Mechanical Ventilation (MV) with positive pressure was first introduced clinically in the 1950s during the polio epidemic (Dries and Perry, 2008). Although positive pressure ventilation is one of the most important medical care interventions nowadays and can be vital in cases with indications, duration of intubation correlates with an increased mortality rate (Dries and Perry, 2008; Peñuelas et al., 2011). Because of the ventilator-associated complications, the weaning process should be initiated as soon as possible (McLean et al., 2006).

About 20–30% of ventilated patients are considered difficult to wean from invasive MV (Heunks and Van Der Hoeven, 2010). The time spent in the weaning process may necessitate 40% of the overall duration of MV (Cohen et al., 2019). Difficulty in weaning can be due to reduced central respiratory stimulants, which is often accompanied by the decreased level of consciousness, nervous system damage, and metabolic encephalopathy (Chao and Scheinhorn, 1998).

In spite of insufficient data regarding the efficacy of respiratory stimulants such as caffeine and doxapram (Giguère et al., 2008), researchers are still seeking for new strategies to reduce duration of intubation and treatment costs (Dasta et al., 2005). Available evidence indicates that muscarinic acetylcholine receptors have potent excitatory consequences on medullary respiratory neurons and motoneurones, and are likely to contribute to changes in central hemosensitive drive to the respiratory control system (Yamada and Ichinose, 2018). On one hand the central role of cholinergic mediators in the respiratory system is the basis for its positive effects in neurological disorders related to respiratory control (Abbasi et al., 2015). On the other hand, the parafacial respiratory group plays an important role in the generation of active expiration and recruitment of expiratory abdominal muscles. It is under GABAergic and cholinergic control and is activated in conditions of high metabolic demand (Pisanski and Pagliardini, 2019). Donepezil, a cholinergic drug that reversibly and non-competitively inhibits central acetyl-cholinesterase, has improved cognitive function significantly (Abbasi et al., 2015). As thalamic cholinergic deficit may contribute to obstructive sleep apnea (OSA), donepezil could be a potential modality to improve OSA (Gilman et al., 2003; Moraes et al., 2008; Sukys-Claudino et al., 2012).

Progesterone is a respiratory stimulant improving ventilation function, ventilation capacity, and exercise efficiency in normal individuals and obstructive airways diseases. Progesterone could enhance ventilation, breathing overnight and respiratory gas exchanges (Schoene et al., 1980; Delaunois et al., 1985; Wagenaar et al., 2003; Golparvar et al., 2005; Saaresranta et al., 2005). The lipophilic properties of progesterone allow it to enter the hypothalamic sites that are mediated by estrogen (E2) receptors in the central nerve system (CNS) (Bayliss and Millhorn, 1992). Another proposed mechanism is that progesterone stimulates leptin hormone release, which may increase ventilation (Saaresranta et al., 2002).

The aim of the current study was to evaluate the effects of donepezil or medroxyprogesterone compared to the placebo in improving the respiratory status and weaning facilitation in critically ill adult patients with non-pulmonary etiologies receiving mechanical ventilation for the first time. In addition to weaning duration, and duration of invasive mechanical ventilation as our primary endpoint, we evaluated secondary endpoints, including successful weaning rate from MV, changes in arterial blood gas (ABG) parameters, GCS and sequential organ failure assessment (SOFA) score, hemoglobin (Hgb), ICU-mortality, and duration of intensive care units (ICUs) stay, were measured before and after the intervention and if successful weaning was recorded.

In total, 152 patients were screened for eligibility in three neurological ICUs of our hospital. We enrolled 78 intubated patients without primary pulmonary diseases. The mean age of the participants was 41.23 ± 24.2 years old. The total intention to treat population were 73 patients who randomly assigned to the following groups: 26 patients each assigned to the control, donepezil, or medroxyprogesterone groups. Five patients were withdrawn from the study subsequently. Eventually, 73 patients completed the study for outcome measurement (Figure 1). Patients in studied groups were balanced in terms of demographic and disease characteristics (Table 1). In order to adjust stroke and head injury covariance analysis was used. By entering these variables into the model, significant difference have been seen between groups (p-Value = 0.015).

Although, the effects of hormones such as progesterone on respiratory and ventilatory performance have been evaluated in previous studies, the present study is the first randomized, controlled clinical trial evaluating the effectiveness of medroxyprogesterone in facilitation of weaning in patients receiving invasive mechanical ventilation. The effect of donepezil was previously assessed in a clinical study to facilitate the weaning course. However, in this non-randomized study, there was no control group and the effect of donepezil on ABG was evaluated in only 16 difficult to wean patients. According to the design of this aforementioned study, it had all the limitations of non-clinical trial studies. Therefore, this study is also the first randomized clinical trial of donepezil in expedition the weaning course in mechanically ventilated patients.

This triple-blind randomized clinical trial designed to compare the improvement in respiratory status and weaning facilitation in mechanical ventilated critically ill adult patients receiving donepezil or medroxyprogesterone vs. placebo. The mean total duration of invasive ventilation was significantly lower in the donepezil compared to the control group while the duration of weaning did differ significantly between the groups. In addition, the rate of successful weaning were greater in the donepezil and medroxyprogesterone groups compared to the control group, this difference was not statistically significant. Donepezil and medroxyprogesterone had no significant effect on the total duration of ICU stay, rate of ICU mortality, and GCS in successfully weaned patients which was not too far from expected, since there are several factors in the ICU setting influencing these parameters and it is not possible to control for all these confounders. In fact, parameters such as age, chronic use of corticosteroid, atrophy of diaphragmatic, or severe limitation of airway flow are far more vigorous factors affecting the successful rate of weaning from mechanical ventilation or outcomes of critically ill patients (Groenewegen et al., 2003; Boles et al., 2007; Levine et al., 2008). Taken together, although patients in donepezil and medroxyprogesterone groups were more successful than the control group in the weaning process, this difference was not statistically significant.

Mechanical ventilation is implemented to improve oxygen delivery and ventilation, and decrease the breathing workload. It is by the physician to and is therefore a means of treating the patient. Physicians adopt MV to stabilize the patient until the diagnosis and therapeutic management of the disease is performed (Boles et al., 2007). In other words, MV is a means to an end and not a treatment in itself. Therefore, the weaning process should be initiated as soon as possible (McLean et al., 2006).

Despite the salvage of MV in critically ill patients, MV is associated with numerous complications. The most common complications are pneumothorax, broncho pleural fistula, nosocomial pneumonia, and respiratory alkalosis, which can impair cerebral perfusion, predispose patients to cardiac dysrhythmias, and prolong the weaning process (Groenewegen et al., 2003). Difficulty in weaning can be due to reduced central respiratory stimulants that suggesting new strategies to reduce the duration of intubation and treatment costs.

Some other agents such as methylphenidate, benzquinamide, ethamivan, bemegride, nikethamide, naloxone, almitrin, theophylline, methyl xanthine, levosimendan, and acetazolamide have been tried as the respiratory stimulants (Dallemagne and Heymans, 1955; Yost, 2006; Roesthuis et al., 2019), but the results of these studies were not encouraging.

The efficacy of acetazolamide in the duration of intubation was evaluated as regards the results did not show reduction in intubation and weaning process (Faisy et al., 2016).

Donepezil and medroxyprogesterone at dose of 10 mg are well tolerated without causing any life-threatening side effect (Soufir et al., 2011; Tan et al., 2014). Mechanically ventilated patients with potential difficulties in respiratory drive were enrolled. Due to the stimulatory properties of progesterone in the central respiratory system and the role of the cholinergic system in the neurological control of respiration, this study was performed. Administration of oral medroxyprogesterone or donepezil in the clinical setting for weaning from MV is limited. No adverse effects were seen in either group.

Medroxyprogesterone could reduce the duration of intubation significantly. We monitored respiratory ventilation function by obtaining serial ABG samples. However, no significant difference observed in all variables of ABG after 24 h and after successful weaning in the medroxyprogesterone group compared with the control group. Contrary to the results of the present study, two previous studies that were conducted on patients with chronic obstructive pulmonary disease (COPD) illustrated the effective role of medroxyprogesterone in PaCO₂ reduction and PO₂ increment (Delaunois et al., 1985; Wagenaar et al., 2003). It should be borne in mind that the dosing of medroxyprogesterone was lower in the current study.

In an interventional pilot study, the effect of donepezil on the facilitation of weaning in difficult to wean patients was evaluated. Donepezil was administered for eligible patients at the dose of 10 mg daily for 2–4 weeks. It was presumed that donepezil could expedite weaning by stimulation of respiratory center and prevent the need for re-intubation in these patients. However, they included a small number of patients (16 patients) as well as non-randomization limited the establishment of a strong relationship between use of donepezil and facilitation of weaning (Abbasi et al., 2015). Our results showed that donepezil was able to facilitate the patient’s weaning but did not alter PaO₂, PaCO₂, HCO₃ concentration, and O₂Sat parameters while contrary to Abbasi´s study pH changes were significant in this study. Although no significant different in pH changes were seen in the donepezil compared to control group after 24 h, changes in pH were significant overtime indicating that several doses of the donepezil are required for an efficient response. It can be argued that the results of ABG parameters such as pH will often influence the weaning process accompanied with better clinical outcome in such patients (Kraut and Madias, 2012).

We also evaluated the effect of donepezil and medroxyprogesterone on the improvement of the patient’s GCS. In the clinical setting, the improvement in GCS is one of the important criteria for initiation of weaning. In other words, low GCS at the beginning of the weaning process is considered a major reason for prolongation of this process (Pu et al., 2015). In this study, despite the increase in GCS over time, this difference was not statistically significant when compared to control group. but this issue, especially in the case of donepezil, requires study in larger populations and longer time because the cholinergic system is one of the most important cognitive centers in the brain (Zhang et al., 2004).

SOFA is a valuable score for the management of patients in ICUs which predicts patients’ outcomes (Ferreira et al., 2001). GCS and PaO₂ are two main indices for calculation of SOFA score. Due to the lack of changes in GCS and PaO₂ in both groups compared to placebo, changes in this index were not significant between intervention and placebo groups, so these two drugs are not effective in reducing the SOFA score and mortality rate.

Duration of weaning was significantly reduced in intervention groups compared to the control group. The underlying mechanisms for donepezil are presumed to be due to the performance of the cholinergic system in improving respiratory coordination, increased neuromuscular transmission, improved upper respiratory muscle function, neuronal control of respiration, and increased salivary secretion (Hedner et al., 2003; Proctor and Carpenter, 2014). The performance of medroxyprogesterone in strengthening the tidal volume (VT), respiratory effort, changes in metabolic rate, lung and chest movements, increase ventilation performance and increasing ventilation capacity (Golparvar et al., 2005; Dempsey et al., 2011).

This study has several limitations. First, the main limitation was the small size of the subject groups. Despite more than 7-month study duration and inclusion of consecutive patients, only limited number of patients entered the study according to inclusion and exclusion criteria. Second, while the dose range of medroxyprogesterone was different in previous data, the effective dose for weaning from MV is yet to be determined. Although the interventions performed in this study were safe and no side effects related to these drugs were reported during the study period, but considering the relative short length of the intervention and follow-up period, the necessary precautions should be taken in this regard. Furthermore, the lack of a fixed and predefined protocol for all patients for whom weaning is to be attempted is another limitation which should be taken into consideration in future studies. The last limitation is the presence of factors more strongly influencing the discontinuation of MV or ICU outcomes (eg, age, diagnosis, long-term use of steroids or diaphragm atrophy).

Various population pharmacokinetic parameters and contribution of different factors in weaning process might be the reasons for medroxyprogesterone or donepezil treatment to achieve its response goal during the studies. Therefore, these results require further confirmation with larger controlled clinical trials to clarify and establish medroxyprogesterone and donepezil role on weaning process. Moreover, other confounding factors that strongly influencing the patients’ outcome should be considered.

Previous investigation found that some respiratory stimulants could facilitate weaning presses. Medroxyprogesterone and donepezil are two safe and successful respiratory stimulants, suggesting that they could be considered as a weaning-facilitating strategy. Our results illustrated that the administered dose of medroxyprogesterone and donepezil can expedite the weaning process presumably by central stimulation of the respiratory system.

The results of the current study have demonstrated that administering medroxyprogesterone or donepezil in the weaning process significantly reduced the weaning duration compared to placebo, while the total duration of invasive ventilation was significantly lower in the donepezil group compared to the control group. There were no statistically significant differences in other evaluated outcomes except pH changes. Although the findings of the present study are interesting, care should be taken in implementing these results.