Low-PEEP Mechanical Ventilation and P/F Ratio Evolution in COVID-19 Patients

Background Critically ill COVID-19 patients are burdened by high mortality. Evaluation to improve patients’ management was performed using strict patient criteria for Intensive Care Unit (ICU) admission, a low- positive end-expiratory pressure (PEEP) setting and standard thromboembolism treatment. Objectives of this study was to report the effects of this strategy on P/F-ratio evolution during mechanical ventilation (MV), ICU length of stay (LOS) and MV length. Methods A retrospective analysis was conducted on all consecutive patients with acute respiratory distress due to COVID-19 pneumonia admitted into ICU from March 2 nd to January 15 th , 2021. Patients were treated with a low-PEEP strategy (PEEP 10 cmH 2 O if BMI < 30 Kg m-2, PEEP 12 cmH 2 O if BMI 30-50 Kg m-2, PEEP 15 cmH 2 O if BMI > 50 Kg m-2) and therapeutic anticoagulation in case of thrombosis or D-dimer greater than 1’500 ng ml-1. Results 79 patients were on invasive MV. Average applied PEEP was 11 ± 2.9 cmH 2 O for BMI < 30 Kg m-2, 16 ± 3.18 cmH 2 O for BMI > 30 Kg m-2. After low-PEEP application, patients’ P/F ratio presented daily improvement from admission during next 72 hours (p<0.001; CI 99%) that resulted statistically signicant for each single day after oro-tracheal intubation (OTI). Median ICU length of stay (LOS) was 15 days (10– 28); median duration of MV was 12 days (8–26). The ICU mortality rate was 31.6%. Conclusions A combination of low-PEEP treatment resulted in P/F persistent daily ratio improvement during rst 72 hours after OTI. A low-PEEP strategy could be benecial in hemodynamic than respiratory terms.


Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, a pandemic that has affected more than 109,000,000 individuals and caused nearly 2,500,000 deaths since initial detection of the virus at the end of January 2019 [1].
Epidemiologic data underline the severity of the syndrome, with a critical load for intensive care units (ICU) and a high mortality [2]. Detailed reports describe appropriate management for COVID-19 patients admitted to the ICU, which is relevant both for a better clinical characterization [3] and for guiding decision making in relation to the severe hypoxemia affecting these subjects [4]. In particular, relevant pathophysiological understanding of the disease, as reported by Cronin [5], Nieman [6], Gattinoni [7] and Bendjelid [8], are of uttermost importance for a better clinical evaluation and management. On the basis of these evidences and with the aim to improve COVID-19 patients management in life-threatening conditions, we conceived and implemented a targeted management based on the following: speci c criteria for ICU admission (paper in progress), intermediate-intensity anticoagulation [9] for Venous Thromboembolism (VTE) and low-PEEP management in patients undergoing mechanical ventilation (MV).
Invasive MV is the gold standard treatment in patients with severe respiratory distress, including critically ill COVID-19 patients; however, barotrauma, volotrauma or biotrauma can occur when MV setting is extremely aggressive and/or prolonged [10][11][12]. The implementation of high PEEP values, which is often used in patients with Acute Respiratory Distress Syndrome (ARDS), has been suggested also for COVID-19 patients [13,14]. However, more recent evidences reported that a less aggressive approach, implementing a "low-PEEP strategy" may be favourable in critically ill COVID-19 patients [13,15,16], who tend to present higher lung compliance when compared to "classic" ARDS patients [7,8,13,14,[17][18][19]. The PaO 2 /FiO 2 -ratio (P/F ratio) determines patients` respiratory e ciency, acting as a primary clinical indicator of hypoxemia and of ventilation setting's e ciency [20] and thus allowing to properly evaluate changes in patients' respiratory status.
Aim of this project was to report and analyze the P/F ratio evolution in a case series of consecutive critically ill COVID-19 patients admitted to our ICU and undergoing MV, strategically managed with the implementation of low-PEEP, with further report of biological, respiratory and clinical data.

Methods
After approval by the Ethical Committee (Ethics Committees of Canton Ticino; Dec 2020, CE TI 3775) and in accordance with local Federal rules, a retrospective analysis was conducted on consecutive patients with acute respiratory distress due to COVID-19 pneumonia, admitted to ICU during two pandemic waves (from March 2nd to April 10th, 2020 and from October 5th 2020 to January 15th, 2021). All critically ill COVID-19 patients' relevant data like demographics, severity score (NEMS -nine equivalents of nursing manpower use score -, SAPS -simpli ed acute physiology score), clinical information and laboratory/radiological results were obtained during patients' hospitalization, from electronic health records. Standard laboratory tests included complete blood count, CRP, ferritin, ASAT, ALAT, blood ionogram, creatinine, urea, D-dimer, Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), brinogen, blood gas analysis, SvO 2 , NT-pro-BNP, blood and urines cultures and urine analysis for Legionella Pneumophila antigen. All patients underwent chest x-ray and transthoracic echocardiography, in order to assess the global cardiac function before any pronation cycle. Performing a chest CT scan was considered at ICU admission, if the examination had not been performed within the proceeding 24 hours.
After endotracheal intubation, a low PEEP strategy based on BMI was adopted: PEEP values of 10, 12 and 15 cmH 2 O were implemented, respectively, for patients with BMI < 30, 30-50 and > 50 kg/m 2 . Once PEEP adjustment was performed, according to ARDSnet PEEP table [17,21] and PV-tools ventilatory measurements, FiO 2 was adapted to maintain a SpO 2 greater than 92% and a PaO 2 > 60 mmHg / 8 kPa. A protective ventilation strategy (TV 6-8 ml Kg-1, P plat < 30 cmH 2 O) with permissive hypercapnia (pH > 7.20) was adopted [22], with pronation cycles of 16-hours beginning at the admission. A deep sedation was maintained to pursue a Richmond Agitation and Sedation Scale (RASS) of -4 during the rst 36 hours, combined with muscle relaxation in case of patient-ventilator asynchrony [23].
VTEs were considered suspected in case of an increase in serum D-dimer values over 1'500 ng/ml, while they were considered con rmed in case of lower legs venous ultrasound or pulmonary angio-CT-scan positive ndings, according to current clinical standards [24]. Given the high risk of Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) in these patients [22], according to American Society of Hematology [25] daily monitoring by ultrasound Color-Doppler lower limbs was performed, in accordance to the American Society of Hematology's suggestions [25]. A VTE intermediate-prophylaxis was implemented since patients' ICU admission (Enoxaparine 60 mg bid SC if weight > 80 Kg, Enoxaparine 40 mg bid SC if weight < 80 Kg, Unfractioned Heparin in case of Acute Kidney Injury -AKI). In case of plasmatic D-dimer level greater than 1'500 ng ml-1 or documented thrombosis, anticoagulation treatment was switched to a therapeutic dose (Enoxaparine 1 mg Kg-1 bid SC -Unfractioned Heparin in case of AKI at 14 UI Kg-1 for day in perfusion, according to anti-Xa values) [24]. All clinical and biological data were reported.
Primary outcome was to report the P/F ratio evolution during MV after application of low-PEEP according to BMI, during the rst three days after oro-tracheal intubation (OTI). Secondary outcomes were to report clinical data about ICU LOS and duration of MV, the description of the demographic characteristics, the incidence of clinical complications (especially VTEs, AKIs and VAPs) and the critical care outcomes in critically ill COVID-19 patients.

Statistical analysis
Descriptive statistic was performed to summarize the clinical collected data. Gaussian distribution was veri ed by Kolmogorov-Smirnov test. Differences between patient outcomes were studied by t-test for independent groups or by Mann-Whitney test if non-parametric analysis was required. Similarly, comparison of clinical evolution over time was performed by t-paired test or by non-parametric Wilcoxon test, depending on data distribution. Study of differences between groups of categorical data was carried out by Chi-square statistics. Signi cance level of p value was established to be < 0.01, with a con dence interval (CI) of 99%. Statistical data analysis was performed using the SPSS.26 package (SPSS Inc., Armonk, NY; USA).

ICU patients' characteristics
During the rst pandemic wave, 46 patients were admitted to the ICU, while during second wave 71 patients were furtherly admitted. Thirty-three patients did not receive invasive MV and were therefore excluded from the analysis; the seventy-nine patients who received invasive MV were instead included in the study (Fig. 1). Mean age was 67 ± 11 years; most patients were men (81%), often with one or more chronic medical conditions, most commonly arterial hypertension (57%) and diabetes (35.7%) ( Table 1). Almost all patients resulted hemodynamically stable (95%). A chest CT-scan was obtained in 64 (76.2%) patients, showing bilateral ground-glass opacities in all cases, as well as concomitant consolidations in 13 of them (15.5%). Demographic and clinical data were reported in Table 1. signi cantly increased compared to the P/F ratio pre-OTI (-75, CI 99%, -97/-52, p < 0.001) (Fig. 2). Seventyeight (92.8%) patients underwent pronation cycles, with a median of 4 cycles per patient (Table 2). ICU respiratory data at admission, during treatment and PEEP strategy, with ICU MV and laboratory data. Continuous measurements were presented as mean ± SD (min-max) otherwise as median (25th -75th ) if they are not normally distributed. Categorical variables were reported as counts and percentages.

ICU patient outcome
The median duration of ICU stay was 15 days (10-28); the median duration of MV was 12 days (8-26) (

Discussion
Acute respiratory distress induced by SARS-CoV-2 is a critical clinical condition associated with COVID-19 infection [26,27]. In a multisystem disease such as COVID-19, a multidisciplinary approach is recommendable [3]; to minimize the high mortality rate potentially associated with COVID-19 pandemics, and to correctly manage this critical condition, adequate hospital resources, structured triage and appropriate clinical training are required. [3]. Clinical evidences led us to consider that, even if the classic criteria de ning the ARDS were present in COVID-19 patients [28], atypical aspects were also evident, especially the lack of a reduced lung compliance with the consequent tendency to hypercapnia [29]. The lack of "baby-lung" pattern [30] and the ARDS-like pattern with low lung elastance [17,19,31], induced us to evaluate a more speci c treatment [15].
According to ARDSnet PEEP table [17,21], we preferred to ventilate patients with PEEP adapted to patients' own BMI, carefully tailored to lungs physiology [28,32]. This approach was consistent with Gattinoni et al [33] and Bendjelid et al [8], who both suggested the presence of two different ICU patient populations in COVID-19 pneumonia. The rst population presents a high lung compliance due to a probable alveolitis, with a shunt effect due to loss of local hypoxic vasoconstriction; this population represented the great majority of our patients. The second population presents a low lung compliance and a pattern of "baby-lung" compatible with "classic ARDS" (only 2 patients in our cohort). Following the abovementioned indication, our mechanically ventilated patients were treated with a "low-PEEP approach", representing thus a different strategy compared to the available literature [34]. More recently, Tsolaki et al [15] Barthélémy et al [16] and Mauri et al [13] suggested a low-PEEP strategy in the management of these "ARDS-like" lungs, on the basis of critically ill patients lung physiology. Agreeing with these evidences, after intubation we found patients easy to ventilate, with a compliance on average above 50 mL/cmH 2 O higher than in "classic ARDS pattern" [33]. In comparison with other groups [24,32,35] our strategy led to less complications (like ICU paralysis, delayed awakening, agitation, etc.), an easier and faster extubation, quickly decreasing deep sedation as in ammation began to diminish, with no need for frequent tracheotomies. Higher PEEP could cause overdistension, resulting in an increased driving pressure, with a subsequent increased risk of lung damage [36-38]; moreover, PEEP levels greater than 10 cmH 2 O can induce the reduction of venous return, with consequent worsening of the circulation status, as well as local biotrauma and a worsening of alveolar damage [16,37,38]. In comparison to Poston JT et al [34], and in agreement with Mauri T et al [13,15] we applied lower PEEP levels; this approach resulted bene cial, with ventilator data such as P/F ratio showed a rapid improvement already in the rst 3 days after OTI. Therefore, the physiology of these ARDS-like lungs, the so-called ARDS L-type [7,14,18,19], appeared to respond appropriately to low PEEP values tailored to patients' BMI.
Into the Shah et al's [39] case series, the daily lower limbs ultrasound in COVID-19 ICU patients identi ed a high prevalence rate of DVTs and PEs, even in patients undergoing prophylactic anticoagulation. In addition, many patients had a marked increase in D-dimers level, possibly linked to VTE in other anatomical districts potentially secondary to PE. In this context, an intermediate anticoagulation seems a reasonable approach, also consequently to recent evidence suggesting the role of endothelial in ammation as a cause of microthrombosis [39,40]. However, other groups showed an increase in spontaneous bleeding in COVID-19 patients, especially in the retroperitoneal space [35]. In our series, 6 patient presented a major bleeding event; this data was in agreement with the literature [39], bringing forward the hypothesis that an intermediate [9] anticoagulation may counterbalance a phenomenon of prothrombotic diathesis without a relevant increase in hemorrhagic complications rate.
Our COVID-19 ICU patients management resulted in a reduction of the mortality rate (31.6%) when compared to other groups, which reported a 50% and a 61.5% of death rate [41]. We supposed that a relatively low-pressure ventilation could prevent the transition from an initial alveolitis to an iatrogenic ARDS, in which the ongoing in ammation is worsened, rather than treated, by high levels of PEEP, through a Ventilation-Induced-Lung Injury (VILI) mechanism. A median ICU LOS was reported to be equivalent to Bhatraju et al [41], even including patients who died in ICU. This data suggests that a low PEEP strategy with a protective MV approach can improve COVID-19 patients' in-hospital management, morbidity and mortality, although further studies are necessary to con rm this interesting hypothesis.
Our project was burdened by several limitations. Firstly, this study compared low PEEP in consecutive critically ill COVID-19 patients, and it was not possible to compare the data to a control group; all patients were treated according to emerging information regarding pathophysiological data about the disease [7,8,19] and for this reason this strategy was implemented in all critically ill patients admitted to ICU. Secondly, it was a monocentric observational retrospective study, with a relatively small series of patients. However, comparison with current literature was performed; even if patient populations differed, results can be assumed to be consistent, as the cohorts are comparable in terms of disease severity and biochemical markers. Moreover, the low PEEP-strategy was maintained in our Center during the two past waves, allowing us to obtain reproducible results.

Conclusion
A combination of low PEEP treatment and prophylactic anticoagulation in mechanically ventilated patients resulted in P/F ratio's rapid and progressive improvement during the rst 72 hours after OTI. This approach was also associated with a rather small duration of MV and of ICU LOS, as well as with lower mortality rates when compared to the literature. As a consequence, this approach may eventually contribute to ameliorate critically ill COVID-19 patients' management. CLM COVID-19 patients Management of COVID-19 patients evaluated at our COVID-19 center during two pandemic waves (from March 2nd to April 10th 2020 and from October 5th 2020 to January 15th 2021).
ICU admission was performed according to standard selection criteria (SpO2 < 85% and/or dyspnea and/or signs of mental confusion). Patients not on invasive MV were excluded from the analysis.