Respiratory Pathophysiology of Mechanically Ventilated COVID-19 Patients

Background and objectives Coronavirus disease 2019 (COVID-19) is mainly a disease of the respiratory system that can lead to acute respiratory distress syndrome (ARDS). The pathophysiology of COVID-19 ARDS and consequently its management is a disputable subject. Early COVID-19 investigators hypothesized that the pathogenesis of COVID-19 ARDS is different from the usual ARDS. The aim of this study was to describe the lung mechanics in mechanically ventilated COVID-19 patients with ARDS. Methodology An observational retrospective cohort study was conducted on adult COVID-19 patients with ARDS who needed mechanical ventilation in the ICU of Ohoud Hospital, Madinah, KSA, from June to September 2020. Data were collected from the patients’ medical charts and electronic medical records and analyzed using Statistical Package for the Social Sciences (SPSS) software package version 22 (IBM Corp., Armonk, NY) for descriptive statistical analysis. Measurements and main results A total of 52 patients were analyzed: on intubation, the median positive end-expiratory pressure (PEEP) was 10 cm H2O (IQR, 2.3-16), the median plateau pressure was 27 cm H2O (IQR, 12-40), and the median driving pressure was 17 cm H2O (IQR, 3-30). The median static compliance of the respiratory system was 24.7 mL/cm H2O (IQR, 12.8-153.3). 59.5% had severe ARDS (the PaO2/FiO2 ratio was less than 100 mmHg), and 33% had moderate ARDS (the PaO2/FiO2 ratio ranged from 100 to 200 mmHg). Conclusion Our results suggest that the lung mechanics in COVID-19 ARDS patients who need mechanical ventilation do not differ from non-COVID-19 patients.


Introduction
In late December 2019, an outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged that was later named coronavirus disease 2019 (COVID-19) [1,2]. About 2.6 million patients have died from the disease with a case fatality rate (CFR) of 2.2% [3]. COVID-19 has not only caused significant loss of human life but also poses an unprecedented challenge to global economy, poverty and public health [4].
COVID-19 is mainly a disease of the respiratory system resulting in pneumonia and then acute respiratory distress syndrome (ARDS) [1,2,5]. ARDS is an acute lung inflammation that affects both lungs and cause leakage of plasma and blood into the alveoli, leading to non-cardiogenic pulmonary edema. Subsequently, this causes shunt-related hypoxemia, low lung compliance and reduced ventilatable lung parenchyma [6,7]. Hence, the treatment of ARDS is focused on improving oxygenation, preventing further lung injury and increasing lung homogeneity [6]. This can be achieved by lung recruitment using high positive endexpiratory pressure (PEEP) and prone positioning, low tidal volume ventilation, preventing applying high pressure from the ventilator on the alveoli (plateau pressure) and maintaining patient-ventilatory synchrony.
Some investigators found that patients with ARDS from COVID-19 had preserved lung mechanics (relatively high lung compliance) despite the presence of severe hypoxemia [8]. Contrary to the usual ARDS where severe hypoxemia is associated with poor lung mechanics. They hypothesized that the pathogenesis of COVID-19 ARDS is different from the usual ARDS and suggested a different approach to ARDS management [8]. They proposed two different types of COVID-19 ARDS: (1) an L-type with high respiratory compliance, low recruitability and lower lung weight. (2) An H-type that is similar to the typical ARDS with low respiratory compliance, high recruitability and higher lung weight with extensive consolidation [9]. For the L-type, they suggested modifying ARDS management using higher tidal volume (8-9 m/kg), lower PEEP, no prone positioning except as a rescue maneuver and early intubation to prevent self-inflicted lung injury. The H-type should be treated with higher PEEP, low tidal volume (6 mL/kg), prone positioning [9].
Many patients with COVID-19 ARDS will end up needing mechanical ventilation. These patients have a high CFR that can range from 47% to 84% according to their age [10]. Understanding the lung mechanics in COVID-19 ARDS patients will help our understanding of the pathophysiology of this disease and the search for the best management. This in turn should improve the hospital and ICU outcomes of COVID-19 patients. In this study, we looked into the respiratory pathophysiology of mechanically ventilated COVID-19 patients with acute respiratory distress syndrome at Ohoud Hospital, Madinah, Saudi Arabia.

Type of study
An observational retrospective cohort study was conducted on adult COVID-19 patients who needed mechanical ventilation in Ohoud Hospital, Madinah, KSA from 22.06.2020 to 27.09.2020.

Ethical approval
Ethical approval was obtained from the Medical Research Ethics Committee, Taibah University, Madinah. Approval was also obtained from: Madinah Health Affairs Directorate, Ministry of Health, and Ohoud Hospital, Ministry of Health, Madinah.

Inclusion criteria
· Adult patients aged more than 18 years. · Acute respiratory distress syndrome from COVID-19.
· Patients who needed mechanical ventilation.

Sample size
A total of 92 patients, 40 (43.4%) of them were excluded because they did not meet the inclusion criteria. Fifty-two (56.6%) patients were included.

Place of study
Intensive Care Department at Ohoud Hospital in Madinah, KSA.

Data collection
Patients admitted to the intensive care unit department with a diagnosis of COVID-19 who developed ARDS needing mechanical ventilation were selected as possible candidates for the study. Subsequently, we reviewed their medical charts and electronic medical records to obtain the necessary data.
The collected data included: Demographic data.
Medical history and comorbidities.

Mechanical ventilation settings and numbers.
Other sources of oxygen used to treat the study patients.
The duration of Intensive Care Unit admission, intubation, and number of days on ventilators were recorded.

Statistical analysis
We performed descriptive statistical analysis using Statistical Package for the Social Sciences (SPSS) software package version 22 (IBM Corp., Armonk, NY) to summarize the following data: changes in oxygenation parameters in COVID-19 respiratory failure patients and response to established management for COVID-19 respiratory failure patients.
Other statistical analyses included calculating the driving pressure by subtracting PEEP from Plateau Pressure and calculating the Static Compliance by dividing Tidal Volume over Driving Pressure and calculating the PaO 2 /FiO 2 ratio.

Results
In this study, a total of 52 intubated patients with laboratory-confirmed COVID-19 were intubated and admitted to the ICU at Ohud Hospital in Medina, KSA. The patients' age range was 41-95 years ( Table 1). The median age was 63 years (range, 41-92 years), most of the participants were males (33 (63.5%)) and 19 (36.5%) were females (

Respiratory parameters on intubation
The Berlin criteria were used to classify ARDS:

ICU therapies
Twenty-seven patients (51.9%) were on non-invasive positive pressure ventilation, and 27 patients (51.9%) were on a high-flow nasal cannula (
Respiratory indices during the first three days after intubation, including the PaO 2 :FiO 2 ratio, plateau pressure (Pplat), positive end-expiratory pressure (PEEP), and static compliance of the respiratory system (CstatRS), were obtained in intubated patients with coronavirus disease (COVID-19) respiratory failure. The number of patients with recorded values is shown below the Y-axis. The X-axis indicates the median value (Figures 1-4).

Discussion
This study aimed to investigate the lung mechanics of COVID-19 patients with ARDS managed with mechanical ventilation. The median respiratory system compliance in this cohort of patients was 24.7, which is similar to previously reported cohorts of non-COVID-19 ARDS [8,11]. Only two patients out of 52 had near-normal respiratory system compliance. These results contradict the early studies on COVID-19 ARDS, which reported that many of these patients have preserved lung compliance and lack of lung recruitability [8,11]. This study supports the findings of other studies that found no difference in lung mechanics between COVID-19 and non-COVID-19 ARDS patients [12]. The median PO2:FiO2 ratio in this study was 85 mmHg, which is significantly lower than in early reports on  [12,13]. This difference can be explained by the fact that early in the pandemic, it was suggested that COVID-19 ARDS patients should be intubated early, which was expected to improve their PaO2:FiO2. Some studies [8,12] intubated almost all hypoxic COVID-19 patients on the first day of ICU admission. Another study recommended against the routine use of a high-flow nasal cannula or non-invasive ventilation and favored immediate invasive mechanical ventilation [12]. In our hospital, we advocated for a trial of high-flow nasal cannula and/or non-invasive ventilation before proceeding to invasive mechanical ventilation. About 51.9% of our cohort of patients had either used high-flow nasal cannula or non-invasive ventilation. Other findings worth mentioning in this cohort of patients is the high percentage of diabetes mellitus and hypertension (51% and 51%, respectively). Another study reported that 26% of their study population had diabetes mellitus and 44% had hypertension. Hypertension and DM have been associated with increased risk of severe COVID-19 infection and ARDS [14,15].
Moreover, although the average BMI of patients in our sample was ideal (18.5-23.1), they showed signs of severe ARDS. Thus, we cannot conclude that a higher BMI is associated with more severe ARDS in COVID-19 patients.
The limitations in our study include small sample size, limited duration of follow-up, and one hospitalbased sample.

Conclusions
Our study found that patients with COVID-19 and ARDS who needed mechanical ventilation had the same lung mechanics when compared to a cohort of patients with non-COVID-19 ARDS. We observed a lower PaO 2 :FiO 2 ratio in these patients after mechanical ventilation. This can be attributed to tolerating a lower level of hypoxia and a trial of high-flow nasal cannula and/or non-invasive ventilation before initiating invasive mechanical ventilation. We need more studies to describe the biological and unique features of COVID-19, which would help clarify the best management of COVID-19 ARDS. Until then, we suggest treating ARDS in COVID-19 patients using conventional ARDS management strategies. .

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board, General Directorate of Health Affairs in Madinah issued approval 74-2021. This is to certify that the Institutional Review Board (IRB), General Directorate of Health Affairs in Madinah has reviewed all the submitted updated and amended Documents from the ethical point view and has approved your study titled: Respiratory pathophysiology of mechanically ventilated COVID-19 patients. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.