key: cord-1049422-goxh0z6r authors: Gidaro, A.; Samartin, F.; Brambilla, A. M.; Cogliati, C.; Ingrassia, S.; Banfi, F.; Cupiraggi, V.; Bonino, C.; Schiuma, M.; Giacomelli, A.; Rusconi, S.; Salvi, E. title: Occurrence of Pneumothorax and Pneumomediastinum in Covid-19 patients during non-invasive ventilation with Continuous Positive Airway Pressure date: 2020-09-02 journal: nan DOI: 10.1101/2020.08.31.20185348 sha: 1afd38ec1f50b8ed694a239d9ce81e57bf97ac41 doc_id: 1049422 cord_uid: goxh0z6r Background: Acute Hypoxemic Respiratory Failure (AHRF) is a common complication of Covid-19 related pneumonia, for which non-invasive ventilation (NIV) with Helmet Continuous Positive Airway Pressure (CPAP) is widely used. During past epidemics of SARS and MERS pneumomediastinum (PNM) and pneumothorax (PNX) were common complications (respectively 1.7-12% and 16,4%) either spontaneous or associated to ventilation. Methods: Aim of our retrospective study was to investigate the incidence of PNX/PNM in COVID-19 pneumonia patients treated with CPAP. Moreover, we examined the correlation between PNX/PNM and Positive end-expiratory pressure (PEEP) values. We collected data from patients admitted to Luigi Sacco University Hospital of Milan from 21/02/2020 to 06/05/2020 with COVID-19 pneumonia requiring CPAP. Results: One-hundred-fifty-four patients were enrolled. During hospitalization 3 PNX and 2 PNM occurred (3.2%). Out of these five patients 2 needed invasive ventilation after PNX, two died. In the overall population, 42 patients (27%) were treated with High-PEEP (>10 cmH2O), and 112 with Low-PEEP ([≤]10 cmH2O). All the PNX/PNM occurred in the High-PEEP group (5/37 vs 0/112, p<0,001). Conclusion: The incidence of PNX appears to be lower in COVID-19 than SARS and MERS, but their occurrence is accompanied by high mortality and worsening of clinical conditions. Considering the association of PNX/PNM with high PEEP we suggest using the lower PEEP as possible to prevent these complications. "Key messages" box Section 1: What is already known on this subject • Elevated incidence of pneumomediastinum (PNM) and pneumothorax (PNX) occurring during SARS and MERS pneumonia (respectively 1.7-12% 9,10 and 16,4% 11 ), either spontaneous or associated to ventilation.Conversely, these complications have not been reported when NIV was used for the treatment of common pneumonia patients 6, 7 . • Some cases of PNX and PNM have been recently reported in patients with pneumonia, most of them spontaneous [12] [13] [14] , in some cases related to NIV 15, 16 or endotracheal intubation (ETI) 17, 18 . • Incidence of PNX/PNM is lower in COVID19 pneumonia patients during CPAP (3,2%) than SARS and MERS. • Considering mortality rate and need of ETI, occurrence of PNX/PNM worsens prognosis. • All the PNX/PNM occurred in the High-PEEP (>10 cmH2O) group (5/37 vs 0/112, p<0,001). • Considering the association of high PEEP (>10 cmH2O) with PNX/PNM, the use of low PEEP values has to be taken into consideration. Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes severe disease (with dyspnoea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours) in 14% of patients, even leading to critical disease -Acute Hypoxemic Respiratory Failure (AHRF) or Acute Respiratory Distress Syndrome (ARDS) -in 5% 1 . During this novel coronavirus pandemic, non-invasive ventilation (NIV) and Continuous Positive Airway Pressure (CPAP) was widely used to treat AHRF gaining respiratory support 2 . NIV was already been used during SARS and MERS epidemic with some evidence of efficacy [3] [4] [5] and some works support its use in pneumonia 6, 7 . Moreover, during COVID-19 outbreak the overcrowding of the ICUs pushed to use a bridge or alternative respiratory support in medical wards. During SARS epidemic in 2002 NIV was used to treat acute respiratory failure in SARS pneumoniae with different device: Helmet CPAP, Nasal CPAP, BiPaP 3,4 . Between many interfaces available for CPAP therapy, the helmet has been proposed to reduce droplet dispersion and consequently preventing health care worker's infection 8 during COVID-19 pandemic. For the same reason, the antimicrobial filter was adopted. In the past epidemics 4 to 15 cmH2O 3,4 of positive end-expiratory pressure (PEEP) have been administered, being higher PEEP contraindicated because of the elevated incidence of pneumomediastinum (PNM) and pneumothorax (PNX) occurring during SARS and MERS pneumonia (respectively 1.7-12% 9,10 and 16,4% 11 ), either spontaneous or associated to ventilation. Conversely, these complications have not been reported when NIV was used for the treatment of common pneumonia patients 6, 7 . Some cases of PNX and PNM have been recently reported in patients with COVID-19 pneumonia, most of them spontaneous [12] [13] [14] , in some cases related to NIV 15, 16 or endotracheal intubation (ETI) 17, 18 . The first aim of our study was to assess the incidence of PNX and PNM in COVID-19 pneumonia patients treated with Helmet CPAP. Moreover, we investigated the correlation between the incidence of PNX or PNM and the PEEP values used during treatment. We retrospectively analysed data from patients admitted in Hospital Wards of "Luigi Sacco" University Hospital of Milan from the Emergency Department (ER) or transferred from other hospitals of Lombardy region from 21/02/2020 to 06/05/2020. PNX and PNM were documented with chest X-ray, usually carried out for worsening of clinical conditions . Sacco COVID-19)" was approved by the local ethical committee with the registration number 2020/16088. Kolmogorov-Smirnov test was done to evaluate the normality of distribution of data. Qualitative data were expressed as number and percentage. Chi square or Fisher exact tests were used in group's comparison. Quantitative data were expressed as mean, standard deviation, median and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 2, 2020. . https://doi.org/10.1101/2020.08.31.20185348 doi: medRxiv preprint range. Student T-test and Mann-Whitney test (for non-parametric data) were used for comparison between groups. P-value less than 0.05 was considered statistically significant. The statistical analysis of data was done by using Excel (Office program 2010) and SPSS (statistical package for social science-SPSS, Inc., Chicago, IL version 20). During the observational period 1016 patients were admitted to our Hospital, 194 (19,1%) met the inclusion criteria. Of them, 40 patients (20,62%) were excluded because they needed ETI. In the end 154 (15.2%) patients were enrolled. In Table 1 are summarized clinical characteristics of the examined population; the average age was 68.8 years (± 14.7), 107 were men (69.5%). CPAP was performed with PEEP set up between 5 to 15 cmH2O (modal value 10 cmH2O) and FiO2 from 30% to 100%. The average duration of CPAP treatment was 174 hours -6,4 days -with a great inhomogeneity (± 141). Mortality rate for the whole population was 25.3%. During the observational period 5 events occurred, of which 3 were PNX and 2 PNM. Between cases, 3 were male patients, no one had a passed story of smoking or underlying lung disease, nobody has undergone invasive manoeuvres (as positioning central venous catheter or thoracentesis). The most relevant features of these five patients are reported in Table 2 . After the event, every patient needed higher FiO2 (from 50-60% to 100%); 2 underwent chest drainage and subsequently ETI ( Figure 1 ) and then died with a mortality rate of 40%. The average time elapsed from starting CPAP to the occurrence of PNX/PMN was 180 hours with great inhomogeneity (±137). No difference was found in the duration of CPAP treatment between PNX/PMN group and No-PNX/PMN patients (p-value 0.931). High-PEEP (>10 cmH2O) was administered to 42 (27,3%) patients, and Low-PEEP (≤10 cmH2O) to 112 (72.7%). As shown in Table 1 , no statistical differences in term of characteristics were found All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 2, 2020. . https://doi.org/10.1101/2020.08.31.20185348 doi: medRxiv preprint comparing High-PEEP vs Low-PEEP group. The PNX/PNM occurred only in the High-PEEP group (5/42, 12% vs 0/112, 0%, p<0,001). In our retrospective observational study PNX/PMN occurred in 3.2% of patients; apparently, nobody had previous risk factors for PNX (no smokers, no lung diseases, no positioning central venous catheter or thoracentesis). Among these cases, the incidence of negative outcome (mortality and ETI) is relevant. Moreover, even in survived patients, events were associated with worsening of clinical conditions with a higher need of FiO2 (50-60% before vs 100% after). PNX and PNM occurred only in the High-PEEP group (11.9%). Considering the homogeneity of these groups in terms of clinical and biochemical features, we may suppose that elevated PEEP may represent a risk factor for PNX/PNM in COVID-19 patients. Conversely, in our population duration of CPAP treatment was quite variable and does not seem to play a determinant role as risk factor for events. The possible effect of barotrauma has to be considered as superimposed to the direct effect of lung damage related to Covid-19 pneumonia. PNX and PNM occurred rather frequently in SARS and MERS patients. Some study addressing evolution of lung lesions on CT imaging showed that in many cases spontaneous PNM occurred when ground glass opacity and consolidations began to resolve 11, 19 . The pathogenesis of this phenomenon has been interpreted as the effect of the peribronchiolar inflammatory nodule formation, leading to interstitial pulmonary emphysema, tracking back along the broncho-vascular sheath and reaching the mediastinum 19 . On the other hand, histologic findings (alveolar damage with pulmonary oedema and hyaline membrane formation) appear to support the hypothesis that severe pulmonary injury predisposes the patient to spontaneous pneumothorax 20 . The diffuse alveolar damage may give rise to dilated cystic air spaces and honeycombing predisposing the lung to air leakage from the rupture of the cystic lesions, with the consequent development of a pneumothorax. Possible shared mechanisms may underly All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 2, 2020. . https://doi.org/10.1101/2020.08.31.20185348 doi: medRxiv preprint PNX/PNM in patients with COVID-19 pneumonia considering the presence of similar lung damages and imaging features as described for SARS 21, 22 . In our study PNX/PNM happened after a long time from onset of symptoms (18 days in average) resembling what previously described in SARS patients 10 and suggesting that a sustained period of lung inflammation might be required. Conversely, we did not find significant differences in the biochemical elements of disease severity (peak LDH and neutrophil count) that seemed to be predictable of spontaneous pneumothorax in SARS patients 10 . Finally, in the past SARS epidemic someone conjectured that steroid therapy may play a role in the pathogenesis of spontaneous pneumothorax because it could delay wound healing and perpetuate air leakage 10 . In our study only 2 out of 5 patients have been treated with steroid therapy, so we can not speculate about this hypothesis. Our study has several limitations. First of all, the number of events is low and for this reason our results, and in particular the association of PNX/PNM with higher PEEP, has to be confirmed in multicentric studies with a wider population. Moreover, our study is retrospective: PEEP values were decided by the clinician for each patient and in particular higher PEEP values have been set in the first weeks and subsequently lowered on the basis of clinical experience and data emerging from literature. In the end, we did not collected data about pneumoperitoneum or subcutaneous emphysema which can be classified as possible barotrauma even if rare. In conclusion, our study indicates that incidence of PNX/PNM is lower in COVID-19 pneumonia patients than SARS and MERS 9 . Nevertheless, the occurrence of these events significantly worsens the prognosis. Considering the association of high PEEP (>10 cmH2O) with PNX/PNM, the use of low PEEP values has to be taken into consideration. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 2, 2020. . https://doi.org/10.1101/2020.08.31.20185348 doi: medRxiv preprint Table 1 . Characteristic of examined population and the 2 groups according to PEEP value Continuous variables are expressed as mean ± standard deviation T0 = before starting CPAP * Respiratory rate before starting CPAP ¥ Partial pressure of oxygen in arterial blood Partial pressure of carbon dyoxide in arterial blood ∆ Oxygen saturation in arterial blood ˜ Charlson Comorbidity Index Θ C-Reactive Protein Granulocytes/Lymphocytes ratio All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 2, 2020. . https://doi.org/10.1101/2020.08.31.20185348 doi: medRxiv preprint Table 2 . Clinical and biochemical features about 5 cases of PNX/PNM Figure 1 : Example of PNX as visualized at Chest X-Ray (Case 3; left PNX, arrows) before (A) and after (B) drainage and ETI. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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