Background: The incidence and prevalence of obesity, metabolic syndrome and diabetes mellitus (DM) is rapidly increasing in modern society. Number of these patients carrying this burden requiring elective or emergency surgery is also increasing. The aim of this study is to establish the possible differences in diabetic (DM) and non-DM patients regarding dose requirements for ultrasound-guided supraclavicular nerve block (SCB). Methods: Retrospective evaluation of department records identified a total of 120 SCB procedures performed at University Hospital Merkur Zagreb between May 2009 and March 2013. Demographic data, co-morbidities and block performance data i.e. type and volumes of local anesthetic (LA) were collected in order to investigate whether DM influences block duration. A multivariate analysis was performed to identify predictor variables associated with prolonged block duration. Results: Significant differences were noted in ASA status (DM had higher ASA score, P<0,001) and in coronary artery disease (CAD) prevalence (P=0,036). Multivariate linear regression model analyzed duration of SCB using two significantly relevant predictor variables: use of lidocaine + levobupivacaine mixture (beta=-0,276, P=0,005) and DM (beta=0,243, P=0,017). DM patients had longer block duration, as well as those who received “pure” levobupivacaine. Conclusion: According to our study, DM patients have longer block duration which implies that their nerve fibers might be more susceptible to LA. Relationship between the dose, volume, and concentration of LA remains unclear. Our suggestion is to use smaller volumes of LA in diabetic patients, preferably those with shorter duration time and to use ultrasound to avoid nerve damage.
The incidence and prevalence of obesity, metabolic syndrome and diabetes mellitus (DM) is rapidly increasing in modern society. Number of these patients requiring elective or emergency surgery is also increasing. Peripheral nerve blocks (PNB) have become a popular anesthetic option for the extremities surgery, because they provide better postoperative analgesia than general anesthesia does, while avoiding the cardiopulmonary and insulin-resistance effects of general anesthesia. Therefore, PNB are useful even for patients with DM. Nevertheless, little has been written regarding the implications of DM on PNB used for surgical anesthesia-analgesia. Increasing incidence of DM and metabolic syndrome means that regional anesthesia specialists need to re-evaluate and potentially improve perioperative anesthetic care for diabetic patients undergoing limb surgery.
During PNB performance in DM patients, one must be vigilant and keep in mind several factors. First, there are inconclusive studies of whether the dose of local anesthetic (LA) for effective PNB differs in the presence of DM. There is only one, to our best knowledge, clinical study by Gebhard et al. that correlates DM with “higher success rate” for supraclavicular nerve block (SCB) . Second, it is unclear whether LA itself is more toxic to peripheral nerves in diabetics and other patients with polyneuropathy, as it has been suggested by a recent report of sensorimotor nerve damage in patients with previously undiagnosed polyneuropathy . Third, a recent study proposes that the use of nerve stimulator for nerves detection exhibits reduced effectiveness in DM patients . Ultrasound, on the other hand, offers the ability to visualize all of the following in real time: relevant anatomical structures, needle advancement, needle–nerve interaction, and local anesthetic spread. Ultrasound therefore permits the use of smaller volumes without compromising either success rates or block duration. This may in turn reduce the risk of systemic LA toxicity, and of unintentional blockade of other nerves in the vicinity. These advantages are of particular importance in the susceptible population (i.e. pediatrics, elderly, and DM) . The aim of this single-center retrospective observational study is to find differences in DM and non-DM patients undergoing upper extremity surgery. Primary outcome is to determine whether there is prolonged block duration in DM patients. Whereas, secondary outcome is to find the factors that influence block duration. Additional comprehensive data about patients’ co-morbidities have been included for better extrapolation for SCB duration.
Materials and Methods
Study design and patients
This study was conducted in accordance with the amended Declaration of Helsinki. Ethical approval for this study (Ethical Committee N° 03/01-1591/1) was provided by the Ethical Committee of University Hospital Merkur, Zagreb, Croatia. Medical records of all patients who had undergone SCB for surgical anesthesia at University Hospital Merkur between May 2009 and March 2013 have been evaluated. For each patient, intraoperative anesthetic record, postoperative surgical ward records, and surgeon’s preoperative consultation, intraoperative report, and follow-up clinic notes were reviewed, in order to determine block success and duration and to identify any associated major complications (e.g., unintentional intravascular injection and persistent neurological deficit). The study included all patients older than 18 years of age, with signed informed consent for anesthesia and surgery. Contraindications for SCB performance were patient’s refusal and anamnestic data of previous preoperative presence of limb neurological deficit. Only patients in whom a single-injection of LA was performed for SCB were included. There were no perineural adjuvants used (i.e. epinephrine, dexamethasone, clonidine). We excluded from the study the patients with inserted peripheral nerve catheter for continuous LA application. According to our hospital protocol, quick orientation neurological examination was carried out prior to SCB performance. If there was a history of tingling or burning, loss of sensation or the muscle weakness, SCB performance was avoided. Only the type 2 DM patients treated with oral antidiabetic medications with no clinical signs of polyneuropathy, were included in the study.
We hypothesize that diabetic patients tend to have prolonged block duration (for the same volume and type of LA) due to peripheral nerves changes long before clinical signs of polyneuropathy as compared to non-diabetic patients. Primary outcome is to determine whether there is prolonged block duration in DM patients. The secondary outcome is to find the factors that influence block duration. Clinical importance should be seen in LA volume reduction for SCB performance. If the block was found to be extremely prolonged in DM patients with the use of reduced LA volume, one might consider not performing such block before detail clinical neurophysiologic testing was made to ensure patients’ safety.
Nerve block procedure and assessment- hospital protocol
The SCBs were performed using ultrasound guidance (Nemio Toshiba Medical System Inc. 2001, Japan) equipped with a linear 7,5- MHz probe and color Doppler. Each SCB was performed by one of 4 attending experienced regional anesthesiologists. The ultrasound probe was placed in supraclavicular fossa to visualize subclavian artery and brachial plexus in the transverse sectional view, with the patient lying in supine position and the head turned to the contra lateral side. In this coronal oblique position three consecutive measurements of the brachial plexus were taken, and presented as cross-sectional area (CSA). After skin preparation, a 25- gauge spinal needle (90 mm, Quincke type, Vygon, France) was placed on the lateral end of the probe and advanced in-plane. Needle movement was observed in real time and the LA was injected gradually to produce a circumferential spread around brachial plexus sheet. Also, the LA spread was observed in the real time to avoid intravascular or intraneural administration. For LA 0.5% levobupivacaine or 50:50 mixtures of 2% lidocaine and 0.5% levobupivacaine were injected. Single dose of LA was calculated for every patient according to lean body mass and CSA. For every mm2 of CSA measured, patients received 0.3-0.4 ml of adjacent LA [7,8]. Patients presenting with fractures had the block performed without removing the splint, and great attention was paid to minimize the magnitude of arm movement to avoid pain at the fracture site. According to our routine clinical practice, all patients during surgery received midazolam intravenously as anxiolytic and oxygen supplementation. For the purposes of block assessment, time zero was defined as the time of removal of the insulated spinal needle from the skin. Sensory deficit was measured using response to pinprick and cold sensation (every 5 consecutive minutes, up to 30 minutes after injection was completed) in the distribution of the major terminal nerves (radial, median, ulnar, and musculocutaneous).Onset time of complete sensory block was defined as the interval between time zero and the occurrence of a complete sensory block, thus indicative as readiness for surgery. Success rate of SCBs, time to perform block and the need for supplemental intraoperative analgesic requirements were noted, as well as the complications related to the procedure. SCB success was graded as complete (no LA supplementation or ‘rescue block’ required for surgical anesthesia), incomplete (LA supplementation or ‘rescue block’ required), or failed (general anesthesia required). Also, the time to first analgesic requirement after surgical completion was recorded. It was defined as time (measured in minutes) from LA administration until patient’s subsequent analgesia request (on ward).
Kolmogorov-Smirnov test has been performed to analyze data distribution and according to results appropriate parametric test were used in following analyses. Differences in measured values between patients with and without DM have been analyzed with independent t-test. Chi square test was used to evaluate differences between categorical and nominal values. Multivariate linear regression model has been performed to analyze duration of supraclavicular block (as a dependent variable). For independent variables co morbidities, age, gender, BMI, ASA status and type of LA were included. All P values below 0.05 were considered significant. Statistical software STATISTICA 10.0 (www.statsoft. com) has been used in the analysis.
A total of 120 SCBs were performed: 32 in DM and 88 in non-DM group. Majority of them were used for bone osteosynthesis 76.6% (n=92) whereas 23.3% (n=28) were performed for soft tissue surgery. Table 1 compares all patients’ characteristics, co-morbidities and factors related to surgery. Significant difference between groups has been noted in patients’ age: DM patients were older (DM 64.72±14.14 vs. non-DM 55.63±14.81 years, P= 0.003). DM patients often have more co-morbidity such as coronary artery disease. It’s prevalence in our patients was DM 21.9% vs. non-DM 8.0%, P= 0.036. These variables (DM, age, co-morbidities) lead to higher ASA status in DM group (P<0.001).
Table 1. Patient characteristics and perioperative data. All data are means with standard deviation or n (%).
Table 2. Performed block characteristics. All data are means with standard deviation or n (%).
Table 3. Linear regression model for prediction of supraclavicular nerve block duration.
Table 2 presents block performance characteristics. Block success rate was higher in DM group (P= 0.032), whereas block onset and duration did not differ between groups. Linear regression model has been implemented to determine variables that significantly influence block duration. Regression model (Table 3.) was statistically significant (P=0.032) and explained 16% of dependent variable variance. Only two predictor variables made significant prediction of block duration: use of lidocaine + levobubivacaine mixture (beta=- 0.276, P=0.005) and DM (beta=0.243, P=0.017) controlled for all other variables in the model. Patients with DM had longer block duration, especially those who received “pure” levobupivacaine. There were no side effects of SCB like pneumothorax, local tissue injury, or unintentional blockade related to peripheral nerve blockade reported. There was no evidence of systemic LA toxicity.
In this single-center retrospective observational study we evaluated patients with and without DM who received SCB for upper extremity surgery. Compared to the other studies, ultrasound has been used during SCB performance. Ultrasound is a useful detection tool because it enhances the performance of the block . Also, it enables avoidance of LA intraneural injections. This is most helpful in diabetic patients since the conductivity of the nerve fibers is reduced and the use of the nerve stimulator is limited . A comprehensive study has been undertaken to investigate differences between groups (age, gender, BMI, CSA, type of LA, block success and duration, as well as the patients’ ASA status and co- morbidities). All these variables have been used in linear regression model to predict duration of SCB. Our study shows that DM affects the SCB duration, as well as the type of LA used for block performance. Our current knowledge of the functional changes in sensory nerves caused by diabetes is limited. The relationship between early metabolic events, vascular damage, and structural and functional changes in nerves is unclear. Conduction abnormalities have been described in human diabetics and in animal models of diabetes, and they are becoming increasingly prominent over a longer period of time . El- Salem et al. recently showed that nerve conduction abnormalities commonly exist in diabetic patients in the subclinical stages of polyneuropathy and that abnormalities highly correlate to glycosylated hemoglobin (HbA1c) levels in a DM patient group . Higher success rate and longer duration of SCB in DM patients could be explained weather with higher sensitivity of diabetic nerve fibers to LA or with pre-existing neuropathy. The frequency of diabetic polyneuropathy (DPN) ranges from 4% to 8% at the time of initial presentation, to approximately 50% in patients with chronic disease . Study by Kalichman et al. proposes that the LA requirements are reduced in diabetes and that the risk of local anesthetic-induced nerve injury is increased . This all may have clinical implications, suggesting a potential risk of nerve injury associated with repeated exposure to LA for anesthesia requirements or continuous infusion of LA with inserted perineural catheter .
Our data indicate that success rate of complete UG-SCBs is higher in diabetic individuals than in non-DM patients. This is consistent with report of Gebhart et al. who also report higher SCB success rate in DM patients . However, we performed SCB by ultrasound guidance, in oppose to their study where landmark-based paresthesia technique and peripheral nerve stimulator for block assessment was used. Use of nerve stimulator and provoking paresthesia may be limited in DM patients due to reduced sensitivity and nerve impulse conduction. With the use of ultrasound technique we minimized adverse effects such as risk for temporary or permanent nerve injury. Williams et al. assessed the quality of SCB using ultrasound guidance compared with peripheral nerve stimulator . These authors recorded a 95% success rate in the ultrasound group compared with 85% in the PNS group. Many other authors emphasize the benefits of ultrasound, primarily regarding safety and quality of the blocks [16-19]. Our data match the recently published ones obtained from large prospective randomized studies concerning the volume and type of LA. The volume of LA did not predict the block duration. The same results reported Cappelleri et al. . They found no evidence to support that varying volume and concentration while maintaining a fixed total dose of LA alters the onset time and duration of peripheral nerve block. In our study, a major predictor of block duration, besides DM, is the type of the LA used to perform the block. However, the rate of recovery is significantly faster with a short acting LA . Similarly, Lindström et al. showed delayed recovery of nerve conduction and vibratory sensibility after ischemic block in patients with DM compared with age-matched controls . Whereas, Sertoz et al. report longer sensory block regression time in diabetic patients with poor glycemic control, indicating higher risk of peripheral polyneuropathy development in these patients . It seems that many factors should be taken into consideration when peripheral nerve blocks are performed in DM patients. One of them is certainly reduced sensory and motor conduction velocity, especially in those patients with poor glycemic control. Impaired nerve conduction leads to reduced dose requirements of LA to produce anesthesia. At the same time, too long exposure to LA can cause damage to the peripheral nerves especially if there are already signs of polyneuropathy present. A large array of studies has revealed disturbances of a diversity of cellular processes that may contribute neuronal damage by LA, but no single pathway is established as the clinically dominant mechanism [24-26]. LA neurotoxicity involves mitochondrial dysfunction with activation of apoptotic pathways.
This is the reason why the recommendations for nerve block performance in patients with DPN were recently issued . Increased attention has been paid to the possibility that DPN may prolong nerve block duration. For this reason, the authors propose reduced doses of LA in order to decrease the chance of adverse outcome. The safety of peripheral nerve block performance in patients with DM or DPN remains high priority in the future. In these patients ultrasound plays a crucial and superior role compared to nerve stimulator. We should also point out two significant differences between the groups: age of patients and their co-morbidities. DM patients were older, had significantly higher ASA score and more co-morbidities, including CAD. Many studies indicate age as a major factor that determinates complete motor and sensory blockade in peripheral nerve blocks. They hypothesize increased sensitivity to LA agents in peripheral nerves in the elderly population, due to involutionary changes that occur with aging [28, 29]. Consequently, there is a need for reduced minimum effective anesthetic volume for brachial plexus block in elderly patients. Our data suggest that age itself, as a single variable, is not a major determinant in SCB assessment or its duration, whereas DM is. It would be interesting to compare other patients’ co-morbidities, i.e. DM, in those earlier conducted studies to see whether they influenced the block success and/or duration in patients with advanced age. This might additionally support our hypothesis. In general, CAD and DM did not overlap and the difference between groups was statistically significant. However, when we included CAD in regression linear model (Table 3) with other parameters, we found that CAD was not a factor that affects block duration. We believe that these data supplement the research by Gebhard et al., due to the fact that since now there has not been described correlation of CAD and block duration in English literature . We can rather say that CAD is more frequent in diabetic than non-diabetic population but it does not affect block duration.
Our single-center, retrospective observational study has several limitations. Data were retrospectively collected from database and medical charts. Also, the non-random allocation of patients to each group can result in potential bias in terms of patient characteristics, as well as surgical variables. Patients were not closely checked for signs of DPN. Electrodiagnostic testing (nerve conduction velocity and response, i.e. EMNG) were not performed. However, there was no neurological deficit prior to block performance, since its existence was considered as a contraindication to block performance. This raises some questions and opens further discussion. Should we routinely detect DPN in all DM patients prior to block performance? And what would be the cut-off point in DPN presence to safely institute SCB? The duration of postoperative follow-up was limited to first postoperative day. Late complications, although unlikely, such as neurologic deterioration occurring beyond this point, could not have been reliably identified. Nevertheless, we believe that our data, although lacking the compelling evidence of randomized controlled trials, allow increased confidence in the detection of SCB duration in DM patients.
Our study emphasizes that DM patients have longer block duration implicating that their nerve fibers might be more susceptible to LA. Clinicians should be aware of this potentially high-risk subgroup of patients when developing and implementing a regional anesthetic care plan. Relationship between the dose, volume, and concentration of LA remains unclear. Our suggestion is to use smaller volume of LA, preferably those with shorter duration and to use ultrasound to avoid nerve damage.
Funding: This study was not funded.
1. Tamai D, Awad AA, Chaudhry HJ, Shelley KH. Optimizing the medical management of diabetic patients undergoing surgery. Conn Med. 2006,70(10): 621-630.
2. Gebhard RE, Nielsen KC, Pietrobon R, Missair A, Williams BA. Diabetes mellitus, independent of body mass index, is associated with a “higher success” rate for supraclavicular brachial plexus blocks. Reg Anesth Pain Med. 2009,34(5): 404-407.
3. Williams BA, Murinson BB, Grable BR, Orebaugh SL. Future considerations for pharmacologic adjuvants in singleinjection peripheral nerve blocks for patients with diabetes mellitus. Reg Anesth Pain Med. 2009,34(5): 445-457.
4. Blumenthal S, Borgeat A, Maurer K, Beck-Schimmer B, Kliesch U.et al. Preexisting subclinical neuropathy as a risk factor for nerve injury after continuous ropivacaine administration through a femoral nerve catheter. Anesthesiology. 2006,105(5): 1053–1056.
5. Sites BD, Gallagher J, Sparks M. Ultrasound-guided popliteal block demonstrates an atypical motor response to nerve stimulation in 2 patients with diabetes mellitus. Reg Anesth Pain Med. 2003,28(5): 479–82.
6. Chin KJ, Chan V. Ultrasound-guided peripheral nerve blockade. Current Opinion in Anaesthesiology. 2008,21(5): 624–631.
7. Eichenberger U, Stöckli S, Marhofer P, Huber G, Willimann P.et al. Minimal local anesthetic volume for peripheral nerve block: a new ultrasound-guided, nerve dimension-based method. Reg Anesth Pain Med. 2009,34(3): 242-246.
8. Keplinger M, Marhofer P, Marhofer D, Schroegendorfer K, Haslik W.et al. Effective local anaesthetic volumes for sciatic nerve blockade: a clinical evaluation of the ED99. Anaesthesia. 2015,70(5): 585-590.
9. Schroeder K, Andrei AC, Furlong MJ, Donnelly MJ, Han S, Becker AM.et al. The perioperative effect of increased body mass index on peripheral nerve blockade: an analysis of 528 ultrasound guided interscalene blocks. Rev Bras Anestesiol. 2012,62(1): 28-38.
10. Sites BD, Gallagher J, Sparks M. Ultrasound-guided popliteal block demonstrates an atypical motor response to nerve stimulation in 2 patients with diabetes mellitus. Reg Anesth Pain Med. 2003,28(5): 479-482.
11. Sima AA, Thibert P. Proximal motor neuropathy in the BB-Wistar rat. Diabetes. 1982,31(9): 784-788.
12. El-Salem K, Ammari F, Khader Y, Dhaimat O. Elevated glycosylated hemoglobin is associated with subclinical neuropathy in neurologically asymptomatic diabetic patients: a prospective study. J Clin Neurophysiol. 2009,26(1): 50-53.
13. Hebl JR, Kopp SL, Schroeder DR, Horlocker TT. Neurologic complications after neuraxial anesthesia or analgesia in patients with preexisting peripheral sensorimotor neuropathy or diabetic polyneuropathy. Anesth Analg. 2006,103(5): 1294-1299.
14. Kalichman MW, Calcutt NA. Local anesthetic-induced conduction block and nerve fiber injury in streptozotocindiabetic rats. Anesthesiology. 1992,77(5): 941-947.
15. Kytta J, Heinonen E, Rosenberg PH, Wahlström T, Gripenberg J.et al. Effects of repeated bupivacaine administration on sciatic nerve and surrounding muscle tissue in rats. Acta Anaesthesiol Scand. 1986,30(8): 625–629.
16. Marhofer P, Schrogendorfer K, Wallner T, Koinig H, Mayer N.et al.Ultrasonographic guidance reduces the amount of local anesthetic for 3-in-1 blocks. Reg Anesth Pain Med. 1998, 23(6):5 84-588.
17. Williams SR, Chouinard P, Arcand G, Harris P, Ruel M.et al. Ultrasound guidance speeds execution and improves the quality of supraclavicular block. Anesth Analg. 2003,97(5): 1518-1523.
18. Casati A, Baciarello M, Di Cianni S, Danelli G, De Marco G.et al. Effects of ultrasound guidance on the minimum effective anaesthetic volume required to block the femoral nerve. Br J Anaesth. 2007,98(6): 823-827.
19. Duggan E, El Beheiry H, Perlas A, Lupu M, Nuica A.et al. Minimum effective volume of local anesthetic for ultrasound-guided supraclavicular brachial plexus block. Reg Anesth Pain Med. 2009,34(3): 215-218.
20. Cappelleri G, Ambrosoli AL, Turconi S, Gemma M, Ricci EB.et al.Effect of local anesthetic dilution on the onset time and duration of double-injection sciatic nerve block: a prospective, randomized, blinded evaluation. Anesth Analg. 2014,119(2): 489-493.
21. Cuvillon P, Reubrecht V, Zoric L, Lemoine L, Belin M.et al. Comparison of subgluteal sciatic nerve block duration in type 2 diabetic and non-diabetic patients. Br J Anaesth. 2013,110(5): 823-830.
22. Lindström P, Lindblom U, Brismar T. Delayed recovery of nerve conduction and vibratory sensibility after ischaemic block in patients with diabetes mellitus. J Neurol Neurosurg Psychiatry. 1997,63(3): 346-350.
23. Sertoz N, Deniz MN, Ayanoglu HO. Relationship between glycosylated hemoglobin level and sciatic nerve block performance in diabetic patients. Foot Ankle Int. 2013,34(1): 85-90.
24. Johnson ME, Saenz JA, DaSilva AD, Uhl CB, Gores GJ. Effects of local anesthetic on neuronal cytoplasmic calcium and plasma membrane lysis (necrosis) in a cell culture model. Anesthesiology. 2002,97(6): 1466–1476.
25. Johnson ME, Uhl CB, Spittler KH, Wang H, Gores GJ. Mitochondrial injury and caspase activation by the local anesthetic lidocaine. Anesthesiology. 2004,101(5): 1184–1194.
26. Unami AY, Shinohara Y, Ichikawa T, Baba Y. Biochemical and microarray analyses of bupivacaine-induced apoptosis. J Toxicol Sci. 2003,28(2): 77–94.
27. Lirk P, Rutten MV, Haller I, Stevens MF, Laudolff-Birmingham J.et al. Management of the patient with diabetic peripheral neuropathy presenting for peripheral regional anesthesia: a European survey and review of literature. Minerva Anestesiol. 2013,79(9): 1039-1048.
28. Paqueron X, Boccara G, Bendahou M, Coriat P, Riou B. Brachial plexus nerve block exhibits prolonged duration in the elderly. Anesthesiology 2002, 97(5): 1245–1249.
29. Pavi?i? Sari? J, Vidjak V, Tomuli? K, Zenko J. Effects of age on minimum effective volume of local anesthetic for ultrasound-guided supraclavicular brachial plexus block. Acta Anaesthesiol Scand. 2013,57(6): 761-766.