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Vlaams Diergeneeskundig Tijdschrift, 2010, 79 Theme: brain perfusion 179

Brain perfusion part 2: and brain perfusion in small animals

Hersenperfusie deel 2: anesthesie en hersenperfusie bij kleine huisdieren

1T. Waelbers, 2K. Peremans, 2I. Gielen, 2S. Vermeire, 1I. Polis

1 Department of Medicine and Clinical Biology of Small Animals Faculty of Veterinary Medicine, University of Ghent 2 Department of Medical Imaging of Domestic Animals and Small Animal Orthopedics Faculty of Veterinary Medicine, University of Ghent Salisburylaan 133, 9820 Merelbeke,

[email protected]

ABSTRACT and can influence cerebral metabolism and respiratory and cardiovascular dynamics, which results in changes in cerebral perfusion. This is of major importance when functional brain imaging techniques are used to measure cerebral blood flow or to evaluate neurotransmitter systems, and also during neurosurgery. In the present review, the influences on brain perfusion of different sedatives including and anesthetics commonly used in veterinary medicine are summarized.

SAMENVATTING Sedativa en anesthetica kunnen de ventilatie, het cardiovasculaire systeem en het metabolisme van de hersenen beïnvloeden. Dit kan resulteren in veranderingen in de hersendoorbloeding, hetgeen van belang kan zijn wanneer functionele beeldvormingstechnieken gebruikt worden om de hersenperfusie te meten, om neurotransmittersystemen te beoordelen of ook tijdens neurochirurgie. In dit tweede deel over hersenperfusie wordt de invloed van diergeneeskundig regelmatig gebruikte sedativa, opiaten en anesthetica op de hersenperfusie besproken.

INTRODUCTION predict. Most anesthetics cause an inhibition of the neuronal activity, resulting in decreased cerebral me- Knowledge of the influences of anesthetics on cere- tabolism, which in turn causes the cerebral vessels to bral blood flow (CBF) and metabolism is an important constrict. Simultaneously, these anesthetics can induce issue in human medicine, especially for patients with hypoventilation, accompanied by hypercapnia, or hy- elevated or who are scheduled for potension. Both hypoventilation and in- neurosurgery. The main goal of the anesthesiologist in duce vasodilation or at least blunt the vasoconstriction these cases is to prevent the occurrence of secondary resulting from the formerly mentioned decreased me- brain injuries and cerebral ischemia (Audibert et al., tabolism. Another concern is the change in cerebral 2005; Van Aken and Van Hemelrijck, 1991). In addi- blood flow in a region dependant manner induced by tion, it is important to be aware of the effect of seda- some agents (Schlunzen et al., 2006). tives or anesthetics on the regional or global brain per- Since anesthesia is mandatory in veterinary medi- fusion when functional brain imaging modalities to cine for procedures where cerebral blood flow is mea- assess (regional) cerebral blood flow (rCBF) are ap- sured, the effects of commonly used sedatives and plied in veterinary patients (Peremans et al., 2001). Fi- anesthetics on the cerebral blood flow are reviewed in nally, altered cerebral circulation induced by anesthe- the present paper. sia can influence the disposability of the radioligands when neurotransmitter systems are evaluated using Influence of α2-agonists specific radioligands, as already reported in (Has- soun et al., 2003). Alpha2-agonists induce a reliable dose dependent Sedatives and anesthetics affect not only the cere- sedation, analgesia and muscle relaxation, and are bral metabolism, but also the respiratory and cardio- widely used in veterinary medicine. The α2-receptors vascular dynamics. All these parameters have clear are located both in neuronal and also in non-neuronal influences on the cerebral blood flow. Consequently, tissues, including in the vascular endothelium and the administration of anesthetics can be accompanied platelets throughout the body; norepinephrine (NE) is by several, sometimes opposing influences on the cere- the most important endogenous ligand for these re- bral blood flow, whereby the final effect is difficult to ceptors (Kanawati et al., 1986; Tsukahara et al., 1986). 180 Vlaams Diergeneeskundig Tijdschrift, 2010, 79

All norepinephrine receptors can be postsynaptic systolic and diastolic pressure, surprisingly this mixture heteroreceptors, but only the α2-receptors can act as did not significantly change the intracranial pressure presynaptic autoreceptors, producing a negative feed- (Keegan et al., 1995). back regulatory signal when stimulated. The most im- In contrast, , which is the S-enan- portant effect of α2- stimulation in the central tiomer of medetomidine, was reported to induce a sig- nervous system is an inhibition of the release of NE, re- nificant decrease in CBF in or sulting in decreased centrally mediated sympathetic ac- anesthetized . However, this decrease in CBF tivity and sedation (Aghajanian and Vandermaelen, could not be associated with a significant increase in 1982; Bhana et al., 2000; Kamibayashi and Maze, mean arterial pressure or a change in the cerebral meta- 2000; Lipscombe et al., 1989; Prielipp et al., 2002; bolic rate of oxygen (CMRO2), most likely because Stahl, 2008). dexmedetomidine was administered as a continuous in- Alpha2-agonists cause an initial peripheral vaso- fusion over 15 minutes. Therefore, the observed CBF constriction, which leads to increased blood pressure, decrease was presumably induced by the occurrence of which in turn causes a reflex bradycardia. The cen- an α2-receptor-mediated vasoconstriction. In addition, trally induced decrease of the sympathetic nervous the possibility of the inhibition of specific brain regions tone also leads to a decreased heart rate and blood with dense concentrations of α2-receptors has also been pressure. Since hypotension was not reported in clini- mentioned (Karlsson et al., 1990; Prielipp et al., 2002; cal studies in dogs, this species might be more sensi- Zornow et al., 1990). The reduction of the volatile tive for the vasoconstrictor effects of α2-agonists com- anesthetic induced vasodilation by dexmedetomidine pared to humans (Khan et al., 1999; Lemke, 2007; was further confirmed in a closed cranial window CBF Murrell and Hellebrekers, 2005; Pypendop and Ver- study in dogs, where the reduction in diameter of pial stegen, 1998). vessels after the intravenous administration of Overall, α2-agonists have cerebral protecting pro - dexmedetomidine was more striking in arterioles than perties as they decrease intracranial pressure (ICP) by in venules and was not dose dependent (Ohata et al., reducing cerebral blood volume. Since most of the 1999). However, cerebral pial venules tended to exhibit blood volume is situated in the venous compartment more prominent constriction compared to arterioles and α2-agonists are potent vasopressors on the venous when dexmedetomidine was administered topically in side of the cerebral pial circulation, a decrease in ICP man, while an opposite effect was noticed in the spinal can be expected. However, a possible autoregulatory vessels. As not only the pial vessels but also the intra- response can counteract the previously mentioned parenchymal arterioles play a role in the regulation of intrinsic effect of α2-agonists on the cerebral perfusion the CBF, conclusions regarding the CBF cannot be (Iida et al., 1999; Ter Minassian et al., 1997). Systemic made by observing only the pial vessel diameters (Iida administration of α2-agonists not only decreases global et al., 1999). CBF but also limits hypercapnia- and -induced Apparently, the vasoconstrictive effects of α2-ago- cerebral vasodilation (Fale et al., 1994; McPherson et nists are of greater importance for the cerebral vascu- al., 1994; Zornow et al., 1990). lature than the autoregulatory mechanisms, resulting in decreased CBF and ICP. Influence of Administration of xylazine in isoflurane anes- thetized rats was reported to induce a region-dependent As benzodiazepines can cause dysphoria and exci- reduction in CBF (largest reduction in the hypothala- tation after intravenous administration in small animals, mus and septum, smallest reduction in the caudate these drugs are seldom used as a sole in these putamen) (Lei et al., 2001). This reduction in CBF species (Court and Greenblatt, 1992; Covey-Crump could partly be explained by the well known effects of and Murison, 2008; Ilkiw et al., 1996; Stegmann and xylazine on the cardiac output, the Bester, 2001). However, these drugs are routinely used and the cerebral perfusion pressure, but also by direct in combination with other sedatives, injectable anes- effects on central and peripheral α2-receptors. Whether thetics and because of their good muscle re- the coupling between CBF and the cerebral metabolic laxant effect and limited effects on cardiovascular and rate of oxygen consumption (CMRO2), which is a re- pulmonary functions. Benzodiazepines are also fre- flection of the oxygen requirements for the brain, re- quently used as anticonvulsants (Itamoto et al., 2000; mains intact under anesthesia including xylazine was Lemke, 2007). left unclear. In a model of intracranial hypertension in Benzodiazepines produce most of their pharmaco- dogs, a significant dose-dependent decrease in ICP af- logical effects by modulating the γ-aminobutyric acid ter administration of xylazine was also demonstrated (GABA)-mediated neurotransmission. GABA is a pri- (Mccormick et al., 1993). mary inhibitory neurotransmitter in the mammalian nervous system since cell membranes of most central Medetomidine and dexmedetomidine nervous system neurons express GABA receptors (Tanelian et al., 1993). When benzodiazepines interact Although the racemic mixture of medetomidine ad- with these specific receptors, the GABA-mediated ministered in isoflurane anesthetized dogs was re- ion conductance is potentiated so the net re- ported to be accompanied by significant increases in sult is enhancement of GABA-mediated inhibitory Vlaams Diergeneeskundig Tijdschrift, 2010, 79 181 synaptic events. As inhibitory changes in neuron ac- man et al., 1993; Matsumiya and Dohi, 1983; Werner tivity of a certain brain region result in decreased re- et al., 1992). gional cerebral blood flow (rCBF) and because of the In conclusion, CBF remains stable or may possibly widespread distribution of GABAergic neurons and decrease after the administration of opioids, on the their corresponding receptors, changes in rCBF can be condition that blood pressure and arterial carbon dio - seen after the administration of benzodiazepines xide tension are kept constant. (Matthew et al., 1995). The administration of benzo- diazepines was indeed associated with decreases in Influence of injectable anesthetics rCBF and glucose utilization in an experimental rat study (Kelly et al., 1986). Moreover, different benzo- Most injectable anesthetic drugs used in veterinary diazepines, including , and lo- medicine (i.e. , , and razepam, significantly reduced both CBF and the cere- ) alter the transmission mediated by the in- bral metabolic rate in humans, dogs and piglets hibitory neurotransmitter GABA (GABAA more speci - (Ahmad et al., 2000; Forster et al., 1982; Roald et al., fically). Prediction of activity and individual drug phar- 1986; Yeh et al., 1988). In another human study, this ef- macology is complicated by the existence of several fect was proven to be mediated, at some level, through GABAA-receptor subunits and drug-specific diffe- the site located on the GABA receptor, rences in GABAA activity (Branson, 2007; Lambert et since , the classic benzodiazepine antagonist, al., 2003; Muir et al., 2009). Overall, barbiturates, was able to reverse this effect. The largest reductions propofol, etomidate and alfaxalone decrease neuronal in rCBF were seen in the thalamus, a region where, sur- activity, thus decreasing the demand for oxygen by the prisingly, the density of benzodiazepine binding sites brain. As metabolism is coupled to CBF, a parallel de- is the lowest. This finding suggests that benzodia - crease in CBF occurs, resulting in a decline of ICP zepines produce changes in the activity of neurons in (Bazin, 1997; Kaisti et al., 2003; Werner, 1995). regions removed from but connected to areas of high binding site density (Matthew et al., 1995). Barbiturates As benzodiazepines produce only minimal effects on cardiovascular and pulmonary functions in dogs, a Barbiturates administered at lower concentrations change in CBF is not induced by changes in arterial cause a neuronal depression by decreasing the rate of partial pressure of oxygen or carbon dioxide or by dissociation of GABA from the GABA receptor. How- fluctuations in blood pressure (Haskins et al., 1986; ever, at higher concentrations they start to activate di- Hellyer et al., 1991; Jones et al., 1979). rectly the chloride ion channel associated with the GABA receptors (Dunwiddie et al., 1986; Huidobro- Influence of opioids toro et al., 1987; Schwartz et al., 1985). In humans and dogs, barbiturates were reported to produce a 50% re- Opioids are frequently used in man and animals in duction in CBF and cerebral metabolism, while cere- combination with sedatives or anesthetics for their po- brovascular reactivity to carbon dioxide was mostly tent effects. They exert their effect on cere- maintained (Akca, 2006; Kassell et al., 1981). Fur- bral hemodynamics mainly through the cardiorespira- thermore, thiopental in humans and in tory changes that they induce. However, most opioids dogs were shown to decrease the CBF, together with a have minimal effects in animals on cardiac output, decrease in cerebral oxygen demand (Chin et al., 1983; cardiac rhythm and arterial blood pressure when clin- Pierce et al., 1962). ically relevant analgesic doses are administered (La- mont and Mathews, 2007). The responsiveness of the Propofol brain-stem respiratory centers to carbon dioxide, on the other hand, is of importance. Indeed, opioids can de- Propofol, an injectable anesthetic unrelated to bar- crease this responsiveness, especially during general biturates, induces depression of the central nervous anesthesia, causing a marked hypercapnia, which re- system by enhancing the effects of the inhibitory neu- sults in an increase in CBF (Akca, 2006; Cullen et al., rotransmitter GABA (Concas et al., 1991). 1999; Lamont and Mathews, 2007). Different studies in healthy human subjects showed Another important issue relating to the use of opi- reductions in CBF, CMRO2 and cerebral blood volume oids in small animals is the occurrence of hypotension, (CBV) after the administration of propofol (Byas- which can influence cerebral hemodynamics (Bedell et Smith et al., 2002; Alkire et al., 1995; Fiset et al., 1999; al., 1998; Lamont and Mathews, 2007; Matsumiya Kaisti et al., 2003; Vandesteene et al., 1988). The re- and Dohi, 1983; Werner et al., 1992). However, several ported reductions in CMRO2 were greater than the one human studies have confirmed that ICP does not in- observed after the administration of thiopental with less crease after the administration of opioids when CO2 cerebral vasoconstriction and reduction of CBF (New- and blood pressure are kept constant (Albanese et al., man et al., 1995). These findings were suggestive that 1997; Bazin, 1997; Bourgoin et al., 2005; Paris et al., propofol might be more justified in relation to the 1998). Studies in dogs showed a decrease in CBF and cerebral oxygen supply/demand ratio. CMRO2, but a stable or even decreased ICP when Similar to its effect in man, propofol was reported , or were adminis- to decrease CBF and CMRO2 in dogs with preservation tered during halothane or isoflurane anesthesia (Hoff- of the vasoconstrictor reflex to hypocapnia. However, 182 Vlaams Diergeneeskundig Tijdschrift, 2010, 79 the autoregulation was impaired, but only at high conscious parts of the brain. There is also evidence of propofol concentrations (Artru et al., 1992). The re- a dissociation between the thalamus and limbic system duction of CBF was dose dependent until electro- (Lin, 2007). Antagonism at the N-methyl-D-aspartate encephalogram (EEG) isoelectricity was obtained and (NMDA) receptor has been proposed as the most likely was also coupled to a reduced cerebral metabolism. molecular mechanism responsible for the anesthetic However, when the larger doses required to obtain and analgesic effects of ketamine. isoelectricity were administered, no further reduction Ketamine does not cause changes in CMRO2 and in cerebral metabolism was observed (Artru et al., CBF in the whole brain. Only regional increases in 1992). In contrast, exceedingly large doses of propofol CMRO2, CBF and glucose utilization have been re- in humans can even increase CBF due to the drug’s in- ported in rats (Cavazzuti et al., 1987; Chi et al., 1994). trinsic vasodilator effect (Akca, 2006). Propofol also However, the influence of ketamine on cerebral he- decreased the ICP in an experimental model of cerebral modynamics depends also on the ventilation mode ap- in cats, (Nimkoff et al., 1997). plied during anesthesia. CBF increases in sponta- Similar to the study by Artru et al. (1992) in dogs, neously breathing human volunteers, but not when cerebral autoregulation and the response to hypercap- ventilation is controlled (Himmelseher and Durieux, nia were reported to be maintained in humans. Only the 2005). This increase in CBF during spontaneous ven- effect of hypocapnia for decreasing CBF may be tilation was also reported in cats and might be caused blunted in patients receiving propofol infusion for the by sympathetically induced hypertension related to maintenance of anesthesia (Conti et al., 2006; Karsli et the occurrence of hypercapnia (Bazin, 1997; Hassoun al., 2004; Van Aken and Van Hemelrijck, 1991). et al., 2003; Lin, 2007). Increased CBF can also be a direct result of hypercapnia because ketamine only Etomidate blunts the cerebrovascular reactivity to CO2 in isoflu- rane anesthetized humans (Nagase et al., 2001). Keta- The derivative etomidate appears to work mine decreased the cerebrovascular reactivity only to through GABA receptor activation in a similar way as some extent and did not block the mechanism com- propofol (Blednov et al., 2003; Lingamaneni and Hem- pletely in spontaneously breathing anaesthetized dogs mings, 2003; Vanlersberghe and Camu, 2008). Etomi- (Ohata et al., 2001). date administered in dogs as a continuous rate infusion The results of studies under controlled ventilation induced decreases in CBF and CMRO2; the decrease of are more conflicting. A significant increase in CBF in CMRO2 continued until the onset of an isoelectric ventilated humans after the administration of subanes- electroencephalogram. The decrease in CBF seemed to thetic doses of racemic ketamine as well as of the S- be the result of a potent intrinsic vasoconstrictive effect enantiomer of ketamine was reported without changes of the drug, as it was not coupled to the decrease in in CMRO2 or glucose metabolic rate (Langsjo et al., CMRO2 (Milde et al., 1985). 2003; Langsjo et al., 2005). Similar results were re- ported in ventilated (Oren et al., 1987). On the Alfaxalone other hand, ketamine caused a decrease in CMRO2 with no change in CBF in ventilated goats (Schwedler Recently, a new formulation of alfaxalone in a cyl- et al., 1982). codextran solution has been developed for use in small The influence of ketamine on cerebral hemody- animals (Alfaxan®, Vétoquinol UK Limited, Buck- namics depends on the combination with other seda- ingham, UK). The effects of this formulation on cere- tive/anesthetic drugs that is used. When ketamine was bral hemodynamics are not known. However, because combined with midazolam in human patients with se- alfaxalone also modulates GABAA receptors, and con- vere head injury that were being mechanically venti- sidering the properties of the older alfaxalone-al- lated (controlled mode), intracranial and cerebral per- fadolone combination in cats and humans, a decrease fusion pressures were maintained to the same extent as in CBF is most likely to occur after the administration when the combination of midazolam with sufentanil of alfaxalone (Baldy-Moulinier et al., 1975; Bendtsen was used. However, with the increasing trend to use va- et al., 1985; Rasmussen et al., 1978; Sari et al., 1976). sopressors to control arterial pressure in the sufentanil group, more fluids were needed (Bourgoin et al., 2003). In conclusion, all four injectable anesthetic agents Ketamine was even associated with a significant de- decrease the oxygen requirements of the brain suffi- crease in ICP when a propofol infusion was used in ciently to provide favorable cerebral protection, al- ventilated patients (Albanese et al., 1997). On the other though propofol decreases CMRO2 to a greater extent hand, ketamine may increase CBF in the presence of compared to etomidate or thiopental. As autoregulation in man, even under controlled ventilation is preserved or a specific drug, namely etomidate, has (Takeshita et al., 1972). Although ketamine reduced the intrinsic cerebral vasoconstrictive effects, CBF is re- isoflurane induced cerebral vasodilation during isoflu- duced after administration of each of these drugs. rane anesthesia in rabbits, an increase or no change in CBF was reported in humans when ketamine was Influence of ketamine added to isoflurane anesthesia (Mayberg et al., 1995; Nagase et al., 2003; Strebel et al., 1995).Moreover, nei- Ketamine is a anesthetic which in- ther topical nor systemic administration of ketamine in- terrupts ascending transmission from unconscious to duced changes in pial arteriolar diameter in dogs anes- Vlaams Diergeneeskundig Tijdschrift, 2010, 79 183 thetized with pentobarbital or isoflurane (Ohata et al., (Algotsson et al., 1988; Hansen et al., 1989; Kuroda et 2001). al., 1996; Oshima et al., 2003; Scheller et al., 1990). Apparently, several factors such as the dosage of ke- Since not all volatile anesthetics suppress the brain me- tamine, the ventilation method, the presence of back- tabolism to the same extent, this difference has been ac- ground anesthesia and species differences contribute to cepted as another confounding factor resulting in the the differences observed. Consequently, ketamine recorded CBF alterations. causes an increase rather than a decrease in CBF, pro- Volatile anesthetics have both a direct intrinsic bably because ketamine does not induce a generalized dilating effect on cerebral vessels and an indirect ex - suppression of the brain metabolism. Additionally, the trinsic constricting effect related to the depression of possibility of regional changes has been mentioned by the brain metabolism (Hans and Bonhomme, 2006; several authors. Ogawa et al., 1997). Consequently, the decrease in cerebral blood flow due to the decreased cerebral Influence of nitrous oxide (N2O) metabolism is less than expected because of this direct vasodilating effect. The intrinsic vasodilating effect is Although N2O has clear analgesic properties, it is dose dependent and more pronounced for halothane not an anesthetic agent for sole use in man or animals, and compared to isoflurane and as it is not potent enough to anesthetize a fit, healthy (De Deyne et al., 2004; Hansen et al., 1989; Kuroda individual. Since the potency of N2O in animals is et al., 1996; Matta and Lam, 1995; Matta et al., 1999; only about half that which has been established in hu- Ogawa et al., 1997). The weaker intrinsic vasodilatory mans, N2O in veterinary clinical practice is primarily action of sevoflurane also explains the well maintained an anesthetic adjuvant (Steffey and Mama, 2007). cerebral autoregulation and cerebrovascular CO2 N2O was reported to induce an increased CBF in reactivity, as well as the constant intracranial pressure, people and goats when used alone (30% to 70% inspi - in both Sevoflurane anesthetized humans and dogs ratory concentration) (Aono et al., 1999; Field et al., (Artru et al., 1997; Cho et al., 1996; Gupta et al., 1997; 1993; Pelligrino et al., 1984). In combination with Takahashi et al., 1993). These characteristics make sevoflurane (1 MAC) or propofol, nitrous oxide also sevoflurane the volatile anesthetic of choice for brain increases cerebral blood flow velocity in healthy compromised patients. children (Rowney et al., 2004; Wilson-Smith et al., In an awake patient or during a light plane of anes- 2003). Simi larly, inhalation of nitrous oxide caused thesia where CMR is high, the reduction in CMR increases in CBV, CMRO2 and CBF in dogs (Archer et caused by the volatile anesthetic produces a decrease al., 1987; Theye and Michenfe, 1968). in CBF (Summors et al., 1999). However, if the CMR Nitrous oxide either has a direct effect on the is already low, CBF increases by direct vasodilation. cerebral vessels or it activates certain brain regions, Therefore, flow-metabolism coupling is preserved at resulting in an increased CMRO2 (Hancock et al., low concentrations of isoflurane and sevoflurane, and 2005; Matta and Lam, 1995; Theye and Michenfe, the net effect is a reduction in CBF. When high con- 1968). Interestingly, studies in both humans and goats centrations of both volatiles are used, CBF increases showed regional differences of the effect of nitrous with a loss of cerebral autoregulation. This conclusion oxide on the CBF (Lorenz et al., 2001; Pelligrino et is supported by the observation of a reduction of CBF al., 1984). In humans, no effect on the dynamic during the administration of sevo- and desflurane, cerebrovascular response to arterial CO2 changes were compared to the awake state, both in man and in dogs observed; cerebral autoregulation, however, was im - (Mielck et al., 1998; Mielck et al., 1999). Halothane paired when N2O was administered without additional seems to be an exception as, at least in cats, CBF is as- anesthetics (Audibert et al., 2005; Girling et al., 1999). sumed to increase compared to the awake state when Unfortunately, studies of these specific issues are not using this volatile anesthetic (Hassoun et al., 2003). available in small animals. In humans, volatile anesthetics produce not only global but also regional CBF alterations due to diffe - Influence of volatile anesthetics rent effects on the anterior and posterior circulation. The location and the magnitude of these flow alter- Volatile anesthetics generally increase CBF in a ations depend on the kind of anesthetic and its con- dose-dependent manner, while progressively depress- centration (Kaisti et al., 2003; Reinstrup et al., 1995; ing cerebral metabolism, thereby challenging the clas- Schlunzen et al., 2006; Schlunzen et al., 2004). sic “neuronal activity ≈ metabolism ≈ blood flow” Besides the ability to change the tone of the cerebral paradigm (Kaisti et al., 2003; Mielck et al., 1999). The resistance vessels, volatile anesthetics can also influ- disproportion between brain perfusion and metabo- ence autoregulation, again in an anesthetic- and dose- lism becomes obvious when the CBF/CMRO2 ratio is dependent manner (De Deyne et al., 2004; Miletich et calculated. All volatile anesthetics cause an increase of al., 1976; Morita et al., 1977). When high doses of this ratio both in humans and in dogs. The increase is volatile anesthetics are administered, the cerebral ves- more pronounced when isoflurane is used, compared to sels are already maximally dilated and therefore can- halothane and sevoflurane. These differences are most not further compensate when the systemic blood pres- likely induced by the weaker vasodilating effect of sure decreases. In humans, it is generally accepted that sevoflurane, whereas some have suggested that the cerebrovascular autoregulation is maintained up to 1.5 metabolism is decreased less when halothane is used MAC, but becomes progressively impaired at higher 184 Vlaams Diergeneeskundig Tijdschrift, 2010, 79 concentrations (Akca, 2006; De Deyne et al., 2004; CONCLUSION Gupta et al., 1997; Summors et al., 1999). The response to CO2, as such, is more or less main- A review of the literature on the effects of anesthe- tained during the administration of volatile anesthetics. sia on the cerebral hemodynamics reveals that every There are two mechanisms altering the tone of the single sedative or anesthetic drug has a clear effect. cerebral vessels, and mutual interference occurs be- These products affect cerebral perfusion not only by tween them. In rats, for example, hypercapnia increases changing the tone of the cerebral vessels themselves, CBF less during isoflurane anesthesia than in the but also by changing the cerebral metabolism. These awake animal (Sicard et al., 2003). Also in dogs and effects have important consequences for the regulation cats, the vasoconstriction of the cerebral vasculature, of CBF during brain surgery. Moreover, when evalua - induced by hypocapnia, is maintained during different ting brain perfusion with imaging modalities, the use levels of isoflurane anesthesia, whereas the vasodila- of different anesthetic protocols may result in unreli- tion response to hypercarbia is impaired, but only at able results. Especially in situations where regional higher isoflurane concentrations (Drummond and cerebral blood flows are compared, anesthetic induced Todd, 1985; McPherson et al., 1989). Halothane, how- regional blood flow changes should be avoided and ever, attenuated the hypocapnia-induced vasoconstric- anesthetics causing only global changes should be pre- tion to a larger extent than isoflurane or sevoflurane in ferred. The use of anesthetics results in regional blood an in vitro study on isolated cerebral arteries flow changes possibly causing significant alterations of (Ogawa et al., 1997). distribution of the ligand in specialized neuroreceptor The data in the literature on the effects on the CBF ligand studies. To be able to compare different brain re- of all volatile anesthetics in general, and of isoflurane gions at a specific moment or to compare specific in particular, are not consistent. Because of counter- measurements in the same animal at different time acting mechanisms, dose dependency, concurrent ad- points, it is justified to avoid anesthetics causing rCBF ministration of other anesthetics, the influence of no- changes. Moreover, the use of a standardized dosage is ciception in surgical studies, different measurement extremely important for these procedures. methods and possible species differences, the results Because changes in CBF can also occur as a result obtained are often difficult to compare. A distinction of changes in arterial oxygen and carbon dioxide ten- has to be made when comparing volatile anesthetics to sions and of blood pressure, all of which are influenced one another or when comparing the awake state to by the level of anesthesia, the results are not easy to anesthetic conditions. Another important factor is the predict. Therefore these secondary changes should be duration of administration of the volatile agent, as minimized by keeping the blood pressure and the ar- CBF has been reported to decrease over time in isoflu- terial oxygen and carbon dioxide tensions within phy- rane anesthetized dogs (Brian et al., 1990; McPherson siological ranges, thereby reducing the influence of the et al., 1991). An overview of the effects of volatile anesthesia on the cerebral hemodynamics. anesthetics on brain perfusion and metabolism is pro- vided in Table 1.

Table 1. Effects of volatile anesthetics on brain perfusion and metabolism.

Anesthetic Species CBF CMRO2 Vmca Compared to Reference

Halothane ↑ Awake Hassoun et al. 2003 Halothane Cat ↑ ↓ N2O+O2 Todd and Drummond, 1984 Halothane Man ↑ Isoflurane Young et al. 1989 Halothane Baboon ↓→↑ ↓ +N2O Brüssel et al. 1991 Halothane Man ↑ ↑ +N2O Algotsson et al, 1988 Sevoflurane Man ↓ Sufentanil+N2O Artru et al. 1997 Sevoflurane Man ↑ ↓ Midazolam+fentanyl Oshima et al. 2003 Sevoflurane Man ↓ Awake Cho et al. 1996 Sevoflurane Man ↓ Awake Conti et al. 2006 Sevoflurane Man ↓ Awake Gupta et al. 1997 Sevoflurane Man ↓ ↓ Awake Mielck et al. 1999 Desflurane Dog ↑ Desflurane (lower concentration) Lutz et al. 1990 Desflurane Man ↓ ↓ Awake Mielck et al. 1998 Desflurane Pig ↑ Isoflurane Holmström and Akeson, 2003 Desflurane Dog ↓ Desflurane (lower concentration) Milde and Milde 1991 Isoflurane Cat ↔ ↓ N2O+O2 Todd and Drummond, 1984 Isoflurane Man ↑ ↓ Midazolam+fentanyl Oshima et al. 2003 Isoflurane Man ↔ ↓ Fentanyl+N2O Algotsson et al, 1988 Isoflurane Man ↓ Sufentanil+N2O Artru et al. 1997 Isoflurane Dog ↓ ↓ Isoflurane (lower concentration) Zornow et al. 1990

CMRO2: cerebral metabolic rate of oxygen consumption CBF: cerebral blood flow Vmca: middle cerebral artery flow velocity Vlaams Diergeneeskundig Tijdschrift, 2010, 79 185

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