Permissive hypercapnia during mechanical ventilation in adults

Authors:: Robert C Hyzy, MD; Jorge Hidalgo, MD
Section Editor:: Ellen L Burnham, MD
Deputy Editor:: Geraldine Finlay, MD

Literature review current through: Jan 2024.

This topic last updated: Oct 31, 2023.

INTRODUCTION — Ventilatory strategies that aim to reduce the risks of mechanical ventilation (eg, low tidal volume ventilation) may result in hypercapnia. Acceptance of the hypercapnia and continuation of the ventilation strategy is called permissive hypercapnia. Permissive hypercapnia does not include patients with chronic hypercapnia whose baseline arterial carbon dioxide tension is targeted during mechanical ventilation to maintain a near-normal pH [1,2].

The indications, contraindications, technique, efficacy, and potential harms of permissive hypercapnia are reviewed here. Routine modes of mechanical ventilation are discussed separately. (See "Modes of mechanical ventilation" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)

INDICATIONS — Hypercapnic respiratory acidosis is not a typical goal when initiating mechanical ventilation. Rather, it is "permitted" as a consequence of ventilation strategies used to treat the following:

●Patients with acute respiratory distress syndrome managed with low tidal volume. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings'.)

●Patients ventilated for exacerbations of asthma or chronic obstructive pulmonary disease who require low tidal volume and/or a low respiratory rate to minimize intrinsic positive end-expiratory pressure. (See "Positive end-expiratory pressure (PEEP)", section on 'Auto (intrinsic) PEEP' and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Prevention and treatment' and "Invasive mechanical ventilation in adults with acute exacerbations of asthma", section on 'Permissive hypercapnia'.)

CONTRAINDICATIONS — Permissive hypercapnia is safe for most patients, and many of the contraindications listed below are theoretical. Nonetheless, when feasible, permissive hypercapnia is generally avoided in the following:

●Patients with acute cerebral disease – Permissive hypercapnia is generally avoided in patients with cerebral disease (eg, mass lesions, trauma, and cerebral edema) or a seizure disorder for several theoretical reasons outlined below (see 'Neurologic' below) [3-5]. However, the data to support clinically impactful harms are poor.

●Patients with coronary artery disease, heart failure, cardiac arrhythmias, or pulmonary hypertension with right ventricular dysfunction – Hypercapnia increases sympathomimetic output that may be poorly tolerated by patients who have cardiac disease. Beta blockade may limit the sympathomimetic effect of hypercapnia. (See 'Cardiovascular' below.)

●Patients with hypovolemia – Hypercapnia can induce systemic vasodilation, predisposing patients to hypotension (especially those who are hypovolemic) [6]. Hypovolemia should be corrected prior to the initiation of hypercapnic ventilatory strategies.

●Pregnant patients – Hypercapnia is generally avoided during pregnancy and can cause uterine contractions.

TECHNIQUE — Once hypercapnia is permitted, then a hypercapnic target level should be set.

Ventilator adjustment — Permissive hypercapnia is a ventilatory strategy in which hypercapnia is tolerated rather than being a ventilatory goal per se. It usually occurs when lowering the tidal volume and/or the respiratory rate, thereby decreasing the minute ventilation. A lower minute ventilation may be desirable in the setting of severe acute respiratory distress syndrome (ARDS) to minimize volutrauma in patients with poor lung compliance. Alternatively, lower minute ventilation may be helpful in severe bronchoconstriction associated with exacerbations of asthma or chronic obstructive pulmonary disease to address intrinsic positive end-expiratory pressure. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings' and "Invasive mechanical ventilation in adults with acute exacerbations of asthma", section on 'Dynamic hyperinflation' and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Dynamic hyperinflation'.)

When hypercapnia occurs in this setting, it may not be desirable to increase tidal volume or respiratory rate, and in fact further decreases may be necessary. There are no set guidelines on the ideal degree of reduction for either parameter. However, clinicians should incrementally decrease one or both parameters and monitor the effect using an arterial blood gas (within one to two hours of ventilator adjustment) to follow the arterial carbon dioxide tension (PaCO₂) and pH. Since rapid changes in PaCO₂ should be avoided, for each adjustment, large changes in respiratory rate or tidal volume should not be made (eg, no greater than two to three breaths per minute below the previously set rate or no greater than a decrease in 25 to 50 mL in the tidal volume). Importantly, when lowering the set respiratory rate, if the patient is spontaneously breathing over this set rate, the patient's spontaneous rate will determine the actual minute ventilation. Therefore, in many cases, it may be necessary to sedate the patient to ensure the patient does not over breathe the set rate. This is particularly true if the patient is already acidotic.

Rate of rise of arterial carbon dioxide tension — PaCO₂ levels should rise gradually during mechanical ventilation rather than rapidly, preferably at a rate of <10 mmHg per hour [3]. The rise should be even slower if the PaCO₂ exceeds 80 mmHg.

Upper limit of arterial carbon dioxide tension — There is no absolute level above which PaCO₂ should not rise, although levels are practically limited by the associated degree of acidosis, and levels higher than 100 mmHg are generally not required.

Lower limit of pH and correction of acidosis — There is no consensus regarding an acceptable lower limit for pH, whether the acidosis should be corrected, or at what level correction should be considered. However, most clinicians agree that the pH should not need to be normalized. We generally correct severe acidosis using the following parameters:

●Patients with pH levels ≤7.2 are generally corrected, typically using a sodium bicarbonate bolus or infusion to maintain a target pH no greater than 7.2 [3,7]. There is no ideal dosing strategy, but we typically use a starting dose of 100 mEq of sodium bicarbonate solution in 1 L of D5W at a rate of 75 to 100 mL/hour, but higher or lower concentrations or rates of fluid administration may be required. Noteworthy is that a large elevation in the plasma bicarbonate concentration is required to produce a modest improvement in the acidemia. As an example, the plasma bicarbonate concentration has to increase from 29 to 41 mEq/L in order to change the arterial pH from 7.00 to 7.15, assuming a PaCO₂ of 120 mmHg. Thus, large volumes of sodium bicarbonate are needed to produce small changes in the pH. These pitfalls may be avoided by using Carbicarb (an equimolar mixture of sodium carbonate and bicarbonate) because these buffers improve acidemia without producing CO₂, but Carbicarb has been shown to elevate PaCO₂ in animal models [8,9].

●Correction for those between 7.21 and 7.24 should be individualized.

●Patients with a pH ≥7.25 are not typically corrected since this level of acidosis is generally well tolerated by most patients.

Most intensivists, including us, correct severe acidosis based upon evidence from a trial in patients with ARDS that demonstrated clinical benefit from use of a low tidal volume ventilation strategy along with efforts to partially correct acidemia using sodium bicarbonate if patients developed a pH ≤7.2 [10] (see "Acute respiratory distress syndrome: Ventilator management strategies for adults" and 'Efficacy' below). However, others argue that correction may not be indicated based upon theoretical benefits of hypercapnia (eg, improved cardiac output) [11-14] or the observations that the CO₂ generated from buffering infusions can worsen the hypercapnia and transiently worsen intracellular acidosis [3].

Cessation of permissive hypercapnia — Permissive hypercapnia is no longer needed when the patient shows evidence of improving gas exchange. Clinically, this may be manifest by normalization of lung compliance in the setting of ARDS or evidence of decreasing airways resistance in the setting of obstructive lung conditions. Ventilator and buffer infusion adjustments are generally made slowly (eg, over 24 hours or longer) and rapid adjustments of the PaCO₂ should be avoided. This is generally achieved by incrementally increasing the tidal volume and/or respiratory rate back to baseline and weaning the buffer infusion off. Although there are no data to facilitate how quickly that can be done, an approach that results in a reduction of no greater than 10 mmHg/hour is appropriate.

EFFICACY

Human trials — Data that report improved patient-important outcomes are derived from studies in patients with acute respiratory distress syndrome (ARDS) that demonstrated benefit from low tidal volume ventilation strategies that also permitted hypercapnic respiratory acidosis. However, the data are confounded by the inability to dissect the effects of permissive hypercapnia from the effects of low tidal volume. Studies that report the effect of hypercapnia per se on mortality in patients with ARDS are limited, and evidence is conflicting [15,16]. In patients with sepsis, including those on mechanical ventilation, hypercapnic acidosis is not associated with an increased risk of mortality when adjusted for key confounding variables [1]. Detailed discussion of these data is provided separately. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings'.)

Similar benefits have been found in patients ventilated for asthma and chronic obstructive pulmonary disease from strategies that limit intrinsic positive expiratory pressure. These data are also discussed separately. (See "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Prevention and treatment' and "Invasive mechanical ventilation in adults with acute exacerbations of asthma", section on 'Permissive hypercapnia'.)

Preclinical studies — Cellular and animal model studies suggest that hypercapnic acidosis itself may have a beneficial impact (eg, decreased free alveolar protein, improved pulmonary compliance, and reduced inflammation and alveolar damage) that is independent of the effect of low minute ventilation [11-13,17-30]. Physiologic benefits also include improved ventilation/perfusion matching from hypoxic pulmonary vasoconstriction and increased local alveolar ventilation from inhibition of airway tone; increased oxygen delivery from an increase in cardiac output, increased tissue unloading (due to a rightward shift in the oxygen-hemoglobin dissociation curve) and microvascular vasodilation; and anti-inflammatory effects [31,32].

ADVERSE EFFECTS — Permissive hypercapnia is usually well tolerated, particularly when the arterial carbon dioxide tension (PaCO₂) rises slowly. Most of the adverse effects are physiologic. However, their impact on meaningful clinical outcomes is unclear, and most do not warrant cessation of a permissive hypercapnia strategy when indicated. Adverse effects are more likely to occur if the PaCO₂ rises too quickly.

Cardiovascular — The cardiovascular consequences of hypercapnia are mediated by hyperactivity of the indirect sympathetic nervous system (ie, elevated levels of epinephrine and norepinephrine) [6,33,34]. Many of these effects can be monitored with clinical examination and telemetry.

●Increased heart rate, arrhythmias, and blood pressure – In the setting of hypercapnia, significant increases in the heart rate and stroke volume elevate the cardiac output. The result is an increase in the blood pressure, which is attenuated by a simultaneous decrease in the systemic vascular resistance (which can conversely result in hypotension) [35]. Remarkably, the increased stroke volume occurs despite the direct myocardial depressant effects of hypercapnia and intracellular acidosis [36-41]. There is also a theoretical potential increased risk of cardiac arrhythmias given the sympathetic hyperactivity [42].

●Exacerbation of right heart dysfunction – Respiratory acidosis can cause pulmonary vasoconstriction, which increases the pulmonary vascular resistance. The elevated right ventricular afterload may lead to circulatory instability in patients with right heart dysfunction [42,43]. While permissive hypercapnia is not absolutely contraindicated in patients with pulmonary hypertension, the approach is cautious with this caveat in mind. Some authors have speculated that permissive hypercapnia may contribute to a detrimental outcome in acute respiratory distress syndrome management resultant from this effect [44].

●Coronary artery steal – Hypercapnia results in coronary vasodilation in the normal heart, but this effect appears to be blunted in patients with underlying cardiac disease (eg, ischemic left ventricular failure [45]). In theory, hypercapnia-induced coronary vasodilation may induce preferential perfusion through nondiseased coronary arteries, causing a steal phenomenon. This effect has not been confirmed in humans, but a similar response has been noted among patients with coronary artery disease following exposure to certain anesthetic agents (although the effect is mild) [46].

Neurologic — Hypercapnia may also have adverse effects on the central nervous system, particularly when it is acute. It is unclear whether these effects are as impactful in those whose PaCO₂ slowly rises during permissive hypercapnia. Cerebral autoregulation is not adversely affected by moderate degrees of hypercapnia [47]. The following clinical changes may be expected:

●Increased intracranial pressure – Hypercapnia induces cerebral arteriole vasodilation [48,49]. The increased cerebral blood flow leads to an increase in the cerebral blood volume, resulting in an increase in the intracranial and cerebral perfusion pressure. This response is usually transient, with cerebral blood flow returning to baseline after approximately 48 hours of continued hypercapnia.

●Altered mental status or encephalopathy – Patients with acute hypercapnia can exhibit alterations in mental status (which may require increased sedation). Other patients may experience depressed consciousness (ie, CO₂ narcosis) [50-52]. Still others may remain fully alert despite PaCO₂ levels that exceed 100 mmHg [53,54], particularly patients with underlying chronic lung conditions (eg, severe chronic obstructive pulmonary disease).

●Decreased seizure threshold – Seizure activity may occur at extreme levels of hypercapnia [55], but it is unknown whether less severe acute hypercapnia may lead to seizures in those with a preexisting seizure disorder or another type of brain injury.

●Cerebral artery steal – A cerebral steal phenomenon, similar to the coronary artery steal described above, may occur in animals [56], although its clinical importance in humans is unknown.

●Intraventricular hemorrhages – Rare reports of intraventricular hemorrhages have been reported with hypercapnia in neonates [3,57], although it has not been reported in adults.

Pulmonary — Adverse pulmonary consequences of hypercapnia include:

●Worsening of hypoxemia – Hypercapnia from alveolar hypoventilation can worsen hypoxemia [58,59]. However, as a compensatory mechanism, hypercapnia also results in improved ventilation/perfusion matching, increases the cardiac output (improves oxygen delivery), and shifts the oxyhemoglobin dissociation curve to the right (improves tissue offloading of oxygen) [59,60]. Hypercapnia-induced hypoxemia can be readily managed by administering supplemental oxygen and positive end-expiratory pressure [7,58]. (See "Positive end-expiratory pressure (PEEP)" and "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

●Worsening of lung injury – Preclinical studies report that hypercapnia may worsen lung injury by reducing wound repair and increasing inflammation in injured lungs, but no human studies have demonstrated the same response [30,61,62].

Other — Hypercapnia causes intracellular acidosis [3], which inhibits contractility via actin-myosin interaction [40], interferes with neuronal electrical activity [63], inhibits cellular division [64], decreases glycolysis, and increases oxidative deamination (which results in amino acid depletion). However, the importance of such effects is unknown and likely minor due to other compensatory cellular mechanisms [30,65,66].

Hypercapnia has been shown to have mixed effects on the host response to bacterial injury [30,67], although an increased risk of infections has not been demonstrated in humans.

FUTURE — Whether new-generation extracorporeal carbon dioxide removal devices will replace permissive hypercapnia is unknown [68,69]. (See "Extracorporeal life support in adults: Extracorporeal carbon dioxide removal (ECCO2R)".)

SUMMARY AND RECOMMENDATIONS

●Indications – Ventilatory strategies that aim to reduce the risks of mechanical ventilation may result in hypercapnia. Acceptance of the hypercapnia and continuation of the ventilation strategy is called permissive hypercapnia. Patients in whom permissive hypercapnia is commonly employed include those with acute respiratory distress syndrome (ARDS) managed with low tidal volume ventilation and those with obstructive pulmonary disease (COPD) managed with a low tidal volume and/or a low respiratory rate to minimize intrinsic positive end-expiratory pressure. (See 'Introduction' above and 'Indications' above.)

●Contraindications – Permissive hypercapnia is generally avoided in patients who have acute cerebral disease (eg, mass lesions, trauma, or cerebral edema) or a seizure disorder. It is also avoided during pregnancy. Other contraindications are considered mostly theoretical (eg, patients with cardiac disease, pulmonary hypertension, or hypovolemia). (See 'Contraindications' above.)

●Technique – Permissive hypercapnia is usually achieved by slowly lowering the tidal volume and/or the respiratory rate using arterial blood gas assessment to follow the arterial carbon dioxide tension (PaCO₂) and pH. (See 'Technique' above.)

•Targets – There is no agreed upon target level for PaCO₂ or pH. However, for patients who develop an acidosis with a permissive hypercapnia strategy, we typically do not correct the acidosis when the pH is ≥7.25; in contrast, patients with pH ≤7.2 are generally corrected using sodium bicarbonate. Correction for those between 7.21 and 7.24 should be individualized.

•Titration – Since rapid changes in PaCO₂should be avoided, for each adjustment, large reductions in respiratory rate or tidal volume should not be made (eg, no greater than two to three breaths per minute below the previously set rate or no greater than 25 to 50 mL per tidal volume breath).

PaCO₂ levels should rise gradually during mechanical ventilation rather than rapidly, preferably at a rate of <10 mmHg per hour. The rise should be even slower if the PaCO₂ exceeds 80 mmHg. There is no absolute level above which PaCO₂ should not rise, although levels higher than 100 mmHg are generally not required.

●Efficacy – Data that suggest benefit from permissive hypercapnia are indirect and derived from trials that examined the effect of low tidal volume ventilation in patients with ARDS, asthma, and COPD. (See 'Efficacy' above and "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings' and "Invasive mechanical ventilation in adults with acute exacerbations of asthma", section on 'Permissive hypercapnia' and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease", section on 'Prevention and treatment'.)

●Adverse effects – Permissive hypercapnia is usually well tolerated, particularly when the PaCO₂ rises slowly. Most of the adverse effects are physiologic (cardiovascular or neurologic dysfunction, hypoxemia). However, their impact on meaningful outcomes is unclear, and most do not warrant cessation of a permissive hypercapnia strategy. (See 'Adverse effects' above.)

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Permissive hypercapnia during mechanical ventilation in adults

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