This study firstly presented pharmacokinetics profile in serum of ropivacaine for combination of paravertebral nerve (T12, L1) and lumbosacral plexus block in elderly patients with hip surgery. Cmax and Tmax for free ropivacaine were 0.1701 (0.1201–0.2499) µg/ml and 23(20.25–26.75) min respectively. The maximal free ropivacaine concentrations accounted for 5.0(4.9–6.3)% of the total concentrations of the same time point. AUC0-24 for free ropivacaine was 54.55༈33.11–78.25༉µg/ml*min. Cmax and Tmax for the total ropivacaine were 3.737(2.580–5.043)µg/ml and 22(18.25–25.75) min, respectively. Of the total maximal ropivacaine concentration, 4.55༈3.575-5.0༉% presented as free concentration. AUC0-24 for total ropivacaine was 1162༈917.9–1938༉µg/ml*min.
The major concern of multiple nerve blocks is systemic toxicity when using high doses of local anesthetic. Knudsen K. had well demonstrated that signs of central nerve system toxicity would emergence at the mean free concentration of 0.56 (0.34–0.85) µg/ml in volunteers’ arterial plasma, while the venous free concentration was 0.15 µg/ml (0.01–0.24)[13]. The arterial samples were detected in this study, which was higher than venous concentration of ropivacaine. The results were consistent with several papers [14–16].
We found that Cmax for total ropivacaine ranged from 1.29 to 5.79µg/ml in this study. In Knudsen’s study, patients would experience systemic toxicities when the total ropivacaine plasma concentration exceeded 4.6 µg/ml. In our study, seven patients’ Cmax were higher than 4.6µg/ml. But no clinically significant signs of systemic toxicities were observed in these patients. Of the plasma total ropivacaine, only free ropivacaine can enter the central nerve system and cause systemic toxicities. The Cmax of free ropivacaine was 0.1701(0.1201–0.2499)ug/ml which is lower than the toxic threshold of 0.56µg/ml in previous study [13]. According to our results, it showed that the free concentration of ropivacaine was approximate 1.6–6.3% of the total ropivacaine in plasma. The ropivacaine in plasma was mainly bound to 1-acid glycoprotein (AAG) and the proportion of free ropivacaine in total concentration was very small. Therefore, multiple peripheral nerve blocks seem to be safe for the elderly [13]
This study demonstrated that Tmax for total and free ropivacaine concentration were 22(18.25–25.75) and 23༈20.25–26.75༉ min respectively. The Tmax was in other studies ranged from 10–120 min. HÜbler M. et al. showed the Tmax would be within 10 min after psoas compartment block (PCB) using 150 mg ropivacaine without epinephrine [12]. However, Schoenmakers K. et al. found that the Cmax and Tmax of total of 450 mg ropivacaine without epinephrine were 2.81±0.94 µg/ml and 1.17±0.30 hours (70.2±18min) respectively during combined femoral and sciatic nerve block in lower extremity surgery [17]. Our results were between these two studies. The differences from these studies may be due to the total four nerve blocks on the elderly in this study. This study considered the effect of duration of injection of ropivacaine on the Cmax and Tmax. We found that duration of injection had no effects on both Cmax and Tmax of free ropivacaine. It seems to be not necessary to recommend increasing the interval time of injection to reduce the opportunity of systemic toxicities during multiple nerve blocks.
Compared to the double peaks in Xiao J.’ paper, our results should show up to 3 concentration peaks after four nerve blocks[7]. 57.5% patients had only one peak, 42.5% patients had two peaks, and 7.5% patient had three peaks. The concentration peaks were defined strictly as the peaks are 0.05µg/ml higher than the lowest concentration before them. The criterion of 0.05µg/ml is close to the lowest maximal concentration in this study and is thought to be enough to exclude the individual variability. The unexpected peak after the first concentration peak may suggest that the patient who experiences neurotoxicity may suffer the toxicity again. Therefore, if the patient who has a LAST from ropivacaine; she or he should be intensively monitored at least 2 hours to prepare for another possibility of neurotoxicity.
Neither the duration of injection had any effects on Cmax, nor did the weight have the effects in this study. The maximum for ropivacaine is recommended by dose of 3–4 mg/kg to avoid local anesthetic systemic toxicity (LAST). In this study, all the patients were given the same dose of ropivacaine of 245 mg. The dose per weight ranged from 2.75 to 4.90 mg/kg, some of which exceeded the recommended dose [18]. However, the weight had no effect on the Cmax of free and total concentration in these elderly patients after injection of 245 mg ropivacaine. It may be the reason that ropivacaine has a high affinity with tissue after local injection and enters the blood by a very small proportion. Kimi H. et al found that radioactive ropivacaine has a higher affinity for soft tissue and tends to remain in the injection location when compared to lidocaine [19]. Latzke D. et al. also revealed that ropivacaine concentration and persistent duration in abdominal wall were far more than that in plasma during transversus abdominis plane block [19].The evidences suggested that high dose of local ropivacaine risks patients with systemic toxicities, but doesn’t mean corresponding high plasma concentration. There are several papers which recommended that the recommended dose for local administration should not be based on weight or body surface area. Even so, an attention should still be paid to LAST when a large dose of ropivacaine is administrated in multiple sites.
There is an always concern of LAST for the patients who don’t obtain complete nerve block during the surgery. In this study, four patients experienced incomplete nerve block and were conversed to general anesthesia. There were no differences in Cmax and Tmax (total and free ropivacaine) between the four patients and the rest patients. It seems that it is unnecessary to worry about the LAST when incomplete nerve blocks occurred without direct injection into blood. However, this is a preliminary study; a further study with more sample size is warranted to confirm the conclusion.
Because four different injection sites were applied in this study, a non-compartmental approach should be used to descript the pharmacokinetics of ropivacaine. Therefore, it was hard to predict the plasma concentration of ropivacaine [12, 17]. We had tried to use one-compartmental model and two-compartmental model to predict the concentration of ropivacaine after nerve blocks [18]. However, in both models, the observed results didn’t match the predicted results.
To further investigate the factors which affect the Cmax and Tmax, a multiple lineal regression was used to analyze the factors such as gender, weight, height, surgery types, surgery time, transfusion, and transfusion, duration of injection of ropivacaine, infusion fluid, operation time, and operation type. The results showed that all these factors have no significant effects on the Cmax. Stephanie Vanterpool also demonstrated that there was no relationship between the Cmax and patient age, weight, or body mass index [20].In plasma, ropivacaine is mainly combining with protein, especially α1-acid glycoprotein. However, HÜbler M. et al found that there also no relationship between ropivacaine concentrations and total protein, albumin, or α1-acid glycoprotein [12]. Therefore, the maximal concentration is hard to predict according to patient’s age, weight, or plasma protein.
This study was designed to describe the pharmacokinetics of ropivacaine during multiple nerve blocks in hip surgery. There was not a previous assigned control group to compare. There may be also a problem to have enough power to discover the difference. The conclusion in this study just came from a description analysis. It would be limited to get any definitive conclusions. A further well-designed study is necessary to confirm these conclusions.