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\begin{document}

\title{Prone Position Improves Survival rate of Covid-19 Invasive Mechanical
Ventilation Patients by Improving Oxygenation Index}



\author[1]{yuwei zheng}%
\author[1]{Xiaojie Bi}%
\author[1]{Chaochao Chen}%
\author[1]{Jing Wang}%
\author[1]{Yufen Zheng}%
\author[1]{Jun Li}%
\author[1]{Shiyong Chen}%
\author[1]{Hongguo Zhu}%
\author[1]{Jiaqin Xu}%
\author[1]{Qiaofei Zheng}%
\author[1]{Yuan Yuan}%
\author[1]{Yafei Wang}%
\author[1]{Wenyuan Zhang}%
\author[1]{Yongpo Jiang}%
\author[1]{Bo Shen}%
\author[1]{Yinghe Xu}%
\affil[1]{Taizhou Hospital of Zhejiang Province}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:}Invasive mechanical ventilation is a crucial
intervention for the management of critical COVID-19 patients. However,
the impact of prone position (PP) on patients undergoing invasive
mechanical ventilation remains uncertain. This study aims to investigate
the potential benefits of PP in terms of improving the oxygenation index
and prognosis. \textbf{Methods:}A total of 289 critically ill COVID-19
patients were retrospectively gathered from ICU of three general
hospitals located in Taizhou, Zhejiang Province from December 1, 2022 to
February 1, 2023, all patients were invasive mechanical ventilated. 78
cases of PP group and 78 cases of non-PP group were matched with
propensity score matching. The study compared clinical data, laboratory
results, and hospitalization survival rate between two groups of
patients. Furthermore, we compared the laboratory results, and
hospitalization survival across varying numbers of PPs.
\textbf{Results:}The mean oxygenation index exhibited a greater increase
in PP group compared to non-PP group (48 \emph{vs} 32mmHg). Hospital
survivors of PP group (63 patients) demonstrated more substantial
decrease in their Sequential Organ Failure Assessment scores and
C-reactive protein levels compared to non-PP group (51 patients). The
initial PP cycle resulted in a significant elevation of the oxygenation
index by 30.8 (-16.4,46.9) mmHg; the second PP cycle demonstrated a
maximum increase of 56.3 (13.0,92.8) mmHg. A higher frequency of PP
yielded a more pronounced improvement in oxygenation and had the
potential to enhance the survival rate. Additionally, the eight patients
who was improvements in their oxygenation index during the initial three
PP cycles and successfully survived had higher lymphocyte counts
(0.2-2.4) \emph{vs} (0.1-0.5)\selectlanguage{ngerman}×10 \textsuperscript{9}/L and a longer
duration of PP (53.0-113.5) \emph{vs} (36.0-98.5)h.
\textbf{Conclusion:}PP has the potential to enhance the oxygenation
index and survival rates among critically ill COVID-19 patients invasive
mechanical ventilated. Notably, a positive correlation was observed
between the frequency of PP and the improvement of oxygenation. Our
investigation further revealed that the efficacy of the PP may be
influenced by lymphocyte count and duration of PP.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Prone position (PP) has the potential to reexpand collapsed alveoli and
improve the oxygenation index significantly{[}1-3{]}. However, it is
complicated to be operated and has high risk of tissue crush injuries,
particularly for the patients invasive mechanical ventilated {[}4, 5{]}.

In December 2022, COVID-19 lockdown in China, a substantial influx of
critically ill patients necessitated admission into the ICU owing to
respiratory failure stemming secondary to COVID-19. Nishikimi, M et al.
revealed that the 28-day survival rate of COVID-19 patients undergoing
invasive mechanical ventilation was merely 37\%{[}6{]}. Consequently,
the implementation of effective measures to mitigate the mortality rate
became an urgent necessity.

Previous researches had demonstrated that PP can enhance the oxygenation
index in COVID-19 patients mechanical ventilated{[}7, 8{]}.
Consequently, the Shanghai Expert Group on Clinical Treatment of Novel
Coronavirus Pneumonia had developed guidelines for the implementation of
PP treatment. And yet, research on the potential of PP to enhance the
survival rate among invasive mechanical ventilated COVID-19 patients was
limited. Particularly, the investigation into the therapeutic efficacy
of repeated PP cycles remains inconclusive.

The study dynamically compared the changes in laboratory indices,
disease severity, and survival rates between PP patients and matched
non-PP patients. Additionally, differences in oxygenation index and
survival rate were examined across varying numbers of PPs. This study
aimed to assess the therapeutic efficacy of PP in critically ill
patients with COVID-19 who required invasive mechanical ventilation.

\textbf{Materials and methods}

\textbf{Study design}

This study conducted a retrospective analysis of 289 critically ill
COVID-19 patients who received invasive mechanical ventilation in the
ICU of three general hospitals in Taizhou City, Zhejiang Province, from
December 1, 2022, to February 1, 2023. Among these cases, 157 were
treated with PP, while 132 were not.

The exclusion criteria for the PP group included {[}7-9{]}: (1)
incomplete case records (67 cases); (2) PP duration less than 12 hours
(10 cases); (3) PP treatment initiated before admission to the ICU (1
case); (4) prior extracorporeal membrane oxygenator treatment before PP
(1 case). The non-PP group (78 cases) was selected through 1:1
propensity score matching (PSM) analysis with the PP group (78 cases)
based on age, sex, underlying disease, and Sequential Organ Failure
Assessment (SOFA) score(Fig.1).

Among the PP group, 21 cases underwent only one PP cycle, 23 cases
underwent two PPcycles, 15 cases underwent three PP cycles, and 19 cases
underwent more than three PP cycles. All patients in PP group were
diagnosed with COVID-19 and required invasive mechanical ventilation
before the first PP. This study specifically examined the initial three
instances of PP. The commencement of PP occurred at 2.0 (2.0, 5.0) days
after admission to the ICU. Furthermore, each PP lasting for a median
duration of 18.0 (16.0, 24.5) hours and an interval between each PP of
8.8 (6.0, 26.9) hours.

None of them developed life-threatening complications during PP (one
case exhibited petechiae on both sides of the abdomen, another case
presented petechiae on the left wrist, and two cases experienced facial
swelling). This study was approved by the Medical Ethics Committee of
Taizhou Hospital, Zhejiang Province, China (Approval NO.: K20230116).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig.1} Flow chart of the study. PSM:propensity score matching

\textbf{COVID-19 diagnostic criteria}

COVID-19 were ascertained through the utilization of real-time reverse
transcription polymerase chain reaction on nasal and pharyngeal swabs
(Ct<35). Clinical diagnosis and typing were conducted in adherence to
the guidelines outlined in the Diagnosis and treatment protocol for
COVID-19 (9th edition) {[}10{]}.

\textbf{Prone positioning protocol}

Guided by the collective agreement among medical professionals and
nursing staff within our institution, we have formulated comprehensive
protocols for postoperative care, implemented a dedicated
interdisciplinary team, and implemented standardized training procedures
to ensure the uniformity of PP treatment for patients.

The indications for PP are as follows:  When ARDS recalcitrant
hypoxemia cannot be corrected by conventional mechanical ventilation; 
It is strongly recommended for severe ARDS when the oxygenation index is
[?]100mmHg;  It is recommended for consideration when the oxygenation
index is \textless{}150mmHg with PEEP [?]5cmH\textsubscript{2}O and FiO2
[?]0.6. (After the patient is admitted to the ICU, the treatment team will
assess the patient's disease condition and preferences, and initiate PP
therapy in accordance with the September 2022 issue of the Shanghai
Expert Recommendations on PP Therapy for Patients with COVID-19.)

The contraindications for PP include:  Severe hemodynamic instability
in critically ill patients;  Craniocerebral trauma accompanied by
moderate or severe intracranial hypertension;  Acute bleeding
disorders;  Severe multiple injuries resulting in significant damage to
the cervical vertebrae, spine, pelvis, chest wall, and abdomen;  Severe
facial trauma or recent facial surgery;  Recent orthopedic and
abdominal surgeries. Patients with cardiac pacemakers or ventricular
arrhythmias implanted within a span of 48 hours;  Patients with deep
vein thrombosis occurring within a period of 48 hours;  Pregnancy.

The termination criteria for PP include:  The occurrence of severe
complications and potential risks during the operation;  The decision
to discontinue treatment made by the physician based on the progression
of the disease;  Voluntary abandonment of treatment by patients and
their families.

\textbf{Data collection}

Data was gathered from the electronic medical system including age,
gender, underlying disease, clinical symptoms, imaging tests, medication
history and laboratory indicators. Indicators with missing data[?]60\%
were excluded from the statistical analysis. (The comparison of dynamic
changes in oxygenation indices between the PP and non-PP groups was
limited to the first 13 days of ICU admission.)

The laboratory indicators obtained within 24 hours of the patient's
admission to the ICU were designated as the initial laboratory
indicators (Entering ICU), while those obtained within 24 hours prior to
discharge were designated as the final laboratory indicators (At
discharge). The time point closest to the beginning/end of PP (within
24h) was designated as the before/end PP laboratory indicator
(B-PP/End-PP).

Detailed information was gathered regarding the PP: encompassing the
initiation and conclusion times of each PP; comprehensive respiratory
and hemodynamic parameters within the 6-hour pre-PP period, throughout
the 12-hour PP duration, and within the 6-hour post-PP period.
Additionally, any complications that transpired during the PP were
documented.

Definition of PP time point: PP1 refers to the first PP , PP2 refers to
the second PP, and PP3 refers to the third PP. T0 represents the time
period of 0-6 hours before the current cycle of PP; T1 represents the
time period of 0-6 hours in the current cycle of PP; T2 represents the
time period of 6-12 hours in the current cycle of PP; and T3 represents
the time period of 0-6 hours after the current cycle of PP.

Definition of changes in oxygenation index: Improvement of oxygenation
represents that the average oxygenation index in T3 of the current cycle
was greater than the average oxygenation index at PP1-T0; No improvement
of oxygenation represents that the average oxygenation index in T3 of
the current cycle was not greater than the average oxygenation index at
PP1-T0.

\textbf{Calculation of scores}

SOFA score: The parameter Include oxygenation index, platelets,
bilirubin, mean arterial pressure, medication, Glasgow Coma Scale (GCS)
score, creatinine, urine output. The worst value observed within a
24-hour period is utilized for the evaluation of SOFA score within a day
It is important to note that a higher SOFA score indicates a poorer
prognosis.

APACHE II: The parameter comprises three components, namely the Acute
Physiology Score , GCS score, and the Age score. The cumulative score is
obtained by summing these three components, with higher scores
indicating a more severe condition. The most critical value within a
24-hour period is selected for inclusion in the APACHE II evaluation
conducted within a day.

\textbf{Biological detection}

The arterial blood gas analysis was conducted utilizing a Siemens RAPID
Point 500. EDTA-K2 anticoagulated blood samples were identified through
the utilization of a Mindray BC-6800 Plus fully automated blood cell
analyzer. Serum samples were subjected to centrifugation at a speed of
3000 rpm for a duration of 10 minutes, and the detection of CRP was
carried out using an AU5831-2 detection module. PCT, TnT, and BNP
analyses were performed using a Roche E801 electrochemiluminescence
analyzer (Roche Diagnostics, Germany). Sodium citrate plasma samples
were centrifuged at 3000 rpm for 10 minutes, and coagulation parameters
were collected utilizing a STAR MAX fully automated hemagglutination
analyzer (Stago, France).

\textbf{Statistical analysis}

Continuous variables were expressed as (mean\selectlanguage{ngerman}±SD) or median (P25, P75),
the Mann-Whitney U test was used for comparisons between two groups.
Categorical variables were expressed as n (\%) and the Chi-square test
was utilized to compare rates between two groups. For the comparison of
survival rates between groups, Kaplan-Meier survival analysis was
employed. Graphs were generated using GraphPad Prism 9 and R (version:
4.2.1). A significance level of p\textless{}0.05 was considered
statistically significant.

\textbf{Results}

\textbf{Clinical information of study cohorts}

This study included 78 PP and 78 non-PP groups, respectively. Among the
PP group, 79.5\% were male, and the BMI was significantly higher {[}25.0
(22.7, 27.4) vs 22.5 (20.8, 25.4), p=0.002{]}. Additionally, the PP
group exhibited higher levels of PEEP, Respiratory Rate, and Peak airway
pressure {[}8.5 (6.3, 10.0) \emph{vs} 5.0 (5.0, 7.0)\selectlanguage{english};16.0 (15.0,
20.0)\emph{vs} 15.0 (15.0, 15.0)\selectlanguage{english};23.0 (18.3, 26.0) \emph{vs} 20.0
(16.0, 24.0), all p \textless{} 0.05{]}. In the PP group, 38.5\% of
patients had Pre-existing pulmonary disease. Furthermore, 84.1\% of
patients exhibited gross glassy/patchy changes in the lungs. The
oxygenation index was found to be lower in the PP group compared to the
non-PP group {[}125.5 (104.3, 169.0) \emph{vs} 212.5 (130.5, 289.5),
p\textless{}0.001{]},and the FiO\textsubscript{2} levels were higher
{[}60.0 (45.8, 80.0) \emph{vs} 50.0 (40.0, 61.0), p=0.003{]}. (Table 1,
Fig.S1)

\textbf{Table 1} Comparison of baseline data between PP group and Non-PP
group patients.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
PP group (n=78)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Non-PP group (n=78)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Male (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62 (79.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
61 (78.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (year)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
77.5 (70.0, 83.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
76.0 (65.0, 86.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.942\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BMI (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25.0 (22.7, 27.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22.5 (20.8, 25.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
SOFA score\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8.0 (6.0, 9.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7.50 (6.0, 9.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.858\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
APACHE II\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22.0 (16.3, 27.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22.0 (18.0, 28.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.865\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{The main reasons for entering the ICU (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mainly due to COVID-19 infection\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35 (44.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23 (29.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.076\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Chronic disease exacerbation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
42 (53.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
51 (65.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Trauma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Intubated (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
66 (84.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
70 (89.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.472\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Confirmed COVID-19 (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60 (76.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
66 (84.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.310\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Infection with sepsis (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PEEP (cmH\textsubscript{2}O)\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8.5 (6.3, 10.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5.0 (5.0, 7.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Respiratory Rate (breaths/min)\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16.0 (15.0, 20.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15.0 (15.0, 15.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Tidal volume (ml)\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
456.5 (392.5, 557.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
452.0 (409.0, 528.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.541\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Peak airway pressure (cmH\textsubscript{2}O)\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23.0 (18.3, 26.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
20.0 (16.0, 24.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.007\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cydn (ml/cmH2O)\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32.6 (23.3, 41.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.5 (25.6, 40.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.892\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Underlying disease (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pre-existing pulmonary disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
30 (38.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (34.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.739\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
47 (60.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
41 (52.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.419\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diabetes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24 (30.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (28.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.861\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (19.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (17.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (19.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18 (23.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.695\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Malignant tumor\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (24.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (12.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.100\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hepatitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Chronic kidney disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Chest CT (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pulmonary plaques or Ground-glass opacity\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58 (84.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62 (86.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.916\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pulmonary fibrosis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (18.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (26.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.385\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pulmonary consolidation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (13.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Medication use (\%)b}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Antibiotic\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
76 (97.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
45 (57.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Anti COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39 (50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
21 (26.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.005\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Immunoglobulin\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35 (44.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Dexamethasone\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71 (91.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58 (74.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.011\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Norepinephrine\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
78 (100.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
63 (80.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Blood gas indicators}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PaO\textsubscript{2}/FiO\textsubscript{2} ratio (mmHg)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
125.5 (104.3, 169.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
212.5 (130.5, 289.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
FiO\textsubscript{2} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60.0 (45.8, 80.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50.0 (40.0, 61.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.003\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LAC (mmol/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.1 (1.6, 2.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.3 (1.6, 3.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.433\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Inflammation}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CRP (mg/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
65.6 (18.4, 129.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
64.1 (27.5, 133.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.414\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PCT (ng/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.4 (0.1, 2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.1 (0.4, 3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.036\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Blood system}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
D-D (mg/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.6 (1.4, 7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.5 (1.6, 8.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.889\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
WBC (\selectlanguage{ngerman}×10\textsuperscript{9}/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10.1 (7.8, 12.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8.9 (6.4, 13.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.562\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LYM (\selectlanguage{ngerman}×10\textsuperscript{9}/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.5 (0.3, 0.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.5 (0.3, 1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.328\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hb (g/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
122.0 (105.3, 138.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
116.5 (90.3, 130.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.034\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PLT (10\textsuperscript{9}/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
162.5 (110.8, 199.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
156.0 (106.5, 216.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.728\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Cardiac function}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BNP (pg/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1537.0 (768.3, 3479.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1672.0 (472.5, 5370.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.928\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TnT (ng/ml)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.04 (0.02, 0.10)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.05 (0.03, 0.12)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.103\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LDH (U/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
516.0 (418.3, 657.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
386.0 (276.0, 610.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.014\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Liver function}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ALT (U/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27.0 (16.5, 43.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25.5 (16.0, 38.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.725\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AST (U/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39.0 (27.5, 59.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
44.0 (27.0, 69.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.508\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
TBIL (\selectlanguage{greek}μ\selectlanguage{english}mol/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11.0 (7.3, 17.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12.1 (8.5, 14.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.523\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Renal function}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cr (\selectlanguage{greek}μ\selectlanguage{english}mol/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
97.5 (72.3, 201.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
112.0 (70.5, 186.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.989\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Urea (mmol/L)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11.7 (8.0, 19.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12.2 (7.9, 18.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.844\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
eGFR {[}ml/(min\selectlanguage{ngerman}×1.73m\textsuperscript{2}){]}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
60.6 (26.9, 81.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50.1 (27.0, 86.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.976\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data are n (\%) or median (P25,P75).The significance level is 0.05.P
values were calculated using Mann-Whitney U test for continuous
variables and the \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test for categorical variables.

BMI:Body Mass Index; SOFA:Sequential Organ Failure Assessment;
APACHE:Acute Physiology and Chronic Health Evaluation; PEEP:Positive
End-Expiratory Pressure; Cydn:Dynamic lung compliance;
FiO\textsubscript{2}:Fractional concentration of oxygen in inspired air;
LAC:Lactic acid; CRP:C-reactive protein; PCT:Procalcitonin; D-D:D-Dimer;
WBC:White blood cell; LYM:Lymphocyte; Hb:Hemoglobin; PLT:Platelet;
BNP:Brain natriuretic peptide; TnT=TroponinT; LDH:Lactate dehydrogenase;
ALT:Alanine aminotransferase; AST:Aspartate aminotransferase; TBIL:Total
bilirubin; Cr:Creatinine; eGFR:Estimated Glomerular Filtration Rate.

\textsuperscript{a} Data at the beginning of invasive mechanically
ventilated.

\textsuperscript{b} Medication during ICU treatment.

\textbf{Dynamics of the oxygenation index in PP group and non-PP group}

We conducted a comparative analysis of the changes in oxygenation
indices between the PP group and the non-PP group over a 13-day
duration. Among the 74 cases in the PP group, their first PP occurred
within (3.2\selectlanguage{ngerman}±2.8) day on ICU admission, and the termination of PP was
observed within (8.0±5.1) day . Notably, the increase in oxygenation
index was more pronounced in the PP group compared to the non-PP group
(48 \emph{vs} 32 mmHg)(Fig 2).(It is worth mentioning that patient
number E28 in the PP group initiated PP on day 25, while E32, E59, and
E66 commenced on day 16.)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig.2} Changes in oxygenation index between patients in PP group
and non-PP group.(A) Dynamic monitoring of oxygenation index; Entering
ICU:Laboratory indicators within 24 hours of entering the ICU;P
values:*p \textless{} 0.05; **p \textless{} 0.01; ***p \textless{}
0.001. (B) Dynamic change amplitude of oxygenation index(compared with
ICU).

\textbf{The Relationship between the frequency of PP and oxygenation
index}

The Improvement of oxygenation in different times of PP showed that PP1
exhibited the highest percentage of oxygenation improvement: PP1
(73.1\%,57/78) \emph{vs} PP2 (71.9\%,41/57) \emph{vs} PP3 (51.5\%,17/33)
(Fig 3A).

The more times of PP, the more pronounced of increase in oxygenation
index (Fig 3B).

The magnitude of change in oxygenation index was compared among patients
who underwent PP at least three times (34 patients), (all compared with
the difference in oxygenation index at T0 of the current PP). At the end
of the PP (T3), it was observed that PP1 had the highest change: PP1
{[}30.8 (-16.4,46.9){]} \emph{vs} PP2 {[}7.0 (-11.8,38.0){]} \emph{vs}
PP3 {[}1.25 (-28,28){]}. Furthermore, during the duration of the PP (T1,
T2), PP2 showed the highest change: PP1 {[}34.5 (17.8,83.4){]} \emph{vs}
to PP2 {[}56.3 (13.0,92.8){]}\emph{vs} PP3 {[}40.0 (7.0,67.0){]} (Fig
3C).

The oxygenation indices at each point (T0, T1, T2, T3) of PP1
demonstrated a continuous increase after the initiation PP: T0 {[}115.0
(98.6,147.5){]} \emph{vs} T1 {[}167.0 (133.0,215.0){]} \emph{vs} T2
{[}185.0 (147.5,230.0){]}. Furthermore, the oxygenation indices were
higher at the end of PP1: T3 {[}161.3 (116.5,213.4){]} \emph{vs} T0
{[}115.0 (98.6,147.5){]} (Fig 3D).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Fig.3} The relationship between the frequency of PP group and
the improvement of patient's oxygenation index. (A) Improvement of
oxygenation in different times of PP; (B) The oxygenation index from PP1
to PP3; (C) Change amplitude of oxygenation index from PP1 to PP3 with
three times or more PP patients (N=34); (D) Arterial blood gas
indicators monitoring during PP1.

PP:Prone position;PP1,PP2,PP3:The 1st, 2nd, and 3rd time of PP;T0:0-6
hours before the current PP;T1:Starting from PP for 0-6
hours;T2:Starting from PP for 6-12 hours; T3:0-6 hours after the end of
the PP. P values: *p \textless{} 0.05; **p \textless{} 0.01;***p
\textless{} 0.001;****p \textless{} 0.0001.

\textbf{The Relationship between PP and survival rate}

Within 10 days after the ICUadmission, the PP group exhibited a notably
higher survival rate compared to the non-PP group (78.2\%
\emph{vs}64.1\%, p=0.049) (Fig.4A). PP group demonstrated survival rates
of 48.7\% and 32.1\% within 20 and 30 days, respectively (Fig.4B, C).
Multiple PP cycles improved hospitalization survival: One time (81.0\%,
17/21) \emph{vs} Two times (82.6\%, 19/23) \emph{vs} Three times
(100.0\%, 15/15). Notably, there was no significant disparity in SOFA
score based on the frequency of PP (Fig.4D, E).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Fig.4} The relationship between prone position and its frequency
with hospital survival rate. (A) 10-day survival analysis; (B) 20-day
survival analysis; (C) 30-day survival analysis; (D) The hospital
survival rate of patients with different prone position frequencies; (E)
SOFA of patients with different prone position frequencies.

\textbf{Comparison of oxygenation index, SOFA score and CRP between PP
group and non-PP group ofhospital survivors}

The \textbf{hospital survivors} of PP group(n=63) exhibited a higher BMI
{[}25.0 (22.5, 27.5) \emph{vs} . 22.2 (20.2, 24.9), p=0.003{]} and a
greater prevalence of malignancies (27.0\% \emph{vs} . 9.8\%, p=0.038)
compared to the non-PP group (n=51). Furthermore, the PP group
demonstrated a higher incidence of bacterial (92.1\% \emph{vs} . 66.7\%,
p=0.001) and mycotic (71.4\% \emph{vs} . 49.0\%, p=0.024)infection
during ICU. Additionally, they had a lower oxygenation index {[}127.0
(101.5, 164.5) \emph{vs} 228.0 (138.0, 314.0), p\textless{}0.001{]} (See
table S1).

The oxygenation index after PP treatment is higher than before {[}168.0
(135.5,195.5) \emph{vs} 111.0 (93.0,132.0){]},while SOFA score, CRP
decreased {[}8.0 (6.0,9.0) \emph{vs} 9.0 (7.0,10.0){]}; {[} 59.7 (24.9,
121.0) \emph{vs} 90.6 (52.1,137.0){]} (Fig 5).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Fig.5} Comparison of laboratory indicators of surviving patients
between PP and non-PP group. (A-D) Dynamic monitoring of oxygenation
index,FiO2,SOFA and CRP.

Entering ICU:Laboratory indicators within 24 hours of entering the ICU;
B-PP:Laboratory indicators closest to the start of prone position(Less
than 24 hours); End-PP:Laboratory indicators closest to the end time of
prone position (Less than 24 hours); At discharge:Laboratory indicators
within 24 hours before discharge. P values: *p \textless{} 0.05; **p
\textless{} 0.01; ***p \textless{} 0.001.

\textbf{Comparison of baseline data between patients of oxygenation
improvement and without improvement in the initital three PP cycles}

Eight hospital survivors who experienced enhanced oxygenation in the
initial three PP cycles exhibited that their lymphocyte counts were
ranging from 0.2 to 2.4 (\selectlanguage{ngerman}×10\textsuperscript{9}/L), WBC were ranging
from 3.3 to 16.2 (×10\textsuperscript{9}/L), and cumulative duration of
PP were 53.0 to 113.5 (h). Additionally, five patients a lymphocyte
count exceeding 0.5 (×10\textsuperscript{9}/L).

Patients who did not experience any improvement in oxygenation exhibited
that lymphocyte counts ranging from 0.1 to 0.5
(×10\textsuperscript{9}/L), white WBC ranging from 2.3 to 11.4 (×109/L),
and a total duration of the first three PP periods ranging from 36.0 to
98.6 hours. Among these patients, four individuals had a total duration
of the first three PP periods of less than 46 hours (Fig 6).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Fig.6} Comparison of baseline data and dynamic laboratory
indicators between Patients who experienced improved or no improvement
in the oxygenation index from PP1 to PP3. (A) Comparison of Baseline
data; (B-D) Dynamic monitoring of LAC, WBC and LYM. The data in the box
plot is based on the average level of each patient at the corresponding
stage.

PP1,PP2,PP3:The 1st, 2nd, and 3rd time of prone position.

\textbf{Discussion}

This study aimed to examine the impact of the PP on critically ill
COVID-19 patients receiving invasive mechanical ventilation. We employed
a matching technique to establish comparable groups. The findings
revealed that PP has the potential to enhance the oxygenation levels and
All-cause survival rate. Furthermore, a positive correlation was
observed between the frequency of PP and the extent of oxygenation
improvement. The potential mechanism underlying the effect of the PP may
be associated with variations in lymphocyte count and the duration of
PP.

According to our data, the utilization of PP appeared to enhance
oxygenation and improve short-term survival rate in COVID-19 patients
who are invasive mechanical ventilated. Within 10 days after ICU
admission,, the survival rate of individuals in the PP group was notably
higher compared to those in the non-PP group, 94.9\% of patients
received PP treatment. However, no significant disparity in survival
rate was observed between the two groups at the 20-day and 30-day.
29.5\% and 6.4\% of patients in the PP group have undergone PP treatment
for 10-20 days and 20-30 days, respectively. Notably, patients who
underwent PP three times exhibited a 100.0\% survival rate during their
hospitalization period.

The survival rate during ICU stay was observed to be lower in patients
with critical COVID-19 infection, ranging from 33.3\% to 47.6\%
{[}11-13{]}. In a retrospective analysis conducted by Douglas, I.S et al
{[}14{]}, a total of 61 critically ill patients receiving invasive
mechanical ventilation for COVID-19 were examined, revealing a hospital
survival rate of 68.9\% in the PP group. However, the study lacked a
control group to ascertain whether the PP intervention influenced the
survival rate. Similarly, Engerstrom, L et al {[}15{]} investigated 1714
patients on mechanical ventilation in the ICU with neocoronary, and
determined that the PP did not have a significant impact on the 30-day
survival rate. Hence, it can be inferred that the implementation of PP
yields enhanced short-term survival rates, and the adoption of multiple
PPs contributes to improved survival rates during hospitalization;
however, their impact on long-term survival appears to be comparatively
limited.

The data presented in our study indicates a positive correlation between
the frequency of PP and the extent of improvement in oxygenation.
Specifically, the oxygenation index continued to rise for a duration of
6 hours following the conclusion of the initial PP, with the most
significant increase observed during the second PP. Among the 14
patients, the second PP resulted in the highest increase in oxygenation
index (ranging from 109 mmHg to 373 mmHg), and 4 patients achieved
normal levels of oxygenation index.

Previous research has established{[}16, 17{]} the efficacy of PP in
enhancing the oxygenation index among patients. In a retrospective
analysis conducted by Tyler T. Weiss et al {[}7{]}, involving 42
COVID-19 patients receiving invasive mechanical ventilation, it was
observed that repeated PP yielded a more significant improvement in
oxygenation. However, the impact of varying frequencies of PP on
oxygenation alteration remained inconclusive. Our study, on the other
hand, determined that PP1 exhibited the longest duration of oxygenation,
while PP2 demonstrated the most substantial increase in oxygenation
levels for the majority of patients.

The current study provides evidence that PP can effectively mitigate the
severity of COVID-19 in critically ill patients who require invasive
mechanical ventilation. Previous research has demonstrated the utility
of the SOFA score in evaluating disease severity among mechanically
ventilated patients. In this study, approximately half of the patients
experienced a decrease in their SOFA score following treatment with PP.
Notably, nearly one-third of the patients exhibited a reduction in SOFA
score exceeding 20\%, while another one-third did not demonstrate any
improvement in their SOFA score.

Patients who did not experience any improvement in SOFA score exhibited
a significantly longer average duration between their admission to ICU
and the commencement of PP (3day \emph{vs} 1day). Additionally, these
patients had a shorter average duration of each PP (15.5h
\emph{vs}22.0h). Previous research studies{[}20, 21{]} have demonstrated
that PP enhances oxygenation in patients, yet it remains uncertain
whether PP effectively reduces the severity of the disease. We
hypothesize that the alteration in disease severity among patients may
be associated with the start time and duration of PP interventions.

Furthermore, a comparison was conducted between patients who exhibited
improvement and survival in the initial three PP oxygenation indices and
those who did not. The findings revealed that the duration of PP was
significantly longer in patients who demonstrated improvement in the
initial three PP oxygenation indices. Previous studies {[}22, 23{]} have
also reported that early and prolonged implementation of PP may yield
enhanced oxygenation outcomes in individuals afflicted with
COVID-19-induced lung infections.

Okin et al. {[}24{]} conducted a study involving 157 patients with
neocoronary who were subjected to invasive mechanical ventilation. Their
analysis revealed that extended durations of PP ([?]24h) led to notable
enhancements in respiratory compliance, oxygenation indices, as well as
30-day and 90-day survival rates. The researchers concluded that
recurrent supine positioning could potentially exacerbate atelectasis
injury and ventilator-induced lung injury. Consequently, they suggest
that initiating and prolonging PP may offer greater benefits in terms of
improving oxygenation.

In the present study, it was observed that lymphocyte counts could
potentially serve as a useful indicator for assessing the efficacy of
PP. The collected data revealed that patients who demonstrated
improvement and survival after undergoing the initial three sessions of
PP with oxygenation exhibited higher WBC and lymphocyte counts upon
admission to the ICU compared to those who did not experience any
enhancement in oxygenation. Furthermore, it was observed that the
lymphocyte counts of patients who failed to exhibit any improvement in
oxygenation were consistently [?]0.5 \selectlanguage{ngerman}× 109/L. Previous studies {[}25,
26{]} have demonstrated that lymphocyte count serves as a valuable and
dependable measure for assessing the severity of COVID-19. Patients with
severe COVID-19 exhibit compromised cellular immune function, resulting
in a diminished lymphocyte count.

However, the current body of academic literature exhibits a dearth of
information pertaining to the correlation between lymphocyte counts and
PP. In a prospective study undertaken by Coppo et al. {[}27{]}, it was
discovered that an active inflammatory response was linked to a more
advantageous PP oxygenation index. Our contention is that PP might
exhibit diminished efficacy in patients with diminished lymphocyte
counts and compromised immune systems.

This study is a retrospective investigation conducted on a limited
sample size. The participants of this study consisted of critically ill
patients diagnosed with COVID-19, who were receiving invasive mechanical
ventilation in ICU. These patients exhibited more severe and intricate
medical conditions, as well as a higher number of influencing factors.
However, we conducted the study in which we included PPs from three
general hospitals simultaneously.The relevant information and inspection
data was complete. Additionally, we employed a 1:1 PSM analysis to
ensure comparability between the PP group and non-PP group, thereby
minimizing differences in objective factors. We then dynamically
compared the oxygenation index, disease severity, and survival rate
between the two groups throughout their hospitalization, thus presenting
the impact of PP in a comprehensive and multi-faceted manner across
multiple centers.

\textbf{Conclusions}

The PP has been found to enhance the oxygenation index and increase the
10-day survival rate of critically ill COVID-19 patients receiving
invasive mechanical ventilation in ICU. The frequency of PP correlates
with a more significant improvement in the oxygenation index. However,
it is worth noting that the effectiveness of PP may be reduced in
patients with lower absolute lymphocyte values, while earlier and longer
PP may yield better outcomes. Despite the challenges associated with
implementing PP in patients on invasive mechanical ventilation, it is
recommended to be performed whenever feasible, provided there are no
clear contraindications to invasive mechanical ventilation.

\textbf{Abbreviations}

PP: Prone position; SOFA: Sequential Organ Failure Assessment;
APACHE:Acute Physiology and Chronic Health Evaluation; BMI:Body Mass
Index; PEEP:Positive End-Expiratory Pressure; Cydn:Dynamic lung
compliance; FiO\textsubscript{2}:Fractional concentration of oxygen in
inspired air; LAC:Lactic acid; CRP:C-reactive protein; WBC:White blood
cell; LYM:Lymphocyte.

\textbf{Acknowledgements}

We would like to thank the nurses in three general hospitals located in
Taizhou, Zhejiang Province for sampling specimens, and thank the
patients for being enrolled in this study.

\textbf{Author contributions}

Yuwei Zheng takes responsibility for the content of the manuscript,
including the data and analysisand wrote the manuscript. Bo Shen,Yinghe
Xu contributed to the conception and design of the study, analysis, and
interpretation of the data , Xiaojie Bi,Chaochao Chen contributed to the
conception and design of the study, collection, analysis, and
interpretation of the data, and revised the manuscript, Jing Wang and
Yufen Zheng contributed to the collection, analysis, and interpretation
of the data and revised the manuscript. Jun Li, Shiyong Chen, Hongguo
Zhu , and Jiaqin Xu contributed to the collection of the data and
revised the manuscript. Qiaofei Zheng, Yuan Yuan,Yafei Wang\selectlanguage{english},Wenyuan
Zhang\selectlanguage{english},and Yongpo Jiang contributed to the conception of the
study.interpretation of the data, and revised the manuscript. All
authors read and approved the final manuscript.

\textbf{Funding}

Support was provided solely from institutional and/or departmental
sources.

\textbf{Availability of data and materials}

The datasets used and analysed during the current study are available
from the corresponding author on reasonable request.

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

This study was approved by the Medical Ethics Committee of Taizhou
Hospital, Zhejiang Province, China (Approval NO.: K20230116).

\textbf{Consent for publication}

None.

\textbf{Competing interests}

The authors declare no competing interests.

\textbf{Author details}

\textsuperscript{1}Department of Clinical Laboratory, Taizhou Hospital
of Zhejiang Province Affiliated to Wenzhou Medical University, 150 Ximen
Road, Linhai, Taizhou, Zhejiang Province, China; \textsuperscript{2}Key
Laboratory of System Medicine and Precision Diagnosis and Treatment of
Taizhou,Zhejiang Province, China; \textsuperscript{3}Department of
Critical Care Medicine, Taizhou Hospital of Zhejiang Province Affiliated
to Wenzhou Medical University, 150 Ximen Road, Linhai, Taizhou, Zhejiang
Province, China;

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