Background Mechanical ventilation is an essential medical intervention in the context of critical illness. However, the intervention is associated with a risk of significant, potentially preventable complications. Among these are ventilator-associated pneumonia, sepsis, acute respiratory distress syndrome, atelectasis, and pulmonary edema.

Ventilator-associated complications commonly increase morbidity and mortality. They may also prolong the duration of mechanical ventilation and the length of stay in the hospital or the intensive care unit, with increased health care costs; so safe, effective therapeutic and preventative strategies are essential to attenuate poor outcomes from ventilator-associated events.

Secretion retention and ineffective cough play a significant role in failed extubation and weaning from ventilator; the presence of the artificial airway, poor humidification of inspired gases, and immobility are the major causes of pulmonary secretion retention in this population. Accumulated secretion in the airways, if extensive, starts a self-sustaining cycle of ventilation/perfusion mismatch, gas-exchange impairment, increased work of breathing.

For decades N-acetyl-L-cysteine (NAC) has been used for its mucolytic properties orally in different respiratory diseases like chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF); but its effects are not known if given by nebulization through endotracheal tube (ETT), studies to date have provided inconclusive results. Despite this uncertainty, mucoactive agents are still used in adult ICUs.

NAC is usually administered orally, with several formulations and dosage forms available for both short- and long-term treatment of respiratory diseases. The inhalation route might also be considered a practical option, with recent interest, as the therapeutic drug acts directly on the bronchial mucosa, promotes continuous local retention of the drug, prolongs anti-inflammatory effects, and avoids the liver first-pass effect, which can help quickly improve airway inflammation.

Contrary to other mucoactive drugs, NAC has been found to exhibit antioxidant, anti-inflammatory, antibacterial, and antibiofilm activities.

In the respiratory infection field, the available data indicate that NAC was associated with inhibition of oxidative stress and reduced the inflammatory factors in community acquired pneumonia, antibiofilm activity specially in pseudomonas aeruginosa infection in pre-clinical and clinical reports and has good antibacterial properties and suggested to interfere with biofilm formation and disruption.

NAC has shown improvement in the respiratory index (PaO₂/FiO₂), with lower rates of mechanical ventilation in COVID-19. When studied in mechanically ventilated patients with acute respiratory distress syndrome (ARDS), which is associated with oxidative stress, increased levels of glutathione, and inflammation, NAC demonstrated improvements in positive end-expiratory pressure (PEEP) and PaO₂/FiO₂.

N-Acetylcysteine contributed to delaying ventilator-associated pneumonia (VAP) in mechanically ventilated patients when administered orally as a preventive medication. It was also effective in attenuating the decline in forced vital capacity (FVC) in mild to moderate idiopathic pulmonary fibrosis (IPF), and it showed a lower rate of postoperative pulmonary complications when given pre-operatively in orthotopic liver transplantation.

Since NAC is relatively low-cost, readily available, and has a favorable side effect profile, it is important to properly assess the clinical benefits of nebulized NAC as an adjunct to standard medical treatments in mechanically ventilated patients.

Aim of the study

This study will assess the role of preventive N-acetylcysteine inhalation on incidence and time to develop VAP in critically ill mechanically ventilated patients.

Objectives

• 1) Assessment of N-acetylcysteine inhalation efficacy in mechanically ventilated patients through monitoring the following parameters: time to develop ventilator-associated pneumonia (VAP), incidence of VAP, PaO₂/FiO₂, pH, oxygen saturation (SaO₂), peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), frequency of endotracheal tube (ETT) suction and tube exchange, and infection parameters (total leukocyte count, body temperature). In addition, hospital mortality, duration of mechanical ventilation (MV), ventilator-free days, and the length of hospital and ICU stay
• 2) Assessment of the safety of N-acetylcysteine inhalation in mechanically ventilated patients by monitoring the incidence of new-onset bronchospasm

Inclusion Criteria:

1. Aged 18-64 years, either male or female.
2. Critically ill patients who have undergone intubation and are on mechanical ventilation.
3. Expected duration of mechanical ventilation of more than 48 hours.
4. Provided consent to participate in this clinical trial by next of kin.

Exclusion Criteria:

1. Patients currently on long-term NAC treatment.

2. Confirmed brain death.

3. Recent chest infection.

4. Immunocompromised patients on immunosuppressive medication.

5. Patients mechanically ventilated in another hospital.

6. Pregnant women.

7. Mean arterial pressure (MAP) <60 mmHg despite adequate resuscitation and vasopressor therapy at the time of randomization.

8. Known intolerance or hypersensitivity to study medication.

9. Presence of a condition or abnormality that would compromise the quality of the data.

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