Extravascular lung water volume measurement by a novel lithium-thermal indicator dilution method: comparison of three techniques to post-mortem gravimetry
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To compare the lithium-thermal double indicator dilution (Li-thermal), indocyanine green-thermal double indicator dilution (ICG-thermal), single thermal indicator dilution (single-thermal) and gravimetric techniques of extravascular lung water volume (EVLW) measurement in porcine models of acute lung injury.
Two animal models designed to invoke a systemic inflammatory response.
A total of 12 immature Deutsches Landschwein pigs.
Extravascular lung water volume was measured at four time points using Li-thermal, ICG-thermal and single-thermal techniques. Measurements were performed using existing technology according to manufacturer’s instructions. Post-mortem gravimetric EVLW measurements were performed by measuring wet and dry mass of lung tissue. Measurements were compared using the Bland–Altman method. Data are presented as mean (SD).
Measurements and main results
Data were collected in 12 animals and comparison between all 4 techniques was possible in 10 animals. EVLW measured by gravimetry was 9.2 (±3.0)ml kg−1. When compared to gravimetry, both Li-thermal and ICG-thermal techniques showed minimal bias but wide limits of agreement (LOA) [Li-thermal: bias −1.8 ml kg−1 (LOA ± 13.1); ICG-thermal bias −1.0 ml kg−1 (LOA ± 6.6)]. Comparison between the single-thermal and gravimetric methods identified both considerable bias and wide LOA [+8.5 ml kg−1 (LOA ± 14.5)].
Clinically significant differences between EVLW measurements obtained with the gravimetric method and three in vivo indicator dilution techniques were identified. While none of the techniques could be considered ideal, the ICG-thermal method appeared more reliable than either the Li-thermal or single thermal techniques. Further research is required to determine whether the accuracy of the prototype Li-thermal technique can be improved.
KeywordsCardiovascular monitoring Intrathoracic blood volume Extravascular lung water Lithium indicator dilution Gravimetry Acute lung injury
Expansion of the extravascular lung water (EVLW) volume during critical illness is associated with increased morbidity and mortality . Improved clinical outcomes may be achieved if therapy is adjusted in response to measurements of EVLW volume . Clinical assessment and chest radiography appear to be unreliable guides to EVLW volume . While a number of techniques have been developed to measure EVLW volume at the bedside, none of the available methods can be considered ideal.
One approach may be to use trans-pulmonary lithium indicator dilution to measure ITBV and, in combination with thermodilution, EVLW volume. Lithium chloride satisfies many of the criteria for an ideal indicator , having a good safety profile  and small displacement volume . Studies have demonstrated minimal lithium indicator loss from the vascular compartment during the measurement period i.e. one circulation time [9, 12]. It is therefore possible that ITBV measurement with lithium chloride might provide a more convenient and reliable alternative to commercially available technology. The aim of this study was to compare the ICG-thermal and single-thermal methods of EVLW volume measurement to the prototype lithium-thermal (Li-thermal) method and all of these to the gravimetric reference technique in porcine models of acute lung injury.
Materials and methods
This study was performed on two porcine models designed to invoke systemic inflammatory and associated cardiovascular and respiratory responses. These were a model of faecal peritonitis induced septic shock and an aortic balloon occlusion model of visceral organ ischaemia. The observational study reported here was incorporated into two ongoing interventional laboratory studies to minimise animal use. The study protocols, described in detail in the Supplementary material, were approved by the Animal Care Committee of the University of Ulm and the Regierungspräsidium Tübingen, Germany.
Post-mortem EVLW volume was calculated by a gravimetric method described in detail in the supplementary material. Indicator dilution measurements were made at four time points in each model. Pre-intervention measurements were made in both models, then at 2, 4 and 24 h in the sepsis model and at 1, 4 and 8 h in the visceral organ ischaemia model. The final indicator dilution measurement performed immediately before killing was used for comparison with gravimetry. ICG-thermal measurements were made using the COLD-Z system, (Pulsion Medical Systems, Munich, Germany) following central injection of 10 ml of iced 5% dextrose solution containing 25 mg of ICG according to the manufacturer’s instructions . The arterial changes in temperature and ICG concentration were measured using a thermistor tipped spectrophotometric catheter (PV 2024; Pulsion Medical Systems, Munich, Germany). Lithium dilution measurements were made using the LiDCOplus system (LiDCO Ltd, Cambridge, UK) following central injection of 0.3 mmol (2 ml) of lithium chloride . The arterial lithium ion concentration was measured using an external lithium ion sensor attached to the femoral arterial catheter via a 0.75 ml extension tube. Flow of arterial blood across the lithium sensor was regulated using a battery powered peristaltic pump. Time of injection was standardised through the use of a visual countdown on the monitor. Lithium cardiac output and lithium mean transit time (MTT) were used to calculate ITBV. Lithium cardiac output and COLD-Z saline thermodilution mean transit time were used to calculate lithium-thermal ITTV. Single-thermal dilution measurements of ITBV, ITTV and therefore EVLW volume were made using the PiCCO system (Pulsion Medical Systems, Munich) following central injection of 10 ml of ice cold saline according to the manufacturer’s instructions . The temperature change of arterial blood was measured using a thermistor tipped catheter (PV2015L20; Pulsion Medical Systems, Munich, Germany). Cardiac output was also measured using a pulmonary artery (PA) catheter at each time-point by injecting 10 ml iced normal saline at the end of expiration (Edwards Lifesciences, Irvine, USA). Three measurements were obtained and then averaged using a cardiac output computer (Sat-2; Baxter Edwards Lifesciences, Irvine, USA). All indicator and thermodilution measurements were performed within a period of 10 min at each time point.
We calculated that, with a type I error rate of 5% and a type II error rate of 10%, 48 comparisons in 12 animals would allow the detection of a 1.0 ml kg−1 (SD ±2.0 ml kg−1) difference in EVLW volume between the Li-thermal and ICG-thermal techniques. ITBV and EVLW volume measurements were compared using the technique of Bland and Altman with comparisons presented as bias [95% limits of agreement (LOA)]. EVLW volume measurements comparing gravimetry to all three techniques were also analysed using linear regression. Percentage error was calculated according to the method reported by Critchley as the limit of agreement (±2SD) of the bias divided by the mean cardiac output from the two methods under comparison. Data are presented as mean (SD) where normally distributed and median [inter-quartile range (IQR)] where not normally distributed. Parametric data were compared using the unpaired t test and non-parametric data were compared with the Mann–Whitney test. Differences in measurements of EVLW volume, ITBV and cardiac output over time were compared using repeated measures analysis of variance (ANOVA) with Tukey’s correction. Analysis was performed using GraphPad Prism version 4 (GraphPad software, San Diego, USA). Significance was set at P < 0.05.
Mean values of ITBV were 28.9 ml kg−1 (±6.2) for the ICG-thermal method, 21.7 ml kg−1 (±5.9) for the Li-thermal method and 24.6 ml kg−1 (±6.1) for the single-thermal method (n = 40). Measurements of ITBV were significantly less than those taken with the ICG-thermal technique for both the lithium-thermal [bias −7.3 ml kg−1 (LOA ± 16.4); P < 0.001] and single-thermal techniques [bias −4.5 ml kg−1 (LOA ± 10.4); P < 0.01] (Supplementary Fig. 3).
Mean cardiac output measured using the PA catheter was 4.5 l min−1 (±1.6) (n = 40). Equivalent values for the techniques under investigation were 4.8 l min−1 (±1.5) for lithium indicator dilution, 6.4 l min−1 (±2.2) for ICG indicator dilution and 5.8 l min−1 (±1.7) for the single-thermal method (n = 40). Lithium indicator dilution measurements of cardiac output were similar to those taken with the PA catheter [bias +0.2 l min−1 (LOA ± 1.6, percentage error 35%); P = 0.13] while both ICG dilution [bias +1.8 l min−1 (LOA ± 2.7, percentage error 50%); P < 0.001] and single thermal measurements [bias +1.3 l min−1 (LOA ± 1.7, percentage error 34%); P < 0.0001] were significantly greater than those made using the PA catheter.
The principal finding of this study was that, when compared to the gravimetric technique, both Li-thermal and ICG-thermal techniques showed minimal bias but wide limits of agreement. The single-thermal indicator technique, however, appeared to over-estimate EVLW volume with similar limits of agreement to the Li-thermal technique. These data suggest that double indicator dilution methods for EVLW volume measurement may be more reliable than the single-thermal technique. Further research is required to establish whether the accuracy of the prototype Li-thermal technique can be improved to provide a method which is as accurate but more convenient than the ICG-thermal method.
Interestingly lithium indicator dilution measurements of cardiac output agreed more closely with the PA catheter reference measurements than either ICG indicator dilution or single-thermal indicator dilution. The importance of cardiac output data to the accurate measurement of EVLW volume is illustrated by Eq. 1. A previous study has suggested that cardiac output measurement error may result in inaccurate determination of EVLW volume by ICG-thermal dilution , perhaps explaining the wide limits of agreement in the current study. However, the findings of a recent investigation suggest thermal indicator loss from oedematous lungs does not affect the accuracy of cardiac output measurement by indicator dilution . The wide limits of agreement between the Li-thermal and gravimetric techniques are likely to be due to errors in the measurement of mean transit time, the most probable explanation being the distal position of the lithium ion sensitive electrode. Ideally, the electrode should be positioned within the aorta at the level of the diaphragm, ensuring a true measurement of mean transit time. In this study, however, an external lithium electrode was used and the MTT measurement adjusted on the assumption that the additional time taken for the indicator to travel from the margin of the thoracic cage to the external lithium sensor was constant. The development of an intra-arterial electrode, incorporating a thermistor, may therefore improve the accuracy of MTT measurements with this method and also allow measurements of EVLW.
Although considered by some to be the ‘gold standard’, the gravimetric method of EVLW volume measurement also has some limitations [18, 19]. Only one post-mortem measurement is possible and fluid re-absorption during the interval between death and lung removal may affect the accuracy of this method. However, the values we obtained were similar to those of previous studies that used the gravimetric technique in models of acute lung injury and sepsis [8, 20] and greater than those in sham operated animals . Similarly, our pre-intervention ICG-thermal measurements of EVLW volume were consistent with those in control animals from a previous study . Also in keeping with the current study, this previous work suggested that the ICG-thermal dilution technique underestimates EVLW volume when compared to gravimetry . Such underestimates may be more frequent during acute lung injury  or the application of positive end-expiratory pressure . It is not clear why none of the indicator dilution methods proved particularly reliable. In every case, measurements were carefully performed by experienced investigators according to the manufacturer’s instructions. While previous comparisons of the ICG-thermal and single-thermal methods suggest good agreement with gravimetric measurements [6, 23], other studies have demonstrated a need for adjustment of the algorithm dependant on the individual circumstances of the experiment [8, 24, 25].
We have demonstrated clinically significant differences between EVLW measurements obtained with the gravimetric method and three in vivo indicator dilution techniques. While none of the EVLW measurement techniques could be considered ideal, the ICG-thermal method appears to be more reliable than both the Li-thermal and single thermal techniques. Further development of the prototype Li-thermal method is required to establish whether this technology can provide EVLW volume measurement with similar reliability to existing double indicator techniques.
The authors wish to thank Mr. Eric Mills of LiDCO Ltd., for his advice during this study. R.M.P. formulated the hypothesis and developed the protocol with C.H. and P.R. The investigation was performed by B.M., R.G., E.C. and P.R. at Universitätsklinikum, Ulm, Germany. CW assisted in the data analysis. The manuscript was drafted by B.M., R.M.P. and C.H. All authors approved the final version.
Conflict of interest statement
This research was supported by an unrestricted educational grant from LiDCO Ltd., Cambridge, UK. R.M.P. has received speaking fees and equipment loans from Pulsion Medical Systems and a research grant from USCOM Ltd.
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