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BJA Educ. 2023 Jun; 23(6): 221–228.
Published online 2023 May 2. doi:10.1016/j.bjae.2023.03.002
PMCID: PMC10201398
PMID: 37223696
J. Pippalapalli1 and A.B. Lumb2,∗
Author information Article notes Copyright and License information PMC Disclaimer
Learning objectives
By reading this article, you should be able to:
•
Explain the role of the respiratory centre in controlling blood CO2 to maintain normal body pH.
•
Describe the causes and physiological consequences of hypo- and hypercapnia.
•
Outline the effects of hypercapnia on biological systems and how these affect the use of permissive hypercapnia in clinical practice.
Key points
•
Blood CO2 is crucial for maintaining body pH and controlled by the respiratory centre altering ventilation.
•
The ventilatory response to CO2 is linear; it is affected by circadian rhythm, pregnancy and sedative, anaesthetic or opioid drugs.
•
Common causes of respiratory alkalosis include hypoxaemia and iatrogenic hyperventilation.
•
Respiratory acidosis caused by type 2 respiratory failure results from decreased alveolar ventilation, increased dead space or both.
•
See AlsoSepsis: Symptoms, Causes, Treatment, Risks, and MoreVenous leg ulcers (ulcus cruris venosum)Sepsis and Septic Shock - Critical Care Medicine - MSD Manual Professional EditionSepsis Alliance Symposium: Healthcare-Associated InfectionsPermissive hypercapnia has a role in reducing ventilator-induced lung injury, but also has biological effects on inflammation and cell repair; these need further characterisation in clinical practice.
In order to facilitate the normal functioning of many biological processes, particularly enzymatic proteins, pH is maintained in health between 7.35 and 7.45, in both extra- and intracellular compartments, which corresponds to a normal hydrogen ion concentration of 40 nmol L−1. The carbonic acid/bicarbonate buffer system in blood is the main buffer controlling extracellular pH; this is commonly represented by the Henderson–Hasselbalch equation, of which blood Pco2 is a component.1 As a result, control of Pco2 by the respiratory system is crucial for acid–base balance. In arterial blood, Pco2 is maintained at a population mean of 5.1 kPa with 95% confidence intervals of 1 kPa, giving a ‘normal’ range of 4.1–6.1 kPa. Unlike arterial Po2, there is no evidence that arterial Pco2 (Paco2) is affected by age.
Carbon dioxide (CO2) is carried in arterial blood in three forms: dissolved in the plasma (1.6 mmol L−1), as bicarbonate (HCO3−, 19.3 mmol L−1), and bound to amino groups on haemoglobin as carbamino compounds (1.1 mmol L−1). Although HCO3− is quantitatively the largest contributor to total blood CO2 content, in terms of CO2 transport within the body about one-third results from carbamino carriage. This is a result of the large difference in the ability of oxygenated and deoxygenated blood to both bind CO2 and buffer the hydrogen ions (H+) from HCO3− production (the Haldane effect).
Influence of carbon dioxide on respiratory control
Physiological control of blood carbon dioxide
Blood CO2 sensors are found both centrally and peripherally.2 The central sensors are located in the respiratory centre of the medulla and account for 80% of the ventilatory response to changes of Pco2. The central chemoreceptors are physically close (<0.2 mm) to the surface of the medulla in the retrotrapezoid nucleus region and contain glutaminergic neurones connected directly to the central pattern generator where the respiratory rhythm originates. Changes in blood Pco2 quickly cause changes in extracellular fluid and brain tissue Pco2 as CO2 diffuses freely across the blood–brain barrier. Tissue carbonic anhydrase in the extracellular fluid immediately converts the CO2 into H+ ions and so decreases extracellular pH because H+ ions cannot cross the blood–brain barrier. The cells of the central chemoreceptors respond to changes in pH by a mechanism which is not fully understood but may involve H+-modulated potassium channels, probably alongside chemoreceptive astrocytes which modify neuronal activity.
Peripheral chemoreceptors are located in the carotid bodies and predominantly respond to hypoxaemia, but their activity is also affected by alterations in Paco2. Increased afferent activity from the carotid bodies in response to hypercapnia acts directly on the medullary respiratory neurones rather than via the central chemoreceptors. Why two separate sensors exist is unknown, but the peripheral chemoreceptor response may be quicker than the central response, and only begins above a threshold level of increased Paco2 and so may act to amplify the response to severe hypercapnia. It is accepted that the peripheral chemoreceptors facilitate the ventilatory interaction between hypercapnia and hypoxaemia, so that the simultaneous presence of hypoxaemia enhances the ventilatory response to hypercapnia, and vice versa. A similar effect is observed with metabolic acidosis.
Ventilatory response to acute increase in Pco2
This reflex is most easily demonstrated by Read's rebreathing method, in which a subject breathes for as long as possible from a closed reservoir bag initially containing 50% O2 and 7% CO2. The subject's own exhaled CO2 causes a linear increase in their inspired CO2 and minute ventilation is continuously measured, until respiratory fatigue or headache causes the subject to end the test. This technique clearly demonstrates that the relationship between Pco2 and ventilatory minute volume is linear (Fig 1); so it may be represented by the equation:
Ventilation=S(Pco2–B)
where S is the slope of the line with a population mean of 15 L min−1 kPa−1, although with wide variation between individuals. B represents the point where the line meets the x-axis, known as the apnoeic threshold, which is the Pco2 at which a subject would theoretically stop breathing. This does not occur in practice in conscious patients with hypocapnia because the cerebral cortex overrides the chemical control of breathing to maintain respiration. This protective role of the cortex does not occur during general anaesthesia (GA), explaining why patients with hypocapnia during GA remain apnoeic for long periods.
Fig 1
Normal and abnormal ventilatory responses to hypercapnia. The solid green line shows the average response in a normal healthy subject, with the dotted section extrapolated back to the apnoeic threshold (B). The red line shows the same challenge in a patient with metabolic acidosis, showing the resting hyperventilation and hypocapnia from the acidosis, but with the same slope of the response to CO2. The fine blue lines show the same responses but in subjects with concurrent hypoxaemia, which increases the slope of the response.
The ventilatory response remains linear until Pco2 is well above 10 kPa, at which point respiratory fatigue and hypercapnia-induced sedation cause respiratory depression and ultimately apnoea. Which of these occurs depends on the slope of the individual's response curve: those with a steep response will develop dyspnoea and respiratory muscle fatigue whereas those with a flatter response will become sedated.
Factors affecting the acute ventilatory response to hypercapnia
The slope of this response can be affected by many factors including a circadian rhythm within subjects and a significantly reduced gradient in severely obese individuals.3 Many drugs affect the response, particularly opioids, although the degree to which the response is decreased by opioids is highly variable between individuals, with those with a baseline brisk response being more susceptible.4 Inhaled anaesthetic agents depress the acute ventilatory response to CO2 by reducing resting ventilation, displacing the ventilatory CO2 response curve to the right and depressing its gradient. These effects are not observed at low doses of anaesthetics (0.2 minimum alveolar concentration [MAC]); this contrasts with their effects on the hypoxic ventilatory response, which is exquisitely sensitive to anaesthetic agents.5 The between-individual variation in the response explains why some patients breathing spontaneously during a GA develop a greater degree of hypercapnia than others.
An infusion of doxapram increases the slope of the response by a specific effect on the respiratory centre, but its more generalised effects as a central nervous system stimulant cause significant adverse effects which limit its use for treating hypercapnia.
Physiological responses to prolonged abnormal Pco2
Metabolic compensation
If an abnormal blood Pco2 is maintained for several hours, the HCO3− concentration in extracellular fluid, including the CSF, will change to partially return the pH towards normal. How this occurs in the central nervous system is not fully understood, with both passive changes in HCO3− concentration and active ion transfer potentially contributing. Whatever the mechanism, a step change in Pco2 after several hours of hypo- or hypercapnia leads to a different ventilatory response than that seen with short-term changes. In practice this can be seen if mechanical ventilation to hypocapnic levels is maintained for several hours, long enough for CSF pH to return towards normal; when the Pco2 is normalised, hyperventilation occurs for a few hours before returning to its baseline.
Within a few hours an abnormal blood pH also induces renal compensation. For example with a respiratory acidosis the kidneys will increase reabsorption of HCO3− in the proximal tubule and increase secretion of H+, which in turn generates more HCO3−, shifting blood pH back towards normal. Other renal changes observed in acidosis include increased chloride excretion within 30 min of the onset of the acidosis, suggesting increased proximal tubular exchange of HCO3– and chloride.6 Although the precise mechanism is unknown, the activity of the anion exchange protein pendrin may be directly downregulated secondary to acidosis.7
Altered central carbon dioxide sensitivity
Pregnancy temporarily modifies the relationship between ventilation and Pco2. From the first trimester, progesterone sensitises the central chemoreceptors to CO2, leading to an increased tidal volume and mostly unchanged ventilatory frequency. The hyperventilation leads to hypocapnia and an increased Pao2, both of which benefit placental transfer of oxygen and CO2, but unfortunately also contribute to the dyspnoea seen in more than half of pregnant women.
Increased Pco2 for long periods (days to weeks) also affect CO2 sensitivity, an example of neuronal plasticity, where a reflex changes its response to a prolonged abnormal stimulus. This occurs most frequently because of respiratory pathology leading to type 2 respiratory failure, which is described below. A less common cause of long-term and small increases in Pco2 is residence in environments where there is an increased atmospheric CO2 concentration. Maintaining a breathable environment away from direct contact with the Earth's atmosphere is a significant challenge which has been achieved in both spacecraft and, more frequently, submarines. However, in both situations the CO2 concentration is maintained around 0.5–1.0% compared with <0.04% in the open air. In submariners, the extra inspired CO2 causes an increase in minute ventilation of 2–3 L min−1 for the first few days, but after this chemoreceptor sensitivity to CO2 reduces, ventilation returns to normal, and Paco2 increases accordingly. Similarly, in a simulated spaceflight lasting 23 days, minute ventilation peaked on day 5 before returning to normal, and there were changes to the carbon dioxide–ventilation response curves. These small increases in Paco2 and respiratory acidosis seem to be below the threshold required to activate renal compensation and so pH remains lower than normal. This small decrease of pH can have adverse effects on calcium metabolism including increased deposition of calcium carbonate in bone because of the carbonate acting as a buffer.8 For occupants of spacecraft, this acidosis-induced altered calcium metabolism may exacerbate the more profound problems with bone metabolism caused by microgravity. Furthermore, inspired CO2 concentrations greater than 1% have been found to impair mental performance, including alertness and visuomotor skills. As a result of both these effects, atmospheric CO2 is routinely maintained at 0.5–0.8% in the International Space Station.9
Respiratory alkalosis
Causes
Hypocapnia results from excessive alveolar ventilation relative to the body's CO2 production. The cerebral cortex may override the central chemoreceptor control of ventilation, for example with anxiety. Some neurological conditions, particularly those associated with blood in the CSF, may also lead to hyperventilation. Activation of nociceptors in the lungs with pulmonary fibrosis or acute respiratory problems such as asthma may also drive respiration to a point where hypocapnia occurs. Iatrogenic hypocapnia in patients receiving mechanical ventilation used to be almost universal, but the widespread adoption of capnography means this is now less common. It does still occur occasionally, particularly in patients with a reduced CO2 production, for example by hypothermia. Finally, the most common cause of hyperventilation is hypoxaemia which, irrespective of the cause, stimulates ventilation via the peripheral chemoreceptors. Any reduction in alveolar Pco2 generates a similar increase of alveolar Po2, which attenuates the severity of the hypoxaemia.
Hypoxaemia leading to respiratory alkalosis may not be pathological. Hypobaric hypoxia at altitude also stimulates breathing, quickly resulting in hypocapnia and alkalosis.10 The acute ventilatory response to hypobaric hypoxia is short-lived, lasting less than 30 min, after which ventilation subsides. Referred to as hypoxic ventilatory decline, this response is mediated by altered neuroglial interactions in the respiratory centre rather than loss of sensitivity of the peripheral chemoreceptors. The ventilatory response to hypobaric hypoxia is also countered by the hypocapnia and alkalosis caused by the hyperventilation. As a result, ventilation is only slightly increased above normal for the first few days at altitude, allowing the hypoxaemia and hypocapnia to generate a range of common symptoms or, in some individuals, acute mountain sickness. Within a few days, altitude acclimatisation begins, and symptoms resolve. This is a multisystem response, an important component of which is a gradual increase in minute ventilation and the associated hypocapnia. For many years this was believed to result from changes in CSF HCO3− concentration; however, this is no longer accepted as the time course differs from the change in ventilation. Animal studies suggest that acclimatisation results from increased sensitivity of central respiratory neurones to hypoxia, possibly mediated via the prolonged maximal input from the carotid bodies.
Respiratory acidosis
Respiratory acidosis most commonly results from respiratory failure, which is defined as a failure to maintain normal arterial blood gas partial pressures, but excluding hypoxaemia caused by extrapulmonary shunting. Respiratory failure is subdivided into type 1 (Paco2 normal or decreased) or type 2 (increased Paco2). Factors contributing to respiratory failure include venous admixture caused by intrapulmonary shunt, ventilation/perfusion (V̇/Q̇) mismatch, and ventilatory failure, with the last two of these potentially resulting in hypercapnia. Ventilatory failure is a pathological reduction of the alveolar ventilation below that required to maintain normal alveolar gas partial pressures. Why only some patients develop type 2 respiratory failure is not clearly understood. Potential factors include the genetics of their ventilatory responses to CO2 and oxygen, and their lung pathophysiology in terms of the relative abnormalities of alveolar ventilation, venous admixture, and increased dead space.
Causes of respiratory acidosis
An increased inspired CO2 concentration will cause hypercapnia. This may arise from breathing in closed environments as described previously, or from rebreathing expired CO2 while receiving respiratory support owing to equipment failure.
Assuming inspired CO2 concentration is close to zero, then hypercapnia will only occur when CO2 production (V̇co2) exceeds the ability of the respiratory system to remove it. In any hypercapnic patient, it is prudent to consider V̇co2 as this is commonly increased by fever or sepsis, by absorption of CO2 from the peritoneum during laparoscopy, and more rarely by conditions such as malignant hyperthermia or thyrotoxicosis. Impaired removal of CO2 by the respiratory system has two main causes: alveolar hypoventilation and increased dead space.
Alveolar hypoventilation
The many causes of reduced alveolar ventilation are shown in Figure2 and Table1.
Anatomical locations of abnormalities that may lead to alveolar hypoventilation. See Table1 for examples at each location.
Table1
Causes of respiratory acidosis based on the anatomical location of the abnormality shown in Figure2.
| Figure1 | Anatomical location | Acute causes | Chronic causes |
|---|---|---|---|
| A | Respiratory centre |
|
|
| B | Upper motor neurone |
|
|
| C | Anterior horn cell |
|
|
| D | Lower motor neurone |
|
|
| E | Neuromuscular junction |
|
|
| F | Respiratory muscles |
|
|
| G | Loss of elasticity of the lungs and chest wall |
|
|
| H | Loss of structural integrity of the chest wall |
|
|
| I | Small airway resistance |
|
|
| J | Upper airway obstruction |
|
|
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Increased dead space
Physiological dead space is defined as all parts of tidal volume that do not take part in gas exchange and has two components, anatomical and alveolar dead space. In a normal healthy adult dead space is around 150 ml or one third of tidal volume. Anatomical dead space is the volume of the conducting airways including the oro- or nasopharynx. Alveolar dead space is the volume of gas reaching the alveoli that does not take part in gas exchange because of incomplete equilibration with blood Pco2 in lung regions where V̇/Q̇ ratio is greater than 1.
Anatomical dead space is reasonably constant in healthy individuals owing to the fixed structure of the larger airways, although this is affected by age, being maximal in early infancy at 3.3 ml kg−1 and decreasing to 2 ml kg−1 in adults. It is also affected by posture being greatest when upright compared with supine. Although intubation or tracheostomy reduces anatomical dead space by bypassing the upper airway, these techniques require the addition of apparatus dead space such as filters and catheter mounts, etc. resulting in no major change to overall dead space. It is easy to see why dead space can be a significant problem when ventilating infants and small children. Anatomical dead space is also affected by decreased tidal volume, which may be iatrogenic or seen in comatose patients or those breathing spontaneously during GA. As tidal volume decreases, the anatomical dead space initially remains approximately constant so this constitutes a greater proportion of each breath. When tidal volumes become very small, the anatomical dead space volume also begins to decrease until this becomes smaller than the normal volume of the conducting airways. The mechanism for this observation is changes in the flow pattern and mixing of gases in the airways rather than changes in the airway calibre.2
Alveolar dead space is insignificant in a normal healthy individual with well-matched V̇ and Q̇. Situations where areas of high V̇/Q̇ ratios develop include GA, particularly with mechanical ventilation, and various pathological conditions such as reduced cardiac output (regardless of the cause), pulmonary embolism and emphysema.
Cellular effects of hypercapnia and acidosis
Carbon dioxide diffuses through an aqueous environment more quickly than most other biologically relevant gases because of its high water solubility, so most of the movement through tissues is along its partial pressure gradient.2 Despite this, there is evidence that CO2 also gains access to the intracellular space via aquaporin channels in cell membranes. Once inside a cell the ubiquitous enzyme carbonic anhydrase quickly establishes an equilibrium with HCO3− and H+. Intracellular buffer systems mitigate pH changes in response to varying CO2 concentrations, but although the buffers act rapidly their power to control pH is finite.11 Intracellular pH control is therefore dependent on transmembrane ion exchange transporters which exchange either H+ or HCO3− ions with sodium.11 The sensing molecule is a soluble adenylyl cyclase (sAC) which responds to CO2 and HCO3− levels and acts via cyclic adenosine monophosphate (cAMP) as a second messenger to modulate a variety of intracellular processes.12 Soluble adenyl cyclase and the downstream molecules it modulates have been suggested as potential pharmacological targets for some of the detrimental effects of hypercapnia.13
Cells of the immune system
Hypercapnia affects both humoral and cell-mediated innate immunity by pH-dependent and pH-independent mechanisms. This includes anti-inflammatory properties on various systems.14 Studies in experimental animals suggest pH-independent effects on nuclear factor kappa B (NF-κB), a transcription factor that plays a pivotal role in tissue inflammation, injury and repair. For example, expression of the proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF) are decreased by hypercapnia, attenuating phagocytosis and bacterial killing by both neutrophils and macrophages.12 The beneficial anti-inflammatory effects that may attenuate the amount of lung injury are therefore balanced by a potentially detrimental effect on the lungs' ability to overcome pulmonary infection.
Alveolar epithelial cells
These cells are critical for maintaining the thin barrier for gas exchange between the alveolus and pulmonary capillary, and contain numerous Na+/K+-ATPase and aquaporin channels to prevent fluid accumulation in the interstitial space. Invitro studies have shown that hypercapnia, independent of pH, reduces Na+/K+-ATPase activity causing the endocytosis of this protein and impaired fluid transfer.12 This effect is likely to be linked to the role of sAC described above in controlling intracellular pH.
Hypercapnia has also been shown to impair proliferation and repair of alveolar epithelial cells (AECs).12 Multiple mechanisms are proposed, one of which is hypercapnia-induced production of miR-183 (micro-RNA-183), a small, non-coding RNA which downregulates one of the enzymes of the tricarboxylic acid cycle causing mitochondrial dysfunction. Micro-RNA-183 also inhibits alveolar cell migration by interfering with the normal function of NF-κB. Recent work has also found sAC to be involved in the hypercapnic impairment of AEC repair.13
Such fundamental effects on AECs may be particularly detrimental in patients with acute lung injury where diffuse alveolar damage and destruction of alveolar epithelium is the main pathological abnormality.
Physiological effects of hypercapnia and hypercapnic acidosis
Hypercapnia leads to activation of the sympathetic nervous system via a direct effect of decreased pH on medullary neurones. The resulting increase in sympathetic activity and catecholamine release tend to oppose direct depressant effects of hypercapnia on organ systems, resulting in unpredictable clinical effects.
Respiratory system
The effects of hypercapnia in ventilatory control and lung tissue are described above. Hypercapnic acidosis causes pulmonary vasoconstriction, and although this response is less dramatic than the effect of hypoxia, it is still significant with, for example, an increase in pulmonary vascular resistance of around a third with a Paco2 of 7 kPa even in healthy subjects. This reflex response also occurs at a regional level, and is believed to serve a similar physiological purpose to hypoxic pulmonary vasoconstriction in helping to match regional V̇andQ̇.
Blood Pco2 also influences oxygen carriage by haemoglobin, causing a pH-dependent shift of the oxyhaemoglobin dissociation curve (the Bohr effect) which will affect oxygen uptake in the lungs and release in the tissues.
Cardiovascular system
Both hypercapnia and hypercapnic acidosis have direct depressant effects on the myocardium and on vascular smooth muscle causing reduced cardiac output and systemic vasodilation respectively, but these changes are opposed by the increased sympathetic activity. As a result, modest hypercapnia (Paco2 of 7 kPa) in healthy subjects leads to an increase in cardiac output from increased stroke volume and heart rate, producing a small increase in blood pressure. Venous dilatation tends to persist despite the increased catecholamine concentrations, and patients with hypercapnia usually appear flushed.
An increased cardiac output at the same time as increased pulmonary vascular resistance inevitably leads to increased pulmonary arterial pressure. In critically ill patients, these changes will exacerbate pulmonary hypertension resulting from hypoxaemia leading to increased right ventricle afterload. Acute cor pulmonale may occur, a pathophysiological response that may be responsible for some of the detrimental clinical outcomes of permissive hypercapnia described below.15
Nervous system
Increased CO2 concentrations cause narcosis, with sedation or delirium at Paco2 levels below around 12 kPa and unconsciousness thereafter. The narcotic effect is often accompanied by signs of central nervous system activation manifesting as a metabolic flap with moderate hypercapnia and seizures at significantly increased Pco2 concentrations. An inspired CO2 concentration of around 30% is an effective and inexpensive GA for animals, but not in humans because of seizures. Carbon dioxide narcosis most likely results from alteration of the intracellular pH in the central nervous system rather than its inert gas effect because the oil solubility of CO2 suggests it is a much weaker narcotic than seen invivo.
Cerebral circulation
Headache is one of the most common symptoms of acute hypercapnia, illustrating the effect of CO2 on the cerebral circulation. Cerebral blood flow (CBF) is very sensitive to changes in Paco2: measurement of internal carotid or vertebral artery blood flow using ultrasound has shown a 22–45% increase or 7–22% decrease in flow per kPa change in CO2 level above and below eupnoeic Paco2, respectively.16 The increase in CBF continues up to a Paco2 of around 10 kPa. Arterial Pco2 also influences the response of the cerebral circulation to hypoxaemia, with hypercapnia enhancing the increased CBF seen with severe hypoxaemia.
Cerebral autoregulation describes the traditional model in which a physiological response of the brain to altered blood pressure maintains a constant CBF when mean arterial pressure is in the range 65–150 mmHg, although this range is likely to be much narrower in humans. The relationship between this model and altered Pco2 is complex.16 With hypotension the response to hypercapnia is progressively attenuated, probably because cerebral vessels are already vasodilated, until at a mean arterial pressure of one third of normal there is no cerebrovascular response at all to Pco2. These observations suggest that blood pressure, rather than Pco2, is the critical component for maintaining CBF.
Major arteries such as the internal carotid and vertebral arteries are themselves directly responsive to changes in Pco2, but smaller vessels are the main site of resistance modulation. The most important site is in pial arterioles which are located in the subarachnoid space, where in addition to responding to blood gases and pH they are influenced by changes in CSF metabolic components. The hypercapnic response in pial arterioles is further modulated as they pass through the pia mater by glial cells which release vasoactive substances allowing direct neuronal control of vessel size.
Permissive hypercapnia
Permissive hypercapnia describes deliberately allowing Paco2 to increase above the normal range (>6.1 kPa) in a patient who is receiving mechanical ventilation.
Clinical uses of permissive hypercapnia
The term was first used by Hickling and colleagues17 in the early 1990s in their descriptions of improved survival in patient receiving mechanical ventilation for acute respiratory distress syndrome (ARDS), when plateau pressures and tidal volumes were limited to decrease stretching of the lungs. After further refinements, this strategy became known as lung protective ventilation (LPV) and was widely adopted for mechanical ventilation of all patients with injured lungs. The strategy has many benefits, such as decreasing barotrauma and volutrauma (by limiting stretch and sheer force), atelectrauma (by less cyclic recruitment and derecruitment of lung tissue), and biotrauma by decreasing cytokine production.
Lung protective ventilation is now also recommended for short-term mechanical ventilation in patients with healthy lungs during GA.18 This is particularly important in patients whose lungs are likely to be difficult to ventilate without generating increased driving pressures, which are associated with poor clinical outcomes in patients with or without injured lungs. In the operating theatre, this means patients who have restrictive lung disease, have morbid obesity, or are having laparoscopic surgery in the head-down position.
Small tidal volume is a key component of LPV, leaving ventilatory frequency as the only option to manage minute ventilation and so Pco2. This strategy for artificial ventilation will actually impair carbon dioxide removal by increasing dead space (see above). Furthermore, abnormal matching in both critically ill patients and those with healthy lungs receiving GA will increase alveolar dead space. Hypercapnia and hypercapnic acidosis are therefore common during LPV, but whether these consequences are beneficial, neutral or detrimental to clinical outcomes remains unknown. This is unsurprising considering the wide range of profound effects of carbon dioxide on biological systems described above.
There is no doubt that LPV itself reduces mortality in patients with ARDS,15 and initially the associated hypercapnia and hypercapnic acidosis were thought also to be potentially therapeutic because of their immune modulatory effects. However, some studies of patients receiving mechanical ventilation suggest that hypercapnia may be harmful. A retrospective study including more than 250 000 patients found that compared with those maintained at normal pH and Pco2, patients with either hypercapnic acidosis (decreased pH and increased Pco2) or compensated hypercapnia (normal pH and increased Pco2) had increased in-hospital mortality.19 A study involving patients from 927 ICUs across 40 countries also found hypercapnia to be associated with higher mortality despite propensity matching patients for multiple factors, including the presence of acidosis, suggesting the hypercapnia itself is potentially harmful.20 Conversely, a recent meta-analysis offers a potential explanation for the variation in studies of clinical outcomes, showing that permissive hypercapnia was only beneficial when used as part of a LPV strategy.21 Without the use of permissive hypercapnia to facilitate LPV, many more of the patients in any of these studies may have succumbed to their ARDS- or ventilator-induced lung injury, highlighting the need for further clinical evidence to inform these complex clinical decisions. Until this is available, current opinion is that severe hypercapnia (Paco2 >6.7) should be avoided if possible.15
Strategies that may be used to limit hypercapnia when using LPV include decreasing dead space by recruitment manoeuvres, altering the driving pressure and PEEP to achieve the desired Paco2 and tidal volume, or increasing the ventilatory frequency. Prone positioning may improve V̇/Q̇ matching, including enhanced removal of carbon dioxide. The use of i.v. HCO3− to treat hypercapnic acidosis (pH <7.15) was permitted in the earlier trials of LPV, but once again, there is no clinical evidence that this is beneficial or harmful.15 Adverse effects of i.v. bicarbonate in a patient with acidosis include worsening hypercapnia and a paradoxical intracellular acidosis. Finally, an option for patients with ARDS of such severity that standard LPV is unhelpful is to use ultra-low tidal volume ventilation facilitated with extracorporeal venovenous carbon dioxide removal. This strategy showed early promise for patients with severe hypoxaemia, but a recent trial found no effect on 90-day mortality; however, the trial was terminated early and so may have been underpowered.22
Conclusions
Carbon dioxide plays a key role in maintaining normal acid–base homeostasis, so its partial pressure in body tissues is carefully maintained by various physiological mechanisms. Abnormal CO2 levels have a variety of physiological, iatrogenic, and pathological causes and lead to unpredictable physiological changes. Permissive hypercapnia as part of LPV has adverse effects on lung immune responses and cellular repair systems, but may still be clinically useful to minimise ventilator-induced lung injury.
Declarations of interest
ABL is a member of the associate editorial board of the British Journal of Anaesthesia and is a former editor of BJA Education. JP declares no conflicts of interest.
MCQs
The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.
Biographies
•
Jyothima Pippalapalli MD DNB FRCA is specialty trainee in anaesthesia at Leeds Teaching Hospitals NHS Trust. She has a keen interest in applied basic sciences.
•
Andy Lumb FRCA is consultant anaesthetist at St James's University Hospital and honorary clinical associate professor at the University of Leeds who specialises in thoracic anaesthesia. His research focuses on respiratory physiology. He teaches at all levels and lectures at postgraduate meetings both in the UK and abroad. He has authored many chapters, reviews, and editorials, and five editions of Nunn and Lumb's Applied Respiratory Physiology. He is an associate editor of the British Journal of Anaesthesia.
Notes
Matrix codes: 1A01, 2C04, 3C00
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