Lung Ultrasound Score as a Predictor of Clinical Severity and Prognosis in Patients of Ventilator-associated Pneumonia

HIGHLIGHTS

• The responders to treatment for ventilator-associated pneumonia (VAP) described by the lung ultrasound aeration score (LUSS) had lower mortality than nonresponders.

INTRODUCTION

Ventilator-associated pneumonia is a commonly occurring hospital-acquired infection, affecting up to one-quarter of mechanically ventilated patients.¹ It adversely affects patient care by prolonging intensive care stay, needs for a prolonged duration of mechanical ventilation, and tremendous use of hospital resources.^2–4 Early diagnosis and monitoring of VAP is an essential step in treatment and reducing the cost arising from the infection.

Although a chest radiograph is an essential element in monitoring VAP, due to its inherent shortcomings, it lacks reliability and diagnostic accuracy in mechanically ventilated patients.^5,6 Although computed tomography (CT) thorax is the most appropriate investigation for measuring lung aeration and its variations, it requires the patient to be transported out of the intensive care unit (ICU). It exposes them to high radiation and the risk of transportation.^7,8 Lung ultrasound (LUS) is a simple, non-invasive bedside tool that was considered unsuitable for lung scanning for decades as the ultrasound beam cannot cross the air-filled structures at the interface of visceral pleura, and ordinarily, aerated lung tissue is ultimately reflected.⁹ However, in lung consolidations, as the air is replaced by fluid, ultrasound transmission is possible if the lesion and the pleural surface are in direct touch.^10,11 Lung ultrasound has been used to diagnose VAP in the previous study.¹² The LUSS has also been proven reliable for quantifying lung aeration compared to the gold standard CT scan in VAP.¹³ Different levels of aeration loss correlate with different ultrasonic imaging patterns. Hence, various treatment options for VAP should change the LUSS. Whether the change in LUSS is correlated to the patient’s clinical outcome during VAP is not yet established. So, this prospective observational study was conducted to establish a correlation between change in LUSS and 28-day mortality in VAP.

MATERIALS AND METHODS

Patients with a diagnosis of VAP as per clinical pulmonary infection score (CPIS) of ages >18 years were included in the study. The diagnosis of VAP was established with CPIS ≥ 6.¹⁴ Patients with morbid obesity, evidence of disseminated malignancy, chronic obstructive pulmonary disease, interstitial lung disease, and subcutaneous emphysema, and the presence of thoracic dressings were excluded from the study.

Ethical approval was granted by the institutional ethics committee, AIIMS, Rishikesh, AIIMS/IEC/19/828 (dated 10/05/19). The trial was prospectively registered with Clinical Trials Registry- India CTRI/2020/10/028480. All procedures followed were by the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Patients meeting the study protocol were enrolled for the trial after receiving informed permission and approval from the institutional ethical committee. An investigator not involved in patient management performed an LUS with an ultrasonography machine using a 2–5 MHz round-tipped probe (LOGIQe, GE Healthcare, USA). Using the parasternal, anterior-axillary, and posterior axillary lines as anatomic landmarks, respectively, it was assessed at six locations of each hemithorax, superior, and inferior area in anterior, lateral, and posterior fields. Outcome data were recorded. A lung ultrasound was performed for five consecutive days since the diagnosis of ventilator-associated pneumonia (Day 1 to Day 5). The change in LUSS between the first and the fifth day was calculated by subtracting the Day 5 LUSS from Day 1 LUSS. We assumed a delta change of 2 in LUSS would favor an improvement in the clinical outcome because the change of 2 in LUSS is required for the diagnosis of VAP.¹⁵ Patients with a decreased LUSS of 2 were leveled as responders. Those patients without a decrease of LUSS of 2 or an increase of LUSS were levelled as nonresponders. The change in LUSS between the first and the third day was also calculated by subtracting the Day 3 LUSS from Day 1 LUSS. Patients with a decrease of LUSS of 2 were levelled as responders on day 3. The partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO₂/FiO₂ ratio) was also calculated within 15 minutes of LUS on those five days by obtaining PaO₂ from arterial blood gas analysis (ABG) (Phox ultra ABG machine; Nova Biomedical, US). Plateau pressure was also measured at the same time by using an inspiratory pause on the ventilator (Nellcor Puritan Bennett, Medtronic, US), and static lung compliance (Cstat) was calculated by using the formula (Cstat = Tidal volume/Plateau PEEP). An independent investigator blinded to other outcome parameters recorded the ABG variables and lung compliance. A physician blinded to the study protocols was involved in patient care and management. Following their ICU hospitalization, all study participants received conventional medical management and care in accordance with evidence-based guidelines, which were monitored for a period of 28 days, if discharged it was followed up with a telephone conversation.

RESULTS

A total of 600 patients were assessed for eligibility during this study period from June 2019 to November 2021, of which 480 patients were excluded due to various reasons as mentioned above. A total of 120 patients were enrolled in the study; of these, 3 patients were lost to follow-up, and finally, 117 patients had complete follow-up at day 28 (Fig. 1). The two groups’ baseline patient characteristics were comparable (Table 1).

Of the 117 patients, 76 were responders and 41 were non-responders. Mortality among responders was 26.3% (20 out of 76) and 87.8% (36 out of 41) among nonresponders. This difference was found to be statistically significant (p < 0.001) (Table 2).

The correlation was calculated for all five days (Day 1–5) between

• LUSS with PaO₂/FiO₂, static compliance and plateau pressure.

A Pearson correlation analysis was performed to explore these relationships, which has been shown using scatter plots. (Figs 2 to 6). Significant correlations were found between LUSS and with PaO₂/FiO₂ ratio on all 5 days.

The first-day results revealed several significant correlations. First, a strong negative correlation (r = -0.601, p < 0.01) was found between LUSS and PaO₂/FiO₂, indicating that as LUSS increased, PaO₂/FiO₂ tended to decrease. Second, a moderate negative correlation (r = –0.229, p < 0.05) was observed between LUSS and static compliance. Third, a significant positive correlation (r = 0.277, p < 0.01) emerged between LUSS and plateau pressure. Furthermore, our analysis revealed a moderate positive correlation (r = 0.347, p < 0.01) between PaO₂/FiO₂ and static compliance, a strong negative correlation (r = –0.543, p < 0.01) between PaO₂/FiO₂ and plateau pressure, and an even stronger negative correlation (r = –0.668, p < 0.01) between static compliance and plateau pressure. These findings provide valuable insights into the relationships among these variables, which may have important implications for understanding and managing the studied condition.

Utilizing Pearson’s correlation analysis, we also observed a moderate positive correlation (r = 0.577) between the responder and responder on day 3 with a p-value of less than 0.001.

DISCUSSION

The preliminary work in this prospective observational study provides validation for the use of change in LUSS in patients with VAP. We found that the decrease of LUSS of 2 on the fifth day of development of VAP in comparison to the first day is associated with reduced 28-day mortality. We also found significant negative correlations between LUSS with oxygenation (PaO₂/FiO₂ ratio) on all 5 days. The correlation of LUSS with static compliance and plateau pressure was also statistically significant in all 5 days.

Chest radiographs, although an essential element in monitoring VAP, lack diagnostic accuracy in mechanically ventilated patients.^5,6 They are limited by the posture of the patient, the presence of several indwellings and monitoring lines, its anteroposterior nature, and the presence of common pathologies like pleural effusion and atelectasis in a critically ill patient.¹⁶ CT, though considered the gold standard for measuring lung aeration and its variations,^7,8 is limited by the risk of high radiation exposure and transportation out of the ICU.^9,10 However, LUS is a simple, nonradiating, noninvasive bedside technique that has been successfully applied to diagnose VAP.^17–19 Bouhemad et al. established a significant correlation between CT thorax and ultrasonography lung reaeration following antibacterial therapy in ventilator-associated pneumonia.¹³ Tsubo et al. also found a significant correlation of consolidated areas in the left lung evaluated using transesophageal echocardiography with those estimated with CT.¹⁹

In this study, we did LUS, ABG, static compliance, and plateau pressure measurements simultaneously to reflect the effect of the particular ventilator settings on each of these parameters. In a prospective study, Luna et al. evaluated the performance of the CPIS and its components to identify the initial course of VAP. They demonstrated that patients who received appropriate therapy saw a significant improvement in their PaO₂/FiO₂ ratio, whereas those who received insufficient therapy saw a deterioration. Only the PaO₂/FiO₂ ratio among the CPIS’s constituent components was able to distinguish survivors from non-survivors.²⁰ We found significant negative correlations between LUSS with oxygenation (PaO₂/FiO₂ ratio) in all 5 days. Our findings are in line with those of Li L et al., who found that LUSS and the PaO₂/FiO₂ ratio in ARDS patients had a comparable negative connection (r = –0.755, p < 0.001).²¹ In line with the earlier research, there was a statistically significant link between LUSS and static compliance throughout each of the 5 days.²² Our study revealed that a decrease of LUSS of 2 on the fifth day of development of VAP in comparison to the first day is associated with reduced 28-day mortality. The association of mortality with lack of improvement in LUSS may be used clinically for escalation of therapy or prolonging the course of antibiotics therapy in VAP. We also found a good correlation between the responder and the non-responder at day 3. Hence, by day 3, there is a good chance to review antibiotics based on LUS findings. After therapeutic interventions such as optimizing positive end expiratory pressure (PEEP) and antibiotics, LUSS significantly decreases as aeration of the lung increases and static lung compliance increases. It might be a useful, non-invasive bedside tool for clinical weaning decision-making. As the calculation of static compliance requires an absence of any spontaneous effort, the use of LUSS can be used for patients with spontaneous respiratory effort. Ntoumenopoulos G et al. in their prospective cohort study involving ten patients on VV ECMO established a robust negative correlation between LUSS and dynamic compliance (r_s (33) = –0.66, p < 0.001).²³ This study provides some insight into the use of LUSS as a surrogate measure of lung aeration and lung mechanics for weaning during VV-ECMO. Tsubo et al. also observed a significant correlation between PaO₂/FiO₂ ratio and consolidated area in ARDS, and during the application of PEEP, as the area of consolidation decreased, oxygenation also improved.¹⁹

Our study has a few limitations; first, LUS detects the infection extending to the visceral pleura so that it can underestimate the severity, and with therapy as pneumonia resolved from visceral sites, it may underestimate LUSS on follow-up. However, a strong correlation between LUSS and PaO₂/FiO₂ ratio suggests that the change at the periphery represents the change in the whole lung. Second, monitoring static compliance in sedated patients who were not on neuromuscular blockade may have a minor influence on the results. Third, LUS is unsuitable for certain conditions like subcutaneous emphysema, morbidly obese patients, and thoracic dressing, which may interfere with optimal ultrasonography image acquisition.

CONCLUSION

The responders to treatment for VAP described by lung ultrasound score had lower mortality than non-responders.

ORCID

Sagarika Panda https://orcid.org/0000-0002-8547-5720

Ankit Agarwal https://orcid.org/0000-0003-4963-7101

Shakti Bedanta Mishra https://orcid.org/0000-0001-6634-1877

Gaurav Jain https://orcid.org/0000-0002-1205-7237

Praveen Talawar https://orcid.org/0000-0002-9931-2316

REFERENCES

1. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. DOI: 10.1164/rccm.200405-644ST.

2. Melsen WG, Rovers MM, Groenwold RH, Bergmans DC, Camus C, Bauer TT, et al. Attributable mortality of ventilator-associated pneumonia: A meta-analysis of individual patient data from randomized prevention studies. Lancet Infect Dis 2013;13(8):665–671. DOI: 10.1016/S1473-3099(13)70081-1.

3. Muscedere JG, Day A, Heyland DK. Mortality, attributable mortality, and clinical events as end points for clinical trials of ventilator-associated pneumonia and hospital-acquired pneumonia. Clin Infect Dis 2010;51:S120–S125. DOI: 10.1086/653060.

4. Gupta A, Agrawal A, Mehrotra S, Singh A, Malik S, Khanna A. Incidence, risk stratification, antibiogram of pathogens isolated and clinical outcome of ventilator-associated pneumonia. Indian J Crit Care Med 2011;15(2):96–101. DOI: 10.4103/0972-5229.83015.

5. Graat ME, Choi G, Wolthuis EK, Korevaar JC, Spronk PE, Stoker J, et al. The clinical value of daily routine chest radiographs in a mixed medical-surgical intensive care unit is low. Crit Care 2006;10(1):R11. DOI: 10.1186/cc3955.

6. Graat ME, Kröner A, Spronk PE, Korevaar JC, Stoker J, Vroom MB, et al. Elimination of daily routine chest radiographs in a mixed medical-surgical intensive care unit. Intensive Care Med 2007;33(4):639–644. DOI: 10.1007/s00134-007-0542-1.

7. Beckmann U, Gillies DM, Berenholtz SM, Wu AW, Pronovost P. Incidents relating to the intra-hospital transfer of critically ill patients. An analysis of the reports submitted to the Australian Incident Monitoring Study in Intensive Care. Intensive Care Med 2004;30:1579–1585. DOI: 10.1007/s00134-004-2177-9.

8. Mayo JR, Aldrich J, Müller NL. Radiation exposure at chest CT: A statement of the Fleischner Society. Radiolog 2003;228:15–21. DOI: 10.1148/radiol.2281020874.

9. Fuhlbrigge AL, Choi AK. Diagnostic Procedures in Respiratory Disease. Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill Education; 2018.

10. Lichtenstein DA, Lascols N, Mezière G, Gepner A. Ultrasound diagnosis of alveolar consolidation in the critically ill. Intensive Care Med 2004;30:276–281. DOI: 10.1007/s00134-003-2075-6.

11. Mathis G. Thorax sonography—Part II: Peripheral pulmonary consolidation. Ultrasound Med Biol 1997;23:1141–1153. DOI: 10.1016/s0301-5629(97)00111-7.

12. Samanta S, Patnaik R, Azim A, Gurjar M, Baronia AK, Poddar B, et al. Incorporating lung ultrasound in clinical pulmonary infection score as an added tool for diagnosing ventilator-associated pneumonia: A prospective observational study from a tertiary care center. Indian J Crit Care Med 2021;25(3):284–291. DOI: 10.5005/jp-journals-10071-23759.

13. Bouhemad B, Liu ZH, Arbelot C, Zhang M, Ferarri F, Le-Guen M, et al. Ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia. Crit Care Med 2010;38:84–92. DOI: 10.1097/CCM.0b013e3181b08cdb.

14. Brégeon F, Papazian L, Gouin F. Elements du diagnostic des pneumopathies acquises sous ventilation mécanique [Diagnostic characteristics of acquired pneumonia in patients under mechanical respiration]. Ann Fr Anesth Reanim 1996;15:1178–1192. DOI: 10.1016/s0750-7658(97)85876-5.

15. Mongodi S, Via G, Girard M, Rouquette I, Misset B, Braschi A, et al. Lung ultrasound for early diagnosis of ventilator-associated pneumonia. Chest 2016;149:969–980. DOI: 10.1016/j.chest.2015.12.012.

16. Esayag Y, Nikitin I, Bar-Ziv J, Cytter R, Hadas-Halpern I, Zalut T, et al. Diagnostic value of chest radiographs in bedridden patients suspected of having pneumonia. Am J Med 2010;123:88. e1–e5. DOI: 10.1016/j.amjmed.2009.09.012.

17. Luna CM, Aruj P, Niederman MS, Garzón J, Violi D, Prignoni A, et al. Appropriateness and delay to initiate therapy in ventilator-associated pneumonia. Eur Respir J 2006;27:158–164. DOI: 10.1183/09031936.06.00049105.

18. Zagli G, Cozzolino M, Terreni A, Biagioli T, Caldini AL, Peris A. Diagnosis of ventilator-associated pneumonia: A pilot, exploratory analysis of a new score based on procalcitonin and chest echography. Chest 2014;146:1578–1585. DOI: 10.1378/chest.13-2922.

19. Tsubo T, Sakai I, Suzuki A, Okawa H, Ishihara H, Matsuki A. Density detection in dependent left lung region using transesophageal echocardiography. Anesthesiology 2001;94:793–798. DOI: 10.1097/00000542-200105000-00017.

20. Luna CM, Blanzaco D, Niederman MS, Matarucco W, Baredes NC, Desmery P, et al. Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome. Crit Care Med 2003;31:676–682. DOI: 10.1097/01.CCM.0000055380.86458.1E.

21. Li L, Yang Q, Li L, Guan J, Liu Z, Han J, et al. The value of lung ultrasound score on evaluating clinical severity and prognosis in patients with acute respiratory distress syndrome]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015;27:579–584. DOI: 10.3760/cma.j.issn.2095-4352.2015.07.008.

22. Gattinoni L, Pesenti A, Avalli L, Rossi F, Bombino M. Pressure-volume curve of the total respiratory system in acute respiratory failure. Computed tomographic scan study. Am Rev Respir Dis 1987;136:730–736. DOI: 10.1164/ajrccm/136.3.730.

23. Ntoumenopoulos G, Buscher H, Scott S. Lung ultrasound score as an indicator of dynamic lung compliance during veno-venous extra-corporeal membrane oxygenation. Int J Artif Organs 2021;44:194–198. DOI: 10.1177/0391398820948870.