Laboratory Investigations

Extravascular lung water after pneumonectomy and one-lungventilation in sheep

Vsevolod V. Kuzkov, MD, PhD; Evgeny V. Suborov, MD; Mikhail Y. Kirov, MD, PhD;Vladimir N. Kuklin, MD, PhD; Mehrdad Sobhkhez, MSci; Solveig Johnsen, MD; Kristine Waerhaug, MD;Lars J. Bjertnaes, MD, PhD

Pneumonectomy still remains achallenging surgical interven-tion. An extensive reduction ofthe pulmonary tissue volume

results in major anatomical and physio-logic changes and carries the risk of life-threatening complications (1, 2).

Postpneumonectomy pulmonary edemarepresents a particularly dangerous subtype

of acute lung injury developing indepen-dently of left ventricular dysfunction or in-fection (3, 4). A widely varying prevalenceof 2.5–14.3% and a mortality rate of 50–100% can, most likely, be explained by thelack of criteria for early detection of thiscomplication (3–5). Despite investigativeefforts to unveil the etiology and the patho-genesis, postpneumonectomy pulmonary

edema remains an elusively defined clinicalentity. Fluid overload, impaired lymphaticdrainage, ischemia–reperfusion injury,shear stress, and ventilator-induced lunginjury by intraoperative or postoperativehyperinflation of the remaining lung haveall been suggested as acting in concert withpneumonectomy as promoting factors (2).Therefore, the development of diagnostictools allowing early identification of thislife-threatening complication is of para-mount importance.

Repeated measurements of extravascu-lar lung water (EVLW) will probably in-crease the awareness of postpneumonec-tomy pulmonary edema. Until recently, thethermal-dye dilution technique (TDD) wasconsidered the method of choice for suchmeasurements, although concerns havebeen raised about the versatility of thismethod (6). Lately, the single indicator

Objective: To compare the single thermodilution and the ther-mal-dye dilution techniques with postmortem gravimetry for as-sessment of changes in extravascular lung water after pneumo-nectomy and to explore the evolution of edema after injuriousventilation of the left lung.

Design: Experimental study.Setting: University laboratory.Subjects: A total of 30 sheep weighing 35.6 � 4.6 kg. The

study included two parts: a pneumonectomy study (n � 18) andan injurious ventilation study (n � 12).

Methods: Sheep were anesthetized and mechanically venti-lated with an FIO2 of 0.5, tidal volume of 6 mL/kg, and positiveend-expiratory pressure of 2 cm H2O. In the pneumonectomystudy, sheep were assigned to right-sided pneumonectomy (n � 7),left-sided pneumonectomy (n � 7), or lateral thoracotomy only(sham operation, n � 4). In the injurious ventilation study, right-sided pneumonectomy was followed by ventilation with a tidalvolume of 12 mL/kg and positive end-expiratory pressure of 0 cmH2O (n � 6) or by ventilation with a tidal volume of 6 mL/kg andpositive end-expiratory pressure of 2 cm H2O for 4 hrs (n � 6).Volumetric variables, including extravascular lung water index(EVLWI), were measured with single thermodilution (STD;

EVLWISTD) and thermal-dye dilution (TDD; EVLWITDD) techniques.We monitored pulmonary hemodynamics and respiratory vari-ables. After the sheep were killed, EVLWI was determined for eachlung by gravimetry (EVLWIG).

Results: In total, the study yielded strong correlations ofEVLWISTD and EVLWITDD with EVLWIG (n � 30; r � .83 and .94,respectively; p < .0001). After pneumonectomy, both the left- andthe right-sided pneumonectomy groups displayed significant de-creases in EVLWISTD and EVLWITDD. The injuriously ventilatedsheep demonstrated significant increases in EVLWI that weredetected by both techniques. The mean biases (�2 SD) comparedwith EVLWIG were 3.0 � 2.6 mL/kg for EVLWISTD and 0.4 � 1.6mL/kg for EVLWITDD.

Conclusions: After pneumonectomy and injurious ventilation ofthe left lung, TDD and STD displayed changes in extravascularlung water with acceptable accuracy when compared with post-mortem gravimetry. Ventilator-induced lung injury seems to be acrucial mechanism of pulmonary edema after pneumonectomy.(Crit Care Med 2007; 35:1550–1559)

KEY WORDS: extravascular lung water; pneumonectomy; venti-lator-induced lung injury; thermodilution; postpneumonectomypulmonary edema; one-lung ventilation

From the Department of Anesthesiology, Instituteof Clinical Medicine, University of Tromsø, Tromsø,Norway (VVK, EVS, MYK, VNK, MS, SJ, KW, LJB); andthe Department of Anesthesiology and Intensive CareMedicine, Northern State Medical University, Arkhan-gelsk, Russian Federation (VVK, EVS, MYK).

Presented, in part, at the 28th Scandinavian Con-gress of Anesthesiologists, Reykjavik, Iceland, July2005; at the Norwegian Anesthesiological Society,Tromsø, Norway, October 2005; and at the Euroanes-thesia Congress 2006, Madrid, Spain, June 2006.

Dr. Kirov is a member of the medical advisoryboard of Pulsion Medical Systems. The other au-

thors have not disclosed any potential conflicts ofinterest.

Supported, in part, by Helse Nord, Norway (project4001.721.477); the Research Council of Norway; Pul-sion Medical Systems, Germany; and departmentalfunds of the Department of Anesthesiology, UniversityHospital of North Norway.

For information regarding this article, E-mail:vkuzkov@atnet.ru; v_kuzkov@mail.ru

Copyright © 2007 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000265739.51887.2B

1550 Crit Care Med 2007 Vol. 35, No. 6

thermodilution technique (STD) has dem-onstrated an acceptable accuracy and re-producibility for EVLW measurements inexperimental and clinical settings (7–9).This method involves injection of a coldcrystalloid solution into a central vein, fol-lowed by transpulmonary dilution and de-tection of the thermal drift in a major ar-tery. However, determination of EVLWwith STD might be suspected of being lessaccurate in comparison with TDD becausepneumonectomy might reduce the pulmo-nary blood volume and shorten the meantransit time of the thermal indicator. Thesecombined effects may distort the results ofEVLW as determined with STD after pneu-monectomy.

Thus, the aim of the present study insheep was two-fold: first, to evaluate theaccuracy of the STD and the TDD meth-ods in comparison with postmortemgravimetry for measurement of EVLW af-ter pneumonectomy, and second, to ex-plore the role of ventilator-induced lunginjury in the pathogenesis of postpneu-monectomy pulmonary edema.

MATERIALS AND METHODS

The study was approved by the NorwegianExperimental Animal Board in accordancewith the European Convention on AnimalCare and conducted on 30 yearling sheep.

Experimental Protocol

In the pneumonectomy study (n � 18;weight, 35.2 � 4.9 kg), animals were assigned tothree groups: a sham-operation group (n � 4), aleft pneumonectomy group (n � 7), and a rightpneumonectomy group (n � 7). The shamgroup was subjected to a right-sided thoracot-omy, and conventional two-lung ventilation wasmaintained throughout the study. The animalswere ventilated for 1 hr after the intervention. Inthe injurious ventilation study (n � 12; weight,36.0 � 4.5 kg), all sheep were subjected to rightpneumonectomy and randomly assigned to aninjurious ventilation group (INJV, n � 6) or aprotective ventilation group (PROTV, n � 6).Both groups were ventilated for 4 hrs after pneu-monectomy.

Anesthesia and MechanicalVentilation

After injection of thiopental sodium (pento-thal natrium, Abbott, Solna, Sweden), the ani-mals were endotracheally intubated, placed inthe lateral position, and conventionally venti-lated. General anesthesia was maintained with acontinuous infusion of ketamine, midazolam,and fentanyl at rates of 3.0 mg·kg�1·hr�1, 0.4mg·kg�1·hr�1, and 12 �g·kg�1·hr�1, respec-

tively. Muscle relaxation was induced with 0.1mg/kg pancuronium bromide as an initial bolus,followed by infusion of 0.06 mg·kg�1·hr�1 afterconfirmation of pain-free anesthesia. Through-out the experiment, all animals received an in-fusion of lactated Ringer solution at a constantrate of 8 mL·kg�1·hr�1. Special attention waspaid to protecting the airways against aspirationof gastric contents by inserting a gastric tube.Animals were killed with a bolus injection ofpentobarbital sodium (50 mg/kg). In the pneu-monectomy study, volume-controlled ventila-tion was delivered with a tidal volume (VT) of 6mL/kg, FIO2 of 0.5, positive end-expiratory pres-sure (PEEP) of 2 cm H2O, inspiration-to-expiration ratio of 1:2, and inspiratory pausetime of 5% (Servo ventilator 900C, Siemens El-ema, Solna, Sweden). Minute ventilation wasadjusted to maintain PaCO2 values within thenormal range.

In the injurious ventilation study, the INJVgroup was subjected to ventilation with zeroPEEP and VT 12 mL/kg after pneumonectomy.The PROTV group received “protective” venti-lation with PEEP 2 cm H2O and VT 6 mL/kgthroughout the experiment. The levels of pro-tective ventilation of 6 mL/kg and injuriousventilation of 12 mL/kg were based mainly onthe results of our own pilot experiments andother recent investigations (10, 11). The VT of12 mL/kg was selected to maintain peak air-way pressure at �50 cm H2O, simultaneouslyminimizing the risk of barotrauma of the leftlung. Other ventilatory settings were not dif-ferent from those specified for the pneumo-nectomy study.

Surgical Preparations. The external jugu-lar vein and femoral artery were cannulatedusing standard introducers (8.5 Fr, I350BF85,Edwards Life Sciences, Irvine, CA). A ther-modilution pulmonary artery catheter (7.0 Fr,F131HF7, Edwards Life Sciences) was intro-duced into the pulmonary artery. A fiberopticthermistor-tipped TDD catheter and a ther-mistor-tipped thermodilution catheter (4FPULSIOCATH; PV2024L and PV2014L50LGW;Pulsion Medical Systems, Germany) were in-serted via a femoral artery through arterialintroducers into the abdominal aorta and con-nected to a Cold Z-021 and a PiCCOplus mon-itor (Pulsion Medical Systems), respectively.The fiberoptic TDD and the pulmonary arterycatheters were connected to standard pressuretransducers (Transpac III, Abbott, North Chi-cago, IL).

Thoracotomy and Pneumonectomy. Inthe pneumonectomy study, left- or right-sided lateral thoracotomy was performed inthe fifth intercostal space. After dissection ofthe mediastinal pleura, the pulmonary rootwas ligated using a cotton band fixed with aclamp. This technique substantially reducedthe time of the procedure and the blood loss.Then, one of the lungs was removed andsubjected to ex vivo determination of EVLWby gravimetry.

Measurements

Mean arterial pressure, pulmonary arterialpressure, pulmonary artery occlusion pres-sure, and right atrial pressure were displayedon a Patient Data Monitor (565A, Kone, Espoo,Finland) and recorded by a Gould 6600 Poly-graph (Gould Instruments, Cleveland, OH).

Volumetric variables were calculated as anaverage of triplicate bolus injections of ice-cold solutions of indocyanine green (1 mg/mL,6 mL) and dextrose (5%, 10 mL) for TDD andSTD, respectively. These indicator solutionswere injected into the right atrium randomlyduring the respiratory cycle. Systemic andpulmonary vascular resistance indexes werecalculated using standard equations (7). Car-diac index (CI) was registered in the pulmo-nary artery and in the aorta.

Using TDD and STD, we determinedEVLW index (EVLWI), intrathoracic bloodvolume index (ITBVI), intrathoracic thermalvolume index (ITTVI), and global end-diastolic volume index (GEDVI). Pulmonaryblood volume index was measured directlyby TDD (PBVITDD) only. We calculated thetrue relationship between ITBVI and GEDVIby using their directly measured values asdetermined with TDD. In addition, pulmo-nary vascular permeability indexes were cal-culated as PVPIPBV � EVLWITDD/PBVITDD

and PVPIITBV � EVLWITDD/ITBVITDD (12,13). Appendix 1 illustrates the methodologyof the TDD and the STD techniques.

Blood samples were drawn from the sys-temic (a) and the pulmonary (v) arteries andanalyzed for pH, blood gases, hemoglobin, andhematocrit (Rapid 860, Chiron DiagnosticsCorporation, East Walpole, MA). Venous ad-mixture (QS/QT) was calculated using the stan-dard equation (7). Peak airway pressure andairway plateau pressure (Pplat) and PEEP weremonitored by the Servo ventilator. Total lungand chest quasistatic compliance (CQS) wascalculated as: CQS � VT/(Pplat � PEEP)/bodyweight.

In the pneumonectomy study, we regis-tered all the variables at baseline, after lateralthoracotomy, shortly after pneumonectomy,and at 1 hr after pneumonectomy. In thesham-operation group, measurements wereperformed at baseline, after right thoracot-omy, and at 1.5 and 2.5 hrs after thoracotomyto match the time of the data collection pointsto the mean duration of the procedures in theleft and right pneumonectomy groups. In theinjurious ventilation study, this protocol wasexpanded, and additional measurements wereperformed at 2 and 4 hrs after pneumonec-tomy in both the INJV and the PROTV groups.

Postmortem Gravimetry. The referencequantification of EVLWI was determined bypostmortem gravimetry (EVLWIG) (14). Be-fore sheep were killed, we sampled 20 mL ofblood from the left ventricle and measured

1551Crit Care Med 2007 Vol. 35, No. 6

hemoglobin and hematocrit to exclude the waterfrom the calculation of residual intrapulmonaryblood. For each animal, EVLWIG was determinedseparately for the left and the right lung. Afterweighing, the lung was homogenized in ablender with an equal amount of distilled water.The aliquots of the whole homogenate wereultracentrifuged to obtain a clear supernatant.In the supernatant, residual hemoglobin wasmeasured using a low hemoglobin concentra-tion analyzer. For the quantification ofEVLWIG, blood, homogenate, and superna-tant samples were dried using a microwaveoven (15). An outline of the equations usedfor calculation of EVLW after postmortemgravimetry is shown in Appendix 2.

Statistical Analysis

Statistical analysis was performed usingSPSS 13 software (13.0.1, SPSS, Chicago, IL).For numbers of observations of �10 subjects,the normality of distribution was checked us-ing the Shapiro-Wilk test. Data were expressedas mean � SD and assessed for intragroup andintergroup differences by analysis of variancefollowed, by post hoc Scheffe test, when ap-propriate. For comparison of two groups ofindependent variables (injurious ventilationstudy only), we used the Mann-Whitney U test.To estimate the accuracy and express the bi-ases of STD and TDD compared with EVLWIG,we used the Pearson correlation coefficientand Bland–Altman analysis. A p value of �.05was considered as statistically significant.

RESULTS

All animals survived until the end ofthe experiments. We did not observe anymacroscopic signs of barotrauma (e.g.,pneumomediastinum, interstitial or sub-cutaneous emphysema), severe bleeding,or aspiration. At baseline, no significantdifferences were found between thegroups. In the sham-operation animals,all variables remained stable throughoutthe experiment.

Volumetric Variables

Pneumonectomy Study. Figure 1 dem-onstrates dynamic changes in EVLWISTD

(A) and EVLWITDD (B). As compared withsham-operated animals, pneumonectomyresulted in significant decreases in bothEVLWISTD and EVLWITDD in the left- andthe right-sided pneumonectomy groups.This decline persisted 1 hr after surgery.Compared with baseline, left-sided pneu-monectomy resulted in reduction ofEVLWISTD and EVLWITDD by 29.5% �5.5% and 33.2% � 8.7%, respectively (p �.05). Correspondingly, after right pneu-monectomy, EVLWISTD and EVLWITDD

decreased by 41.6% � 8.2% and 56.4% �15.6%, respectively (p � .001).

As displayed in Table 1, other volu-metric variables, including ITBVISTD,ITBVITDD, and PBVITDD, also showedsubstantial reductions after pneumonec-tomy in both groups (p � .05). In con-trast, ITBVITDD/GEDVITDD did not changeduring the course of the experiments. Afterthoracotomy, the left pneumonectomygroup demonstrated a decreased ITBVISTD

compared with the sham group (p � .05).In the right pneumonectomy group, bothPVPIPBV and PVPIITBV decreased signifi-cantly after pneumonectomy comparedwith baseline and the sham group.

Injurious Ventilation Study. Changesin EVLWITDD and EVLWISTD are shown inFigure 2. Other variables from the INJVand the PROTV groups are presented inTable 2. After thoracotomy, we found nosignificant intergroup differences inEVLWI, ITBVI, or other variables deter-mined with the TDD and the STD tech-niques.

After pneumonectomy, EVLWISTD andEVLWITDD decreased both in the INJV(p � .02) and the PROTV (p � .05)groups. In the INJV group, EVLWISTD andEVLWITDD decreased by 40.3% � 1.7%and 43.1% � 13.7%, respectively, com-pared with baseline. Correspondingly, inthe PROTV group, EVLWISTD and

EVLWITDD decreased by 38.7% � 9.9%and 43.1% � 14.3%, respectively (p � .05).

After 4 hrs of injurious ventilation, weobserved significant elevations in EVLWSTD

and EVLWITDD as compared with the val-ues after pneumonectomy (p � .001 andp � .02, respectively). In contrast, pneu-monectomy followed by protective venti-lation did not result in significantchanges in EVLW indexes. By 4 hrs afterpneumonectomy, both EVLWISTD andEVLWITDD were significantly higher inthe INJV group. After pneumonectomy,PBVITDD decreased both in the PROTVand the INJV groups. In parallel, injuri-ous ventilation was associated with in-creased ITBVISTD, PVPIPBV, and PVPIITBV

(p � .05) and a significantly decreasedITBVITDD/GEDVITDD ratio compared withthe PROTV group.

Pulmonary and SystemicHemodynamics

We did not find any significant differ-ences in heart rate, mean arterial pres-sure, pulmonary arterial cardiac index,aortic cardiac index, or systemic vascularresistance index either within or betweenthe groups (not shown). Changes in pul-monary hemodynamics are shown in Ta-bles 1 and 2 for the pneumonectomy andthe injurious ventilation studies, respec-

Figure 1. Changes in extravascular lung water index (EVLWI) determined with single thermodilution(A) and thermal-dye dilution (B) after pneumonectomy (PE) in sheep (pneumonectomy study). Dataare presented as mean � SD. EVLWITDD, EVLWI determined with thermal-dye dilution; EVLWISTD,EVLWI determined with single thermodilution. *p � .05 compared with the sham group; **p � .05compared with the left pneumonectomy (LPE) group; †p � .05 within the group compared with thebaseline value.

1552 Crit Care Med 2007 Vol. 35, No. 6

tively. In the pneumonectomy study, pul-monary arterial pressure and pulmonaryvascular resistance index were signifi-cantly increased after right pneumonec-tomy and 1 hr later compared with base-line (Table 1).

During injurious ventilation, pulmo-nary arterial pressure, pulmonary arteryocclusion pressure, and right atrial pres-sure increased significantly comparedwith baseline at 4 hrs after pneumonec-tomy, and pulmonary vascular resistanceindex remained increased from the pneu-monectomy until the end of the study(Table 2). At 2 and 4 hrs after pneumo-nectomy, pulmonary arterial pressure,

pulmonary artery occlusion pressure,right atrial pressure, and pulmonary vas-cular resistance index were significantlyhigher in the INJV group.

Changes in Respiratory andVentilation Variables

During the course of the pneumonec-tomy study, no significant intragroupchanges in blood temperature, pH, hemo-globin concentration, hematocrit, PaO2,PaCO2, or QS/QT were found (not shown).After both left and right pneumonectomy,peak airway pressure and airway plateaupressure increased and CQS decreased (Ta-

ble 1). After right pneumonectomy and at 1hr, peak airway pressure increased and CQS

decreased significantly compared with thesham-operation group.

In the INJV group, PaO2 decreased andQS/QT increased significantly after thethoracotomy. After pneumonectomy, air-way pressures increased substantially andCQS decreased in both groups; however,these changes were more prominent inthe INJV group (p � .05). In addition, at4 hrs after pneumonectomy, the INJVgroup showed a significant increase incentral temperature, hematocrit, and he-moglobin concentration when comparedwith the PROTV group (not shown).

Table 1. Changes in volumetric, hemodynamic, and respiratory variables in the pneumonectomy study

Variable Group

Measurement Points

Baseline Thoracotomy Pneumonectomy 1 Hr After PE

ITBVITDD, mL/m2 Sham-operation 840 � 168 814 � 138 852 � 124 953 � 60Left pneumonectomy 747 � 89 716 � 77 597 � 72a,b 615 � 59a,b

Right pneumonectomy 829 � 137 817 � 215 646 � 102b 671 � 96b

PBVITDD, mL/m2 Sham-operation 248 � 62 267 � 35 285 � 108 303 � 101Left pneumonectomy 237 � 33 233 � 37 179 � 28a,b 185 � 25a,b

Right pneumonectomy 268 � 51 283 � 73 200 � 51 207 � 49b

ITBVISTD, mL/m2 Sham-operation 696 � 117 713 � 131 696 � 146 733 � 138Left pneumonectomy 610 � 83 546 � 67b 492 � 115b 506 � 82b

Right pneumonectomy 627 � 98 600 � 89 445 � 102a,b 455 � 69a,b

ITBVI/GEDVI, rel. Sham-operation 1.42 � 0.09 1.51 � 0.13 1.50 � 0.45 1.48 � 0.20Left pneumonectomy 1.47 � 0.06 1.49 � 0.08 1.43 � 0.07 1.43 � 0.05Right pneumonectomy 1.48 � 0.07 1.54 � 0.12 1.45 � 0.10 1.45 � 0.09

PVPIPBV, rel. Sham-operation 1.17 � 0.41 1.13 � 0.32 1.09 � 0.25 1.02 � 0.29Left pneumonectomy 1.11 � 0.27 1.22 � 0.41 1.00 � 0.32 0.93 � 0.32Right pneumonectomy 1.06 � 0.22 1.08 � 0.37 0.65 � 0.32 0.55 � 0.17a,b

PVPIITBV, rel. Sham-operation 0.34 � 0.08 0.37 � 0.12 0.35 � 0.06 0.30 � 0.04Left pneumonectomy 0.35 � 0.07 0.39 � 0.08 0.29 � 0.07 0.27 � 0.07Right pneumonectomy 0.34 � 0.07 0.37 � 0.12 0.19 � 0.08a,b,c 0.17 � 0.04a,b,c

PAP, mm Hg Sham-operation 12 � 2 15 � 5 17 � 6 18 � 5Left pneumonectomy 14 � 2 15 � 3 18 � 2 18 � 2Right pneumonectomy 14 � 1 15 � 2 20 � 3a 21 � 3a

PVRI, dynes � sec·cm�5·m�2 Sham-operation 119 � 19 142 � 79 173 � 104 216 � 108Left pneumonectomy 110 � 46 124 � 75 172 � 67 156 � 83Right pneumonectomy 127 � 36 178 � 84 260 � 87a 269 � 60a

PaO2/FIO2, mm Hg Sham-operation 372 � 95 338 � 46 345 � 20 342 � 47Left pneumonectomy 445 � 101 401 � 128 283 � 112 345 � 150Right pneumonectomy 354 � 106 286 � 150 230 � 89 248 � 106

QS/QT, rel. Sham-operation 0.03 � 0.03 0.03 � 0.004 0.03 � 0.004 0.02 � 0.004Left pneumonectomy 0.02 � 0.01 0.03 � 0.01 0.04 � 0.05 0.04 � 0.05Right pneumonectomy 0.04 � 0.03 0.04 � 0.04 0.14 � 0.16 0.08 � 0.12

Ppeak, cm H2O Sham-operation 22.3 � 4.2 25.8 � 5.6 25.5 � 3.7 25.3 � 2.1Left pneumonectomy 21.4 � 2.5 21.7 � 3.8 30.7 � 5.0a 31.0 � 6.6a

Right pneumonectomy 25.1 � 5.2 27.4 � 7.3 38.4 � 4.8a,b,c 37.7 � 6.8a

Pplat, cm H2O Sham-operation 19.3 � 3.6 21.0 � 5.9 19.5 � 4.1 19.3 � 3.3Left pneumonectomy 15.7 � 1.6 16.0 � 2.8 24.0 � 3.5a, 23.3 � 3.8a,

Right pneumonectomy 20.1 � 4.8 20.4 � 6.7 28.1 � 6.1b 26.6 � 5.2b

CQS, mL·cm H2O�1·kg�1 Sham-operation 0.40 � 0.07 0.35 � 0.09 0.37 � 0.08 0.37 � 0.07Left pneumonectomy 0.45 � 0.06 0.45 � 0.09 0.28 � 0.04a 0.29 � 0.04a

Right pneumonectomy 0.41 � 0.10 0.37 � 0.10 0.26 � 0.07a 0.26 � 0.06a,b

PE, pneumonectomy; ITBVITDD, intrathoracic blood volume index determined by thermal-dye dilution; PBVITDD, pulmonary blood volume indexdetermined by thermal-dye dilution; ITBVISTD, intrathoracic blood volume index determined by single thermodilution; GEDVI, global end-diastolic volumeindex; rel., relative value; PVPIPBV, pulmonary vascular permeability index determined as EVLWITDD/PBVITDD; PVPIITBV, pulmonary vascular permeabilityindex determined as EVLWITDD/ITBVITDD; PAP, pulmonary artery pressure; PVRI, pulmonary vascular resistance index; QS/QT, venous admixture; Ppeak,peak airway pressure; Pplat, plateau airway pressure; CQS, total lung and chest quasistatic compliance.

ap � .05 within the group compared with baseline; bp � .05 between the groups vs. sham; cp � .05 between the groups vs. left pneumonectomy group.Data are presented as mean� SD.

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Postmortem Gravimetry

From both studies, a total of 60 sam-ples were gravimetrically processed. Fig-ure 3 depicts the results of EVLWIG forthe right and the left lung separately.According to the results of the gravimetrypostmortem, the left and the right lungsare expected to account for 42.7% and57.3%, respectively, of the total EVLWI.We found no differences in EVLWIG be-tween groups in the pneumonectomystudy. In the sham group, after left- andright-sided pneumonectomy, and in thePROTV group, EVLWIG of the left lungwas lower than that of the right lung(p � .05). By contrast, the INJV groupdemonstrated significantly increasedEVLWIG of the residual left lung.

There were strong correlations be-tween in vivo EVLW measurements andgravimetry in both the pneumonectomystudy (r � .89 for STD and 0.96 for TDD;n � 18; p � .0001) and the injuriousventilation study (r � .81 for STD and0.95 for TDD; n � 12; p � .005).

Figure 2. Changes in extravascular lung water index (EVLWI) determined with single thermodilution (A)and thermal-dye dilution (B) in sheep subjected to pneumonectomy followed by injurious ventilation of theresidual lung. Data are presented as mean � SD. EVLWITDD, EVLWI determined with thermal-dye dilution;EVLWISTD, EVLWI determined with single thermodilution. *p � .05 between the groups; †p � .05 withinthe group compared with baseline; ‡p � .05 within the group compared with pneumonectomy (PE).

Table 2. Changes in volumetric, hemodynamic, and respiratory variables in sheep exposed to injurious ventilation

Variable Group

Measurement Points

Baseline Thoracotomy Pneumonectomy 1 hr After PE 2 hrs After PE 4 hrs After PE

ITBVITDD, mL/m2 INJV 895 � 133 854 � 139 739 � 159 798 � 125 804 � 132 762 � 96PROTV 806 � 131 793 � 192 678 � 112 680 � 148 713 � 102 682 � 109

PBVITDD, mL/m2 INJV 280 � 63 230 � 34 166 � 49a 182 � 50 184 � 42 174 � 51a

PROTV 261 � 50 231 � 55 175 � 34a 187 � 45 196 � 37 178 � 30a

ITBVISTD, mL/m2 INJV 700 � 129 735 � 94 614 � 98 655 � 92 672 � 73c 649 � 94PROTV 700 � 137 646 � 92 543 � 90 548 � 70 571 � 55 600 � 84

ITBVI/GEDVI, rel. INJV 1.46 � 0.09 1.38 � 0.10 1.29 � 0.04a,c 1.29 � 0.05a,c 1.29 � 0.03a,c 1.30 � 0.09a

PROTV 1.39 � 0.15 1.42 � 0.07 1.45 � 0.17 1.37 � 0.04 1.41 � 0.07 1.37 � 0.05PVPIPBV, rel. INJV 1.05 � 0.44 1.36 � 0.49 1.02 � 0.47 1.07 � 0.77 1.29 � 0.66c 1.92 � 0.77c

PROTV 0.93 � 0.25 1.29 � 0.31 0.79 � 0.29 0.66 � 0.20 0.66 � 0.21 0.71 � 0.25PVPIITBV, rel. INJV 0.32 � 0.11 0.36 � 0.12 0.22 � 0.09 0.22 � 0.12 0.28 � 0.12c 0.40 � 0.09c

PROTV 0.31 � 0.09 0.38 � 0.11 0.20 � 0.05 0.18 � 0.06 0.18 � 0.05 0.19 � 0.06PAP, mm Hg INJV 12 � 2 12 � 2 16 � 3 18 � 4 23 � 6a 29 � 7a,b,c

PROTV 12 � 2 12 � 3 16 � 2 17 � 4 17 � 3 16 � 3PVRI, dyn � sec·cm�5·m�2 INJV 135 � 62 112 � 50 206 � 146 254 � 160 321 � 113c 461 � 138a,b,c

PROTV 121 � 26 148 � 43 270 � 71a 214 � 42a 213 � 24a 213 � 40a,b

PaO2/FIO2, mm Hg INJV 323 � 30 257 � 54c 214 � 41a,c 225 � 49a,c 196 � 41a,c 117 � 36a,b,c

PROTV 394 � 82 372 � 85 321 � 50 370 � 79 399 � 67 396 � 78QS/QT, % INJV 2.8 � 0.8 3.6 � 1.9 3.3 � 0.5 3.5 � 1.4 4.3 � 2.9 27.8 � 14.8a,b,c

PROTV 2.0 � 1.1 2.5 � 0.5 2.5 � 1.0 2.3 � 0.5 2.1 � 0.8 2.2 � 1Ppeak, cm H2O INJV 20.7 � 2.8 20.5 � 3.7b 36.6 � 3.7a 45.8 � 4.5a,b,c 48.7 � 4.5a,b,c 50.0 � 1.5a,b,c

PROTV 19.1 � 3.9 16.4 � 3.0b 37.0 � 6.7a 34.1 � 6.3a 34.3 � 6.1a 35.1 � 6.7a

Pplat, cm H2O INJV 17.0 � 3.9 16.0 � 5.0b 27.3 � 4.1a 36.4 � 4.7a,c 43.1 � 7.3a,b,c 44.6 � 4.4a,b,c

PROTV 16.5 � 4.3 13.3 � 2.6b 29.3 � 4.2a 26.4 � 3.0a 26.8 � 5.4a 26.7 � 6.9a

CQS, mL·cm H2O�1·kg�1 INJV 0.49 � 0.12 0.48 � 0.13b 0.26 � 0.06a 0.34 � 0.05c 0.30 � 0.06a,c 0.27 � 0.06a

PROTV 0.43 � 0.10 0.55 � 0.14b 0.22 � 0.02a 0.24 � 0.03a 0.24 � 0.04a 0.25 � 0.08a

PE, pneumonectomy; ITBVITDD, intrathoracic blood volume index determined by thermal-dye dilution; INJV, injurious ventilation group; PROTV, protectiveventilation group; PBVITDD, pulmonary blood volume index determined by thermal-dye dilution; ITBVISTD, intrathoracic blood volume index determined bysingle thermodilution; GEDVI, global end-diastolic volume index; rel., relative value; PVPIPBV, pulmonary vascular permeability index determinedas extravascular lung water index determined by thermal-dye dilution (EVLWITDD)/PBVITDD; PVPIITBV, pulmonary vascular permeability index determinedas EVLWITDD/ITBVITDD; PAP, pulmonary artery pressure; PVRI, pulmonary vascular resistance index; QS/QT, venous admixture; Ppeak, peak airway pressure;Pplat, plateau airway pressure; CQS, total lung and chest quasistatic compliance.

ap � .05 within the groups compared with baseline; bp � .05 within the groups compared with pneumonectomy; cp � .05 between groups(Mann-Whitney U test). Data are presented as mean� SD.

1554 Crit Care Med 2007 Vol. 35, No. 6

Pooled correlations of EVLWSTD andEVLWITDD with the gravimetric valuesyielded r � .83 (95% confidence intervalfor r, .67 to .92) and r � .94 (95% con-fidence interval for r, .88 to .97), respec-tively (n � 30; p � .0001). Figure 4shows scatter diagrams with regression

lines and Bland–Altman plots. Themean bias with EVLWIG � 2 SD waslower for EVLWITDD compared with thatfor EVLWSTD (0.4 � 1.7 and 3.0 � 2.6mL/kg, respectively; p � .0001). Thecorresponding regression equations forTDD and STD were EVLWITDD � 0.97 �

EVLWIG � 0.5 and EVLWISTD � 0.70 �EVLWIG � 4.3, respectively. We ob-served a moderate correlation betweenEVLWISTD bias and ITBVITDD/GEDVITDD

ratio (n � 30; r � .49; p � .01).

DISCUSSION

The present study demonstrates thatafter pneumonectomy, EVLW, as mea-sured with the STD and the TDD tech-niques, both correlate significantly withpostmortem gravimetry in sheep. Bothmethods seem to be sufficiently accuratefor determining changes in EVLW afterpneumonectomy and after injurious ven-tilation of the remaining lung with mod-erately increased VT and zero PEEP.

Concerns have been raised regardingthe accuracy of the STD technique fordetermination of EVLW after pneumo-nectomy (16, 17). First, the assumed lin-ear relationship between intrathoracicblood volume (ITBV) and global end-diastolic volume (GEDV) does not allowfor the possibility of independent changesin pulmonary blood volume (PBV). Sec-ond, the down-slope time of the ther-modilution curve is assumed to estimatepulmonary thermal volume (PTV) cor-rectly, despite changes in pulmonaryblood flow. Because pneumonectomymost likely decreases PBV and shortensthe time the thermal indicator takes totransit the pulmonary vascular bed, theseeffects should be expected to reduce PTV,thereby decreasing GEDV and, conse-quently, ITBV. These influences on fac-tors involved in the calculation of ITBVmay jeopardize the accuracy of STD forassessment of volumetric variables.

We noticed a significant decrease inEVLWI after both left and right pneumo-nectomy. Taking into account that EVLWdid not change substantially during 1 hrof protective ventilation, the EVLW val-ues summarized for both lungs ought tomake up 100%. Hence, both the TDD andthe STD methods underestimated the ac-tual decrease in EVLWI after pneumonec-tomy. In addition, STD demonstrated anexpected overestimation of the gravimet-rically determined EVLWI values, with amean bias of 3.0 mL/kg, which agreeswith previous studies (7, 8, 16, 18).

In the pneumonectomy study, theITBVITDD/GEDVITDD ratio displayed nosignificant changes within or betweengroups. This finding might be importantfor measurements based on the STDtechnique because the calculation ofEVLWISTD is dependent on the empiri-

Figure 3. Results of postmortem gravimetry of the left and the right lung after pneumonectomy (A)and after injurious ventilation of the residual lung in sheep subjected to pneumonectomy (B). Data arepresented as mean � SD. EVLWIG, extravascular lung water index determined with postmortemgravimetry. *p � .05 between right and left lungs; †p � .05 compared with corresponding lungbetween groups.

Figure 4. Linear regression analysis and Bland–Altman plots for single thermodilution (A) andthermal-dye dilution (B). Pooled data from studies of pneumonectomy and of pneumonectomyfollowed by injurious ventilation in sheep. Solid lines are regression lines; dashed lines indicate 95%confidence intervals (CI) and line of identity. Respective regression equations and values of 95%confidence intervals are presented. EVLWIG, extravascular lung water index determined with post-mortem gravimetry; EVLWITDD, extravascular lung water index determined with thermal-dye dilution;EVLWISTD, extravascular lung water index determined with single thermodilution.

1555Crit Care Med 2007 Vol. 35, No. 6

cally determined ratio of 1.25 betweenITBV and GEDV (9). The latter value istailored for human use and integrated inthe software of the PiCCOplus monitor forcalculation of ITBVISTD and EVLWISTD. Inthe anesthetized and ventilated sheep ofthe pneumonectomy study, we noticeda mean baseline value of ITBVITDD/GEDVITDD of 1.46, with relatively smalldeviations between the groups. This co-efficient is close to recently published val-ues determined in ventilated animals of asimilar size (8, 18) but higher than thatcalculated in spontaneously breathingsheep (7, 17). We found a decrease inboth PVPIPBV and PVPIITBV after rightpneumonectomy as compared with base-line values and the corresponding indexesof the sham group. Taking into accountthe decrease in EVLWI and a preservedcardiac function with stable cardiac indexand pulmonary artery occlusion pressure,these minor changes can be explained bya discordant reduction in PBVI and canhardly be construed as predisposing forhydrostatic pulmonary edema.

After 4 hrs of injurious ventilation(doubled VT and zero PEEP), we observedsubstantial increments in EVLWISTD andEVLWITDD compared with the values ob-served after pneumonectomy and duringprotective ventilation. In the INJV group,the pulmonary edema was paralleled byarterial hypoxemia, hemoconcentration,hyperthermia, and increases in the per-meability indexes. These changes, and themoderate pulmonary hypertension, re-flect the development of acute lung in-jury and were accompanied neither by adecrease in cardiac index nor by an in-crease in ITBVI. The derangement of gasexchange in the INJV group, as assessedby a decrease in PaO2/FIO2 after thoracot-omy and pneumonectomy, with a subse-quent increase in QS/QT by 4 hrs (Table2), may be explained by a more extensivecollapse of the exposed left lung becauseno PEEP was used compared with thePROTV group.

During injurious ventilation, theITBVITDD/GEDVITDD ratio was signifi-cantly lower than that found in the groupof protectively ventilated animals. Thisdecrease might be explained by the effectof a higher intrathoracic pressure on IT-BVI in the former group (19, 20). As ex-pected, this effect contributed to an in-crease in EVLW after pneumonectomy, asdetermined with STD and confirmedgravimetrically.

The measurements of EVLWI withboth STD and TDD demonstrated strong

correlations with the reference gravimet-ric values independently of whether theywere considered separately, in parts ofthe study population, or pooled. Recently,we assessed changes in EVLW after botholeic acid– and lipopolysaccharide-induced lung injuries with the STD tech-nique. Previously, we noticed that thegreater the actual EVLWI, the greater theoverestimation of its numeric value bySTD (7). Conversely, in the present study,we observed that the overestimation bySTD declined in parallel with the evolu-tion of edema as determined by gravim-etry (Fig. 4). The latter findings are con-sistent with the results of Rossi et al. (8)and Katzenelson et al. (18) and contrastswith other studies (7, 16). It is likely,albeit not proven in the present study,that the trend for overestimation of STDdepends on the model and severity ofdisease. In part, we believe these resultscan be explained by the decrease inITBVITDD/GEDVTDD ratio after pneumo-nectomy. Notably, the moderate correla-tions between the bias of EVLWISTD vs.EVLWIG and vs. ITBVITDD/GEDVTDD ratiomay confirm some influence of the latteron the accuracy of STD. We recentlyaddressed the changes in ITBVITDD/GEDVTDD under different experimentalconditions, including spontaneousbreathing, ventilation, and pneumonec-tomy (17).

The left and the right pneumonec-tomy groups demonstrated significantdecreases in ITBVITDD, PBVITDD, andITBVISTD compared with sham-operationanimals. The reduction in ITBVITDD com-plies, in part, with the changes describedby Roch et al (16). During injurious ven-tilation, ITBVITDD remained unchanged,whereas ITBVISTD and permeability in-dexes increased significantly in parallelwith the development of ventilator-induced lung injury. The discrepancy be-tween the stable ITBVITDD and the in-creased ITBVISTD in the INJV groupmight be explained by the summarizedeffects of zero PEEP and the aforemen-tioned overestimation of pulmonaryblood volume by STD. Correspondingly,Roch et al. (16) observed a significantlydecreased ITBVITDD and moderately in-creased ITBVISTD after right pneumonec-tomy. Indeed, protective ventilation em-ploying low VT and PEEP has beenassociated with a decreased preload (19).On the other hand, the overestimation ofITBVI by STD might increase because thePiCCO system assumes a constant rela-tionship of PBV/GEDV � 1/4 (Appendix

1). Pneumonectomy primarily reducesPBV by removing a part of the pulmonaryvascular bed. However, this interventiondoes not seem to affect GEDV directly.The latter finding supports the conten-tion of ITBVI as a truthful marker ofpreload, which seems to preserve its ac-curacy even at high intrathoracic pres-sures (20, 21). Our findings agree withexperimental and clinical studies sug-gesting that other factors than fluid over-load alone contribute to the severity andrisk of postpneumonectomy pulmonaryedema (2, 10, 11). In dogs, pneumonec-tomy does not acutely increase suscepti-bility to accumulation of EVLW caused byhemodynamic challenges (11). However,excessive fluid load along with high VT

may worsen outcome from acute lunginjury and increase its prevalence, re-gardless of pathogenesis (22, 23).

The increase in pulmonary arterialpressure and pulmonary vascular resis-tance index registered after right pneu-monectomy could result from increasedblood flow through a substantially re-duced pulmonary vascular bed. Some an-imals of the right pneumonectomy grouppresented with a transient, albeit not sig-nificant, increase in QS/QT immediatelyafter pneumonectomy. These short-termchanges, most likely, reflect rapid redis-tribution of pulmonary blood flow topoorly ventilated and perfused areas ofresidual lung. On the other hand, theincrease in airway pressures subsequentto a doubling of the VT to the injuriouslyventilated lung was not surprising. How-ever, our findings agree with those ofGarcia-Delgado et al. (24), who showedthat pulmonary edema did not developduring a period of �4 hrs in large ani-mals subjected to mechanical ventilationwith VT as high as 50 mL/kg. In our ownpilot experiments on anesthetized sheep(unpublished data), almost all the ani-mals developed barotrauma (e.g., pneu-mothorax or pneumomediastinum) after8–12 hrs of ventilation with VT of 30–50mL/kg, without being preceded by pul-monary edema or derangements of gasexchange. These observations are consis-tent with a recent study on sheep sub-jected to mechanical ventilation at highinflation pressures, resulting in pneumo-thorax and death after 18 hrs in nearlyhalf of the animals (25). Thus, in contrastto small animals that develop stable andreproducible ventilator-induced pulmo-nary edema when exposed to high VT,large animals tend to respond with baro-trauma on mechanical ventilation at high

1556 Crit Care Med 2007 Vol. 35, No. 6

volumes and pressures. Thus, establish-ing a model of ventilator-induced lunginjury in large animals seems to be ratherpuzzling (25).

The present results comply with ex-perimental and clinical studies showingthat prevention of intraoperative andpostoperative lung hyperinflation cansubstantially reduce the risk of postpneu-monectomy pulmonary edema. Higherventilatory pressures and longer durationof one-lung ventilation have been lookedon as independent clinical predictors ofpostpneumonectomy pulmonary edema(5, 26, 27). Accordingly, recent investiga-tions have shown a declining prevalenceof postpneumonectomy pulmonaryedema when measures were taken toavoid negative intrapleural pressure andlung hyperinflation during the postoper-ative period (28, 29). A few years ago,investigators demonstrated that mechan-ical ventilation employing high VT pro-moted lung injury due to pulmonary cap-illary stress (30). Ventilator-induced lunginjury associated with capillary stress dueto overperfusion may also result in severelung impairment. Notably, recent ex-perts’ opinion supports the contentionthat pneumonectomy may be an ideal an-imal model of acute lung injury (2).

In an ongoing clinical study, we haveobserved a significant increase inEVLWISTD after pneumonectomy in eightof nine patients, peaking by 36–48 hrspostoperatively, but without developingmanifest lung edema (31). This time pointmight be critical in terms of an adaptivepostoperative redistribution of pulmonaryblood flow. We hypothesize that an unno-ticed intraoperative or early postoperativelung hyperinflation could be potentiallyhazardous by causing changes that eventu-ally could lead to manifest postpneumonec-tomy pulmonary edema around this criticaltime point.

Taking into account a growing body ofevidence of ventilator-induced lung injury,anesthesiologists and intensivists should beaware of one-lung ventilation with evenmoderately enhanced VT and airway pres-sures as factors that might result in intra-operative and postoperative complicationsrelated to pneumonectomy. Recent reportshave shown that traditionally used VT caneasily exceed 10–12 mL/kg during one-lung ventilation (1, 4, 29). Based on whatwe have learned from these experiments,we speculate that continued use of VT of�10 mL/kg after removal of one lung runsthe same or even higher risks than expos-ing two intact lungs to a VT of 18–22 mL/

kg. Similar concerns have been expressedby the ARDS [Acute Respiratory DistressSyndrome] Network, alerting thoracic an-esthesiologists against the hazards of apply-ing excessive ventilatory volumes and pres-sures during one-lung ventilation (32).

Pneumonectomy can pose the risk ofreleasing a life-threatening acute lung in-jury manifested as a permeability pulmo-nary edema. Clinical signs of postpneumo-nectomy pulmonary edema are nonspecificand include dyspnea, hypoxemia, and re-duced lung compliance that is usuallydelayed by 6 hrs to 3 days after surgery(33, 34). Radiographic changes generallylag behind the onset of physical symp-toms and may be concealed by lung hy-perinflation (4, 5). The pulmonary arterycatheter is of less clinical value for diag-nosing permeability edema (34), and itsreadings may be particularly misleadingafter pneumonectomy (35, 36). There-fore, monitoring of EVLW might be ofvalue as an early warning so that protec-tive ventilatory measures can be takenafter pneumonectomy.

Limitations. The lack of a group dem-onstrating the effects of fluid overloadfollowed by early development of pulmo-nary edema might be considered as apotential limitation of the present study.Notably, variables recorded with the pul-monary artery catheter after pneumonec-tomy, particularly pulmonary artery oc-clusion pressure, have been criticizedpreviously (36). In contrast to Roch et al.(16), we did not use fluoroscopic controlfor the placement of the arterial cathetersor synchronization of indicator injectionwith the respiratory phase. Acquisition ofabsolute amounts of EVLW (in milliliters)instead of indexed ones (in milliliters perkilogram) might be advantageous. Ap-proximated EVLWI values provided by thePiCCOplus monitor lack decimals, whichcan potentially hide minor changes in thevariable. Actually, these maneuvers arenot adhered to in routine clinical practiceusing dilutional measurements (37).Moreover, the possible influence of anaccidentally undue position of the arterialcatheter and respiratory interactions withthe measurements are mutually consid-ered in the present study.

CONCLUSION

Our findings confirm an acceptable ac-curacy of the STD and the TDD techniquesfor quantification of EVLW after pneumo-nectomy and pulmonary edema induced byinjurious one-lung ventilation. The resid-

ual lung tissue, particularly after rightpneumonectomy, seems to be predisposedto the injurious effects of mechanical ven-tilation. Thus, the results of our study mayreinforce the importance of ventilator-induced lung injury as a factor triggeringpostpneumonectomy pulmonary edema.However, this causal link should be delin-eated in future studies.

ACKNOWLEDGMENTS

We thank Dr. Timofey Kondratiev, Dr.Truls Myrmel, and Mrs. Randi Olsen (Uni-versity of Tromsø, Tromsø, Norway) fortheir skillful technical assistance and Dr.Alexander V. Kudryavtsev (NorthernState Medical University, Arkhangelsk,Russian Federation) for statistical reviewof the manuscript.

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16. Roch A, Michelet P, D’journo B, et al: Accuracyand limits of transpulmonary dilution methodsin estimating extravascular lung water afterpneumonectomy. Chest 2005; 128:927–933

17. Kirov MY, Kuzkov VV, Fernandez-MondejarE, et al: Measuring extravascular lung water:Animals and humans are not the same. CritCare 2006; 10:415

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APPENDIX 1

Thermal-dye dilution and single ther-modilution calculate cardiac output basedon the transpulmonary thermodilutioncurve according to Stuart (38).

Thermal-dye dilution determines thedistribution volumes of the thermal andthe dye indicators between the point ofinjection in the right atrium and thepoint of detection in the aorta by using acombination of thermal and dye indica-tors (ice-cold indocyanine green solu-tion). This technique works by exchang-ing cold (temperature) extravascularly,whereas indocyanine green binds to in-travascular albumin. Therefore, intratho-racic thermal volume and intrathoracicblood volume are calculated as cardiac out-put � mean transit time of the thermalindicator dextrose and as cardiac output �mean transit time of the dye indicator, re-spectively. The difference between intratho-racic thermal volume and intrathoracicblood volume gives extravascular lung wa-ter volume.

Single thermodilution only utilizes atemperature indicator (usually, ice-cold 5%dextrose solution). Single thermodilutioncannot measure intrathoracic blood vol-ume directly but calculates pulmonarythermal volume by multiplying cardiacoutput with the down-slope (curve expo-nential decay) time, assuming pulmonarythermal volume to be the largest mixingvolume for the thermal indicator made upby the pulmonary blood volume (PBV) andextravascular lung water volume. The dif-ference between intrathoracic thermal vol-ume and pulmonary thermal volume givesthe maximum end-diastolic volume of thefour heart chambers (i.e., global end-diastolic volume [GEDV]). Because singlethermodilution assumes a constant rela-tionship between PBV and GEDV � 1:4,intrathoracic blood volume is estimatedas GEDV � PBV � 1.25 � GEDV (Fig.5). The difference between intrathoracicthermal volume and estimated intrathoracicblood volume gives extravascular lung watervolume.

Crucial methodologic assumptions oftranspulmonary dilution techniques formeasurement of extravascular lung waterare as follows:

1. Extravascular lung water must bein contact with blood to be “de-tected” by the thermal indicator.Therefore, accuracy of thermal-dyedilution and single thermodilutioncan be compromised by an unevendistribution of pulmonary bloodflow.

2. Down-slope time is supposed togive true pulmonary thermal vol-ume. If down-slope time is too

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long, recirculation of thermal indi-cator may jeopardize the measure-ments by single thermodilution.

3. Changes in PBV are assumed to beproportional to changes in GEDV,

as the GEDV/PBV ratio is assumeduniformly equal to 4/1. Any discor-dant shift in PBV affects the calcu-lation of extravascular lung waterby single thermodilution.

APPENDIX 2

Mathematical outline of equationsused for calculation of extravascular lungwater after postmortem gravimetry(Pearce et al. [14] and Selinger [39]) arepresented below:

EVLWIG � Qwl/BW [1]

Qwl � (Qh � Fwh) � (Qb � Fwb) � Qwt

[2]

Qh � Qlb � Qwt [3]

Qb � Qr � Qr � (1 � Ht)/Ht [4]

Qr � Qh � (Hbs/Hbb) � (Fwh/Fws) � Ht

[5]

where EVLWIG is extravascular lung wa-ter index determined by postmortemgravimetry, Qwl is total extravascularlung water content, Qh is the weight oflung homogenate, Fwh is the fractionalwater content of lung homogenate, Qb isthe residual blood content of the lung,Fwb is the fractional water content ofwhole blood, Qwt is the weight of wateradded during homogenization, Qlb isweight of the wet lung, Qr is the red cellmass of the lung, Ht is blood hematocrit,Hbs is hemoglobin of supernatant, Hbb ishemoglobin of whole blood, and Fws isthe fractional water content of superna-tant.

Figure 5. Illustration and mathematical outline of the thermal-dye dilution (TDD) and the single-indicator thermodilution (STD) techniques used for determination of hemodynamic and volumetricvariables. Where: MTt, indicator of mean transit time; DSt, indicator of down slope (exponential decay)time; TI, thermal indicator; DI, dye indicator. Calculated volumetric variables: ITTV, intrathoracicthermal volume; ITBV, intrathoracic blood volume; GEDV, global end-diastolic volume; PTV, pulmo-nary thermal volume; PBV, pulmonary blood volume, EVLW, extravascular lung water; PVPI, pulmo-nary vascular permeability indexes used in the study. Heart volumes: RAEDV, right atrial end-diastolicvolume; RVEDV, right ventricular end-diastolic volume; LAEDV, left atrial end-diastolic volume;LVEDV, left ventricular end-diastolic volume.

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