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Ann Thorac Surg 2005;80:2221-2228
© 2005 The Society of Thoracic Surgeons
Cardiac Surgery Unit, Magna Graecia University, Catanzaro, Italy
Accepted for publication June 3, 2005.
* Address correspondence to Dr Onorati, Viale dei Pini, 28, 80131 Napoli, Italy (Email: frankono{at}libero.it).
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Abstract |
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METHODS: Between January and November 2004, 40 patients undergoing preoperative IABP were randomized to receive either standard nonpulsatile CPB with IABP discontinued during cardioplegic arrest (20 patients; group A) or IABP-induced pulsatile (automatic 80 bpm) CPB (20 patients; group B). Hospital outcome was recorded. Urine output, blood urea nitrogen (BUN), creatine, creatinine clearance, peripheral lactate, recovery of gut motility, alanine-amino-transferase (ALT), aspartate-amino-transferase (AST), lactic dehydrogenase (LDH), bilirubin, and amylase (AMY) were compared.
RESULTS: There were no IABP-related complications, nor perioperative renal or liver failures, nor hospital deaths, nor myocardial infarctions. Intensive care and hospital stay, urine output, and recovery of gut motility were comparable. Group B showed lower creatine on the first (p = 0.01) and second (p = 0.005) postoperative days, higher creatinine clearance (first day: p = 0.01; second day: p = 0.03), lower lactate after CPB termination (p = 0.0001) and during the first day (p = 0.001). The ALT, AST, and AMY were lower in group B (first day ALT: p = 0.01; AST: p = 0.04; AMY: p = 0.017; second day ALT: p = 0.01; AST: p = 0.02; AMY: p = 0.027), as well as total bilirubin (first day: p = 0.05; second day: p = 0.02).
CONCLUSIONS: Automatic 80 bpm IABP during cardioplegic arrest improves creatinine clearance and splanchnic enzymes. There is no reason to suspend preoperative IABP support during cardioplegic arrest.
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Introduction |
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However, although the nonpulsatile blood flow obtained with standard CPB circuits is considered an acceptable, nonphysiologic compromise with few disadvantages (including the induction of such inflammatory response), the theoretical benefits of pulsatile blood flow include the reduction of vasoconstrictive reflexes, the optimization of oxygen consumption, and the reduction of acidosis, secondary to the improvement of organ perfusion [10]. However, pulsatile CPB still represents an open question: some studies have reported beneficial effects of pulsatile systemic perfusion on microcirculation, metabolism, and organ functions [11–13], with notable beneficial effects on splanchnic and myocardial function [14–18]; on the other hand, others did not observe any superiority of pulsatile CPB over nonpulsatile CPB [19, 20]. Therefore, we designed a prospective randomized study to evaluate what happens when IABP is turned off versus maintaining pulsatile circulation by switching IABP to an automatic 80 bpm mode during cardioplegic arrest in patients undergoing preoperative insertion of IABP for first-time isolated coronary artery bypass grafting.
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Material and Methods |
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In order to avoid misleading data, patients older than 70 years, or with splanchnic organ comorbidities (renal, liver or mesenteric impairment, abdominal aortic aneurysm, abdominal arteries vasculopathy, or severe autoimmune disease), were excluded from the study.
The study protocol was approved by the Institution's Ethical Committee/Institutional Review Board (September 2003). Informed consent was obtained from each patient enrolled in the study.
Anesthesia
All patients underwent Swan-Ganz catheter insertion through the right internal jugular vein for continuous hemodynamic monitoring before anesthetic induction. Postoperative chest x-ray confirmed its exact positioning.
Anesthetic technique was the same for all patients: induction of anesthesia consisted of intravenous propofol infusion at 3 mg/kg combined with fentanyl administration at 0.10 mg/kg. Neuromuscular blockade was achieved by 4 mg/hour pancuronium bromide, and lungs were ventilated to normocapnia with air and oxygen (45% to 50%). Propofol infusion (150–200 µg/kg per minute) and isoflurane (0.5% inspired concentration) maintained anesthesia. Arterial and central venous catheters were the standard. Inotropes were started immediately after aortic cross-clamp removal to maintain adequate mean systemic pressure, always starting with enoximone at a dosage of 5 µg/kg per minute. The need for further increase in inotropes was recorded: inotropic support was defined as low-dose when enoximone was administered at a dosage lower than or equal to 5 µg/kg per minute; medium-dose when enoximone was employed at a dosage between 6 and 10 µg/kg per minute, or dobutamine was added at a dosage between 5 and 10 µg/kg per minute; or high-dose when enoximone or dobutamine infusion was greater than 10 µg/kg per minute or epinephrine was added at any dose.
Surgical Technique and Cardiopulmonary Bypass
It was institutional policy to insert IABP (8 Fr, 34 or 40 mL according to the body surface area; balloon connected to a Datascope pump [Datascope Corp, Fairfield, NJ]) percutaneously through the best femoral artery, before induction of anesthesia, in order to better support the perioperative hemodynamic of patients undergoing surgery for severe left main stem disease. The correct placement of IABP was always assessed by postoperative chest x-ray or transesophageal echocardiography.
Patients received anticoagulation with enoxaparin, with a target-activated partial thromboplastin time greater than 40 seconds, starting when the postoperative bleeding was controlled (usually within 6 hours). The IABP was withdrawn when hemodynamic stability was restored (ie, a cardiac index 
2.0 L/m2 per minute with only minimal pharmacologic inotropic support, dobutamine or enoximone at 5 µg/kg per minute). The CPB and surgical techniques were standardized and did not change during the study period.
Surgery was performed by the same senior surgeon (AR) in all cases. In all patients CABG was performed through a median sternotomy. The left internal mammary artery was harvested as a pedicle and anastomosed to the left anterior descending artery in all cases. The right internal mammary artery was harvested as a pedicle and never used as a free graft. The radial artery was always anastomosed to the ascending aorta. Proximal anastomoses were always performed with partial clamping after aortic cross-clamp removal.
Cardiopulmonary bypass was conducted by the same perfusionist in all cases. Heparin was given at a dose of 300 international units (IU)/kg to achieve a target-activated clotting time of 480 seconds or above. Blood recovery with an autotransfusion device (Autotrans Dideco, Mirandola, Modena, Italy) was performed intraoperatively in all cases. A level of hemoglobin lower than 8 g/dL suggested blood transfusion. Standard CPB circuit was used: a Dideco (Mirandola) tubing set, which included a 40 micron filter, a Stockert roller pump (Stockert Instrumente, Munich, Germany), and a hollow fiber membrane oxygenator (Monolyth, Sorin Biomedica, Saluggia, Italy). The extracorporeal circuit was primed with 1,000 mL of Ringer's lactate solution and 40 mg of heparin. Systemic temperature was kept between 32 and 34°C. Myocardial protection was always hieved with intermittent antegrade and retrograde hyperkalemic blood cardioplegia, as previously reported [21]. Total CPB flow was maintained at 2.6 L·min-1 · m-2.
In group A patients, IABP was turned off during cardioplegic arrest, maintaining a standard nonpulsatile CPB; group B patients underwent IABP-induced pulsatile CPB during cardioplegic arrest with pulsatile flow being maintained by an automatic 80 bpm mode until aortic declamping.
Endpoints
The primary endpoints were in-hospital mortality and morbidity, perioperative myocardial infarction, in-hospital and intensive therapy unit (ITU) stay, IABP-related complications, and investigation of splanchnic function. In-hospital mortality was defined as any death occurring during hospital stay or in the first 30 postoperative days. Hospital morbidity was defined as any complication requiring specific therapy or causing a delay in hospital or ITU discharge.
Perioperative acute myocardial infarction was defined by new Q waves of greater than 0.04 ms, and/or a greater than 25% reduction in R waves in at least two leads on ECG, by new akinetic or dyskinetic segments at echocardiography, with a peak troponin I (TnI) greater than 3.7 µg/L, or TnI concentration greater than 3.1 µg/L at 12 hours postoperatively, as determined by Mair and colleagues [22]. The IABP-related complications were defined as any aortic dissection or perforation, limb or mesenteric ischemia, or infection or hemorrhage at the balloon entry point.
Splanchnic function was investigated by urine output, need for diuretics, incidence of renal failure, blood urea nitrogen (BUN), creatine, blood lactate, and creatinine clearance for the kidney. Renal failure was defined as any postoperative renal insufficiency requiring first-time hemofiltration, dialysis, or any other renal replacement therapy. Urine output less than 200 mL/12 hours or anuria in association with an acute rise in urea ( 160 mg/dL) or serum creatine ( 2.0 mg/dL) similarly suggested renal failure. Creatinine clearance was calculated using the Cockroft and Gault formula: creatinine clearance = (140 - age) x weight (kg)/(serum creatinine x 72 [x 0.85 for women]). Postoperative recovery of gut motility, liver injury (defined as an acute increase in serum alanine-amino-transferase [ALT] levels to more than 500 IU/L within 48 hours of surgery), aspartate-amino-transferase (AST), lactic dehydrogenase (LDH), bilirubin (total and fractioned), and amylase (AMY) investigated perioperative mesenteric, liver, and pancreatic function. Ileus was defined as a delay in gut motility lasting for more than 72 hours.
Biochemical Analysis
Blood samples were collected from the central venous line; the tip of the cannula was located in the lower part of the right atrium as confirmed by chest x-ray postoperative control. Determinations of blood concentration of cardiac TnI were conducted preoperatively before anesthetic induction and at 12, 24, 48, and 72 hours postoperatively. In order to evaluate the adequacy of myocardial protection techniques, TnI and lactate were measured on coronary sinus blood samples obtained from the retrograde cardioplegic cannula 10 minutes after completion of proximal anastomoses. The TnI assays were carried out using diagnostic kits provided by Beckman Coulter (AccuTnI Access Immunoassay System, Fullerton, CA). Peripheral blood lactate was measured preoperatively, immediately after CPB termination, and on the first and second postoperative days. The BUN, creatine, creatinine clearance, ALT, AST, LDH, total and direct bilirubin, and AMY were measured at hospital admission, at admission to the ITU, and at 24 and 48 postoperative hours.
Statistical Analysis
Statistical analysis was performed by the SPSS program for Windows, version 10.1 (SPSS Inc, Chicago, IL). Continuous variables are presented as mean ± SD, and categorical variables are presented as absolute numbers and/or percentages. Data were checked for normality before statistical analysis.
Normally distributed continuous variables were compared using the unpaired t test, whereas the Mann-Whitney U test was used for those variables that were not normally distributed. Categorical variables were analyzed using either the 
2 test or Fischer's exact test. Comparison between and within groups was made using two-way analysis of variance for repeated measures. Comparisons were considered significant if p is less than 0.05.
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Results |
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Perioperative hemodynamic data were comparable between the two groups (Table 3).
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Mean intubation time (group A: 15.8 ± 4.2 hours vs group B: 12.6 ± 3.7; p = 0.822), in-ITU stay (group A: 39.9 ± 8.3 hours vs group B: 41.4 ± 9.9; p = 0.683), and mean postoperative hospital stay (group A: 7.2 ± 1.3 days vs group B: 7.7 ± 2.0; p = 0.841) were all similar between groups.
There were no major or minor IABP-related complications in either group. There were two postoperative complications among the study population: one patient (5%; p = 0.317) in group B experienced pneumothorax on the second postoperative day, requiring tube drainage. One patient in group A (5%; p = 0.317) developed perioperative ileus lasting for 80 hours and requiring rehydration and intravenous fenoldopam administration. However, both patients recovered during hospital stay and were discharged home in healthy condition on the eighth and ninth postoperative days, respectively.
Similarly, no patients developed perioperative renal failure or oligoanuria requiring renal replacement therapy. No cases of liver failure were registered among the entire population.
No differences were detected in urine output between the two groups (Fig 1) or in need for diuretics during the hospital stay (group A: 85% vs group B: 65%; p = 0.273). However, although no differences were detectable in perioperative BUN, group B patients demonstrated significantly lower values of creatine and significantly higher values of creatinine clearance during the postoperative period (Table 4). It should be noted that creatinine clearance demonstrated a progressive improvement during the postoperative period in group B patients, whereas group A patients showed reduced creatinine clearance in the first 24 postoperative hours versus the preoperative values.
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Although there were no demonstrated differences in LDH between the two groups, group B showed significantly lower values of ALT and AST at admission in ITU and on the first and the second postoperative days. Total and direct bilirubin also showed lower leakage in group B during the postoperative period, reaching the statistical significance at admission to the ITU, on the first and on the second postoperative days for the total bilirubin, and on the second day for the direct fraction (Table 4). Amylase similarly showed significantly less leakage in patients belonging to group B (Table 4); postoperative AMY showed progressively increasing leakage in group A, whereas group B demonstrated a progressive decline of serum values.
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Comment |
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As a result, short-term circulatory support with IABP during the perioperative period may be required. There is growing evidence to support the use of preoperative IABP in those patients having open-heart surgery who are thought to be at high risk (on the basis of poor left ventricular function), who are redo patients, or who have characteristics of critically ischemic hearts such as severe left main lesions, diffuse critical coronary lesions, and unstable angina despite maximal medical therapy [1, 2, 24]. According to the low values of troponin I and lactate sampled intraoperatively from the coronary sinus and to the postoperative troponin leakage, as well as to the absence of perioperative myocardial infarctions, our study confirmed the potential benefit of preoperative IABP in high-risk left main lesions.
Moreover, major and minor IABP-related complications continue to decrease: this trend may be explained by more experienced surgical teams, by improved balloon catheters, by better education and surveillance of patients treated with IABP, and by increased early detection of, and adequate reaction to, vascular complications. In fact, the overall complication rate in the Benchmark Counterpulsation Outcome registry was 6.5%, and the rate of major complications requiring surgery or blood transfusion was only 2.1% [25]. In accordance with these data, and likely due to the small number of patients enrolled, our study registered no IABP-related complications at any time, in either group.
On the other hand, despite advances in CPB circuits, pumps, membranes, and pharmacologic management, patients undergoing CPB remain at risk for the development of postperfusion systemic inflammatory response syndrome, which can result in organ insufficiency, hemodynamic instability, and (rarely) multiorgan failure in the postoperative period [4, 5]. This is particularly true of the patients with multiorgan comorbidities regularly referred to surgery in current practice. However, although the mechanisms of organ injury are not fully understood, the mode of perfusion (pulsatile versus nonpulsatile) may affect this process. In fact, if standard nonpulsatile CPB is considered an acceptable compromise with few disadvantages, such as the induction of such inflammatory response, some theoretical benefits of pulsatile blood have been postulated over the decades, ranging from the vasodilative effect on peripheral resistances to the optimization of oxygen consumption, to the reduction of peripheral acidosis; all of which result from improved organ perfusion [10]. However, pulsatile CPB still represents a neverending debate and no definitive conclusions have been reached. Some studies have reported beneficial effects of pulsatile systemic perfusion on microcirculation, metabolism, and organ functions [11–13], with notable beneficial effects on splanchnic and myocardial function [14–18]; others did not observe any superiority in the pulsatile CPB over nonpulsatile CPB [19, 20]. Moreover, there is no certainty about the best pulsatile model. Finally, it has to be considered that a lot of these trials were conducted with previous CPB circuits and membranes [11–14] or were animal experimental studies [17, 18].
However, in concordance with the majority of recent studies, we did not observe significant differences in in-hospital outcomes or major clinical endpoints (in-hospital mortality, organ morbidity, recovery of heart function after CABG, urine output, need for diuretics during postoperative stay, or recovery of gut motility). It is possible that the short difference in the time course of linear versus pulsatile flow (ie, the duration of the aortic cross-clamp time, presently ranging from about 20 to 60 minutes), did not account for significant impairment in organ perfusion in patients in whom IABP was turned off during cardioplegic arrest.
However, we demonstrated significant biochemical differences between the two groups, despite the short cross-clamp time. Again the brevity of the cardioplegic arrest may have been responsible for subclinical differences, such as the metabolic and biochemical features of the splanchnic function. It may be that patients with longer cross-clamp time would also demonstrate differences in outcome, though trials on this subset of patients are needed.
In fact, we found better creatinine clearance and creatine plasma levels in patients undergoing automatic 80 bpm pulsatile IABP-induced CPB. The higher creatinine clearance in these patients confirm some previous studies, such as that of Boucher and colleagues [19], who demonstrated the preservation of renal blood flow under pulsatile conditions, or that of Landymore and colleagues [26], who showed enhanced urine filtration with pulsatile flow. Moreover, lower lactate plasma levels were detected in these patients, confirming the findings of German and colleagues [27], who found that nonpulsatile flow is associated with renal hypoxia and acidosis, and those of Mukherjee and colleagues [14], who demonstrated decreased tissue oxygen pressure in the renal medulla and increased local lactate level in nonpulsatile conditions. Similarly, in a recent review of pulsatile perfusion, Hornick and Taylor [28] observed that progressive systemic arterial vasoconstriction is the inevitable consequence of nonpulsatile CPB, leading to reduced visceral perfusion and acidosis. It is noteworthy that coronary sinus lactate proved to be comparable between the two groups, implying similar myocardial protective techniques, whereas peripheral lactate was lower in group B, demonstrating lower peripheral tissue acidosis.
Similarly, lower leakage of pancreatic and hepatic enzymes was detected in the pulsatile CPB group. As for kidney function, our study similarly confirmed some previous data, such as those of Saggau and colleagues [29], who demonstrated that pulsatile CPB preserves pancreatic function better than nonpulsatile CPB, either in humans or animals, and those of Murray and colleagues [15], who showed a reduced incidence of elevated amylase levels in patients undergoing CPB with pulsatile flow. In the same direction, Pappas and colleagues [16], using AST as a marker of hepatic injury, found that pulsatile flow preserves hepatic tissues and function; Chiu and colleagues [30] reached the same conclusions.
Limitations
The main limitation of the study is related to the small sample size of patients enrolled in the study.
This is a result of the single-center design of the study itself, which, on the other hand, guarantees uniformity of the perioperative management of the patient population throughout the experimentation. Moreover, on an intention-to-treat basis, we enrolled patients with the most similar risk profile, as patients with severe left main stem disease, without severe organ comorbidities or extensive extracardiac atherosclerosis, which may mislead the results.
Finally, patients were operated on by the same senior surgeon, and underwent the same CPB, led by the same perfusionist, thus reducing the risk of human biases.
Conclusions
Despite our finding that automatic 80 bpm IABP during cardioplegic arrest does not influence major clinical outcomes, it does significantly improve creatinine clearance and whole splanchnic enzymatic release. These differences were already evident even for cross-clamp time lower than 60 minutes. Consequently, there is no reason, in patients undergoing preoperative IABP support, to turn off the pump during cardioplegic arrest, but our data suggest that switching to the automatic mode is ideal.
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