Single Dose Administration of Alpha-1 Anti-Trypsin for the Amelioration of Organ Injury and Post Operative Bleeding in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: Double-blind, Placebo-controlled Pilot Study
试验速览
- 阶段
- 1 期
- 入组人数
- 20
- 主要终点
- Brain injury assessment:
研究概览
简要总结
Protocol Summary STUDY DESIGN A pilot, prospective, double blind, randomized, placebo controlled study.
STUDY POPULATION Patients assigned to elective CABG with cardiopulmonary bypass (CPB) at the Department of Cardiothoracic Surgery, Soroka University Medical Center.
OBJECTIVE To evaluate anti-inflammatory effects, effects on organ function preservation, and postoperative blood loss reduction following AAT-1 administration in patients undergoing CABG with CPB.
PRIMARY ENDPOINT Postoperative organ function preservation and blood loss following preoperative single-dose AAT-1 administration.
SAMPLE SIZE CONSIDERATIONS A cohort of 20 patients will be recruited. Patients will be randomized to receive either AAT-1 or placebo prior to surgery. Whereas this is a proof of concept pilot study, statistical significance is not the primary objective.
INCLUSION CRITERIA 1. The study population will comprise patients between 40 and 70 years of age, irrespective of gender, at low or intermediate operative risk (calculated Logistic Euroscore stratification of 5% or less), assigned to elective CABG with CPB. Recruitment depending on patients informed consent.
EXCLUSION CRITERIA Co-existing conditions including:
- Coagulation abnormalities
- Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of less than 60% of predicted.
- Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,
- Abnormal liver function tests
- Uncontrolled diabetes mellitus,
- Severe peripheral vascular disease
- Prior cerebrovascular neurological event.
- Abnormal left or right ventricular function.
- Treatment with warfarin or thienopyridine class of anti platelet agents.
详细描述
3 Background The use of cardiopulmonary bypass (CPB) during cardiac surgery elicits generalized non-specific systemic inflammatory response syndrome (SIRS) and subsequent activation of the cytokine, complement, and coagulation-fibrinolytic cascades (1). In approximately 11% of the patients SIRS may deteriorate to severe multi-organ failure (MOF) resulting in mortality rate of 40-98%.
Inflammatory modulation by intraoperative administration of anti-inflammatory substances has been advocated to attenuate the effects of SIRS. Attempts have subsequently focused on aprotinin which inhibits proteases that are key mediators in the complement, coagulation, and fibrinolytic system. Related anti-inflammatory properties of aprotinin include the inhibition of platelets, neutrophils and kallikrein activation. Reduction in blood loss and reduced need for allogenic blood transfusions have been proposed as additional mechanisms by which aprotinin limits the inflammatory response (2). The use of aprotinin during cardiac surgery, however, was discontinued following alarming results in terms of higher rate of bypass graft occlusion and overall inferior postoperative outcome.
AAT-1 mechanism of action:
Similar to aprotinin, α1-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor classified as a SERPIN protein. Besides its ability to inhibit serine proteases, accumulating data suggest that AAT-1 possesses independent anti-inflammatory and tissue-protective effects (3). AAT-1 modifies dendritic cell maturation and promotes regulatory T-cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activities and inhibits IL-1 production and activity (4). Contradictory to classic immunosuppressants, AAT-1 allows undeterred isolated T-lymphocyte responses (5).These effects have been repeatedly corroborated.
Unlike aprotinin, AAT-1 is produced from human plasma, and does not have strong pro coagulant characteristics.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The study population will comprise patients between 40 and 70 years of age, irrespective of gender, at low or intermediate operative risk (calculated Logistic Euroscore stratification of 5% or less), assigned to elective CABG with CPB. Recruitment depending on patients informed consent.
排除标准
- •Co-existing conditions including:
- •Coagulation abnormalities
- •Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of less than 60% of predicted.
- •Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,
- •Abnormal liver function tests
- •Uncontrolled diabetes mellitus,
- •Severe peripheral vascular disease
- •Prior cerebrovascular neurological event.
- •Abnormal left or right ventricular function.
- •Treatment with warfarin or thienopyridine class of anti platelet agents -
研究组 & 干预措施
alpha 1 antitrypsin
patients receive 4 grams of IV alpha 1 antitrypsin preoperatively
干预措施: Alpha 1-Antitrypsin (Drug)
结局指标
主要结局
Brain injury assessment:
时间窗: post op day 1-5
The degree of insult to the brain will be measured by plasma S-100 proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by magnetical resonance imaging (MRI) modality
Renal function:
时间窗: post op day 1-5
Daily measurements of urine output, serum creatinine levels, creatinine clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in the ICU.
post operative inflammatory response
时间窗: post operative day 1-5
1. The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be recorded and quantified by laboratory markers. Related laboratory markers will be monitored on a daily basis during the recovery period (in the intensive care unit and at the ward).
Cardiac function:
时间窗: post op day 1-5
Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment; occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac arrhythmias. Transthoracic echocardiography examination will be performed on postoperative day 5 and assessed by an independent cardiologist.
Pulmonary function:
时间窗: post op day 1-5
Pulmonary function will be evaluated by measured overall mechanical ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead space and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed 3 hours after operation (while the patient is anesthetised and intubated) and extracted fluid will be analyzed for inflammatory markers. A-a DO2 calculation \[AaDO2 = (713 x FiO2) - (pCO2 / 0.8) - (paO2)\] will be measured daily. Complete pulmonary function test will be performed before and 4 days after the operation. Chest radiographs will be evaluated and quantified by an independent radiologist for the occurrence of atelectasis, pulmonary edema, or pleural changes.
Hepatic function:
时间窗: post op day 1-5
Daily measurements of serum hepatic enzymes levels.
Blood loss:
时间窗: post op day 1-2
Operative and postoperative blood loss will be monitored as well as daily hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The distribution of blood products and total administered will be recorded daily. Postoperative CRP levels will be evaluated daily.
次要结局
未报告次要终点
研究者
Dan Abramov
Dr
Soroka University Medical Center