Combined Ultrasound and Nerve Stimulator-guided Deep Nerve Block May Decrease the Rate of Local Anesthetics Systemic Toxicity

A Randomized Clinical Trial

Xu-hao Zhang; Yu-jie Li; Wen-quan He; Chun-yong Yang; Jian-teng Gu; Kai-zhi Lu; Bin Y


BMC Anesthesiol. 2019;19(103) 

In This Article


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 Table 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.