Management of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in Hospitalized Patients From Admission to Discharge: A Comprehensive Review of Therapeutic Interventions

Chronic obstructive pulmonary disease (COPD) is a common and debilitating condition that often necessitates hospitalization for exacerbations. Since COPD exacerbations can cause significant morbidity and mortality, managing them is crucial for patient care. Effective management of COPD exacerbations is essential to prevent complications, as COPD exacerbations are associated with increased healthcare costs and decreased quality of life. This review aims to comprehensively discuss the management of COPD exacerbations, covering various pharmacologic and non-pharmacologic strategies. These include inhaled bronchodilators, systemic steroids, antibiotics, invasive and non-invasive ventilation, oxygen therapy, smoking cessation, immunization with pneumococcal vaccine, inhalers at discharge, pulmonary rehabilitation, long-term oxygen therapy (LTOT), ambulatory oxygen therapy, short-burst oxygen therapy, extracorporeal membrane oxygenation (ECMO), lung volume reduction surgery (LVRS), endobronchial procedures, and lung transplant. It is drawn upon various sources, including clinical studies, systemic reviews, and observational studies, to provide a comprehensive overview of current practices and identify areas for future research and innovation in managing COPD exacerbations. Addressing these areas of interest can improve patient outcomes and quality of life.


Clinical presentation, diagnostic criteria, and factors leading to chronic obstructive pulmonary disease (COPD) exacerbation
Chronic obstructive pulmonary disease (COPD) is often preventable and treatable, characterized by persistent airflow limitation, chronic inflammation, and progressive lung disease.Chronic obstructive pulmonary disease is comprised of emphysema and obstructive bronchiolitis.A patient can present with either or both of these manifestations simultaneously.Previously, chronic bronchitis was considered a type of COPD but has recently been replaced by obstructive bronchiolitis [1].Chronic obstructive pulmonary disease is a persistent and advancing disease in which an individual may experience sporadic acute exacerbations characterized by respiratory symptoms that worsen beyond the typical presentation during a regular day.These exacerbations have a cumulative effect on the overall function of the respiratory system [2].These exacerbations of COPD can result in hospitalization, a decrease in lung function, and increased mortality.According to the World Health Organization (WHO), COPD is the third leading cause of death worldwide, causing 3.23 million deaths in 2019 [3].Unfortunately, it is expected to be the leading cause of death worldwide by 2030 [4].Therefore, the effective management of COPD exacerbations is crucial to improving the quality of life and reducing the burden of the disease.Numerous guidelines and recommendations exist for managing COPD exacerbations; however, the optimal approach is still under debate.Managing COPD exacerbations is a complex and multifaceted process requiring a personalized approach based on the patient's clinical characteristics and comorbidities.
Chronic obstructive pulmonary disease is primarily seen in individuals aged 40 and above, usually in individuals who smoke [5].These patients often present late, when significant damage to the airway tract has already occurred.Patients with COPD can present with several physical findings listed below: A) Shortness of breath (dyspnea): Patients may experience breathlessness, especially during physical activity or exertion.These patients naturally adopt a sitting, forward-leaning position with their hands on their knees during episodes of respiratory distress, known as the tripod position.This position helps alleviate dyspnea by fixing and lifting the shoulder girdle, improving the length-tension relationship of accessory muscles, restoring the diaphragm's normal shape and function, decreasing the recruitment of specific muscles, and improving thoracoabdominal movement [6].However, according to a study conducted in 2009, no significant difference was observed in COPD patients in the tripod position compared to sitting or supine positions [7].B) Wheezing: Wheezing is a high-pitched whistling sound that occurs during breathing due to the narrowing of the airways.Unforced wheezing has a likelihood ratio of 2.6 for COPD diagnosis [6].C) Cough: A persistent, productive cough consisting of sputum or phlegm is a common symptom of COPD.D) Increased sputum production: Patients with COPD may produce more mucus than normal, which can cause difficulty breathing.Furthermore, this excess sputum plays a role in developing both temporary respiratory infections and the pathogenesis of various respiratory diseases, worsening COPD [8].E) Cyanosis: Blue or grayish skin discoloration, especially around the lips and fingernails, due to low oxygen levels in the blood.F) Barrel-shaped chest: Patients with COPD may have a rounded and bulging chest due to air trapping in the lungs.In most cases, the curvature of the spine, known as dorsal kyphosis, and the horizontal orientation of the ribs are observed.Other physical features include a prominent sternum, raised clavicles, a shortened neck, and wider spaces between the ribs.Developing a barrel-shaped chest is common in severe emphysema while aging alone can result in a similar chest deformity without lung disease [6].G) Use of accessory muscles: Patients may use their neck, shoulder, and chest muscles to assist with breathing, especially during exertion.Despite the limitation in airflow, most patients employ both their expiratory and sternomastoid muscles.The expiratory muscles cannot decrease lung volume due to the airflow constraint [9].H) Reduced breath sounds: Breath sounds at the mouth may be diminished or absent due to air trapping in the lungs.Patients with emphysema typically have quiet breathing at the mouth because the disease does not cause bronchial narrowing [6].I) Decreased lung function: Pulmonary function tests (PFTs) may reveal decreased lung function, including decreased forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).However, according to a study, if patients get regular treatment during the cycles of remissions and exacerbations, the decrease in FEV1 and FVC is significantly less [10].
It is important to note that not all patients with COPD will exhibit all of these physical findings, and some patients may exhibit additional symptoms and signs depending on the severity of their disease.The diagnosis of COPD is usually made by a combination of patient history, physical examination, PFTs, and imaging studies.According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report of 2023, confirmation of COPD diagnosis is achieved through the identification of non-fully reversible airflow limitation using spirometry, where the FEV1/FVC ratio after bronchodilation is <0.7 [11].The Global Initiative for Chronic Obstructive Lung Disease classifies obstruction in COPD patients into four stages, as shown below and in Figure 1: GOLD 1: Mild; FEV1 ≥80% predicted GOLD 2: Moderate; 50% ≤ FEV1 <80% predicted GOLD 3: Severe; 30% ≤ FEV1 <50% predicted GOLD 4: Very severe; FEV1 <30% predicted [11,12].However, COPD can often be misdiagnosed, and the disease can advance before it is clinically detected.For this purpose, spirometry can detect COPD before symptoms become apparent [13].Other lung function tests can also be performed, such as peak expiratory flow (PEF) tests, fractional exhaled nitric oxide (FeNO) tests, and arterial blood gas (ABG) analyses.Lung imaging modalities can also help in the diagnosis of COPD.These include chest X-rays and computed tomography (CT) scans [13].According to epidemiological studies, a significant percentage of individuals globally suffering from COPD have never smoked, ranging from 20% to 40%.Therefore, while smoking remains the primary risk factor for COPD, other factors should also be considered [14].There are many factors contributing to COPD.These include: A) Smoking: This is the most significant risk factor for COPD.About 85% to 90% of all COPD cases are caused by smoking [15].According to a study conducted in India in 2021, smokers exhibited a greater degree of dyspnea, more advanced COPD, reduced FEV1 after using a bronchodilator, and a more significant number of emphysematous alterations on X-ray imaging [16].B) Exposure to air pollution: In COPD patients, exposure to outdoor air pollutants is linked to a decline in lung function and a rise in respiratory symptoms.Moreover, outdoor air pollutants are related to more frequent COPD flare-ups and higher mortality rates [17].C) Temperature: There is a connection between extreme temperatures, whether hot or cold and elevated respiratory morbidity in COPD [17].D) Passive smoking: Inflammation caused by second-hand smoke through cells and mediators, combined with the production of reactive oxygen species, destroys the alveolar walls.This suggests that second-hand smoke could be a potential cause of emphysema through this mechanism [18].E) Genetic alpha-1 antitrypsin deficiency: This is commonly underdiagnosed and causes liver and lung damage.If the patient shows signs of liver damage and typical symptoms of COPD, one should order a blood test to rule out the possibility of alpha-1 antitrypsin deficiency [19].during childhood, thus playing a role in developing COPD in later life [20].Tobacco exposure to the child as far back as life in utero can also play a part in the development of COPD [21].G) Gender: Females tend to exhibit symptoms of emphysema at earlier stages and with less exposure to tobacco compared to males, which can contribute to the development of the disease [22].
H) Non-adherence to treatment plan: Failure to follow prescribed medications, not using oxygen therapy as prescribed, or not attending pulmonary rehabilitation can contribute to exacerbations.I) Respiratory infections: Viral or bacterial infections of the respiratory tract can cause inflammation and worsen COPD symptoms.
Although there has been ongoing research, there have not been any significant advancements in diseasemodifying treatment for COPD lately.Smoking cessation is the only intervention known to change the course of the disease and increase the survival rate [23].

Review Pharmacological treatments
Pharmacological treatment for COPD is intended to improve exercise tolerance and general health status and lessen the burden of symptoms and the frequency and severity of exacerbations [11].Bronchodilators, systemic corticosteroids, and antibiotics are the primary treatment options used in the management plan for acute exacerbations of COPD in the hospital setting [11].

Bronchodilators
Bronchodilators are considered one of the mainstays in treating COPD at all levels of severity [24].They include beta-2 agonists and antimuscarinic drugs.

Beta-2 Agonists
Beta-2 agonists improve symptoms of COPD exacerbation and FEV1 [25] by activating beta-2 adrenergic receptors, which relax the smooth muscle of the airways, thus raising cyclic adenosine monophosphate (cAMP) and functionally opposing bronchoconstriction [11].Beta-2 agonists are of two types: short-acting beta-2 agonists (SABAs) and long-acting beta-2 agonists (LABAs).The short-acting are salbutamol (albuterol), levalbuterol, terbutaline, and fenoterol [11].Long-acting beta-2 agonists significantly reduce the severity of dyspnea, rate of exacerbation, and number of hospitalizations.However, these medicines have no impact on mortality or decline in lung function [11,26].The drugs are further classified according to their duration of action and daily dosage.Some are used twice a day, which includes formoterol and salmeterol [26], while indacaterol, oladaterol, and vilanterol are required once a day as they have a duration of action of 24 hours [11, [27][28][29].In addition to the clinical benefits, beta-2 agonists possess several harmful effects, too, such as sinus tachycardia, palpitations, somatic tremors, variations in blood pressure, hypokalemia, and increased oxygen consumption [11,30].

Antimuscarinics
Antimuscarinic drugs cause bronchodilation by inhibiting the acetylcholine effects on muscarinic 3 (M3) muscarinic receptors in smooth airway muscles [11,31].Ipratropium and oxitropium are two examples of short-acting antimuscarinics (SAMAs) that additionally block the inhibitory neuronal receptor M2, potentially contributing to vagally induced bronchoconstriction [11,32].Tiotropium, glycopyrronium bromide, aclidinium, and umeclidinium are a few examples of long-acting muscarinic antagonists (LAMAs), which prolong the duration of the bronchodilator effect by prolonged binding to M3 muscarinic receptors and quicker dissociation from M2 muscarinic receptors [11,31].Unlike beta-2 agonists, these drugs have fewer side effects, which are not severe and are similar to all drugs in this class.It includes dry mouth, urinary symptoms, and a bitter and metallic taste [11].
The model showing the treatment strategy according to symptoms and severity is given in Figure 2.  CAT: COPD assessment test; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist; mMRC: modified Medical Research Council dyspnea scale [33] In the initial management of COPD exacerbations, SABAs with or without SAMA are highly preferred, regardless of the inadequacy of high-quality evidence from randomized controlled trials [30,34].Moreover, as per the GOLD 2023 report, no clinical evidence determines the advantageous role of LABAs with or without LAMAs in acute exacerbations of COPD.However, it is recommended to start these drugs during exacerbations or as soon as possible before hospital discharge [11].Dual LABA therapy and LAMA are highly preferred in moderate-to-severe exacerbations or patients requiring hospitalization.It is also evident from a Cochrane systematic review and network meta-analysis that the combination therapy of LABA in conjugation with LAMA was considered the top-ranked therapy for reducing the exacerbation of COPD [11,35].

Beta Blockers
The effects of beta (β)-receptor activation are countered by beta blockers, which bind specifically to beta receptors and prevent beta-receptor agonists from binding to those receptors.Beta blockers are divided into cardio-selective and non-selective blockers as per different receptor subtypes.Non-selective β-blockers, including propranolol and carvedilol, act on both β-1 and β-2 receptors [36], whereas cardioselective β-1 blockers such as atenolol, bisoprolol, and metoprolol have a 20-fold higher affinity for β-1 receptors as compared to β-2 receptors, which makes them less susceptible to causing bronchoconstriction [36,37].When respiratory conditions are present, review articles and practice recommendations demonstrate a clinical reluctance to administer selective beta-1 blockers; however, a Cochrane review found that beta-1 blockers did not impair beta agonist responsiveness or the ability to treat COPD [38,39].Different observational studies have shown evidence that suggests that β blockers cause a marked reduction in hospital admissions, mortality, hospital visits, especially in the emergency room (ER), and COPD exacerbations in patients with COPD with or without cardiovascular disease (CVD) [37,[40][41][42][43].Despite various studies showing the positive effects of β-blockers, especially cardio selective β1 blockers, on COPD exacerbation and mortality, the recent GOLD report 2023 recommended that selective β1 blockers should only be used in patients having COPD concomitantly with a CVD [11,44]

TABLE 3: Use of antibiotics in COPD exacerbations
COPD: chronic obstructive pulmonary disease; N/A: not available; mg: miligrams

Non-invasive and invasive ventilation
Ventilation refers to providing oxygen (O 2 ) and removing carbon dioxide (CO 2 ).Ventilation is required in patients to halt the progression of cardiorespiratory compromise, which can either manifest as a rising respiratory rate, an asynchronous pattern of respiration, an alteration in mental status and consciousness level, persistent oxygen desaturation despite increasing oxygen concentration, hypercapnia and respiratory acidosis, or circulatory problems, including hypotension and atrial dysrhythmias [67].The modern ventilator combines air with variable concentrations of O 2 under high pressure, providing inspiration and expiration.
Three operator-adjusted factors constitute a 'breath' [67].They are : A) Trigger: A specific rate (ventilator-initiated/ mandatory breaths) at which the ventilator will deliver the breath or alteration in pressure or flow in the ventilator occurring due to conscious breathing by the patient (patient-initiated/spontaneous breaths) [67].
B) Target: Air flowing into the lungs at a fixed rate (volume control) or pressure (pressure control; pressure support; bi-level) [67].
C) Termination: The halting of inspiration and the beginning of expiration are conveyed via a signal to the ventilator.This process can be volume controlled (volume cycled), time held (time cycled: pressure control/bi-level), or flow controlled (decreasing inspiratory flow to a preset level: flow cycled: pressure support) [67].
There are two significant divisions in ventilation practices: non-invasive and invasive.

Non-invasive Ventilation (NIV)
As the name suggests, NIV means providing respiratory assistance while avoiding tracheal intubation.This allows us to prevent harm from complications arising from invasive ventilation, including the requirement of sedation, which poses a risk for hemodynamic compromise as well as delirium, hospital-acquired infections, etc. [68].Figure 3 shows different types of NIV interfaces.

FIGURE 3: Different types of NIV interfaces
Reproduced under the terms of the Creative Commons Attribution license.
NIV: non-invasive ventilation [67] Recent guidelines from the American Thoracic Society (ATS) in 2020 recommend the following uses of noninvasive positive pressure (NPPV) in acute respiratory failure (ARF) [69].Bilevel-positive airway pressure (BiPAP) can be used for COPD exacerbation with acute or acute chronic respiratory acidosis with a pH</=7.35[69].Bilevel-positive airway pressure can be used in order to avoid invasive ventilation in relatively stable patients who are not deteriorating at the moment [69].Bilevel-positive airway pressure, or continuous positive airway pressure (CPAP), can be used in cardiogenic pulmonary edema [69].Guidelines also provide conditional recommendations in ARF [69], such as early use of NIV for immunocompromised patients with ARF, postoperative ARF, use in patients with dyspnea suffering from terminal conditions like cancer as a means to provide palliative care, chest trauma patients with ARF, and in order to protect high-risk patients from post-extubation respiratory failure.

Invasive Ventilation
It requires access to the trachea, usually via an endotracheal tube.Although this method is associated with numerous complications, its indications are extremely rigid.

Different Modes of Ventilation
Mechanical ventilation mode should be selected based on the safety profile, which can be achieved by optimizing the efficiency of ventilation-perfusion matching and pressure-volume mechanics of the lungs [71].Intensive care units (ICUs) use assist-control (AC) mode, which is one of the most common methods of mechanical ventilation [72].In the AC mode, volume cycling is an important feature; this means that a particular volume will always be delivered, with lung compliance playing an important role in determining the pressure being generated.Low plateau pressures are generated by lungs with high compliance; likewise, very high pressures are generated by lungs with low compliance (i.e., stiff lungs), as seen in patients with acute respiratory distress syndrome (ARDS), pulmonary edema, fibrosis, and pneumonia.This knowledge allows us to make changes to prevent barotrauma [73,74].

Benefits of the AC Mode [73]
The feature of triggering breath as needed leads to enhanced patient comfort.Respiratory alkalosis/acidosis can easily be resolved by the operator seamlessly correcting the CO 2 levels.This mode requires less breathing work for the patient.

Drawbacks of the AC Mode [73]
Barotrauma remains an important concern in stiff lungs as this system is volume-cycled, but it could be avoided by regularly checking the plateau pressures.Breath stacking leading to auto-positive end-expiratory pressure (PEEP) can occur if a patient does not have enough time for exhalation, as in the case of tachypnea.Not exhaling the entire volume leads to a progressive accumulation of air in the patient's lungs.Consequently, the plateau and intrathoracic pressures are increased, interfering with the venous return and causing hypotension.This is managed by taking the patient off the ventilator to allow for proper exhalation and readjusting the settings for further use.
Voluntary control to initiate breaths can lead to respiratory alkalosis due to hyperventilation.Adequate sedation resolves this problem.New ventilator modes are designed to counteract some of the drawbacks of AC mode [74,75]: Neurally adjusted ventilator assist (NAVA): The timing and intensity of the diaphragm measured via the sensors are matched with the timing and intensity of the ventilator.This allows us to fulfill the ventilator demand and avoid barotrauma [76][77][78].
Adaptive support ventilation (ASV): Reaching a target minute ventilation via automatic adaptation of inspiratory pressure and respiratory rate.This mode has the added benefit of requiring minimum effort on the part of the patient [79].
Airway pressure release ventilation (APRV): In this pressure-cycled mode, the air is delivered at a particular pressure for a specified amount of time, then the lung is allowed to deflate for a short period, which helps in preventing alveolar damage.This mode is particularly useful when AC cannot be used safely because of constantly elevated plateau pressures and poor oxygenation [80].

Clinical outcomes
A randomized, prospective study was conducted in the ICU of the pulmonology unit of a civil hospital in Jamshoro, Pakistan.The study enrolled patients with diagnosed cases of COPD who were admitted to the ICU due to acute respiratory failure during the period from January to December 2018 [81].Patients with both hypercapnic (partial pressure of arterial carbon dioxide (PaCO 2 ) > 50 mmHg; pH < 7.30) and hypoxemic (partial pressure of oxygen (PaO 2 ) <60 mmHg) respiratory failure [82] were included.Treating pulmonologists and critical care specialists decided whether to give non-invasive positive pressure ventilation (NIPPV) or invasive positive pressure ventilation (IPPV) on the basis of biochemical impairments and clinical findings.Table 5 summarizes the criteria used to select and exclude patients for NIPPV and the indications for IPPV.However, in the IPPV group, this reduction was found to be significant (p=0.08).Regarding PaO 2 improvement with 24 hours of ventilation, the NIPPV group exhibited a statistically significant improvement (p=0.009), while such improvement was not significant in the IPPV group (p=0.23)[81].The NIPPV group demonstrated a statistically significant improvement in respiratory rate (p=0.008),whereas the IPPV group failed to demonstrate any significant improvement [81].The NIPPV group showed a noteworthy and statistically significant improvement in heart rate (p<0.0001).Both groups experienced a significant reduction in systolic blood pressure, while diastolic blood pressure reduction was observed solely in the NIPPV group.All demographic and clinical profile variables can be found in Table 6 [81].PaCO 2 , PaO 2 , respiratory rate, heart rate, and blood pressure of the NIPPV and IPPV groups at baseline (before any medical intervention) and after 24 hours of ventilation are also shown and compared in Table 6 [82].

Criteria
The patient outcomes were evaluated and compared between the two groups.The group that received NIPPV demonstrated significantly reduced durations of ventilation, ICU stays, and post-ICU hospitalization.The mortality rate within the ICU was 13.3% for the NIPPV group, while it was 40% for the group receiving IPPV (p=0.01)[81].In comparison to the NIPPV group, which received ICU care, the mortality rate was 6.7% versus 16.% for the IPPV group.However, it was discovered that there was no statistically significant difference between these groups.Within the first 24 hours of being hospitalized, no reported deaths occurred.A transfer to invasive ventilation was necessary for 20% (n=6) of the NIPPV patients who had unsuccessful non-invasive ventilation.Six of these patients underwent ICU treatment; three (or 50%) of them died there; the other three recovered and were released.After extubation, no cases of ICU readmission or re-ventilation requirements were noticed [81].When compared to IPPV, NIPPV has been shown to significantly improve patient outcomes, even in ARF secondary to causes other than COPD [81].In a meta-analysis of 13 observational studies involving immunocompromised patients admitted to the ICU with ARF, NIPPV significantly decreased in-hospital mortality (odds ratio (OR): 0.43, p-value = 0.007) and 30-day mortality (OR: 0.34, p-value) [84].Non-invasive ventilation was used in a different meta-analysis with more than 2000 patients who had orders to do without intubation (DNI) and only use comfort measures.When patients with DNI were discharged, the combined survival rate was 56% and 32% after a year.The hospital survival rate with NIPPV was 68% in COPD patients with DNI orders [85].

Smoking Cessation
The hallmarks of COPD are increased resistance to the airflow of the small conducting airways, increased compliance, or elastic deformation of the lungs, trapping of air leading to irreversible airflow obstruction, and a hyperinflammatory response, particularly in the small airways of the lungs.This hyperinflammatory response, or abnormal immune response, is an adaptive defense mechanism to long-term exposure to noxious particles and gases like cigarette smoke, and this leads to hypersecretion (chronic bronchitis), destruction of lung tissue (emphysema), and impairment of normal defense mechanisms, which causes further inflammation and fibrosis (bronchiolitis) [86].Figure 4 summarizes the pathogenesis of COPD.

FIGURE 4: The pathogenesis of COPD
Reproduced under the terms of the Creative Commons Attribution license.
Dashed bars represent inhibitory effects.
COPD: chronic obstructive pulmonary disease [86] In all smokers, inflammation in the small airways is evident and gets further amplified in smokers with COPD, causing structural changes that increase with disease severity and even persist after cessation of smoking [86].Pathological processes in COPD, such as inflammation, the imbalance between proteases and anti-proteases, and oxidative stress in the lung [86], are interconnected and related to exposure to cigarette smoke.This explains why smoking is the main aggravating factor in COPD and why the cessation of smoking in COPD patients is of utmost importance.Smoking cessation is the most effective method to limit the progression of the disease, leading to positive outcomes such as reduced dyspnea, decreased frequency of exacerbations and hospitalizations, slowed-down decline in lung function, and decreased mortality [87].
Strategies for smoking cessation could either be pharmacological or non-pharmacological approaches, but first, the healthcare professional needs to identify whether the patient is an active or passive smoker.Together with a thorough medical assessment, the healthcare professional has to follow up until the goal is achieved.The strategy termed 'brief advice' motivates patients to quit smoking and to seek treatment through a single intervention.This has shown a higher frequency of quit attempts than without interventions, and studies show that behavioral support shows better results than offering medication [88].
A model on how to give brief advice has been proposed, which includes five steps known as "The 5 A's Approach" (Ask, Assess, Advice, Assist, Arrange) [88,89] and is as follows: 1) Ask: Inquire about tobacco use and smoking status.
2) Assess: Evaluate the patient's willingness to quit smoking and assess their nicotine dependence.
3) Advice: Strongly and clearly counsel patients into quitting smoking.4) Assist: Set up a plan to begin quitting, and if the patient is nicotine dependent, pharmacological approaches have to be explained.Motivate the patient and provide assistance in the forms needed by the patient.
5) Arrange: Follow-ups have to be arranged during the week of the quit day and encourage the patient to continue the progress.Monitor the patient and review if there are any problems.
Studies suggest that light smokers (those who smoke less than 10 cigarettes per day) do not require pharmacotherapy for smoking cessation, but a small percentage of patients seek medications to quit.Studies also show that more than 50% of light smokers failed in their quitting attempts, suggesting they need pharmacological or psychological support since even smoking less than 10 cigarettes per day still predisposes them to COPD and other tobacco consumption-related diseases [88].Non-pharmacological approaches include one-to-one counseling, individual or group cognitive behavioral therapy (CBT), counseling via telephone, and mobile apps designed with programs to help smoking cessation.Studies suggest that individual behavioral interventions play a significant role in achieving smoking cessation goals [88].

Further Pharmacological Approaches for Smoking Cessation
Varenicline: Varenicline is the most effective drug of choice for smoking cessation, but it is associated with adverse effects that result in early discontinuation of the drug, leading to failure of the goal [90].Compared to nicotine replacement therapy, varenicline is not associated with an increased risk of depression and can be prescribed to COPD patients [88].
Nicotine replacement therapy (NRT): The aim is to reduce nicotine withdrawal symptoms, and from studies, it has been found that using two types of NRT is more effective with increased rates of smoking cessation than using one.The combination of a rapid delivery form of NRT like chewing gum, lozenges, nasal spray, and inhalers, with a slow-releasing form like a nicotine patch is more effective [91].
Bupropion: It is the first non-nicotinic drug approved by the Food and Drug Administration (FDA), has shown a higher abstinence rate in the long term, and therefore it is a first-line drug for smoking cessation [88].When comparing the quitting rate, studies show that it is approximately similar for varenicline and NRT but less for bupropion compared to varenicline and NRT [87].
Cytisine: It is a plant-based alkaloid, and its mechanism of action is similar to that of varenicline as it is a selective partial agonist of nicotinic acetylcholine receptors.A study comparing cytisine and varenicline reported that quitline referrals and retention rates were similar.However, the reported adverse effects for cytisine were less frequent than those for varenicline, and the most frequently reported adverse effects, which were abnormal dreams and nausea, were more frequently reported for varenicline [90].
Vaccine: The mechanism of action will be to produce antibodies to bind to nicotine and reduce its effect.A vaccine is indicated for patients who have failed at many different methods of quitting.Vaccine development is still under study, and modifications that are designed to improve the affinity of serum antibodies are still being tested [88].
Electronic cigarettes: The smoking cessation rates when using electronic cigarettes with nicotine were increased when compared to those with placebo or nicotine patches, but due to the inclusion of other chemicals like lung irritants, less knowledge about the long-term effects of electronic cigarettes, and no FDA approval, it is less effective as a treatment for smoking cessation [91].
Combined treatment with medications: Trials have demonstrated that combined treatment methods increase the probability of successful outcomes.This can either be a psychological intervention with medication or a combined pharmacological treatment [88].Clinical trials carried out to assess effective smoking cessation interventions in patients with COPD found that gradual smoking cessation gave better positive results than abrupt cessation [92].However, in studies carried out to assess whether the commitment to smoking cessation has an impact on smoking cessation efficacy, it was found that adherence or commitment to smoking cessation treatment significantly affects and improves smoking cessation efficacy [93].

Oxygen prescription
Oxygen therapy systems used in COPD can be categorized as low-flow and high-flow devices [94].
Low-flow devices include [94]: 1) Nasal cannula: This is an old method that involves the use of nasal cannula prongs of various sizes and types.It succeeded in using an elastic band that could fit over the patient's ears.
2) Simple mask: This is used when a higher fraction of inspired oxygen (FiO 2 ) needs to be given to the patient.It fits over the bridge of the nose and is kept in place using an elastic band that goes over the head.
3) Non-rebreather: It is comparable to a mask but also includes a reservoir bag connected to the mask by a valve.
4) Venturi mask: This type of face mask allows a certain controlled amount of previously determined FiO 2 .
Modern oxygen delivery methods incorporate therapies like CPAP and BPAP into noninvasive ventilation (NIV).Continuous positive airway pressure (CPAP) therapy is a method used to provide a continuous level of PEEP during both inspiration and expiration, thus increasing the patient's FRC [94].Bilevel positive airway pressure (BPAP) therapy uses a pressure cycling mode for delivering NIV [94].
High-flow devices include [94]: 1) Optiflow TM (Fisher & Paykel Healthcare): It allows the mixing of 100% oxygen with room air and creates the necessary FiO 2 while providing a high flow rate of humidified gas.It is known to reduce the risk of endotracheal intubation in COPD patients with acute exacerbations (AECOPD) [95].
2) Airvo TM 2 (Fisher & Paykel Healthcare): It is a humidifier with a built-in flow generator that provides high-flow-warmed and humidified respiratory gases to spontaneously breathing patients.This can improve mucociliary clearance of secretions more effectively.
The flow rates for the devices used for oxygen delivery are mentioned in Table 7 as follows:

Method of Oxygen Delivery Flow Rate FiO 2 Reservoir Size
Nasal cannula [94] 1-6 L/min 0.22 to 0.24 at 1 L/min, 0.4 at 5-6 L/min -Simple mask [94] 5-10 L/min 0.3-0.8L/min 100-200 mL Non-rebreather [94] 15 L/min 0.6-0.9L/min 300-600 mL Optiflow TM [94,95] 60 L/min 0.3 L/min - Based on the data in Table 8, we can see that NIV and high-flow oxygen delivery methods do not show significant differences in the outcome of treating AECOPD patients, especially the criteria for intubation.PaCO 2 within two hours of treatment [96], and the use of high-flow methods in AECOPD with sputum stasis showed good tolerance among these patients [97].

Immunization With the Pneumococcal Vaccine
Of the different types of bacteria and viruses that cause AECOPD, Streptococcus pneumoniae is the most significant, and hence the administration of pneumococcal vaccines (pneumococcal polysaccharide vaccine 23 (PPSV23) and pneumococcal conjugate vaccine 13 (PCV13)) is recommended for COPD patients as a prophylactic measure.The significant virulence factor of Pneumococci is their capsular polysaccharide, and it is the basis for serotyping and developing vaccines.This capsular polysaccharide has invasive disease potential [99].In early 2000, the vaccine used for children was the 7-valent pneumococcal conjugate vaccine (PCV7).In 2010, it was replaced by PCV13, which decreased the incidence of invasive pneumococcal infections in children and adults.In 2017, PCV13 was introduced into the official vaccination calendar for children under five years of age, and for adults with high risk, PCV13 is given with a booster of PPSV23 after two months.Generally, PPSV23 is recommended for adults [99].Table 9 is a summary of three types of pneumococcal vaccines and their efficacy.For prophylaxis of community-acquired pneumonia (CAP) in patients with COPD, the effectiveness of PPV is higher for patients with severe airflow obstructions and for those under the age of 65 years [100].Studies have been conducted to compare the clinical effectiveness of the above-mentioned vaccines and their effect on the health status of patients with COPD and it was found that both PCV13 and PCV23 are effective during the first one to two years after vaccination.But PCV13 showed a higher level of protection for five-year follow-ups than PCV23 where PCV23 ensured protection only within two years.The risk of complications for patients with PCV23 vaccination also increased after vaccination [101].The existing recommendations for pneumococcal vaccination are that both PCV13 and PCV23 have to be routinely administered in a series to all adults >65 years of age, for adults over 19 years who have an immunocompromized state, functional or anatomic asplenia, cerebrospinal fluid leak or cochlear implants PCV13 is recommended to be routinely administered [102].

Hospital Discharge
Depending on the severity of the exacerbation, a suitable discharge plan should be made after reassessing and reclassifying the patients according to the GOLD criteria.It includes bronchodilation optimization, comorbidity management, anti-pneumococcal vaccination, smoking cessation, and pulmonary rehabilitation [11].

Inhalers Prescribed at Discharge
Inhaled bronchodilators are crucial to symptom management and are frequently given to prevent or lessen symptoms.They include single (LABA or LAMA alone), dual (LABA/LAMA, LABA/inhaled corticosteroids (ICS)), and triple therapy (LABA/LAMA/ICS) [11].Usually, on discharge after a moderate or severe exacerbation, dual therapy or triple therapy should be prescribed.A combination therapy of ICS along with LABA is more effective in reducing the rate of exacerbation and improving health status and lung function as compared to a single therapy.Alternatively, if the response to dual therapy is not appropriate in patients with severe and further exacerbations, i.e., ≥2/year and a blood eosinophil count of ≥300 cells/microL, triple therapy of LAMA, LABA, and ICS is recommended as it causes a reduction in the number of exacerbations and severity [11].Recently, the two large randomized controlled trials named InforMing the PAthway of COPD Treatment (IMPACT) [103] and Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) [104] have provided evidence that the fixed-dose inhaled triple combination improves the overall health status and reduces all-cause mortality when compared with the dual therapy of inhaled long-acting bronchodilation [11].However, ICS should be given cautiously and should not be given alone as it is associated with serious side effects, which are pneumonia, cataracts, oropharyngeal candidiasis, and an increased risk of osteoporosis [11,105].

Pulmonary Rehabilitation
Pulmonary rehabilitation is a key component in COPD management in conjunction with pharmacological therapies [106].Pulmonary rehabilitation programs are usually delivered by multidisciplinary teams in outpatient departments, including exercise training, education, nutritional support, and psychosocial support.It is the most beneficial therapeutic approach for enhancing exercise tolerance, health status, and dyspnea [11,107].It improves the overall quality of life and exercise capacity at all levels of COPD severity; however, the evidence is more compelling in individuals with moderate to severe disease [11,108].
Additionally, it significantly lowers the risk of readmissions in patients who have recently experienced an exacerbation [11].It has been reported from the studies that post-exacerbation rehabilitation can reduce readmissions over a three-month period [109,110].Moreover, it helps in reducing anxiety, depression [111], and all-cause mortality [11].According to a comprehensive analysis of randomized controlled trials, patients who had pulmonary rehabilitation started during their hospital stay or four weeks after discharge had a lower mortality rate than those without rehabilitation [112].Empirical data from a sizable population-based cohort of 190,000 hospitalized COPD patients, in which starting pulmonary rehabilitation within 90 days of discharge was associated with a statistically significant decrease in mortality, has supported these conclusions [113].

Oxygen Therapy
Exacerbation of COPD can cause acute hypoxic and hypercapnic respiratory failure.Hypoxemia is due to a worsening of the ventilation-perfusion (V/Q) mismatch [114].In hospitalized patients with COPD exacerbations, the goal oxygen saturation is 88%-92%, or an arterial oxygen pressure (PaO 2 ) of approximately 60-70 mmHg.This goal minimizes the risk of worsening hypercapnia associated with liberal oxygen supplementation [11,115,116].Compared with a higher target of oxygen saturation, a target of 88%-92% is associated with a lower risk of mortality, according to two small randomized trials [116].
Oxygen is delivered through the following devices during COPD exacerbations in hospitalized patients: The nasal cannula provides flow rates of up to 6 L/min with FiO 2 of 40%.
A simple face mask can provide a FiO 2 of up to 55% with flow rates of 6 to 10 L/min.
Non-rebreathing masks can provide FiO 2 of up to 90%, but they are generally not needed in COPD exacerbations.
The high-flow nasal cannula can provide oxygen with adjustable FiO 2 at higher flow rates (up to 60 L/min).
The indication of high-flow nasal cannula oxygen remains unclear in COPD exacerbation, and the comparison of high-flow nasal cannula with noninvasive ventilation in COPD exacerbation needs more research [11,117,118].
Patients should be assessed for the need for home oxygen within two days prior to discharge.This can be accomplished by measuring oxygen saturation at rest or during a six-minute walk.Patients with COPD often need long-term oxygen therapy (LTOT), defined as oxygen supplementation for at least 15 hours per day.Long-term oxygen therapy is prescribed if a patient has chronic severe hypoxemia, defined as an oxygen saturation <88%, a partial pressure of oxygen of <55 mmHg, an oxygen saturation of 89%, or a partial pressure of 56%-59% associated with cor pulmonale, right ventricular failure, or a hematocrit >55% [119].
Long-term oxygen therapy should be prescribed only when a patient has chronic, persistent hypoxia, is clinically stable, and is on goal-directed therapy for COPD.According to results from the nocturnal oxygen therapy trial (NOTT) and the medical research council (MRC) trial, LTOT increases survival in patients with severe chronic hypoxemia brought on by COPD [120,121].In COPD patients with chronic moderate hypoxemia, nocturnal oxygen therapy (NOT), additional oxygen for moderate hypoxemia, and LOTT revealed no effect [122,123].Patients prescribed LTOT should be reassessed at three months to evaluate the ongoing need for LTOT and followed at six-to 12-month intervals [127].Ambulatory oxygen therapy is defined as oxygen supplementation during exercise and daily activities in patients who become hypoxic during exertion.The American Thoracic Society (ATS) suggests using ambulatory oxygen for patients with severe exertional hypoxemia [128].While the British Thoracic Society (BTS) does not recommend ambulatory oxygen therapy for isolated severe exertional hypoxemia, it should be prescribed to individuals who qualify for LTOT if they are mobile outdoors [129].

FIGURE 5: A typical extracorporeal membrane oxygenation circuit (ECMO)
Reproduced under the terms of the Commons Creative Attribution license. [130] Through the use of a drainage cannula, the patient's venous blood is drawn out and pumped (blood pump) to the oxygenator.After passing through the oxygenator, which contains the oxygenation membrane, the blood is returned to the patient either through an artery (venoarterial-ECMO) or a vein (venovenous-ECMO).
Along with pressure sensors (pre-membrane and post-membrane) and flow sensors, the ECMO circuit has access routes (venous and arterial access points) for the infusion of medications and fluids as well as a collection of laboratory tests.

Lung Volume Reduction Surgery (LVRS)
This is another procedure that can be used for severe emphysema or COPD [140].In 2003, the National Emphysema Treatment Trial (NETT) was published, which was a large, randomized trial for LVRS involving multiple centers with a collaborative approach.This trial shed light on the impact of LVRS in providing benefits in survival ratios and improving the quality of life [141].This trial's results currently help select patients for the LVRS procedure.Although this trial proved to be a monumental achievement for severe emphysema patients, further study was required and is still being conducted to assess the long-term outcomes of LVRS, cost efficiency, exploring LVRS as a potential path for definite lung transplantation, and unilateral vs. bilateral surgery [142][143][144][145][146].There are many bronchoscopic lung reduction devices, but some common ones are foam sealants, metallic coils, airway bypass stents, endobronchial valves, and vapor thermal ablation.Coils are particularly useful for patients with severe emphysema and hyperinflation [147].Figures 6A-6B below show endobronchial valves (Zephyr valve system, Pulmonx) and intrabronchial valves (Spiration valve system, Spiration/Olympus), respectively.Reproduced under the terms of the Creative Commons Attribution license. [148] Endobronchial valves keep the air from re-entering the emphysematous regions, leading to their atelectasis.This makes it a valuable tool for bronchoscopic lung volume reduction [149].The Endobronchial Valve for Emphysema Palliation (VENT) trial results, a significant study, showed only modest improvements in FEV1, dyspnea severity, distance covered in six minutes, and overall quality of life.But compared to regular care, this treatment method was associated with an increased risk of complications such as pneumonia and pneumothorax [150].The details of the major studies that assessed the effectiveness of venous extracorporeal membrane oxygenation in treating patients with acute respiratory distress syndrome are presented in Table 11 below.People with incurable, advanced lung disease who have a short life expectancy are given the option of a lung transplant.A double lung transplant is most commonly done for severe COPD patients [150].The International Society for Heart and Lung Transplantation (ISHLT) dictates the criteria for referral of COPD patients for lung transplantation; it includes an FEV1 ≤ 30% despite being on maximum pharmacological and non-pharmacological therapy, including bronchodilators, home oxygen, smoking cessation, and pulmonary rehabilitation.Additionally, a BMI, Obstruction, Dyspnea, and Exercise Capacity (BODE) index >5 [151] is important in timing the listing of patients for a lung transplant.It is also used as an indicator of death in COPD patients.Unfortunately, COPD patients receiving transplants do not see the same significant improvement in their survivability as those with other conditions such as idiopathic pulmonary fibrosis, cystic fibrosis, and primary pulmonary hypertension [152].However, COPD patients have improved respiratory function, endurance, and quality of life [152].Reproduced under the terms of the Creative Commons Attribution license. [132] Survival rates were calculated using the Kaplan-Meier method.The log-rank test statistic was used to compare survival rates.
The University of Michigan healthcare staff has thoroughly penned a checklist on the key elements of hospital discharge for patients with AECOPD (Table 12).

FIGURE 1 :
FIGURE 1: The GOLD classification of COPD Reproduced under the terms of the Creative Commons Attribution license.GOLD: Global Initiative for Chronic Obstructive Lung Disease; FEV1: forced expiratory volume in 1 second; COPD: chronic obstructive pulmonary disease [11]

FIGURE 2 :
FIGURE 2: Initial pharmacologic treatment of COPD Reproduced with permission under the Creative Commons Attribution License.
in oxygenation, breathing, FEV1, and recurrence risk.A short duration has a better outcome than a longer duration of the drug.Improvement in FEV1 and reduction in hospital stay.(There is no evidence of benefit of the route of administration as both have the same adverse effects.Also, low oral doses, compared to high intravenous doses, should be preferred because there is no associated benefit with the latter.However, a decrease in adverse effects was seen with low oral doses).In other words, both routes have shown the same is noted for a longer therapy.Also, this dose decreases the time of recovery, improvement in lung function, improvement in oxygenation, decreases the risk of recurrence, and decreases the chances of , severe exacerbations, history of antibiotic use, and history of oral corticosteroid use.Efficient against resistant strains of Haemophilus influenzae and Streptococcus pneumoniae.Severe COPD with colonization of Pseudomonas.Decreases sputum inflammatory markers and colonies of bacteria.preventing acute exacerbations in patients requiring systemic steroids and antibiotics.The most significant advantage was seen in older patients.No benefit for current smokers was seen.

SeverityTABLE 5 : 83 ]
Selection criteria for NIPPV (at least two should be present) Moderate to severe dyspnea, accompanied by the use of accessory muscles and paradoxical abdominal motion Moderate to severe acidosis (pH 7.30-7.35)and hypercapnia (PaCO 2 45-60 mmHg) Respiratory frequency > 25 breaths/minute Moderate to severe hypoxemia (PaO 2 < 60 and PaCO 2 <45 mmHg) Exclusion criteria for NIPPV (any of these may be present) Respiratory arrest Cardiovascular instability (hypotension, arrhythmias, myocardial infarction) Somnolence, impaired mental status, uncooperative patient High aspiration risk; viscous or copious secretions Extreme obesity Recent facial or gastroesophageal surgery Craniofacial trauma, fixed nasopharyngeal abnormalities Indications of IPPV Severe dyspnea accompanied by the use of accessory muscles and paradoxical abdominal motion Respiratory frequency > 35 breaths/min Life-threatening hypoxemia (PaO 2 40 mmHg) Severe acidosis (pH < 7.25) and hypercapnia (PaCO 2 > 60 mmHg) Respiratory arrest Somnolence and impaired mental status Cardiovascular complications (hypotension, shock, heart failure) Other complications (metabolic abnormalities, sepsis, pneumonia, pulmonary embolism, barotrauma, massive pleural effusion) NIPPV failure Selection and exclusion criteria for NIPPV and indications of IPPV Reproduced under the terms of the Creative Commons Attribution License.IPPV: invasive positive pressure ventilation; NIPPV: non-invasive positive pressure ventilation; PaO 2 : partial pressure of oxygen; PaCO 2 : partial pressure of carbon dioxide [Devi et al. conducted a study that evaluated the following outcomes: duration of ventilation, length of ICU stay, length of hospital stay, mortality within the ICU or post-ICU within the hospital, and failure of NIPPV, requiring the need to start IPPV.

FiO 2 :
fraction of inspired oxygen

TABLE 8 :
Outcomes of high-flow rate methods of oxygen delivery and noninvasive ventilationSpO2: oxygen saturation; FiO 2 : fraction of inspired oxygen; AECOPD: acute exacerbations of COPD, GOLD: Global Initiative for Chronic Obstructive Lung Disease; NIV: non-invasive ventilation; PaCO 2 : particle pressure of carbon dioxide But a few points worth mentioning would be that high-flow methods were non-inferior to NIV in decreasing 2023 Khan et al.Cureus 15(8): e43694.DOI 10.7759/cureus.43694

Figure 7
Figure 7 below illustrates a Kaplan-Meier plot of the survival of patients who underwent a bronchoscopic lung volume reduction (BLVR) treatment instead of those that did not.

FIGURE 7 : 133 ]
FIGURE 7: Kaplan-Meier plot of survival of patients who underwent BLVR treatment and who did not.Reproduced under the terms of the Commons Creative Attribution License.BLVR: bronchoscopic lung volume reduction; non-BLVR; non-bronchoscopic lung volume reduction; CI: confidence interval *BLVR: patients who underwent a bronchoscopic lung volume reduction treatment.Non-BLVR: patients who did not undergo a bronchoscopic lung volume reduction treatment.The confidence interval was 95%.[133]

FIGURE 8 :
FIGURE 8: Thirty-sixth Adult Lung and Heart-Lung Transplantation Report (2019) of the International Thoracic Organ Transplant Registry (ITOTR) of the International Society for Heart and Lung Transplantation (ISHLT)

Table 2
below comprehensively sheds light on studies reporting the use of systemic corticosteroids to manage COPD exacerbations.

TABLE 2 : Use of systemic corticosteroids in the management of COPD exacerbations
mg: milligrams; COPD: chronic obstructive pulmonary disease; N/A: not available; FEV1: forced expiratory volume in 1 second

Table 3
outlines studies from the literature that have used antibiotics to treat COPD exacerbations.

Table 4
shows indications for the use of invasive ventilation.

TABLE 4 : Indications for the use of invasive ventilation
Reproduced under the terms of the Common Creative Attribution license.

Table 6
presents data indicating that within the NIPPV group, there was no statistically significant reduction in PaCO 2 after 24 hours of ventilation (p=0.28).

TABLE 6 : Comparison of demographic and clinical characteristics of patients on invasive and non-invasive positive pressure ventilation
[81]oduced under the terms of the Creative Commons Attribution license.*Forboth groups (NIPPV and IPPV), values at baseline were compared with those after 24 hours of ventilation.BP: blood pressure; IPPV: invasive positive pressure ventilation; NIPPV: non-invasive positive pressure ventilation; PaO 2 : partial pressure of oxygen; PaCO 2 : partial pressure of carbon dioxide; SD: standard deviation[81] Table 10 summarizes LTOT trials in COPD.

TABLE 10 : Randomized trials of long-term oxygen therapy in COPD Reproduced
[126] the terms of the Creative Commons Attribution license.PaO 2 : partial pressure of oxygen; ECG: electrocardiography; aVF: augmented vector foot; FEV1: forced expiratory volume in 1 second; h/d: hours per day; LTOT: long-term oxygen therapy; PaCO 2 : partial pressure of carbon dioxide; SpO 2 : oxygen saturation; MWT: maintenance of wakefulness test[126]