EUROANESTHESIA 2008 Copenhagen, Denmark, 31 May - 3 June 2008 THE EVIDENCE BASIS REGARDING POSTOPERATIVE PULMONARY COMPLICATIONS 05RC1 JAUME CANET, VALENTÍN MAZO, ZAHARA BRIONES Department of Anaesthesiology Hospital Universitari Germans Trias i Pujol Barcelona, Spain Saturday, May 31, 2008 14:00-14:45 Auditorium 12 Postoperative pulmonary complications account for a substantial part of the risk related to surgery and anaesthesia and are a source of postoperative morbidity and mortality and longer hospital stays [1]. Postoperative pulmonary complications are at least as prevalent as cardiac postoperative complications, yet much of the literature on the assessment of peri-operative risk has been focussed on identifying cardiac risk factors [2], while information on risk factors for pulmonary complications is less complete. The aim of this Refresher Course lecture is to review the current evidence basis underpinning our understanding of postoperative pulmonary complications, particularly the identification of peri-operative risk factors. DEFINITION AND INCIDENCE Various study design flaws explain the lack of information on risk factors for postoperative pulmonary complications. One of the most important flaws is the absence of a definition. The majority of investigators include postoperative pneumonia (definite or suspected), respiratory failure (usually defined as the need for ventilatory support) and bronchospasm, but analysis of the literature shows that other complications such as unexplained fever, excessive bronchial secretions, productive cough, abnormal breath sounds, atelectasis or hypoxaemia may also be included. Furthermore, the definition of each of these categories can vary widely, and the incidence of pulmonary complications varies depending on the clinical setting patients are treated in and the kind of surgery studied. For all these reasons, the incidence rates vary dramatically, ranging between 2% and 40% [3]. CAUSES OF POSTOPERATIVE PULMONARY COMPLICATIONS The factors affecting the development of postoperative pulmonary complications are related to the prior health status of the patient and the effects of anaesthesia and surgical trauma. The synergy between these factors determines risk [4, 5]. GENERAL HEALTH STATUS The overall health of the patient has a strong influence on the development of these complications. Preexisting disorders affecting normal respiratory and cardiovascular function and those associated with an abnormal immunological response favour their development. GENERAL ANAESTHESIA General anaesthesia has biological effects that include decreasing the number and activity of alveolar macrophages, inhibiting mucociliary clearance, increasing alveolar-capillary permeability, inhibiting surfactant release, increasing the activity of pulmonary nitric oxide synthetase, and enhancing the sensitivity of the pulmonary vasculature to neurohumoral mediators [6]. Anaesthesia also results in mechanical and functional changes in the respiratory system. These begin with anaesthetic induction and can extend into the postoperative period. Anaesthesia reduces functional residual capacity with an immediate and universal development of atelectasis in the dependent regions of the lung through three mechanisms: compression of lung tissue, absorption of alveolar air, and impairment of surfactant function. As a consequence it produces a disruption of the normal activity of the respiratory muscles, in particular the diaphragm. The resulting mismatch between ventilation and perfusion leads to increased shunt and dead space and hypoxaemia. The effects of anaesthetic, analgesic and other peri-operative drugs on the central regulation of breathing change the neural drive to the upper airway and chest wall muscles and are additional factors contributing to postoperative pulmonary complications. Overall, the intensity and co-ordination of the activity of several muscle groups and the preservation of pulmonary biological mechanisms is the key to walking the thin line between recovery and severe respiratory complications [6]. - 39 -
SURGICAL TRAUMA The surgical insult contributes greatly to the development of pulmonary complications. All thoracic and abdominal surgery produces trauma near the diaphragm. At least three types of trauma are involved: functional disruption of respiratory muscles by incisions, postoperative pain causing limitation of respiratory motion, and stimulation of the viscera by mechanical traction producing reflex inhibition of the phrenic and other nerves innervating respiratory muscles [5]. Factors related to the degree of surgical insult, such as duration of the procedure or blood loss by themselves or through an interaction with the local effects described above, increase the risk of developing pulmonary complications. The postoperative immune response is extremely complex and has detrimental (pro-coagulant and immunosuppressive) effects. Pro-inflammatory cytokines, especially tumour necrosis factor and interleukin-6, play a major role in the systemic inflammatory response syndrome and multiple organ dysfunction after trauma. Again, immunological depression, in this case provoked by the surgical insult, might be invoked as a mediator to favour postoperative respiratory infection and other complications. SYSTEMATIC REVIEW: EVIDENCE THAT IS NOT SO EVIDENT Recently, guidelines for the reduction of postoperative pulmonary complications in patients undergoing non-cardiac surgery were published by the American College of Physicians. The recommendations, based on a systematic review of the literature, represent the largest attempt to find an evidence basis for our understanding of this subject [7]. The authors found 16,959 articles addressing the issue. After careful reading, 145 studies were selected. Eighty-three provided univariate data and 73 of them were cohort studies, of which less than half were prospective. Only 10 were of good quality. Another 27 studies reported multivariable analyses meeting the authors inclusion criteria. In addition to these studies, the authors collected data on 10,960 events among 324,648 patients. However, 89.8% of these patients were included in three studies which used subsets of patients from the Veterans National Surgical Quality Improvement Project (NSQIP) [8, 9]. The crude postoperative pulmonary complication rate among the cohort studies was 3.4%. Table 1 shows risk factors for postoperative pulmonary complications with good (Class A) or fair (Class B evidence according to the systematic review by the American College of Physicians). The same meta-analysis shows that there is fair or good evidence that the following factors do not increase the risk of these complications: diabetes, obesity, asthma, and hip, gynaecological and urologic surgery. TABLE 1. SIGNIFICANT RISK FACTORS ACCORDING THE SYSTEMATIC REVIEW OF THE AMERICAN COLLEGE OF PHYSICIANS - 40 -
This extensive systematic review detected literature with important limitations, including study sample sizes that were too small to measure clinically relevant pulmonary outcomes, unblinded outcome assessment, inconsistencies in how complications were defined, dependence on observational studies, and statistical issues. Most of the literature consists of observational studies that focus on the discovery of potential risk factors rather than direct hypothesis testing, and many studies use univariate pre-screening and multivariable selection methods to identify a subset of statistically significant risk factors. In addition, as has been already mentioned, the NSQUIP studies, due to the large number of patients, have excessive weight in the meta-analysis, producing a significant bias. THE VETERANS AFFAIRS NSQUIP INDEX FOR PREDICTING POSTOPERATIVE PNEUMONIA The NSQUIP study was the largest study, using data from 160,805 patients to develop a risk index for predicting postoperative pneumonia after non-cardiac surgery and its 30-day mortality [9]. The crude incidence of pneumonia was 1.5%, and the 30-day postoperative mortality rate of patients who developed pneumonia was 21%. The 14-item risk index score, divided into five classes, is shown in Table 2. Pneumonia rates were 0.2% among those with 0-15 points, 1.2% for those with 16-25 points, 4.0% for those with 26-40 points, 9.4% for those with 41-55 points, and 15.3% for those with more than 55 points. TABLE 2. POSTOPERATIVE PNEUMONIA RISK INDEX Table taken from Arozullah AM, et al. Ann Intern Med 2001; 135: 847 57 [9]. - 41 -
There are a number of limitations to this study. Firstly, the study population was atypical: the patients were virtually all male veterans with high co-morbidity. Thus, the performance of the risk index in women or healthier populations is unknown. Secondly, data collection was not uniform from institution to institution. Thirdly, the 1.5% incidence of pneumonia is lower than frequencies reported in most studies of pneumonia in selected high-risk patient cohorts. Finally, as the NSQUIP database was not designed primarily to evaluate respiratory risk, it is possible that data on relevant respiratory risk factors were missed. FURTHER ANALYSIS More recently, McAlister et al [10, 11] found only eight small studies (averaging 207 patients and 16 outcomes per study) that compared the pre-operative evaluation and postoperative pulmonary outcomes in an independent and blinded fashion in patients undergoing non-thoracic surgery. These studies were limited by non-representative samples and reported conflicting results. Although 20 variables were found to be significantly associated with postoperative pulmonary complications in at least one of the studies, only seven were significant in more than one study. For this reason they conducted a prospective cohort study in 1,055 consecutive patients attending the pre-admission clinic of a university hospital (with postoperative pulmonary complications scored by an investigator blinded to peri-operative variables) to determine the risk factors for after elective non-thoracic surgery. The mean length of stay was substantially longer for those patients who developed pulmonary complications within 7 days of surgery: 27.9 days vs. 4.5 days, p<0.006. They confirmed that eight of the 20 previously reported peri-operative variables were associated with postoperative pulmonary complications: age, pack-years smoked, positive cough test (performed by having the patient take a deep inspiration and cough once, a positive finding defined as recurrent coughing after the first cough), FEV 1, FEV 1 /FVC ratio, duration of anaesthesia, upper abdominal incision, and peri-operative placement of a nasogastric tube. However, multivariate analyses revealed that only four were independently associated with increased risk of pulmonary complications: age (odds ratio (OR) 5.9 for age 65 yr, p<0.001), positive cough test (OR 3.8, p<0.01), peri-operative nasogastric tube (OR 7.7, p<0.001), and duration of anaesthesia (OR 3.3 for operations lasting at least 2.5 h, p< 0.008). ASSESSMENT OF PERIOPERATIVE COMPLICATIONS ASSOCIATED WITH SMOKING AND ANAESTHESIA IN CATALONIA (ARISCAT) ARISCAT is a multicentre prospective cohort study conducted in Catalonia that finished at the beginning of 2007. This study included a large randomised general surgical population (2,991 patients in 59 hospitals) and aimed to explore risk factors for general postoperative outcome and particularly for postoperative pulmonary complications. Detailed pre-, intra- and postoperative questionnaires (until 3 months after surgery), described demographic, medical and quality of life characteristics. In particular, the respiratory status of all patients was recorded through detailed structured questionnaires investigating pre-existing respiratory disorders, respiratory symptoms, cough test and past and current smoking habits. Structured follow-up of intra- and postoperative complications was also performed. Complications were defined based on a medical intervention and recorded in the chart. The average rate of postoperative pulmonary complications was 5% for the in-patient surgery population overall. 1.6% of pulmonary complications were respiratory infections and 2.5% were respiratory failure. Table 3 shows the variables found to be independently associated with increased risk of pulmonary complications (predictive capacity of 90.46 %) in the multivariate analysis. Postoperative length of hospital stay for patients who did not develop pulmonary complications was 3 days, compared with 12 days for those who did (p<0.001). Mortality 3 months after surgery was 1.3% vs. 24% (p<0.001), respectively. - 42 -
TABLE 3. SIGNIFICANT VARIABLES FOR POSTOPERATIVE PULMONARY COMPLICATIONS FROM MULTIVARIANT ANALYSIS (ARISCAT STUDY, SEE TEXT) Intrathoracic surgery (incl. cardiac surgery) Male gender Age Emergency surgery Positive cough test COPD Previous upper respiratory tract infection Chronic renal disease Upper abdominal surgery Duration of surgery >2.5 h Oncologic diagnosis Surgical insult scale 3 CONCLUSIONS The first step in reducing postoperative pulmonary complications is to identify which patients are at increased risk. By doing so, we can more closely follow high-risk patients and target future interventions toward those patients most likely to benefit. Current evidence indicates that certain peri-operative factors can be used to identify patients awaiting surgery who are at increased risk. These factors are related to the previous health status of the patients and to the anaesthetic and surgical procedure. However, the currently available information on what risk factors have true a impact on the development of postoperative pulmonary complications has important limitations. Firstly, there is a shortage of good quality studies. Secondly, the investigation of risk factors is based on observational studies which are not necessarily well designed. Such studies should be prospective with blinded analysis, although even these will never have the power to indicate causality, as can be achieved through controlled studies. Furthermore, extrapolation to a general surgical population is difficult because the majority of studies are conducted in single institutions and restricted clinical settings (specific patient types and operations) and lack a uniform definition of postoperative pulmonary complications. Thirdly, in spite of advances in epidemiology and statistics, important bias can result from the selection of variables to be introduced into the multivariate analysis. Particular attention should be paid if the ASA class is introduced as a variable. In spite of the large inter-observer variability, the ASA class is a potent predictor of all kinds of postoperative outcomes because it assesses all co-morbidities. For this reason, a multivariate analysis that includes the ASA class should be interpreted cautiously because particular co-morbidities, that could be managed clinically, will disappear from the statistical model [12]. Finally, the results obtained can be very discouraging because many of the risk factors described cannot be modified. In future investigations an effort should be made to try to reduce these multiple biases in order to more precisely determine the factors associated with postoperative pulmonary complications and strategies that limit their effect. KEY LEARNING POINTS Postoperative pulmonary complications account for a substantial part of the risk related to surgery and anaesthesia and are a source of postoperative morbidity and mortality and longer hospital stays. The current evidence basis informing us of the nature of postoperative pulmonary complications is biased because of flaws such as the inclusion of a small number of studies of good quality, the lack of a uniform definition, and the reliance on studies restricted to specific patients and kinds of surg e r y. The evidence supports that risk factors for postoperative pulmonary complications are related to the health status of the patient and with the anaesthetic and surgical procedure. Age, co-morbidity in general and pre-existing respiratory and cardiac diseases in particular, the use of general anaesthesia and overall surgical insult are the most significant factors related to the development of postoperative pulmonary complications. ACKNOWLEDGEMENT Supported by Fundació La Marató de TV3 grant: 041610 (2003). - 43 -
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