Ultrasound Versus Landmark-Based Technique for Ilioinguinal-Iliohypogastric Nerve Blockade in Children: The Implications on Plasma Levels of Ropivacaine

Abstract

BACKGROUND: 

Ilioinguinal-iliohypogastric nerve blockade (INB) is associated with high plasma concentrations of local anesthetics (LAs) in children. Ultrasonographic guidance enables exact anatomical administration of LA, which may alter plasma levels. Accordingly, we compared plasma levels of ropivacaine after ultrasonographic versus landmark-based INB.

METHODS: 

After induction of general anesthesia, 66 children (8–84 mo) scheduled for inguinal hernia repair received INB with 0.25 mL/kg of ropivacaine 0.5% (1.25 mg/kg) either by a landmark-based (n = 31) or by an ultrasound-guided technique (n = 35). Ropivacaine plasma levels were measured before (0) and 5, 10, 20, and 30 min after the LA injection, using high-performance liquid chromatography. Maximum plasma concentrations (C_max), time to C_max (t_max), the absorption rate constant (k_a), the speed of rise of the plasma concentration at Time 0 (dC₀/dt), and area under the curve value (AUC) were determined.

RESULTS: 

The ultrasound-guided technique resulted in higher C_max (sd), k_a, dC₀/dt, and AUC values and shorter t_max compared with the landmark-based technique (C_max: 1.78 [0.62] vs 1.23 [0.70] μg/mL, P < 0.01; k_a: 14.4 [10.7] vs 11.7 [11.4] h⁻¹, P < 0.05; dC₀/dt: 0.26 [0.12] vs 0.15 [0.03] μg/mL · min, P < 0.01; AUC: 42.4 [15.9] vs 27.2 [18.1] μg · 30 min/mL, P < 0.001; t_max: 20.4 [8.6] vs 25.3 [7.6] min, P < 0.05).

CONCLUSIONS: 

The pharmacokinetic data indicate faster absorption and higher maximal plasma concentration of LA when ultrasound was used as a guidance technique for INB compared with the landmark-based technique. Thus, a reduction of the volume of LA should be considered when using an ultrasound-guided technique for INB.

In Brief

IMPLICATIONS: Faster absorption and higher maximal plasma concentration of local anesthetic were observed when ultrasound was used as a guidance technique for ilioinguinal-iliohypogastric nerve blocks in children compared with the landmark-based technique. These results highlight the importance of using low volumes of local anesthetics during ultrasonographic guided ilioinguinal-iliohypogastric nerve blockade in children.

Ilioinguinal-iliohypogastric nerve blockade (INB) is one of the most common peripheral nerve block techniques in pediatric anesthesia and has been shown to be equally effective compared with caudal blockade for inguinal hernia repair.¹ When using the traditional landmark-based technique, a volume of 0.25–0.5 mL/kg local anesthetic (LA) is recommended to achieve a sufficient block because this technique is less exact compared with direct visualization.²

An ultrasound-guided technique for INB has been described with significantly better block qualities compared with the landmark-based technique.² According to this new technique, the needle tip will be placed in close proximity to the two nerves in the correct anatomical plane between the internal oblique and the transverse abdominis muscles. Therefore, IM and intraperitoneal injection of LA is safely avoided. In contrast, the performance of landmark-based INB is associated with multiple administration of LA in adjacent anatomical structures, particularly is muscle tissue.³

Inter or IM administration of LA, which depends mainly on the block technique, should result in different absorption kinetics. Thus, we designed a prospective, blinded and randomized study to compare the pharmacokinetics of equal volumes of 1.25 mg/kg ropivacaine using either the landmark-based or the ultrasound-guided technique for INB in children undergoing inguinal hernia repair.

METHODS

After receiving ethics committee approval and written parental informed consent, 70 children (8–84 mo of age, ASA 1–2) scheduled for inguinal hernia repair were included in the study. The children were prospectively randomized to receive either a landmark-based (LB group) or an ultrasound-guided (US group) INB, in addition to a standardized general anesthesia method (see later). The anesthesiologist who performed general anesthesia was blinded to the method of performance of the INB. The computer-generated randomization protocol was prepared outside the study center and delivered in opaque envelopes that were sealed and sequentially numbered.

Exclusion criteria were prior surgical procedures in the groin area, general contraindications for INB, known allergy to amino-amide LAs, inability of the parents to understand the study protocol, or lack of parental informed consent.

Anesthesia Method

After premedication with oral midazolam (0.5 mg/kg) and application of standard monitoring devices (electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure), anesthesia was induced with 8 vol% sevoflurane in air/O₂ (1:2) via face mask. The IV access was thereafter established and anesthesia was subsequently maintained with one minimum alveolar concentration halothane in air/O₂ (Fio₂ 30%). After insertion of a laryngeal mask, spontaneous breathing was maintained and, if necessary, manually assisted to maintain an end-tidal CO₂ at 35–40 mm Hg throughout the intraoperative period. At the beginning of skin closure, anesthesia was discontinued and children received 1 mg/kg of propofol IV to avoid postoperative agitation.

Establishment of Nerve Blockade

The blocks were performed by experienced anesthesiologists (MW, AB). After disinfection of the skin with chlorhexidine, a 22-gauge facette tip needle (Pajunk™, Geisingen, Germany) was used for all blocks. In both study groups, 0.25 mL/kg ropivacaine 0.5% (1.25 mg/kg) was administered after careful aspiration before and after 50% of the administered volume of LA to detect inadvertent intravascular needle position. Single-injection techniques were used in both study groups. The 0.25 mL/kg LA volume was used because it is the appropriate and recommended dose for landmark-based INBs.^4,5 Skin incision was performed 15 min after the block.

Landmark-Based Technique

In the LB group, INBs were performed according to the landmarks previously described by van Schoor et al.⁶ using a “single pop” technique. We did not control the actual site of injection by ultrasonography to imitate realistic conditions during the landmark-based technique for the INB.

Ultrasonographic-Guided Technique

In the US group, the INBs were performed under direct ultrasonographic guidance using a SonoSite 180plus transportable ultrasound unit and a 5–10 MHz linear “hockey stick” probe (SonoSite, Bothell, WA). After an initial ultrasound survey of the area medial of the anterior superior iliac spine and identification of the ilioinguinal and iliohypogastric nerves, the ultrasound probe was prepared in a sterile manner. The block was then performed in an “out-of-plane” technique under direct visualization of the cannula tip, which was placed lateral to the nerve structures between the internal oblique and transverse abdominal muscles.

Blood Samples and Pharmacokinetic Investigation

Venous blood samples (1 mL each) were collected for analysis of total plasma concentration of ropivacaine before (0) and 5, 10, 20, 30 min after the injection of the LA. The total amount of blood collected (5 mL) did not to exceed 5% of the patient's estimated blood volume. If aspiration of blood through the venous access was not possible throughout the study period, we did not establish a second venous access and the individual patient was excluded from statistical evaluation.

The blood samples were collected via the venous access after initial aspiration of 0.5 mL blood (to avoid dilution of the collected blood by fluid administration) in heparinized test tubes, and plasma was separated by gentle centrifugation and stored at −30°C until quantitative drug assay was performed by high-performance liquid chromatography with ultraviolet detection.

One hundred microliters of plasma was mixed with 50 μL of chlorzoxazone in water (internal standard) and extracted with 50 μL1 M Na₂CO₃ plus tertiary butylmethylether. The samples were shaken for 1 min, and the organic phase was dried by evaporation at 40°C and reconstituted in the mobile phase (50 mM phosphate buffer, pH 3.5, +28% acetonitrile). Fifty microliters of this solution was injected into the analytical column (Spherisorb S5 C6, 150 × 4.6 mm) at 25°C. The lower detection limit of ropivacaine was 0.08 μg/mL. The range of the calibration curve used for quantitative ropivacaine assay with high-performance liquid chromatography was 0.8–6.62 μg/mL. Chromatograms were analyzed using the Agilent Chemstation software (Agilent Technologies, Santa Clara, CA).

Pharmacokinetic Data Analysis: Determination of the Absorption Constant

The plasma concentration-time curve of a drug after administration into a nonvascular space of the body can be described by the Bateman function, assuming that both absorption and elimination follow first-order processes.⁷ The elimination constant, k_e, can be easily obtained from the slope of the logarithmic decline of the drug plasma concentration versus time, but there is no method available that permits the direct determination of the absorption constant, k_a. Hence, early-on approximation procedures were developed; one of the more convenient sets was the first derivative of the Bateman function equal to zero to calculate the maximum blood concentration, C_max, and the time of the maximum, t_max,⁷ the later being

where ξ = k_a/k_e. When k_e and t_max are known, k_a can be calculated from k_a = k_e · ξ. Because Eq. 1 is transcendental and cannot be solved for ξ, values for ξ as a function of k_e · t_max were reported in tabulated form.⁷ These data permit the calculation of k_a when t_max is taken from the concentration—time curve after nonvascular injection of ropivacaine in each individual patient, and k_e (or t₁/₂) from the age-dependent values of these parameters reported by AstraZeneca, the producer of ropivacaine. Based on the pharmacokinetics of ropivacaine in 192 children aged 0–12 yr, k_e was found to be low after birth but matures to the adult value after 1–4 yr (Table 1).

Table 1: Age Dependence of k _e of Ropivacaine, Calculated from t _1/2, in Children

Another parameter for the absorption rate of ropivacaine is rate of rise of the plasma concentration of ropivacaine at time zero, dC₀/dt, which was calculated from the ratio of C_first/t_first. Further, an increase in k_a with k_e being unchanged is expected to result in an elevation of C_max and a decrease in t_max.

In the range of the plasma concentrations that are clinically relevant, pharmacokinetics of ropivacaine are linear.

C_max and t_max were determined from the individual plasma concentration time profiles. The initial distribution half-life is calculated from the linear phases of the semilogarithmic concentration time curves of each patient.

We did not measure α₁-acid glycoprotein levels to calculate the free fraction of ropivacaine because in the present study our primary interest was based on total ropivacaine concentrations.

Secondary Study Parameters

An intraoperative decrease in mean arterial blood pressure and heart rate of more than 30% from baseline was defined as hypotension or bradycardia and was treated with rapid infusion of 10 mL/kg lactated Ringer's solution or atropine in a dose of 0.01 mg/kg, respectively. If unsuccessful, etilefrine 0.02 mg/kg was administered for treatment of hypotension. An increase in HR or mean arterial blood pressure of more than 10% compared with baseline during operation was defined as insufficient analgesia and treated with fentanyl 1 μg/kg IV, which is our clinical standard.

Intraoperative respiratory depression was defined as a decrease in Spo₂ of <93% and was corrected by increasing the Fio₂ and manually assisted ventilation.

Statistics

The end point used for power calculation was C_max of ropivacaine. To detect a 25% difference in C_max between the two study groups with a level of significance of 5% and a power of 80%, the power calculation resulted in 28 patients in each group. To allow for potential protocol violations and problems with acquiring an acceptable number of blood samples, it was decided to include 70 patients in the study.

Differences between the groups for pharmacokinetic parameters were calculated by Mann–Whitney U-test. The failure rate of the nerve blocks was compared using a Fisher's exact test. Statistical significance was considered for P value of <0.05. The SPSS for Windows statistical package (Version 12.0, SPSS, Chicago, IL) was used.

RESULTS

A flow chart (Fig. 1) according to the CONSORT statement⁸ illustrates the patient selection process. The demographic and pharmacokinetic data are presented in Table 2. Ropivacaine plasma levels in individual patients are presented in Figure 2.

Figure 1.: Flow chart according to the CONSORT statement.⁸

Table 2: Patient and Pharmacokinetic Data

Figure 2.: Ropivacaine plasma levels in individual patients (left side: ultrasound- guided technique; right side: landmark- based technique). Thick lines represent the mean values.

Intraoperatively, more patients received supplemental fentanyl because of insufficient analgesia as judged by an increase in HR or noninvasive arterial blood pressure in group LB (n = 8) versus group US (n = 2) (P < 0.05). None of the patients required treatment for hypoxia, bradycardia, or hypotension.

DISCUSSION

This is the first study that investigated the role of ultrasonographic guidance on absorption of LAs. The main finding of the present study was faster resorption and higher plasma concentrations of ropivacaine when using an ultrasound-guided injection technique compared with a landmark-based technique for INB in children.

As shown previously, the landmark-based technique for INB results in IM injection in >80% with a 40% failure rate,³ whereas the ultrasound-guided technique is associated with a success rate of >95% because of exact intermuscular administration of the LA around the nerve structures.² Because of the more abundant vascularization of muscle tissue compared with that of fascial planes, it would be intuitive to assume faster absorption and higher plasma levels after the IM injection associated with the landmark-based technique compared with the intermuscular administration associated with the ultrasound-guided approach. However, our results show the opposite situation in which an injection of the same volume and amount of LA, in fact, was associated with higher plasma levels of ropivacaine in the US-guided group.

A possible explanation for these findings could be that intermuscular injection is associated with an increase in the area available for absorption when compared with an IM injection. Assuming that an IM injection could result in a “sphere” of LA within the muscle, whereas an intermuscular injection could cause a “pancake-shaped” disk of LA between various structures, this would then set the scene for a substantial increase in the area for possible absorption. This notion is, of course, hypothetical because we analyzed only two-dimensional ultrasound figures but does illustrate that the difference in absorption and the plasma levels may be explained by such a mechanism. Another explanation for higher plasma levels and faster increase of plasma concentration of the LA in the US group could be the close proximity of large vessels (e.g., inferior epigastric artery) relative to the site of LA. Nevertheless, the LA is also administered close to large vessels during axillary brachial plexus or femoral nerve blockade, and high plasma levels, dC₀/dt values, and a short t_max are usually not observed during these regional anesthetic techniques.

The main consequence of these findings is that ultrasonographic-guided INB should be performed with low volumes of LA as described by Willschke et al., where a volume of only 0.075 mL/kg LA provided sufficient intra- and postoperative analgesia. This is in accordance with other studies, in which ultrasonographic guidance enabled successful block qualities with low volumes of LA.^9–11

The pharmacokinetics described in the present study is probably applicable to other regional anesthetic techniques with similar distribution patterns of the LA (e.g., rectus sheath block). On the other hand, no data are available about alteration of distribution patterns of the LA dependent on the specific guidance techniques for all other nerve blocks. Future studies are needed to show whether ultrasound guidance is regularly associated with higher plasma levels.

A possible point of criticism of our study could be the number and defined points of time of blood samples. INB is associated with faster absorption than, for example, caudal blocks, and thus, on the basis of the publication by Smith et al.,¹² we decided to limit our sampling period to 30 min.

Toxic plasma levels of ropivacaine are not well reported in children. Most findings are based on experimental designs (e.g., IV administration of the drug in volunteers¹³) and cannot be adapted to pediatric regional anesthesia. Dalens et al.¹⁴ measured plasma levels up to 4.77 μg/mL after administration of 3 mg/kg ropivacaine for INB in children without toxic side effects, and Ala-Kokko et al.¹⁵ observed plasma levels up to 1.22 μg/mL after administration of 2 mg/kg ropivacaine for caudal blocks. The highest plasma concentrations in our study, when we administered 1.25 mg/kg ropivacaine, were reported to be 2.97 μg/mL after ultrasound guidance and 2.28 μg/mL after the conventional landmark-based technique. All plasma levels in the more recent literature^14,15 and in our study were never associated with clinical signs of LA toxicity.

In conclusion, the main finding of the present study was the observation of higher plasma concentrations of ropivacaine when using an ultrasound-guided approach when compared with a landmark-based technique for INB in children, when using the same concentration and volume of LA. One possible explanation for this observation would be an increased area of absorption in the US group and consequently a reduction of the volume of LA. The results of this study are a strong argument to reduce the volumes of LA for ultrasonographic-guided INB blocks in pediatric anesthesia.