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Therapeutic strategy in acute or chronic airflow limitation 

Therapeutic strategy in acute or chronic airflow limitation
Therapeutic strategy in acute or chronic airflow limitation

Francesco Macagno

and Massimo Antonelli

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date: 26 January 2021

Key points

  • Oxygen therapy is used for the hypoxia in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The objective is to reach PaO2 60 mmHg (8 kPa; SpO2 90%.). The Venturi mask is the best method for administering oxygen.

  • Inhalation therapy with beta 2 agonists, and anticholinergics reduce bronchial tone and dynamic hyperinflation. This type of administration is superior to intravenous administration and has significantly reduced side effects. Prednisolone at the daily dosage of 0.5 mg/kg for a duration of 8–15 days causes a reduction of hospital stay and therapeutic failures.

  • In AECOPD patients, bacterial infections account for 50% of the cases of exacerbation. The first-line antibiotics are co-amoxiclav, third-generation cephalosporin, or fluoroquinolones.

  • The early use of non-invasive ventilation (NIV) with conventional medical therapies decreases the need for intubation, and reduces the risk of complications and mortality in patients with acute or chronic respiratory failure. The treatment can be started for pH values between 7.25 and 7.35. Pressure support is the most used mode of ventilation and different interfaces can be used to improve tolerance and increase the success rate. In case of In AECOPD patients with previous negative trials of weaning, NIV can be used for reducing the weaning time, and prevent re-intubation.

  • The failure of non-invasive treatment requires endotracheal intubation and mechanical ventilation. To reduce the risk of volutrauma and the worsening of the hyperinflation, tidal volumes between 6 and 8 mL/kg can be used with low respiratory rates and longer expiratory times.


The medical history of a chronic obstructive pulmonary disorder (COPD) patient is characterized by the recurrence of worsening symptoms whose severity is closely related to compromised respiratory function, modifications in the intrapulmonary gas exchanges and comorbidities.

The objective of the initial evaluation of these patients is to increase the success of diagnostic tools, in order to provide the assistance proportional to the severity of the clinical condition. The fragility of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) accounts for their frequent hospitalization and their high intensive care unit (ICU) risk.

The decision-making process for hospital admission of a patient with AECOPD must take into account various aspects, including the severity of the clinical picture, the socio-economic situations, and family context. Advanced age, male gender, previous or current tobacco use, concomitant illnesses, nutritional state, important respiratory function deterioration, frequency of hospitalizations, altered intrapulmonary gas exchange, and long-term oxygen therapy constitute all negative predictors for the development of AECOPD.

In addition to clinical evaluation, arterial blood gas sampling (ABG), chest X-ray evaluation, serum electrolytes, albumin depletion, and biomarkers, such as NTproBNP, C reactive protein (CRP) and pro-calcitonin (PCT) also play an important role for prognosis. In a differential diagnosis of AECOPD patients, pneumothorax or a pulmonary embolism must be ruled out, especially when inflammation markers are negative [1]‌.

Therapy for AECOPD is varied and the need for hospitalization must be always carefully evaluated, considering the risk factors related to the presence of multi-resistant pathogens or the need of invasive procedures.

Oxygen therapy

Oxygen therapy is the most effective and commonly used therapy for the treatment of hypoxia. The prolonged use of oxygen requires an accurate monitoring of blood gases and continuous oximetry. Arterial blood gas analysis allows the simultaneous evaluation of PaO2, PaCO2, and pH. A reasonable target for hospitalized patients might be PaO2 60 mmHg (8 kPa), which correspond to a peripheral oxygen saturation (SpO2) close to 90%. The attempt to improve PaO2 values through the progressive increase of FiO2 is not justified, due to the haemoglobin dissociation curve–small increases of SpO2 require high inhaled fractions (FiO2). The consequent risk is the respiratory centres depression, due to the altered physiologic response, resulting in CO2 retention and subsequent pH worsening. The Venturi mask is the most used method for administering oxygen. This equipment ensures a quite precise administration of FiO2. As an alternative, nasal cannula or transtracheal catheters can be used. A useful decisional algorithm is that proposed by the Infectious Disease Society of America and American Thoracic Society (IDSA_ATS) illustrated in Fig. 112.1 [2]‌.

Fig. 112.1 ATS/ERS TASK FORCE: Standards for the diagnosis and treatment of patients with COPD.

Fig. 112.1 ATS/ERS TASK FORCE: Standards for the diagnosis and treatment of patients with COPD.

Reproduced with permission of the European Respiratory Society: Eur Respir J June 2004 23, 932–46; doi:10.1183/09031936.04.00014304.


At present, three kinds of bronchodilators are normally used—beta 2 agonists, anticholinergics, and methylxantine. Their main effect is to reduce bronchial tone, dynamic hyperinflation, respiratory fatigue, and dyspnoea.

In AECOPD, beta 2 agonists and anticholinergics are commonly administered via inhalation. This route is superior to intravenous administration and significantly reduces side effects. Usually the nebulized dose of salbutamol (the most used beta 2 agonist) varies from 2.5 to 5 mg qds. Nebulized ipratropium (the most used anticholinergic) dose is 0.5 mg bd. Due to its many side effects, theophylline has a narrow therapeutic index. Theophylline serum levels correlate with both therapeutic and toxic effects. Concentrations of 10–20 mg/L are needed to produce bronchodilation with a minimum of side effects. Serum levels exceeding 20 mg/L are associated with an unacceptable incidence of adverse reactions. Theophylline levels above 35 mg/L increase the incidence of seizures and cardiac arrhythmias. Studies have suggested that low dose theophylline (at plasma concentrations below 10 mg/L) has some anti-inflammatory effect on the COPD airway. Low doses seem to increase the anti-inflammatory effects of steroids by increasing the activity of the histone deacetylase [3]‌.

Inhalation therapy can be performed using nebulizers, pre-dosed aerosols, or powders for inhalation. The choice depends on the method, circumstances, and clinical conditions of the patient.


Corticosteroids for oral and systemic use now play an established role in AECOPD. Random control clinical studies have confirmed the effectiveness of prednisolone at the dosage of 0.5 mg/kg daily for a duration of 8–15 days. In particular, a reduction in hospital stay and therapeutic failures has been observed with an improvement in lung function and the reduction of dyspnoea. Longer treatments have not confirmed their effectiveness, with high risk of side effects as hyperglycaemia, osteoporosis, and muscular weakness.


The use of antibiotics in AECOPD plays an important role because bacterial infections account for 50% of exacerbations. The presence of symptoms including leukocytosis, fever, variation of secretion volume, and characteristics, and the presence of markers such as the PCT or reactive protein C RPC) can help the diagnosis, limiting the prescription of empirical antibiotics to cases with high suspicion of infection. The overall objective is to decrease the development of multiresistant strains and mortality risk. Although there is no definite consensus regarding the most appropriate therapy and given the heterogeneousness of various pathogens in question, the proposed first-line antibiotics are co-amoxiclav, third-generation cephalosporin or fluoroquinolones. In case of community-acquired pneumonia the presence of comorbidities, such as COPD requires a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg]; strong recommendation; level I evidence) or a β‎-lactam plus a macrolide (strong recommendation; level I evidence; Table 112.1) [4]‌.

Table 112.1 Antimicrobial therapy in acute exacerbations of chronic obstructive pulmonary disease (AECOPD)


Likely pathogens

Antimicrobial treatment

Uncomplicated AECOPD

  • Age <65 years; FEV1 > 50% predicted; <4 exacerbations/year; no comorbid conditions

H. influenza (more prevalent); S. pneumoniae; M. catarrhalis; H. parainfluenzale; viral; M- pneumonie; C. pneumonie.

Macrolide (azithromycin and clarithromycin); Doxycycline; 2nd or 3rd generation cephalosporin; Respiratory quinolone (moxifloxacin, gatifloxacin, gemifloxacin: against penicillin-resistant S. pneumonie)

Complicated AECOPD

  • Age ≥65 years; FEV1 < 50% predicted; ≥4 exacerbations/year; Comorbid conditions

H. influenza (more prevalent); S. pneumoniae; M. catarrhalis; H. parainfluenzale; viral; M. pneumonie; C. pneumonie; Gram-negative enteric bacilli

Respiratory quinolone (moxifloxacin, gatifloxacin, gemifloxacin: against penicillin-resistant S. pneumonie); amoxicillin/clavulanate

Complicated AECOPD at risk for Pseudomonas aeruginosa infection

  • FEV1 < 35% predicted; recurrent courses of antibiotics or steroids; bronchiectasis

H. influenza (more prevalent); S. pneumoniae; M. catarrhalis; H. parainfluenzale; viral; M. pneumonie; C. pneumonie; Gram-negative enteric bacilli; Pseudomonas aeruginosa.

Fluoroquinolone with antipseudomonal activity (ciprofloxacin and levofloxacin)

Martinez et al., Expert Review of Anti-infective Therapy, 2006, 4(1), pp. 101–124, copyright © 2006, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Mechanical ventilator support

In AECOPD, the increase of the airway resistances and the need for greater minute ventilation exacerbate the limitation of expiratory flow, increasing dynamic hyperinflation and intrinsic PEEP (positive end-expiratory pressure). This leads to an increase in respiratory effort with deterioration of respiratory muscle function. When respiratory muscles have exhausted their capacity to maintain adequate alveolar ventilation, CO2 retention leads to worsening respiratory acidosis. Ventilatory support represents a milestone of the treatment of exacerbated AECOPD patients.

The rationale to start a form of ventilator assistance is well summarized in Fig. 112.2.

Fig. 112.2 ATS/ ERS TASK FORCE: Standards for the diagnosis and treatment of patients with COPD.

Fig. 112.2 ATS/ ERS TASK FORCE: Standards for the diagnosis and treatment of patients with COPD.

Reproduced with permission of the European Respiratory Society: Eur Respir J June 2004 23, 932–46; doi:10.1183/09031936.04.00014304.

Non-invasive ventilation

NIV must be considered the first option in AECOPD patients and acute respiratory failure if there are no contraindications, such as severe impairment of consciousness, facial trauma, or incapability to control the airways or intolerance. The effectiveness of NIV lies in the reduction of the workload of the respiratory muscles with reduction of dyspnoea and respiratory rate and a subsequent improvement of the respiratory gases and pH [5]‌.

The main advantages of an early trial of NIV are the easy and prompt application, and its possible use outside the ICU. Many prospective randomized and controlled studies have verified the effectiveness of NIV in the treatment of acute or chronic respiratory failure. Compared with traditional treatments, early application of NIV improves survival, reduces the need for endotracheal intubation and related complications, and reduces the length of stay in ICU and hospital. Treatment of patients with light to moderate respiratory failure characterized by pH values between 7.25 and 7.35 has shown a failure rate not higher than 20%. The treatment of more severe and later conditions had failure rates close to 50% and inversely correlated to the severity of respiratory acidosis. In these cases, the use of NIV as an alternative to invasive ventilation does not increase mortality, while reducing the risk of complications as ventilator-associated pneumonia (VAP) or difficult weaning [6]‌. The use of NIV in critically-ill patients should be avoided when contraindications or the impairment of consciousness (Glasgow coma scale <10) are present and, in case of shock, serious arrhythmias or acute coronary syndrome, serious agitation, and vomiting with the risk of inhalation. NIV failures are more frequent during the first hours of use and are mainly related to the severity of the acidosis, mental deterioration, and comordities. The lack of improvement of gas exchanges during the first hours of ventilation is a predictor of failure. Patients with COPD and severe respiratory failure, who have already been evaluated with precrisis functional respiratory damage, are more prone to fail NIV, requiring endotracheal intubation, notwithstanding an initial improvement [7,8].

When the case of exacerbation is a community acquired pneumonia the failure rate is higher.

In hypercarbic AECOPD with respiratory failure with a cardiac component, NIV has shown a high success rate with rapid resolution of the lung oedema [9]‌.

One crucial element for the success of NIV is due to the choice of ventilators and interfaces. Air leaks from the mask have significant effects on the triggering of the ventilator and patient–ventilator interaction. The majority of the ventilators conceived for home-use have an efficient internal algorithm for leak compensation. Old ICU ventilators are without these features and, if used for delivering NIV, require a fine-tuned set-up of the trigger sensitivity to avoid auto-triggering phenomena and asynchrony. Recently, the introduction of specific modules, based on sophisticated algorithms for leaks compensation, have resolved this inconvenience

The preferred interfaces for delivering NIV are oro-nasal or face masks. However, lack of tolerance, skin lesions, and leaks can cause a failure requiring endotracheal intubation. Recently, helmets introduced for NIV therapy have reduced discomfort, cutaneous pressure lesions, eye irritation, and gastric distension. The main limitations of this interface are, however, determined by a quote of potential rebreathing and the possibility of dyssynchrony that need specific settings [10].

Several ventilation modes can be used. The ones most frequently used are pressometric techniques.

PSV is the most common mode applied for NIV. It allows the patient to determine the respiratory frequency and tidal volume (VT). The main limitation of this modality is the possible decrease in volume occurring as a result of an increase of resistance of the respiratory apparatus and the need for proper synchronization between patient and machine, more difficult in case of leaks. Pressure support is given to reduce the work of breathing and prevent barotrauma. In general, the level of pressure support are tuned between 10 and 20 cmH2O according to clinical response, the relief of the accessory muscles of respiration and the reduction of respiratory frequency. PEEP is set between 4 and 6 cmH2O to compensate the intrinsic PEEP and ineffective respiratory efforts.

Pressure assisted and controlled modes can be also used. They allow a better control of the effective volume, but are preferred substitute at least in part for spontaneous respiratory activity.

Controlled volume modes are rarely used, in the absence of leakage ensure respiratory frequency and a determined current volume, but invariably cause discomfort with possible asynchrony, and increase ineffective respiratory efforts and work. This ventilator mode is more commonly adopted in the early phases of invasive mechanical ventilation of the most severe patients, after intubation, to assure adequate ventilation and control hyperinflation.

The careful monitoring of the patient and the response to NIV are indispensable elements for therapeutic success. Peripheral oxygen saturation monitoring, blood gas analyses, evaluation of arterial pressure, respiratory and cardiac frequency are aimed to constantly adapting ventilation parameters to the changing needs of the patient. The therapeutic response will therefore establish the assistance needs and the duration of ventilation support.

NIV weaning can be achieved by reducing the duration of ventilation periods during the day and keeping patient on nocturnal sessions to lighten the work of respiratory muscles and improve sleep quality [11].

The resolution of the causes of exacerbation, the adequate oxygen saturation with a PaO2/FiO2 above 120, a PEEP level below 5 cmH2O, a pH above 7.35 with a stable haemodynamic condition without sign of cardiac ischaemia, dyspnoea, or tachypnoea suggest the suspension of ventilation support.

Invasive mechanical ventilation

The failure of non-invasive treatments, the need to protect airways, shock, and changes in the state of consciousness, serious arrhythmias or severe cardiac failure require endotracheal intubation and mechanical ventilation.

The initial regulation of the ventilator is usually adjusted in Volume controlled mode with great attention to minimize the effects of auto-PEEP. In order to reduce the risk of volutrauma, low current volumes are used in the order of 6-8 ml/kg with low respiratory frequencies and with an I/E ratio adequate to allow a longer expiration time to avoid hyperinflation. In general, high respiratory flows should be used, usually greater than 60 litres/minute in order to reduce the length of insufflations.

The improvement of clinical conditions with low level or absent sedation are crucial to start weaning from invasive mechanical ventilation. The preferred techniques of weaning are the progressive decrease to Pressure Support and PEEP up to value respectively of 8 cmH2O Pressure support and 3–5 cmH2O PEEP, or T piece trials [12].

The weaning failure in chronic patients is high. The stability of vital parameters, a respiratory rate lower than 35 breath/min and the capacity to maintain adequate peripheral O2 saturation for at least 2 hours are predictors of success.

In AECOPD patients with previous negative weaning trials, NIV can be applied immediately after extubation to improve the chances of success and prevent re-intubation.


The authors gratefully acknowledge the input of Luca Montini.


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