Methylene Blue and Catecholamine Nonresponsive
Download
Report
Transcript Methylene Blue and Catecholamine Nonresponsive
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.
References:
1.
Gomes et al. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg 1194.
2.
Gomes et al. Vasoplegic syndrome after off-pump coronary artery bypass surgery. Eur J Cardiothorac Surg
2003.
3.
Ulusoy HB, Gul H, Seyrek M, Yildiz O, Ulku C, Yildirim V, et al. The concentration-dependent contractile
effect of methylene blue in the human internal mammary artery: a quantitative approach to its use in the
vasoplegic syndrome. J Cardiothorac Vasc Anesth. 2008; 22(4): 560-4.
4. Mekontso-Dessap A, Houel R, Soustelle C, Kirsch M, Thebert D, Loisance DY. Risk factors for postcardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg
2001;71:1428-1432.
5.
Leyh RG, Kofidis T, Strüber M, Fischer S, Knobloch K, Wachsmann B, et al. Methylene blue: the drug of
choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg.
2003; 125(6): 1426-31.
6. Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, et al. Methylene blue reduces
mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004; 77(2): 496-9.
7.
Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kücükarslan N, et al. Preoperative methylene blue
administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg.
2005; 79(5): 1615-9.
8.
10. Evora PR, Levin RL. Methylene blue as drug of choice for cate- cholamine-refractory vasoplegia after
cardiopulmonary bypass. J Thorac Cardiovasc Surg 2004; 127: 895-896 .
9.
Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: a pilot,
randomised, controlled study. Crit Care Med 2001; 29: 1860-1867
10. Kwok ES, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med 2006; 21: 359363
11. Evora PR, Oliveira Neto AM, Duarte NM, Vicente WV. Methylene blue as treatment for contrast mediuminduced anaphylaxis. J Postgrad Med 2002; 48: 327-328.
12. Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB. Methylene blue in the treatment
and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J
Cancer 2000; 82: 291-294.
13. Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in
septic endocarditis. J Thorac Cardiovasc Surg 2003; 125: 426-427
14. Maslow AD, Stearns G, Butala P, Schwartz CS, Gough J, Singh AK. The hemodynamic effects of methylene
blue when administered at the onset of cardiopulmonary bypass. Anesth Analg 2006; 103: 2-8 .
15. Mathew S, Linhartova L, Raghuraman G. Hyperpyrexia and pro- longed postoperative disorientation
following methylene blue infusion during parathyroidectomy. Anaesthesia 2006; 61: 580- 583.
16. Vutskits L, Briner A, Klauser P, et al. Adverse effects of methylene blue on central nervous system.
Anesthesiology 2008; 108: 684- 692.
17. Burrows GE. Methylene blue: effects and disposition in sheep. J Vet Pharmacol Ther 1984; 7: 225-231
18. Zhang H, Rogiers P, Preiser JC, et al. Effects of methylene blue on oxygen availability and regional blood flow
during endotoxic shock. Crit Care Med 1995; 23: 1711-1721
19. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide syn- thesis by methylene blue. Biochem Pharmacol
1993; 45: 367- 374.
20. Mayer B, Brunner F, Schmidt K. Novel actions of methylene blue. Eur Heart J 1993; 14; Suppl I: 22-26.
21. Martin W,Villani GM, Jothianandan D, Furchgott RF. Selective blockade of endothelium-dependent and
glyceryl trinitrate- induced relaxation by hemoglobin and by methylene blue in rabbit aorta. J Pharmacol
Exp Ther 1985; 232: 708-716.
22. Tsai SC, Adamik R, Manganiello VC, Vaughan M. Regulation of activity of purified guanylate cyclase from
liver that is unresponsive to nitric oxide. Biochem J 1983; 215: 447-455
23. Schneider F, Luton PH, Hasselmann M, et al. Methylene blue increases systemic vascular resistance in
human septic shock. Intensive Care Med 1992; 9: 309-311.
24. Schneider F, Bucher B, Schott C, Andre A, Julou-Schaeffer G, Stoclet JC. Effect of bacterial lipopolysaccharide
on function of rat small femoral arteries. Am J Physiol 1994; 266: H191-198
25. Schenk P, Madl C, Rezaie-Majd S, Lehr S, Muller C. Methylene blue improves the hepatopulmonary
syndrome. Ann Inten Med 2000; 133: 701-706.
26. Kalambokis G, Economou M, Fotopouslos A, Bokharhii JA, Christos P, Paraskevi K, Kontanstinos P, Katsaraki
A, Tsinas EV. Effects of nitric oxide inhibition by methylene blue in cirrhotic patients with ascites. Dig Liver
Dis 2003; 50:1771-1777.
27. Almeida JA, Riordan SM, Liu J, Galhenage S, Kim R, Bihari D, Wegner EA, Cranney GB, Thomas PS.
Deleterious effects of nitric oxide inhibition in chronic hepatopulmonary syndrome. Eur J Gastroenterol
Hepatol.2007;19:34-134.6.
28. Peer G, Itzhakov E, Wollman Y, Chernihovsky T, Grosskopf I, Segev D, Silverberg D, Blum M, Schwartz D,
Iaina A. Methylene blue, a nitric oxide inhibitor, prevents haemodialysis hypotension. Nephrol Dial
Transplant 2001; 16:14361441.
29. Daemen-Gubbels CR, Groeneveld PH, Groeneveld AB, van Kamp GJ, Bronsveld W, Thijs LG. Methylene blue
increases myocardial function in septic shock. Crit Care Med 1995;23:1363–70.
30. Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of methylene blue infusion on
cytokine levels during severe sepsis. Anaesth Intensive Care 2002;30:755–62.
31. Andrade JCS, Batista Filho ML, Evora PRB, Tavares JR, Buffolo E, Ribeiro EE, Silva LA, Teles CA, Petrizzo A,
Barata F, Vitor V, Duprat R. Methylene blue administration in the treatment of the vasoplegic syndrome after
cardiac surgery. Revista Brasileira de Cirurgia Cardiovascular (Rev Bras Cir Cardiovasc) 1996;11:107-114.