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European Journal of Cardio-Thoracic Surgery Advance Access published December 31, 2012
European Journal of Cardio-Thoracic Surgery 0 (2012) 1-6 Measurement of extravascular lung water following human brain death; implications for lung donor assessment and transplantation Rajamiyer V. Venkateswarana,*, Vamsidhar Dronavallia, Val Patchellb, Ian Wilsona, Jorge Mascaroa, a Department of Heart and Lung Transplantation, University Hospital Birmingham NHS Foundation Trust, Birmingham, UKb Department of Physiology, Division of Medical Sciences, University of Birmingham, Birmingham, UK * Corresponding author. Department of Cardiothoracic Surgery and Transplantation, University Hospital South Manchester NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Tel: +0161-291-2509; fax: +0161-291-2092; e-mail: rajamiyer.venkateswaran@uhsm.nhs.uk(R.V. Venkateswaran).
Received 5 March 2012; received in revised form 15 August 2012; accepted 7 September 2012 OBJECTIVES: The measurement of extravascular lung water could aid the assessment and guide the management of potential lungdonors following brain death. We therefore sought to validate a single indicator thermodilution extravascular lung water index (EVLWI-T) measurement using gravimetry and to assess the impact and clinical correlates of elevated EVLWI-T in potential lung donors andtransplant recipients.
METHODS: In a prospective study, we measured serial EVLWI-T and haemodynamic and oxygenation data in 60 potential lung donors.
To validate the EVLWI-T measurement, we measured in vivo thermodilution EVLWI (EVLWI-T) and gravimetric ex vivo EVLWI (EVLWI-G)in donor lungs rejected for transplant using the Holcroft and Trunkey modification of Pearce's method. We assessed the clinical corre-lates of elevated lung water and measured interleukin-8 and hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid.
RESULTS: The mean EVLWI-T (n = 60) was 9.7 (4.5) ml kg−1, being >7-10 ml kg−1 in 23/60 and >10 ml kg−1 in 16/60 potential donors.
Donor lungs with EVLWI >10 ml kg−1 were more likely to be receiving norepinephrine (P = 0.04), have higher pulmonary capillarywedge pressures (P = 0.008), be unsuitable for transplantation (P = 0.007) and, if transplanted, have worse survival (P = 0.04).
Lungs submitted to gravimetric analysis [n = 20 in 11 donors (9 double and 2 single)] had EVWLI-T of 10.8 (2.7) and EVLWI-G was 10.1(2.5). There was a strong correlation between EVLW-T and EVLW-G (r = 0.7; P = 0.014), but EVLWI-T over-predicted the EVLWI-G by 1 ml kg−1 (EVLW-T = 1.05 × EVLW-G). Cytokine levels in BAL fluid were elevated.
CONCLUSIONS: Elevated lung water is found in >50% of potential lung donors, predicts lung suitability for transplant and may adverse-ly affect recipient outcome. Although EVLWI-T intrinsically overestimates gravimetric lung water, its measurement may aid the assess-ment of organ suitability. Lung water accumulation and the proinflammatory response may both be targets for modifying therapy.
Keywords: Lung water • Extravascular lung water • Gravimetric lung water • Lung transplantation • Donor management very significant increases in lung water observed immediately aftertransplantation []. The measurement of EVLW could thus be an In the circumstances of brain death, extravascular lung water additional facile and real-time method of assessment of potential (EVLW) could increase due to direct lung injury associated with the cardiovascular events of coning [and secondary effects EVLW can be measured in different ways including a single related to proinflammatory response or cardiac dysfunction ].
indicator trans-pulmonary thermodilution technique based on Each of these could be exacerbated by over-zealous fluid re- the Stewart-Hamilton principle [, ]. Using this thermodilution placement. Current, in vivo assessment of donor lungs is inexact technique, the EVLW, indexed to predicted body weight (PBW; and reliant on donor history, chest-X-ray evaluation, arterial and extravascular lung water index (EVLWI-T)), has a normal range of pulmonary venous blood gas measurement, bronchoscopy and 3-7 ml kg−1 and values >10 ml kg−1 are believed to indicate direct inspection [, ]. As in other clinical scenarios, significant significant lung water excess [and predict adverse outcome lung water increases might precede clinical, radiological and oxy- genation manifestations of lung oedema and could potentiate the Early EVLW studies, using a thermal dye double indicator dilution technique suggested potential clinical utility in brain Prof. Robert Bonser has unfortunately passed away after this paper was -lung donors [], but the single indicator technique has not been investigated or validated in this setting.
The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
R.V. Venkateswaran et al. / European Journal of Cardio-Thoracic Surgery In a previous report, we found that potential donor lungs identified during assessment at direct inspection. Interleukin-8 deemed unsuitable for transplantation had higher EVLWI-T. The (IL-8) and hepatocyte growth factor (HGF) as possible markers of aims of the current study were therefore to validate the single lung injury were measured in a single thaw cycle of the BAL indicator thermodilution measurement against gravimetric meth- supernatant sample using commercially available ELISA kits odology in patients following brain death, and to assess the clin- (Quantikine® by R&D Systems, Inc., MN, USA). As the kits were ical and haemodynamic correlates of EVLWI-T measurements not previously validated for use on BAL samples, for each of the markers, spike/ recovery and linearity experiments were per-formed based on the manufacturer's protocol (R&D Systems,Inc.), ensuring measurement accuracy up to maximal alloweddilution.
Donor lungs for transplantation were flush perfused with a single pulmonary artery flush of blood-based pneumoplegia This prospective observational study was approved by a multi- (Ringer's lactate 700 ml, human albumin solution (20%) 200 ml, centre research ethics committee, and informed consent was mannitol solution (20%) 100 ml, sodium heparin 10 000 units, obtained from the next of kin of all participating donors. We venesected donor blood 300 ml, citrate/phosphate/dextrose performed EVLWI-T measurements using a single thermal indi- buffer 56 ml and a single dose of epoprostenol infusion (0.5 mg cator technique in brainstem dead potential lung donors in 20 ml (Flolan; GlaxoSmithKline UK, Ltd)) and retrieved as a defined as a donor with a PaO2/fractional inspired oxygen (FiO2) whole block after explanting the donor heart. The trachea was ratio at initial assessment of ≥200 mmHg, provided available stapled after expansion of both lungs, and the block or individual chest radiographs did not demonstrate gross parenchymal lung transported in 4°C Ringer's lactate solution to the transplant change. Demographic and clinical data, including time of coning (detection of fixed dilated pupils and arterial blood pressuresurge) were recorded and arterial blood samples drawn for (i)blood gas measurements at fractional inspired oxygen (FiO2) 1.0 and 5 cmH2O positive end-expiratory pressure and (ii) for bio-marker analysis. A femoral arterial thermodilution catheter Specific, additional next-of-kin consent was requested to retain (PiCCO, Pulsion Medical UK, Ltd) was then inserted for the lungs not accepted for transplantation for gravimetric lung water measurement of EVLW and pulmonary vascular permeability assessment. Gravimetric measurement of EVLW was determined (PVP) both indexed (I) to PBW according to the formulae: using the Holcroft and Trunkey modification of the Pearcemethod []. Peripheral venous (5 ml) and pulmonary venous ef- Females : 45:5 þ 0:91½heightðcmÞ À 152:4Š fluent blood (10 ml) were collected prior to retrieval of lungs forhaemoglobin estimation. Lungs were then retrieved in a standard Males : 50:0 þ 0:91½heightðcmÞ À 152:4Š manner, but without pneumoplegia or epoprostenol infusion The underlying principles of this lung water assessment have and transported, inflated at 4°C in Ringer's lactate solution.
been previously reported [The pulmonary vascular permeabil- Within 8 h, lung blocks were separated, and non-parenchymal ity index (PVPI) is the EVLW to pulmonary blood volume ratio tissue excised and weighed. Large representative samples from (normal range 1-3 kg−1). Elevated EVLW with a low PVPI implies upper and lower lobes were weighed and then homogenized a greater pulmonary blood volume and hydrostatic oedema, with a known amount of distilled water and centrifuged at whereas a high EVLW with a high PVPI implies permeability 12 000 rpm for 30 min at 4°C. The wet weights of supernatant, oedema. A Swan-Ganz catheter was also inserted, allowing the lung sediments and the pulmonary venous blood were obtained.
measurement of pulmonary capillary wedge pressure (PCWP) Haemoglobin levels from the pulmonary venous effluent blood and supernatant samples were measured. Supernatant, blood A bronchoscopy was performed to assess anatomy, confirm and the lung sediments were then freeze dried for 72 h and endotracheal tube placement, aspirate secretions, and to obtain weighed again to obtain their dry weight. EVLW was then calcu- bronchoalveolar lavage (BAL) specimens. Blood and BAL speci- lated, linearly extrapolated to the total lung weight and indexed mens were kept on ice until return to the transplant centre where they were immediately processed. Blood samples werecentrifuged and serum then frozen at −80°C for later analysis.
One aliquot of BAL fluid was despatched for microbiological culture and the centrifuged supernatant of a second specimenfrozen at −80°C for later cytokine analysis. ABG, EVLWI and PVPI Data were analyzed using SPSS v15.0 (Chicago, IL, USA) and measurements were obtained at baseline, repeated after bron- STATA (Release 10; Stata Corp., College Station, TX). Continuous choscopy, 1 h thereafter and immediately preretrieval.
data were assessed for normality and are presented as mean After initial measurements and BAL, donors received either (standard deviation) or median (25th, 75th quartiles). Normally T3, methylprednisolone, both T3 and MP or placebo (dextrose distributed variables were compared using the paired or inde- 5%) in a 1:1:1:1 randomization as previously described [ pendent t-test as appropriate. Skewed data were tested using Details of blinding, randomization, donor management, a non-parametric tests (Mann-Whitney and Kruskal-Wallis test).
CONSORT flow diagram and hormonal group allocation out- Categorical data were analyzed using Chi-square and Fisher's comes for this trial have been previously reported [Lung suitability for transplantation was predefined as an arterial PaO2/ Comparison between gravimetry and thermodilution was per- FiO2 ≥300 mmHg immediately prior to retrieval without lung formed using Spearman's correlation and Bland-Altman analysis.
trauma, aspiration, infection or non-recruitable atelectasis being We analysed donor EVLWI-T and corresponding lung EVLWI-G R.V. Venkateswaran et al. / European Journal of Cardio-Thoracic Surgery (averaged if both lungs were available for gravimetric analysis).
Clinical and laboratory data according to EVLWI-T dichotomized The receiver operating curve characteristic for the ability of as ≤ or >10 ml kg−1 are shown in Table. High EVLW-T donors EVLWI-T to predict lung suitability for transplantation at retrieval had higher PVPI, higher PCWP and were more likely to be re- assessment is reported as area under the curve (AUC; standard ceiving a higher dose of norepinephrine and less likely to be error). Statistical significance was assigned when P < 0.05, and all suitable for transplantation at end inspection. Positive BAL culture rates were not different between lung water groups.
Additionally, BAL levels of IL-8 [1472 (223, >2000) vs 2000 (663, >2000) pg ml−1] and HGF [325 (125, 1160) vs 402 (222-1707) pg ml−1; P = 0.47] were observed for the ≤10 and >10 ml kg−1 groups, respectively. IL-8 levels were highly elevated and were Sixty donors, median age 47 (36, 56) years, underwent the in beyond the measurable range despite maximal allowed dilution vivo studies (Table ). The mean initial PaO2/FiO2 ratio was 396 (79) mmHg. Donors commenced investigations 2 (0.5, 3.5) h Overall, both EVLWI-T and PVPI increased significantly after consent, within 12.5 (8.1) h of coning. During a manage- between initial and preretrieval measurements from 9.7 (4.5) to ment period of 6.9 (1.2) h, donors received limited amounts of 10.8 (5.2); P = 0.009 and 2.4 (0.9) to 2.7 (1.2); P = 0.025, respect- fluid [376 (353) ml of colloid and 27 (94) ml of crystalloid].
ively, while the PaO2/FiO2 ratio fell [397 (78) to 359 (126); P = 0.028] and PCWP increased [8.4 (4.9) to 11.1 (4.2); P < 0.001].
On receiver operating characteristic curve analysis, initial EVLWI EVLWI-T and gravimetric lung water validation [AUC = 0.67 (0.07); 95% CI 0.53, 0.81; P = 0.025] (Fig. was pre-dictive of suitability at final inspection with a positive and nega- Consent was obtained in 11 donors (20 lungs; 9 lung pairs and 2 tive predictive value of 72 and 63%, respectively.
single lungs) for gravimetric analysis. When comparing techni- A total of 27 lung transplants were performed from the study cohort; 30-day survival (60%) was lower in recipients of lungs before lung explantation were considered. The gravimetric lung with EVLWI-T >10 ml kg−1 (n = 5); P = 0.03 vs those with lower study donors had a similar EVLWI-T [10.8 (2.7)] when compared with others [10.6 (5.4) ml kg−1], but as expected, a lower PaO2/FiO2 ratio (265 (135) vs 373 (111) mmHg) than non-gravimetrically studied lungs. There was strong, direct correlation between EVLWI-T and EVLWI-G (Fig. ; r = 0.7; Spearman's cor-relation P = 0.014; regression analysis EVLW-T = 1.05 × EVLW-G) Following transplantation, there is a disturbing incidence (15- with modest over-prediction [Bland-Altmann analysis of 0.5 35%) of post-transplantation lung injury with impaired gas ex- (2.1) ml kg−1] and increased positive bias with higher EVLWI change and pulmonary infiltrates and worse outcome measurements (Fig. The upper and lower limits of agreement Increased lung water occurs uniformly [Our study suggests (±2 standard deviations) were 4.6 and −3.7 ml kg−1, respectively.
that the process of oedema generation begins in the donor. Wehave demonstrated that EVLWI-T is elevated (>7 ml kg−1) in themajority of potential lung donors following brain death and is 6 h prior to final inspection, predicts the ultimate suit- ability of lungs for transplantation and recipient outcome.
The initial EVLWI-T was 9.7 (4.5) ml kg−1; 85% (51/60) donors had EVLWI-T >7 ml kg−1, with 27% (16/60) having values >10 ml methods (EVLWI-T) have been shown to correlate well with lung kg−1. PVPI values rose in parallel with increasing EVLWI-T (Fig. Characteristics of 60 potential lung donors Data are presented in mean (standard deviation), median (25th, 75thpercentiles) or number/denominator (%). CNS: central nervous system.
Figure 1: Correlation between EVLWI measurement by thermodilution andgravimetry (r = 0.7; Spearman's correlation P = 0.002).
R.V. Venkateswaran et al. / European Journal of Cardio-Thoracic Surgery Figure 2: Bland-Altman plot demonstrating limits of agreement between EVLWI measurement by thermodilution and gravimetry. EVLWI-T over-predicted theEVLWI-G and there was a positive bias which increased with higher EVLWI-T. However the limits of agreement values lie between the two standard deviation.
although the validity of PVPI as an index of permeabilityoedema has not been validated. All the mechanisms describedcould lead to pulmonary oedema and worsening lung function,and our data are consistent with findings in lungs rejected fortransplantation [The higher PCWP in the >10 ml kg−1 groupis consistent with greater overall fluid overload or associated leftventricular dysfunction.
The huge circulating levels of catecholamines during the 'storm' of brainstem death may provoke pulmonary endothelialinjury and combined hydrostatic and permeability oedema.
Thereafter, vasoparetic hypotension is commonly treated by NEinfusion, a potent but cardiotoxic α-adrenergic agonist. Donorpressor support with NE has been associated with a worse prog-nosis in heart and lung transplantation and inferior post-transplant gas exchange. In our study, more donors in theEVLWI-T >10 ml kg−1 group were receiving NE at higher dosage.
Higher NE exposure could certainly influence lung water viahydrostatic mechanisms that increase fluid filtration, includingpost-capillary vasconstriction and cardiac dysfunction with Figure 3: Scatter plot of EVLWI-T and PVPI.
The epithelial Na+/K+ channels in alveolar epithelium have an water measured by gravimetry (EVLW-G) , , ]. A number of important role in the clearance of excessive fluid from the alveo- experimental studies have allowed validation of the single indica- lar space. Alveolar fluid clearance (AFC) mechanisms are known tor thermodilution method used in this study vs gravimetric to be maintained following brainstem death and retrieval and measurement , In each study, EVLWI-T has been may respond to pharmacological manipulation. Both thyroid shown to over-predict EVLWI-G by 2-5 ml kg−1. In our study, the hormone and steroids may up-regulate AFC and could be of first to attempt to validate the measurement in potential donor benefit in this clinical scenario [, ]. However, we previously lungs, we noted a similar over-prediction of gravimetric values, a reported that in this cohort, T3 had no effect on EVLWI-T while positive bias that increases with higher EVLWI values, but which MP attenuated the increased Δ-EVLWI-T observed in non- may not limit the clinical value of this measurement.
treated donors. Early steroid administration is reported to Lung water may increase in donor lungs by various mechan- improve oxygenation and yield and, in this regard, augmentation isms of injury such as trauma, aspiration, infection, fluid overload of AFC rather than an anti-inflammatory effect may be the dom- and ventilatory barotrauma. These may occur before or after brain death, and donor smoking may be an additional risk Importantly, our finding of elevated EVLWI-T in >50% donors factor. Also, during the circulatory changes associated with brain provides an opportunity for modulation using diuretics to coun- death, haemodynamic shear forces and pro-oedematous hydro- teract fluid overload and nebulized β-adrenergic agonists to static pressures may cause direct injury. Each of these modes of augment AFC. As post-transplantation increases in EVLWI occur injury may be further exacerbated by a proinflammatory uniformly following transplantation commencement of AFC post-BSD environment, and our finding of elevated PVPI in augmentation in the donor holds promise as a protective strat- higher lung water donors suggests that this may be occurring egy [Post-transplantation AFC manipulation has been shown R.V. Venkateswaran et al. / European Journal of Cardio-Thoracic Surgery Characteristics of donors and transplant outcome according to initially measured lung water content The assessment time represents the period between initial and final measurements. The prefix Δ indicates the change in measurement between final andinitial sampling. Lungs matching suitability indicates those attaining the predefined transplant suitability criteria (see text).
PVPI: pulmonary vascular permeability index: PCWP: initial pulmonary capillary wedge pressure.
to be associated with rapid resolution of hypoxia and improve-ment in radiological changes ].
Our study suggests that the measurement of EVLWI-T may be a facile tool that may improve donor care. It may guide donorfluid management and prompt measures to improve AFC. Thestudy was performed prior to the widespread introduction of ex vivo lung resuscitation ], but we speculate that the identifica-tion of adverse lung water measurements, rather than being aprompt for lung rejection, may allow direct transfer to lungreconditioning.
Our study has a number of limitations. Although our sample sizeis larger than many laboratory experimental studies, the hetero-geneity of the population may have affected our findings.
Gravimetric validation was performed on lungs rejected fortransplantation that had worse gas exchange than those trans-planted. Caution must therefore be advised when extrapolatingthese data clinically. As patients were transplanted in a numberof centres, we used recipient survival as a surrogate measure of Figure 4: Receiver operating curve characteristic assessing lung suitability and graft function and cannot report whether differences in outcome extravascular lung water index. The area under the curve is 0.67 (standard R.V. Venkateswaran et al. / European Journal of Cardio-Thoracic Surgery In conclusion, we have validated the simple measurement of [11] Mihm F, Feeley T, Rosenthal M, Lewis F. Measurement of extravascular EVLWI by a single indicator thermodilution technique in post- lung water in dogs using the thermal-green dye indicator dilutionmethod. Anesthesiology 1982;57:116-22.
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Conflict of interest: none declared.
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