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Review Articles
Hypocapnia and the injured brain: More harm than benefit
Gerard Curley, MB, FCARCSI; Brian P. Kavanagh, MD, FRCPC; John G. Laffey, MD, MA, BSc, FCARCSI
Traditional approaches in man-aging acute brain injury havefocused on the potential for
hypocapnia to reduce intracra-nial pressure (ICP) (1, 2). Because ele-
vated ICP is generally adverse and hypo-c ap ni a i s t ho ug ht t o b e b en ig n,hyperventilation was widely practiced inpatients with acute brain injury. This rea-
soning led to the idea that more profoundhyperventilation might be even betterand extremes of hypocapnia—for pro-longed periods—were advocated for acutebrain injury (3–7).
This review re-examines the rationalefor the use of hypocapnia in acute braininjury (both traumatic and other causes).
We conducted a literature search onMEDLINE and PubMed (1966–August 1,2009) using the search terms: “hyperven-tilation,” “hypocapnia,” “alkalosis,” “car-bon dioxide,” “brain,” “lung,” and “myo-cardium,” alone and in combination.
Bibliographies of retrieved articles werealso reviewed. The prevalence of hypocap-nia in the management of brain-injuredpatients and the evidence for beneficialand deleterious effects of hypocapnia
were evaluated.
Hypocapnia: Definitions and
Severity
Arterial CO2 tension (Paco2) is a bal-ance between production and elimina-tion. Because endogenous productionrarely falls below normal, hypocapnia is
usually caused by deliberate or accidentalhyperventilation. In the setting of acutebrain injury, the severity of hypocapnia
when used “therapeutically” has beengraded (Table 1) (8).
Why Do We Use Hypocapnia in
Patients After Acute Brain
Injury?
The Monro-Kellie doctrine states thatthe total volume of the intracranial con-
tents must remain constant because thecranial cavity represents a fixed volume.
An increase in the volume of any intra-cranial compartment (e.g., cerebraledema, hematoma, or brain tumor) caninitially be compensated by displacementfrom another compartment. However,
when intracranial content volume ex-ceeds a threshold, ICP increases precipi-
tously (Fig. 1). Intracranial hypertension(sustained ICP Ͼ20 mm Hg) may causesecondary brain injury by impairing ce-rebral perfusion, direct pressure, or bybrainstem herniation.
Hypocapnia is induced to lower ICP bydecreasing the cerebral blood volume(CBV) via cerebral arterial vasoconstric-tion (Fig. 1). The effects are potent: cere-bral blood flow (CBF) decreases by ap-proximately 3% per mm Hg change inPaco2 (range, 60 to 20 mm Hg PCO2) inpatients with traumatic brain injury
(TBI) (9).
How Often Do We Use
Hypocapnia in Clinical Practice?
Hypocapnia is widely used in adultsand children with acute brain injury fromthe earliest phases of the injury process,even in the absence of elevated ICP (8, 10).This widespread use of hypocapnia persistsdespite recognition of its dangers andguidelines—for adults (11) and children
From Department of Anaesthesia (GC, JGL), Uni-versity College Hospital, Galway, Ireland; Departmentsof Critical Care Medicine and Anesthesia and the Pro-gram in Physiology and Experimental Medicine (BPK),The Hospital for Sick Children, University of Toronto,Toronto, Canada; Department of Anaesthesia (JGL),
School of Medicine, Clinical Sciences Institute, Na-tional University of Ireland, Galway, Ireland.
This manuscript was supported in part by a fel-lowship from Molecular Medicine Ireland under theProgramme for Research in Third Level Institutions(GC) and by funding from the European ResearchCouncil (JGL) under the Framework 7 program.
The authors have not disclosed any potential con-flicts of interest.
For information regarding this article, E-mail: [email protected]
Copyright © 2010 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3181d8cf2b
Objectives: Hypocapnia is used in the management of acute
brain injury and may be life-saving in specific circumstances, but
it can produce neuronal ischemia and injury, potentially worsen-
ing outcome. This review re-examines the rationale for the use of
hypocapnia in acute brain injury and evaluates the evidence for
therapeutic and deleterious effects in this context.
Data Sources and Study Selection: A MEDLINE/PubMed search
from 1966 to August 1, 2009, was conducted using the search
terms “hyperventilation,” “hypocapnia,” “alkalosis,” “carbon di-
oxide,” “brain,” “lung,” and “myocardium,” alone and in combi-
nation. Bibliographies of retrieved articles were also reviewed.
Data Extraction and Synthesis: Hypocapnia— often for pro-
longed periods of time—remains prevalent in the management of
severely brain-injured children and adults. Despite this, there is
no proof beyond clinical experience with incipient herniation thathypocapnia improves neurologic outcome in any context. On the
contrary, hypocapnia can cause or worsen cerebral ischemia. The
effect of sustained hypocapnia on cerebral blood flow decreases
progressively because of buffering; subsequent normocapnia can
cause rebound cerebral hyperemia and increase intracranial pres-
sure. Hypocapnia may also injure other organs. Accidental hypo-
capnia should always be avoided and prophylactic hypocapnia
has no current role.
Conclusions: Hypocapnia can cause harm and should be
strictly limited to the emergent management of life-threatening
intracranial hypertension pending definitive measures or to facil-
itate intraoperative neurosurgery. When it is used, Paco2 should
be normalized as soon as is feasible. Outside these settings
hypocapnia is likely to produce more harm than benefit. (Crit Care
Med 2010; 38:1348–1359)
K EY WORDS: carbon dioxide; hypocapnia; alkalosis; hyperventi-lation; acute brain injury; trauma
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(12)—that recommend limitation of hypo-
capnia to intracranial hypertension accom-panied by neurologic deterioration.
Hypocapnia in Adults. The Brain ITinitiative, a collaboration of 38 Europeancenters that provide care for brain-injured patients, has established a TBIdatabase from which Neumann et al (10)recently analyzed arterial blood gas datafrom 2269 ventilation episodes. Earlyprophylactic hyperventilation, i.e., hypo-capnia in the first 24 hrs, was used in54% of episodes (10) (Fig. 2). Further-more, the majority of patients who did
not have increased ICP had significanthypocapnia for up to 50% of their total
ventilation time. More than 90% of pa-tients with Paco2 Յ30 mm Hg receivedno monitoring of brain oxygenation (10).In the United States, 36% of U.S. board-certified neurosurgeons routinely useprophylactic hyperventilation in patients
with severe TBI (13). Hypocapnia in Children. Hypocapnia
remains prominent in the managementof brain-injured children (8). Retrospec-
tive analysis suggests that hypocapnia oc-curs in 52% of patients and that the 2003Pediatric Brain Trauma guidelines (12),
which recommend strict limitation of hy-pocapnia, did not alter this (Fig. 3). The
youngest children (Ͻ2 yrs) had the high-est incidence of severe hypocapnia, whichis a concern given the vulnerability of theneonatal brain and potential for associ-ated intraventricular hemorrhage (14)
(Fig. 4). Severe hypocapnia was commonin children without elevated ICP (8). Thisis of particular concern because hypocap-nia predicted inpatient mortality (oddsratio, 2.8; 95% confidence interval, 1.3–5.9) independent of the severity of braininjury (8).
Hypocapnia in Early Brain Injury.Hypocapnia occurs in brain-injured pa-tients even before intensive care unit ad-mission. Almost 50% of Michigan emer-gency physicians routinely use prophylactichyperventilation in patients with severeTBI (15), and accidental hyperventilation isalso common (16). The net result is thatsevere hypocapnia (end expired CO2 Ͻ30mm Hg) is seen in 70% of patients trans-ferred by helicopter to a U.S. urban level Itrauma center (17). More recently, Warneret al (18) reported that 16% of intubatedTBI patients en route to a level I traumacenter had Paco2 levels Ͻ30 mm Hg,
whereas 30% had levels of 30 to 35 mm Hg.Such prehospital hypocapnia is clearly asso-ciated with adverse outcome in TBI (16, 19).
What Happens to Cerebral
Blood Flow and OxygenRequirements in the Injured
Brain?
Cerebral Blood Flow. Hypocapnia isoften used in brain injury to reduce “lux-ury perfusion,” which is thought to
worsen edema, especially in children(20). Furthermore, because injury impairs
vascular control, if hypocapnia-induced va-soconstriction were more pronounced inuninjured vs. injured brain (21), then per-fusion might be shunted from normal to
vulnerable (injured) brain, a concepttermed “inverse steal” (21).
These concepts are now largely dis-credited. CBF and cerebral oxygen deliv-ery are generally decreased after braininjury (22–28), and regional CBF is oftenmarkedly decreased particularly in thefirst 24 hrs (24–26). In 31% of patients
with TBI (26), CBF is below an “ischemicthreshold” in which ischemia and celldeath may occur (29). Transcranial Dopp-ler demonstrates low-flow early after TBI
in two-thirds of patients (30), a situationassociated with poor outcome (24, 31).Such hypoperfusion may be worsened bycerebral vasospasm, further worseningoutcome (32). Of particular concern, 80%of patients who die of head injury dem-onstrate profound ischemic neuronalchanges (27).
Cerebral Oxygen Utilization. Brain-injured patients commonly have lower
metabolisms and cerebral metabolic re-quirements for oxygen (CMRO2) (33, 34).The “mitochondrial dysfunction hypoth-esis” (22, 35) suggests that low CBF issecondary to the reduced CMRO2, whichis, in turn, caused by mitochondrial fail-ure attributable to injury. If true, then itcould be that the injured brain can toler-ate lower levels of O2 supply and thatfurther reducing CBF (e.g., hyperventila-tion) is possible without causing harm(36). Hypocapnia-induced reduction of CBF may be tolerated after TBI because of this lower metabolic rate and perhapshigher oxygen extraction (22). However,assumptions about global events requirecaution in heterogenous injury becauseof focal limitation of oxygen diffusion at-tributable to endothelial swelling, micro-
vascular collapse, and perivascular edema(37). Finally, lowered jugular venous ox-
ygen extraction (e.g., SjO2) may reflectreduced brain O2 consumption ratherthan increased CBF.
How Does Hypocapnia Reduce
CBV?
The aim of hypocapnia in acute braininjury is to reduce intracranial volume.However, the effect of hypocapnia on CBV is indirect and is mediated via reductionsin CBF (38). Positron emission tomogra-phy demonstrates that only 30% of theCBV resides in the arteries (39). Hypocap-nia has little effect on cerebral venoustone, and dynamic positron emission to-mography confirms that CO2-inducedchanges in CBV are mediated by alteredarterial, not capillary or venous, volume
(38). Thus, the effect of changing Paco2
on CBF (i.e., arterial) is proportionallygreater than its effect on CBV. ReducingCBF by Ͼ30% with hyperventilation cor-responds to a reduction of only 7% inCBV (40). Greater degrees of hypocapniafurther reduce CBF but do not reduceCBV or ICP (40).
The effect of CO2 on CBF depends onthe individual patient, baseline bloodflow, and the part of the central nervoussystem in question. In individuals CBF is
Figure 1. Relationship between intracranial vol-ume and intracranial pressure. Because the cra-nial cavity represents a fixed volume, an increasein the volume of brain tissue, tumor, or hema-toma can initially be compensated by displace-ment of volume from another compartment.
Acute hypocapnia can reduce cerebral blood vol-ume, thereby attenuating the increase in intra-cranial pressure.
Table 1. Classification of severity of hypocapnia
Target Paco2Range Classification
Ͻ26 mm Hg
(Ͻ3.5 kPa)
Intensified forced
hyperventilation26–30 mm Hg
(3.5–3.9 kPa)
Forced hyperventilation
31–35 mm Hg
(4.0–4.7 kPa)
Moderate hyperventilation
36–45 mm Hg
(4.8–6.0 kPa)
Normoventilation
Modified with permission from Neuman et al
(10).
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not homogeneous, and areas with higherCBF have a steeper response to altered
CO2 (41). Overall, there is a 3% change inCBF per 1-mm Hg change in Paco2 (42–44). In different regions, the principle ismaintained such that in the cat, a changein Paco2 of 1 mm Hg results in a bloodflow change of 1.7 mL/100 g/min in thecerebral cortex (baseline flow, 86 mL/100g/min) but a blood flow change of 0.9mL/100g/min in the spinal cord (baselineflow, 46 mL/100 g/min) (45). Similar CBFresponses occur in rabbits (46) and inhumans (41). In contrast, the effect on
CBV is far smaller than that on CBF (47).Thus, the capacity for hypocapnia to re-
duce CBV is limited and is achieved at adisproportionate cost to arterial CBF. Be-cause low CBF is common in the first 24hrs after TBI, early hypocapnia may beparticularly harmful (48).
Mechanism of Cerebral Vasoconstric-tion. The effects of CO2 are primarily onthe cerebral arteries (38), are pH-medi-ated rather than CO2-mediated (49, 50),and occur via a direct effect on the arte-riole smooth muscle (49–51). The largerarteries are less sensitive and the small
pial arterioles are most responsive (52).The endothelium and smooth muscleplay central roles. Multiple mechanismsinvolving nitric oxide, vasoactive prosta-noids, potassium channels, and intracel-lular calcium have been implicated. En-dothelial release of nitric oxide inresponse to alterations in CO2 tensionappears to be key (53). Impaired endothe-lium lessens nitric oxide release and
blunts CO2 reactivity (54), as does inhi-bition of nitric oxide synthase (55–57).Other mechanisms are nitric oxide-independent. Endothelial synthesis andrelease of vasodilator prostanoids may bemore important in children than in adults(58, 59). Smooth muscle Kϩ channels (e.g.,
ATP-sensitive Kϩ) have also been impli-cated (60–62). Ultimately, CO2 modulatessmooth muscle intracellular calcium con-centration and sensitivity (63).
How Can Hypocapnia Cause
Cerebral Hypoxia? Reduced Cereb ral Oxygen Supply.
The most serious concern with hypocap-nia in brain injury is cerebral hypoperfu-sion (37, 40, 64–72). Hypocapnia may
worsen cerebral vasospasm, which inturn can worsen outcome (32) and exac-erbate preexisting impairment of CBF(65). Hypocapnia does not appear to pro-duce “inverse steal” (i.e., diverting perfu-sion to ischemic areas) (73). In fact, in-
jured areas may have incre ased CO2
responsiveness, raising the possibility
that hypocapnia may aggravate secondaryischemic injury by diverting flow frominjured brain (74).
Hypocapnia may reduce cerebral O2
supply via additional mechanisms. Hypo-capnic alkalosis may cause bronchocon-striction and attenuation of hypoxic pul-monary vasoconstriction, resulting in netlowering of PaO2 (75–77); at any given O2
tension, the leftward shift of the oxyhe-moglobin dissociation curve may reduceO2 off-loading to tissues (78).
Increased Cerebral Oxygen Demand.
Hypocapnia may aggravate brain isch-emia by increasing cerebral oxygen de-mand (Figure 5) because of increasedneuronal excitability (79, 80). This con-tributes to increased cerebral utilizationand depletion of glucose (81, 82), and aswitch to anaerobic metabolism (65, 83).Hypocapnia increases CMRO2 in TBI (84)and prolongs seizure activity (80). Suchseizure potentiation further heightens O2
demand and results in production of sei-zure-associated cytotoxic excitatory
Figure 2. Frequency of hypocapnia in adults with traumatic brain injury in a recent study (10). Thedistribution of Paco2 values in blood gas analyses is skewed toward hypocapnia, with a maximum inthe range 30 to 35 mm Hg. Reproduced with permission from Neumann et al (10).
Figure 3. Percentage of children with one or more episodes of hypocapnia in the initial 48 hrs afterhospital admission with traumatic brain injury in a recent study (8). The gray bars represent data frompatients before and the black bars represent patients after the publication of guidelines suggestinglimited use of hypocapnia. Reproduced with permission from Curry et al (8). PG, pediatric traumaguidelines.
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amino acids (e.g., N-methyl-D-aspartate)(85), which also may be increased by hy-pocapnia-induced neuronal dopamine(86). Finally, alkalosis inhibits the nega-tive feedback whereby low pH reducesongoing endogenous acid production(e.g., lactate) (87), potentially worseninginjury further.
Evi den ce for Hyp oca pni a-I ndu ced Brain Ischemia. Concerns regarding hy-
pocapnia and adverse neuronal O2 supplyand demand are supported by multiplefindings from clinical and experimentalstudies. First, in children (88) and adults(84, 89) with TBI, hypocapnia causes re-gional cerebral ischemia. In adults resus-citated after cardiac arrest, hypocapniareduces SjO2 (and increases lactate) (90).In experimental studies, hypocapnia re-duces regional CBF and local cortical tis-sue PO2 (91) and reduces cerebral oxyhe-mo gl ob in ( 92 , 9 3) a nd o xi di ze dcytochrome aa3 (93) while increasing ce-rebral deoxyhemoglobin (93). Second,hypocapnia produces ischemic changesin functional magnetic resonance imag-ing (64) and with electroencephalography(94). Third, brain lactate production (i.e.,anaerobic metabolism) is increased byhyperventilation (95), which may bemore severe earlier in TBI (96). However,alkalosis may directly stimulate glycolysis(to buffer alkalosis) and further elevatelactate (97).
Why Is Sustained Hypocapnia
Particularly Deleterious?
Progressive Loss of Effect on ICP. Hy-pocapnia rapidly elevates the pH of boththe CSF and the central nervous systemextracellular fluid, and the CBF declinescorrespondingly. Severinghaus et al (98)demonstrated, 4 decades ago, that duringprolonged hypocapnia the CSF pH is buff-ered toward normal and the CBF normal-izes. The buffering is a biphasic process.First, there is “tissue buffering” (99, 100),in which hypocapnia immediately lowersthe intracellular fluid CO2, resulting in
exit of ClϪ
from intracellular fluid to ex-tracellular fluid and a reciprocal shift of HCO3
Ϫ from extracellular fluid to intra-cellular fluid, thereby lowering the extra-cellular fluid concentration of HCO3
Ϫ.Second, the renal response—inhibitionof Hϩ secretion and HCO3
Ϫ resorption inthe proximal tubule—begins immedi-ately and takes effect over hours to days(99, 100). Buffering of CSF pH normal-izes CBF as quickly as 6 hrs (101), even if the Paco2 remains low (2). In healthy
Figure 4. This figure summarizes the role of hypocapnia in the pathogenesis of neonatal intraventricularhemorrhage. Hypocapnia has been implicated in the pathogenesis of neonatal white matter injury (e.g.,periventricular leukomalacia), which results in intraventricular hemorrhage. Antioxidant depletion byexcitatory amino acids and sepsis-induced lipopolysaccharide and cytokines further potentiate white matter
destruction. Hypocapnia induced brain ischemia in watershed vascular territories, and hyperemia afterhypocapnia may contribute to intraventricular hemorrhage. Reproduced with permission from Laffey et al(140). LPS, lipopolysaccharide; TNF , tumor necrosis factor.
Figure 5. An integrated scheme of mechanisms underlying neurologic effects of hypocapnia. Induction of systemic hypocapnia results in a cerebrospinal fluid alkalosis, reducing cerebral blood flow, cerebral oxygendelivery, and, to a lesser extent, cerebral blood volume. This is potentially life-saving in the settingof criticallyelevated intracranial pressure. However, critical brain ischemia may result, exacerbated by an increase inhemoglobin oxygen affinity and an increase in neuronal excitability. Over time, cerebrospinal fluid pH and,hence, cerebral blood flow gradually return to normal. Normalization of Paco2 results in cerebral hyperemia andreperfusion injury to previously ischemicbrain regions. In addition, hypocapniamay cause glutamate release andneuronal excitotoxicity. Reproduced with permission from Laffey et al (140).
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volunteers, whereas a sustained 20-mmHg reduction in Paco2 decreased CBF by40% immediately, CBF was restored to90% of normal by 4 hrs (2).
Rebound Intracranial Hypertension with Restoration of Normocapnia. Re-bound elevation in ICP after restorationof normocapnia is well-described. Be-cause HCO3
Ϫ is the only buffer in extra-cellular brain fluid, loss of bicarbonate,
an obligatory consequence of hypocapnia,greatly reduces its buffering capacity.Therefore, normalization of Paco2 leadsto an overshoot in CSF pH and a corre-sponding overshoot increase in CBF. Ex-perimental induction of hypocapnia(Paco2 25 mm Hg, anesthetized rabbit)followed by normocapnia for 10 mins ev-ery 4 hrs was associated with progres-sively less effective hypocapnic vasocon-striction (102). Temporary restoration of normocapnia every 4 hrs caused vasodi-lation. At 20 hrs arterial pH had returnedto baseline and by 24 hrs the CSF pH wasnormal. Similar results were reported inthe anesthetized goat in which restora-tion of normocapnia caused marked ce-rebral hyperemia (103).
These findings have important impli-cations. First, buffering of CSF pH ablatesthe effectiveness of ongoing hypocapnia,and CBF may return to baseline levels by4 hrs. Second, when hypocapnia is con-tinued, it is difficult to further reduceCO2 to decrease ICP acutely, should thisbecome necessary later (e.g., incipientherniation), without causing lung dam-
age. Third, rebound intracranial hyper-tension should be anticipated after resto-ration of normocapnia and could result inbrainstem herniation (or, in prematureinfants, intracranial hemorrhage) (68,104–106) (Fig. 5). This is particularly im-portant in severe hypocapnia because theslope of the relationship between CSF pH
vs. CBF is steepest at this level (107).Thus, if hypocapnia is induced, then itshould be brief while definitive measuresto control ICP are undertaken, and Paco2
should be targeted toward normal as soon
as possible.
Does Hypocapnia Damage
Neurons?
Hypocapnia and Neurotransmission.Hypocapnia mediates increases in neuro-nal excitability and potentiates seizureactivity that may result in local productionof seizure-associated excitatory amino ac-ids, including N-methyl-D-aspartate, thatare locally cytotoxic (Fig. 5). Severe hypo-
capnia increases N-methyl-D-aspartate-receptor–mediated neurotoxicity (85) andincreases neuronal dopamine, particularlyin the striatum, which may worsen reper-fusion injury, especially in the immaturebrain (86). Finally, hypocapnia may be di-rectly neurotoxic through increased incor-poration of choline into membrane phos-pholipids (108).
Cerebral Ischemia and Reperfusion
Injury. Hypocapnia may worsen neuronalischemia and reperfusion injury. Hypo-capnia during resuscitation after cardiacarrest is associated with worsened braininjury (109) and it aggravates hypoxic-ischemic central nervous system damage(110, 111). These findings are consistent
with its potentiation of reperfusion injuryin the myocardium (112) and the lung(113). The central nervous system effectsof hypocapnia are particularly prominentin the immature brain (110, 111).
What Is the Role of Hypocapniain Specific Neurologic
Conditions?
Spontaneous vs. Induced Hypocapnia. Whereas induced hypocapnia is the focusof this article, hypocapnia is often spon-taneous. Spontaneous hyperventilationhas long been associated with adverseoutcome in TBI and subarachnoid hem-orrhage (114) and after stroke (115);however, whether the spontaneous hy-perventilation reflected severity of the le-sion or caused/contributed to it is un-
clear. More recently, spontaneous andinduced hyperventilation have been asso-ciated with adverse outcome in trauma,but only induced hyperventilation was in-dependently predictive (116).
TBI. There is no evidence to suggestthat hypocapnia improves outcome inacute brain injury; in fact, prolonged hy-perventilation worsens outcome. In alandmark, randomized, clinical trial, pa-tients with TBI were assigned to receivenormal ventilation (target Paco2, 35 mmHg) vs. prophylactic hyperventilation
(target Paco2, 25 mm Hg); the prophylac-tic hyperventilation resulted in fewer of theless severely injured patients (GlasgowComa Scale motor score, 4 –5) having afavorable outcome at 3, 6, and 12 months(117). Beyond the outcome disadvantages,prolonged hypocapnia in these patients in-creased the overall level and variability of ICP, especially after 60 hrs of hyperventila-tion, indicating that hypocapnia became in-effective or counterproductive in control-ling ICP over time (117).
Neonatal Brain Injury. Hypocapnia iscommon in neonatal practice. It is inju-rious to the premature brain and is asso-ciated with multiple neonatal brain con-ditions, including neonatal white matterinjury (69, 118–122) (Fig. 4; Table 2).Hypocapnia is often the sole risk factor forperiventricular leukomalacia (123), a syn-drome associated with significant neonatalmortality and neurodevelopmental deficit,and may be a cause of pontosubicular ne-crosis, another acute brain injury syn-drome of prematurity (120). Whether hy-pocapnia contributes to cerebral palsyremains unanswered (124).
Even brief exposure of preterm infantsto severe hypocapnia (Paco2 Ͻ15 mmHg) is associated with considerable long-term neurologic abnormalities (14), in-cluding sensorineural hearing loss (68).In this setting, predisposing factors mayinclude vulnerable areas with poorly de-
veloped vascular supply (125), antioxi-dant depletion by excitatory amino acids(126), and the effects of lipopolysaccharide(127) and cytokines (128) in potentiating
white matter destruction (Fig. 4). Outcome
data indicate an adverse role of hypocapniaafter hyperventilation (14), high-frequency
ventilation (129), or extracorporeal mem-brane oxygenation (68). Finally, abrupt ter-mination of hyperventilation results in re-active hyperemia, which may precipitateintracranial hemorrhage in premature ne-onates (106).
Acute Stroke. Hyperventilation hasclassically been advocated as a therapy instroke for two reasons. First, hypocapnia
was considered to result in shunting of blood to the ischemic brain area by con-
stricting the normally autoregulatedbrain, the so-called inverse steal phenom-enon that is now known not to occur(73). Second, hypocapnia was believed tocorrect acidosis in areas adjacent to theischemic zone to minimize the extensionof the infarct (21). In fact, hypocapnia isassociated with poor prognosis in stroke(115, 130). Although separating cause vs.effect is difficult (because large strokesare commonly accompanied by spontane-ous hyperventilation), the recurrence of a
Table 2. Neonatal brain conditions associated
with hypocapnia
Multicystic encephalomalacia (195)Cystic periventricular leukomalacia (69, 118,
119, 121–123)Pontosubicular necrosis (196)
Watershed infarction (119)Reactive hyperemia and hemorrhage (106)
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right hemiplegia and aphasia while un-dergoing a hyperventilation provocativetest has been reported (131).
Impairment of Neurologic Function.The potential for neurologic dysfunctionafter (even brief) hypocapnia is mostclearly documented in postoperative pa-tients. Healthy patients subjected to hy-pocapnia have significantly impaired psy-chomotor function for up to 48 hrs
postoperatively, and such effects aremore marked and occur with less severehypocapnia in older patients (132). Moreprofound intraoperative hypocapnia (Ͻ24mm Hg), even for a relatively short dura-tion, can delay reaction times for up to 6days (133). Hypocapnia may impair atten-tion and learning and can induce person-ality changes (134, 135). At severe levels(Paco2 15 mm Hg), hypocapnia decreasesbasic psychomotor performance inhealthy volunteers (136). That hypocap-nia causes such dysfunction is supportedby the finding that exposure to elevatedPaco2 during anesthesia enhances neuro-psychologic performance (132, 137). Re-assuringly, the adverse effects of hypo-capnia in studies of postoperativecognition in healthy patients, while oftenprolonged, seem ultimately reversible(132, 133).
Prolonged exposure to hypocapnia mayresult in sustained impairment. The neuro-logic impairment seen in healthy moun-taineers at extreme altitude is most closelycorrelated to the degree of hypocapnia, notthe level of hypoxia (138). The basis for
acute central nervous system symptoms ataltitude appears to be alkalosis, and suchalkalosis can be prevented by pretreatment
with acetazolamide (139).
Can Hypocapnia Damage Other
Organs?
Hypocapnia can injure other organs,and the effects on the lung and vascula-ture are well-described (140). Hypocapniadecreases perfusion to the heart (141),liver, gastrointestinal tract (142), skeletal
muscle (143), and skin (144). This reviewfocuses on brain injury and, because ox-
ygenation and perfusion are central, thissection summarizes the effects of hypo-capnia on lung injury and on myocardialoxygenation.
Acute Lung Injury. More than 20% of patients with severe brain injury haveacute lung injury or acute respiratory dis-tress syndrome develop (145, 146), which
worsens outcome (147) and is indepen-dently predicted by the use of high tidal
volume to produce hypocapnia (145), afinding confirmed prospectively in a mul-ticenter European study (145). Unfortu-nately, patients with confirmed lung injurycontinue to be hyperventilated (145) de-spite the known association between hightidal volume and mortality in acute respi-ratory distress syndrome (148).
The concept that hypocapnia might be
pathogenic in acute lung injury/acute re-spiratory distress syndrome was sug-gested in 1971 by Trimble et al (149).Hypocapnia may contribute to acute lunginjury because high tidal volume ventila-tion (usually used to achieve hypocapnia)directly causes lung injury (148), and thehypocapnia per se may injure the lung viaseveral mechanisms (Table 3), includingincreased lung permeability and edema(113), decreased compliance (150), per-haps by surfactant inhibition (151), and
potentiating acute inflammation (152–154). Many of these adverse effects can beameliorated by normalizing alveolar CO2
(151, 152, 154, 155) and, conversely, hy-percapnic acidosis reduces experimentallung injury (154, 156–159). Finally, hy-pocapnia attenuates hypoxic pulmonary
vasoconstriction, thereby increasing in-trapulmonary shunt (160). After acutebrain injury, it is difficult to discern the
individual contributions of high tidal vol-ume vs. hypocapnia to lung injury. Myocardial Ischemia. Acute hypocap-
nia lowers myocardial O2 delivery (161–167) and increases demand (141, 164,168–170) through a variety of mecha-nisms including increased contractility(168, 171), left ventricular afterload(172), and heart rate (173), thereby wors-ening the supply-and-demand balance(164, 167) (Table 4). Hypocapnia reducescoronary flow (163), increases tissue cap-illary permeability (165), and may causefrank coronary spasm, resulting in “vari-ant angina” that classically occurs withspontaneous hyperventilation (167). Fi-nally, hypocapnia may precipitate throm-bosis through increased platelet levels oraggregation (174). Thus, clinically rele-
vant acute coronary phenomena exist inbrain-injured patients managed with hy-pocapnia.
Cardiac Dysrhythmias. Hypocapniacauses dysrhythmias (175) (Table 4), in-cluding paroxysmal atrial arrhythmia (176)and (rarely) ventricular tachycardia (177)or fibrillation (178). Aside from potentiat-
ing myocardial ischemia, the mechanismsare unclear. However, hypocapnic alkalosismay be an effective therapy for toxicity at-tributable to local anesthetic (179) or tricy-clic antidepressant (180).
Can We Use Hypocapnia to
Produce Benefit While
Minimizing Harm?
Whether hypocapnia can be used toproduce benefit while minimizing harmis a key question. Hyperventilation is the
most effective means for acutely loweringICP (181). The deleterious effects of hy-pocapnia in the injured brain stem, atleast in part, form limitations regardinghow we use hypocapnia in brain-injuredpatients. Therefore, monitoring of indicesof cerebral cellular oxygenation mightenhance the safety of using more moder-ate levels of hypocapnia for shorter peri-ods to control ICP.
Safety of Moderate Hypocapnia. Themore severe the hypocapnia and the greater
Table 3. Deleterious pulmonary effects of
hypocapnia
Reduced lung compliance (150)Dysfunctional surfactant production (151)Lamellar body depletion. (155)
Increased airway resistanceIncreased bronchial tone (75, 197, 198)Bronchial release of tachykinins (199)
Direct parenchymal lung injury (152, 153)Increased pulmonary capillary permeability
(113)
Increased tracheal mucosal permeability(200)Increased stretch induced lung injury (153,
154)Reduced systemic oxygenation
Reduced ventilation/perfusion matching (160)Increased intrapulmonary shunt (160)Reduced hypoxic vasoconstriction (201)Increased ventilation heterogeneity (77, 160)
Table 4. Deleterious cardiovascular effects of
hypocapnia
Reduced myocardial oxygen supplyDecreased coronary flow (161, 164)Decreased collateral flow (163)
Increased coronary vascular resistance (162,166)
Increased coronary artery spasm (167, 177)Increased hemoglobin oxygen affinity (202)Increased coronary microvascular leak (165)Increased platelet number (203)Increased platelet aggregation (174)
Increased myocardial oxygen demandIncreased heart rate (173)
Increased O2 extraction (164, 170)Increased (later decreased) contractility (169,
171)Increased intracellular Ca2ϩ (169)Increased systemic vascular resistance (141)
Myocardial ischemia (164, 167, 204)Increased myocardial reperfusion injury (112)
Ventricular and atrial arrhythmias (176–178)
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the duration of its use, the greater the po-tential there is for harm. This potential forharm is reduced when mild-to-moderatehypocapnia is used for limited periods of time. Brief moderate hyperventilation maytransiently restore autoregulation of CBFin head-injured patients (182, 183). Auto-regulation of CBF protects the brain fromexcessive shifts in CBF attributable to alter-ations in systemic blood pressure and is
impaired in 50% to 90% of patients withsevere TBI (184, 185). One study demon-strated that moderate hypocapnia (PCO2 28mm Hg) temporarily improved cerebral au-toregulation in head-injured patients(182). Conversely, more severe hypocap-nia (PCO2 23 mm Hg) impaired autoreg-ulation (182). In addition, the effect of hypocapnia on autoregulation of CBF
with hypocapnia is quite variable (183)and the duration of any beneficial effect isunclear, but it may be short-lived (182).Furthermore, any beneficial effects of hy-pocapnia on autoregulation must be setagainst the potential for hypocapnia-induced cerebral ischemia. The potentialfor brief “moderate” hypocapnia to causeischemia is clear from the finding that 20mins of moderate hypocapnia (Paco2
27–32 mm Hg) can produce critical re-ductions in regional brain tissue PO2 in20% of patients with TBI (23). Thus, theidea of a safe “threshold” level of hypo-capnia is not an idea that can be gener-alized to populations of brain-injured pa-tients.
Titrated Hypocapnia: A Feasible
Str ate gy? Several investigators haveraised the potential that hypocapniamight safely be titrated, in individual pa-tients, against indices of cerebral oxygen-ation. It has been proposed that 20% of TBI patients with intracranial hyperten-sion may have CBF in excess of thatneeded for metabolism on the basis of SjO2 measurements (186, 187). In suchpatients, “optimized hyperventilation”has been proposed in which hypocapnia(lowering ICP) is titrated against SjO2 (tomonitor global O2 supply-and-demand
balance) (186, 187). However, global in-dices of oxygenation are insensitive toregional imbalances. Placement of re-gional monitors of brain oxygenationnear the penumbra of focal lesions clearlydemonstrates the limitations of global in-dices of cerebral oxygenation (188). Ti-trating hyperventilation to CMRO2 hasalso been proposed on the basis that brief (10 mins) episodes of severe hypocapniadid not reduce global or regional CMRO2,even in areas of the brain where CBF was
low (22). However, baseline CMRO2 was very low in areas of poor cerebral perfusion,and hypocapnia did greatly increased oxy-gen extraction ratio in the venous bloodfrom these areas (22). Nevertheless, thesedata suggested that O2 supply to these tis-sues was adequate and that hypocapniacould be used safely (22).
In contrast, other positron emissiontomography studies indicate that moder-
ate hypocapnia (Paco2 30 mm Hg) maycause focal brain ischemia (89) based onthe calculation of a critical oxygen extrac-tion fraction for each subject and estima-tion of the volume of brain tissue withoxygen extraction fraction values belowthis threshold as determined by positronemission tomography scanning. Usingthis approach, hypoventilation elevatesCPP and lowers ICP, but the volume of severely hypoperfused tissue within theinjured brain is raised (89). This groupfurther demonstrated that the injuredbrain is less able to increase O2 extractionin response to reduced O2 delivery (37),phenomena not detectable using routinecentral nervous system monitors (includ-ing SjO2) (84). Most worrisome is themore recent observation that in TBI, hy-pocapnia may increase focal brain CMRO2
associated with increased cortical electri-cal activity (84).
An overriding concern is that becausehypocapnia can directly modulate CMRO2
(84), it may invalidate the use of CMRO2
to define thresholds for cerebral isch-emia. This may explain why hypocapnia
did not reduce CMRO2 despite large re-ductions in CBF and increases in oxygenextraction ratio (22).
It is increasingly clear that there issignificant heterogeneity in regional ox-
ygenation in the injured brain. Substan-tial intercompartmental pressure differ-entials can exist in the injured brain(189–191) and these, rather than globallyincreased ICP, may be the proximatecause of herniation syndromes (190,191). Finally, because vasoresponsivenessto CO2 may be increased (up to three-
fold) after TBI (74), hypocapnia could ex-acerbate intercompartmental pressuredifferentials, increasing the risk of localherniation.
Regional Cerebral Monitoring: The Future? There is no safe “threshold” levelof hypocapnia that can be used in allbrain-injured patients. Furthermore, thepresence of significant regional heteroge-neity in TBI renders global indices of cerebral perfusion or oxygenation inade-quate. An alternative approach may be
the use of brief episodes of moderate hy-pocapnia titrated against regional indicesof cerebral oxygen and against intercom-partmental pressure gradients. Techno-logical advances such as regional braintissue PO2 monitoring, bedside imaging,and microdialysis, as well as regional ICPmonitoring, may together enhance out-come. In this paradigm, the ultimateclinical utility of hypocapnia in acute
brain injury will depend on its potentialto cause direct harm in the injured brain.
What Is the Current Role for
Hypocapnia in Acute Brain
Injury?
Imminent Brain Herniation. There isa strong physiologic (and empirical) ra-tionale for brief use of hypocapnia toacutely reduce ICP. Although the evi-dence is limited, the rapidity of inductionand its immediate effect on CBF make ita useful strategy while definitive mea-sures are being instituted.
Intraoperative Use During Neurosur- gery. Hypocapnia is used during neuro-surgery to facilitate access or to acutelyreduce brain bulk (192). This was suc-cessfully demonstrated in a prospective,randomized, crossover study in patients
with supratentorial brain tumors (193) in which brief (20 mins) intraoperative hy-perventilation reduced brain bulk and re-duced ICP, although the longer-term ef-fects were not reported.
It is important to remember that
when acute hypocapnia is used in thesesettings, normocapnia should be restoredas soon as is feasible, because hypocapniabecomes ineffective within hours. Thismeans that hypocapnia can be used laterto control further worsening of ICP and itavoids the risk of rebound hyperemia
with delayed CO2 normalization.
CONCLUSIONS
Hypocapnia, often prolonged, remainsprevalent in the management of brain
injury. Despite this, there is no proof (other than experience with incipientherniation) that hypocapnia improvesneurologic outcome in any context. Onthe contrary, hypocapnia can certainlycause or worsen cerebral ischemia,
worsen outcome, and cause (direct or in-direct) injury to other organs. The deci-sion to institute hypocapnia for therapeu-tic purposes in the setting of acute braininjury should be undertaken only aftercareful consideration of the risks and
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benefits. Accidental hypocapnia shouldalways be avoided, and prophylactic usehas no clinical role. The use of hypocap-nia might be best limited to the emer-gency management of life-threateningICP or to acutely reduce brain bulk in theoperating room, pending institution of definitive measures. In these settings,normocapnia should be re-instituted assoon as is feasible. Contrary to sugges-
tions that prospective trials of prophylac-tic hyperventilation in head injury areneeded (194), we believe, based on thedata presented, that such studies are dif-ficult to justify at this stage given theincreasing recognition that this approachis frequently harmful and rarely, if ever,beneficial.
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