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Abstract
Background: Several studies have demonstrated the utility of methylene blue (MB) to treat vasoplegic syndrome (VS), but some have cautioned against its routine use in lung transplantation with only two cases described in prominent literature. Cystic fibrosis patients commonly have chronic infections which predispose them to a systemic inflammatory syndrome-like vasoplegic response during lung transplantation. We present 13 cystic fibrosis patients who underwent lung transplantation and received MB for vasoplegic syndrome while on cardiopulmonary bypass, with or without inhaled pulmonary vasodilator therapy.
Methods: Single-center, retrospective, case series analysis of cystic fibrosis patients who underwent lung transplant and received MB for vasoplegia. We defined the primary outcome as 30-day mortality, and secondary outcomes as primary graft failure, 1-year mortality, postoperative complications, and hemodynamic response to MB.
Results: MB was associated with a significant increase in mean arterial pressure (MAP) (P < 0.001) in all patients, and 84.6% (11/13) of the patients had either a decrease or no change in vasopressor requirement. No patients developed acute primary graft dysfunction and there was 100% 30-day and 1-year survival. One patient required Extracorporeal membrane oxygenation (ECMO) for hypoxemia and 69% (9/13) of the patients had evidence of postoperative right ventricular dysfunction, but no patients required a right ventricular assist device.
Conclusion: This case series demonstrates the effectiveness of MB in treating vasoplegia in cystic fibrosis patients during lung transplantation, without evidence of primary graft dysfunction, 30-day or 1-year mortality. The safety of MB regarding hypoxemia and increased pulmonary vascular resistance requires further investigation.
Keywords: Cystic fibrosis, lung transplant, methylene blue, primary graft dysfunction, pulmonary transplant, vasoplegia syndrome, vasoplegia
How to cite this article: Introduction 
Methylene blue (MB) is a reagent with numerous applications and several studies have demonstrated its use in the treatment of vasoplegic syndrome (VS), particularly following cardiac surgery.[1],[2],[3] VS is characterized by low systemic vascular resistance in the setting of normal or increased cardiac output. VS after cardiac surgery is multifactorial and dependent on several patient and surgical factors in addition to the effects of the cardiopulmonary bypass (CPB) circuit that releases vasoactive proinflammatory cytokines. The inflammatory cytokines released can trigger vasodilation.[1],[4],[5] This response may be exaggerated in cystic fibrosis (CF) patients whose respiratory tracts are chronically colonized with various organisms and suffer recurrent lower respiratory tract infections secondary to impaired mucociliary clearance. During native lung pneumonectomy, CF patients may experience a more pronounced inflammatory response resulting in or contributing to profound vasoplegia. In the setting of VS, MB acts to inhibit guanylyl cyclase, thus reducing the presence of nitric oxide (NO) and increasing vascular tone.
Several studies have shown that MB is associated with improved outcomes for VS including increased MAP and decreased morbidity and mortality.[2],[6],[7] Studies suggest that it may even confer benefit when used prophylactically in patients who are at higher risk of VS.[8] MB is typically used in a single dose of 1–2 mg/kg administered over 20–60 min. It is metabolized in the liver and largely excreted in the urine. The most common complications of MB include hypertension, precordial pain, limb pain, allergic reaction, headache, staining of skin, discoloration of urine, hemolytic anemia, nausea, vomiting, and abdominal pain. The dye may also interfere with pulse oximetry readings. It has also been associated with serotonin syndrome, particularly in patients on chronic serotonergic drugs such as selective serotonin reuptake inhibitors or monoamine oxidase inhibitors. A few studies detail the use of MB in the setting of lung transplantation, and some have cautioned against the routine use of MB in patients undergoing lung transplantation.[9],[10] The mechanism of action of MB as well as results from animal studies have led to the theory that MB may cause hypoxemia, increased pulmonary vascular resistance, and primary graft rejection in lung transplant recipients.[11],[12] On the contrary, animal studies have suggested that MB may have lung-protective effects when used with inhaled NO (iNO).[13]
There are very few published reports of lung transplant patients with VS who have received MB. Carley et al. reported the use of MB to treat VS in a CF patient undergoing CPB for double lung transplant with concomitant use of iNO.[10] Additionally, Flynn et al.[14] 2009 detailed the successful use of MB with concomitant iNO for a pediatric patient with CF who had postoperative VS following lung transplantation. Neither of the two patients is known to have suffered primary graft dysfunction, though long-term outcomes were not reported. There are no reports in the literature of lung allograft rejection attributed to the use of MB. Further, the lack of published data suggests that the use of MB in lung transplants may be underreported. Here, we present 13 consecutive cases to highlight the use of MB for VS in the setting of lung transplantation for CF patients on CPB with favorable 1-year outcomes.
Materials and Methods The protocols and policies followed in this study were approved by our Institutional Review Board (IRB # 47289). Due to the retrospective nature and minimal risk of our study, individual participant consent was waived. Retrospective analysis of the database identified 342 lung transplant procedures between January 1, 2010 and July 1, 2018. The electronic health record was queried to identify patients who underwent lung transplants and also received MB for vasoplegia within 72 h of the procedure. To minimize the heterogeneity of preoperative diagnoses, we chose to focus on CF patients—a population that we have empirically seen to be prone to VS during native lung pneumonectomy. This is likely secondary to chronic bacterial colonization that, when coupled with the inflammatory response generated by CPB, makes them high risk for intraoperative vasoplegia. Vasoplegia while on CPB was defined as a MAP ≤60 mmHg for greater than 5 min requiring treatment with two or more vasopressors. Those who did not meet the criteria for receiving MB were excluded, resulting in a total of 13/342 (3.8%) patients. Demographic data, basic health information, hemodynamic data, and factors associated with lung transplant rejection were collected for each patient.
Results Forty-six percent (6/13) of the cases were female patients and ages ranged from 16 to 40 years old at the time of surgery. All of the operations were en-bloc double lung transplants. Lung allocation scores (LAS) ranged from 33.0 to 70.5 with an average LAS of 48.2 [Table 1]. Only one patient was on an angiotensin-converting enzyme inhibitor preoperatively, a known risk factor for vasoplegia. No patients received angiotensin receptor blockers preoperatively.
Hemodynamic and pharmacy data were collected to assess the response to MB. Patients received MB at a total dose between 0.9 and 2.1 mg/kg with one patient receiving a notably higher dose at 5.0 mg/kg during the perioperative period for refractory vasoplegia. Eight patients received only one dose of MB intraoperatively, while three patients received intraoperative MB with repeat bolus in the ICU. Patients 5 and 6 received one dose of MB postoperatively while in the ICU.
Minute-by-minute MAP data were plotted pre- and post-MB administration and simple linear regression was used to evaluate the slope and elevation of best-fit lines for significant difference (GraphPad Prism version 8.4, GraphPad Software, La Jolla, CA). MB was associated with a significant (P < 0.001) increase in MAP when patients were analyzed in aggregate [Figure 1]. Vasopressor doses were converted to norepinephrine equivalents (NEE) using the definition for NEE as described in the Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS) trial (NEE = [norepinephrine (mcg/kg/min)] + [epi (mcg/kg/min)] + [dopamine (mcg/kg/min) * (0.1/15)] + [phenylephrine (mcg/kg/min) * (1.0/10)] + [vasopressin (units/min) *(0.1/0.04)].[15] For 11/13 patients, there was a reduction or no change in pressor requirement as measured in NEE [Table 1], [Figure 2] following MB administration, but there was a significant increase in MAP (P-value < 0.05 by simple linear regression analysis) in all 13 patients individually [Figure 2].
Figure 1: Mean arterial pressure response to methylene blue. Aggregate minute-by-minute mean arterial pressure (MAP) collected for 30 min prior to methylene blue (MB) administration (time = 0.0 h) to 3 h (3.0 h) after MB. MAP values for all 13 patients were averaged at each time point. Simple linear regression analysis was used to analyze the slope and elevation between the best-fit lines pre- and post- MB. ***= P < 0.001
Figure 2: (a) Patient-specific mean arterial pressure and norepinephrine equivalent response to methylene blue treatment. Individual patient mean arterial pressure (MAP) readings with corresponding vasopressor requirement expressed as norepinephrine equivalents (NEE) to show hemodynamic response to methylene blue (MB). Time zero indicates when MB was administered. Time points were recorded for each patient every 1 or 5 min. Final time points reflect end of procedure following administration of MB. (b) Figure does not include medication boluses in this time frame. MAP values prior to MB are depicted in red, MAP values following MB are depicted in orange. Simple linear regression analysis was used to analyze the slope and elevation between the best-fit lines pre- and post-MB. *=P < 0.10, **= P < 0.05, ***= P < 0.001Pulmonary artery catheter (PAC) data and post-CPB transesophageal echocardiographic (TEE) data were collected when available. Three of the six patients had mean pulmonary artery pressure (MPAP) >25 mmHg immediately following lung transplant [Table 1]. Given that less than 50% of the patients received a PAC, we attempted to further characterize the effect of MB on pulmonary vascular resistance (PVR) using the reported right ventricular (RV) systolic function on post-CPB TEE [Table 1]. Four of thirteen (31%) patients had normal RV function following CPB. The remaining 9 patients had normal RV function on ionotropic support or mild or moderate RV systolic dysfunction [Table 1].
Medical records (chest X-rays, progress notes, discharge summaries, and follow-up clinic notes) were used to evaluate for primary graft dysfunction, respiratory failure, mortality, and the incidence of additional adverse outcomes. All of the patients survived for at least 1 year [Table 1]. No patients had primary graft dysfunction in the perioperative period or evidence of rejection within the first year. The average ICU length of stay was 5.7 days [Table 1]. Five patients required re-intubation within 30 days of transplant and one patient required venovenous extracorporeal membrane oxygenation (VV ECMO) for hypoxemia [Table 1]. She underwent aggressive diuresis and was successfully decannulated on postoperative day 2. In this study, no patients required a right ventricular assist device for RV failure, and none developed bowel ischemia or digital necrosis. No episodes of supraventricular tachycardia were attributed to MB.
Discussion The patients in this case series contribute valuable data to the conversation regarding the role of MB in lung transplantation. The study shows that among 13 consecutive patients with CF who received MB for VS while on CPB, none experienced primary graft dysfunction or death within 1 year. The findings here are consistent with previous case studies in the literature such as those presented by Carley et al. and Flynn et al. which note successful use of MB in lung transplant patients with concomitant use of iNO. Our case series provides the largest and most detailed account of consecutive patients with longer follow-up intervals and more detailed hemodynamic and pharmacologic data than previous reports.
The definition of vasoplegia is consistent among patients as they were all on CPB which excludes a cardiogenic or hypovolemic etiology as the cause of VS. MB was associated with a statistically significant increase in MAP, a finding that is expected and consistent with multiple sources in the literature. Additionally, 46% of the patients had a decrease in NEE following MB. NEE is a useful yet imperfect proxy for response to MB because providers did not wean pressors in a protocolized manner in this retrospective study. In this cohort, only one patient progressed to acute renal failure. No patients required ventricular assist device support, and there were no cases of bowel ischemia, digital necrosis, or arrhythmias which may occur in patients with VS. With regards to hypoxemia, 5/13 patients experienced acute respiratory failure defined as the need for re-intubation with 30 days of transplant, and 1 patient required postoperative VV ECMO for 2 days.
MB has been reported to cause an increase in PVR which is in part why some have cautioned against its routine use in lung transplant patients. As our patient cohort (relatively young CF patients) did not routinely have pulmonary artery catheters, pulmonary arterial pressures were available for 6 out of 13 cases. In three of the six patients, MPAP was >25 mmHg immediately postop suggestive of elevated right-sided pressures, of which two patients had elevated PA pressures prior to surgery. Thirty-one percent (4/13) of the patients had normal RV systolic function and another 69% (9/13) had evidence of RV dysfunction requiring inotropic support. Though there is some suggestion of elevated PVR in the cohort, it is difficult to discern whether this is entirely attributable to MB given the pathophysiologic complexity of lung transplantation and the lack of control population with which to compare these results. Our data indicate that the elevated pulmonary vascular tone in our study population did not result in severe consequences as patients did not have graft rejection or require mechanical circulatory support for cardiogenic failure. Previous case studies have used concomitant iNO, but our population includes patients that did and did not receive iNO. Given that the data suggest some evidence of increased PVR and RV strain in patients receiving MB, it may be beneficial to use inhaled pulmonary vasodilators in patients who will receive MB for additional RV support and protection.
It is uncertain whether the outcomes seen here are applicable to all subsets of lung transplant patients who experience VS. The study comprises CF patients receiving lung transplantation on CPB and thus may not apply to chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH) patients. The physiology in these patients is distinct in that it may be more inflammatory than other end-stage lung diseases given the common history of chronic infections. Additionally, these procedures may take longer on average than other lung transplants due to scar tissue and adhesions which may further predispose these patients to VS. Several studies have found that patients with PAH have a higher risk of primary graft dysfunction.[16] Though our study includes a few patients with a concomitant diagnosis of World Health Organization (WHO) group 3 PAH, there were no patients with WHO Group 1 PAH. Further studies in lung transplant patients with PAH are needed to identify whether there are differences in vascular response to MB.
The retrospective nature of this study has certain limitations for data extrapolation. The sample size is limited and there is no control group with which to compare the treatment of vasoplegia with standard catecholaminergic agents. The study does not include other agents used to treat VS for comparison including angiotensin II, intravenous hydroxocobalamin, ascorbic acid, and thiamine. For future studies on MB use, it may be favorable to use iNO or other pulmonary vasodilators to mitigate possible risk of hypoxemia, increased PVR, and RV strain.
Though limited, this study demonstrates some benefit to using MB to treat VS in patients undergoing lung transplantation, particularly in patients with CF who are vasoplegic while on CPB. The theoretical risks of hypoxemia or increased PVR might be minimized by the concomitant use of inhaled pulmonary vasodilators. The safety and efficacy cannot be determined based on these data and more studies are needed to further elucidate the potential risks and benefits of MB to determine when MB may be safely used or whether other agents such as angiotensin II and hydroxocobalamin may be more favorable.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
Correspondence Address:
Charles C Hill
Department Cardiac Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305
USA
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aca.aca_276_20
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