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(Chest. 2005;127:1190-1195.)
© 2005 American College of Chest Physicians

Pneumoproteins as a Lung-Specific Biomarker of Alveolar Permeability in Conventional On-pump Coronary Artery Bypass Graft Surgery vs Mini-Extracorporeal Circuit*

A Pilot Study

Wim-Jan P. van Boven, MD; W. B. M. Gerritsen, MSc; P. Zanen, PhD; J. C. Grutters, MD, PhD; H. P. A. van Dongen, MD, PhD; A. Bernard, PhD and L. P. H. J. Aarts, MD, PhD

* From the Departments of Cardio Thoracic Surgery (Dr. van Bowen), Clinical Chemistry (Dr. Gerritsen), Pulmonology (Drs. Zanen and Grutters), and Anaesthesiology (Dr. van Dongen), St Antonius Hospital, Nieuwegein, the Netherlands; Department of Anaesthesiology (Dr. Aarts), University Hospital Groningen, Groningen, the Netherlands; and Unit of Industrial Toxicology and Occupational Medicine (Dr. Bernard), Faculty of Medicine, Catholic University of Leuven, Belgium.

Correspondence to:: Wim-Jan P. van Boven, MD, Sint Antonius Hospital, Department of Cardio Thoracic Surgery, Koekoekslaan 1, PO Box 2500, 3430 EM Nieuwegein, the Netherlands; e-mail: w.boven{at}antonius.net


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Background: Despite improvements of the heart-lung machine (HLM), oxidative stress and subsequent damage to the alveolar capillary membrane still occur after conventional on-pump coronary artery bypass graft (CCABG) surgery. In an attempt to further improve the conventional HLM, a mini-extracorporeal circuit (MECC) was introduced. This new concept is based on minimal volume shifts. The extent of alveolar injury that is associated with this new technique is unknown. The lung-specific biomarkers Clara-cell 16 (CC16) and KL-6 are applied in this study to quantify alveolar dysfunction in both techniques.

Methods: In a prospective observational setting, the concentrations of CC16 and KL-6 were measured during and after 10 consecutive CCABG operations and 10 consecutive coronary artery bypass graft (CABG) operations using MECC (MCABGs). These pneumoproteins were measured after the induction of anesthesia, before clamping of the ascending aorta, after unclamping of the aorta, on arrival to the ICU, and on the following days until discharge. Quantification of the differences of KL-6 and CC16 leakage through the alveolar membranes between the two techniques was realized by calculation of the Student t test. Perioperative and postoperative shunt fractions and clinical observations were monitored simultaneously. The potential value of pneumoproteins as biomarkers for quantification of alveolar permeability during CABG surgery was tested.

Results: Significantly reduced concentrations of CC16 were found early after MCABG as compared to CCABG surgery (p = 0.033). KL-6 showed no consistent pattern during both treatment modalities. Early after CCABG surgery, shunt fractions tended to show reduced oxygen transport over the alveolar membrane as compared to MCABG surgery.

Conclusion: CC16 appears to be a useful biomarker for alveolar permeability during CABG surgery. Injury of the alveolar capillary membrane appears significantly reduced during MCABG surgery. Consistently early postoperative alveolar shunt fractions showed an increased value in CCABG compared to MCABG surgery in the early postoperative phase. Further randomized studies need to confirm the value of CC16 as marker in monitoring alveolar capillary damage during coronary bypass grafting.

Key Words: Clara-cell 16 • coronary artery bypass grafting • F-shunt • KL-6 • lung-specific proteins


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Despite improvements of the heart-lung machine (HLM), its use is still associated with inflammatory response and oxidative stress.12 As a consequence, reactive oxygen species are formed that are responsible for increased endothelial leakage, causing impaired gas exchange.3456

The patient population referred for coronary artery bypass graft (CABG) surgery has changed significantly during the last decade, ie, the number of older patients with all kinds of comorbidities has increased. Due to a more pronounced fragility of the pulmonary membranes of elderly patients, it is known that the total amount of extravascular lung water is significantly increased during CABG surgery.578

Recently, the concept of the HLM has been revised. A new HLM using a mini-extracorporeal circuit (MECC) was introduced to further minimize its side effects. This new concept is based on the following items: the MECC system consists of a reduced priming volume (< 500 mL); the system is closed; venous blood returns by active drainage instead of gravity; shed blood is processed with help of a cell saver; tubing is heparin coated; and blood cardioplegia replaces crystalloid cardioplegia.910 It is expected that reduced volume shifts, less traumatic blood treatment. and conservation, together with advanced myocardial protection techniques and lower heparinization will have a beneficial effect on perioperative gas exchange and clinical outcome.111213

Concentrations of pneumoproteins (Clara-cell 16 [CC16] and KL-6) are known to be significantly elevated in serum after exposure to certain toxins and in chronic interstitial lung diseases.141516 Pneumoproteins might also be applied as biomarkers for alveolar permeability in time.1718 Pivotal then is quantifying the degree of perioperative lung damage for which there is presently no "gold standard" and which is presently best done by measuring an array of physiologic and biochemical parameters.

CC16, a Clara-cell protein, plays an important immunosuppressive and antiinflammatory role in the lung.19 It can also prevent degradation of lung surfactant phospholipids.20 Besides this, CC16 is involved in the sequestration or clearance of some harmful substances deposited in the respiratory tract. Elevated blood levels during and after coronary surgery may reflect discontinuity of alveolar membranes in lung tissue.21

Mucin-associated antigen KL-6 is a protein that is almost exclusively secreted by pneumocyte II cells within the respiratory tract.22 Their occurrence in the vascular compartment can only be explained by assuming their leakage from the lung into the bloodstream. Functionally this protein seems to be involved in the pneumocyte regeneration system. Otherwise, it is suggested to be implicated in lung fibrinogenic process.2324 This protein shows variations in the serum of patients with different lung diseases and subjects exposed to lung toxicants, suggesting that their assay represent a new approach in the assessment of lung disorders. The value of KL-6 as a marker for lung tissue damage was shown in several interstitial lung diseases.25 The aim of this study was to compare these parameters during and after the two mentioned techniques for CABG surgery. By doing so we want to tailor the least damaging technique for the vulnerable (older and comorbid) patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Twenty patients, 13 men and 7 women, undergoing elective coronary bypass surgery were consecutively enrolled in this prospective observational study. Ten patients were operated on using conventional on-pump CABG (CCABG) technique, and 10 patients were operated on using CABG and the MECC technique (MCABG). No exclusion criteria other than redo CABG and a minimum of three distal anastomoses were defined.

Conventional Perfusion Protocol
The ECC closed circuit was composed of a roller pump (Sarns), a hollow-fiber polypropylene oxygenator (Quadrox BE-HMO 1010; Jostra; Hirrlingen Germany), a venous reservoir (Quadrox BMR 1900G; Jostra), a cardiotomy reservoir (Quadrox BE-AC2811; Jostra), and Rehau Bioline-coated tubing (Maquet/Jostra). The pump was primed with 1,600 mL. The heart was protected with topical cooling, together with 1,000 mL of cold cardioplegic solution based on hydroxyethyl starch. Blood from the surgical field will was collected in and processed by a cell-saving device (BRAT 2; Cobe).

MECC Protocol
The MECC system consists of a closed system containing a centrifugal pump (Rotaflow; Jostra) and a membrane oxygenator (Quadrox D; Jostra). The venous line is directly connected to a centrifugal pump. All the components are Bioline coated (Jostra). Priming volume of the system is 500 mL of NaCl 0.9% (this solution contains 14.4% hydroxyethyl starch). Depending on the patient’s hemostability, the amount of prime solution was returned to zero by starting MECC. Myocardial protection was performed by using a modified Calafiori technique. Blood from the surgical field was collected in a cell-saving device (BRAT 2; Cobe).

Sample Collection and Analyses
Samples were obtained from the radial artery, and collected in tubes containing K3, ethylenediamine-tetra acetic acid, or lithium heparin before, during, and after CABG surgery. All results were corrected for hemodilution according to the method described by van Beaumont26 and Hermans et al.27 Albumin remained constant during all time points (data not shown). Sample points are defined as follows: T0 = just after induction of anesthesia; T1 = just before starting extracorporeal circuit; T2 = 10 min after removal of the cross-clamp on the aorta; T3 = arrival at the ICU; T4 = 3 h after arrival at the ICU; T5, 9 h after arrival at the ICU; T6 = 15 h after arrival at the ICU; and time 7 = 7 AM every following day until dismissal.

Blood gas analysis was processed in a routine way with the help of a standard laboratory system. The samples were immediately placed on ice and delivered to the laboratory within 15 min after collection. Plasma was obtained by centrifugation (lithium heparin blood) at 2,200g for 10 min, and the samples were frozen to – 80°C until analysis. Routine analyses were performed within 1 h. Laboratory analysts were blinded for the clinical data.

Measurement of Damage to the Alveolar Membrane
The concentration of CC16 was determined by an immunoassay relying on the agglutination of latex particles, as described previously.16 The KL-6 level was measured by a sandwich-type enzyme-linked immunosorbent assay technique using a KL-6 antibody kit (ED046; Eisai; Tokyo, Japan) kindly provided by the manufacturer. All samples were run in duplicate, and mean values were used for subsequent values.28

Pulmonary Function Testing
F-shunt was calculated using software (Oxygen Status Algorithm, version 2.0; Mads&Ole Siggaard; Radiometer). This program needs the arterial blood gas and the fraction of inspired oxygen. It calculates the percentage of blood that is not supplied by oxygen.

Statistical Analysis
Data were expressed as mean (SD). The Student t test was used to compare pneumoprotein concentrations between groups. Statistical analyses were performed using software (SPSS 11.5; SPSS; Chicago, IL); p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
All patients included were admitted for elective revascularization of the heart. The preoperative clinical and surgical data are presented in Tables 1 and 2 , respectively. The preoperative clinical data show no significance between both groups with respect to gender, age, severity of coronary disease, diabetes mellitus, New York Heart Association functional class, left ventricle function, and extent of vessel disease. Preoperative laboratory analysis revealed no patients with renal dysfunction (plasma creatinine levels > 120 µmol/L). For the surgical data, the groups were similar with respect to the number and distribution of distal anastomoses. In the two study groups, no hospital mortality, neurologic accidents, incidences of myocardial infarction, or acute renal failure occurred.


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  		Table 1. Demographics and Clinical Data*

 

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  		Table 2. Surgical Data*

 
CC16 and KL-6 Measurements
There were significant differences for mean CC16 concentration for the CCABG patient group at the sampling moments T2 and T3 compared to T0 (T2 vs T0, p = 0.001; T3 vs T0, p < 0.001). For both groups, there was an increase in mean CC16 concentration compared to the baseline sampling moment (T0) from 9.1 ± 2.6 to 22.6 ± 10.0 µg/L (T3) for the CCABG patient group and from 7.5 ± 3.4 µg/L (T0) to 14.0 ± 9.1 µg/L (T3) for the MECC patient group. For all sampling moments, the mean CC16 concentration was lower for the MECC patient group compared to the CCABG patient group (T0, p = 0.245; T1, p = 0.054; T2, p = 0.058; T3, p = 0.069) [Table 3 ].


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  		Table 3. Concentrations of the Pneumoproteins KL-6 and CC16*

 
For KL-6, the highest mean concentration was at T0, after which the mean concentration decreases. We found a big scatter of the KL-6 concentrations at all sampling moments in each patient for both groups. The concentration of KL-6 was for none of the patients above the normal reference value (Table 3).

Shunting
At arrival ICU (T3), the F-shunt was significantly increased for the CCABG group (mean, 0.17 ± 0.059% [p = 0.022]) as compared to the MCABG patient group (mean, 0.11 ± 0.048%); just before weaning of the ventilator; the F-shunt for the CCABG patient group decreased from 0.17 ± 0.059 to 0.14 ± 0.048% and remained stable for the MCABG patient group. Despite the decrease of the F-shunt after weaning of the ventilator for the CCABG patient group, the F-shunt remained higher. The time for extubation for the CCABG patient group was 6.3 ± 2.0 h and 5.1 ± 2.3 h for the MCABG patient group (Table 4 ).


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  		Table 4. Shunt Calculations*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In this pilot study, the potential value of CC16 as a biomarker for damage of the alveolar capillary membrane during CABG is suggested. A significantly increased leakage of CC16 into the bloodstream in CCABG was found as compared to MCABG (Student t test, p = 0.035; Table 3). In addition and compatible with these results, we found significantly increased alveolar shunt fractions on arrival at the ICU; these values normalized during the first postoperative 4 to 6 h (Table 4). By that time, all patients in this comparison study were successfully extubated. The other pneumoprotein KL-6 did not show a consistent pattern, and no significant elevation during the study period was observed (Table 3).

Until now, no biomarkers have been available indicating the extent of alveolar damage during CABG surgery. Usually, the extent of alveolar dysfunction is determined by the amount of extravascular lung water (transpulmonary thermodilution) or chest radiograph scores. Further clinical parameters such as shunt fractions and oxygen gradients are valuable methods to measure the percentage of blood that is not oxygenated during lung passage. However, these values are difficult to interpret, since the contribution of atelectases responsible for the outcome of these parameters is a major confounder. The use of a biomarker like CC16 might be of additional value in this respect, since its presence in the bloodstream purely reflects alveolar dysfunction as a result of a destructive process at membrane level. Because CC16 is a small molecule (104 d), leakage into the bloodstream can be expected after minimal damage to the alveolus. In this pilot study, we were able to show significantly increased leakage in CCABG surgery as compared to MCABG surgery. The finding suggests that MECC causes less functional impairment of the alveolar compartment compared to the conventional HLM procedure. The mechanisms responsible are not well understood yet but might include the following: first, it is known that the MECC system consists of a reduced priming volume and active drainage. These two components may contribute to a beneficial effect at the level of the alveolus in MCABG surgery because of reduced differences in hydrostatic capillary diffusion as it reduced changes in osmolarity during surgery. Second, the reduction of inflammatory response during MCABG as compared to CCABG can contribute to a reduction of alveolar permeability.11 Third, due to ischemia, the alveolar membranes are also likely to be affected by oxidative stress. Finally, a reduced need for blood transfusion in MCABG surgery may also reduce inflammatory response and its effects on alveolar membranes. All four mechanisms are presumed to be involved in the mechanism of destruction of alveolar membranes, and as such reduction of each might contribute to preserved alveolar function. Importantly in this context, it has to be noted that perioperative stress caused by mechanical ventilation was presumed to be similar in both study groups.29 Mechanical ventilation has an uncertain impact on alveolar function, since it can provoke barotraumas and toxic response to anesthetic agents. But in this comparison, the lungs were not ventilated during suturing of the distal anastomoses in both patient groups.

KL-6 is a valuable biomarker in chronic pulmonary diseases. The reason we did not find a consistent response of KL-6 to ECC in this pilot study is unclear. It can be speculated that KL-6 is a larger-size molecule that does not penetrate the defects caused by extracorporeal circulation. More likely the explanation lays in the presumed role of KL-6 in alveolar epithelial regeneration.25 Therefore, its presence in the bloodstream cannot be expected until the regeneration process has started, a process that goes beyond the sampling period of this study.

CC16 seems to be a promising biomarker in monitoring of the alveolar compartment during heart surgery. Especially, it might be able to distinguish subtle differences in alveolar function during different techniques. If the suggested results of CC16 can be confirmed in a randomized set-up, CC16 monitoring might help tailoring a minimal traumatic technique for the more vulnerable patient in need for cardiothoracic surgery.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
In this pilot study, the usefulness of CC16 as biomarker for alveolar capillary membrane damage during CABG surgery is suggested. CC16 concentrations in blood showed significantly increased alveolar membrane dysfunction in CCABG patients as compared to MCABG patients. Concomitantly, these results were supported by F-shunts, which showed similar trends.


   Acknowledgements
 
The authors thank David Boss, student of Biomedical Science, University of Utrecht, for his assistance.


   Footnotes
 
Abbreviations: CABG = coronary artery bypass graft; CC16 = Clara cell 16; CCABG = conventional on-pump coronary artery bypass graft; HLM = heart-lung machine; MCABG = coronary artery bypass graft operations using mini-extracorporeal circuit; MECC = mini-extracorporeal circuit; T0 = just after induction of anesthesia; T1 = just before start extracorporeal circuit; T2 = 10 min after removal of the cross-clamp on the aorta; T3 = arrival at the ICU; T4 = 3 h after arrival at the ICU; T5 = 9 h after arrival at the ICU; T6 = 15 h after arrival at the ICU

Received for publication May 18, 2004. Accepted for publication September 30, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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