LETTERS TO THE EDITOR
Prevention of Gastrointestinal Injury by Glutamine in Cardiac Surgery: Negative Results of Pilot Double-Blind, Placebo-Controlled, Randomized Study To the Editor: Prophylaxis of extracardiac organ dysfunction is an important issue of management of cardiothoracic patients. Postoperative gastrointestinal complications are among the most dangerous sequelae of cardiac surgery, associated with high mortality and costs.1,2 Cytoprotective properties of glutamine (GLN) on gut mucosa are well known3 and have been reported in different clinical conditions,4 including burns5 and critical illness.6 GLN attenuates intestinal permeability, bacterial translocation, and systemic infection and modulates immune function of the gastrointestinal tract.4 We hypothesized that perioperative administration of GLN at a dosage of 0.4 g/kg/day in cardiac surgery patients undergoing cardiopulmonary bypass (CPB) would protect intestinal integrity as assessed by highly specific markers of intestinal damage. This pilot double-blind, placebo-controlled, randomized study was approved by the local ethics committee before the patient enrollment started; written informed consent was obtained from all the patients enrolled in the study. Patients scheduled for elective coronary artery bypass graft surgery
under CPB were recruited. Twelve patients received GLN (20% solution of N(2)-L-alanyl-L-glutamine (Dipeptiven, Fresenius Kabi, Germany); 0.4 g/kg a day). The remaining 12 patients were given an equivalent amount of placebo (0.9% NaCl). The infusion of both drugs was initiated immediately after induction of anesthesia and sustained for 24 hours postoperatively. Dynamics of intestinal fatty acid binding protein (I-FABP), liver fatty acid binding protein (L-FABP), alpha glutathione S-transferase (αGST), and heat shock protein 70 (HSP 70) were analyzed. Perioperative dynamics of I-FABP, L-FABP, αGST, and HSP 70 are presented in Table 1. There were no betweengroup differences in any studied parameters. There were no differences in characteristics of postoperative course. Ventilation time was 6 (5-8) hours in the GLN group and 6 (6-7) hours in the placebo group; lengths of stay in the intensive care unit were 1 (1-2) days and 1 (1-1) days, respectively, and lengths of hospital stay were 16 (15-18) days and 17 (15-18) days, respectively (p40.05). In the present small pilot study, no tendency toward lesser intestinal damage was demonstrated in cardiac surgery patients receiving perioperative infusion of GLN. Our study had limitations. First, lack of power did not permit drawing definitive conclusions concerning both biochemical results and clinical data. Second, dosing of GLN was equal to 0.4 g/kg/day, whereas in most studies, benefits of GLN were associated with a daily dose of GLN exceeding 0.5 g/kg/ day. Despite all the serious limitations of the study, the authors believe it has added to the evidence concerning GLN administration
Table 1. Perioperative Biochemical Data 5 Minutes After Aortic Unclamping
2 Hours After CPB
6 Hours After CPB
24 hours after CPB
N
I-FABP, pg/ml L-FABP, mg/ml αGST, mg/l HSP 70, ng/ml
12 591 (432-790) 340 (254-559) 962 (577-2,067)*† 790 (448-1,663)† 936 (681-1,510)*† 435 (292-656) ‡¶ 12 316 (201-529) 338 (168-493) 882 (443-1625)*† 962 (443-1211)*† 794 (505-951)*† 432 (166-722)‡¶ 12 19,248 (4,970-23,831) 16,865 (7,123-23,233) 20,697 (6,577-40,768) 22,037 (8,882-34,290) 17,727 (13,398-25,099) 5,084 (3,936-19,031) 12 17,670 (6,789-28,711) 14,394 (6,800-21,000) 20,089 (13,814-30,311) 15,600 (5,061-26,578) 15,730 (3,931-21,059) 4,574 (3,209-14,163) 12 8.2 (0-22) 4.5 (0-12.1) 5 (0-20) 25.1 (10.6-84.3)*†‡ 9.9 (0-31.8)§ 0 (0-0) ‡§ 12 2.3 (0-11.5) 6.5 (0-12.7) 15.6 (4.1-28.8)*† 23.4 (0-35.5)*†‡ 1.9 (0-18)§ 0 (0-0)¶ 12 0.07 (0-0.1) 0.14 (0-0.3) 0.56 (0.2-1.3)*† 1.6 (0.4-2.2)*† 0.8 (0.43-1.07)*† 0.3 (0.1-0.6)¶ 12 0.08 (0-0.4) 0.04 (0-0.2) 0.49 (0.07-0.7)† 1.1 (0.48-1.83)†‡ 0.66 (0.15-1.3)*†§ 0.34 (0.01-0.46)*§
GLN Placebo GLN Placebo GLN Placebo GLN Placebo
Baseline
Before Heparinization
Variable Group
Abbreviations: CPB, cardiopulmonary bypass; GLN, glutamine; HSP 70, heat shock 70; I-FABP, intestinal fatty acid binding protein; L-FABP, liver fatty acid binding protein; αGST, alpha glutathione S-transferase. Data presented as median (25th to 75th percentile). Comparative intergroup analyses of data were performed using repeated measures analysis of variance (ANOVA). Comparative analyses of data within groups were performed using the Friedman test. Within group differences: *p o 0.05 compared with baseline. †p o 0.05 compared with “before heparinization” stage. ‡p o 0.05 compared with 5 minutes after aortic unclamping. §p o 0.05 compared with 2 hours after CPB. ¶p o 0.05 compared with 6 hours after CPB.
Journal of Cardiothoracic and Vascular Anesthesia, Vol 28, No 6 (December), 2014: pp e51–e62
e51
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LETTERS TO THE EDITOR
for organ protection in the cardiac surgery setting. Also, variability patterns for biochemical parameters were obtained, which could be used in future studies of intestinal protection during CPB, with the impact on patient outcome. Sergey M. Efremov, MD, PhD Vladimir V. Lomivorotov, MD, PhD Vladimir A. Shmyrev, MD, PhD Dmitry N. Ponomarev, MD, MSc Mihail N. Deryagin, MD, PhD Vladimir A. Boboshko, MD, PhD Anna N. Shilova, MD, PhD Novosibirsk State Research Institute of Circulation Pathology Novosibirsk, Russian Federation
REFERENCES 1. D’Ancona G, Baillot R, Poirier B, et al: Determinants of gastrointestinal complications in cardiac surgery. Tex Heart Inst J 30: 280-285, 2003 2. Geissler HJ, Fischer UM, Grunert S, et al: Incidence and outcome of gastrointestinal complications after cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 5:239-242, 2006 3. Lomivorotov VV, Efremov SM, Shmirev VA, et al: Glutamine is cardioprotective in patients with ischemic heart disease following cardiopulmonary bypass. Heart Surg Forum 14:E384-E388, 2011 4. Sufit A, Weitzel LB, Hamiel C, et al: Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery: a randomized pilot feasibility trial. JPEN J Parenter Nutr 36: 556-561, 2012 5. Ziegler TR, Bazargan N, Leader LM, et al: Glutamine and the gastrointestinal tract. Curr Opin Clin Nutr Metab Care 3:355-362, 2000 6. De-Souza DA, Greene LJ: Intestinal permeability and systemic infections in critically ill patients: Effect of glutamine. Crit Care Med 33:1125-1135, 2005
general anesthesia, following current practice guidelines1 and in the absence of absolute or relative contraindications. The patient was weaned from cardiopulmonary bypass on milrinone and norepinephrine infusions, and the probe was removed at the end of the procedure, after confirming a good surgical result. Postoperatively, the patient had high systemic vascular resistance, poor cardiac output and was metabolically acidotic. These parameters improved over the first 24 hours with fluid optimization and vasoactive support. The patient was extubated on the first postoperative day and resumed oral intake. He was discharged to the ward 1 day later with chest drains left in situ because of persistent drainage. On the third postoperative day, the right chest drain began producing a large amount of straw colored fluid. The patient was readmitted to the Intensive Care Unit (ICU) with respiratory failure, which progressed rapidly and required intubation and ventilation. As the clinical context at that stage was suspicious of an esophageal perforation, he underwent computed tomography of the chest, which revealed a moderate right-sided pleural effusion and a small anterior pneumothorax with several pockets of air adjacent to the esophagus (Fig 1). The gastrografin study showed a significant amount of contrast within the mediastinum at the vertebral level T8/T9. An esophagogastroduodenoscopy (EGD) that followed identified a round, smooth-edged, small (1 cm) esophageal perforation located at 35 cm from the incisors and a small hiatus hernia. In view of the high risk associated with open surgery, the endoscopic approach was chosen. The defect was closed with a metallic stent (WallFlex, 23 mm 125 mm, Boston Scientific, Natick, MA) and the mediastinitis treated with thoracoscopically assisted washout of the right hemithorax (Fig 2). Over the course of the next weeks, the patient was weaned from the ventilator. Fifty days after the cardiac surgery, the EGD showed complete healing of the perforation and the stent
http://dx.doi.org/10.1053/j.jvca.2014.04.027
Esophageal Perforation After Transesophageal Echocardiography in a Malnourished Patient and Repair With an Esophageal Stent
To the Editor: We are writing to report a case of esophageal perforation after cardiac surgery. The patient was a 56-year-old male scheduled for elective coronary artery bypass graft and mitral valve repair. He had a background of schizophrenia and hypothyroidism and had reported reduced appetite and significant weight loss in the months preceding surgery, which had not been further investigated. He did not report dysphagia or any other associated symptoms. A multiplane TEE probe (General Electric Company, Fairfield, CT) was inserted under direct vision after the induction of
Fig 1. Computed tomography on the third postoperative day confirms the diagnosis of esophageal perforation.
Prevention of Gastrointestinal Injury by Glutamine in Cardiac Surgery: Negative Results of Pilot Double-Blind, Placebo-Controlled, Randomized Study To the Editor: Prophylaxis of extracardiac organ dysfunction is an important issue of management of cardiothoracic patients. Postoperative gastrointestinal complications are among the most dangerous sequelae of cardiac surgery, associated with high mortality and costs.1,2 Cytoprotective properties of glutamine (GLN) on gut mucosa are well known3 and have been reported in different clinical conditions,4 including burns5 and critical illness.6 GLN attenuates intestinal permeability, bacterial translocation, and systemic infection and modulates immune function of the gastrointestinal tract.4 We hypothesized that perioperative administration of GLN at a dosage of 0.4 g/kg/day in cardiac surgery patients undergoing cardiopulmonary bypass (CPB) would protect intestinal integrity as assessed by highly specific markers of intestinal damage. This pilot double-blind, placebo-controlled, randomized study was approved by the local ethics committee before the patient enrollment started; written informed consent was obtained from all the patients enrolled in the study. Patients scheduled for elective coronary artery bypass graft surgery
under CPB were recruited. Twelve patients received GLN (20% solution of N(2)-L-alanyl-L-glutamine (Dipeptiven, Fresenius Kabi, Germany); 0.4 g/kg a day). The remaining 12 patients were given an equivalent amount of placebo (0.9% NaCl). The infusion of both drugs was initiated immediately after induction of anesthesia and sustained for 24 hours postoperatively. Dynamics of intestinal fatty acid binding protein (I-FABP), liver fatty acid binding protein (L-FABP), alpha glutathione S-transferase (αGST), and heat shock protein 70 (HSP 70) were analyzed. Perioperative dynamics of I-FABP, L-FABP, αGST, and HSP 70 are presented in Table 1. There were no betweengroup differences in any studied parameters. There were no differences in characteristics of postoperative course. Ventilation time was 6 (5-8) hours in the GLN group and 6 (6-7) hours in the placebo group; lengths of stay in the intensive care unit were 1 (1-2) days and 1 (1-1) days, respectively, and lengths of hospital stay were 16 (15-18) days and 17 (15-18) days, respectively (p40.05). In the present small pilot study, no tendency toward lesser intestinal damage was demonstrated in cardiac surgery patients receiving perioperative infusion of GLN. Our study had limitations. First, lack of power did not permit drawing definitive conclusions concerning both biochemical results and clinical data. Second, dosing of GLN was equal to 0.4 g/kg/day, whereas in most studies, benefits of GLN were associated with a daily dose of GLN exceeding 0.5 g/kg/ day. Despite all the serious limitations of the study, the authors believe it has added to the evidence concerning GLN administration
Table 1. Perioperative Biochemical Data 5 Minutes After Aortic Unclamping
2 Hours After CPB
6 Hours After CPB
24 hours after CPB
N
I-FABP, pg/ml L-FABP, mg/ml αGST, mg/l HSP 70, ng/ml
12 591 (432-790) 340 (254-559) 962 (577-2,067)*† 790 (448-1,663)† 936 (681-1,510)*† 435 (292-656) ‡¶ 12 316 (201-529) 338 (168-493) 882 (443-1625)*† 962 (443-1211)*† 794 (505-951)*† 432 (166-722)‡¶ 12 19,248 (4,970-23,831) 16,865 (7,123-23,233) 20,697 (6,577-40,768) 22,037 (8,882-34,290) 17,727 (13,398-25,099) 5,084 (3,936-19,031) 12 17,670 (6,789-28,711) 14,394 (6,800-21,000) 20,089 (13,814-30,311) 15,600 (5,061-26,578) 15,730 (3,931-21,059) 4,574 (3,209-14,163) 12 8.2 (0-22) 4.5 (0-12.1) 5 (0-20) 25.1 (10.6-84.3)*†‡ 9.9 (0-31.8)§ 0 (0-0) ‡§ 12 2.3 (0-11.5) 6.5 (0-12.7) 15.6 (4.1-28.8)*† 23.4 (0-35.5)*†‡ 1.9 (0-18)§ 0 (0-0)¶ 12 0.07 (0-0.1) 0.14 (0-0.3) 0.56 (0.2-1.3)*† 1.6 (0.4-2.2)*† 0.8 (0.43-1.07)*† 0.3 (0.1-0.6)¶ 12 0.08 (0-0.4) 0.04 (0-0.2) 0.49 (0.07-0.7)† 1.1 (0.48-1.83)†‡ 0.66 (0.15-1.3)*†§ 0.34 (0.01-0.46)*§
GLN Placebo GLN Placebo GLN Placebo GLN Placebo
Baseline
Before Heparinization
Variable Group
Abbreviations: CPB, cardiopulmonary bypass; GLN, glutamine; HSP 70, heat shock 70; I-FABP, intestinal fatty acid binding protein; L-FABP, liver fatty acid binding protein; αGST, alpha glutathione S-transferase. Data presented as median (25th to 75th percentile). Comparative intergroup analyses of data were performed using repeated measures analysis of variance (ANOVA). Comparative analyses of data within groups were performed using the Friedman test. Within group differences: *p o 0.05 compared with baseline. †p o 0.05 compared with “before heparinization” stage. ‡p o 0.05 compared with 5 minutes after aortic unclamping. §p o 0.05 compared with 2 hours after CPB. ¶p o 0.05 compared with 6 hours after CPB.
Journal of Cardiothoracic and Vascular Anesthesia, Vol 28, No 6 (December), 2014: pp e51–e62
e51
e52
LETTERS TO THE EDITOR
for organ protection in the cardiac surgery setting. Also, variability patterns for biochemical parameters were obtained, which could be used in future studies of intestinal protection during CPB, with the impact on patient outcome. Sergey M. Efremov, MD, PhD Vladimir V. Lomivorotov, MD, PhD Vladimir A. Shmyrev, MD, PhD Dmitry N. Ponomarev, MD, MSc Mihail N. Deryagin, MD, PhD Vladimir A. Boboshko, MD, PhD Anna N. Shilova, MD, PhD Novosibirsk State Research Institute of Circulation Pathology Novosibirsk, Russian Federation
REFERENCES 1. D’Ancona G, Baillot R, Poirier B, et al: Determinants of gastrointestinal complications in cardiac surgery. Tex Heart Inst J 30: 280-285, 2003 2. Geissler HJ, Fischer UM, Grunert S, et al: Incidence and outcome of gastrointestinal complications after cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 5:239-242, 2006 3. Lomivorotov VV, Efremov SM, Shmirev VA, et al: Glutamine is cardioprotective in patients with ischemic heart disease following cardiopulmonary bypass. Heart Surg Forum 14:E384-E388, 2011 4. Sufit A, Weitzel LB, Hamiel C, et al: Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery: a randomized pilot feasibility trial. JPEN J Parenter Nutr 36: 556-561, 2012 5. Ziegler TR, Bazargan N, Leader LM, et al: Glutamine and the gastrointestinal tract. Curr Opin Clin Nutr Metab Care 3:355-362, 2000 6. De-Souza DA, Greene LJ: Intestinal permeability and systemic infections in critically ill patients: Effect of glutamine. Crit Care Med 33:1125-1135, 2005
general anesthesia, following current practice guidelines1 and in the absence of absolute or relative contraindications. The patient was weaned from cardiopulmonary bypass on milrinone and norepinephrine infusions, and the probe was removed at the end of the procedure, after confirming a good surgical result. Postoperatively, the patient had high systemic vascular resistance, poor cardiac output and was metabolically acidotic. These parameters improved over the first 24 hours with fluid optimization and vasoactive support. The patient was extubated on the first postoperative day and resumed oral intake. He was discharged to the ward 1 day later with chest drains left in situ because of persistent drainage. On the third postoperative day, the right chest drain began producing a large amount of straw colored fluid. The patient was readmitted to the Intensive Care Unit (ICU) with respiratory failure, which progressed rapidly and required intubation and ventilation. As the clinical context at that stage was suspicious of an esophageal perforation, he underwent computed tomography of the chest, which revealed a moderate right-sided pleural effusion and a small anterior pneumothorax with several pockets of air adjacent to the esophagus (Fig 1). The gastrografin study showed a significant amount of contrast within the mediastinum at the vertebral level T8/T9. An esophagogastroduodenoscopy (EGD) that followed identified a round, smooth-edged, small (1 cm) esophageal perforation located at 35 cm from the incisors and a small hiatus hernia. In view of the high risk associated with open surgery, the endoscopic approach was chosen. The defect was closed with a metallic stent (WallFlex, 23 mm 125 mm, Boston Scientific, Natick, MA) and the mediastinitis treated with thoracoscopically assisted washout of the right hemithorax (Fig 2). Over the course of the next weeks, the patient was weaned from the ventilator. Fifty days after the cardiac surgery, the EGD showed complete healing of the perforation and the stent
http://dx.doi.org/10.1053/j.jvca.2014.04.027
Esophageal Perforation After Transesophageal Echocardiography in a Malnourished Patient and Repair With an Esophageal Stent
To the Editor: We are writing to report a case of esophageal perforation after cardiac surgery. The patient was a 56-year-old male scheduled for elective coronary artery bypass graft and mitral valve repair. He had a background of schizophrenia and hypothyroidism and had reported reduced appetite and significant weight loss in the months preceding surgery, which had not been further investigated. He did not report dysphagia or any other associated symptoms. A multiplane TEE probe (General Electric Company, Fairfield, CT) was inserted under direct vision after the induction of
Fig 1. Computed tomography on the third postoperative day confirms the diagnosis of esophageal perforation.
