Aerosol delivery systems for treating obstructive airway diseases during the SARS-CoV-2 pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes CoronaVirus Disease 2019 (COVID-19), has resulted in a worldwide pandemic and currently represents a major public health crisis. It has caused outbreaks of illness through person-to-person transmission of the virus mainly via close contacts, and droplets produced by an infected person's cough or sneeze. Aerosolised inhaled therapy is the mainstay for treating obstructive airway diseases at home and in healthcare settings, but there is heightened particular concern about the potential risk for transmission of SARS-CoV-2 in the form of aerosolised respiratory droplets during the nebulised treatment of patients with COVID-19. As a consequence of this concern, the use of hand-held inhalers, especially pressurised metered dose inhalers, has risen considerably as an alternative to nebulisers, and this switch has led to inadequate supplies of inhalers in some countries. However, there is no evidence supporting an increased risk of viral transmission during nebulisation in COVID-19 patients. Furthermore, some patients may be unable to adequately use their new device and may not benefit fully from the switch to treatment via hand-held inhalers. Thus, there is no compelling reason to alter aerosol delivery devices for patients with established nebuliser-based regimens. The purpose of this paper is to discuss the current evidence and understanding of the use of aerosolised inhaled therapies during the SARS-CoV-2 pandemic and to provide some guidance on the measures to be taken to minimise the risk of transmitting infection, if any, during aerosol therapies.

Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19 patients: A systematic review.

OBJECTIVE: Present systematic review aimed to analyze the effect of inhaled nitric oxide (iNO) in the treatment of severe COVID-19 and to compare it to standard of care (SOC), antiviral medications, and other medicines. MATERIALS AND METHODS: Medline (PubMed), Scopus, Embase, Ovid, Web of Science, Science Direct, Wiley Online Library, BioRxiv and MedRxiv, and Cochrane (up to April 20, 2021) were the search databases. Two reviewers (SK and CK) independently selected the electronic published literature that studied the effect of nitric oxide with SOC or control. The clinical and physiological outcomes such as prevention of progressive systemic de-oxygenation/clinical improvement, mortality, duration of mechanical ventilation, improvement in pulmonary arterial pressure, and adverse events were assessed. RESULTS: The 14 retrospective/protective studies randomly assigning 423 patients met the inclusion criteria. Cumulative study of the selected articles showed that iNO has a mild impact on ventilation time or ventilator-free days. iNO has increased the partial pressure of oxygen/fraction of inspired oxygen ratio of fraction of inspired oxygen in a few patients as compared to baseline. However, in most of the studies, it does not have better outcome when compared to the baseline improvement. CONCLUSIONS: In patients with COVID-19 with acute respiratory distress syndrome, nitric oxide is linked to a slight increase in oxygenation but has no effect on mortality.

Bronchodilator reversibility testing in post-COVID-19 patients undergoing pulmonary rehabilitation.

BACKGROUND: The usefulness of bronchodilators in coronavirus diseases 2019 (COVID-19) survivors is still uncertain, especially for patients with a concomitant obstructive lung disease. We aimed at verifying the level of bronchodilator reversibility in COVID-19 patients undergoing multidisciplinary pulmonary rehabilitation after the acute phase. METHODS: We enrolled 105 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. All subjects performed a spirometry before and after inhalation of salbutamol 400 µg to determine the bronchodilation response within 48 h of admission to the unit. RESULTS: All patients had suffered from a moderate to severe COVID-19, classified 3 or 4 according to the WHO classification, Seventeen patients had concomitant obstructive lung disease (14 suffering from COPD and 3 from asthma). FEV1 after salbutamol improved on average by 41.7 mL in the entire examined sample, by 29.4 mL in subjects without concomitant obstructive lung diseases, by 59.3 mL in COPD patients and by 320.0 mL in asthma patients. Mean FVC after salbutamol improved by 65.7 mL in the entire examined sample, by 52.5 mL in subjects without concomitant obstructive lung diseases, by 120.0 mL in COPD patients, and by 200.0 mL in asthma patients. CONCLUSIONS: This study suggests that a treatment with bronchodilators must always be taken into consideration in post-COVID-19 patients because it can induce a functional improvement that, even if small, can facilitate the breathing of these patients.

The outcomes and acceptance of pressurized metered-dose inhaler bronchodilators with venturi mask modified spacer in the outpatient emergency department during the COVID-19 pandemic.

WHAT IS KNOWN AND OBJECTIVE: Nebulizer use has been suspended in Malaysian public health facilities due to the potential to aggravate COVID-19 nosocomial transmission. Currently, our facility uses the pressurized metered-dose inhaler (pMDI) bronchodilator with Venturi mask modified spacer (VMMS) in patients visiting the Emergency Department (ED) for mild to moderate exacerbation of asthma and chronic obstructive pulmonary disease (COPD). We sought to assess the outcomes and acceptance of pMDI-VMMS in the outpatient ED of a tertiary hospital in Malaysia. METHODS: We analysed the total visits and discharge rates during periods of using the nebulizer and current pMDI-VMMS methods. The acceptance of pMDI-VMMS by patients and assistant medical officers (AMOs) were assessed by questionnaire. RESULTS AND DISCUSSION: We analysed 3184 ED visits and responses from 103 patients and 32 AMOs. The direct discharge rate was similar for both nebulizer (n = 2162, 92.5%) and pMDI-VMMS method (n = 768, 90.7%) (p-value = 0.120). Twenty-eight patients (27.2%) favoured the pMDI-VMMS over the nebulizer, whereas 36 patients (35.0%) had no preference for either method. Sixty-four patients (62.1%) felt that the current pMDI-VMMS method was better or at least as effective in relieving their symptoms as a nebulizer. The current method was favoured over the nebulizer by twenty-seven AMOs (84.4%). Twenty-eight (87.5%) AMOs suggested that the current method was more effective than the nebulizer. WHAT IS NEW AND CONCLUSION: The bronchodilator delivered via pMDI-VMMS appeared to be comparable to nebulizer in treating mild to moderate asthma and COPD exacerbations in the outpatient ED. Most patients and AMOs accepted the use of pMDI-VMMS in the outpatient ED during the current COVID-19 pandemic. The Venturi mask modified spacer can be a cheap and effective alternative to the commercial spacer in a resource-limited situation.

In vitro comparison of unit dose vs infusion pump administration of albuterol via high-flow nasal cannula in toddlers.

OBJECTIVES: Transnasal pulmonary aerosol delivery using high-flow nasal cannula (HFNC) devices has become a popular route of aerosol administration in toddlers. Clinically, albuterol is administered using an infusion pump or unit doses. However, little evidence is available to compare the two administration strategies. METHODS: A toddler manikin (15 kg) with appropriate anatomic airway was connected with collecting filter to a simulator of distressed breathing. HFNC device with mesh nebulizer placed at the inlet of a humidifier at 37°C, with the gas flow set at 25 and 3.75 L/min. Five milligrams of albuterol was delivered in all experiments. With infusion pump administration, albuterol concentrations of 5 and 1 mg/mL were delivered at 4 and 20 mL/hr for 15 minutes. With unit dose administration, 1 mL (5 mg/mL) and 2 mL (2.5 mg/mL) of albuterol were nebulized. Additional tests with mouth open and nebulizers via mask were using 5 mg/1 mL for mesh nebulizer and 5 mg/3 mL for jet nebulizer (n = 3). The drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). RESULTS: The inhaled dose was higher with unit dose than infusion pump administration with gas flows of 25 L/min (2.66 ± 0.38 vs 1.16 ± 0.28%; P = .004) and 3.75 L/min (10.51 ± 1.29 vs 8.58 ± 0.68%; P = .025). During unit dose administration, compared with closed-mouth breathing, open-mouth breathing generated a higher inhaled dose at 3.75 L/min and lower inhaled dose at 25 L/min. Compared to the nebulizers via mask with both open and closed-mouth breathing, nebulization via HFNC at 3.75 L/min generated greater inhaled dose, while HFNC at 25 L/min generated lower inhaled dose. CONCLUSIONS: During transnasal aerosol delivery, the inhaled dose was higher with medication administrated using unit dose than using an infusion pump.

Homemade valved holding chambers for children with airway hyperresponsiveness: A randomized crossover trial.

BACKGROUND: During the COVID-19 pandemic, a metered-dose inhaler (MDI) with a valved holding chamber (VHC) is a preferred route of bronchodilator delivery. We have developed a new homemade VHC, made of a paper coffee cup, and a drinking water bottle. This study was conducted to compare the bronchodilator response in children with airway hyperresponsiveness after the use of our homemade VHC and that of a standard commercial one. METHODS: In a randomized, two-period, two-sequence crossover trial, we recruited 20 children, aged 6-15 years, who had a greater than 12% increase in FEV1 after inhaled salbutamol. They were randomized into Group A and B. Group A used our VHC on the first day and Aerochamber® on the second day. Group B used the same VHCs but in alternate sequence. Spirometries were performed before and after 400 µg of salbutamol, MDI was administered via those VHCs. RESULTS: Baseline demographic data and spirometric values did not have statistically significant differences between group A and B and between the first and second day (p > .05). After giving salbutamol MDI, both VHCs produced significant increases in FVC, FEV1 , and FEF25-75% (p < .005). The improvement in FEV1 did not significantly differ between our homemade VHC and Aerochamber® (p > .05). CONCLUSION: Our homemade VHC is effective for an MDI bronchodilator delivery. Since it is very cheap and easy to make, it may be used as a disposable device to minimize airborne transmission especially when commercial VHC is not available.

Evidence-based treatment during the SARS-CoV-2 pandemic: Identifying the knowns and unknowns of nebulization.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus 19 (COVID-19), has resulted in a worldwide pandemic and currently represents a major public health issue. Among the considerations for patients with respiratory disease is the optimal delivery of inhaled bronchodilators to maximize patient care. Despite the lack of evidence, there is heightened concern about the potential risk for transmission of SARS-CoV-2 in the form of aerosolized respiratory droplets during the nebulized treatment of patients with COVID-19. In this commentary, the lack of evidence regarding nebulization and transmission of coronaviruses are discussed.

Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: a case series.

BACKGROUND: Mechanically ventilated patients with COVID-19 have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. DNA from neutrophil extracellular traps (NETs) contribute to the viscosity of mucopurulent secretions and NETs are found in the serum of COVID-19 patients. Dornase alfa is recombinant human DNase 1 and is used to digest DNA in mucoid sputum. Here, we report a single-center case series where dornase alfa was co-administered with albuterol through an in-line nebulizer system. METHODS: Demographic and clinical data were collected from the electronic medical records of five mechanically ventilated patients with COVID-19-including three requiring veno-venous extracorporeal membrane oxygenation-treated with nebulized in-line endotracheal dornase alfa and albuterol, between March 31 and April 24, 2020. Data on tolerability and response were analyzed. RESULTS: The fraction of inspired oxygen requirements was reduced for all five patients after initiating dornase alfa administration. All patients were successfully extubated, discharged from hospital and remain alive. No drug-associated toxicities were identified. CONCLUSIONS: Results suggest that dornase alfa will be well-tolerated by patients with severe COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and several have been recently registered.

Uninterrupted Continuous and Intermittent Nebulizer Therapy in a COVID-19 Patient Using Sequential Vibratory Mesh Nebulizers: A Case Report.

Interruptions in continuous nebulized pulmonary vasodilators, such as epoprostenol, can potentially result in clinical deterioration in respiratory status. Coadministration of other intermittent nebulized therapies may require opening the ventilator circuit to facilitate administration. However, in patients with SARS-CoV2 infection, it is preferred to avoid opening the circuit whenever feasible to prevent aerosolization of the virus and exposure of health care workers. In this study, we describe a unique method of administering continuous epoprostenol nebulization and intermittent nebulized antibiotics, mucolytics, and bronchodilators, using Aerogen vibrating mesh nebulizers without interruptions in epoprostenol or opening the ventilator circuit. This technique set up consisted of stacking two Aerogen nebulizer cups, each with its own controller. This approach was successful in allowing concomitant delivery of intermittent and continuous nebulized therapy without interruptions. To our knowledge, this method has not been previously described in the literature and may be helpful to bedside clinicians facing a similar clinical scenario.