Pulmonary dysfunction after cardiac surgery is a well-established sequela1 and an important cause of postoperative morbidity, leading to prolonged tracheal intubation, continuing impairment of gas exchange, and extended stay in the intensive care unit. The etiology of this pulmonary dysfunction is multifactorial and includes the combined effects of anesthesia, cardiopulmonary bypass (CPB), and surgical trauma.2
Cardiac surgery with CPB is associated with a systemic inflammatory response. This process involves activation of humoral inflammatory cascades and blood cells. Neutrophils in particular, and also monocytes, become activated and adhere to vascular endothelium before their transmigration into the subendothelial space. Transmigration and endothelial disruption is followed by tissue edema and organ dysfunction.3
Cardiopulmonary bypass has been implicated as a major determinant of pulmonary dysfunction and remains an important cause of morbidity.4–6 Coronary artery bypass grafting (CABG) surgery using mechanical stabilization has been shown to produce a reduced inflammatory response.7,8 Previous clinical studies have suggested that patients having CABG using mechanical stabilization rather than CPB have improved lung function postoperatively and can be extubation earlier,9,10 but not all studies are in agreement with these findings.2,11,12
In this study, we investigated pulmonary function in patients undergoing CABG via median sternotomy on-CPB versus off-CPB to elucidate whether the off-CPB condition results in improved postoperative pulmonary function. We assessed pulmonary function by measuring arterial partial pressure of oxygen on FiO2 1.0 and by evaluating spirometry and diffusion studies. To measure diffusion we evaluated the transfer factor for carbon monoxide (TLCO). Previous studies have not extensively evaluated this phenomenon, and it requires further understanding. The TLCO is a unique noninvasive window on pulmonary microcirculation.13 It measures the potential of the lung for gas exchange.14 Its importance lies in the fact that in the presence of normal lung volumes and spirometry, it may be the sole abnormal test result suggesting a pulmonary vascular disorder or other causes of pulmonary vascular obliteration. Conditions resulting in a low TLCO can be divided into those that cause or are due to incomplete lung expansion, discrete loss of alveolar units, diffuse loss of alveolar units, obstructive lung lesions, and pulmonary vascular disorders.13
This study also evaluated postoperative intubation time, intensive care stay, and total hospital stay.
The protocol was approved by the Ethical Committee, and informed consent was obtained from all patients. Forty patients undergoing primary CABG were randomized into 2 groups: those on-CPB (group A), and those off-CPB (group B). Randomization was achieved by mixing nontransparent envelopes containing cards marked with the code of each group. Envelopes were mixed several times to avoid potential allocation bias. Consecutive patients meeting the criteria and attending the Cardiothoracic Department at our institution were invited to participate in the trial. Exclusion criteria for patients were known inflammatory diseases, existing infections, emergent surgery, use of long-term corticosteroids and nonsteroidal antiinflammatory drugs, use of antiplatelet agents in the week before surgery, severe preexisting renal (creatinine > 200 μmol/L) or lung dysfunction (forced vital capacity [FVC] or forced expiratory volume in 1 second [FEV1]< 80% of predicted), left ventricular ejection fraction < 40%, known coagulopathy or long-term anticoagulation with warfarin, and refusal to consent to participating in the trial. To be included in the study, patients were required to have at least 3-vessel disease on their preoperative angiogram or, in the view of the chief physician, require at least 3 coronary bypass grafts. The patient groups were well matched in terms of age, sex, preoperative risk factors, angina class, and left ventricular ejection fraction (Table 1).
Patients who met the criteria and agreed to participate in the trial underwent formal pulmonary function testing, including spirometry and diffusion studies. Patients whose results were within the required levels were then available for randomization. Randomization was undertaken the day before surgery.
Anesthetic and Operative Techniques
Standardized techniques were used for anesthesia and CPB. Anesthetic premedication included morphine (10 mg) and hyoscine (0.3 mg) administered intramuscularly. Anesthesia was induced with midazolam (100–200 mg/kg), fentanyl (150–200 mg), and pancuronium (50–100 mg/kg), and was sustained with propofol (5–10 mg · kg–1 · h–1).
In the on-CPB patient group, the operation was performed through a median sternotomy. Heparin (300 IU/kg) was administered to achieve an activated clotting time of over 480 seconds before aortic and venous cannulation. The CPB circuit used during the study period in our Cardiothoracic Department consisted of a roller pump (Stockert Instruments, Munich, Germany), a Bardâ William Harveyâ HF-570 membrane oxygenator (Bard Inc.), and polyvinylchloride coated tubing (Sorinâ). Nonpulsatile extracorporeal circulation was used at 2.4 to 2.8 L2·m–1·min–1. Moderate hypothermia of 32°C was used in all patients. Myocardial protection was administered with a Sorinâ cardioplegia delivery system using initially 800–1000 mL cold blood antegrade cardioplegia, mixed with St Thomas’ crystalloid solution in a 4:1 ratio, with an additional 300 mL every 20 minutes. Mean arterial pressure was maintained between 50 and 70 mm Hg using metaraminol as required. Mechanical ventilation was discontinued during CPB and was restarted before separation. Protamine sulfate was used at the end of the procedure to reverse the activated clotting time to preoperative values.
When CABG was performed without CPB, anticoagulation was achieved using 150 IU/kg heparin. The activated clotting time was maintained above 250 seconds. The operation was performed through median sternotomy using the Guidant Acrobat SUV (Guidant, IN) stabilization device. Mean arterial blood pressure was maintained between 50 and 70 mmHg during the procedure by means of adequate filling, repositioning the heart, and selective use of vasoconstrictors. A standby perfusionist with a primed bypass circuit was available for all cases. Esophageal echocardiography was used intraoperatively to assess right and left ventricular function and to identify localized wall motion abnormalities. Protamine sulfate was used at the end of the procedure to reverse activated clotting time to preoperative values.
Intensive Care Unit Management
All patients were initially transferred to the cardiothoracic intensive care unit (CTICU). Patients were ventilated initially with FiO2 of 1.0, synchronized intermittent mandatory ventilation at 10 breaths/min (SIMV 10), and positive-end expiratory pressure of 5 cmH2O. Adjustments in FiO2 and respiratory rate were made according to routine blood gas analysis to maintain a PaO2 > 10 kPa and a PaCO2 between 4 and 5.5 kPa. Fluid management postoperatively consisted of dextrose saline infused at a rate of 1 mL · kg–1 · h–1 with additional colloid to maintain normovolemia. Patients were transfused homologous blood if their hemoglobin fell below 8 g/dL. Patients received inotropes to maintain their mean arterial pressure above 70 mm Hg.
Measurement of Clinical Parameters
Preoperatively, patients underwent lung function testing including spirometry (forced expiratory volume in one second and forced vital capacity) and diffusion studies (TLCO and carbon monoxide transfer coefficient). These tests were repeated again on the fifth postoperative day.
Intraoperatively, patients received routine cardiovascular and pulmonary monitoring. Arterial blood gas (ABG) analysis was determined by the anesthetist and perfusionist. Immediately after intubation, an ABG on FiO2 1.0 (time point 1, TP1) was taken for measurement of the partial pressure of oxygen (PaO2). Further ABGs on FiO2 1.0 were obtained 15 minutes after sternal closure (TP2) and 3 hours postoperatively (TP3). The duration of cardiopulmonary bypass, aortic cross clamp time, number of grafts per patient, vessels grafted, and conduits used were recorded.
Postoperatively, data were prospectively collected on the following parameters: length of intubation, use of inotropic agents, postoperative chest tube drainage in the CTICU, homologous blood transfusion requirements, and length of CTICU stay. Postoperative complications including atrial fibrillation, renal dysfunction, chest problems (chest infection, pneumothorax or hemothorax, and atelectasis), and cerebrovascular accidents were all recorded until the patient was discharged home. The total postoperative length of stay was also recorded.
Results were expected to follow a normal distribution. Data were expressed as mean and standard deviation or mean and standard error of the mean. For demographic data, the t test was used to compare continuous variables and the χ2 test was used to compare nominal data between groups. A mixed model analysis of variance techniques was used to look for effects over time and between treatment groups. Bonferroni corrections were applied to the P values to allow for the multiple comparisons that were made with preoperative values. Significance was assumed for P values less than 0.05.
There were no differences in the patient demographics or intraoperative details between the two groups (Tables 1 and 2). Although blood loss from the chest drains in the intensive therapy unit was not significantly different between the two groups, the on-CPB group had significantly more homologous blood transfusion during this time (P = 0.015; Table 3).
Data are presented as number (percentage) of patients unless otherwise indicated.
The partial pressure of oxygen decreased significantly in both groups from TP1 to TP2 (59.5 ± 11.5 kPa and 55.7 ± 12.2 kPa at TP1 falling to 39.5 ± 16.3 kPa and 39.7 ± 13.1 kPa at TP2 in groups A and B, respectively; P < 0.001). There was no difference between the groups (P = 0.4). The PaO2 partially recovered toward preoperative levels at TP3 in both groups (49.7 ± 16.5 and 49.5 ± 11.6, respectively). Spirometry showed a significant reduction postoperatively in FEV1 and FVC (Figs. 1a and 1b, respectively) in both groups (P < 0.005). There was no difference between the groups.
The TLCOc (corrected TLCO for hemoglobin) was significantly reduced postoperatively in the on-CPB group only (P < 0.05). In the off-CPB group the reduction was not significant postoperatively (Fig. 2). The carbon monoxide transfer coefficient was not significantly changed postoperatively in either group (1.44 ± 0.27 and 1.33 ± 0.24 preoperatively and 1.33 ± 0.24 and 1.42 ± 0.39 postoperatively in groups A and B, respectively).
No deaths occurred during the study. The occurrence of postoperative complications was not significantly different between the groups (Table 3), although there were more respiratory complications in the form of chest infections, lung collapse, and pneumothoraces in the on-CPB group. Intubation time, CTICU stay, and total hospital stay were not significantly different between the two groups, but were consistently shorter in the off-CPB group.
Severe lung injury after CABG is uncommon but still remains a significant cause of morbidity and mortality. Numerous studies have shown a decrease in pulmonary gas exchange in patients undergoing CABG. The reasons for this include decreased lung compliance, decrease in functional residual capacity, an increased shunt caused by leukocyte migration to the lungs, and increased permeability of the alveolar-capillary barrier.6,15,16 CPB is a major determinant of pulmonary dysfunction and remains an important cause of morbidity. Cardiac surgery with CPB is associated with a systemic inflammatory response, and this has been mentioned as a potentially important cause of pulmonary dysfunction.17,18 Deterioration after CPB is thought to be multifactorial and due to the effects of anesthesia, surgical trauma, and CPB. Further studies show that CABG off-CPB results in a marked reduction in the inflammatory response compared with on-CPB CABG.7,8,19
We found a significant reduction in the partial pressure of oxygen on a FiO2 of 1.0 in both the on-CPB and off-CPB groups, with no difference between the groups. These findings have been reported in previous studies either in the form we have mentioned or in the form of PaO2/FiO2 when the PaO2 has been taken at various FiO2 levels.12,20 Kochamba et al.20 reported a similar degree of pulmonary dysfunction in both groups, as assessed by alveolar-arterial oxygen gradient. Cox et al.2 found no significant difference between groups when looking at the A-a oxygen gradient and concluded that pulmonary dysfunction after CABG is more likely due to the effects of the surgery itself and the anesthesia than to the effects of CPB.
The significant reduction in FEV1 and FVC seen in both groups on the fifth postoperative day, with no significant difference between groups, has again been reported in previous studies,12 with the reduction persisting for up to 4 months postoperatively.21 The reasons for this reduction are multifactorial, and the present data suggest that this is not totally attributable to CPB. Potential causes of impairment include poor coughing and pain from sternotomy and associated surgical trauma, mechanical alteration in rib cage and sternal alignment, phrenic nerve dysfunction and reflex mediated decreases in diaphragmatic function, and possible muscle weakness and dysfunction.12
Regarding the diffusion studies, we found that the TLCOc was significantly better preserved from preoperative levels in the off-pump group. This investigation has not been evaluated in other studies. The TLCO is a unique noninvasive window on pulmonary microcirculation.13 It measures the potential of the lung for gas exchange.14 Its importance lies in the fact that in the presence of normal lung volumes and spirometry, it may be the sole abnormal test result hinting at a pulmonary vascular disorder or other causes of pulmonary vascular obliteration. Conditions resulting in a low TLCO can be divided into those that cause or are due to incomplete lung expansion, discrete loss of alveolar units, diffuse loss of alveolar units, obstructive lung lesions, and pulmonary vascular disorders.13
At the alveolar-capillary membrane during lung injury, there is a breakdown of the blood endothelial barrier that results in increased capillary permeability, which leads to extravasation of plasma components and leukocytes into interstitial tissue and then into alveoli resulting in lung dysfunction. The significant reduction in TLCO seen in on-CPB patients could be explained by an increased alveolar inflammatory infiltrate and increase in diffusion distance in this patient group leading to a diffuse loss of alveolar units and hence abnormal gas exchange. Tschernko et al.22 showed that intrapulmonary shunting and hypoxemia after CABG was significantly higher in patients on-CPB than in the those having surgery off-CPB. Hachenberg et al.,23 in concurrence with other investigators, suggested that atelectasis after on-CPB CABG is a major cause of intrapulmonary shunting. Atelectasis can further lead to decreasing the TLCO in this on-CPB group by causing incomplete lung expansion.1 TLCO is probably a better way to assess lung function than PaO2, lung volumes, and spirometry, which have been looked at exhaustively in previous studies that have concluded that the level of pulmonary dysfunction is no different between on-CPB and off-CPB conditions.
In conclusion, our study demonstrates that avoidance of CPB is beneficial in maintaining pulmonary gas exchange at the alveolar-capillary level and ameliorates the unwanted impairment of oxygenation in the postoperative period in patients undergoing CABG with no significant preoperative impairment of respiratory function. There was no significant difference in intubation time, intensive care stay, and length of hospital stay between groups. However, all of these variables were decreased in the off-CPB group, and with larger numbers of patients this difference may have been significant. We looked at a group of patients with no preoperative impairment of lung function. The next stage would be to evaluate a group of patients with preexisting impairment of lung function in whom this effect might be more pronounced.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
Coronary artery bypass grafting; Cardiopulmonary bypass; Off-pump coronary artery bypass; Lung function; Pulmonary gas exchange