University of Sheffield, Division of Clinical Sciences (South), Academic Anaesthesia Unit and Microcirculation Research Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
* Corresponding author. E-mail: zoe.brookes{at}sheffield.ac.uk
Accepted for publication March 12, 2004.
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Abstract |
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Methods. Three weeks following implantation of the DMC in WKY (n=8) and SHR (n=6) (130 g) 0.25 ml 100 g1 FITCBSA (i.v.) was administered and the microcirculation viewed using fluorescent in vivo microscopy for a 30 min baseline (t=030 min). This was followed by either propofol, thiopental, ketamine, or saline (i.v. bolus induction over 5 min (t=3035 min)), then maintenance step-up infusion for 60 min (t=45105 min), so that animals received all four agents 1 week apart (56 experiments).
Results. Dilation of A3 arterioles (1530 µm) and V3 venules (2040 µm) with propofol was greater in SHR (t=95 min, A3 36.7 (12)%, V3 15.5 (2.3)%) than WKY (t=95 min, A3 19.4 (7.4)%, V3 8.0 (2.3)%) (P<0.05). Constriction of A3 with ketamine was greater in SHR (t=95 min, A3 29.1 (6.4)%) than WKY (A3 17.5 (8.8)%) (P<0.05). This was accompanied by hypotension with propofol in SHR (32% decrease in systolic arterial pressure), but not WKY (6%) and hypertension with ketamine in WKY (15%) and SHR (24%) (P<0.05). During thiopental anaesthesia there was dilation of A1 (80180 µm), A3, and V3 in WKY (P<0.05). Conversely, in SHR dilation of venules (29.2 (8.7)%) was accompanied by constriction of A1 and A3 (t=95 min, A1 25.1 (5.9)%, A3 45.2 (3.1)%) (P<0.05).
Conclusion. Within the skeletal muscle microcirculation of hypertensive rats there is enhanced dilation with propofol and constriction with ketamine, associated with exaggerated changes in arterial pressure. Thus, dysfunctional control mechanisms at the level of the microcirculation alter responses to anaesthesia during hypertension.
Keywords: anaesthetics i.v., ketamine ; anaesthetics i.v., propofol ; anaesthetics i.v., thiopental ; muscle, skeletal
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Introduction |
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The aim of this study therefore, is to determine the effects of induction and maintenance doses of i.v. propofol, ketamine, and thiopental anaesthesia on cardiovascular and microcirculatory variables in normotensive and genetically spontaneously hypertensive rats. The dorsal microcirculatory chamber (DMC) will be implanted chronically and fluorescent in vivo microscopy used to determine vessel diameter and macromolecular leak, a measure of vessel endothelial cell integrity,16 in conscious and anaesthetized animals. Our previous studies using the DMC demonstrated that i.v. anaesthetics produce different responses during induction and maintenance of anaesthesia in the skeletal muscle microcirculation of normotensive rats in vivo.17 A second aim of this study therefore, is to establish whether these differences are a dose-dependent phenomena by performing a controlled doseresponse study during the maintenance period.
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Materials and methods |
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Experimental design
In weeks 1 and 2 animals weighing 8090 g (age 5 weeks, n=14) underwent daily training; being placed in a restraining device. Surgery was performed in week 3 and then animals were allowed 1 week to recover before recommencing training in weeks 4 and 5. At week 6 animals were entered into the experimental protocol, receiving saline, propofol, ketamine, and thiopental over a 3-week period (weeks 69, weight 220350 g, age 1113 weeks). It has been shown previously that at this age animals have developed hypertension.20 A total of 56 experiments were performed in total, but before commencing this study we randomized the use of anaesthesia so that agents administered first were: saline (n=3), propofol (n=4), ketamine (n=4), and thiopental (n=3).
Surgery
In week 3, rats weighing 130140 g (78 weeks old) were anaesthetized with 0.1 ml 100 g1 hypnorm/diazepam (1:1, hypnorm (0.315 mg ml1 fentanyl citrate, 10 mg ml1 fluanisone); Janssen-Cilag Ltd, High Wycome, Bucks, UK). Diazemuls (10 mg ml1; Dumex Ltd, Tring, Herts, UK) was administered intraperitoneally (i.p.). The DMC was then implanted according to methods described previously in detail18 19 and modified by the authors. The DMC consists of two halves of light weight polycarbonate (Carolina Medical Electronics, King, NC, USA), which when implanted into the dorsal skinfold allows sufficient space to enclose one layer of cutaneous maximus muscle.
Experimental protocol
The experimental protocol (165 min) was repeated on four occasions in weeks 69 so that each animal randomly received saline, propofol, ketamine, and thiopental 1 week apart. The rat was placed in the restrainer and 0.25 ml 100 g1 fluoroscein isothiocyanate conjugated to bovine serum albumin (FITCBSA) administered into the tail vein using a winged needle infusion set (Venisystems, Butterfly, 25-short), followed by 30 min with no infusion (t=030 min, baseline). Anaesthesia or saline (i.v.) was then administered over 5 min (t=3540 min, induction) followed by 60 min of a continuous saline or anaesthetic infusion (t=45105 min, maintenance), which was increased in equal step-up increments over this period. The infusion was then stopped for the remainder of the study (t=105165, recovery).
Animals were given sterile solutions of either: propofol (10 mg kg1 i.v. induction, 1060 mg kg1 h1 step-up maintenance; WKY, n=8; SHR, n=6 experiments), ketamine (30 mg kg1, 4090 mg kg1 h1; WKY, n=8; SHR, n=6), thiopental (30 mg kg1, 4090 mg kg1 h1; WKY, n=8; SHR, n=6), or saline (1 ml kg1 bolus, 510 ml kg1 h1 infusion; WKY, n=8; SHR, n=6). Animals always received 3 ml kg1 of fluid during induction and 59 ml kg1 h1 (step-up) during maintenance. We have determined previously that these anaesthetic doses maintain a surgical plane of anaesthesia with blood gases, pH, and plasma anaesthetic concentration all within the physiological range.21
During anaesthesia, air containing oxygen 30% was blown into a chamber positioned over the animal (1.5 litre min1).21 The animal was also placed on a warming pad during unconsciousness to maintain body temperature at 3637°C, which was monitored by an oesophageal thermistor probe. Cardiovascular variables (heart rate, SAP and DAP) were measured every 15 min non-invasively using a tail cuff.
After the final experiment at week 9, rats were killed with a lethal dose of i.v. thiopental.
In vivo microscopy
During the experimental protocol (t=0165 min) animals were placed in the Perspex restrainer fixed to the stage of a modified horizontally mounted Nikon Optiphot microscope, equipped with transmitted and epi-illuminated blue fluorescent light (450490 nm) to observe the microcirculation of the DMC, which protruded through a longitudinal slot. Images were displayed on a high-resolution monitor (Sony PVM-1443) via a black and white CCD camera (Hitachi, KP161, UK). Three to five areas were then pre-selected to include A1A4 arterioles (10120 µm) and V1V4 venules (15250 µm), classified according to their order of branching.22 Images were then recorded for 30 s every 10 min, and 5 min after induction, throughout the experiment on to VHS videotape (JVC E180-SX) for later off-line analysis.
Image analysis
Following completion of the study (after week 9) vessel diameters and macromolecular leak were determined off-line using computerized image analysis (Capiscope, KK Technology, UK) and the assessor was blinded to the drug administered. The system was calibrated to produce values in microns and diameters of arterioles and venules were measured from the outside edge of the vessel wall (<5% variability).23 Macromolecular leak from post-capillary venules (V3 and V4, <40 µm) was measured by placing three boxes (3 mm2 on screen) just outside the vessel wall and determining the mean of the grey levels obtained. Grey levels were determined using a software package (Capiscope) that assigned an integer value to the brightness of interstitial fluorescence (0, black; 255, white).
Statistical analysis
Changes in variables (Y), that is heart rate, arterial pressure, vessel diameter, and macromolecular leak are presented as mean (SEM) percentage change from baseline (t=30 min) (y): (Yy)/(yx100). In each group (WKY, n=8, 32 experiments; SHR, n=6, 24 experiments) raw data for saline, propofol, ketamine, and thiopental were compared with the pre-anaesthetic baseline (t=30 min) using a one-way ANOVA for repeated measures. Responses induced by each anaesthetic agent were also compared with conscious controls (six experiments, saline) using a two-way ANOVA for repeated measures. Post hoc analysis was performed using the StudentsNewmanKeuls test. Results were considered statistically significant at P<0.05. A commercially available software package was used to perform the relevant statistical tests and regression analysis (Sigmastat, 2.0).
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Results |
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Ketamine
Heart rate increased following induction and during maintenance, but was greater in SHR than WKY during maintenance. After induction and during maintenance SAP increased in both WKY and SHR (Fig. 1C) and this increase was greater in SHR during maintenance. DAP increased from 65 (5) and 50 (5) at baseline to 89 (9) and 78 (9) mm Hg following induction in WKY and SHR, respectively (P<0.05).
Thiopental
Following induction with thiopental heart rate decreased in WKY, but not in SHR, and no changes occurred during maintenance. Following induction and maintenance there was little change in SAP, with only the decreased SAP following induction in SHR reaching significance (P<0.05, Fig. 1D).
During the recovery period MAP did not return to baseline values in both WKY and SHR 1-h after all anaesthetic infusions were terminated (Fig. 1AD).
Microvascular variables
Diameter
Propofol: in WKY and SHR there was dilation of all arterioles and venules following induction and maintenance, but greater dilation of A3 and V3 in SHR was observed during maintenance (P<0.05, Fig. 2).
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Thiopental: following induction there was dilation of A1, A3, and V3 in WKY, but only dilation of A3 and V3 in SHR. During maintenance there was dilation of A1 and A3 in WKY, conversely there was constriction of these vessels in SHR (P<0.05, Fig. 2).
During the recovery period microvascular variables did not return to baseline values in both WKY and SHR 1-h after all anaesthetic infusions were terminated (Fig. 2).
Diameter: dose-dependent response
Dose-dependent responses were only assessed at the higher infusion rates as we considered that at t=55 min the induction dose would have been influencing the maintenance response.
Propofol: at higher infusion rates during maintenance there was a trend for increasing dilation of V3 with increasing dose in both WKY (r2=0.04, slope=0.79, P=0.05) (t=75105) and SHR (r2=0.05, slope=0.45, P=0.01) (t=6595 min) (Fig. 3).
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Thiopental: during maintenance (t=65105 min) in WKY there was a dose-dependent dilation of A1 (r2=0.3, slope=0.29, P=0.01), A3 (r2=0.11, slope=0.63, P=0.02) and V3 (r2=0.19, slope=0.48, P=0.008). Conversely, in SHR only A3 (r2=0.16, slope=0.72, P<0.000) exhibited a dose-dependent constriction (Fig. 3).
Macromolecular leak
Macromolecular leak occurred during induction with propofol in WKY and then at higher infusion rates during maintenance (t=85105 min, P<0.05, Fig. 4 at 95 min), with a trend to increase with increasing dose. Macromolecular leak was not observed with ketamine or thiopental in WKY. In SHR however, there was macromolecular leak with propofol, thiopental, and ketamine following induction and during maintenance (P<0.05, Fig. 4).
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Discussion |
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In normotensive and hypertensive rats, arterioles and venules dilated during induction and maintenance of propofol anaesthesia, which is in agreement with an increased vasodilation to propofol in aortic rings of SHR in vitro.24 In our study, concurrent with this vasodilation, we also observed an enhanced decrease in arterial pressure. Small arterioles and venules in SHR appeared more sensitive to the vasodilator effects of propofol, but the V3 in particular exhibited the most significant difference. An important mechanism of direct vasodilation by propofol is inhibition of L-type Ca2+ channels;12 13 25 most notably it is the small vessels (<40 µm) that receive greater control from such intrinsic mechanisms. In hypertension Ca2+ channels are known to be up-regulated in the cremaster muscle arterioles and the portal vein.5 26 The dihydropyridine sensitive calcium ion channel blocker felodipine also increases venular blood flow in SHR, but not WKY.26 In our in vivo study, venules in hypertensive rats were particularly sensitive to the vasodilator effects of propofol. Hence, it may be proposed that in the microcirculation of SHR, there is up-regulation of Ca2+ channels, which is greater on the venous side, and this in turn confers a greater sensitivity to the vasodilator and hypotensive effects of propofol.
During induction and maintenance of thiopental anaesthesia, there was dilation of arterioles and venules in WKY, but constriction of arterioles and dilation of venules in SHR. Similarly, in normotensive animals thiopental is known to cause arteriolar and venular dilation in both rat skeletal muscle and the bat wing in vivo when compared with a conscious baseline,17 27 an effect mediated by inhibition of L-type Ca2+ channels.14 In hypertensive rats, however, we observed greater dilation of venules with thiopental in SHR compared with WKY, mirroring responses to propofol. Conversely, dilation occurring in arterioles in WKY was completely reversed to a pattern of constriction in SHR (Fig. 5). It is probable that this compensatory constriction of arterioles contributed to the maintenance of SAP we observed in SHR (Figs 1C and 2). As a result of its apparent haemodynamic stability, thiopental is often the induction agent of choice in patients with hypertension. Interestingly, therefore, we have identified that this stability is not mirrored within the microcirculation; indeed, constriction of the arterioles supplying skeletal muscle would cause a decrease in blood flow and tissue perfusion.
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If we consider the dose-dependent responses in WKY and SHR during maintenance, first during propofol anaesthesia, there was increasing dilation of V3 with increasing dose. This is in agreement with previous studies in WKY reporting greater dilation after a prolonged (4 h) as opposed to a short i.v. infusion of propofol.13 There was also a dose-dependent dilation in SHR, but earlier in the maintenance period, perhaps suggesting that the venules of SHR are more sensitive to propofol and reach their maximal dilation at a lower dose.
Thiopental, however, demonstrated the most convincing evidence for dose-dependent responses. In WKY, there was increasing dilation of A1, A3, and V3 with increasing dose. Consequently the dilation we have reported previously following induction with thiopental, could be a dose-dependent phenomenon.17 Interestingly, dose-dependent vasodilation with pentobarbital and thiopental also occurs in the bat wing.27 Our previous studies of the microcirculation in WKY observed constriction of arterioles during maintenance.17 This is not a discrepancy, rather in our previous study the most frequently used maintenance infusion doses throughout the entire study were 40 and 50 mg kg1 h1. Constriction was observed in the present study at the same doses (t=55 and 65 min) and only at the higher infusion rates (t=95 and 105 min) did significant dilation emerge. Confirmation of dose-dependent dilation not only explains differential responses to induction and maintenance, but may also explain why both contraction and relaxation of vascular smooth muscle in response to anaesthesia are reported in the literature.31 32
We describe diameters of arterioles and venules in skeletal muscle that are greater in SHR than WKY, which appears surprising in a hypertensive disease state. However, previous studies do demonstrate increased diameters of arterioles in skeletal muscle in SHR during the early stages of hypertension, between 6 and 18 weeks.20 33 Our studies were performed in this time frame (aged 1113 weeks). Struijker Boudier and colleagues, also reported increased diameters of V3 venules in SHR using the DMC in rats.20 In the present study venodilation was not a result of tissue damage, as vessels were vasoactive and vessel integrity was not compromised in the control animals. These observations are therefore in agreement with rarefaction as the mechanism of increased peripheral resistance in the early stages of hypertension, as opposed to decreases in resting diameter.34
In WKY, macromolecular leak occurred during propofol anaesthesia. A known side effect of Ca2+ antagonist drugs is oedema.35 36 Indeed, inhibition of dihydropyridine sensitive Ca2+ channels by nifedipine increases extravasation of albumin from postcapillary venules in skeletal muscle in vivo.35 36 It is possible therefore, that propofol also causes increases in venular permeability via inhibition of this mechanism. However, it must not be ignored that propofol may also have a number of pro-inflammatory effects, including up-regulation of leukocyteendothelial interactions, which increase venular permeability and therefore, macromolecular leak.37 In hypertensive rats macromolecular leak occurred with all three anaesthetic agents indicating that post-capillary venules in these animals are more sensitive to the mechanisms that affect endothelial integrity possibly, including increased sensitivity of L-type Ca2+ channels.5 24
In conclusion, the skeletal muscle microcirculation in normotensive and hypertensive rats exhibits very differing responses to propofol, ketamine, and thiopental anaesthesia. We appreciate that a limitation of this study is its lack of direct mechanistic insight. However, having identified substantial differences between WKY and SHR these data will form the foundation of future research to confirm the precise mechanisms involved. In hypertensive rats we elucidated that thiopental causes dilation of venules compensated for by intense constriction of arterioles, and whilst this may explain its ability to maintain a stable arterial pressure in hypertension, this agent has very potent effects within the microcirculation. In hypertensive rats we also identified increased sensitivity to dilation with propofol and increased sensitivity to constriction with ketamine, responses that were in agreement with their respective exaggerated hypotensive and hypertensive effects on arterial pressure. It appears that dysfunctional control mechanisms at the level of the microcirculation (10180 µm) contribute to altered responses to i.v. anaesthesia during hypertension.
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Acknowledgments |
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Footnotes |
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References |
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