Methylene Blue and Catecholamine Nonresponsive

Report
Yordanka Lambova, BSN, RRNA 2
Webster University Nurse Anesthesia Program
Objectives
 Vasoplegic Syndrome
 Definition
 Risk Factors
 Pathophysiology
 Methylene Blue
 Pharmacology
 Application
 Side Effects
 Evidence Based Practice
“Vasoplegic Syndrome”(VS) --Gomez (1994)—vasodilatory phenomenon
refractory to high dose catecholamines in adult cardiac surgery1,2
Gomes W. J. et al.; J Thorac Cardiovasc Surg 1994;107:942-a-943-a
Copyright ©1994 The American Association for Thoracic Surgery
Vasoplegic Syndrome
 Observed in all age groups and clinical settings
 Sepsis
 Systemic inflammatory response syndrome (SIRS)
 Cardiac surgery
 Anaphylactic shock
 Cardiac Surgery
 Heparin and renin-angiotensin system (RAS) antagonists are
the only medications considered risk factor for VS3
 Incidence with cardiac surgery is ranging from 0.21 to 13%, up
to 50% when patients on RAS antagonists4
 Mortality rate is 16 to 27%5,6,7
Vasoplegic Syndrome
Common Etiology Pathway
 Endothelial injury and
release of vasodilatory
inflammatory mediators
 Tumor necrosis factor alpha
(TNF-α)
 Interferon gamma (IFN-γ)
 Interleukin-1 (IL-1)
 Atrial Natriuretic Peptide
(ANP)
 Arginine-vasopressin system
dysfunction and deficiency of
vasopressin hormone
 KATP channel activation in the
plasma membrane
 Inducible Nitric Oxide
Synthase (iNOS) activation
•Nitric oxide (NO) production from L-
arginine is catalyzed by a family of NO
synthases (NOS)
•Endothelial NOS (eNOS) provides a basal
release of NO to maintain smooth muscle
vascular tone
•iNOS in heart, lungs, and vascular smooth
muscle cells is up regulated by the influence
of proinflammatory cytokines and/or
endotoxin
•Large amount of NO is produced
•Soluble guanylate cyclase (sGC) is released
•Cyclic guanosine 3’-5’ monophosphate
(cGMP) is generated
•Smooth muscle cell cGMP-mediated
vasodilation and decrease myocyte
contractility—relaxation of myocardial and
vascular smooth muscle
What do I reach for with catecholamine
nonresponsive hypotension?
•Persistent hypotension
•Tachycardia
•Normal or increased
cardiac output
•Decreased systemic
vascular resistance
•Low filling pressure
•Poor or no response to
fluid resuscitation and
vasopressors
Methylene Blue (MB)
Something Old, Something Blue
 Prepared by Caro in 1876 as a dye for textiles
 First fully synthetic drug used in medicine
 1891 Paul Ehrlich identified the compound as an anti-malarial
 1899 positive psychotropic effects observed (Potent, but
reversible MAOI)
 1933 used as an antidote to cyanide poisoning
 Beginning of the 20th century MB used in a wide variety of
medical, hygienic, and microbiology compounds
MB: Chemical Properties
 Heterocyclic aromatic




chemical compound
Chemical formula
C16H18N3SCl
Melting temperature 180
degrees
Solubility in water 35.5
g/1
pH value—3 (10g/l H2O)
 Solid, odorless, dark
green powder at room
temperature
 Blue solution when
dissolved in water or
alcohol
 Three molecules of MB
per molecule of water
MB: Pharmacokinetics
 Oral absorption is between 53 to 97%
 Completely ionized at gastric pH
 Peak plasma concentration in 30-60 min
 Volume of distribution 20 ml/kg
 Plasma half-life 5-6 hrs
 Metabolism reduced in peripheral
tissues to leucomethylene blue (65-85%)
 Does not bind to plasma proteins
 Eliminated in bile, feces, and urine as
leucomethylene blue
MB: Dosing in Humans
 Sepsis9,10
 1-2 mg/kg/10-20 min IV bolus
 0.25-1 mg/kg/hr for 6hrs IV
continuous infusion

Anaphylactic shock11
 1.5-2 mg/kg IV bolus
 Hereditary
methemoglobinemia
 Up to 300mg/day PO
 Ifosfamide encephalopathy
 50 mg three times a day PO12
 Vasodilation with
hypotension5,6
 1-2 mg/kg/10-20 min IV bolus
 VS8
 1-2 mg/kg/10-20 min IV bolus
 0.25-1 mg/kg/hr IV 48-72 hrs
IV continuous infusion
 Surgery for septic
endocarditis13,
Cardiopulmonary bypass
(CPB)5,11,14
 2 mg/kg IV bolus prior to CPB
 0.5 mg/kg/hr after bolus for 30
min after CPB
MB: Dose Related Toxicity
Human Studies
Studies
Dose
mg/kg
Toxic Manifestations14,15
Dose
mg/kg
Animal
Toxic Manifestations
2-4
Hemolytic anemia, skin desquamation
in infants
5-50
Rat16
Neuronal apoptosis
1250 mg/kg LD50
7
Nausea, vomiting, abdominal pain, chest
pain, fever, hemolysis
3500
Mouse
7.5
Hyperpyrexia, confusion
40
Sheep17
20
Hypotension
10-20
Dog18
80
Bluish discoloration of skin (similar to
cyanosis)
Hypotension, decreased
SVR, renal blood flow;
pulmonary hypertension
MB: Contraindications
 Glucose-6-phosphate
dehydrogenase deficiency-may precipitate hemolytic
anemia
 Renal impairment—
acceptable if on dialysis
 Intrathecal and subcutaneous
injection
 Hypersensitivity and allergy
to MB
 Dapsone- forms
hydroxylamine causing
hemolysis
 FDA recommendation-MB
should not be given to
patients taking serotonergic
drugs. However, there are
some conditions that may be
life-threatening or require
urgent treatment with MB
such as methemoglobinemia,
ifosfamide-induced
encephalopathy, or cyanide
poisoning.
MB: Mechanism of Action in VS

Direct inhibitory effect on NOS19,20

Blocks accumulation of cGMP by inhibiting the
enzyme guanylate cyclase19

Blocks the activity of NO-dependent guanylate
cyclase via oxidation of the active haemo center
or by inactivation of its haemo center.19,20

More specific and potent inhibitor of NOS than
guanylyl cyclase– NO-donating compounds in the
presence of MB can still partially activate c-GMP
signaling pathways21,22

Effects due to NO inhibition

MB restores vascular reactivity to endogenous
catecholamines in the setting of excessive NO
production23

Not a vasoconstrictor, rather it acts as a liberator
of cAMP, thus allowing norepinephrine to exert
its vasoconstrictive effect24
MB: Hepatic Failure

Schenk et al (2000)25
 Case Series (n=10) of hepatic cirrhosis and hepatopulmonary syndrome patients
 Reports improvement of hypoxemia and hyperdynamic circulation evidenced by
significant increase in PaO2, SVR; and decrease in MPAP, PVR, CO
 MB 3 mg/kg IV over 15 minutes
 No significant side effects noted

Kalambokis (2005)26
 Investigational study (n=20, 10 experimental group, 10 placebo group) on cirrhosis and
ascites patients
 MB 3 mg/kg IV
 No change in MAP, HR, CO, SVR; plasma renin, aldosterone, antidiuretic hormone, urea,
Cr, Na, GFR,
 Serum NO, and urinary Na decreased 4 hrs, but returned to basal levels in 8 hrs

Almeida et al (2007)27
 Case report (n=1) on use of MB in hepatopulmonary syndrome
 Large right to left intrapulmonary shunt and subsequent improvement of vascular tone
and hyperdynamic circulation at the cost of worsening hypoxemia
MB: Renal Failure

Peer (2001)28
 Investigational study (n=41, 18 HD/HoTN, 18 HD/no HoTN, 5 healthy controls)
 MB IV bolus 1 mg/kg followed by infusion of 0.1 mg/kg for 210 minutes until completion
of HD, bolus dose only on days without HD
 Results
 HD/HoTN—completely prevented HoTN during HD, increased BP on non HD days,
blood NO measurements higher than other groups
 HD/no HoTN—increase of BP during first hour of HD, and 90 minutes on non HD
days.
 Healthy controls—no significant change in BP
MB: Sepsis

Daemen-Gubbels et al (1995)29
 Prospective observational (n=9)
 MB 2 mg/kg/20 min
 Increase in MAP, MPAP, LVSWI, RVSWI (p<0.01); increase in oxygen delivery and uptake
index (p<0.05)
 Mortality: 89%

Kirov et al (2001)9
 Prospective, randomized, placebo controlled study (n=20, 10 MB treatment and 10
placebo isotonic saline)
 MB 2 mg/kg/20min, 0.25 mg/kg/hr at 2hrs, 0.5 mg/kg/hr at 3hrs, 1 mg/kg/hr at 4 hrs, 2
mg/kg/hr at 5hrs for 1 hr
 Improvement in hemodynamics and decrease in vasoconstrictors and inotropes (p<0.05)
 Mortality: 5 patients vs. 7 in placebo group

Memmis et al (2002)30
 prospective, randomized, double blind, placebo controlled (n=30, 15 MB and 15 placebo
isotonic saline)
 MB 0.5 mg/kg/hg 6 hrs
 MB group increase in MAP (p<0.001)
 Mortality: 27% in both cohorts
MB: Cardiac Surgery

Andrade et al.(1996)31
 Cohort (n=6), with and without cardiopulmonary bypass (CBP)
 Criteria—tachycardia, oliguria, refractory hypoperfusion to high dose catecholamine
 MB 1.5 mg/kg/1 hr
 Results: restoration of blood pressure; pre-MB vs. post-MB SVR=868 vs. 1693 dyne/s/cm5;
no adverse effect on CO or PVR
 2b level of evidence—small cohort, limited data

Leyh et al. (2003)5
 Cohort (n=54) out of 1111 cardiac surgery patients in 12 months
 Criteria –CO 4l/min, SVR<600 dyne/s/cm5, norepinephrine 0.5 mcg/kg/min
 MB 2mg/kg/20 min
 Results (0 hr vs. 1hr vs. 6hrs vs. 12 hrs):

MAP 68 vs. 72 vs. 73, (p<0.02)
 CO 7.6 vs. 6.5 vs. 5.8, (p<0.001)
 SVR 547 vs. 766 vs. 876, (p<0.001)
 4/54 (7.4%) no response to treatment
 3/54 (5.6%) mortality rate—2/4 nonresponders)
 2b level of evidence—wide range of cardiac surgical procedures, no control group, 76%
male patients
MB: Cardiac Surgery

Levin et al. (2004)6
 Cohort progressing to PRCT (n=56) out of 638 cardiac surgery patients in 5 months
 Criteria—MAP<50 mmHg, CVP<5 mmHg, PCWP<10mmHg, CI=2.5 l/min/m3, SVR<800
dyne/s/cm5, vasopressor requirement
 MB 1.5 mg/kg/1 hr vs. placebo
 Results: MB VS vs. Placebo VS
 Duration of VS:
 less than 2 hrs vs. up to 48 hrs (p<0.0007)
 Vasopressor requirement:

at 2 hrs (p<0.002); at 3, 6, 12, 24 hrs postop (p<0.00)
 Renal failure, respiratory failure, myopathy: 2 vs. 8, (p<0.03)
 Sepsis and MODS: 0 vs. 7, (p<0.005)
 Mortality:

0% vs. 21.4%, (p<0.01)
 1b level of evidence—small numbers progressing to RCT with patients from 4 centers,
questionable random assignment due to uneven distribution of patients in different
hospitals (2,9,14, 31)
MB: Cardiac Surgery

Ozar et al. (2005)7
 PRCT (n=100), high VS risk patients divided equally in MB and placebo group
 Criteria—MAP<50 mmHg, CVP<5 mmHg, PCWP<10mmHg, CI=2.5 l/min/m3, SVR<800
dyne/s/cm5, norepinephrine requirement 0.5 mcg/kg/min
 MB 2 mg/kg/30 min 1 hr preoperatively
 Results: MB vs. Placebo
 Incidence of VS:
 0 vs. 13 (p<0.001)
 Progress of VS:
 6 placebo patients had refractory to norepinephrine VS (p<0.001)
 4/6 resolved in up to 8 hours, 2/6 died of MSOF
 SVR on CBP significantly higher in MB group (p<0.001)
 Norepinephrine requirement:
 To keep MAP on CBP >45: 4% vs. 82 %
 Required NE 0.5 mcg/kg/min (p<0.001)
 Fluid Requirement on CBP:
 Crystalloid (p=0.024)
 Colloid (p=0.027)
 RBC (p<0.001)
 Length of stay:
 ICU: 1.2 vs. 2.1, (p<0.001)
 Hospital 6.1 vs. 8.4, (p<0.001)
 1b level of evidence
Conclusion
 MB is a novel therapeutic option for patients with
VS
 Despite the abundance of case reports on the use of
MB as a rescue drug there are limited number of
cohort/RCTs evaluating the use of the drug
 Further large studies should be performed before
MB can be recommended as a first line therapy.
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