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Home , Hypercapnia, Perfusion, Permissive hypercapnia

Optimizing the intraoperative management of Ozan Akc¸a

Purpose of review Abbreviation This review assesses whether there is a carbon dioxide CBF cerebral flow concentration range that provides optimum benefit to the patient intraoperatively. It includes the physiological # 2006 Lippincott Williams & Wilkins 0952-7907 effects of carbon dioxide on various systems in awake and anesthetized individuals and its clinical effects in the /reperfusion setting. This review will present views on end-tidal or arterial carbon dioxide Introduction tension management in the perioperative period. The normal range of carbon dioxide tension is Recent findings 35–45 mmHg. However, there are various times, how- reduces intracranial and is used by ever, when, as anesthesiologists, we accept or clinically clinicians during acute , acute tolerate hypocapnia (PaCO2 < 35 mmHg) or hypercapnia intracranial hemorrhage, and acutely growing brain (PaCO2 > 45 mmHg). Intraoperatively, in neurosurgical tumors. There is mounting evidence, however, that cases when increased is expected, improves and oxygenation. hypocapnia is generally achieved by , Therefore, clinicians may want to induce mild-to-moderate which appears to be well tolerated. In addition, in spon- hypercapnia during reperfusion states such as major taneously patients or patients undergoing vascular , organ transplantation, tissue-graft laparoscopic surgery, mild intraoperative hypercapnia is surgery, and cases managed with low mean arterial a well tolerated, but unintentional, byproduct. There- to control bleeding. As hypercapnia preserves fore, it is valid to ask whether there is an optimum car- cerebral blood flow even under relatively low perfusion bon dioxide pressure that should be maintained intrao- pressures, it may be beneficial during global reperfusion peratively, or whether carbon dioxide pressures outside scenarios. This hypothesis needs to be tested extensively the normal range provide better perfusion or any other before being considered for clinical applications. From a benefits to organ systems. This mini review aims to pre- different perspective, American Association sent the physiological effects of a wide range of clinical Guidelines recommend 12–15 breaths/min during carbon dioxide . Additionally, the poten- cardiopulmonary and stress the potential tial benefits and consequences of mild-to-moderate negative role of inadvertent hyperventilation on survival hypercapnia in different clinical environments will be outcome. The importance of this concept is discussed discussed. briefly. Summary Carbon dioxide, , tissue Overall, the benefits of managing carbon dioxide perfusion, and oxygenation concentration intraoperatively for the maintenance of Peripheral tissue perfusion and oxygenation depend on cardiac output, tissue oxygenation, perfusion, intracranial various factors, including inspired concentration, pressure, and cerebrovascular reactivity are well defined. arterial oxygen tension [1], concentration [2], cardiac output [3], local perfusion [4,5], and the Keywords • carbon dioxide, cardiac output, hypercapnia, hypocapnia, autonomic stress response to pain [6,7 ]. Different con- ischemia, oxygen, perfusion, reperfusion, tissue centrations of carbon dioxide are known to alter some of oxygenation these parameters and may contribute to tissue perfusion and oxygenation. Increasing arterial carbon dioxide ten- sion (PaCO2) by about 10 mmHg increases the cardiac # Curr Opin Anaesthesiol 19:19–25. 2006 Lippincott Williams & Wilkins. index by about 10–15% [8,9]. Hypercapnia causes a Department of and Perioperative , OUTCOMES RESEARCH rightward shift of the oxyhemoglobin dissociation Institute, and Neuroscience and Anesthesia , University of Louisville, Kentucky, USA curve, decreases systemic , and, over- all, increases oxygen availability to tissue [9]. Thus, Correspondence to Ozan Akc¸a MD, Assistant Professor, 501 East Broadway, Suite 210, Louisville, KY 40202, USA changes in carbon dioxide concentration alter tissue oxy- Tel: +1 502 852 5851; fax: +1 502 852 2610; e-mail: [email protected] genation as confirmed previously by our group [8,10] Current Opinion in Anaesthesiology 2006, 19:19–25 (Fig. 1).

19 20 Thoracic anaesthesia

Increasing PaCO2 also increases cardiac output [8,9,11], Increasing carbon dioxide concentration both stimulates which appears to be directly related to both hypercapnic and depresses the cardiovascular system [8,11,13,14]. per se and to hypercapnia-induced sympathetic Potentially, the most significant effect is myocardial activation and release of catecholamines [12]. In the depression, which is associated with an increased output awake individual hypercapnia triggers sympathetic acti- [15]. Cardiac output increases gradually by about 30–35% vation with mild tachycardia; but in anesthetized within the PaCO2 range 20–60 mmHg [8,16]. Most patients it causes only mild bradycardia ([CO2] > 10%), myocardial depression occurs at CO2 concentrations which does not generally alter [12]. greater than 10–15% (i.e., PaCO2 > 75 mmHg) [11,14]. According to the systemic vascular resistance formula, does not appear to be affected up under normal hydration status, if hypercapnia increases to a PaCO2 of 75 mmHg [14]. Hypercapnia directly cardiac output (CO) but does not change mean arterial depresses the myocardium [17,18]. Hypercapnia, how- pressure, then systemic vascular resistance has to ever, also stimulates the myocardium indirectly through decrease to maintain the equilibrium. the sympathetic nervous system activation [18,19]. In the early 1970s, Blackburn et al. [18,20] showed that CO2 had inotropic effects through β-adrenergic receptors in dogs Figure 1 (CI), muscle tissue and human patients. They concluded that the main effect (SmO2), blood flow (laser doppler flow velocity, LDF), and of hypercapnia on the heart was β-adrenergic receptor- subcutaneous tissue oxygen tension (PsqO2) all increased as a mediated inotropy, which has a threshold of between 70 linear function of PaCO2 and 100 mmHg PCO2 (Table 1).

Carbon dioxide and cerebral perfusion and oxygenation The cerebral circulation is well innervated by sympa- thetic, parasympathetic, and sensory nerves. Sympa- thetic stimulation causes constriction of the cortical con- ducting ; however, this does not appear to produce any changes in cerebral blood flow (CBF) because downstream vessels dilate, possibly as a com- pensation for the upstream constriction. The parasympa- thetic innervation is less well studied, although it has been demonstrated that stimulation of the sphenopala- tine ganglion increases CBF. Overall, the autonomic nervous system may help to determine the set point for homeostatic mechanisms [21••]. Normally, there is a relatively constant perfusion of brain tissue at perfu- sion pressures of between 50 and 150 mmHg. This auto- regulatory response may rapidly shift to the left and the right, depending on each patient’s physiology.

Carbon dioxide is a very potent modulator of CBF. There is a 3-to-5% alteration in CBF for every mmHg change in PaCO2. Hypercapnia causes cerebral vessels to vasodilate, while hypocapnia causes them to constrict. The graph of the relationship between carbon dioxide

Table 1 Summary of , oxygenation and perfusion

Mild-to-moderate hypercapnia within the clinical range linearly increases cardiac index Mild-to-moderate hypercapnia improves oxygen availability to tissue by altering cardiac index, shifting the oxyhemoglobin dissociation curve, and decreasing systemic vascular resistance Therefore, it may be preferable to allow the patient to develop mild-to- P values were obtained from linear regression formula (reproduced moderate hypercapnia in order to improve peripheral tissue from [8]). perfusion and oxygenation in cases that have the potential of severe peripheral perfusion compromise Optimum intraoperative CO2 Akca 21 and CBF is sigmoid with two plateaus, one below 25 (CPR) may exacerbate brain injury [25]. During pro- mmHg and the other above 75 mmHg (Fig. 2 [22]). longed hypocapnia, there is a decrease in extracellular Within the clinical range, however, the relationship fluid bicarbonate concentration, which results in the gra- appears to be linear. As blood pressure decreases and dual return of extracellular fluid pH toward normal. In autoregulatory occurs, there is a progressive brain tissue, this normalization of local pH also nor- reduction in carbon dioxide responsiveness. In contrast, malizes cerebral blood flow. Therefore, prolonged hypo- anesthetics, such as and isoflurane, that capnia eventually causes tolerance and might even cause induce vasodilation increase the slope of the dose– a rebound effect in intracranial pressure and lead to neu- response relationship, perhaps indicating that mechan- ronal ischemia [26]. isms that alter basal tone modify the response to CO2 [21••]. It is well known that cerebrovascular responses are mediated by nitric oxide (NO) related mechanisms; Due to the skull’s bony structure, the cranial cavity is a however, there is also evidence that the effects of hyper- fixed space, and when the volume of its contents capnia are mediated through adenosine triphosphate increases, regardless of cause (hematoma, edema, (ATP)-sensitive potassium (KATP) channels [27]. , or mass), intracranial pressure rises. Because the response to CO2 is a continuum, as recently Increased intracranial pressure may result in impaired shown by Wei and Kontos [28], so hypercapnic acidosis cerebral perfusion and brain-stem herniation. To reduce triggers KATP channel opening and hypocapnic alkalosis intracranial pressure, the volume of the cranial contents triggers channel closing. must be reduced. Hypocapnic alkalosis decreases the cerebral owing to its potent cerebral vaso- CBF is preserved better during hypercapnia than during constriction effect and, thereby, lowers intracranial pres- normocapnia or hypocapnia. Hypercapnia causes greater sure. oxygen delivery, which in turn promotes cerebral glu- cose utilization and oxidative for optimal The beneficial effects of hypocapnia on intracranial maintenance of tissue high-energy phosphate reserves pressure may be outweighed, however, by the reduced [29]. Increasing carbon dioxide increases oxygen supply [23]. There are signs that hypocapnia oxygenation in the tissues, including brain [8,30,31], and increases cerebral oxygen demand by increasing neuro- doubles CBF without causing a major change in cerebral nal excitability and seizure activity [24]. Additionally, metabolism [32]. Most of the effects of carbon dioxide hypocapnia during cardiopulmonary resuscitation on cerebroarterial blood flow are maintained by regulat- ing extracellular fluid pH [33]. Hypercapnia exhausts the cerebral vasodilator response to changes in perfusion Figure 2 CBF as a function of arterial blood- carbon pressure and reduces autoregulatory capacity. In con- dioxide partial pressure (PaCO2). trast, hypocapnia increases cerebral vascular tone and results in improved cerebral .

Carbon dioxide and cerebrovascular reactivity under general anesthesia: anesthetics Inhalation anesthetics generally increase CBF in a dose- dependent manner. At the same time, they progres- sively depress cerebral metabolism. The increase in CBF is generally more pronounced when nitrous oxide is used as an adjunct. The anesthetic-induced vaso- dilation might involve nitric oxide, ATP-dependent potassium channel related pathways, or both.

Isoflurane increases CBF in a dose-dependent fashion. The increase in subcortical CBF is reported to be greater than in neocortical. Cerebrovascular reactivity to carbon dioxide is maintained during general anesthe- sia with isoflurane, although the CBF response to carbon dioxide is greater during isoflurane anesthesia than in The CBF–PaCO2 relationship appears to be sinusoidal (reproduced from [22]). the awake state.The effects of sevoflurane and desflur- ane on CBF are similar to those of isoflurane. Generally, 22 Thoracic anaesthesia however, autoregulation is abolished as the concentra- Table 3 Carbon dioxide and cerebrovascular reactivity with tion of anesthesia increases. Cerebrovascular autoregula- intravenous anesthetics tion is adequately maintained up to 1–1.5 minimum Intravenous anesthetics reduce CBF in a dose-dependent fashion that alveolar concentration (MAC), but it is progressively is coupled to the reduction in metabolism impaired by higher concentrations. Although none of Cerebrovascular reactivity to CO2 is maintained with barbiturates and propofol the studies compared all inhalation anesthetics at the Large doses of propofol may cause vasodilation, which may overcome same time, within the inhalation anesthetics, sevoflur- the response to CO2 ane appears to increase CBF slightly more than the Hypocapnia’s ability to decrease CBF may be blunted during propofol infusion others and isoflurane appears to preserve the response Ketamine appears to preserve CBF, but blunts the response to CO2 to carbon dioxide tension changes best [21••,34–39]. Thiopental appears to be the best choice of intravenous anesthesia if the cerebrovascular reactivity to CO2 is needed intraoperatively Nitrous oxide acts as an N-methyl-D-aspartate (NMDA) receptor antagonism, and like other NMDA antagonists, it has been shown to reduce damage from excessive glu- might change either or both of these. Additionally, the tamate release. On the other hand, because NMDA also effect of hypocapnia in decreasing CBF may be blunted excites inhibitory neurons, NMDA blockade causes in patients receiving propofol infusion maintenance inhibition of gamma-aminobutyric acid (GABA) release anesthesia. Ketamine appears to preserve CBF, but and, thus, general disinhibition. When nitrous oxide is blunts the responses to carbon dioxide. Lastly, opioids administered on its own, it increases both CBF and at doses do not produce any significant effect metabolism. When used as an adjunct to another inhala- on CBF or on the response to carbon dioxide •• tion anesthetic, however, it increases CBF without chan- [43 ,44–47] (Table 3). ging metabolism. It is known to be a potent cerebral vasodilator. Its vasodilator effect may blunt the CBF Effects of carbon dioxide on respiratory response to hypocapnia when used with isoflurane or and cardiovascular systems sevoflurane as compared with isoflurane or sevoflurane In animal trials, hypocapnia and hypocapnic alkalosis alone [21••,37,39,40•,41,42] (Table 2). were shown to aggravate injury. In an isolated buf- fer-perfused rabbit lung, Laffey et al. [48] showed that Intravenous anesthetics hypocapnic alkalosis damaged previously uninjured lung Intravenous anesthetics reduce CBF in a dose-depen- tissue. Prolonged ventilation with hypocapnia, which dent fashion that is coupled to a reduction in metabo- was maintained with lower inspiratory carbon dioxide lism. Once maximal suppression of metabolism occurs, concentrations not by altering ventilation (pH ~ 7.9, •• there is also no further reduction in CBF [21 ]. PCO2 ~ 12 mmHg), increased pulmonary pres- sure, airway pressure, and wet-lung . Barbiturates produce about a 50% reduction in CBF and metabolism. Cerebrovascular reactivity to carbon diox- High ventilatory techniques cause a ide is mostly maintained in patients given barbiturates, stretch-induced acute lung injury called ventilator-asso- but the response is smaller than in the awake individual. ciated lung injury (VALI). Reducing lung stretch means Propofol also produces a coupled dose-dependent reduc- reducing volumes or pressures applied to the . tion in CBF and metabolism. If exceedingly large doses Unless is altered, smaller tidal volumes are given, however, the drug’s intrinsic vasodilator effect often lead to an elevation of PaCO2, which eventually may overcome the coupling so that CBF increases. As leads to . Smaller tidal volumes, with barbiturates, and the in addition to elevating PaCO2, prevent damage from response to carbon dioxide are maintained with propo- VALI. Permissive hypercapnia is associated with fol; however, in patients with head injury propofol use improved outcome [49,50]. Elevated concentrations of carbon dioxide might have important additive or even Table 2 Carbon dioxide and cerebrovascular reactivity with synergistic benefits independent of lung stretch [51,52]. inhalation anesthetics et al Inhalation anesthetics generally increase CBF in a dose-dependent Shibata . [53] used ischemia-reperfusion and free- manner radical injury models in isolated buffer-perfused rabbit Cerebrovascular autoregulation, including the response to CO2,is lungs to demonstrate that hypercapnic acidosis pre- maintained up to 1–1.5 MAC Sevoflurane appears to increase CBF slightly more than other vented an increase in permeability after both inhalation anesthetics types of lung injury and had no adverse microvascular Of the inhalation anesthetics, isoflurane best preserves the response effects on the uninjured lung. The mechanism of such to CO2 Nitrous oxide increases both CBF and metabolism, but preserves the protection appeared to be xanthine oxidase inhibition by response to CO2 hypercapnic acidosis. These same investigators found Optimum intraoperative CO2 Akca 23

Table 4 Hyperventilation during CPR that animals with hypercapnia (PaCO2 ~ 100 mmHg, pH ~ 7.10) had attenuated protein leakage, reduced pul- Hyperventilation increases intrathoracic pressure and decreases monary edema, improved oxygenation, and reduced coronary perfusion pressure during CPR Hyperventilation increases mortality during CPR in animals lung-tissue nitrotyrosine during ischemia-reperfusion It is recommended that the AHA guidelines are strictly followed to lung injury in an in-vivo rabbit model [54]. All of these keep respiratory rate at 12–15 breaths/min findings support the hypothesis that hypercapnic acido- sis preserves lung mechanics, attenuates pulmonary inflammation, and reduces free radical injury in the of 12–15 breaths/min during CPR [61]. Unfortunately, ischemia-reperfusion setting. professional rescuers consistently hyperventilate patients during CPR [62••], and excessive ventilation In the light of the animal studies presented above, one rates are associated with decreased survival rates in ani- •• may suggest that, compared with hypocapnia, hypercap- mals [62 ]. Even animals that received supplemental nia may protect lungs during ventilated and well per- carbon dioxide to maintain normocapnia during hyper- fused conditions as well as during non-ventilated and ventilation had survival outcomes similar to those that poorly perfused conditions. Such conditions might be were hyperventilated but allowed to develop hypocap- experienced during on-pump , glo- nia. Hyperventilation elevated intrathoracic pressures, bal ischemia/ requiring hemodynamic which decreased overall venous return to the heart, resuscitation, or even routine general anesthesia for and resulted in decreased coronary perfusion pressures upper abdominal procedures. In addition, hypercapnia during CPR. Therefore, CPR providers need to be edu- potentiates the benefits of hypoxic pulmonary vasocon- cated about the -threatening outcomes of hyperven- striction and provides better oxygen availability in tilation during CPR • anesthetized dogs [55]. [22,63 ]. The author has been informed that the Amer- ican Heart Association is considering upgrading their Hypocapnia alters myocardial oxygenation and cardiac recommendations to address this important issue rhythm. Acute hypocapnia decreases myocardial oxygen (Table 4). delivery while increasing oxygen demand, which is increased because of the greater myocardial contractility Conclusions [56] and systemic vascular resistance [57]. Thus, hypo- There are various potential advantages of managing car- capnia may contribute to clinically relevant acute coron- bon dioxide tensions intraoperatively. Most of these ary syndromes. Nomura et al. [58] tested whether hyper- potential applications are summarized in this review. capnic acidosis would provide improved recovery of the Overall, the benefits of managing carbon dioxide con- stunned myocardium. They showed that the hypercap- centration intraoperatively for the maintenance of car- nic acidotic group had the best indices of contractility, diac output and tissue oxygenation and perfusion, as coronary blood flow, and myocardial oxygen consump- well as for the maintenance of intracranial pressure and tion [58]. cerebrovascular reactivity, are well defined. It is advan- tageous to anesthesiologists to be familiar with the phy- In a recent study in postoperative cardiac surgery siological effects of carbon dioxide and manage it patients, increasing carbon dioxide pressure increased according to their patient’s situation. the cardiac index, as well as the mixed venous oxygen saturation [59]. This global oxygenation improvement compliments the previously mentioned tissue oxygena- Acknowledgements tion effects. Hypercapnia also causes a complex interac- This work was supported by NIH Grants GM 61655 and DE 14879- tion of altered cardiac output, hypoxic pulmonary vaso- 01A1 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, constriction, and intrapulmonary shunt, with the result CA), the Gheens Foundation (Louisville, KY), and the Common- wealth of Kentucky Research Challenge Trust Fund (Louisville, being a net increase in PaO2 at a given inspired oxygen KY). Dr Akc¸a is the recipient of a Research Training Grant from the concentration [60]. Foundation for Anesthesia Education and Research. The author appreciates the editorial assistance of Nancy Alsip, PhD.

Hyperventilation during cardiopulmonary . resuscitation References and recommended reading Papers of particular interest, published within the annual period of review, have Although hyperventilation does not always cause hypo- been highlighted as: capnia and CPR is not necessarily a topic that needs to • of special interest •• of outstanding interest be covered in this article, a short review of these topics Additional references related to this topic can also be found in the Current is presented because of their importance. Current Amer- World Literature section in this issue (p. 96). ican Heart Association Guidelines for CPR and emer- 1 Greif R, Akc¸a O, Horn E-P, et al. Supplemental perioperative oxygen to reduce the incidence of surgical wound infection. N Engl J Med 2000; gency cardiovascular care recommend a rate 342:161–167. 24 Thoracic anaesthesia

2 Gosain A, Rabin J, Reymond JP, et al. Tissue oxygen tension and other indi- 28 Wei E, Kontos H. Blockage of ATP-sensitive potassium channels in cerebral cators of blood loss or organ perfusion during graded hemorrhage. Surgery inhibits from hypocapnoc alkalosis in cats. 1991; 109:523–532. 1999; 30:851–854. 3 Shoemaker W, Appel P, Kram H. Oxygen transport measurements to evalu- 29 Vannucci R, Brucklacher R, Vannucci S. Effect of carbon dioxide on cerebral ate tissue perfusion and titrate therapy: dobutamine and dopamine effects. metabolism during -ischemia in the immature rat. Pediatr Res 1997; Crit Care Med 1991; 19:672–688. 42:24–29. 4 Ikeda T, Tayefeh F, Sessler DI, et al. Local radiant heating increases subcuta- 30 Akca O, Payne R, Sessler D, et al. Hypercapnic acidosis –but neither meta- neous oxygen tension. Am J Surg 1998; 175:33–37. bolic acidosis nor hypercapnia without acidosis- preconditions brain slices 5 Plattner O, Akc¸a O, Herbst F, et al. The influence of two surgical bandage to ischemia-reperfusion injury. In: American Society of Anesthesiologists; systems on wound tissue oxygen tension. Arch Surg 2000; 135:818–822. 2004. Las Vegas, Nevada: Liipincott Williams & Wilkins; 2004. et al 6 Akc¸a O, Melischek M, Scheck T, et al. Postoperative pain and subcutaneous 31 Manley G, Hemphill J, Morabito D, . Cerebral oxygenation during hemor- oxygen tension. Lancet 1999; 354:41–42. rhagic : perils of hyperventilation and therapeutic potential of hypoven- tilation. J Trauma 2000; 48:1025–1033. 7 Ragheb J, Buggy D. Editorial III: Tissue oxygen tension (PTO2) in anaesthe-  sia and perioperative medicine. Br J Anaesth 2004; 92:464–468. 32 Alberti E, Hoyer S, Hamer J, et al. The effect of carbon dioxide on cerebral A very good editorial on tissue oxygenation in the perioperative period. blood flow and cerebral metabolism in dogs. Br J Anaesth 1975; 47:941– 947. 8 Akc¸a O, Doufas A, Morioka N, et al. Hypercapnia improves tissue oxygena- tion. Anesthesiology 2002; 97:801–806. 33 Kontos H, Raper A, Patterson J. Analysis of vasoactivity of local pH, PCO2, and bicarbonate on pial vessels. Stroke 1977; 8:358–360. 9 Mas A, Saura P, Joseph D, et al. Effects of acute moderate changes in PaCO2 on global hemodynamics and gastric perfusion. Crit Care Med 34 Leon JE, Bissonnette B. Cerebrovascular responses to carbon dioxide in 2000; 28:360–365. children anaesthetized with halothane and isoflurane. Can J Anaesth 1991; 38:817–825. 10 Akca O, Liem E, Suleman M, et al. Effect of intra-operative end-tidal carbon dioxide partial pressure on tissue oxygenation. Anaesthesia 2003; 58:536– 35 Matta BF, Heath KJ, Tipping K, et al. Direct cerebral vasodilatory effects of 542. sevoflurane and isoflurane. Anesthesiology 1999; 91:677–680. 11 Andersen M, Mouritzen C. Effect of acute respiratory and metabolic acidosis 36 Nishiyama T, Matsukawa T, Yokoyama T, et al. Cerebrovascular carbon diox- on cardiac output and peripheral resistance. Ann Surg 1966; 63:161–168. ide reactivity during general anesthesia: a comparison between sevoflurane 12 Manley J, E.S. Nash C, Woodbury R. Cardiovascular responses to severe and isoflurane. Anesth Analg 1999; 89:1437–1441. hypercapnia of short duration. Am J Physiol 1964; 207:634–640. 37 Strebel S, Kaufmann M, Baggi M, et al. Cerebrovascular carbon dioxide 13 Boniface K, Brown J. Effect of carbon dioxide excess on contractile of reactivity during exposure to equipotent isoflurane and isoflurane in nitrous heart, in situ. Am J Physiol 1953; 172:752–756. oxide anaesthesia. Br J Anaesth 1993; 71:272–276. 14 Monroe R, French G, Whittenberger J. Effect of hypocapnia and hypercapnia 38 Young WL, Prohovnik I, Correll JW, et al. A comparison of cerebral blood on myocardial contractility. Am J Physiol 1960; 199:1121–1124. flow reactivity to CO2 during halothane versus isoflurane anesthesia for car- otid endarterectomy. Anesth Analg 1991; 73:416–421. 15 Wolley K, Lewis T, Wood L. Acute decreases left ventri- cular contractility but increases cardiac output in dogs. Circ Res 1990; 100: 39 Wilson-Smith E, Karsli C, Luginbuehl I, et al. Effect of nitrous oxide on cere- 102–106. brovascular reactivity to carbon dioxide in children during sevoflurane anaes- thesia. Br J Anaesth 2003; 91:190–195. 16 Cullen D, Eger E, Gregory G. The cardiovascular effects of carbon dioxide in man, conscious and during cyclopropane anesthesia. Anesthesiology 1969; 40 Cottrell J. Brain protection in neurosurgery. In: American Society of Anesthe- 31:407–413.  siologists - Anuual Meeting Refresher Course Lectures; 2004 October 23- 27, 2004; Las Vegas, Nevada. 2004. pp. 145. 17 Ng M, Levy M, Zieske H. Effects of changes of pH and of carbon dioxide tension on left ventricular performance. Am J Physiol 1967; 213:115–120. Excellent refresher course lecture notes from an expert about perioperative brain protection with excellent physiology. 18 Blackburn JP, Conway CM, Leigh JM, et al. PaCO2 and the pre-ejection per- 41 Karsli C, Wilson-Smith E, Luginbuehl I, et al. The effect of nitrous oxide on iod: the PaCO2 inotropy response curve. Anesthesiology 1972; 37:268– 276. cerebrovascular reactivity to carbon dioxide in children during propofol anesthesia. Anesth Analg 2003; 97:694–698. 19 Noble M, Trenchard D, Guz A. Effect of changes in Pa-CO2 and Pa-O2 on cardiac performance in conscious dogs. J Appl Physiol 1967; 22:147–152. 42 Matta BF, Mayberg TS, Lam AM. Direct cerebrovasodilatory effects of halothane, isoflurane, and desflurane during propofol-induced isoelectric et al 20 Blackburn JP, Conway CM, Leigh JM, . Myocardial carbon dioxide electroencephalogram in humans. Anesthesiology 1995; 83:980–985 (dis- response curves. Br J Anaesth 1970; 42:559. cussion 27A). 21 Gelb A. Control of the cerebral circulation - What clinician needs to know. 43 Karsli C, Luginbuehl I, Bissonnette B. The cerebrovascular response to  In: American Society of Anesthesiologists - Anuual Meeting Refresher  hypocapnia in children receiving propofol. Anesth Analg 2004; 99:1049– Course Lectures; 2004 October 23-27, 2004; Las Vegas, Nevada. 2004. 1052. pp. 377. An excellent original article on cerebrovascular effects of carbon dioxide under Outstanding refresher course lecture notes from an expert about clinical effects propofol anesthesia in children. This article also includes some notes about the of anesthetic agents on cerebrovascular reactivity. comparison of the effects of sevoflurane and propofol. 22 Duong T, Iadecola C, Kim S-G. Effect of , Hypercapnia, and 44 Karsli C, Luginbuehl I, Farrar M, et al. Cerebrovascular carbon dioxide reac- Hypoxia on Cerebral Interstitial Oxygen Tension and Cerebral Blood Flow. tivity in children anaesthetized with propofol. Paediatr Anaesth 2003; 13: Magn Reson Med 2001; 45:61–70. 26–31. 23 et al Weckesser M, Posse S, Olthoff U, . Functional imaging of the visual cor- et al tex with bold-contrast MRI: hyperventilation decreases signal response. 45 Kaisti KK, Langsjo JW, Aalto S, . Effects of sevoflurane, propofol, and Magn Reson Med 1999; 41:213–216. adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology 2003; 99:603–613. 24 Huttunen J, Tolvanen H, Heinonen E, et al. Effects of voluntary hyperventila- et al tion on cortical sensory responses: electroencephalographic and magne- 46 Mirzai H, Tekin I, Tarhan S, . Effect of propofol and clonidine on cerebral toencephalographic studies. Exp Brain Res 1999; 125:248–254. blood flow velocity and carbon dioxide reactivity in the middle cerebral artery. J Neurosurg Anesthesiol 2004; 16:1–5. 25 Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from car- diac arrest in dogs with mild plus blood flow promotion. Stroke 47 Nagase K, Iida H, Ohata H, et al. Ketamine, not propofol, attenuates cere- 1996; 27:105–113. brovascular response to carbon dioxide in humans with isoflurane anesthe- sia. J Clin Anesth 2001; 13:551–555. 26 Gleason C, Short B, Jones MJ. Cerebral blood flow and metabolism during and after prolonged hypocapnia in newborn lambs. J Pediatr 1989; 115: 48 Laffey JG, Engelberts D, Kavanagh BP. Injurious effects of hypocapnic alka- 309–314. losis in the isolated lung. Am J Respir Crit Care Med 2000; 162:399–405.

27 Rosenblum W, Kontos H, Wei E. Evidence for a KATP ion channel link in the 49 Amato M, Barbas C, Medeiros D, et al. Effect of protective-ventilation stra- inhibition of hypercapnic dilation of pial artrioles by 7-nitroindazole and tetro- getgy on mortality in the acute respiratory distress syndrome. N Engl J Med dotoxin. Eur J Pharmacol 2001; 417:203–215. 1998; 338:347–354. Optimum intraoperative CO2 Akca 25

50 Hickling KG, Walsh J, Henderson S, et al. Low mortality rate in adult respira- 58 Nomura F, Aoki M, Forbess J, et al. Effects of hypercarbic acidotic reperfu- tory distress syndrome using low-volume, pressure-limited ventilation with sion on recovery of myocardial function after cardiopleghic ischemia in neo- permissive hypercapnia: a prospective study. Crit Care Med 1994; 22: natal lambs. Circulation 1994; 90:321–327. 1568–1578. 59 Ali S, Hahn H, Jacobsohn E, et al. Therapeutic effects of carbon dioxide 51 Laffey J, Kavanagh B. Carbon dioxide and the critically ill - too little of a good administration following cardiac surgery. In: American Society of Anesthe- thing? Lancet 1999; 354:1283–1286. siologists (ASA) Annual Meeting; 2003 October 11-15, 2003. San Fran- cisco, CA: Lippincott Williams & Wilkins; 2003. pp. A431. 52 Laffey J, Kavanagh B. Biological effects of hypercapnia. Intensive Care Med 2000; 26:133–138. 60 Hickling K, Joyce C. Permissive hypercapnia in ARDS and its effects on tis- sue oxygenation. Acta Anaesthesiol Scand 1995; 107:201–208. 53 Shibata K, Cregg N, Engelberts D, et al. Hypercapnic acidosis may attenu- ate acute lung injury by inhibition of endogenous xanthine oxidase. Am J 61 Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardi- Respir Crit Care Med 1998; 158:1578–1584. ovascular Care: International Consensus on Science, Part I: Introduction. Circulation 2000; 102 (8 Suppl.):I1–I11. 54 Laffey JG, Tanaka M, Engelberts D, et al. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir 62 Aufderheide T, Sigurdsson G, Pirrallo R, et al. Hyperventilation-induced Crit Care Med 2000; 162:2287–2294.  during cardiopulmonary resuscitation. Circulation 2004; 109: 1960–1965. 55 Noble W, Kay J, Fisher J. The effect of PCO2 on hypoxic pulmonary vaso- Outstanding original studies on the detrimental effects of hyperventilation during constriction. Can Anaesth Soc J 1981; 28:422–430. CPR. 56 Boix JH, Marin J, Enrique E, et al. Modifications of tissular oxygenation and 63 Aufderheide T, Lurie K. by hyperventilation: a common and life-threa- systemic hemodynamics after the correction of hypocapnia induced by  tening problem during cardiopulmonary resuscitation. Crit Care Med 2004; . Rev Esp Fisiol 1994; 50:19–26. 32 (9 Suppl):S345–S351. 57 Richardson D, Kontos H, Raper A, et al. Systemic circulatory responses to An excellent review article on the detrimental effects of hyperventilation during hypocapnia in man. Am J Physiol 1972; 223:1308–1312. CPR.