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Clinical Investigations in Critical Care |

Incidence and Predictors of ARDS After Cardiac Surgery* FREE TO VIEW

Julie Milot, MD, PhD; Jean Perron, MD; Yves Lacasse, MD, MSc; Louis Létourneau, MD; Paul C. Cartier, MD; François Maltais, MD
Author and Funding Information

*From the Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, Sainte-Foy, Québec, Canada.

Correspondence to: François Maltais, MD, Centre de pneumologie, Hôpital Laval, 2725 chemin Ste Foy, Ste-Foy, QC, Canada, G1V 4G5; e-mail: medfma@hermes.ulaval.ca



Chest. 2001;119(3):884-888. doi:10.1378/chest.119.3.884
Text Size: A A A
Published online

Background: Severe pulmonary injury with the development of ARDS is a potential complication of cardiac surgery and cardiopulmonary bypass (CPB).

Study objectives: This retrospective, case-control study was designed to determine the incidence and mortality of ARDS after cardiac surgery and CPB, as well as to identify preoperative and perioperative predisposing factors of this complication.

Methods: Of 3,278 patients who underwent cardiac surgery and CPB between January 1995 and December 1998, 13 patients developed ARDS during the postoperative period. Each patient was matched with four or five control subjects who had the same type of surgery on the same day but did not develop postoperative respiratory complications.

Results: The incidence of ARDS was 0.4%, with an ARDS mortality of 15%. In the ARDS group, 38% had previous cardiac surgery, as compared to 3.5% in the control group (p < 0.002). During the postoperative period, ARDS patients received more blood products (4 ± 5 vs 2 ± 3; p < 0.01) and developed shock more frequently (31% vs 5%; p < 0.02) than patients in the control group. Multivariate regression analysis identified previous cardiac surgery, shock, and the number of transfused blood products as significant independent predictors for ARDS, with odds ratios of 31.5 (p = 0.015), 10.8 (p = 0.03), and 1.6 (p = 0.03), respectively.

Conclusions: ARDS following cardiac surgery and CPB was a rare complication that carried a 15% mortality rate. Previous cardiac surgery, shock, and number of blood products received are important predicting factors for this complication.

The ARDS is characterized by an increased-permeability pulmonary edema associated with local and systemic inflammation. The resulting clinical, radiologic, and physiologic abnormalities are not explained by left atrial hypertension.1This syndrome is associated with sepsis, shock, aspiration, and trauma, and carries a mortality rate of 40 to 70%.24 ARDS has also been reported after cardiac surgery involving cardiopulmonary bypass (CPB); in this context, it has a significant impact on patient outcome because of its high related mortality (30 to 70%).56

Although CPB triggers a systemic inflammatory response,7 only subtle evidences of pulmonary dysfunction can be detected in most patients; indeed, a minority will develop the full clinical picture of the syndrome. The occurrence of ARDS after cardiac surgery is also unpredictable, and little is known about risk factors for the development of this complication. Currently, those risk factors are thought to include older age (> 60 years) total volume of blood pumped during bypass > 300 L, smoking, emergency surgery, preoperative New York Heart Association classes 3 and 4, low cardiac output, left ventricular ejection fraction < 40%, and systemic hypertension.56

We undertook this case-control study to determine the incidence and mortality of ARDS following cardiac surgery involving CPB as well as to identify associated preoperative and perioperative predicting factors. Since a larger number of high-risk patients now undergo cardiac surgery 8and because reperformed surgery has become very common,9 we believed it was important to reassess some of the possible predisposing factors for the development of ARDS after cardiac surgery.

Study Population

Between January 1995 and December 1997, 3,278 patients underwent cardiac surgery with CPB at our hospital. The clinical data of each patient were entered in the National Cardiac Surgery database. From this database, 70 patients who developed acute respiratory failure within 30 days of surgery were identified. The medical chart of each patient was carefully reviewed, and their chest radiographs were reexamined by a radiologist (L.L.) who was unaware of the clinical status of the patient. From these 70 patients, 13 fulfilled the criteria used for the diagnosis of ARDS (see below). Each ARDS patient was then matched with four or five control subjects (57 control subjects for 13 ARDS patients), identified from the database, and who had similar surgery on the same day but did not develop postoperative respiratory complications.

Definitions

The diagnosis of ARDS was based on tachypnea (respiratory rate> 30 breaths/min), bilateral pulmonary infiltrates on chest radiograph, severe hypoxemia (Pao2/fraction of inspired oxygen ratio of < 200), requirement of positive end-expiratory pressure> 5 cm H2O, no evidence of left heart failure (wedge pressure < 18 mm Hg), and no other pathology to explain these findings.10Septic shock was diagnosed when two or more of the following findings were present: (1) core temperature > 38.5°C or < 36°C; (2) WBC count > 12×106/L or< 3.5×106/L or 20% immature form; (3) one positive blood culture of a common pathogen; or (4) a strongly suspected site of infection from which a known pathogen was cultured, and one or more of the following: (A) systemic arterial hypotension for at least 2 h (systolic BP < 85 mm Hg or a reduction of > 40 mm Hg from baseline, or the need for inotropes to maintain systolic BP> 85 mm Hg), (B) systemic vascular resistance < 800 dyne·s·cm2, as measured by a pulmonary catheter, and (C) unexplained metabolic acidosis (base deficit > 5 mEq/L).11 Hypovolemic shock was defined as an episode of bleeding with hypotension lasting ≥ 2 h (systolic BP < 85 mm Hg or reduction of > 40 mm Hg from baseline, or need for inotropes to maintain systolic BP > 85 mm Hg) and which necessitated thoracotomy for control.11 Cardiogenic shock was defined as a low cardiac output status, with a cardiac index < 2.0 L/min/m2 and low arterial BP.

CPB Technique

After the insertion of a pulmonary artery catheter, general anesthesia was administered with sufentanil, 2 to 15 μg/kg; midazolam, 1 to 3 mg; and pancuronium, 0.1 mg/kg. A propofol infusion was also started at the beginning of CPB and stopped before extubation. Eight patients received IV methylprednisolone, 1 g, at the beginning of CPB and this was given at the discretion of the surgeon and on an empirical basis. During CPB, all patients were heparinized with 9,000 U/m2 of body surface plus 5,000 U in the CBP circuit. They received protamine sulfate (1 g/100 mg of heparin utilized) at the end to CPB. Most coronary bypass grafts and aortic valve replacements were done with a single double-stage venous cannula and aortic cannulation. Mitral valve procedures were carried out with two single stage cannula in the superior and inferior vena cava. Either cold (ARDS patients, n = 1; control subjects, n = 10) or warm (ARDS patients, n = 12; control subjects, n = 47) oxygenated blood cardioplegia was infused into the aortic root or coronary sinus in an antegrade or retrograde fashion. Mild hypothermia (mean, 31 ± 1.6°C; range, 23.4 to 37°C) was reached passively, and all surgeries were performed using a membrane oxygenator (Terumo; Somerset NJ). A roller pump (Sarns; Ann Arbor, MI) was used in 64 patients (ARDS patients, n = 11; control subjects, n = 53). In six patients (ARDS patients, n = 2; control subjects, n = 4) expected to have prolonged CPB time, a centrifugal pump (Medtronic; Minneapolis, MN) was used. Most patients were extubated within 12 h postoperatively.

Statistical Analysis

Preoperative patient characteristics, surgical procedure, and perioperative data were compared between the two groups. Mean and standard deviation were determined for the continuous variables, and categorical variables were expressed using the count of observed events. For continuous variables (age, body surface area, left ventricular ejection fraction, CPB time, temperature during CPB, number of transfused blood products during the perioperative period, fluid balance) comparisons between the two groups were made using Student’s t tests on values transformed by their rank as normality and variance assumption were rejected. Categorical variables (gender, preoperative risk factors, surgical procedure data, postoperative complications, and use of systemic methylprednisolone at the beginning of CPB) were compared with the Fisher’s Exact Test. A model to predict the occurrence of ARDS was developed using a multivariate logistic regression analysis with the variables that were different between the two groups in the univariate analysis (p < 0.05). Chronic renal failure, basal temperature during CPB, and use of methylprednisolone were also included in this analysis because of their possible influence in the development of the systemic inflammatory process following CPB.1214 Data analysis was performed using software (SAS statistical package; SAS Institute; Cary, NC).

The cumulative incidence of ARDS was 0.4% (13 of 3,278), with an overall mortality of 15% (2 of 13). One of the two patients who died had multiorgan failure. During the same period, the operative mortality of all patients who underwent open-heart surgery in our hospital was 5.6% (184 of 3,278 patients). ARDS patients had mean (± SD) wedge pressures of 11± 3 mm Hg, Pao2/fraction of inspired oxygen ratios of 94 ± 28, and positive end-expiratory pressure levels of 7 ± 2 cm H2O. ARDS was diagnosed on average 5 ± 5 days after operation (range, 2 to 20 days), although it occurred > 7 days after the procedure in two patients (day 10 and day 20). Nine patients (69%) required intubation for an average of 17 ± 17 days, whereas four patients (31%) were treated with noninvasive positive-pressure mask ventilation for an average of 3 ± 2 days.

A history of prior cardiac surgery was more common in the ARDS group (n = 5, 38%) than in the control group (n = 2, 3.5%; p = 0.002), but there were no significant differences for other preoperative characteristics (Table 1 ). As illustrated in Table 2 , type of surgery (coronary artery bypass graft and/or valves), urgency of surgical procedure, prophylactic use of methylprednisolone before CPB, basal temperature during CPB, CPB time, and number of postoperative GI complications were not significantly different between the two groups. By contrast, there was a significant difference for the number of transfused blood products (packed erythrocytes, plasma, cryoprecipitates, or platelets) during the perioperative period (4 ± 5 vs 2 ± 3 for the ARDS and control groups, respectively; p = 0.01). In the ARDS group, 31% of patients developed a status of shock simultaneously or prior to ARDS (septic, n = 2; hypovolemic, n = 1; and cardiogenic, n = 1) as opposed to 5% in the control group (cardiogenic, n = 3; p = 0.004). On average, fluid balance at the time of ARDS was negative (Table 2).

Multivariate regression analysis (Table 3 ) demonstrated that prior cardiac surgery, shock, and number of transfused blood products were significant independent predictors for ARDS, with odds ratios of 31.5 (p = 0.015), 10.8 (p = 0.03) and 1.6 (p = 0.03), respectively, while chronic renal failure, basal temperature during CPB, and use of methylprednisolone did not influence the development of ARDS. The results of the multivariate regression analysis were not significantly altered if we included or not in the analysis the two patients in whom ARDS occurred > 7 days after operation.

In this study, ARDS was an uncommon complication of cardiac surgery and CPB but it carried a 15% mortality rate. Our analysis showed that previous cardiac surgery, shock, and number of transfused blood products were significant independent predictors for the development of this complication.

The pathophysiology of ARDS occurring after CPB is not totally clear. Complement activation, primarily through the alternative pathway, occurs during the initial phase of CPB15 with release of anaphylatoxins C3a and C5a. This results in an accumulation of activated neutrophils in the pulmonary circulation and subsequent release of lysosomal granular contents such as elastase and myeloperoxidase leading to diffuse pulmonary injury.13,16 This systemic inflammatory response has been shown to be amplified by postoperative low cardiac output, splanchnic hypoperfusion, and transient gut mucosal ischemia with bacterial endotoxins translocation.1718 Protamine used to neutralize heparin at the end of CPB, is also known to be an activator of the “second phase” classic pathway complement.1920 Postoperative systemic inflammation may also involve the coagulation cascade and the kallikrein and fibrinolytic systems.7 When CPB is terminated, the initiating stimulus is removed and several endogenous factors such as tumor necrosis factor-α receptors, interleukin-1 receptor antagonist, and interleukin-10 limit the inflammatory response 7 and in most patients prevent important organ damage.21

In recent years, reperformed cardiac surgery has become increasingly more common,9 and the identification of this factor as a predictor of ARDS following subsequent cardiac surgery is particularly important since it allows the targeting of a subgroup of high-risk patients. Longer CPB time does not appear to explain why patients with previous cardiac surgery were at greater risk of developing ARDS, since their CPB time was similar to that of patients undergoing cardiac surgery for the first time. One possible explanation is that prior protamine sensitization might have triggered a severe immune reaction to protamine administration at the end of CPB. Protamine-heparine complexes may activate the release of anaphylatoxins C4a and C3a and contribute to the inflammatory state after CPB,1920 while an immune reaction to protamine might be explained by IgE-mediated anaphylaxis to protamine, complement-mediated anaphylactoid reactions caused by heparin-protamine complexes, or protamine-antiprotamine complexes, or direct toxicity.20,2223 Few articles have reported possible protamine-induced ARDS following CPB.2425 For instance, Kindler et al26 described a patient with a positive skin test and protamine-specific IgG antibodies who develop ARDS after a third exposure to IV protamine suggesting an immunologic reaction to this drug. The potential role of prior IV protamine as a risk factor for adverse events after subsequent protamine administration is still much debated,27 and whether or not the greater incidence of ARDS in patient with a previous cardiac surgery is linked to an earlier sensibilization to protamine will require further investigation.

Modern anesthetic and surgical techniques allow cardiac surgery to be carried out in high-risk patients. Nevertheless, one has to recognize that apart from CPB, these patients are also exposed to other adverse conditions often associated with increased risk of developing ARDS. In the present study, shock, and multiple transfusions of blood products, two known risk factors for ARDS,2830 were found to be associated with an increased risk of ARDS.

Pre-CPB treatment with high-dose methylprednisolone significantly reduces the complement activation of second-phase classic pathway during heparin neutralization with protamine,12 and previous studies have suggested that corticosteroids may also reduce the initial inflammatory response during CPB.7 There is, however, no general agreement about these theories this because of small number of patients, variable end points, and different types and doses of steroids used.7 Further investigations need to be done to evaluate the protective effect of preoperative corticosteroids, and indeed it would be of particular interest to evaluate their efficacy in high-risk patients such as those who had a prior cardiac surgery.

The incidence of ARDS following cardiac surgery and CPB varies from 1 to 3%, and the mortality rate ranges from 30 to 70%.2,56,31In the current study, these numbers were considerably lower; a possible explanation is that all CPBs were done using a membrane oxygenator that does not induce complement activation as much as a bubble oxygenator,3233 a commonly used technique in other reported studies. Multiple organ failure, a frequent cause of death in ARDS patients, was also much less commonly found in our study, compared to previous investigations.6

In summary, this study shows that ARDS following cardiac surgery and CPB was a rare complication. Although the outcome of our patients was more favorable than in other studies, the mortality related to this problem remains significant. Previous cardiac surgery, multiple transfusions, and shock were found to be important predictors of the occurrence ARDS after CPB and based on these findings, possible prophylactic measures should be investigated.

Abbreviation: CPB = cardiopulmonary bypass

Dr. Maltais is a clinician-scientist of the Fonds de la recherche en santé du Québec.

Table Graphic Jump Location
Table 1. Preoperative Patient Characteristics*
* 

Data are presented as No. (%) or mean ± SD unless otherwise indicated. BMI = body mass index; LVEF = left ventricular ejection fraction; NS = not significant; CRF = chronic renal failure.

Table Graphic Jump Location
Table 2. Surgical Procedure and Perioperative Data*
* 

Data are presented as No. (%) or mean ± SD. CABG = coronary artery bypass graft. N/A = not available; see Table 1 for other abbreviation.

Table Graphic Jump Location
Table 3. Multivariate Regression for Predicting Factors for ARDS*
* 

See Table 1 for abbreviation.

The authors thank Hugette Brochu for technical support, Serge Simard for statistical assistance, and Dr. Jean Deslauriers for helpful comments on the article.

Bernard, GR, Artigas, A, Brigham, KL, et al (1994) The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med149,818-824. [PubMed]
 
Meyrick, B Pathology of the adult respiratory distress syndrome.Crit Care Clin1986;2,405-428. [PubMed]
 
Pepe, PE The clinical entity of adult respiratory distress syndrome: definition, prediction, and prognosis.Crit Care Clin1986;2,377-403
 
Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993; JAMA 1995; 273:306–309.
 
Messent, M, Sullivan, K, Keogh, BF, et al Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction.Anesthesia1992;47,267-268. [CrossRef]
 
Christenson, JT, Aeberhardt, JM, Badelt, P, et al Adult respiratory distress syndrome after cardiac surgery.Cardiovasc Surg1996;4,15-21. [CrossRef] [PubMed]
 
Hall, RI, Stafford Smith, M, Rocker, G The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerationsAnesth Analg1997;85,766-782. [PubMed]
 
Sevray, B, Logeais, Y, Chaperon, J, et al Évolution du risque opératoire et de ses facteurs prédictifs en chirurgie coronarienne.Arch Mal Coeur1995;88,847-854. [PubMed]
 
Frank, RA, Mills, NL Reoperative coronary artery bypass grafting.Curr Opin Cardiol1994;9,680-684. [CrossRef] [PubMed]
 
Murray, JF, Matthay, MA, Luce, J, et al An expanded definition of the adult respiratory distress syndrome.Am Rev Respir Dis1988;138,720-723. [PubMed]
 
Ranieri, VM, Suter, PM, Tortorella, C, et al Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome.JAMA1999;282,54-61. [CrossRef] [PubMed]
 
Loubser, PG Effect of methylprednisolone on complement activation during heparin neutralization.J Cardiovasc Pharmacol1997;29,23-27. [CrossRef] [PubMed]
 
Tönz, M, Mihaljevic, T, von Segesser, LK, et al Acute lung injury during cardiopulmonary bypass: are the neutrophils responsible?Chest1995;108,1551-1556. [CrossRef] [PubMed]
 
Ranucci, M, Frigiola, A, Menicanti, L, et al Normothermic perfusion and lung function after cardiopulmonary bypass: effects in pulmonary risk patients.Perfusion1997;12,309-315. [PubMed]
 
Chenoweth, DE, Cooper, SW, Hugli, TE, et al Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins.N Engl J Med1981;304,497-503. [CrossRef] [PubMed]
 
Sinclair, DG, Haslam, PL, Quinlan, GJ, et al The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability.Chest1995;108,718-724. [CrossRef] [PubMed]
 
Ohri, SK, Bjarnason, I, Pathi, V, et al Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability.Ann Thorac Surg1993;55,1080-1086. [CrossRef] [PubMed]
 
Baue, AE The role of the gut in the development of multiple organ dysfunction in cardiothoracic patients.Ann Thorac Surg1993;55,822-829. [CrossRef] [PubMed]
 
Cavarocchi, NC, Schaff, HV, Orszulak, TA, et al Evidence for complement activation by protamine-heparin interaction after cardiopulmonary bypass.Surgery1985;98,525-531. [PubMed]
 
Kirklin, JK, Chenoweth, DE, Naftel, DC, et al Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state.Ann Thorac Surg1986;41,193-199. [CrossRef] [PubMed]
 
Kirklin, JK Prospects for understanding and eliminating the deleterious effects of cardiopulmonary bypass.Ann Thorac Surg1991;51,529-531. [CrossRef] [PubMed]
 
Sharath, MD, Metzger, WJ, Richerson, HB, et al Protamine-induced fatal anaphylaxis: prevalence of antiprotamine immunoglobulin E antibody.J Thorac Cardiovasc Surg1985;90,86-90. [PubMed]
 
Weiler, JM, Freiman, P, Sharath, MD, et al Serious adverse reactions to protamine sulfate: are alternative needed?Allergy Clin Immunol1985;75,297-303. [CrossRef]
 
Holland, CL, Singh, AK, McMaster, PR, et al Adverse reactions to protamine sulfate following cardiac surgery.Clin Cardiol1984;7,157-162. [CrossRef] [PubMed]
 
Olinger, GN, Becker, RM, Bonchek, LI Noncardiogenic pulmonary edema and peripheral collapse following cardiopulmonary bypass: rare protamine reaction?Ann Thorac Surg1980;29,20-25. [CrossRef] [PubMed]
 
Kindler, C, Bircher, A, Stulz, P Protamine-induced fulminating non-cardiogenic pulmonary edema following cardiopulmonary bypass.Eur J Cardiothorac Surg1996;10,463-466. [CrossRef] [PubMed]
 
Kimmel, SE, Sekeres, MA, Berlin, JA, et al Risk factors for clinically important adverse events after protamine administration following cardiopulmonary bypass.J Am Coll Cardiol1998;32,1916-1922. [CrossRef] [PubMed]
 
Fowler, AA, Hamman, RF, Good, JT, et al Adult respiratory distress syndrome: risk with common predispositions.Ann Intern Med1983;98,593-597. [PubMed]
 
Pepe, PE, Potkin, RT, Reus, DH, et al Clinical predictors of adult respiratory distress syndrome.Am J Surg1982;144,124-130. [CrossRef] [PubMed]
 
Zimmerman, GA, Morris, AH, Cengiz, M Cardiovascular alterations in the adult respiratory distress syndrome.Am J Med1982;73,25-34. [CrossRef] [PubMed]
 
Kaul, TK, Fields, BL, Riggins, LS, et al Adult respiratory distress syndrome following cardiopulmonary bypass: incidence, prophylaxis and management.J Cardiovasc Surg1988;39,777-781
 
Gu, YJ, Wang, YS, Chiang, BY, et al Membrane oxygenator prevents lung reperfusion injury in canine cardiopulmonary bypass.Ann Thorac Surg1991;51,573-578. [CrossRef] [PubMed]
 
Tamiya, T, Yamasaki, M, Maeo, Y, et al Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators.Ann Thorac Surg1988;46,47-57. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Preoperative Patient Characteristics*
* 

Data are presented as No. (%) or mean ± SD unless otherwise indicated. BMI = body mass index; LVEF = left ventricular ejection fraction; NS = not significant; CRF = chronic renal failure.

Table Graphic Jump Location
Table 2. Surgical Procedure and Perioperative Data*
* 

Data are presented as No. (%) or mean ± SD. CABG = coronary artery bypass graft. N/A = not available; see Table 1 for other abbreviation.

Table Graphic Jump Location
Table 3. Multivariate Regression for Predicting Factors for ARDS*
* 

See Table 1 for abbreviation.

References

Bernard, GR, Artigas, A, Brigham, KL, et al (1994) The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med149,818-824. [PubMed]
 
Meyrick, B Pathology of the adult respiratory distress syndrome.Crit Care Clin1986;2,405-428. [PubMed]
 
Pepe, PE The clinical entity of adult respiratory distress syndrome: definition, prediction, and prognosis.Crit Care Clin1986;2,377-403
 
Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993; JAMA 1995; 273:306–309.
 
Messent, M, Sullivan, K, Keogh, BF, et al Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction.Anesthesia1992;47,267-268. [CrossRef]
 
Christenson, JT, Aeberhardt, JM, Badelt, P, et al Adult respiratory distress syndrome after cardiac surgery.Cardiovasc Surg1996;4,15-21. [CrossRef] [PubMed]
 
Hall, RI, Stafford Smith, M, Rocker, G The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerationsAnesth Analg1997;85,766-782. [PubMed]
 
Sevray, B, Logeais, Y, Chaperon, J, et al Évolution du risque opératoire et de ses facteurs prédictifs en chirurgie coronarienne.Arch Mal Coeur1995;88,847-854. [PubMed]
 
Frank, RA, Mills, NL Reoperative coronary artery bypass grafting.Curr Opin Cardiol1994;9,680-684. [CrossRef] [PubMed]
 
Murray, JF, Matthay, MA, Luce, J, et al An expanded definition of the adult respiratory distress syndrome.Am Rev Respir Dis1988;138,720-723. [PubMed]
 
Ranieri, VM, Suter, PM, Tortorella, C, et al Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome.JAMA1999;282,54-61. [CrossRef] [PubMed]
 
Loubser, PG Effect of methylprednisolone on complement activation during heparin neutralization.J Cardiovasc Pharmacol1997;29,23-27. [CrossRef] [PubMed]
 
Tönz, M, Mihaljevic, T, von Segesser, LK, et al Acute lung injury during cardiopulmonary bypass: are the neutrophils responsible?Chest1995;108,1551-1556. [CrossRef] [PubMed]
 
Ranucci, M, Frigiola, A, Menicanti, L, et al Normothermic perfusion and lung function after cardiopulmonary bypass: effects in pulmonary risk patients.Perfusion1997;12,309-315. [PubMed]
 
Chenoweth, DE, Cooper, SW, Hugli, TE, et al Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins.N Engl J Med1981;304,497-503. [CrossRef] [PubMed]
 
Sinclair, DG, Haslam, PL, Quinlan, GJ, et al The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability.Chest1995;108,718-724. [CrossRef] [PubMed]
 
Ohri, SK, Bjarnason, I, Pathi, V, et al Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability.Ann Thorac Surg1993;55,1080-1086. [CrossRef] [PubMed]
 
Baue, AE The role of the gut in the development of multiple organ dysfunction in cardiothoracic patients.Ann Thorac Surg1993;55,822-829. [CrossRef] [PubMed]
 
Cavarocchi, NC, Schaff, HV, Orszulak, TA, et al Evidence for complement activation by protamine-heparin interaction after cardiopulmonary bypass.Surgery1985;98,525-531. [PubMed]
 
Kirklin, JK, Chenoweth, DE, Naftel, DC, et al Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state.Ann Thorac Surg1986;41,193-199. [CrossRef] [PubMed]
 
Kirklin, JK Prospects for understanding and eliminating the deleterious effects of cardiopulmonary bypass.Ann Thorac Surg1991;51,529-531. [CrossRef] [PubMed]
 
Sharath, MD, Metzger, WJ, Richerson, HB, et al Protamine-induced fatal anaphylaxis: prevalence of antiprotamine immunoglobulin E antibody.J Thorac Cardiovasc Surg1985;90,86-90. [PubMed]
 
Weiler, JM, Freiman, P, Sharath, MD, et al Serious adverse reactions to protamine sulfate: are alternative needed?Allergy Clin Immunol1985;75,297-303. [CrossRef]
 
Holland, CL, Singh, AK, McMaster, PR, et al Adverse reactions to protamine sulfate following cardiac surgery.Clin Cardiol1984;7,157-162. [CrossRef] [PubMed]
 
Olinger, GN, Becker, RM, Bonchek, LI Noncardiogenic pulmonary edema and peripheral collapse following cardiopulmonary bypass: rare protamine reaction?Ann Thorac Surg1980;29,20-25. [CrossRef] [PubMed]
 
Kindler, C, Bircher, A, Stulz, P Protamine-induced fulminating non-cardiogenic pulmonary edema following cardiopulmonary bypass.Eur J Cardiothorac Surg1996;10,463-466. [CrossRef] [PubMed]
 
Kimmel, SE, Sekeres, MA, Berlin, JA, et al Risk factors for clinically important adverse events after protamine administration following cardiopulmonary bypass.J Am Coll Cardiol1998;32,1916-1922. [CrossRef] [PubMed]
 
Fowler, AA, Hamman, RF, Good, JT, et al Adult respiratory distress syndrome: risk with common predispositions.Ann Intern Med1983;98,593-597. [PubMed]
 
Pepe, PE, Potkin, RT, Reus, DH, et al Clinical predictors of adult respiratory distress syndrome.Am J Surg1982;144,124-130. [CrossRef] [PubMed]
 
Zimmerman, GA, Morris, AH, Cengiz, M Cardiovascular alterations in the adult respiratory distress syndrome.Am J Med1982;73,25-34. [CrossRef] [PubMed]
 
Kaul, TK, Fields, BL, Riggins, LS, et al Adult respiratory distress syndrome following cardiopulmonary bypass: incidence, prophylaxis and management.J Cardiovasc Surg1988;39,777-781
 
Gu, YJ, Wang, YS, Chiang, BY, et al Membrane oxygenator prevents lung reperfusion injury in canine cardiopulmonary bypass.Ann Thorac Surg1991;51,573-578. [CrossRef] [PubMed]
 
Tamiya, T, Yamasaki, M, Maeo, Y, et al Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators.Ann Thorac Surg1988;46,47-57. [CrossRef] [PubMed]
 
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