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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES NGO TRONG TOAN RESEARCH EFFECTS OF MECHANICAL VENTILATION WITH TIRATING POSITIVE EN[.]

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

-

NGO TRONG TOAN

RESEARCH EFFECTS OF MECHANICAL

VENTILATION WITH TIRATING POSITIVE EXPIRATORY PRESSURE GUIDED BY ESOPHAGEAL PRSSURE IN PATIENTS WITH ACUTE RESPIRATORY

THE THESIS WAS DONE IN: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

Supervisor:

1 Prof PhD Nguyen Thi Du

2 Ass Prof PhD Dao Xuan Co

Day Month Year

The thesis can be found at:

1 National Library of Vietnam

2 Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

INTRODUCTION

Acute respiratory distress syndrome (ARDS) is a syndrome with highly prevalent rate in intensive care units Despite recent therapeutic advances in patients with ARDS, in-hospital mortality rate remains unacceptably high from 14.2% to 84% according to each study, average of 40%

Mechanical ventilation that to secure oxygenation for patient is very important to manage patients with ARDS Positive end-expiratory pressure (PEEP) is an important parameter of mechanical ventilation in treating ARDS patients Whereas low tidal volumes are clearly beneficial in patients with ARDS, how to choose a PEEP to obtain the best benefit is uncertain and has many opinions

A new approach is that ideally, mechanical ventilation should provide sufficient transpulmonary pressure (plateau airway pressure minus pleural pressure) to maintain oxygenation while minimizing repeated alveolar collapse or overdistention leading to lung injury In critical illness, there is marked variability among patients in abdomal and pleural pressures; thus, for a given level of PEEP, transpulmonary pressures may vary unpredictably from patient to patient Pleural pressures can be estimated by using an esophageal balloon catheter PEEP are adjusted according to each patient’s lung and chest-wall mechanics In patients with high estimated pleural pressure who are undergoing ventilation with conventional ventilator settings, underinflation may cause hypoxemia In such patients, raising PEEP to maintain a positive transpulmonary pressure might improve aeration and oxygenation without causing overdistention Conversely, in patients with low pleural pressure, maintaining low

PEEP would keep transpulmonary pressure low, preventing overdistention and minimizing the adverse hemodynamic effects of high PEEP

On the world, using an esophageal balloon catheter to measure esophageal pressures then adjusting PEEP according to measured esophageal pressures has been studied by Talmor, Sarge, Fessler, Yang…These researchers showed some initial benefits of adjusting PEEP depending on esophageal pressures are

However, in Vietnam studies about esophageal pressure and its

use in treating patients with ARDS have been rare So the thesis

“Research effects of mechanical ventilation with titrating positive

end-expiratory pressure guided by esophageal pressure in

patients with acute respiratory distress syndrome” has been

conducted with two following purposes:

1 Study change of esophageal pressure measured by adult esophageal balloon catheter set and correlation between esophageal pressure and lung mechanical indexes in ARDS patients

2 Evaluate efficacy about improving arterial blood oxygenation of mechanical ventilation with titrating positive end-expiratory pressure guided by esophageal pressure in ARDS patients

Chapter 1 OVERVIEW

1.1 Acute respiratory distress syndrome

1.1.1 The Berlin definition of ARDS

CHARACTERISTICS ACUTE RESPIRATORY

DISTRESS SYNDROME Timing

Within 1 week of a known clinical insult or new/worsening respiratory symptoms

Chest imaging a

Bilateral opacities-not fully explained

by effusions, lobar/lung collapse, or nodules

Origin of edema

Respiratory failure not fully explained

by cardiac failure or fluid overload; Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present

Oxygenation b

Mild 200 <PaOCPAP ≥ 5 cmH2/FiO22O ≤ 300 with PEEP or c

Moderate 100 <PaO2/FiO2 ≤ 200 with PEEP ≥ 5

cmH2O

Severe PaO2/FiO2 ≤ 100 with PEEP ≥ 5

cmH2O

a Chest X-ray or CT scan

b If altitude higher than 1000 m, correction factor should be made as follows: PaO2/FiO2 x (barometric pressure/760)

c This may be delivered non-invasively in the mild ARDS group

1.1.2 Etiology

ARDS is caused by a multitude of disorders (There are over 60 ill disorders associating with ARDS); sepsis and pneumonia are the

most common Recently, cause due to virus has been considered especially when the world has been undergoing covid-19 pandemic

1.1.3 Pathophysiology

Although the mechanism of the lung injury varies with cause, widespread injured capillary-alveolar membrane is common and leads to increased permeability of this membrane, release edema fluid with a lot of protein into interstitial spaces and alveoli

- Artery blood gas:

+ PaO2 is very low and only partially responsive to O2

+ Infiltrates develop rapidly

+ Infiltrates are symmetrical or asymmetrical

ARDSD, ensures adequate oxygenation of arterial blood, provides sufficient oxygen transport to vital organs and tissues, assists in eliminating CO2, relieves excessive burdens placed upon the respiratory muscles, helps maintain alveolar stability, and allows therapeutic measures that require controlled ventilation However, mechanical ventilation also has the potential to inflict adverse clinical outcomes

PEEP is an important parameter in ventilating patients with ARDS Now, how to set up PEEP to obtain the best benefit is uncertain According to Gattinoni, ideally, a “best PEEP” simultaneously: (1) provides appropriate gas-exchange; (2) keeps the lungs open (prevents phasic airway collapse); (3) avoids alveolar overdistention; and (4) does not compromise hemodynamics Any PEEP selected is always a compromise among these objectives Now, in the world, there are a variety of approaches to set up PEEP for ARDS patients

1.2 Esophageal-pressure guided mechanical ventilation (EPVENT)

Transpulmonary pressure is the most important in mechanical ventilation because it really stress on lung Ptp (transpulmonary pressure) = Pplat - Ppl Two patients that have the same Pplat (plateau airway pressure) but have different Ppl (pleural pressure) will have different risk of VILI (ventilation-induced lung injury) and need different PEEP In clinical practice, Pplat is easy to measure, but directly measuring Ppl is invasive and complicated To resolve this issue, correlation between Ppl and Pes is used, Pes at under third

of esophagus can be measured by an adult esophageal balloon catheter

According to Talmor, Pleural pressure varies widely and unpredictably among patients with ARDS, likely due to factors such

as obesity, abdominal fluid accumulation and oedema, which influence the mechanical behaviour of the chest wall and diaphragm This wide range of pleural pressure among individuals could significantly affect lung inflation produced by mechanical ventilation For example, a relatively high level of PEEP of 18 cmH2O could be too low in a patient with a pleural pressure of 20 cmH2O, allowing collapse of some airspaces with each expiration and leading to atelectrauma (end-expiratory Ptp = -2 cmH2O), but too high in a patient with a pleural pressure of 5 cmH2O (end-expiratory Ptp = 13 cmH2O), causing haemodynamic compromise, increased dead space ventilation and overdistension of the lungs at end-inflation Thus, ideally, adjusting PEEP for patients with ADRS should individualise how keeping Ptp PEEP ≥ 0 cm H2O to avoid atelectasis at end-expiration and Ptp plat ≤ 25 cmH2O to avoid lung over-distention at end-inspiration

In 2014, Talmor introduced the Esophageal Pressure-Guided Ventilation 2 (EPVent2), a new table about adjusting PEEP in patients with ARDS based on mesuring Pes This table is used for sdudies about ARDS

Table 1.6 The esophageal pressure-guided ventilation 2 (EPVent2)

Bước 1 2 3 4 5 6 7 8 9 10 11 12 13 FiO 2 0.3 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0

PtpPEEP 0 0 0 2 2 3 3 4 4 5 5 6 6

Chapter 2 SUBJECTS AND METHODS 2.1 STUDYING SUBJECTS

68 ARDS patients from 3 centers (Intensive Care Departement, Emercency Department of Bach Mai Hospital and Intensive Care Departement of Central Geriatric Hospital) were studied from July

2015 to July 2018

2.1.1 Selection criteria for study patients

- Adults patients aged 16 years and older with moderate-to-severe ARDS will be enrolled The Berlin Conference definition is used to identify patients with moderate-to-severe ARDS (see table 1.2.)

- Patients who agree to participate in the research

2.1.2 Exclusive criteria

- Patients who did not agree to participate in the research

- Recently treated for bleeding varices, stricture, heamatemesis, esophageal trauma, recent esophageal surgery

- Severe coagulophathy (platelet count <5000/µL or international normalized ratio > 4)

- History of lung or liver transplantation

- Elevated intracranial pressure or conditions where induced elevations in intracranial pressure should be avoided (including intracranial bleeding, cerebral contusion, cerebral eodema, mass effect (midline shift on CT scan)

- Evidence of active air leak from the lung (including pleural fistula, pneumothorax, pneumomediastinum or air leak from existing chest tube)

- Neuromuscular disease that impairs ability to ventilate spontaneously (including C5 or higher spinal cord injury, amyo-

trophic lateral sclerosis, Guillain-Barre syndrome or myasthenia gravis)

- Severe chronic liver disease (Child-Pigh Score ≥ 12)

- Use of rescue therapies prior to enrolment (including nitric oxide, ECMO, prone posisioning or high frequency oscillation), unless therapies were used as the initial mode of ventilation

2.1.5 Criteria for getting patients out the study

- Treating clinician refusal, or unwillingness to commit to trolled ventilation for at least 24 h

- Patients not commited to full support

- Inability to get informed consent from the patient or surrogate

- Patients were unably sedated

- Adult esophageal balloon catheter set (USA)

- AVEA ventilator with esophageal maneuver screen (USA)

2.2.2 Sample size

- In objective 1, 34 patients with ARDS

- In objective 2, our primary end point is average between-2 groups difference of PaO2/FiO2 To determine sample size, we chose the following equation:

(α, β) = 10,5 (α = 0.05, β = 0.1)

∆ = 280-191 (from 2 previous studies)

S (maxium standard diviation) = 109 (from 2 previous studies)

We have:

𝑛 = 10,5 2 × 109

2

(280 − 191)2≈ 32 Thus, minimal sample of each group is about 32

2.2.3 Study procedure

Objective 1: 34 ARDS patients were supine with the bed at 300 head up

An adult esophageal balloon catheter was first passed by nose or mouth into the stomach with its tip 60 cm from the incisors or nares (placement of the balloon in the stomach was confirmed by a transient increase in pressure during a gentle compression of the abdomen) and then withdrawn to 40 cm

to record Pes (esophageal inspiratory pressure and esophageal expiratory pressure) during mechanical ventilation at To (before intervention of each group), T1, T2, T3 Ppeak, PEEP, CRS (respiratory system compliance), Ccw (chest wall compliance), Vte/kg, ect were measured simultaneously at each time Proper balloon position in the esophagus was confirmed in all patients by observing an appropriate change

end-in the pressure tracend-ing as the balloon was withdrawn end-into the thorax (changes in pressure waveform, mean pressure, and cardiac oscillations) In patients who were making respiratory efforts, correct balloon position could

be confirmed by the presence of nearly equal fluctuations in Paw and Pes during inspiratory efforts against an occlusion

2

2 2

) , (

Objective 2: ARDS patients were randomly assigned with the use of a

block-randomization scheme to the control or esophageal-pressure-guided group (each group had 34 patients) 68 ARDS patients of both two groups were supine, with the head of the bed elevated to 300 Airway pressure, tidal volume, air flow and arterial blood gas were recorded during mechanical ventilation All patients of both two groups, while under heavy sedation or paralysis, underwent a recruitment maneuver to standardize the history of lung volume, in which airway pressure was increased to 40 cmH2O for 30 seconds After the recruitment maneuver, the patient underwent mechanical ventilation according to the treatment assignment The patients in the esophageal-pressure-guided group underwent mechanical ventilation with settings determined by the initial esophageal-pressure measurements Tidal volume was set at 6 ml per kilogram of predicted body weight PEEP levels were to achieve a transpulmonary pressure of 0 to 6 cmH2O at end expiration, according to a sliding scale based on the partial pressure of arterial oxygen (PaO2) and the fraction of inspired oxygen (FiO2) (Table 1.6)

Patients in the control group were treated according to the volume stratery reported by the ARDSNet study of the National Heart, Lung, and Blood Institute This stratery specifies that the tidal volume is set

low-tidal-at 6 ml per kilogram of predicted body weight and PEEP is based on the patient’s PaO2 and FiO2 (low PEEP table)

All measurements (arterial blood gas, indexes of lung michanics) were repeated 5 minutes after the initiation of experimental or control ventilation and again at 24, 48, 72 hours, ect Measurements were also performed as needed after changes (about 20 minutes) were made to ventilator settings because of any clinically significant change in the patient’s condition

The primary end point of the study was arterial oxygenation, as measred

by the ratio of PaO2 to FiO2 at 24, 48, 72 hours, ect after randomization The secondary end points included indexes of lung mechanics (respiratory system compliance), ventilator-related complications (pneumothorax, pneumomediastinum), as well as outcomes of the patients (the numbers of ventilator-free days at 28 days, death within 28 days)

2.2.4 Research variables

- General characteristics of target population: Age, gender, index

body mass (BMI), risk factors of ARDS, APACHE II, SOFA, medical history

- Characteristics of arterial blood gas: pH, PaCO2, PaO2, HCO3, PaO2/FiO2

- Indexes of lung mechanics: PesENDin, PesENDex, Ptpplat,

PtpPEEP and Ppeak, Pplat, Pmean, PEEP, CRS, Vte/ideal body weight

- Interventional result and related undesired effects:

+ Death within 28 days

+ Nose bleeding, gut bleeding

+ Changes of arterial blood pressure and ECG when adjusting PEEP

2.2.5 Accessment points

For objective 1

- Change of Pes: