A 71-year-old male presented to our hospital because of an incidentally discovered subpleural tubercle on right inferior lobe. Biopsy showed non-small cell lung carcinoma and had a right lower lobectomy under general anesthesia to remove the lesion. On the 5th day postoperative，the patient was noted to be short of breath and dyspneic. On examination，his heart rate was 122 beats per minute, respiratory rate 30 breaths per minute, and oxygen saturation 86 to 90% on 10 liters of oxygen by face mask. He was intubated and transferred to the ICU.
Upon ICU arrival, the patient was sedated with propofol, remifentanil and mechanically ventilated using volume control mode, with low tidal volumes (6 ml per kilogram of predicted body weight), positive end-expiratory pressure（PEEP）of 7cmH2O, respiratory rate of 20 breaths per minute and the fraction of inspired oxygen（FiO2）of 100%. With these settings, the patient continued to have respiratory distress. Physical examination revealed bilateral lung moist rale, normal heart sounds, and yellowish, viscous sputum in the endotracheal tube. His chest radiograph revealed bilateral diffuse and heterogeneous opacities(Fig.1a).
Meeting the criteria of severe ADRS, he was treated with analgesia，deep sedation，neuromuscular blocking agents (NMBAs) and fluid restrictive management strategy. His respiratory status improved in the ensuing 5 days. Anteroposterior chest radiograph showed decreased pulmonary opacities (Fig.1b). Mechanical ventilation was weaned to a FiO2 of 40%, respiratory rate of 20 breaths per minute and pressure support (PS) of 13cmH2O with PEEP of 5cmH2O. Cumulative fluid balance was negative about 3050ml during the ICU admission.
On the 6th day after ICU admission，the patient had increased sputum. On examination，the respiratory rate was 19 breaths per minute, oxygen saturation declined to 91% on mechanical ventilation with FiO2 of 50% and his pulmonary exam demonstrated bilateral rales. A diagnosis of acute pulmonary edema was established and 40 mg of intravenous furosemide was delivered immediately. Fluid balance was negative about 970ml in the ensuing eight hours. However， the patient continued to have dyspnea and worsening hypoxemia. His respiratory rate was 31 breaths per minute, heart rate 129 beats per minute and oxygen saturation 91% on mechanical ventilation with FiO2 of 70% and PS of 12cmH2O with PEEP of 5cmH2O. In addition，he was noted to be fever of 38.4℃.
Evaluation and Management
An immediate point-of-care-ultrasound (POCUS) showed a inferior vena cava (IVC) diameter was 0.92cm with inspiratory collapse(Fig.2a，video in supplementary file 1).Right ventricular(RV)/ LV end-diastolic area ratio was more than 0.6 in the apical four chamber view. The LV size was small (LV end-diastolic dimension, 33mm) with vigorous contraction (LV ejection fraction, 76%). Most notably, in systole，an aliasing of color flow doppler images was found across left ventricular outflow tract (LVOT) (Fig.3a left panel, video in supplementary file 3) and the maximal pressure gradient was 29mmHg estimated by a continuous-wave Doppler flow（Fig.3b left panel），implying increased resistance of LV ejection. Meanwhile, a paradoxical dynamic obstruction with a jet flow from the apex LV chamber to the basal in diastole was recognized（Fig.3c left panel, video in supplementary file 3），with an early diastolic mitral inflow velocity (E) of 1.1 meters per sec and an early diastolic mitral annulus velocity (e') at the lateral of 0.07 meters per sec(E/e' ratio 15.7)，implying that there is underlying LV diastolic dysfunction [1]. Putting this all together, this shows that the left atrial pressure was elevated, and the LV filling was impaired. At this time, lung ultrasound evaluation showed increased B lines in both lungs and no A lines. This is consistent with a substantially increased amount of extra vascular lung water, despite diuresis. (Fig.1d)
Based on the result of the POCUS evaluation the low cardiac preload due to the rapid volume loss resulted in hyperdynamic LV contractions. This lead to increased resistance of LV ejection during systole and difficulty with LV filling during diastole. The increased LV end-diastolic pressure and left atrial pressure were then transmitted to the pulmonary capillaries and pushed fluid out of the vessels, which ultimate resulted in worsening of the patient’s pulmonary edema. Although the pulmonary arterial wedge pressure estimated from E/e‘ was not high enough to induce hydrostatic pulmonary edema, the effect of hydrostatic pressure on the pulmonary edema was amplified by the high pulmonary capillary permeability due to ARDS and pneumonia. Eventually, the patient had worsening pulmonary edema and worsening respiratory distress，then，which triggered negative pressure pulmonary edema (NPPE) attributed to the marked negative intrapleural pressure[2-4].
If this mechanism is not recognized, then the typicaly treatment would involve extra diuresis and possibly vasodilators, inotropic agents, and increased mechanical ventilation support. Unfortunately, these treatment would result in worsening of the patient’s suffer pulmonary edema.
Treatment
After determining that the patient required fluid despite pulmonary edema, the patient received fluid therapy, beta-blocker (intravenous esmolol), and increased sedation to mitigate LV stress. In order to eliminate the side effects of deep spontaneous breath, the patient was deeply sedated and paralyzed with NMBAs (cisatracurium besylate, 5mg per hour). After 2 days, the fluid balance was positive about 1390ml. Meanwhile，the patient was stabilized again on mechanical ventilation requiring an FiO2 of 45%, respiratory rate of 20 breaths per minute and PS of 12cmH2O with PEEP of 6cmH2O. Repeat POCUS showed the LV cavity enlarged and IVC diameter increased to 2.1cm(Fig.2b, video in supplementary file 2), with a laminar LVOT blood flow in systole(Fig.3a right panel) and a laminar LV cavity blood flow from base to apex in diastole(Fig.3c right panel) (video in supplementary file 4). The LVOT pressure gradient decreased to 9.0mmHg in systole (Fig.3b right panel) and the LV E/e’ratio decreased to 9. This indicated that the left atrial pressure decreased. Lung ultrasound examination showed decreased B lines compared to 48 hours before and A lines reappeared in both lungs. (Fig.1e)