Early Empirical Versus Pre-emptive Systemic Anti-fungal Therapy in Acute-on-Chronic Liver Failure Patients With Suspected Invasive Fungal Infections: a Randomized Controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 216
- 试验地点
- 2
- 主要终点
- Overall Survival
研究概览
简要总结
Early treatment of invasive fungal infections (IFI) may prevent undue mortality in acute on chronic liver failure (ACLF) patients. We aim to study the impact of early empiric treatment (based on clinical suspicion) of IFI as compared to pre-emptive treatment (based on biomarkers and culture positivity) on the outcomes in ACLF patients with suspected IFI in a randomized trial. The ACLF patients with clinically suspected IFI would be randomly allocated to empiric treatment or pre-emptive treatment group and followed up clinically to assess the impact on survival, clinical outcomes and cost-effectiveness and safety of such an approach. The protocol is designed to cut- down unnecessary usage and to curtail the duration of antifungals use in ICUs based on biomarkers/culture-driven stoppage rules. The results will fuel further studies on formal cost-effective analysis and antimicrobial stewardship protocols in ACLF patients.
详细描述
Research question: Does an early empiric antifungal therapy improve 28-day overall survival as compared to pre-emptive antifungal therapy in critically ill, non-neutropenic adult ACLF patients with suspected IFI?
This study will be a single-center prospective randomized open-label with blinded end-point PROBE assessment and conducted at Liver ICU.
ACLF patients aged 18 to 75 years with all three criteria will be included
- ICU stay of 48 hours or recent hospitalization
- Two or more risk factors for IFI 3. Clinical suspicion of IFI
Exclusion criteria A Neutrophil count of less than 500 per mm3 B Recent antifungal treatment in the past 1months C Hepatocellular carcinoma or other active malignancy D Known hypersensitivity or contraindication to Liposomal AmB E HIV positivity or on HAART F Pregnancy or lactation G Moribund patients
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
- Single (Outcomes Assessor)
盲法说明
Single-center, prospective randomized, open-labeled with blinded end-point (PROBE) assessment
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(All three must be present):
- •ICU stay >48 hours or admission in a tertiary care hospital prior to the current admission
- •Two or more risk factors for IFI from amongst the following:-
- •Mechanically ventilated at least ≥ 48 hours
- •Treatment with broad-spectrum antibacterial agents for more than 3 days
- •Arterial or central vein catheter ≥ 2days
- •Diabetes Mellitus
- •Total parenteral nutrition ≥ 48 hours
- •Acute renal failure requiring any form of renal replacement therapy ≥48hours
- •Pancreatitis related hospitalization > 7days in last 3 months
- •Steroid use, immunosuppressant use in the preceding 30 days
- •High disease score as defined as MELD≥20 or APACHE II ≥16
- •Refractory ascites, norfloxacin prophylaxis
- •Gastrointestinal tract surgery, abdominal perforation or anastomotic leaks or any invasive procedures or surgeries in the last 7days
- •Chronic pulmonary diseases including COPD or Tuberculosis
- •Moderate to severe sarcopenia as defined by The Royal Free Hospital-global assessment (RFH-GA) scale60 (As per Appendix "4" )
- •Firm diagnosis of H1N1 influenza infection in the last 3 months
- •Clinical suspicion of IFI as defined by any of the following:
- •Evidence of unresolved sepsis/SIRS(≥ 2/4) despite appropriate broad-spectrum antibiotics beyond 3days
- •Recrudescence of fever after a period of defervescence of at least 48 hours while still on antibiotics and without other apparent cause
- •Tracheobronchial ulcer, nodule, plaque or pseudo-membrane
- •Sino-nasal infection: features of acute sinusitis with at least 1 of acute localized pain, nasal ulcer, eschar, orbital involvement or
- •Respiratory symptoms:
- •Worsening respiratory insufficiency despite appropriate ventilator support and antibiotics
- •Any 2 of Pleuritic chest pain, pleural rub, dyspnea, hemoptysis
- •Characteristic skin lesions suspected of fungal infection
- •Unexplained worsening of encephalopathy after initial improvement
排除标准
- •Neutrophil count of less than 500/mm3
- •Current or recent antifungal treatment in the past 1 months
- •Hepatocellular carcinoma or other active malignancy
- •Known hypersensitivity or contraindication to Liposomal AmB or any other AmB preparation
- •Human immunodeficiency virus seropositivity on rapid card test/ELISA, or currently on combination antiretroviral therapy (cART)
- •Pregnancy as confirmed by urine pregnancy test or lactation
- •Moribund patients as defined as
- •≥ 4 organ failure as per CLIF-SOFA score
- •Signs of brainstem death- absent brainstem reflexes
- •Expected ICU stay <48 hours
结局指标
主要结局
Overall Survival
时间窗: 28 day
28-day overall survival
次要结局
- Incidence of proven or probable IFI(28 day)
- In-hospital mortality(28 day)
- Evolution of organ failures as assessed by chronic liver failure-sequential organ failure score (CLIF-SOFA)(28 day)
- Evolution of serum 1, 3 Beta-D Glucan (BDG; in pg/ml) levels throughout the study period(28 day)
- Evolution of serum Galactomannan index (GM; in %) throughout the study period(28 day)
- Incidence of key events like new onset ventilator associated pneumonia, urinary tract infection, spontaneous fungal peritonitis(28 day)
- Mechanical ventilation free days(28 day)
- Length of ICU and hospital stay(28 day)
- Treatment success rate(28 day)
研究者
Dr. Nipun Verma
Additional Professor
Post Graduate Institute of Medical Education and Research, Chandigarh