinephrine; Epi=epinephrine; CVP = Central venous pressure; NO= nitric oxide

Flynn BC, et al. J Cardiothorac Vasc Anesth. 2009. ©2015 Seton 45

Bhalla T, et al. World J Pediatr Congenit Heart Surg. 2011. ©2015 Seton 46

Bhalla, 2011 – Case Report Rutledge, 2015 – The Patient

Intervention • 1 mg/kg MB over 5 minutes

Norepinephrine Vasopressin
• ↑ MAP 1 mcg/kg/min 0.04 units/kg/min
Results • Epinephrine, Norepinephrine, and vasopressin weaned over
12 hours

• Skin discoloration Dopamine

Side Effects • Falsely low pulse oximeter reading
Fluids
100 mL/kg 20 mcg/kg/min
22 mo old
with septic
• ↑ MAP 10 minutes post MB administration
Key Point • Short infusion time shock

MB = methylene blue; MAP = mean arterial pressure

Bhalla T, et al. World J Pediatr Congenit Heart Surg. 2011. ©2015 Seton 47 Rutledge C, et al. Pediatrics. 2015. ©2015 Seton 48

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Rutledge, 2015 – Case Report

• 1 mg/kg MB
Intervention • 0.25 mg/kg/hr MB x 25 hours

• ↑ SBP 40%

Result •
•
•
↑ DBP 46%
Dopamine weaned in 6 hours; norepinephrine weaned 14 hours
Vasopressin weaned 5 hours after MB stopped Conclusions
• Skin discoloration
Side Effects • Urine discoloration

Key Point • Long duration of MB infusion

MB = methylene blue; SBP = systolic blood pressure; DBP = diastolic blood pressure

Rutledge C, et al. Pediatrics. 2015. ©2015 Seton 49 ©2015 Seton 50

Adverse Effects Conclusions about MB

Advantages
Blue-green discoloration of urine
• Patients require less
vasopressors
Blue discoloration of skin
• Improves MAP
Skewing of pulse oximeter reading • Does not change oxygen
consumption or delivery
Methemoglobinemia • No toxic side effects
Disadvantages
• Evidence is from small case
reports/studies
• No established regimen
• No consistent demonstrated
difference in mortality

©2015 Seton 51 ©2015 Seton 52

Patient Population for MB MB Dosing Recommendation

Consider for Do Not Recommend
Patients with: for Patients with: 1 – 3 mg/kg administered
over 5-60 minutes
Vasodilatory G6PD
shock deficiency

No additional 1 – 3 mg/kg 0.25 – 1

Decreased
MAP
Cold shock MB repeated bolus mg/kg/hr

≥1
Vasopressor 4 – 25 hours

©2015 Seton 53 ©2015 Seton 54

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Methylene Blue for Refractory Shock in 10/28/2016
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MB Recommendation Patient Case

• 12 hours later Current vitals:
– MAP 57 mmHg despite Temp HR RR BP MAP
adequate fluids and
Monitoring vasopressors
98.8
°C
122 39 83/44
beats/min breaths/min mmHg mmHg
57

• Current Medications:
• Mean arterial pressure – Norepinephrine 1 mcg/kg/min
• Blood gas – Vasopressin 0.04 units/kg/min
• Lactate – Epinephrine 0.5 mcg/kg/min
• Serum creatinine
– Hydrocortisone 2 mg/kg x1, 1
• Hemoglobin mg/kg Q8H

©2015 Seton 55 https://canaanhesterman.files.wordpress.com/2011/08/img_3916.jpg ©2015 Seton 56

Acknowledgements
• Carolyn Ragsdale, Pharm.D., BCPS, BCPPS
• Ronda Machen, Pharm.D., RD, BCPPS
• Molly Curran, Pharm.D.

©2015 Seton 57 ©2015 Seton 58

Methylene Blue for Refractory

Shock in Pediatric Patients
Kristin Bohannon, Pharm.D.
PGY1 Pediatric Focused Pharmacy Resident
Seton Healthcare Family

http://www.superchurch.com/wp-content/uploads/5-Big-Questions.jpg ©2015 Seton 59 ©2015 Seton 60

Bohannon 10
 Appendix A – Abbreviations

BP = blood pressure

CI = cardiac index

CO = cardiac output

CrCl = creatinine clearance

CVP = Central venous pressure

DBP = diastolic blood pressure

DOL = day of life

Epi = epinephrine

HR = heart rate

MAP = mean arterial pressure

MB = methylene blue

NE = norepinephrine

NO = nitric oxide

PaO2:FiO2 = ratio of partial pressure arterial oxygen and fraction of inspired oxygen

POD = postoperative day

PVR = pulmonary vascular resistance

SBP = systolic blood pressure

SV = stroke volume

SVR = systemic vascular resistance

11
 Appendix B – Mechanism of Methylene Blue in Shock

MB

↑Ca2+ 
vasoconstriction

Jang et al. J Med Toxicol. 2013. 12

 Appendix C – Results: Driscoll, 1996

Driscoll W, et al. J Pediatr. 1996. 13

 Appendix D – References

1. Andresen M, Dougnac A, Díaz O, et al. Use of methylene blue in patients with refractory septic
shock: impact on hemodynamics and gas exchange. J Crit Care. 1998;13(4):164-8.
2. Bhalla T, Sawardekar A, Russell H, Tobias JD. The role of methylene blue in the pediatric patient
with vasoplegic syndrome. World J Pediatr Congenit Heart Surg. 2011;2(4):652-5. doi:
10.1177/2150135111410992.
3. Daemen-Gubbels CR, Groeneveld PH, Groeneveld AB, et al. Methylene blue increases
myocardial function in septic shock. Crit Care Med. 1995;23(8):1363-70.
4. Donati A, Conti G, Loggi S, et al. Does methylene blue administration to septic shock patients
affect vascular permeability and blood volume?. Crit Care Med. 2002;30(10):2271-7.
5. Driscoll W, Thurin S, Carrion V, Steinhorn RH, Morin FC 3rd. Effect of methylene blue on
refractory neonatal hypotension. J Pediatr. 1996;129(6):904-8.
6. Flynn BC, Sladen RN. The use of methylene blue for vasodilatory shock in a pediatric lung
transplant patient. J Cardiothorac Vasc Anesth. 2009;23(4):529-30. doi:
10.1053/j.jvca.2008.11.016. Epub 2009.
7. Gachot B, Bedos JP, Veber B, Wolff M, Regnier B. Short-term effects of methylene blue on
hemodynamics and gas exchange in humans with septic shock. Intensive Care Med.
1995;21(12):1027-31.
8. Heemskerk S, van Haren FM, Foudraine NA, et al. Short-term beneficial effects of methylene
blue on kidney damage in septic shock patients. Intensive Care Med. 2008;34(2):350-4. Epub
2007.
9. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a new use of an old
antidote. J Med Toxicol. 2013;9:242-249. doi: 10.1007/s13181-013-0298-7.
10. Juffermans NP, Vervloet MG, Daemen-Gubbels CR, et al. A dose-finding study of methylene blue
to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide.
2010;22(4):275-80. doi: 10.1016/j.niox.2010.01.006. Epub 2010 Jan 28.
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