Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine.

The Covid-19 outbreak challenged health systems around the world to design and implement cost-effective devices produced locally to meet the increased demand of mechanical ventilators worldwide. This study evaluates the physiological responses of healthy swine maintained under volume- or pressure-controlled mechanical ventilation by a mechanical ventilator implemented to bring life-support by automating a resuscitation bag and closely controlling ventilatory parameters. Physiological parameters were monitored in eight sedated animals (t0) prior to inducing deep anaesthesia, and during the next six hours of mechanical ventilation (t1-7). Hemodynamic conditions were monitored periodically using a portable gas analyser machine (i.e. BEecf, carbonate, SaO2, lactate, pH, PaO2, PaCO2) and a capnometer (i.e. ETCO2). Electrocardiogram, echocardiography and lung ultrasonography were performed to detect in vivo alterations in these vital organs and pathological findings from necropsy were reported. The mechanical ventilator properly controlled physiological levels of blood biochemistry such as oxygenation parameters (PaO2, PaCO2, SaO2, ETCO2), acid-base equilibrium (pH, carbonate, BEecf), and perfusion of tissues (lactate levels). In addition, histopathological analysis showed no evidence of acute tissue damage in lung, heart, liver, kidney, or brain. All animals were able to breathe spontaneously after undergoing mechanical ventilation. These preclinical data, supports the biological safety of the medical device to move forward to further evaluation in clinical studies.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Tocilizumab in critically ill COVID-19 patients: An observational study.

Tocilizumab decreases inflammatory response in the cytokine storm which is one of the mechanisms behind the development of ARDS in COVID-19 patients. The objective of our study was to determine response of tocilizumab in patients suffering from COVID-19 by analyzing clinical parameters and inflammatory markers. A single-arm observational retrospective study was conducted from March 15, 2020 to March 15, 2021. Clinical outcomes in terms of mortality, weaning from mechanical ventilator, improvement in laboratory parameters including inflammatory cytokines, and length of hospital stay were documented. Reduction in values of inflammatory markers, and patients discharged home in stable condition were defined as an improvement after tocilizumab administration. A total of 514 patients received tocilizumab, majority of whom were critically sick 333 (64.8%). Out of the total sample 363 (70.6%) patients were discharged home in stable condition. Overall mean length of stay was 11.50 ± 8.4 days. There was significant difference in length of stay of patients who required invasive mechanical ventilation as compared to those who were kept only on supplemental oxygen (p < 0.05). Patients who were discharged home showed significant improvement in inflammatory markers and neutrophil to lymphocyte ratio as compared to those who expired (p < 0.05). A total of 21 (4.1%) patients had positive blood culture while 57 (11.1%) had positive culture of tracheal aspirate. Hence, tocilizumab is found to be a reasonable therapeutic option for worsening COVID-19 pneumonia by decreasing the need for mechanical ventilation. However, it is associated with adverse events including bacterial and fungal infections.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Innovations to automate manual ventilation during Covid-19 pandemic and beyond.

Manual ventilation by compressing self-inflating bags is a life-saving option for respiratory support in many resource-limited settings. Previous efforts to automate manual ventilation using mechatronic systems were unsuccessful. The Covid-19 pandemic stimulated re-exploration of automating manual ventilation as an economically viable alternative to address the anticipated shortage of mechanical ventilators. Many devices have been developed and displayed in the lay press and social media platforms. However, most are unsuitable for clinical use for a variety of reasons. These include failure to understand the clinical needs, complex ventilatory requirements in Covid-19 patients, lack of technical specifications to guide innovators, technical challenges in delivering ventilation parameters in a physiological manner, absence of guidelines for bench testing of innovative devices and lack of clinical validation in patients. The insights gained during the design, development, laboratory testing and clinical validation of a novel device designated the 'Artificial Breathing Capability Device' are shared here to assist innovators in developing clinically usable devices. A detailed set of clinical requirements from such devices, technical specifications to meet these requirements and framework for bench testing are presented. In addition, regulatory and certification issues, as well as concerns related to the protection of intellectual property, are highlighted. These insights are designed to foster an innovation ecosystem whereby clinically useful automated manual ventilation devices can be developed and deployed to meet the needs associated with the Covid-19 pandemic and beyond.

Exhalatory dynamic interactions between patients connected to a shared ventilation device.

In this work a shared pressure-controlled ventilation device for two patients is considered. By the use of different valves incorporated to the circuit, the device enables the restriction of possible cross contamination and the individualization of tidal volumes, driving pressures, and positive end expiratory pressure PEEP. Possible interactions in the expiratory dynamics of different pairs of patients are evaluated in terms of the characteristic exhalatory times. These characteristic times can not be easily established using simple linear lumped element models. For this purpose, a 1D model using the Hydraulic and Mechanical libraries in Matlab Simulink was developed. In this sense, experiments accompany this study to validate the model and characterize the different valves of the circuit. Our results show that connecting two patients in parallel to a ventilator always resulted in delays of time during the exhalation. The size of this effect depends on different parameters associated with the patients, the circuit and the ventilator. The dynamics of the exhalation of both patients is determined by the ratios between patients exhalatory resistances, compliances, driving pressures and PEEPs. Adverse effects on exhalations became less noticeable when respiratory parameters of both patients were similar, flow resistances of valves added to the circuit were negligible, and when the ventilator exhalatory valve resistance was also negligible. The asymmetries of driving pressures, compliances or resistances exacerbated the possibility of auto-PEEP and the increase in relaxation times became greater in one patient than in the other. In contrast, exhalatory dynamics were less sensitive to the ratio of PEEP imposed to the patients.

The repurposed use of anesthesia machines to ventilate critically ill patients with coronavirus disease 2019 (COVID-19).

BACKGROUND: The surge of critically ill patients due to the coronavirus disease-2019 (COVID-19) overwhelmed critical care capacity in areas of northern Italy. Anesthesia machines have been used as alternatives to traditional ICU mechanical ventilators. However, the outcomes for patients with COVID-19 respiratory failure cared for with Anesthesia Machines is currently unknow. We hypothesized that COVID-19 patients receiving care with Anesthesia Machines would have worse outcomes compared to standard practice. METHODS: We designed a retrospective study of patients admitted with a confirmed COVID-19 diagnosis at a large tertiary urban hospital in northern Italy. Two care units were included: a 27-bed standard ICU and a 15-bed temporary unit emergently opened in an operating room setting. Intubated patients assigned to Anesthesia Machines (AM group) were compared to a control cohort treated with standard mechanical ventilators (ICU-VENT group). Outcomes were assessed at 60-day follow-up. A multivariable Cox regression analysis of risk factors between survivors and non-survivors was conducted to determine the adjusted risk of death for patients assigned to AM group. RESULTS: Complete daily data from 89 mechanically ventilated patients consecutively admitted to the two units were analyzed. Seventeen patients were included in the AM group, whereas 72 were in the ICU-VENT group. Disease severity and intensity of treatment were comparable between the two groups. The 60-day mortality was significantly higher in the AM group compared to the ICU-vent group (12/17 vs. 27/72, 70.6% vs. 37.5%, respectively, p = 0.016). Allocation to AM group was associated with a significantly increased risk of death after adjusting for covariates (HR 4.05, 95% CI: 1.75-9.33, p = 0.001). Several incidents and complications were reported with Anesthesia Machine care, raising safety concerns. CONCLUSIONS: Our results support the hypothesis that care associated with the use of Anesthesia Machines is inadequate to provide long-term critical care to patients with COVID-19. Added safety risks must be considered if no other option is available to treat severely ill patients during the ongoing pandemic. CLINICAL TRIAL NUMBER: Not applicable.

Coronavirus Disease 2019: Anesthesia Machine Circuit Pressure During Use as an Improvised Intensive Care Unit Ventilator.

BACKGROUND: Use of anesthesia machines as improvised intensive care unit (ICU) ventilators may occur in locations where waste anesthesia gas suction (WAGS) is unavailable. Anecdotal reports suggest as much as 18 cm H2O positive end-expiratory pressure (PEEP) being inadvertently applied under these circumstances, accompanied by inaccurate pressure readings by the anesthesia machine. We hypothesized that resistance within closed anesthesia gas scavenging systems (AGSS) disconnected from WAGS may inadvertently increase circuit pressures. METHODS: An anesthesia machine was connected to an anesthesia breathing circuit, a reference manometer, and a standard bag reservoir to simulate a lung. Ventilation was initiated as follows: volume control, tidal volume (TV) 500 mL, respiratory rate 12, ratio of inspiration to expiration times (I:E) 1:1.9, fraction of inspired oxygen (Fio2) 1.0, fresh gas flow (FGF) rate 2.0 liters per minute (LPM), and PEEP 0 cm H2O. After engaging the ventilator, PEEP and peak inspiratory pressure (PIP) were measured by the reference manometer and the anesthesia machine display simultaneously. The process was repeated using prescribed PEEP levels of 5, 10, 15, and 20 cm H2O. Measurements were repeated with the WAGS disconnected and then were performed again at FGF of 4, 6, 8, 10, and 15 LPM. This process was completed on 3 anesthesia machines: Dräger Perseus A500, Dräger Apollo, and the GE Avance CS2. Simple linear regression was used to assess differences. RESULTS: Utilizing nonparametric Bland-Altman analysis, the reference and machine manometer measurements of PIP demonstrated median differences of -0.40 cm H2O (95% limits of agreement [LOA], -1.00 to 0.55) for the Dräger Apollo, -0.40 cm H2O (95% LOA, -1.10 to 0.41) for the Dräger Perseus, and 1.70 cm H2O (95% LOA, 0.80-3.00) for the GE Avance CS2. At FGF 2 LPM and PEEP 0 cm H2O with the WAGS disconnected, the Dräger Apollo had a difference in PEEP of 0.02 cm H2O (95% confidence interval [CI], -0.04 to 0.08; P = .53); the Dräger Perseus A500, <0.0001 cm H2O (95% CI, -0.11 to 0.11; P = 1.00); and the GE Avance CS2, 8.62 cm H2O (95% CI, 8.55-8.69; P < .0001). After removing the hose connected to the AGSS and the visual indicator bag on the GE Avance CS2, the PEEP difference was 0.12 cm H2O (95% CI, 0.059-0.181; P = .0002). CONCLUSIONS: Displayed airway pressure measurements are clinically accurate in the setting of disconnected WAGS. The Dräger Perseus A500 and Apollo with open scavenging systems do not deliver inadvertent continuous positive airway pressure (CPAP) with WAGS disconnected, but the GE Avance CS2 with a closed AGSS does. This increase in airway pressure can be mitigated by the manufacturer's recommended alterations. Anesthesiologists should be aware of the potential clinically important increases in pressure that may be inadvertently delivered on some anesthesia machines, should the WAGS not be properly connected.

In vitro evaluation of disposable transport ventilators with combination aerosol therapy.

BACKGROUND: The COVID-19 pandemic has highlighted the need for alternative short-term, reliable means to aid in the treatment of patients requiring ventilatory support. Concurrent aerosol drug delivery is often prescribed to such patients. As such, this study examines one such short-term option, the disposable gas-powered transport ventilator to effectively deliver aerosol therapy. Factors such as aerosol generator type, patient breathing pattern, humidification and nebuliser position within the respiratory circuit were also examined. METHODS: Aerosol drug delivery characterisation was undertaken using two different disposable transport ventilators (DTVs). Two different nebuliser types, a closed circuit vibrating mesh nebuliser (VMN) and an open circuit jet nebuliser (JN), at different locations in a respiratory circuit, proximal and distal to an endotracheal tube (ETT), with and without passive humidification, were evaluated in simulated adult and paediatric patients. RESULTS: Placement of a nebuliser proximal to the ETT (VMN: 25.19%-34.15% and JN: 3.14%-8.92%), and the addition of a heat and moisture exchange filter (VMN: 32.37%-40.43% and JN: 5.60%-9.91%) resulted in the largest potential lung dose in the adult patient model. Irrespective of nebuliser position and humidification in the respiratory circuit, use of the VMN resulted in the largest potential lung dose (%). A similar trend was recorded in the paediatric model data, where the largest potential lung dose was recorded with both nebuliser types placed proximal to the ETT (VMN: 8.12%-10.89% and JN: 2.15%-3.82%). However, the addition of a heat and moisture exchange filter had no statistically significant effect on the potential lung dose (%) a paediatric patient would receive (p>>0.05). CONCLUSIONS: This study demonstrates that transport ventilators, such as DTVs, can be used concurrently with aerosol generators to effectively deliver aerosolised medication in both adult and paediatric patients.

Performance of EasyBreath Decathlon Snorkeling mask for delivering continuous positive airway pressure.

During the COVID-19 pandemic, the need for noninvasive respiratory support devices has dramatically increased, sometimes exceeding hospital capacity. The full-face Decathlon snorkeling mask, EasyBreath (EB mask), has been adapted to deliver continuous positive airway pressure (CPAP) as an emergency respiratory interface. We aimed to assess the performance of this modified EB mask and to test its use during different gas mixture supplies. CPAP set at 5, 10, and 15 cmH2O was delivered to 10 healthy volunteers with a high-flow system generator set at 40, 80, and 120 L min-1 and with a turbine-driven ventilator during both spontaneous and loaded (resistor) breathing. Inspiratory CO2 partial pressure (PiCO2), pressure inside the mask, breathing pattern and electrical activity of the diaphragm (EAdi) were measured at all combinations of CPAP/flows delivered, with and without the resistor. Using the high-flow generator set at 40 L min-1, the PiCO2 significantly increased and the system was unable to maintain the target CPAP of 10 and 15 cmH2O and a stable pressure within the respiratory cycle; conversely, the turbine-driven ventilator did. EAdi significantly increased with flow rates of 40 and 80 L min-1 but not at 120 L min-1 and with the turbine-driven ventilator. EB mask can be safely used to deliver CPAP only under strict constraints, using either a high-flow generator at a flow rate greater than 80 L min-1, or a high-performance turbine-driven ventilator.

The use of oxygen hoods in patients failing on conventional high-flow oxygen delivery systems, the effects on oxygenation, mechanical ventilation and mortality rates in hypoxic patients with COVID-19. A Prospective Controlled Cohort Study.

INTRODUCTION: Efforts to meet increased oxygen demands in COVID-19 patients are a priority in averting mechanical ventilation (MV), associated with high mortality approaching 76.4-97.2%. Novel methods of oxygen delivery could mitigate that risk. Oxygen hoods/helmets may improve: O2-saturation (SaO2), reduce in-hospital mechanical ventilation and mortality rates, and reduce length of hospitalization in hypoxic Covid-19 patients failing on conventional high-flow oxygen delivery systems. METHODS: DesignProspective Controlled Cohort Study. SettingSingle Center. ParticipantsAll patients admitted with a diagnosis of COVID-19 were reviewed and 136/347 patients met inclusion criteria. Study period3/6/2020 to 5/1/2020. 136 participants completed the study with known status for all outcome measures. Intervention or exposureOxygen hoods/helmets as compared to conventional high-flow oxygen delivery systems. MAIN OUTCOME(S) AND MEASURE(S): 1) Pre and post change in oxygen saturation (SaO2). 2) In-hospital Mechanical Ventilation (MV). 3) In-hospital Mortality. 4) Length of hospitalization. RESULTS: 136 patients including 58-intervention and 78-control patients were studied. Age, gender, and other demographics/prognostic indicators were comparable between cohorts. Oxygen hoods averted imminent or immediate intubation/MV in all 58 COVID-19 patients failing on conventional high-flow oxygen delivery systems with a mean improvement in SaO2 of 8.8%, p < 0.001. MV rates were observed to be higher in the control 37/78 (47.4%) as compared to the intervention cohort 23/58 (39.7%), a difference of 7.7%, a 27% risk reduction, not statistically significant, OR 95%CI 0.73 (0.37-1.5). Mortality rates were observed higher in the control 54/78 (69.2%) as compared to the intervention cohort 36/58 (62.1%), a difference of 7.1%, a 27% risk reduction, not statistically significant OR 95%CI 0.73 (0.36-1.5). CONCLUSION: Oxygen hoods demonstrate improvement in SaO2 for patients failing on conventional high-flow oxygen-delivery systems and prevented imminent mechanical ventilation. In-hospital mechanical ventilation and mortality rates were reduced with the use of oxygen hoods but not found to be statistically significant. The oxygen hood is a safe, effective oxygen-delivery system which may reduce intubation/MV and mortality rates. Their use should be considered in treating hypoxic COVID-19 patients. Further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04407260.