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J Thorac Cardiovasc Surg 2000;120:1-11
© 2000 The American Association for Thoracic Surgery
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (E-mail: mg50@le.ac.uk).
This study was partially supported by grants from The Glenfield Hospital NHS Trust, Leicester, The University of Leicester, and Heart Link Trust.
Address for reprints: Manuel Galiñanes, MD, PhD, FRCS, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Groby Rd, Leicester, LE3 9QP, United Kingdom.
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Abstract |
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 Top Abstract IntroductionPatients and methods Results Discussion References |
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). in both groups. Infusion of nitroglycerin significantly reduced the increase in lipid hydroperoxides and protein carbonyls in patients who have diabetes without affecting levels in patients without diabetes. Nitroglycerin infusion markedly reduced protein nitrotyrosine and tumor necrosis factor levels in both groups. In contrast, nitroglycerin infusion significantly increased C3a in patients without diabetes and increased elastase and interleukin 8 levels in patients with diabetes. |
Introduction |
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TopAbstractIntroductionPatients and methods Results Discussion References |
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1 Diabetes mellitus is an independent risk factor for early postoperative mortality and complications after bypass graft surgery, 2,3 although the reason for this heightened risk is unclear. One possibility may be the presence of a greater oxidative stress. Indeed, it has been suggested that nitric oxide (NO) and superoxide anion levels are already elevated in persons with diabetes under basal conditions. 4 The reaction between NO and superoxide anions results in the formation of the potent oxidant peroxynitrite (ONOO-), 5 a factor that may exacerbate oxidative stress in patients with diabetes. Peroxynitrite is also a major source of hydroxyl radicals that are known to cause severe cellular injury and death. 6 NO donors are regularly used during and after CPB to control the patient’s hemodynamics, but the effect of exogenous NO on oxidation in clinical conditions is unknown.
Another possible explanation for the greater surgical risk associated with diabetes is an altered inflammatory response to CPB. This thesis may be supported by the evidence that patients with diabetes are predisposed to increased surgical wound infections 7; however, to the best of our knowledge, the medical literature contains no information on the subject. In this article, we speculate that exogenous NO may affect the inflammatory response to CPB since (1) inhalation of NO reduces the production of interleukin 8 (IL-8) and interleukin 6 (IL-6) in alveolar neutrophils from patients with adult respiratory distress syndrome 8 and (2) inhaled NO modulates the leukosequestration induced by tumor necrosis factor (TNF-) and the IL-8 release in guinea pig airways. 9
The present study was designed to identify the type and degree of oxidative stress and inflammatory response induced by CPB in patients with diabetes compared with patients without diabetes and to investigate the effects of clinical administration of exogenous NO on these reactions.
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Patients and methods |
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TopAbstractIntroductionPatients and methods Results Discussion References |
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Study groups and selection criteria
A total of 172 patients were operated on by one surgeon (M.G.) within the period of the study. Patients with ventricular aneurysm, heart failure, valvular disease, and poor left ventricular function were excluded from the study. Only 92 patients, all undergoing elective coronary bypass graft surgery, met the selection criteria, and 40 of these patients (both with and without diabetes) consented to take part in the study. The patients were blinded as to the mode of treatment, and data from all the patients were included in the final analysis. Patients (both with and without diabetes) were assigned numbers, and a computer random number generator was used to create 2 groups. One group received physiologic saline solution and the other received the NO-donor nitroglycerin (GTN) infused at a rate of 1 µg · kg–1 · min–1 for 4 hours, starting 10 minutes before the initiation of CPB. Administration of aspirin was discontinued at least 7 days before the operation.
Anesthesia
All the patients received morphine (10 mg) and prochlorperazine (12.5 mg) administered intramuscularly at least 1 hour before the operation. Central venous and radial artery cannulas were inserted with the aid of local anesthesia (1% lidocaine) and sedation with midazolam (3-4 mg intravenously). Anesthesia was induced by infusion of propofol (8 mg · kg–1 · h–1 intravenously) and by the administration of fentanyl (1 mg intravenously) and pancuronium (12 mg intravenously). Anesthesia was then maintained by continuous infusion of propofol (4 mg · kg–1 · h–1 intravenously). Hypotension was controlled by intravenous infusion of fluids or 0.5 mg of metaraminol with increments where appropriate. Heparin (300 IU/kg) was administered in all study patients before CPB to achieve an activated clotting time greater than 450 seconds. A further 5000 IU of heparin was given in the CPB prime for the CPB group. Heparin was reversed after CPB by the administration of protamine (3 mg/kg).
Patients were sedated with propofol (1.5-2 mg · kg–1 · h–1 intravenously) while in the intensive care unit until their core temperature was higher than 36°C and bleeding through the chest drains was less than 50 mL/h. Then if the blood PO 2 level was greater than 75 mm Hg and the fixed inspired oxygen fraction (FIO 2) was 40% or less, the rate of propofol infusion was reduced. When the patient was able to respond coherently to simple instructions, propofol was discontinued and the trachea extubated. Morphine (5 mg intravenously) and diclofenac (100 mg intravenously), a nonsteroidal, nonnarcotic drug, were given to treat pain when required.
Surgical procedure
A standard CPB technique and median sternotomy were used. The CPB circuit was composed of a roller pump (Stöckert Instrumentation, Munich, Germany), a hollow-fiber polypropylene oxygenator with an incorporated cardiotomy reservoir (Cobe CML, Cobe Laboratories, Gloucester, United Kingdom), and plasticized polyvinyl chloride tubing. The pump was primed with 1.4 L of Hartmann solution, with a flow rate of 2.0 L · min–1 · m–2 body surface area and a hypothermic temperature of 32°C maintained throughout CPB. Coronary bypass grafting was performed with intermittent ischemia achieved by crossclamping the aorta followed by fibrillation without the use of cold cardioplegic solution.
Blood sampling
Blood samples were collected at different times: before the induction of anesthesia, before the initiation of CPB and coronary artery clamping (time 0), and 0.5, 1, 2, 4, 8, 24, and 48 hours thereafter. Blood samples were collected into sterile tubes in 3 aliquots containing potassium ethylenediaminetetraacetic acid (EDTA). An aliquot of blood in EDTA tubes was used for total leukocyte counts. Circulating leukocytes were counted by an automatic cell counter (Cell-Dyn 610; Sequoia-Turner, Mountain View, Calif). The other aliquots were centrifuged immediately at 1500g for 12 minutes at 4°C. The resultant plasma was divided into aliquots and stored at –80°C until analysis.
Measurement of NO
The plasma was assayed for the stable end products of NO, nitrite and nitrate (NOx), by the Griess reaction method with kits from Cayman Chemical Co (Ann Arbor, Mich). The resultant NOx levels were corrected by plasma creatinine concentration to minimize the influence of changes in renal excretory function, 10 and the values were expressed as micromoles per millimole of creatinine. Plasma creatinine concentration was determined with a kit from Sigma Chemicals (Poole, Dorset, United Kingdom).
Assessment of oxidative stress and protein nitration
Lipid hydroperoxides, protein carbonyls, and protein nitrotyrosine levels were determined in plasma and served as indices of oxidative stress. Plasma lipid hydroperoxides 11 and protein carbonyls 12 were determined as previously described. Protein nitrotyrosine was determined by an enzyme-linked immunosorbent assay (ELISA) method also described previously. 13
Assessment of the inflammatory reaction
The inflammatory reaction was assessed by examining the blood leukocyte count, the degree of activation of complement and neutrophils, and the plasma levels of the proinflammatory cytokines TNF- and IL-8. Activation of complement was determined by the measurement in plasma of complement C3a by means of a sandwich ELISA (Quidel, San Diego, Calif). Activation of neutrophils was determined by the measurement of plasma elastase in complex with 1-proteinase by means of an ELISA previously described. 14 An interassay and intra-assay variability of less than 8% was considered acceptable. The plasma levels of TNF- and IL-8 were quantified by means of commercially available sandwich ELISAs (Pharmingen, San Diego, Calif). Soluble E-selectin and thrombomodulin in plasma were determined as markers of endothelial activation and endothelial injury, respectively, 15,16 by sandwich ELISAs for soluble E-selectin (Amersham International Inc, Amersham, United Kingdom) and thrombomodulin (Diagnostica Stago, Asniéres-Sur-Seine, France).
Clinical outcome
The time of mechanical ventilatory support, postoperative blood loss, and transfusion requirements (blood transfusion was performed when hemoglobin values fell below 10 mg/dL), the presence of postoperative fever (defined as a tympanic temperature 
37.5°C and maintained for 24 hours), and the length of hospitalization were recorded. Patients were discharged from the hospital when they were apyrexic, in an overall satisfactory stable condition, and able to perform basic routine tasks.
Statistical analysis and expression of results
Descriptive data were presented as mean ± SD and nondescriptive data as mean ± SEM. Descriptive data with a skewed distribution were presented as median and quartiles. Analysis of variance for repeated measurements was used to compare the outcome parameters measured in series, that is, between-subjects effect (whether mean values vary by group), group time-response curve (whether values in groups change in different ways), and the time-trend effect (whether values change with time). This allowed us to evaluate the interaction between the CPB, diabetes, and NO effects. All the data were logarithm-transformed before analysis to minimize skewness. The data (normal distribution) determined only once during the experiment were analyzed for differences between the 2 groups by means of analysis of variance for nonrepeated measurements. The Mood median test was used to compare data measured once and also judged to be skewed. Tests were carried out at a 5% level of statistical significance with the SPSS statistical package (SPSS Inc, Chicago, Ill). Hemodilution occurs during CPB. So that we could correct for this, all values for inflammatory factors and oxidative stress markers were expressed relative to the protein content as previously described. 17
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Results |
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TopAbstractIntroductionPatients and methods Results Discussion References |
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Clinical outcome
The clinical characteristics and operative data are shown in Tables I and II. They demonstrate that these were similar in all study groups. No hospital mortality, neurologic accidents, or myocardial infarctions occurred in the 4 study groups. The mean time of mechanical ventilatory support was not significantly different among the groups, and the total postoperative blood loss, the mean values for blood transfusion, and the incidence of postoperative fever were also similar in all the groups. However, patients treated with GTN were discharged from the hospital an average of 2 days earlier than those without GTN, although the overall difference between the groups did not achieve a statistical significance (P = .08). A modest but significant increase in blood leukocyte count was observed for the first 4 postoperative days both in patients without diabetes and in those with diabetes when compared with the values seen before anesthesia (P = .02). GTN infusion had no significant effect on leukocyte count (P = .85) in either group of patients.
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in patients without diabetes that lasted for the duration of the study (P < .001) and only a moderate but significant increase limited to the first hour in patients with diabetes (P = .018). The effect of GTN infusion on TNF- release contrasts with that observed on IL-8 in that GTN completely suppressed the rise in TNF- both in patients without diabetes (P < .001) and in those with diabetes (P < .001).
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Discussion |
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TopAbstractIntroductionPatients and methods Results Discussion References |
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Oxidative stress
Previous studies have demonstrated that oxygen-derived free radicals are generated during CPB, 18 that lipid peroxidation occurs during CPB, 17 and that pretreatment with antioxidants before CPB minimizes lipid peroxidation. 19 However, to our knowledge, the present study is the first in reporting that CPB-induced oxidative stress is approximately 2-fold greater in patients with diabetes than in those without diabetes, a factor that may contribute to a poorer surgical outcome in the former group of patients. 3 Yet the results were not unexpected because previous reports have suggested that persons with diabetes generate more free radicals 4 and that their antioxidant defenses are diminished. 20
A novel finding in our study was that not only lipids but also proteins are attacked by free radicals during CPB. Our results contrast with those reported by Pepper, Mumby, and Gutteridge. 17 Like us, these authors showed formation of lipid hydroperoxides but, unlike us, they found no increase in protein carbonyls during CPB. The reason for these conflicting results is not clear, but differences in the type of patients investigated (valve replacement in their study versus coronary bypass graft surgery in ours) or the myocardial preservation techniques (intermittent ischemic arrest in this study versus cold cardioplegic arrest in their study) may offer an explanation for the differences between the 2 studies. However, both studies strengthen the view that oxidative stress may be a mechanism by which CPB exerts its undesirable effects and that antioxidant interventions may represent a potential therapeutic target.
The rapid formation of protein nitrotyrosine, an index of peroxynitrite generation, even before the initiation of CPB both in patients with and in those without diabetes (Fig 3
, A and B ) suggests that the metabolism of NO may play an important role in the modulation of oxidative stress observed during cardiac surgery. This thesis is further supported by the effects of GTN on decreasing the production of protein nitrotyrosine in all patients (Fig 3, A and B ) and on reducing the formation of lipid hydroperoxides (Fig 1, B ) and protein carbonyls (Fig 2, B ) in patients with diabetes. The effects of GTN on oxidative stress may be due to the reduction in the formation of endogenous NO seen in our study (Table III) and also reported in the literature. 21 Therefore, it appears that exogenous NO has potent antioxidant properties in human beings and that its clinical usefulness may be extended beyond the control of the hemodynamic state.
Inflammatory reaction
The increase in CPB-induced inflammatory reaction in terms of complement and neutrophil activation in patients with diabetes may be a contributory factor to the reported higher operative mortality and greater rate of perioperative complications in this group of patients undergoing cardiac surgery. 3 The cause of this reaction and the pathophysiologic implication of the lack of increase in proinflammatory cytokines in patients with diabetes are unclear. A possible explanation may be that the inflammatory reaction is initiated or facilitated by oxidative stress. At first sight this thesis would appear to be supported by our findings that oxidative stress is greater in patients with diabetes than in those without diabetes and by the reported correlation between complement activation and oxidative stress during CPB. 18 However, in our study the reduction in the CPB-induced oxidative stress by GTN in patients with diabetes resulted in a partially corresponding decrease in the CPB-induced inflammatory response. On the contrary, GTN increased plasma elastase (Fig 5, B ) and IL-8 (Fig 6, B ), without affecting complement activation (Fig 4, B ) and TNF- (Fig 7, B ). Therefore, results do in fact contradict the thesis that there is a direct relationship between the CPB-induced inflammatory reaction and oxidative stress.
An alternative explanation for the specific inflammatory reaction induced by CPB in patients with diabetes is that the regulation of the genes coding for a variety of inflammatory factors and their signal transduction pathways may be altered in this group of patients. This proposition is supported by the demonstration that protein kinase C is chronically activated in diabetic tissues, 22,23 which in turn may activate the stress/mitogen protein kinase–associated transcription factor activator protein–1. 24 Our demonstration of higher complement activation (Fig 4, B ) with prolonged release of elastase (Fig 5, B ) in patients with diabetes would also support this thesis. However, the validity of this thesis has to be questioned in view of our findings that the release of IL-8 and TNF- was lower in patients with diabetes. The diversity of these results may be owed to the involvement of different gene transcription factors and signal transduction mechanisms and to the fact that these may be differently affected in patients who do and do not have diabetes. This is an area that clearly requires further investigation.
The results of the administration of exogenous NO on the CPB-induced release of inflammatory factors seen in the present study are also novel. The observed increase in complement activation in patients without diabetes (Fig 4, A ) and the higher plasma elastase (Fig 5, B ) and IL-8 (Fig 6, B ) in patients with diabetes when GTN was administered are indicative that exogenous NO exacerbates the CPB-induced inflammatory reaction. Since NO is known to possess anti-inflammatory properties, the action of exogenous NO in promoting inflammation may be explained by its effect in reducing the formation of endogenous NO, as mentioned before. Our results contrast with those of Seghaye and colleagues, 25 who observed the inhibition of complement activation by sodium nitroprusside. However, in contrast to our study, these investigators used sodium nitroprusside instead of GTN. In addition, their study was carried out in children with congenital heart defects instead of adults with coronary artery disease, and a sodium nitroprusside dose ranging from 0.6 to 2.9 µg · kg–1 · min–1 was variably administered only during the cooling and rewarming periods of extracorporeal circulation. In our study, GTN was administered at the dose of 1 µg · kg–1 · min–1 starting 10 minutes before the initiation of CPB and then for the next 4 hours, which included the entire period of CPB. Indeed, the type of NO donor and the time and dose of its administration may be important factors in determining the effect of these agents on the inflammatory cascade.
In the present study, GTN also reduced the formation of TNF- in patients without diabetes (Fig 7, A ), and this may suggest that the effect of exogenous NO on inflammation is complex and dependent on the disease state. The literature is also conflicting in that NO has been shown to inhibit 26 and activate 27,28 the production of inflammatory cytokines. The understanding of this effect is crucial to elucidate the dynamics and the clinical potential of NO. Clearly, this topic also requires further investigation.
The results on soluble E-selectin, an endothelial molecule that facilitates the recruitment of monocytes and lymphocytes to the lesion site, 29 showing that its plasma values remained elevated for a longer period in patients with diabetes than in those without diabetes (Fig 8, A ), are in agreement with our own data that the inflammatory reaction induced by CPB is exacerbated in patients with diabetes. However, at this point it could also be speculated that the release of soluble E-selectin into the plasma compartment may not be indicative of parallel changes in the density and expression of the molecule on the endothelium; instead, it may represent a protective mechanism that allows the clearance of these molecules from the cell surfaces, therefore limiting leukocyte attachment and cell injury. 30 As seen with plasma elastase and IL-8, GTN also increased soluble E-selectin in patients with diabetes (Fig 8, B ). At first sight, one might be tempted to conclude that the effect in patients with diabetes would be proinflammatory. However, using the above argument, if the elevation of soluble E-selectin in plasma represents an increase of the shedding of the molecule and not an increase of its expression, then it should be concluded that the effect of GTN is anti-inflammatory. Indeed, the latter thesis is supported by the demonstration that shedding of molecules from the endothelium may be influenced by a number of factors, 30 possibly including NO, as shown by our own results. As discussed earlier, whether this effect is due to the exogenous NO or to the inhibition of production of endogenous NO by exogenous NO also needs to be clarified. De Caterina and coworkers 26 reported that NO significantly inhibits the expression of vascular cell adhesion molecule 1 and soluble E-selectin in lipopolysaccharide and cytokine-stimulated human saphenous vein endothelial cells in vitro. However, their findings do not completely elucidate the mechanism of this effect, because the expression and activity of endothelial and inducible NO synthases and the levels of NO in the preparation were not studied.
Despite the different response to CPB and the infusion of GTN between patients with and without diabetes, in terms of both oxidative stress and inflammatory reaction, plasma thrombomodulin, a marker of endothelial injury, 16 was similar in the 2 groups of patients and this was unaffected by GTN (Fig 9, A and B ). These results appear to strengthen the thesis that the vascular endothelium is well equipped to withstand the changes occurring during elective cardiac surgery and that disruption of its integrity may require more severe challenges.
Clinical implications
Our results have shown that oxidative stress is greater in patients with diabetes than in those without diabetes and that its reduction by NO-donor agents may represent a potential target to improve the clinical outcome in this group of patients undergoing cardiac surgery. Our study, performed in a selected reduced number of patients, was not designed to investigate the clinical benefit of this therapy. However, despite this, a shorter hospital stay (marginally not significant) was seen in patients receiving GTN. It should be conceded that the shorter hospital stay was also observed in patients without diabetes, in whom oxidative stress was unaffected by GTN, an observation that would suggest that the action of GTN in reducing oxidative stress may not be the sole mechanism responsible for the improved recovery.
This study has also demonstrated that GTN may increase the release of some components of the inflammatory reaction induced by CPB both in patients with diabetes and in those without diabetes. As a result and despite the observed benefits in reducing oxidative stress in patients with diabetes, caution should be exercised regarding the use of NO donors, particularly when treating patients with an underlying proinflammatory condition. Certainly, the elucidation of the mechanisms underlying the above effects is a prerequisite for safer use of NO donors and for improvement of the clinical outcome in cardiac surgery.
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Acknowledgments |
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References |
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-induced leukosequestration and IL-8 in guinea-pigs airways in vivo. Br J Pharmacol 1997;122:103-11. [Medline]1-proteinase inhibitor complex. In: Bergermeyer HU, Bergermeyer J, Grassl M, editors. Methods of enzymatic analysis 5. Weinheim: Verlag Chemie; 1984. p. 184-95. This article has been cited by other articles:
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 M. Galinanes, M. James, V. Codd, A. Baxi, and L. Hadjinikolaou TNF-alpha gene promoter polymorphism at nucleotide -308 and the inflammatory response and oxidative stress induced by cardiac surgery: role of heart failure and medical treatment. Eur. J. Cardiothorac. Surg., August 1, 2008; 34(2): 332 - 337. [Abstract] [Full Text] [PDF]
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