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CRITICAL CARE AND TRAUMA

Cerebral Blood Flow Is Not Altered in Sheep with Pseudomonas aeruginosa Sepsis Treated with Norepinephrine or Nitric Oxide Synthase Inhibition

Michael Booke, MD^*, Martin Westphal, MD, Frank Hinder, MD, Lillian D. Traber, and Daniel L. Traber, PhD

*Department of Anesthesiology, Klinikum des Main-Taunus-Kreises GmbH, Bad Soden am Taunus, Germany; Department of Anesthesiology and Intensive Care, University of Münster, Münster, Germany; and Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas

Address correspondence and reprint requests to Michael Booke, MD, Department of Anesthesiology, Klinikum des Main-Taunus-Kreises GmbH, 65812 Bad Soden am Taunus, Germany. Address e-mail to mbooke{at}klinikum-mtk.de

	Abstract

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The origin of cerebral dysfunction in patients with sepsis is still unclear. However, altered cerebral perfusion may play an important role in its pathogenesis. Using an established, chronic model of hyperdynamic ovine sepsis, we examined cerebral perfusion in 20 sheep subjected to a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, the hypotensive sheep (reduction in mean arterial blood pressure by 16%; P < 0.05) received the nitric oxide synthase inhibitor N^G-mono-methyl-L-arginine (L-NMMA; 7 mg · kg^-1 · h^-1; n = 7), norepinephrine (NE; n = 7), or normal saline (control; n = 6). NE infusion was individually targeted to achieve the same increase in mean arterial blood pressure as that observed in matched sheep of the L-NMMA group. Regional perfusion was measured by using colored microspheres. Although L-NMMA caused a significant increase in systemic vascular resistance index (1167 ± 104 versus 793 ± 59 dyne · cm^-5 · m²; P < 0.05), it caused a change neither in cerebrovascular resistance nor in cerebral blood flow. When related to systemic blood flow, a redistribution of blood flow to the brain became obvious. The NE-associated increase in systemic blood pressure (98 ± 5 versus 83 ± 5; P < 0.05) was accompanied by an increase in cardiac output (7.8 ± 0.5 versus 6.7 ± 0.6; P < 0.05) and, hence, systemic perfusion. However, blood flow to the brain remained unaffected. Although detrimental vasoconstrictive effects of NE and L-NMMA, including cerebral hypoperfusion, are discussed, neither drug had any effect on cerebral perfusion during experimental hyperdynamic sepsis.

IMPLICATIONS: Cerebral dysfunction is often found in septic patients. In this regard, it is debated whether vasopressor drugs, such as norepinephrine and L^G-mono-methyl-L-arginine, have harmful effects on the cerebral circulation. During experimental hyperdynamic sepsis, however, neither drug altered cerebral vascular resistance or cerebral blood flow.

	Introduction

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The sepsis-associated impairment of regional and microregional blood flow is often accompanied by cellular hypoxia and multiple organ failure. Although cerebral dysfunction often occurs in septic patients, the pathophysiologic background is still not fully understood (1,2) . One explanation could be an altered cerebral blood flow. In this view, some studies demonstrated cerebral blood flow to be unchanged during experimental sepsis in rats (3) and sheep (4), whereas others reported either an increase in cerebral blood flow with an ovine model (5,6) or a decrease in cerebral blood flow with a canine model of sepsis (7). These different findings may be related to the type of sepsis induction (endotoxin versus bacteria, bolus versus continuous infusion, and so on) and to the species used.

One therapeutic approach for the treatment of hyperdynamic sepsis and hypotension, however, is the inhibition of nitric oxide synthase (NOS). Although nitric oxide (NO) is produced by calcium-dependent constitutive NOS during physiologic conditions to regulate local vascular tone (8), under septic conditions the expression of an inducible isoform of NOS increases NO plasma levels, leading not only to local but also to general vasodilation (9–11) . NO is mainly responsible for the intense vasodilation seen in sepsis (12). Thus, blocking NOS leads to a reversal of NO-related hypotension, and this is accompanied by a reduction in systemic blood flow (13). A potential risk of NOS inhibition, however, is a more pronounced decrease in regional blood flow, potentially leading to ischemia and tissue damage. In addition, NO is considered a potent cerebral vasodilator (14), and NO-dependent regulation of brain blood flow is an early event in vertebrate evolution (>400 million years) (15). Blocking NOS with the goal of improving systemic hemodynamics may, therefore, cause cerebral perfusion to deteriorate.

Accordingly, our objective was to investigate the effects of NOS inhibition with N^G-mono-methyl-L-arginine (L-NMMA) on systemic and cerebral hemodynamics by using the microsphere technique in an established ovine model of hyperdynamic sepsis (16). Because norepinephrine (NE) is the most frequently used vasopressor in septic patients and because very little is known about its effect on cerebral perfusion during sepsis, we additionally compared the L-NMMA-associated effects with those obtained by NE infusion.

	Methods

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After approval by the Animal Research Committee of the University of Texas Medical Branch, female range ewes, weighing 42 ± 3 kg (n = 20), of the Merino breed were instrumented for chronic study. After a 24-h fasting period, the animals were anesthetized with halothane (2.5–3.5 vol% in oxygen) through an animal anesthesia mask until depth of anesthesia allowed endotracheal intubation (inner diameter, 10 mm; Mallinckrodt, Glen Falls, NY). The sheep were then mechanically ventilated with 1.5–2.5 vol% halothane in oxygen. The respiratory frequency was adjusted to maintain arterial CO₂ levels within normal range; the tidal volume was fixed at 12 mL/kg. Under sterile conditions, femoral arterial and venous catheters were inserted percutaneously. In addition, a pulmonary artery catheter (Model 93A-131-7F; American Edwards Laboratories, Irvine, CA) was placed via the jugular vein into the pulmonary artery. Through a left-sided thoracotomy (fifth intercostal space), a silastic catheter was positioned in the left atrium. Once all wounds were closed, the anesthetic was discontinued, and the animals were weaned from mechanical ventilation and allowed to recover for at least 5 days.

When the animals were fully recovered and showed no signs of postoperative inflammatory processes, such as increased temperature or white blood cell count, the catheters were connected to pressure transducers (Statham P23 ID; Gould, Oxnard, CA) and a physiological recorder (Honeywell OMJ9; Electronics for Medicine, Pleasantville, NY). A cardiac output (CO) computer (Model 9529; American Edwards Laboratory) was used for CO measurements by thermodilution technique. Ice-cold dextrose solution (5%; 10 mL) served as the indicator and was injected in triplicate into the proximal port of the Swan-Ganz catheter. CO was calculated as the average of these three measurements.

Regional blood flow was analyzed by injecting colored microspheres (E-Z TRAC; Interactive Medical Technology, Los Angeles, CA). Approximately 3.75 million colored microspheres with a diameter of 15 µm were injected into the left atrium. Simultaneously, reference blood was continuously withdrawn from the femoral artery. Withdrawal at a rate of 10 mL/min began 30 s before injection of the microspheres and was stopped 2 min after the injection. Microspheres were injected at baseline as well as after 24 and 48 h of sepsis. The different colors of microspheres were administered in a randomly assigned order at the three time points to be studied.

After a baseline measurement in the healthy state, the sheep received a continuous infusion of live Pseudomonas aeruginosa (2.5 x10⁶ colony-forming units per minute). In a pilot study, this dose reliably induced a hypotensive-hyperdynamic circulation and was associated with a lethality of 10% during the 48-h observation time. In this study, the Pseudomonas aeruginosa infusion was maintained for the remainder of the experiment (48 h). Further, all sheep received an infusion of lactated Ringer’s solution, individually adjusted to keep the left atrial pressure at baseline ±3 mm Hg. After 24 h of a continuous Pseudomonas aeruginosa infusion, the septic sheep were randomly assigned to one of the following study groups:

1. L-NMMA: sheep (n = 7) received a continuous infusion of L-NMMA (7 mg · kg^-1 · h^-1) for the second 24 h.
   
2. NE: sheep (n = 7) received a continuous infusion of NE for the remainder of the experiment. The dosage was continuously adjusted to achieve the same increase in mean arterial blood pressure (MAP) as that observed in a matched sheep receiving L-NMMA. NE at a concentration of 0.1 mg/mL was administered by means of a Harvard pump. When larger doses of NE were needed, the concentration of NE was doubled to 0.2 mg/mL to prevent unintended rates of fluid administration that could change blood volume.
   
3. Control: sheep (n = 6) received the carrier solution alone (saline 0.9%). They were treated with neither L-NMMA nor NE.
   

Hemodynamic measurements were performed every 4 h, except immediately after starting the treatment at 24 h, when data were obtained every hour. Colored microspheres were injected at baseline (preseptic), after 24 h of sepsis (pretreatment), and after 48 h of sepsis (24 h of treatment).

After 48 h of sepsis, the sheep were anesthetized with ketamine and received a lethal injection of potassium chloride (7.4%). Immediately thereafter, a craniotomy was performed, and the entire brain was harvested. Tissue samples were then taken from the following parts of the brain: medulla oblongata, cerebellum, thalamus, and cortex. Samples of the left and right kidney cortex were taken to verify adequate mixing of the injected microspheres. Together with the reference blood, these samples were sent to Interactive Medical Technology for analysis of regional blood flows. This technique has previously been described and validated (17,18) . In our sheep model, we have already demonstrated that regional blood flows mea-sured with colored microspheres are comparable to those measured with radioactive microspheres (19); however, they are easier to use.

All data are presented as mean ± SEM. For statistical analysis, Statview II^TM (Version 1.04; Abacus Concepts, Inc., Berkeley, CA) was used. Using a two-way analysis of variance with appropriate post hoc comparisons (Scheffé F-test), we calculated the differences between the two treatment regimens versus control and versus baseline within groups. Values of regional blood flows are expressed in milliliters per minute per 100 g of tissue. To allow conclusions concerning the redistribution of blood flow, we calculated the ratio of change in regional blood flow in percentage of baseline divided by the change in CO in percentage of baseline. Values >1.0 imply a redistribution of blood flow to the region; a value of 1.0 indicates that regional perfusion underwent the same changes as systemic blood flow, reflected by CO; and a value of <1.0 implies a distribution of blood flow away from the analyzed region. Because tissue blood flow is dependent on the local vascular resistance, we also calculated the cerebral vascular resistance as the ratio of MAP over local tissue blood flow in milliliters per gram of tissue. For all statistical tests, P values of <0.05 were considered to be significant.

	Results

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In all sheep, infusion of live bacteria caused a significant increase in CO and a simultaneous decrease in MAP, which, in combination, led to a decrease in systemic vascular resistance index (SVRI) (Table 1). The continuous infusion of live bacteria not only was associated with an increase in systemic blood flow, as reflected by the CO, but was also accompanied by changes in regional blood flows. The raw data of all blood flows from the analyzed tissue samples are summarized in Table 2. Blood flow data are also presented as the ratio of change in regional blood flow in percentage of baseline over change in CO in percentage of baseline (Table 3).

The vascular resistance significantly decreased in the cerebellum and thalamus, whereas it remained unchanged in the medulla and cortex (Table 4). Neither L-NMMA nor NE had any significant effect on cerebral vascular resistance.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major finding of this study is that whereas L-NMMA and NE increased systemic blood pressure in septic sheep, both cerebral vascular resistance and cerebral blood flow remained unchanged. The continuous infusion of live bacteria into sheep resulted in a sustained hyperdynamic circulation characterized by a decrease in MAP with a simultaneous increase in CO and, thus, a reduction in SVRI. Whereas other animal models of sepsis are based on hypodynamic forms of septic shock (20), our sheep model shows hyperdynamic circulatory deterioration, similar to what is seen in human septic shock. Therefore, it appears that this model is ideal to study the pathophysiology of sepsis, as well as the effects of various treatment strategies (16).

A decrease in cerebral perfusion is discussed as a potential cause for the cerebral dysfunction (e.g., cognitive dysfunction, dizziness, hallucination, and so on) found in septic patients (1,2) . However, the pathophysiology responsible for these neurologic changes is still not fully understood. On the one hand, it is possible that sepsis per se causes such alterations, and on the other hand, it may well be that the vasoconstrictors used for hemodynamic support in sepsis could induce cerebral hypoperfusion. Although it is impossible to characterize or grade the symptoms of cerebral dysfunction in sheep, we were interested to elucidate possible vasopressor-associated changes. Specifically, we hypothesized that NE, L-NMMA, or both, while augmenting SVRI, could increase cerebral vascular resistance, thereby decreasing regional cerebral blood flow.

Both forms of treatment restored the blood pressure immediately, but only L-NMMA reversed the hyperdynamic circulation. Although NE restored MAP, CO increased further. Interestingly, some clinicians fear the use of NE because of the potential risk of excessive vasoconstriction. Although NE causes severe vasoconstriction in nonseptic individuals, several clinical studies have shown that NE causes no vasoconstriction during sepsis (21,22) . Nonetheless, even an increase in CO during NE infusion does not guarantee that in certain areas excessive vasoconstriction may occur. In this study, we focused on the cerebral perfusion, which was unaffected by NE infusion.

During sepsis, the inducible form of NOS is expressed. It takes some hours to stimulate this enzyme, but after stimulation, it continuously produces large quantities of NO (11). Simultaneously, the constitutive isoform of NOS is downregulated or even inactive (11,23,24) . NO produces a systemic vasodilation, which is accompanied by a significant increase in systemic blood flow. However, in this study, cerebral blood flow remained unchanged despite the increase in cardiac index. Even treatment with NE and L-NMMA did not affect cerebral vascular resistance or cerebral blood flow. Meyer et al. (5) and Lingnau et al. (6) observed a significant decrease in cerebral blood flow after NOS inhibition with N^G-nitro-L-arginine-methyl-ester (L-NAME). This discrepancy may be explained by differences in the animal models, in the measurement technique, and in the NOS inhibitor. Whereas Lingnau et al. used the same bacteremic sheep model as we did, Meyer et al. induced sepsis by a continuous infusion of endotoxin. However, Lingnau used ultrasonic flowprobes on the carotid artery to measure cerebral blood flow, a technique with less regional resolution than the microsphere technique used by Meyer et al. and our group. In addition, ultrasonic flowprobes may underestimate blood flow when used in vessels with asymmetrical flow profiles or where constraints prevent appropriate probe alignment (25). Therefore, only microspheres allow an analysis of blood flow to different areas of the brain. This technique can be performed with either radioactive or colored microspheres. The latter methodology is based on light extinction and requires no radioactive linkage. Because both techniques have been validated to detect changes in microvascular blood flow in the same manner (17–19) , color-labeled microspheres were used in the present study. To ensure that the microspheres were distributed uniformly, they were injected into the left atrium and not into the left ventricular, as performed by Rosenberg et al. (26). The relatively large variance of regional tissue perfusion observed in this study was most likely due to inconsistencies in the CO of the awake and spontaneously breathing ewes. Because sedation alters hemodynamics, we did not anesthetize and intubate the sheep. However, we made every effort to provide a tranquil atmosphere.

In addition, Lingnau et al. (6) found only L-NAME to reduce cerebral blood flow dose-dependently, whereas L-NMMA had no effect on cerebral perfusion during sepsis. This finding is in accordance with the results of Meyer et al. (5) using L-NAME. In this study we confirmed these data by using L-NMMA. However, it is still unclear why L-NAME causes a decrease in cerebral perfusion and L-NMMA does not. In this regard, Lingnau et al. (6) argued that because L-NMMA blocks the inducible NOS more selectively compared with L-NAME, this would leave the constitutive NOS untouched and thus prevent excessive cerebral vasoconstriction. However, this explanation is unlikely to be correct, because the constitutive NOS is inactivated during sepsis (11,23,24) .

As demonstrated, L-NMMA had no effect on cerebral vascular resistance or cerebral blood flow, despite the fact that it caused a significant decrease in cardiac index and a significant increase in systemic vasoconstriction, as shown previously (10,27) . In this regard, it is also noteworthy that no infarcts or signs of ischemia were found in the slices analyzed by the pathologist. Although NO is a potent cerebral vasodilator (9,21) , the brain blood flow obviously is regulated by other mechanisms than NO during sepsis.

There are some limitations in the clinical applicability of this study to humans. We cannot exclude the possibility that the exogenous application of L-NMMA and NE may produce different responses in sheep than in patients under comparable conditions. However, in this regard, it is noteworthy that all sheep exhibited a hypotensive-hyperdynamic circulation that was almost identical to that observed in clinical practice in patients with severe sepsis (28). However, although in humans a MAP between 70 and 80 mm Hg would not justify the use of vasoconstrictors, sheep are used to a much higher MAP. Therefore, a MAP of 70–80 mm Hg reflects hypotension in this model (29,30) .

In conclusion, the findings of our study suggest that the administration of NOS inhibitors and NE during hyperdynamic sepsis does not compromise cerebral blood flow, and, thus, it is unlikely that they aggravate sepsis-associated cerebral dysfunction. However, because NO is a neurotransmitter, the inhibition of NOS may cause functional changes independent of cerebral perfusion that might contribute to the functional cerebral dysfunction seen in humans.

	Acknowledgments

 
Funded in part by the Burroughs Wellcome Company.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999