Early fluid loading in acute respiratory distress syndrome with septic shock deteriorates lung aeration without impairing arterial oxygenation: a lung ultrasound observational study

This prospective observational study was performed in the multidisciplinary ICU of La Pitié-Salpêtrière hospital. The protocol was approved by the local Ethical Committee (Comité de Protection des Personnes, Ile de France VI, Groupe Hospitalier Pitié-Salpêtrière, Paris, France, session nº18/2011) who considered the study an integral part of care provided to patients with ARDS and septic shock and waived the need for patients to give written informed consent. In our ICU, such patients are routinely monitored using a PiCCO or a fiber optic Swan-Ganz catheter [14‐16] and transthoracic lung ultrasound is a common procedure to assess changes in lung aeration [6, 7, 17]. Thirty-two mechanically ventilated patients were included within 48 h following onset of septic shock and ARDS, defined according to referent recommendations [18, 19]. Patients’ relatives were orally informed of the study, including the results.

Exclusion criteria were age under 18 years, past history of chronic lung disease, active bleeding, ARDS and septic shock lasting more than 48 h, body positioning in the prone position, left ventricular ejection fraction lower than 50%, PCWP ≥18 mmHg, cardiogenic shock as the possible etiology, and pregnancy.

In each patient, fluid loading was directed by the attending physician following the criteria recommended by the Survival Sepsis Campaign: [12] within 6 h following onset of septic shock, 20 mL.kg⁻¹ of saline were rapidly administered before norepinephrine administration; during the next 48 h, fluid loading was continued to obtain a central venous pressure (CVP) ≥12 mmHg and reduce the level of vasopressor support. At the time of inclusion, none of the patients had CVP ≥12 mmHg, thereby justifying the fluid loading they received. Patients were included between the 24th and the 48th hour. Twenty-nine patients included were previously monitored with an arterial catheter and a fiber optic pulmonary arterial catheter (Swan-Ganz Standard Thermodilution Pulmonary Artery Catheter, Edwards Lifescience, Irvine, CA, USA) and three with the PiCCO system (PULSION medical systems AG, Munich, Germany).

Respiratory, hemodynamic, echocardiographic and lung ultrasound measurements were performed at baseline before loading (T0). Then 1,000 mL of saline were infused over 30 minutes and, respiratory, hemodynamic and lung ultrasound parameters were measured at the end of volume expansion (T1) and 40 minutes later (T2). Arterial and mixed venous blood gas, red blood cell count, hematocrit and blood lactate were also measured at T0, T1 and T2.

All patients were sedated using midazolam 0.15 mg.kg⁻¹.h⁻¹ and sulfentanyl 0.2 μg.kg⁻¹.h⁻¹ and paralyzed using atracurium 50 mg.h⁻¹ whenever it was needed [20]. Patients were ventilated using a volume-control mode with a constant inspiratory flow and a tidal volume of 5 to 6 mL.kg⁻¹, the fraction of inspired oxygen (FiO₂) was maintained at 0.6 or above if the arterial oxygen saturation (SaO₂) remained <95%, the respiratory rate was optimized according to previous studies and recommendations [21] and the inspiratory/expiratory ratio was fixed at 0.5 (0.33 to 0.50). Positive end-expiratory pressure (PEEP) was set according to lung morphology as previously described [22, 23]. Plateau pressure, PEEP and auto PEEP were recorded throughout the study. Ventilation settings were kept constant throughout the study.

Arterial pressure was continuously measured and recorded from the arterial line. In patients equipped with a fiber optic Swan-Ganz catheter pulmonary arterial pressure and right atrial pressure were continuously recorded on MetaVision Clinical Information Management System for ICUs (ICU electronic medical records system, iMDsoft, Tel-Aviv, Israel) and PCWP and CVP was intermittently measured at end-expiration. CO was measured with simultaneous withdrawing of systemic and pulmonary arterial blood samples within 1 minute. Arterial oxygen tension (PaO₂), arterial carbon dioxide tension (PaCO₂) and pH, hemoglobin and methemoglobin concentrations and arterial and mixed venous oxygen saturations were measured using an ABL 825 hemoximeter (Radiometer Copenhagen, Denmark). Standard formulas were used to calculate the CI, the systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), the QVa/Qt, oxygen delivery (DO₂), and oxygen consumption (VO₂). In patients equipped with a PiCCO catheter, QVa/Qt and left ventricular cardiac filling pressures could not be measured.

In patients lying in the supine position or in the semi-recumbent position who were hemodynamically stable, echocardiographic measurements were performed offline, by an experienced observer with level-3 certification, who was unaware of the clinical data and other hemodynamic measurements. All measurements were made at end-expiration over five consecutive cardiac cycles. Transthoracic echocardiography was performed using a Siemens Acuson CV70 (Siemens Healthcare, Erlangen, Germany) and images were stored digitally for later playback and analysis. Left ventricular ejection fraction was assessed using the Simpson modified biplane method. Transmitral flow was recorded by pulsed Doppler with the sample volume placed at the mitral valve tips. Mitral inflow velocity was analyzed for peak velocity of early (E) and late (A) filling and deceleration time (DT) of E was measured. In the presence of arrhythmia, the peak velocity of early mitral inflow (E) was measured over five cardiac cycles [24]. Velocities of mitral annulus were recorded by a tissue Doppler imaging program with a 5-mm sample volume placed at the lateral corner of the mitral annulus. The early diastolic (E/e’) velocity of mitral annular displacement was measured from the tissue Doppler imaging recording.

Transthoracic lung ultrasound was performed offline by an experienced investigator with level-3 certification [25], who was unaware of any other hemodynamic measures. A Siemens Acuson CV70 and a 2- to 4-MHz round-tipped or convex probe were used. As shown in Figure 1B and 1C, 12 regions of interest were examined and the quantification of aeration was calculated applying a lung ultrasound score (LUS) as previously described [26, 27]. For a given region of interest, all intercostal spaces were carefully and extensively examined. Four ultrasound patterns corresponding to different degrees of aeration loss were looked for in each intercostal space: 0) normal aeration, characterized by the presence of lung sliding with horizontal A lines and, occasionally, one or two isolated vertical B lines; 1) moderate loss of lung aeration: either multiple well-defined and spaced B1 lines, issued from the pleural line or from small juxtapleural consolidations and corresponding to interstitial edema; or coalescent B2 lines, issued from the pleural line or from small juxtapleural consolidations, present in a limited portion of the intercostal space and corresponding to localized alveolar edema; 2) severe loss of lung aeration, characterized by multiple coalescent vertical B2 lines issued either from the pleural line (Figure 2D) or from juxtapleural consolidations (Figure 2F), detected in the whole area of one or several intercostal spaces and corresponding to diffuse alveolar edema; 3) complete loss of lung aeration resulting in lung consolidation and characterized by the presence of tissue pattern containing either hyperechoïc punctiform images representative of static air bronchograms, or hyperechoïc tubular images, representative of dynamic air bronchograms. The worst ultrasound pattern observed in one or several intercostal spaces was considered as characterizing the region of interest. A value (0, 1, 2 or 3) was attributed to each region examined and the LUS was calculated as the sum of the 12 regions examined. More detailed information on transthoracic lung ultrasound can be obtained online [28] by clicking on Basic skills in transthoracic lung ultrasound to download the corresponding PowerPoint presentation. Using Doppler with color-flow mapping, regional pulmonary blood flow present within consolidated lung areas was assessed as previously described [29]. Pulmonary arterial and venous blood flow signals were obtained by positioning the sample volume into the center of the lumen of the detected vessel and placing the ultrasound beam as parallel as possible to the flow. The spectral waveforms were considered good if 1) pulmonary artery blood flow could be differentiated from pulmonary vein blood flow; 2) the resolution was adequate for serial measurements. As previously described [9] arterial waveform consists principally of a rapid systolic acceleration phase, followed by rapid deceleration. Peak velocity, mean velocity and velocity time-interval were measured before and after fluid loading in the pulmonary artery supplying a consolidated lung region and characterized by a biphasic flow (Figure 3).

The primary endpoint of the study was the increase in LUS after fluid loading. In a previous study, patients with ARDS had a mean LUS of 15 ± 4.8 [7]. Expecting a 30% increase in LUS resulting from fluid loading, we calculated that 31 patients would be needed based on 90% statistical power and an actual alpha value of 0.05. The secondary endpoints were changes in regional pulmonary blood flow, heart rate, mean arterial pressure, mean pulmonary arterial pressure, PCWP, right atrial pressure, CI, SvO_2, systemic and pulmonary vascular resistance indices, arteriovenous oxygen difference, oxygen delivery, oxygen consumption, lactate, hemoglobin, PaO₂/FiO₂ and QVa/Qt. Data are expressed as mean ± SD or median and interquartile range (25 to 75%) according to the data distribution. Cardiorespiratory variables, LUS, peak velocity, mean velocity and velocity time-intervals measured at T0, T1 and T2 were compared using one-way analysis of variance (ANOVA) for repeated measures or Friedman repeated measures ANOVA on ranks followed by post hoc Tukey test, using software Sigmastat 3.1 e Sigmaplot 11.0 (Systat Software Inc., Point Richmond, CA, USA). The statistical significance level was fixed at 0.05.