Refresher Course. European Society of Anaesthesiologists BEDSIDE MEASUREMENT OF EXTRA-VASCULAR LUNG WATER TECHNIQUE AND CLINICAL IMPLICATIONS 12 RC 9

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1 European Society of Anaesthesiologists BEDSIDE MEASUREMENT OF EXTRA-VASCULAR LUNG WATER TECHNIQUE AND CLINICAL IMPLICATIONS Azriel PEREL Department of Anesthesiology and Intensive care, Sheba Medical Center, Tel Aviv University, Tel Hashomer, 52621, Israel Refresher Course 12 RC 9 Sunday June 1, 2003 Euroanaesthesia Glasgow DISCLOSURE:THE AUTHOR IS A MEMBER OF THE MEDICAL ADVISORY BOARD OF PULSION MEDICAL SYSTEMS. Pulmonary edema (PE) is defined as the abnormal accumulation of fluid in the extravascular space of the lung. It is associated with disturbances of lung volume, lung mechanics and gas exchange, and always represents a potential threat to life. Although the excess of extra-vascular lung water (EVLW) is such a frequent component of the pathophysiology of criticallly ill patients, and although so much effort is being directed at its detection, assessment and treatment, current clinical practice does not include its routine quantification. Indeed, early recognition and differential diagnosis of both hydrostatic and increased-permeability PE may be challenging, since its most common clinical manifestations, such as as dyspnea, reduced lung compliance and hypoxemia, are nonspecific, and may appear rather late. Rather than measure EVLW, we normally assess it indirectly through the chest X-ray and the arterial blood gases, although there is ample evidence that these parameters poorly reflect lung water [1,2]. Very often there is a characteristic lag period between edema formation and the typical radiological changes, which often do not appear until EVLW doubles or triples. In addition, the technical difficulties associated with the chest roentgenogram, such as quality obtained under routine bedside conditions, position of the patient, lung volume and the presence of other radiographic abnormalities (pleural effusion, COPD), may explain the significant variability of individual interpretations [3]. Other imaging techniques for the assessment of PE, like CT scan, nuclear magnetic resonance imaging, and positron emission tomography, are not available at the bedside, and the information obtained is limited to one point in time. The method that was most frequently used to measure EVLW at the bedside was the double indicator (thermo-dye) dilution technique. This technique is based on the injection of a cold dye (indocyanine green) through a central venous line, and the detection of the simultaneous dye- and thermodilution curves in the arterial circulation. However, the double indicator dilution technique is relatively time-consuming, cumbersome and relatively expensive, and therefore has not been widely incorporated into clinical practice. Nevertheless, in many recent studies this technique is still being used to measure EVLW in a variety of patients [4, 5, 6]. The most recent development in the bedside measurement of EVLW has been the introduction of the transpulmonary thermodilution technique, which uses a single (cold) indicator only. This technique is based on a bolus injection of saline (cold or room-temperature) through a central venous line with the thermodilution curve measured by a thermistor-tipped arterial catheter. Improved analysis of the transpulmonary thermodilution curve yields, beside the measurement of cardiac output, volumetric parameters of preload (global end-diastolic and intrathoracic blood volumes) as well as the EVLW value itself (normal values are 4-7 ml/kg). The method has been validated against the double indicator dilution technique [7,8], as well as against the gravimetric method of EVLW measurement [9], which is the gold standard for this parameter. Hence the availability of a simple less-invasive technique for EVLW measurement merits a re-examination of the need and potential benefit of the bedside measurement of this important parameter. THE ROLE OF EVLW IN THE DEFINITION AND DIAGNOSIS OF ARDS/ALI One of the major fields in which quantification of lung water can be of significant value is in the definition, diagnosis and assessment of ARDS and acute lung injury (ALI). The first major effort to accurately define ARDS started in 1988, when the lung injury score (LIS) was proposed as a system to grade the extent of lung injury. The four components of the LIS include the chest roentgenogram, hypoxemia, PEEP level, and respiratory system compliance. Subsequent studies found, however, that neither the LIS nor its individual components were predictive of mortality. The problems encountered in trying to define ARDS and ALI by the LIS were also addressed by the North American-European consensus conference on ARDS [10]. That conference concluded that both definitions of ALI and ARDS require the presence of bilateral pulmonary 181

2 infiltrates on the chest radiograph, and that in the case of clinical ALI, the cutoff for arterial oxygenation is a PaO2 /FiO2 < 300, whereas for ARDS, the PaO2 /FiO2 cutoff is < 200. However, differentiating ALI and ARDS by oxygenation criteria alone is associated with many problems which were clearly described in a summary of the 1998 conference on acute lung injury [11]. The dissatisfaction with the criteria for the definition of ALI and ARDS prompted the participants of that conference to ask for better guidelines for interpretation of the chest radiograph, since the term bilateral pulmonary infiltrates consistent with pulmonary edema was considered to be qualitative and non-specific [11]. The well known difficulties that have always been associated with the assessment of pulmonary edema based on the chest X-ray, were highlighted again by the study of Rubenfeld and al, which found considerable disagreement and high interobserver variability among ARDS experts regarding what constitutes bilateral pulmonary infiltrates in chest X-rays [2]. In summary, it seems that both the Lung Injury Score and the PaO2 /FiO2 ratio as criteria of ARDS or ALI are still a source of constant debate, and better criteria should be sought for this purpose. A different approach was suggested by Schuster who criticized the current algorithm to diagnose ARDS mainly because of its exclusion of pulmonary edema due to lung injury and left atrial hyprtension, its dependence on the unreliable clinical assessment of heart failure, and its failure to provide adequate measure of severity-of-injury by the PaO2/FiO2 ratio [12]. In addition, impaired oxygenation neither help identify the cause of pulmonary edema, nor help predict its outcome, since the degree of hypoxemia which is used as a major criterion for the definition of ALI and ARDS is not a function of lung injury alone, but involves multiple other factors. For all these reasons Schuster suggested that the definition of ALI should include bilateral pulmonary edema and increased pulmonary vascular permeability, and that pulmonary edema should be measured by clinically appropriate methods, normal values for EWLW being less than 7ml/Kg. The need for the inclusion of EVLW in the definition of ARDS has been recently demonstrated in a group of patients who fulfilled the criteria of ARDS/ALI, and yet in 30% of them EVLW values were found to be normal [13]. The ability to measure pulmonary edema and its resolution may also make EVLW an appropriate outcome variable of ARDS, since pulmonary edema is a consequence of lung injury. EVLW measurement may be used not only to assess the degree of PE, but also to follow the rate of clearance of PE fluid which has been found to be associated with better clinical outcome. Indeed the ability to accurately quantify and follow the changes in EVLW may at times be more informative than the dubious distinction between cardiogenic and non-cardiogenic pulmonary edema. Such distinction is very difficult in clinical practice since current methods that assess lung vascular permeability are invasive and difficult to apply [11]. The presence of high protein content in the pulmonary edema fluid by itself (in the rare cases when it can be easily collected) does not necessarily indicate a more severe prognosis if repeated measurements of EVLW show that pulmonary edema is resolving fast. In addition, calculating the ratio of EVLW to the intra-thoracic blood volume (ITBV) or to the pulmonary blood volume (PBV), which are both measured by the transpulmonary thermodilution method in addition to EVLW, may prove to be a useful tool of assessing pulmonary microvascular permeability in critically ill patients, as has been very recently reported [5]. The rationale of using the EVLW/ITBV or the EVLW/PBV ratios as a measure of pulmonary microvascular permeability is based on the fact that EVLW is increased in both permeability and hydrostatic pulmonary edema. Since the increase in EVLW in hydrostatic pulmonary edema is due to an increase in pulmonary blood volume and pressure, the ratio of EVLW to PBV should be much lower than in permeability pulmonary edema. We have recently found in dogs that the mean EVLW/ITBV ratio in oleic-acid induced PE was , compared to in cardiogenic PE (left atrial balloon) and in controls [9]. This parameter may therefore be useful to discriminate between hydrostatic and permeability edema, as well as to assess the effects of various disease states and therapeutic interventions on pulmonary vascular permeability. POSTOPERATIVE PULMONARY EDEMA Pulmonary edema in the postoperative period is a relatively rare but potentially lethal event. Cooperman and Price described 40 cases of PE and calculated that its overall incidence is 1:4500 [14]. In their series of 1004 patients that formed the basis of the cardiac risk index, Goldman et al found 36 patients who developed perioperative PE, 58% of whom had no prior history of congestive heart failure [15]. The mortality in this subgroup was 57%, whereas those patients who developed heart failure without PE had a lower overall mortality of 15%. More recently, Arrief found among 8,195 major operations a 7.6% incidence of PE with a mortality of 11.9% [16]. The true incidence of postoperative PE is probably higher, since many patients have an increase in EVLW without overt alveolar PE. According to Arieff s estimates, in the US alone there may be 622,000 annual cases of postoperative PE with 74,000 deaths. Arieff described a group of 13 patients who developed postoperative PE which was associated with a net fluid retention of at least 67 ml/kg in the initial 24 postoperative hours. Arieff found no measurement, laboratory value, or clinical finding that was predictive of 182

3 impending PE, and the most common clinical manifestation following its onset was cardiorespiratory arrest. Arieff concludes that the monitoring systems currently in use neither detect nor predict impending PE, and as yet, there are no known panic values for excessive fluid administration or retention. The direct measurement of EVLW in high-risk patients undergoing surgery may certainly improve the early detection and appropriate treatment of this serious complication. EVLW AND FLUID MANAGEMENT IN CRITICALLY ILL PATIENTS Critically ill patients are often in need of large amounts of fluids in order to stabilize their cardiovascular system. Moreover, it is still quite prevalent to try and optimize cardiac output to normal or supra-normal values by aggressive fluid resuscitation. However, aggressive fluid resuscitation may increase EVLW, impair respiratory function, prolong the period of mechanical ventilation and become a reason in itself for increased morbidity and mortality. Currently, the most commonly used monitor for guidance of fluid therapy in critically ill patients is the pulmonary artery catheter (PAC). The filling pressures that are measured by the PAC, namely the CVP and the PCWP, have however been repeatedly shown to reflect poorly both volume status and volume responsiveness [17, 18]. It is therefore quite possible that the increased morbidity and mortality that have been repeatedly shown to be associated with the use of the PAC may be due, in part at least, to an aggressive style of treatment [19]. Polanczyk et al [20] have shown that in patients undergoing non-cardiac surgery, the PAC was associated with a significantly higher rate of postoperative congestive heart failure (odds ratio 2.9) and a longer average length of hospital stay. Another study, which is very suggestive of the fact that the use of the PAC is associated with overzealous fluid therapy, and hence with increased morbidity and mortality, is that of Sandison et al [21]. In 145 non-elective repairs of abdominal aortic aneurysms at 2 hospitals, under the care of a single vascular surgeon, mortality was higher at hospital 2 than hospital 1 (28% vs. 9%, p<0.0068). Patients APACHE scores, operative time, blood loss, etc, were similar in both hospitals. PACs were placed in 18% of patients in hospital 1 compared with 96% at hospital 2. Patients at hospital 2 received more crystalloid, more colloid (median 4775 vs ml) and more inotropes than those at hospital 2 in their first 24 h on ICU. Hence, the hospital that used less PACs and administered less fluids showed a reduced mortality. The ability to monitor EVLW in critically ill patients who are hemodynamically unstable may therefore contribute significantly to decision-making during fluid resuscitation, since an increasing EVLW values may serve as an early warning sign against overhydration and the development of pulmonary edema. A clinical approach that is based on the monitoring of preload and cardiac output only may not be enough in this patient population. The monitoring of EVLW may have an even more pronounced benefit in the guidance of fluid therapy in ARDS patients, which has been a subject of much controversy in critical care medicine. The most common approach is keeping the patient dry by active efforts to achieve minimally positive fluid balance [22]. Many studies provide evidence that outcome is improved in patients with pulmonary edema in whom such approach was taken. Schuller et al [23] found that medical ICU patients with pulmonary edema who survived had no significant fluid gain or increases in EVLW. Patients with a low fluid gain (<1 L) had a better chance of survival, a shorter duration of mechanical ventilation requirement, and a shorter ICU stay compared with patients with a highly positive fluid balance. They concluded that increased fluid administration is partially responsible for some patients poor outcomes, and that if it is hemodynamically tolerated, a strategy of keeping patients dry is appropriate. In another study, patients with an initial EVLW greater than 14 ml/kg had a significantly greater mortality (87%) than patients with normal initial EVLW values (41%) (p < 0.05) [24]. Using EVLW to guide the management of patients with pulmonary edema has also been shown to reduce the duration of mechanical ventilation and length of stay in the intensive care unit [25]. Very recently, Sakka et al found in 373 critically ill patients that EVLW, measured by the thermal-dye technique, correlated well with survival and was an independent predictor of prognosis [26]. In an accompanying editorial, Matthay addresses the question whether measurement of EVLW is useful for research purposes or for the clinical management of patients with pulmonary edema [27]. He mentions that the potential benefit of reducing the amount of EVLW in patients with ARDS is being studied in a large multicenter prospective NIH-supported clinical study, and that if the results of this study will demonstrate that an aggressive approach to diuresis is beneficial, then there might be reason to measure EVLW in patients with ALI. He further recommends that while awaiting the results of the NIH clinical trial of ARDS, investigators who are interested in measuring EVLW should focus on patients with ARDS and sepsis, in whom an increase in EVLW is likely to be a major determinant of outcome. In view of the simplicity of EVLW measurement with the transpulmonary single-indicator dilution technique, and based on our own extensive clinical experience with this method, it seems that this parameter is of tremendous usefulness in the management of such patients. 183

4 EVLW MEASUREMENT THEORY AND TECHNIQUE The direct measurement of EVLW can be done with a double (thermal-dye) indicator dilution technique, using a cold solution with indocyanine green dye. The freely diffusable indicator ( cold ) and the plasma-bound intravascular indicator (indocyanine green) are injected simultaneously as a bolus of cold dye. EVLW is calculated from the mean transit times of the indicators, by subtracting the distribution volume of the dye from that of the thermal indicator (see below). This technique requires the use of fiberoptic intra-arterial catheteras well as the use of the relatively expensive dye, and has not gained wide clinical use. Since the introduction of the PiCCO monitor (Pulsion Medical Systems, Munich, Germany) which uses the transpulmonary thermodilution technoque, EVLW can be measured at the bedside by the using a single (cold) indicator. A bolus injection of cold or room-temperature saline is injected via a CVP catheter, and a thermistortipped catheter, placed in the femoral, axillary or brachial arteries is used to measure the thermodilution curve. This transpulmonary indicator dilution technique provides, in addition, the measurement of cardiac output (CO) and volumetric preload parameters (ITBV and GEDV, see below). By using the pulse contour method this monitor also provides continuous CO measurement, as well as parameters of volume responsiveness (stroke volume and pulse pressure variations). The transpulmonary thermodilution technique is base on the measurement of the mean transit times (MTt) of the indicator from the site of injection to the site of measurement. The product of CO and MTt is the total volume of distribution of the indicator (cold saline), so called intrathoracic total thermal volume (ITTV) (fig 1): ITTV=CO MTt (1) According to Newman s theory, if an indicator is injected into a series of mixing chambers, the volume of the largest mixing chamber between the point of injection and point of detection is given by the product of the CO and the exponential decay time of the signal (DSt). When the indicator is injected into the right atrium and measured in a systemic artery, the largest mixing chamber is the pulmonary thermal volume (PTV): PTV= CO DSt (2) Subtracting the PTV from the ITTV provides the value of the global end-diastolic volume (GEDV). The GEDV enables the calculation of the the intrathoracic blood volume (ITBV) which has been shown to be consistently larger than the GEDV by 25% [8]. Therefore, the ITBV is estimated as 1.25 x GEDV, the linear regression being ITBV= a GEDV + b (3) where a- specific coefficient = 1,16; b-specific constant=86ml/m 2 [8]. The EVLW is the difference between ITTV and ITBV: EVLW=ITTV-ITBV (4) The normal ranges are GEDVI= ml/m 2, ITBVI= ml/m 2, EVLWI= 4-7 ml/kg. The method has been validated against the double indicator dilution technique [7,8], as well as against the gravimetric method of EVLW measurement [9], which is the gold standard for this parameter. In this last study, which was done in dogs with cardiogenic and non-cardiogenic PE, the correlation coefficient (R 2 ) between the PiCCO and the gravimetrically measured EVLW was 0.952, the precision (mean difference between measurements) was 3.28 ± 2.0 ml/kg, and the limits of agreement (mean difference ± 2SD) from 0.72 to 7.28 ml/kg [9]. Hence, even though EVLW values that were measured with the PiCCO showed a slight consistent overestimation compared with gravimetric values, we found the transpulmonary thermodilution technique to be provide extremely reliable values of EVLW. 184

5 FIGURE 1 C0 x MTt = GEDV + PBV + EVLW EVLW RA RV PBV LA LV C0 x DSt = PBV + EVLW EVLW PBV GEDV RA RV LA LV ITBV = GEDV + PBV = 1.25 x GEDV RA RV PBV LA LV EVLW = (CO x MTt) - ITBV EVLW Figure 1. Assessment of global end-diastolic volume (GEDV) and extravascular lung water 9EVLW) by transpulmonary thermodilution. CO = cardiac output, MTt = mean transit time, RA = right atrium, RV = right ventricle, PBV = pulmonary blood volume, LA = left atrium, LV = left ventricle, DSt = downslope time, ITBV = intrathoracic blood volume. SUMMARY The vast majority of ICU and high risk surgical patients undergo central venous and arterial cannulation as part of their standard management. The use of a thermistor-tipped arterial catheter can therefore easily enable the use of the transpulmonary single-indicator dilution technique. The measurement of EVLW as part of routine monitoring of these patients may contribute to early identification of pulmonary edema, aid in decisions regarding fluid management in critically ill patients, and allow a better management of patients in respiratory failure. REFERENCES 1. Halperin BD, Feeley TW, Mihm FG, et al. Evaluation of the portable chest roentgenogram for quantitating extravascular lung water in critically ill adults. Chest 1985; 88: Demling RH, Lalonde C, Ikegami K. Pulmonary edema: pathophysiology, methods of measurement, and clinical importance in acute respiratory failure. New Horizons 1993; 1: Rubenfeld GD, Caldwell E, Granton J, et al. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116; Von Spiegel T, Giannaris S, Wietasch GJK, et al. Effects of dexamethasone on intravascular and extravascular fluid balance in patients undergoing coronary bypass surgery with cardiopulmonary bypass. Anesthesiology 2002; 96: Holm C, Tegeler J, Mayr M, et al. Effect of crystalloid resuscitation and inhalation injury on extravascular lung water. Chest 2002; 121:

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