BREAKING! Egyptian Randomized Clinical Trial Shows That Inhalable Sodium Bicarbonate Could Be Used As Adjuvant In COVID-19 Treatment Protocols!
: A randomized clinical trial conducted by researchers from the Faculty of Medicine, Mansoura University - Egypt has found that inhalable sodium bicarbonate could be used as adjuvant in COVID-19 prophylactic and treatment protocols!
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outlets have not been covering on the various clinical trials involving cheaper repurposed drugs or compounds that can be used as adjuvants or as main therapeutics in COVID-19 treatment protocols or even as prophylactics.
The study team said that entry of the SARS-CoV-2 coronavirus into human host cells is pH dependent.
Accordingly, intracellular alkalinization by sodium bicarbonate (SB) could elevate endosomal pH and block viral entry into the host cells.
The study team assessed the role of inhalable SB as an adjuvant treatment for COVID-19 in the study groups of this randomized, controlled trial.
The clinical trial findings showed a significantly shorter duration to clinical improvement and hospital stay in the study group, while the number of deaths is significantly less only in severe grade of the study group.
However, the time to death is not significantly different in both groups.
Importantly, CRP and d-dimer levels are significantly lower in the severe cases of the study group. The overall median CT score is significantly better in the study group at one & 2 months.
The study findings suggest that inhaled SB (8.4%) could be a possible adjuvant therapy for patients with moderate and severe COVID 19 pneumonia. Furthermore, more studies are also warranted to assess of inhaled sodium bicarbonate can be used as an adjuvant in prophylactic protocols as well.
The study findings were published on a preprint server and are currently being peer reviewed.
Sodium bicarbonate is an easily available compound that is extremely cheap and also has a safe toxic profile.
The study team was motivated by the fact that the entry of SARS-CoV-2 into a host cell is pH dependent, since when the virus fuses with a human cell via the S glycoprotein, it is subsequently endocytosed into clathrin-coated pits and fuses with the endosomal membrane when the pH is lowered.
A past study had shown that human primary monocytes cultivated in low pH showed increased ACE2
expression and a higher viral load for SARS-CoV-2 infection, indicating that pH has a significant impact on the severity of SARS-CoV-2 infection.
A previous controlled study concluded that SB 8.4% inhalation with its nasal instillation could be a possible adjuvant therapy for patients with non-severe
COVID-19 pneumonia. Nevertheless, that study had several shortcomings, being nonrandomized, with limited number of patients and short duration of follow-up. Moreover, that study excluded mild and severe cases of COVID-19 and included moderate cases only identified according to CT findings.
The current study is the continuation of the above study on the role of SB inhalation as an adjuvant nontoxic tool for enhancing both clinical and radiological recoveries of non-severe COVID-19 pneumonia as a controlled randomized study including 182 patients.
However, in the current study, SB inhalation was added to conventional treatment in a randomized order to reduce bias, and a larger sample size of 546 patients, including all COVID-19 severity grades, was used.
The trial participants received conventional treatment according to the protocol of the Egyptian Ministry of Health as well as inhalation of SB 8.4% via jet nebulizer and nasal instillation, while the control group received only conventional treatment.
22.2% of the cases in the trial were classified as having a mild illness, 46.7% as moderate, 22.3% as severe, and 8.8% as critical.
COVID-19 has a wide variety of presentations, from asymptomatic to severe pneumonia with respiratory failure that can result in invasive mechanical ventilation and even death.
The median age of the 546 patients in this trial was 50.7 ± 16.8, with 215 men and 331 women participating. The following clinical symptoms were most frequently reported: bone ache (96.5%), headache (94.7%), fever (91.6%), cough (87.0%), sore throat (82.4%), dyspnea (81%), sputum production (57%), anosmia (58.4%), loss of taste (58.2%), dizziness (48.5%), and diarrhea (26.7%).
The study findings showed that the addition of inhaled SB considerably shortened the duration to clinical improvement, with 3 days (2–18) in the study group and 5 (2–22) in the control group, respectively (p < 0.001). This improvement was maintained in all the grades.
However, the subjective clinical improvement was noticed only in the moderate grade of the study group starting from the first week, in the score of each of dyspnea, cough, and expectoration (p = 0.021, p = 0.009, and p = 0.002, respectively) as compared to the control group. For these direct-acting antivirals to be effective, they must be administered early during infection before the virus reaches its replication peak and are therefore used to prevent progression to severe disease.
Direct-acting antivirals, in addition to corticosteroid and/or immunomodulatory medications, have a role in promoting viral clearance and, thus, reducing hyperinflammatory responses in the severe grade based on COVID-19 pathogenesis.
But at the same time, antivirals have been shown to be ineffective when administered late in critically ill patients who develop ARDS and diffuse alveolar injury. In these cases, anti-inflammatory medications may be more effective in managing the condition.
Interestingly, there was a statistically significant difference in SpO2 between the study and control groups at one and two months of follow-up, however this was only noticeable in moderate cases. It has little clinical significance because resting oxygen saturation is only regarded abnormal if it is less than 95% and both groups' means were within normal range and practically comparable (97.8 ± 0.54 in the study group and 97.4 ± 0. 84 in the control group).
The study findings showed that the COVID-19 related mortality rate was 13.5%. SB inhalation didn’t significantly lower the overall frequency of COVID-19–related deaths (32 cases in the study group versus 42 cases in the control group, p = 0.224). The sub-analysis done according to the disease severity showed that the number of deaths was significantly lower in the severe grade of the study group (11 cases in the study group versus 22 cases in the control group, p = 0.014) and also in the moderate grade (one case in the study group versus 5 in the control group but without statistical significance). Notably, there was no impact of SB inhalation in the mortality detected in the critical cases (20 cases in the study group versus 15 cases in the control group, p = 0.335). this could be explained in part by the small number of critical cases.
Importantly, the level of D-dimer and CRP in the study showed variable results and were not useful to differentiate between the results of treatment of both groups but sub-analysis done according to the grade severity showed that CRP and D-dimer levels measured at one week were significantly improved with SB inhalation in the severe grade. Typically in cases with severe pneumonia, lung injury is resulting from the cytokine storm and the subsequent inflammation where the virus-laden pneumocytes release many different cytokines and inflammatory markers such as interleukins (IL-1, IL-6, and IL-8), tumor necrosis factor-α (TNF-α), IFN-λ and IFN-β, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) and this was associated with elevated concentrations of inflammatory markers, including D-dimer, ferritin and C-reactive protein (CRP).
As the COVID-19 infection subsides, one would anticipate a steady decline in both D-dimer and CRP blood levels.
CRP levels have been reported to be higher in severe cases than in non-severe patients, suggesting that the role of CRP levels as a biomarker of disease severity and progression in patients with COVID-19. This is consistent with the study findings, which showed the importance of inflammatory markers in monitoring the treatment response in severe cases as opposed to mild and moderate cases.
It has been known that higher CT scores are associated with worse outcomes, including a higher mortality risk, showing the importance of imaging when managing patients and evaluating their prognosis. Both moderate and severe grades in the study group showed radiological improvement in the severity of lung involvement at all points of follow up; one week, one month and 2 months.
But there was no noticed radiological improvement in the critically ill cases of the study group when compared to the control group. In the context of that, the results of this study showed that SB inhalation significantly reduced the overall length of hospital stay for patients who needed to be admitted, but only in moderate and severe grades - not in critical cases.
In the study, no hospitalization was required in mild-grade COVID cases. Although some of the mild cases in the study had radiological infiltrates during the follow up, all cases in both groups were minimal.
A past study has showed that lung opacities in 53.0% of patients with mild COVID-19 disappeared without causing any negative side effects.
However, since fibrosis is the primary side effect of persistent infection and associated inflammation, it is crucial to reduce the viral load and, subsequently, the duration of viral pneumonia.
At the 6-month follow-up, a chest CT revealed that almost half of patients who were recovering from severe COVID-2019 pneumonia had lung fibrosis. Age over 50, ARDS, noninvasive mechanical ventilation, a total chest CT score of 18 or higher on first CT scans, and a hospital stay of at least 17 days are all suggestive independent predictors. The significance of SB inhalation in this context should, therefore, be assessed following the correlation of the other risk factors mentioned above in future studies.
The study is the first randomized clinical trial or RCT with adequately calculated sample size that sheds the light on the role of SB in the treatment of different grades of COVID-19.
The study team concluded that inhaled SB (8.4%) together with nasal drops is an effective adjuvant therapy for patients with COVID 19 pneumonia, as it shortens the overall duration to clinical improvement, hospital stay for the admitted cases, improving their CT score, and lowering the mortality only in the severe grade of COVID 19 pneumonia patients.
More importantly, based on the theory that combination therapies using two or more direct-acting antivirals from different classes (e.g., a nucleotide analog as favipiravir or remdesivir plus a monoclonal antibody) will likely reduce the probability of mutant variants to emerge and may enhance the clinical benefit of treatment, hence SB inhalation has been regarded as a safe add-on therapy to the standard treatment of COVID-19.
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