Nebulized Heparin and Salbutamol in Mechanically Ventilated Patients With AECOPD
Condition: Mechanically Ventilated Patients
Study type: Interventional
Phase: Phase 4

Summary: 
      This randomised study was designed to assess the efficacy of nebulised heparin and salbutamol
      in improving lung function in mechanically ventilated patients with AECOPD.
    

Detailed description: 
      Methods:

      Patients:

      This study was performed between February 2017 and September 2017. Admitted Patients to the
      Internal Medicine ICU of Ain-Shams University Hospitals were screened for meeting enrollment
      criteria. Written informed consent was taken from all patients, their parents or their
      guardians before any study procedure was done. Patients were included in the study if they
      were > or = 18 years of age, body weight 70-110Kg, height 160-180 cm with clinically evident
      AECOPD and in need for mechanical ventilation confirmed by arterial blood gases (ABGs).

      Excluded Patients from the study were those who were not enrolled within the first 24 hours
      of mechanical ventilation and those who were likely to be extubated within 24 hours. Patients
      were also excluded if they have any history of ischemic heart disease, pulmonary bleeding
      within the previous 3 months, history of bleeding diathesis, known to be allergic to heparin
      or history of thrombocytopenia after previous treatment with heparin. Female patients were
      excluded if they are pregnant or breast feeding.

      Study design:

      This study was a double-blind, randomized controlled trial. Block randomization was performed
      in random blocks of two to eight. After enrollment, patients were randomly allocated into
      either of the two groups, HS and S. Allocations were concealed in opaque, sequentially
      numbered, sealed envelopes.

      Study medications:

      Patients in either group were treated by nebulization of 7.5 ml of study medication every 6
      hours (4imes a day). The study medications were prepared by the local pharmacist who gave
      them to the nurse in charge and they were not involved in any other part of the study.

      The study medications were either a HS Group medications (study group) (30 patients) which
      was prepared by adding Heparin 25000 IU in 5ml (5 ampoules of Heparin Sodium 5000 I.U/ML,
      Nile company for Pharmaceuticals and Chemical Industries-A.R.E.) to Salbutamol 5mg/2.5ml
      Nebulizer Solution (one Ventolin nebule containing a preservative-free solution of Salbutamol
      Sulphate BP 2.5mg, GlaxoSmithKline Inc.) or S Group medications (control group) (30 patients)
      which was prepared by adding Salbutamol 5mg/2.5ml Nebulizer Solution + Na cl 0.9% 5ml.

      Standard medications were used in both groups which included analgesics, sedatives, fluid
      management, antibiotic prophylaxis, steroids and thrombo-prophylaxis according to local
      guidelines.

      Nebulization and Ventilation:

      Nebulization was conducted by adding the nebulization medication to a nebulization chamber
      (Ameco Technology, particle size 0.5 To 10um, Nebulization rate> 0.3ml/min) connected to the
      inspiratory limb of the breathing circuit by a T-piece (22M-22M/15F, with port- TNTAIR
      medical) close to the patient but after the moist exchanger if applied. An expiratory filter
      was applied in the expiratory limb of the breathing circuit. The nebulization session was
      continued for at least 20 minutes.

      Patients in the heparin group were eliminated (drop-out) if they developed a heparin-induced
      thrombocytopenia, an increase in APTT more than double normal,an evident bleeding that
      necessitated blood transfusion or if an excessive blood tinged sputum or bleeding appeared
      during suctioning or bronchial lavage.

      All patients were mechanically ventilated using SIMV mode, with a targeted TV: 6-8 ml/kg,
      rate: 10-12 bpm, PEEP: 5-10 cm H2O, and FIO2:40%-60%.

      Data collection:

      The PaO2/FiO2 ratio and, PaCo2 were measured each day at 7 a.m. No changes in the ventilator
      settings or the patient's position were permitted for the 10 minutes before this measurement.

      Demographic data including history of smoking (never, former, current) were collected on
      study entry, and ventilation parameters, clinical and radiological data, sputum character,
      medication usage, and adverse events, including blood-stained sputum or frank blood in sputum
      and red cell transfusions, were recorded daily while the patient remained mechanically
      ventilated.

      Ventilator- free days were defined as the number of days patients were breathing without
      mechanical ventilation during the first 14 days.

      Development of acute lung injury (ALI) was defined using the consensus criteria (15).
      Vasopressor usage was defined by the administration of any of the following: dopamine,
      dobutamine, norepinephrine, or epinephrine. Renal failure was defined as a serum creatinine
      of greater than 300 μmol/L or urine output of less than 500 mL per day or renal replacement
      therapy for acute renal impairment. Respiratory failure was defined as the acute requirement
      for mechanical ventilation primarily due to acute exacerbation of COPD evident clinically by
      severe shortness of breath, with or without Co2 narcosis, and by ABG as PH <7.3, PaO2<60 mmHg
      and PaCO2 >50 mmHg.

      Outcomes:

      The following data were collected and compared for each group with respect to:

      The primary outcome was:

        -  The number of ventilator hours; number of hours during which the patient was
           mechanically ventilated.

        -  The average daily ratio of partial pressure of oxygen to FiO2 (PaO2/FiO2) while the
           patient remained ventilated for a maximum of 14 days from randomization and

      The secondary outcome was:

        -  The length of ICU stays.

        -  CRP quantitative titer was measured daily as part of the routine clinical care. The
           maximum serum CRP level during the ICU stay was designated as max- CRP as a prognostic
           factor. Normal concentration of CRP in healthy human serum is between 5 and 10 mg/L,
           increasing with aging(14).

        -  Platelets count and

        -  The number of suctions with blood tinged sputum.

      Analysis of Data:

      Depending on Dixon et al.,2010(16) who found that the ventilation free days (22.6 ±4.0 and
      18.0 ± 7.1 in heparin and control groups respectively, and assuming the power= 0.80 and
      α=0.05, and by using PASS 11th release the minimal sample size for an equal size controlled
      clinical trial is 26 in each group. We will recruit 30 in each group for possible attrition
      (17,18).

      The collected data were coded, tabulated, and statistically analyzed using IBM SPSS
      statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp.,
      Chicago, USA, 2013.
    

Intervention name(s): Nebulized heparin and salbutamol; Nebulized salbutamol
Intervention type(s): Drug; Drug
Intervention description(s): HS Group medications (study group) (30 patients) which was prepared by adding Heparin 25000 IU in 5ml (5 ampoules of Heparin Sodium 5000 I.U/ML, Nile company for Pharmaceuticals and Chemical Industries-A.R.E.) to Salbutamol 5mg/2.5ml Nebulizer Solution (one Ventolin nebule containing a preservative-free solution of Salbutamol Sulphate BP 2.5mg, GlaxoSmithKline Inc.); S Group medications (control group) (30 patients) which was prepared by adding Salbutamol 5mg/2.5ml Nebulizer Solution + Na cl 0.9% 5ml.
Intervention MeSH terms: Heparin; Albuterol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Mechanical ventilation; Acute Exacerbation of chronic obstructive airway disease (AECOPD); Nebulized heparin; C-Reactive Protein (CRP