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Ann Thorac Surg 2000;69:77-83
© 2000 The Society of Thoracic Surgeons
a Departments of Anesthesiology and Cardiovascular Surgery, German Heart Center, Technical University of Munich, Munich, Germany
Address reprint requests to Dr Richter, Institute of Anesthesiology, German Heart Center Munich, Lazarettstrasse 36, D-80636 Munich, Germany
e-mail: richter{at}dhm.mhn.de
| Abstract |
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Methods. A prospective randomized controlled trial involving 30 patients, divided in two groups of 15 patients each, undergoing elective coronary artery bypass grafting, was undertaken. In the Drew-group bilateral extracorporeal circulation using patients lung as oxygenator was performed. The other patients served as control group, where standard cardiopulmonary bypass procedure was used.
Results. Pro-inflammatory and anti-inflammatory mediators were measured. Peak concentrations of pro-inflammatory interleukin-6, interleukin-8, were significantly lower in 15 patients undergoing Drew-Anderson Technique compared with the concentrations measured in 15 patients treated with standard cardiopulmonary bypass technique. Differences in patient recovery were analyzed with respect to time of intubation, blood loss, intrapulmonary shunting, oxygenation, and respiratory index. In patients undergoing uncomplicated coronary artery bypass grafting procedures bilateral extracorporeal circulation using the patients own lung as oxygenator provided significant biochemical and clinical benefit in comparison to the standard cardiopulmonary bypass procedure.
Conclusions. This prospective randomized clinical study has demonstrated that exclusion of an artificial oxygenator from cardiopulmonary bypass circuit significantly decreases the activation of inflammatory reaction, and that interventions that attenuate this response may result in more favorable clinical outcome.
| Introduction |
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(TNF-
), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and endotoxin. Plasma levels of pro-inflammatory cytokines vary widely, as reported in the literature. Certain organs and tissues are considered to be at higher risk of developing deranged function after CPB. At the greatest risk are formed elements of blood (platelets and leukocytes), and in particular, the pulmonary system [24]. No study has specifically evaluated the role of the oxygenator, as an independent predictor of the inflammatory cytokine response to CPB. The goal of the present study was to assess the feasibility and the effects using the patients own lungs as oxygenator in a bilateral cardiac bypass circuit during coronary artery bypass grafting (CABG), thus excluding the possible damaging effects of an artificial oxygenator. Bilateral bypass without an oxygenator and with deep hypothermic circulatory arrest was introduced by Drew and Anderson to cardiac surgery in 1959. In some reports the method proved to be successful in clinical practice [5, 6].
In this paper we focus on the course of various parameters of systemic inflammatory response syndrome (SIRS), on the perioperative oxygenating potential of the lungs, and on patients outcome. The primary hypothesis of this study was, that perfusing and ventilating the patients lung might help to minimize inflammatory response, defined as the change and difference in the plasma concentration of IL-6, IL-8, IL-1ra, and IL-10 influenced by the exclusion of the oxygenator, as compared to a control-group. As secondary efficacy variables, we also were interested in the clinical outcome of the patients in terms of duration of postoperative respiratory therapy, blood loss, gas exchange, oxygen transport and intrapulmonary right-to-left shunting.
| Material and methods |
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The criteria for inclusion in the study were (1) preoperative two-, or multi-vessel coronary artery disease; (2) LV-ejection fraction greater than 0.5, LVEDP less than 15 mm Hg; and (3) no obstructive or restrictive respiratory disease, and otherwise healthy adult patients. The criterion for the selection of patients was that the procedure would be a closed one, so that patients with LV-aneurysms or undergoing concomitant valve procedures, were not included.
Anesthetic techniques and monitoring
Anesthesia and monitoring techniques were performed according to our clinical routine. It has been described in detail elsewhere [7]. Patients were heparinized with bovine heparin 375 IU/kg. Anticoagulation was controlled by measuring the activated clotting time (ACT), which was maintained at more than 500 s, a cell separator system was used in both groups to wash and centrifugate blood remaining in the extracorporeal circuit after termination of CPB. Corticoids have not been given intraoperatively.
Cardiopulmonary bypass technique
Control group
Membrane oxygenator (Dideco, Module 7500, Mirandola, Italy) primed with 2.000 mL Ringers lactate, 100 mL 20% mannitol, 5000 IU heparin, and a roller pump (Stöckert-Shiley Instrumente GmbH, Munich, Germany) was used for CPB. Systemic hypothermia (nasopharyngeal and rectal temperature 28° to 30°C),
-stat pH management and a pulsatile pump flow rate of 2.4 L · min-1 · m-2 were used. One liter 4°C cold crystalloid cardioplegic solution (Custodiol, Bretschneider, Dr. Köhler Chemie, Germany) was given antegrade to maintain electromechanical quiescence. Hemoglobin concentration was maintained at equal to or greater than 7.0 g/dL during CPB, and at equal to or greater than 9.0 g/dL after CPB.
Before separation of patients from CPB an infusion of dopamine (5 mcg/kg/min) was used as a first line drug in both groups. After termination of CPB its infusion rate was adapted according to the patients circulatory state. Protamine was given to neutralize anticoagulation according to the patients ACT.
Drew group
The extracorporeal bypass circuit consisted of a reservoir (Venocard 20 m, D 772 Dideco) for each side of the heart, connected by a shunt (Fig 1). The heat exchanger was connected to the left heart system. The extracorporeal system was primed with comparable priming volume as the CPB circuit in the control-group. Roller pulsatile pump (Stöckert-Shiley Instrumente GmbH, Munich, Germany) was used for CPB. Probes for continuous blood gas analysis (CDI 400 3M, Health Care, Tustin, CA) were attached on the venous inline port (venous sensor 6702) and on the arterial line (Quickwell 6740).
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Postoperative respiratory management
After arrival at the intensive care unit, all patients were treated according to the clinical standards. Inotropic agents were used, when cardiac index was less than 3.0 L · min-1 · m-2 despite volume expansion to ensure PCWP between 12 and 15 mm Hg. Patients were sedated for 4 hours with incremental doses of morphine sulfate (2 mg IV). Thereafter sedation was stopped, if the following criteria were fulfilled: cardiocirculatory stable condition on CPAP ventilation, with dopamine less then 7.5 mcg/kg/min, chest-drainage less than 100 mL/h, PCWP less than 15 mm Hg; patient warm and cooperative. If the patient was awake at spontaneous ventilation on Y-connector with an oxygen-flow of 6.0 L/min, if PaO2 greater than 80 mm Hg, PaCO2 less than 50 mm Hg, tidal volume greater than 10 mL/kg, respiration frequency 10 to 15 breaths/min extubation was performed. The minimum required postoperative intubation time was registered.
Blood loss and homologous blood requirements were recorded until the chest tubes were removed. Outcome variables were obtained by investigators who were blinded to each patients treatment assignment.
Data collection and blood sampling
For each patient we collected relevant demographic, and intraoperative data: aortic cross-clamp time, CPB duration, and postoperative data. Blood samples were taken for measurements at eight time points. During CPB blood was drawn from the arterial and venous line of the circuit.
Biochemical measurements
The blood specimen were collected in different phlebotomy tubes (Sarstedt, Nürnbrecht, Germany): EDTA containing tubes for blood counts, interleukin-10 and interleukin 1-ra, NH4-heparin-tubes for electrolytes, and serum tubes containing no anticoagulant for the measurement of colloid osmotic pressure, interleukin-6, and interleukin-8 were measured using solid-phase, two-site chemiluminescent enzyme immunometric assay (Immulite system, Diagnostic Products Corporation, Los Angeles, CA). Interleukin 1-ra (R&D Systems, Minneapolis, MN) and interleukin-10 (PerSeptive Biosystems, Framingham, MA) were measured with solid-phase ELISAs in microtiter plates. The samples for determination of interleukins were immediately centrifuged for 10 minutes (3000 rpm), all plasma samples were frozen in aliquots at -70°C, and were thawed for analysis.
Arterial and mixed-venous oxygen blood gas analysis were determined by standard techniques using an automated analyzer, and total hemoglobin concentration (Hb) as well as hemoglobin oxygen saturation (SaO2) by spectrophotometer (CO-Oxymeter 482; Instrumentation Laboratory, Lexington, MA). Oxygen content was calculated as 1.34 x hemoglobin concentration x oxygen saturation + dissolved oxygen. When the dissolved oxygen was calculated the actual body temperature was taken into account. Intrapulmonary venous admixture, AaDO2, oxygenation index, respiratory index, intrapulmonary shunting (Qs/Qt) was calculated using standard formula.
Statistics
Students t-test for independent samples for continuous and chi-squared tests for categorical data were used to evaluate differences between groups. Interleukins have been analyzed using one-way analysis of variance (ANOVA). A correction for baseline values has been performed before using absolute differences (concentration - baseline concentration) for statistical evaluation. A p of less than 0.05 was considered statistically significant. The data were presented as mean±sem. A power analysis was performed for the arterial PO2 after CPB as the primary end point. A two-sided test with p = 0.05 and a statistical power of 95% were used. It was assumed that a difference of 40% between the Drew-group and the control-group would occur. Therefore each group had to consist of at least 15 patients.
| Results |
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Cardiopulmonary bypass: pulmonary dysfunction
During CPB the lungs are effectively excluded from the circulation, consequently heparinized blood remains relatively static within the pulmonary vasculature for this period. The diminished pulmonary blood flow on CPB may result in postoperative impairment of pulmonary vascular endothelial function, and inability to release nitric oxide. Structural damage to the pulmonary endothelium is demonstrable after CPB [9]. The pathogenesis is secondary to CPB and may be multifactorial in origin, involving hemostatic, cellular and inflammatory mechanisms. Pulmonary vascular endothelial dysfunction may also be a contributing factor in post-CPB pulmonary hypertension [10]. Clinically, these tissue damaging effects of bodys inflammatory response to CPB produce dysfunction of the organ systems, with the collective clinical picture being termed as "postperfusion syndrome." The magnitude of this clinical syndrome has been seen to be associated with the extent of activation of the inflammatory response during CPB [11]. The most common clinical manifestation of this syndrome is seen in the respiratory system, possibly because of the ischemic injury to the lungs endothelial cells while they are excluded from the circulation during total CPB or because the lungs are the only organ to receive the entire cardiac output, and therefore are highly exposed to the activated inflammatory process [1, 12].
Many investigators reported on pathophysiological changes that occur during reperfusion at the end of CPB. The lungs have been found to sequester neutrophils [13]. Once neutrophils have been trapped in the lungs, endothelial cells swell, fluid and plasma protein extravasate into the interstitial tissues, proteolytic enzymes released from neutrophil granules disrupt alveolar pneumocytes, and alveoli fill with inflammatory debris, and red blood cells, leading to severe respiratory dysfunction [14]. The overall effect is that blood is shunted through the lungs, either perfusing inadequately ventilated alveoli or being not sufficiently oxygenated because of alveolar-capillary block.
Several studies have also demonstrated that TNF-
, IL-6, and IL-8 release are stimulated by CPB in adults [14, 15]. Interleukin-8 is suspected to be a trigger of neutrophil-induced endothelial injury, and therefore, responsible for some of the postoperative CPB adverse effects. Also a correlation betweenIL-6 and IL-8 release and the length of CPB has been demonstrated [16, 17]. Hennein and colleagues [18] found a correlation between post-CPB left ventricular wall motion abnormality scores with increasing IL-6 and IL-8 plasma concentrations.
Possible therapeutic strategies
Efforts to attenuate this process were undertaken including the administration of corticosteroids, aprotinin, and anticytokine monoclonal antibodies. Various modifications of the extracorporeal circuit, and use of ultrafiltration techniques were introduced in clinical practice, as a result, no single intervention is able to prevent the deleterious effects of the inflammatory response to CPB [19]. On the other hand, more recent studies also suggest that activation of the inflammatory response by CPB may have detrimental effects, and that interventions that attenuate this response may result in favorable clinical outcomes [20].
Recent findings underline the fact that steroids may inhibit the elevation of pro-inflammatory cytokines including IL-6, and IL-8, also enhancing the production of anti-inflammatory cytokine IL-10 [19, 20]. Steroid treatment has become a fundamental strategy in the "fast-track recovery" protocol, and has been shown to improve postoperative recovery in patients undergoing CPB procedures.
Drew-Anderson technique: inflammatory reaction
Proinflammatory cytokines
The primary efficacy hypothesis of this study was that perfusing and ventilating the patients lung might help to minimize inflammatory response, influenced by the exclusion of the oxygenator, and defined as the change and difference in the plasma concentration of IL-6, IL-8, compared to a control-group. On the other hand perfusion of the lungs can provide sufficient preservation of the pulmonary endothelial function during and after extracorporeal bypass procedures [6].
In our study, using the Drew-Anderson Technique, the attenuation of inflammatory response was comparable with the results achieved by using high dose steroids [7, 19, 2022]. As demonstrated in previous studies, we did not see statistically significant changes in IL-6, and IL-8 after anesthesia induction or after surgical stimulation during the pre-bypass period. The highest IL-6 values were measured late, that is, four hours after termination of CPB (Fig 2). This elevation of IL-6 was threefold higher in the control group as compared to patients undergoing Drew Technique (p = 0.007) (Fig 2).
IL-8 may have a substantial role in directing polymorphonuclear cells in the development of the systemic inflammatory response during cardiac surgery [16, 19]. Figure 3 demonstrates the course of IL-8 plasma concentrations in both groups. The highest values were measured two hours after the end of CPB. There was a difference between the two groups indicating a consistent higher release of IL-8 in the control group (p < 0.05). Like in other studies, peaks in circulating IL-8 levels seem to precede or be coincident with the peak in IL-6 levels. IL-8 and other cytokines play a pivotal role by increasing the expression of cell surface receptors known as integrins. The appearance of IL-8 in plasma during cardiac surgery is associated with an increase in elastase, which is released in response to cellular activation and is associated with organ dysfunction after CPB [16, 22]. The degree of inflammation and postoperative pulmonary dysfunction seems to be related to the serum levels of IL-8, which was earlier metabolized. Decreasing levels of inflammatory mediators such as IL-8, especially during the post-CPB course, may be advantageous for attenuation of postperfusion syndrome.
Anti-inflammatory cytokines
The systemic inflammatory response is self-limiting in most patients. Once the stimulus is removed (eg, after termination of CPB) processes initiated either during the procedure or in the early period thereafter, serve to terminate the systemic inflammatory response [19]. Endogenous factors that also serve to limit the response have been identified, including IL-1-ra, and IL-10. IL-10 exerts a number of anti-inflammatory effects, including the inhibition of the synthesis on the pro-inflammatory cytokines. Increased levels of IL-10 have been found during CPB following pro-inflammatory cytokines, and may represent the endogenous response to limit the inflammatory response [19]. In our study IL-10 concentration peaked 30 minutes after CPB in both groups (Fig 4). A sevenfold increase of IL-10 was detected in both groups, indicating the enhanced anti-inflammatory response. Two hours after CPB there was no statistically significant difference between the two groups. Four hours after CPB a second peak of IL-10 concentration was seen in the control-group, corresponding with higher levels of IL-6, and IL-8 concentrations registered in the control-group (p < 0.01) (Figs 24). Circulating IL-1ra levels peaked four hours after commencement of CPB, and did not differ in both groups, following closely the course of elevated IL-6 concentrations (Fig 5).
Pulmonary function
As secondary efficacy variables, we also were interested in the clinical outcome of the patients in terms of duration of postoperative respiratory therapy, blood loss, gas exchange, oxygen transport and intrapulmonary right-to-left shunting. It was assumed that when significant changes can be observed in such a low-risk patient population, a much higher effect should be expected in high-risk patients undergoing CPB procedures.
In a study by Ranucci and associates [23] pulmonary shunt fraction was judged to be the best index determining the respiratory dysfunction after cardiac operations. They also noted that in patients population, free of preoperative lung dysfunction, changes in shunt fraction did not result in delay of extubation or discharge from the ICU. As in the above study, our patient selection included only patients with unimpaired preoperative lung function, so that the significant differences in intrapulmonary shunt fraction between the groups did not necessarily result in prolonged stay at the ICU. Time to extubation was significantly shorter in the Drew-group (p < 0.0025), however in clinical practice extubation time is influenced by a number of other clinical factors so that duration of respiratory therapy never strictly reflects pulmonary function. On the other hand, it is conceivable that the observed differences in intrapulmonary shunt fraction (p < 0.013), AaDO2, (p < 0.001), respiratory index (p < 0.001), which is an index of oxygenation and reflects the presence of pulmonary shunting in a variety of circumstances, could potentially improve clinical course in patients with pre-existing pulmonary dysfunction undergoing CPB without the use of an artificial oxygenator (Table 2). The lower respiratory index in the Drew-group may be related to the suppression of neutrophil activation, which may cause leukosequestration in the pulmonary microcirculation or the generation of free radical species on reperfusion. In future studies simultaneous sampling from the left and right circuit should be performed to underline the effectiveness of the Drew-Technique.
Influence on hemostasis
More intriguing is the association between IL-6 and IL-8 levels and hemostasis impairment. Clinical reports have already demonstrated the beneficial effects of perioperative hemofiltration on both IL-6 and IL-8 levels and transfusion requirements or thrombocytopenia. Thus, inflammation and hematological disorders seem to have clinical associations. In our study we also found a significant reduced blood loss and transfusion requirement in the Drew-group (Table 1).
In a recent study the question was raised: "Is the reduction of the inflammatory response to CPB of clinical significance?" Studies have documented that SIRS increases morbidity and mortality. The data presented may suggest a link between increased duration of CPB and the magnitude of IL-6 response [17]. Other investigations have demonstrated, that attenuation of the inflammatory response may help to reduce adverse outcomes following CPB [18, 24]. However, since the inflammatory response is multifactorial, combined therapies may be more efficient than a single intervention to improve outcome. Both pharmacological interventions and modifications of extracorporeal techniques might improve clinical results. Administration of corticosteroids, aprotinin, as well as heparin coated CPB circuits, using the patients lungs as oxygenator, and intraoperative modified ultrafiltration may have important clinical implications. It is conceivable that by reducing inflammatory response to CPB, cardiac surgery may achieve greater success in the treatment of high-risk patient population.
In addition, the Drew-Anderson Technique may also provide the technical background for CABG procedures in underdeveloped countries, with restricted resources for disposal of oxygenators in cardiac surgery.
Limitations are the restricted use of this technique only for patients undergoing CABG procedures and missing the safety of an oxygenator in emergency situations. In case of complications after CPB, like severe myocardial ischemia, making surgical revision necessary, a conventional CPB-circuit must be available. Safe application of the technique requires trained surgeons, anesthesiologist and perfusionists. However, the surgical access is considerably better, than under condition of minimally invasive or MIDCAB surgical procedures.
This prospective randomized clinical study has demonstrated that ventilation and perfusion of the lungs during CPB and exclusion of artificial oxygenators from CPB circuit significantly decreases the activation of inflammatory response. All interventions that attenuate this response may result in some cases in more favorable clinical outcome.
We conclude that in patients undergoing CABG procedures the bilateral extracorporeal circulation using the patients own lung as oxygenator provided significant biochemical and clinical benefit over the standard CPB procedure.
| Acknowledgments |
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| Footnotes |
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| References |
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