This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kumagai, M. Articles by Tobe, Y. Search for Related Content PubMed PubMed Citation Articles by Kumagai, M. Articles by Tobe, Y. Related Collections Neuroanesthesia Preclinical Pharmacology Pharmacology

---

NEUROSURGICAL ANESTHESIOLOGY

Intravenous Dexmedetomidine Decreases Lung Permeability Induced by Intracranial Hypertension in Rats

From the Department of Anesthesia and Intensive Care, Akita University School of Medicine, Akita, Japan.

Address correspondence and reprint requests to Takashi Horiguchi, MD, Department of Anesthesia and Intensive Care, Akita University School of Medicine, Hondo 1-1-1, Akita City, Akita 010-8543, Japan. Address e-mail to thorigu{at}doc.med.akita-u.ac.jp.

Abstract

BACKGROUND: Intracisternal dexmedetomidine (Dex) attenuates cardiac dysfunction in rats with intracranial hypertension (ICH). However, the effects of IV Dex on cardiac function and lung permeability during ICH have not been evaluated. We tested the hypothesis that IV Dex attenuates hemodynamic changes and decreases lung permeability induced by ICH in rats.

METHODS: Halothane-anesthetized and mechanically ventilated rats were divided into four groups. In two groups, a subdural balloon catheter was inflated for 60 s to produce ICH. Arterial blood gas analysis was performed before and 30 min after ICH. Mean arterial blood pressure, heart rate (HR) and intracranial pressure were monitored for 30 min. The Dex group (n = 8) received IV Dex 80 µg/kg, followed by 6 µg · kg^–1 · min^–1 (40 µg/mL) for 10 min and the control group (n = 8) received IV saline 2 mL/kg, followed by at 0.15 mL · kg^–1 · min^–1 for 10 min. Surgery was performed without ICH with Dex (Sham-Dex group, n = 5) and without Dex (Sham-control, n = 5). In all groups, pulmonary permeability was measured using a modification of the Evans blue dye extravasation technique. IV Evans blue dye 20 mg/kg was administered 2 h before being killed and Evans blue dye in plasma and lung tissue was quantified by dual-wavelength spectrophotometric analysis.

RESULTS: There were no significant differences in basal arterial blood pressure, HR, and Pao₂ among groups. In the control group, ICH resulted in transient increases in mean arterial blood pressure and HR, followed by a rapid decline and a plateau. In the Dex group, mean arterial blood pressure showed a transient increase and subsequent, rapid decrease to baseline, whereas HR did not change during ICH. Pao₂ was higher in the Dex group than in the control group after ICH [138 (127–169) vs 78 (59–124) mm Hg, median (range), P < 0.01]. The pulmonary permeability index was lower in the Dex group than the control group [430 (182–450) vs 570 (427–1170), P < 0.01]. It was however, higher in the Sham-Dex group than the Sham-Control group [25 (24–35) vs 6 (4–7), P < 0.01].

CONCLUSIONS: Prophylactic IV Dex decreases lung permeability as well as hemodynamic changes induced by ICH in rats.

Traumatic brain injury with intracranial hypertension (ICH) initiates a cascade of deleterious events that result in cardiac dysfunction and the development of pulmonary edema.1 In experimental animals, a sudden increase in intracranial pressure (ICP) and significant electrocardiographic (ECG) abnormalities correspond well with elevated levels of plasma norepinephrine and epinephrine.2 Sympathetic hyperactivity during sudden ICH leads to cardiovascular instability, myocardial dysfunction, and neurogenic pulmonary edema, which is characterized by elevated pulmonary vascular permeability.3

Dexmedetomidine (Dex) is a highly selective ₂-adrenergic receptor agonist with anesthetic, analgesic, and sympatholytic properties.4 The sympatholytic effect is manifested by decreases in arterial blood pressure (BP), heart rate (HR), and norepinephrine release. Dex thus has the potential to attenuate increases in lung permeability associated with sympathetic over activity. In fact, intracisternal Dex attenuates cardiac dysfunction in rats with ICH.5 However, administration of Dex into cisterns is clinically impractical and the effects of IV Dex on hemodynamics and lung permeability have not been evaluated with ICH. Accordingly, we tested the hypothesis that IV Dex attenuates hemodynamic changes and decreases lung permeability induced by ICH in rats.

METHODS

The present experimental protocol was approved by the Laboratory Animal Care Committee in Akita University School of Medicine. Male Sprague-Dawley rats weighing 350–450 g were quarantined in quiet, humidified rooms for 2–3 wks before use. Rats were allowed proper access to food and water up to the time of experimentation.

Experimental Protocols
Tracheotomy was performed under general anesthesia with halothane 0.75%. Subsequently, rats were mechanically ventilated with a fraction of inspired oxygen of 0.3, to maintain Paco₂ at approximately 35 mm Hg (Ugo Basile Muromachi Kikai CO, Ltd., Japan). Rectal temperature was maintained at 37°C by placing rats on a thermostatically controlled heating pad connected to a temperature controller (CMA/150, Stockholm, Sweden). Mean arterial blood pressure (MAP) was monitored via a left femoral arterial catheter. Rats were divided into four groups. All groups received IV normal saline infusion (10 mL · kg^–1 · h^–1) for 90 min, and received IV 20 mg/kg of Evans blue dye 10 min after starting IV saline infusion. Medications were given via a left femoral vein catheter. Rats were positioned prone in a stereotaxic frame (tooth bar—10 mm). Through burr holes in the skull, a 3F Fogarty catheter was inserted into the left frontoparietal subdural space, and another catheter (PE-50) was placed in the right frontoparietal subdural space to monitor ICP. Holes were sealed using ethyl-2-cyanoacrylate (Aron Alpha, Toagosei CO, Ltd, Tokyo, Japan). ICP and MAP were continuously monitored using calibrated pressure transducers (Baxter, IL) and recorded on a multichannel recorder (Nihon Koden, RM 6000, Tokyo, Japan). HR and ECG were monitored using standard lead II subcutaneous needle electrodes and recorded. After IV saline infusion for 90 min, rats (n = 8) were treated with IV bolus Dex 80 µg/kg, followed by infusion of 6 µg · kg^–1 · min^–1 (40 µg/mL) for 10 min (Dex group). The subdural balloon catheter was inflated with about 0.3 mL of saline for 60 s to produce ICH. Arterial blood gas analysis was performed 5 min before and 30 min after ICH (ABL 510, Radiometer CO, Ltd., Copenhagen, Denmark). ICP, MAP, HR, cardiac rhythm, and ECG changes were recorded during balloon inflation and at 1-min intervals for the first 5 min, then 5-min intervals for the next 25 min. Dysrhythmias was defined as a cardiac rhythm with 3 consecutive beats not originating from the sinus node, or bigeminy, or a trigeminy pattern. The control group (n = 8) received IV saline 2 mL/kg, followed by continuous infusion of saline at 0.15 mL · kg^–1 · min^–1 for 10 min. The experimental protocol was otherwise the same as in the Dex group. In the two Sham groups surgery was performed but without ICH. In the sham-Dex group the (n = 5) protocol was the same as the Dex group without ICH, whereas in the sham-control group (n = 5) the protocol was the same as the control group without ICH.

Analysis of Lung Permeability
Pulmonary microvascular permeability index was measured in all groups using a modification of the Evans blue dye extravasation technique described previously.6,7 Briefly, rats received IV 20 mg/kg of Evans blue dye 2 h before being killed. At the time of death, a heparinized sample of blood was taken from the cannulated femoral vein, and plasma was removed by centrifugation. The lungs were then perfused free of blood with 20 mL of 0.9% saline, after which they were removed from the thoracic cavity and surrounding mediastinal structures and weighed. Pulmonary tissue was then homogenized in 3 mL of 0.9% saline added to two volumes of deionized formamide and incubated at 60°C for 12 h. Supernatant was then separated from the lung tissue by centrifugation at 2000g for 30 min. Evans blue dye in plasma and lung tissue was quantified by dual-wavelength spectrophotometric analysis as described by Linderkamp et al.8 This method corrects specimen absorbance at 620 nm for the absorbance of contaminating heme pigments. Correction was calculated using the following formula: corrected absorbance at 620 nm = actual absorbance at 620 nm – [1.426 (absorbance at 740 nm) + 0.03]. The amount of Evans blue dye measured in pulmonary tissues was then normalized to tissue weight, after which a permeability index that reflects the degree of extravasation of Evans blue dye into the extravascular pulmonary tissue compartment was calculated by dividing corrected pulmonary tissue Evans blue dye absorbance (620 nm/g of lung tissue) by the corrected plasma Evans blue dye absorbance (620 nm).9

Blood gas analysis and lung permeability data were expressed as median and range. Values were compared among groups using Mann–Whitney U-test. ICP, MAP, and HR values were expressed as mean ± sd. Unpaired Student’s t-test was used to compare measured variables of ICP, MAP, and HR between Dex and control groups. Fisher’s exact test was used to analyze the frequency of ECG changes and cardiac dysrhythmias. One-way repeated measures analysis of valiance and post hoc Student–Newman–Keuls testing were used to analyze measured variables across time within the two groups. Significance was determined at P < 0.05 for all comparisons.

RESULTS

There were no significant differences in basal BP and arterial blood gas analysis among groups. Although ICP decreased after injection of IV Dex from 19 ± 3 to 11 ± 3, no significant differences in ICP were noted among groups at inflation of a subdural balloon catheter (201 ± 27 in the control group vs 196 ± 31 mm Hg in the Dex group). After deflation of the balloon catheter, ICP was higher in the Dex group than in the control group (Fig. 1). MAP increased transiently at the sudden increase in ICP after subdural balloon inflation in the control group (from 138 ± 17 to 207 ± 29 mm Hg). After this hypertensive response, MAP rapidly decreased and remained lowered at the end of the experiment. In contrast, MAP in the Dex group showed a transient increase from 150 ± 21 to 185 ± 29 mm Hg and a subsequent rapid decrease to baseline (Fig. 2). HR decreased after injection of IV Dex from 458 ± 30 to 401 ± 40 bpm, and returned to baseline after ICH. In the control group, HR initially increase with a subsequent rapid return to baseline (Fig. 3). Abnormalities in ECG were observed more frequently in the control group (seven of eight) than in the Dex group (one of eight) after subdural balloon inflation. ECG abnormalities, such as premature ventricular contractions, ST segment, or T-wave changes, appeared and continued after balloon deflation in the control group but disappeared in the Dex group.

View larger version (10K): [in this window] [in a new window]   Figure 1. Effect of a 60-s subdural balloon inflation over the left frontoparietal lobe on intracranial pressure in rats treated with saline, or IV dexmedetomidine (Dex). IV infusion of Dex or saline was started 10 min before the beginning (time 0) of 60-s intracranial hypertension (ICH) and was continued for the remaining period. Each point represents mean ± sd. *P < 0.05, IV saline versus IV Dex.

View larger version (12K): [in this window] [in a new window]   Figure 2. Effect of a 60-s subdural balloon inflation over the left frontoparietal lobe on mean arterial blood pressure (MAP) in rats treated with saline, or IV dexmedetomidine (Dex). IV infusion of Dex or saline was started 10 min before the beginning (time 0) of 60-s intracranial hypertension (ICH) and was continued for the remaining period. Each point represents mean ± sd. *P < 0.05, IV saline versus IV Dex.

View larger version (14K): [in this window] [in a new window]   Figure 3. Effect of a 60-s subdural balloon inflation over the left frontoparietal lobe on heart rate (HR) in rats treated with saline, or IV dexmedetomidine (Dex). IV infusion of Dex or saline was started 10 min before the beginning (time 0) of 60-s intracranial hypertension (ICH) and was continued for the remaining period. Each point represents mean ± sd. *P < 0.05, IV saline versus IV Dex.

Pao₂, pH, and base excess were higher in the Dex group than in the control group after ICH (Table 1). The pulmonary permeability index was significantly lower in the Dex group (median, 430; range, 182–450) than the control group (median, 570; range, 427–1170; P < 0.01), however, it was higher in the sham-Dex group than the sham-control group [25(24–35) vs 6,(4–7) P < 0.01]. (Fig. 4).

View larger version (9K): [in this window] [in a new window]   Figure 4. Pulmonary permeability index measured as a function of Evans blue dye extravasation. Rats in the Sham-dexmedetomidine (Dex) group showed significantly higher pulmonary permeability than those in the sham-control group. Rats in the Dex group showed significantly lower pulmonary permeability than those in the control group. P < 0.05, sham-control versus sham-Dex. *P < 0.05, control versus Dex. Horizontal line in the square is median, and square values represent median ± 25–75 percentiles and vertical bar values represent 10–90 percentiles.

DISCUSSION

We found that IV Dex attenuated the increase in lung permeability and attenuated hemodynamic changes induced by acute ICH in rats.

Neurogenic pulmonary edema is characterized by an increase in extravascular lung water as a result of a sudden change in intracranial neurological condition.10 The mechanism by which neurogenic pulmonary edema occurs is unclear and two different mechanisms have been proposed: increased lung capillary permeability and/or increased pulmonary vascular hydrostatic pressures. A neurally induced transient increase in intravascular pressure may damage the endothelium causing protein-rich plasma to escape into the interstitial and alveolar spaces.11 In support of this theory, high intravascular pressure has been shown to damage pulmonary capillaries.12 The hypertensive response to acute ICH is associated with massive increases in plasma catecholamines.2 The initial hyperadrenergic state caused by sudden ICH plays an important role in the development of subsequent cardiopulmonary complications.5 Disturbance in central sympathetic control has been suggested as the most likely mechanism responsible for cardiovascular dysfunction and the subsequent increase in lung permeability associated with ICH. Norepinephrine and neuropeptide Y, which are colocated in large dense vesicles in sympathetic nerve endings, are secreted locally in large quantities in response to a sympathetic storm.13,14 They likely play an important role in the development of neurogenic pulmonary edema through their vasoconstrictive action and increasing pulmonary vascular permeability.15

Dex reduces sympathetic activity by inhibiting presympathetic C1 adrenergic neurons and modulates central cardiovascular responses.16 Dex passes through the blood–brain barrier, and the concentration of Dex in the brain peaks 15 min after IV injection in rats (manufacturer’s unpublished data). The decreased frequency of cardiac dysarythmias and ECG changes in our Dex-treated rats was similar to the observations of a previous study,5 and this finding also seems to support our assumption that sympathetic depression by Dex accounts for amelioration of cardiopulmonary perturbations. The control group had a dramatic decrease in MAP and Pao₂, which most likely explains the acidosis and large negative base excess in this group.

The ₂ receptors are involved in regulating the autonomic and cardiovascular systems and their subtypes have been isolated from rats and humans. However, their effects have been determined only in mice.17 The _2A-receptors that inhibit central nervous system sympathetic activity, especially at the locus ceruleus in the brainstem, likely decrease BP and HR.4 This can result in decreased HR and cardiac output.16 In our study, MAP increased after injection of IV Dex. Both the _2A- and _2B-adrenoceptors in vascular smooth muscle lead to vasoconstriction, causing the initial hypertension after administration of ₂-adrenoceptor agonists.18 It has also been reported that pulmonary artery pressure and pulmonary artery occlusion pressure increased after IV Dex (2 µg/kg) in sheep and hydrostatic stress may be the cause of pulmonary edema formation after _2B-agonist administration.19 In our study, the pulmonary permeability index was significantly higher in the sham-Dex group than the sham-control group, perhaps reflecting this effect. Zornow et al. also reported that 80 µg/kg of dexmedetomidine (i.e., the same as we used), increased MAP in rabbits.20 This dose of Dex is higher than that used clincically. Follow-up infusion of Dex may not have been needed after bolus injection because the elimination half-life of Dex is about 3 h in humans.21

ICP decreased after injection of IV Dex before ICH. The failure of ICP to increase after injection of Dex despite significant increases in BP suggests that this drug may have cerebral vasoconstricting properties. In a human study, Dex produced significant decreases in both regional and global cerebral blood flow, possibly due to activation of vascular _2B receptors, resulting in cerebral vasoconstriction and decreasing cerebral blood flow in most cortical and subcortical brain regions.22 After deflation of the balloon, ICP was higher in the Dex group than in the control group, perhaps due to the higher BP in the Dex group.

To analyze Pao₂ and Paco₂, arterial blood mixed with Evans blue dye was used for blood gas analysis. Data on oxygen tension were reliable even if arterial blood contained Evans blue dye. Oxygen in a sample will diffuse across the polypropylene membrane and cause reactions at the cathode. However, Evans blue dye affects oxygen saturation measured by the blood gas analyzer because the basis for analysis is the measurement of light transmission through the sample in relation to that through a clear solution.23 We thus did not present data on oxygen saturation (Table 1).

In a preliminary study, we confirmed that a small quantity of IV saline infusion before starting the experiment did not necessarily cause pulmonary edema after ICH in the control group. We therefore infused IV saline at a rate of 10 mL · kg^–1 · h^–1 for 90 min, which is a higher rate than that used in previous studies.5,24 The fluid was given to ensure that the animals were not dehydrated before the study.

One limitation of our study is that we did not measure sympathetic nerves activity or catecholamine release monitoring. If we had measured sympathetic nerves activity, we might have been able to demonstrate the mechanism of decreased lung permeability by Dex induced by ICH.

In conclusion, the present study demonstrated that ICH causes pulmonary edema after dramatic hemodynamic changes in a rat model of intracranial balloon inflation. Prophylactic IV Dex decreases lung permeability and attenuates hemodynamic changes induced by ICH in rats.

Footnotes

Accepted for publication March 20, 2008.

Supported solely by Institutional or departmental sources.

Presented, in part, at the Annual Meeting of the American Society of Anesthesiologists, Chicago, IL, October 14–18, 2006.

REFERENCES

1. Mackersie RC, Chistensen JM, Pitts LH, Lewis FR. Pulmonary extravascular fluid accumulation following intracranial injury. J Trauma 1983;23:968–75[Web of Science][Medline]
2. Shanlin RJ, Sole MJ, Rahimifar M, Tator CH, Factor SM. Increased intracranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damages in rats. J Am Coll Cardiol 1988;12:727–36[Abstract]
3. Baumann A, Audibert G, McDonnell J, Mertes PM. Neurogenic pulmonary edema. Acta Anaesthesiol Scand 2007;51:447–55[Web of Science][Medline]
4. Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology 2000;93:1345–9[Web of Science][Medline]
5. Hall SRR, Wang L, Miline B, Hong M. Central dexmedetomidine attenuates cardiac dysfunction in a rodent model of intracranial hypertension. Can J Anaesth 2004;51:1025–33[Web of Science][Medline]
6. Green TP, Johnson DE, Marchessault RP, Gatto CW. Transvascular flux and tissue accrual of Evans blue: effects of endotoxin and histamine. J Lab Clin Med 1988;111:173–83[Web of Science][Medline]
7. Saria A, Lundberg JM. Evans blue fluorescence: quantative and morphological evaluation of vascular permeability in animal tissues. J Neurosci Methods 1983;8:41–9[Web of Science][Medline]
8. Linderkamp O, Mader T, Butenandt O, Riegel KP. Plasma volume estimation in severely ill infants and children using a simplified Evans blue method. Eur J Pediatr 1977;125:135–41[Web of Science][Medline]
9. Patterson CE, Rhoades RA, Garcia JGN. Evans blue dye as a marker of albumin clearance in cultured endothelial monolayer and isolated lung. J Appl Phyiol 1992;72:865–73
10. Simon RP. Neurogenic pulmonary edema. Neurol Clin 1993;11:309–23[Web of Science][Medline]
11. Theodore J, Robin ED. Speculations on neurogenic pulmonary edema (MPE). Am Rev Respir Dis 1976;113:405–11[Web of Science][Medline]
12. Bachofen H, Schurch S, Weibel ER. Experimental hydrostatic pulmonary edema in rabbit lung. Am Rev Respir Dis 1993;147:997–1004[Web of Science][Medline]
13. Mertes PM, Beck B, Jaboin Y, Stricker A, Carteaux JP, Pinelli G, el Abassi K, Villemot JP, Burlet C, Boulange M. Microdyalysis in the estimation of interstitial myocardial neuropeptide Y release. Regul Pept 1993;49:81–90[Web of Science][Medline]
14. Mertes PM, Carteaux JP, Jaboin Y, Pinelli G, Abassi KE, Dopff C, Atkinson J, Villemot JP, Burlet C, Boulange M. Estimation of myocardial interstitial norepinephrine release after brain death using cardiac microdialysis. Transplantation 1994;57:371–7[Web of Science][Medline]
15. Hong M, Milne B, Loomis C, Jhamandas K. Stereoselective effects of central ₂-adrenergic agonist medetomidine on in vivo catechol activity in the rat rostral ventrolateral medulla (RVLM). Brain Res 1992;592:163–9[Web of Science][Medline]
16. Ebert TJ, Hall JE, Barney LA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382–94[Web of Science][Medline]
17. Hein L, Limbird LE, Eglen MR, Kobilka BK. Gene substitution/knockout to delineate the role of alpha2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines. Ann NY Acad Sci 1999;881:265–71[Web of Science][Medline]
18. Makaritsis KP, Johns C, Gavras I, Gavras H. Role of alpha (2)-adrenergic receptor subtypes in the acute hypertensive responses to hypertonic saline infusion in anephric mice. Hypertension 2000;35:609–13[Abstract/Free Full Text]
19. Kastner SBR, Ohlerth S, Pospischil A, Boller J, Huhtinen MK. Dexmedetomidine-induced pulmonary alterations in sheep. Res Vet Sci 2007;83:217–26[Web of Science][Medline]
20. Zornow MH, Scheller MS, Sheehan PB, Strnat MA, Matsumoto M. Intracranial pressure effects of dexmedetomidine in rabbits. Anesth Analg 1992;75:232–7[Abstract/Free Full Text]
21. Venn RM, Karol MD, Grounds RM. Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive care. Br J Anaesth 2002;88:669–75[Abstract/Free Full Text]
22. Prielipp RC, Wall MH, Tobin JR, Groban L, Cannon MA, Fahey FH, Gage HD, Stump DA, James RL, Bennett J, Butterworth J. Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow. Anesth Analg 2002;95:1052–9[Abstract/Free Full Text]
23. Ewing GW. Instrumental methods of chemical analysis. 3rd ed. McGraw-Hill Book Company Ltd, International student edition,1969:48–51
24. Hall SRR, Wang L, Milne B, Ford S, Hong M. Intrathecal lidocaine prevents cardiopulmonary collapse and neurogenic pulmonary edema in a rat model of acute intracranial hypertension. Anesth Analg 2002;94:948–53[Abstract/Free Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kumagai, M. Articles by Tobe, Y. Search for Related Content PubMed PubMed Citation Articles by Kumagai, M. Articles by Tobe, Y. Related Collections Neuroanesthesia Preclinical Pharmacology Pharmacology