Complications of major vascular surgery include lung gas exchange and mechanical disturbances, and the need for prolonged mechanical ventilation after surgery [1-7]. There is ample experimental evidence to suggest that lower body or gut ischaemia/reperfusion (I/R) releases a wide variety of humoral and cellular mediators contributing to lung vascular damage [5,8]. In humans, we demonstrated before that the permeability to intravenously (i.v.) injected and 67Ga- or 111In-labelled transferrin is increased in the lungs directly but not remotely after aortic surgery, as compared to preoperative values and probably associated with a proinflammatory response originating from the I/R area and affecting the lungs [7,9,10]. This was accompanied by subtle lung gas exchange, mechanical and radiographic abnormalities, but a relation of the latter phenomena with release of inflammatory mediators and increased permeability could not be established [9,10]. Nevertheless, increased permeability might contribute to a postoperative elevation of extravascular lung water (EVLW) observed in some patients, since pulmonary fluid accumulation may only partially relate to a high hydrostatic and/or low colloid osmotic pressures (COP) [1,2,11]. However, lung gas exchange, mechanical and radiographic variables may only partially relate to EVLW in critically ill patients [4,12,13]. A postoperative increase in elastance or a decrease in compliance may thus relate to postoperative pulmonary vascular congestion or atelectasis rather than oedema [4,6,14]. Insight into the pathogenesis and interrelations of pulmonary abnormalities after major vascular surgery and I/R could help in designing preventive or therapeutic measures beyond the current practise to mechanically ventilate patients until gas exchange has recovered and extubation can be carried out [4,6].
The current study was thus performed to elucidate the mechanisms of pulmonary ventilatory and radiographic abnormalities in relation to oedema and increased capillary permeability, in patients after major vascular surgery and I/R, in the absence of heart failure.
Patients and methods
This study is a single-centre observational study. The study was approved by the Ethics Committee of the Vrije Universiteit Medical Centre. Written informed consent was obtained in each of the 16 study patients, before planned laparotomy for major vascular surgery. The inclusion criteria, judged when the patients arrived at the intensive care unit (ICU), were absence of heart failure, defined as a pulmonary capillary wedge pressure (PCWP) at or below 15 mmHg in the presence of a pulmonary artery catheter (n = 3) or a central venous pressure (CVP) at or below 12 mmHg in the presence of a central venous catheter (CVC), and a (transpulmonary) cardiac index >2.0L min−1 m−2. Patients were thus only included if they had arterial and pulmonary artery catheters/CVCs. Exclusion criteria were: age > 75 yr, pregnancy, and a life expectancy of < 24 h. On the day of the surgery, anaesthesia was induced with sufentanil 3 μg kg−1 i.v., pancuronium 0.1 mg kg−1 i.v. and midazolam 0.1 mg kg−1 i.v., and maintained with a continuous infusion of propofol. Radial artery, CVCs or pulmonary artery catheters (n = 3) were inserted for haemodynamic measurements and blood sampling. After tracheal intubation, the lungs were ventilated with a tidal volume of 8 mL kg−1 resulting in an end-tidal CO2 concentration between 4 and 5% using an O2-air mixture with an inspiratory O2 concentration of minimum 40%, depending on partial pressure of arterial oxygen (PaO2). A positive end-expiratory pressure (PEEP) of 5 cmH2O was applied, without recruitment manoeuvres. Crystalloid and colloid fluids were infused, when necessary in the presence of low systemic and filling pressures. If volume therapy did not suffice, vasoactive drugs were given. In the presence of a haemoglobin concentration > 6 mmol L−1, packed red blood cells were infused. Preoperative use of aspirin and excessive bleeding prompted for administration of donor platelet concentrates. At the end of surgery, a 4-F introducing sheath (Arrow, Reading, USA) was inserted into the femoral artery, when feasible, for use in the study protocol. The aortic clamping time was recorded.
At the arrival of the patient in the ICU, the patient was connected to the ventilator (Evita 3; Dräger, Lübeck, Germany) and volume-controlled ventilation was started with similar settings as during surgery. The study protocol was started within 3 h after arrival. Patient characteristics were recorded, including the acute physiology and chronic health evaluation (APACHE-II) score and baseline (t = 0 min) measurements of haemodynamics were performed. Pressures were measured after calibration and zeroing to atmospheric pressure at midchest level (Tramscope®; Marquette, GEMS, Milwaukee, Wisconsin, USA). Mean pulmonary artery pressure, CVP and, after balloon inflation, the PCWP were taken at end-expiration, with patients in the supine position. The COP was measured by a membrane osmometer (Osmomat 050; Gonotex, Berlin, Germany; molecular cut-off at 20 kDa), in arterial blood samples. Arterial and mixed (n = 3) or central venous (n = 13) were taken for determination of PO2 and O2 saturation, for calculation of the oxygenation ratio (PaO2 over inspiratory O2 fraction (FiO2)) and shunt fraction Qs/Qt (Rapidlab 865; Bayer Diagnostics, Tarrytown, NY, USA), according to standard formulae. The FiO2, tidal volume, plateau inspiratory pressure and PEEP (cmH2O) were taken from the ventilator. A chest radiograph was taken. Doses of vasoactive drugs were recorded.
Transpulmonary thermal-dye dilution
The measurement involves a central venous injection of 15 mL of ice-cold indocyanine green (ICG) 1 mg mL−1 in 5% dextrose solution. The thermal-dye dilution curve was obtained at the femoral artery (COLD Z-021; Pulsion Medical Systems, Muenchen, Germany), with help of a 3-F catheter (PV 2024; Pulsion Medical Systems, Munich, Germany), introduced via the introducing sheath. This allowed calculation of the transpulmonary thermodilution cardiac output and both the thermal as well as the ICG distribution volume, the intrathoracic blood volume (ITBV). The difference between the volumes is the extravascular thermal volume in the lungs as an estimate of EVLW (normal < 7 mL kg−1), as described and validated before [13,15,16]. The pulmonary blood volume (PBV) is derived from cardiac output and the downslope time of the ICG dilution, as described before . The global end-diastolic volume (GEDV) is derived from intrathoracic thermal volume minus pulmonary thermal volume, the latter derived from the downslope time of thermal dilution. The normal ratio of EVLW/ITBV (mL mL−1) is 0.2-0.3 and the normal EVLW/PBV ratio is about 1. The indices have been proposed to reflect permeability [15,17]. Measurements were done in duplicate, irrespective of the ventilatory cycle, and averaged. GEDV and cardiac output were indexed to body surface area calculated from weight and height, while EVLW was indexed to body weight.
Pulmonary leak index
The pulmonary leak index (PLI) was measured according to previously described methods [9,10]. In brief, autologous red blood cells were labelled with 99mTc (11 MBq, physical half-life 6 h; Mallinckrodt Diagnostica, Petten, The Netherlands), using a modified in vitro method, to correct for blood volume under the probe. Ten minutes after administration of pyrophosphate (TechneScan; Mallinckrodt Medical, Petten, The Netherlands), 10 mL of blood was obtained and equilibrated with 99mTc. Ten minutes later the blood was reinjected. Transferrin was labelled in vivo, following i.v. injection of 67Ga-citrate, 4.5 MBq (physical half-life 78 h; Mallinckrodt Diagnostica, Petten, The Netherlands). Patients were in the supine position and two cesium-iodide scintillation detection probes (Eurorad C.T.T., Strasburg, France) were positioned over the right and left lung apices. Starting at the time of infection of 67Ga, radioactivity was detected every minute for 30 min. The count rates were corrected for background radioactivity, physical half-life and spillover, and expressed as counts per minute (CPM) per lung field. Until 30 min after 67Ga injection, blood samples (2 mL aliquots) were taken. Each blood sample was weighed and radioactivity was determined with a single-well counter, corrected for background, spillover and decay (LKB Wallac 1480 Wizard; Perkin Elmer, Life Science, Zaventem, Belgium). Results were expressed as CPM g−1. For each blood sample, a time-matched CPM over each lung was taken. A radioactivity ratio was calculated as (67Galung/99mTclung)/(67Gablood/99mTcblood), and plotted against time. The PLI was calculated, using linear regression analysis, from the slope of increase of the radioactivity ratio divided by the intercept, to correct for physical factors in radioactivity detection. By taking PBV and thus presumably surface area into account, the radioactivity ratio represents the ratio of extravascular vs. intravascular 67Ga radioactivity. The PLI represents the transport rate of 67Ga from the intravascular to the extravascular space of the lungs and is therefore a measure of pulmonary capillary permeability [9,10]. The values for both lungs were averaged. The upper limit of normal for the PLI is 14.1 × 10−3 min−1 and the measurement error is about 10% . The value is typically elevated three- to fourfold in case of acute respiratory distress syndrome (ARDS) .
Radiography and the lung injury score
The lung injury score (LIS) was calculated from the number of quadrants on the chest radiograph with densities, the PEEP level, the PaO2/FiO2 and the dynamic total respiratory compliance . The latter was calculated from tidal volume/(plateau pressure - PEEP), mL cmH2O−1. The chest radiograph was scored by a consultant radiologist, blinded to the study, who evaluated the number of quadrants with alveolar densities, ranging from 1 to 4. The LIS ranges between 0 (no injury) and 4, with a value above 2.5 indicative of ARDS and between 0 and 2.5 of acute lung injury (ALI) .
We arbitrarily created groups with normal and supranormal EVLW (>7 mL kg−1), and with LIS below and above 1. Comparisons were made with the Fisher’s exact test and the non-parametric U-test. The non-parametric Spearman’s correlation coefficient was used to express relations. Data were summarized as median (range). All tests were two-sided and a P < 0.05 was considered statistically significant.
Table 1 describes the characteristics of the patients, who all survived to discharge, and Table 2 describes the haemodynamic variables. The EVLW was elevated (>7 mL kg−1) in 5/16 (31%) of patients, while the PLI was elevated in 11/16 (69%). An elevated EVLW was associated with an elevated ratio of EVLW to ITBV or PBV as well as with a higher PLI. EVLW directly correlated to GEDV index (GEDVI) (rs = 0.58, P < 0.05). Table 3 shows that all patients had ALI, since PaO2/FiO2 (n > 480) and compliance (n > 80 mL cmH2O−1) had decreased, among others. There was a difference in EVLW/PBV between high and low LIS patients. The latter also differed in the components of the LIS, including gas exchange, mechanical and radiographic abnormalities, while EVLW did not relate to the components. A LIS >1 was associated with prolonged need for mechanical ventilatory support. Conversely, aortic clamping time was higher, and tidal volume and compliance were lower in patients with high vs. low PLI (P < 0.05).
Our study suggests that an elevated EVLW is common after I/R associated with major vascular surgery and that this is mainly caused by increased capillary permeability. However, many of the ventilatory and radiographic abnormalities could be explained by atelectasis rather than mild permeability oedema, since the PLI and EVLW did not differ among LIS groups.
We have shown before that, directly after aortic surgery associated with I/R, the PLI increases two- to threefold, at least temporarily [9,10]. This increase was accompanied by an elevated LIS, but there was no relation between the PLI and the LIS or its components [9,10]. The current study supplements the former [9,10] by documenting an increased EVLW, even though preoperative values were not taken in the same patients. Thus, our current study suggests that an increase in EVLW is associated with mildly elevated alveolar-capillary permeability, as in animal studies , for a given hydrostatic pressure. Indeed, EVLW related to GEDVI, suggesting a contribution by hydrostatic factors as observed during sepsis , since oedema formation by increased permeability may be promoted by hydrostatic factors . In any case, the data are consistent with absence of overt heart failure, by virtue of the inclusion criteria.
Patients with a high LIS had an elevated EVLW as fraction of PBV, suggesting that increased permeability was in part responsible for some of the ventilatory and radiographic abnormalities. However, our data also suggest that increased permeability oedema only partially explained the postoperative increase in LIS, so that unmeasured factors including atelectasis must have contributed. Indeed, atelectasis is common in anaesthetized and mechanically ventilated patients with prior normal lungs, may be difficult to discern on routine supine chest radiographs rather than computed tomography (CT) scans, and may persist for some time after surgery . We did not perform CT scanning because of the transport involved. Moreover, CT scanning does not unequivocally differentiate between oedema and atelectasis. Finally, our patients had a relatively uneventful postoperative course, allowing extubation on the first postoperative day, again arguing in favour of recruitable atelectasis.
There was no relation between compliance on the one hand and EVLW or ITBV/PBV on the other, suggesting that atelectasis was a major cause of a low postoperative compliance [6,14]. We did not separate total respiratory compliance in lung and chest wall compliances in the absence of pleural pressure measurements. Nevertheless, both lung and chest wall elastances may increase and compliances decrease during and after aortic surgery . The lack of relation between radiographic densities and EVLW may agree with the literature [12,13], and this may thus point, again, to, mainly basal, atelectatic areas.
In conclusion, our results suggest that, directly after major vascular surgery-associated I/R, mild and ‘subclinical’ pulmonary oedema formation is common and mainly caused by increased permeability, in the absence of overt heart failure. However, increased permeability oedema only partly contributes to gas exchange, mechanical and radiographic abnormalities, suggesting atelectasis as a contributory factor to lung injury and need for mechanical ventilatory support, after surgery.
1. Virgilio RW, Rice CL, Smith DE et al
. Crystalloid vs. colloid resuscitation: is one better? A randomized clinical study. Surgery
2. Shires GT, Peitzman AB, Albert SA et al
. Response of extravascular lung
water to intraoperative fluids. Ann Surg
3. Vodinh J, Bonnet F, Touboul C, Lefloch JP, Becquemin JP, Harf A. Risk factors of postoperative pulmonary complications after vascular surgery. Surgery
4. Jayr C, Matthay MA, Goldstone J, Gold WM, Wiener-Kronish JP. Preoperative and intraoperative factors associated with prolonged mechanical ventilation. A study in patients following major abdominal vascular surgery. Chest
5. Gelman S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology
6. Volta CA, Ferri E, Marangoni E et al
. Respiratory function after aortic aneurysm repair: a comparison between retroperitoneal and transperitoneal approaches. Intens Care Med
7. Adembri C, Kastamoniti E, Bertolozzi I et al
. Pulmonary injury follows systemic inflammatory reaction in infrarenal aortic surgery. Crit Care Med
8. Iglesias JL, LaNoue JL, Rogers TE, Inman L, Turnage RTH. Physiologic basis of pulmonary edema during intestinal reperfusion. J Surg Res
9. Raijmakers PGHM, Groeneveld ABJ, Rauwerda JA et al
. Transient increase in interleukin-8 and pulmonary microvascular permeability following aortic surgery. Am J Respir Crit Care Med
10. Raijmakers PGHM, Groeneveld ABJ, Rauwerda JA, Teule GJJ, Hack CE. Acute lung
injury after aortic surgery: the relation between lung
and leg microvascular permeability to 111
indium-labelled transferrin and circulating mediators. Thorax
11. Skillman JJ, Restall S, Salzman EW. Randomized trial of albumin vs. electrolyte solutions during abdominal aortic operations. Surgery
12. Halperin BD, Feeley TW, Mihm FG, Chiles C, Guthaner DF, Blank NE. Evaluation of the portable chest roentgenogram for quantitating extravascular lung
water in critically ill adults. Chest
13. Sibbald WJ, Short AK, Warshawski FJ, Cunningham DG, Cheung H. Thermal dye measurements of extravascular lung
water in critically ill patients. Intravascular Starling forces and extravascular lung
water in the adult respiratory distress syndrome. Chest
14. Magnusson L, Spahn DR. New concepts of atelectasis during general anaesthesia. Br J Anaesth
15. Gödje O, Peyerl M, Seebauer T, Dewald O, Reichart B. Reproducibility of double indicator dilution measurement of intrathoracic blood volume compartments, extravascular lung
water, and liver function. Chest
16. Boussat S, Jacques T, Levy B et al
. Intravascular volume monitoring and extravascular lung
water in septic patients with pulmonary edema. Intens Care Med
17. Honore PM, Jacquet LM, Beale RJ et al
. Effects of normothermia vs. hypothermia on extravascular lung
water and serum cytokines during cardiopulmonary bypass: a randomized, controlled trial. Crit Care Med
18. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis