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Ann Thorac Surg 2003;76:737-743
© 2003 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, Milan, Italy
b Biostatistics Unit, Milan, Italy
c Department of Anesthesiology and Intensive Care, Centro Cardiologico Monzino IRCCS, University of Milan, Milan, Italy
Accepted for publication April 4, 2003.
* Address reprint requests to Dr Parolari, Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, Via Parea, 4, 20138 Milan, Italy
e-mail: aparolari{at}ccfm.it
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Abstract |
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METHODS: Twenty-five patients were randomized to undergo CABG (n = 14) or OPCAB (n = 11). All patients received the same anesthetic management. Oxygen metabolism variables were assessed before induction of anesthesia and up to 18-hours after surgery.
RESULTS: At baseline, before induction of anesthesia, there were no differences between CABG and OPCAB in oxygen consumption (VO2), delivery (DO2), or extraction (ExO2). After surgery VO2 and ExO2 increased in both groups, while DO2 decreased. No significant differences between CABG and OPCAB were detected in postoperative VO2, DO2, and ExO2 levels. The relation between VO2 and DO2 was very similar in CABG and OPCAB patients throughout the study, and no significant differences were detected in slopes and intercepts of the regression lines between CABG and OPCAB at all time points. There was, however, a significant effect of time on the relation between VO2 and DO2: this relation was stronger in the postoperative period, and the slope of this relation increased over time as well.
CONCLUSIONS: A hypermetabolic state and progressive and significant increases in the strength of the relationship between VO2 and DO2 and in the slope of this relationship occur after both CABG and OPCAB. Cardiopulmonary bypass is not responsible for these changes in oxygen metabolism.
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Introduction |
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The relation between the O2 transported to body tissues (oxygen delivery, DO2) and O2 effectively utilized (oxygen consumption, VO2) is, under normal conditions, biphasic; this relation, however, shifts towards a linear one both in the intraoperative [2, 8] and early postoperative period of cardiac surgery [2, 5, 9], and is similar to the behavior of the relation between VO2 and DO2 during critical conditions like shock.
Previous reports have suggested that CPB could the main cause of the increased metabolism seen after cardiac surgery [1–4, 6], and of the perioperative changes that occur to the relation between VO2 and DO2 [2, 5, 7].
This study was designed to verify the hypotheses that CPB gives rise to the postoperative hypermetabolic response and that it also sensibly influences the relation between VO2 and DO2 in the early perioperative period after adult cardiac surgery.
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Material and methods |
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Intraoperative management
Anesthesia
Patient management during and after surgery was the same in both groups of patients. All patients continued their cardiac medications until surgery. Anesthetic premedication was atropine, 0.5 mg, and morphine sulfate, 0.1 mg/kg, given intramuscularly 1-hour before surgery. In order to assess baseline hemodynamic variables, each patient received, under local anesthesia, a 4F arterial thermodilution catheter (PiCCO; Pulsion Medical Systems, Munich, Germany) inserted through the brachial or the femoral artery, and a 7.5F Swan-Ganz catheter (Baxter Healthcare Corp, Irvine, CA) inserted through an 8.5F internal jugular vein introducer before anesthesia induction.
Anesthesia was then induced by the administration of sodium thiopental (4 to 5 mg/kg), fentanil (100 µg), succinilcholine (1 mg/kg), and pancuronium bromide (0.1 mg/kg). After the induction of anesthesia, all the patients underwent orotracheal intubation.
Patients were ventilated with oxygen and air (fraction of inspired oxygen 50%), keeping PaCO2 between 35 and 38 mm Hg.
Cefuroxime (2 g) was given intravenously for infection prophylaxis. A continuous infusion of propofol was started after anesthesia induction (3 to 4 mg · kg-1 · hour-1), and boluses of sufentanil (25 µg for a maximum total dose of 0.3 mg) and pancuronium bromide (2 mg) were given when necessary.
Rectal and cervical esophageal temperature probes were used; also, arterial blood temperature was measured by PiCCO monitor. Acid-base equilibrium was maintained by the 
-STAT method and serial determinations of the blood gases were performed using an IL-813 blood gas analyzer, while oxygen saturation and hemoglobin concentration were measured with the use of an IL-282 cooxymeter (Instrumentation Laboratories Inc, Lexington, MA); the hematocrit was measured by centrifugation.
CABG surgery
A nonpulsatile roller pump, hollow-fiber oxygenator with integrated heat exchanger, arterial filter, cardiotomy reservoir, and polyvinyl tubing system were used in all patients. Each operation was performed with tepid hypothermia (32 to 34°C) and hemodilution. Blood flow during CPB was maintained at 2.4 L · min-1 · m-2, and hematocrit at 18% to 25%. Myocardial protection was achieved by the administration of cool (4°C) multidose (every 15 to 20 minutes) blood cardioplegia (Buckberg) infused through the aortic root and the coronary sinus.
OPCAB surgery
All OPCABs were performed by a midline sternotomy; mechanical stability of the coronary arteriotomy area was achieved with Octopus III system (Medtronic Inc, Minneapolis, MN) and a soft plastic coronary flow-shunt was always introduced into the coronary arteriotomy to maintain some degree of distal flow, to reduce myocardial ischemia and to improve visualization of the anastomosis area. Coronary artery exposure was achieved with stay sutures applied on the left lateral side of pericardium or with deep pericardial stay sutures placed above the entry of the left lower pulmonary vein and laterally to the entry of the inferior vena cava.
The hemodynamic management of patients for distal coronary anastomoses consisted mainly in careful and progressive elevation of the heart, associated to substantial volume administration so as to allow the heart to adapt to position changes; this strategy usually avoids the occurrence of major hemodynamic changes and the need of inotropic agents administration.
Postoperative management
Patients were admitted to the intensive care unit (ICU) and treated according to a standardized protocol, with the aim of a progressive emergence from anesthesia, using a relatively prolonged postoperative sedation with propofol drip, which was continued at a rate of 1 to 2 mg per kg per hour until full rewarming of the patient was obtained, and until bleeding had subsided (< 100 mL/hour for 2 consecutive hours); rapid rewarming, shivering, and agitation were carefully avoided. Mean arterial blood pressure was kept at 70 to 90 mm Hg, heart rate at 70 to 90 bpm, and cardiac index greater than 2.0 L · min-1 · m-2. Fluid balance, rectal temperature, and hemodynamic variables were recorded every hour. Physicians caring for the patients postoperatively were blinded to the treatment group.
Blood sampling and data collection
Blood samples were collected at the following times:
Blood was collected from the arterial catheter and from the distal venous port of the Swan-Ganz catheter in heparinized syringes. The syringes were immediately put in ice, and the samples were subsequently analyzed at 37°C for blood gases, pH, bicarbonates, base excess, hematocrit, hemoglobin concentration and oxygen saturation.
The DO2, VO2, and oxygen extraction (ExO2) were calculated at each time point by means of standard formulas [8]. In addition, temperatures (rectal and arterial blood), and hemodynamic and blood gas variables were recorded and collected at each time point.
Statistical analysis
Continuous variables are presented as mean ± 1 standard error of mean (SEM), categorical variables as percentage. Group differences in clinical variables between CABG and OPCAB were assessed with ANOVA and Fischer’s exact test when indicated.
Oxygen metabolism, hemodynamic variables, and temperatures in CABG and OPCAB over time
General linear model (GLM) ANOVA and ANCOVA models were used for statistical analysis of time, group (CABG vs OPCAB), and interaction (time*group) effects;ANOVA was used to study hemodynamic variables and temperatures, whereas ANCOVA was used to study oxygen metabolism variables (VO2, DO2, and ExO2), in order to adjust oxygen metabolism data for rectal temperature, as a preliminary analysis of temperatures behavior in CABG and OPCAB patients demonstrated significant differences in rectal temperature between the two study groups. When time, group, or interaction effects were significant (p < 0.05), repeated measures ANOVA with Bonferroni correction was used to establish significant differences.
Study of the relation between VO2 and DO2
The relation between VO2 and DO2 in CABG and OPCAB was explored with linear regression analysis at each time point.
The effects of treatment (CABG vs OPCAB) and of time were explored as follows: first, the slopes and intercepts of the regression lines obtained in CABG and OPCAB patients were compared at each time point using the method described by Zar [10]. With this method a p value (two-tailed) is calculated in order to test the null hypothesis that the regression slopes are not different in the two groups (the regression lines are parallel). If the p value for comparing slopes is greater than 0.05, a second p value testing the null hypothesis that the intercepts are identical is computed. If this second p value is not statistically significant, there is no compelling evidence that the lines are different, and it is possible to calculate one slope and one intercept for all the data. On the other hand, if the p value comparing the slopes is less than 0.05, the lines are significantly different, and it is useless to compare the intercepts.
Then, the effect of time on the parameters (slopes, intercepts) of the relation between VO2 and DO2 was investigated, and the same methods described in the previous paragraph were used. If no differences between CABG and OPCAB on the relation between VO2 and DO2 were demonstrated at each time point, data from CABG and OPCAB groups were pooled together.
A p value less than 0.05 was considered for statistical significance.
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Results |
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Oxygen metabolism, hemodynamic variables, and temperatures
There were no differences between CABG and OPCAB in oxygen metabolism, hemodynamic variables and temperatures at baseline.
Oxygen metabolism
Only time effect for changes in VO2 was significant (Table 2):
after surgery, starting from "skin" time point, VO2 significantly increased in both groups with respect to baseline levels. No differences between CABG and OPCAB in VO2 levels were detected (Fig 1
and Table 2).
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Both time and group effects for changes in DO2 were significant. There was a significant postoperative DO2 decrease in both groups, starting after anesthesia induction and lasting up to 18 and up to 9 postoperative hours in CABG and OPCAB, respectively. No significant differences between CABG and OPCAB in postoperative DO2 levels were detected at a point-by-point comparison with repeated measures ANOVA (Table 2).
Hemodynamic variables and temperatures
There were no significant differences between CABG and OPCAB in the time course of mean arterial pressure and peripheral arterial resistances (data not shown). There was, however, a significant effect of CPB on the behavior of cardiac index, and significantly greater values were demonstrated at "skin" time point in CABG patients (Table 2). The cardiac index levels were, however, in the normal range in both groups at all time points.
About temperatures, there was a significant effect only of time on the behavior of arterial blood temperatures, with an intraoperative decrease followed by a postoperative increase in both groups (Table 2); on the other hand, both time and group effects for changes in rectal temperature were significant, and significantly higher rectal temperature levels were detected in CABG group both at "protamine" and at "9-hours post" time points (Table 2).
Behavior of the relation between VO2 and DO2
No significant relation between VO2 and DO2 both in CABG and in OPCAB could be demonstrated before anesthesia induction ("pre-anesthesia" time point, Table 3).
Starting from "post-anesthesia" time point in OPCAB and from "protamine" in CABG a constantly significant linear relation between VO2 and DO2 was demonstrated up to 18 hours postoperatively. The slopes and intercepts of these relations did not differ between CABG and OPCAB at each time point (Table 3). On the other hand, there was a significant effect of time on the strength and factors of this relation: the slopes of this relation progressively increased over time and were significantly higher at postoperative time points (p = 0.013 for trend, Fig 2); furthermore, the strength of the linear relation between VO2 and DO2 progressively increased over time (Table 3).
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Comment |
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CPB was believed for a long time to be the main or the sole mechanism of this hypermetabolic response. In fact, it can cause and heart and lung ischemia, tissue hypoperfusion, and impairment of tissue oxygen utilization as well [2–4]; it can also induce a whole-body response that triggers the production and release of oxygen-derived free radicals and of cytokines [4], and it can stimulate the neuroendocrine response [1, 6]. Some authors, including ourselves, formulated the hypothesis that CPB was also the cause of the change in the shape (from biphasic to linear) of the relation between VO2 and DO2 that occurs during and early after cardiac surgery [2, 5, 8].
The definitive demonstration that CPB is the main cause of these changes has been, however, lacking, as a control group of patients undergoing a major cardiac surgical procedure without CPB use was not available since the recent introduction of OPCAB in routinary clinical practice.
The results of this study question the hypothesis that CPB is the main responsible of the increased metabolism and of the changes to the relation between VO2 and DO2 seen after cardiac surgery.
Our data demonstrate that an hypermetabolic status ensues after both on-pump and off-pump coronary surgery, as reflected by significant increases in oxygen consumption (35% to 40% with respect to baseline) and extraction (75% with respect to baseline). No significant differences were, however, detected between CABG and OPCAB in the timing and extent of this response which was similar between the two study groups.
A similar postoperative hypermetabolic response was previously demonstrated in general surgery both in high-risk surgical candidates [13] and in patients with normal preoperative base line cardiac and respiratory values [14]. Thus, the most likely hypothesis concerning perioperative oxygen metabolism increase is that general surgical trauma is the main cause of it. An alternative explanation is that, during surgery, both general and cardiac, both on-pump and off- pump, an intraoperative oxygen debt ensues; as the levels of cardiac index were at all time points widely above critical levels both in our protocol and also in previous experiences performed on general surgery patients [14], the occurrence of reduced tissue perfusion is very unlikely. In addition, it is also very unlikely that even properly done surgery might sensibly interfere with oxygen metabolism causing oxygen debt.
Finally, another possible explanation is that the increase in the metabolic rate observed both in general and cardiac surgery is caused by the perioperative changes in some inflammatory pathways or mediators that are not sensibly affected by CPB use but are influenced by surgical trauma itself.
About the relation between VO2 and DO2, this study confirms that, in the intraoperative and early postoperative period of cardiac surgery, oxygen metabolism is substantially different from normal conditions, where a biphasic relation can be demonstrated [2, 5, 8, 9]. In fact, a plateau level where further DO2 increases do not rise VO2 in a similar way was not found, and a constantly linear relation between these two variables was documented instead.
There are two possible reasons for that: the first one, which is, in our opinion, by far the most likely, is that surgical stress or some of the actions related to coronary surgery cause a major change of oxygen metabolism behavior during and early after surgery. The second possible reason is that the variations in DO2 and VO2 that can be achieved in clinical setting are too narrow to allow the detection of the horizontal phase of a possibly biphasic relation. The relatively wide range of delivery levels detected in our patients without any external intervention to modify DO2 levels both in CABG (10th and 90th percentiles 297 and 697 mL O2/min per m2, respectively) and in OPCAB (10th and 90th percentiles 204 and 633 mL O2/min per m2, respectively) allow us to exclude this as a possible explanation.
Interestingly, there were no differences between coronary surgery performed on-pump or off-pump both in the slopes and the intercepts of the regression lines at all six time points. It is also noteworthy that no significant differences between CABG and OPCAB were found even when, in order to increase sample size and the chances to detect statistically significant differences between study groups, preoperative (pre-anesthesia and post-anesthesia), intraoperative (protamine and skin) and postoperative (9-hours post and 18-hours post) time points were pooled together (data not shown). Finally, even when all the time points were pooled and analyzed together, no differences between CABG and OPCAB were detected, and the slopes and intercepts of the lines were remarkably similar (data not shown).
On the other hand, there was a significant effect of time and, consequently, of surgery, on this relation: the slopes and the and strength of the relation between VO2 and DO2 increased over time, peaking after surgery. These findings suggest that careful management of the patients remains an important issue, especially in the early postoperative period, when patients are much more at risk for the occurrence of oxygen debt and, consequently, of anaerobic metabolism.
About limitations of this study, there was a significant difference in rectal temperature between groups, being higher in CABG at some of the time points. This can be ascribed to the fact that we chose to manage patients undergoing CABG during CPB with some degree of hypothermic perfusion ("tepid" hypothermia); patients were not actively cooled during CPB, but the temperature of patient was allowed to drift until the rewarming phase, when patient were rewarmed up to 35°C. The choice to use tepid hypothermia instead of active rewarming of the patient during the perfusion (warm heart surgery) was taken because of the potential risks of increased neurologic complications related with warm heart surgery [15].
Another limitation of the study is that our protocol followed patients only up to 18 hours after surgery, and no information can be drawn about the behavior of oxygen metabolism in CABG versus OPCAB for longer observation times; but it was deemed to be unethical to leave intravascular catheters for hemodynamic and metabolic determinations (PiCCO and Swan-Ganz) for longer periods of time in otherwise low-risk coronary patients; this also would have prolonged ICU stay of the patients with no reason.
In conclusion, our study confirms that, in early postoperative period after coronary surgery an hypermetabolic status ensues together with significant changes in the relation between VO2 and DO2. Both these changes occur irrespectively of CPB use. Other factors, such as whole-body response to general surgical trauma, are the likely main causes.
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This article has been cited by other articles:
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  C. H. Moller, L. Penninga, J. Wetterslev, D. A. Steinbruchel, and C. Gluud Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses Eur. Heart J., November 1, 2008; 29(21): 2601 - 2616. [Abstract] [Full Text] [PDF]
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 A. Sedrakyan, A. W. Wu, A. Parashar, E. B. Bass, and T. Treasure Off-Pump Surgery Is Associated With Reduced Occurrence of Stroke and Other Morbidity as Compared With Traditional Coronary Artery Bypass Grafting: A Meta-Analysis of Systematically Reviewed Trials * Supplemental Appendix I Stroke, November 1, 2006; 37(11): 2759 - 2769. [Full Text] [PDF]
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 E. M. Elmistekawy Evaluation of surgical trauma and cardiopulmonary bypass as factors in inflammatory status after cardiac surgery J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1226 - 1226. [Full Text] [PDF]
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= CABG group; 
= OPCAB group; *p < 0.05 versus baseline (Pre-Ane); **p < 0.01 versus baseline (Pre-Ane). (CABG = coronary artery bypass graft; OPCAB = off-pump coronary artery bypass; Pre-Ane = pre-anesthesia; Post-Ane = post-anesthesia; 9h post = 9-hours postoperative; 18h post = 18-hours postoperative.)