Extravascular lung water assessed by transpulmonary single thermodilution and postmortem gravimetry in sheep

Introduction  

Acute lung injury is associated with accumulation of extravascular lung water (EVLW). The aim of the present study was to compare two methods for quantification of EVLW: transpulmonary single thermodilution (EVLW_ST) and postmortem gravimetric (EVLW_G).     

Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution

Objective: Transpulmonary double-indicator dilution is a useful monitoring technique for measurement of intrathoracic blood volume (ITBV) and extravascular lung water (EVLW). In this study, we compared a simpler approach using single arterial thermodilution derived measurements of ITBV and EVLW with the double-indicator dilution technique.¶Design: Prospective observational clinical study.¶Setting: Surgical intensive care units of two university hospitals.¶Patients and methods: Global end-diastolic volume (GEDV) derived from single thermodilution was used for calculation of ITBV. Structural regression analysis of the first two thermo-dye dilution measurements in a derivation population of 57 critically ill patients (38 male, 19 female, 18–79 years, 56 ± 15 years) revealed ITBV = (1.25 · GEDV)–28.4 (ml). This equation was then applied to all first measurements in a validation population of 209 critically ill patients (139 male, 70 female, 10–88 years, mean 53 ± 19 years), and single-thermodilution ITBV (ITBV_ST) and EVLW (EVLW_ST) was calculated and compared to thermo-dye dilution derived values (ITBV_TD, EVLW_TD). For inter-individual comparison, absolute values for ITBV and EVLW were normalised as indexed by body surface area (ITBVI) and body weight (EVLWI), respectively.¶Measurements and results: Linear regression analysis yielded a correlation of ITBVI_ST = (1.05 · ITBVI_TD)–58.0 (ml/m²), r = 0.97, P < 0.0001. Bias between ITBVI_TD and ITBVI_ST was 7.6 (ml/m²) with a standard deviation of 57.4 (ml/m²). Single-thermodilution EVLWI (EVLWI_ST) was calculated using ITBVI_ST and revealed the correlation EVLWI_ST = (0.83 · EVLWI_TD) + 1.6 (ml/kg), r = 0.96, P < 0.0001. Bias between EVLWI_TD and EVLWI_ST was –0.2 (ml/kg) with a standard deviation of 1.4 (ml/kg). In detail, EVLWI_ST systematically overestimated EVLWI_TD at low-normal values for EVLWI and underestimated EVLWI at higher values (above 12 ml/kg).¶Conclusion: Determinations of ITBV and EVLW by single thermodilution agreed closely with the corresponding values from the double-indicator technique. Since transpulmonary single thermodilution is simple to apply, less invasive and cheaper, all these features make it a promising technique for the bedside. Nevertheless, further validation studies are needed in the future.     

Validation of extravascular lung water measurement by single transpulmonary thermodilution: human autopsy study

Introduction

Gravimetric validation of single-indicator extravascular lung water (EVLW) and normal EVLW values has not been well studied in humans thus far. The aims of this study were (1) to validate the accuracy of EVLW measurement by single transpulmonary thermodilution with postmortem lung weight measurement in humans and (2) to define the statistically normal EVLW values.

Methods

We evaluated the correlation between pre-mortem EVLW value by single transpulmonary thermodilution and post-mortem lung weight from 30 consecutive autopsies completed within 48 hours following the final thermodilution measurement. A linear regression equation for the correlation was calculated. In order to clarify the normal lung weight value by statistical analysis, we conducted a literature search and obtained the normal reference ranges for post-mortem lung weight. These values were substituted into the equation for the correlation between EVLW and lung weight to estimate the normal EVLW values.

Results

EVLW determined using transpulmonary single thermodilution correlated closely with post-mortem lung weight (r = 0.904, P < 0.001). A linear regression equation was calculated: EVLW (mL) = 0.56 × lung weight (g) - 58.0. The normal EVLW values indexed by predicted body weight were approximately 7.4 ± 3.3 mL/kg (7.5 ± 3.3 mL/kg for males and 7.3 ± 3.3 mL/kg for females).

Conclusions

A definite correlation exists between EVLW measured by the single-indicator transpulmonary thermodilution technique and post-mortem lung weight in humans. The normal EVLW value is approximately 7.4 ± 3.3 mL/kg.

Trial registration

UMIN000002780.     

Quantification of lung water by transpulmonary thermodilution in normal and edematous lung

PURPOSE: To analyze the accuracy of the transpulmonary thermodilution method in the determination of extravascular lung water (EVLW). MATERIAL AND METHODS: Acute lung injury was produced in eight adolescent pigs weighing 28 to 35 kg by bronchoalveolar lung lavage. EVLW was measured by transpulmonary thermodilution method before and after the intratracheal introduction of 250 or 500 mL of saline solution in different lung injury conditions. No corrections for anatomic dead space were made. RESULTS: When 250 mL was introduced, 195 +/- 17 mL was detected in normal (uninjured) lungs versus 74 +/- 57 mL in edematous (injured) lungs (P <.05). When 500 mL was introduced, 343 +/- 67 mL was detected in normal lungs versus 160 +/- 51 mL in edematous lungs (P <.001). Considering all determinations together, there was a very high negative correlation between the baseline EVLW and the percentage of EVLW detected (r = -0.92, P <.001). CONCLUSION: The transpulmonary thermodilution method is very accurate to detect changes in EVLW in normal lungs. In edematous lung, this method may underestimate the EVLW.     

Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water

OBJECTIVE: Pulmonary edema is a severe and often life-threatening condition. The diagnosis of pulmonary edema and its quantification have great clinical significance and yet can be difficult. A new technique based on thermodilution measurement using a single indicator has recently been developed (PiCCO, Pulsion Medical Systems, AG Germany). This method allows the measurement of extravascular lung water and thus can quantify degree of pulmonary edema. The technique has not been compared with a gold standard, gravimetric measurement of extravascular lung water. Therefore, the objective of this study was to determine the ability of extravascular lung water measurement with the PiCCO to reflect the extravascular lung water as measured with a gravimetric technique in a dog model of pulmonary edema. DESIGN: Prospective, randomized animal study. SETTING: A university animal research laboratory. SUBJECTS: Fifteen mongrel dogs (n = 5/group) weighing 20-30 kg. INTERVENTIONS: The dogs were anesthetized and mechanically ventilated. Five dogs served as controls; in five dogs hydrostatic pulmonary edema was induced using inflation of a left atrial balloon combined with fluid administration to maintain a high pulmonary artery occlusion pressure; and in five dogs pulmonary edema was induced by intravenous injection of oleic acid. After a period of stabilization in a state of pulmonary edema, extravascular lung water was measured with the PiCCO monitor. The animals were then killed, and extravascular lung water was measured using a gravimetric technique. MEASUREMENTS AND MAIN RESULTS: There was a very close (r =.967, p <.001) relationship between transpulmonary thermodilution and gravimetric measurements. The measurement with the PiCCO was consistently higher, by 3.01 +/- 1.34 mL/kg, than the gravimetric measurement. CONCLUSIONS: Measurement of extravascular lung water using transpulmonary thermodilution with a single indicator is very closely correlated with gravimetric measurement of lung water in both increased permeability and hydrostatic pulmonary edema.     

经肺热稀释技术对急性肺损伤犬血管外肺水的监测

目的探讨经肺热稀释技术对不同原因急性肺损伤（ALI）血管外肺水（EVLW）测定的准确性。方法18只杂种犬随机分为正常组、外源性急性肺损伤组和内源性急性肺损伤组,每组6只,通过静脉注射油酸制备外源性ALI模型,气管内注入十六烷磺基丁二酸钠盐制备内源性ALI模型,然后分别向肺内灌注一定量的生理盐水,采用经肺热稀释法在灌注的前后测定EVLW,观察灌注前后EVLW变化与所灌注生理盐水量之间相关性。结果正常肺组织EVLW含量为（254．5±413．0）ml,肺泡灌注前后EVLW的变化与实际肺泡灌注生理盐水量之间具有良好的相关性（r=0．986,P〈0．01）;外源性ALI组EVLW含量为（483．3±11．5）ml,与正常组比较差异有统计学意义（P〈0．01）,ALI组肺泡灌注前后EVLW的变化与实际肺泡灌注生理盐水量之间也具有良好的相关性（r=0．978,P〈0．01）。内源性ALI组EVLW含量为（526．2±12．9）ml,与正常组比较差异有统计学意义（P〈0．01）。肺内源性ALI组肺泡灌注前后EVLW的变化与实际肺泡灌注生理盐水量之间具有较好的相关性（r=0．890,P〈0．01）,但不如外源性ALI组相关性高。结论经肺热稀释技术对EVLW的监测具有良好的准确性,但不同原因导致的EVLW增加的监测准确性不同。     

Factors influencing the estimation of extravascular lung water by transpulmonary thermodilution in critically ill patients

OBJECTIVE: To investigate factors that may influence the estimation of extravascular lung water (EVLW) with a single (cold) indicator compared with assessment using two indicators (thermo-dye dilution). DESIGN: Post hoc analysis of an electronic hemodynamic database. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Forty-eight critically ill patients monitored by the thermo-dye dilution technique in the postoperative period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The EVLW was simultaneously assessed by the thermo-dye dilution technique (EVLWref) and estimated by transpulmonary thermodilution (EVLWest). EVLWref index ranged between 1 and 40 mL/kg (mean 10 +/- 7 mL/kg) and EVLWest between 2 and 39 mL/kg (mean 9 +/- 6 mL/kg). EVLWref was closely correlated (r = .96) with EVLWest. The mean difference (bias) between EVLWref and EVLWest was -0.5 +/- 1.9 mL/kg. The bias was not influenced by the weight, height, body surface area, body mass index, Pao2, intrathoracic blood volume, cardiac output, or dosage of vasoactive agents. In contrast, the bias was slightly but significantly influenced by EVLWref, Pao2/Fio2 ratio, tidal volume, and level of positive end-expiratory pressure. CONCLUSIONS: In our surgical intensive care unit population, the estimation of EVLW by transpulmonary thermodilution was influenced by the amount of EVLW, the Pao2/Fio2 ratio, the tidal volume, and the level of positive end-expiratory pressure. However, compared with the double indicator method, transpulmonary thermodilution estimation remained clinically acceptable even in patients with severe lung disease.     

Estimation of left ventricular systolic function by single transpulmonary thermodilution

Objective The single-indicator transpulmonary thermodilution technique (PiCCO system) provides two derived indices of cardiac systolic function: the cardiac function index and the global ejection fraction. We used transesophageal echocardiography to compare theses indices with left ventricular fractional area of change only for patients with no isolated right ventricular dysfunction. (The global cardiac systolic function may be decreased despite preserved left ventricular function in this situation.)Design Prospective, open, clinical study.Setting Intensive care unit (ICU) in a university hospital.Patients Thirty-three mechanically ventilated patients.Intervention Left ventricular fractional area of change (LVFAC) was measured using transesophageal echocardiography. The cardiac function index (CFI) and the global ejection fraction (GEF) were determined from transpulmonary thermodilution-derived cardiac output and thoracic volumes.Measurements and main results Transesophageal echocardiography identified 3 patients with isolated right ventricular failure (PiCCO underestimated LVFAC in this situation). Significant correlations were established between LVFAC and CFI (r=0.87, n=30, p<0.0001) or GEF (r=0.82, n=30, p<0.0001). The mean differences between measured LVFAC and LVFAC estimated with CFI or GEF were 0.8±8.5% (range: –17 to 14%) and 0.8±9.0% (range: –21 to 19%), respectively. Area under the receiver operating characteristics curves for the estimation of LVFAC 40% using CFI or GEF was 0.92. CFI >4 and GEF >18% estimated LVFAC 40% with respective sensitivities of 86 and 88% and specificities of 88 and 79%. Significant correlations were established between changes of LVFAC and CFI/GEF over time.Conclusions In mechanically ventilated ICU patients, PiCCO-derived cardiac function index and global ejection fraction provide reliable estimations of LV systolic function but may underestimate it in the cases of isolated right ventricular failure.     

Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock

Introduction  

The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock.     

Precision of the transpulmonary thermodilution measurements

Introduction  

We wanted to determine the number of cold bolus injections that are necessary for achieving an acceptable level of precision for measuring cardiac index (CI), indexed global end-diastolic volume (GEDVi) and indexed extravascular lung water (EVLWi) by transpulmonary thermodilution.     

胸腔积液对经肺热稀释法血管外肺水监测准确性的影响

目的 探讨胸腔积液对经肺热稀释技术监测血管外肺水(EVLW)准确性的影响.方法 6只北京长条猪通过静脉注射油酸制备急性肺损伤(ALI)模型,然后先后分别向肺泡内及胸膜腔内灌注一定量的生理盐水,在两种不同灌注方式的前后均采用经肺热稀释法测定EVLW,观察肺泡灌注前后EVLW变化与所灌注生理盐水量之间的相关性,同时观察胸腔内灌注生理盐水前后EVLW含量的变化.结果 基础状态下正常肺组织EVLW含量(276.6±10.8)mL,ALI模型成功后EVLW含量(378.9±12.2) mL,与基础状态比较差异有统计学意义(P＜0.001);肺泡灌注前后EVLW的变化与实际肺泡灌注生理盐水量之间具有良好的相关性(r=0.973,P＜0.001);胸腔内灌注前后测定的EVLW含量无变化(P＞0.05).结论 经肺热稀释技术对血管外肺水的监测具有良好的准确性,胸腔积液对血管外肺水监测准确性无影响.     

Extravascular lung water to blood volume ratios as measures of permeability in sepsis-induced ALI/ARDS

Objective We studied the relationship, and the effect of fluid loading on this, between the ratio of extravascular lung water (EVLW) to intrathoracic/pulmonary blood volumes (ITBV, PBV) and the radionuclide pulmonary leak index (PLI) to protein during sepsis-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS).Design and setting A prospective observational study, in the intensive care unit of a university hospital.Patients Twenty-two consecutive mechanically ventilated patients with sepsis-related ALI/ARDS from pneumonia (n = 12) or extrapulmonary sources (n = 10), without elevated cardiac filling pressures.Intervention Crystalloid (1700–1800 ml) or colloid (1000–1800 ml) fluid loading until target filling pressures.Measurements and results Protein permeability was assessed noninvasively over the lungs with help of ⁶⁷Ga-labeled transferrin and ^99mTc-labeled red blood cells (Pulmonary leak index, upper limit normal 14.1 × 10⁻³ /min) and EVLW and blood volumes by the thermal-dye transpulmonary dilution technique before and after fluid loading. Prior to fluids the pulmonary leak index related to the ratio of EVLW/ITBV and EVLW/PBV (r _s = 0.46) particularly when the pulmonary leak index was below 100 × 10⁻³ /min and in extrapulmonary sepsis (PLI vs. EVLW/PBV r _s = 0.71). Fluid loading did not alter EVLW, EVLW/ITBV, or EVLW/PBV or the relationship to PLI.Conclusion The data demonstrate that EVLW/ITBV or EVLW/PBV are imperfect measures of increased protein permeability in mechanically ventilated patients with sepsis-induced ALI/ARDS particularly when the PLI is severely increased and during pneumonia, independent of fluid status.     

Validation of a new transpulmonary thermodilution system to assess global end-diastolic volume and extravascular lung water

Introduction  

A new system has been developed to assess global end-diastolic volume (GEDV), a volumetric marker of cardiac preload, and extravascular lung water (EVLW) from a transpulmonary thermodilution curve. Our goal was to compare this new system with the system currently in clinical use.     

Iced versus room temperature injectate for assessment of cardiac output, intrathoracic blood volume, and extravascular lung water by single transpulmonary thermodilution

PURPOSE: To assess the accuracy of iced versus room (RT) temperature single transpulmonary thermodilution (STPD) measurements for cardiac output, intra-thoracic blood, volume and extravascular lung water. MATERIALS AND METHODS: We studied 15 critically ill patients in a surgical intensive care unit with sepsis/septic shock (n = 8), pancreatitis (n = 2), acute liver failure (n = 2), orthotopic liver transplantation (n = 2) and lung resection (n = 1). All patients were sedated and mechanically ventilated. A 4-French femoral arterial catheter was inserted into each patient and connected to the pulse contour computer system (PiCCO). The pulse contour computer was then consecutively calibrated by triplicate STPD with 20 mL of RT and iced saline solution. The measurements with RT injectate were performed with a special in-line sensor adapted for measurement with RT injectate. All measurements were completed in less than 10 min. RESULTS: A total of 144 measurements were carried out. Linear regression analysis revealed good correlation between the two methods [r = 0.95; r = 0.91 and r = 0.97 for iced v RT cardiac index (CI), intrathoracic blood volume index (ITBVI) and extravascular lung water index (ELWI) respectively]. The bias +/- 2 * standard deviation of difference was -0.2 +/- 0.7 L/min/m2 for CIIT v CIRT; -4,9 +/- 194 mL/m2 for ITBVIIT v ITBVIRT and -0.535 +/- 1,5 mL/kg for ELWIIT v ELWIRT. CIRT and ELWIRT were measured slightly higher compared to IT injectate (P <.05). CONCLUSIONS: CI, ITBVI, and ELWI assessed by STPD with RT injectate are well correlated with measurements by iced injectates. According to our results room temperature injectates can be used in critically ill patients for assessment of CI, ITBVI and ELWI, which is more convenient for both the patients and medical staff and is also less expensive.     

Silencing airway epithelial cell-derived hepcidin exacerbates sepsis-induced acute lung injury

Introduction

The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury.

Methods

Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated.

Results

The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice.

Conclusions

Airway epithelial cell-derived hepcidin plays an important role in CLP-induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.     

Neutralization of osteopontin attenuates neutrophil migration in sepsis-induced acute lung injury

IntroductionSepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis.MethodsSepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 μg/mouse, was intravenously injected at the time of CLP. After 20 hours, the expression of OPN and proinflammatory cytokines in tissues and plasma was examined by real-time PCR, Western blot, and ELISA. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and the lung myeloperoxidase (MPO) levels were determined by colorimetric assays. Lung damage and neutrophil infiltrations were determined by histological H&E and Gr-1 staining, respectively. The effect of recombinant mouse OPN (rmOPN) on human neutrophil-like cell (HL-60) migration was performed by Boyden chamber assays and the involvement of intracellular signaling molecules in HL-60 cells was revealed by Western blot.ResultsAfter 20 hours of sepsis, mRNA and protein levels of OPN were significantly induced in lungs, spleen, and plasma. Treatment with an anti-OPN Ab in septic mice significantly reduced the plasma levels of ALT, AST, and LDH, and the proinflammatory cytokines IL-6, IL-1β and the chemokine MIP-2, compared with the vehicle group. Similarly, the lung mRNA and protein expressions of proinflammatory cytokines and chemokine were greatly reduced in anti-OPN Ab-treated animals. The lung histological architecture, MPO and neutrophil infiltration were significantly improved in anti-OPN Ab-treated mice compared with the vehicle animals. Treatment of rmOPN in HL-60 cells significantly increased their migration, in vitro. The neutrophils treated with rmOPN remarkably increased the levels of phospho focal adhesion kinase (pFAK), phospho extracellular signal-regulated kinase (pERK) and phospho p38.ConclusionsOur findings clearly demonstrate the beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic strategy in sepsis.