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Hypercapnia in the critically ill 

Hypercapnia in the critically ill
Hypercapnia in the critically ill

John G. Laffey

and Brian P. Kavanagh

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date: 05 July 2022

Key points

  • Hypercapnia is a central component of current ‘protective’ ventilator management.

  • Hypercapnia and the associated acidosis, has potentially important biological effects on immune responses, injury, and repair.

  • There are distinct patient groups, such as patients with limited intracranial compliance or elevated pulmonary vascular pressures, in which hypercapnia may be poorly tolerated and must be carefully titrated.

  • Hypercapnia can suppress the immune response to bacterial infection.

  • Hypercapnia is usually well tolerated in health and in the critically ill, with intact survival reported even following exposure to extreme levels.

Causes of hypercapnia

The causes of elevated (or lowered) arterial carbon dioxide tension (PaCO2) reflect the balance of its production, elimination and (rarely) the presence of any CO2 in the inspired gas:

P a C O 2     [ ( Produced   C O 2 / Eliminated   C O 2 )   +   Inspired   C O 2 ]
[eqn 1]

The key cause of hypercapnia in critical illness is reduced elimination. CO2 elimination depends on alveolar ventilation ( V ˙ A ) , i.e. the minute ventilation (tidal volume × respiratory rate) minus the dead space ventilation ( V ˙ D ) . In severe lung or neurological disease states, a combination of low minute ventilation and/or elevated V ˙ D , means that the alveolar ventilation—and, hence CO2 elimination—is reduced. Increased V ˙ D , e.g. due to a pulmonary embolism, also decreases CO2 elimination unless minute ventilation is significantly increased.

Inspired CO2 is usually negligible, but it can be elevated due to circuit misconnection, or with rebreathing circuits if CO2 absorption fails. Increased CO2 production is common, but rarely results in hypercapnia except in rare crises, such as malignant hyperthermia or thyroid storm, where production is massively increased. Administration of bicarbonate to buffer H+ can transiently increase CO2 production.

Physiological responses to hypercapnia

Physiological buffering

Hypercapnia results in higher concentrations of H+, by combining with H2O to form carbonic acid (H2CO3), which then dissociates into bicarbonate (HCO3) and H+. Because acidosis suppresses many cellular functions, physiological strategies maintain intra- and extracellular pH within narrow ranges. First, tissue buffering occurs over minutes to hours via active cell membrane ion transporters that extrude H+ in exchange for sodium. Secondly, acidaemia inhibits production of organic acids. Finally, the kidney (if function is preserved) generates additional HCO3 and, by different mechanisms, directly excretes H+; such ‘renal compensation’ occurs over hours to days.

Physiologic effects of paCo2 versus H+

While many effects of hypercapnia appear to be mediated by changes in H+, CO2 may also have direct effects. CO2 molecules may react directly with free amine groups, forming carbamate residues that can modify protein structure and function, e.g. the rightward shift of the Hb-O2 dissociation curve induced by elevated PaCO2 (the Bohr effect). This may explain why at a similar pH, metabolic, and hypercapnic acidosis can have different consequences.

Respiratory physiology

Hypercapnic acidosis has important effects on the pulmonary vasculature, the airways and on control of breathing. Hypercapnic acidosis increases pulmonary vascular resistance and intensifies hypoxic pulmonary vasoconstriction. CO2 administration improves V ˙ / Q ˙ matching (and oxygenation) in healthy volunteers. In ARDS, the increase in venous admixture during permissive hypercapnia probably occurs due to airway closure and atelectasis, rather than from a direct effect of the hypercapnic acidosis [1]‌.

Hypercapnia can directly dilate small airways and, by indirect vagus nerve-mediated mechanisms, constrict larger airways; However, there is little net impact on airway resistance. Finally, hypercapnic acidosis stimulates respiration predominately via central chemoreceptors, which respond to increased H+ levels in the cerebrospinal fluid. In addition, both hypercapnia and acidosis augment the responses of the peripheral chemoreceptors to hypoxia.

Cardiovascular physiology

The cardiovascular impact of hypercapnic acidosis is complex, with direct effects including diminished vascular and myocardial contractility opposed by the indirect sympatho-adrenal stimulation causing increased preload and heart rate, and decreased afterload. The net effect is an increase in cardiac output.

Hypercapnia enhances tissue oxygen delivery by increasing cardiac output, improving lung V ˙ / Q ˙ matching and tissue blood flow. Both hypercapnia and acidosis cause a shift to the right of the Hb-O2 dissociation curve, augmenting O2 release at the tissues. In addition, hypercapnic acidosis may slightly elevate haematocrit, incrementally increasing O2 delivery. At the cellular level, hypercapnic acidosis may reduce oxygen consumption; thus, in aggregate, hypercapnic acidosis tends to augment O2 supply and reduce demand.

Central nervous system effects

Hypercapnic acidosis causes cerebral vasodilation, mediated predominantly by local pH altering potassium channels and neuronal nitric oxide synthase, which results in an increase in cerebral blood flow and blood volume. However, when administered over a prolonged period, hypercapnic acidosis becomes buffered and the cerebral vascular tone returns towards normal. Exposure to profound levels of CO2 (e.g. accidental exposure) causes acute narcosis and coma.

There are significant neuromuscular effects. Short-term exposure may cause reversible impairment in muscle contractility, whereas prolonged hypercapnia (e.g. for weeks) can result in structural alterations including increased slow-twitch (and decreased fast-twitch) fibres.

Mechanisms of action

Immunology and inflammation

Hypercapnia and acidosis modulate diverse components of the host immune system, especially in terms of mediator and cellular responses. Important signalling molecules, such as IL-6, IL-8, TNFα‎, and IL-1 are suppressed by hypercapnic acidosis. In addition, hypercapnia can inhibit expression of binding molecules, such as selectins and intercellular adhesion molecules.

Hypercapnic acidosis can inhibit NF-κ‎B activation [2]‌, an important early step in inflammatory gene activation; while this may have useful anti-inflammatory effects, it may also impair resolution of injury [2].

Elevated CO2 may directly alter cellular immune responses, including neutrophil [3]‌ and macrophage recruitment and phagocytosis. Oxidant generation, a critical step in neutrophil and macrophage function, is reduced by hypercapnia (and increased by hypocapnia). Hypercapnia can minimize depletion of (the anti-oxidant) glutathione and directly inhibit xanthine oxidase [4]. However, while free radicals contribute to tissue injury, they are also necessary for bacterial killing. The impact of hypercapnic acidosis on free radical injury may be injury-specific; e.g. hypercapnic acidosis decreases tissue nitration following reperfusion injury [5], but increases it in sepsis [6].

Injury effects: hypercapnia versus acidosis

Most of the protective effects of hypercapnic acidosis are due to acidosis, rather than hypercapnia. In the lung, buffering hypercapnia reduces the protection against injury [5]‌, while in cultured cells it inhibits epithelial wound healing [7]. Metabolic acidosis attenuates reperfusion injury less effectively than hypercapnic acidosis [5]. Some effects of hypercapnia appear to be a function of CO2 and not pH, such as the worsening injury in prolonged pulmonary sepsis [3], inhibition of the NF-кB pathway and altering development, as demonstrated in Drosophila [8].

Organ-specific effects in acute injury (laboratory and clinical)

Acute respiratory failure

The alveolus

Hypercapnia reduces alveolar-capillary permeability [4]‌, but can also inhibit fluid clearance by alveolar epithelial cells whereby CO2, (but not H+) activates AMP-activated protein kinase, which promotes endocytosis (and sequestration) of Na/K-ATPase [9]. In addition, hypercapnia inhibits pulmonary epithelial healing by reducing activation of NF-κ‎B, effects more closely associated with elevations in PCO2 than H+ [7].

Status asthmaticus

Although the studies of limiting tidal volume predominantly focus on ARDS, the practice was first described in status asthmaticus—the result was greater survival (and less barotrauma) versus historical controls [10].

Ventilator-associated lung injury

The potential for reduced tidal volume (VT) to lessen mortality in ARDS was first demonstrated by Hickling et al. in two pivotal studies [11,12]. A retrospective analysis of 50 patients with severe ARDS who had limitation of PAW (<30 cmH2O) resulting in significant hypercapnia, demonstrated mortality was far less than predicted by APACHE II score (16 versus 40%) [11]. A survival advantage was again found in a series of prospectively studied patients, managed with ‘permissive hypercapnia’ with an actual mortality of 26.4% (versus predicted 53.3%) [12]. These pivotal studies, coining the term ‘permissive hypercapnia’, are the clinical basis for adoption of protective mechanical ventilation in adults with ARDS.

A retrospective analysis of the largest randomized controlled trial of tidal volume in ARDS [13] suggested that the presence of hypercapnic acidosis was associated with increased survival among patients randomized to higher—but not lower—VT [14].

Hypercapnic acidosis directly reduces ventilator-induced lung injury in pre-clinical studies (Fig. 86.1) [15], and a key mechanism of this is attenuation of stretch-induced activation of the NF-кB pathway [16].

Fig. 86.1 Hypercapnic acidosis attenuates ventilation-induced lung injury. Histological injury is less in the setting of hypercapnic acidosis (PCO2 80–100 mmHg; Panel a) compared with normocapnia (PCO2 40 mmHg; Panel b).

Fig. 86.1 Hypercapnic acidosis attenuates ventilation-induced lung injury. Histological injury is less in the setting of hypercapnic acidosis (PCO2 80–100 mmHg; Panel a) compared with normocapnia (PCO2 40 mmHg; Panel b).

Symbols: Arrow, macrophage; arrowhead, hyaline membrane formation; ‘BR’, bronchiole.

Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Sinclair SE et al., 2002, ‘Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury’, American Journal of Respiratory and Critical Care Medicine, 166, pp. 403–8. Official journal of the American Thoracic Society.

Gas exchange in ARDS

In patients with ARDS, reduction of VT, with concomitant permissive hypercapnia, increases both cardiac output and intrapulmonary shunt [1]‌. The modest decrease in PaO2 is a result of increased shunt fraction (because of atelectasis caused by low VT without recruitment), as well as the decrease in alveolar ventilation; these effects are countered by the increased cardiac output and central venous oxygenation.

Pulmonary hypertension

Acute hypercapnic acidosis worsens pulmonary hypertension in patients. However, prolonged experimental hypercapnia can lower pulmonary hypertension and reverse vascular hypertrophy, in part by increasing expression of L-arginase (produces local NO) or inhibiting expression of the vasoconstrictor endothelin [17].

Pulmonary infection

Hypercapnia reduces the severity of lung injury following endotoxin [6]‌, and in the short-term, following experimental E. coli inoculation [18]. However, in the longer term (~72 hours) E. coli pneumonia, hypercapnic acidosis worsens injury because of neutrophil inhibition (Fig. 86.2) [3]. Mortality in Drosophilia infected with different bacteria (S. aureus, E. fecalius, E. coli) is increased by the presence of elevated CO2 (but not by lowered pH), and this is mediated in part by suppression of Rel/NF-κ‎B, an important signalling pathway that is conserved in higher mammals [8].

Fig. 86.2 Hypercapnic acidosis worsens lung injury and increases bacterial load in model of prolonged pneumonia. Lung tissue sections at 48 hours after infection with E. coli (normocapnia control; Panel a) demonstrated more severe lung injury in the setting of environmental hypercapnia (Panel b; inspired CO2 5%). The bacterial load was greater following hypercapnia compared with normocapnia (Panel c), and neutrophils from animals exposed to hypercapnia (versus normocapnia) demonstrated reduced capacity to phagocytose fluorescent latex beads (Panel d).

Fig. 86.2 Hypercapnic acidosis worsens lung injury and increases bacterial load in model of prolonged pneumonia. Lung tissue sections at 48 hours after infection with E. coli (normocapnia control; Panel a) demonstrated more severe lung injury in the setting of environmental hypercapnia (Panel b; inspired CO2 5%). The bacterial load was greater following hypercapnia compared with normocapnia (Panel c), and neutrophils from animals exposed to hypercapnia (versus normocapnia) demonstrated reduced capacity to phagocytose fluorescent latex beads (Panel d).

Reproduced from O’Croinin DF et al., ‘Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury’, Critical Care Medicine, 36, pp. 2128–35, copyright 2008, with permission from Wolters Kluwer Health.

The circulation in critical illness

Effects on the myocardium

Hypercapnic acidosis protects against experimental myocardial ischaemia-reperfusion injury; in addition, it directly reduces contractility and in vivo infarct size by reducing myocardial calcium loading and increasing coronary vasodilation.

Effects on the vasculature

In experimental abdominal sepsis, hypercapnic acidosis mitigates the onset of shock, with a comparable haemodynamic profile to dobutamine (i.e. augmentation of cardiac output and D ˙ O 2) [9]‌; this appears to be due to the elevated CO2 and not acidosis [7]. Finally, hypercapnia augments microcirculation in experimental models, and enhances tissue oxygenation in patients during surgery.

Hypercapnia and brain injury

Perfusion and intracranial pressure

Hypercapnia increases cerebral blood flow, and can raise intracranial pressure and, in the setting of critically raised intracranial pressure (ICP), potentially cause brainstem herniation; at very high levels it causes narcosis and coma.

Brain protection

Several studies have demonstrated protection in experimental brain injury. One study reported that hypercapnic acidosis protected against hypoxic-ischemic injury in the immature rat brain [19], although it is possible that the magnitude of the effect (i.e. the between-group difference) reflected a lowering of the PaCO2 in the control group, rather than an elevation of the CO2 in the intervention group. Hypercapnia reduces excitatory amino acids (e.g. glutamate) in cerebrospinal fluid, and coupled with inhibition of oxyradicals and neuronal apoptosis, this may contribute to CNS protection.

Renal, hepatic, and splanchnic impact

Acidosis can delay the onset of cell death in anoxic hepatocytes and renal tubules. In the gastrointestinal mucosa, elevated CO2 preserves oxygenation during experimental haemorrhage; in addition, raised PaCO2 during experimental sepsis lessens depletion of ATP and protects the mucosal permeability barrier. However, patients with ARDS exposed to permissive hypercapnia demonstrated no important alterations in splanchnic circulation.

Tolerance and contraindications

Tolerance to hypercapnia

The potential for full recovery exists following exposure to extreme levels of hypercapnia, sometimes called ‘supercarbia’. Several children exposed to high levels (e.g. PaCO2 150–270 mmHg), as well as one patient with asthma (PaCO2 293 mmHg, pH 6.77) have been described with no long-term sequelae. However, extremes of hypercapnia are less likely to be well tolerated in the critically ill.


Contraindications are more apparent when the underlying concerns (e.g. pulmonary hypertension, raised ICP, uncontrolled metabolic acidosis) are more severe, when the extent hypercapnic acidosis is greater and its onset more acute.

Management of hypercapnic acidosis

Buffering hypercapnic acidosis

Buffering of the hypercapnic acidosis in patients with ARDS remains a common intervention with uncertain benefit. There are several buffers in clinical use.

Sodium bicarbonate

Buffering hypercapnic acidosis with bicarbonate was undertaken in several ARDS clinical trials, but concerns remain. Bicarbonate causes generation of additional CO2, which must be excreted in order for pH to be buffered. In permissive hypercapnia, the excretion of CO2 is limited because a lower VT is targeted. Bicarbonate has been removed from most routine cardiac arrest algorithms.


Tromethamine (tris-hydroxymethylaminomethane, THAM) readily penetrates cell membranes and buffers pH, while reducing PaCO2. In contrast to bicarbonate, THAM is effective in a closed system. In a study of 12 patients with ARDS, acute hypercapnic acidosis decreased systemic vascular resistance, myocardial contractility and systemic mean arterial pressure, and increased cardiac output and pulmonary arterial pressure; buffering with THAM lessened these changes [20].


Carbicarb is an equimolar mixture of sodium carbonate and sodium bicarbonate (Na2CO3 0.33 M with NaHCO3 0.33 M). It buffers hypercapnic acidosis without increasing lactate, but has no haemodynamic advantages.

To summarize, no outcome data support buffering hypercapnic acidosis. In the absence of correcting the primary problem, buffering hypercapnic acidosis with bicarbonate is not likely to be of long-term benefit. If the clinician elects to buffer hypercapnic acidosis in individual cases, the immediate rationale should be clear (e.g., to ameliorate potentially deleterious haemodynamic consequences) and the responses measured. THAM and carbicarb may have a role in such clinical situations.

Augmenting CO2 clearance

Tracheal gas insufflation (TGI)

This approach delivers fresh gas into the trachea so that each inspiration commences with lower concentrations of CO2 (than would otherwise exist from the terminal stages of the previous exhalation). However, intrinsic PEEP in invariable elevated and the overall safety profile has not been established.

Extracorporeal support

Extracorporeal membrane oxygenation (ECMO) provides oxygenation and CO2 removal. Extracorporeal CO2 removal can be achieved using a simpler (pumpless) circuit operating at a lower flow, which removes CO2 from the blood at a membrane and returns blood via a venous cannula.


Permissive hypercapnia means accepting the hypercapnia that results from VT reduction, and is undertaken to reduce the likelihood of ventilator-associated lung injury. Elevated PaCO2 causes many physiological alterations, which may be neutral, harmful, or potentially beneficial. Nonetheless, high VT can clearly cause harm and the physician must decide, for each patient individually, the optimal balance between avoiding high VT and the potential cost of hypercapnia.


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