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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 25-32

Methylene blue treatment for moderate-to-severe cases of acute respiratory syndrome due to COVID-19 infection: clinical outcomes—a prospective study


1 Department of General Medicine, MGM Hospital and Research Centre, Sector 1A, CBD Belapur, Navi Mumbai 400614, Maharashtra, India
2 Department of Orthopedics, MGM Hospital and Research Centre, Sector 1A, CBD Belapur, Navi Mumbai 400614, Maharashtra, India
3 MGM Hospital and Research Centre, Sector 1A, CBD Belapur, Navi Mumbai 400614, Maharashtra, India

Date of Submission14-Feb-2022
Date of Acceptance25-Feb-2022
Date of Web Publication23-Mar-2022

Correspondence Address:
Dr. Babita A Ghodke
Department of General Medicine, MGM Hospital and Research Centre, Sector 1A, CBD Belapur, Navi Mumbai 400614, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_18_22

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  Abstract 

Background: We studied the real-life experience with Methylene blue administration among the moderate and severe cases of acute respiratory distress syndrome due to Covid-19 infection with the standard of care. Materials and Methods: This study is a prospective, single-center study including 103 hospitalized patients conducted in a tertiary healthcare center from June 2020 to July 2021. The route of administration of Methylene blue was through nebulization (0.5 mL 0.5% solution of Methylene blue + 2.5 mL of distilled water) three times a day as long as the patient was admitted. An ampoule of 10 mL of Methylene blue with 90 mL of potable water through oxygen port was administered as long as they needed oxygen. About 2 mg/kg body weight of Methylene blue in 300 mL of N.S. over 3 h was given once a day for 5 days. Results: Approximately 103 patients were seen with a mean age of 56.49 years. The most prevalent comorbid condition was diabetes. The SpO2 improved by 7.827%. On post-Methylene blue administration, the serum ferritin, C-reactive protein, lactate dehydrogenase, and D-dimer were reduced in comparison to pre-Methylene blue administration. Also, the average total length of stay was 14 ± 4.20, 13 ± 5.66, and 14 ± 3.50 days in 26.78% of patients in intensive care unit, 17.51% of patients in high dependency unit, and 58.71% of patients in Covid general ward, respectively. About 86.4% of the patients recovered and got discharged post-Methylene blue administration. The all-cause mortality was 13.59%, which could be due to underlying comorbidities and complications of Covid-19 infections. Conclusion: Methylene blue administration accelerated recovery in our patients with moderate and severe Covid-19 disease by controlling the hyperimmune response. The clinical improvement was seen by decreased levels of inflammatory markers, improved oxygen saturation, reduced length of hospital stay, and clinical improvements. Methylene blue administered in nebulization form, through oxygen port, and through intravenous infusion in the dose of 2 mg/kg body weight for 5 days and improved patients’ recovery, so it can be considered as a therapeutic option in moderate and severe Covid-19 disease.

Keywords: Covid-19, Methylene blue, moderate and severe ARDS


How to cite this article:
Ghodke BA, Ghodke A, Mahadik V, Thorat P. Methylene blue treatment for moderate-to-severe cases of acute respiratory syndrome due to COVID-19 infection: clinical outcomes—a prospective study. MGM J Med Sci 2022;9:25-32

How to cite this URL:
Ghodke BA, Ghodke A, Mahadik V, Thorat P. Methylene blue treatment for moderate-to-severe cases of acute respiratory syndrome due to COVID-19 infection: clinical outcomes—a prospective study. MGM J Med Sci [serial online] 2022 [cited 2022 May 18];9:25-32. Available from: http://www.mgmjms.com/text.asp?2022/9/1/25/340582




  Introduction Top


The Covid-19 pandemic has resulted in high rates of morbidity and mortality ever since its initial identification in Wuhan, China.[1] Currently, 2.71 billion subjects have been affected worldwide. In India, 3.47 crores have been actively detected and deaths of 4.75 lacs have been reported as of December 12, 2021.[2] The current treatment recommended is anti-viral, steroids, and anti-cytokines.[3]

Methylene blue, an antioxidant and an intense anti-NO (anti-nitric oxide) drug,[4] inhibits the SARS-COV-2 spike-ACE2 protein–protein interaction: a mechanism that can contribute to its antiviral activity against Covid-19.[5] Thus, Methylene blue has the potential to be used in the management of COVID-19. In an era of the uncertainty of the prognosis of disease, a severe shortage of resources of treatment, and large financial constraints, this cost-effective drug, Methylene blue, has the least effect on the coagulation pathway and has effect throughout the vascular system of the whole body.[5] During an unprecedented time when proven effective therapies are lacking, we aimed to describe our real-life experience using Methylene blue for COVID-19.


  Materials and methods Top


Ethics

The study protocol was approved by the Healing Hands Independent Ethics Committee Protocol ID: TARDS/HEC/05/2020.

Selection criteria

It is a hospital-based prospective single-center study of a minimum of 103 hospitalized COVID-19-positive patients with moderate and severe COVID-19 disease without G6PD deficiency. The study was conducted at MGM Hospital and Research Centre, CBD Belapur, Navi Mumbai, Maharashtra, India. The study group involved patients of adult age group with no gender specification. Inclusion criteria were as follows: patients willing to give written informed consent, those confirmed by reverse transcriptase–polymerase chain reaction, Rapid Antigen Test (RAT), high-resolution computed tomography (HRCT)-positive for COVID-19, patients with respiratory distress and respiratory rate >24 to <48 breaths/min, SpO2 (oxygen saturation) < 94% to as low as 19%, patients presenting with respiratory failure and requiring non-invasive and invasive mechanical ventilation, PaO2/FiO2 200 and 100 mmHg (1 mmHg = 0.133 kPa). Exclusions were patients less than 18 years of age, G6PD-deficient, those who refused to take the drug or participate, those who were on antidepressants and serotonergic medications, and severely affected glomerular filtration rate, pregnant or breastfeeding patients.

The extracted data included demographic and clinical characteristics, laboratory parameters, percentage of study subjects according to the HRCT scoring, analysis of SpO2 data, distribution of the outcome of cases co-related with oxygen requirements, non-invasive ventilation, high flow nasal cannula (HFNC), and mechanical ventilation and treatment with standard of care and Methylene blue; the route of administration of Methylene blue was through nebulization (0.5 mL of 0.5% solution of Methylene blue + 2.5 mL of distilled water) three times a day as long as the patients were admitted. An aliquot of 10 mL of Methylene blue was administered with 90 mL of potable water through oxygen port as long as they needed oxygen. About 2 mg/kg body weight of Methylene blue in 300 mL of N.S. was given over 3 h once a day for 5 days. The outcome was measured in terms of improvement of SpO2, improvement in inflammatory markers, improvement in respiratory rate, and terms of duration of hospitalization, discharge, and death of the patients.

Statistical methods

All the data obtained were analyzed using Microsoft Excel SPSS version 21.0. Categorical variables were expressed as numbers and percentages. Continuous variables were presented as mean ± SD. The statistical analysis was carried out to test the significance of the difference between pre- and post-changes in the study parameter. As data satisfy the condition of normality, paired t-test, 95% confidence intervals were used to test the pre- and post-significance. Also, bar charts were used to present information graphically.

Ethical consideration

The present study, the informed consent document, and any subsequent modifications were reviewed and approved by the Institutional Ethics Committee (IEC), Healing Hands Clinic, Pune, Maharashtra, India, vide their letter no. TARDS/HEC/05/2020 dated June 15, 2020.


  Results Top


In the present study, 103 cases were enrolled, of which 59 cases (57.3%) were males and 44 cases (42.7%) were females. In the population studied, maximum cases were in the age group 51–60 (27 cases, 26.21%) and 25 cases were in the age group of 41–50 years (24.28%). Among all the subjects studied, the eldest was two patients of 91 years of age and the youngest was 26 years old (mean 56.49 years) (SD 14.00). Patients comorbid conditions included diabetes (34%), hypertension (11.7%), others (13%) and no complications (31%). The HRCT scores were mild in 1.9% cases, but later progressed toward moderate acute respiratory distress syndrome (ARDS): moderate in 68% of the cases and severe in 33% of the cases [Table 1].
Table 1: Baseline characteristics and demographics

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The patients who were on oxygen less than 15 L through the nasal cannula, face mask, non-rebreathers mask, 56.31% of patients on high flow nasal oxygen (HFNO), 1.94% of patients on non-invasive ventilation (NIV) 8.7%, on invasive ventilation 9.7% (P = 0.000, χ2 = 91.081) indicate that there was a significant association between the types of method for oxygen. For outcome analysis in the form of clinical and laboratory parameters, the last follow-up values were considered as post-dose values.

The median SpO2 levels improved from 81.90% (SD 11.55) (95% confidence interval [CI] 79.65, 84.16) (pre-Methylene blue) to 88.31% (SD 17.08) (95% CI 84.97, 91.65) (post-Methylene blue). P-value for the paired t-test is less than that of 0.05, indicating that the average change in SpO2 is significant. The average SpO2 has increased significantly. The % rise of SpO2 is 7.827% [Figure 1]A. The mean serum ferritin (ng/mL) levels improved from 407.86 (SD 214.03) (95% CI 366.03, 449.69) (pre-Methylene blue) to 285.60 (SD 371.64) (95% CI 212.96, 358.23) (post-Methylene blue). The P-value for the paired t-test is less than that of 0.05, indicating that the average change in serum ferritin (ng/mL) is significant. The serum ferritin levels decreased significantly. The % decrease of serum ferritin was 29.976% [Figure 1]B. The mean C-reactive protein (CRP) (mg/L) decreased from 54.26 (SD 39.68) (95% CI 46.5, 62.01) (pre-Methylene blue) to 34.78 (SD 44.83) (95% CI 26.02, 43.54) (post-Methylene blue). The P-value for the paired t-test is less than that of 0.05, indicating that the change in CRP (mg/L) is significant. The serum CRP levels decreased significantly. The % decrease of serum CRP was 35.901% [Figure 1]C. The mean lactate dehydrogenase (LDH) levels decreased from 425.78 (SD 180.81) (95% CI 390.34, 461.01) (pre-Methylene blue) to 288.11 (SD 225.12) (95% CI 244.11, 332.1) (post-Methylene blue). The P-value for the paired t-test is less than that of 0.05, indicating that the average change in LDH (International Unit [IU]) is significant. The average LDH has decreased significantly. The % decrease of serum LDH is 32.318% [Figure 1]D. A significant decrease in the proinflammatory markers is seen [Table 2]. The D-dimer assay (IU) decreased from 2926.31 (SD 3052.84) (95% CI 232.67, 3522.96) (pre-Methylene blue) to 1713.38 (SD 2395.92) (95% CI 1245.12, 2181.64) (post-Methylene blue). The P-value for the paired t-test is less than that of 0.05, indicating that the average change in D-dimer (IU) is significant. The average D-dimer (IU) has decreased significantly. The % decrease of D-dimer is 41.449% [Figure 1]E.
Figure 1: Changes in hyperinflammatory markers and D-dimer assay. A: Changes in SpO2 (%) levels pre (n=103)- and post (n=102)-Methylene blue administration. B: Changes in ferritin levels (mg/L) pre (n=103)- and post (n=102)-Methylene blue administration. C: Changes in CRP (mg/L) pre (n=103)- and post (n=102)-Methylene blue administration. D: Changes in LDH (IU) pre (n=103)- and post (n=102)-Methylene blue administration. E: Changes in D-dimer (IU) pre (n=103)- and post (n=102)-Methylene blue administration. F: Duration of hospitalization and oxygen therapy among the patients

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Table 2: Laboratory parameters in Covid-19 patients pre- and post-Methylene blue administration

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Among the 103 patients, 26.78% required intensive care unit (ICU) admission during hospitalization with an average total length of stay of 14 ± 4.20 days in ICU, 17.51% of the patients required high dependency unit with an average length of 13 ± 5.66 days, and 58.71% of the patients were in COVID general ward with oxygen facility up to 15 L where the length of stay was 14 ± 3.50 days in Covid general ward [Figure 1]F.

The HRCT score of 12 patients was above 20 out of 25 during the course. Nine (9.27%) patients recovered with the standard of care treatment along with Methylene blue used as an adjuvant drug in nebulization, through oxygen port. Intravenously 2 mg/kg in 300 mL of normal saline was administered for 5 days only for those who suffered from severe Covid-19 infections and 3.09% died with HRCT score above 20. Two patients with HRCT score of 25/25 (1.9%) have recovered.

Eighty-two patients (84.46%) were on oxygen through the nasal cannula, face mask, or non-rebreather mask. Two patients (2.06%) were on HFNC oxygen. Nine patients were (9.27%) on non-invasive ventilation and 10 patients (10.3%) were on invasive ventilation.

Eighty-nine patients were discharged with a recovery rate of 86.4%. Fifty-eight patients (56.33%) recovered on the 10th day, 14 patients (13.6%) recovered on the 14th day, 16 patients (15.5%) recovered on the 18th day, 1 (1%) patient left against medical advice (LAMA) on the 15th day with 15 L of oxygen and outcome could not be traced [Table 3].
Table 3: Outcome

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The average total length of stay in the hospital was 14 ± 4 days. The χ2 test value is 91.081 (P = 0.000), which indicates a P-value less than 0.005 has the significance of association between type of method for oxygen and the outcome. The all-cause mortality in our study was 14 patients (13.59%). The χ2 test value is 61.695 (P = 0.000), which indicates a significant association between the type of method for oxygen and the outcome. Those who died required a more precise method of oxygen. About 9.70% of the patients who died due to Covid-19 were comorbid; 3.88% of the patients who died had no comorbidities.

Best supportive care for all patients included anticoagulants, low molecular weight heparins, steroids either injectable dexamethasone or injectable methylprednisolone, antivirals (lopinavir+ritonavir), remdesivir, favipiravir, ivermectin, tocilizumab, or bevacizumab in severe cases whichever was available, and hydroxychloroquine (HCQS) during the first wave. Most of the patients died (13.59% cases): 9 patients out of 10 on mechanical ventilation accounting for 8.73% of the deaths, 3 (2.9%) deaths on NIV, and 2 (1.9%) deaths on oxygen. Most of the deaths were due to severe hypoxia, multi-organ dysfunction syndrome, and sepsis [Table 4] and [Table 5].
Table 4: Outcome

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Table 5: Outcome of the patients in terms of recovery and death

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  Discussion Top


New drug development is impractical in the face of the current global pandemic. An effective alternative is repurposing an existing drug with a known safety profile and showing effectiveness in managing Covid-19 complications.[6] Methylene blue, the oldest synthetic substance synthesized by BASF in 1876, is a promising candidate for an active treatment against SARS-CoV-2-infected people.[7] We administered Methylene blue to patients who exhibited high levels of inflammatory markers and showed deteriorations, despite being provided with the best supportive care.

In our study, the outcome of the critically ill patients who have received Methylene blue showed significant improvement.

The mean age of patients was 56.49 years (SD 14.00) with male predominance 59 in numbers (57.3%), with diabetes mellitus 35 patients (34.0%), hypertension 12 patients (11.7%), being the most common morbidities. Twenty-five patients (24.7%) had a combination of comorbidities such as diabetes mellitus, hypertension, ischemic heart disease, and chronic obstructive airway disease. About 31 patients (30.1%) had no comorbidities. The overall survival was 86.4%. In a similar Indian study, the demographic data on age (58 ± 13.2) and male gender (70.8%) were less compared with that in our study. Nevertheless, the at least one comorbidity data was much lower (40.56%) when compared with 47% in our study, and survival among the critical patients was 86.4% in our study, compared with 52.3%.[8]

Severe illness of Covid-19 disease is characterized by moderate and severe ARDS. The important parameter that decides admission in ICU was the SpO2 levels. The patients’ SpO2 improved from a mean of 81.90 to a mean of 88.31 post-Methylene blue treatment in our study, which was statistically significant (P < 0.000). An improvement in oxygen saturation and patients’ clinical status was seen. Alamdari et al.[9] found that in the Methylene blue group, a significant improvement in SpO2 and respiratory rate was observed on the 3rd day (for both, P < 0.0001) and also on the 5th day (for both, P < 0.0001).

In our study, the serum ferritin levels decreased significantly. The % decrease of serum ferritin was 29.976% (P < 0.000). As per a recent retrospective study with 150 confirmed Covid-19 patients, a significant difference in ferritin levels was observed between the non-survivor group and the survivor group (P < 0.001).[10]

In our study, the CRP level decreased significantly on post-Methylene blue administration. The mean CRP (mg/L) was 34.78 (SD 44.83) (post-Methylene blue). The percentage decrease of CRP was 35.901% (P < 0.000). CRP levels >41.8 mg/L develop COVID-19 complications.[11],[12],[13]

The mean LDH levels were reduced to 288.11 (SD 225.12) (post-Methylene blue). The average LDH decreased significantly (P < 0.005). The % decrease in LDH was 32.318%. Elevated LDH values were associated with a 6-fold increased odds of severe COVID-19 disease. Early data of Henry et al.[14] reported in COVID-19 patients have suggested significant differences in LDH levels between patients with and without the severe disease.

Twenty-eight studies reported LDH levels in severe vs. non-severe groups. A statistically significant higher level of LDH was also observed in terms of ICU vs. non-ICU patients (MD = 272.98; 95% CI 195.46, 350.51; P < 0.001; I2 = 99%) and non-survival vs. survival patients (MD = 259.21; 95% CI 166.91, 351.51; P < 0.001, I2 = 100%).[15]

The D-dimer assay (IU) was 1713.38 (SD 2395.92) (post-Methylene blue). The average D-dimer (IU) decreased significantly. The percentage decrease of D-dimer is 41.449% (P < 0.005). D-dimer is commonly elevated in patients with COVID-19. D-dimer levels correlate with disease severity and are a reliable prognostic marker for in-hospital mortality in patients admitted for COVID-19. Median D-dimer levels showed a 7-fold increase from moderate to critically ill patients (4.76 [2.02–13.30] vs. 0.6 [0.33–1.49] mg/L, P = 0.000) and a 5-fold increase from patients with ≤ 30% affected lung area to ≥ 50% change (3.93 [1.28–12.31] vs. 0.6 [0.33–1.42] mg/L, P = 0.042).[16]

Eighty-nine patients were discharged with a recovery rate of 86.4% and took an average recovery time of 9.50 ± 3.75 days. Fifty-eight patients (56.3%) recovered on the 10th day, 14 patients (13.6%) recovered on the 14th day, 16 patients (15.5%) recovered on the 18th day, 1 (1%) patient LAMA on 15th day with 15 L of oxygen and whose outcome could not be traced. The average total length of stay in the hospital was 14 ± 4 days. The χ2 test value is 91.081 (P = 0.000), which indicates that a P-value less than 0.005 has the significance of association between types of method for oxygen and the outcome. The all-cause mortality in our study was 14 patients (13.6%). The χ2 test value is 61.695 (P = 0.000), which indicates a significant association between the type of method for oxygen and the outcome. Those who died required a more precise method of oxygen.

The hospital stay was significantly shortened in the Methylene blue group (P = 0.004), and the mortality was 12.5% and 22.5% in the MB and SOC groups, respectively.[9] A mortality rate of 39–72% has been reported among patients admitted in the ICU with COVID-19 complications.[17],[18],[19],[20] Most patients died accounting for 13.59% cases, 9 patients out of 10 on mechanical ventilation accounting for 8.7% deaths, 2.9% deaths on NIV, and 1.9% death on oxygen. Most of the deaths were due to severe hypoxia, multi-organ dysfunction syndrome, and sepsis.

So adding Methylene blue as an adjuvant drug to the SOC may improve the outcome at an early stage. In the Covanta trial, the median time to hospital discharge was 20 days in the TOCI group and 28 days in the placebo group; in the Impact trial, the median time was 6.0 and 7.5 days, respectively, whereas in our Methylene blue trial, it was 14 ± 6 days.[21],[22]

During the disease course, evaluation of parameters such as ferritin, CRP, serum LDH, and D-dimer assay may help identify patients at risk of respiratory failure, help in triage planning, and prompt intervention to improve outcomes.

The severity of COVID-19 disease is characterized by ARDS. The SpO2 level is an important parameter to decide the need for admitting the patients in the ICU. The clinical assessment of patients was done at hospitalization, oxygen supplementation by nasal canula, Non-Rebreather Mask (NRBM), Bilevel Positive Airway Pressure (BiPAP), or Pressure Control Ventilation (PCV), at mechanical ventilation to all patients. An improvement in oxygen saturation (95% SpO2) and patient’s clinical status were observed post-Methylene blue administration in the majority of the patients. The patients were weaned off oxygen within an average of 5.5 days post-Methylene blue administration with the majority of the patients getting discharged by the 10th day.[23]


  Limitations Top


  1. This is a single-center, prospective study.


  2. In patients with severe comorbidities whether the death was related to COVID itself or to the underlying comorbidity cannot be ascertained in all the cases.


  3. There would be a referral bias as it is a study from a tertiary care center and hence there is a higher rate of mortality as many critically ill patients were admitted.


  4. There is no control in selecting patients, as all the referred Covid-positives were with moderate and severe symptoms.



  Conclusion Top


Intravenous Methylene blue was given for all the patients of moderate and severe cases of COVID-19, and it helped by controlling immune hyperactivation. The clinical improvement was demonstrated by the reduction of inflammatory markers, weaning off oxygen, and reduced length of hospital stay. Methylene blue was well tolerated and, when administered in the early phase of the inflammatory cascade, is an efficient therapeutic option for moderate and severe cases of COVID-19 patients. The randomized controlled clinical trials in large patient populations may help in further findings.

Acknowledgements

We are grateful for the support of Dr. Sudhirchandra N. Kadam (Director of MGM Hospitals, Navi Mumbai, Maharashtra, India), Dr. Virendra J. Mahadik (Medical Superintendent, MGM Hospitals, Navi Mumbai, Maharashtra, India), Jayalaxmi Shinde (Medical writer), and Statistician S.B. Mule. I thank the unprecedented support of the general and emergency Department of Medicine, the residents, the duty medical officers, the casualty medical officer, the administration, the paramedical staff, the other departments working in Covid, the healthcare providers of our hospital, and my gratitude toward the patient who participated in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Gupta A, Nayan N, Nair R, Kumar K, Joshi A, Sharma S, et al. Diabetes mellitus and hypertension increase risk of death in novel corona virus patients irrespective of age: A prospective observational study of co-morbidities and Covid-19 from India. Sn Compr Clin Med 2021;3:937-44.  Back to cited text no. 8
    
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