The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure

INTRODUCTION — Acute hypercapnic respiratory failure can be encountered in the emergency department and inpatient units, as well as in postoperative and intensive care units. Acute hypercapnia is often not suspected, leading to delayed diagnosis. If left untreated, acute hypercapnic respiratory failure may become life-threatening resulting in respiratory arrest, seizures, coma, and death.

The approach to adult patients with suspected hypercapnia, as well as the diagnosis and treatment of acute hypercapnic respiratory failure are discussed in this topic. For the most part, this topic discusses the approach in patients who are spontaneously breathing, although many of the same principles can be applied to patients who are receiving invasive or noninvasive ventilatory support. The mechanisms, etiologies, and end-organ effects associated with hypercapnia are discussed more extensively separately.

MECHANISM AND ETIOLOGY — Hypercapnia is defined as an elevation in the arterial carbon dioxide (CO₂) tension (PaCO₂). The CO₂ level in arterial blood is directly proportional to the rate of CO₂ (VCO₂) production and inversely proportional to the rate of CO₂ elimination by the lung (alveolar ventilation). Alveolar ventilation (V_A) is, in turn, determined by minute ventilation (V_E) and the ratio of dead space (V_D) to tidal volume (V_T) (V_A = V_E x [1 - V_D/V_T]). Increased dead space and reduced minute ventilation are common causes of hypercapnia. By contrast, unless a patient has limited pulmonary reserve or has fixed ventilation with a mechanical ventilator, increased CO₂ production rarely results in clinically important hypercapnia. Etiologies associated with hypercapnia are listed in the table (table 1). Detailed discussion of the mechanisms and etiologies of hypercapnia is provided separately. (See "Mechanisms, causes, and effects of hypercapnia".)

WHEN TO SUSPECT ACUTE HYPERCAPNIA — Hypercapnia should always be suspected in those who are at risk for hypoventilation (eg, sedative use, history of sleep apnea) or have increased physiologic dead space and limited pulmonary reserve (eg, chronic obstructive pulmonary disease [COPD] exacerbation) who present with shortness of breath, a change in mental status, new hypoxemia, and/or hypersomnolence.

The presenting features of acute hypercapnia are variable with no signs or symptoms that are sensitive or specific for the diagnosis. Patients can present with the manifestations of hypercapnia itself as well as with the manifestations associated with the underlying disorder, both of which are discussed in detail in the sections below. It is important to remember that tachypnea does not always equate to increased alveolar ventilation; patients with increased dead space and mechanical abnormalities of the respiratory system may have elevated respiratory rate and accessory muscle use, yet still be hypercapnic.

Clinical features of hypercapnia — The clinical features of hypercapnia are mostly neurologic and pulmonary, and vary depending upon the level and rate of carbon dioxide (CO₂) accumulation in arterial blood:

●Patients with mild to moderate hypercapnia or hypercapnia that develops slowly may be anxious, and/or complain of mild dyspnea, daytime sluggishness, headaches, or hypersomnolence.

●Patients with higher levels of CO₂ or rapidly developing hypercapnia develop frank alterations in sensorium including delirium, paranoia, depression, and confusion, which progress to somnolence and then coma (CO₂ narcosis) as levels continue to rise.

●Patients with severe hypercapnia may present with asterixis, myoclonus, and seizures as well as papilledema, and dilated superficial veins.

Normal individuals do not exhibit a depressed level of consciousness until the arterial CO₂ tension (PaCO₂) is greater than 75 to 80 mmHg (9.9 to 10.9 kPa), while patients with chronic hypercapnia may not develop symptoms until the PaCO₂ rises acutely to greater than 90 to 100 mmHg (11.9 to 13.3 kPa). The mechanisms that underlie the cerebral and cardiorespiratory effects of hypercapnia are discussed separately. (See "Mechanisms, causes, and effects of hypercapnia", section on 'Effects of hypercapnia'.)

Clinical features of the underlying cause — Due to the wide range of etiologies for hypercapnia (table 1), the presenting features from the underlying disorder can be variable and frequently overlap. However, the presence of an underlying disorder or risk factor should increase the suspicion for hypercapnia and prompt arterial blood gas analysis (though venous blood gas analysis can also be used). Clinicians should look for a history of common risk factors, including sedative use/abuse, the signs and symptoms of chronic lung disease (eg, clubbing with bronchiectasis or cystic fibrosis, hyperinflation, thoracic cage abnormalities, cyanosis from associated hypoxemia), and obvious central or peripheral neuromuscular disorders (eg, hemiplegia, obesity, snoring, neuromuscular weakness). A commonly missed presentation of acute hypercapnia is the postoperative patient/post anesthetic patient who becomes hypoxemic due to hypoventilation. There is a tendency to treat hypoxemia by giving supplemental oxygen, which may worsen the hypercapnia, lead to more hypoxemia, and further increases in supplemental oxygen ultimately resulting in a vicious cycle and respiratory failure. (See 'Titration of oxygen' below.)

A thorough history and examination should be elicited to confirm or rule out the following common etiologies:

●Sedative use – Patients may exhibit a history of illicit or prescribed sedative use with drugs including narcotics and benzodiazepines, as well as anesthetic agents.

●COPD or other lung disorders – During an exacerbation or in response to oxygen administration, some patients with COPD (but not all) develop acute or acute-on-chronic hypercapnia. Similarly, patients with end-stage interstitial lung disease (ILD) may present with acute hypercapnia. The diagnosis of COPD or ILD may be known or may be evident by a long smoking history together with the typical clinical signs of COPD or ILD, which are discussed separately.

●Central, neuromuscular, and thoracic cage disorders – Similar to patients with COPD, patients with central, neuromuscular, and thoracic cage disorders may develop acute or acute-on-chronic hypercapnia during times of acute stress (eg, infection, dehydration, postoperative states). The clinical manifestations of the common neuromuscular disorders associated with hypercapnia are discussed separately:

•Central disorders:

-Encephalitis

-Stroke

-Central and obstructive sleep apnea

-Obesity hypoventilation

-Congenital central alveolar hypoventilation and other disorders of ventilatory control

-Brainstem disease

-Hypothyroidism

-Hypothermia

•Respiratory muscle or thoracic cage disorders:

-Cervical spine injury

-Amyotrophic lateral sclerosis

-Poliomyelitis

-Guillain-Barré syndrome

-Phrenic nerve injury

-Critical illness polymyoneuropathy

-Myasthenia gravis

-Muscular dystrophy

-Polymyositis

-Kyphoscoliosis, thoracoplasty, and flail chest

-Ankylosing spondylitis

-Pectus excavatum

-Hypophosphatemia and hypomagnesemia

Other features — Laboratory (eg, elevated bicarbonate level), imaging (eg, signs of hyperinflation), and other supportive testing that may identify conditions associated with hypercapnia are discussed below.

INITIAL EVALUATION AND DIAGNOSTIC APPROACH — When patients present with suspected hypercapnia (mental status changes, somnolence, hemodynamic instability, acute-onset dyspnea, and respiratory distress), the clinician should simultaneously perform the following [1]:

●Assess and stabilize the airway, breathing, and circulation

●Perform a brief clinical bedside assessment with telemetry and oxygen monitoring

●Draw an arterial blood gas (ABG)

●Administer initial bedside therapies

Once the diagnosis is made and the patient is stabilized, the etiology can usually be determined or narrowed to a few possibilities, such that subsequent testing and therapies can be appropriately tailored.

For the most part, this section discusses the approach in patients who are breathing spontaneously, although many of the same principles apply to patients receiving invasive or noninvasive ventilatory support.

Assess airway, breathing, circulation — The first priorities are to stabilize the airway and breathing with oxygen and/or mechanical ventilation when necessary, and to secure intravenous access while ABGs are being drawn.

●Airway – Patients should be assessed for upper airway obstruction, which could be the result of carbon dioxide (CO₂) narcosis or a contributing factor in the development of hypercapnia. Oral or nasal airways as well as a chin lift/jaw thrust can be used to achieve airway patency.

●Oxygen – Oxygen should be administered to patients with evidence of clinically significant desaturation (eg, peripheral saturation <90 percent). However, when oxygen-associated hypercapnic respiratory failure is suspected and the peripheral oxygen saturation is in the high normal range (eg, ≥95 percent), supplemental oxygen can be gradually reduced to maintain peripheral saturation between 90 and 93 percent, while results from ABGs are pending. The administration of oxygen to patients with hypercapnia is discussed below.

●Ventilatory support – Patients with severe respiratory distress are usually intubated. Rapid sequence intubation, typically with propofol (1 to 2 mg/kg intravenously), etomidate (0.3 mg/kg intravenously; unless septic shock is suspected) or ketamine (1 to 2 mg/kg intravenously), and a rapidly acting neuromuscular blocker (eg, rocuronium 1 to 1.5 mg/kg intravenously), is the preferred approach. For patients who are hemodynamically unstable, agents that worsen hypotension (eg, propofol, midazolam) should be avoided.

For patients with hypercapnic respiratory failure from upper airway obstruction, in whom an endotracheal tube cannot be placed, an emergent cricothyrotomy can be performed, the details of which are discussed separately. In those with mild to moderate distress with a known treatable cause for the upper airway obstruction, eg, laryngeal edema, initiation of supplemental oxygen via a mixture of helium and oxygen (heliox) may reduce turbulent flow and the work of breathing while treatment for the underlying problem is started.

For patients with mild to moderate respiratory failure, particularly if due to chronic obstructive pulmonary disease (COPD) or congestive heart failure exacerbation without severely impaired consciousness, noninvasive ventilation or bag-mask valve ventilation may stabilize the patient's condition and avert endotracheal intubation. The indications for and application of these therapies are discussed below.

●Intravenous access – Peripheral venous access is sufficient for the initial management of acidosis-associated hypotension or shock with intravenous fluids and/or vasopressors.

●Intra-arterial access – Arterial access is not typically necessary unless the patient requires multiple arterial blood draws or arterial access is needed for an alternative reason (eg, hemodynamic monitoring).

Arterial blood gas analysis — Even a low clinical suspicion should prompt ABG analysis for the diagnosis of acute hypercapnic respiratory failure. The identification of an elevated partial pressure of CO₂ is diagnostic of hypercapnia (arterial CO₂ tension [PaCO₂] >45 mmHg). Once identified, hypercapnic respiratory failure should be classified as acute, acute-on-chronic, or chronic. Acute hypercapnia is always accompanied by a respiratory acidosis (pH <7.35) that is appropriate for the degree of hypercapnia, whereas chronic hypercapnia is associated with a low-normal or near normal pH (assuming the patient has normal renal function and the ability to excrete acid by the kidney), and acute-on chronic hypercapnia lies in between these parameters (figure 1 and figure 2).

Due to greater accuracy, we prefer that ABG analysis be performed in patients with suspected hypercapnic respiratory failure rather than venous blood gas (VBG) analysis. Peripheral VBGs tend to have a slightly higher PaCO₂ and bicarbonate level, and a lower pH, but can be used if ABGs cannot be obtained and/or if frequent samples are necessary to follow therapy. Detailed discussion on the use and interpretation of VBGs is provided separately.

Distinguishing acute and chronic hypercapnia — Acute respiratory acidosis is present when an abrupt failure of ventilation occurs (eg, central nervous system disease or drug-induced respiratory depression, severe acute airways disease) or there is an acute process that worsens alveolar ventilation in a patient with limited pulmonary reserve (eg, pneumonia in a patient with COPD). Chronic respiratory acidosis develops over days to weeks such that bicarbonate rises as an indication that renal compensation, ie, secretion of acid, has occurred (usually more than three to five days; eg, COPD, chronic neuromuscular disorders). In mild acute respiratory acidosis, the serum bicarbonate typically rises by a 2 to 5 meq/L as CO₂ and H₂O combine to form carbonic acid, which dissociates to a bicarbonate molecule and a proton. Buffering of carbonic acid in red blood cells by hemoglobin also contributes to the acute rise in serum bicarbonate. It is important to note that the metabolic compensation for chronic respiratory acidosis is secretion of acid by the kidney; the elevated serum bicarbonate in this scenario is a byproduct of acid secretion and does not play a role in buffering the respiratory acid.

When interpreting ABGs for hypercapnia, the following generally applies:

●In acute or acute-on-chronic respiratory acidosis, the PaCO₂ is elevated above the upper limit of the reference range (ie, >45 mmHg) with an accompanying acidemia (ie, pH <7.35). In patients with pure acute respiratory acidosis and previous normocapnia, the measured level of hypercapnia and bicarbonate accurately predicts the pH (figure 1 and figure 2). In contrast, for patients who develop acute-on-chronic respiratory acidosis, the measured pH will be higher than predicted.

●In mild to moderate chronic compensated respiratory acidosis, the PaCO₂ is elevated above the upper limit of the normal reference range (ie, >45 mmHg), but the pH is at the lower limit of normal or near-normal pH (eg, pH 7.33 to 7.35) secondary to renal compensation (secretion of acid from the distal tubule) (figure 1 and figure 3).

Importantly, these rules are general principles and may be influenced by the presence of mixed and complex acid-base disturbances, such that we prefer a systematic approach to ABG interpretation. The assessment of acid-base disturbance as well as the interpretation of ABGs are discussed separately.

Determining the alveolar-arterial gradient — Hypoxemia frequently coexists with hypercapnic respiratory failure. When feasible, the alveolar-arterial gradient (PAO₂ – PaO₂ also known as the A-a gradient) should be calculated (from a room air blood gas) to distinguish hypercapnic respiratory failure due to global hypoventilation (extrapulmonary respiratory failure) from respiratory failure due to abnormal gas exchange from intrinsic lung disease. Since the range for a normal gradient increases with age, the expected gradient for an individual can be approximated by the equation A-a gradient = age x 0.3. An A-a gradient within the normal range in the setting of an elevated PaCO₂ is highly suggestive of global hypoventilation, whereas a widened gradient suggests that underlying lung disease may be contributing to the measured hypercapnia. Measuring the A-a gradient is more readily applied to patients in the chronic stable state and difficult to perform in patients with acute presentations because patients with acute hypercapnia often require the immediate application of supplemental oxygen, which precludes calculating a room air A-a gradient; however, if feasible, it is appropriate to draw an ABG prior to initiation of supplemental oxygen. An A-a gradient can also be reliably determined in situations where the fraction of inspired oxygen (FiO₂) is accurate (eg, mechanical ventilation).

As an example, global hypoventilation from sedatives is likely the primary cause of hypercapnic respiratory acidosis in an otherwise healthy young drug abuser with somnolence, a normal chest radiograph, positive toxicology screen, and a normal A-a gradient of <20 mmHg. In contrast, abnormal gas exchange from increased dead space in patients with a COPD exacerbation or end stage interstitial lung disease (ILD) is typically associated with the usual clinical signs and symptoms of a COPD or ILD exacerbation and an ABG that reveals hypercapnia and a widened A-a gradient.

Bedside clinical assessment — A brief history and examination should be performed at the bedside so that therapies targeted at a specific underlying cause can be administered quickly. In addition to ABGs, a complete blood count, serum chemistries including bicarbonate and electrolytes, and a chest radiograph should be performed. Once the patient is stable, subsequent testing (eg, toxicology screen, thyroid function tests, chest or brain imaging) and therapies can then be appropriately tailored.

History and examination — A high clinical suspicion for the presence of hypercapnic respiratory failure is critical for diagnosis. An initial efficient and targeted history from prehospital or hospital providers, the patient, their relatives, and/or the medical record should provide ample information on a patient's risk for hypercapnia, as well as the potential etiology (table 1). For the detection of common etiologies, this may include a review of prescribed medications, a drug history, past history of chronic lung disease, sleep apnea, or a neuromuscular disorder, a smoking and travel history as well as a history of recent trauma. For patients on oxygen, recent changes in the flow settings should be assessed. Once patients are stable and the diagnosis of hypercapnic respiratory failure is made, a more detailed approach to the history should be undertaken with a specific etiology in mind.

Physical examination should be directed towards uncovering the cause of hypercapnia. The evaluation should include an assessment of sensorium, mucous membranes, asterixis, lungs, heart, thoracic cage, and abdomen, as well as skin and joints. A brief neurologic examination should also be performed to distinguish the many central and peripheral neurologic etiologies associated with the development of acute and/or chronic hypercapnia.

A more detailed discussion of the clinical presentation of the many causes of hypercapnic respiratory failure is provided above.

Laboratory assessment — Common laboratory tests should be obtained to assess for clues to the presence of hypercapnia and/or identify a potential etiology of hypercapnic respiratory failure, which include:

●Serum chemistries, bicarbonate, and electrolytes – An elevated bicarbonate level may suggest underlying chronic hypercapnia at baseline, although this feature is nonspecific as other etiologies (eg, volume contraction, diuretics) can increase the bicarbonate concentration. Similarly, arterial blood gases drawn on previous admissions or in the chronic stable state may identify the presence of normocapnia or chronic hypercapnia at baseline.

Additional abnormalities that may suggest a contributing etiology for hypercapnia include electrolyte disturbances, especially low phosphate and magnesium levels. Rarely does hypermagnesemia, hypokalemia, or hypercalcemia cause respiratory muscle weakness that is severe enough to result in hypercapnia.

●Complete blood count – Chronic hypoxemia from underlying lung disease may be associated with polycythemia. Although rare, an elevated eosinophil fraction on a complete blood count may be consistent with eosinophilic myalgia.

Additional tests that may be considered on a case-by-case basis include:

●Toxicology screen – A toxicology screen (opiates, benzodiazepines, tricyclic antidepressants, barbiturates) should be drawn when an overdose is suspected and drug history unavailable.

●Thyroid function tests – Thyroid function tests may reveal an elevated thyroid stimulating hormone (TSH) and low thyroxine (T4) consistent with hypothyroidism.

●Creatine phosphokinase – An elevated creatine phosphokinase (CPK) may suggest infectious or autoimmune polymyositis, hypothyroidism, rhabdomyolysis secondary to colchicine or chloroquine toxicity, or procainamide myopathy.

●Other – Additional testing aimed at identifying other specific etiologies are discussed separately.

Imaging assessment — There are no imaging abnormalities that are sensitive or specific for the diagnosis of hypercapnia. A chest radiograph should be performed in most patients who present with acute hypercapnia to look for intrapulmonary pathology that may be associated with the development of hypercapnia. Additional imaging tests can be obtained on an individual basis to identify suspected etiological risk factors. As examples:

●Chest imaging – A chest radiograph or computed tomography of the chest may reveal underlying COPD (eg, hyperinflation, flattened diaphragms) and interstitial lung disease (reticular nodular shadows), as well as thoracic cage abnormalities (kyphoscoliosis, pectus excavatum, ankylosing spondylitis, fractured ribs) or diaphragmatic paralysis (unilateral or bilateral elevation of diaphragmatic leaflets). The latter may also readily be diagnosed with point of care ultrasound.

●Brain and spinal cord imaging – Computed tomography or magnetic resonance imaging of the neck or brain may reveal additional central (especially brainstem) or peripheral nervous system etiologies for hypercapnia (eg, stroke, tumor, traumatic transection of the spinal cord).

●Other – Additional imaging aimed at identifying other specific etiologies are discussed separately.

Physiologic assessment — Serial bedside measurement of vital capacity and negative inspiratory force is of value in predicting progressive or resolving hypercapnic respiratory failure in patients with myasthenic crisis, the details of which are discussed separately. A vital capacity less than 1 L in a patient with normal baseline lung function warrants observation in an intensive care unit because of the increased risk of acute respiratory failure. Notably, the fall in vital capacity may occur prior to the rise in PaCO₂.

While typically there is no value in obtaining a full set of pulmonary function tests (PFTs) in patients who present with acute hypercapnic respiratory failure, some patients may have previous PFTs with obstructive or restrictive physiology that may help to determine any underlying etiology.

Similarly, previous sleep studies, nerve conduction studies (NCS), or electromyography (EMG), including phrenic NCS and diaphragmatic EMG may suggest underlying sleep apnea or neuromyopathy, respectively.

INITIAL BEDSIDE THERAPIES — The initial therapies discussed below may be administered at the bedside based upon a brief history obtained from prehospital providers, hospital staff, family members, and/or the patient. Although the results of arterial blood gas (ABG) analysis and other investigative tests are preferred, their absence should not preclude the administration of these potentially life-saving therapies.

Once the diagnosis of hypercapnic respiratory failure is in place and an etiology identified, ongoing treatment should be administered in a monitored setting.

Reversal and avoidance of sedatives — For patients with suspected overdose, antidotes may be administered when considered safe by the clinician. Antidotes that are available for common agents that induce hypercapnia are naloxone for opiate overdoses and flumazenil for benzodiazepine (BDZ) overdose. Gastric decontamination is considered by many experts as risky and is only administered when the benefit is clear and the airway is protected.

●Naloxone is the antidote of choice for patients with an overdose of opiates. When spontaneous ventilations are present, an initial dose of 0.05 mg intravenously (IV) is an appropriate starting point, and the dose should be titrated upward every few minutes until the respiratory rate is 12 or greater. Apneic patients should receive higher initial doses of naloxone (0.2 to 1 mg). Patients in cardiorespiratory arrest following possible opioid overdose should be given a minimum of 2 mg of naloxone. The intravenous route is preferred with careful titration of the dose so as not to induce opiate withdrawal. Further details regarding the administration of naloxone (including via the intranasal route) are provided in the table (table 2) and discussed separately.

●Flumazenil administration in chronic users of BDZ is controversial due to the risk of withdrawal seizures and the inconsistent effect on the reversal of respiratory depression. However, it appears to be safe and effective when used to reverse the sedating effects of a BDZ given acutely in patients who do not use them chronically (eg, for procedural sedation). In adults, the recommended initial dose is 0.2 mg given IV over 30 seconds. Repeated doses of 0.2 mg, to a maximum dose of 1 mg, can be given until the desired effect is achieved. The biggest disadvantage of flumazenil is that it is short-acting. In the event of resedation after initial administration, the dosing regimen described here can be repeated, but no more than 3 mg of flumazenil should be given within any one hour. Although infusions are available they are rarely used. Further details regarding flumazenil are provided separately.

●For many patients with oral sedative overdoses, gastric emptying and activated charcoal administration is of unproven benefit and considered by most physicians as risky especially in somnolent patients due to the increased risk of aspiration, even when given through a through a nasogastric tube. It should only be administered in patients for whom there is a known benefit as recommended by toxicology experts and in whom the airway is protected (eg, intubated patients).

●In general, sedatives should be avoided in patients with hypercapnic respiratory failure due to the potential worsening of respiratory acidosis and respiratory arrest. However, in rare cases (eg, hypercapnia associated with anxiety and rapid shallow breathing) small doses of anxiolytic or morphine may be beneficial and allow more effective ventilation due to a reduced respiratory rate, reduced dynamic hyperinflation in patients with moderate-to-severe expiratory airflow obstruction, and increased vital volume (ie, slower but deeper breaths) [2].

Bag-valve mask or noninvasive ventilation — Some patients with acute hypercapnic respiratory failure benefit from the application of bag-valve mask or noninvasive ventilation (NIV). While the major focus of both of these maneuvers is a reduction in the partial pressure of arterial carbon dioxide (arterial carbon dioxide tension [PaCO₂]; ie, improved ventilation), most patients gain the additional benefit of improved oxygenation if the treatment is effective in reducing the PaCO₂. While many patients improve on NIV, those who fail should undergo endotracheal intubation and be started on full mechanical ventilation.

Bag-valve mask administration may be used to temporarily ventilate patients in whom a rapid reversal of hypercapnic respiratory failure is expected (minutes). As an example, a somnolent but spontaneously breathing patient with a narcotic overdose may receive this form of ventilation while naloxone is being administered, thereby avoiding invasive mechanical ventilation. However, in most cases it is administered to pre-ventilate patients prior to intubation and mechanical ventilation.

Patients most likely to benefit from NIV are those with an acute exacerbation of chronic obstructive pulmonary disease (COPD). Additional patients who may benefit include those with coexistent hypoxic respiratory failure from cardiogenic pulmonary edema, postextubation respiratory failure, patients with obstructive sleep apnea, and patients with neuromuscular disorders. Details supporting the value of NIV in these patient groups are provided separately.

●Patients suitable for NIV – While there are no specific criteria on arterial blood gas analysis that determine when NIV should be applied, in general, patients with a moderate acute acidosis (eg, pH <7.3) who are in moderate-to-severe respiratory distress, with tachypnea (respiratory rate >25) and an increased work of breathing are frequently suitable candidates for a trial of early NIV. However, patients with mild-to-moderate carbon dioxide (CO₂)-induced somnolence from sleep apnea or sedatives ("won't breathe"), and patients with neuromuscular disorders frequently do not exhibit respiratory distress ("can't breathe""); in such cases NIV can be applied to temporarily treat hypercapnia while the underlying cause is being assessed and therapy initiated.

●Patients not suitable for NIV – In general, patients who are not considered suitable candidates for NIV include those who are hemodynamically unstable or in severe cardiorespiratory distress, those with severely impaired consciousness, an inability to protect their airway and excess secretions, as well as patients with facial, esophageal, or gastric bypass surgery.

The optimal mode, mask, and initial settings are unknown and vary depending upon the underlying disease and patient comfort.

●Mode – While most patients are started on pressure-controlled NIV (eg, bilevel positive airway pressure [BiPAP]) some patients may demonstrate improved tolerance on volume-controlled NIV (eg, patients with neuromuscular disease).

●Mask – An oronasal mask is often chosen initially rather than full-face mask, a nasal mask, or nasal prongs.

●Settings – The optimal initial settings vary depending upon the mode of NIV chosen. Most clinicians opt for lower settings and titrate up depending upon the patient's ability to tolerate it and their response. Examples of initial settings for bedside NIV include:

•Bilevel positive airway pressure (BPAP) – 8 to 12 cm H₂O (inspiratory pressure) and 3 to 5 cm H₂O (expiratory pressure).

•Pressure support NIV (PSV-NIV) – 8 to 12 cm H₂O (pressure support) and 3 to 5 cm H₂O (positive end expiratory pressure).

•Volume-controlled NIV – Tidal volume 6 to 8 mL/kg and 5 cm H₂O positive end expiratory pressure; rate 10 to 12 breaths/minute.

Close monitoring and early reevaluation are critical to the success of NIV. Thus, vigilant clinical monitoring of vital signs and follow up blood gas analysis is necessary to identify those in whom NIV is successful as well as those who fail NIV, in whom mechanical ventilation is indicated. The optimal trial period for NIV is unknown. However, based upon data derived from patients with COPD, those who respond are likely to do so in the first two hours and patients who fail to respond within that time period have an increased chance of requiring mechanical ventilation.

Titration of oxygen — Patients who present with acute hypercapnic acidosis frequently (but not always) have co-existing hypoxemia that necessitates supplemental oxygen therapy. The degree of hypoxemia is variable and depends upon the cause of respiratory failure and presence of underlying chronic lung disease. The major concern with the delivery of oxygen to this population is the development of worsening hypercapnia and consequently acidosis. In this section, we discuss the risk of developing hypercapnia and how to safely administer and titrate oxygen in this population.

Administration of oxygen — It is essential to administer oxygen to patients with significant hypoxemia to avoid the life-threatening complications of a low arterial oxygen tension (PaO₂) while remembering that efforts that lower PaCO₂ will also improve oxygenation. Thus, the primary goal of oxygen therapy in patients with hypoxemic hypercapnic respiratory failure is the adequate treatment of hypoxemia while the secondary goal is the avoidance of clinically significant worsening of hypercapnia [3-6]. Although the absolute lower limit of acceptable oxygenation in this population is unknown, in general, the target pulse oxygen saturation (SpO₂) should be 90 to 93 percent or a PaO₂ of 60 to 70 mmHg (8 to 9.3 kPa). However, on rare occasions in patients with severe chronic hypoxic hypercapnic respiratory failure, levels lower than that (eg, ≥88 percent or PaO₂ >55 to 60 mmHg) may be maintained especially if it is close to their baseline and the patient is clinically stable (eg, normal mentation).

Our approach is the following [3,7]:

●For most patients with hypoxemic hypercapnic respiratory failure who are not already on oxygen, we initiate oxygen therapy with a fraction of inspired oxygen (FiO₂) to reach a target SpO₂ of 90 to 93 percent or a PaO₂ of 60 to 70 mmHg (8 to 9.3 kPa).

•For those who are estimated to require small amounts of supplemental oxygen, starting with low flow (eg, 1 to 2 L/min or 24 to 28 percent FiO₂) to achieve a SpO₂ at or close to this goal is appropriate. Gradual increases in increments of 1 L/min (via nasal cannula) or 4 to 7 percent (via venturi mask) with close monitoring of both PaO₂ and PaCO₂ may be necessary to finally achieve the target SpO₂ of 90 to 93 percent. Once the target goal is achieved, supplemental oxygen can be maintained at this level and then weaned as the underlying disorder and hypercapnia resolves. The optimal rate of incremental increase is unknown; we prefer to increase the FiO₂ every 5 to 15 minutes; shorter periods of 5 minutes are usually adequate for patients with no underlying ventilation/perfusion mismatch while those with significant mismatch require longer periods for the change in FiO₂ to be fully reflected at the alveolar level (PAO₂).

Nasal cannulae are generally used initially by most clinicians for titrating oxygen. When using nasal cannula, the oxygen flow rate should generally be increased by 1 L per minute at a time; remembering that it is very difficult to predict the FiO₂ when administering supplemental oxygen by nasal cannula; this is because the FiO₂ associated with any given flow of oxygen delivered via nasal cannula depends on the patient's total ventilation (higher ventilation dilutes the oxygen being supplied via nasal cannula) and also depends upon whether the patient is breathing through their mouth or nose (many patients in respiratory distress primarily breathe through their mouth). Venturi masks may also be used to permit tight regulation of the maximum FiO₂ administered to the patient (figure 4), but in general are employed when the patient is more stable after initial therapy.

By keeping the SpO₂ at or just above 90 percent, worsening hypoventilation can be detected via alarms triggered to a drop in O₂ saturation below 88 percent. Since hypoventilation leads to a decrease in alveolar PAO₂ and a consequent drop in arterial PaO₂, keeping the O₂ saturation at the intersection between the ascending limb and the plateau of the hemoglobin-oxygen saturation curve (eg, PaO₂ 60 to 70 mmHg) will allow the clinician to closely monitor for the onset of hypoventilation (figure 5). A fall in the SpO₂ should not be treated by giving more oxygen unless an ABG has demonstrated that hypercapnia is not the cause of the falling O₂ saturation.

Importantly, prolonged episodes of severe hypoxemia should not be tolerated while titrating oxygen such that this approach works for patients who respond quickly (within 15 to 20 minutes) or who have no evidence of complications of hypoxemia (eg, chest pain, altered mental status, lactic acidosis) and require only small amounts of supplemental oxygen or minor adjustments to their FiO₂ to achieve adequate oxygenation.

•For patients who present with severe hypoxemia (eg, SpO₂ 65 percent) or for patients in whom the above strategy fails, supplemental oxygen should be administered at a FiO₂ that achieves adequate oxygenation (ie, SpO₂ 90 to 93 percent) and should worsening hypercapnia develop, noninvasive ventilation or invasive mechanical ventilation is required.

•For patients who develop severe respiratory acidosis (eg, pH <7.2) and/or a marked depression in the level of consciousness using these strategies for oxygen administration, intubation and mechanical ventilation are indicated. Lesser amounts of acidosis and milder symptoms may be treated with noninvasive ventilation and reductions in FiO₂ as tolerated. It is important to remember that bicarbonate is not an effective buffer for respiratory acid; acute severe respiratory acidosis must be addressed by increasing ventilation, not by administering sodium bicarbonate.

●In patients in whom oxygen-induced hypercapnic respiratory failure is suspected and in whom the oxygen saturation is in the high normal range (eg, >95 percent), lowering the supplemental oxygen to provide peripheral saturations between 90 and 93 percent is prudent while arterial blood gases are being drawn.

As an example, a patient with obstructive sleep apnea may desaturate postoperatively due to global hypoventilation and be placed on 100 percent oxygen to improve peripheral saturation. While this may improve oxygenation, it may worsen hypercapnia and induce frank hypercapnic respiratory failure. In such cases, mechanical ventilation can be avoided by a reduction in supplemental oxygen with or without noninvasive ventilation. However, the clinician should avoid marked hypoxemia as FiO₂ is being reduced as this may result in both hypercapnia and hypoxemia, requiring endotracheal intubation.

For patients who develop oxygen-induced hypercapnic respiratory failure and have an oxygen saturation in the low normal range (eg, 88 to 93 percent in a patient with severe underlying chronic hypoxic hypercapnic respiratory failure), depending on the degree of respiratory failure, fine titration of supplemental oxygen with or without noninvasive ventilation or mechanical ventilation are options. Choosing among these options should be individualized and involve a pulmonologist or intensivist to facilitate management. Oxygen should not be removed entirely from the patient in an effort to avert intubation as this may aggravate tissue hypoxemia and worsen acidosis.

While high flow nasal oxygen has a proven role in the treatment of hypoxemic respiratory failure, it has no proven role in the treatment of hypercapnic respiratory failure and should not be used [8].

Risk of hypercapnia — The hypercapnic effects of oxygen therapy have been studied in patients with COPD. In this population, most patients do not retain CO₂ when supplemental oxygen is administered (non-retainers). However, in a small proportion, hypercapnic respiratory acidosis is due to or exacerbated by supplemental oxygen (retainers). There is no ideal way to predict retainers from non-retainers other than utilizing a history of prior hypercapnia. In our experience and that of others, risk factors for CO₂ retention in COPD due to oxygen administration include [9-11]:

●A history of CO₂ retention at baseline (sometimes suggested by an elevated serum bicarbonate) and/or with oxygen administration.

●A low initial pH (<7.33) and/or arterial oxygen tension (PaO₂).

Thus, there are three possible outcomes when administering uncontrolled oxygen therapy to a patient with COPD and respiratory insufficiency [11]:

●The patient's clinical state and PaCO₂ may improve or not change.

●The patient may become drowsy but can be roused to cooperate with therapy; in these cases, the PaCO₂ generally rises slowly by up to 20 mmHg and then stabilizes after approximately 12 hours.

●The patient rapidly becomes unconscious and the PaCO₂ rises at a rate of 30 mmHg or more per hour.

The risk of hypercapnia in patients with neuromuscular disease (eg, amyotrophic lateral sclerosis) when supplemental oxygen is administered has been less well studied than among patients with COPD. One retrospective series found that among eight patients identified with neuromuscular disease, seven had baseline hypercapnia, and six had worsening of their hypercapnia by a mean of 28 mmHg after receiving low flow supplemental oxygen [12]. There were no measurements of breathing pattern, respiratory drive, or dead space, and it is unclear if these findings are due to the same mechanisms that are operative in patients with COPD.

Empiric therapies for underlying etiology — Provided the patient's airway and circulation are stable, empiric therapies should be administered to treat the underlying cause. In most cases, this involves reversing the effects of sedatives when indicated, treating a COPD exacerbation with bronchodilators and corticosteroids, or treating a pneumonia and dehydration with antibiotics and fluids in patients with neuromuscular disorders. In many cases, these therapies are administered with or without the application of noninvasive or invasive mechanical ventilation while diagnostic investigations are underway.

Other — In patients with hypercapnic respiratory failure suspected to be due to angioedema, intramuscular epinephrine can be administered at the bedside. The typical adult dose is 0.3 mg of 1:1000 epinephrine injected into the mid-outer thigh and repeated every 5 to 15 minutes as needed (table 3). Other pharmacologic agents frequently administered following epinephrine include antihistamines (eg, diphenhydramine 25 to 50 mg and famotidine 20 mg intravenously), nebulized albuterol (2.5 mg in 3 mL of normal saline), and methylprednisolone (1 to 2 mg/kg intravenously). Blood for total tryptase or histamine should be drawn prior to or shortly after treatment.

In those with mild to moderate distress with a known treatable cause for the upper airway obstruction, eg, laryngeal edema, initiation of supplemental oxygen via a mixture of helium and oxygen (heliox) may reduce turbulent flow and the work of breathing while treatment for the underlying problem is started. (See "Physiology and clinical use of heliox".)

Criteria for intensive care unit admission — Once the patient has been evaluated at the bedside, there are no agreed upon criteria for intensive care unit (ICU) admission other than the need for NIV or intubation and mechanical ventilation. ICU admission for severe hypercapnia respiratory failure is typically due to COPD or obesity hypoventilation syndrome [13].

However, common reasons for admission may include the need for frequent monitoring, fine titration of supplemental oxygen, and the prolonged application of noninvasive ventilation. Examples of patients who may be considered for ICU care include patients with severely impaired consciousness, patients with respiratory muscle fatigue (eg, neuromuscular disorders) and patients not improving on NIV, as well as and patients with severe acidosis (eg, <7.25) and indications for admission other than hypercapnic respiratory failure. In patients with neuromuscular disease, vital capacity less than 1 L is also an indication for monitoring in an intensive care setting.

In contrast, other patients with an etiology for acute hypercapnia that is easily reversible may require minor additional supervision and may not even require hospital admission (eg, benzodiazepine-induced hypercapnia following conscious sedation for a minor procedure) once it has been established that it will not recur.

In complex cases, consultation with intensivists, pulmonologists, neurologists, and other subspecialists is prudent for management.

DIAGNOSIS — Acute hypercapnia should always be suspected in those who are at risk for retaining carbon dioxide (CO₂) who present with shortness of breath and/or a change in mental status, or new hypoxemia. The identification of an elevated partial pressure of CO₂ on arterial blood gas (ABG) analysis is diagnostic of hypercapnia (arterial CO₂ tension [PaCO₂] >45 mmHg). Acute hypercapnia is always accompanied by a respiratory acidosis (pH <7.35) whereas chronic hypercapnia is associated with a low-normal or near normal pH. Detailed discussion of ABG analysis is provided separately. When hypercapnia is associated with an alkaline pH, one must consider a mixed acid-based disorder (eg, a primary metabolic alkalosis with a secondary, compensatory respiratory acidosis); with correction of the metabolic alkalosis, the hypercapnia should resolve.

The diagnosis of the etiologies associated with acute hypercapnic respiratory failure is also provided separately.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the symptoms of hypercapnia and the ability to distinguish the etiologies of hypercapnia from one another are typically dependent upon a collection of clinical features supported by laboratory, imaging, and physiologic findings.

●Differential diagnosis of the symptoms of hypercapnia – Because hypercapnia most frequently presents with dyspnea and altered sensorium, many of the additional etiologies associated with both of these symptoms (eg, pulmonary embolus, heart failure, encephalopathy, sepsis) are distinguished by a thorough history and examination, the differential of which is discussed separately.

●Differential diagnosis of hypercapnic respiratory failure – Once hypercapnia is diagnosed, the etiologies associated with the development of hypercapnia can be distinguished from each other by clinical, laboratory, radiologic, and physiologic assessment. The clinical features of the various etiologies of hypercapnic respiratory failure are discussed separately.

The value of measuring the alveolar-arterial gradient on arterial blood gas analysis to distinguish patients with hypercapnia due to global hypoventilation from hypercapnia due to intrinsic pulmonary disease is discussed above.

DEFINITIVE MAINTENANCE THERAPY — Maintenance therapy of acute respiratory acidosis is primarily directed at treating the underlying disorder and reversing the acute hypercapnia back to baseline levels. Baseline for many patients is normocapnia. However, in patients who are chronically hypercapnic prior to admission, a partial pressure of arterial carbon dioxide (PaCO₂) that approximates their premorbid state should be targeted. Caution should be exercised in the overcorrection of chronic hypercapnia which can result in alkalemia, which in turn can reduce respiratory drive and, if severe, induce seizures.

Reverse the cause — The mainstay of maintenance therapy for hypercapnic respiratory acidosis is identifying and treating the underlying cause. In most cases, this involves completing the diagnostic investigation when the patient is clinically stable. Specific therapies administered for the varied etiologies associated with acute hypercapnic respiratory failure, are discussed separately.

Reverse hypercapnia — The continued treatment of the hypercapnia per se is achieved using noninvasive ventilation (NIV) or invasive mechanical ventilation, when necessary. However, overcorrecting hypercapnia with these modes of ventilation can result in alkalemia. Accordingly, these techniques should be used with attention to the patient's baseline PaCO₂ and the arterial pH.

●Noninvasive ventilation – Not every patient with acute hypercapnia requires NIV. However, for patients in whom bedside therapy is beneficial, it is appropriate to continue NIV until the hypercapnia has resolved. The indications for and application of NIV are discussed above.

●Mechanical ventilation – Mechanical ventilation should be continued in those in whom it was initiated until the hypercapnia has resolved. Alternatively, it should be administered to those who fail initial therapies. The indications for and management of patients mechanically ventilated for acute respiratory failure, including those with underlying chronic obstructive pulmonary disease (COPD), are discussed separately.

Extracorporeal carbon dioxide removal (ECCO₂ R) is a newer technique for removing carbon dioxide via venovenous bypass without affecting oxygenation [14]. ECCO₂ R is being evaluated in the treatment of respiratory acidosis as a complication of the low tidal volume lung-protective ventilation with permissive hypercapnia. However, this technique requires more investigation before it can be routinely applied to this population as a specific treatment for hypercapnia. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

THERAPIES OF UNPROVEN BENEFIT — While respiratory stimulants have been used in the past (eg, medroxyprogesterone, acetazolamide, theophylline), they have no proven benefit in the treatment of acute (or chronic) hypercapnic states and have largely fallen out of favor. As such, we suggest not routinely using these agents. Similarly, sodium bicarbonate infusions should only be considered in patients with a true indication for its use (eg, severe symptomatic metabolic acidosis, tricyclic antidepressant overdose) because bicarbonate is not an effective buffer for acute respiratory acidosis.

SUMMARY AND RECOMMENDATIONS

●Mechanisms and etiology – Hypercapnia is defined as an elevation in the arterial carbon dioxide (CO₂) tension (PaCO₂). The CO₂ level in arterial blood is directly proportional to the rate of CO₂ (VCO₂) production and indirectly proportional to the rate of CO₂ elimination by the lung (alveolar ventilation). Alveolar ventilation is, in turn, determined by minute ventilation (V_E) and the ratio of dead space (V_D) to tidal volume (V_T). Etiologies associated with hypercapnia are listed in the table (table 1). (See 'Mechanism and etiology' above.)

●Suspecting hypercapnia – Hypercapnia should always be suspected in those who are at risk for hypoventilation (eg, sedatives) or increased physiologic dead space and limited pulmonary reserve (eg, chronic obstructive pulmonary disease [COPD] exacerbation) who present with shortness of breath, a change in mental status, new hypoxemia, and/or hypersomnolence. There are no clinical features that are sensitive or specific for the diagnosis of hypercapnia, because the presenting features are usually those of hypercapnia itself as well as features due to the underlying disorder (eg, oxygen administration, sedatives, COPD). (See 'When to suspect acute hypercapnia' above.)

●Initial evaluation – When patients present with suspected hypercapnia, the clinician should simultaneously assess and stabilize the airway, breathing, and circulation; perform a brief clinical bedside assessment with telemetry and oxygen monitoring; draw an arterial blood gas (ABG); and administer initial empiric bedside therapies. With this approach, once the diagnosis is made and the patient is stabilized, the etiology can usually be determined or narrowed to a few possibilities, such that subsequent testing and therapies can be appropriately tailored. (See 'Initial evaluation and diagnostic approach' above and 'Assess airway, breathing, circulation' above.)

•Arterial blood gas analysis – A low clinical suspicion is all that is necessary to prompt ABG analysis for the diagnosis of acute hypercapnic respiratory failure. The identification of an elevated PaCO₂ >45 mmHg is diagnostic of hypercapnia. Hypercapnia should then be classified as acute (accompanying appropriate respiratory acidosis), chronic (a low-normal or near-normal pH), or acute-on-chronic (figure 1 and figure 2 and figure 3). (See 'Arterial blood gas analysis' above.)

•Bedside assessment – A brief history and examination should be performed at the bedside, so that therapies targeted at a specific underlying cause can be administered quickly. In addition to ABGs, a complete blood count, serum chemistries including bicarbonate and electrolytes, and a chest radiograph should be performed. Once the patient is stable, subsequent testing (eg, toxicology screen, thyroid function tests, chest or brain imaging) and therapies can then be appropriately tailored. (See 'Bedside clinical assessment' above.)

●Initial bedside therapies – Based upon a brief history, ABGs and/or laboratory tests initial therapies that may be administered at the bedside include antidotes for sedative overdoses, bag-valve and noninvasive ventilation (NIV), oxygen titration, and empiric therapies targeted at the underlying etiology. (See 'Initial bedside therapies' above and 'Reversal and avoidance of sedatives' above.)

•Noninvasive ventilation – Suitable candidates for NIV are patients with a moderate acute acidosis (eg, pH <7.3) who are in moderate-to-severe respiratory distress, with tachypnea (respiratory rate >25), and an increased work of breathing due to acute exacerbation of COPD. Additional candidates include those with cardiogenic pulmonary edema, postextubation respiratory failure, and patients with obstructive sleep apnea and neuromuscular disorders. (See 'Bag-valve mask or noninvasive ventilation' above.)

•Oxygen therapy – For most patients with hypoxemic hypercapnic respiratory failure, we initiate oxygen therapy with a fraction of inspired oxygen (FiO₂) to reach a target peripheral oxygen saturation (SpO₂) of 90 to 93 percent or a PaO₂ of 60 to 70 mmHg (8 to 9.3 kPa) rather than higher saturations or PaO₂ levels. (Grade 2C). (See 'Titration of oxygen' above.)

-Mild hypoxemia – For patients who are estimated to require small amounts of supplemental FiO₂, low-flow oxygen should be administered (eg, 1 to 2 L/min or 24 to 28 percent FiO₂) to achieve a SpO₂ at or close to this goal. Gradual increases (every 10 to 15 minutes) in increments of 1 L/min (via nasal cannula) or 4 to 7 percent (via Venturi mask) with close monitoring of both PaO₂ and PaCO₂ may be necessary to finally achieve the target SpO₂ (figure 4). Prolonged episodes of hypoxemia should be avoided during titration. (See 'Administration of oxygen' above and 'Risk of hypercapnia' above.)

-Severe hypoxemia – For patients who present with severe hypoxemia (eg, SpO₂ 65 percent) or for patients in whom the above strategy fails, supplemental oxygen should be administered at a FiO₂ that achieves adequate oxygenation (ie, SpO₂ 90 to 93 percent) and should worsening hypercapnia develop, NIV or mechanical ventilation is required.

•Mechanical ventilation – The development of acute hypercapnia with significant acidemia (eg, pH <7.2) and/or a marked depression in the level of consciousness is usually an indication for intubation and mechanical ventilation. Lesser amounts of acidosis and milder symptoms may be treated with NIV and reductions in FiO₂ as tolerated. Oxygen should not be removed entirely from the patient in an effort to avert intubation as this may aggravate tissue hypoxemia and worsen acidosis.

●Diagnosis – Acute hypercapnic respiratory failure is diagnosed on ABG analysis by the demonstration of an elevated PaCO₂ >45 mmHg with an accompanying appropriate respiratory acidosis. The differential diagnosis of the symptoms of hypercapnia and distinguishing the etiologies of hypercapnia from one another are typically dependent upon a collection of clinical features supported by laboratory, imaging, and physiologic findings. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Maintenance therapy – Maintenance therapy is primarily directed at treating the underlying disorder and reversing the acute hypercapnia back to baseline levels. Baseline for most patients is normocapnia. However, in patients who are chronically hypercapnic prior to admission, targeting a PaCO₂ that approximates their premorbid state is prudent. (See 'Definitive maintenance therapy' above.)