R complication of cardiopulmonary bypass (CPB) since. Respiratory Dysfunction After Uncomplicated Cardiomlmonarv Bvpass

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1 Respiratory Dysfunction After Uncomplicated Cardiomlmonarv Bvpass I J J I David P. Taggart, MD(Hons), Mohammed El-Fiky, MB, Rodger Carter, MSc, Adrian Bowman, PhD, and David J. Wheatley, FRCS Departments of Cardiac Surgery and Respiratory Medicine, Royal Infirmary, Glasgow, and Department of Statistics, Glasgow University, Glasgow, Scotland Respiratory dysfunction is a well-recognized complication of cardiac operations. To quantify its current incidence and severity after uncomplicated cardiopulmonary bypass, serial measurements of arterial oxygen tension (Pao,), alveolar-arterial oxygen gradient (Aao,), and percentage pulmonary shunt fraction (%PSF) measured by a noninvasive technique were made in 129 patients (age, years (mean f standard deviation) with good left ventricular function (left ventricular end-diastolic pressure <15 mm Hg) undergoing isolated coronary artery operations (group 1) and 30 patients undergoing general surgical procedures (group 2). Measurements were made before operation and on the first, second, and sixth postoperative days. Seven patients in group 1 who required prolonged ventilation were excluded from further study. In group 1, between the preoperative and second postoperative days, there was a marked fall in Pao, [ versus mm Hg; p < and a marked increase in the Aao, gradient [ versus 50 f 11 mm Hg; p < 0.00l)l and %PSF [3 2 1% versus %; p < 0.00l)l with only modest improvement by the sixth postoperative day [Pao,, 67 * 11 mm Hg; Aao,, 45 * 11 mm Hg; %PSF, There were similar but less severe changes in Pao, and Aao, gradients in group 2 patients, with a return to baseline values by day 6. Regression analysis in group 1 patients showed a weak correlation between postoperative respiratory dysfunction and preoperative impairment of the Aao, gradient, but no correlation with age, sex, smoking status, New York Heart Association status, bypass time, or violation of the pleural sacb). To determine the duration of respiratory dysfunction after cardiac surgery, serial Pao, and Aao, gradient measurements were continued until the sixth postoperative week in a further 30 patients (group 3). Group 3 patients demonstrated similar early impairment of respiratory function to group 1 patients but with complete resolution by the sixth postoperative week. This study demonstrates that respiratory dysfunction is both common and frequently severe even after uncomplicated cardiopulmonary bypass but resolves by the sixth postoperative week. Respiratory dysfunction is also common after a major general operation but is less severe and resolves by the sixth postoperative day. (Ann Thoruc Surg 2993;56:1123-8) espiratory dysfunction has been a well-documented R complication of cardiopulmonary bypass (CPB) since the earliest days of cardiac surgery [l-lo]. Although it remains a well-recognized complication of CPB, its incidence and severity in current practice are not clearly documented. Kirklin's group [ll] reported a 30% incidence of pulmonary complications after CPB, but the methods of measurement were subjective and relatively insensitive. Furthermore, the last decade has seen changes in surgical patients toward an increasingly elderly and sicker population [ who may be more susceptible to respiratory dysfunction because of a significant age-related decline in respiratory reserve after the middle of the sixth decade [15, 161. To evaluate the frequency and severity of respiratory dysfunction after uncomplicated CPB, we compared 129 coronary artery surgery patients (group 1) and 30 general surgery patients. Serial measurements of arterial oxygen Accepted for publication Dec 31, 1992 Address reprint requests to MI Taggart, Department of Cardiothoracic Surgery, Royal Brompton National Heart and Lung Hospital, Sydney St, London SW3 6NP, England. tension (Pao,), alveolar-arterial oxygen gradients (Aao,), and percentage pulmonary shunt fractions (%PSF) measured by a noninvasive technique were made before operation and on the first, second, and sixth postoperative days. In a further group of 30 patients undergoing coronary revascularization (group 3), measurement of Pao, and Aao, were repeated 6 weeks after operation. The effects of age, sex, smoking status, New York Heart Association (NYHA) status, Pao,, Aao, gradient, %PSF, bypass time, ischemic time, and violation of the pleural sac(s) on respiratory dysfunction were investigated by regression analyses. Material and Methods Ethical permission for the studies was given by the Hospital Ethical Committee, and patients gave informed consent before inclusion. Patients We initially studied 129 patients undergoing elective isolated coronary artery operations (group 1) and 30 patients undergoing major general surgical procedures by The Society of Thoracic Surgeons $6.00

2 1124 TAGGART ET AL Ann Thorac Surg 1993; (group 2). A further 30 patients undergoing coronary revascularization were studied again at 6 weeks (group 3). No patient had overt clinical evidence of respiratory or cardiac impairment. No patient had suffered a myocardial infarction in the 3 months before the study. Cardiac patients requiring diuretic therapy in excess of 40 mgday of furosemide or with a left ventricular end-diastolic pressure greater than 15 mm Hg were excluded. Valvular heart disease was excluded on clinical grounds and by left ventricular injection during coronary angiography. In the postoperative period, patients requiring ventilatory assistance for greater than 24 hours were excluded from further study. Measurement of Respiratory Dysfunction Serial examination of Pao,, Aao, gradient, and %PSF was performed in the preoperative period and on the first, second, and sixth postoperative days (and at 6 weeks in group 3 patients). The Pao, was measured from a blood sample obtained by direct arterial puncture of the radial artery for the preoperative, sixth-day, and 6-week samples and from an in-dwelling radial artery cannula for all other samples. All samples were collected with the patient having breathed room air for at least 10 minutes. The samples were processed immediately for Pao, and ph using a calibrated Corning 178 phblood Gas Analyser (Ciba-Corning Diagnostics, Medfield, MA) and for arterial oxygen content using a Corning 2500 Co-oximeter. The Aao, gradient was measured simultaneously with arterial oxygen tension with the patient initially breathing room air and then after the patient had breathed 100% oxygen for 10 minutes. The partial pressure of alveolar oxygen was calculated with reference to the respiratory exchange ratio measured on samples of expired air collected through a nasal cannula into an anesthetic bag. These samples, obtained simultaneously with arterial blood samples, were analyzed for the fractional concentrations of oxygen and carbon dioxide using a paramagnetic and infrared analyzer, respectively (P.K. Morgan, Rainham, Kent, UK). The partial pressure of alveolar oxygen (PAo,) is given by the "ideal" alveolar air equation P71 PAO~ = Fiop(BP - 47) - PacodR Pacoz(1 - R)R, where Fio, is the fractional concentration of oxygen in inspired air, BP the barometric pressure, 47 the saturated vapor pressure, the fractional concentration of oxygen in room air, Paco, arterial carbon dioxide tension, and R the respiratory exchange ratio: R = Feco,(Fio, - Feo,), where Feo, and Feco, are the fractional expired oxygen and carbon dioxide concentrations. Measurement of the %PSF was calculated without the need for Swan-Ganz catheterization as described in the mathematical model of Riley and Permutt [MI, and which we have previously validated in cardiac surgery patients [19]. This model is essentially based on the difference in Aao, gradient present when the patient initially breathed room air and then breathed 100% oxygen [MI. To confirm its validity in postoperative cardiac patients, we previ- ously measured the %PSF using this model and compared it with the value simultaneously obtained by Swan-Ganz catheterization [19] and demonstrated excellent correlation between the two techniques (r = 0.94, p < 0.001). Anesthetic Regimen and Cardiopulmonary Bypass A standard anesthetic regimen was followed. Anesthesia was induced with midazolam and fentanyl, and intubation was performed after administration of atracurium or pancuronium. Anesthesia was maintained with morphine, fentanyl, midazolam, and atracurium or pancuronium. The lungs were not ventilated during CPB. Cardiopulmonary bypass was performed with pulsatile perfusion, bubble oxygenation, moderate systemic hypothermia (28" to 30"C), a 40+m arterial line filter, and 2 L of crystalloid prime. Flow rates were based on the formula that at normothermia flow was equal to 2.4 x Body Surface Area and was reduced to two-thirds at 28 C. Pulsatile flow, achieved with a Stockert pump, was defined as 72 pulsedmin, a 50% run time at 130% base flow. Mean arterial pressure was maintained between 40 and 60 mm Hg, and vasopressors or vasodilators were administered as necessary to maintain this. The Pao, in the arterial line was continuously monitored using a Polystan Po, monitor (Polystan UK, Nottingham, UK) to maintain Pao, between 100 and 200 mm Hg. Arterial Paco, was maintained between 27 and 35 mm Hg, and the ph between 7.4 and Packed cell volume was maintained between 20% and 28%. Postoperative Management All cardiac patients were transferred to the intensive care unit receiving ventilatory assistance, paralyzed, and monitored. Ventilation was in a controlled mandatory ventilation mode (Erica Ventilator) with a tidal volume of 10 to 12 mlkg and a respiratory rate of 10 to 12 breathdmin. Fractional concentration of oxygen in inspired air was adjusted to maintain the Pao, between 80 and 110 mm Hg, and the respiratory rate was adjusted to maintain the Paco, between 35 and 45 mm Hg. Positive end-expiratory pressure (5 cm H,O) was administered routinely during assisted ventilation. Extubation was undertaken with the patient fully rewarmed, mentally alert, and hernodynamically stable, usually 10 to 12 hours after operation. All general surgical patients were extubated within a few hours of operation. Data Presentation and Statistical Analysis Statistical analysis was performed using the S-PLUS statistical package [20]. Data presented as means and standard deviations are summarized in Table 1 and presented graphically, as means and standard errors, in Figures 1 to 3. Changes in respiratory function over time were assessed by paired t tests between measurements obtained before operation and those on the first, second, and sixth postoperative days. Certain preoperative and intraoperative covariates considered to be possible predictors or determinants of respiratory injury were examined. In particular, the effects of age, sex, and NYHA status, preoperative measurements of forced expiratory volume

3 Ann Thorac Surg 1993;56: TAGGART ET AL 1125 Table 1. Serial Changes in Arterial Oxygen Tension, Alveolar-Arterial Oxygen Gradient, and Pulmonary Shunt Fraction Alveolar-Arterial Oxygen Gradient Arterial Oxygen Tension (mm Hg) (mm Hg) Pulmonary Shunt Fraction (%) Group Preop 24 h 48 h 6days 6wk Preop 24 h 48 h 6days 6wk Preop 24 h 48 h 6days 1 (n = 122) 89 (11) 59 (9)b 57 (9)b 67 (ll)b (10) 48 (13)b 50 (ll)b 45 (ll)b 3 (1) 19 (5)b 19 (6)b 15 (4)b 2 (n = 30) 86 (7) 69 (11) 67 (9) 79 (6) (4) 21 (4) 19 (6) 15 (6) 3 (n = 30) 91 (6) 60 (5)b 58 (5)b 67 (5)b 93 (6) 17 (6) 43 (12)b 45 (12)b 39 (ll)b 17 (8) a Numbers within parentheses are standard deviations. p < versus preoperative value. p < 0.05 versus preoperative value in 1 second, Pao,, Aao, gradient, and %PSF, together with bypass and ischemic time and violation of one or both pleural sacs, were studied. The potential effects of these variables were investigated by including them as covariates in multiple regression analyses, using measurements of Pao,, Aao, gradient, and %PSF on days 1,2, and 6 as separate response variables. In the case of %PSF, the average of measurements on days 1 and 2 was used as a response, as there was no evidence of change over this period. Results The study comprised 129 patients undergoing elective coronary artery operations (group l), 30 patients undergoing major general surgical procedures (group 2), and a further 30 coronary artery surgery patients followed up until 6 weeks after operation (group 3). The general surgical operations comprised 25 bowel resections and 5 portacaval shunts. As the aim of the study was to examine the effects of uncomplicated CPB on respiratory function, 7 patients in group 1 who required prolonged ventilatory assistance were excluded from analysis. All other cardiac surgery patients received ventilatory assistance for less than 24 hours, with a time to extubation of 11 k 4 hours (mean k standard deviation). All general surgical patients received ventilatory assistance for less than 4 hours. There were 103 men and 19 women in group 1 with an age (mean * standard deviation) of 59 f 8 years, and 26 (21%) were more than 65 years old. Twenty-five patients were in NYHA class I (20%), 75 in NYHA class I1 (61%), and 22 in NYHA class I11 (18%). Twenty-one patients had never smoked (17%), 78 were ex-smokers (64%) of at least 1-year duration, and 23 still occasionally smoked (19%). The group 2 patients comprised 18 men and 12 women with an age (mean k standard deviation) of 61 f 8 years, and 10 (33%) were more than 65 years old. All group 2 patients were smokers up to the time of operation. All cardiac patients underwent isolated coronary artery bypass grafting; 101 (83%) received one left internal mammary artery and a mean of 2.4 vein grafts, 20 (16%) received a mean of 3.1 vein grafts without an internal mammary artery, and 1 patient received two internal mammary artery grafts. Pleurae were maintained intact in 22 patients (18%), one or both pleural sacs were opened in 98 patients (82%), and this information was not recorded in 2 patients. Serial postoperative changes in Pao,, Aao, gradient, and %PSF for the three groups are summarized in Table 1 and graphically illustrated for group 1 in Figures 1 to 3. In group 1 between the preoperative and second postoperative days there was a highly significant decrease in Pao, [89 f 11 versus 57 f 9 mm Hg; p < O.OOl)] accompanied by a highly significant increase in the Aao, gradient [18 f 10 versus 50 f 11 mm Hg; p < O.OOl)], and %PSF[3 f 1% versus 19 f 6%; p < O.OOl)]. There was only modest Pre-op. Day 1 Day 2 Time Fig 1. Serial changes in arterial oxygen tension (pa02) (mean 2 standard error) at various time points. (* p < versus preoperative value.) Day 6 Pre-op. Day 1 Day 2 Time Day 6 Fig 2. Serial changes in alveolar-arterial oxygen gradient (Aa02) (mean & standard error) at various time points. (* p < versus preoperative value.)

4 1126 TAGGART ET AL Ann Thorac Surg 1993; Pre-op. Day 1 Day 2 Day 6 Time Fig 3. Serial changes in pulmonary shunt fraction (mean f standard error) at various time points. ( p < versus preoperative value.) improvement in these parameters by the sixth postoperative day [Pao,, 67 t 11 mm Hg; Aao,, 45 t 11 mm Hg; %PSF, 15 t 41. Group 2 patients also showed a significant but less marked decrease in Pao, over the first and second postoperative days but had essentially returned to preoperative values by the sixth postoperative day. There was a significant increase in the Aao, gradient in group 2 patients only on the first postoperative day, with a return to preoperative values by the sixth postoperative day. As shown in Table 2, in the preoperative period 35% of group 1 patients had a Pao, greater than 90 mm Hg, 65% of patients a Pao, between 60 and 90 mm Hg, and no patient had a Pao, less than 60 mm Hg (the conventional definition of respiratory failure). By the second postoperative day the percentage of patients in the same groups were 0%, 34%, and 66%, and by the sixth postoperative day 0%, 74%, and 26%, respectively. Thus one-quarter of the cardiac surgical patients had significant respiratory impairment by the end of the first postoperative week. The 30 coronary artery surgery patients in group 3 demonstrated identical changes in Pao, and Aao, to group 1 patients over the first postoperative week. In group 3 patients, Pao, and Aao, gradient returned to baseline values by the sixth postoperative week. The following variables were included as potential covariates for respiratory dysfunction: age, sex, NYHA grade, smoking status, bypass time, ischemic time, opening of one or both pleural sacs, and preoperative measurements of forced expiratory volume in 1 second, Pao,, Aao, gradient, and %PSF. The only consistent correlation was with impairment of the preoperative Aao, gradient, which was significant for all three postoperative measurements at all time points (p value between 0.03 and 0.01). Age, sex, smoking status, NYHA status, duration of CPB and the ischemic time, and inadvertent pleurotomy (Table 3) did not influence the degree of postoperative respiratory impairment. Comment Respiratory dysfunction is a familiar complication of CPB, but its exact prevalence and severity in current surgical practice is not precisely documented. Almost a decade ago, approximately one-third of patients were reported to experience pulmonary dysfunction after CPB [ll]. Improvements in medical, anesthetic, and surgical practice as well as extracorporeal perfusion technology, which might have been expected to reduce this incidence, may have been offset by the less favorable features of the current surgical population. Patients undergoing coronary operations today are older and have poorer left ventricular function and a higher prevalence of other diseases than those operated on even 5 years ago [ The number of patients more than 65 years of age now exceeds 40% in some current series [12-141, and this is of particular relevance as there is an age-related decline in respiratory function particularly marked after 65 years of age [15, 161. Both these factors are likely to increase the incidence and severity of respiratory dysfunction in cardiac surgical patients. Kirklin s group [ll] reported a 30% incidence of pulmonary dysfunction after CPB, but the methods of quantification, such as measurement of tracheal secretions, were relatively insensitive and nonspecific. At the most severe end of the spectrum, Hammermeister and colleagues [21] reported that prolonged ventilation (>48 hours) was required in 8% of more than 8,000 patients undergoing coronary operations (with a 25% mortality), similar to the 5% incidence observed in our series (7 of 129 patients). Consequently, to assess the current incidence and severity of pulmonary dysfunction in patients after uncomplicated CPB, we measured three sensitive and objective parameters of functional gas exchange. Although hypoxia Table 2. Number of Patients in Group 1 With Varying Degrees of Respiratory Dysfunction at Different Timesa Po, (mm Hg) Aao, gradient (mm Hg) %PSF Time > <60 <20 >20 <3% >3% Preop 43 (35) 79 (65) 0 (0) 78 (64) 44 (36) 77 (68) 36 (32) 24 hours 0 (0) 47 (40) 71 (60) 4 (3) 114 (97) 0 (0) 110 (100) 44 hours 0 (0) 38 (34) 75 (66) 2 (2) 111 (98) 2 (2) 102 (98) 6 days 0 (0) 73 (74) 25 (26) 0 (0) 97 (100) 0 (0) 87 (100) a Numbers within parentheses are percentages. Aao, = alveolar-arterial oxygen gradient; Po, = arterial oxygen tension; PSF = pulmonary shunt fraction.

5 Ann Thorac Surg 1993; TAGGART ET AL 1127 Table 3. Effect of Pleurotomy on Respiratoy Dysfunction" Po, (mm Hg) Aao, Gradient (mm Hg) PSF (%) Pre Day 2 Day 6 Pre Day 2 Day 6 Pre Day 2 Day 6 Pleurae intact (22 patients) (13) (9) (9) (10) (9) (12) (2) (5) (4) Pleura open (98 patients) (11) (8) (11) (10) (12) (11) (1) (6) (4) a Numbers in parentheses are standard deviations. may reflect poor ventilation, the Aao, gradient remains relatively independent of ventilatory effort. Whereas an increase in %PSF invariably leads to an increase in the Aao, gradient, an increase in this gradient does not necessarily produce an increase in the %PSF. We measured the %PSF without the need for Swan-Ganz catheterization based on the difference in Aao, gradient with the patient breathing room air and 100% oxygen as described by Riley and Permutt [MI. We have previously confirmed the validity of this method in postoperative cardiac surgical patients by comparing the %PSF obtained by this technique with that simultaneously obtained by Swan-Ganz catheterization [ 191, demonstrating excellent correlation between the two techniques (r = 0.94, p < 0.001). Our study demonstrates that respiratory dysfunction is both common and frequently severe even after uncomplicated CPB. The degree of impairment is significant (Pao, < 60 mm Hg breathing room air) in 66% of patients on the second postoperative day and 26% of patients on the sixth postoperative day. Nevertheless, most patients merely required supplemental oxygen in the early postoperative period and were discharged on the seventh or eighth postoperative day. Furthermore, follow-up studies at 6 weeks showed complete resolution of this respiratory dysfunction as witnessed by a complete return to normal of arterial oxygen tension and alveolar-arterial oxygen gradients. The pathophysiology of hypoxia in patients after CPB is different from that in general surgical patients. The latter patients showed hypoxia without a proportional increase in the Aao, gradient, implying that hypoxia is due to a decrease in alveolar oxygen from hypoventilation probably owing to morphine analgesia. In contrast, the increase in the Aao, gradient and %PSF that accompanies hypoxia in the CPB patients reflects ventilation-perfusion inequality (ie, blood is delivered to nonventilated alveoli), resulting in a more severe and longer lasting degree of dysfunction. The continuing Aao, gradient in patients after CPB while breathing 100% oxygen is due to true shunting and, therefore, atelectasis. The precise pathologic mechanism producing such dramatic atelectasis in patients after CPB is not clear but is probably multifactorial. Postoperative changes in respiratory function are influenced by numerous factors including preexisting cardiac or respiratory impairment, general anesthesia, and the effects of CPB itself. Median sternotomy may impair pulmonary function tests [22, 231 by reducing chest wall movement, but this does not explain changes in Pao,, Aao, gradient, or %PSF. Nonventilation of the lungs during CPB is probably one mechanism contributing to atelectasis. Stimulation of humoral and cellular immune systems during CPB results in activation of a myriad of inflammatory mediators including complement and white blood cells. This inflammatory cascade system [ll, 241 is at least partially responsible for increased capillary permeability after CPB, producing flooding of the pulmonary interstitium [25, 261 and leading to intrapulmonary shunting [lo]. Diaphgramatic paralysis, probably as a result of phrenic nerve cold injury, is reported to occur in up to 30% of patients after CPB and to persist in one-third at 1 year [27]. Although topical hypothermia was used as an adjunct to cardioplegic myocardial protection in our patients, diaphgramatic paralysis neither explains the frequency nor resolution within 6 weeks of the pulmonary dysfunction witnessed in our study. Left-sided pleural effusions can be detected in 40% of patients after a coronary artery operation regardless of whether the pleura is opened or remains intact [28]. In our patients, there was no difference in the degree of respiratory dysfunction between those whose pleural sacs were opened during harvesting of the internal mammary artery and those in whom they remained intact (patients receiving only vein grafts). The only consistently significant predictor of postoperative respiratory dysfunction was impairment of the preoperative Aao, gradient, although the correlation was relatively weak. Age did not appear as a covariate of respiratory impairment after CPB. Although there is a sharp decline in respiratory function after the age of 65 years [12, 131, only 26 (21%) of our post-cpb patients exceeded this age. We may therefore have missed an age-related effect that would be apparent in an older population. Likewise we could not demonstrate a significant correlation between respiratory dysfunction after CPB and deteriorating NYHA status between grades I and I11 (those in NYHA grade IV were excluded) or with current cigarette smoking (although most such patients only smoked a few cigarettes per day). This implies that the important determinants of respiratory dysfunction are intraoperative factors. Nevertheless, we failed to demonstrate an effect of the duration of CPB (up to 160 minutes), ischemic times (up to 65 minutes), or violation of one or more pleural sacs on postoperative respiratory dysfunction. It is probable that respiratory injury may be an

6 1128 TAGGART ET AL Ann Thorac Surg 1993;5611- inevitable sequela of the systemic activation of inflammatory mediators even after a short period of extracorporeal circulation. The results of our study need to be interpreted cautiously before being applied to the general cardiac surgical population. In particular, the following points should be considered. First, our study almost certainly underestimates the true incidence and severity of respiratory dysfunction after CPB. We only studied patients at the better end of the surgical spectrum (mean age 59 years, majority in NYHA class I or I1 with good left ventricular function and no other disease). Furthermore, we excluded from analysis 7 patients who required prolonged ventilatory support (>24 hours). Second, in the current study a bubble rather than membrane oxygenator was used during CPB. Although some studies have demonstrated that membrane oxygenators may reduce complement activation and transpulmonary sequestration of leukocytes, there has been no consistent demonstration of clinical benefit for routine CPB. However, we are currently comparing the pulmonary consequences of membrane and bubble oxygenators during routine CPB. In summary, our study demonstrates that respiratory impairment after uncomplicated CPB even in low-risk patients is common, frequently severe, and still marked in at least one-quarter of the patients at the end of the first postoperative week but resolves completely by the sixth postoperative week. It is likely, however, that the incidence and severity of respiratory dysfunction would be higher in older patients with poorer cardiac function and an increased prevalence of other disease. We acknowledge the Biomedical Research Committee of Scotland for funding this study. References 1. Dodrill FD. The effects of total body perfusion upon the lungs. 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