Eur J Cardiothorac Surg 2007;32:326-332. doi:10.1016/j.ejcts.2007.04.038
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfusion: a randomised double-blind study
Khalil Fattouch*,
Giuseppe Bianco,
Giuseppe Speziale,
Roberta Sampognaro,
Carlo Lavalle,
Francesco Guccione,
Pietro Dioguardi,
Giovanni Ruvolo
Unit of Cardiac Surgery, University of Palermo, Palermo, Italy
Received 15 February 2007;
received in revised form 10 April 2007;
accepted 27 April 2007.
* Corresponding author. Address: University of Palermo, Cardiac Surgery Unit, Via Liborio Giuffré 5, 90100 Palermo, Italy. Tel.: +39 091 6554713; fax: +39 091 6554710. (Email: khalilfattouch{at}hotmail.com).
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Abstract
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Background: The inflammatory cascade has been hypothesized to be an important mechanism of post-ischaemic myocardial reperfusion injury and several studies demonstrated that C1 esterase inhibitor (C1-INH) is effective in post-ischaemia myocardial protection. Therefore, we aimed to investigate prospectively in a randomised double-blind study the cardioprotective effects of C1-INH in ST segment elevation myocardial infarction (STEMI) in patients who underwent emergent reperfusion with coronary artery bypass grafting (CABG). Methods: In this study, we enrolled 80 patients affected with STEMI who underwent emergent CABG. Patients were assigned in two groups (C1-INH group: receive 1000 UI of C1-INH; and placebo group: receive a saline solution). The effects of C1-INH on complement inhibition, myocardial cell injury extension and clinical outcome were studied. Haemodynamic data and myocardial function were monitored. C1-INH, C3a, C4a complement activation fragments and cardiac troponin I (cTnI) serum levels were measured before, during and after surgery. Results: Patient characteristics were not different between the two groups. The overall in-hospital mortality rate was 6.2%. No statistical significant difference was observed between the two groups with regard to early mortality (p
= 0.36). Statistical significant difference between the two groups was showed for cardiopulmonary bypass support (p
= 0.04), administration of high dose of inotropes drugs (p
= 0.001), time of intubation (p
= 0.03), intensive care unit (ICU) stay (p
= 0.04) and in-hospital stay (p
= 0.03). A significant improvement in mean arterial pressure (p
= 0.03), cardiac index (p
= 0.02) and stroke volume (p
= 0.03) was showed in C1-INH group versus placebo group. The serum cTnI levels were significantly low in the C1-INH group versus placebo group after reperfusion, during the observation period. Plasma levels of C3a and C4a complement fragments were reduced significantly in C1-INH group. No drugs-related adverse effects were observed. Conclusions: The inhibition of the classic complement pathway by C1-INH appears to be an effective mean of preserving ischaemic myocardium from reperfusion injury as demonstrated by low serum cTnI levels in C1-INH group. Therefore, the use of C1-INH during CABG as a rescue therapy in STEMI patients is probably an effective treatment to inhibit complement activity and to improve cardiac function and haemodynamic performance without impacting early mortality. Large randomised study should be performed to support our results.
Key Words: STEMI patients • CABG • C1 esterase inhibitor • Reperfusion injury • Complement cascade • Myocardial function recovery
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1. Introduction
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Patients with ST segment elevation myocardial infarction (STEMI) undergoing urgent or emergent coronary artery bypass grafting (CABG) may suffer from postoperative ischaemia-reperfusion injury resulting in myocardial dysfunction or stunning. This leads to intra-operative more cardiopulmonary bypass (CPB) support for myocardial recovery and high postoperative mortality and morbidity rates. Today, several studies have shown that the complement system is involved in the inflammatory reaction after reperfusion [1–4]. The activation of the complement cascade in response to myocardial ischaemia and cardiopulmonary bypass could result in either direct complement-mediated damage due to neutrophil activation and infiltration with the generation of toxic oxygen-free radicals. It has been suggested that the activation of complement pathway within ischaemic myocardium can promote the increased recruitment of intra-cardiac inflammatory cells. Moreover, it generates the complement spilt products as C3a and C5a resulting in increased activation of polymorphonuclear leukocytes which adhere to the vascular endothelium and promoves the constriction of vascular smooth muscle, causing a significant decrease in coronary flow and microvascular dysfunction [1,5].
In the last decade, several authors showed that the administration of soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the post-ischaemic heart [6–10]. Although, several experimental and clinical investigations demonstrated the cardioprotective effects of C1 esterase inhibitor (C1-INH) administration from ischaemia-reperfusion injury, only one previous study has been performed randomly and prospectively in human to investigate the role of C1-INH in STEMI patients who underwent CABG [11].
Furthermore, we designed this prospective, randomised, double-blind study aimed to evaluate the effects of C1-INH infusion on early clinical outcome in patients with STEMI underwent CABG.
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2. Patients and methods
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2.1 Patients, study design and protocol
Between February 2003 and April 2006, patients with STEMI admitted to our cardiac surgery department in order to undergo an emergent CABG were consecutively and prospectively screened for this study. This was a prospective, randomised, placebo-controlled, double-blind study. Each patient signed an informed consent form. When patients were in shock state, permission to C1-INH treatment was obtained from the family. The study was approved by a local ethical committee.
Patients were enrolled into the study, if they were admitted with a STEMI and had undergone coronary artery reperfusion with CABG within 12 h after the onset of symptoms or the ischaemic event (coronary reperfusion is defined as aortic unclamping).
Indications for surgery were recurrent myocardial ischaemia refractory to medical therapy in patients with a significant area of myocardium at risk and are not candidates for fibrinolytic or primary percutaneous transluminal coronary angioplasty (PTCA), primary PTCA failure with persistent symptoms or haemodynamic instability, life-threatening ventricular arrhythmias in patients with left main stenosis and/or three vessels disease, and patients with multi-vessels or left main disease and haemodynamic instability. Exclusion criteria were mechanical complications of myocardial infarction, patients requiring cardiopulmonary resuscitation, onset of cardiac shock >6 h, concomitant cardiac surgical procedures, associated renal, hepatic or pulmonary diseases, patients with known complement deficiency or immune deficiency syndrome, known autoimmune disease or evidence of infection. In case of any suspicious coagulation disorder, patients were excluded and C1-INH therapy was discontinued. Patients were randomly assigned in two groups: C1-INH group (38 patients): receive 1000 units of C1-INH; and placebo group (42 patients): receive a 9% NaCl solution.
Patients in C1-INH group receive 500 UI as intravenous bolus 10 min before reperfusion (aortic unclamping) followed by an intravenous infusion of 500 UI for 3 h after surgery.
2.2 Clinical study endpoints
The primary endpoint of the study was the incidence of in-hospital death and the myocardial infarct size or the extent of irreversible myocardial cell injury, as measured by the perioperative serum release of cardiac troponin I (cTnI). Secondary endpoint was the improvement of contractile cardiac function evaluated by transoesophageal echocardiography and the postoperative major adverse events like the incidence of low cardiac output syndrome (LCOS), intra-aortic balloon pump (IABP) and CPB support, and the administration of the high doses of inotropes drugs (dopamine or dobutamine >6 µg/(kg min), adrenaline >0.08 µg/(kg min)). Other postoperative data like prolonged mechanical ventilation support (>24 h), postoperative length of stay in intensive care unit (ICU) and in-hospital, major bleeding, infection, and renal failure requiring temporary haemodialysis were also recorded.
2.3 Surgical technique and management
Standard anaesthesia was induced with fentanyl (20–50 µg/kg), midazolam (0.1 mg/kg) and pancuronium bromide (0.1 mg/kg) and maintained with a continuous infusion of fentanyl (0.5–1 µg/(kg h)) and propofol (50–200 µg/(kg h)). Intra-aortic balloon pump was implanted preoperatively, if ventricular function was poor (EF% < 30) and systemic haemodynamic appeared to be inadequate. Emergent CABG was performed using CPB carried out under moderate systemic hypothermia (32 °C), keeping a continuous flow at 2–2.5 ml/(min m2) and perfusion pressure between 50 and 80 mmHg. Systemic heparinization was achieved by intravenous bolus of heparin at dose of 300–400 UI/kg body weight; additional heparin was given, as needed, to achieve an activated clotting time (ACT) of greater than 400 s. Protamine sulfate was given at the end of CPB at the dosage of 1.0–1.5 mg for each 100 units of heparin. Myocardial protection was achieved with intermittent antegrade cold blood cardioplegia solution. When the haemodynamic condition was stable, the left internal thoracic artery was harvested and used as in-situ graft to the left internal anterior descending coronary artery. CABG was completed using saphenous vein grafts. All distal anastomoses were performed during a single aortic cross clamping. The proximal grafts anastomoses to the aorta were performed with partial occlusion of the ascending aorta. After weaning from CPB, the mean graft flow was assessed by Doppler transit time flowmetry for each graft using a Transonic Systems INC® Flowmeter. Postoperative ICU management was standardized for all patients.
All patients underwent intra-operative and postoperative haemodynamics monitoring by a 12-lead ECG, invasive radial artery and Swan-Ganz catheters. Systolic, diastolic and mean systemic arterial blood pressure (MAP), cardiac output (CO), stroke volume (SV), cardiac index (CI), central venous pressure (CVP), systolic, diastolic and main pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), systemic vascular resistances (SVR), pulmonary vascular resistances (PVR), were recorded.
2.4 Myocardial regional wall motion analysis
Intra-operative transoesophageal echocardiographic (TEE) control was performed in all patients to evaluate global and regional myocardial function. A two-dimensional cardiac ultrasound from Hewlett-Packard (Sonos 4500) equipped with a transoesophageal echocardiographic probe was used. Myocardial kinesia was evaluated according to the guidelines of the American Society of Echocardiography [12].
2.5 Blood samples
In all patients, serum C1-INH concentrations were measured before, during and after surgery at six different times: T1 = before induction of anaesthesia; T2 = after heparin dose; T3 = 10 min after drug administration; T4 = 2 h post-CPB; T5 = 12 h post-CPB; T6 = 24 h after surgery (Fig. 1
).
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Fig. 1. Total serum C1-INH levels in both groups of patients at the following measurement times: T1 = before induction of anaesthesia; T2 = after heparin dose; T3 = 10 min after drug administration; T4 = 2 h post-CPB; T5 = 12 h post-CPB; T6 = 24 h after surgery. *Statistical significant difference between the two groups.  Statistical significant difference for time 3 vs 1, 4 vs 1 and 5 vs 1.
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Blood samples were allowed to clot at room temperature for 30 min and then placed on ice for 1 h. Separation occurred at 2–4 °C. Samples were aliquots stored at –70 °C as quickly as practicable. For use, samples were thawed at 37 °C then immediately placed on ice. Blood was collected into ethylenediaminetetracetic acid (EDTA) that prevents further complement activation by chelating calcium and magnesium. Moreover, blood was kept on ice for as short a time as possible before being spun to produce platelet-poor plasma, which was stored as for serum. Although, even immunochemical methods such as nephelometry and turbidimetry can be used to measure serum C1-INH levels, we used the enzyme-linked immunosorbent assay (ELISA) because it is a robust and sensitive technique. Normal C1-INH value ranged from 0.19 to 0.43 mg/dl.
Serum C3a and C4a levels were measured at six different times: T1 = pre-CPB; T2 = 10 min post-CPB; T3 = 40 min post-CPB; T4 = 2 h post-CPB; T5 = 12 h post-CPB; T6 = 24 h post-CPB. For assays of complements C3a and C4a, samples were also collected into tubes containing EDTA-2Na and centrifuged at 1500 rpm for 5 min. The plasma was frozen at –70 °C. The plasma concentrations of complements C3a and C4a were determined by radioimmunoassay (two-antibody method) [13].
Serum cTnI levels were measured preoperatively, during and after surgery, at six different times: T1 = preoperative; T2 = 1 h post-reperfusion (aortic unclamping); T3 = 6 h post-reperfusion; T4 = 12 h post-reperfusion; T5 = 24 h post-reperfusion; T6 = 48 h post-reperfusion.
2.6 Statistical analyses
Differences between two groups for demographics and perioperative data were determined with 
2-test. If value did not show a normal distribution, the Irwin–Fisher test was performed. Average values are mean ± SD. For repeated measures of C1-INH at different times, ANOVA with the multiple comparison method (Student–Newman–Keuls test) was used. Statistical significance was accepted at a value of p
< 0.05 between two groups.
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3. Results
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Demographic characteristics, intra-operative and postoperative data are summarized in Tables 1–3
. The two groups did not differ in age, gender, incidence of previous myocardial infarction, area of the acute myocardial infarction, incidence of thrombolysis or primary PTCA treatment, shock and perioperative IABP support. Preoperatively, total serum C1-INH concentrations was 0.32 ± 0.06 and 0.33 ± 0.04 in C1-INH and placebo groups, respectively (Table 1). Complete myocardial revascularization was performed in all patients and no differences were observed between groups with regard to mean number of grafts/patient, number of LIMA graft and mean value graft flow.
3.1 Early mortality and outcomes
The overall in-hospital mortality rate was 6.2% (five patients): four patients (9.5%) died in placebo group and one patient died (2.6%) in C1-INH group (p
= 0.36). Cause of death in the placebo group was LCOS in two patients, ventricular fibrillation resistant to treatment in one patient and sepsis in one; in C1-INH group, one patient dead for LCOS. Statistical significant differences were observed between the two groups with regard to CPB support (p
= 0.04), postoperative inotropes drugs administration (p
= 0.001), time of intubation (p
= 0.03), ICU stay (p
= 0.04) and in-hospital stay (p
= 0.03) (Table 2).
The haemodynamics data are summarized in Table 3. In C1-INH group, we showed a significant improvement in MAP (p
= 0.03), CI (p
= 0.02) and SV (p
= 0.03) with respect to placebo group.
3.2 C1-INH, C3a and C4a activities
In both groups, total serum C1-INH levels decreased during CPB with respect to basal value. However, in the C1-INH group, during the observation period, the serum levels were maintained next to basal value without significant difference. On the other hand, in the placebo group, statistical significant difference was showed at time 3 versus 1 (p
= 0.001), time 4 versus 1 (p
= 0.002) and time 5 versus 1 (p
= 0.001) (Fig. 1). Moreover, statistical significant differences between the two groups were observed at times 3 (p
= 0.02), 4 (p
= 0.03) and 5 (p
= 0.02). In both groups, serum C1-INH levels increased progressively after weaning from the CPB and reached a normal value in the first postoperative day (Fig. 1). Complement activation, as evidenced by C3a and C4a generation, was observed mostly during CPB up to 2 h after weaning from CPB and was profoundly inhibited in patients receiving C1-INH (Figs. 2 and 3
).
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Fig. 2. Total serum C3a levels in both groups at the following measurement times: T1 = pre-CPB; T2 = 10 min post-CPB; T3 = 40 min post-CPB; T4 = 2 h post-CPB; T5 = 12 h post-CPB; T6 = 24 h post-CPB.
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Fig. 3. Total serum C4 levels in both groups at the following measurement times: T1 = pre-CPB; T2 = 10 min post-CPB; T3 = 40 min post-CPB; T4 = 2 h post-CPB; T5 = 12 h post-CPB; T6 = 24 h post-CPB.
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3.3 C1-INH treatment adverse effects
Intravenous administration of C1-INH during surgery was well tolerated by all patients and there were no perioperative adverse events. There was no difference between the two groups with respect to postoperative incidence of infection and coagulation disorder.
3.4 Cardiac contractile function
TEE was used to evaluate myocardial contractility, which showed an improvement in the global and regional myocardial kinesia in the group of patients who received C1-INH treatment versus placebo group. Values of the wall motion score index in the two groups are summarized in Fig. 4
. In the placebo group, the contractile myocardium function was slightly depressed without statistical significant difference with respect to basal level after weaning from CPB despite successful myocardial revascularization. On the other hand, improvement in myocardial kinesia was observed in the C1-INH group with statistical significant difference with respect to placebo group (Fig. 4).
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Fig. 4. Wall motion score index: time 1 = preoperative; time 2 = 10 min after CPB; time 3 = 30 min after CPB; time 4 = 1 h after CPB; time 5 = 3 h after CPB.
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3.5 Serum cTnI levels
Preoperative peak maximum serum cTnI levels were not significantly different between the two groups. STEMI patients treated with C1-INH had significantly lower peak maximum serum cTnI levels as compared to those without C1-INH treatment.
In all patients, mean cTnI serum levels progressively increased in both groups after reperfusion as compared with preoperative values, reaching its peak value at 24 h after reperfusion. Statistical significant difference was observed between the two groups at 6 h after reperfusion and through the observation period (Fig. 5
).
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Fig. 5. Total serum cardiac troponin I levels (cTnI) in both groups at the following measurement times: T1 = preoperative; T2 = 1 h post-reperfusion (aortic unclamping); T3 = 6 h post-reperfusion; T4 = 12 h post-reperfusion; T5 = 24 h post-reperfusion; T6 = 48 h post-reperfusion.
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4. Discussion
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Myocardial contractile dysfunction could occur in patients undergoing CABG after STEMI, due to ischaemia-reperfusion damage despite successful myocardial revascularization. In the last decade, several studies have investigated the reperfusion injury followed by acute myocardial ischaemia and have shown that this phenomenon is preceded by endothelial dysfunction and a change in homeostatic balance between neutrophils and the coronary vasculature [1–4,14,15]. The neutrophil adhesion to the coronary endothelial cell surface observed after the onset of reperfusion is triggered by the decrease in the release of basal nitric oxide. The events lead to enhanced myocardial cell injury and increased myocardial necrosis. Activation of the complement cascade appears to play an important role in local inflammatory response occurring in ischaemia-reperfusion injury [2–4]. Activation and chemotaxis of neutrophils, the cellular calcium loading, cytokine release and accumulation of the complement spilt products in ischaemic myocardium have been reported, and the generation of toxic oxygen-free radicals and anaphylatoxins were proposed to mediate reperfusion injury and supposed to lead to reduce contractile function. Several studies have demonstrated that polymorphonuclear leukocytes (PMN) could play a central role in the induction or amplification of reperfusion injury and that PMN depletion can decrease infarct size and prevent myocardial stunning [1–3,16,17]. Rossen et al. have shown that sub-cellular constituents of injured myocardium can bind the first component of complement, with activation of the complement cascade and generation of C3a and C5a, both of which can induce PMN chemotaxis and activation [2,3]. Bennet et al. demonstrated that plasma levels of C3a and C5a are increased after reperfusion in patients with acute myocardial infarction [18]. Moreover, it has been suggested by Ito et al. that complement activation alone may cause a significant degree of myocardial contractile dysfunction and can exacerbate ischaemic injury [19]. Therefore, it has been suggested that the use of an inhibitor of the complement cascade may have beneficial effects in the treatment of ischaemia-reperfusion damage. Weisman et al. proved that the soluble human complement receptor type I in vivo inhibitor of complement is a potential agent for suppression of post-ischaemic myocardial inflammation and necrosis [10]. Buerke et al. showed cardioprotective effects of C1-INH, possibly mediated by an inhibition of an endothelium–leukocyte interaction [6]. Horstick et al. [7] and Shandelya et al. [9] described the role of C1-INH in improvement of cardiac function and reduction of myocardial necrosis in an experimental model of ischaemia and reperfusion. In addition, the effective role of C1-INH during coronary artery surgery in human was described recently by several authors [11,20,21].
As shown in the present study, an administration of C1-INH during CPB in STEMI patients who underwent CABG within 12 h from symptom onset did attenuate myocardial ischaemic-reperfusion injury. The time dependency of the effectiveness of complement inhibition confirms several previous studies in which complement activation was shown to be initiated either within 2–4 h after coronary occlusion in animals [22] or <12 h after AMI in human autopsies [23]. In our series, the significant reduction of postoperative serum cTnI release and the improvement of myocardial contractility in the C1-INH group with respect to the placebo group may indeed be attributed to adjunctive C1-INH therapy, since all baseline characteristics of the two study groups were comparable and no statistical significant difference concerning preoperative extent of acute myocardial ischaemia, LVEF%, preoperative cTnI levels, preoperative clinical presentation or intra-operative management was present.
In our series, overall in-hospital mortality rate was 6.2%. Four patients (9.5%) died in group II and one patient (2.6%) died in group I. We were unable to observe any statistical significant differences between the two groups with regard to early mortality (p
= 0.36).
Patients treated with C1-INH in this series need less postoperative catecholamine doses (p
= 0.001) and intra-operative CPB support (p
= 0.04) than patients in placebo group. Moreover, there was an improvement in MAP (p
= 0.03), cardiac index (p
= 0.02) and stroke volume (p
= 0.03) postoperatively in the C1-INH group versus the placebo group (Table 3). We think that the less catecholamine doses and CPB time support in C1-INH group could found the advantage of C1 esterase inhibitor therapy, since the preoperative and intra-operative patients characteristics (preoperative cTnI serum levels, LVEF, number of patients on shock state, aortic cross clamping time, number and patency of grafts and operation time) were similar between the two groups.
From our observations, we suggest that the improvement in myocardial contractility and the limitation on myocardial infarct extension demonstrated by the reduction in serum cTnI release in the C1-INH group may be attributed to the complement inhibition that prevents the ischaemia-reperfusion injury.
Moreover, it is known that the use of CPB leads to depletion in C1-INH serum level. First, the haemodilution applied in CPB reduces the serum C1-INH level by 30–50% [19,24]. Second, complement activation occurs during CPB and with the administration of protamine. On the other hand, the safe lower serum level of C1-INH during CPB has not been fully elucidated so far. As shown in the present study, administration of C1-INH could maintain its serum levels next to basal value during and after CPB, whereas normally serum C1-INH level progressively decreases after start of CPB and slowly recovers towards 24–48 h after surgery, indicating an intra-operative and postoperative C1-INH consumption (Fig. 1).
Recently, several authors have demonstrated that preoperative complement fragment concentrations are significantly higher in patients with STEMI and that the administration of C1-INH could be effective in complement inhibition during CPB [11]. In our study, the serum C3a and C4a levels were significantly reduced in C1-INH versus placebo group during and after CPB (Figs. 2 and 3).
It is known that in patients suffering from acute myocardial ischaemia and ischaemic-reperfusion injury, some factors such as depressed ejection fraction, long CPB support and concomitant inflammatory response can add up to fatal combination. Because ischaemia-reperfusion injury and the inflammatory response to CPB are both complement dependent, the systemic effects of C1-INH may also contribute to the patient's recovery. Furthermore, it seemed reasonable to use C1-INH as an adjunctive therapy in patients suffering from STEMI who underwent emergent CABG within 12 h from the symptom onset, despite that we didn’t observe any statistical significant impact on early mortality, because we found an effective role of C1-INH therapy on limitation of the infarct size that contributed to improve myocardial contractility, haemodynamic performance, and the postoperative course.
The C1-INH dose administrated in the present study was in accordance to the other doses used in a recent report in literature where cardioprotective effects were found with intravenous doses of 10–40 IU/kg without side effects [25]. It was further reported that high C1-INH doses can provoke procoagulatory effects without having any cardioprotective effects. In our series, constant plasma levels of C1-INH could be held by bolus during CPB before the reperfusion (aortic unclamping) and additional intravenous C1-INH infusion after surgery for 3 h, and no drug-related adverse events were observed.
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5. Conclusion
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The present study is the second randomised clinical study designed to show beneficial effects of adjunctive C1-INH therapy with regard to myocardial infarct size, early mortality and outcome in STEMI patients following emergent surgical revascularization within 12 h from the symptom onset. In this report, we are unable to achieve all primary endpoints because we showed a significant statistical difference between the two groups with regard to post-reperfusion serum cTnI release but not for early mortality. Concerning the secondary endpoint, we showed statistical significant difference between the two groups with regard to improvement on myocardial contractility, to catecholamine drugs administration, to CPB support and to complement activity suppression, but we are unable to see any statistical significant difference with regard to postoperative IABP support and incidence of postoperative LCOS.
On the other hand, statistical significant difference between the two groups was shown during the observation study time with regard to postoperative data like time of ventilation and postoperative length of stay in ICU and in-hospital, but we were enable to observe any significant statistical difference with regard to major bleeding, infection and renal failure requiring temporary haemodialysis (Table 2).
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Acknowledgments
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We wish to thank Prof. Raffaele Masciangelo from the Institute of Experimental Medicine and Pathology of the University of Rome "La Sapienza", for statistical analysis. We thank also, all department chiefs of Coronary Care Units and Haemodynamic Laboratories in Western Sicily Region, Italy, that contributed to this study referring this cohort of patients in our Institution.
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Footnotes
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\#9734; Presented at the joint 20th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 14th Annual Meeting of the European Society of Thoracic Surgeons, Stockholm, Sweden, September 10–13, 2006.
\#9734;\#9734; This work is supported by the Italian National Council of Research (CNR).
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Abstract
1. Introduction
