Non-invasive Ventilation in Terminally Ill Cancer Patients
Condition: Cancer
MeSH terms: Respiratory Insufficiency
Study type: Interventional
Phase: Phase 4

Summary: 
      The occurrence of acute respiratory failure (ARF) is often seen by oncologists as a terminal
      phase of the disease, this view being based on studies reporting limited survival at
      considerable costs in such patients. A large proportion of cancer patients with severe
      respiratory failure are denied admission to an ICU because intensive care specialists are
      aware that intubation and mechanical ventilation are both strong predictors of mortality in
      critically ill cancer patients. This holds particularly true in the subset of patients who
      are not receiving chemotherapy or radiotherapy because of the advanced stage of their
      disease, and who are also not affected by an episode of ARF, related to a reversible cause.

      These patients often receive oxygen therapy and morphine in an attempt to improve oxygenation
      and/or relieve the ensuing dyspnea.

      Non-invasive mechanical ventilation (NIV) is now the first line treatment of ARF in selected
      populations (e.g., those with COPD) and has been used sporadically as a potential treatment
      of acute respiratory failure in patients with a "do-not-intubate" order. The International
      Consensus Conference on Intensive Care Medicine stated that "the use of NIV may be justified
      in selected patients who are "not to be intubated" and may provide patient comfort and
      facilitate physician-patient interaction." "Early" NIV has been successfully used so far in
      cancer patients only to prevent intubation among those with hematologic malignancies, while a
      pilot study has assessed the feasibility of NIV also as a "palliative" treatment of end-stage
      solid cancer patients. So far we are lacking data about the "pure palliative" effects of
      NIV,in patients with end-stage solid cancer.

      The aim of this multicenter randomised study will be to evaluate on a large scale the
      feasibility, clinical efficacy and impact on quality of life and dyspnea of NIV versus
      standard medical in patients with respiratory failure, not related to a reversible cause, and
      solid cancer needing palliative care treatment.
    

Detailed description: 
      Rationale:

      The occurrence of ARF is often seen by oncologists as a terminal phase of the disease, this
      view being based on studies reporting limited survival at considerable costs in such patients
      (1, 2, 3, 4, 5, 6). A large proportion of cancer patients with severe respiratory failure are
      denied admission to an ICU because intensive care specialists are aware that intubation and
      mechanical ventilation are both strong predictors of mortality in critically ill cancer
      patients (1, 3, 5, 7). This holds particularly true in the subset of patients who are not
      receiving chemotherapy or radiotherapy because of the advanced stage of their disease, and
      who are also not affected by an episode of ARF, related to a reversible cause.

      These patients often receive oxygen therapy and morphine in an attempt to improve oxygenation
      and/or relief the ensuing dyspnea.

      Non-invasive mechanical ventilation (NIV) is now the first line treatment of ARF in selected
      populations (e.g. those with COPD) (8) and has been used sporadically as a potential
      treatment of acute respiratory failure in patients with a "do-not-intubate" order (9). The
      International Consensus Conference on Intensive Care Medicine stated that "the use of NIV may
      be justified in selected patients who are "not to be intubated" and may provide patient
      comfort and facilitate physician-patient interaction" (8). "Early" NIV has been successfully
      used so far in cancer patients only to prevent intubation among those with hematologic
      malignancies (10), while a pilot study has assessed the feasibility of NIV also as a
      "palliative" treatment of end-stage solid cancer patients (11). So far we are lacking data
      about the "pure palliative" effects of NIV,in patients with end-stage solid cancer.

      Aim. The aim of this multicenter randomised study will be to evaluate on a large scale the
      feasibility, clinical efficacy and impact on quality of life and dyspnea of NIV vs standard
      medical in patients with respiratory failure, not related to a reversible cause, and solid
      cancer needing palliative care treatment.

      Study design Multicenter randomised study. The sample size has been estimated on about 50
      patients for each group (i.e. hypercapnic and hypoxic ARF, with different randomisation) ,
      TOTAL= 200 pts based on the survival rate of cancer patients with acute respiratory failure
      and DNR order (18%) (2) versus that of patients treated with NIV in a pilot study (57%) (14).

      You will receive separate random sequence according to the degree of PaCO2. Methods
      Consecutive solid cancer patients with ARF, in which palliative treatment is the only one
      indicated, and: 1) have signed or expressed a DNI order or 2) judged by the attending
      physician having < 6 months or life expectancy (Mc Crabe index= class 3-4) or PPI > 5
      (Palliative Prognostic Index) and not deserve to be intubated by a "blind" ICU physician.

      A brief trial lasting < 5 minutes will be performed before randomization using either NIV or
      Venturi mask to assess the willing of the patient to be enroll in the protocol (since they
      are not familiar with both techniques).

      Major criteria for enrollment into the study were one of the following: 1) PaO2/FiO2 ratio <
      250 + one of the two following: 1) dyspnea with recruitment of the accessory muscles and/or
      abdominal muscles recruitment and 2) respiratory rate > 30 b/ min. Hypercapnia per se is not
      a criteria of inclusion, but it is not an exclusion criteria if chronic.

      Exclusion criteria were: potentially reversible causes of exacerbation such as (CPE,
      pneumonia or exacerbation of chronic pulmonary disorders) coma, refusal of treatment,
      inability to protect the airways, an agitated or uncooperative patient, anatomical
      abnormalities interfering with mask fit, uncontrolled cardiac ischemia or arrhythmias,
      failure of more than two organs.

      NIV settings. The positive end-expiratory pressure initially set at 5 cm H2O and could be
      increased by 1 cm H2O until a brisk increase in oxygen saturation (SaO2) is observed, whereas
      the inspiratory pressure support is initially set at 10 cm H2O and then increased in
      increments of 2 cm H2O up to the maximum tolerated.

      For patients with hypercapnic respiratory failure the inspiratory pressure is adjusted
      according to the patient's tolerance, with the external PEEP not exceeding 6 cm H2O.

      In any case both settings are aimed to achieve a respiratory rate < 25 breaths/min, no
      evident sign of wasted respiratory efforts on the flow trace, expired VT > 6 mL/kg and < 10
      mL/kg and satisfactory gas exchange (i.e. SaO2 > 90%, with pH > 7.35). The inspiratory
      trigger is set at the minimal level to avoid auto-triggering or that delivered by default by
      the ventilator, while the initial pressurization rate was adjusted according to subjective
      comfort. The fractional concentration of oxygen is such to achieve an SaO2 > 90%.

      Standard Medical Therapy The usual standard of care. Sedatives and morphine could be
      administrated, but the dosage should be recorded in a data sheet (se data base)

      The following variables will be recorded:

        -  Age, sex, chronic health care status measured using the McCrabe index, the number of
           co-morbid conditions, and the SAPS II index (Simplified Acute Physiology Score).
           Neurological status was assessed by the Kelly and Matthay scale, which is specifically
           designed for respiratory patients and Glasgow coma scale

        -  Causes of ARF (if apparent)

        -  Type and cancer status before respiratory failure

        -  Arterial blood was withdrawn from a radial artery at baseline and at fixed intervals
           (see protocol) and analyzed immediately (ABL 300 and ABL 625 Radiometer, Copenhagen,
           Denmark)

        -  Breathing frequency and hemodynamic variables (i.e. heart rate and blood pressure)

        -  Dyspnea score measured with a modified Borg scale

        -  Symptom Distress Scale (at enrollment and at discharge) as a surrogate of QoL "easy"
           measurements

        -  Palliative Prognostic Index (PPI)

        -  Types and dosages of sedatives or morphine

        -  Total days on NIV

        -  Total days of hospital stay

        -  Mortality at hospital discharge, at 6 and 12 months

        -  Causes of death ABG, respiratory rate and hemodynamic variables, Kelly score, Glasgow
           scale, PPI, Mc Cabe and dyspnea will be recorded at fixed intervals: baseline (T0), 1 h
           after beginning the treatment (T1), after 3 h (T2), after 24 h (T3), after 48 h (T4) and
           at discharge from the hospital (T5).

      The SAPS II score is recorded at the end of the first day of admission. QoL questionnaire
      will be recorded at enrollment and hospital discharge Primary outcomes of the study were:
      hospital death, treatment failure, use of morphine or other sedatives and dyspnea and QoL
      scores. Treatment failure will be considered the "theoretical need of intubation"= MEET the
      INTUBATION CRITERIA defined as: 1) intolerance to NIV (only NIV group clearly) 2) no changes
      or worsening of ABG after 2 h of ventilation (pH < 7.35 or 20% decrease in PaO2/FiO2 ratio)
      3) alteration of neurological status (1 point higher than admission in the Kelly score) 4)
      gasping for air or come. Secondary outcomes were: 6-month and 12-month mortality, the
      duration of hospital stay, changes of some physiological variables over time (i.e. ABG,
      respiratory rate) and QoL.
    

Intervention name(s): non invasive ventilation (NIV)
Intervention type(s): Other
Intervention description(s): NIV is a form of mechanical ventilation delivered through a face or nasal mask and therefore not requiring endotracheal intubation. It will be delivered according to the compliance and tolerance of the patients.
Other intervention name(s): oxygen therapy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Supportive Care
Keywords: Solid cancer patient; Non-invasive ventilation; Acute Respiratory Failure