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Anesth Analg 1999;89:1510
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Attenuated Additional Hypocapnic Constriction, but Not Hypercapnic Dilation, of Spinal Pial Arterioles During Spinal Ropivacaine

Hiroki Iida, MD*, Hiroto Ohata, MD*, Mami Iida, MD{dagger}, Yukinaga Watanabe, MD*, Kiyoshi Nagase, MD*, and Shuji Dohi, MD*

Departments of *Anesthesiology and Critical Care Medicine and {dagger}Second Department of Internal Medicine, Gifu University School of Medicine, Gifu City, Gifu, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Ropivacaine constricts spinal vessels. Because the CO2 response of spinal vessels is similar to that of cerebral vessels, we tested to see if hypocapnia would cause further spinal vasoconstriction during ropivacaine administration. In 12 pentobarbital-anesthetized dogs, spinal pial arteriolar diameter was measured using a closed spinal window preparation. Either ropivacaine solution (0.1%; n = 6) or artificial cerebrospinal fluid (n = 6) was infused continuously into the spinal window. After a period of hypocapnia (PaCO2, 20–25 mm Hg) had been induced, inspired CO2 levels were adjusted to produce normocapnia (35–40 mm Hg) followed by hypercapnia (55–60 mm Hg). When the desired PaCO2 was reached, measurements were made of the arteriolar diameter and physiological variables. During normocapnia, ropivacaine infusion produced a significant constriction of pial arterioles, whereas artificial cerebrospinal fluid caused no change. Hypocapnia induced a much smaller (almost nonexistent) additional vasoconstriction in the ropivacaine group than in the control group (P < 0.01). The final hypercapnic vasodilation was somewhat greater during ropivacaine (P < 0.05 versus control group). Topical ropivacaine induced no change in hemodynamic variables. We conclude that hypocapnia of the magnitude tested did not cause further constriction in spinal vessels during spinal ropivacaine.

Implications: During topical application of the local anesthetic ropivacaine in dogs, hypocapnia (PaCO2, 20–25 mm Hg) induced almost no additional constriction of spinal arterioles, and the hypercapnic vasodilation was maintained. These data suggest that an additional constriction in spinal vessels is unlikely when hypocapnia occurs during spinal ropivacaine.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Local anesthetics have vasoactive effects on peripheral vascular beds (1,2). They affect spinal cord vessels when given into the spinal or epidural space (3,4). We reported previously that spinal ropivacaine produced a concentration-dependent vasoconstriction of spinal pial vessels (5). The response of spinal vessel diameter and blood flow to changes in PaCO2 is almost the same as in the cerebral circulation (6,7). Therefore, we hypothesized that hypocapnia might cause a further spinal vasoconstriction during spinal anesthesia produced with ropivacaine. To test this, we used the spinal window technique in dogs to investigate the CO2 responses of spinal pial arterioles during the topical application of ropivacaine.


   Methods
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 Abstract
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 Methods
Results
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 References
 
After the experimental protocols had been approved by our institutional committee for animal care, experiments were performed on 12 anesthetized dogs weighing 6 to 10 kg. Anesthesia was induced with pentobarbital sodium (20 mg/kg, IV) and maintained with a continuous infusion (2 mg · kg-1 · min-1). After tracheal intubation, each dog was mechanically ventilated with oxygen-enriched room air. The tidal volume and ventilation rate were adjusted to maintain an end-tidal CO2 of 35 to 40 mm Hg. Polyvinyl chloride catheters were placed in the femoral vein and artery for administration of fluids as well as for blood pressure monitoring and blood sampling. The rectal temperature was maintained between 36.5 and 37.5°C by a warming blanket.

A closed spinal window was used to observe the spinal pial microcirculation. We made the spinal window as described in a previous article (5). Briefly, a ring with a cover glass was placed over the hole in the bone and secured with dental acrylic. Four polyvinyl chloride catheters were inserted into the ring. The space under the window was filled with artificial cerebrospinal fluid (aCSF). The compositions of aCSF were Na+, 151 mEq/L; K+, 4 mEq/L; Ca2+, 3 mEq/L; Cl-, 110 mEq/L; and glucose, 100 mg/dL. The pH was adjusted to 7.48, and the solution bubbled with 5% CO2 in air at 37.0°C (8). One catheter was attached to a reservoir bottle containing aCSF to maintain a constant intrawindow pressure of 5 mm Hg. Two catheters were used for infusion and drainage of aCSF and experimental drug solutions, and the final one was used for continuous monitoring of intrawindow pressure. The volume below the window was 0.5 and 1 mL.

Ropivacaine was freshly dissolved in aCSF. A 0.1% ropivacaine solution was prepared and used. The diameters of two spinal pial arterioles were measured sequentially by means of a videomicrometer (Olympus Flovel Videomicrometer, Model VM-20; Flovel, Tokyo, Japan) attached to a microscope (Model SZH-10; Olympus, Tokyo, Japan). The data acquired from each pial view were stored on videotape for later playback and analysis.

All in vivo experiments were performed in the following manner: Dogs (n = 12) were assigned to one of two groups (control, n = 6; ropivacaine, n = 6). The animals were allowed to stabilize after the surgical preparation for at least 30 min. Then, spinal pial arteriolar diameters, mean arterial pressure, heart rate, rectal temperature, arterial blood gas tensions, pH, blood glucose, and serum electrolytes were measured ("preinfusion" period). For the remainder of the experiment, ropivacaine solution (0.1%; 3.0 x 10-3 M) or aCSF was infused continuously at a rate of 60 mL/h into the spinal window. We determined the concentration of ropivacaine solution from the results of our previous study which demonstrated that 10-3 M solution of ropivacaine constricted the spinal vessels clearly (5). Fifteen minutes after the start of this continuous infusion, we obtained baseline data. Then, sequentially (i) the minute ventilation was increased to achieve hypocapnia (20–25 mm Hg), and (ii) CO2 was added to the inspired gas to achieve the chosen PaCO2 levels (first for normocapnia [35–40 mm Hg], then for hypercapnia [55–60 mm Hg]). Thus, during the three experimental periods (hypocapnia, normocapnia, and hypercapnia) the minute ventilation was kept constant. After reaching a desired PaCO2, the dogs were allowed to stabilize for 15 min while end-tidal CO2 was being monitored, and then measurements were made as under preinfusion and baseline conditions.

Data were tested by a two-way analysis of variance. If the F test indicated significance (P < 0.05), differences among the values obtained at the various PaCO2 levels were subjected to a paired t-test with Bonferroni’s correction or an unpaired t-test among control and ropivacaine groups. A paired t-test was used to identify differences between the preinfusion and baseline period. Significance was considered to be established at P < 0.05. All results are expressed as mean ± SD.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Topical application of either 0.1% ropivacaine (ropivacaine group) or aCSF (control group) induced no change in mean arterial pressure or HR, or in the other systemic variables. For hemodynamic variables, PaO2, serum electrolytes, and blood glucose concentration, there was no difference among the various experimental periods (with the exception that pH and PaCO2 differed from baseline during hypocapnia and hypercapnia). The pH values were significantly altered in accordance with the changes of PaCO2 tension (Table 1).


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  		Table 1. Hemodynamic and Physiologic Measurements
 
By comparison with the values recorded in the preinfusion period, ropivacaine infusion produced a significant vasoconstriction in pial arterioles (–8.3% ± 4.0%), whereas aCSF did not induce any change. These baseline diameters were recorded during the initial period of normocapnia (data not shown). The changes in diameter after this point in the experiment (see Figure 1) are expressed relative to these baseline values. The hypocapnia-induced vasoconstriction was significantly smaller in the ropivacaine group than in the control group (–9.7% ± 5.7% for control and –0.3% ± 1.3% for ropivacaine). The subsequent presentation of hypercapnia led to dilation of pial arterioles that was significantly larger in the ropivacaine group than in the control group.



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  		Figure 1. Changes in pial arteriolar diameter induced by changes in PaCO2 during topical application of artificial cerebrospinal fluid (control) or ropivacaine via a spinal window in 12 dogs. Data are expressed as percentage changes under ropivacaine from the diameter in the baseline period. Changes are additional to those induced by ropivacaine or artificial cerebrospinal fluid themselves during normocapnia. These periods were sequential (i.e., the normocapnia shown is not the baseline period of normocapnia). Hypocapnia did not induce an additional vasoconstriction, but hypercapnic vasodilation was maintained or enhanced during the topical application of ropivacaine. Values are mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of our study are that although the topical application of ropivacaine during normocapnia produces a vasoconstriction of spinal pial arterioles, a further significant vasoconstriction does not occur when hypocapnia is induced, but the hypercapnic vasodilation is maintained or enhanced. These alterations in the diameter of spinal vessels were not accompanied by any change in systemic hemodynamics.

There are many factors that can affect vessels in the spinal cord during spinal anesthesia (3), and the mechanisms by which ropivacaine affects spinal pial vessels are not clear. It seems unlikely that a local anesthetic action per se induces the changes in the diameter of spinal vessels seen with ropivacaine because bupivacaine and ropivacaine caused opposite effects in our previous study (5). Previous investigators have speculated that local anesthetics cause vasoconstriction in vessels via a mechanism involving a direct smooth muscle activation in precapillary and/or postcapillary vessels (9), an indirect release of a vasoactive substance or a blockade of vasoactive substance release (10), an increase in cytoplasmic calcium (2), or a decrease in metabolic demands (11). Moreover, the ropivacaine supplied commercially contains exclusively the S (–) stereoisomer, which may be the main reason for its observed vasoconstrictor property. However, our study was not designed to investigate the mechanism underlying the vasoconstrictor effect of ropivacaine.

It is well known that alterations in PaCO2 induce changes in the diameter of pial vessels (12,13). The most important factor in this alteration is the change in the perivascular pH caused directly by the altered PaCO2 tension. This pH change can exert effects on vascular smooth muscle tone through second messenger systems that involve nitric oxide (14), prostanoids (15), potassium channels (16), and cyclic nucleotides (17).

In our study, hypocapnia did not induce an additional constriction in spinal pial vessels during spinal ropivacaine, whereas hypercapnic vasodilation was maintained or enhanced. Previous reports indicated that sodium channel blocking by tetrodotoxin does not reduce CO2-mediated cerebral vasodilation (18). Although the reactivity of spinal and cerebral vessels is not the same, the above report is consistent with our results. The mechanism underlying the attenuated arteriolar response to hypocapnia is not clear. A previous study demonstrated that a reduction in PaCO2 to below 20 mm Hg does not reduce cerebral blood flow (19). In addition, it has been reported that the hyperventilation-induced slowing of the electroencephalogram can be reversed by hyperbaric oxygen,1which suggests that this effect of hyperventilation is caused by reduced oxygen delivery rather than hypocapnia. Two studies have shown that brain levels of high-energy compounds such as adenosine triphosphate are unchanged during severe hypocapnia (20,21). However, because of the preexisting vasoconstriction of arterioles induced by spinal ropivacaine, it is possible that some counteracting mechanism(s) such as activation of adenosine triphosphate-sensitive K channels are stimulated by the induction of hypocapnia; this might tend to prevent further vasoconstriction. Whatever the mechanism involved, the fact that ropivacaine had already induced an arteriolar constriction during normocapnia is probably a relevant factor in the failure of hypocapnia to induce a significant vasoconstriction. Nevertheless, the absence of an additional spinal pial vasoconstriction when hypocapnia happens to occur under spinal ropivacaine could be important for its safe use.

In conclusion, our study demonstrates that hypocapnia does not induce additional constriction in spinal pial arterioles during spinal ropivacaine, whereas hypercapnic vasodilation is maintained. Thus, when hypocapnia of the magnitude described herein occurs during the spinal administration of ropivacaine, it is unlikely to cause a further decrease in spinal cord blood flow.


   Acknowledgments
 
This study was supported by Grant-in-Aid 09671555 and 11671489 for Scientific Research from the Ministry of Education, Science, and Culture, Japan.


   Footnotes
 
1Reivich M, Cohen PJ, Greenbaum L. Alterations in the electroencephalogram of awake man produced by hyperventilation: effects of 100% oxygen at 3 atomospheres (absolute) pressure. Neurology 1966;16:304. Back


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 27, 1999.




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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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press