The Effect Of A Series Of Doses Of Methylprednisolone Treatment On The Cardiopulmonary Bypass-induced Systemic Inflammatory Response

Objective: Methylprednisolone (MP) have been administered to patients undergoing cardiac surgery to ward off the systemic inflammatory response syndrome(SIRS) induced by cardiopulmonary bypass (CPB) since at least 30 years before, but up to nowadays, current MP administration practices about timing and route, the formulation and dosage among pediatric cardiac surgical centers are highly variable. In recent years, more and more clinical investigations indicate that low-dose of methylprednisolone could inhibit SIRS obviously. On the other hand, it has been known for many years that the more greater dose of methylprednisolone administered to patients the more serious metabolic disturbance induced. Even unexpected, some clinical investigations indicate that administration of MP to patients undergoing cardiac surgery with CPB not only offers no clinical benefits, its use in this setting may in fact be detrimental to patients, while larger dose of methylprednisolone used in these clinical investigations.Few domestic linical investigations about dosage of methylprednisolone using in this setting has been found. The very popular route and timing of methylprednisolone administration is delivery of a single dose to the CPB circuit prime. This practice has not been studied in either animals or humans. In the present study, we tried to demonstrate the efficacy of the practice (delivery of a single dose to the CPB circuit prime) , and identify a more scientific and reasonable dosage by examining both clinical benefits and adverse reactions offered by administration of a series of doses of methylprednisolone. Methylprednisolone's effects assessed by many aspects including patients'plasma cytokines concentration, free radical generation, plasma glucose, lactic acid, Microstructure and Ultrastructure changes of cardiac muscle, and clinical outcomes.Methods: 50 pediatric patients undergoing repair of ventricular septal defect procedures with cardiopulmonary bypass (CPB) were studied in a randomized trial. Patients were randomized Equally to one of the five following groups: groupⅠ, control group, no treatment; groupⅡ, methylprednisolone 5 mg/kg; groupⅢ, methylprednisolone 10 mg/kg; groupⅣ, methylprednisolone 20 mg/kg; groupⅤ, methylprednisolone 30 mg/kg. Methylprednisolone was administered to the CPB circuit prime as a single dose. Blood samples were taken from the arterial line at the following time-points: (1) after anesthesia induction; (2) before aortic cannulation; (3) 10 min after aortic crossclamp release; and (4)–(6) 5 min, 4 and 24 h after protamine sulfate administration, respectively. Blood samples were immediately brought to the laboratory, centrifuged at 3000 rpm/min for 10 min and the plasma was frozen and stored at -80℃for TNF-α, IL-6, IL-10 and MDA assays. cardiac muscle cuted from right auricular before and afer CPB were immediately brought to the laboratory and processed for light microscop(LM) and transmission electron microscope (TEM) observation.CPB time, Aortic Cross-clamp Time, mechanical ventilation, ICU stay time and blood loss were recorded, preparing for statistical analysis. Before, during and after the CPB, blood samples were taken for analysis of blood gas, serum glucose and lactates levels.Results: 1. No significant differences in gender ratio, age, body weight were observed between the five groups. CPB time, aortic cross-clamp time were similar between groups.2. The microstructure and Ultrastructure damages in cardiac muscle tissue. Cardiac muscle tissue slightly to midrange swelling was observed in control group patients, no significant damages was observed in any treatment group when samples observed with light microscop. Examined with TEM, different degree damages were observed. mitochondria (M) swelling, brokened or disappeared, glycogen particle diminished, endoplasmic reticulum also dilated, capillary endothial cell swelling, microvillus diminished, were seen extensively in groupⅠ. In groupⅡ,abnormal changes mentioned in groupⅠwas midrange attenuated. Ultrastructure damages of cardiac muscle cell seen from groupⅢ,Ⅳ,Ⅴ,were no significant difference.3. The changes of plasma cytokines concentration: CPB induced a obvious increase both in proinflammatory factor(TNF-a,IL-6) and anti-inflammatory factor(IL-10). The data showed that plasma concentration of any kinds of cytokine did not differ significantly before CPB. After the beginning of CPB, each of the three cytokines showed significant differences in between-subjects effec(tP<0.0001). Values of each cytokine at different time point showed significant differences in within-subjects effect(P<0.0001). A signigicant decrease of TNF-αand IL-6 plasma concentration was observed in any group treated by MP compared with control group. A signigicant increase in IL-10 plasma concentration was observed in any group treated by MP compared with control group. About TNF-αand IL-6 plasma concentration, groupⅢis signigicantly lower than groupⅡ. About IL-10 plasma concentration, groupⅢis signigicantly higher than groupⅡ. No significant between-subjects difference observed between groupⅢ, groupⅣ, and groupⅤin any kinds of cytokine.4. The changes of MDA plasma concentration. CPB induced a obvious increase in MDA plasma concentration. The data showed that plasma concentration of MDA did not differ significantly before CPB. After the beginning of CPB, MDA plasma concentration showed significant differences in between-subjects effec(tP<0.0001). Values of each cytokine at different time point showed significant differences in within-subjects effect(P<0.0001). A signigicant decrease of MDA plasma concentration was observed in any group treated by MP compared with control group. About MDA plasma concentration, groupⅢis signigicantly lower than groupⅡ(Group-Ⅰvs. Group-Ⅱ, P<0.00001; Group-Ⅱv s. Group-Ⅲ, P<0.05,P=0.001). No significant between-subjects difference observed between groupⅢ, groupⅣand groupⅤ: Group-Ⅲvs. Group-Ⅳ, P>0.05(P=0.240); Group-Ⅳvs. Group-Ⅴ, P>0.05(P=0.646);Group-Ⅲvs. Group-Ⅴ, P>0.05(P=0.239)5. The changes of Glucose plasma concentration. CPB induced a obvious increase in Glucose plasma concentration. The data showed that plasma concentration of Glucose did not differ significantly before CPB. After the beginning of CPB, Glucose plasma concentration showed significant differences in between-subjects effect(P<0.0001). Values of Glucose plasma concentration at different time point showed significant differences in within-subjects effect(P<0.0001). A signigicant increase of Glucose plasma concentration was observed in any group treated by MP compared with control group. The more greater dose of MP administered, the more higher Glucose plasma concentration observed, between-subjects effect showed significant differences: Group-Ⅰvs. Group-Ⅱ, P<0.00001; Group-Ⅱvs. Group-Ⅲ, P<0.05(P=0.001);Group-Ⅲvs. Group-Ⅳ, P<0.05(P=0.002).6. The changes of Lactic acid plasma concentration. CPB induced a obvious increase in Lactic acid plasma concentration. The data showed that plasma concentration of Lactic acid did not differ significantly before CPB. After the beginning of CPB, Lactic acid plasma concentration showed significant differences in between-subjects effect(P<0.0001). Values of Lactic acid at different time point showed significant differences in within-subjects effect(P<0.0001). A signigicant increase of Lactic acid plasma concentration was observed in any group treated by MP compared with control group. The more greater dose of MP administered, the more higher Lactic acid plasma concentration observed, between-subjects effect showed significant differences: Group-Ⅰvs. Group-Ⅱ, p>0.05(p=0.289); Group-Ⅱv s. Group-Ⅲ, P<0.00001;Group-Ⅲvs. Group-Ⅳ, P<0.00001; Group-Ⅳvs. Group-Ⅴ, P<0.00001.7. No significant differences in post-operative mechanical ventilation, ICU stay time and blood loss were observed between the five groups.Conclusions: By quantifying cytokines (TNF-a, IL-6 and IL-10), and free radical generation throughout CPB surgery, observating the Microstructure Ultrastructure changes of cardiac muscle we demonstrated that the MP administration method of delivery of a single dose to the CPB circuit prime is effective. The present study indicate that the effect of a single low-dose of methylprednisolone (5-10 mg/kg) is not insufficient contrasted with that of greater dose, adverse reactions are obviously diminished. Our study indicates that methylprednisolone 5-10 mg/kg is a scientific and reasonable dose in the setting that approach to our study.