Streptokinase Versus Unfractionated Heparin Nebulization in Severe ARDS
Condition: Acute Respiratory Distress Syndrome; Severe Acute Respiratory Syndrome
MeSH terms: Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      Background: Intra-alveolar clotting and alveolar collapse in ARDS is due to alveolar
      capillaries epithelial and leakage. Subsequently, collapse induces hypoxemia that is
      resistant to recruitment (RM). Heparin and Streptokinase may prevent or dissolve
      intra-alveolar fibrin clot respectively helping alveolar re-expansion. We examined and
      compared the effect of nebulizing Heparin versus Streptokinase on reversing this pathology.

      Methods: Sixty severe ARDS (PaO2/FiO2<100) patients and failure of RM, prone position (PP)
      and neuromuscular block (NMB) were partially randomised into Group (I): (n=20) received
      nebulized Heparin 10000 IU/4h. Group (II): (n=20) received nebulized Streptokinase 250,000
      IU/4h. Group (III): (n=20) received conservative management. Randomization to either Heparin
      or Streptokinase groups was applied to patients whom guardian accepted participation, while
      those who declined participation were followed-up as a control. The primary outcome was the
      change in PaO2/FiO2; the secondary outcomes included the change in compliance, plateau
      pressure, ventilation-off days, coagulation and ICU mortality.
    

Detailed description: 
      Methods:

      The current study was carried out in the Intensive Care Unit of a tertiary University
      Hospital following approval by the local Research and Ethics Committee and after obtaining of
      a written informed consent from the first of kin of the recruited patients.

      The guardians of the patients with severe ARDS fulfilling the inclusion criteria of our study
      were offered to participate in the trial. Randomization to either Heparin or Streptokinase
      groups was applied to patients whom first of kin agreed to participate in the trial, while
      patients whom first of kin declined to participate were followed up as a control group.
      Written informed consent to participate in the trial and to undergo randomization to either
      Heparin or Streptokinase group was signed by the guardians who approved their patients to
      participate. Written informed consent to use patients data was signed by the guardians who
      declined their patients to participate.

      Adult patients aged 21-60 years and admitted to our ICU with the diagnosis of ARDS according
      to Berlin definition (12) were examined and followed up for the presence of the following
      inclusion criteria;

        -  Severe ARDS with PO2/FiO2 ratio<100.

        -  Failure of Recruitment Maneuver (RM), (13) Prone Position (PP) (14) or Neuro-Muscular
           Block (NMB) (15) to improve hypoxemia.

        -  No contraindications to thrombolytic or anticoagulant therapy (e.g. Coagulopathy,
           Heparin-Induced Thrombocytopenia, Previous administration of streptokinase, Known or
           suspected allergy to heparin or streptokinase, History of intracranial hemorrhage in the
           past 12 months, Patients with an epidural catheter in place or likely to be placed
           within the next 48 h.).

      Only patients who have all the three criteria were included in the trial following consenting
      the first of kin.

      Sixty severe ARDS patients with failure of RM, PP and NMB and the absence of a
      contraindication to thrombolytic or anticoagulant therapy were recruited.

      Forty patients whom guardian agreed to participate actively in the study were randomly
      assigned to one of the two groups:

      Group (I): 20 patients received inhaled Unfractionated Heparin at a dose of 10000 IU/4h by
      nebulizer, with the total daily dose of nebulized Unfractionated Heparin 60,000 IU

      Group (II): 20 patients received inhaled Streptokinase at a dose of 250,000 IU/4h by
      nebulizer, with the total daily dose of nebulized Streptokinase 1,500,000 IU.

      A random set of numbers were generated by the computer (www.randomizer.org), and each number
      was sealed in an opaque envelope, and the envelopes were kept in the ICU. One envelope was
      randomly selected after a patient was selected for recruitment and his/her first of kin
      consented. The key for assigning numbers to either group was stored on encrypted USB device
      with one of the investigators. One of the investigators was responsible for preparing the
      medication nebulizer while the nurse and the ICU physician attending the case and recording
      the data were blinded to the patients group.

      Twenty patients whom guardian declined to participate actively in the study but accepted to
      participate passively by consenting for using their data, were assigned as Group III, or the
      control group.

      All patients received the routine intensive care protocol for cases of ARDS including the
      specific ventilatory protocol (16) with monitoring and recording of the following parameters:
      PaO2 [arterial partial pressure of oxygen], FiO2 [Fraction of inspired oxygen], PaO2/FiO2
      ratio, Lung compliance [ml/cmH2o], Peak airway pressure [cmH2o], Coagulation profile
      [platelets count, prothrombin concentration, INR (International Normalized Ratio), bleeding
      time] and any side effects or complications as bleeding, coagulopathy, HIT (Heparin Induced
      Thrombocytopenia) and allergic reactions.

      Start and termination of therapy:

      Heparin nebulizer or Streptokinase nebulizer (according to the study group) will continue
      till the occurrence of one or more of the following: (1) Improvement of the hypoxemia as
      determined by PaO2/FiO2 ratio >300. (2) Improvement of the pulmonary compliance of the
      patient measured by ventilator defined as dynamic compliance > 50 ml/cmH2O. (3) The
      occurrence of complications as bleeding or coagulopathy. (4) Failure of the therapy to
      produce improvement in hypoxemia or compliance after 72 hours of initiation of therapy.

      Considering that in case of improvement in either parameter; oxygenation or pulmonary
      compliance will mandate continuation of therapy for a maximum of 4 days.

      Nebulization

      Heparin or Streptokinase were nebulized by Aeroneb Pro@ Lab mesh nebulizer (Aerogen Limited,
      Galway, Ireland) which is incorporated within GE Healthcare's Engström Carestation ventilator
      (General Electric Company, Finland). Aeroneb nebulizer is a palladium vibrating mesh
      nebulizer. The central aperture plate of the nebulizer is 5mm in diameter and is perforated
      with 1000 precision formed holes, that vibrate at 128,000 times per second, to produce the
      particles with size 1-5 micron in diameter with average MMAD (Mean Mass Aerodynamic Diameter)
      is 2.1 microns. The nebulized medication (either streptokinase 250,000 IU or heparin 10.000
      IU) was prepared in 3 ml volume of distilled water and nebulized for a period of 15 minutes
      every 4 hours. As per the manufacturer, 0.3 ml of residual volume remains in the nebulizer
      after each nebulization. Nebulized medications were delivered to the circuit at the junction
      between the Y-piece and the ETT (Figure 1) to allow the minimal distance between the
      nebulization delivery port and the ETT. A filter in the expiratory limb (between the
      ventilator end of the breathing circuit and the ventilator machine) prevented contamination
      of the circuit. Humidification was supplied by Fisher& Paykel MR 370 humidifier, with the
      humidifier was stopped and disconnected from the breathing circuit 10 minutes before
      nebulization and restored 10 minutes after the end of nebulization. During the nebulization,
      to ensure adequate drug delivery, the ventilatory settings were changed to volume controlled
      ventilation with TV 500 ml, RR 14/min., I: E ratio of 1:1.5, inspiratory pause 75% of the
      inspiratory time, PEEP 10 cmH2O with FIO2 of 1. In case of high peak airway pressure ≥40
      cmH2O, the tidal volume was decreased gradually to keep peak airway pressure <40 cmH2O. The
      initial ventilatory settings were restored 10 minutes after the end of nebulization.

      The day of start of nebulization is considered day 0 and readings for day 1 was recorded 24
      hours after the start of nebulizers.

      Ventilation:

      A pressure-regulated volume-controlled mode (auto flow) of mechanical ventilation was used.
      The target tidal volume was set at a range from 4 to 8 ml /kg we started by 6 ml/kg then
      increased or decreased according to Plateau pressure and CO2 level. Plateau pressure limit up
      to 30 CmH2o, and CO2 was maintained within normal limit (35 - 45 mmHg), PEEP was maintained
      10 mmHg; the Respiratory rate was adjusted according to CO2 level and I: E ratio was
      maintained at 1: 2. this was routine practice at the time of the study. The trial of weaning
      used a spontaneous pressure support mode. The level of pressure support was adjusted to
      maintain the target tidal volume. Extubation was considered if patients meet the criteria of
      weaning such as being hemodynamically stable and cooperative in addition to minimal
      ventilator parameter (SpO2> 95% on a pressure support mode < 10 cm H2O, PEEP < 5 cm H2O and
      FiO2 < 50%).

      Outcomes

      The primary outcome was the mean daily ratio of PaO2 to FiO2 (PaO2/FiO2). The Secondary
      outcomes included; static lung compliance, plateau pressure, change in PaCO2, ventilator-off
      days in surviving patients at ICU discharge, ICU mortality at discharge from ICU and
      coagulation profile and occurrence of any bleeding complications.

      Sample size estimation and Statistical analysis:

      Sample size calculated after obtaining preliminary data from 5 patients in control group that
      revealed mean (SD) of PaO2/FiO2 ratio at day 8 was 82(13). Assuming 30% difference between
      groups and by using G power software (version 3.1.3, Düsseldorf, Germany) with power 95% and
      alpha error and with doubling SD, total sample size was 57 patients rolled up to 60 for
      possible dropout.

      The data were examined for normality of distribution by Kolmogorov-Smirnov test (P <0.05).
      Continuous variables with normal distribution were expressed as mean ± SD (range) and were
      compared for significant differences between groups by using independent t-test. Paired
      t-test was used for intragroup comparisons between day-1 and day-8 for each group. Comparison
      of the means of normally distributed data was done using Two-way analysis (Two Factors (Group
      and Time)) of variance (between within mixed design) to test Group, Time and Group*Time
      interaction. The categorical variables were presented in numbers and were compared for
      significance by using chi squared (χ2) test or Fisher's exact test when appropriate. For all
      comparisons, a P value < 0.05 will be considered significant. IBM SPSS Advanced Statistics
      Version 22.0 was used for Data Analysis (SPSS Inc., Chicago, IL).
    

Intervention name(s): Unfractionated heparin; Streptokinase
Intervention type(s): Drug; Drug
Intervention description(s): Heparin or Streptokinase were nebulized by Aeroneb Pro@ Lab mesh nebulizer (Aerogen Limited, Galway, Ireland) which is incorporated within GE Healthcare's Engström Carestation ventilator (General Electric Company, Finland). Aeroneb nebulizer is a palladium vibrating mesh nebulizer. The central aperture plate of the nebulizer is 5mm in diameter and is perforated with 1000 precision formed holes, that vibrate at 128,000 times per second, to produce the particles with size 1-5 micron in diameter with average MMAD (Mean Mass Aerodynamic Diameter) is 2.1 microns. The nebulized medication (either streptokinase 250,000 IU or heparin 10.000 IU) was prepared in 3 ml volume of distilled water and nebulized for a period of 15 minutes every 4 hours.; Heparin or Streptokinase were nebulized by Aeroneb Pro@ Lab mesh nebulizer (Aerogen Limited, Galway, Ireland) which is incorporated within GE Healthcare's Engström Carestation ventilator (General Electric Company, Finland). Aeroneb nebulizer is a palladium vibrating mesh nebulizer. The central aperture plate of the nebulizer is 5mm in diameter and is perforated with 1000 precision formed holes, that vibrate at 128,000 times per second, to produce the particles with size 1-5 micron in diameter with average MMAD (Mean Mass Aerodynamic Diameter) is 2.1 microns. The nebulized medication (either streptokinase 250,000 IU or heparin 10.000 IU) was prepared in 3 ml volume of distilled water and nebulized for a period of 15 minutes every 4 hours.
Other intervention name(s): Heparin-Sodium Injection 5.000 I.U./ml (B BRAUN); Streptase (Aventis Behring GmbH, Marburg, Germany U.S)
Intervention MeSH terms: Heparin; Calcium heparin; Streptokinase
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: Group (I): Heparin group (n=20) received nebulized Heparin 10000 IU/4h. Group (II): Streptokinase group (n=20) received nebulized Streptokinase 250,000 IU/4h.
Group (III): Control group (n=20) received conservative management
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ARDS; Streptokinase; Heparin; Nebulization; Inhaled Thrombolytics; Inhaled Anticoagulation