Ventilator management for acute respiratory distress syndrome associated with avian in fl uenza A (H7N9)virus infection: A case series

Hui Xie, Zhi-gang Zhou, Wei Jin, Cheng-bin Yuan, Jiang Du, Jian Lu, Rui-lan Wang

Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine,Shanghai, China

INTRODUCTION

The new human H7N9 viruses are the product of reassortment that are of avian origin, which can cause severe illness, including pneumonia and acute respiratory distress syndrome (ARDS), with high rates of ICU admission and death. Since the identification of H7N9 on 30 March 2013,[1]a second wave of H7N9 virus infection has occurred in 2014 with the number of new cases reported thus far exceeding twice the number from the previous year.[2]

The disease progresses rapidly in severe cases and may develop into ARDS associated with both acute pneumonia and acute interstitial inflammation.[3,4]It is reported that 97.3% patients with confirmed H7N9 virus infection had findings that were consistent with pneumonia and 76.6% patients were admitted to an intensive care unit (ICU). Moderate-to-severe ARDS was the most common complication and 58.6% patients needed invasive mechanical ventilation(MV).[5]The risks of admission to an ICU, mechanical ventilation, and fatality were high.[6]

The situation of the increasing number of new cases and the high rate of death associated with these infections has raised global public health concerns.[7]The data on the clinical characteristics and laboratory abnormalities of the illnesses and risk factors for severe illness among patients who were hospitalized for the treatment of H7N9 virus infection were also provided.[5,6]However, data on the MV characteristics for the cases with ARDS were still lacking. In this report, we describe MV characteristics and radiologic features with a lung-protective strategy,recruitment maneuvers, prone positioning.

METHO DS

This study was approved by the Regional Ethics Committee of our hospital (No: 2016KY155). The requirement for written informed consent from the patients was waived by the institutional review board because the design of this study was a retrospective study.

Patients

Eight adult Chinese patients, who were admitted to the ICU with severe bilateral pneumonia and ARDS,were confirmed to be infected with H7N9 avian flu by Shanghai Public Health Clinical Center, the Shanghai Centers for Disease Control and Prevention (CDC)and the Chinese National Influenza Center (CNIC) in 2014 (all of them were admitted in first quarter). All the patients required invasive mechanical ventilation in the ICU and underwent at least one chest computed tomography (CT) scan in the hospital. All patients were defined as severe ARDS according to the Berlin Definition.[8]The general severity of disease was assigned an APACHE II score. The extent of multiple organ failure was evaluated by means of the SOFA score. These scores were calculated on the days of ICU admission and days 3,7, and 14 after ICU admission.

Ventilator management

The ventilatory strategy of the low tidal volume by limiting tidal volume (VT) to 4-6 mL/kg and plateau pressure(PPlat) to 30 cmH2O and open-lung approach was chosen using conventional modes of mechanical ventilation.

Recruitment maneuvers (RM) were used to make improvements in oxygenation in the patients with refractory hypoxemia as a rescue strategy. Optimal PEEP was considered if the step preceding the drop of oxygen saturation to below 90%.[9]We use bedside ultrasound and pressure volume curve (P-V curve) to identify which collapsed lung units have a high potential for reopening.Prone positioning was performed following the protocol[10]to improve oxygenation on t he patients who had poor response to the RM without contraindications.

Pressure-volume curves and measurement of PEEP-induced RM

P-V curves were measured using a ventilator equipped with specific software. Decrease in endexpiratory lung volume (EELV) was defined as the difference in lung volume before and after a PEEP release maneuver. In patients with focal loss of aeration,PEEP-induced lung recruitment was quantified as previously described.[11]In patients with diffuse loss of aeration, PEEP-induced lung recruitment was defined asEELV. We also used lung ultrasound (LUS) to provide a bedside estimate of potentially recruitable lung.[11,12]

CT examination

All patients underwent first CT scan of the chest once within 2 days after the admission to the ICU. Ventilator management at the time of the CT examination was designed to limit plateau pressure at 30 cmH2O or less,with positive end-expiratory pressure of 5-8 cmH2O.None of the patients experienced a deterioration in condition as a result of undergoing the CT examination.We used the first CT scan to score the CT findings. The CT findings were graded on a scale of 1-6 on the basis of the classification system previously described.[13-15]

RESULTS

Clinical characteristics

Over a 3-month period, our medical ICU managed 8 patients with severe H7N9 infection complicated by ARDS. The clinical characteristics of the patients are presented in Tables 1 and 2. The mean age was 57.38±16.75 years, and men comprised 62.5% of all the patients. The baseline severity of illness assessed by APACHE II and SOFA score was 11.77±6.32 and 7.71±3.12, respectively. Four patients had one or more comorbidities, the most common of which was hypertension (n=3). Interestedly, all of patients did not have underlying pulmonary disease. All patients received oral oseltamivir (150 mg twice daily) for 7 days following the guideline[16]and parenteral antibiotics. Five patients were proven to have secondary infections. Three patients already required intubation before ICU admission.The other five patients were intubated in 24 hours after the admission of ICU. The mean duration of MV was 14.63±6.14 days. Two patients without contraindications underwent prone positioning to improve oxygenation which had poor response to the RM. Three patients died within the first 28 days after ICU admission. One of them died from multiple organ dysfunction syndrome(MODS) after refractory hypoxemia, one patient died of secondary infection (Candida) and the other patient died of pneumothorax after long-term MV.

CT findings

The Murray’s lung injury score at the time of first CT examination was 2.97±1.03. The CT finding in the 8 patients is summarized in Table 2 (Figures 1, 2) and the extent of each CT finding is summarized in Table 3.Figure 1 shows the CT Finding in a 35-year-old man who survived (patient 2). First CT shows a wide range of ai rspace consolidation with air bronchograms posteriorly and areas of ground-glass attenuation anteriorly(Figure 1A). The follow-up CT shows (6 months after discharge from hospital) irregular reticular opacities,traction bronchiolectasis (arrows) and bronchiectasis.The chest X-ray shows elevation of right diaphragm induced by restricted lung expansion (Figure 1B).Architectural distortion, ground-glass attenuation and air-space consolidation were the most commonly seen in the patients with ARDS caused by H7N9 infection.The extent of ground-glass attenuation and air-space consolidation combined with or without traction bronchiolectasis or bronchiectasis was about 65% of the whole lung. The abnormalities were bilateral in all the patients. Th e overall CT scores of the patients was 247.68±34.28 and the range of CT scores was 196.3 to 294.7. The 2 observers showed good agreement in their evaluations of the presence of lung abnormalities(Kappa statistic 0.73), and the assessments of the extent of abnormalities made by the two observers were also well correlated (Spearman rank correlation coefficient,r=0.78,P＜0.01).

Table 1. Cli nical characteristics of 8 patients infected wi th H7N9 virus

Table 2. CT findings in 8 patients infected with H7N9 virus, n (%)

Figure 1. Finding in a 35-year-old man who survived (patient 2). A:first CT; B: six months after discharge from hospital.

Figure 2. Finding in a 54-year-old man who did not survive (patient 3). CT shows diffuse interstitial exudation and areas of ground glass attenuation associated with traction bronchiolectasis (arrows),bronchiectasisand architectural distortion. This patient died of pneumothorax after long-term MV.

Evaluation of RM

We used the ultrasound reaeration score (Figure 3),the change of P-V curve and PaO2/FiO2ratio to evaluate the effect of RM. The result is summarized in Table 4.There were 4 patients who did not need RM with set PEEP limitedly (≤20 cmH2O, PaO2/FIO2≥150 mmHg).RM was performed on the other 4 patients with lifethreatening hypoxemia in the early stage of ARDS.We did not perform RM again on patient 4 who had poor response to the RM and the patient 1 who without hemodynamic stability.

Prone positioning

Two patients (No. 1 and No. 4) underwent prone positioning to improve oxygenation which had poor response to the RM. Figures 4 and 5 illustrate the PaO2/FiO2ratio, PaCO2, PEEP, FiO2values obtained during the prone positioning of the two patients. Improvements in oxygenation were immediate in the prone position in both 2 patients. The PaCO2value got higher in one patient (No. 1) and the prone treatment was stopped in this patient because of the following hypercapnia (PaCO2108.5 mmHg), acute kidney injury (AKI) and continues renal replacement therapy (CRRT). The other patient(No. 4) met the criteria (PaO2/FiO2≥150 mmHg with PEEP≤10 cmH2O and FiO2≤0.6, these criteria had to be met in supine at least 4 hours after the end of the last prone session) in the second day of the prone positioning and we decided to stop the prone intervention.

Table 3. Extent of each CT finding in 8 patients infected with H7N9 virus

Figure 3. Illustration of PEEP induced lung recruitment detected by bedside ultrasound in patient 2. A: The images of upper part of anterior region of left chest wall before and after RM. Left: Transversal view of a lung region with alveolar syndrome. Multiple well-defined B lines(B1 lines) arising from the pleural line are present. Right: After RM,the same lung region appears normally aerated. The pleural line can be seen. B: The images of upper part of anterior region of right chest wall before and after RM. Left: Coalescent B lines (B2 lines) arising from the pleural line are present. Right: After RM, the same lung region appears normally aerated. The pleural line can be seen with two isolated B lines. These artifacts correspond to ground-glass areas on chest computed tomography. C: The images of lower part of lateral region of right chest wall before and after RM. Left: Transversal view of consolidated right lobe. Lung consolidation appears as a tissue structure can be seen. Right: After RM, the same lung region appears normally aerated. The pleural line can be seen with an isolated B line.These artifacts correspond to air-space consolidation areas on chest computed tomography.

Table 4. Extent of each CT finding in 8 patients infected with H7N9 virus

DISCUSSION

The A (H7N9) virus are one of the most virulent respiratory tract viruses infecting humans.[17]Previous studies have showed that the histopathological damages could be divided into 3 stages after avian influenza infection.[18-21]An exudative inflammatory phase is seen in H7N9 infection within 8 days after symptom onset,characterized by intra-alveolar hemorrhage, diffuse alveolar damage, edema, fibrous exudates and hyaline formation. And the H7N9-infected patients who died on day 11 after symptom onset developed pneumocyte hyperplasia and interstitial fibrosis in addition to the diffuse alveolar damage, which were compatible with the fibro-proliferative phase.[18]In our cases, the mean CT scores of the eight patients was 247.68±34.28, which means H7N9 caused serious damage to the lung. The patient 2 who survived underwent a follow-up CT that showed extensive interstitial fibrosis in right lung six months after discharge from hospital. Thus, it is crucial to reduce iatrogenic lung damage and the formation of fibrosis during respiratory support.

Figure 4. The PaO2/FiO2 ratio, PaCO2, PEEP, FiO2 values of the 61-year-old female patient (No. 1) during the prone positioning.This patient died of multiple organ failure (MOF) after refractory hypoxemia.

Currently, the low tidal volume strategy is recommended for the management of patients with ARDS to protect the lung from ventilator-induced lung injury (VILI) and hopefully improve outcomes.[22-24]During the H7N9 pandemic, the ventilator strategy of low tidal volume and open-lung approach was chosen in our ICU as the conventional mode of mechanical ventilation. And high levels of PEEP were often used to achieve adequate oxygenation. In our cases, PEEP was increased to levels of 18-30 cmH2O, with variable response in terms of oxygenation. This variable response seems not to correlate with extent of alveolar infiltrates or severity of hypoxemia. Alternative modes of ventilation such as airway pressure release ventilation(APRV) and high-frequency oscillatory ventilation(HFOV), if available, may be considered in the setting of persistent hypoxemia (SaO2＜88%-90%, with high PEEP and FiO2＞0.8) or when the goals of lung-protective ventilation cannot be met (PPlat＞30-35, VT＞8 mL/kg),particularly in the setting of progressive patient decline.[25]

Figure 5. The PaO2/FiO2 ratio, PaCO2, PEEP, FiO2 values of the 34-year-old male patient (No. 4) during the prone positioning.

RM with the transient application of high levels of PEEP is one of the options to improve the oxygenation in patients with life-threatening hypoxemia, which aim to open collapsed lung units and increase functional residual capacity by increasing transpulmonary pressure.Its positive effect on the final mortality is still under debate.[26]And the optimal method for delivering RM is unknown.[27]In our practice, we used ultrasound reaeration score, the change of P-V curve and PaO2/FiO2ratio to provide a bedside estimate of potentially recruitable lung before RM. The optimal PEEP after RM is the minimum PEEP level that sustains the oxygenation benefit of the recruitment maneuver. Like ARDS induced by H1N1 infection,[25]the variability in response to RM also may have been related to differences in the percentage of collapsed lung vs. ground-glass infiltrates o n chest computed tomography. Two out of the 4 patients (no. 2 and 3) with H7N9 infection responded to the RM with decremental PEEP titration. But patient 2 developed extensive interstitial fibrosis in right lung which may occur secondary to lung damage induced by RM. And although patient 3 with diffuse architectural distortion (the highest CT score, 294.7) at early stage responded to RM, he died of pneumothorax which is a common complication of RM. Our H7N9-infected patients with pulmonary endogenous ARDS were found t o have serious architectural distortion and high CT scores. Use of high transpulmonary pressures in these patients may cause further lung damage, and induce bad outcomes. Thus, application of RM in H7N9-infected patients with ARDS requires serious consideration.Once patients improved and the weaning process should started to decrease PEEP. The best approach was that of watchful waiting with very small changes made daily to the ventilator settings, and an attempt was often made to decrease PEEP＜20 cmH2O before weaning FiO2significantly.[25]

Prone position has been utilized to improve oxygenation in patients with ARDS. Alveolar recruitment, improvement in ventilation/perfusion matching from redistribution of ventilation to dorsal lung regions, elimination of the heart’s compressive effects on the lungs, better drainage of respiratory secretions and reduction of parenchymal lung stress/strain are the physiologic mechanisms to explain the improvement in oxygenation.[28,29]The recent study on prone positioning have showed a significant improvement in 28-day and 90-day mortality.[10]Recently,two meta-analysis of randomized control trials on prone ventilation in adults found to significantly reduce overall mortality in patients with ARDS in the low tidal volume era.[30,31]Gattinoni et al[32]had demonstrated that ARDS patients who respond to prone positioning with reduction of their PaCO2(decreased physiologic dead space ratio)show an increased survival at 28 days. In patient 4 who had a poor chest wall compliance (BMI=35.49),the total respiratory system compliance increased depending on the increased lung compliance because of lung recruitment in prone position while chest wall compliance didn’t change too much. Thus, improvement in oxygenation was immediate in the prone position in this patient and the PaCO2value got lower. The other patient (No. 1) who died of refractory hypoxemia got higher PaO2value in the prone position with a higher PaCO2value. Therefore, in our experience, prone position is an intervention that can be used in the setting of hypoxemia with mortality benefit in the early stage of ARDS. Patients who are hemodynamically unstable would be poor candidates because of the difficulty resuscitating a patient in the prone position. In these patients, other interventions like neuromuscular blockade and extracorporeal membrane oxygenation (ECMO)should be tried to adjust the hypoxemia (ECMO was refused by patient 1’s family).

CONCLUSION

In summary, in H7N9-infected patients with severe ARDS who need MV, low tidal volume strategy with the use of PEEP was the conventional mode. Application of RM as one of rescue therapies to refractory hypoxemia in these patients with serious architectural distortion and high CT scores, which could cause further lung damage, may induce bad outcomes and requires serious consideration. Prone ventilation may improve mortality,and should be performed at the early stage of the disease,not as a rescue therapy.

Funding:This work was supported by the National Natural Science Foundation of China (grant number 81501654)and Natural Science Foundation of Shanghai (grant number 14ZR1433700).

Ethical approval:This study was approved by the Regional Ethics Committee of our hospital (No: 2016KY155).

Conflicts of interest:The authors state they have no competing interests.

Contributors:HX and ZGZ contributed equally to this work. All authors read and approved the final version of the manuscript.

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