Artigo pós - hipocapnia

7/27/2019 Artigo pós - hipocapnia

http://slidepdf.com/reader/full/artigo-pos-hipocapnia 1/12

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

1348 Crit Care Med 2010 Vol. 38, No. 5



(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).

1349Crit Care Med 2010 Vol. 38, No. 5



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.




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).




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)




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)




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




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.

REFERENCES

1. Raichle ME, Plum F: Hyperventilation and

c ereb ra l b lo od fl ow . Stroke 1972;

3:566–575

2. Raichle ME, Posner JB, Plum F: Cerebralblood flow during and after hyperventila-

tion. Arch Neurol 1970; 23:394–403

3. Brown M: ICU—Critical care. In: Clinical

Anesthesia. Barash PG, Cullen BF, Stoelting

RK (Eds). Philadephia, PA, JB Lippincott,

1989, pp 1455–1476

4. Hayek DA, Veremakis C: Physiologic con-

cerns during brain resuscitation. In: Criti-

cal Care. Second Edition. Civetta JM, Taylor

RW, Kirby RR (Eds). Philadelphia, PA, JB

Lippincott, 1992, pp 1449–1466

5. Heffner JE, Sahn SA: Controlled hyperven-

tilation in patients with intracranial hyper-

tension. Application and management. Arch

Intern Med 1983; 143:765–769

6. Miller JD: Medical management of acute

head injury. In: Clinical Neurology. Swash

M, Oxbury J (Eds). Edinburgh, Churchill

Livingstone, 1991, pp 694–697

7. Ruben BH, Greenberg J: Neurologic injury:

Prevention and initial care. In: Critical

Care. Second Edition. Civetta JM, Taylor

RW, Kirby RR (Eds). Philadelphia, PA: JB

Lippincott, 1992, pp 725–745

8. Curry R, Hollingworth W, Ellenbogen RG,

et al: Incidence of hypo- and hypercarbia in

severe traumatic brain injury before and

after 2003 pediatric guidelines. Pediatr Crit

Care Med 2008; 9:141–1469. Cold GE: Cerebral blood flow in acute head

injury. The regulation of cerebral blood

flow and metabolism during the acute

phase of head injury, and its significance for

therapy. Acta Neurochir Suppl (Wien) 1990;

49:1–64

10. Neumann JO, Chambers IR, Citerio G, et al:

The use of hyperventilation therapy after

traumatic brain injury in Europe: An anal-

ysis of the BrainIT database. Intensive Care

Med 2008; 34:1676–1682

11. Carney NA, Ghajar J: Guidelines for the

management of severe traumatic brain in-

jury. Introduction. J Neurotrauma 2007;

24(Suppl 1):S1–S2

12. Brain Trauma Foundation: Use of hyperven-

tilation in the acute management of severe

pediatric traumatic brain injury. Pediatr

Crit Care Med 2003; 4:45–47

13. Marion DW, Spiegel TP: Changes in the

management of severe traumatic brain in-

jury: 1991–1997. Crit Care Med 2000; 28:

16–18

14. Greisen G, Munck H, Lou H: Severe hypo-carbia in preterm infants and neurodevel-

opmental deficit. Acta Paediatr Scand 1987;

76:401–404

15. Huizenga JE, Zink B, Maio R, et al: The

penetrance of head injury management

guidelines into the practice patterns of

Michigan emergency physicians. Acad

Emerg Med 2000; 7:1171

16. Davis DP, Heister R, Poste JC, et al: Venti-

lation patterns in patients with severe trau-

matic brain injury following paramedic

rapid sequence intubation. Neurocrit Care

2005; 2:165–171

17. Thomas SH, Orf J, Wedel SK, et al: Hyper-

ventilation in traumatic brain injury pa-tients: Inconsistency between consensus

guidelines and clinical practice. J Trauma

2002; 52:47–52

18. Warner KJ, Cuschieri J, Copass MK, et al:

The impact of prehospital ventilation on

outcome after severe traumatic brain in-

jury. J Trauma 2007; 62:1330–1336

19. Caulfield EV, Dutton RP, Floccare DJ, et al:

Prehospital hypocapnia and poor outcome

after severe traumatic brain injury.

J Trauma 2009; 66:1577–1582

20. Zwienenberg M, Muizelaar JP: Severe pedi-

atric head injury: The role of hyperemia

revisited. J Neurotrauma 1999; 16:937–943

21. Harrington T, Di Chiro G: Effect of hypo-

carbia and hypercarbia in experimental

brain infarction. A microangiographic study

in the monkey. Neurology 1973; 23:

294–299

22. Diringer MN, Videen TO, Yundt K, et al:

Regional cerebrovascular and metabolic ef-

fects of hyperventilation after severe trau-

matic brain injury. J Neurosurg 2002; 96:

103–108

23. Imberti R, Bellinzona G, Langer M: Cere-

bral tissue PO2 and SjvO2 changes during

moderate hyperventilation in patients with

severe traumatic brain injury. J Neurosurg

2002; 96:97–10224. Bouma GJ, Muizelaar JP: Cerebral blood flow,

cerebral blood volume, and cerebrovascular

reactivity after severe head injury. J Neuro-

trauma 1992; 9(Suppl 1):S333–S348

25. Fieschi C, Battistini N, Beduschi A, et al:

Regional cerebral blood flow and intraven-

tricular pressure in acute head injuries.

J Neurol Neurosurg Psychiatry 1974; 37:

1378–1388

26. Bouma GJ, Muizelaar JP, Stringer WA, et al:

Ultra-early evaluation of regional cerebral

blood flow in severely head-injured patients

using xenon-enhanced computerized to-

mography. J Neurosurg 1992; 77:360–368

27. Bouma GJ, Muizelaar JP, Choi SC, et al:

Cerebral circulation and metabolism after

severe traumatic brain injury: The elusive

role of ischemia. J Neurosurg 1991; 75:

685–693

28. Obrist WD, Langfitt TW, Jaggi JL, et al:

Cerebral blood flow and metabolism in co-

matose patients with acute head injury. Re-

lationship to intracranial hypertension.

J Neurosurg 1984; 61:241–25329. Heiss WD, Rosner G: Functional recovery of

cortical neurons as related to degree and

duration of ischemia. Ann Neurol 1983; 14:

294–301

30. van Santbrink H, Schouten JW, Steyerberg

EW, et al: Serial transcranial Doppler mea-

surements in traumatic brain injury with

special focus on the early posttraumatic pe-

riod. Acta Neurochir (Wien) 2002; 144:

1141–1149

31. Jaggi JL, Obrist WD, Gennarelli TA, et al:

Relationship of early cerebral blood flow

and metabolism to outcome in acute head

injury. J Neurosurg 1990; 72:176–182

32. Ojha BK, Jha DK, Kale SS, et al: Trans-cranial Doppler in severe head injury: eval-

uation of pattern of changes in cerebral

blood flow velocity and its impact on out-

come. Surg Neurol 2005; 64:174–179

33. Bergsneider M, Hovda DA, Lee SM, et al:

Dissociation of cerebral glucose metabolism

and level of consciousness during the pe-

riod of metabolic depression following hu-

man traumatic brain injury. J Neurotrauma

2000; 17:389–401

34. Vespa P, Bergsneider M, Hattori N, et al:

Metabolic crisis without brain ischemia is

common after traumatic brain injury: A

combined microdialysis and positron emis-

sion tomography study. J Cereb Blood Flow

Metab 2005; 25:763–774

35. Bullock R. Hyperventilation. J Neurosurg

2002; 96:157–159

36. Diringer MN, Yundt K, Videen TO, et al: No

reduction in cerebral metabolism as a result

of early moderate hyperventilation follow-

ing severe traumatic brain injury. J Neuro-

surg 2000; 92:7–13

37. Menon DK, Coles JP, Gupta AK, et al: Dif-

fusion limited oxygen delivery following

head injury. Crit Care Med 2004; 32:

1384–1390

38. Ito H, Ibaraki M, Kanno I, et al: Changes in

the arterial fraction of human cerebralblood volume during hypercapnia and hy-

pocapnia measured by positron emission to-

mography. J Cereb Blood Flow Metab 2005;

25:852–857

39. Ito H, Kanno I, Iida H, et al: Arterial frac-

tion of cerebral blood volume in humans

measured by positron emission tomogra-

phy. Ann Nucl Med 2001; 15:111–116

40. Fortune JB, Feustel PJ, deLuna C, et al:

Cerebral blood flow and blood volume in

response to O2 and CO2 changes in normal

humans. J Trauma 1995; 39:463–471




41. Wilkinson IM, Browne DR: The influence of

anaesthesia and of arterial hypocapnia on

regional blood flow in the normal human

cerebral hemisphere. Br J Anaesth 1970;

42:472–482

42. Smith AL, Neufeld GR, Ominsky AJ, et al:

Effect of arterial CO2 tension on cerebral

blood flow, mean transit time, and vascular

volume. J Appl Physiol 1971; 31:701–707

43. Alberti E, Hoyer S, Hamer J, et al: The effect

of carbon dioxide on cerebral blood flow and

cerebral metabolism in dogs. Br J Anaesth1975; 47:941–947

44. Alexander SC, Wollman H, Cohen PJ, et al:

Cerebrovascular response to Paco2 during

halothane anesthesia in man. J Appl Physiol

1964; 19:561–565

45. Sato M, Pawlik G, Heiss WD: Comparative

studies of regional CNS blood flow autoreg-

ulation and responses to CO2 in the cat.

Effects of altering arterial blood pressure

and PaCO2 on rCBF of cerebrum, cerebel-

lum, and spinal cord. Stroke 1984; 15:91–97

46. Scheller MS, Todd MM, Drummond JC:

Isoflurane, halothane, and regional cerebral

blood flow at various levels of PaCO2 in

rabbits. Anesthesiology 1986; 64:598–60447. Greenberg JH, Alavi A, Reivich M, et al:

Local cerebral blood volume response to

carbon dioxide in man. Circ Res 1978; 43:

324–331

48. Marion DW, Firlik A, McLaughlin MR: Hy-

perventilation therapy for severe traumatic

brain injury. New Horiz 1995; 3:439–447

49. Wahl M, Deetjen P, Thurau K, et al: Mi-

cropuncture evaluation of the importance

of perivascular pH for the arteriolar diame-

ter on the brain surface. Pflugers Arch

1970; 316:152–163

50. Kontos HA, Raper AJ, Patterson JL: Analysis

of vasoactivity of local pH, PCO2 and bicar-

bonate on pial vessels. Stroke 1977;

8:358–360

51. Betz E, Enzenrobb HG, Vlahov V: Interac-

tion of Hϩ and Caϩϩ in the regulation of

local pial vascular resistance. Pflugers Arch

1973; 343:79–88

52. Giller CA, Bowman G, Dyer H, et al: Cere-

bral arterial diameters during changes in

blood pressure and carbon dioxide during

craniotomy. Neurosurgery 1993; 32:

737–741

53. Lavi S, Egbarya R, Lavi R, et al: Role of

nitric oxide in the regulation of cerebral

blood flow in humans: chemoregulation

versus mech anor egul atio n. Circulation2003; 107:1901–1905

54. Lavi S, Gaitini D, Milloul V, et al: Impaired

cerebral CO2 vasoreactivity: Association with

endothelial dysfunction. Am J Physiol Heart

Circ Physiol 2006; 291:H1856–H1861

55. Iadecola C, Zhang F: Nitric oxide-dependent

and -independent components of cerebro-

vasodilation elicited by hypercapnia. Am J

Physiol 1994; 266(2 Pt 2):R546–R552

56. Niwa K, Lindauer U, Villringer A, et al:

Blockade of nitric oxide synthesis in rats

strongly attenuates the CBF response to

extracellular acidosis. J Cereb Blood Flow

Metab 1993; 13:535–539

57. Zhang F, Xu S, Iadecola C: Role of nitric

oxide and acetylcholine in neocortical hy-

peremia elicited by basal forebrain stimula-

tion: Evidence for an involvement of endo-

thelial nitric oxide. Neuroscience 1995; 69:

1195–1204

58. Armstead WM, Zuckerman SL, Shibata M,

et al: Different pial arteriolar responses to

acetylcholine in the newborn and juvenile

pig. J Cereb Blood Flow Metab 1994; 14:1088–1095

59. Markus HS, Vallance P, Brown MM: Differ-

ential effect of three cyclooxygenase inhib-

itors on human cerebral blood flow velocity

and carbon dioxide reactivity. Stroke 1994;

25:1760–1764

60. Kitazono T, Faraci FM, Taguchi H, et al:

Role of potassium channels in cerebral

blood vessels. Stroke 1995; 26:1713–1723

61. Nakahata K, Kinoshita H, Hirano Y, et al:

Mild hypercapnia induces vasodilation via

adenosine triphosphate-sensitive Kϩ chan-

nels in parenchymal microvessels of the rat

cerebral cortex. Anesthesiology 2003; 99:

1333–133962. Lindauer U, Vogt J, Schuh-Hofer S, et al:

Cerebrovascular vasodilation to extralumi-

nal acidosis occurs via combined activation

of ATP-sensitive and Ca2ϩ-activated potas-

sium channels. J Cereb Blood Flow Metab

2003; 23:1227–1238

63. Austin C, Wray S: The effects of extracellu-

lar pH and calcium change on force and

intracellular calcium in rat vascular smooth

muscle. J Physiol 1995; 488(Pt 2):281–291

64. Weckesser M, Posse S, Olthoff U, et al:

Functional imaging of the visual cortex

with bold-contrast MRI: Hyperventilation

decreases signal response. Magn Reson Med

1999; 41:213–216

65. Soustiel JF, Mahamid E, Chistyakov A, et al:

Comparison of moderate hyperventilation

and mannitol for control of intracranial

pressure control in patients with severe

traumatic brain injury–a study of cerebral

blood flow and metabolism. Acta Neurochir

(Wien) 2006; 148:845–851

66. Harkin CP, Schmeling WT, Kampine JP, et

al: The effects of hyper- and hypocarbia on

intraparenchymal arterioles in rat brain

slices. Neuroreport 1997; 8:1841–1844

67. Ishii K, Sasaki M, Yamaji S, et al: Cerebral

blood flow changes in the primary motor

and premotor cortices during hyperventila-tion. Ann Nucl Med 1998; 12:29–33

68. Graziani LJ, Gringlas M, Baumgart S: Cere-

brovascular complications and neurodevel-

opmental sequelae of neonatal ECMO. Clin

Perinatol 1997; 24:655–675

69. Ikonen RS, Janas MO, Koivikko MJ, et al:

Hyperbilirubinemia, hypocarbia and

periventricular leukomalacia in preterm in-

fants: Relationship to cerebral palsy. Acta

Paediatr 1992; 81:802–807

70. Unterberg AW, Kiening KL, Hartl R, et al:

Multimodal monitoring in patients with

head injury: Evaluation of the effects of

treatment on cerebral oxygenation.

J Trauma 1997; 42(5 Suppl):S32–S37

71. Nevin M, Colchester AC, Adams S, et al:

Evidence for involvement of hypocapnia

and hypoperfusion in aetiology of neurolog-

ical deficit after cardiopulmonary bypass.

Lancet 1987; 2:1493–1495

72. Klinger G, Beyene J, Shah P, et al: Do hy-

peroxaemia and hypocapnia add to the risk

of brain injury after intrapartum asphyxia?

Arch Dis Child Fetal Neonatal Ed 2005;90:F49–F52

73. Ruta TS, Drummond JC, Cole DJ: The effect

of acute hypocapnia on local cerebral blood

flow during middle cerebral artery occlu-

sion in isoflurane anesthetized rats. Anes-

thesiology 1993; 78:134–140

74. McLaughlin MR, Marion DW: Cerebral

blood flow and vasoresponsivity within and

around cerebral contusions. J Neurosurg

1996; 85:871–876

75. O’Cain CF, Hensley MJ, McFadden ER Jr, et

al: Pattern and mechanism of airway re-

sponse to hypocapnia in normal subjects.

J Appl Physiol 1979; 47:8–12

76. Domino KB, Swenson ER, Hlastala MP: Hy-pocapnia-induced ventilation/perfusion

mismatch: A direct CO2 or pH-mediated ef-

fect? Am J Respir Crit Care Med 1995; 152(5

Pt 1):1534–1539

77. Domino KB, Emery MJ, Swenson ER, et al:

Ventilation heterogeneity is increased in

hypocapnic dogs but not pigs. Respir

Physiol 1998; 111:89–100

78. Nunn JF: Applied Respiratory Physiology.

Third Edition. London, Butterworths, 1987

79. Huttunen J, Tolvanen H, Heinonen E, et al:

Effects of voluntary hyperventilation on

cortical sensory responses. Electroencepha-

lographic and magnetoencephalographic

studies. Exp Brain Res 1999; 125:248–254

80. Bergsholm P, Gran L, Bleie H: Seizure du-

ration in unilateral electroconvulsive ther-

apy. The effect of hypocapnia induced by

hyperventilation and the effect of ventila-

tion with oxygen. Acta Psychiatr Scand

1984; 69:121–128

81. Berson FG, Spatz M, Klatzo I: Effects of

oxygen saturation and PCO2 on brain up-

take of glucose analogues in rabbits. Stroke

1975; 6:691–696

82. Samra SK, Turk P, Arens JF: Effect of hy-

pocapnia on local cerebral glucose utiliza-

tion in rats. Anesthesiology 1989; 70:

523–52683. Alexander SC, Smith TC, Strobel G, et al:

Cerebral carbohydrate metabolism of man

during respiratory and metabolic alkalosis.

J Appl Physiol 1968; 24:66–72

84. Coles JP, Fryer TD, Coleman MR, et al:

Hyperventilation following head injury: Ef-

fect on ischemic burden and cerebral oxi-

dative metabolism. Crit Care Med 2007; 35:

568–578

85. Graham EM, Apostolou M, Mishra OP, et al:

Modification of the N-methyl-D-aspartate

(NMDA) receptor in the brain of newborn




piglets following hyperventilation induced

ischemia. Neurosci Lett 1996; 218:29–32

86. Pastuszko P, Wilson DF: Activation of ty-

rosine hydroxylase in striatum of newborn

piglets in response to hypocapnic ischemia

and recovery. Adv Exp Med Biol 1997; 411:

65–73

87. Hood VL, Tannen RL: Protection of acid-

base balance by pH regulation of acid pro-

duction. N Engl J Med 1998; 339:819–826

88. Skippen P, Seear M, Poskitt K, et al: Effect

of hyperventilation on regional cerebralblood flow in head-injured children. Crit

Care Med 1997; 25:1402–1409

89. Coles JP, Minhas PS, Fryer TD, et al: Effect

of hyperventilation on cerebral blood flow

in traumatic head injury: Clinical relevance

and monitoring correlates. Crit Care Med

2002; 30:1950–1959

90. Buunk G, van der Hoeven JG, Meinders AE:

Cerebrovascular reactivity in comatose pa-

tients resuscitated from a cardiac arrest.

Stroke 1997; 28:1569–1573

91. Bickler PE, Julian D: Regional cerebral

blood flow and tissue oxygenation during

hypocarbia in geese. Am J Physiol 1992;

263(2 Pt 2):R221–R22592. Liem KD, Kollee LA, Hopman JC, et al: The

influence of arterial carbon dioxide on ce-

rebral oxygenation and haemodynamics

during ECMO in normoxaemic and hy-

poxaemic piglets. Acta Anaesthesiol Scand

Suppl 1995; 107:157–164

93. Kamei A, Ozaki T, Takashima S: Monitoring

of the intracranial hemodynamics and oxy-

genation during and after hyperventilation

in newborn rabbits with near-infrared spec-

troscopy. Pediatr Res 1994; 35:334–338

94. Stoddart JC: Electroencephalographic ac-

tivity during voluntarily controlled alveolar

hyperventilation. Br J Anaesth 1967; 39:2

95. Dager SR, Strauss WL, Marro KI, et al:

Proton magnetic resonance spectroscopy

investigation of hyperventilation in subjects

with panic disorder and comparison sub-

jects. Am J Psychiatry 1995; 152:666–672

96. Marion DW, Puccio A, Wisniewski SR, et al:

Effect of hyperventilation on extracellular

concentrations of glutamate, lactate, pyru-

vate, and local cerebral blood flow in pa-

tients with severe traumatic brain injury.

Crit Care Med 2002; 30:2619–2625

97. Ui M: A role of phosphofructokinase in pH-

dependent regulation of glycolysis. Biochim

Biophys Acta 1966; 124:310–322

98. Severinghaus JW, Chiodi H, Eger EI II, etal: Cerebral blood flow in man at high alti-

tude. Role of cerebrospinal fluid pH in nor-

malization of flow in chronic hypocapnia.

Circ Res 1966; 19:274–282

99. Adrogue HJ, Madias NE: Management of

life-threatening acid-base disorders. Second

of two parts. N Engl J Med 1998; 338:

107–111

100. Gluck SL: Acid-base. Lancet 1998; 352:

474–479

101. Fencl V, Vale JR, Broch JR: Cerebral blood

flow and pulmonary ventilation in meta-

bolic acidosis and alkalosis. Scand J Clin

Lab Invest Suppl 1968; 102:VIII:B

102. Muizelaar JP, van der Poel HG, Li ZC, et al:

Pial arteriolar vessel diameter and CO2 re-

activity during prolonged hyperventilation

in the rabbit. J Neurosurg 1988; 69:923–927

103. Albrecht RF, Miletich DJ, Ruttle M: Cere-

bral effects of extended hyperventilation in

unanesthetized goats. Stroke 1987; 18:

649–655

104. Erickson SJ, Grauaug A, Gurrin L, et al:

Hypocarbia in the ventilated preterm infantand its effect on intraventricular haemor-

rhage and bronchopulmonary dysplasia.

J Paediatr Child Health 2002; 38:560–562

105. Fabres J, Carlo WA, Phillips V, et al: Both

extremes of arterial carbon dioxide pressure

and the magnitude of fluctuations in arte-

rial carbon dioxide pressure are associated

with severe intraventricular hemorrhage in

preterm infants. Pediatrics 2007; 119:

299–305

106. Gleason CA, Short BL, Jones MD Jr: Cere-

bral blood flow and metabolism during and

after prolonged hypocapnia in newborn

lambs. J Pediatr 1989; 115:309–314

107. Tasker RC, Lutman D, Peters MJ: Hyperven-tilation in severe diabetic ketoacidosis. Pe-

diatr Crit Care Med 2005; 6:405–411

108. Mykita S, Golly F, Dreyfus H, et al: Effect of

CDP-choline on hypocapnic neurons in cul-

ture. J Neurochem 1986; 47:223–231

109. Safar P, Xiao F, Radovsky A, et al: Improved

cerebral resuscitation from cardiac arrest in

dogs with mild hypothermia plus blood flow

promotion. Stroke 1996; 27:105–113

110. Vannucci RC, Brucklacher RM, Vannucci

SJ: Effect of carbon dioxide on cerebral me-

tabolism during hypoxia-ischemia in the

immature rat. Pediatr Res 1997; 42:24–29

111. Vannucci RC, Towfighi J, Heitjan DF, et al:

Carbon dioxide protects the perinatal brain

from hypoxic-ischemic damage: An experi-

mental study in the immature rat. Pediat-

rics 1995; 95:868–874

112. Nomura F, Aoki M, Forbess JM, et al: Effects

of hypercarbic acidotic reperfusion on re-

covery of myocardial function after car-

dioplegic ischemia in neonatal lambs. Cir-

culation 1994; 90:321–327

113. Laffey JG, Engelberts D, Kavanagh BP: In-

jurious effects of hypocapnic alkalosis in the

isolated lung. Am J Respir Crit Care Med

2000; 162:399–405

114. North JB, Jennett S: Abnormal breathing

patterns associated with acute brain dam-age. Arch Neurol 1974; 31:338–344

115. Rout MW, Lane DJ, Wollner L: Prognosis in

acute cerebrovascular accidents in relation

to respiratory pattern and blood gas ten-

sions. Br Med J 1971; 3:7–9

116. Davis DP, Idris AH, Sise MJ, et al: Early

ventilation and outcome in patients with

moderate to severe traumatic brain injury.

Crit Care Med 2006; 34:1202–1208

117. Muizelaar JP, Marmarou A, Ward JD, et al:

Adverse effects of prolonged hyperventila-

tion in patients with severe head injury: A

randomized trial. J Neurosurg 1991; 75:

731–739

118. Wiswell TE, Graziani LJ, Kornhauser MS, et

al: Effects of hypocarbia on the develop-

ment of cystic periventricular leukomalacia

in premature infants treated with high-

frequency jet ventilation. Pediatrics 1996;

98:918–924

119. Perlman JM: White matter injury in the

preterm infant: An important determina-

tion of abnormal neurodevelopment out-

come. Early Hum Dev 1998; 53:99–120120. Hashimoto K, Takeuchi Y, Takashima S:

Hypocarbia as a pathogenic factor in pon-

tosubicular necrosis. Brain Dev 1991; 13:

155–157

121. Fujimoto S, Togari H, Yamaguchi N, et al:

Hypocarbia and cystic periventricular leu-

komalacia in premature infants. Arch Dis

Child 1994; 71:F107–F110

122. Calvert SA, Hoskins EM, Fong KW, et al:

Etiological factors associated with the de-

velopment of periventricular leukomalacia.

Acta Paediatr Scand 1987; 76:254–259

123. Kubota M, Matsuda F, Hashizume M, et al:

Periventricular leukomalacia associated

with hypocarbia. Acta Paediatr Jpn 1996;38:57–60

124. Salokorpi T, Rajantie I, Viitala J, et al: Does

perinatal hypocarbia play a role in the

pathogenesis of cerebral palsy? Acta Paedi-

atr 1999; 88:571–575

125. De Rueck J: Cerebral angioarchitecture and

perinatal brain lesions in premature and

full term infants. Acta Neurol Scand 1984;

70:391–395

126. Oka A, Belliveau MJ, Rosenborg PA, et al:

Vulnerability of oligodendroglia to gluta-

mate: Pharmacology, mechanisms and pre-

vention. J Neurosci 1993; 13:1441–1453

127. Gilles FH, Leviton A, Kerr CS: Endotoxin

leukoencephalopathy in the telencephalon

of the newborn kitten. J Neurol Sci 1976;

27:183–191

128. Yoon BH, Romero R, Kim CJ, et al: High

expression of tumour necrosis factor ␣ and

interleukin 6 in periventricular leukomala-

cia. Am J Obstet Gynecol 1997; 177:

406–411

129. Riphagen S, Bohn D: High frequency oscil-

latory ventilation. Intens Care Med 1999;

25:1459–1462

130. Plum F: Hyperpnea, hyperventilation, and

brain dysfunction. Ann Intern Med 1972;

76:328

131. Fatunde OJ, Sodeinde O, Familusi JB: Hy-perventilation-precipitated cerebrovascular

accident in a patient with sickle cell anae-

mia. Afr J Med Med Sci 2000; 29:227–228

132. Hovorka J: Carbon dioxide homeostasis and

recovery after general anaesthesia. Acta An-

aesthesiol Scand 1982; 26:498–504

133. Wollman SB, Orkin LR: Postoperative hu-

man reaction time and hypocarbia during

anaesthesia. Br J Anaesth 1968; 40:920–926

134. Robinson JS, Gray TC: Observations on the

cerebral effects of passive hyperventilation.

Br J Anaesth 1961; 33:62–68




135. Murrin KR, Nagarajan TM: Hyperventila-

tion and psychometric testing. A prelimi-

nary study. Anaesthesia 1974; 29:50–58

136. Gibson TM: Effects of hypocapnia on psy-

chomotor and intellectual performance.

Aviat Space Environ Med 1978; 49:943–946

137. Harter MR: Effects of carbon dioxide on the

alpha frequency and reaction time in hu-

mans. Electroencephalogr Clin Neuro-

physiol 1967; 23:561–563

138. Hornbein TF, Townes BD, Schoene RB, et

al: The cost to the central nervous system of climbing to extremely high altitude. N Engl

J Med 1989; 321:1714 –1719

139. Hackett PH, Roach RC: High-altitude ill-

ness. N Engl J Med 2001; 345:107–114

140. Laffey JG, Kavanagh BP: Mechanisms of dis-

ease: Hypocapnia. N Engl J Med 2002; 347:

43–53

141. Kazmaier S, Weyland A, Buhre W, et al:

Effects of respiratory alkalosis and acidosis

on myocardial blood flow and metabolism

in patients with coronary artery disease.

Anesthesiology 1998; 89:831–837

142. Fujita Y, Sakai T, Ohsumi A, et al: Effects of

hypocapnia and hypercapnia on splanchnic

circulation and hepatic function in the bea-gle. Anesth Analg 1989; 69:152–157

143. Gustafsson U, Sjoberg F, Lewis DH, et al:

The effect of hypocapnia on skeletal muscle

microcirculatory blood flow, oxygenation

and pH. Int J Microcirc Clin Exp 1993;

12:131–141

144. Barker SJ, Hyatt J, Clarke C, et al: Hyper-

ventilation reduces transcutaneous oxygen

tension and skin blood flow. Anesthesiology

1991; 75:619–624

145. Mascia L, Zavala E, Bosma K, et al: High

tidal volume is associated with the develop-

ment of acute lung injury after severe brain

injury: An international observational

study. Crit Care Med 2007; 35:1815–1820

146. Bratton SL, Davis RL: Acute lung injury in

isolated traumatic brain injury. Neurosur-

gery 1997; 40:707–712

147. Salim A, Martin M, Brown C, et al: The

presence of the adult respiratory distress

syndrome does not worsen mortality or dis-

charge disability in blunt trauma patients

with severe traumatic brain injury. Injury

2008; 39:30–35

148. Ventilation with lower tidal volumes as

compared with traditional tidal volumes for

acute lung injury and the acute respiratory

distress syndrome. The Acute Respiratory

Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308

149. Trimble C, Smith DE, Rosenthal MH, et al:

Pathophysiologic role of hypocarbia in post-

traumatic pulmonary insufficiency. Am J

Surg 1971; 122:633–638

150. Cutillo A, Omboni E, Perondi R, et al: Effect

of hypocapnia on pulmonary mechanics in

normal subjects and in patients with

chronic obstructive lung disease. Am Rev

Respir Dis 1974; 110:25–33

151. Oyarzun MJ, Donoso P, Quijada D: Role of

hypocapnia in the alveolar surfactant in-

crease induced by free fatty acid intrave-

nous infusion in the rabbit. Respiration

1986; 49:187–194

152. Edmunds LH Jr, Holm JC: Effect of inhaled

CO2 on hemorrhagic consolidation due to

unilateral pulmonary arterial ligation.

J Appl Physiol 1969; 26:710–715

153. Kolobow T, Moretti MP, Fumagalli R, et al:

Severe impairment in lung function in-

duced by high peak airway pressure during

mechanical ventilation: an experimental

study. Am Rev Respir Dis 1987; 135:312–315

154. Laffey JG, Engelberts D, Duggan M, et al:

Carbon dioxide attenuates pulmonary im-

pairment resulting from hyperventilation.

Crit Care Med 2003; 31:2634–2640

155. Shepard JW, Hauer D, Miyai K, et al: Lamel-

lar body depletion in dogs undergoing pul-

monary artery occlusion. J Clin Invest 1980;

66:36–42

156. Laffey JG, Engelberts D, Kavanagh BP: Buff-

ering hypercapnic acidosis worsens acute

lung injury. Am J Resp Crit Care Med 2000;

161:141–146

157. Laffey JG, Honan D, Hopkins N, et al: Hy-

percapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit

Care Med 2004; 169:46–56

158. Laffey JG, Jankov RP, Engelberts D, et al:

Effects of therapeutic hypercapnia on mes-

enteric ischemia-reperfusion injury. Am J

Respir Crit Care Med 2003; 168:1383–1390

159. Laffey JG, Tanaka M, Engelberts D, et al:

Therapeutic hypercapnia reduces pulmo-

nary and systemic injury following in vivo

lung reperfusion. Am J Respir Crit Care

Med 2000; 162:2287–2294

160. Domino KB, Lu Y, Eisenstein BL, et al:

Hypocapnia worsens arterial blood oxygen-

ation and increases VA/Q heterogeneity in

canine pulmonary edema. Anesthesiology

1993; 78:91–99

161. Alexander CS, Liu SM: Effect of hypercapnia

and hypocapnia on myocardial blood flow

and performance in anaesthetized dogs.

Cardiovasc Res 1976; 10:341–348

162. Case RB, Greenberg H: The response of ca-

nine coronary vascular resistance to local

alterations in coronary arterial PCO2. Circ

Res 1976; 39:558–566

163. Coetzee A, Holland D, Foex P, et al: The

effect of hypocapnia on coronary blood flow

and myocardial function in the dog. Anesth

Analg 1984; 63:991–997

164. Foex P, Ryder WA: Effect of CO2 on thesystemic and coronary circulations and on

coronary sinus blood gas tensions. Bull Eur

Physiopathol Respir 1979; 15:625–638

165. Morgan DJ, Xu CL: Effect of perfusate pH

on reduction of quinidine capillary perme-

ability by albumin in isolated perfused rat

heart. Pharmaceutical Res 1994; 11:

1820–1824

166. Rowe GG, Castillo CA, Crumpton CW: Ef-

fects of hyperventilation on systemic and

coronary hemodynamics. Am Heart J 1962;

63:67–77

167. Yasue H, Nagao M, Omote S, et al: Coronary

arterial spasm and Prinzmetal’s variant

form of angina induced by hyperventilation

and Tris-buffer infusion. Circulation 1978;

58:56–62

168. Boix JH, Marin J, Enrique E, et al: Modifi-

cations of tissular oxygenation and systemic

hemodynamics after the correction of hypo-

capnia induced by mechanical ventilation.

Rev Esp Fisiol 1994; 50:19–26

169. Kusuoka H, Backx PH, Camilion de Hur-

tado M, et al: Relative roles of intracellularCa2ϩ and pH in shaping myocardial con-

tractile response to acute respiratory alka-

losis. Am J Physiol 1993; 265(5 Pt 2):

H1696–H1703

170. Wexels JC: Myocardial oxygen supply dur-

ing hypocapnia and hypercapnia in the dog.

Can J Physiol Pharmacol 1986; 64:

1376–1380

171. Mosca SM, Gelpi RJ, Borelli R, et al: The

effects of hypocapnic alkalosis on the myo-

cardial contractility of isovolumic perfused

rabbit hearts. Arch Int Physiol Biochim

Biophys 1993; 101:179–183

172. Richardson DW, Kontos HA, Raper AJ, et al:Systemic circulatory responses to hypocap-

nia in man. Am J Physiol 1972; 223:

1308–1312

173. Samuelsson RG, Nagy G: Effects of respira-

tory alkalosis and acidosis on myocardial

excitation. Acta Physiol Scand 1976; 97:

158–165

174. Lasierra J, Ferreira IJ, Mostacero C, et al:

Changes in platelet aggregation during vol-

untary hyperventilation. Rev Esp Fisiol

1972; 28:255–259

175. Mazzara JT, Ayres SM, Grace WJ: Extreme

hypocapnia in the critically ill patient. Am J

Med 1974; 56:450–456176. Wildenthal K, Fuller DS, Shapiro W: Parox-

ysmal atrial arrhythmias induced by hyper-

ventilation. Am J Cardiol 1968; 21:436–441

177. Hisano K, Matsuguchi T, Ootsubo H, et al:

Hyperventilation-induced variant angina

with ventricular tachycardia. Am Heart J

1984; 108:423–425

178. Brown EB Jr, Miller F: Ventricular fibrilla-

tion following a rapid fall in alveolar carbon

dioxide concentration. Am J Physiol 1952;

169:56–60

179. Porter JM, Markos F, Snow HM, et al: Ef-

fects of respiratory and metabolic pH

changes and hypoxia on ropivacaine-

induced cardiotoxicity in dogs. Br J Anaesth

2000; 84:92–94

180. Dziukas LJ, Vohra J: Tricyclic antidepres-

sant poisoning. Med J Aust 1991; 154:

344–350

181. Oertel M, Kelly DF, Lee JH, et al: Efficacy of

hyperventilation, blood pressure elevation,

and metabolic suppression therapy in con-

trolling intracranial pressure after head in-

jury. J Neurosurg 2002; 97:1045–1053

182. Newell DW, Weber JP, Watson R, et al: Ef-

fect of transient moderate hyperventilation




on dynamic cerebral autoregulation after

severe head injury. Neurosurgery 1996; 39:

35–43

183. Steiner LA, Balestreri M, Johnston AJ, et al:

Effects of moderate hyperventilation on ce-

rebrovascular pressure-reactivity after head

injury. Acta Neurochir Suppl 2005; 95:

17–20

184. Bouma GJ, Muizelaar JP, Bandoh K, et al:

Blood pressure and intracranial pressure-

volume dynamics in severe head injury: Re-

lationship with cerebral blood flow.J Neu- rosurg 1992; 77:15–19

185. Hlatky R, Valadka AB, Robertson CS: Intra-

cranial pressure response to induced hyper-

tension: Role of dynamic pressure autoreg-

ulation. Neurosurgery 2005; 57:917–923

186. Cruz J: The first decade of continuous mon-

itoring of jugular bulb oxyhemoglobin sat-

uration: Management strategies and clinical

outcome. Crit Care Med 1998; 26:344–351

187. Cruz J, Jaggi JL, Hoffstad OJ: Cerebral

blood flow, vascular resistance, and oxygen

metabolism in acute brain trauma: Redefin-

ing the role of cerebral perfusion pressure?

Crit Care Med 1995; 23:1412–1417

188. Gupta AK, Hutchinson PJ, Al-Rawi P, et al:Measuring brain tissue oxygenation com-

pared with jugular venous oxygen satura-

tion for monitoring cerebral oxygenation

after traumatic brain injury. Anesth Analg

1999; 88:549–553

189. Cardoso ER, Kupchak JA: Evaluation of in-

tracranial pressure gradients by means of

transcranial Doppler sonography. Acta Neu-

rochir Suppl (Wien) 1992; 55:1–5

190. Mindermann T, Gratzl O: Interhemispheric

pressure gradients in severe head trauma in

humans. Acta Neurochir Suppl 1998; 71:

56–58

191. Sahuquillo J, Poca MA, Arribas M, et al:

Interhemispheric supratentorial intracra-

nial pressure gradients in head-injured pa-

tients: Are they clinically important? J Neu-

rosurg1999; 90:16–26

192. Lundberg N, Kjallquist A, Bien C: Reduc-

tion of increased intracranial pressure by

hyperventilation. A therapeutic aid in neu-

rological surgery. Acta Psychiatr Scand

Suppl 1959; 34:1–64

193. Gelb AW, Craen RA, Rao GS, et al: Does

hyperventilation improve operating condi-

tion during supratentorial craniotomy? A

multicenter randomized crossover trial.

Anesth Analg 2008; 106:585–594

194. Schierhout G, Roberts I: Hyperventilation

therapy for acute traumatic brain injury. Co-

chrane Database Syst Rev 2000; 2:CD000566

195. Iida K, Takashima S, Takeuchi Y: Etiologies

and distribution of neonatal leukomalacia. Pediatr Neurol 1992; 8:205–209

196. Hashimoto K, Kida Y, Takeuchi Y: Progno-

sis of periventricular echodensities–Its rela-

tionship with periventricular leukomalacia.

No To Hattatsu 1993; 25:412–416

197. Jamison JP, Glover PJ, Wallace WF: Com-

parison of the effects of inhaled ipratropium

bromide and salbutamol on the broncho-

constrictor response to hypocapnic hyper-

ventil ation in normal subje cts. Thorax

1987; 42:809–814

198. Kolbe J, Kleeberger SR, Menkes HA, et al:

Hypocapnia-induced constriction of the ca-

nine peripheral airways exhibits tachyphy-

laxis. J Appl Physiol 1987; 63:497–504

199. Reynolds AM, McEvoy RD: Tachykinins me-

diate hypocapnia-induced bronchoconstric-

tion in guinea pigs. J Appl Physiol 1989;67:2454–2460

200. Reynolds AM, Zadow SP, Scicchitano R, et

al: Airway hypocapnia increases microvas-

cular leakage in the guinea pig trachea. Am

Rev Resp Dis 1992; 145:80–84

201. Noble WH, Kay JC, Fisher JA: The effect of

PCO2 on hypoxic pulmonary vasoconstric-

tion. Can Anaesth Soc J 1981; 28:422–430

202. Neill WA, Hattenhauer M: Impairment of

myocardial O2 supply due to hyperventila-

tion. Circulation 1975; 52:854–858

203. Staubli M, Vogel F, Bartsch P, et al: Hyper-

ventilation-induced changes of blood cell

counts depend on hypocapnia. Eur J Appl Physiol 1994; 69:402–407

204. Okazaki K, Hashimoto K, Okutsu Y, et al:

Effect of carbon dioxide (hypocapnia and

hypercapnia) on regional myocardial tissue

oxygen tension in dogs with coronary ste-

nosis. Masui 1992; 41:221–224


Artigo pós - hipocapnia

Documents

Transcript of Artigo pós - hipocapnia