The ROTAtional-USE of Interface STUDY

Study Overview
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Brief Summary
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In this trial investigators will explore if a protocolized rotational use of interfaces i.e., masks, during noninvasive positive pressure ventilation (NPPV) compared to standard care is clinically effective and cost-effective in reducing the incidence of pressure sores in patients with hypercapnic acute respiratory failure (AHRF) treated continuously i.e., for more than 24 hours, with NPPV (to avoid intubation, as alternative to invasive ventilation and after early extubation and weaning).

Detailed Description
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Objectives: Primary objective To determine if a protocolized rotational use of interfaces during NPPV compared to standard care is effective in reducing the development of new pressure sores in patients with hypercapnic ARF treated continuously i.e., for more than 24 hours, with NPPV (to avoid intubation, as alternative to invasive ventilation, and during early extubation and weaning). Measurements of effectiveness include: The primary effectiveness outcome will be the proportion of patients who develop new pressure sores at 36 hours from randomization. Secondary outcomes will be the onset of pressure sores measured at different time points (12, 24, 36, 48, 60, 72, 84, 96 hours), number and stage of pressure sores and comfort measured at the same time points of the primary outcome. The location of pressure sores per patient will be also collected. The study will also monitor the number of patients that will interrupt NPPV treatment for discomfort, the presence of eyes irritation, the adherence to the protocol (duration of NPPV treatment/day, interface change, hygiene protocol application) and the presence of vasoactive medications. Variables like nutritional status at randomization, Braden Scale and Frailty Index at hospital entrance, total duration of NPPV from randomization, duration of NPPV per day, hospital length of stay and in-hospital mortality will be recorded. The economic impact of the protocolized rotational use of interfaces will be assessed through a cost-effectiveness analysis evaluating the additional costs needed to avoid a pressure sore due to the planned intervention as well as the costs needed to actively treat skin ulcers due to failure of preventing measures in both groups of patients. Randomization: A 1:1 stratified randomization will be performed to assigned patients to the protocolized rotational use of interfaces (experimental treatment) or standard of care (comparison group). Subjects will be stratified according to center and ward (intensive care unit, intermediate respiratory care unit, respiratory medicine service or internal medicine service according to hospital organization). Within each stratum, subjects will be randomly assigned to one of the treatments using a predefined randomization list. To ensure masking, randomization schemes will be input directly into the Research Electronic Data Capture (REDCap) system. In the treatment group, the first interface will be randomly assigned. Randomization scheme will be input directly into REDCap system. Study treatments: In both arms, the treatment according to the assigned protocol will be continued until patients require NPPV. Skin underneath the mask and occipital region, will be inspected every 12 hours to check for any possible damage by assessors blind to the study protocol. Assessors (physicians or nurses) will be instructed to recognize pressure sores and their stage. Before starting the study recruitment, the assessors will take a test aiming to correctly stage 10 pressure sores. Only assessors who will recognize all of them, participate to the study. Test will be taken trough google forms and results will be registered for the study. To minimize detection bias, assessors will not participate to the care of the patient and will be blind on patient group of assignment. If a pressure sore will be detected, physician in charge of the patient will be promptly informed and a note will be written on the nursing record. Pressure sores will be stage as follows: stage I: A reddened, painful area on the skin that does not turn white when pressed. This is a sign that a pressure ulcer may be forming. The skin may be warm or cool, firm or soft. stage II: The skin blisters or forms an open sore. The area around the sore may be red and irritated. stage III: The skin now develops an open, sunken hole called a crater. The tissue below the skin is damaged. You may be able to see body fat in the crater. stage IV: The pressure ulcer has become so deep that there is damage to the muscle and bone, and sometimes to tendons and joints. In addition to the 4 main stages for pressure sores, there are 2 others: 1) Unstageable is when you can't see the bottom of the sore, so you don't know how deep it is; 2) Suspected Deep Tissue Injury when the surface of the skin looks like a Stage 1 or 2 sore, but underneath the surface it's a Stage III or IV. Discomfort due to the mask will be evaluated every 12 hours using a 5-level Likert-like scale to answer the questions How is your level of discomfort related to the mask? (in Italian). The extremes of the scale are 1 - no discomfort and 5 - unbearable discomfort, with three intermediate levels (light discomfort, moderate discomfort, and intense discomfort). NPPV standard management: In both arms, standard care (diagnostic tests, administration of systemic therapy including antibiotics, steroids and inhaled bronchodilator therapy and hemodynamic management) will be applied according to the clinical practice of each institution. The right size of the mask will be selected according to the indications provided by the manufacturer. The mask straps will be adjusted according to the  two-finger rule  not to tighten to hard the headgear. Following international guidelines, patients who benefit from NPPV during the first four hours of treatment will receive NPPV for as long as possible during the first 24 hours. Target saturation range will be 88-92% either spontaneously breathing or when receiving NPPV. NPPV treatment will last until the acute cause has resolved, commonly about two to three days. NPPV will be started as suggested by the British Thoracic Society/Intensive Care Society Guideline for the ventilatory management of AHRF in adults. NIV will be started when pH <7.35 and PaCO2 >6.5 kilopascal (kPa) persist or develop despite optimal medical therapy, targeting an oxygen saturation of 88-92%. Blood gas exchange will be performed before starting NPPV treatment and after 2 hours from its starting and thereafter, when clinically indicated. NPPV will be initially set in a pressure support mode with a ventilator designed specifically to deliver NPPV or with an ICU ventilator provided with noninvasive ventilation mode. Expiratory positive airway pressure (EPAP) will be set at 3-5 Centimeters of Water (cmH2O) while inspiratory positive airway pressure (IPAP) will be set to achieve adequate augmentation of chest/abdomen movement with an expiratory tidal volume of 6-8ml/kg and a reduction of respiratory rate (< 30 breath/min) together with a good patient ventilator interaction (i.e., pressure-flow curve monitoring). The presence of active humidification will be left to the choice of the doctor in charge for that patient, although heated humidification should be considered if the patient complains of mucosal dryness or if respiratory secretions are thick and tenacious. The weaning strategy will be documented in the medical and nursing records. The following might be use as general indication: continue NPPV for 16 hours on day 2; 12 hours on day 3 including 6-8 hours overnight use; NPPV may be discontinued on day 4 unless continuation is clinically indicated. The suggested monitoring during NPPV will be continuous peripheral oxygen saturation, intermittent measurement of PaCO2 and pH, ECG monitoring in the patient with a pulse rate >120 bpm or if there is dysrhythmia or possible cardiomyopathy. As guidelines recommend keeping the skin dry and clean under medical equipment, a protocol for skin will be adopted by all centers included in the study. If a patient needs prolonged continuous NPPV, brakes will be programmed and annotated in the case report form, in case of instability, interface will be removed for about 10 minutes only to ensure oxygenation. When signs of skin trauma become apparent, a barrier dressing and a strategy of regular breaks and alternating between two interface types will be used. In case of mask-related rash even in the absence of allergy, topical steroids may be indicated and/or antibiotics if the wound becomes infected. In case NPPV causes severe gastric distension, a nasogastric tube will be inserted. Early extubation and weaning with NPPV: According to the guidelines, NPPV is recommended to aid weaning from invasive mechanical ventilation in patients with AHRF, secondary to COPD and to other causes of AHRF, when local expertise in its use exists. Patients during invasive mechanical ventilation will be treated according to the clinical guidelines. After setting maximum medical treatment, once with ventilation in a controlled mode pH and PaCO2 will be normalized in presence of neurological, hemodynamic and respiratory stability, patients will be extubated and put in NPPV. The ventilator will be set with the same positive end expiratory pressure (PEEP) and inspiratory pressure support (PS) level applied during invasive mechanical ventilation, setting the fastest pressure rise time at least during the first 24 hours after extubation. Then, NPPV will be gradually withdrawn if patients tolerated spontaneous breathing until they could permanently sustain spontaneous breathing. Data collection: A RedCap database will be set up to collect the information needed for the study. The database will be made of 10 sheets: the first one collecting the baseline demographic and clinical characteristics of the patients and the others will be made to collect the outcomes' information at each time point and a discharge sheet including information on the overall treatment. The randomization procedure will be implemented within Redcap. Sample size: Given a type I error of 0.05, a power of 0.8, an expected proportion of patients who develop pressure sores in the control group of 23% and an expected dropout rate of 5%, 239 subjects per group are estimated to identify a 10% absolute difference in the proportion of patients developing pressure sores between intervention and control groups measured at 36 h from randomization. Statistical analysis: The analyses will be performed according to the intention to treat principle. Descriptive statistics will be calculated to summarized patient characteristics collected at study entry according to randomization group. Categorical variables will be reported as absolute frequencies and percentages and continuous variables as mean and standard deviation or median first and third quartiles if not normally distributed according to the Shapiro-Wilks test. The raw risk of pressure sore will be calculated ad each time point as the ratio between the number of subjects who developed a pressure sore at the time point divided by the number of subjects undergoing NPPV at the time point. Patients having a planned break at the time-point considered, but not been weaned off the NPPV treatment yet, will be considered undergoing NPPV. Mixed effect logistic regression models will be used to estimate the risk of pressure sores and the difference between interfaces including a random intercept to account for clustering of the subjects within center and repeated measures within patients. The response variable will be the presence/absence of pressure sores and the independent variables the treatment, time (12, 24, 36, 48, 60, 72, 84, 96) and their interaction. The marginal and center specific predicted probabilities estimated by the model will provide the incidence of pressure sores at different times and overall. The inclusion of time as covariate will allow to test the presence of a time trend in incidence of pressure sores and to investigate the variation of time trends according to treatment group. Regarding the number of pressure sores, different mixed effect Poisson regression models will be applied: one for each time point to estimate the average number of pressure sores at each time point and a model in which only the highest number of pressure sores will be considered for each patient. Time will be included as offset to evaluate the average number of pressure sores per day. The grade and location of pressure sores will be summarize using descriptive statistics at each time point. Regarding the economic evaluation. the incremental cost effectiveness ratio (ICER) will be calculated considering two outcomes: i) the proportion of pressure sores and ii) the comfort. The ICER as the ratio between the difference each outcome in the two groups (difference in the proportion of pressure sores or comfort score) and the difference in the average cost for each treatment allowing to evaluate the incremental costs needed to reduce of 1 point the outcomes thanks to the rotational use of interfaces. The confidence intervals of the ICER will be calculated using the non-parametric bootstrap method, specifically the 2.5th and 9.75th percentiles of the bootstrap distribution of ICER will be considered as the lower and higher limits of the confidence interval. The cost-effectiveness acceptability curve will be also drawn to evaluate the probability of the intervention to be cost-effective considering different thresholds. Safety monitoring: A single interim analysis will be performed when a number of patients equal to two-thirds of the predefined sample are randomized and complete the study. Early stopping criteria will be a predetermined 2-sided p value < 0.01 for the rejection of the null hypothesis that the strategies are equivalent in terms of rate of pressure sores.

Official Title
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A Pragmatic Open Label, Multi-center, Spontaneous, No-profit, Randomized Controlled Clinical Trial With Non-significant Risk Medical Device on the Rotational Use of Interfaces Versus Standard of Care for Patients Treated With NPPV for AHRF.

Conditions
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Pressure Ulcer, Noninvasive Positive Pressure Ventilation, Acute Hypercapnic Respiratory Failure

Intervention / Treatment
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* Procedure: Protocolized rotational use of interfaces
* Procedure: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age>18 years old Patients with chronic obstructive pulmonary disease (COPD) exacerbation or with AHRF of a different etiology needing NPPV to avoid intubation (pH < 7.35 with PaCO2 > 45 mmHg and partial pressure of oxygen (PaO2) < 65 mmHg plus respiratory rate > 25 breath/min with clinical signs of respiratory muscle distress); or as alternative to invasive ventilation with a forecast of treatment of at least 24 hours admitted to the intensive care unit, intermediate respiratory care unit, respiratory medicine service or internal medicine service according to hospital organization; or patients with chronic pulmonary disease intubated for a COPD exacerbation or for pneumonia who are early extubated and weaned in the intensive care unit with NPPV with a forecast of treatment of at least 24 hours. Exclusion Criteria: Patient with skin breakdown or non-blanchable erythema in one of the following areas i.e., nasal bridge, nasolabial fold, cheek or scalp at hospital entrance; Patients who refuse to consent to the study protocol; Patient known to be pregnant; Patients with contraindication to NPPV (lack of spontaneous breathing; gasping; anatomical or functional airway obstruction; gastrointestinal bleeding or ileus; coma; massive agitation; massive retention of secretions despite bronchoscopy and aggressive physiotherapy; hemodynamic instability (cardiogenic shock, myocardial infarction); status post upper gastrointestinal surgery); Patients entering hospital with asthma, with cardiogenic pulmonary edema; Patients with tracheostomy; Patients needing NPPV only for palliation of symptoms (relief of dyspnea) i.e., category 3 defined by the Task Force on the Palliative Use of NPPV of the Society of Critical Care Medicine; Use of high flow nasal cannula integrated with NPPV for weaning strategy; Pre-existing skin erythematosus diseases; Known hypersensitivity to skin protective devices (i.e., polyurethan films, colloids, foams); More than 2 hours of NPPV application before randomization; Patients already included in the study protocol at an earlier stage of the hospitalization; Refuse to wear NPPV interface due to comfort;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>In the intervention group the first mask will be randomly chosen between the two most used in that center among those available i.e., oro-nasal, total face or hybrid mask. Thereafter, NPPV mask will be changed every 6 hours, alternating the two different interfaces. Patients wearing oro-nasal masks will receive protective dressings on nasal bridge before starting NPPV. | Procedure: Protocolized rotational use of interfaces<br>* The NIV mask will be changed every 6 hours, alternating two different interfaces between the two most used in that center among those available i.e., oro-nasal, total face or hybrid mask.<br>|
| Active Comparator: Control group<br>In the control group, mask will be chosen according to the standard of care of the participating centers among the three types of masks available i.e., oro-nasal, total face or hybrid mask. Patients wearing oro-nasal masks will receive protective dressings on nasal bridge before starting NPPV. Interface will be changed in case of discomfort judged by the patient as unbearable or in case of the presence of a pressure sore. | Procedure: Standard of care<br>* Mask will be chosen according to the standard of care of the participating centers among the three types of masks available i.e., oro-nasal, total face or hybrid mask. Interface will be changed in case of discomfort judged by the patient as unbearable or in case of the presence of a pressure sore.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who develop new pressure sores | To determine if a protocolized rotational use of interfaces during NPPV compared to standard care is effective in reducing the development of new pressure sores in patients with AHRF treated continuously i.e., for more than 24 hours, with NIV (to avoid intubation, as alternative to invasive ventilation, and during early extubation and weaning). | At 36 hours from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Onset of pressure sores at different timepoints | To determine if a protocolized rotational use of interfaces during NPPV compared to standard care is effective in reducing the development of new pressure sores in patients with AHRF treated continuously i.e., for more than 24 hours, with NPPV (to avoid intubation, as alternative to invasive ventilation, and during early extubation and weaning). | At 12, 24, 36, 48, 60, 72, 84, 96 hours from the randomization | 
| Number, stage and location of pressure sores | Pressure sores will be counted, staged (Stage I, II, III, IV, Unstageable, Suspected Deep tissue Injury) and localized. | At 12, 24, 36, 48, 60, 72, 84, 96 hours from the randomization | 
| NPPV treatment interruption | The study will also monitor the number of patients that will interrupt NPPV treatment for discomfort, the presence of eyes irritation, the adherence to the protocol (duration of NPPV treatment/day, interface change, hygiene protocol application). | At 12, 24, 36, 48, 60, 72, 84, 96 hours from the randomization | 
| Cost-effectiveness analysis | The economic impact of the protocolized rotational use of interfaces will be assessed through a cost-effectiveness analysis evaluating the additional costs needed to avoid a pressure sore due to the planned intervention as well as the costs needed to actively treat skin ulcers due to failure of preventing measures in both groups of patients. | At 12, 24, 36, 48, 60, 72, 84, 96 hours from the randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotational use of noninvasive interfaces