Permissive hypercapnia — role in protective lung ventilatory strategies

SYMPOSIUM: INTENSIVE CARE

Permissive hypercapnia inprotective lung ventilatorystrategies

Brendan D Higgins

Joseph F Costello

Martina Ni Chonghaile

John G Laffey

Abstract

Hypercapnia has traditionally been avoided in paediatric critical illness;

indeed, traditional approaches advocated hypocapnia in a number of

disease states. However, recent advances in understanding of the role of

excessive tidal stretch has prompted clinicians to avoid high tidal

volumes or plateau pressures, and to tolerate the resulting ‘permissive’

hypercapnia. Advances in understanding of the biology of hypercapnia

have led to consideration of an active role for hypercapnia in the

pathogenesis of inflammation and tissue injury. Newer data suggest that

elevated CO2 may be protective, but in some experimental situations can

cause harm. This review assesses the role of ventilatory strategies

involving permissive hypercapnia in the management of neonates and

children with acute severe respiratory failure. The physiological effects of

hypercapnia on the lung and systemic organs are discussed, and

evidence from laboratory models of lung and systemic organ injury is

considered, demonstrating the potential for hypercapnia to modulate the

injury process. The role of permissive hypercapnia in various clinical

settings relevant to neonatal and paediatric practice, and the risks

and benefits of hypercapnia in specific clinical situations are also

considered.

Brendan D Higgins BSc PhD is Postdoctoral Fellow at the Department of

Anaesthesia Clinical Sciences Institute and National Centre for

Biomedical Engineering Sciences, National University of Ireland, Galway,

Ireland.

Joseph F Costello MB FCARCSI is Research Fellow at the Department of

Anaesthesia, Clinical Sciences Institute and National Centre for


Ireland.

Martina Ni Chonghaile MB FCARCSI is Research Fellow at the Department of



Ireland.

John G Laffey MD MA BSc FCARCSI MB FCARCSI is Professor at the Department of



Ireland.

PAEDIATRICS AND CHILD HEALTH 17:3 94

Keywords hypercapnia; acidosis; mechanical ventilation; acute lung

injury; acute respiratory distress syndrome; congenital heart disease;

congenital diaphragmatic hernia; asthma; neonatal respiratory distress

syndrome; pulmonary hypertension; intracranial pressure; buffering

Introduction

Traditional approaches to the management of CO2 in neonates

and children with acute respiratory failure have focused on the

potential deleterious effects of hypercapnia and therefore on

targeted normocapnia or even hypocapnia. Support for this

strategy is derived from the link between hypercapnia and

adverse outcome in diverse clinical contexts, including cardiac

arrest1 sepsis2 and neonatal asphyxia.3 However, it has been

increasingly questioned. Accumulating evidence from experi-

mental and clinical studies supports the contention that

mechanical ventilation may directly injure the lungs, a phenom-

enon termed ‘ventilator-induced lung injury’. Permissive hyper-

capnia (PHC) is a ventilatory strategy in which relatively high

PaCO2 is tolerated in an effort to avoid high tidal volumes and

pulmonary over-distension, thereby potentially reducing lung

injury and increasing survival.4,5 PHC has been progressively

accepted in the critical care of patients requiring mechanical

ventilation.

Conventionally, the protective effect of ventilatory strategies

incorporating PHC is considered to be solely due to reductions in

lung stretch, with hypercapnia permitted to achieve this goal.

However, protective ventilatory strategies involving hypoventila-

tion result in both limitation of lung stretch and elevation of

systemic PCO2. Lung stretch is distinct from elevated PCO2, and

by manipulation of respiratory parameters (frequency, tidal

volume, dead-space, inspired CO2) can, at least to some extent,

be separately controlled. Thus, it is important to determine

whether hypercapnia might exert direct effects in critically ill

children. If hypercapnia were proved to have independent

benefits, deliberately elevating PaCO2 (therapeutic hypercapnia)

could provide an additional advantage over low tidal volume

strategies alone. Conversely, in patients managed with conven-

tional PHC, adverse effects of elevated PaCO2 might be concealed

by the benefits of lower lung stretch. Because ICU outcome might

be related to the development of multi-organ failure (as opposed

to simply lung injury) it is also necessary to determine the effects

of hypercapnia on systemic organs.

This review assesses the role of ventilatory strategies involving

PHC in the management of neonates and children with acute

respiratory failure. The physiological effects of hypercapnia in the

lung and systemic organs are discussed, and evidence from

laboratory models of lung and systemic organ injury is

considered, demonstrating the potential for hypercapnia to

modulate the injury process. The role of PHC in various clinical

settings relevant to neonatal and paediatric practice, and the risks

and benefits of PHC are also considered in specific clinical

situations.

Physiological effects of hypercapnia

If PHC is to be used rationally and safely in critically ill neonates

and children, its physiological effects must be considered. These

r 2007 Elsevier Ltd. All rights reserved.

Figure 1 Brain tissue oxygen tension, in addition to cerebral perfusion,

is progressively increased with increases in inspired CO2 concentration.

(Reproduced with permission, Hare GM, et al. Can J Anaesth 2003; 50:

1061–8.)


effects are diverse and incompletely understood, however, and

direct effects are often counterbalanced by indirect effects. In

addition, the net effect of hypercapnia may occur as a function of

acidosis or of CO2 per se.

Pulmonary system

In the normal lung, CO2 may either regulate regional ventilation

in response to primary changes in perfusion, or alter regional

perfusion to match primary changes in ventilation. An example is

the phenomenon of hypocapnic bronchoconstriction that occurs

following acute regional pulmonary artery occlusion.6

It is of concern that hypercapnia can increase pulmonary

vascular resistance. This might aggravate primary pulmonary

hypertension in newborns managed with a strategy of PHC.

Reassuringly, however, data from an animal model of chronic

hypoxia-induced pulmonary hypertension suggests that the effect

of hypercapnia on pulmonary vascular resistance does not appear

to be exacerbated in the setting of pre-existing pulmonary

hypertension.7 Administration of CO2 improves matching of

ventilation and perfusion and increases arterial oxygenation by

this mechanism in both health8,9 and disease.10 A dose–response

relationship exists whereby increased FiCO2 results in progressive

augmentation of PaO29,11 (Figure 1). In acute respiratory distress

syndrome (ARDS), the potential for PHC to increase shunt is due

to reduced tidal volume and airway closure rather than

hypercapnia per se.12

Hypercapnia has been variably reported to either increase13 or

decrease14 airway resistance. These effects may be explained by

the direct dilatation of small airways and indirect (vagally

mediated) large airway constriction.6 These opposing balanced

airway actions of CO2 may result in little net alteration in airway

resistance. Parenchymal lung compliance increases in response to

hypercapnic acidosis. This may be due to increased surfactant

secretion or more effective surface tension-lowering properties

under acidic conditions.15

Central nervous system

Hypercapnic acidosis increases cerebral tissue oxygen tension

through both augmentation of PaO2 and increased cerebral blood

flow9 (Figure 1). Hypercapnia is a potent ventilatory stimulant.16

A modest increase in ventilatory chemosensitivity has been

shown in response to acute hypoxia, but no change occurred with

acute elevations in CO2.

Cardiovascular system

Hypercapnic acidosis directly reduces the contractility of cardi-

ac17 and vascular smooth muscle.6 This is counterbalanced by

the hypercapnia-mediated sympathoadrenal effects of increased

preload and heart rate, increased myocardial contractility and

decreased afterload, leading to a net increase in cardiac output.6

Hypercapnia results in a complex interaction of altered cardiac

output, hypoxic pulmonary vasoconstriction, and intrapulmon-

ary shunt to produce a net increase in PaO2. Because hypercapnia

generally elevates cardiac output, global oxygen delivery is

increased. Regional (including mesenteric) blood flow is also

increased,18 thereby increasing organ oxygen delivery. Hyper-

capnia and acidosis shifts the hemoglobin–oxygen dissociation

curve to the right, reducing the oxygen affinity of haemoglobin,

and may cause an elevation in haematocrit, further increasing

tissue oxygen delivery. Acidosis may reduce cellular respiration


and oxygen consumption, which may further benefit a supply/

demand imbalance.19

Insights from laboratory studies

It is not currently feasible to examine the direct effects of

hypercapnic acidosis in humans independent of alterations in

ventilatory strategies. An alternative approach, which has been

the focus of much recent attention, is to determine the effects of

hypercapnic acidosis in various animal models of experimental

acute lung and systemic organ injury.

Pulmonary

Hypercapnic acidosis attenuates the increased lung permeability

seen following free radical-mediated20 and ischaemia–reperfu-

sion-induced reperfusion-induced lung injury.20,21 Hypercapnic

acidosis preserved lung mechanics, attenuated protein leakage,

reduced pulmonary oedema and improved oxygenation com-

pared with control conditions following in vivo pulmonary

ischaemia–reperfusion22 as well as in secondary reperfusion-

induced lung injury.11 Such protective effects of hypercapnic

acidosis are not mediated via a decrease in pulmonary artery

resistance; indeed, protection occurred despite elevated pulmon-

ary artery pressures.11



Hypercapnic acidosis appears to attenuate the development of

pulmonary hypertension and vascular remodelling induced by

chronic hypoxia in newborn rats.23 Newborn rats were main-

tained under atmospheric CO2 of less than 0.5% (normocapnia),

5.5% or 10% during exposure from birth for 14 days to normoxia

or moderate hypoxia (13%). Inspired CO2 attenuated the increase

in pulmonary arterial resistance, right ventricular hypertrophy

and dysfunction, medial thickening of pulmonary resistance

arteries and distal arterial muscularisation that occurred in rats

exposed to hypoxia. A dose–response was seen; 10% CO2

significantly attenuated pulmonary vascular remodelling and

alterations in pulmonary arterial resistance, and both increased

concentrations of CO2 normalised right ventricular performance.

Exposure to 10% CO2 also reduced lung oxidative injury, and

prevented up-regulation of endothelin-1, a critical mediator of

pulmonary vascular remodelling.23

The effect of hypercapnia in ventilator-induced lung injury

(VILI) is more complex. In two key studies, addition of inspired

CO2 reduced VILI in isolated rabbit lung24 and in rabbits in vivo.25

However, not all data are so positive. Supplemental CO2 has more

modest protective effects in the context of more clinically relevant

tidal stretch. Strand et al. showed that significant hypercapnic

acidosis (mean PaCO2 95 mmHg) was well tolerated in preterm

lambs, and appeared to reduce lung injury.26 In the context of a

clinically relevant high tidal volume strategy (tidal volume

12 mL/kg, positive end-expiratory pressure (PEEP) 0 cmH2O, rate

42/min) in an adult model, hypocapnia was potentially deleter-

ious and hypercapnic acidosis somewhat protective.11 However,

inspired CO2 did not significantly attenuate lung injury induced

by an atelectasis-prone model of lung injury, which may mimic

neonatal respiratory distress syndrome more closely than pure

stretch models of injury.27 Hypercapnia produced by hypoventi-

lation rather than by increased inspired CO2 did not protect

against stretch-induced injury.28 In a subsequent study, hyper-

capnia was found to minimise the adverse effects of high-volume

ventilation on vascular barrier function, but it impaired the

ability of lung cells to repair the stretch-induced injury.29 Taken

together, these findings suggest that while hypercapnic acidosis

substantially attenuates injury due to excessive stretch, its effects

in the context of more clinically relevant lung stretch or extensive

atelectasis are modest, and there are concerns regarding the

effects of hypercapnia on cellular repair following injury.

ARDS commonly develops in the context of severe sepsis in

children. Hypercapnia may have deleterious effects by impairing

the immune system response to bacterial sepsis.30,31 The

mechanisms of lung injury in sepsis-induced ARDS are distinct

from those in many experimental models. Lipopolysaccharide

(LPS), a key endotoxin of Gram-negative bacteria, initiates lung

injury by activating a specific receptor called toll-like receptor-4.

Hypercapnia appears to have different effects in lung injury

caused by pulmonary vs systemic administration of endotoxin.

Hypercapnic acidosis induced by the administration of CO2 has

been shown to directly protect against acute lung injury induced

by intratracheal instillation of endotoxin.32 Conversely, hyper-

capnia induced by reduced tidal volume and respiratory rate

appears to worsen the lung damage induced by systemic

administration of endotoxin.33 These issues underline the need

to take into account both the means of achieving hypercapnia

and the diversity of experimental models.


Prolonged hypercapnia may impair diaphragmatic function in

rats by interfering with neuromuscular transmission and histo-

logical structure.34 Alterations in diaphragmatic function could

lead to delayed weaning from ventilatory support. However,

clinical trials of PHC in infants and children to date do not

support this concern.

Cardiovascular

Hypercapnic acidosis appears to have beneficial effects on the

myocardium, and protects the heart from ischaemia–reperfusion

injury.35 Both hypercapnic and metabolic acidosis have been

shown to reduce infarct size in an in vivo canine model of

coronary artery ischemia–reperfusion.36 Possible mechanisms for

the protective effects of acidosis include reduction of calcium

loading to the myocardium through H+ inhibition of calcium

uptake, and, in the case of hypercapnic acidosis, the induction of

coronary vasodilatation. Nomura et al. found that the greatest

coronary artery blood flow occurred with maximal hypercap-

nia,35 while acute hypercapnia increased both collateral and

global coronary blood flow in a swine model of chronic coronary

artery obstruction.37 However, normocapnic acidosis protected

the myocardium from coronary artery occlusion-induced ischae-

mia–reperfusion injury in a canine model.38 In contrast,

hypercapnic acidosis was found to reduce the success of

resuscitation following ventricular fibrillation arrest in a rodent

model.39

Neurological

Several studies have demonstrated protective effects of hyper-

capnia in brain injury. Hypercapnic acidosis protects the new-

born porcine brain from hypoxia/reoxygenation-induced

injury.40,41 Hypercapnia also attenuates hypoxic–ischaemic brain

injury in immature rats, while hypocapnia is deleterious.42,43

Cerebral blood flow was better preserved during hypercapnia,

and the greater oxygen delivery promoted cerebral glucose

utilisation and oxidative metabolism for optimal maintenance

of high-energy phosphate reserves in the tissues.42 However, an

important dose–response phenomenon was found; mild-to-

moderate hypercapnia (PaCO2 40–55 mmHg) was significantly

more neuroprotective than higher PaCO2 (470 mmHg).43 Indeed,

extremely high PaCO2, which is not generally seen in the clinical

context, appeared to have detrimental effects on the developing

brain.44 Potential mechanisms underlying these protective effects

include reduced levels of glutamate, an excitatory amino acid

neurotransmitter, in the CSF,42 free radical inhibition40,41 and

attenuation of neuronal apoptosis.45

Hypercapnia may contribute to the pathogenesis of retino-

pathy of prematurity, an important concern in the context of

neonatal respiratory failure. Hypercapnia causes retinal vasodi-

latation and increases retinal oxygen delivery in newborn (and

adult) rats.46 However, hypercapnia was shown to produce

preretinal neovascularisation similar to that seen in oxygen-

induced retinopathy in a neonatal rat model.47

Others

Acidosis markedly delays the onset of cell death in isolated

hepatocytes exposed to anoxia48 or chemical hypoxia.49 Buffering

of the pH accelerated cell death. This phenomenon may represent

a protective adaptation against hypoxic and ischaemic stress.

Isolated renal cortical tubules exposed to anoxia have greater ATP


Figure 2 Hypercapnia suppresses the degradation of IkB-a (panel A) but

not IkB-b (panel B) following exposure to lipopolysaccharide, thereby

inhibiting the nuclear translocation of NF-kB and downstream cytokine

production. The effects of isocapnic acidosis and buffered hypercapnia

(panel C) on IkB-a degradation were intermediate between normocapnic

control and hypercapnic acidosis conditions. BH, buffered hypercapnia;

HA, hypercapnic acidosis; IA, isocapnic acidosis; LPS, lipopolysacchar-

ide; NC, normocapnia; NF-kB, nuclear factor kappa-B. (Reproduced with

permission, Takeshita K, et al. Am J Respir Cell Mol Biol 2003; 29:

124–32.)


levels on reoxygenation at acidotic pH compared with tubules

incubated at pH 7.548. In contrast, the combination of hypoxia

and hypercapnia induced apoptosis in rat renal tubular cell

cultures.50

Cellular and molecular effects of hypercapnia

A clear understanding of the cellular and biochemical mechan-

isms underlying the effects of hypercapnia is essential. It is a

prerequisite for the successful translation of laboratory findings

to the bedside, and allows prediction of potential side effects,

enabling identification of those in whom hypercapnia should be

avoided.

Acidosis vs hypercapnia

The protective effects of hypercapnic acidosis in experimental

lung and systemic organ injury appear to be primarily a function

of the acidosis.21,51 In isolated lung, the protective effect of

hypercapnic acidosis in ischemia–reperfusion was greatly atte-

nuated if the pH was buffered towards normal.21 The myocardial

protective effects of hypercapnic acidosis are also seen with

metabolic acidosis in both ex vivo52 and in vivo36,38 models.

Furthermore, as discussed earlier, metabolic acidosis exerts

protective effects in other organs, including the liver and the

kidney.48,49

Anti-inflammatory effects

Several key components of the inflammatory response appear to

be attenuated by hypercapnic acidosis. It inhibits the release of

tumour necrosis factor-a (TNF-a) and interleukin (IL)-1 from

stimulated macrophages in vitro53 and reduces bronchoalveolar

lavage levels of TNF-a following in vivo pulmonary ischaemia–

reperfusion.22 Both hypercapnia and acidosis impair intracellular

pH regulation by neutrophils, potentially overwhelming their

capacity (especially when activated54) to regulate cytosolic pH.

This failure impairs important neutrophil functions such as

chemotaxis55 and the release of IL-8 following stimulation by

LPS.56 Such effects also occur in vivo; lung neutrophil recruit-

ment is inhibited during ventilator-induced25 and endotoxin-

induced32 lung injury.

Free radical generation and activity

In common with most biological enzymes, the enzymes that

produce oxidising free radicals function optimally at physiologi-

cal pH. Generation of oxidants by both basal and stimulated

neutrophils appears to be regulated by ambient CO2 levels;

oxidant generation is reduced by hypercapnia and increased by

hypocapnia.56 The production of superoxide by stimulated

neutrophils in vitro is decreased at acidic pH.57 In the brain,

hypercapnic acidosis attenuates glutathione depletion and lipid

peroxidation,40 which reflect free radical activity and tissue

damage, respectively. In the lung, hypercapnic acidosis reduces

free radical tissue injury following ischaemia–reperfusion22 and

attenuates production of the higher oxides of NO (e.g. NO2, NO3)

following both ventilator-induced24 and endotoxin-induced32

injury. Hypercapnic acidosis inhibits injury mediated by xanthine

oxidase, and directly inhibits the enzyme.20

There are concerns regarding the potential for hypercapnia to

potentiate tissue nitration by peroxynitrite, a potent free radical.

Buffered hypercapnia promotes the formation of nitration


products from peroxynitrite in vitro.51 The potential for hyper-

capnic acidosis to promote nitration of lung tissue in vivo appears

to depend on the injury process. Hypercapnic acidosis decreased

tissue nitration following pulmonary ischaemia–reperfusion,22

but increased nitration following endotoxin exposure.32,33,51

Regulation of gene expression

Hypercapnic acidosis appears to regulate the expression of genes

central to the inflammatory response in models of cell injury.

Nuclear factor kappa B (NF-kB) is a key regulator of the

expression of multiple genes involved in the inflammatory

response, and its activation is a pivotal early step. Hypercapnic

acidosis inhibits endotoxin-induced NF-kB activation and DNA

binding in pulmonary endothelial cells by decreasing IkB-adegradation (Figure 2).58 Hypercapnic acidosis also suppressed

endothelial production of intercellular adhesion molecule-1 and

IL-8, which are critically regulated by the NF-kB pathway.58

Role of PHC in specific clinical settings

The use of PHC in neonatal and paediatric respiratory failure has

long been recognised. The potential deleterious effects of

barotrauma on the developing lung were first noted almost 30

years ago.

Neonatal respiratory distress syndrome

Acute respiratory failure in the preterm newborn results from

parenchymal stiffness due to immaturity and surfactant defi-

ciency, and may be complicated by adverse events such as sepsis

and aspiration of meconium. Lung injury remains a leading cause

of morbidity in neonates who receive ventilatory support.59 The

duration and intensity of mechanical ventilation may be

important determinants of the development of bronchopulmon-

ary dysplasia (BPD)/chronic lung disease (CLD). The immature

lung may be particularly susceptible to barotrauma. The risk of



CLD in premature neonates may be lowered if barotrauma is

reduced by the acceptance of higher PaCO2.60 Conversely, the

presence of hypocapnia at 48 and 96 hours of life in neonates

with respiratory failure has been demonstrated to be the best

predictor of BPD.61

In the first randomized controlled trial of PHC, Mariani et al.

reported beneficial effects of hypercapnia in infants with neonatal

respiratory distress syndrome.59 Preterm infants (birth weight

8547163 g, gestational age 2671.4 weeks) were randomly

allocated to a target PaCO2 of 35–45 mmHg or 45–55 mmHg for

the first 96 hours of life. Infants randomised to the higher PaCO2

required less intensive ventilation and were weaned from

mechanical ventilation significantly faster. The total number of

days on assisted ventilation was 2.5 (1.5–11.5) in the PHC group

and 9.5 (2.0–22.5) in the control group (p ¼ 0.17), and the

number of infants requiring assisted ventilation during the first

96 hours was lower (po0.005) in the PHC group (Figure 3). No

obvious adverse effects were seen, though such a small study

would not detect a low incidence of adverse effects.

A larger, multi-centre trial of PHC randomised extremely low

birth weight infants (501–1000 g) mechanically ventilated before

12 hours of life to a target PaCO2 of below 48 mmHg (routine) or

above 52 mmHg (PHC group), and a tapered course of

dexamethasone or a saline placebo, using a 2� 2 factorial

design, for the first 10 post-natal days.62 Unfortunately, the trial

was stopped early, because of unanticipated non-respiratory

adverse events related to the dexamethasone therapy. There was

a trend towards a lower incidence of death and CLD in the PHC

group. Importantly, only 1% of the PHC group required

mechanical ventilation at 36 weeks’ gestational age, compared

with 16% in the routine group (po0.01). However, the reduced

Figure 3 Duration of mechanical ventilation in neonates with respiratory

failure randomised to conventional therapy or permissive hypercapnia.

(Reproduced with permission from Mariani G et al. Pediatrics 1999; 104:1082–8.)


sample size limits the conclusions that can be drawn from

this study.

A prospective multi-centre study of extremely premature

neonates in Denmark (1994–1995) reported that a ventilatory

strategy incorporating PHC, early use of nasal continuous

positive airway pressure and surfactant significantly reduced

the incidence of CLD.63

Persistent pulmonary hypertension of the newborn (PPHN)

PPHN is a complication of neonatal sepsis, aspiration of

meconium or severe neonatal respiratory failure, or occurs in

an idiopathic form in term or near-term neonates. Traditional

management has emphasised hyperventilation to reduce pul-

monary arterial pressure. To achieve a significant effect with a

resultant increase in oxygenation, extreme reduction of PaCO2

(420 mmHg) resulting in a pH of more than 7.60 has been

advocated.64 However, the resultant hypocapnia has been clearly

associated with adverse neurological outcome in the survivors of

PPHN, in terms of sensorineural hearing loss and low psycho-

motor developmental scores.65,66

In marked contrast to this traditional approach, Wung et al.67

described lower than previous mortality, and a reduced incidence

of CLD, in 15 neonates with persistent foetal circulation in severe

respiratory failure. PaCO2 was allowed to increase as high as

60 mmHg, while hyperventilation and muscle relaxants were

avoided. All of the neonates survived, and only one developed

CLD as defined by a need for supplemental oxygen beyond 30

days of life.67 In a more recent study, Marron et al.68 reported

100% survival in a case series of 34 infants with severe PPHN and

severe respiratory failure at birth managed with PHC. Subsequent

detailed neurological and audiological testing of 27 of these

patients revealed a good neurological outcome, with average IQ

in the normal range, no cases of sensorineural hearing loss, and a

relatively low incidence of neurological abnormalities not

attributable to birth asphyxia. Only two infants developed BPD,

and neither required supplemental oxygen at follow-up.68

Congenital diaphragmatic hernia

Permissive hypercapnia is playing an increasing role in the

ventilatory management of infants with congenital diaphragmatic

hernia.69 This contrasts sharply with traditional management

strategies, which involved aggressive hyperventilation with the

aim of producing systemic alkalinisation. However, high levels of

barotrauma, poor long-term respiratory outcomes and poor

survival rates led to the recognition that it is the hypoplastic

lung that is the major pathophysiological defect. Accordingly,

avoidance of barotrauma has assumed increasing importance,

and ventilation strategies involving PHC are increasingly used in

this clinical setting. A retrospective analysis of the effect of three

treatment protocols on the outcome in high-risk infants with

congenital diaphragmatic hernia reported that prioritizing PHC

was associated with a substantial increase in survival, reduced

barotrauma, and reduced morbidity at 6 months. In contrast,

earlier introduction of high-frequency oscillatory ventilation

(which readily controls PaCO2) appeared to have a minimal

impact. Despite limitations of this study, the finding of a clear

survival benefit with a treatment protocol in which PHC appears

to be the sole addition is persuasive.70



Congenital heart disease

Control of CO2 has traditionally played an integral role in the

management of patients with complex congenital heart defects.

In the context of single ventricle physiology, pulmonary vascular

resistance can be controlled by inducing alveolar hypoxia or

alveolar hypercapnia. The potential of hypercapnia to improve

brain and other systemic organ oxygenation is increasingly

recognised. In neonates with severe congenital heart defects, low

cerebral blood flow has been associated with periventricular

leucomalacia and adverse neurological outcome.71 These deficits

in cerebral blood flow were reversible when CO2 was adminis-

tered.71 Furthermore, addition of inspired CO2 increased cerebral

oxygenation and mean arterial pressure compared with reducing

FiO2 in hypoplastic left heart syndrome72 and following

cavopulmonary connection,73 respectively. Hypoventilation has

also been shown to improve systemic oxygenation after bidirec-

tional superior cavopulmonary connection, potentially via a

hypercarbia-induced decrease in cerebral vascular resistance,

thereby increasing cerebral, superior vena caval and pulmonary

blood flow.74 A more detailed recent study showed that, without

altering tidal volume or mean airway pressure, addition of CO2 to

the inspired gas resulted in improved cerebral blood flow and

systemic oxygenation following cavopulmonary connection.75

Taken together, these studies raise the possibility that inhaled

CO2 might have a future therapeutic role in this context.

Acute severe asthma

Although much of the current research on ventilatory strategies

involving PHC concentrates on its therapeutic potential in lung

injury, its use was first described in patients with status

asthmaticus.76 PHC facilitates reduction of dynamic hyperinfla-

tion during mechanical ventilation in acute severe asthma, by

allowing increased expiratory time, reduced inspiratory flow rate,

and reduced tidal volume. This reduces the end-inspiratory lung

volume and the risk of auto-PEEP. Others have supported the

case for morbidity and mortality being reduced when PHC is used

in patients with severe asthma who require mechanical ventila-

tion,77 and modest PHC (mean highest levels 62 mmHg) is

routinely used in patients with acute severe asthma admitted to

ICUs in mainland Europe.78

ARDS

The potential for protective lung ventilation strategies, with

varying degrees of PHC, to improve survival in patients with

acute lung injury and ARDS was suggested initially by Hickling

et al.5,79 Two studies by this group, one retrospective79 and one

prospective,5 strongly indicated that a low tidal volume approach

was beneficial. Of the five prospective randomized controlled

trials of protective ventilation strategies4,80–83 conducted in the

last decade, two showed an impact of ventilatory strategy on

mortality,4,80 though three did not.81–83 To some extent, PHC

developed in all of the trials, though there was much variability.

In the four major trials, the post-randomization ranges of PaCO2

(mean7SD, mmHg) in the control (i.e. higher tidal volume)

groups were 35.878.0,80 36.071.5,4 41.077.582 and 46.0710.81

In contrast, the post-randomisation ranges of PaCO2 in the

protective (i.e. lower tidal volume) groups were 40.0710,80

58.073.0,4 59.571582 and 54.5719.81 Thus, though it is clear

that ventilation strategy can affect mortality (in the positive


trials), these dats show no discernable relationship between level

of hypercapnia and survival.

The database of the largest of these studies80 has been

subsequently analysed to determine whether, in addition to the

effect of tidal volume, there might also have been an independent

effect of hypercapnic acidosis.84 Mortality was examined as a

function of PHC on the day of enrolment, and using multivariate

analysis and controlling for other co-morbidities and the severity

of the lung injury. It was found that PHC reduced mortality in

patients randomised to the higher tidal volume, but not in those

receiving lower tidal volumes.84 If these data are supported, there

may be a good case for concluding that hypercapnic acidosis

directly attenuates ventilator-associated lung injury, rather than

simply being a side effect tolerated to reduce lung stretch.

Balancing risks and benefits

Although hypercapnia and acidosis exert a myriad of biologically

important effects, in practice there are few complications.

Nevertheless, in certain clinical contexts, the potential deleter-

ious effects of hypercapnia must be carefully considered.

PHC and the immature brain

Rapid changes in CO2 levels in very low birth weight infants may

lead to substantial fluctuations in cerebral blood flow, and

predispose to intraventricular haemorrhage in the immature

brain.85 In one study of very low birth weight infants,

hypercapnia was associated with progressive loss of cerebral

autoregulation.86 As a consequence, fluctuations in blood

pressure in premature neonates in the presence of hypercapnia

may increase the risk of intraventricular haemorrhage. This risk

may be reduced by avoiding abrupt changes in PCO2, and by

modest rather than severe hypercapnia (or hypocapnia). Reassur-

ingly, neither Mariani et al.,59 nor Carlo et al.62 found any

increase in intraventricular haemorrhage rates in their rando-

mised controlled trials of PHC in preterm infants with respiratory

failure.

Hypercapnia may protect the immature brain. As discussed

above, there is laboratory evidence that hypercapnia may directly

protect the immature brain from hypoxic�ischaemic injury.42,43

Of potentially more importance, PHC may indirectly protect the

developing brain by avoiding accidental hypocapnia. Preterm

infants exposed to severe hypocapnia (PaCO2o15 torr (o2 kPa)),

even of relatively short duration, develop considerable long-term

neurological abnormalities,87 probably due to reduced cerebral

perfusion. In addition, abrupt termination of hyperventilation

can result in reactive cerebral hyperaemia, and precipitate

intracranial haemorrhage.88

PHC and intracranial pressure (ICP) regulation

A key concern regarding PHC is the potential for hypercapnia-

induced increases in cerebral blood flow to critically elevate ICP

in situations where intracranial compliance is diminished.89

However, clinical conditions predisposing to intracranial hyper-

tension constitute a relative rather than an absolute contra-

indication to PHC. Consideration should be given to the insertion

of an ICP monitor or a jugular venous oximetry catheter, which

can facilitate the gradual titration (or avoidance) of PHC in

patients with a brain injury. The successful use of such an

approach was described in the management of a child with


Figure 4 Chest radiograph and brain CT scan of a child with both acute

respiratory distress syndrome and cerebral oedema, illustrating the

‘trade-off’ involved in instituting permissive hypercapnia to protect

against ventilator-associated lung injury. (Reproduced with permission,

Tasker RC and Peters MJ. Intensive Care Med 1998; 24: 616–9.)


meningococcal septicaemia complicated by both significantly

elevated ICP and severe acute lung injury (Figure 4).89

PHC and pulmonary vascular resistance

Clinical conditions predisposing to pulmonary hypertension

should be considered a relative rather than an absolute contra-

indication to PHC strategies. As discussed above, PHC is

increasingly used in the setting of severe neonatal respiratory

failure resulting in persistent fetal circulation and pulmonary

hypertension.67 In addition, laboratory studies have shown that

hypercapnic acidosis may retard the development of hypoxia-

induced pulmonary hypertension in newborn rodents.23 Con-

cerns about significant pulmonary hypertension can be most

rationally dealt with by assessing the degree of pulmonary

hypertension or its sequelae (e.g. right ventricular failure,

tricuspid regurgitation, increased right to left shunting) and the

effect of hypercapnia on pulmonary vascular resistance, and

titrating the degree of hypercapnia accordingly. In this context,

monitoring by transthoracic echocardiography or the placement

of a pulmonary artery catheter may be indicated.

The role of buffering

Buffering of the acidosis induced by hypercapnia remains a

common, albeit controversial clinical practice. Buffering with

sodium bicarbonate was permitted in the ARDS Network tidal

volume study.80 The need to consider the effects of buffering of

hypercapnic acidosis is emphasized by the fact that both

hypercapnia and acidosis per se may have distinct biological

effects. However, as discussed above, there is evidence that the

protective effects of hypercapnic acidosis in ARDS are a function

of the acidosis rather than the elevated CO2 per se.21,51 Buffering

may simply ablate any protective effects, while not addressing

the primary problem.

There are specific concerns regarding sodium bicarbonate, the

buffer used most commonly in clinical settings. The effectiveness

of bicarbonate infusion as a buffer depends on the ability to

excrete CO2, rendering it less effective in buffering hypercapnic

acidosis. Indeed, bicarbonate may further raise PaCO2 when

alveolar ventilation is limited, such as in ARDS.90 Although

bicarbonate may correct arterial pH, it may worsen intracellular


acidosis91 because the CO2 produced when bicarbonate reacts

with metabolic acids diffuses readily across cell membranes,

whereas bicarbonate cannot.92

Conclusion

Ventilatory strategies involving hypercapnia are widely used in

critically ill neonates and children, with the aim of realising the

benefits of reduced lung stretch. The potential for hypercapnia to

directly contribute to the beneficial effects of protective lung

ventilatory strategies is clear from experimental studies demon-

strating protective effects in models of acute lung and systemic

organ injury. These findings raise the possibility that hypercapnia

might be induced for therapeutic effect in certain clinical

contexts. However, concerns persist regarding the potential

deleterious effects of hypercapnia and/or acidosis, and the need

for caution before extrapolation to clinical settings must be

emphasised.

The optimal ventilatory strategies, and the precise contribution

of hypercapnia to them, remains unclear. At present, clinicians

must continue to decide the benefits and costs of avoiding high

tidal volumes and the associated hypercapnia in individual

patients. A clearer understanding of the effects and the

mechanisms of action of hypercapnia is central to determining

its safety and therapeutic utility. ~

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Practice points

� Traditional approaches to the management of CO2 in neonates

and children have focused on deleterious effects of hypercap-

nia

� Mechanical ventilation strategies involving high lung stretch

are directly injurious to the lung

� Protective ventilatory strategies aimed at reducing lung stretch

generally require tolerance of ‘permissive’ hypercapnia

� There is increasing evidence from laboratory studies that

hypercapnia may attenuate lung and systemic organ injury

� The potential for deleterious physiological effects of hyper-

capnia when intracranial compliance is reduced, or where

increases in pulmonary vascular resistance may be deleter-

ious, must be considered; however, these are not absolute

contraindications to the careful use of PHC in these patients

� There is increasing evidence supporting the use of PHC in

neonatal respiratory failure, congenital diaphragmatic hernia,

acute respiratory distress syndrome, persistent pulmonary

hypertension, congenital heart disease and severe asthma

� There is no evidence to support the clinical practice of

buffering hypercapnic acidosis with bicarbonate


Permissive hypercapnia — role in protective lung ventilatory strategies

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