Review Articles

Hypocapnia and the injured brain: More harm than benet

Gerard Curley, MB, FCARCSI; Brian P. Kavanagh, MD, FRCPC; John G. Laffey, MD, MA, BSc, FCARCSI
Objectives: Hypocapnia is used in the management of acute brain injury and may be life-saving in specic circumstances, but it can produce neuronal ischemia and injury, potentially worsening 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 dioxide, brain, lung, and myocardium, alone and in combination. Bibliographies of retrieved articles were also reviewed. Data Extraction and Synthesis: Hypocapnia often for prolonged periods of timeremains prevalent in the management of severely brain-injured children and adults. Despite this, there is no proof beyond clinical experience with incipient herniation that hypocapnia improves neurologic outcome in any context. On the contrary, hypocapnia can cause or worsen cerebral ischemia. The effect of sustained hypocapnia on cerebral blood ow decreases progressively because of buffering; subsequent normocapnia can cause rebound cerebral hyperemia and increase intracranial pressure. Hypocapnia may also injure other organs. Accidental hypocapnia 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 denitive measures or to facilitate 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 benet. (Crit Care Med 2010; 38:1348 1359) KEY WORDS: carbon dioxide; hypocapnia; alkalosis; hyperventilation; acute brain injury; trauma

raditional approaches in managing acute brain injury have focused on the potential for hypocapnia to reduce intracranial pressure (ICP) (1, 2). Because elevated ICP is generally adverse and hypocapnia is thought to be benign, hyperventilation was widely practiced in patients with acute brain injury. This reasoning led to the idea that more profound hyperventilation might be even better and extremes of hypocapniafor prolonged periodswere advocated for acute brain injury (37).

This review re-examines the rationale for the use of hypocapnia in acute brain injury (both traumatic and other causes). We conducted a literature search on MEDLINE and PubMed (1966 August 1, 2009) using the search terms: hyperventilation, hypocapnia, alkalosis, carbon dioxide, brain, lung, and myocardium, alone and in combination. Bibliographies of retrieved articles were also reviewed. The prevalence of hypocapnia in the management of brain-injured patients and the evidence for benecial and deleterious effects of hypocapnia were evaluated.

From Department of Anaesthesia (GC, JGL), University College Hospital, Galway, Ireland; Departments of Critical Care Medicine and Anesthesia and the Program 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, National University of Ireland, Galway, Ireland. This manuscript was supported in part by a fellowship from Molecular Medicine Ireland under the Programme for Research in Third Level Institutions (GC) and by funding from the European Research Council (JGL) under the Framework 7 program. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: john.laffey@nuigalway.ie Copyright 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3181d8cf2b

Hypocapnia: Denitions and Severity

Arterial CO2 tension (Paco2) is a balance between production and elimination. Because endogenous production rarely falls below normal, hypocapnia is usually caused by deliberate or accidental hyperventilation. In the setting of acute brain injury, the severity of hypocapnia when used therapeutically has been graded (Table 1) (8).

tents must remain constant because the cranial cavity represents a xed volume. An increase in the volume of any intracranial compartment (e.g., cerebral edema, hematoma, or brain tumor) can initially be compensated by displacement from another compartment. However, when intracranial content volume exceeds a threshold, ICP increases precipitously (Fig. 1). Intracranial hypertension (sustained ICP 20 mm Hg) may cause secondary brain injury by impairing cerebral perfusion, direct pressure, or by brainstem herniation. Hypocapnia is induced to lower ICP by decreasing the cerebral blood volume (CBV) via cerebral arterial vasoconstriction (Fig. 1). The effects are potent: cerebral blood ow (CBF) decreases by approximately 3% per mm Hg change in Paco2 (range, 60 to 20 mm Hg PCO2) in patients with traumatic brain injury (TBI) (9).

How Often Do We Use Hypocapnia in Clinical Practice?

Hypocapnia is widely used in adults and children with acute brain injury from the earliest phases of the injury process, even in the absence of elevated ICP (8, 10). This widespread use of hypocapnia persists despite recognition of its dangers and guidelinesfor adults (11) and children
Crit Care Med 2010 Vol. 38, No. 5

Why Do We Use Hypocapnia in Patients After Acute Brain Injury?

The Monro-Kellie doctrine states that the total volume of the intracranial con-

1348

Table 1. Classication of severity of hypocapnia Target Paco2 Range 26 mm Hg (3.5 kPa) 2630 mm Hg (3.53.9 kPa) 3135 mm Hg (4.04.7 kPa) 3645 mm Hg (4.86.0 kPa)

Classication Intensied forced hyperventilation Forced hyperventilation Moderate hyperventilation Normoventilation

Modied with permission from Neuman et al (10).

Figure 1. Relationship between intracranial volume and intracranial pressure. Because the cranial cavity represents a xed volume, an increase in the volume of brain tissue, tumor, or hematoma can initially be compensated by displacement of volume from another compartment. Acute hypocapnia can reduce cerebral blood volume, thereby attenuating the increase in intracranial pressure.

tive analysis suggests that hypocapnia occurs in 52% of patients and that the 2003 Pediatric Brain Trauma guidelines (12), which recommend strict limitation of hypocapnia, did not alter this (Fig. 3). The youngest children (2 yrs) had the highest incidence of severe hypocapnia, which is a concern given the vulnerability of the neonatal brain and potential for associated intraventricular hemorrhage (14) (Fig. 4). Severe hypocapnia was common in children without elevated ICP (8). This is of particular concern because hypocapnia predicted inpatient mortality (odds ratio, 2.8; 95% condence interval, 1.3 5.9) independent of the severity of brain injury (8). Hypocapnia in Early Brain Injury. Hypocapnia occurs in brain-injured patients even before intensive care unit admission. Almost 50% of Michigan emergency physicians routinely use prophylactic hyperventilation in patients with severe TBI (15), and accidental hyperventilation is also common (16). The net result is that severe hypocapnia (end expired CO2 30 mm Hg) is seen in 70% of patients transferred by helicopter to a U.S. urban level I trauma center (17). More recently, Warner et al (18) reported that 16% of intubated TBI patients en route to a level I trauma center had Paco2 levels 30 mm Hg, whereas 30% had levels of 30 to 35 mm Hg. Such prehospital hypocapnia is clearly associated with adverse outcome in TBI (16, 19).

in two-thirds of patients (30), a situation associated with poor outcome (24, 31). Such hypoperfusion may be worsened by cerebral vasospasm, further worsening outcome (32). Of particular concern, 80% of patients who die of head injury demonstrate profound ischemic neuronal changes (27). Cerebral Oxygen Utilization. Braininjured patients commonly have lower metabolisms and cerebral metabolic requirements for oxygen (CMRO2) (33, 34). The mitochondrial dysfunction hypothesis (22, 35) suggests that low CBF is secondary to the reduced CMRO2, which is, in turn, caused by mitochondrial failure attributable to injury. If true, then it could be that the injured brain can tolerate lower levels of O2 supply and that further reducing CBF (e.g., hyperventilation) is possible without causing harm (36). Hypocapnia-induced reduction of CBF may be tolerated after TBI because of this lower metabolic rate and perhaps higher oxygen extraction (22). However, assumptions about global events require caution in heterogenous injury because of focal limitation of oxygen diffusion attributable to endothelial swelling, microvascular collapse, and perivascular edema (37). Finally, lowered jugular venous oxygen extraction (e.g., SjO2) may reect reduced brain O2 consumption rather than increased CBF.

(12)that recommend limitation of hypocapnia to intracranial hypertension accompanied by neurologic deterioration. Hypocapnia in Adults. The Brain IT initiative, a collaboration of 38 European centers that provide care for braininjured patients, has established a TBI database from which Neumann et al (10) recently analyzed arterial blood gas data from 2269 ventilation episodes. Early prophylactic hyperventilation, i.e., hypocapnia in the rst 24 hrs, was used in 54% of episodes (10) (Fig. 2). Furthermore, the majority of patients who did not have increased ICP had signicant hypocapnia for up to 50% of their total ventilation time. More than 90% of patients with Paco2 30 mm Hg received no monitoring of brain oxygenation (10). In the United States, 36% of U.S. boardcertied neurosurgeons routinely use prophylactic hyperventilation in patients with severe TBI (13). Hypocapnia in Children. Hypocapnia remains prominent in the management of brain-injured children (8). RetrospecCrit Care Med 2010 Vol. 38, No. 5

What Happens to Cerebral Blood Flow and Oxygen Requirements in the Injured Brain?
Cerebral Blood Flow. Hypocapnia is often used in brain injury to reduce luxury perfusion, which is thought to worsen edema, especially in children (20). Furthermore, because injury impairs vascular control, if hypocapnia-induced vasoconstriction were more pronounced in uninjured vs. injured brain (21), then perfusion might be shunted from normal to vulnerable (injured) brain, a concept termed inverse steal (21). These concepts are now largely discredited. CBF and cerebral oxygen delivery are generally decreased after brain injury (2228), and regional CBF is often markedly decreased particularly in the rst 24 hrs (24 26). In 31% of patients with TBI (26), CBF is below an ischemic threshold in which ischemia and cell death may occur (29). Transcranial Doppler demonstrates low-ow early after TBI

How Does Hypocapnia Reduce CBV?

The aim of hypocapnia in acute brain injury is to reduce intracranial volume. However, the effect of hypocapnia on CBV is indirect and is mediated via reductions in CBF (38). Positron emission tomography demonstrates that only 30% of the CBV resides in the arteries (39). Hypocapnia has little effect on cerebral venous tone, and dynamic positron emission tomography conrms that CO2-induced changes in CBV are mediated by altered arterial, not capillary or venous, volume (38). Thus, the effect of changing Paco2 on CBF (i.e., arterial) is proportionally greater than its effect on CBV. Reducing CBF by 30% with hyperventilation corresponds to a reduction of only 7% in CBV (40). Greater degrees of hypocapnia further reduce CBF but do not reduce CBV or ICP (40). The effect of CO2 on CBF depends on the individual patient, baseline blood ow, and the part of the central nervous system in question. In individuals CBF is
1349

pial arterioles are most responsive (52). The endothelium and smooth muscle play central roles. Multiple mechanisms involving nitric oxide, vasoactive prostanoids, potassium channels, and intracellular calcium have been implicated. Endothelial release of nitric oxide in response to alterations in CO2 tension appears to be key (53). Impaired endothelium lessens nitric oxide release and blunts CO2 reactivity (54), as does inhibition of nitric oxide synthase (5557). Other mechanisms are nitric oxideindependent. Endothelial synthesis and release of vasodilator prostanoids may be more important in children than in adults (58, 59). Smooth muscle K channels (e.g., ATP-sensitive K) have also been implicated (60 62). Ultimately, CO2 modulates smooth muscle intracellular calcium concentration and sensitivity (63).
Figure 2. Frequency of hypocapnia in adults with traumatic brain injury in a recent study (10). The distribution of Paco2 values in blood gas analyses is skewed toward hypocapnia, with a maximum in the range 30 to 35 mm Hg. Reproduced with permission from Neumann et al (10).

How Can Hypocapnia Cause Cerebral Hypoxia?

Reduced Cerebral Oxygen Supply. The most serious concern with hypocapnia in brain injury is cerebral hypoperfusion (37, 40, 64 72). Hypocapnia may worsen cerebral vasospasm, which in turn can worsen outcome (32) and exacerbate preexisting impairment of CBF (65). Hypocapnia does not appear to produce inverse steal (i.e., diverting perfusion to ischemic areas) (73). In fact, injured areas may have increased CO2 responsiveness, raising the possibility that hypocapnia may aggravate secondary ischemic injury by diverting ow from injured brain (74). Hypocapnia may reduce cerebral O2 supply via additional mechanisms. Hypocapnic alkalosis may cause bronchoconstriction and attenuation of hypoxic pulmonary vasoconstriction, resulting in net lowering of PaO2 (7577); at any given O2 tension, the leftward shift of the oxyhemoglobin dissociation curve may reduce O2 off-loading to tissues (78). Increased Cerebral Oxygen Demand. Hypocapnia may aggravate brain ischemia by increasing cerebral oxygen demand (Figure 5) because of increased neuronal excitability (79, 80). This contributes to increased cerebral utilization and depletion of glucose (81, 82), and a switch to anaerobic metabolism (65, 83). Hypocapnia increases CMRO2 in TBI (84) and prolongs seizure activity (80). Such seizure potentiation further heightens O2 demand and results in production of seizure-associated cytotoxic excitatory
Crit Care Med 2010 Vol. 38, No. 5

Figure 3. Percentage of children with one or more episodes of hypocapnia in the initial 48 hrs after hospital admission with traumatic brain injury in a recent study (8). The gray bars represent data from patients before and the black bars represent patients after the publication of guidelines suggesting limited use of hypocapnia. Reproduced with permission from Curry et al (8). PG, pediatric trauma guidelines.

not homogeneous, and areas with higher CBF have a steeper response to altered CO2 (41). Overall, there is a 3% change in CBF per 1-mm Hg change in Paco2 (42 44). In different regions, the principle is maintained such that in the cat, a change in Paco2 of 1 mm Hg results in a blood ow change of 1.7 mL/100 g/min in the cerebral cortex (baseline ow, 86 mL/100 g/min) but a blood ow change of 0.9 mL/100g/min in the spinal cord (baseline ow, 46 mL/100 g/min) (45). Similar CBF responses occur in rabbits (46) and in humans (41). In contrast, the effect on
1350

CBV is far smaller than that on CBF (47). Thus, the capacity for hypocapnia to reduce CBV is limited and is achieved at a disproportionate cost to arterial CBF. Because low CBF is common in the rst 24 hrs after TBI, early hypocapnia may be particularly harmful (48). Mechanism of Cerebral Vasoconstriction. The effects of CO2 are primarily on the cerebral arteries (38), are pH-mediated rather than CO2-mediated (49, 50), and occur via a direct effect on the arteriole smooth muscle (49 51). The larger arteries are less sensitive and the small

Figure 4. This gure summarizes the role of hypocapnia in the pathogenesis of neonatal intraventricular hemorrhage. Hypocapnia has been implicated in the pathogenesis of neonatal white matter injury (e.g., periventricular leukomalacia), which results in intraventricular hemorrhage. Antioxidant depletion by excitatory amino acids and sepsis-induced lipopolysaccharide and cytokines further potentiate white matter destruction. Hypocapnia induced brain ischemia in watershed vascular territories, and hyperemia after hypocapnia may contribute to intraventricular hemorrhage. Reproduced with permission from Laffey et al (140). LPS, lipopolysaccharide; TNF, tumor necrosis factor.

amino acids (e.g., N-methyl-D-aspartate) (85), which also may be increased by hypocapnia-induced neuronal dopamine (86). Finally, alkalosis inhibits the negative feedback whereby low pH reduces ongoing endogenous acid production (e.g., lactate) (87), potentially worsening injury further. Evidence for Hypocapnia-Induced Brain Ischemia. Concerns regarding hypocapnia and adverse neuronal O2 supply and demand are supported by multiple ndings from clinical and experimental studies. First, in children (88) and adults (84, 89) with TBI, hypocapnia causes regional cerebral ischemia. In adults resuscitated after cardiac arrest, hypocapnia reduces SjO2 (and increases lactate) (90). In experimental studies, hypocapnia reduces regional CBF and local cortical tissue PO2 (91) and reduces cerebral oxyhemoglobin (92, 93) and oxidized cytochrome aa3 (93) while increasing cerebral deoxyhemoglobin (93). Second, hypocapnia produces ischemic changes in functional magnetic resonance imaging (64) and with electroencephalography (94). Third, brain lactate production (i.e., anaerobic metabolism) is increased by hyperventilation (95), which may be more severe earlier in TBI (96). However, alkalosis may directly stimulate glycolysis (to buffer alkalosis) and further elevate lactate (97).

Why Is Sustained Hypocapnia Particularly Deleterious?

Progressive Loss of Effect on ICP. Hypocapnia rapidly elevates the pH of both the CSF and the central nervous system extracellular uid, and the CBF declines correspondingly. Severinghaus et al (98) demonstrated, 4 decades ago, that during prolonged hypocapnia the CSF pH is buffered toward normal and the CBF normalizes. The buffering is a biphasic process. First, there is tissue buffering (99, 100), in which hypocapnia immediately lowers the intracellular uid CO2, resulting in exit of Cl from intracellular uid to extracellular uid and a reciprocal shift of HCO3 from extracellular uid to intracellular uid, thereby lowering the extracellular uid concentration of HCO3. Second, the renal responseinhibition of H secretion and HCO3 resorption in the proximal tubule begins immediately and takes effect over hours to days (99, 100). Buffering of CSF pH normalizes CBF as quickly as 6 hrs (101), even if the Paco2 remains low (2). In healthy
1351

Figure 5. An integrated scheme of mechanisms underlying neurologic effects of hypocapnia. Induction of systemic hypocapnia results in a cerebrospinal uid alkalosis, reducing cerebral blood ow, cerebral oxygen delivery, and, to a lesser extent, cerebral blood volume. This is potentially life-saving in the setting of critically elevated intracranial pressure. However, critical brain ischemia may result, exacerbated by an increase in hemoglobin oxygen afnity and an increase in neuronal excitability. Over time, cerebrospinal uid pH and, hence, cerebral blood ow gradually return to normal. Normalization of Paco2 results in cerebral hyperemia and reperfusion injury to previously ischemic brain regions. In addition, hypocapnia may cause glutamate release and neuronal excitotoxicity. Reproduced with permission from Laffey et al (140).

Crit Care Med 2010 Vol. 38, No. 5

volunteers, whereas a sustained 20-mm Hg reduction in Paco2 decreased CBF by 40% immediately, CBF was restored to 90% of normal by 4 hrs (2). Rebound Intracranial Hypertension with Restoration of Normocapnia. Rebound elevation in ICP after restoration of normocapnia is well-described. Because HCO3 is the only buffer in extracellular brain uid, loss of bicarbonate, an obligatory consequence of hypocapnia, greatly reduces its buffering capacity. Therefore, normalization of Paco2 leads to an overshoot in CSF pH and a corresponding overshoot increase in CBF. Experimental induction of hypocapnia (Paco2 25 mm Hg, anesthetized rabbit) followed by normocapnia for 10 mins every 4 hrs was associated with progressively less effective hypocapnic vasoconstriction (102). Temporary restoration of normocapnia every 4 hrs caused vasodilation. At 20 hrs arterial pH had returned to baseline and by 24 hrs the CSF pH was normal. Similar results were reported in the anesthetized goat in which restoration of normocapnia caused marked cerebral hyperemia (103). These ndings have important implications. First, buffering of CSF pH ablates the effectiveness of ongoing hypocapnia, and CBF may return to baseline levels by 4 hrs. Second, when hypocapnia is continued, it is difcult to further reduce CO2 to decrease ICP acutely, should this become necessary later (e.g., incipient herniation), without causing lung damage. Third, rebound intracranial hypertension should be anticipated after restoration of normocapnia and could result in brainstem herniation (or, in premature infants, intracranial hemorrhage) (68, 104 106) (Fig. 5). This is particularly important in severe hypocapnia because the slope of the relationship between CSF pH vs. CBF is steepest at this level (107). Thus, if hypocapnia is induced, then it should be brief while denitive measures to control ICP are undertaken, and Paco2 should be targeted toward normal as soon as possible.

capnia increases N-methyl-D-aspartatereceptormediated neurotoxicity (85) and increases neuronal dopamine, particularly in the striatum, which may worsen reperfusion injury, especially in the immature brain (86). Finally, hypocapnia may be directly neurotoxic through increased incorporation of choline into membrane phospholipids (108). Cerebral Ischemia and Reperfusion Injury. Hypocapnia may worsen neuronal ischemia and reperfusion injury. Hypocapnia during resuscitation after cardiac arrest is associated with worsened brain injury (109) and it aggravates hypoxicischemic central nervous system damage (110, 111). These ndings are consistent with its potentiation of reperfusion injury in the myocardium (112) and the lung (113). The central nervous system effects of hypocapnia are particularly prominent in the immature brain (110, 111).

Table 2. Neonatal brain conditions associated with hypocapnia Multicystic encephalomalacia (195) Cystic periventricular leukomalacia (69, 118, 119, 121123) Pontosubicular necrosis (196) Watershed infarction (119) Reactive hyperemia and hemorrhage (106)

What Is the Role of Hypocapnia in Specic Neurologic Conditions?

Spontaneous vs. Induced Hypocapnia. Whereas induced hypocapnia is the focus of this article, hypocapnia is often spontaneous. Spontaneous hyperventilation has long been associated with adverse outcome in TBI and subarachnoid hemorrhage (114) and after stroke (115); however, whether the spontaneous hyperventilation reected severity of the lesion or caused/contributed to it is unclear. More recently, spontaneous and induced hyperventilation have been associated with adverse outcome in trauma, but only induced hyperventilation was independently predictive (116). TBI. There is no evidence to suggest that hypocapnia improves outcome in acute brain injury; in fact, prolonged hyperventilation worsens outcome. In a landmark, randomized, clinical trial, patients with TBI were assigned to receive normal ventilation (target Paco2, 35 mm Hg) vs. prophylactic hyperventilation (target Paco2, 25 mm Hg); the prophylactic hyperventilation resulted in fewer of the less severely injured patients (Glasgow Coma Scale motor score, 4 5) having a favorable outcome at 3, 6, and 12 months (117). Beyond the outcome disadvantages, prolonged hypocapnia in these patients increased the overall level and variability of ICP, especially after 60 hrs of hyperventilation, indicating that hypocapnia became ineffective or counterproductive in controlling ICP over time (117).

Does Hypocapnia Damage Neurons?

Hypocapnia and Neurotransmission. Hypocapnia mediates increases in neuronal excitability and potentiates seizure activity that may result in local production of seizure-associated excitatory amino acids, including N-methyl-D-aspartate, that are locally cytotoxic (Fig. 5). Severe hypo1352

Neonatal Brain Injury. Hypocapnia is common in neonatal practice. It is injurious to the premature brain and is associated with multiple neonatal brain conditions, including neonatal white matter injury (69, 118 122) (Fig. 4; Table 2). Hypocapnia is often the sole risk factor for periventricular leukomalacia (123), a syndrome associated with signicant neonatal mortality and neurodevelopmental decit, and may be a cause of pontosubicular necrosis, another acute brain injury syndrome of prematurity (120). Whether hypocapnia contributes to cerebral palsy remains unanswered (124). Even brief exposure of preterm infants to severe hypocapnia (Paco2 15 mm Hg) is associated with considerable longterm neurologic abnormalities (14), including sensorineural hearing loss (68). In this setting, predisposing factors may include vulnerable areas with poorly developed vascular supply (125), antioxidant 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 hypocapnia after hyperventilation (14), high-frequency ventilation (129), or extracorporeal membrane oxygenation (68). Finally, abrupt termination of hyperventilation results in reactive hyperemia, which may precipitate intracranial hemorrhage in premature neonates (106). Acute Stroke. Hyperventilation has classically been advocated as a therapy in stroke for two reasons. First, hypocapnia was considered to result in shunting of blood to the ischemic brain area by constricting the normally autoregulated brain, the so-called inverse steal phenomenon that is now known not to occur (73). Second, hypocapnia was believed to correct acidosis in areas adjacent to the ischemic zone to minimize the extension of the infarct (21). In fact, hypocapnia is associated with poor prognosis in stroke (115, 130). Although separating cause vs. effect is difcult (because large strokes are commonly accompanied by spontaneous hyperventilation), the recurrence of a
Crit Care Med 2010 Vol. 38, No. 5

right hemiplegia and aphasia while undergoing a hyperventilation provocative test has been reported (131). Impairment of Neurologic Function. The potential for neurologic dysfunction after (even brief) hypocapnia is most clearly documented in postoperative patients. Healthy patients subjected to hypocapnia have signicantly impaired psychomotor function for up to 48 hrs postoperatively, and such effects are more marked and occur with less severe hypocapnia in older patients (132). More profound intraoperative hypocapnia (24 mm Hg), even for a relatively short duration, can delay reaction times for up to 6 days (133). Hypocapnia may impair attention and learning and can induce personality changes (134, 135). At severe levels (Paco2 15 mm Hg), hypocapnia decreases basic psychomotor performance in healthy volunteers (136). That hypocapnia causes such dysfunction is supported by the nding that exposure to elevated Paco2 during anesthesia enhances neuropsychologic performance (132, 137). Reassuringly, the adverse effects of hypocapnia in studies of postoperative cognition in healthy patients, while often prolonged, seem ultimately reversible (132, 133). Prolonged exposure to hypocapnia may result in sustained impairment. The neurologic impairment seen in healthy mountaineers at extreme altitude is most closely correlated to the degree of hypocapnia, not the level of hypoxia (138). The basis for acute central nervous system symptoms at altitude appears to be alkalosis, and such alkalosis can be prevented by pretreatment with acetazolamide (139).

Table 3. Deleterious pulmonary effects of hypocapnia Reduced lung compliance (150) Dysfunctional surfactant production (151) Lamellar body depletion. (155) Increased airway resistance Increased 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 supply Decreased coronary ow (161, 164) Decreased collateral ow (163) Increased coronary vascular resistance (162, 166) Increased coronary artery spasm (167, 177) Increased hemoglobin oxygen afnity (202) Increased coronary microvascular leak (165) Increased platelet number (203) Increased platelet aggregation (174) Increased myocardial oxygen demand Increased heart rate (173) Increased O2 extraction (164, 170) Increased (later decreased) contractility (169, 171) Increased intracellular Ca2 (169) Increased systemic vascular resistance (141) Myocardial ischemia (164, 167, 204) Increased myocardial reperfusion injury (112) Ventricular and atrial arrhythmias (176178)

Can Hypocapnia Damage Other Organs?

Hypocapnia can injure other organs, and the effects on the lung and vasculature are well-described (140). Hypocapnia decreases perfusion to the heart (141), liver, gastrointestinal tract (142), skeletal muscle (143), and skin (144). This review focuses on brain injury and, because oxygenation and perfusion are central, this section summarizes the effects of hypocapnia on lung injury and on myocardial oxygenation. Acute Lung Injury. More than 20% of patients with severe brain injury have acute lung injury or acute respiratory distress syndrome develop (145, 146), which worsens outcome (147) and is independently predicted by the use of high tidal
Crit Care Med 2010 Vol. 38, No. 5

volume to produce hypocapnia (145), a nding conrmed prospectively in a multicenter European study (145). Unfortunately, patients with conrmed lung injury continue to be hyperventilated (145) despite the known association between high tidal volume and mortality in acute respiratory distress syndrome (148). The concept that hypocapnia might be pathogenic in acute lung injury/acute respiratory distress syndrome was suggested in 1971 by Trimble et al (149). Hypocapnia may contribute to acute lung injury because high tidal volume ventilation (usually used to achieve hypocapnia) directly causes lung injury (148), and the hypocapnia per se may injure the lung via several mechanisms (Table 3), including increased lung permeability and edema (113), decreased compliance (150), perhaps by surfactant inhibition (151), and

potentiating acute inammation (152 154). Many of these adverse effects can be ameliorated by normalizing alveolar CO2 (151, 152, 154, 155) and, conversely, hypercapnic acidosis reduces experimental lung injury (154, 156 159). Finally, hypocapnia attenuates hypoxic pulmonary vasoconstriction, thereby increasing intrapulmonary shunt (160). After acute brain injury, it is difcult to discern the individual contributions of high tidal volume vs. hypocapnia to lung injury. Myocardial Ischemia. Acute hypocapnia lowers myocardial O2 delivery (161 167) and increases demand (141, 164, 168 170) through a variety of mechanisms including increased contractility (168, 171), left ventricular afterload (172), and heart rate (173), thereby worsening the supply-and-demand balance (164, 167) (Table 4). Hypocapnia reduces coronary ow (163), increases tissue capillary permeability (165), and may cause frank coronary spasm, resulting in variant angina that classically occurs with spontaneous hyperventilation (167). Finally, hypocapnia may precipitate thrombosis through increased platelet levels or aggregation (174). Thus, clinically relevant acute coronary phenomena exist in brain-injured patients managed with hypocapnia. Cardiac Dysrhythmias. Hypocapnia causes dysrhythmias (175) (Table 4), including paroxysmal atrial arrhythmia (176) and (rarely) ventricular tachycardia (177) or brillation (178). Aside from potentiating myocardial ischemia, the mechanisms are unclear. However, hypocapnic alkalosis may be an effective therapy for toxicity attributable to local anesthetic (179) or tricyclic antidepressant (180).

Can We Use Hypocapnia to Produce Benet While Minimizing Harm?

Whether hypocapnia can be used to produce benet while minimizing harm is a key question. Hyperventilation is the most effective means for acutely lowering ICP (181). The deleterious effects of hypocapnia in the injured brain stem, at least in part, form limitations regarding how we use hypocapnia in brain-injured patients. Therefore, monitoring of indices of cerebral cellular oxygenation might enhance the safety of using more moderate levels of hypocapnia for shorter periods to control ICP. Safety of Moderate Hypocapnia. The more severe the hypocapnia and the greater
1353

the duration of its use, the greater the potential there is for harm. This potential for harm is reduced when mild-to-moderate hypocapnia is used for limited periods of time. Brief moderate hyperventilation may transiently restore autoregulation of CBF in head-injured patients (182, 183). Autoregulation of CBF protects the brain from excessive shifts in CBF attributable to alterations in systemic blood pressure and is impaired in 50% to 90% of patients with severe TBI (184, 185). One study demonstrated that moderate hypocapnia (PCO2 28 mm Hg) temporarily improved cerebral autoregulation in head-injured patients (182). Conversely, more severe hypocapnia (PCO2 23 mm Hg) impaired autoregulation (182). In addition, the effect of hypocapnia on autoregulation of CBF with hypocapnia is quite variable (183) and the duration of any benecial effect is unclear, but it may be short-lived (182). Furthermore, any benecial effects of hypocapnia on autoregulation must be set against the potential for hypocapniainduced cerebral ischemia. The potential for brief moderate hypocapnia to cause ischemia is clear from the nding that 20 mins of moderate hypocapnia (Paco2 2732 mm Hg) can produce critical reductions in regional brain tissue PO2 in 20% of patients with TBI (23). Thus, the idea of a safe threshold level of hypocapnia is not an idea that can be generalized to populations of brain-injured patients. Titrated Hypocapnia: A Feasible Strategy? Several investigators have raised the potential that hypocapnia might safely be titrated, in individual patients, against indices of cerebral oxygenation. It has been proposed that 20% of TBI patients with intracranial hypertension may have CBF in excess of that needed for metabolism on the basis of SjO2 measurements (186, 187). In such patients, optimized hyperventilation has been proposed in which hypocapnia (lowering ICP) is titrated against SjO2 (to monitor global O2 supply-and-demand balance) (186, 187). However, global indices of oxygenation are insensitive to regional imbalances. Placement of regional monitors of brain oxygenation near the penumbra of focal lesions clearly demonstrates the limitations of global indices of cerebral oxygenation (188). Titrating hyperventilation to CMRO2 has also been proposed on the basis that brief (10 mins) episodes of severe hypocapnia did not reduce global or regional CMRO2, even in areas of the brain where CBF was
1354

low (22). However, baseline CMRO2 was very low in areas of poor cerebral perfusion, and hypocapnia did greatly increased oxygen extraction ratio in the venous blood from these areas (22). Nevertheless, these data suggested that O2 supply to these tissues was adequate and that hypocapnia could be used safely (22). In contrast, other positron emission tomography studies indicate that moderate hypocapnia (Paco2 30 mm Hg) may cause focal brain ischemia (89) based on the calculation of a critical oxygen extraction fraction for each subject and estimation of the volume of brain tissue with oxygen extraction fraction values below this threshold as determined by positron emission tomography scanning. Using this approach, hypoventilation elevates CPP and lowers ICP, but the volume of severely hypoperfused tissue within the injured brain is raised (89). This group further demonstrated that the injured brain is less able to increase O2 extraction in response to reduced O2 delivery (37), phenomena not detectable using routine central nervous system monitors (including SjO2) (84). Most worrisome is the more recent observation that in TBI, hypocapnia may increase focal brain CMRO2 associated with increased cortical electrical activity (84). An overriding concern is that because hypocapnia can directly modulate CMRO2 (84), it may invalidate the use of CMRO2 to dene thresholds for cerebral ischemia. This may explain why hypocapnia did not reduce CMRO2 despite large reductions in CBF and increases in oxygen extraction ratio (22). It is increasingly clear that there is signicant heterogeneity in regional oxygenation in the injured brain. Substantial intercompartmental pressure differentials can exist in the injured brain (189 191) and these, rather than globally increased ICP, may be the proximate cause of herniation syndromes (190, 191). Finally, because vasoresponsiveness to CO2 may be increased (up to threefold) after TBI (74), hypocapnia could exacerbate intercompartmental pressure differentials, increasing the risk of local herniation. Regional Cerebral Monitoring: The Future? There is no safe threshold level of hypocapnia that can be used in all brain-injured patients. Furthermore, the presence of signicant regional heterogeneity in TBI renders global indices of cerebral perfusion or oxygenation inadequate. An alternative approach may be

the use of brief episodes of moderate hypocapnia titrated against regional indices of cerebral oxygen and against intercompartmental pressure gradients. Technological advances such as regional brain tissue PO2 monitoring, bedside imaging, and microdialysis, as well as regional ICP monitoring, may together enhance outcome. In this paradigm, the ultimate clinical utility of hypocapnia in acute brain injury will depend on its potential to cause direct harm in the injured brain.

What Is the Current Role for Hypocapnia in Acute Brain Injury?

Imminent Brain Herniation. There is a strong physiologic (and empirical) rationale for brief use of hypocapnia to acutely reduce ICP. Although the evidence is limited, the rapidity of induction and its immediate effect on CBF make it a useful strategy while denitive measures are being instituted. Intraoperative Use During Neurosurgery. Hypocapnia is used during neurosurgery to facilitate access or to acutely reduce brain bulk (192). This was successfully demonstrated in a prospective, randomized, crossover study in patients with supratentorial brain tumors (193) in which brief (20 mins) intraoperative hyperventilation reduced brain bulk and reduced ICP, although the longer-term effects were not reported. It is important to remember that when acute hypocapnia is used in these settings, normocapnia should be restored as soon as is feasible, because hypocapnia becomes ineffective within hours. This means that hypocapnia can be used later to control further worsening of ICP and it avoids the risk of rebound hyperemia with delayed CO2 normalization.

CONCLUSIONS
Hypocapnia, often prolonged, remains prevalent in the management of brain injury. Despite this, there is no proof (other than experience with incipient herniation) that hypocapnia improves neurologic outcome in any context. On the contrary, hypocapnia can certainly cause or worsen cerebral ischemia, worsen outcome, and cause (direct or indirect) injury to other organs. The decision to institute hypocapnia for therapeutic purposes in the setting of acute brain injury should be undertaken only after careful consideration of the risks and
Crit Care Med 2010 Vol. 38, No. 5

benets. Accidental hypocapnia should always be avoided, and prophylactic use has no clinical role. The use of hypocapnia might be best limited to the emergency management of life-threatening ICP or to acutely reduce brain bulk in the operating room, pending institution of denitive measures. In these settings, normocapnia should be re-instituted as soon as is feasible. Contrary to suggestions that prospective trials of prophylactic hyperventilation in head injury are needed (194), we believe, based on the data presented, that such studies are difcult to justify at this stage given the increasing recognition that this approach is frequently harmful and rarely, if ever, benecial.

12.

13.

14.

15.

16.

REFERENCES
1. Raichle ME, Plum F: Hyperventilation and cerebral blood ow. Stroke 1972; 3:566 575 2. Raichle ME, Posner JB, Plum F: Cerebral blood ow during and after hyperventilation. Arch Neurol 1970; 23:394 403 3. Brown M: ICUCritical care. In: Clinical Anesthesia. Barash PG, Cullen BF, Stoelting RK (Eds). Philadephia, PA, JB Lippincott, 1989, pp 14551476 4. Hayek DA, Veremakis C: Physiologic concerns during brain resuscitation. In: Critical Care. Second Edition. Civetta JM, Taylor RW, Kirby RR (Eds). Philadelphia, PA, JB Lippincott, 1992, pp 1449 1466 5. Heffner JE, Sahn SA: Controlled hyperventilation in patients with intracranial hypertension. Application and management. Arch Intern Med 1983; 143:765769 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 725745 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; 9:141146 9. Cold GE: Cerebral blood ow in acute head injury. The regulation of cerebral blood ow and metabolism during the acute phase of head injury, and its signicance 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 analysis of the BrainIT database. Intensive Care Med 2008; 34:1676 1682 11. Carney NA, Ghajar J: Guidelines for the

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

management of severe traumatic brain injury. Introduction. J Neurotrauma 2007; 24(Suppl 1):S1S2 Brain Trauma Foundation: Use of hyperventilation in the acute management of severe pediatric traumatic brain injury. Pediatr Crit Care Med 2003; 4:45 47 Marion DW, Spiegel TP: Changes in the management of severe traumatic brain injury: 19911997. Crit Care Med 2000; 28: 16 18 Greisen G, Munck H, Lou H: Severe hypocarbia in preterm infants and neurodevelopmental decit. Acta Paediatr Scand 1987; 76:401 404 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 Davis DP, Heister R, Poste JC, et al: Ventilation patterns in patients with severe traumatic brain injury following paramedic rapid sequence intubation. Neurocrit Care 2005; 2:165171 Thomas SH, Orf J, Wedel SK, et al: Hyperventilation in traumatic brain injury patients: Inconsistency between consensus guidelines and clinical practice. J Trauma 2002; 52:4752 Warner KJ, Cuschieri J, Copass MK, et al: The impact of prehospital ventilation on outcome after severe traumatic brain injury. J Trauma 2007; 62:1330 1336 Cauleld EV, Dutton RP, Floccare DJ, et al: Prehospital hypocapnia and poor outcome after severe traumatic brain injury. J Trauma 2009; 66:15771582 Zwienenberg M, Muizelaar JP: Severe pediatric head injury: The role of hyperemia revisited. J Neurotrauma 1999; 16:937943 Harrington T, Di Chiro G: Effect of hypocarbia and hypercarbia in experimental brain infarction. A microangiographic study in the monkey. Neurology 1973; 23: 294 299 Diringer MN, Videen TO, Yundt K, et al: Regional cerebrovascular and metabolic effects of hyperventilation after severe traumatic brain injury. J Neurosurg 2002; 96: 103108 Imberti R, Bellinzona G, Langer M: Cerebral tissue PO2 and SjvO2 changes during moderate hyperventilation in patients with severe traumatic brain injury. J Neurosurg 2002; 96:97102 Bouma GJ, Muizelaar JP: Cerebral blood ow, cerebral blood volume, and cerebrovascular reactivity after severe head injury. J Neurotrauma 1992; 9(Suppl 1):S333S348 Fieschi C, Battistini N, Beduschi A, et al: Regional cerebral blood ow and intraventricular pressure in acute head injuries. J Neurol Neurosurg Psychiatry 1974; 37: 1378 1388 Bouma GJ, Muizelaar JP, Stringer WA, et al: Ultra-early evaluation of regional cerebral blood ow in severely head-injured patients

27.

28.

29.

30.

31.

32.

33.

34.

35. 36.

37.

38.

39.

40.

using xenon-enhanced computerized tomography. J Neurosurg 1992; 77:360 368 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 Obrist WD, Langtt TW, Jaggi JL, et al: Cerebral blood ow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg 1984; 61:241253 Heiss WD, Rosner G: Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983; 14: 294 301 van Santbrink H, Schouten JW, Steyerberg EW, et al: Serial transcranial Doppler measurements in traumatic brain injury with special focus on the early posttraumatic period. Acta Neurochir (Wien) 2002; 144: 11411149 Jaggi JL, Obrist WD, Gennarelli TA, et al: Relationship of early cerebral blood ow and metabolism to outcome in acute head injury. J Neurosurg 1990; 72:176 182 Ojha BK, Jha DK, Kale SS, et al: Transcranial Doppler in severe head injury: evaluation of pattern of changes in cerebral blood ow velocity and its impact on outcome. Surg Neurol 2005; 64:174 179 Bergsneider M, Hovda DA, Lee SM, et al: Dissociation of cerebral glucose metabolism and level of consciousness during the period of metabolic depression following human traumatic brain injury. J Neurotrauma 2000; 17:389 401 Vespa P, Bergsneider M, Hattori N, et al: Metabolic crisis without brain ischemia is common after traumatic brain injury: A combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 2005; 25:763774 Bullock R. Hyperventilation. J Neurosurg 2002; 96:157159 Diringer MN, Yundt K, Videen TO, et al: No reduction in cerebral metabolism as a result of early moderate hyperventilation following severe traumatic brain injury. J Neurosurg 2000; 92:713 Menon DK, Coles JP, Gupta AK, et al: Diffusion limited oxygen delivery following head injury. Crit Care Med 2004; 32: 1384 1390 Ito H, Ibaraki M, Kanno I, et al: Changes in the arterial fraction of human cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography. J Cereb Blood Flow Metab 2005; 25:852 857 Ito H, Kanno I, Iida H, et al: Arterial fraction of cerebral blood volume in humans measured by positron emission tomography. Ann Nucl Med 2001; 15:111116 Fortune JB, Feustel PJ, deLuna C, et al: Cerebral blood ow and blood volume in response to O2 and CO2 changes in normal humans. J Trauma 1995; 39:463 471

Crit Care Med 2010 Vol. 38, No. 5

1355

41. Wilkinson IM, Browne DR: The inuence of anaesthesia and of arterial hypocapnia on regional blood ow 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 ow, mean transit time, and vascular volume. J Appl Physiol 1971; 31:701707 43. Alberti E, Hoyer S, Hamer J, et al: The effect of carbon dioxide on cerebral blood ow and cerebral metabolism in dogs. Br J Anaesth 1975; 47:941947 44. Alexander SC, Wollman H, Cohen PJ, et al: Cerebrovascular response to Paco2 during halothane anesthesia in man. J Appl Physiol 1964; 19:561565 45. Sato M, Pawlik G, Heiss WD: Comparative studies of regional CNS blood ow autoregulation and responses to CO2 in the cat. Effects of altering arterial blood pressure and PaCO2 on rCBF of cerebrum, cerebellum, and spinal cord. Stroke 1984; 15:9197 46. Scheller MS, Todd MM, Drummond JC: Isourane, halothane, and regional cerebral blood ow at various levels of PaCO2 in rabbits. Anesthesiology 1986; 64:598 604 47. 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: Hyperventilation therapy for severe traumatic brain injury. New Horiz 1995; 3:439 447 49. Wahl M, Deetjen P, Thurau K, et al: Micropuncture evaluation of the importance of perivascular pH for the arteriolar diameter on the brain surface. Pugers Arch 1970; 316:152163 50. Kontos HA, Raper AJ, Patterson JL: Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels. Stroke 1977; 8:358 360 51. Betz E, Enzenrobb HG, Vlahov V: Interaction of H and Ca in the regulation of local pial vascular resistance. Pugers Arch 1973; 343:79 88 52. Giller CA, Bowman G, Dyer H, et al: Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993; 32: 737741 53. Lavi S, Egbarya R, Lavi R, et al: Role of nitric oxide in the regulation of cerebral blood ow in humans: chemoregulation versus mechanoregulation. Circulation 2003; 107:19011905 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 cerebrovasodilation 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

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

extracellular acidosis. J Cereb Blood Flow Metab 1993; 13:535539 Zhang F, Xu S, Iadecola C: Role of nitric oxide and acetylcholine in neocortical hyperemia elicited by basal forebrain stimulation: Evidence for an involvement of endothelial nitric oxide. Neuroscience 1995; 69: 11951204 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 Markus HS, Vallance P, Brown MM: Differential effect of three cyclooxygenase inhibitors on human cerebral blood ow velocity and carbon dioxide reactivity. Stroke 1994; 25:1760 1764 Kitazono T, Faraci FM, Taguchi H, et al: Role of potassium channels in cerebral blood vessels. Stroke 1995; 26:17131723 Nakahata K, Kinoshita H, Hirano Y, et al: Mild hypercapnia induces vasodilation via adenosine triphosphate-sensitive K channels in parenchymal microvessels of the rat cerebral cortex. Anesthesiology 2003; 99: 13331339 Lindauer U, Vogt J, Schuh-Hofer S, et al: Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2-activated potassium channels. J Cereb Blood Flow Metab 2003; 23:12271238 Austin C, Wray S: The effects of extracellular pH and calcium change on force and intracellular calcium in rat vascular smooth muscle. J Physiol 1995; 488(Pt 2):281291 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; 41:213216 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 injurya study of cerebral blood ow and metabolism. Acta Neurochir (Wien) 2006; 148:845 851 Harkin CP, Schmeling WT, Kampine JP, et al: The effects of hyper- and hypocarbia on intraparenchymal arterioles in rat brain slices. Neuroreport 1997; 8:18411844 Ishii K, Sasaki M, Yamaji S, et al: Cerebral blood ow changes in the primary motor and premotor cortices during hyperventilation. Ann Nucl Med 1998; 12:29 33 Graziani LJ, Gringlas M, Baumgart S: Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO. Clin Perinatol 1997; 24:655 675 Ikonen RS, Janas MO, Koivikko MJ, et al: Hyperbilirubinemia, hypocarbia and periventricular leukomalacia in preterm infants: Relationship to cerebral palsy. Acta Paediatr 1992; 81:802 807 Unterberg AW, Kiening KL, Hartl R, et al: Multimodal monitoring in patients with

71.

72.

73.

74.

75.

76.

77.

78. 79.

80.

81.

82.

83.

84.

85.

head injury: Evaluation of the effects of treatment on cerebral oxygenation. J Trauma 1997; 42(5 Suppl):S32S37 Nevin M, Colchester AC, Adams S, et al: Evidence for involvement of hypocapnia and hypoperfusion in aetiology of neurological decit after cardiopulmonary bypass. Lancet 1987; 2:14931495 Klinger G, Beyene J, Shah P, et al: Do hyperoxaemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed 2005; 90:F49 F52 Ruta TS, Drummond JC, Cole DJ: The effect of acute hypocapnia on local cerebral blood ow during middle cerebral artery occlusion in isourane anesthetized rats. Anesthesiology 1993; 78:134 140 McLaughlin MR, Marion DW: Cerebral blood ow and vasoresponsivity within and around cerebral contusions. J Neurosurg 1996; 85:871 876 OCain CF, Hensley MJ, McFadden ER Jr, et al: Pattern and mechanism of airway response to hypocapnia in normal subjects. J Appl Physiol 1979; 47:8 12 Domino KB, Swenson ER, Hlastala MP: Hypocapnia-induced ventilation/perfusion mismatch: A direct CO2 or pH-mediated effect? Am J Respir Crit Care Med 1995; 152(5 Pt 1):1534 1539 Domino KB, Emery MJ, Swenson ER, et al: Ventilation heterogeneity is increased in hypocapnic dogs but not pigs. Respir Physiol 1998; 111:89 100 Nunn JF: Applied Respiratory Physiology. Third Edition. London, Butterworths, 1987 Huttunen J, Tolvanen H, Heinonen E, et al: Effects of voluntary hyperventilation on cortical sensory responses. Electroencephalographic and magnetoencephalographic studies. Exp Brain Res 1999; 125:248 254 Bergsholm P, Gran L, Bleie H: Seizure duration in unilateral electroconvulsive therapy. The effect of hypocapnia induced by hyperventilation and the effect of ventilation with oxygen. Acta Psychiatr Scand 1984; 69:121128 Berson FG, Spatz M, Klatzo I: Effects of oxygen saturation and PCO2 on brain uptake of glucose analogues in rabbits. Stroke 1975; 6:691 696 Samra SK, Turk P, Arens JF: Effect of hypocapnia on local cerebral glucose utilization in rats. Anesthesiology 1989; 70: 523526 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 Coles JP, Fryer TD, Coleman MR, et al: Hyperventilation following head injury: Effect on ischemic burden and cerebral oxidative metabolism. Crit Care Med 2007; 35: 568 578 Graham EM, Apostolou M, Mishra OP, et al: Modication of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn

1356

Crit Care Med 2010 Vol. 38, No. 5

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100. 101.

piglets following hyperventilation induced ischemia. Neurosci Lett 1996; 218:29 32 Pastuszko P, Wilson DF: Activation of tyrosine hydroxylase in striatum of newborn piglets in response to hypocapnic ischemia and recovery. Adv Exp Med Biol 1997; 411: 6573 Hood VL, Tannen RL: Protection of acidbase balance by pH regulation of acid production. N Engl J Med 1998; 339:819 826 Skippen P, Seear M, Poskitt K, et al: Effect of hyperventilation on regional cerebral blood ow in head-injured children. Crit Care Med 1997; 25:14021409 Coles JP, Minhas PS, Fryer TD, et al: Effect of hyperventilation on cerebral blood ow in traumatic head injury: Clinical relevance and monitoring correlates. Crit Care Med 2002; 30:1950 1959 Buunk G, van der Hoeven JG, Meinders AE: Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke 1997; 28:1569 1573 Bickler PE, Julian D: Regional cerebral blood ow and tissue oxygenation during hypocarbia in geese. Am J Physiol 1992; 263(2 Pt 2):R221R225 Liem KD, Kollee LA, Hopman JC, et al: The inuence of arterial carbon dioxide on cerebral oxygenation and haemodynamics during ECMO in normoxaemic and hypoxaemic piglets. Acta Anaesthesiol Scand Suppl 1995; 107:157164 Kamei A, Ozaki T, Takashima S: Monitoring of the intracranial hemodynamics and oxygenation during and after hyperventilation in newborn rabbits with near-infrared spectroscopy. Pediatr Res 1994; 35:334 338 Stoddart JC: Electroencephalographic activity during voluntarily controlled alveolar hyperventilation. Br J Anaesth 1967; 39:2 Dager SR, Strauss WL, Marro KI, et al: Proton magnetic resonance spectroscopy investigation of hyperventilation in subjects with panic disorder and comparison subjects. Am J Psychiatry 1995; 152:666 672 Marion DW, Puccio A, Wisniewski SR, et al: Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate, and local cerebral blood ow in patients with severe traumatic brain injury. Crit Care Med 2002; 30:2619 2625 Ui M: A role of phosphofructokinase in pHdependent regulation of glycolysis. Biochim Biophys Acta 1966; 124:310 322 Severinghaus JW, Chiodi H, Eger EI II, et al: Cerebral blood ow in man at high altitude. Role of cerebrospinal uid pH in normalization of ow in chronic hypocapnia. Circ Res 1966; 19:274 282 Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. Second of two parts. N Engl J Med 1998; 338: 107111 Gluck SL: Acid-base. Lancet 1998; 352: 474 479 Fencl V, Vale JR, Broch JR: Cerebral blood ow and pulmonary ventilation in meta-

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

bolic acidosis and alkalosis. Scand J Clin Lab Invest Suppl 1968; 102:VIII:B Muizelaar JP, van der Poel HG, Li ZC, et al: Pial arteriolar vessel diameter and CO2 reactivity during prolonged hyperventilation in the rabbit. J Neurosurg 1988; 69:923927 Albrecht RF, Miletich DJ, Ruttle M: Cerebral effects of extended hyperventilation in unanesthetized goats. Stroke 1987; 18: 649 655 Erickson SJ, Grauaug A, Gurrin L, et al: Hypocarbia in the ventilated preterm infant and its effect on intraventricular haemorrhage and bronchopulmonary dysplasia. J Paediatr Child Health 2002; 38:560 562 Fabres J, Carlo WA, Phillips V, et al: Both extremes of arterial carbon dioxide pressure and the magnitude of uctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics 2007; 119: 299 305 Gleason CA, Short BL, Jones MD Jr: Cerebral blood ow and metabolism during and after prolonged hypocapnia in newborn lambs. J Pediatr 1989; 115:309 314 Tasker RC, Lutman D, Peters MJ: Hyperventilation in severe diabetic ketoacidosis. Pediatr Crit Care Med 2005; 6:405 411 Mykita S, Golly F, Dreyfus H, et al: Effect of CDP-choline on hypocapnic neurons in culture. J Neurochem 1986; 47:223231 Safar P, Xiao F, Radovsky A, et al: Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood ow promotion. Stroke 1996; 27:105113 Vannucci RC, Brucklacher RM, Vannucci SJ: Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Pediatr Res 1997; 42:24 29 Vannucci RC, Towghi J, Heitjan DF, et al: Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An experimental study in the immature rat. Pediatrics 1995; 95:868 874 Nomura F, Aoki M, Forbess JM, et al: Effects of hypercarbic acidotic reperfusion on recovery of myocardial function after cardioplegic ischemia in neonatal lambs. Circulation 1994; 90:321327 Laffey JG, Engelberts D, Kavanagh BP: Injurious effects of hypocapnic alkalosis in the isolated lung. Am J Respir Crit Care Med 2000; 162:399 405 North JB, Jennett S: Abnormal breathing patterns associated with acute brain damage. Arch Neurol 1974; 31:338 344 Rout MW, Lane DJ, Wollner L: Prognosis in acute cerebrovascular accidents in relation to respiratory pattern and blood gas tensions. Br Med J 1971; 3:79 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; 34:12021208 Muizelaar JP, Marmarou A, Ward JD, et al: Adverse effects of prolonged hyperventilation in patients with severe head injury: A

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

randomized trial. J Neurosurg 1991; 75: 731739 Wiswell TE, Graziani LJ, Kornhauser MS, et al: Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with highfrequency jet ventilation. Pediatrics 1996; 98:918 924 Perlman JM: White matter injury in the preterm infant: An important determination of abnormal neurodevelopment outcome. Early Hum Dev 1998; 53:99 120 Hashimoto K, Takeuchi Y, Takashima S: Hypocarbia as a pathogenic factor in pontosubicular necrosis. Brain Dev 1991; 13: 155157 Fujimoto S, Togari H, Yamaguchi N, et al: Hypocarbia and cystic periventricular leukomalacia in premature infants. Arch Dis Child 1994; 71:F107F110 Calvert SA, Hoskins EM, Fong KW, et al: Etiological factors associated with the development of periventricular leukomalacia. Acta Paediatr Scand 1987; 76:254 259 Kubota M, Matsuda F, Hashizume M, et al: Periventricular leukomalacia associated with hypocarbia. Acta Paediatr Jpn 1996; 38:57 60 Salokorpi T, Rajantie I, Viitala J, et al: Does perinatal hypocarbia play a role in the pathogenesis of cerebral palsy? Acta Paediatr 1999; 88:571575 De Rueck J: Cerebral angioarchitecture and perinatal brain lesions in premature and full term infants. Acta Neurol Scand 1984; 70:391395 Oka A, Belliveau MJ, Rosenborg PA, et al: Vulnerability of oligodendroglia to glutamate: Pharmacology, mechanisms and prevention. J Neurosci 1993; 13:14411453 Gilles FH, Leviton A, Kerr CS: Endotoxin leukoencephalopathy in the telencephalon of the newborn kitten. J Neurol Sci 1976; 27:183191 Yoon BH, Romero R, Kim CJ, et al: High expression of tumour necrosis factor and interleukin 6 in periventricular leukomalacia. Am J Obstet Gynecol 1997; 177: 406 411 Riphagen S, Bohn D: High frequency oscillatory ventilation. Intens Care Med 1999; 25:1459 1462 Plum F: Hyperpnea, hyperventilation, and brain dysfunction. Ann Intern Med 1972; 76:328 Fatunde OJ, Sodeinde O, Familusi JB: Hyperventilation-precipitated cerebrovascular accident in a patient with sickle cell anaemia. Afr J Med Med Sci 2000; 29:227228 Hovorka J: Carbon dioxide homeostasis and recovery after general anaesthesia. Acta Anaesthesiol Scand 1982; 26:498 504 Wollman SB, Orkin LR: Postoperative human reaction time and hypocarbia during anaesthesia. Br J Anaesth 1968; 40:920 926 Robinson JS, Gray TC: Observations on the cerebral effects of passive hyperventilation. Br J Anaesth 1961; 33:62 68

Crit Care Med 2010 Vol. 38, No. 5

1357

135. Murrin KR, Nagarajan TM: Hyperventilation and psychometric testing. A preliminary study. Anaesthesia 1974; 29:50 58 136. Gibson TM: Effects of hypocapnia on psychomotor and intellectual performance. Aviat Space Environ Med 1978; 49:943946 137. Harter MR: Effects of carbon dioxide on the alpha frequency and reaction time in humans. Electroencephalogr Clin Neurophysiol 1967; 23:561563 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 illness. N Engl J Med 2001; 345:107114 140. Laffey JG, Kavanagh BP: Mechanisms of disease: Hypocapnia. N Engl J Med 2002; 347: 4353 141. Kazmaier S, Weyland A, Buhre W, et al: Effects of respiratory alkalosis and acidosis on myocardial blood ow 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 beagle. Anesth Analg 1989; 69:152157 143. Gustafsson U, Sjoberg F, Lewis DH, et al: The effect of hypocapnia on skeletal muscle microcirculatory blood ow, oxygenation and pH. Int J Microcirc Clin Exp 1993; 12:131141 144. Barker SJ, Hyatt J, Clarke C, et al: Hyperventilation reduces transcutaneous oxygen tension and skin blood ow. Anesthesiology 1991; 75:619 624 145. Mascia L, Zavala E, Bosma K, et al: High tidal volume is associated with the development of acute lung injury after severe brain injury: An international observational study. Crit Care Med 2007; 35:18151820 146. Bratton SL, Davis RL: Acute lung injury in isolated traumatic brain injury. Neurosurgery 1997; 40:707712 147. Salim A, Martin M, Brown C, et al: The presence of the adult respiratory distress syndrome does not worsen mortality or discharge 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; 342:13011308 149. Trimble C, Smith DE, Rosenthal MH, et al: Pathophysiologic role of hypocarbia in posttraumatic pulmonary insufciency. 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; 110:2533 151. Oyarzu n MJ, Donoso P, Quijada D: Role of hypocapnia in the alveolar surfactant in-

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

crease induced by free fatty acid intravenous infusion in the rabbit. Respiration 1986; 49:187194 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 Kolobow T, Moretti MP, Fumagalli R, et al: Severe impairment in lung function induced by high peak airway pressure during mechanical ventilation: an experimental study. Am Rev Respir Dis 1987; 135: 312315 Laffey JG, Engelberts D, Duggan M, et al: Carbon dioxide attenuates pulmonary impairment resulting from hyperventilation. Crit Care Med 2003; 31:2634 2640 Shepard JW, Hauer D, Miyai K, et al: Lamellar body depletion in dogs undergoing pulmonary artery occlusion. J Clin Invest 1980; 66:36 42 Laffey JG, Engelberts D, Kavanagh BP: Buffering hypercapnic acidosis worsens acute lung injury. Am J Resp Crit Care Med 2000; 161:141146 Laffey JG, Honan D, Hopkins N, et al: Hypercapnic acidosis attenuates endotoxininduced acute lung injury. Am J Respir Crit Care Med 2004; 169:46 56 Laffey JG, Jankov RP, Engelberts D, et al: Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury. Am J Respir Crit Care Med 2003; 168:13831390 Laffey JG, Tanaka M, Engelberts D, et al: Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 2000; 162:22872294 Domino KB, Lu Y, Eisenstein BL, et al: Hypocapnia worsens arterial blood oxygenation and increases VA/Q heterogeneity in canine pulmonary edema. Anesthesiology 1993; 78:9199 Alexander CS, Liu SM: Effect of hypercapnia and hypocapnia on myocardial blood ow and performance in anaesthetized dogs. Cardiovasc Res 1976; 10:341348 Case RB, Greenberg H: The response of canine coronary vascular resistance to local alterations in coronary arterial PCO2. Circ Res 1976; 39:558 566 Coetzee A, Holland D, Foex P, et al: The effect of hypocapnia on coronary blood ow and myocardial function in the dog. Anesth Analg 1984; 63:991997 Foex P, Ryder WA: Effect of CO2 on the systemic and coronary circulations and on coronary sinus blood gas tensions. Bull Eur Physiopathol Respir 1979; 15:625 638 Morgan DJ, Xu CL: Effect of perfusate pH on reduction of quinidine capillary permeability by albumin in isolated perfused rat heart. Pharmaceutical Res 1994; 11: 1820 1824 Rowe GG, Castillo CA, Crumpton CW: Effects of hyperventilation on systemic and coronary hemodynamics. Am Heart J 1962; 63:6777

167. Yasue H, Nagao M, Omote S, et al: Coronary arterial spasm and Prinzmetals 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: Modications of tissular oxygenation and systemic hemodynamics after the correction of hypocapnia induced by mechanical ventilation. Rev Esp Fisiol 1994; 50:19 26 169. Kusuoka H, Backx PH, Camilion de Hurtado M, et al: Relative roles of intracellular Ca2 and pH in shaping myocardial contractile response to acute respiratory alkalosis. Am J Physiol 1993; 265(5 Pt 2): H1696 H1703 170. Wexels JC: Myocardial oxygen supply during 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 myocardial 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 hypocapnia in man. Am J Physiol 1972; 223: 1308 1312 173. Samuelsson RG, Nagy G: Effects of respiratory 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 voluntary hyperventilation. Rev Esp Fisiol 1972; 28:255259 175. Mazzara JT, Ayres SM, Grace WJ: Extreme hypocapnia in the critically ill patient. Am J Med 1974; 56:450 456 176. Wildenthal K, Fuller DS, Shapiro W: Paroxysmal atrial arrhythmias induced by hyperventilation. 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 brillation 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: Effects of respiratory and metabolic pH changes and hypoxia on ropivacaineinduced cardiotoxicity in dogs. Br J Anaesth 2000; 84:9294 180. Dziukas LJ, Vohra J: Tricyclic antidepressant poisoning. Med J Aust 1991; 154: 344 350 181. Oertel M, Kelly DF, Lee JH, et al: Efcacy of hyperventilation, blood pressure elevation, and metabolic suppression therapy in controlling intracranial pressure after head injury. J Neurosurg 2002; 97:10451053 182. Newell DW, Weber JP, Watson R, et al: Effect of transient moderate hyperventilation

1358

Crit Care Med 2010 Vol. 38, No. 5

183.

184.

185.

186.

187.

188.

189.

on dynamic cerebral autoregulation after severe head injury. Neurosurgery 1996; 39: 35 43 Steiner LA, Balestreri M, Johnston AJ, et al: Effects of moderate hyperventilation on cerebrovascular pressure-reactivity after head injury. Acta Neurochir Suppl 2005; 95: 1720 Bouma GJ, Muizelaar JP, Bandoh K, et al: Blood pressure and intracranial pressurevolume dynamics in severe head injury: Relationship with cerebral blood ow. J Neurosurg 1992; 77:1519 Hlatky R, Valadka AB, Robertson CS: Intracranial pressure response to induced hypertension: Role of dynamic pressure autoregulation. Neurosurgery 2005; 57:917923 Cruz J: The rst decade of continuous monitoring of jugular bulb oxyhemoglobin saturation: Management strategies and clinical outcome. Crit Care Med 1998; 26:344 351 Cruz J, Jaggi JL, Hoffstad OJ: Cerebral blood ow, vascular resistance, and oxygen metabolism in acute brain trauma: Redening the role of cerebral perfusion pressure? Crit Care Med 1995; 23:14121417 Gupta AK, Hutchinson PJ, Al-Rawi P, et al: Measuring brain tissue oxygenation compared with jugular venous oxygen saturation for monitoring cerebral oxygenation after traumatic brain injury. Anesth Analg 1999; 88:549 553 Cardoso ER, Kupchak JA: Evaluation of in-

190.

191.

192.

193.

194.

195.

196.

197.

tracranial pressure gradients by means of transcranial Doppler sonography. Acta Neurochir Suppl (Wien) 1992; 55:15 Mindermann T, Gratzl O: Interhemispheric pressure gradients in severe head trauma in humans. Acta Neurochir Suppl 1998; 71: 56 58 Sahuquillo J, Poca MA, Arribas M, et al: Interhemispheric supratentorial intracranial pressure gradients in head-injured patients: Are they clinically important? J Neurosurg 1999; 90:16 26 Lundberg N, Kjallquist A, Bien C: Reduction of increased intracranial pressure by hyperventilation. A therapeutic aid in neurological surgery. Acta Psychiatr Scand Suppl 1959; 34:1 64 Gelb AW, Craen RA, Rao GS, et al: Does hyperventilation improve operating condition during supratentorial craniotomy? A multicenter randomized crossover trial. Anesth Analg 2008; 106:585594 Schierhout G, Roberts I: Hyperventilation therapy for acute traumatic brain injury. Cochrane Database Syst Rev 2000; 2:CD000566 Iida K, Takashima S, Takeuchi Y: Etiologies and distribution of neonatal leukomalacia. Pediatr Neurol 1992; 8:205209 Hashimoto K, Kida Y, Takeuchi Y: Prognosis of periventricular echodensitiesIts relationship with periventricular leukomalacia. No To Hattatsu 1993; 25:412 416 Jamison JP, Glover PJ, Wallace WF: Com-

198.

199.

200.

201.

202.

203.

204.

parison of the effects of inhaled ipratropium bromide and salbutamol on the bronchoconstrictor response to hypocapnic hyperventilation in normal subjects. Thorax 1987; 42:809 814 Kolbe J, Kleeberger SR, Menkes HA, et al: Hypocapnia-induced constriction of the canine peripheral airways exhibits tachyphylaxis. J Appl Physiol 1987; 63:497504 Reynolds AM, McEvoy RD: Tachykinins mediate hypocapnia-induced bronchoconstriction in guinea pigs. J Appl Physiol 1989; 67:2454 2460 Reynolds AM, Zadow SP, Scicchitano R, et al: Airway hypocapnia increases microvascular leakage in the guinea pig trachea. Am Rev Resp Dis 1992; 145:80 84 Noble WH, Kay JC, Fisher JA: The effect of PCO2 on hypoxic pulmonary vasoconstriction. Can Anaesth Soc J 1981; 28:422 430 Neill WA, Hattenhauer M: Impairment of myocardial O2 supply due to hyperventilation. Circulation 1975; 52:854 858 Staubli M, Vogel F, Bartsch P, et al: Hyperventilation-induced changes of blood cell counts depend on hypocapnia. Eur J Appl Physiol 1994; 69:402 407 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 stenosis. Masui 1992; 41:221224

Crit Care Med 2010 Vol. 38, No. 5

1359