|Ahead of print publication
Air leak syndromes (Pneumomediastinum, pneumothorax, and subcutaneous emphysema) in critically ill COVID-19 patients – Prevalence, risk factors, and outcome
Parth Sharma1, Rakesh Mohanty1, Preethi Kurian1, David Vincent1, Aditi Dadsena2, Manisha Mane2, Sankara Narayanan1, Sheetal Babu1, Pritish John Korula1
1 Department of Critical Care, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Radiodiagnosis, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||29-Jan-2022|
|Date of Decision||24-Apr-2022|
|Date of Acceptance||11-May-2022|
|Date of Web Publication||19-Jul-2022|
Pritish John Korula,
Department of Critical Care, Christian Medical College, Vellore, Tamil Nadu – 632004
Source of Support: None, Conflict of Interest: None
Background: A high incidence of air leak syndromes (ALSs) has been reported in critically ill coronavirus disease 2019 (COVID-19) patients, which affects disease outcome. Objective: To evaluate the incidence, outcome, and risk factors associated with ALSs in critically ill COVID-19 patients receiving invasive or non-invasive positive pressure ventilation. Result: Out of 79 patients, 16 (20.2%) patients had ALS. The mean age of the ALS group was 48.6 ± 13.1 years as compared to 52.8 ± 13.1 (p = 0.260) years in the non-ALS group. The study group had a lower median body mass index (25.9 kg/m2 vs 27.6 kg/m2, P = 0.096), a higher D-dimer value (1179.5 vs 762.0, P = 0.024), lower saturation (74% vs 88%, P = 0.006), and a lower PF ratio (134 vs 189, P = 0.028) at presentation as compared to the non-ALS group. Patients with ALS had received a higher median positive end-expiratory pressure (PEEP) (10 cm vs 8 cm of water, P = 0.005). The pressure support, highest driving pressure, and peak airway pressure were not significantly different in the two groups. The ALS group had a significantly longer duration of hospital stay (17.5 vs 9 days, P = 0.003). Multiple logistic regression analyses indicated that patients who received inj. dexamethasone were less likely to develop ALS (OR: 12.6 (95% CI 1.6-95.4), P = 0.015). Conclusion: A high incidence of ALS is present in critically ill COVID-19 patients. High inflammatory parameters, severe hypoxia at presentation, and use of high PEEP are significant risk factors associated with ALS. The risk of developing ALS was lower in patients who received inj. dexamethasone.
Keywords: COVID-19, pneumothorax, respiratory distress syndrome
|How to cite this URL:|
Sharma P, Mohanty R, Kurian P, Vincent D, Dadsena A, Mane M, Narayanan S, Babu S, Korula PJ. Air leak syndromes (Pneumomediastinum, pneumothorax, and subcutaneous emphysema) in critically ill COVID-19 patients – Prevalence, risk factors, and outcome. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2022 Dec 1]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=351337
| Introduction|| |
The coronavirus disease 2019 (COVID-19) has affected millions of people worldwide. As of December 2020, COVID-19 was the leading cause of death in USA. Nearly one in ten patients suffering from COVID-19 progresses to develop acute respiratory distress syndrome (ARDS) with 72% of them requiring mechanical ventilation. High mortality is associated with critically ill patients requiring intensive care unit (ICU) care.
Air leak syndromes (ALSs) have been reported to be a common problem in mechanically ventilated patients which affects disease outcomes.[4–7] The high incidence of air leak in critically ill COVID-19 patients makes understanding the risk factors leading to it in the critical care setting all the more important.[8–10] Furthermore, ALS in COVID-19 patients has been shown, in some settings, to be associated with longer hospital stay and increased mortality in patients more than 70 years of age. The higher incidence of air leak in COVID-19 ARDS independent of transpulmonary pressure and various cases of spontaneous air leaks without any previous risk factors suggest pathogenesis beyond pulmonary barotrauma. The Macklin effect has been considered as a possible explanation for the curious and disproportionate development of pneumomediastinum in COVID-19 patients (compared to pneumothoraxes).[12–14]
Understanding the risk factors leading to air leak syndromes in critically ill COVID-19 patients will help in identifying high-risk patients who would benefit from early specific interventions. The impact of ALS on the outcome will aid in the prognostication of patients, which is crucial in an intensive care setting.
| Methodology|| |
Study design and participants
This was a retrospective, observational cohort study conducted in a single-center, tertiary health care center located in South India. Patients admitted to the ICU from 25/07/2020 to 31/10/2020 with a confirmed diagnosis of COVID-19 [defined by a positive reverse-transcriptase polymerase chain reaction (RT-PCR)] with mild to severe ARDS based on Berlin criteria and any form of oxygen therapy (invasive or non-invasive) were included.
Ethical approval was obtained from the institutional review board – IRB Min. No. 13594 [Retro] dated: 25.11.2020. Patient consent was waived by the review board as this was a retrospective study.
In-patient medical records of the patients who were admitted to the ICU from 25/07/2020 to 31/10/2020 were reviewed. All patients included were evaluated for the occurrence of ALSs (pneumomediastinum, pneumothorax, and subcutaneous emphysema) on chest x-rays or computed tomography (CT) scan by a team of two radiologists. Only the study authors were permitted access to the data collected, which were stored securely. Patients who met the inclusion criteria were studied in detail to collect information about their age, gender, body mass index (BMI), co-morbidities, baseline inflammatory parameters, ARDS severity, ventilator, non-invasive positive pressure ventilation settings, duration of ventilation, intervention for barotrauma, mortality, and hospital length of stay in ICU and the hospital. The highest values of tidal volumes, pressure support (PS), positive end-expiratory pressure (PEEP), and driving pressure delivered for at least 2 hours were documented. For patients who developed ALS, the highest value of PS, PEEP, and peak inspiratory pressure delivered on the day before the onset of ALS for at least 2 hours were documented. Telephonic follow-up was performed to assess the mortality at 6 months.
Continuous variables were summarized using descriptive statistics. We used mean and standard deviation for variables with a Gaussian distribution and median and inter-quartile range for variables with a skewed distribution. Normally distributed continuous variables were analyzed using independent sample T-test, whereas non-normally distributed variables were analyzed using the Mann–Whitney U test. The risk factors for ALS were analyzed in three steps. First, the association of potential risk factors with observed ALS (yes/no) was examined. Second, the three most significant variables with a P value <0.05 in bivariate analysis were entered in a step-wise logistic regression model. Third, only the risk factors with a significant P value were studied. The result of multiple logistic regression analysis was presented with an adjusted odds ratio, 95% confidence intervals (95% CI), and P values. Significance levels were defined at 0.05. Survival analysis was performed using Kaplan–Meir analysis and the log-rank test. All analyses were conducted in IBM SPSS Statistics 25 and RStudio (Versio1.4.1717).
| Results|| |
Patient characteristics and prevalence of ALS
Out of the 100 patients who were admitted to the ICU during the study period, a total of 89 patients tested positive for COVID-19, out of whom 79 patients met the inclusion criteria. Ten patients did not satisfy the inclusion criteria as their PF ratio was more than 300 and were admitted to the ICU for complications other than ARDS and were incidentally tested positive for COVID-19.
Radiological images [Figure 1] and [Figure 2] of these patients were assessed by a team of two radiologists, and a total of 16 (20.2%) patients were detected to have ALSs. Isolated pneumomediastinum was detected in 13 patients, isolated pneumothorax was seen in one patient, and a combination of the two was seen in two patients. Seven patients had subcutaneous emphysema along with pneumomediastinum or pneumothorax. Spontaneous pneumomediastinum was noticed in three patients at presentation before administration of positive pressure ventilation. None of the patients in the study developed ALS secondary to procedural complications (e.g., central line insertion). ALS developed after a mean of 12.6 ± 3.8 days since the onset of symptoms. Only one patient required chest tube insertion for management of pneumothorax. Patients who did not succumb to the illness showed spontaneous resolution of ALS following conservative management after a median of 4 days (IQR – 1.75–9.5).
|Figure 2: CT thorax of a patient with pneumothorax and pneumomediastinum|
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The mean age of the ALS group was 48.6 ± 13.1 years as compared to 52.8 ± 13.1 years in the non-ALS group. The ALS group had a lesser median BMI as compared to the non-ALS group (25.9 kg/m2 vs 27.6 kg/m2). However, these two correlations were not statistically significant. The other baseline characteristics are mentioned in [Table 1].
A total of 18 possible risk factors were studied and analyzed. Three inflammatory markers [ferritin, D-dimer, and C-reactive protein (CRP)] were studied. Out of the three, only the D-dimer value at presentation showed a statistically significant correlation, with patients who developed ALS having a higher D-dimer value at presentation (1179.5 vs 762.0, P = 0.024). The patients who developed ALS were found to be more hypoxic at presentation, which was assessed in terms of saturation (74% vs 88%, P = 0.006) and PF ratio at presentation (134 vs 189, P = 0.028).
Ventilatory settings were compared between the two groups [Table 2]. The overall duration of ventilation was significantly longer in the ALS group. Invasive ventilation was more prevalent as compared to non-invasive ventilation in the ALS group (43.8%) as compared to the non-ALS group (37.5%). Patients who developed ALS were found to have received a higher median PEEP (10 cm of water vs 8 cm of water, P = 0.005). The PS, higher driving pressure, and peak airway pressure were not significantly different in the ALS and non-ALS groups. Tidal Volume values were not reliably recorded for most patients and therefore were not taken for analysis.
As per the institutional treatment protocol, patients received either inj. dexamethasone 6 mg once daily or inj. methylprednisolone 1mg/kg once daily for a total of 10 days from the onset of oxygen therapy (invasive or non-invasive). Patients who received inj. dexamethasone during their ICU stay were less likely to develop ALS with a protective odds ratio of 17.6 (95% CI – 3.86–80.54, P < 0.001).
The three most significant variables were included in the multiple logistic regression analysis [Table 3]. Only the type of steroid given was observed to have a statistically significant relation with adjusted OR – 12.57 (95% CI – 1.63–96.41, P value – 0.015) after eliminating possible confounders.
|Table 3: Multiple logistic regression analysis of three most significant risk factors|
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The ALS group was seen to have a significantly longer duration of ICU stay (17.5 days vs 9 days, P = 0.003). A greater percentage of patients in the ALS group developed secondary bacterial pneumonia (50% vs 20.6%, P = 0.023). A total of nine (56.3%) patients died or were terminally discharged in the ALS group as compared to 24 (38.1%) patients in the non-ALS group. These findings are summarized in [Table 4]. Kaplan–Meir analysis [Figure 3] showed a trend toward increased mortality in patients with ALS. However, this was not statistically significant.
Seven patients were discharged against medical advice. Out of these, five patients succumbed to illness within a maximum of 3 weeks following discharge and two patients were lost to follow-up.
| Discussion|| |
In our study, we observed a high incidence of ALSs in patients with COVID-19-related ARDS requiring intensive care. We prefer the terminology 'Air leak syndrome' over 'Barotrauma' as not all patients were on positive pressure ventilation when they were found to have pneumomediastinum, pneumothorax, or subcutaneous emphysema. A total of 16 (20.2%) patients developed ALS, which is significantly higher when compared with ALS incidence in other ARDS patient populations (5–8%)., Out of the 16 patients, six patients were on non-invasive ventilation, seven patients were on invasive mechanical ventilation, and three patients were found to have spontaneous pneumomediastinum.
Multiple cases have reported spontaneous pneumomediastinum in patients with COVID-19.[18–22] Many of these reports indicate that patients were not on mechanical ventilation and did not have a history of prior pneumothorax. Thus, the cause of spontaneous ALSs and specifically pneumomediastina in the realm of COVID-19 ARDS remains an enigma. The predominant mechanism of air leak may not be barotrauma or related to ventilatory pressures, although positive pressure may be contributory to their development. The high incidence of ALS in critically ill COVID-19 patients may be related to excessive lung inflammation. Indeed, high plasma levels of inflammatory mediators such as IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα have been observed in ICU patients as compared to non-ICU patients with COVID-19. It is plausible that excessively inflamed lung tissues may be friable and prone to lung tears. Alternatively, there also may be a predisposition to fibrosis and or worsening of swings in transpulmonary pressures with the excessive respiratory efforts of ventilation. This may be considered in effect a form of patient self-inflicted lung injury (PSILI). Macklin and Macklin first noticed that air released from alveolar rupture centripetally dissects through the interstitium of the lungs, along the broncho vascular sheaths toward the pulmonary hila and into the mediastinum. The Macklin effect is commonly seen in patients with blunt chest trauma. The Macklin effect has been observed in COVID-19 patients and could explain the high incidence of spontaneous pneumomediastinum often leading to pneumothorax.,,, We studied D-dimer, CRP, and ferritin at admission to assess the role of inflammation. D-dimer at admission in the ALS group was observed to be higher and reached statistical significance. Both baseline hypoxia and a low PF ratio at presentation were significantly lower in the ALS group, which may indicate that the severity of the disease has a role in the tendency for air leak.
Before COVID-19, ALSs in ARDS have been known not only to increase hospital stay but also to be associated with morbidity and mortality. In our cohort of patients, the requirement of prolonged ventilation in the ALS group was associated with a higher incidence of ventilator-associated pneumonia in these patients which may have adversely impacted their outcome.
Ventilatory management of COVID-19 patients has been a tough challenge throughout the pandemic. Different ventilatory managements have been suggested based on the COVID phenotypes: L-type pneumonia and H-type pneumonia. Some previously performed studies have found a relationship between PEEP and barotrauma, whereas others have found no relation between airway pressures and barotrauma.[30–32] In our study, higher PEEP was observed in the ALS group, which was statistically significant. The pressure support, driving pressures, and peak airway pressures were found to be higher in the ALS group. However, this trend was not found to be statistically significant. The higher PEEP settings in the ALS group may have been set by clinicians to tackle poorer oxygenation and severity of disease in that group relative to the non-ALS group (and therefore may be a confounder).
The use of corticosteroids has shown a reduction in the severity of ARDS, an increase in ventilator-free days, and a reduction in mortality. An observational study showed better results with high-dose methylprednisolone as compared with conventional-dose dexamethasone in COVID-19 patients in terms of the progression of ARDS. In our study, we observed that patients who received inj. dexamethasone were less likely to develop ALS as opposed to patients who received inj. methylprednisolone. Although this could be a chance finding, fluid retention associated with the mineralocorticoid properties of methylprednisolone may have rendered the lung more friable or amenable to injury as opposed to dexamethasone. Further studies need to be performed to understand the difference in the effect of dexamethasone and methylprednisolone on outcomes in COVID-19 patients.
A limitation of our study is a small sample size from a single center; however, our study adds to the volume of data available on this topic as well as supports results from other settings. Another key limitation was our inability to capture tidal volume data from our cohort appropriately. However, the classic teaching is that pressure is the chief variable involved in air leaks. Also, other studies have not demonstrated that volume is a predictor of ALS. The unique incidence and pattern of ALS in COVID-19 patients, such as predisposition to pneumomediastinum, give us a window into understanding the pathophysiology and course of COVID-19 ARDS. Prospective studies need to continue to look into how to mitigate ALS to improve outcomes. With early recognition and emerging treatment options, there could be a reduced level of inflammation and severity of disease leading to less incidence of ALS and perhaps better outcomes.
| Conclusion|| |
COVID-19 is still an evolving disease that is still not entirely understood. ALSs are disproportionately higher in COVID ARDS as compared to other causes of ARDS with a preponderance to form pneumomediastinum. Inflammatory markers such as D-dimer and severity of hypoxemia may help in predicting the predisposition to ALS and eventual outcomes of patients. Patients with ALS tend to have an increased duration of hospital stay, a high incidence of secondary respiratory tract infections, and poorer long-term outcomes. Dexamethasone may be more protective than methylprednisolone in critically ill COVID-19 patients, although more prospective studies are required to confirm this.
We would like to thank Mr. Muthukumar, Department of Medical Records, for providing all the inpatient medical records within short notice.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]