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Anesth Analg 2005;101:509-516
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000160586.71403.A4

NEUROSURGICAL ANESTHESIA

Sevoflurane Impairs Cerebral Blood Flow Autoregulation in Rats: Reversal by Nonselective Nitric Oxide Synthase Inhibition

Christian Werner, MD*, Hong Lu, MD{dagger}, Kristin Engelhard, MD*, Nikolaus Unbehaun, MD{ddagger}, and Eberhard Kochs, MD{dagger}

*Klinik für Anästhesiologie, Johannes Gutenberg-Universität, Mainz; {dagger}Klinik für Anaesthesiologie and {ddagger}Chirurgische Klinik und Poliklinik, Technische Universität, München, Germany

Address correspondence and reprint requests to Kristin Engelhard, MD, Klinik für Anästhesiologie, Johannes Gutenberg-Universität, Langenbeck Str. 1, 55131 Mainz, Germany. Address e-mail to engelhak{at}uni-mainz.de.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we investigated the effects of 1.0 and 2.0 minimum alveolar anesthetic concentration (MAC) sevoflurane on cerebral blood flow (CBF) autoregulation before and after nonselective inhibition of nitric oxide (NO) synthase in rats. Rats were randomly assigned as follows: Group 1 (n = 8): 1.0 MAC sevoflurane; Groups 2 and 3 (n = 8 per group): 2.0 MAC sevoflurane. Assessment of autoregulation within a mean arterial blood pressure range of 140–60 mm Hg was performed by graded hemorrhage before and after administration of l-arginine methyl ester (l-NAME, 30 mg/kg IV, Groups 1 and 2) or during hypocapnia (Group 3). In 10 additional animals, brain tissue NO2– concentrations were measured at 1.0 and 2.0 MAC sevoflurane. CBF autoregulation was maintained with 1.0 MAC sevoflurane (Group 1) regardless of NO synthase status indicating that CBF autoregulation might not be related to NO availability. Sevoflurane dose-dependently increased brain tissue NO2– and impaired CBF autoregulation. Administration of l-NAME (Group 2) but not hypocapnia (Group 3) restored CBF autoregulation. This suggests that sevoflurane impairs the autoregulatory capacity secondary to an increase of the perivascular NO availability and questions the importance of basal cerebrovascular tone in terms of vasodilatory capacity during hypotensive challenges.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Previous data from our laboratory have shown that cerebral blood flow (CBF) autoregulation is intact in rats anesthetized with 1.0 minimum alveolar anesthetic concentration (MAC) sevoflurane whereas CBF is pressure-passive with 2.0 MAC sevoflurane (1). This observation is consistent with CBF measurements in rats, dogs, goats, and humans showing a dose-dependent impairment of CBF autoregulation with volatile anesthetics (2–5). Modulation of CBF autoregulation seems to be related to the individual resting (basal) cerebrovascular tone that is the status of smooth muscle contraction defining a particular cross-sectional area of a vessel during baseline conditions. With low basal tone (i.e., low cerebrovascular resistance induced by vasodilators such as volatile anesthetics), any decrease in cerebral perfusion pressure (CPP) cannot be compensated by further vasodilation. However, the mechanisms by which volatile anesthetics impair CBF regulation in response to CPP changes are still unclear. Whereas myogenic, metabolic, neurogenic, and endothelial factors are involved in the physiological response of cerebral vessels to CPP changes, the reduction in basal tone seen with larger concentrations of volatile anesthetics may be related to nitric oxide (NO) pathways (6,7). For example, it is possible that sevoflurane increases the production of NO by stimulating NO synthesis resulting in cerebrovascular dilation and a decrease in vasodilatory capacity as CPP decreases. It is also possible that volatile anesthetics increase the sensitivity of vascular smooth muscle to normal concentrations of NO. To test the hypothesis that resting cerebrovascular tone affects CBF autoregulation, two sets of experiments were performed. Experiment 1 investigated the dose-dependent effects of sevoflurane on CBF autoregulation in the absence and presence of nonselective NO synthase (NOS) inhibition. Because NOS inhibition causes cerebral vasoconstriction, CBF autoregulation was also tested during vasoconstriction produced by arterial hypocapnia. Experiment 2 investigated the concentration of NO metabolites in brain tissue at different concentrations of sevoflurane.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study investigating 34 rats was approved by the Institutional Animal Care Committee.

Experiment 1: CBF Autoregulation
Twenty-four male Sprague-Dawley rats (280–460 g) were anesthetized in a bell jar filled with sevoflurane. The tracheas were intubated and the lungs were mechanically ventilated (Small Animal Ventilator, Model 683; Harvard Apparatus, Holliston, MA) with 2.0 MAC sevoflurane (4.0 vol % end-tidal) plus N2O in O2 (fraction of inspired oxygen [Fio2]: 0.3) during surgery. Catheters (PE 50, ID 0.58 mm) were placed into the right femoral artery, both femoral veins, and the right jugular vein for continuous measurement of mean arterial blood pressure (MAP), drug administration, and hemorrhage. A nonpenetrating burr hole 2 mm in diameter was drilled into the cranium over the right parietal cortex 2 mm posterior to the bregma and 2 mm to the right of the midline. Red blood cell flow velocity as an index of local CBF was measured continuously using a laser Doppler flowmeter (LDF) (PeriFlux System 4001; Perimed, Stockholm, Sweden). The LDF probe (PF 403, Stainless Steel Probe; Perimed) was placed over the burr hole, avoiding a probe position next to larger cortical cerebral vessels and was then fixed in a stereotactic frame. Responsivity of the system was confirmed by transient hyperventilation. Arterial blood gases and pH were maintained at normal values. Pericranial temperature was servocontrolled at 38°C using a 22-gauge needle thermistor (Yellow Springs Instruments, Yellow Springs, OH). Upon completion of surgical preparation, N2O was stopped and the animals were randomly assigned to one of the following treatments: Animals in Group 1 (n = 8) received 1.0 MAC sevoflurane (2.0 vol % end-tidal) in O2/air (Fio2: 0.3). Animals in Group 2 (n = 8) and Group 3 (n = 8) received 2.0 MAC sevoflurane (4.0 vol % end-tidal) in O2 and air (Fio2: 0.3). Forty-five minutes was allowed for equilibration before baseline measurements. IV norepinephrine infusion was used to support baseline MAP. There were two sets of measurements: After baseline measurements at 140 mm Hg MAP, norepinephrine infusion was reduced and combined with graded hemorrhage to achieve target pressures of 120, 100, 80, and 60 mm Hg MAP for measurements of CBF autoregulation. All animals were allowed to stabilize for 8 min at each MAP target pressure before respective CBF measurements. After this first set of measurements, the withdrawn blood was reinfused over a period of 15 min to return MAP to baseline levels of 140 mm Hg in combination with norepinephrine infusion. With complete hemodynamic recovery and return of CBF to baseline values, the nonselective NOS inhibitor l-arginine methyl ester (l-NAME; 30 mg/kg IV) was administered to animals in Groups 1 and 2. Animals in Group 3 were hyperventilated to the target arterial carbon dioxide partial pressure (Paco2) of 25 mm Hg. After an equilibration period of 30 min, measurements of CBF autoregulation were repeated using graded hemorrhage to adjust MAP to target levels of 120, 100, 80, and 60 mm Hg. At the end of the experiment, the rats were killed with an IV bolus of 1% potassium chloride.

Experiment 2: Brain Tissue NO Concentrations
To determine the brain tissue concentrations of NO as a function of the anesthetic dose, 10 male Sprague-Dawley rats (310–430 g) were anesthetized and surgically prepared as above. The animals were randomly assigned to one of the following anesthetic treatments: Animals in Group 1 (n = 5) received 1.0 MAC sevoflurane (2.0 vol % end-tidal) in O2/air (Fio2: 0.3). Animals in Group 2 (n = 5) received 2.0 MAC sevoflurane (4.0 vol % end-tidal) in O2/air (Fio2: 0.3). After an equilibration period of 45 min, arterial, central venous, and cerebrospinal fluid (CSF) samples were withdrawn and immediately frozen in liquid nitrogen (–196°C). The chest of the animals was then opened and the rats were killed by injection of isotonic saline into the left cardiac ventricle. Within 2 min, the brains and hearts were removed and immediately frozen in liquid nitrogen (–196°C). The entire material was subsequently stored at –70°C for further analysis. NO synthesis was assessed by measuring blood, CSF, and tissue NO2– concentrations, which are stable end products of NO oxidation, using high-performance liquid chromatography and spectrophotometry based on the Griess reaction (8).

Statistical Analysis
Data are reported as mean ± sd. Friedman two-way analysis of variance (ANOVA) was used for comparison of changes in CBF (%) within each group. Intact CBF autoregulation was defined as changes in CBF of <15% from baseline (1). For comparisons of changes in CBF (%) between groups, Kruskal-Wallis one-way ANOVA was used. Student’s t-test with a Levene correction was used for comparison of brain NO metabolites among groups. A P value of < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Experiment 1
Table 1 shows physiological values during graded hemorrhage. There were no differences in arterial blood gases and pH over time as these variables were maintained constant with the exception of Group 3 in which Paco2 was reduced according to the study protocol. The infusion rate of norepinephrine to increase MAP and the maximal amount of withdrawn blood necessary to decrease MAP to 60 mm Hg are shown in Table 2. Table 3 provides absolute (raw) numbers of perfusion units for individual animals.


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  		Table 1. Physiological Variables During Cerebral Autoregulatory Tests

 

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  		Table 2. Amount of Norepinephrine Used to Increase Blood Pressure and Maximal Withdrawn Blood Volume at 60 mm Hg

 

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  		Table 3. Absolute (Raw) Numbers of Perfusion Units for Each Individual Animal

 

The correct LDF probe position to measure CBF within 1 mm3 of cortical tissue was confirmed by transient hyperventilation in each animal. Hyperventilation ({Delta}Paco2 = 10 mm Hg) decreased CBF in all animals to a similar extent (1.0 MAC sevoflurane: 2.7% ± 1.6%/mm Hg Paco2; 2.0 MAC sevoflurane: 2.4% ± 1.4%/mm Hg Paco2). Figures 1–3 show percentage changes in cortical CBF as a function of graded hemorrhagic hypotension. In animals anesthetized with 1.0 MAC sevoflurane (Group 1), CBF did not change within the MAP range of 140–60 mm Hg (Fig. 1). In contrast, CBF decreased with graded hemorrhagic hypotension in animals anesthetized with 2.0 MAC sevoflurane (Groups 2 and 3) indicating loss of autoregulation (Figs. 2 and 3). Infusion of l-NAME to animals anesthetized with 1.0 MAC (Group 1) and 2.0 MAC sevoflurane (Group 2) increased baseline MAP and decreased baseline CBF by 25%–30% with no further change in CBF during graded hemorrhagic hypotension indicating restoration of autoregulation in the 2.0 MAC sevoflurane group (Fig. 1 and 2). Hypocapnia was associated with a 25% decrease in CBF in Group 3 animals (2.0 MAC sevoflurane) whereas CBF further decreased with graded hemorrhagic hypotension (Fig. 3).



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  		Figure 1. Cerebral blood flow (CBF) as a function of decreasing mean arterial blood pressure (MAP) with 1.0 minimum alveolar concentration (MAC) sevoflurane before and after administration of l-arginine methyl ester (l-NAME) ($P < 0.05 versus 1.0 MAC sevoflurane at each respective MAP level). Values = mean ± sd.

 


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  		Figure 2. Changes in cerebral blood flow (CBF) with 2.0 minimum alveolar concentration (MAC) sevoflurane before and after administration of l-arginine methyl ester (l-NAME) (*P < 0.05 versus 140 mm Hg mean arterial pressure [MAP]; $P < 0.05 versus 2.0 MAC sevoflurane at each respective MAP level). Values = mean ± sd.

 


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  		Figure 3. Changes in cerebral blood flow (CBF) with 2.0 minimum alveolar concentration (MAC) sevoflurane with normo- and hypocapnia (*P < 0.05 versus 140 mm Hg mean arterial pressure [MAP]; $P < 0.05 versus normocapnia at each respective MAP level).

 

Experiment 2
The concentrations of NO2– in brain tissue, CSF, and arterial and central venous blood are shown in Figure 4. Brain tissue, myocardial, and central venous NO2–concentrations were larger with 2.0 MAC sevoflurane anesthesia compared with 1.0 MAC sevoflurane.



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  		Figure 4. NO2– concentrations for two different sevoflurane concentrations with a mean arterial pressure of 140 mm Hg (*P < 0.05 compared with 1.0 minimum alveolar concentration [MAC] sevoflurane). Values = mean ± sd.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present data show that cortical CBF autoregulation is intact with 1.0 MAC sevoflurane within the pressure range of 140–60 mm Hg MAP. In contrast, CBF autoregulation was impaired with 2.0 MAC sevoflurane along with increased NO production. In the presence of nonselective NOS inhibition with l-NAME, autoregulation was intact at both 1.0 and 2.0 MAC sevoflurane. When a second group of 2.0 MAC sevoflurane anesthetized rats was hyperventilated, autoregulation was not restored. This indicates that increased availability of NO or increased smooth muscle sensitivity to NO, rather than sheer vasodilation, is a factor in autoregulatory impairment associated with larger concentrations of sevoflurane.

Studies in laboratory animals and humans have shown that volatile anesthetics induce cerebrovascular dilation in a dose-dependent manner (1–5). This decrease in cerebrovascular tone is induced by NO. For example, studies in rats, primates, and pigs have shown that increases in CBF seen with volatile anesthetics were reversed by inhibition of NOS (9–13). This suggests that volatile anesthetics reduce cerebrovascular resistance by either increasing the availability/concentration of perivascular NO or by increasing the sensitivity of vascular smooth muscle to normal concentrations of NO. During the present experiments, brain tissue NO2– concentrations were larger with 2.0 MAC compared with 1.0 MAC sevoflurane anesthesia. This is consistent with experiments in rats showing increased concentrations of NO in cortical tissue and cerebellar microdialysate during isoflurane and sevoflurane anesthesia and indicates that increased production/release of NO is induced by volatile anesthetics (14,15).

It is thought that autoregulation of CBF is related to basal cerebrovascular tone (1,16). Low basal cerebrovascular tone i.e., preexisting cerebrovascular dilation results in a decreased capacity to vasodilate in response to low perfusion pressures whereas high cerebrovascular tone i.e., preexisting cerebral vasoconstriction expands the autoregulatory range during hypotension (16,17). However, the extent of cerebral vasoconstriction does not seem to be as important as is the mechanism by which cerebrovascular tone is determined. This is indicated by the fact that impaired CBF autoregulation was restored by the l-NAME but not hypocapnia, another cerebral vasoconstrictor. Although the extent of vasoconstriction may have differed between NOS-inhibition and hypocapnia, restoration of the autoregulatory response by l-NAME suggests mechanisms beyond just increasing cerebrovascular resistance.

The contribution of NO pathways to static and dynamic CBF autoregulation remains controversial. In vitro experiments, using isolated rat arterioles, have shown that inhibition of NO synthesis by extraluminal N-monomethyl-l-arginine (l-NMMA) application inhibited autoregulatory vasodilation in response to low transmural pressures (18). This is consistent with studies in rats subjected to NOS inhibition using N-nitro-l-arginine (NLA) in which the autoregulatory curve was shifted to the right (19). Likewise, experiments in pigs, rats, and cats have shown that administration of nonselective NOS inhibitors impaired autoregulatory cerebrovascular dilation to hypotension (20–22). In rats, selective neuronal NOS inhibition using 7-nitro indazole did not affect CBF autoregulation, which suggests that endothelial rather than neuronal NO regulates cerebrovascular responses to hypotension (23). In contrast, experiments in rats, primates, and newborn lambs subjected to hypoxia and ischemia have shown that cerebrovascular responses to subsequent arterial hypotension were not affected when NOS was inhibited using nonselective NOS inhibitors (l-NAME, l-NMMA, NLA) despite an increase in basal cerebrovascular resistance (24–29). This is consistent with the present experiments in which cerebrovascular resistance increased in the presence of l-NAME whereas CBF autoregulation was intact. The different results of these studies can be explained in part by substantial differences in methodology: regional versus global and continuous versus discontinuous CBF measurements, use of videomicroscopy to assess vascular diameter as opposed to CBF measurements, different species and hypotensive challenges (pharmacological versus hemorrhage), choice of NOS inhibitor and route of administration (intraperitoneal versus IV versus intracarotid), and background anesthetic state (awake versus volatile anesthetic versus barbiturate).

LDF measurements are sensitive to the velocity increase of red blood cells during CO2 challenges (30). Studies using cerebral intravital microscopy and LDF have shown that capillary recruitment and derecruitment relates to the extent of CO2 challenge. For example, capillary red blood cell flow was more homogenous during severe compared with moderate hypercapnia. It is, therefore, possible that the inhomogeneity of red cell blood flow during resting conditions increased as hypocapnia was induced in the present study. Likewise, LDF measurements are sensitive to changes in hematocrit as the major determinant of blood viscosity. Hemodilution increases cerebral blood volume via active pial arteriolar dilation in response to reduced oxygen delivery and improved rheology (30–32). This mechanism maintains CBF constant as viscosity decreases (33,34). In the present experiments, plasma hemoglobin concentration progressively decreased during hemorrhagic hypotension. This was likely compensated for by increases in capillary red blood cell velocity, cerebral vasodilation, enhanced shunting of flow, and redistribution of capillary flow to slow perfusion territories (31,35–37). In support of this, the CBF pattern (as measured by radiolabeled microspheres) during reduction of systemic hematocrit was almost identical to the present CBF data (38). This confirms the use of LDF as a valid technique to continuously assess CBF autoregulation and suggests that the CBF response to CPP and blood viscosity changes share a similar control mechanism (39). In the present study, administration of l-NAME was not randomized because we wanted to follow CBF responses as a function of NOS activity in the same animal.

Norepinephrine infusion of 0.5–2 µg/min was required to maintain baseline MAP at 140 mm Hg. This could confound measurements of cerebral hemodynamics. However, norepinephrine concentrations <4 µg/min do not affect cerebrovascular resistance as long as the blood-brain barrier is intact (40–42). It is, therefore, unlikely that the norepinephrine infusion changed cerebrovascular resistance during the present study.

In conclusion, the present data show that sevoflurane dose-dependently increases brain tissue NO2– concentrations and impairs cerebrovascular dilation to hemorrhagic hypotension. This suggests that sevoflurane impairs the autoregulatory capacity by decreasing basal cerebrovascular tone secondary to an increase of perivascular NO availability. However, administration of l-NAME reset CBF autoregulation whereas hypocapnia, another vasoconstrictive stimulus, did not restore the cerebrovascular response to hypotension in the presence of large sevoflurane concentrations. This questions the importance of basal cerebrovascular tone in terms of vasodilatory capacity during hypotensive challenges. Additionally, autoregulation was not impaired by l-NAME with 1.0 MAC sevoflurane, which indicates that CBF autoregulation might not be related to NO availability.


   Footnotes
 
This study was supported by the Klinik für Anaesthesiologie, Technische Universität München, Germany.

Accepted for publication February 9, 2005.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press