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Ann Thorac Surg 2006;82:1436-1444
© 2006 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
Accepted for publication April 19, 2006.
* Address correspondence to Dr Tatoulis, Suite 28, Private Medical Centre, Royal Melbourne Hospital, Victoria 3050, Australia (Email: james.tatoulis{at}mh.org.au).
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Abstract |
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METHODS: One hundred consecutive patients were randomized to OPCAB or ONCAB, 50 in each group. Antifibrinolytics and steroids were not used. All protocols were identical except for cardiopulmonary bypass. Temperature, SVR index, cardiac index, and blood pressure were measured continuously for the first 24 hours postoperatively. All patients were reviewed at 30 days.
RESULTS: There was no 30-day mortality, no stroke, and no acute renal failure. Mean temperature peaked at 37.5°C at 12 hours (p = 0.700 between groups). Mean SVR index fell to 1,900 dyne · cm–5 · m–2 at 12 to 18 hours; 42% of OPCAB and 32% of ONCAB patients developed very low SVR index (<1,500 dyne · cm–5 · m–2). The incidence of high SVR (>2,500 dyne · cm–5 · m–2) fell from 20% to 2% by 12 to 18 hours. The extent and pattern of SVR index responses were similar in both groups (p = 0.840). Mean cardiac index peaked at 3.0 L · min–1 · m–2, 12 to 18 hours postoperatively (p = 0.815 between groups); 84% of OPCAB and 90% of ONCAB had cardiac index greater than 2.2 L · min–1 · m–2 at all times. Only 10% of patients required vasopressors. Blood pressure responses were also similar (p = 0.314).
CONCLUSIONS: The incidence of low SVR, and patterns of SVR changes were similar in ONCAB and OPCAB, and were clinically unimportant as few patients required vasopressor support. Cardiac outputs and clinical outcomes were excellent in both groups.
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Introduction |
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. The circulating levels of all these inflammatory mediators are less after off-pump surgery by comparison to coronary artery surgery using cardiopulmonary bypass (CPB) [1–6]. Leukocyte counts are also lower in OPCAB [1, 6]. The release of interleukin 10, an antiinflammatory compound, during CPB supports the concept of an interaction between proinflammatory and antiinflammatory cytokines determining the severity of the inflammatory response to CPB and subsequent clinical manifestations [2, 6, 7].
Independent of CPB, surgical trauma has a major role in activating the inflammatory process and complement pathway. The cytokine interleukin 6 is a marker for response to tissue injury, and is released in similar amounts in both on-pump and off-pump surgery in which a sternotomy is performed [2, 6, 8]. Surgical trauma also encompasses pericardiotomy and harvesting of internal thoracic arteries and other arterial (radial) or saphenous vein grafts, as well as cardiac manipulation, the effects of coronary stabilizers, vascular slings, and microvascular clamps. The inflammatory response to surgical trauma in coronary surgery (irrespective of on-pump or off-pump) may comprise a greater component than that caused by CPB [8].
Clinical outcomes of coronary artery bypass grafting (CABG), which may be influenced by the severity of the inflammatory response, including pulmonary function, do not appear to be different in on-pump or off-pump CABG surgery, except possibly for blood loss and blood use [9–14].
A postoperative inflammatory response is associated with vasodilatation and reduced systemic vascular resistance (SVR), and it would be expected that the magnitude of the inflammatory response would be proportional to the effects (reduction) on SVR postoperatively.
There is little in the literature relating to objectively measured SVR responses in off-pump coronary surgery—and whether they are less or more profound than for conventional on-pump CABG.
We studied SVR as a physiologic and hemodynamic response to inflammation to determine (1) the extent and time course of SVR changes postoperatively, (2) any differences in the severity of the SVR changes between on-pump and off-pump CABG, (3) extent and patterns of temperature, blood pressure, cardiac output, and cardiac index responses, and (4) clinical outcomes, in a randomized group of patients.
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Material and Methods |
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Randomization
Inclusion criteria comprised all patients in whom the surgeons thought that either an OPCAB or on-pump technique could be used based on the angiogram.
Exclusion criteria included known calcification or atheroma of the ascending aorta in which an off-pump technique was predetermined, those with extensive diffuse coronary artery calcification or in whom a deeply intramyocardial course was suspected preoperatively. Patients operated on urgently (ie, same day as angiogram) were excluded, as informed consent was not uniformly possible.
Randomization was by a computer program, with the allocation concealed in sealed envelopes. The result of the randomization was made known to the surgeon at skin incision.
Institutional ethics committee approval was granted for this trial, and thorough, informed consent obtained from each patient.
Anesthetic Technique
All patients had an arterial monitoring line, an internal jugular central venous line, and a Swan-Ganz pulmonary artery catheter, capable of measuring continuous cardiac outputs, updating measurements every 90 seconds.
All patients received antibiotic prophylaxis, flucloxacillin 2 g intravenously before anesthesia, and 1 g intravenously every 4 hours for 24 hours in addition to ceftriaxone 2 g intravenously, a once-only dose. Patients allergic to penicillin, or who had been in hospital for more than 5 days, received vancomycin 1 g intravenously before anesthesia, and 1 g intravenously every 12 hours for 24 hours. Anesthesia was by an intravenous propofol infusion combined with midazolam and fentanyl. Muscle relaxation was achieved with vecuronium. Pancuronium was also commonly used for on-pump CABG to reduce the tendency toward bradycardia in the induction and pregrafting period. Ventilation was maintained with tidal volumes of 10 mL/kg.
Heparin Management
For on-pump CABG, the initial heparin dose was 300 U (3 mg) per kilogram to achieve an activated clotting time (ACT) of greater than 500 seconds. Further heparin was given as required (1,000 to 5,000 U) to maintain the ACT greater than 500 seconds. After CPB, heparin was neutralized by protamine at a ratio of 1 mg/1 mg. Target end ACT was less than 150 seconds.
For OPCAB, an initial dose of 100 U of heparin (1 mg) per kilogram was given, with a target ACT of greater than 250 seconds. Further doses of 1,000 to 2,000 U were given, as required to maintain ACT greater than 250 seconds until the last anastomosis was completed. In general, the heparin was not reversed. If the patient was "wet" at the time of sternal closure and if the ACT was greater than 180 seconds, then after a further check of surgical hemostasis, 10 to 20 mg of protamine was given intraoperatively.
Additional Hemodynamic Monitoring
All patients had transesophageal echocardiography, and all had continuous cardiac output measurements. Intraoperative epiaortic echocardiography was used at the surgeon's discretion.
For OPCAB, target blood pressure (BP) was greater than 100 mm Hg systolic and greater than 70 mm Hg mean using volume preload, intermittent doses of Aramine (metaraminol; 0.5 mg) or a dopamine infusion (2 to 3 µg · kg–1 · min–1), and Trendelenburg position. A temperature of 35° to 36°C was maintained by ambient operating room temperature (21°C) and a heating blanket (Bair Hugger; Arizant Healthcare, Minneapolis, MN).
Surgical Technique
All patients had a midline sternotomy. All had a left internal thoracic artery harvested. Additional grafts comprised, as required, the right internal thoracic artery, one or both radial arteries, and rarely lower leg saphenous vein. Only 2 (4%) patients in the OPCAB group and 5 (10%) in the on-pump group had saphenous vein conduits used (p = 0.166). All arterial grafts in both groups had identical antispasmodic prophylaxis with topical and intraluminal papaverine, previously reported in detail [15].
If a left internal thoracic artery to radial artery Y graft was to be constructed, this was performed after heparinization, but before CPB, or grafting in the OPCAB group.
All distal anastomoses were constructed with continuous 7-0 polypropylene suture, as were left internal thoracic artery to radial artery anastomoses. Proximal aorta to graft anastomoses were constructed with continuous 6-0 polypropylene suture.
On-Pump Coronary Artery Bypass Grafting
Cardiopulmonary bypass was established by distal ascending aorta and right atrial (two-stage venous) cannulation. Flows of 2.5 L · min–1
· m–2 or greater, temperature 35° to 37°C, and mean BP of 70 mm Hg or greater were maintained. A standard (noncoated) CPB circuit was used with a membrane oxygenator and a 20-µm arterial filter. Any patient rewarming was achieved slowly by using minimal circulating blood to core body temperature gradients.
Myocardial protection was by combined antegrade aortic root (700 mL) and retrograde coronary sinus (300 mL) blood cardioplegia at 20°C (measured septal myocardial temperature 25°C) with a further retrograde dose (300 mL) after the completion of each anastomosis. A further antegrade dose (300 mL) was given when the aortic clamp time exceeded 30 minutes. All distal and proximal anastomoses were constructed during a single period of cross-clamping. Shed mediastinal blood within the pericardium or the left pleura was returned to the pump on a regular basis (after each anastomosis—approximately every 10 minutes).
A cell-saving device sucker was used before and after CPB in all cases, and was routinely used in OPCAB. Salvaged blood was processed if the final volume of packed red blood cells was estimated to be greater than 250 mL.
Off-Pump Coronary Artery Bypass Grafting
Exposure of the coronary vessels was by deep pericardial traction sutures between the left inferior pulmonary vein and the inferior vena cava, table rotation toward the surgeon (circumflex marginal exposure), and steep Trendelenburg (posterior descending artery exposure). These maneuvers were performed gradually to allow hemodynamic compensation. Coronary stabilization was by the Medtronic Octopus III epicardial suction stabilizer (Medtronic, Minneapolis, MN) or a reusable compression style stabilizer (Platypus, Wolfram, Sydney, Australia).
Coronary artery control was by small atraumatic plastic clamps placed widely across the coronary artery proximally, to include muscle and fat on either side and cushion the lateral compression, or by silicone elastomer sling. Intracoronary shunts were used at the surgeon's discretion.
As most off-pump coronary reconstructions were a left internal thoracic artery to radial artery Y graft, the left internal thoracic artery to LAD anastomosis was constructed first, then sequential construction of anastomoses to the marginal arteries, and finally the left ventricular branch or posterior descending branch, with progressive perfusion of each of the grafted territories. Proximal aortocoronary graft anastomoses using a side-biting clamp were avoided.
Antifibrinolytics, aprotinin, aminocaproic acid, and tranexamic acid, and steroids were not used in any patient.
Additional Temperature Management
A Bair Hugger (Arizant Healthcare) warming blanket was used in all patients (sterile if required intraoperatively) and for the first 24 hours postoperatively.
Postoperative Hemodynamic and Systemic Vascular Resistance Measurements
Heart rate, arterial blood pressure, pulmonary artery, central venous pressure, and temperature were monitored continuously. Urine output and blood loss were monitored hourly. Cardiac output was measured continuously (90-second updates). It was noted each hour (for the first 24 hours), and a mean for each 6-hour period was calculated and documented. Systemic vascular resistance and systemic vascular resistance index (SVRI) was calculated hourly for the first 24-hour period, and a mean value for each 6-hour period was documented. Hence there were at least 24 individual cardiac output, SVR, and SVRI measurements per patient in the study. The use of vasoactive infusions (norepinephrine) and of inotropic solutions (dopamine) were noted.
Postoperative Intensive Care Management
The propofol infusion was continued until satisfactory arterial blood gases (arterial partial pressure of oxygen of 80 mm Hg or greater) were achieved on an inspired oxygen concentration of 40%. Analgesia was achieved by intravenous morphine 1 to 2 mg/h as required, tramadol 50 to 100 mg intravenously as required every 6 hours, or paracetamol 1 g orally as required every 4 hours after extubation.
Statistical Methods
All data were collected prospectively, stored on a computer database, and analyzed using StatXact V 6.1 with Studio (Cytel Software Corp, Cambridge, MA). Clinical data are shown as mean ± standard deviation. For categorical variables, Fisher's exact test was used for 2 x 2 tables of frequency. For 2 x 3, 2 x 4, or 2 x 5 tables, the Fisher-Freeman-Halton exact test was used for unordered categories. The exact Cochran-Armitage test was used for ordered categories. For continuous variables, an exact permutation test was used for the difference between means.
Actual, two-sided probability values are presented. A probability less than or equal to 0.05 is considered statistically significant. When multiple hypothesis were presented, the raw probability values were adjusted to p' to control for type 1 error by backward, stepwise, Ryan-Holm, Bonferroni technique [16].
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Temperature
The mean temperature on arrival to the intensive care unit was 35.8°C for ONCAB and 36.1°C for OPCAB. The mean temperature rose early after surgery, to maximum levels (37.5°C) 12 hours postoperatively before settling at 37.0° to 37.1°C 24 hours postoperatively. There was no difference between the on-pump and off-pump groups (p = 0.700; Fig 1).
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Cardiac Index
A cardiac index (CI) of 2.2 L · min–1
· m–2 or greater was considered desirable postoperatively. Excellent CIs were observed during the first 24 hours. The mean CI in each group rose from an initial level of 2.9 L · min–1
· m–2 at 6 hours, peaked at 3.0 L · min–1
· m–2 at 12 to 18 hours, and fell a little to 2.6 to 2.8 L · min–1
· m–2 at 24 hours. The lowest mean CI was 2.6 L · min–1
· m–2 at 24 hours. There was a trend toward slightly higher mean CI values in the ONCAB group; however, there was no statistical difference in these values, or in the pattern of response during the first 24 hours between the two groups (p = 0.815). The mean values at the different time intervals are presented in Figure 2.
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Postoperative SVRI was consistently low normal for both groups in the 24-hour period. For OPCAB, mean SVRI values ranged from 1,898 to 2,180 dyne · cm–5 · m–2. For ONCAB, mean SVRI values ranged from 1,882 to 2,282 dyne · cm–5 · m–2. The lowest mean values for SVRI in both groups was similar (1,900 dyne · cm–5 · m–2) and occurred in the 12- to 18-hour postoperative time frame (p = 0.840; Fig 3).
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Where the SVRI was less than 1,500 dyne · cm–5 · m–2, the CI was always greater than 2.2 L · min–1 · m–2 except in two OPCAB cases in the first 6 hours (Table 3). The majority of patients in both groups had mean SVRI values in the normal range (from 50% at 6 hours to 92% at 24 hours; Fig 4). The proportion of patients with high SVRI (>2,900 dyne · cm–5 · m–2) was highest in the first 6 hours postoperatively (28% for OPCAB, and 12% for ONCAB) and lowest at the 12- to 18-hour intervals (2% for each group; Fig 4). The relatively higher SVR in the early postoperative phase may have been secondary to patients returning from the operating room in a relatively cool state (Fig 1).
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16%) and tended to occur early (1 to 6 hours postoperatively). All the patients who had a low CI had a correspondingly high SVRI (>2,900 dyne · cm–5
· m–2), except two in the OPCAB group (first 6-hour period) who had a low CI and a relatively high SVRI (>2,500 dyne · cm–5
· m–2), but did not exceed 2,900 dyne · cm–5
· m–2, which was the study's definition of high SVRI (Table 4).
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Off-pump CABG may result in improved perioperative outcomes, particularly in reduced frequency of renal dysfunction, blood loss, blood requirements, ventilation and intensive care unit times, and length of stay [1, 6, 11, 12]. This in part has been ascribed to the minimization of the systemic inflammatory response by avoiding CPB. However, other studies, including randomized trials, found no difference in clinical outcomes between on-pump and off-pump CABG [9, 10, 13, 14, 17, 18]. This suggests that the extent and influence of the systemic inflammatory response may not be as profound as previously thought, and also that there may not be a major clinical translation of the biochemical response, with little differential between off-pump or on-pump CABG.
Despite substantial experience in CABG including OPCAB, there were fewer anastomoses in the OPCAB group (as in most other reports), possibly because of lack of grafting of small vessels, those supplying scar, or in situations in which severe wall disease is unexpectedly encountered. This relative undergrafting may affect long-term outcomes.
This study was concerned with postoperative hemodynamics, and in particular patterns and changes in SVR as a clinical surrogate of systemic inflammatory response after CABG. Systemic vascular resistance was selected as it is measurable in real time (as opposed to cytokine levels), and because of its practical, relevant physiologic ramifications and clinical management requirements. The randomization allowed comparison of two identical groups, with respect to these postoperative hemodynamic variables. Our study examined the extent, and patterns of SVR changes in the 24 hours after CABG in a randomized comparison between on-pump and off-pump CABG.
Traditional teaching has been that the SVR (and SVRI) rises within 2 hours postoperatively to counteract depression of left ventricular function [19]. We found the opposite (in both on-pump and off-pump groups) in that mean SVR fell immediately postoperatively, and continued to fall during the first 18 hours postoperatively, so that the lowest mean SVRI was recorded 18 hours postoperatively. Mean CI rose, and the highest mean CI was also achieved at this time, as would be expected, complementing the SVRI changes. Furthermore, 70% to 90% of all patients had low or normal SVR (and excellent CI) at all times in the first 24 hours postoperatively. Velissaris and colleagues [10] recently reported similar findings of a fall in SVRI during the first 6 hours postoperatively—with no difference between on-pump and off-pump groups in a randomized study. However, their observations were limited to only the first 6 hours postoperatively.
Although a fall in SVR accompanies systemic inflammation, there are potentially both advantageous and negative consequences. A low SVR results in reduction in afterload and preload, resulting in a beneficial milieu for the myocardium in the immediate postoperative setting. However, profound falls in SVR may result in significant hypotension with potentially poor distal organ (particularly kidney) perfusion.
The pattern and time frame of the SVR changes correlate well with observed changes in cytokine and complement product C3a and C5a concentrations observed by Ascione and colleagues [1] and Wan and colleagues [9], in which the highest levels occur within the first 4 hours, attenuating to preoperative levels by 24 hours.
The highest incidence of low SVR (and also the lowest mean values for SVRI) was at 6 to 12 hours postoperatively. This delay may be related to the release of the inflammatory mediators in the 0- to 4-hour postoperative period, and observation of the subsequent clinical effects of these on temperature, SVR, and blood pressure in the hours after (ie, 4 to 12 hours postoperatively).
The SVRI normalized at 24 hours, correlating with depletion of cytokine levels. Approximately 40% of the patients had an initial significant fall in SVR, and the extent and patterns of the changes were similar in both groups.
Although we expected to find some reduction in SVR in the OPCAB group, we were surprised to observe a significant incidence of low SVR in OPCAB, which was similar (and indeed higher, 42% versus 28%) by comparison with conventional on-pump CABG.
The CI responses were reciprocal to the SVR changes (as would be expected), with the highest CI values in both groups corresponding to the time of the lowest mean SVR at 12 to 18 hours postoperatively. The fact that excellent and similar CIs were obtained in both groups underlay the applicability of both techniques to CABG surgery.
The incidence of relative hypotension (mean arterial pressure less than 70 mm Hg) paralleled the incidence of low SVR, thus validating and reinforcing the data. It was not associated with any clinical sequelae. The CI was uniformly excellent in this group. The OPCAB group had an unexpectedly high incidence of relative hypotension (up to 46% of patients at 6 hours), which is surprising as a less intense perioperative inflammatory and physiologic response would have been expected.
In summary, despite expectations (based on cytokine and plasma mediator release and concentrations) that the effects on SVR and the incidence of low SVR syndrome would be significant and more pronounced in the conventional on-pump CABG group, our findings did not support this. The incidence of low SVR was similar in both on-pump and off-pump groups, and was clinically unimportant, as few patients required vasopressor support, and clinical outcomes were excellent.
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