Combined ultrasound and nerve stimulator-guided deep nerve block may decrease the rate of local anesthetics systemic toxicity: a randomized clinical trial

Although peripheral nerve blocks have been a safe and effective way to provide analgesia for procedures in a variety of settings, using this type of anesthesia does have risks that should not be overlooked. The incidence of Local Anesthetics Systemic Toxicity (LAST) was reported to be 0.04/1000 to 1.8/1000 in a recent summary [1]. LAST, a life-threatening and sometimes fatal condition, was reported to be related to patient characteristics (such as advanced age, low muscle mass, liver disease, cardiac disease, renal disease or diabetes), local anesthetic characteristics and practice settings [1].

Lumbar plexus blocks (LPBs) combined with sciatic nerve blocks (SNBs) for lower extremity surgery are becoming increasingly popular. Due to the depth of the lumbar plexus and sciatic nerves, LPBs and SNBs were advanced regional anesthesia techniques and may be more likely to lead to LAST [2]. LPBs and SNBs are traditionally performed using surface anatomical landmarks and nerve stimulation guidance. Ultrasound could offer direct visualization of the nerve structures, needle pathway and local anesthetics (LAs) spread in real time and is thus widely used in peripheral nerve blocks. Accumulating published data suggests higher efficacy and safety of nerve blocks with ultrasound guidance (US) [3, 4], specifically for interscalene [5], supraclavicular [6], infraclavicular [7], and axillary [8] blocks. Michael et al. [9] reported that the use of ultrasound reduced the risk of LAST throughout its continuum by 60 to 65% compared to without ultrasound. However, most studies have focused on upper extremity blocks. Due to the deep location of the lumbar plexus and sciatic nerves, whether the use of ultrasound in LPBs and SNBs would be beneficial in terms of efficacy and safety remains a matter of debate. Most relevant published studies have suggested that ultrasound guidance would shorten both the time required to perform the block and the onset time [10‐12]. However, there are limited studies comparing the incidence of LAST for LPBs and SNBs with ultrasound and nerve stimulator.

We designed this study to determine whether ultrasound guidance deep nerve blocks would decrease the incidence of LAST compare with nerve stimulation guidance and to identify associated risk factors of LAST.

This study was approved by the Ethical Committee of the First Affiliated Hospital of Army Medical University (previous name: Southwest Hospital of the Third Military Medical University). The protocol was registered prospectively with the Chinese Clinical Trial Registry (ChiCTR-IOR-16008099) on March 15, 2016. The principal investigator was Bin Yi. The study took place at the Department of Anesthesia, the First Affiliated Hospital, Army Medical University, Chongqing, from August 25, 2016, to August 14, 2017.

Patients scheduled for elective lower limb surgery in the Southwest Hospital and desiring LPBs and SNBs were offered enrolment. Written informed consent was obtained from the participants for publication of this article and any accompanying Tables. A copy of the written consent is available for review by the Editor of this journal. The inclusion criteria were as follows: willingness to participate in the study (written informed consent); ASA classification of I to III; older than 18 years old. The exclusion criteria were as follows: refusal to participate; history of neurological diseases; coagulopathy or infection at the site of the block, allergy to local anesthetics (LAs), and any contraindication to peripheral nerve blockade noted by the attending anesthesiologist. All patients were randomly allocated to group U (ultrasound guidance), group N (nerve stimulator guidance) or group M (combined guidance) by a random number table.

The anesthesiologist who performed the LPBs and SNBs was strictly blinded to the patient’s group assignment before the procedure. Only when the anesthesiologist commenced with the block was a prepared sealed opaque envelope containing the patient’s group assignment opened. Then the anesthesiologist completed the block with the indicated technique. There were two investigators in the study. One investigator blinded to the technique used was present in the block area to assess the procedure-related outcomes. To ensure blindness of the patient to the method, all procedures performed behind an opaque screen and investigators were required not to say anything about the technique in use. Another investigator assessing the block quality was blinded to the group allocation and remained outside the block area until completion of the procedure. Finally, a statistician blinded to the entire process performed the statistical analysis, with group data labelled only as numbers until all analyses were completed.

LPBs and SNBs were performed preoperatively by 1 of 3 attending anesthesiologists who were skilled in peripheral nerve blocks with both ultrasound guidance (US) and nerve stimulator guidance (NS). All of them had been in clinical practice with a focus on regional anesthesia for at least 5 years. After arriving in the operating room, the patient was placed in the lateral decubitus position with the surgical limb uppermost and monitored continuously via electrocardiography, SpO₂ measurements, and non-invasive blood pressure monitoring during the nerve blockade and surgery. Both the ultrasound and nerve stimulation systems were prepared and positioned conventionally in each group. The ultrasound machine and nerve stimulator were turned on, and a grounding lead was placed on the lateral aspect of the leg being blocked for each group. The patient’s group allocation was given to the anesthesiologist only after the preparation of both systems and just before the block procedure. The patient was pretreated with 0.05 mg/kg midazolam and 1.5 μg/kg fentanyl. The injection site was prepared with chlorhexidine gluconate. Five millilitres of 0.5% lidocaine was injected subcutaneously at the site of needle insertion. The LA mixture was composed of 200 mg of ropivacaine, 200 mg of lidocaine and 20 ml of 0.9% sodium chloride solution. The concentration of ropivacaine and lidocaine was 0.4%. The total amount of LAs used was determined by the dosage of ropivacaine needed, namely, 3 mg/kg. The patient and investigators assessing the block quality prevented from seeing both the block procedure itself and the sonographic image displayed by an opaque screen. According to the group allocation, the patient received the nerve blocks under one of the following three techniques.

The study flow diagram is presented in Fig. 1. A total of 319 patients were evaluated for eligibility and offered enrolment in this study. Eighteen were excluded; 3 did not meet the inclusion criteria, 13 declined to participate, and 2 were excluded for other reasons. There were no failed or aborted blocks in either group. One patient in group U was lost to follow-up.

The patient characteristics are presented in Tab 1. There was no statistically significant difference in age, sex, weight or height among the three groups. Only one patient in group M had an ASA III status. Most of the operations were performed on the knee or ankle. There was a statistically significant difference in the operative time between group U (41.0 ± 24.21 min) and in group M (51.5 ± 30.8 min).

The primary and secondary outcomes are shown in Tab 2. The incidence of LAST in all three groups was 6%. Moreover, there was a statistically significant difference in the incidence of LAST among the three groups. By multiple comparisons among the three groups, we found that the incidence of LAST in group U (12%) was significantly higher than that in group N (4%)(P = 0.037) and group M (2%)(P = 0.006). (shown in Tab 4). Regarding the LPBs, the motor onset time was significantly shorter in group N (9.5 ± 3.55 s) than in group U (11.30 ± 4.94 s) and group M (11.10 ± 4.38 s) (shown in Tab 2). There was no statistically significant difference in the sensory onset time or sensory and motor restoration time among the three groups. Regarding the SNBs, the motor and sensory onset time was significantly shorter in group N than in groups U and M. Meanwhile, the sensory and motor restoration time in group N was statistically significantly longer than that in groups U and M.

Detailed information of the 18 patients who developed LAST is summarized in Tab 3. There were 12 patients from group U (66.7%), 4 from group N (22.2%) and 2 from group M (11.1%) who experienced LAST during the process. Most of the symptoms were CNS symptoms. None of the 18 patients developed permanent complications after correct and timely treatment. To our interest, 16 of the 18 patients were female. The age of the 18 patients ranged from 19 to 81. The shortest occurrence time was 1 min after finishing the block, and the longest occurrence time was 22 min. The shortest duration time was 3 min without any treatment. The longest duration time was 100 min due to the use of propofol.

We analysed risk factors such as age, sex, liver disease, and diabetes according to The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity [1]. In the current study, 52 patients were infected with HBV, and 7 of these patients experienced LAST. As shown in Tab 4, the OR of LAST for HBV infection and the female sex was 3.352(95% CI,1.233–9.108, P = 0.013) and 9.488(95% CI,2.142–42.093, P = 0.0004), respectively. However, age, needle passes, renal disease and diabetes did not increase the risk of LAST in the current study. Overall, the use of ultrasound, HBV infection and the female sex may be related to the increased incidence of LAST in the current study.

There were three main findings in the current study. First, the use of ultrasound did not improve the quality of deep nerve block. Second, the use of ultrasound increased the incidence of LAST. Third, the use of ultrasound, HBV infection and the female sex may be risk factors of LAST.

In the present study, we found that LPBs and SNBs with US were not superior to those with NS in terms of the onset or restoration time. Spencer S. Liu et al. [19] found that 8 of 10 RCTs reported that the use of ultrasound would shorten the onset time of lower extremity blocks, 2 of 10 reported no difference, and no RCTs reported slower onset with ultrasound. However, most of the RCTs were about the femoral and peroneal nerves. Recently, Arnuntasupakul et al. [12] reported that ultrasound with nerve stimulation guidance for LPBs resulted in a shorter total anesthesia and onset times than US alone. Due to the size and location of the lumbar plexus and sciatic nerves, LPBs and SNBs are advanced regional anesthesia techniques. Different induction pathways for the nerve block may result in different outcomes. Furthermore, due to comorbidities, some of the enrolled patients may have already had minor pathological changes in the targeted nerves, which may have affected the onset and restoration times.

The incidence of LAST was 6%,which is much higher than previously reported [1]. LAST can occur as a result of the patient’s risk factors and current medications, inadvertent injection of LAs directly into the vascular system, exceeding the maximum LA dose, or immediate LA absorption upon injection into an extremely vascularized area [18]. It has been widely reported that US is safer than NS because US can provide direct visualization of the target nerve, surrounding tissues, and LA spread [9, 20]. However, in our study, approximately two-thirds of the patients who experienced LAST were in group U. There are two main reasons for this finding. First, a fair number of patients in our study were infected with HBV or had a renal diseases and thus may be more susceptible to LAST [21]. Second, the lumbar plexus and sciatic nerves are difficult to visualize due to their depth. To obtain a better view of tissues near the nerve, the block needle and the injected LAs, an ultrasonic probe must be applied with some pressure near the injection site. This pressure slows the blood flow in the deep, small vessels, and it is difficult to examine the deep, small vessels using Doppler ultrasonography, especially with slow flow [22]. The continuous pressure caused by the ultrasonic probe makes deep, small vessels “invisible” and thus increased the difficulty of avoiding injecting LAs into extremely vascularized areas, resulting in LAST. The nerve stimulator has advantages over US in terms of determining the relative positions of the needle tip and nerves. When the needle tip is near an extremely vascularized area, the electric current decreases, resulting in failure to induce muscle twitching. In group M, after ultrasound guidance, the rate of failure to induce twitching in the quadriceps and gastrocnemius distribution was 10 and 12%, respectively. Under these circumstances, the distance between the tip and the targeted nerve needed to be adjusted. Therefore, the likelihood of injecting LAs into extremely vascularized areas was less than that with US alone.

The patient’s weight, comorbidities, use of other medications, genetics, allergies, and other physiological limitations also affecting the incidence of LAST [23]. Factors affected systemic LA absorption, the peak plasma LA concentration and the time to reach that peak are all related to LAST. Bupivacaine and ropivacaine are degraded in the liver by α1-acid glycoprotein (AAG) [21]. Patients with liver diseases would have a decreased rate of LAs clearance due to a reduced AAG concentration, which may increase the incidence of LAST. However, even in patients with advanced liver dysfunction, the synthesis of AAG is still maintained [21, 24]. In patients with hepatic dysfunction, single-dose blocks can usually be performed safely with a normal dose of LAs [25]. This finding indicates that the decreased clearance of LAs caused by isolated hepatic dysfunction is not the main reason for LAST in this study. However, as shown in Tab 4, patients infected with HBV had a higher risk of LAST in this study. Patients who are infected with HBV may develop chronic liver disease. Patients with chronic liver disease usually have vascular dysfunction, especially angiogenesis, microvascular derangements and microcirculatory dysfunction [26, 27]. Cirrhosis causes numerous microscopic vessel aberrations, and these vessels may become entangled with each other, resulting in sharp bends, anomalous branching patterns, abnormal branching angles and tortuosity [28]. McAvoy et al. [29] demonstrated that patients with cirrhosis had selective regional increases in blood flow in the splanchnic and hepatic circulations but diminished flow in the peripheral limbs. Neovascularization and slower blood flow make it easier to inject LAs into extremely vascularized areas, especially for the use of ultrasound, resulting in an increased incidence of LAST. Vascular endothelial growth factor (VEGF) and bone morphogenetic protein 9 (BMP-9) have been widely reported to promote angiogenesis [30]. Higher BMP-9 levels in human serum are accompanied by advanced stages of liver fibrosis, while BMP-9 overexpression accelerated liver fibrosis and BMP-9 knockdown attenuated the liver fibrosis in a mouse model [31]. The plasma VEGF level was elevated in patients with cirrhosis, especially in those with spider angiomas [27]. Higher serum levels of BMP-9 and VEGF in patients with HBV indicated more advanced stages of liver dysfunction and increased new blood vessel formation. However, further efforts are needed to determine the relationship of VEGF and BMP-9 with HBV infection. VEGF and BMP-9 may be promising prognostic indicators for the incidence of LAST after deep nerve block in patients with HBV.

Herein, women were more likely to experience LAST, which is in consistent with the latest regional anesthesia and pain medicine practice advisory on LAST [1]. Some enrolled patients who experienced LAST were HBV carriers. The increased risk of LAST in females may be related to HBV infection. Under physiological conditions, the estrogen/estrogen receptor α (ER/ER α) axis has a protective effect against HBV-associated liver damage, and postmenopausal hormone replacement therapy results in a lower risk of hepatocellular carcinoma in HBV positive women [32]. In a female cirrhosis rat model the mRNA expression of ER α was lower in that of a sham rats and the ability of 17β-estradiol to alleviate relevant complications was diminished [33]. This finding indicates that female HBV carriers might have a lower level of ER/ER α, which made them more susceptible to LAST. Further efforts are needed to investigate the underlying mechanism.

There are a number of limitations to this study. First, it was not possible to blind the anesthesiologist performing the nerve block, and we could not exclude the potential influence of a performance bias in this study. Second, although we made efforts to maintain blinding among the investigators, patients, and statistician, it may be partial blinding due to the muscle contractions elicited by nerve stimulation, counting the number of needle redirections and so on. We attempted to minimize this bias by only involving staff anesthesiologists experienced in peripheral nerve blockades using both guidance modalities. Third, there is some limitation related to the techniques and equipment used in this single-center study, so the results cannot be generalized to other techniques or peripheral nerve block locations. The degree of advantages and disadvantages provided by ultrasound guided deep nerve block, especially in HBV carriers, is likely to vary by the nerve block site as well. We only demonstrated some interesting phenomenon and did not determine the underlying mechanisms in the present single-center study. A multicenter study and more detailed experiments are needed to verify our results and reveal the mechanisms.

Our results suggest that ultrasound guidance, HBV infection and the female sex are risk factors of LAST in LPBs and SNBs. For patients infected with HBV or female patients undergoing LPBs and SNBs, combined ultrasound and nerve stimulation guidance should be used to improve the safety. The probable mechanisms are as follows:1) angiogenesis and slower blood flow in deeply located small vessels; and 2) the use of nerve stimulation to avoid injecting LAs into extremely vascularized areas.