severe undifferentiated vasoplegic shock refractory to

$: Severe Undifferentiated Vasoplegic Shock Refractory to$
Case ReportSevere Undifferentiated Vasoplegic Shock Refractory toVasoactive Agents Treated with Methylene Blue

FarheenManji12 BenjaminWierstra13 and Juan Posadas13

1University of Calgary and Alberta Health Services Calgary AB Canada2Department of Medicine University of Calgary Calgary AB Canada3Department of Critical Care University of Calgary Calgary AB Canada

Correspondence should be addressed to Farheen Manji farheenmanjiahsca

Received 3 July 2017 Accepted 27 August 2017 Published 2 October 2017

Academic Editor Moritoki Egi

Copyright copy 2017 Farheen Manji et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Methylene blue is a phenothiazine-related heterocyclic aromatic molecule presently used in the treatment of methemoglobinemiaRecently it has been implicated in the treatment of severe refractory vasoplegic shock caused by anaphylaxis sepsis orpostcardiopulmonary bypass We present a case of a 27-year-old male with profound vasoplegic shock of unknown etiology whichwas refractory to vasopressors who responded within hours to a single dose ofmethylene blue Additionally we review the evidenceof methylene bluersquos role in the treatment of shock This case illustrates a diagnostic approach and treatment options in the settingof undifferentiated vasodilatory shock and outlines a new and emerging role for methylene blue in this clinical setting

1 Introduction

Vasodilatory shock is a state of hypoperfusion characterizedby a significant decrease of vasomotor tone and consequentlya decrease of systemic vascular resistance [1] There aremany prevailing theories regarding the pathophysiology ofvasodilation that center around the inappropriate activa-tion of vasodilator mechanisms and the dysregulation ofvasoconstriction One such mechanism involves excessiveproduction of nitric oxide (NO) and upregulation of cyclicguanosine 3101584051015840-monophosphate (cGMP) which results indephosphorylation of myosin and subsequent vasodilation[1] Vasodilatory shock has multiple etiologies including sep-sis anaphylaxis adrenal insufficiency drug-induced shockand postcardiopulmonary bypass vasoplegia [1] Treatmentusually includes addressing the underlying cause and theprovision of supportive care including intravenous fluids andvasoactive agents [2] In addition to conventional therapiesthere has been research into inhibiting the cellular pathwaysat the level of NO and cGMP to prevent vasodilation andtissue hypoperfusion [2] One such therapy for refractoryvasodilatory shock is methylene blue which is a guanylylcyclase inhibitor and inhibits production of cGMP and

therefore inhibits dephosphorylation of myosin decreasingvasodilation [1]

We present the case of a 27-year-old male with profoundvasoplegic shock refractory to vasoactive agents in the settingof intravenousmethamphetamine use who responded withinhours to methylene blue therapy Additionally we reviewthe current literature on the use of methylene blue in thesetting of distributive shock of various etiologies includinganaphylaxis sepsis and postcardiac bypass

2 Case Presentation

A 27-year-old with past medical history of polysubstanceabuse including methamphetamines cocaine opioids andalcohol presented to the emergency department after twodays of intravenous methamphetamine use with generalizedmalaise nausea dizziness and blurry vision He denied feverchills chest pain or shortness of breath He had no recentsick contacts He purchased his methamphetamines from hisregular dealer but did admit to feeling unwell a fewhours afterinjecting it

His vitals on arrival to the emergency department werea temperature of 361 Celsius heart rate of 122 bpm blood

HindawiCase Reports in Critical CareVolume 2017 Article ID 8747326 4 pageshttpsdoiorg10115520178747326

2 Case Reports in Critical Care

Table 1 Bloodwork on initial presentation to the emergencydepartment

At admission Normal rangeHemoglobin 128 137ndash180 gLWhite blood cell 86 40ndash110 times 109LPlatelets 66 150ndash400 times 109LSodium 129 133ndash145mmolLPotassium 37 33ndash51mmolLChloride 94 98ndash111mmolLBicarbonate 15 21ndash31mmolLCreatinine 418 50ndash120 120583molLTotal bilirubin 47 0ndash24 120583molLINR 22 09ndash11PTT 392 27ndash37 sLactate dehydrogenase (LDH) 377 100ndash235ULFerritin 754 30ndash400 120583gLD-Dimer gt10 lt046mgLFibrinogen 11 16ndash41 gLCreatinine kinase 929 0ndash195ULLactate 80 lt2mmolLRandom cortisol 626 nmolLArterial pH 720 735ndash745Arterial pCO2 21 35ndash45mmHgArterial pO2 61 80ndash100mmHgArterial bicarbonate 9 24ndash26mmgHg

pressure of 8060mmHg with O2 saturation of 92 onroom air On examination his extremities were warm Hewas alert and oriented to person place and time Hisneurological exam revealed no motor or sensory deficitsHis neck was supple His cardiovascular exam revealed aregular tachycardia but nomurmurHis respiratory examwasunremarkable His abdomen was mildly tender in the rightupper quadrant

His initial laboratory work is shown in Table 1 In sum-mary he presented with a mild normocytic anemia newthrombocytopenia and new renal failure with a urinal-ysis showing no casts with trace blood and protein Hehad coagulation abnormalities consistent with disseminatedintravascular coagulation (DIC) His initial arterial bloodgas showed a primary metabolic acidosis secondary to lacticacidosis with a partially compensated by a respiratory alka-losis Computed Tomography (CT) scan of his head chestabdomen and pelvis was only significant for mild atelectasisin the posterior aspect of both lower lobes and splenomegaly(measured at 158 cm normal lt 12 cm) An echocardiogramrevealed normal right and left ventricular function with nohemodynamically significant valvular disease One out ofthree sets of blood cultures was positive for coryneformbacilli at 65 hours which was thought to be a contaminantHIV and hepatitis serologies were negative

In the emergency department his blood pressuredeclined to 6234mmHg He was given three liters of normalsaline initially with no response in blood pressure Hewas then started on escalating doses of norepinephrine

Vasopressor requirements aer methylene blue administration

Norepinephrine (mcgkgmin)Vasopressin (unitmin)

00102030405060708

Nor

epin

ephr

ine d

ose (

mcg

kg

min

)

5 10 15 20 25 300Hours aer methylene blue administration

0

001

002

003

004

005

Vaso

pres

sin d

ose (

unit

min

)

Figure 1 Vasopressor requirements hours after methylene blueadministration

up to 09mcgkgmin after which his blood pressureincreased to 7040mmHg Epinephrine was then added at02mcgkgmin resulting in his blood pressure increasing to10050mmHg He was empirically started on piperacillin-tazobactam and vancomycin Given that he had no bio-chemical evidence of adrenal insufficiency steroids werenot given Upon transfer to the ICU the patient wasintubated and his hemodynamic profile remained tenuouswith his blood pressure dropping to 7426mmHg Hisnorepinephrine was increased to 1mcgkgmin epinephrinewas increased to 035mcgkgmin and vasopressin wasadded at 004 unitmin Forty-eight hours into his admissionhis lactate normalized but he was still requiring 09mcgkgmin of norepinephrine and 004 unitmin of vasopressin tomaintain a mean arterial pressure greater than 60mmHgHe was given methylene blue dosed at 2mgkg for a totaldose of 190mg once His blood pressure and vasoactiveagent requirements are illustrated in Figure 1 in relation tothe number of hours after methylene blue administrationWithin two hours of administration the norepinephrinedosage was halved within 15 hours he was weaned offvasopressin and within 24 hours he was off vasoactivesupport completely and successfully extubated

No septic or anaphylactic etiology was identified as acause of the patientrsquos distributive shockThere was no clinicalor biochemical evidence of adrenal insufficiency He deniedany overdoses of medications known to commonly causevasoplegic shock such as calcium channel blockers As suchthe etiology of his shock remained undifferentiated

3 Discussion

Methylene blue is a phenothiazine-related heterocyclic aro-matic molecule that has a long history of use dating backto the 1800s for treatment of malaria and more commonlymethemoglobinemia [3] Recently there has been emerg-ing use of methylene blue in the treatment of refractorydistributive shock via inhibition of the nitric-oxide cyclicguanosine monophosphate pathway (Figure 2) [1] An initialinsult results in an increase in nitric oxide synthase and nitric

Case Reports in Critical Care 3

Initial insult

Nitric oxide

Vasomotor tone

Dephosphorylation of myosin

cGMP

Guanylyl cyclase

Nitric oxide synthase

(a)

Initial insult

Nitric oxide

Vasomotor tone

Guanylyl cyclase

Methylene blue



cGMP

(b)

Figure 2 (a) The biochemical pathway of vasodilatory shock as a result of upregulation of the nitric oxide-cGMP pathway (b) Methylenebluersquos site of action as a guanylyl cyclase inhibitor resulting in increased vasomotor tone

oxidewhich via guanylyl cyclase increases cGMP anddown-stream signaling ultimately resulting in dephosphorylationof myosin and vasodilation [1]

Various in vitro and in vivo animal studies have shownmethylene blue as a selective inhibitor of cGMP coun-teracting its downstream vasodilatory effects in shock [3]Clinically the most well-established use of methylene bluein shock is with patients after cardiac bypass surgery with arange of observational data as well as randomized controlledtrials [4] While not proven as a first line agent it has beenshown to improve systemic vascular resistance if therapywith norepinephrine fails [4] There have been case reportsand series demonstrating the efficacy of methylene blue incases of anaphylactic shock with resolution of hypotensionwithin one hour of administration [3] In septic shock severalsmall randomized control trials support the use of methyleneblue suggesting improved hemodynamics through increaseinmean arterial pressure and systemic vascular resistance butno mortality benefit likely a factor of the small sample sizes[5] The use of methylene blue in drug-induced vasoplegicshock has very little data to corroborate its regular use someobservational studies have shown a benefit in hemodynamicswhile others have showed no change A recent systematicanalysis reviewed 17 cases of drug-induced shock described inthe literature most commonly as a result of calcium channelblocker overdose which showed that there was varying evi-dence for the use efficacy and dosing of methylene blue [6]

There are various dosing regimens for treating shock withmethylene blue Overall experimental and clinical data sug-gest that 1-2mgkg as a single one-time dose is effective [3]There are other regimens which include continuous infusions

and repeat boluses but there is no evidence suggesting thatthose are more efficacious Consideration must also be takenof the side effect profile for methylene blue It can commonlycause dizziness tremors nausea vomiting and discolorationof bodily fluids [3] Less commonly it can cause an acutehemolytic anemia or precipitation of serotonin syndrome [3]Higher doses of methylene blue are associated with moreserious adverse effects [3]

Our patient presented with severe undifferentiated vaso-plegic shock that was not of septic or anaphylactic etiologyand was refractory to vasoactive agents Based on a literaturesearch there is minimal evidence for use of methylene bluein patients who present with a vasoplegic syndrome thatis not postcardiac bypass or due to sepsis or anaphylaxisThere are no case reports or observational studies describingthe use of methylene blue in undifferentiated vasoplegicshock The patientrsquos hemodynamics improved within hoursof administration of methylene blue and he was completelyoff vasoactive support within twenty-four hours (Figure 1)This case report further adds to the growing body of literaturethat methylene blue has a significant role in the treatmentof vasoplegic shock but additionally highlights its effects onshock that is of an unclear etiology having ruled out sepsisanaphylaxis and adrenal insufficiency

4 Conclusion

Methylene blue has growing evidence of its use as anadjunctive therapy in refractory vasoplegic shock caused aftercardiac bypass or by sepsis or anaphylactic shock This casereport suggests that in patients with severe undifferentiated


vasoplegic shock that is unresponsive to vasoactive agentsthere is potentially a role for use of a single dose of methyleneblue as a rescue therapy

Consent

Informed consent has been obtained from the patientdescribed in this article

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this article

References

[1] F H Epstein D W Landry and J A Oliver ldquoThe pathogenesisof vasodilatory shockrdquo New England Journal of Medicine vol345 no 8 pp 588ndash595 2001

[2] L Hosseinian M Weiner M A Levin and G W FischerldquoMethylene bluerdquo Anesthesia amp Analgesia vol 122 no 1 pp194ndash201 2016

[3] D H Jang L S Nelson and R S Hoffman ldquoMethylene bluefor distributive shock a potential new use of an old antidoterdquoJournal of Medical Toxicology vol 9 no 3 pp 242ndash249 2013

[4] R L Levin M A Degrange G F Bruno et al ldquoMethylene bluereduces mortality and morbidity in vasoplegic patients aftercardiac surgeryrdquo The Annals of Thoracic Surgery vol 77 no 2pp 496ndash499 2004

[5] C A Paciullo D McMahon Horner K W Hatton and JD Flynn ldquoMethylene blue for the treatment of septic shockrdquoPharmacotherapy vol 30 no 7 pp 702ndash715 2010

[6] B J Warrick A P Tataru and S Smolinske ldquoA systematicanalysis of methylene blue for drug-induced shockrdquo ClinicalToxicology vol 54 no 7 pp 547ndash555 2016

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Bloodwork on initial presentation to the emergencydepartment

At admission Normal rangeHemoglobin 128 137ndash180 gLWhite blood cell 86 40ndash110 times 109LPlatelets 66 150ndash400 times 109LSodium 129 133ndash145mmolLPotassium 37 33ndash51mmolLChloride 94 98ndash111mmolLBicarbonate 15 21ndash31mmolLCreatinine 418 50ndash120 120583molLTotal bilirubin 47 0ndash24 120583molLINR 22 09ndash11PTT 392 27ndash37 sLactate dehydrogenase (LDH) 377 100ndash235ULFerritin 754 30ndash400 120583gLD-Dimer gt10 lt046mgLFibrinogen 11 16ndash41 gLCreatinine kinase 929 0ndash195ULLactate 80 lt2mmolLRandom cortisol 626 nmolLArterial pH 720 735ndash745Arterial pCO2 21 35ndash45mmHgArterial pO2 61 80ndash100mmHgArterial bicarbonate 9 24ndash26mmgHg

pressure of 8060mmHg with O2 saturation of 92 onroom air On examination his extremities were warm Hewas alert and oriented to person place and time Hisneurological exam revealed no motor or sensory deficitsHis neck was supple His cardiovascular exam revealed aregular tachycardia but nomurmurHis respiratory examwasunremarkable His abdomen was mildly tender in the rightupper quadrant

His initial laboratory work is shown in Table 1 In sum-mary he presented with a mild normocytic anemia newthrombocytopenia and new renal failure with a urinal-ysis showing no casts with trace blood and protein Hehad coagulation abnormalities consistent with disseminatedintravascular coagulation (DIC) His initial arterial bloodgas showed a primary metabolic acidosis secondary to lacticacidosis with a partially compensated by a respiratory alka-losis Computed Tomography (CT) scan of his head chestabdomen and pelvis was only significant for mild atelectasisin the posterior aspect of both lower lobes and splenomegaly(measured at 158 cm normal lt 12 cm) An echocardiogramrevealed normal right and left ventricular function with nohemodynamically significant valvular disease One out ofthree sets of blood cultures was positive for coryneformbacilli at 65 hours which was thought to be a contaminantHIV and hepatitis serologies were negative

In the emergency department his blood pressuredeclined to 6234mmHg He was given three liters of normalsaline initially with no response in blood pressure Hewas then started on escalating doses of norepinephrine

Vasopressor requirements aer methylene blue administration

Norepinephrine (mcgkgmin)Vasopressin (unitmin)

00102030405060708

Nor

epin

ephr

ine d

ose (

mcg

kg

min

)

5 10 15 20 25 300Hours aer methylene blue administration

0

001

002

003

004

005

Vaso

pres

sin d

ose (

unit

min

)

Figure 1 Vasopressor requirements hours after methylene blueadministration

up to 09mcgkgmin after which his blood pressureincreased to 7040mmHg Epinephrine was then added at02mcgkgmin resulting in his blood pressure increasing to10050mmHg He was empirically started on piperacillin-tazobactam and vancomycin Given that he had no bio-chemical evidence of adrenal insufficiency steroids werenot given Upon transfer to the ICU the patient wasintubated and his hemodynamic profile remained tenuouswith his blood pressure dropping to 7426mmHg Hisnorepinephrine was increased to 1mcgkgmin epinephrinewas increased to 035mcgkgmin and vasopressin wasadded at 004 unitmin Forty-eight hours into his admissionhis lactate normalized but he was still requiring 09mcgkgmin of norepinephrine and 004 unitmin of vasopressin tomaintain a mean arterial pressure greater than 60mmHgHe was given methylene blue dosed at 2mgkg for a totaldose of 190mg once His blood pressure and vasoactiveagent requirements are illustrated in Figure 1 in relation tothe number of hours after methylene blue administrationWithin two hours of administration the norepinephrinedosage was halved within 15 hours he was weaned offvasopressin and within 24 hours he was off vasoactivesupport completely and successfully extubated

No septic or anaphylactic etiology was identified as acause of the patientrsquos distributive shockThere was no clinicalor biochemical evidence of adrenal insufficiency He deniedany overdoses of medications known to commonly causevasoplegic shock such as calcium channel blockers As suchthe etiology of his shock remained undifferentiated

3 Discussion

Methylene blue is a phenothiazine-related heterocyclic aro-matic molecule that has a long history of use dating backto the 1800s for treatment of malaria and more commonlymethemoglobinemia [3] Recently there has been emerg-ing use of methylene blue in the treatment of refractorydistributive shock via inhibition of the nitric-oxide cyclicguanosine monophosphate pathway (Figure 2) [1] An initialinsult results in an increase in nitric oxide synthase and nitric


Initial insult

Nitric oxide

Vasomotor tone


cGMP

Guanylyl cyclase


(a)

Initial insult

Nitric oxide

Vasomotor tone

Guanylyl cyclase

Methylene blue



cGMP

(b)







4 Conclusion




Consent




References












of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Initial insult

Nitric oxide

Vasomotor tone


cGMP

Guanylyl cyclase


(a)

Initial insult

Nitric oxide

Vasomotor tone

Guanylyl cyclase

Methylene blue



cGMP

(b)







4 Conclusion




Consent




References












of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Consent




References












of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















severe undifferentiated vasoplegic shock refractory to

Documents