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From the *Department of Anesthesiology, Kyoto Prefectural University of Medicine, Japan; Department of Outcomes Research, Cleveland Clinic Foundation, Cleveland, Ohio; Outcomes Research Institute, and Department of Anesthesiology, University of Louisville, Kentucky; and ||Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Japan.
Address correspondence and reprint requests to Yasufumi Nakajima, MD, PhD, Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Address e-mail to nakajima{at}koto.kpu-m.ac.jp.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Mild hypothermia (i.e., 
1.5–2.0°C) can cause numerous complications, including morbid myocardial outcomes (4), reduced resistance to surgical wound infection (5), extended hospitalization (5), and coagulopathy (6). Mild hypothermia also decreases drug metabolism (7) and has also been shown to prolong postoperative recovery (8). To achieve early tracheal extubation after CABG (e.g., 1–6 h postoperatively), known as fast-track cardiac anesthesia, some measures to prevent perioperative hypothermia should be considered.
Numerous previous studies, mostly by Sellden et al. (9), have shown that perioperative amino acid infusion provokes thermogenesis. We (10) reported that the core temperature increase in response to amino acid infusion in volunteers results from the combined effect of thermogenesis and an increase in the vasoconstriction threshold. Consequently, core temperatures in patients undergoing noncardiac surgery given amino acids are generally 0.5°C more than those in patients given control fluids (9,11), although not during cardiopulmonary bypass (12).
Sellden et al. (13) also reported that amino acid infusions shorten the duration of postoperative hospitalization after abdominal surgery. It seems unlikely that marked improvements in patients outcome resulted simply from the core temperature difference of only 0.5°C; instead, shortened hospitalization seems more likely to have resulted from the effects of amino acids other than thermogenesis (e.g., acceleration of recovery from surgical stress and reduction of inflammatory response). A limitation of this study (13), though, is that it was retrospective with all the consequent limitations of this design. It was also conducted in a relatively healthy general surgical population. We, therefore, tested the hypothesis that perioperative amino acid infusion improves three aspects of recovery from off-pump CABG: intubation time, intensive care unit (ICU) stay, and days until fit for discharge from hospital.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Historically, patients in our institution who would be eligible for this study remain intubated postoperatively for 6 ± 3 h (mean ± sd), in the ICU for 44 ± 20 h, and in the hospital after surgery (days until fit for discharge from hospital) for 13 ± 4 days. Perioperative amino acid infusion hastens the recovery from neuromuscular blockade (14), which may reduce the period of intubation. More important would be reducing the ICU time and the duration of hospitalization (5). Thus, our goal was to determine whether amino acid infusions would reduce postoperative intubation time by at least 1 h, ICU stay by a day, and the duration of hospitalization by 2 days. A sample-size estimate indicated that 65 patients per group would provide 80% power for detecting these differences at an 
-level of 0.05 for each primary outcome.
About 30% of patients scheduled for off-pump CABG in our institution are switched to either surgery with bypass or to minimally invasive direct coronary artery repair. We enrolled 180 consecutive consenting patients scheduled for elective or urgent (but not emergent) off-pump CABG surgery via median sternotomy between December 1, 2000 and December 31, 2003. Surgery was defined as urgent when patients had medical factors that required them to remain hospitalized and have the operation before discharge, but the risk of immediate morbidity and death was believed to be small. Surgery was defined as emergent if the patient's cardiac disease dictated that it should be performed within hours to avoid unnecessary morbidity or death (15).
All patients were of ASA Physical Status class 2 or 3 and were aged 40–85 yr. Patients having minimally invasive, direct coronary artery bypass surgery were excluded, as were those having concomitant major surgery. Patients were also excluded from the study when they had previous CABG or valvular heart operation, current intraaortic balloon pump support, severe hepatic disease (alanine aminotransferase or aspartate aminotransferase >100 IU/L), renal insufficiency (creatinine >1.5 mg/dL), or severe chronic obstructive pulmonary disease (forced expiratory volume in 1 s <0.8 L).
Protocol
Patients were randomly assigned, according to a computer-generated randomization sequence, to either saline (N = 86) or amino acid (N = 94) infusion. Sequentially numbered envelopes with computer-generated randomizations were opened after informed consent was obtained.
Patients assigned to the amino acid group were given an infusion of Teruamino (Terumo, Tokyo, Japan). Teruamino is a mixture of 18 amino acids that provides 18 g nitrogen/L (Appendix C). The solution was infused via the antecubital vein for 6 h starting 2 h before induction of the general anesthesia. It was infused at a rate of 2 mL kg–1 h–1, which corresponded to 4 kJ energy kg–1 h–1. The remaining patients were given an identical volume of nutrient-free standard saline solutions. Both solutions were covered with opaque foil to prevent physicians from determining group assignment.
All preoperative medications except ß-adrenergic-blockers, diuretics, angiotensin-converting enzyme inhibitors, and Ca-channel blockers were routinely omitted on the day of surgery. Preoperative ß-adrenergic-blockers were resumed postoperatively to avoid withdrawal. All patients fasted at least 8 h before the study.
Diazepam (5 mg) was given orally 3 h before induction of anesthesia, and 0.5 mg of atropine sulfate along with 50 mg of pethidine sulfate was given IM 30 min before induction of anesthesia. Anesthesia was induced with 5 µg/kg fentanyl and 0.15 mg/kg vecuronium bromide, followed by maintenance with continuous infusion of fentanyl (0.8 µg kg–1 h–1) and vecuronium bromide (0.04 mg kg–1 h–1). Propofol was also infused at 4 mg kg–1 h–1. Minute ventilation was adjusted to maintain end-tidal Pco2 at 35–40 mm Hg using controlled mechanical ventilation.
All surgical procedures started near 9:00 am and were performed by the same surgical team. Anticoagulation was provided by IV administration of heparin (125 U/kg) which was given after graft harvesting. A mechanical stabilizer (Octopus, Medtronic, Minneapolis, MN) and a heart positioner (Starfish or Urchin, Medtronic) were used to control motion of the beating heart.
Intraoperative hemodynamic management was standardized. Hypotension (systolic blood pressure <90 mm Hg) was treated with intravascular volume replacement, ephedrine (0.05 mg/kg), or methoxamine (0.02 mg/kg) as indicated. Persistent hypertension (systolic blood pressure >140 mm Hg) was treated by increasing the depth of anesthesia or by administration of nitroglycerin (0.8 µg kg–1 min–1). Tachycardia (heart rate >100 bpm) was also treated by increasing the depth of anesthesia or by using an ultra-short-acting ß-adrenergic-blocker (landiolol hydrochloride, 0.02 mg kg–1 min–1) and edrophonium chloride (0.05 mg/kg). Bradycardia (heart rate <50 bpm) was treated with pericardial ventricular pacing. Intraoperatively, both groups were given 12 mL kg–1 h–1 of lactated Ringer's solution. IV fluids were not warmed.
Ambient operating room temperature was maintained near 23°C. Patients were covered with one layer of a sheet during surgery, and a circulating-water warming mattress positioned under patients was set to 37°C. Patients were tracheally extubated in the operating room or ICU and were discharged from ICU when they fulfilled prospective criteria (Appendixes A and B). Physicians who were blinded to the experimental treatment made all clinical decisions.
Measurements
Morphometric and demographic characteristics were recorded, along with selected cardiac risk factors. Euroscores, a method to identify preoperative risk factors associated with postoperative mortality from cardiac surgery, were generated for each patient (16,17).
After induction of anesthesia, a pulmonary artery catheter (Swan-Ganz CCOmbo V, Edwards Lifesciences, Irvine, CA) was inserted. Arterial blood pressure, heart rate, and oxygen saturation were recorded at 5-min intervals during surgery. Core temperature was measured in the distal esophagus every 5 min using a thermistor probe (Mon-a-therm, Tyco-Mallinckrodt Anesthesiology Product, St. Louis, MO); the probe was inserted at a distance one-quarter of the subject's standing height from the external nares.
Our main outcomes were the number of hours that patients remained intubated after surgery, time in ICU, and number of days until patients were deemed fit for discharge from hospital (Appendix B). The length of hospitalization for this procedure is generally longer in Japan than in the United States because the Japanese health care system does not demand a short hospital stay and allows patients to stay until a nursing home bed becomes available. Thus our third major outcome was when patients met the discharge criteria, rather than the actual duration of hospitalization.
Data Analysis
The effects of amino acid infusion and surgical duration on the cardiovascular responses and core temperatures were analyzed by general linear regression modeling for two-way ANOVA with repeated measures (one-between factor and one-within factor), followed by Student–Newman–Keuls multiple comparison testing. Other continuous variables were analyzed by two-tailed, unpaired t-tests. 
2 test was used to compare categorical variables.
The time required for successful weaning from mechanical ventilation, discharge from ICU, and fitness for discharge in each study group was calculated with Kaplan–Meier statistics and log-rank tests. Results are presented as mean (95% confidence interval) when the results were normally distributed, and median (95% confidence interval range) when they were not. P < 0.05 was considered statistically significant.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Amino acid infusion starting 2 h before induction of anesthesia did not have a significant effect on esophageal temperature before surgery. However, esophageal core temperatures became significantly higher in the amino acid infusion group than in the saline infusion group from 150 min after induction of anesthesia until the end of surgery (P = 0.005; Fig. 2). At the end of surgery, temperatures in the two groups were 35.6°C (35.3– 35.8)°C in the control group vs 36.1°C (35.9–36.3)°C in the amino acid group (P = 0.01).
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Atrial fibrillation occurred in 42% of patients in the saline infusion group, and 30% of patients in the amino acid infusion group. Pleural effusion occurred in 40% of patients in the saline infusion group and 32% of patients in the amino acid infusion group. While neither difference was statistically significant, both were among the factors that prolonged discharge. The postoperative time until fitness-for-discharge criteria were met was 5 days shorter in the 57 patients who developed neither atrial fibrillation nor pleural effusion than that in the 20 who experienced both [8 (7–9) vs 13 (12–14) days; P < 0.001].
Figure 3 shows Kaplan–Meier plots of the duration of mechanical ventilation, duration of critical care, and fitness for discharge from hospital. In patients given amino acids, there was a shorter duration of mechanical ventilation after surgery [median (95% confidence interval range), 3.0 (2.5–3.9) vs 4.5 (3.8–5.8) h; P = 0.01], time in the ICU stay [20 (19.5–38.4) vs 44 (21–45) h; P = 0.001], and days until fit for discharge from hospital after surgery [10 (9–11) vs 12 (11–13) days; P = 0.004] than those given saline.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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One possible mechanism is that core temperatures were better maintained by 0.5°C in patients given an infusion of amino acid solution than those given saline. This observation is consistent with previous studies showing that amino acids promote normothermia during general surgery (9), although not during cardiopulmonary bypass (12). Perioperative hypothermia is associated with numerous complications, including morbid myocardial outcomes (4), surgical wound infections (5), and coagulopathy (6). However, only blood loss has been shown to be influenced by temperature differences near 0.5°C. In fact, blood loss was similar in our two groups, suggesting that some other mechanism contributed to the observed benefits of amino acid administration (18,19).
A second potential mechanism is that IV amino acid infusion may facilitate recovery from surgical stress. One clinical study reports that l-arginine-enriched cardioplegia increases nitric oxide levels and attenuates free-radical-mediated myocardial injury, which consequently improves CABG patients' outcomes (20,21). Further, perioperative amino acid infusion reduces nitrogen excretion along with reduced stress response (22,23). This may indicate a shift from protein wasting to protein synthesis and an acceleration of the healing process required for better patient outcomes after surgery. In animals, preoperative glutamine infusion induces heat shock protein 70 expression and heme oxygenase-1, which subsequently attenuate perioperative inflammatory cytokine response (24,25). Taken together, these mechanisms might contribute to improved patient outcome.
A third potential mechanism is reduced translocation of intestinal bacteria. Numerous reports have shown that amino acid nutrition administered via the gastrointestinal tract reduces bacterial translocation (26–28). This seems especially the case with glutamine-enriched enteral nutrition. Enteral glutamine stimulates renal production of arginine by increasing the plasma concentration of the precursor, citruline (29). These reports speculate that an increased plasma concentration of glutamine, as well as arginine, can be attributed to a reduced inflammatory response. Our previous reports have already confirmed that the plasma arginine concentration is comparably increased by amino acid infusions having the same composition as in the present study (10). But whether IV amino acids comparably protect against translocation of gut bacteria remains speculative in humans, although a recent paper reported that IV amino acids reduced bacterial translocation in animals (25).
A final potential mechanism is that amino acid infusion may reduce the risk of atrial fibrillation. Postoperative atrial fibrillation or flutter is associated with both an increased risk of stroke and prolonged hospitalization (30,31). It is a common complication, occurring in 20%–50% of patients recovering from on-pump or off-pump CABG. Although a recent article reported that perioperative inflammation provokes atrial fibrillation (32,33), the pathophysiology of postoperative atrial fibrillation is uncertain, and its prevention remains suboptimal; consequently, its incidence has changed little over the past 20 yr. Prophylactic preoperative ß-adrenergic-blocker administration has been recommended to reduce the risk of atrial fibrillation, especially in patients with a history of ß-adrenergic-blocker use (34). But whether prophylactic ß-adrenergic-blocker administration reduces the length of hospitalization remains to be elucidated (35). Atrial fibrillation or flutter was among the major factors delaying discharge from hospital in our patients, and the number of days until patients were deemed fit for discharge was, in fact, consistent with previous reports (30,31).
A previous paper reported that higher Euroscore value predicts a significantly increased average time for bypass and total time for surgery (16). In our study, however, the Euroscore was similar in the two groups. This may reflect the fact that our study was preformed in Japanese patients. The adaptation of the Euroscore for patient populations other than Europeans has been criticized (17).
Previous investigators have demonstrated that initiation of amino acid infusion at 1 or 2 h before the onset of anesthesia is effective for preventing initial redistribution of heat from the core of the body to the peripheral tissues (9), as at least 1 h is required for the amino acid infusion to exert its thermal effects. We thus started amino acid administration 2 h before induction of anesthesia, and continued for a total of 6 h. It remains possible, though, that starting even earlier would have provided even more benefit, because glutamine infusion started 1 wk before cardiopulmonary bypass also reduces inflammatory cytokine production (24), which is believed to mediate a number of adverse outcomes.
Because amino acid catabolism per hour is limited, large amounts of amino acid infusion increase plasma osmolality. Our amino acid infusion protocol was based on a previous study protocol and the daily amounts recommended by the manufacturer. Furthermore, amino acid infusion increases oxygen demand, which in turn, elevates the need for increased cardiac output, and therefore, potentially increases adverse cardiac events. However, the increase in cardiac output is modest with recommended amino acid doses (9,36) and there are no reports suggesting adverse cardiac events.
The time until patients were fit for discharge from hospital was longer than previously reported (30,37–41), possibly because our patients were older and had longer procedures. However, the duration of postoperative intubation and time in the ICU were similar to those in previous reports (30,37–41). Most likely, delayed discharge from hospital is simply a consequence of the study being conducted in a health care system in which prolonged hospitalization is common.
A limitation of our study is that we did not address the mechanisms responsible for accelerating the patients' recovery from cardiovascular surgery. Future studies focused on the perioperative inflammatory response in relation to amino acid infusion should be considered.
In summary, perioperative amino acids infusion in patients undergoing off-pump CABG helps maintain normothermia and speeds tracheal extubation, shortens ICU stays, and decreases the time until patients are fit for discharge from hospital by mechanisms not yet fully understood. This simple intervention thus appears to provide substantial benefit.
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ACKNOWLEDGMENTS |
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APPENDIX A: TRACHEAL EXTUBATION CRITERIA |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Blood Gas Analysis
Muscle relaxants were not antagonized.
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APPENDIX B: DISCHARGE CRITERIA |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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From the Hospital
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APPENDIX C: CONSTITUENT AND AMOUNT OF AMINO ACID INFUSION PER 200 mL |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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Footnotes |
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The first two authors contributed equally to this work.
None of the authors has a personal financial relationship with any company related to this research.
Supported by Japanese Ministry of Education, Science, Culture, and Sports (Tokyo, Japan); National Institute of Health Grant GM 061655 (Bethesda, MD); the Gheens Foundation (Louisville, KY); the Joseph Drown Foundation (Los Angels, CA); and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).
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REFERENCES |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONAPPENDIX A: TRACHEAL EXTUBATION...APPENDIX B: DISCHARGE CRITERIAAPPENDIX C: CONSTITUENT AND...REFERENCES |
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