Methylene Blue and Catecholamine Nonresponsive Hypotension

Yordanka Lambova, BSN, RRNA 2Webster University Nurse Anesthesia Program

ObjectivesVasoplegic Syndrome

DefinitionRisk FactorsPathophysiology

Methylene Blue PharmacologyApplicationSide Effects Evidence Based Practice

Copyright ©1994 The American Association for Thoracic Surgery

Gomes W. J. et al.; J Thorac Cardiovasc Surg 1994;107:942-a-943-a

“Vasoplegic Syndrome”(VS) --Gomez (1994)—vasodilatory phenomenon refractory to high dose catecholamines in adult cardiac surgery1,2

Vasoplegic SyndromeObserved in all age groups and clinical settings

SepsisSystemic inflammatory response syndrome (SIRS)Cardiac surgeryAnaphylactic shock

Cardiac SurgeryHeparin 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 SyndromeCommon Etiology Pathway

Endothelial injury and release of vasodilatory inflammatory mediatorsTumor 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 BluePrepared 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 HumansSepsis9,10

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 StudiesDose mg/kg

Toxic Manifestations14,15

2-4 Hemolytic anemia, skin desquamation in infants

7 Nausea, vomiting, abdominal pain, chest pain, fever, hemolysis

7.5 Hyperpyrexia, confusion

20 Hypotension

80 Bluish discoloration of skin (similar to cyanosis)

Dose mg/kg

Animal Toxic Manifestations

5-50 Rat16 Neuronal apoptosis1250 mg/kg LD50

3500 Mouse

40 Sheep17

10-20 Dog18 Hypotension, decreased SVR, renal blood flow; pulmonary hypertension

MB: ContraindicationsGlucose-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

ConclusionMB is a novel therapeutic option for

patients with VSDespite 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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