Refractory Hypoxemia Clinical Trial
Official title:
Extracorporeal Membrane Oxygenation Support for Middle East Respiratory Syndrome Induced Respiratory Failure
A highly pathogenic human coronavirus causing respiratory disease emerged in Saudi Arabia in
2012. This viral infection termed Middle East respiratory syndrome coronavirus (MERS-CoV) is
associated with high mortality rate in approximately 36% of reported patients.
The World Health Organization (WHO) reported 1,374 laboratory-confirmed worldwide
infections, including at least 490 related deaths, from September, 2012, to July 24, 2015.2
The higher incidence of MERS-CoV infections in Saudi Arabia may be related to multiple
factors, including seasonality, increased proactive screening, poor infection control
measures, low relative humidity, and high temperature.
Infected patients with MERS-CoV usually have abnormal findings on chest radiography, ranging
from subtle to extensive unilateral and bilateral abnormalities. MERS progresses rapidly to
respiratory failure, in approximately 2/3 of infected patients, which has a high mortality
rate, particularly in immunocompromised patients.
Extracorporeal membrane oxygenation (ECMO) has emerged as a rescue therapy in patients with
refractory hypoxemia during the H1N1 epidemic.The use of veno-venous (VV)-ECMO provides
respiratory support for patients with respiratory failure, whereas the use of veno-arterial
(VA)-ECMO could be helpful in those with cardiorespiratory failure.10 However, the survival
rate of the infected patients with H1N1 who required the use of ECMO varies considerably
among the Caucasian and Asian countries (90% survival in Sweden and 83% in the UK13 vs. 35%
in Japan). This large discrepancy could be explained with lack of satisfactory equipment,
therapeutic guidelines, training of staff, and effective systems allowing patient transfer
to the dedicated ECMO centres.
Guery and co-investigators described the use of ECMO in two French patients with
cardiorespiratory failure secondary to MERS-CoV infection.This has been extended for
treatment of refractory hypoxemic respiratory failure during the Saudi MERS-CoV outbreak.
The Saudi Ministry of Health has implemented a national ECMO program since 2014 in three
major cities including Jeddah, Al Madinah and Riyadh which have most of the reported
infected cases with MERS-CoV. The Saudi ECMO program provides a rapid transportation chain
system (Medevac system), adequate number of intensive care beds and ECMO machines, and
highly trained perfusionists and staff.
The investigators hypothesized that the early use of ECMO for treatment of severe acute
hypoxemic respiratory failure, defined as a ratio of the PaO2 to the fraction of inspired
oxygen (PaO2/FiO2 ratio) less than 80 despite optimized ventilator management, in infected
patients with MERS-CoV, would be associated with reduced in-hospital mortality rate.
Patient Selection:
The investigators obtained a centralized ethics approval from the Ministry of Health to
avoid delays and to facilitate the conduct of this timely important study. Eligible patients
or their legal guardians were contacted to request their participation and obtaining of
their written consent.
Patients who are 18 years or older who received ECMO support for MERS-CoV associated
hypoxemic respiratory failure were included. MERS-CoV infection is defined using the WHO
case definition. A positive polymerase chain reaction (PCR) on nasopharyngeal or
oropharyngeal swabs, sputum, tracheal aspirate, or bronchial alveolar lavage is sufficient
to establish the diagnosis of infection.
Description of Standardized National Protocol
The participating Saudi centers had adopted a standardized protocol based on the
evidence-based guidelines for the treatment of acute respiratory distress syndrome (ARDS)
associated with the H1N1 virus infection using low-tidal volume, lung-protective mechanical
ventilation as the initial strategy. A lung-protective strategy was applied using volume
assist-control mode, pressure-controlled synchronized intermittent mandatory ventilation
mode or pressure-controlled ventilation mode, with a tidal volume of 6 to 8 mL/kg of
predicted body weight and variable FiO2 and the positive end-expiratory pressure (PEEP) to
achieve arterial oxygen saturation (SaO2) from 88% to 95% or a partial pressure of oxygen
(PaO2) of 55 to 80 mm Hg.Then a full spectrum of ventilator modes, including airway pressure
release ventilation, prone ventilation and high frequency ventilation was used.
If, despite and after the above measures, a patient cannot achieve a ratio of the PaO2 to
the fraction of inspired oxygen (FiO2) (PaO2/FiO2 ratio) greater than 100 on ''safe''
settings (i.e. FiO2 less than 80%, peak inspiratory (Ppk) and plateau (Ppl) pressures less
than 40 and 35 cm H2O, respectively and tidal volume less than 6 to 8 ml/kg), the patient
was assessed for eligibility for ECMO support. Veno-venous (VV-ECMO) was used for
respiratory support for those with respiratory failure, whereas the veno-arterial (VA-ECMO)
was used for those with cardiorespiratory failure.
Once adequate ECMO support was instituted, the ventilator was set to low ''recruitment''
settings. When a patient began to show evidence of pulmonary recovery, the ECMO support was
weaned off with gradual reducing blood flow, gas flow, and FIO2 over the membrane, when the
PaO2/FiO2 ratio was greater than 200 with an FiO2 of 50% and pressures less than 38 cm H2O.
Selection of Historical Cohort
The control group was identified retrospectively, patient who did not receive ECMO due to
lack of access but who fulfill the criteria for initiating treatment will be selected.
Data Collection:
National database was used to identify patients who met our eligibility criteria. Trained
research investigators collected the relevant datafor eligible patients. The investigators
used pre-designed case report forms (CRF) to abstract data. The investigators collected data
on: baseline characteristics including age, sex, height, weight, and ethnicity, as well as
the presence of a number of predefined comorbidities, ICU pharmacologic interventions,
ventilation data including days of mechanical ventilation, ventilation mode, and mean values
of tidal volumes, positive end expiratory pressure (PEEP) levels, FiO2, and PaO2/FiO2 ratio
before, during and after the initiation of ECMO support, and the administration of antiviral
and antibiotic medications, the type, gas flow (liter/min), blood flow (liter/min/m2) and
duration of ECMO, circulatory support, length of ICU and hospital stays, mortality during
hospital stay.
In addition, the need for renal replacement therapy; tracheostomy; bacterial co-infection
duringICU stay; ventilator-associated pneumonia was recorded.
The investigators will document whether the ECMO treatment was initiatedatthe participating
centeror whether the patient was transferred to an ECMO center.
Data on eligible patients was recorded retrospectively during ICU stay. Data on hospital
discharge or death will be recorded as well.
Statistical Analysis:
Descriptive data were reported as numbers and percentages for dichotomous variables; and
median [interquartile ranges] or and mean (SD) for continuous variables. All outcome data
from the Cohort-Controlled groupand ECMO group were compared using independent Student t
test, Mann Whitney U test or X2 test as appropriate. P values < 0.05 were considered
statistically significant.
To determine the predictors of the need for ECMO and factors associated with death in
ECMO-treated patients were entered in a multivariate stepwise backward logistic regression
model.
;
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Supportive Care
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