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Original Articles – Cardiovascular

Cardiovascular parameters and liver blood flow after infusion of a colloid solution and epidural administration of ropivacaine 0.75%: the influence of age and level of analgesia

Simon, Mischa JG; Reekers, Marije; Veering, Bernadette T; Boer, Fred; Burm, Anton GL; van Kleef, Jack W; Vuyk, Jaap

Author Information
European Journal of Anaesthesiology: February 2009 - Volume 26 - Issue 2 - p 166-174
doi: 10.1097/EJA.0b013e32831ac298



Both spinal and epidural anaesthesia may be accompanied by profound cardiovascular effects because of the extent of sympathetic blockade [1,2]. As the upper level of analgesia, and thus extent of sympathetic blockade, is generally higher in elderly than in young adult patients [3,4], the cardiovascular effects of epidural anaesthesia are often more profound in elderly patients [4]. The effects after spinal administration of local anaesthetics [5] and the impact of age [6,7] upon the haemodynamics are well described. In contrast, the effect of epidural anaesthesia [8] and the possible influence of age on cardiac output (CO) after epidural administration of local anaesthetics have not been investigated extensively. So far, most studies on the cardiovascular effects of epidural anaesthesia have focused on changes in BP and heart rate (HR) only [9].

In the present study, the influence of fluid loading and epidural analgesia on blood volume, CO and hepatic blood flow is studied using pulse dye densitometry (PDD), which allows for noninvasive measurement of the blood concentration–time curve of indocyanine green (ICG). From the ICG concentration–time data the CO [10,11], blood volume [12,13] and the hepatic ICG clearance [5,8,14,15] can be determined with sufficient accuracy.

The aims of the study were to determine the effects of fluid loading and epidural analgesia on blood volume, CO and the liver blood flow (Qh). In addition, the effect of age, the highest level of analgesia and their combination on the haemodynamic variables were evaluated.

Materials and methods


The protocol of this study was reviewed and approved by the Committee on Medical Ethics of the Leiden University Medical Centre. We aimed at inclusion of 30 patients, ASA physical status I or II, equally distributed over three age groups (group 1, 20–44 years; group 2, 45–70 years; group 3, >70 years), who completed all three experiments. Patients were scheduled to have elective orthopaedic, urological, gynaecological (excluding obstetrics) or abdominal surgery under epidural anaesthesia with or without supplemental general anaesthesia; however, the experiments described below took place before the possible induction of general anaesthesia and the onset of surgery.

Patients with a history of cardiac or vascular disease, including hypertension, were excluded from the study. Hypertension was defined as a mean diastolic blood pressure (DBP) more than 100 mmHg or a mean systolic blood pressure (SBP) more than 160 mmHg or both at three measurements. Patients taking antihypertensive drugs, including diuretics, as well as antiarrhythmics or α1-sympathicolytic medications for benign prostate hypertrophy, were excluded. Furthermore, patients who had a history of known hypersensitivity to amide local anaesthetics, severe respiratory, renal or hepatic disease, diabetes mellitus, or neurological, psychiatric or seizure disorders were excluded. In addition, pregnant women as well as patients with a positive Allen's test (no collateral flow in the ulnar artery) at both upper extremities were excluded.


Patients fasted from midnight. They received temazepam 20 mg (<60 years) or 10 mg (≥60 years) orally approximately 45–60 min before the procedure. After the patient was attached to standard equipment to monitor the blood pressure noninvasively and for continuous registration of HR and rhythm, an intravenous cannula was inserted into a large vein in the forearm or the antecubital fossa for fluid and drug administration. An amount of 20 ml h−1 saline 0.9% was infused continuously to assure the patency of the intravenous cannula. After local infiltration of the skin with lidocaine 1%, an arterial cannula was inserted in the radial artery, preferentially in the nondominant arm. This arterial cannula was used for blood pressure measurements. The arterial catheter was removed after completion of surgery.

Subsequently, after local infiltration of the skin with lidocaine 1.0%, the epidural space was accessed under sterile conditions with a 16-gauge Hustead needle at the L2–L3 or L3–L4 lumbar interspace with the patient in the sitting position. Using a median or paramedian approach, the epidural space was identified using the loss of resistance to saline technique (volume of saline ≤10 ml). An epidural catheter was inserted 5 cm into the epidural space. After excluding an intravascular or subarachnoid positioning of the catheter by aspiration, a bacterial filter was attached and the catheter was capped sterilely. Thereafter, the patient was placed again in a supine horizontal position.

Experimental procedure

The experiment consisted of three parts. The first part of the experiment was aimed at obtaining base line values. After full preparation for the experiment (including the placement of intravenous, arterial and epidural catheters), a 10-min stabilization period was observed. Thereafter, patients received a rapid intravenously (≤2 s) injected bolus administration of 4 ml of ICG 2.5 mg ml−1 (total amount of ICG: 10 mg), followed by measurement of ICG concentration using the pulse densitometer for a period of 10 min. Simultaneously, HR and invasive arterial blood pressure were recorded continuously.

The second part of the experiment was aimed at measuring the effect of fluid loading on haemodynamics and was performed directly after baseline measurements. The patients received 500 ml of a colloid solution [hydroxyethyl starch (HES) 6%; Voluven, Fresenius Kabi, Bad Homburg, Germany] within 10 min by rapid intravenous infusion. After completion of the infusion, the assessment of haemodynamics with HR, BP and PDD was repeated immediately, as in the first part of the experiment.

The third part of the experiment was aimed at assessing the effects of epidural analgesia on haemodynamics. Using the epidural catheter that had been installed before the experiment, a test dose of 3 ml prilocaine 1% with epinephrine 5 μg ml−1 was epidurally administered at a rate of 1 ml s−1. If after 3 min there were no signs of intravascular or subarachnoid location of the epidural catheter, 15 ml ropivacaine 0.75% was administered at a rate of 1 ml s−1. During the period following epidural administration, HR and invasive arterial blood pressure were continuously recorded. Hypotension (decrease in SBP >30% of the preexperimental value or SBP <90 mmHg) was treated by administering ephedrine 5 mg intravenously. Bradycardia (<55 beats min−1) was treated by administering atropine 0.5 mg intravenously. Waiting periods of 20 min after the start of the epidural administration or 15 min after a bolus administration of ephedrine to treat hypotension after epidural was injected were observed before ICG was administered to measure haemodynamics. When a stable sensory blockade had been established (see the section Assessment of level of analgesia), patients received a third ICG injection and the ICG concentrations were measured as described above.

Haemodynamic assessment

The arterial blood pressure was monitored throughout the study period using a pressure transducer (Edward Lifesciences LLC, Irvine, California, USA). SBP, mean arterial pressure (MAP), DBP and HR during the above-mentioned periods were recorded at 1-min intervals in a data file. Further haemodynamic values (blood volumes, CO and Qh) were assessed using an indicator dilution method. ICG was used as an indicator. ICG concentrations after injection were measured noninvasively using a pulse dye densitometer (DDG-2001, Nihon-Kohden, Tokyo, Japan). The pulse dye densitometer was set up with an optical probe connected to a monitor. The principles and techniques of pulse spectrophotometry have been described elsewhere [11]. The ICG concentration data were collected from the monitor, using the data acquisition program. Pharmacokinetic analysis of the ICG data was performed using standard equations and recirculatory pharmacokinetic modelling as described by Krejcie et al.[16]. Details about the data analysis are described below [15,17–19].

Plasma concentration–time data of ICG, determined by the pulse dye densitometer were sent to a laptop computer, and parameters were calculated using a spreadsheet program (Excel 2000, Microsoft Corporation, Seattle, USA). Pharmacokinetic analysis of the ICG data was performed using a recirculatory pharmacokinetic model as described by Krejcie et al.[17]. In this model, it is assumed that ICG is confined to the intravascular space. The central intravascular part of the model, which represents blood flow through the heart and the lungs, was described by two combined parallel pathways, a fast and a slow central pathway. The shape of the first pass concentration–time curve, that is, data before evidence of ICG recirculation, was described by the sum of two Erlang functions, each representing the convolution of n one-compartment models connected in series:

where n1 and n2 are the number of compartments in series in the central delay elements; k1 and k2 are the rate constants between the compartments in series; n1/k1 and n2/k2 are the mean transit times of the central delay elements; A1 and A2 are the areas under the first-pass concentration–time curves. The two Erlang functions were fitted to the data using the solver function in the spreadsheet program, whereby data were uniformly weighted [18].

CO was calculated by dividing the administered dose of ICG by the area under the first-pass concentration–time curve. Total blood volume (TBV) was estimated as TBV = D/C0, in which D is the dose administered and C0 is the back-extrapolated concentration at mean transit time (MTT), when first mixing, but no elimination of ICG has occurred during the first circulation. MTT can be determined using the modified Stewart–Hamilton technique as follows:

where AUMCfirst is the area under the curve of the product of concentration and time versus time during the first circulation.

Central blood volume (CBV), also known as the intrathoracic blood volume, is the volume of blood present between the intravenous site of injection and the arterial sampling site. This corresponds to the total volume of blood present in the pulmonary circulation and in the cardiac chambers [19]. It is an index of the cardiac preload and an indicator of the intravascular volume [20]. CBV is determined as the product of CO and MTT [19].

Pharmacokinetic parameters were also derived by noncompartmental modelling. The areas under the plasma concentration–time curves were determined with the logarithmic trapezoidal rule with addition of the extrapolated area from the last sampling time until infinity, which were calculated after log-linear regression of the terminal log-linear part of the ICG concentration–time curve. The so-determined areas under the curve were used to estimate the plasma clearance of ICG, using the equation:

Subsequently, Qh was estimated as:

where Qh is the liver blood flow, CLICG is the clearance of ICG and Eh is the estimated liver extraction ratio. The value of Eh for ICG was assumed to be 0.7 [15]. The data analysis resulted in an estimation of CO, CBV and TBV and Qh.

Assessment of level of analgesia

The highest level of analgesia was determined bilaterally in the anterior axillary line using a short-bevelled 25-gauge needle. Analgesia was defined as the inability to detect a sharp pinprick. Assessments were made at 5 min intervals during the first 30 min after epidural administration or until a stable level of analgesia had developed. A stable level of analgesia was defined as an unchanged upper level during two consecutive assessments.

Statistical analysis

Measured cardiovascular parameters (HR, SBP, MAP, DBP) were analysed, using analysis of variance (ANOVA, repeated measures design), allowing evaluation of the effects of the intervention and age groups. Post hoc tests with a Bonferroni correction for multiple comparisons were performed for age groups. Normality of the data was evaluated by plotting the unstandardized residuals against the unstandardized predicted values, derived from ANOVA. The residuals for the relevant subgroups in the analysis were then checked graphically. Subsequently, the residuals were checked for a normal distribution by performing a Kolmogorov–Smirnov test.

The cardiovascular parameters derived from pulse densitometry, CO and blood volumes (TBV, CBV and Qh), derived from the plasma concentration time data of ICG, were analysed by ANOVA between experiments 1 and 2 and between experiments 2 and 3. These data were log-transformed because the residuals of the initial data did not show a normal distribution in some of the subgroups. Therefore, the statistical results for these variables are based on log-transformed data. After log-transformation, the residuals of these variables were normally distributed.

The highest levels of analgesia between the three age groups were compared using the Kruskal–Wallis test. In case of a significant difference, age groups were compared two by two using the Mann–Whitney U test. A correction for multiple comparisons was made using the sequentially rejective Bonferroni–Holm method.

Correlations between age or the highest level of analgesia or both and the mean difference in cardiovascular parameters during the first 30 min after the start of epidural anaesthesia (Δm) were analysed by Kendall's tau (τ). All statistical analyses were performed using the software package SPSS for Windows, version 12.0.1.



Thirty-six patients were included in the study, of whom 30 completed all three parts of the experiment. For the remaining six patients, only the data for parts 1 and 2 (baseline and fluid load) were available; in five patients, this was due to the absence of complete epidural block (no block in two patients, patchy block or unilateral block each in one patient, radicular pain at the start of epidural administration in one patient). Furthermore, plasma ICG concentration–time data for one patient in the oldest age group could not be fitted and, therefore, those data were excluded from analysis. In one patient in group 2, only the CO was obtained for the first two ICG experiments. Patients' characteristics are shown in Table 1 and apart from age did not differ between age groups.

Table 1
Table 1:
Characteristics of patients included (intention-to-treat)

Epidural analgesia level and age

The upper level of analgesia [median (range)] was higher in the eldest patients [T4 (T10–C7)] than in the youngest age group [T7 (L2–Th4), P = 0.04]. The levels of analgesia for the three age groups are shown in Fig. 1. During the first 30 min of lumbar epidural anaesthesia, 10% (1/10), 45% (5/11) and 60% (6/10) of the young, middle-aged and the oldest patients, respectively, experienced at least one episode of hypotension. Ephedrine was administered in 0% (0/10), 9% (1/11) and 60% (6/10) of the young, middle-aged and the oldest patients, respectively.

Fig. 1
Fig. 1


Haemodynamic variables, such as HR, SBP, MAP and DBP, remained stable during the collection of ICG plasma concentration–time data in all three experiments. Heart rate (P = 1.10−5), SBP (P = 0.03) and MAP (P = 0.04) increased during rapid colloid infusion. Mean differences between mean values at the start of the infusion and those 10 min thereafter were (mean difference ± SE) 2.1 ± 0.74 beats min−1, 4.1 ± 2.2 mmHg and 2.7 ± 1.5 mmHg for HR, SBP and MAP, respectively. The mean values of HR and SBP for the three age groups are shown in Fig. 2. No difference between the age groups was present for all above-mentioned variables.

Fig. 2
Fig. 2

After lumbar epidural administration of ropivacaine, HR increased over the first 15–20 min, then returned to normal. In contrast, SBP (P = 1.10−7), MAP (P = 1.10−9) and DBP (P = 1.10−8) decreased during epidural anaesthesia. Changes in HR and SBP after lumbar epidural administration of ropivacaine are presented in Fig. 2c and d. The oldest patients experienced a larger decrease in SBP (P = 0.04) and DBP (P = 0.03), compared with the middle aged and younger patients, respectively; however, interaction between the intervention, that is, epidural administration of ropivacaine (test of within participants effects), and age group (test of between-participants effects) was present, indicating that both epidural blockade and age had an effect on the arterial blood pressure.

The circulatory haemodynamic values during the experiment are given in Table 2. Although there was a trend to lower CO in the older age group at baseline, differences were not significant. Qh (P < 0.05) increased {162 ml min−1 [ratio 0.90, 95% confidence interval (CI) 0.81–0.99]} during the colloid infusion. No difference between age groups was present for Qh and the blood volumes (Fig. 3). After induction of epidural anaesthesia Qh decreased [265 ml min−1 (ratio 1.20, 95% CI 1.07–1.35)], whereas CO, CBV and TBV did not change. No differences were observed for these parameters between age groups before and after epidural induction.

Table 2
Table 2:
Measurements at baseline, after intravenous infusion of a colloid solution and after epidural administration of ropivacaine 0.75%
Fig. 3
Fig. 3


Correlations between age and the mean difference (Δm) during the first 30 min after induction of epidural anaesthesia were as follows: HR, τ = 0.06 (P = 0.65); SBP, τ = −0.38 (P = 0.003); MAP, τ = −0.44 (P = 4.10−4); and DBP, τ = −0.41 (P = 0.001). These correlations were in the same range as the correlations between the highest level of analgesia and each of the above mentioned cardiovascular parameters [ΔmHR (τ = −0.03, P = 0.82), ΔmSBP (τ = −0.52, P = 9.10−5), ΔmMAP (τ = −0.56, P = 2.10−5) and ΔmDBP (τ = −0.48, P = 3.10−4)]. Age and highest level of analgesia showed a moderate relationship (τ = 0.42, P = 0.002).


The aims of the study were to determine the effects of fluid loading and epidural analgesia on blood volume, CO and Qh. In addition, the effect of age, the highest level of analgesia and their combination on the haemodynamic variables were evaluated. We demonstrated that, during colloid infusion, HR, SBP, MAP and Qh change, but that this was not affected by age. In addition, after epidural administration of ropivacaine, the HR increased during the first 15 min, and SBP, MAP and DBP decreased. Older patients had a higher risk of hypotension and showed a larger decrease in SBP and DBP than their younger counterparts. Both the highest level of analgesia and age correlated to the same degree with the mean decrease in SBP, MAP and DBP during the first 30 min after epidural administration of ropivacaine.

The haemodynamic effects of preloading have been described by Ueyama et al.[20]. They also observed a modest, though not significant, increase in HR and SBP and, in contrast to our study, an increase in CO after administration of 0.5 l of a colloid solution (HES 6%). These dissimilarities in results may be explained by differences in study population (healthy full-term parturients in their study versus nonpregnant patients with a wide range of ages in our study). Fluid administration before spinal anaesthesia is used to minimize the risk of hypotension in the elderly [7]. The effectiveness of fluid administration before epidural anaesthesia in the elderly is yet unknown. Hardly any data exist on the haemodynamic effects of colloid fluids during epidural blockade in the elderly. In this epidural study, the CO was not influenced by age. When haemodynamic effects after subarachnoid blockade in elderly patients were assessed, SBP decreased by 25% and the CO was unaffected [6]. In another study, administration of 8 ml kg−1 colloid solution in elderly patients undergoing spinal anaesthesia, cardiac index increased by 12% [7]. Differences in results between the above-mentioned studies and our study may be due to the faster onset of sympathetic blockade after spinal anaesthesia than after epidural anaesthesia, and to differences between study populations. We excluded patients with cardiovascular disease or those taking antihypertensive, cardiac or vasoactive medication.

High levels of analgesia, and thus of sympathetic blockade, are associated with a larger decrease in arterial blood pressure after epidural anaesthesia [2,4]. In this study, increased age was associated with higher levels of analgesia, confirming earlier observations with epidurally administered bupivacaine [3] and ropivacaine [4]. Consequently, the higher incidence of hypotension and the larger decrease in blood pressure in the elderly may be attributed to the higher level of analgesia attained in this population; however, age itself may be a factor as well, contributing to hypotension after epidural anaesthesia. This may be related to the anatomic and physiologic changes in the cardiovascular [21,22] and autonomic nervous system [23,24] that occur with age. In addition, cardiovascular compensatory mechanisms may be less than optimal in the elderly [22].

For spinal anaesthesia, Carpenter et al.[25] determined the risk factors related to the occurrence of hypotension and bradycardia. Peak block height in excess of T5 and age over 40 years were associated with a higher incidence of hypotension, whereas only the first factor was associated with a higher incidence of bradycardia. In this study, the older patients exhibited both a higher analgesic blockade and more profound blood pressure changes, but it is not possible to conclude which factor, that is, the highest level of analgesia or age per se, is the most important in the development of hypotension after epidural anaesthesia. The low incidence of bradycardia observed in this study may be related to the small number of patients who attained a sensory blockade above T5.

PDD has been shown to estimate with good accuracy the CO, compared with a dye dilution method, using frequent sampling and spectrometric determination of the concentration of ICG (bias ± SD: 0.15 ± 0.72 l min−1) [11]. The bias between the determination of the CO by noninvasive PDD and an invasive method, such as thermodilution appeared to be 4.5 ± 19.6% [10]. In addition, the TBV (bias ±5%, standard deviation: ±10%) and CBV (bias 2.3 ± 27.5%) were accurately estimated using this method [12,13]. Further, the liver function after partial hepatectomy or liver transplantation has been adequately assessed by PDD [26,27]. Therefore, noninvasive PDD was used to derive the ICG–concentration curves, from which CO, CBV, TBV and Qh were estimated (Fig. 3).

ICG binds avidly to plasma proteins, so that its distribution volume equals the blood plasma volume. ICG is exclusively eliminated from the blood by the liver with a half-life of 150–180 s and without enterohepatic circulation [28]. The plasma clearance of ICG was determined by noncompartmental modelling, as described above. The elimination of ICG strongly correlates to hepatic blood flow, but is not similar to hepatic flow as the extraction ratio may differ between patients and clinical conditions. Given the short time span of the experiment it is reasonable to assume that the extraction ratio over the liver remained constant [29]. Therefore, it is reasonable to assume that any change in ICG clearance is the result of a change of hepatic blood flow. Qh was calculated by dividing the plasma clearance of ICG by a fixed extraction ratio, as described by Darling et al.[15]. Thus, rather than provide absolute figures, the Qh was calculated to show differences between the parts of the experiments or age groups or both.

The observed increase in Qh in this study after preloading with a colloid solution may be explained by the concurrent increase in MAP. This is because Qh depends primarily on the mean systemic arterial pressure, rather than the CO [5,8,14]. So far, little was known on the central neuraxis blockade related changes in Qh [15]. Epidural anaesthesia decreased Qh in this study, which confirms earlier observations of changes in hepatic blood flow during epidural analgesia [8,14]. Administration of a colloid solution before epidural administration did not prevent a decline in Qh. Tanaka et al.[14] showed that continuous infusion of a colloid solution (HES) and maintaining normotension did not prevent a decrease in hepatic blood flow after epidural anaesthesia, but that infusion of dopamine could reverse a decline in hepatic blood flow. Wynne et al.[30] showed a negative correlation between advancing age and Qh; however, no difference between age groups was observed in this study with regard to Qh as well as to the decrease in Qh after induction of epidural anaesthesia. The consequence of these observations may be that the pharmacokinetics of such highly extracted drugs as propofol and midazolam is not altered by increased age when coadministered intravenously during epidural anaesthesia. The decreased effective doses, experienced clinically in elderly patients, may be influenced by pharmacodynamic rather than pharmacokinetic factors.

We did not perform a power analysis before the start of the study because a-priori data on the variability, using this method in this particular setting, were lacking. Post-hoc analysis of the data, derived after the epidural administration of ropivacaine 0.75% showed that, with a power of at least 0.80, α = 0.05 and n = 10 patients per group, a difference for Qh of 500 ml min−1 could be detected. This is about 35% of the obtained mean values for Qh, which is in our opinion reasonable. Therefore, we postulate that there is no statistical difference in Qh between the age groups, or that differences are quite small and probably not clinically relevant.

For the detection of differences in CO, however, the method may be less reliable than originally thought. With the same power and α, only differences of 3.5 l in CO between groups could be detected. Therefore, smaller differences in CO between age groups could have been missed. With regard to the CO, the accuracy of the PDD in this study was unacceptably high.

Another possible drawback in this study may be that we had to administer ephedrine in 60% of the oldest patients. Although we tried to minimize the effects by starting the experiment after an interval of at least 15 min after a bolus of ephedrine, an interference with the results cannot be ruled out completely. Nakayama et al.[5] studied the effect of the continuous administration of ephedrine during spinal anaesthesia on cardiovascular parameters and hepatic clearance of ICG. They found that the administration of ephedrine did not change HR and CO, but maintained the mean arterial pressure (MAP). In addition, the detrimental effects of the neuraxial blockade on the hepatic clearance were attenuated. Therefore, it may be possible that this is the reason that the decrease in MAP, in contrast to the decrease in SBP and DBP, was not significant in the elderly patients in our study. Secondly, this may have influenced the results of the Qh; however, there was a significant decrease in Qh after epidural administration of ropivacaine, but no difference between age groups. In our opinion, the influence of the bolus administration of ephedrine in the older patients may have had a minimal effect on the results. Although we have tried to minimize the influence of clinically manifest cardiovascular disease by employing strict inclusion criteria, it cannot be ruled out completely that undiagnosed cardiac and vascular disease have influenced the results.

In conclusion, we determined changes in haemodynamics, blood volumes and Qh after infusion of 500 ml of a colloid solution and after consecutive lumbar epidural administration of ropivacaine. After colloidal infusion, a modest increase in HR, SBP and MAP, as well as an increase in CBV and Qh, occurred. After epidural administration of ropivacaine, HR increased during the first 15 min and the SBP, MAP and DBP, as well as Qh, decreased. Old age was associated with a higher incidence of hypotension and a larger decrease in SBP and DBP. These observations may be explained by the higher level of analgesia attained in the older patients, in addition to the changes in the cardiovascular and autonomic nervous system that occur with age. Age did not affect the response in CO, CBV, TBV and Qh to colloid infusion or induction of epidural anaesthesia, but a high percentage of elderly patients received ephedrine to treat hypotension. Although rapid colloid infusion only had a mild effect on the haemodynamics in the elderly, this did not prevent the Qh from decreasing after epidural anaesthesia.


The authors wish to thank Ron Wolterbeek from the Department of Medical Statistics, and Marnix Sigtermans, Anouk Kabboord, Nelleke Schouten and Jenaida Cicilia, medical students, for their valuable clinical assistance.


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age; blood pressure; blood volume; cardiac output; epidural; haemodynamic phenomena; heart rate; liver blood flow; local anaesthetics; ropivacaine

© 2009 European Society of Anaesthesiology