Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06162455 |
| Other study ID # |
RECORD Pilot |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 17, 2023 |
| Est. completion date |
February 6, 2024 |
Study information
| Verified date |
March 2024 |
| Source |
Tomsk National Research Medical Center of the Russian Academy of Sciences |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The primary aim of this single-center, prospective, randomized, controlled, pilot study is to
test the hypothesis that inhalation of NO 200 ppm prevents the development of nosocomial
pneumonia in patients at risk after cardiac surgery with CPB. The study is interventional.
Examination and treatment of patients is carried out in accordance with the approved
standards of medical care for the relevant diseases. During the study, no experimental or
unregistered (not approved for use) medical or diagnostic procedures in the territory of the
Russian Federation will be carried out. The study includes patients admitted to the Cardiac
Surgery Department of Cardiology Research Institute of Tomsk National Research Medical Center
for elective surgery with CPB.
Description:
NOSOCOMIAL PNEUMONIA AFTER CARDIAC SURGERY WITH CADIOPULMONARY BYPASS. Nosocomial pneumonia
(NP) is one of the most common complications of cardiac surgery with cardiopulmonary bypass
(CPB), its frequency according to various sources ranges from 2 to 10% . This complication is
accompanied by higher mortality (0.7-4% in patients without pneumonia vs. 25.1-28.2% in
patients with pneumonia) , prolonged hospital stay and increased economic costs.
In the retrospective analysis of medical histories of patients operated on CPB for 2020, 2021
and 2022, 3 main risk factors for the development of NP in the postoperative period were
identified: time of CPB ≥ 96 minutes, duration of mechanical ventilation ≥ 14 hours, and the
presence of atrial fibrillation (AF) before surgery.
STUDY NATURE In relation to medical procedures, this study is observational. The examination
and treatment of patients will be carried out in accordance with the approved standards of
medical care for the respective diseases. In this study, no experimental or unregistered (not
approved for use) medical or diagnostic procedures on the territory of the Russian Federation
will be carried out.
STUDY TYPE Single-center, prospective, double-blind, randomized, controlled, parallel group
study.
STUDY OBJECTIVES
PRIMARY OBJECTIVE To test the hypothesis that inhalation of NO 200 ppm prevents the
development of NP in patients at risk after cardiac surgery with CPB.
SECONDARY OBJECTIVES
1. To test the hypothesis that inhalation of NO 200 ppm twice a day for 30 minutes for 5
days is safe for patients.
2. To compare the level of acute-phase reactants and their dynamics in the main and control
groups
RATIONALE FOR RANDOMIZATION There is currently no convincing evidence of benefits or harms of
NO inhalation as part of the prevention of NP after cardiac surgery with CPB. Thus, there is
no reason to believe that randomization to study groups creates additional risks / benefits
for patients. Nevertheless, regardless of the results of randomization, the decision on the
possibility of prophylactic NO inhalation after cardiac surgery in each case will be made by
a special medical commission consisting of a cardiac surgeon, anesthesiologist and
cardiologist, immediately after the patient is enrolled in the study.
PATIENT RANDOMIZATION Patients eligible for this study will be randomized to the intervention
group (NO group) and Control group in a 1: 1 ratio according to the randomization sequence
generated by a computer program with random numbers by 37 people in each group.
Patients will be randomized immediately after screening and signing the informed consent.
Patients in both groups will not receive NO outside of the study protocol until discharged
from the hospital. Patient randomization will be performed by a non-blinded NO delivery
investigator who is not involved in the clinical management of the patient and the evaluation
of treatment outcomes. Patients in the intervention group will receive inhaled NO therapy at
a dose of 200 ppm 2 times a day for 5 days or until pneumonia is detected. In the control
group, instead of inhaled NO therapy, patients will receive "Sham treatment": similar
equipment and observation protocol during the intervention will be used as in the main group,
but NO will not be added to the delivered gas mixture.
BLINDING The gas supply systems will look the same for patients of both NO group and Control
group. Patients, treating physicians, investigators and other professionals involved in the
interpretation of the results will not be aware of the nature of the therapy until the end of
the study. The investigating doctor who is responsible for the delivery and monitoring of the
investigated gas will remain unblinded and will be responsible for blinding the gas delivery
systems, monitoring and securing the delivery, and maintaining the randomization codes.
Randomization codes will be sealed in sequentially numbered opaque envelopes. The sequential
envelope numbers will serve as randomization numbers that will be recorded in patient's case
report form (CRF) and used when necessary, for example, to treat complications.
DOSAGE REGIMEN AND DURATION OF THERAPY
When choosing the dose and timing of NO exposure, clinicians should be guided by 2 basic
principles:
1. The dose of NO used and its exposure time must be safe for patients;
2. The dose of NO used and its exposure time must be sufficient to provide potential
preventive effects.
NO dosing guidelines for the prevention of pneumonia after cardiac surgery with CPB have not
currently been developed, however, there is extensive data from experimental and clinical
studies indicating the potential efficacy of a gas concentration of 200 ppm and an exposure
time of 30 minutes, which will be implemented in the study.
The safety of using NO for humans in doses of 160-200 ppm for 15-30 minutes 2 to 5 times a
day has been demonstrated in a number of clinical studies, including in pregnant women and
newborns. The absence of toxic effects of NO at a dose of 200 ppm has been proven on cultured
skin fibroblasts, monocytes, macrophages and pulmonary epithelium. Most researchers emphasize
the efficacy of intermittent multiple high-dose (160-200 ppm) NO therapy with an average
duration of each inhalation for 30 minutes.
NO DELIVERY After screening and signing the informed consent, patients will be randomized
into one of the study groups: a control group with sham-treatment and a study group, in which
participants will receive inhalation of NO 200 ppm for 30 minutes twice a day for 5 days
after extubation and transfer from the intensive care unit. NO delivery will be carried out
using a semi-open circuit.
The source of NO is the certified device, which synthesizes NO from atmospheric air using the
method of plasma-chemical synthesis directly during therapy. The supply line for the studied
gas is built into the supply line for the carrier gas (atmospheric air), the flow of which is
provided by a compressor with a maximum flow of 18 l/min, which can be adjusted. The carrier
gas flow and NO synthesis rate will be adjusted automatically so that the NO concentration is
up to 200 ppm. Next, the gas mixture enters a 3-liter reservoir bag, from where the patient
actively breathes it in. To separate the inspiratory and expiratory parts, inhalation and
exhalation valves are provided in the circuit. To create an air tight seal with the circuit
and patient's airways, correct sized air cushion anesthesia masks will be used. Gas is
continuously sampled from the proximal end of the inspiratory part of the circuit to
determine the concentration of NO and NO2 in it.
MetHb levels during NO inhalation will be estimated continuously using a peripheral pulse
oximeter with fractional saturation capability. During NO therapy, MetHb levels will be
maintained at <5%.
NO undergoes a chemical reaction to form NO2, which is an extremely toxic gas and can cause
airway inflammation and lung tissue injury. This study regulates the control and maintenance
of inhaled NO2 levels below 3 ppm.
During NO therapy, vital functions and safety will be assessed immediately before the
initiation of the session, after 15 minutes of NO and after its completion (Heart Rate, Blood
Pressure, Respiratory Rate, Oxygen Saturation, MetHb).
In addition, as part of the exploratory endpoint study, exhaled NO levels will be measured
immediately before and after inhalation, 10 and 20 minutes after the end of inhalation.
Patients from the control group will undergo sham-treatment, the algorithm of which is
similar to inhalation in the main group, but NO will not be added to the gas mixture.
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS OF NO-THERAPY NO undergoes a chemical
reaction to form NO2. NO2 is an extremely toxic gas that can cause airway inflammation and
lung tissue injury. Protocols in use today require that inhaled NO2 levels should be
maintained below 3 ppm during NO therapy. The rate of NO2 formation depends on the
concentration of NO and O2 in the inhaled gas-air mixture. This fact is important: sources
with high concentrations of NO should be avoided; NO and inspiratory fraction of O2 (FiO2)
should be used in the minimum clinically acceptable doses. During bench tests of the delivery
system, NO2 concentration did not exceed 3 ppm when 200 ppm NO was supplied against the
background of FiO2 = 100% (due to the use of a chemical sorbent), however, the minimum
sufficient inspiratory fraction of O2 will be used when carrying out the study. NO oxidizes
hemoglobin (Hb) (Fe+2) to form (MetHb) (Fe+3), which is unable to transport and release
oxygen into the tissue and, as a result, can cause tissue hypoxia. Cyanosis is observed when
MetHb levels approach 15-20%. The Institutional Review Board for this study recommended
monitoring and maintaining MetHb levels below 5% of total hemoglobin concentration. MetHb
levels will be continuously monitored using a peripheral pulse oximeter with the ability to
measure fractional saturation (non-invasive pulse co-oximetry). If MetHb levels exceed 5% of
the total Hb concentration, NO delivery will be stopped. An increase in MetHb levels > 30% as
a critical incident in the study requires intravenous administration of methylene blue in
0.1-0.2 ml/kg of 1% solution (1-2 mg/kg).
After half of the patients are recruited and preliminary statistical analysis is completed, a
report on possible complications associated with the potentially negative effects of NO will
be submitted.
ASSESSMENT OF CLINICAL EFFECTIVENESS Assessment of clinical effectiveness will be based on
the incidence of NP in participants in the study groups.
LABORATORY ASSESSMENT Laboratory efficiency will be assessed by the dynamics of leukocyte and
CRP levels.
ASSESSMENT OF INSTRUMENTAL EFFICIENCY Instrumental efficiency will be assessed based on the
dynamics of the S/F index and temperature curve.
OBSERVATION PERIOD Monitoring of patients and registration of study data will be carried out
until discharge from the hospital. The expected length of hospital stay after uncomplicated
cardiac surgery will be approximately 2 weeks.
If complications occur during the perioperative period, patients will be monitored until the
event resolves/stabilizes.
