|REVIEW ARTICLE: REPUBLICATION
|Year : 2017 | Volume
| Issue : 3 | Page : 101-111
Utilization of methylene blue in the setting of hypotension associated with concurrent renal and hepatic failure: A concise review
Dimitry Bosoy1, Jennifer Axelband2, Robert N Pursell3, John J Lukaszczyk4, Stanislaw P Stawicki5
1 Department of Emergency Medicine, St. Luke's Hospital and Health Network, Bethlehem, PA, USA
2 Department of Medical Critical Care, St. Luke's Hospital and Health Network, Bethlehem, PA, USA
3 Department of Medicine, St. Luke's Hospital and Health Network, Bethlehem, PA, USA
4 Department of Surgery, St. Luke's Hospital and Health Network, Bethlehem, PA, USA
5 OPUS 12 Foundation, Bethlehem, PA, USA
|Date of Web Publication||21-Apr-2017|
Stanislaw P Stawicki
Department of Research and Innovation, St. Luke's University Health Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
Source of Support: None, Conflict of Interest: None
Renal failure, hepatic failure, and hepatorenal syndrome can be associated with clinically significant hypotension, a clinical state often referred to as vasoplegia or vasoplegic syndrome (VS). Vasoplegia is thought to be related to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction due to direct and indirect effects of various inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, including sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate pathway appears to play a prominent role. Methylene blue (MB), an inhibitor of NO synthase and guanylate cyclase, has been found to improve the hypotension associated with various clinical states. Evidence also suggests that MB may be effective in improving systemic hemodynamics and vasoplegia associated with hepatic failure. We describe two cases of vasoplegia associated with concurrent hepatic and renal failure – both demonstrating a favorable hemodynamic response to MB without apparent side effects. A review of MB use in the setting of hepatic and renal failure then follows.
The following core competencies are addressed in this article: Medical knowledge, Patient care.
Republished with permission from: Bosoy D, Axelband J, Pursell RN, Lukaszczyk JJ, Stawicki SP. Utilization of methylene blue in the setting of hypotension associated with concurrent renal and hepatic failure: A concise review. OPUS 12 Scientist 2008;2(1):21-29.
Keywords: Hepatic failure, hypotension, methylene blue, renal failure, vasoplegia, vasoplegic syndrome, vasopressors
|How to cite this article:|
Bosoy D, Axelband J, Pursell RN, Lukaszczyk JJ, Stawicki SP. Utilization of methylene blue in the setting of hypotension associated with concurrent renal and hepatic failure: A concise review. Int J Acad Med 2017;3, Suppl S1:101-11
|How to cite this URL:|
Bosoy D, Axelband J, Pursell RN, Lukaszczyk JJ, Stawicki SP. Utilization of methylene blue in the setting of hypotension associated with concurrent renal and hepatic failure: A concise review. Int J Acad Med [serial online] 2017 [cited 2022 Jun 27];3, Suppl S1:101-11. Available from: https://www.ijam-web.org/text.asp?2017/3/3/101/204970
| Introduction|| |
Systemic inflammatory response associated with profound vasodilation, known as vasoplegia or vasoplegic syndrome (VS), has been observed in various clinical settings. The classic description of VS includes hypotension, low systemic vascular resistance (SVR), and increased requirement for intravenous fluid and vasopressor administration., Vasoplegia has been associated with cardiopulmonary bypass (CPB), severe sepsis, anaphylaxis, and hemodialysis.,,, Episodic and persistent hypotension has also been described in chronic liver disease.,
VS has been observed in all age groups., The incidence of VS varies but can reach 10% in postcardiac surgery patients and may be as high as 42%, following left ventricular-assist device placement for end-stage heart failure.,, Vasoplegia may be present in up to 50% of patients who die from sepsis and has been observed in association with anaphylaxis and protamine administration for reversal of systemic heparinization., 5, ,,,,
There is evidence that methylene blue (MB), an inhibitor of the vasodilatory effects of nitric oxide (NO) and other nitrovasodilators on endothelium and vascular smooth muscle, may be therapeutically beneficial in vasoplegia. It may be that dysfunction of a common pathophysiologic effector pathway is responsible for vasoplegia attributable to various clinical states and that MB might be helpful in the treatment of hypotension mediated by this pathway.,,,, There is also evidence that MB may be effective in improving systemic hemodynamics in vasoplegia associated with chronic liver disease.,
This review discusses the administration of MB in the setting of simultaneous hepatic and renal failure. Special emphasis is placed on potential risks and benefits of MB therapy in this clinical setting. In addition, we present two illustrative cases of persistent hypotension in the setting of concurrent renal and hepatic failure, both with favorable hemodynamic responses to MB.
| Illustrative Case #1|| |
A 56-year-old male with a history of morbid obesity, hypertension, nonalcoholic steatohepatitis (NASH), Type II diabetes, and renal insufficiency developed severe panniculitis complicated by Gram-positive bacteremia and sepsis. Despite aggressive antimicrobial therapy, surgical debridement, and hemodynamic support, the patient developed multiorgan dysfunction, including pulmonary failure, renal failure, and progressive hepatic failure (encephalopathy and coagulopathy).
Shortly after recovering from the initial infection, the patient experienced an episode of Gram-negative bacteremia and sepsis. Despite recovery from the latter episode, the patient's renal failure worsened and he became dialysis-dependent. At that time, he also underwent tracheostomy and percutaneous endoscopic gastrostomy tube placement.
Approximately 2 weeks later, the patient began experiencing recurrent episodes of hypotension. These hypotensive episodes initially responded to intermittent vasopressor administration and intravenous fluid therapy, with transient responses to stress-dose hydrocortisone replacement therapy. However, he progressively deteriorated, requiring continuous vasopressor administration, and escalating intravenous fluid boluses. His laboratory and radiographic (computed tomography, abdominal ultrasound) findings repeatedly failed to reveal an infectious source. Diagnosis of concurrent hepatic and renal failure was made due to worsening hepatic function parameters (total bilirubin 3.6 mg/dL, international normalized ratio [INR] of 1.9) with clinically apparent jaundice and encephalopathy. Of note, broad-spectrum antibiotics were administered during each of the above episodes, with planned re-adjustment or discontinuation of antibiotic therapy based on microbiology culture and sensitivity data. Because of the continued requirement for large-volume intravenous fluid resuscitation and vasopressors, a trial dose of MB was administered in hopes of liberating the patient from vasopressors.
After a single intravenous dose of MB (1 mg/kg diluted in 100 mL of dextrose 5% in water [D5W], administered over 1 h), the patient's norepinephrine infusion was weaned over a period of 4 h, followed by discontinuation of vasopressin infusion [Figure 1]. He returned to baseline blood pressure for 12 h. At that time, the patient experienced another episode of hypotension, and an additional dose of MB (0.5 mg/kg in 100 mL D5W) was administered. Following the second dose of MB, the patient's blood pressure improved again, and he remained normotensive for an additional 96 h. Note that the patient's central venous pressure also gradually increased, following MB administration [Figure 2]. The patient's arterial oxygen saturation remained unchanged during both MB infusions (range, 97%–100%). No side effects were noted during MB use.
|Figure 1: Graphical representation of blood pressure and norepinephrine infusion rate, following the initial administration of methylene blue in patient #1. The X-axis shows time in hours. Systolic blood pressure (dashed diamond line), mean arterial pressure (dashed triangle line), and diastolic blood pressure (solid square line) are represented in mmHg on the Y-axis. Please note that the values of the norepinephrine infusion rate on the graph (solid diamond line, mcg/min) are multiplied by 10 (i.e., 40 mcg/min on the graph represents an actual infusion rate of 4 mcg/min)|
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|Figure 2: Graphical representation of blood pressure and central venous pressure, following the second administration of methylene blue in patient #1. The X-axis shows time in hours. Systolic blood pressure (dashed diamond line), mean arterial pressure (solid triangle line), and diastolic blood pressure (dashed square line) are represented in mmHg on the Y-axis. Note the gradual increase in central venous pressure (solid diamond line) from 14 mmHg to 28 mmHg over the 5-h period following methylene blue administration|
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| Illustrative Case #2|| |
A 62-year-old male with end-stage liver disease due to NASH and known hepatorenal syndrome presented to the emergency department complaining of chest pain and abdominal discomfort. He was noted to have significantly increased abdominal girth despite undergoing paracentesis approximately every 4 days for difficult-to-treat ascites. The patient also complained of increasing generalized edema and significant weight gain over the past several weeks. He denied any fevers, chills, nausea, vomiting, or diarrhea. His medical history was also significant for Type I diabetes, thrombocytopenia, and recently diagnosed Stage IV adenocarcinoma of the lung (making him ineligible for combined hepatic-renal transplantation).
On admission, he was found to be hypotensive, with blood pressure of 58/40 mmHg (baseline blood pressure approximately 70/50 mmHg). He was afebrile, with a heart rate of 83 beats/min and respiratory rate of 20 breaths/min. The patient was cachectic and appeared to be in mild distress. His chest examination revealed bibasilar rales. His abdomen was distended, mildly tender, with shifting dullness. There was no rebound, guarding, or focal peritonitis. The remainder of his physical examination was normal.
Initial laboratory studies included sodium 125 mmol/L (normal 136–145); chloride 92 mmol/L (normal 100–108); blood urea nitrogen 25 mg/dL (normal 5–25); creatinine 4.8 mg/dL (normal 0.5–1.4); phosphorus 4.4 mg/dL (normal 2.3–4.1); lactic acid 4.8 mmol/L (normal 0.3–2.1); albumin 2.4 g/dL (normal 3.5–5.0), and INR 1.54. Chest radiogram demonstrated bibasilar atelectasis. Electrocardiogram showed normal sinus rhythm.
The patient was admitted to the intensive care unit, where he remained hypotensive (systolic blood pressure [SBP] between 70 and 80 mmHg) despite adequate fluid resuscitation by both invasive (central venous pressure of 10–12 mmHg) and noninvasive criteria (essentially normal echocardiogram). He was also noted to have hypotension-related lightheadedness and somnolence. At this point, norepinephrine infusion was added to treat the vasoplegic state and titrated to maintain mean arterial pressure (MAP) ≥60 mmHg. Despite otherwise unremarkable workup, the patient remained norepinephrine-dependent for ten subsequent days (SBP between 75 and 100 mmHg).
The patient underwent numerous diagnostic tests to help establish the cause of his hypotension. Echocardiography demonstrated normal left ventricular function and ejection fraction (70%). Computer tomography of the abdomen and pelvis demonstrated moderate ascites, for which the patient was already undergoing serial paracentesis with periprocedural volume replacement using 25% albumin solution. Ascitic fluid, blood and urine cultures showed no bacterial growth. The patient underwent scheduled hemodialysis sessions three times a week. He remained afebrile during this period.
After 10 days of continued norepinephrine dependence, the patient was given intravenous MB (1 mg/kg in D5W) to help facilitate the weaning of the norepinephrine drip. A slow but sustained and reproducible response to MB was noted [Figure 3]. The patient was subsequently placed on an oral regimen of MB (1 mg/kg) given twice daily, with equally reliable responses. After liberation from norepinephrine drip and transfer to the general medical ward, the patient was discharged from the hospital on continued twice daily oral MB regimen. No side effects were noted during MB therapy in this patient.
|Figure 3: Graphical representation of blood oxygen saturation, blood pressure and norepinephrine infusion rate following the initial administration of methylene blue in patient #2. The X-axis shows time in hours. Systolic blood pressure (solid diamond line), diastolic blood pressure (dashed square line) are represented in mmHg on the Y-axis. Arterial oxygen saturation is represented by the dashed triangle line. Please note that the values of the norepinephrine infusion rate on the graph (dotted diamond line, mcg/min) are multiplied by 10 (i.e., 60 mcg/min on the graph represents an actual infusion rate of 6 mcg/min)|
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| Discussion|| |
Vasoplegia or VS is a state of endothelial dysregulation, resulting in persistent hypotension despite adequate fluid resuscitation and vasopressor administration. While different definitions have been proposed for VS in the setting of cardiac surgery and sepsis, there are no formalized definitions for vasoplegia associated with other conditions, such as anaphylaxis, renal, or hepatic failure.,,,
There is evidence to suggest that MB may be effective in improving systemic hemodynamics in the setting of vasoplegia related to chronic liver disease, hepatopulmonary and hepatorenal syndromes., This report describes two cases of vasoplegia in the setting of simultaneous hepatic and renal failure – both associated with favorable hemodynamic response to MB administration. A focused review of MB use in the setting of hepatic and renal failure then follows.
| Vasoplegic Syndrome: Risk Factors and Pathophysiology|| |
Numerous potential risk factors for VS have been identified. In cardiac surgery, independent risk factors for postoperative vasoplegia include preoperative intravenous heparin use, angiotensin-converting enzyme inhibitor use, and calcium channel blocker use.,, While the incidence of VS among patients with these predisposing factors varies, it is important to be aware of these clinical associations. With anaphylactic shock, refractory vasoplegia is encountered in relatively few cases, with no clearly defined risk factors. In the setting of septic shock, the vasoplegic response may or may not depend on adequate source control but may be based on how advanced is the underlying pathophysiologic process. While the search continues for more precise determination of risk factors for VS in different clinical settings, significant evidence exists to support the presence of a common physiologic pathway that leads to vasoplegia.
Normal physiologic response to an injurious stimulus is usually self-limited and commensurate to the magnitude of that stimulus. In more severe cases, the response may inappropriately persist, progressing through the spectrum of severe systemic inflammatory response syndrome (SIRS), multiorgan dysfunction, multiorgan failure, and ultimately, death. One of the most important manifestations of severe SIRS is circulatory failure with low SVR, low MAP, systemic hypoperfusion, and tissue malperfusion. The physiologic response of SIRS appears to be mediated by (a) various neurotransmitters (including acetylcholine, adenosine triphosphate and substance P); (b) factors responsible for hemostasis (including adenosine diphosphate, serotonin, bradykinin, and thrombin); as well as (c) biologic amines (including norepinephrine and histamine). These mediators, in turn, induce the synthesis of two endothelial autacoids – endothelium-derived relaxing factor (or NO) and prostacyclin (PGI2) – resulting in vasoplegia. Vasoplegia due to nonseptic mechanisms can be thought of as a type of “pure” form of SIRS, including VS associated with CPB, hemodialysis, or hepatic failure.,,
Regardless of the initial etiology, VS appears to represent a dysregulation of NO synthesis/release and vascular smooth muscle cell guanylate cyclase (GC) activation. NO is produced by two types of NO synthase (NOS) relevant to this review – a constitutive endothelial NOS (eNOS) type and an inducible NOS (iNOS) type. Upregulation of iNOS and increased NO production lead to generation of cyclic guanosine 3'-5'monophosphate (cGMP), with resultant hypotension. NO-dependent pathways also participate in the pathophysiology of hypotension following hemorrhagic shock and postcardiac arrest states., VS has been attributed to a combination of endothelial injury, arginine-vasopressin system dysfunction, and release of other vasodilatory inflammatory mediators, including tumor necrosis factor alpha and interferon gamma.,,, Elevated interleukin-1 levels in inflammatory states can also promote vasodilation through increasing the levels of intracellular cGMP [Figure 4].
|Figure 4: Schematic representation of NO/cGMP-dependent pathways. Note the eNOS and iNOS isoforms of the nitric oxide synthase and their associated functional steps. NO = Nitric oxide, cGMP = Cyclic guanosine 3'-5' monophosphate, eNOS = Endothelial nitric oxide synthase, iNOS = Inducible nitric oxide synthase|
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The pathophysiologic changes of VS are thought to be due to actions induced by NO production from L-arginine by a family of NOSs. A de novo synthesis of iNOS takes place under the influence of proinflammatory cytokines and/or endotoxin in the heart, lungs, and vascular smooth muscle cells.,, Subsequently, NO stimulates soluble GC (sGC) which, in turn, generates cGMP. This leads to smooth muscle cell cGMP-mediated vasodilation and decreased myocyte contractility, including relaxation of myocardial and vascular smooth muscle.,,,, Additional harmful effects of iNOS-produced NO include impaired gas exchange, vascular leakage, and multiorgan failure.,,,,, In contrast, the constitutive eNOS produces minute amounts of NO, maintaining basal regional vascular tone and blood flow.
| Methylene Blue: the Molecule and Its Pharmacology|| |
MB USP (3,7-dipropan-2-ylphenothiazine chloride and 3,7-dipropan-2-ylphenothiazine chloride trihydrate, molecular formula C16H18 Cl N3S·3H20, [Figure 5]) has a molecular weight of 371.923 and consists of dark green crystals that turn to deep blue color when dissolved in water or alcohol. It is approved for oral or intravenous administration in the setting of methemoglobinemia (especially following topical benzocaine use), hemolysis, and as a surgical “tracer” dye for detection of fluid leaks (mainly from gastrointestinal and urinary systems)., MB is available as a solution (10 mg/mL) and is usually administered enterally or intravenously. Oral absorption ranges from 53% to 97%. The onset of the hemodynamic effects of MB is relatively rapid. Of interest, intratracheal MB administration has been described experimentally.
MB readily enters the erythrocyte and at low concentrations is reduced to leucomethylene blue [Figure 6]. MB is eliminated in bile, feces, and urine as leucomethylene blue., At higher doses, MB itself becomes an oxidant, and in the presence of excess MB or a defect in the methemoglobin reduction mechanisms, the dye accumulates and functions as a hemoglobin oxidizing agent, resulting in hemolysis, methemoglobinemia, and hyperbilirubinemia.
MB has been used in patients of all age groups., Overall, the recommended safe oral dose of MB appears to be between 1–2 mg/kg and 3–4 mg/kg, depending on source., MB lacks sulfonic acid groups and does not bind to plasma proteins. MB is an sGC inhibitor that blocks sGC action in vascular smooth muscle, scavenges NO, and inhibits NO synthesis.,,,
MB seems to counteract the effects of NO and other nitrovasodilators in endothelium and vascular smooth muscle and is believed to act competitively with NO. By binding to the iron heme moiety of the sGC and blocking sGC action in vascular smooth muscle, NO decreases the levels of cGMP and alleviates the vasorelaxant effect seen in VS., 24, ,, A single dose of intravenous MB (1–2 mg/kg with 20-min infusion time) has been used as a “rescue” treatment in the setting of vasoplegia of anaphylaxis and cardiac surgery.,, In pediatrics, MB has been used as adjunctive medical therapy in severe sepsis and acquired methemoglobinemia, with recommended doses of 1–2 mg/kg for a full-term infant.
Continuous MB infusion has been described in patients who do not respond to a single dose of MB and has been administered for variable lengths of time (120 mg of MB diluted in D5W, given continuously from 1 to 6 h)., Escalating doses of MB infusion have also been used. Several reports describe administration of MB intraoperatively during CPB to treat vasoplegia., In one report, MB was added to the pump prime as a treatment of vasoplegia associated with septic endocarditis during a valve operation and followed postoperatively as an infusion. In another report, CPB was reinstituted due to norepinephrine-refractory protamine reaction, with improvement noted only after MB infusion.
MB has been used in oncology for sentinel lymph node detection, in the treatment of methemoglobinemia complicating topical benzocaine use (MB hastens the conversion of methemoglobin to hemoglobin),, congenital methemoglobinemia, priapism, neonatal hypotension, as an anti-malarial agent, and in the setting of vasoplegia related to cardiac surgery, sepsis, anaphylaxis, liver failure, and hemodialysis.,,,,,,
| Methylene Blue: Side Effects and Contraindications|| |
MB should not be used is patients with documented hypersensitivity to this drug. Although contraindicated in severe renal insufficiency, MB has been used safely in hemodialysis-dependent patients., MB should be used cautiously in patients with glucose-6-phosphate dehydrogenase deficiency and low levels of endogenous NADPH (essential to the production of leucomethylene) because of the risk of a Heinz body hemolytic anemia. MB can also exacerbate dapsone-induced hemolytic anemia because of the formation of dapsone-reactive metabolite hydroxylamine, which oxidizes hemoglobin., Pathway steps relevant to these phenomena are outlined in [Figure 7].
|Figure 7: Outline of important steps involved in the metabolism of methylene blue|
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A number of side effects have been described in association with MB use. Although rare, adverse reactions to intravenous MB include cardiac arrhythmias (transient nodal rhythm and ventricular ectopy), coronary vasoconstriction, angina, decreased cardiac output, decreased renal blood flow, reduced mesenteric blood flow, increases in pulmonary vascular resistance, and worsening gas exchange.,,, Arrhythmias and precordial pain associated with MB administration are usually transient and self-limiting.
Adverse reactions have also been noted after oral administration of MB. In the neonatal population, enteral administration of more than 2 mg/kg of MB has been reported to result in severe methemoglobinemia and hemolysis. Use of MB has been associated with Heinz body hemolytic anemia and hyperbilirubinemia after intra-amniotic injections and oral administration in the pediatric patient.,
MB is reduced in the erythrocyte to leucomethylene blue and is excreted primarily in the urine as leucomethylene blue and MB. Hemolytic anemia, Heinz body anemia, and hyperbilirubinemia have been reported with MB doses exceeding 2 mg/kg. Anemia associated with MB usually manifests itself within 24 h of injection and can be seen up to 12 days after MB use. The timing of anemia and hyperbilirubinemia complicating MB administration are similar, with the bilirubin peak at approximately 4 days after use and the anemia peak at approximately 5 days.
Most side effects of MB appear to be dose-dependent and do not occur with doses <2 mg/kg., Most studies report normal renal function and pulmonary gas exchange (expressed as the ratio of PaO2 to inspired oxygen fraction), following MB administration. Transient and self-limiting elevations in serum aspartate aminotransferase and alanine aminotransferase have been reported in one study although it is not clear whether these elevations were due to MB, concurrent administration of norepinephrine, or both. In one series, five patients who received preoperative intravenous MB infusion (3–5 mg/kg MB in 500 mL of normal saline) for localization of parathyroid adenomas developed self-limiting postoperative encephalopathy. It was noted that the common factors in all five cases of encephalopathy were (a) female gender of the patients and (b) preoperative use of serotonin metabolism modifying agents.
MB is known to turn urine greenish-blue., This benign discoloration can be alarming to patients although it is self-limiting and disappears 1–2 days after discontinuing the drug. Mild skin discoloration can occur, but is also self-limiting, and can be treated with administration of dilute hypochlorite solution.
Other reported side effects associated with MB include confusion, headache, fever, nausea, vomiting, abdominal pain, and diaphoresis. Subcutaneous and intradermal injections of MB have been reported to cause necrotic abscesses., A rare but devastating photosensitivity epithelial desquamation has been reported in infants undergoing phototherapy after receiving MB., This serious reaction has been attributed to breakdown of lysosomal membranes after interacting with light in the presence of the photosensitizing MB., Anaphylactic reactions have been known to occur, although rarely, following MB administration. Of note, MB interferes with the pulse oximeter's light emission (wavelength of ~660 nm), resulting in falsely depressed oxygen saturation readings.
| Methylene Blue Use in Vasoplegia of Renal and Hepatic Failure|| |
There are very few reports of MB use in the setting of hemodialysis, renal, and/or hepatic failure. The rationale for MB use in vasoplegia associated with hemodialysis/renal failure and hepatic failure is based on the fact that NO and iNOS are known to play a role in these clinical states.,, It has long been postulated that antagonists of NO and NO production may prevent hypotension associated with both hepatic and renal failure.,
Hypotension is one of the most common complications encountered during hemodialysis. Although fluid removal and relative hypovolemia during dialysis can contribute to transient hypotension, many patients without hypovolemia experience moderate to severe hypotensive episodes during hemodialysis., This phenomenon is thought to be related to intra-dialysis NO elevations, leading to significant and relatively rapid vasodilation.,, In the setting of hemodialysis-associated vasoplegia, MB has been shown to be effective in preventing hypotension when given as a bolus of 1 mg/kg body weight, followed by an infusion at 0.1 mg/kg for 210 min on dialysis days and as a bolus-only on nondialysis days. In the current study, both patients were dialysis-dependent. However, their hypotension did not appear to be associated with hemodialysis. In illustrative case #1, the patient was initially receiving continuous renal replacement therapy and was later transitioned to intermittent hemodialysis. No clinical differences in patient hemodynamic status were noted between these two modes of renal support. In illustrative case #2, the patient was undergoing scheduled hemodialysis sessions, with no apparent decline in blood pressure during dialysis sessions.
Hepatic failure is often complicated by hypotension, low SVR, and reduced sensitivity to vasoconstrictor drugs. This state is similar to the vasoplegia associated with sepsis and endotoxic shock and has been reproduced in humans by injection of endotoxin., Moreover, plasma concentrations of endotoxins are known to be elevated in hepatic cirrhosis. While increased endogenous production of NO has been proposed as a mediator of peripheral arterial vasodilation and hyperdynamic circulatory changes in cirrhosis, decreased intrahepatic NO production has been suggested as one of the contributing factors to portal hypertension., Of note, up to 15% of patients with cirrhosis develop hepatopulmonary syndrome  and it is estimated that up to 40% of patients with cirrhosis and ascites will develop hepatorenal syndrome within 5 years of the onset of their disease.
The use of MB has not been widely reported in the setting of hepatorenal syndrome [Table 1]. One study examined the effects of MB on renal function, portal and systemic hemodynamics in cirrhotic patients with ascites. In that study, MB was administered at 3 mg/kg (MB in 100 mL D5W, infused over a 20-min period). There were no significant differences in MAP, heart rate, cardiac output, SVR, plasma active renin, and portal vein velocities between MB and placebo. However, urinary sodium excretion, fractional excretion of sodium, and serum NO levels were all significantly decreased 4 h after MB administration and returned to baseline over an additional 4 h period.
|Table 1: Clinical studies of methylene blue in the setting of hepatic and/or renal failure|
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Another NOS inhibitor, L-NMMA, was found to impair renal hemodynamics and function despite being able to improve overall systemic hemodynamics., Given these findings, along with its overall side effect profile, MB administration may be contraindicated in patients with hepatorenal syndrome-associated vasoplegia who are not expected to need long-term hemodialysis. On the other hand, in the setting of long-term renal replacement therapy, MB use to improve systemic hemodynamics may be indicated, especially if it leads to significant improvement in patient quality of life, much like in illustrative case #2, where the patient was able to be discharged from the hospital on oral MB therapy. In the current report, both patients showed favorable hemodynamic responses to MB administration and were able to come off continuous vasopressor therapy. It is unclear whether effects due to hepatic and/or renal failure were primarily responsible for vasoplegia observed in both cases. However, our observations suggest that MB may indeed be effective in improving systemic hemodynamics in the setting of hypotension associated with simultaneous hepatic-renal failure.
Reports of MB use in the setting of hepatopulmonary syndrome demonstrate beneficial effects of MB on vascular tone and hyperdynamic circulatory changes in patients with hepatic cirrhosis., However, there is conflicting evidence with regard to the effect of MB on oxygenation in the setting of hepatopulmonary syndrome., While Schenk et al. report that MB improves hypoxemia in this setting, others observed reproducible and reversible worsening of hypoxemia in association with MB use in patients with hepatopulmonary syndrome and right-to-left intrapulmonary shunting. Thus, NO-cGMP pathway inhibitors must be used with extreme caution in patients with hepatopulmonary syndrome and right-to-left intrapulmonary shunting until more evidence is available to support this practice. None of the patients in the current report had hepatopulmonary syndrome, and we did not note any apparent change in patient oxygenation, following MB administration.
| Conclusions|| |
Although much has been learned about MB and its applications in the setting of vasoplegia, many questions remain. Administration of MB in patients with VS increases blood pressure and SVR and decreases vasopressor administration requirements. We presented a review of MB use in the setting of hepatic and renal failure and two illustrative cases of vasoplegia associated with simultaneous hepatic and renal failure, both of which demonstrated favorable hemodynamic response to MB, with no apparent side effects. Future studies of MB in the setting of hepatic and/or renal failure will need to be conducted in multi-institutional, prospective, blinded, and randomized fashion and will need to be designed to answer specific clinical questions with sufficient statistical power. Until such studies are available, the use of MB in these clinical settings should be considered very carefully, with full knowledge of indications, contraindications, and potential side effects of this drug.
Justifications for re-publishing this scholarly content include: (a) The phasing out of the original publication after a formal merger of OPUS 12 Scientist with the International Journal of Academic Medicine and (b) Wider dissemination of the research outcome(s) and the associated scientific knowledge.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Friedrich M, Bräuer A, Tirilomis T, Lotfi S, Mielck F, Busch T. Methylene blue administration in severe systemic inflammatory response syndrome (SIRS) after thoracic surgery. Ann Thorac Cardiovasc Surg 2002;8:306-10.
Shanmugam G. Vasoplegic syndrome – The role of methylene blue. Eur J Cardiothorac Surg 2005;28:705-10.
Donati A, Conti G, Loggi S, Münch C, Coltrinari R, Pelaia P, et al.
Does methylene blue administration to septic shock patients affect vascular permeability and blood volume? Crit Care Med 2002;30:2271-7.
Evora PR, Oliveira Neto AM, Duarte NM, Vicente WV. Methylene blue as treatment for contrast medium-induced anaphylaxis. J Postgrad Med 2002;48:327.
] [Full text]
Kwok ES, Howes D. Use of methylene blue in sepsis: A systematic review. J Intensive Care Med 2006;21:359-63.
Schenk P, Madl C, Rezaie-Majd S, Lehr S, Müller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000;133:701-6.
Smith RE, Robinson NM, McPeake JR, Baylis SA, Charles IG, Heaton ND, et al.
Induction and role of NO synthase in hypotensive hepatic failure. Arterioscler Thromb Vasc Biol 1997;17:3079-82.
Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: A case report and review of the literature. Pediatrics 2006;117:e806-9.
Taylor K, Holtby H. Methylene blue revisited: Management of hypotension in a pediatric patient with bacterial endocarditis. J Thorac Cardiovasc Surg 2005;130:566.
Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, et al.
Management of vasodilatory shock after cardiac surgery: Identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116:973-80.
Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, et al.
Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714-20.
Brown SG. Cardiovascular aspects of anaphylaxis: Implications for treatment and diagnosis. Curr Opin Allergy Clin Immunol 2005;5:359-64.
Kemp SF, Lockey RF. Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341-8.
Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: An investigation into its epidemiology. Arch Intern Med 2001;161:15-21.
Takakura K, Mizogami M, Fukuda S. Protamine sulfate causes endothelium-independent vasorelaxation via inducible nitric oxide synthase pathway. Can J Anaesth 2006;53:162-7.
Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: Should methylene blue be the treatment of choice? Chest 2002;122:1061-6.
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;125:1426-31.
Almeida JA, Riordan SM, Liu J, Galhenage S, Kim R, Bihari D, et al.
Deleterious effect of nitric oxide inhibition in chronic hepatopulmonary syndrome. Eur J Gastroenterol Hepatol 2007;19:341-6.
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74.
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;79:1615-9.
Gomes WJ, Carvalho AC, Palma JH, Teles CA, Branco JN, Silas MG, et al.
Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg (Torino) 1998;39:619-23.
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;77:496-9.
Mekontso-Dessap A, Houël R, Soustelle C, Kirsch M, Thébert D, Loisance DY. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428-32.
Oliveira Neto AM, Duarte NM, Vicente WV, Viaro F, Evora PR. Methylene blue: An effective treatment for contrast medium-induced anaphylaxis. Med Sci Monit 2003;9:CS102-6.
Peer G, Itzhakov E, Wollman Y, Chernihovsky T, Grosskopf I, Segev D, et al.
Methylene blue, a nitric oxide inhibitor, prevents haemodialysis hypotension. Nephrol Dial Transplant 2001;16:1436-41.
Evgenov OV, Sveinbjørnsson B, Bjertnaes LJ. Continuously infused methylene blue modulates the early cardiopulmonary response to endotoxin in awake sheep. Acta Anaesthesiol Scand 2001;45:1246-54.
Ghiassi S, Sun YS, Kim VB, Scott CM, Nifong LW, Rotondo MF, et al.
Methylene blue enhancement of resuscitation after refractory hemorrhagic shock. J Trauma 2004;57:515-21.
Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit Care Med 2006;34:2806-13.
Boyle EM Jr., Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: The systemic inflammatory response. Ann Thorac Surg 1997;63:277-84.
Downing SW, Edmunds LH Jr. Release of vasoactive substances during cardiopulmonary bypass. Ann Thorac Surg 1992;54:1236-43.
Kilbourn R, Gross S, Jubran A, Adams J, Griffith O, Levi R, et al
. N-G-Methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: Implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A 1990;87:3629-32.
Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-42.
Vincent JL, Zhang H, Szabo C, Preiser JC. Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000;161:1781-5.
Singh S, Evans TW. Nitric oxide, the biological mediator of the decade: Fact or fiction? Eur Respir J 1997;10:699-707.
Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992;105:575-80.
Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg 2003;125:426-7.
Grocott-Mason RM, Shah AM. Cardiac dysfunction in sepsis: New theories and clinical implications. Intensive Care Med 1998;24:286-95.
Kumar A, Brar R, Wang P, Dee L, Skorupa G, Khadour F, et al.
Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 1999;276(1 Pt 2):R265-76.
Brady AJ, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992;263(6 Pt 2):H1963-6.
Scherer K, Bircher AJ, Figueiredo V. Blue dyes in medicine – A confusing terminology. Contact Dermatitis 2006;54:231-2.
41Allegaert K, Miserez M, Lerut T, Naulaers G, Vanhole C, Devlieger H. Methemoglobinemia and hemolysis after enteral administration of methylene blue in a preterm infant: Relevance for pediatric surgeons. J Pediatr Surg 2004;39:E35-7.
Weinbroum AA. Methylene blue attenuates lung injury after mesenteric artery clamping/unclamping. Eur J Clin Invest 2004;34:436-42.
Clifton J 2nd
, Leikin JB. Methylene blue. Am J Ther 2003;10:289-91.
Albert M, Lessin MS, Gilchrist BF. Methylene blue: Dangerous dye for neonates. J Pediatr Surg 2003;38:1244-5.
Tsopelas C, Sutton R. Why certain dyes are useful for localizing the sentinel lymph node. J Nucl Med 2002;43:1377-82.
Marczin N, Ryan US, Catravas JD. Methylene blue inhibits nitrovasodilator- and endothelium-derived relaxin factor-induced cyclic GMP accumulation in cultured pulmonary arterial smooth muscle cells via generation of superoxide anion. J Pharmacol Exp Ther 1992;263:170-9.
Mayer B, Brunner F, Schmidt K. Novel actions of methylene blue. Eur Heart J 1993;14 Suppl I: 22-6.
Evora PR, Roselino CH, Schiaveto PM. Methylene blue in anaphylactic shock. Ann Emerg Med 1997;30:240.
Yiu P, Robin J, Pattison CW. Reversal of refractory hypotension with single-dose methylene blue after coronary artery bypass surgery. J Thorac Cardiovasc Surg 1999;118:195-6.
Cauwels A, Janssen B, Buys E, Sips P, Brouckaert P. Anaphylactic shock depends on PI3K and eNOS-derived NO. J Clin Invest 2006;116:2244-51.
Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 1993;45:367-74.
Palmer RM. The discovery of nitric oxide in the vessel wall. A unifying concept in the pathogenesis of sepsis. Arch Surg 1993;128:396-401.
Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003;19:167-9.
Rodrigues JM, Pazin Filho A, Rodrigues AJ, Vicente WV, Evora PR. Methylene blue for clinical anaphylaxis treatment: A case report. Sao Paulo Med J 2007;125:60-2.
Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjørnsson B, et al.
Infusion of methylene blue in human septic shock: A pilot, randomized, controlled study. Crit Care Med 2001;29:1860-7.
Evora PR. Should methylene blue be the drug of choice to treat vasoplegias caused by cardiopulmonary bypass and anaphylactic shock? J Thorac Cardiovasc Surg 2000;119:632-4.
Varghese P, Mostafa A, Abdel-Rahman AT, Akberali S, Gattuso J, Canizales A, et al.
Methylene blue dye versus combined dye-radioactive tracer technique for sentinel lymph node localisation in early breast cancer. Eur J Surg Oncol 2007;33:147-52.
Baraka AS, Ayoub CM, Yazbeck-Karam V, Kaddoum RN, Gerges FJ, Hadi UM, et al.
Prophylactic methylene blue in a patient with congenital methemoglobinemia. Can J Anaesth 2005;52:258-61.
Martínez Portillo F, Hoang-Boehm J, Weiss J, Alken P, Jünemann K. Methylene blue as a successful treatment alternative for pharmacologically induced priapism. Eur Urol 2001;39:20-3.
Driscoll W, Thurin S, Carrion V, Steinhorn RH, Morin FC 3rd
. Effect of methylene blue on refractory neonatal hypotension. J Pediatr 1996;129:904-8.
Meissner PE, Mandi G, Coulibaly B, Witte S, Tapsoba T, Mansmann U, et al.
Methylene blue for malaria in Africa: Results from a dose-finding study in combination with chloroquine. Malar J 2006;5:84.
Nishimura M, Takahashi H, Yoshimura M. Role of nitric oxide in haemodialysis hypotension. Acta Physiol Scand 2000;168:181-6.
Brown G, Frankl D, Phang T. Continuous infusion of methylene blue for septic shock. Postgrad Med J 1996;72:612-4.
Liao YP, Hung DZ, Yang DY. Hemolytic anemia after methylene blue therapy for aniline-induced methemoglobinemia. Vet Hum Toxicol 2002;44:19-21.
Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methaemoglobinaemia. Med Toxicol Adverse Drug Exp 1989;4:387-92.
Goldstein BD. Exacerbation of dapsone-induced Heinz body hemolytic anemia following treatment with methylene blue. Am J Med Sci 1974;267:291-7.
Sills MR, Zinkham WH. Methylene blue-induced Heinz body hemolytic anemia. Arch Pediatr Adolesc Med 1994;148:306-10.
DiSanto AR, Wagner JG. Pharmacokinetics of highly ionized drugs. II. Methylene blue – Absorption, metabolism, and excretion in man and dog after oral administration. J Pharm Sci 1972;61:1086-90.
Andresen M, Dougnac A, Díaz O, Hernández G, Castillo L, Bugedo G, et al.
Use of methylene blue in patients with refractory septic shock: Impact on hemodynamics and gas exchange. J Crit Care 1998;13:164-8.
Zhang H, Rogiers P, Preiser JC, Spapen H, Manikis P, Metz G, et al.
Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock. Crit Care Med 1995;23:1711-21.
Sweet G, Standiford SB. Methylene-blue-associated encephalopathy. J Am Coll Surg 2007;204:454-8.
Yap KP, Chng HC. Urinary discoloration after rectal instillation of methylene blue dye. Singapore Med J 2003;44:268.
Stradling B, Aranha G, Gabram S. Adverse skin lesions after methylene blue injections for sentinel lymph node localization. Am J Surg 2002;184:350-2.
Porat R, Gilbert S, Magilner D. Methylene blue-induced phototoxicity: An unrecognized complication. Pediatrics 1996;97:717-21.
George M. Methylene-blue-induced hyperbilirubinemia and phototoxicity in a neonate. Clin Pediatr (Phila) 2000;39:659-61.
Dewachter P, Mouton-Faivre C, Tréchot P, Lleu JC, Mertes PM. Severe anaphylactic shock with methylene blue instillation. Anesth Analg 2005;101:149-50.
Kessler MR, Eide T, Humayun B, Poppers PJ. Spurious pulse oximeter desaturation with methylene blue injection. Anesthesiology 1986;65:435-6.
Schreiber V. EDRF-NO. The endothelium-derived relaxing factor is nitric oxide. Cas Lek Cesk 1992;131:388-90.
Daugirdas JT. Dialysis hypotension: A hemodynamic analysis. Kidney Int 1991;39:233-46.
London G, Marchais S, Guerin AP. Blood pressure control in hemodialysis patients. In: Jacobs C, Kjellstrand CM, Koch KM, Winchester JF, editors. Replacement of Renal Function by Dialysis. 4th
ed. Dordrecht: Kluwer; 1996. p. 966-82.
Beasley D, Brenner BM. Role of nitric oxide in hemodialysis hypotension. Kidney Int Suppl 1992;38:S96-100.
Amore A, Bonaudo R, Ghigo D, Arese M, Costamagna C, Cirina P, et al.
Enhanced production of nitric oxide by blood-dialysis membrane interaction. J Am Soc Nephrol 1995;6:1278-83.
Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al.
Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990;113:227-42.
Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, et al.
The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321:280-7.
Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 1988;8:232-6.
Fiorucci S, Antonelli E, Morelli A. Nitric oxide and portal hypertension: A nitric oxide-releasing derivative of ursodeoxycholic acid that selectively releases nitric oxide in the liver. Dig Liver Dis 2003;35 Suppl 2:S61-9.
Kalambokis G, Economou M, Fotopoulos A, Bokharhii JA, Christos P, Paraskevi K, et al.
Effects of nitric oxide inhibition by methylene blue in cirrhotic patients with ascites. Dig Dis Sci 2005;50:1771-7.
Fallon MB. Methylene blue and cirrhosis: Pathophysiologic insights, therapeutic dilemmas. Ann Intern Med 2000 7;133:738-40.
Lenz K, Hörtnagl H, Druml W, Reither H, Schmid R, Schneeweiss B, et al.
Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis. Effects on renal hemodynamics and atrial natriuretic factor. Gastroenterology 1991;101:1060-7.
Bech JN, Nielsen CB, Pedersen EB. Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans. Am J Physiol 1996;270(5 Pt 2):F845-51.
Dijkhorst-Oei LT, Koomans HA. Effects of a nitric oxide synthesis inhibitor on renal sodium handling and diluting capacity in humans. Nephrol Dial Transplant 1998;13:587-93.
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