Efficacy of Morphine in Reducing the Rate of Early Non-Invasive Ventilation (NIV) Failure in Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD), Phase I/IIa
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Efficacy and toxicity
研究概览
简要总结
Acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a major source of morbidity and mortality for patients and cost to the society. In case of acute respiratory failure with hypercapnia and acidosis, Non Invasive Ventilation (NIV) is preferred as a first line treatment.
NIV failures are not uncommon, from 15% in intensive care to 25 - 30% in emergency departments. They most often occur at the start of the NIV or in the hours that follow. There are many reasons for these failure. Among these are; dyspnea, discomfort, the pain related to the exacerbation and also to the NIV are frequently noted.
The use of certain drugs with anxiolytic, hypnotic and/or analgesic properties could also be useful. Some sedatives and opioids have already been studied in this indication but without a therapeutic trial and satisfactory methodology. Among the molecules of interest, Morphine seems interesting . It's administration could reduce the ventilatory rate, intensity of dyspnea, pain and anxiety as well as dynamic hyperinflation.
The investigators believe that morphine administration will decrease the rate of early NIV failure by improving comfort (decreased dyspnea and pain) and ventilation (decreased respiratory rate and increase in tidal volume) in patients with exacerbations of COPD.
However, before considering a randomized phase III efficacy study, it is necessary to determine the optimal dose of morphine in this indication, through a phase I/II dose-finding study taking into accounts both the efficacy and toxicity of morphine.
The main objective of this study, is to determine the optimal dose of morphine administered at the initiation of NIV in patient with acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD), which is defined as the maximum gain function combining the probability of dose-limiting toxicity with PaCO2.Therefore, the impact of morphine administration on the physiological parameters of NIV- COPD exacerbation patients will be assessed.
详细描述
Patients included in this dose-finding study will be enrolled consecutively after consent and verification of the selection criteria, with a minimum of 24 hours after completion of previous patient follow-up.
Prior to the administration of morphine, the following exams will be performed: clinical, paraclinical and biological parameters.
NIV will be started and performed in BiPAP pressure mode with facial mask. A Tidal Volume (Vt) to the maximum of 6 - 8ml/kg, an expiratory positive airway pressure (EPAP) of 5cm H2O and the FiO2 set at 35%. The settings will be adapted according to the SpO2 (88%≤SpO2≤92%) and the clinical tolerance.
Thereafter, the patients included will receive a single open-label injection of morphine (T0) at the dose closest to that defined by the model (estimation by Bayesian method) from among the following 4 doses: 0.02; 0.04; 0.07 and 0.1mg/kg.
A double check of the preparation of the dose administered will be carried out by a physician and a nurse in an emergency department.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients Aged ≥ 18 years
- •Current or former smoker at least 10 packs-years
- •Patient with a history of COPD according to the Gold guidelines , after review of the medical record by the physician in charge
- •Acute exacerbation of COPD (greater degradation of respiratory symptoms than the usual daily variations and requiring a modification of therapeutic management)
- •Need to implement NIV treatment (respiratory acidosis with pH<7.35)
- •Ventilation frequency > 20min
- •Affiliation to the French security system (or equivalent)
- •Written informed consent from the patient or his surrogates. In patients who are not able to consent on admission an emergency inclusion procedure will be allowed, with a mandatory delayed consent.
排除标准
- •Patient already treated by NIV during admission (e. g. introduction in pre-hospital by SMUR) or started more than one hour ago in the department.
- •Sedative (barbiturates, benzodiazepines and related substances and other sedatives) or morphine treatment within 24 hours before inclusion
- •Chronic alcoholism
- •Contra-indication to NIV: disturbances of consciousness (Glasgow < 11) except moderate hypercapnic encephalopathy; indication of immediate intubation; risk of inhalation; sputum impossible; hemodynamic instability; inability to remove the mask; trauma, surgery or facial malformation; patients with pH < 7.25 can only be included in intensive care unit or in the vital emergency room of the emergency department, under continuous monitoring
- •NIV with palliative purpose from the outset with death expected within 24 hours of inclusion
- •Non-communicative patient or significant dementia making them unable to participate in the study
- •Contra-indication to morphine without acute respiratory distress
- •Pregnant or breastfeeding women
- •Major mentioned in Articles L1121-6 and 1121-8 of French public health cod
- •Patients in a period of exclusion from other research involving the human person type 1 or 2
- •Subject cannot be contacted in case of emergency
研究组 & 干预措施
Patient admitted for acute Exacerbation of Chronic Obstructive
Patient admitted for acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) and required NIV
干预措施: Morphine hydrochloride (Drug)
结局指标
主要结局
Efficacy and toxicity
时间窗: 1 hour
PaCO2 1 hour after morphine injection, according to the hormetic dose-response model
The probability of dose - limiting toxicity (DTL), defined as the occurrence of one or more of the following criteria occurring within 4 hours of morphine administration
时间窗: 4 hours
Respiratory Rate ≤ 10/min; Richmond Agitation-Sedation Scale (RASS) \< -2;Vomiting and Naloxone administration
次要结局
- Percentage of adverse events(1, 4 and 24 hours)