Prospective, randomized, controlled trial assessing the effects of a driving pressure–limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan

,; Maia, Israel Silva; Medrado Jr, Fernando Azevedo; Tramujas, Lucas; Tomazini, Bruno Martins; Oliveira, Júlia Souza; Sady, Erica Regina Ribeiro; Barbante, Letícia Galvão; Nicola, Marina Lazzari; Gurgel, Rodrigo Magalhães; Damiani, Lucas Petri; Negrelli, Karina Leal; Miranda, Tamiris Abait; Santucci, Eliana; Valeis, Nanci; Laranjeira, Ligia Nasi; Westphal, Glauco Adrieno; Fernandes, Ruthy Perotto; Zandonai, Cássio Luis; Pincelli, Mariangela Pimentel; Figueiredo, Rodrigo Cruvinel; Bustamante, Cíntia Loss Sartori; Norbin, Luiz Fernando; Boschi, Emerson; Lessa, Rafael; Romano, Marcelo Pereira; Miura, Mieko Cláudia; Alencar Filho, Meton Soares de; Dantas, Vicente Cés de Souza; Barreto, Priscilla Alves; Hernandes, Mauro Esteves; Grion, Cintia Magalhães Carvalho; Laranjeira, Alexandre Sanches; Mezzaroba, Ana Luiza; Bahl, Marina; Starke, Ana Carolina; Biondi, Rodrigo Santos; Dal-Pizzol, Felipe; Caser, Eliana Bernadete; Thompson, Marlus Muri; Padial, Andrea Allegrini; Veiga, Viviane Cordeiro; Leite, Rodrigo Thot; Araújo, Gustavo; Guimarães, Mário; Martins, Priscilla de Aquino; Lacerda, Fábio Holanda; Hoffmann Filho, Conrado Roberto; Melro, Livia; Pacheco, Eduardo; Ospina-Táscon, Gustavo Adolfo; Ferreira, Juliana Carvalho; Freires, Fabricio Jocundo Calado; Machado, Flávia Ribeiro; Cavalcanti, Alexandre Biasi; Zampieri, Fernando Godinho

doi:10.62675/2965-2774.20240210-en

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Clinical Report • Crit. Care Sci. 36 • 2024 • https://doi.org/10.62675/2965-2774.20240210-en linkcopy

Prospective, randomized, controlled trial assessing the effects of a driving pressure–limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan

SCIMAGO INSTITUTIONS RANKINGS

Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear.

Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia.

Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance.

Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide.

Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Keywords:
Extracorporeal membrane oxygenation; Respiratory distress syndrome; Positive pressure respiration; Respiration, artificial; Ventilator-induced lung injury; Pneumonia

Outcomes
Primary	Ventilator-free days within 28 days from randomization or until hospital discharge measured as follows:
	D = zero (if the patient dies within 28 days in the hospital or remains on respiratory support with MV ≥ 28 days)
	D = 28 - x (if the patient is released from the hospital in < 28 days, where x represents the number of days with MV during hospitalization)
	The number of days on MV will be counted as every day the patient spent at least 12 hours on MV. If there is an interruption of MV followed by restart within 48 hours (extubation failure), the entire period will be computed as a single period. For tracheostomized patients, the same criterion is valid. One day of ventilation is computed whenever the patient persists more than 12 hours ventilated
Secondary	1. In-hospital mortality within 90 days
	2. ICU mortality within 90 days
	3. Need for rescue therapies (extracorporeal circulation, recruitment maneuver outside the study protocol, inhaled nitric oxide) within 28 days
Exploratory	1. Oxygenation, measured by the PaO₂/FiO₂ ratio during the first 3 days
	2. Driving pressure during the first 3 days
	3. Ventilatory ratio, defined as PaCO₂ multiplied by minute ventilation divided by 100 × predicted body weight in kilograms × 37.5, measured in the first 3 days
	4. Oxygenation index, defined by MAP × FiO₂ × 100 ÷ PaO₂, measured in the first 3 days
	5. Mechanical power, defined by energy transfer (0.098) x respiratory rate x tidal volume x [peak airway pressure – 0.5 x (plateau pressure – PEEP)], measured in the first 3 days
	6. ICU-free days in 28 days
	7. ICU length of stay
	8. Hospital length of stay
Safety outcomes	1. Occurrence of barotrauma (subcutaneous emphysema, pneumothorax, or pneumomediastinum)
Safety outcomes	2. Other serious adverse events possibly related to MV within 28 days

Inclusion criteria

Exclusion criteria

Patients with community acquired pneumonia on invasive MV (pneumonia must have been the cause for initiation of mechanical ventilation)
Acute bilateral infiltrate of nonexclusively cardiogenic origin, at the judgment of the attending physician
One of the below:
1. Inspired oxygen fraction above 50% with PEEP of at least 8cmH₂O to maintain saturation above 93%
  
  OR
2. PaO₂/FiO₂ < 200 with PEEP > 5cmH₂O

Patients with inclusion criteria for more than 36 hours
Intracranial hypertension or acute neurological disease (stroke, subarachnoid hemorrhage
Refusal of the legal representative
Patients under 18 years of age
Patients considered not to be candidates for measures of full invasive support at the time of randomization, that is, patients who have some clear indication, at the time of randomization, for not instituting other invasive support measures
Patient with bronchial fistula or barotrauma
Patients with a history of home use of oxygen by chronic respiratory disease

Variable	ARDSnet strategy	STAMINA strategy
Baseline adjustments
Ventilator mode	Volume assist-control	Volume assist-control
Plateau pressure (cmH₂O)	≤ 30	≤ 30
Initial tidal volume (mL/kg of predicted body weight)	6 or lower in order to maintain Pplat ≤ 30cmH₂O	6 or lower in order to maintain Pplat ≤ 30cmH₂O
Respiratory rate setting needed to achieve pH ≥ 7.2	Up to 35 breaths/minute	Up to 35 breaths/minute
Oxygenation goal	SpO₂ 90 - 94% and PaO₂ ≥ 60mmHg	SpO₂ 90 - 94% and PaO₂ ≥ 60mmHg
Flow wave format	Descending or squared	Descending or squared
Inspiratory pause	Maximum 0.5 seconds	Maximum 0.5 seconds
Flow (L/minute)	30 - 60	30 - 60
I:E	1:1 - 1:2	1:1 - 1:2
PEEP titration adjustments
PEEP titration*	Low PEEP - FiO₂ table	Incremental phase: up to PEEP of 20cmH₂O Decremental phase: reduction in PEEP in steps of 2cmH₂O PEEP titrated by best static respiratory system compliance
Peep titration stopping criteria		Peak airway pressure ≥ 40cmH₂O Pplat pressure ≥ 33cmH₂O Unstable cardiac arrythmias increase vasopressor dose > 20micg/minute†
Decremental phase		Inspiratory pause of 2 seconds at the end of each step to measure compliance value up to PEEP of 8cmH₂O‡ Best PEEP will be the immediately previous value of a drop in compliance by at least 2mL/cmH₂O in one decrease or by at least 1mL/cmH₂O in two sequential decreases‡
Driving pressure	Not allowed to be controlled	Controlled to keep ≤ 14
Additional adjustments	If plateau pressure > 30cmH₂O: – Reduction of tidal volume up to 4mL/kg of predicted body weight, followed by reduction in PEEP in steps of 2cmH₂O (if not solved with reduction of TV) – If necessary, is permitted to increase RR up to 40 breaths/minute if pH < 7.2 and PaCO₂ > 70mmHg with auto PEEP not greater than 2cmH₂O	If DP > 14 and/or plateau pressure > 30: – Reduction of tidal volume up to 4mL/kg of predicted body weight, followed by reduction in PEEP in steps of 2cmH₂O (if not solved with reduction of tidal volume) – If necessary, is permitted to increase RR up to 40 breaths/min if pH < 7.2 and PaCO₂ > 70mmHg with auto PEEP not greater than 2cmH₂O
Mechanics monitoring	Two times per day apart 8 hours from each assessment	Two times per day apart 8 hours from each assessment
Sedation	Deep sedation with RASS -5 and neuromuscular blockade in the first 72 hours if patient maintains in controlled ventilation. After this time, light sedation (RASS 0 to -2)	Deep sedation with RASS -5 and neuromuscular blockade in the first 72 hours if patient maintains in controlled ventilation. After this time, light sedation (RASS 0 to -2)
New titration procedure in less than 24 hours	Pplat > 30cmH₂O, change body position (prone or supine), circuit depressurization	Pplat > 30cmH₂O and/or DP > 14cmH₂O, change body position (prone or supine), circuit depressurization
Titration routine	D0, D1, D2, D3 24 hours apart and any time if necessary	D0, D1, D2, D3 24 hours apart and anytime if necessary
PEEP weaning after 24 hours with PaO₂/FiO₂ ratio > 200	Decrease 2cmH₂O at 8 hours intervals	Decrease 2cmH₂O at 8 hours intervals
Ventilation weaning	FiO₂ ≤ 50% with PEEP ≤ 10cmH₂O	FiO2 ≤ 50% with PEEP ≤ 10cmH₂O

	D-1	D0	D1	D2	D3	D28	ICU discharge	Hospital discharge
Eligibility criteria	X
Randomization		X
Informed Consent	X
Time between ICU admission and randomization		X
Time of MV before randomization		X
Date of birth		X
Ventilatory parameters		X	X	X	X
Arterial blood gas		X	X	X	X
Sex at birth	X
Height	X
Comorbidities	X
Pneumonia etiology	X
Vasopressor dose		X	X	X	X	X	X
RASS at randomization		X
SAPS 3 parameters		X
Protocol support: interventions		X	X	X	X
Prone position		X	X	X	X		X
Rescue therapies		X	X	X	X		X
Vasopressors use		X	X	X	X		X
Creatinine	X	X	X	X	X
Total bilirubin	X	X	X	X	X
Date and time of extubation			X	X	X	X	X
Data and time of reintubation			X	X	X	X	X
Vital status at ICU discharge						X	X
Date of death						X	X	X
Number of days in use of MV in hospital						X	X	X
Date of tracheostomy						X	X	X
Data of ICU discharge							X
Data of hospital discharge								X
Vital status on hospital discharge								X

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E-mail: ccs@amib.org.br

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[TFN1] MV - mechanical ventilation; ICU - intensive care unit; PaO₂ - partial pressure of arterial oxygen; FiO₂ - fraction of inspired oxygen; PaCO₂ - partial pressure of arterial carbon dioxide; MAP - mean airway pressure; PEEP - positive end-expiration pressure.

FiO₂ (%)	30	40	40	50	50	60	70	70	70	80	90	90	90	100
PEEP (cmH₂O)	5	5	8	8	10	10	10	12	14	14	14	16	18	18 - 24