Pneumothorax in Tertiary Intensive Care With COVID-19 is Associated With Increased Mortality

Background: To examine the laboratory ndings with clinical characteristics and treatments of patients who were hospitalized in a tertiary intensive care unit with the diagnosis of COVID-19 and developed pneumothorax and to determine epidemiology and risks of pneumothorax. Methods: The study was conducted by retrospectively examining the electronic records of 681 COVID-19 patients who were followed up between 1 April 2020 and 1 January 2021 in 3 tertiary care units (each was 24 beds). Patients demographic and clinical characteristics, laboratory ndings, mechanical ventilator parameters and chest imaging were collected retrospectively,. Results: Pneumothorax in 22 (3.2%) of 681 with COVID-19 patients were detected and ARDS in 481 (70.6). All the study patients met ARDS diagnostic criterias. Mortality rates were 43.4% (296/681) in all patients, 52.8% (254/481) in patients with ARDS, and 86.3% (19/22) in patients with pneumothorax. Pneumothorax occurred in the patients within a mean of 17.4 ± 4.8 days. The computed tomographies of patients were observed common ground-glass opacities, heterogenic distribution with patch inltrates, alveolar exudates, interstitial thickening in the 1 st week of their follow-up. Conclusion: We observed that pneumothorax signicantly increased mortality in COVID-19 patients with ARDS. We believe that understanding and preventing the characteristics of pneumothorax will make an important contribution to mortality reduction. the of and describe their and These may shed light on by early in ill and be We used high dose methylprednisolone in all our patients. We found a signicant difference between the baseline LDH level of our patients and the LDH levels at the time of pneumothorax occurrence. In the same manner, we observed that acute phase reactants increased signicantly.


Introduction
The frequency of pneumothorax occurrence due to COVID-19 in the rst series has been reported to be between 1-2% [1][2][3]. The literature published subjecting pneumothorax in COVID-19 patients with ARDS are mostly case reports or case series [4][5][6]. Among the reported series, the number of cases was high only in a multi-center study, but the patients included were not intubated [7]. While pneumothorax in ARDS patients varied between 1.5-77% in previous publications, pneumothorax was reported as 10% in COVID-19 related ARDS [4,[8][9][10]. Both the reported case series and the number of cases was de cient, especially in critically ill patients [4]. Experience on this matter needed to be published.
Herein, we report the largest case series with the diagnosis of COVID-19 related pneumothorax in single center tertiary intensive care units and describe their clinical characteristics and outcomes. These results may shed light on preventing pneumothorax by early diagnosis in critically ill patients, and mortality can be reduced.

Methods
This study was approved by the Local Ethics Committee.and conducted with the method of retrospective screening of 681 coronavirus disease  patients hospitalized between April 2020 and January 2021 in the tertiary care unit of the Ankara City General Hospital. Laboratory-con rmed COVID-19 patients (with real time reverse transcription-polymerase reaction; RT-PCR) older than 18 years who were followed by ICU and developed a pneumothorax (with/without pneumomediastinum or subcutaneous emphysema) during the course were included in the study. Patients who had pneumothorax for any reason without COVİD-19 were excluded from the study.
Pateints demographics, comorbidities, and APACHE II scores, laboratory tests [complete blood count, biochemical and coagulation tests, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) levels] and outcomes were recorded. Diagnosis of ARDS was based on Berlin standards. Invasive procedures and all respiratory and mechanical ventilator parameters prior to baroutrauma were recorded. X-ray and chest CT scans of all patients were examined. Initial chest CT was taken in all patients between the 1st and the 7th day after hospitalization.The follow-up of the patients was usually performed with a portable X-ray.

Statistical Analysis
Statistical analyses were performed using the SPSS software (version; 15 SSPSS Inc. Chicago) for windows. All variables were checked for normal distribution. Variables were reported as mean and standard deviation or as median when appropriate. Continuous variables were compared with Student's t-test or the Mann-Whitney U test. The chi-square test was used to test for proportions. A p-value of ≤ 0.05 was considered as statistically signi cant.

Results
A total of 681 patients were followed up in the ICU with the diagnosis of COVID-19 and 296 (43.4 %) of them died during their follow-up and 481 (%70.6) of them patients met ARDS diagnostic criterias. The mortality of ARDS patients was 254 (52.8%). The overall incidence of pneumothorax was 3.2% (22/681), 4.5% (22/481) in patients with ARDS. Nineteen of the 22 patients died during hospitalization, with a mortality as high as 86.3 % (19/22). In 3 of 22 patients with pneumothorax, pneumomediastinum was seen subcutaneous emphysema in 5. All patients who developed pneumothorax were treated with invasive mechanical ventilation (Fig. 1).

Discussion
Pneumothorax is a fatal complication in patients with ARDS, especially those undergoing invasive mechanical ventilation [11]. In a previous study in which 84 severe ARDS patients were examined, the pneumothorax rate was 48.8%, and the mortality (66% vs 46%) was higher in patients with pneumothorax [12]. In the presence of COVID-19 and ARDS, This rate was found to be 80% [4]. Since our intensive care is one of our country's reference centers, severe patients were accepted from other intensive care units and hospitals. Hence, our mortality rate was 43.4% in all patients, 52.8% in patients with ARDS. This rate was found as 87% in the case of pneumothorax with ARDS occurrence. Therefore, we believe that preventing pneumothorax in a tertiary intensive care unit will signi cantly reduce mortality rates.
In a case series conducted on SARS patients in Hong Kong, it was observed that high neutrophil count and LDH level increased the tendency to pneumothorax [9]. It was also thought that high-dose methylprednisolone administration affected the improvement of the lung tissue and contributed to the pneumothorax occurrence [9]. Hameed et al. reported that high LDH and acute phase reactants were higher in COVID-19 patients who received high-dose prednisolone and developed pneumothorax [13]. We used high dose methylprednisolone in all our patients. We found a signi cant difference between the baseline LDH level of our patients and the LDH levels at the time of pneumothorax occurrence. In the same manner, we observed that acute phase reactants increased signi cantly. Increases in acute phase reactants and LDH may be an early indicator for pneumothorax. Besides, we think that it would be bene cial to reconsider high-dose methylprednisolone treatment in this respect in the patient group requiring intensive care.
The duration of ARDS can explain the incidence of pneumothorax in ARDS. ARDS consists of three phases: exudative phase (1-7 days), proliferative phase (8-21 days), and brotic phase (> 21 days) [14]. Gattinoni L et al. found the incidence of pneumothorax in late ARDS (longer than two weeks) patients as 87% and early ARDS (less than seven days) as 30% [11]. Wang et al. reported that pneumothorax occurred two weeks after symptom onset in 5 COVID-19 patients with ARDS [4]. In line with the literature, we found that pneumothorax's occurrence time was 17.4 ± 4.8 days in our patients. We did not nd a signi cant relationship between pneumothorax occurrence time and mortality.
ARDS development is one of the most important prognostic factors in COVID-19 patients. In ARDS pathophysiology, neutrophil count is characterized by increased activation of proin ammatory cytokines and complement cascade, which results in microvascular permeability and uid exudation [15]. Eventually, uid accumulation, alveolar atelectasis, and brin accumulation are seen in the lung [15]. The occurrence of pneumothorax in mechanically ventilated patients is closely related to the underlying pulmonary pathology, and ARDS has been proven to be closely related to the occurrence of this complication [16]. As it has been marvelously described by computed tomographic studies in patients with ARDS, the affected lung parenchyma, seems to have a remarkable heterogenic distribution which causes a multi-compartmental lung, with patchy in ltrates interspersed with normal-appearing lung areas [11]. We performed tomography on our patients in the 1st week of their follow-up (table 4, Fig. 1-2). As seen in the literature, we observed common ground-glass opacities, heterogenic distribution with patch in ltrates, alveolar exudates in our patients' tomographic images. Interstitial thickening was observed in patients, although the computed tomography was performed in the early period. Emphysematous appearance and bullous formations occur in the affected lung areas in the late period, explaining the increase in pneumothorax incidence in this period [10].
Patients with ARDS who are under mechanical ventilation are at the highest risk for pneumothorax development [11].
Many ventilation parameters, such as tidal volume, PIP, PEEP, and respiratory rate are considered important in the development of barotrauma. It was shown that there is a high correlation between the development of endinspiratory pressure [P( plat )], especially when exceeding 35 cm H 2 O and pneumothorax [17]. Furthermore, large tidal volume might elicit injury to the pulmonary epithelium; therefore tidal volume reduction is another parameter presented for the prevention of ventilator-induced injury in ARDS [18]. P plat pressure did not exceed 35 cm H 2 O in the patients we followed up. P plat pressure was aimed to be kept below 30 cm H 2 O, and only four patients were observed to have over 30 cm H 2 O pressure at the time of pneumothorax occurrence. Also, V T was aimed to be kept between 4-6 ml/kg to prevent pulmonary epithelium damage. Neuromuscular blockers and fentanyl were used to minimize oxygen consumption and provide lung-protective settings. High PEEP levels are associated with the persistence of lung air leaks as well as the occurrence of pneumothorax. PEEP level was kept at 5-9 cm H 2 O level in our patients. In conclusion, we applied AC protective ventilation in almost all ARDS patients who developed pneumothorax in ICU, but we still could not avoid pneumothorax occurrence.
Data on pneumothorax treatment in ARDS patients are limited. Tube thoracostomy, open thoracotomy, pleurodesis, and thoracoscopic surgical methods are among the treatment methods. It was shown in the previous studies that thoracotomy increases mortality in patients with ARDS [19]. A limited number of successful results have been published using thoracoscopic surgical methods, but further studies are needed on this subject [20]. We placed chest tubes in all of our patients during the treatment, except for ve patients with subcutaneous emphysema together with pneumothorax. Also, ECMO was used in one severe ARDS patient whose oxygenation could not be achieved. The patient's survival time who had diffuse lung involvement was extended, but mortality could not be avoided. Nevertheless, we think that administering ECMO can be one of the most promising options in patients who develop ARDS and pneumothorax due to COVID-19 since it reduces lung effort and provides a time gap for the treatment of pneumothorax and the elimination of the virus.
This study had some limitations. The study was conducted retrospectively, and further studies may ll some of the de ciencies of this study. First of all, the number of patients was limited. A multi-center study with a larger sample size may contribute to treatment improvement. Second, the risk factors can be compared by expanding the study population with patients who do not require intensive care conditions, who do not have ARDS, and who have a milder manifestation. Third, since it is di cult to use CT scan as an imaging method in the patients' follow-up, bedside Xray criteria or USG administration methods can be de ned for follow-up. Besides, it can be discussed to administer early treatment to patients to reduce mortality. Also, the relationship between high-dose methylprednisolone treatment and pneumothorax can be examined.
In conclusion, although lung-protective ventilation parameters were applied, we found that mortality was high in our COVID-19 patients with ARDS. We have seen that the pneumothorax tendency was more common in patients after two weeks. We also observed that acute phase reactants and LDH increased signi cantly on the day of pneumothorax occurrence. According to our ndings, pneumothorax with ARDS increased mortality, and we believe that the prevention of pneumothorax will make an important contribution to reducing mortality. Therefore, more comprehensive studies are needed on this subject in the future to prevent and treatment pneumothorax occurrence in critically ill COVID-19 patients.

Ethic Declarations
Ethics approval and consent to participate Written informed consent was obtained either from the participants (ıf alive)or their relatives (ıf dead) because of the unprecedented situation (COVID-19 pandemic) and in this informed consent, it is clearly stated that the data may be used in retrospective studies anonymously. Then this study was approved by the Local Ethics Committee. Ankara City General Hospital (Number: E2-21-105)

Consent for publication
Not applicable.
Availability of data and materials The datasets during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests AGA participated in the design of the study. SI conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the nal manuscript.