Intravenous Regional Anesthesia Research Articles

Comparative study of 0.5% lignocaine with dexmedetomidine and 0.5% lignocaine in intravenous regional anesthesia

Comparative study of 0.5% lignocaine with dexmedetomidine and 0.5% lignocaine in intravenous regional anesthesia

A Study of Effectiveness of Dexmedetomidine in Intravenous Regional Anesthesia as an Adjuvant to Lignocaine

A Study of Effectiveness of Dexmedetomidine in Intravenous Regional Anesthesia as an Adjuvant to Lignocaine

Comparison of Tramadol and Butorphanol as Adjuncts to Lignocaine for Intravenous Regional Anaesthesia for Upper Limb Surgeries

Comparison of Tramadol and Butorphanol as Adjuncts to Lignocaine for Intravenous Regional Anaesthesia for Upper Limb Surgeries

Comparative Clinical Study of 0.5% Lignocaine Alone and Combination of 0.25% Lignocaine Withpentazocine and Pancuronium In Intravenous Regional Anaesthesia for Upper Limb Orthopaedic Surgeries

Comparative Clinical Study of 0.5% Lignocaine Alone and Combination of 0.25% Lignocaine Withpentazocine and Pancuronium In Intravenous Regional Anaesthesia for Upper Limb Orthopaedic Surgeries

Simulation and Web-based learning increases utilization of Bier block for forearm fracture reduction in the pediatric emergency department.

Bier block (BB) is a safe and effective alternative to procedural sedation for analgesia during forearm fracture reductions, yet remains infrequently used in the pediatric emergency department (PED). No standardized methods of BB training have previously been described. The objective of this study was to determine whether a multimodal instructional course increases comfort with BB and translates to increased use of this technique. A novel interdisciplinary simulation and Web-based training course was developed to teach the use of BB for forearm fracture reduction at a tertiary PED. Participants were surveyed pre-/post-training, and at 2 and 6 months regarding their comfort with BB. In parallel, we prospectively assessed the clinical use of BB for children ages 6 to 18 years requiring closed reduction of forearm fractures during the 24-month post-course period. Course participation included 26 physicians and 12 nurses. Survey response rate was 100%. Course participation increased both comfort (10% pre-training v. 89% post-training, p<0.001) and the willingness to use BB (51% pre-training v. 95% post-training, p<0.001), an effect sustained at 6 months post-course (66% and 92%, respectively, p<0.001 for both). In clinical practice, there were no BBs performed prior to course administration. We observed a consistent and sustained increase in clinical use among the BB-trained physicians, with 37% of all forearm reductions performed using BB at 24 months post-course completion. A novel combined simulation and Web-based training course increased comfort and willingness to use BB and was associated with increased use of this technique for forearm fracture reduction in the PED.

Analgesic Effect of Nalbuphine When Added to Intravenous Regional Anesthesia: A Randomized Control Trial

Background: Different adjuvant drugs are currently added to lidocaine for intravenous regional anesthesia (IVRA) to decrease tourniquet and postoperative pain. Objective: The aim of the study was to examine the effect of nalbuphine when added to IVRA. Study Design: Prospective, randomized, double-blind, controlled clinical trial. Setting: Assiut University Hospitals. Methods: One hundred-six adult patients scheduled for unilateral hand surgery under IVRA were randomized into 2 equal groups. The lidocaine-nalbuphine (LN) group received nalbuphine plus lidocaine and the lidocaine (L) group received lidocaine. A tourniquet and postoperative pain were assessed using a visual analogue scale (VAS). The following parameters were measured: onset and recovery time for both sensory and motor blocks, intra- and postoperative analgesic consumption, time to first analgesic request, postoperative nausea and/or vomiting (PONV), hemodynamics, and cortisol levels. Results: Early tourniquet and postoperative pain were significantly lower in the LN group. The onset time for both sensory and motor blocks was significantly shorter in the LN group. In addition, the recovery time for both sensory and motor blocks was longer in the LN group. Intra- and postoperative fentanyl consumption was significantly lower in the LN group with no significance in postoperative diclofenac consumption. The patient first analgesic request was significantly delayed in the LN group (P &lt; 0.0001). There were no significant differences between the 2 groups in PONV, hemodynamic parameters abnormalities, medications adverse events or cortisol levels. Limitations: The inclusion of a study group in which the nalbuphine administered systemically could determine whether its beneficial effects were due to its local or systemic action. Conclusions: Nalbuphine decreases early tourniquet and postoperative pain after IVRA and delays the need for analgesic rescue. In addition, nalbuphine accelerates the onset and prolongs the recovery time for both sensory and motor blocks with no significant adverse events. However, it has no effect on postoperative cortisol levels. Key words: Intravenous, regional anesthesia, lidocaine, nalbuphine, pain, postoperative

Anesthesia for medical students : A brief guide to practical anesthesia in adults with a web-based video illustration

In Germany, Austria and Switzerland, anesthesiologists are the second largest group of physicians in hospitals, but this does not correspond to the amount of anesthesiology teaching that medical students receive in medical schools. Accordingly, the chances of medical students recognizing anesthesiology as apromising personal professional career are smaller than in other disciplines with large teaching components. Subsequent difficulties to recruit anesthesiology residents are likely, although many reasons support anesthesiology as aprofessional career.Traditional strategies to teach medical students in anesthesiology in medical school consist of airway management or cardiopulmonary resuscitation attempts in manikins. Anesthesiology is acomplex interaction consisting of anatomy, physiology, pharmacology, clinical evaluation, experience, knowledge, and manual skills. While some medical schools offer teaching in high fidelity simulators, clinical teaching in the operating room is often limited. When medical students opt for aclinical rotation in anesthesiology, there is achance to demonstrate the fascinating world of anesthesiology, but this chance has to be utilized carefully by anesthesiologists, as young talents have to be discovered, supported, and challenged.We have put together ashort guide for medical students for aclinical rotation in anesthesiology in adults in order to generate basic knowledge and interest in anesthesiology as well as asense of achievement. Basic knowledge about premedication, induction, maintenance and strategies for anesthesia is discussed. Further, the most important anesthesia drugs are discussed and manual skills, such as intravenous cannulation, mask ventilation, intubation, and regional anesthesia are featured with QR-code based video illustrations on asmartphone or personal computer. We did not discuss possible local mannerism and special patient groups (e. g., children, special medical history), local guidelines, or standard operating procedures.Medical students can be inspired by anesthesiology when not simply told about the tools of the trade and strategies, but instead by gaining knowledge and clinical skills that render asense of achievement, likely during aclinical rotation into anesthesiology. Ashort theoretical instruction of anesthesiology enables rapid and targeted orientation even before aclinical rotation. Whether this subsequently results in ahigher recruiting chance is currently unknown.

6 Intravenous Regional Anesthesia for Pediatric Forearm Fractures in a Pediatric Emergency Department: Experience in the Last 12 Years 2003-2014

6 Intravenous Regional Anesthesia for Pediatric Forearm Fractures in a Pediatric Emergency Department: Experience in the Last 12 Years 2003-2014

Study of Efficacy of Tramadol as an Adjuvant to Lignocaine in Intravenous Regional Anesthesia at a Tertiary Care Teaching Centre

Introduction: Tramadol is a central analgesic with an opioid agonistic activity with some selectivity for µ-receptors. Several studies showed that tramadol is beneficial as an additive to local anesthetics in different regional nerve blocks including infiltration, caudal block, brachial plexus block and IVRA. However, the existing data on its role as an additive for IVRA are conflicting. Therefore, a prospective, randomized controlled trial was conducted to determine efficacy of Tramadol (100mg) as an intra-operative, post-operative and pre-emptive analgesic as an adjuvant to lignocaine in IVRA. Materials and Methods: Present study was carried out in 80 patients undergoing upper arm orthopedic surgery at Sharda Hospital, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India. All patients selected were planned for forearm surgeries, of ASA Grade I or II, aged 16-60 years. Patients received 0.5% lignocaine 40 ml in one group and we added Tramadol 100 mg in the other group. All the patients were monitored for onset of effect, quality of anesthesia, post op analgesia after deflation of tourniquet, time of first analgesic drug and number of analgesic drug required in first 24 hrs. Results: Onset of sensory analgesia was significantly earlier in group B (59.7±23.8 sec v/s 196.3±42.7) while onset of motor paralysis was similar in both groups. The post-operative analgesia was significantly longer in group B (304.7 ± 87.9 mins) then group A (12.6 ± 5.1 mins). Accordingly the number of analgesics consumed in post-operative first 24 hours was significantly less in group B (1.2±0.6) then group A (2.9±0.8). Conclusion: Tramadol has favorable effects as an adjuvant to lignocaine for IVRA. Tramadol substantially shortens the onset of sensory block, improves patient’s tolerance of tourniquet, prolongs the duration of analgesia after deflation of tourniquet and reduces the postoperative analgesic consumption.

NEOSTIGMINE

Objectives: To compare the effect of Neostigmine as an Adjunct to 0.5%Lignocaine for increasing the duration of anesthesia and analgesia. Study Design: Randomizedcontrolled trial. Setting: Department of Anesthesiology, Nishtar Hospital, Multan. Period: January20014 to January 2015. Material and Methods: One hundred (100) patients were selected forthis study. Microsoft Excel 2013 was used for data analysis. Frequacy and percentage wereused to present categorical varibales and mean+standard deviation for numerical variables.Results: There was a rapid onset of Sensory and motor blocks in neostigmine group, 3.9+2.5minutes for sensory block and 5.8+2.3 minutes for motor block versus 9.3+2.2 minutes and13.3+2.0 minutes respectively in control group. The time of recovery of sensory and motorblocks was delayed in neostigmine group as compared to the control group patients. Thesurgeons agreed that the anesthesia was perfect in 46 (92.0%) cases in neostigmine groupand in control group IVRA declared to be perfect in only 34 (68.0%) cases. Dryness of operativefield was same between the two groups. Conclusion: The addition of neostigmine in lignocainesolution for intravenous regional anesthesia improves the quality of anesthesia and analgesia.

Addition of Dexmedetomidine to Low Dose Solution of Lidocaine for Intravenous Regional Anesthesia A Randomized Study

Background and Aims: Intravenous Regional Anesthesia (IVRA) provides analgesia of distal part of limb by intravenous injection of local anesthesia in to the vein of the same limb, while the circulation to the limb is occluded by application of tourniquet. However, IVRAis limited by local anesthesia toxicity, tourniquet pain and absence of postoperative analgesia. Various additives to local anesthetics such as ketamine, clonidine, opiods, NSAIDs are used to address these issues. The aim of our study was to evaluate the effectiveness of Dexmedetomidine to low dose Lidocaine solution for IVRA.Patients and Methods: A prospective, randomized double blind study was conducted on 60 patients divided in to two groups of thirty each; Group I patients received 40 ml of Lidocaine 0.25% while Group II patients received 40 ml of 0.25% of lidocaine mixed with I mcg/kg of dexmedetomidine. The motor and sensory block onset and recovery times were assessed. Tourniquet pain and sedation score were assessed intraoperatively and postoperatively.Results: Sensory and motor block onset times were shorter and recovery times were prolonged in Dexmedetomidine group. The quality of anesthesia was better in the Dexmedetomidine group and the fentanyl dose required was also lower in the dexmedetomidine group. There was a significant difference in the postoperative analgesia time which was demonstrated by less use of intramuscular diclofenac in dexmedetomidine group.Conclusions: A safe intravenous dose of lidocaine can be used for IVRA for superficial hand surgery, and the addition of I mcg /kg dexmedetomidine shortened the onset times for both sensory and motor blockade and improved the quality of anesthesia, with prolonged postoperative analgesia time. By adding dexmedetomidine we were able to reduce the dose of lidocaine to 0.25% concentration without compromising analgesia. JMS 2016; 19(1):21-25

Anaesthetic management of forearm fractures using a combination of haematoma block and intravenous regional anaesthesia

BackgroundIntravenous regional anaesthesia (IVRA) has been successfully used as a sole technique for forearm fractures and has high success rates. However, it is uncomfortable for the patient when the fresh fracture is manipulated for conduct of IVRA. Haematoma block (HB) has also been demonstrated as an effective anaesthetic technique for treatment of radial fractures in the ER. Unfortunately, HB does not provide muscular relaxation and may not be sufficient for operative intervention. MethodsAn observational case series was designed with the hypothesis that a combination of HB and IVRA would overcome the aforementioned drawbacks. A standardized protocol was followed for HB with 0.1ml/kg of 0.5% bupivacaine preceding the conduct of IVRA, which permitted adequate exsanguination of the extremity (using compression bandage). For IVRA, 0.5% lignocaine at 3mg/kg was used with an electro-pneumatic tourniquet. Pain scores were noted after the HB, at exsanguination and during surgery. Results100 cases were studied. Average time of onset of block after HB was 2min 18s. By the time the IVRA procedure was performed, 99% of patients had a pain score of zero. The quality of surgical anaesthesia revealed that 94% of the patients did not have any pain of incision, tourniquet or positioning at any time during surgery. ConclusionThe use of dual technique of HB and IVRA improved patient acceptance and compliance, and the safety and efficacy of the IVRA. The combination anaesthesia was found to be easy to administer, effective and safe with no complications.

Randomized Controlled Study of Intravenous Regional Anaesthesia for Forearm &amp; Hand Surgery: Comparison of Lignocaine, Lignocaine with Ketamine &amp; Lignocaine with Dexmedetomidine

Randomized Controlled Study of Intravenous Regional Anaesthesia for Forearm &amp; Hand Surgery: Comparison of Lignocaine, Lignocaine with Ketamine &amp; Lignocaine with Dexmedetomidine

Simple Arm Tourniquet as an Adjunct to Double-Cuff Tourniquet in Intravenous Regional Anesthesia.

Background:Intravenous Regional Anesthesia (IVRA) is a well-known technique for producing analgesia during surgical procedures in the extremities. However, the rapid onset of pain following the deflation of a double-cuff tourniquet during IVRA is a serious disadvantage, leading patient suffering.Objectives:The aim of this study was to evaluate the clinical effectiveness of a pneumatic arm tourniquet applied 2 cm above the double-cuff tourniquet in controlling the pain that occurs after its deflation.Patients and Methods:Twenty patients undergoing outpatient hand surgery were operated on under IVRA, using 40 - 50 mL of a solution containing 3 mg/kg of lignocaine. A simple pneumatic tourniquet was applied proximal to the double-cuff tourniquet, 3 min before its deflation, while the procedure was being conducted. The severity of pain on the basis of the Numerical Rating Scale (NRS) was assessed throughout the operation, and continued until an hour after the double-cuff tourniquet was removed.Results:The mean operation time after the deflation of the double-cuff tourniquet was 20.12 ± 6.1 minutes. Moreover, the mean NRS for the post-deflation time was insignificant (NRS = 2), and only one patient during first 20 minutes received opioids.Conclusions:This study showed that a pneumatic arm tourniquet as an adjunct to IVRA provides acceptable analgesia following the deflation of the double- cuff tourniquet for relieving surgical pain.

LO055: Increased utilization of Bier block for pediatric forearm fracture reduction following simulation and web-based training

Introduction: Bier block (BB) regional intravenous anesthesia is a safe and effective alternative to procedural sedation for analgesia during forearm fracture reductions, yet BB remains infrequently utilized in the Pediatric Emergency Department (PED). No standardized methods of BB training have previously been described. The objectives of this study were to evaluate comfort and level of experience with BB in the PED, and to determine if a multimodal instructional course increases these from baseline and translates to increased utilization of this technique. Methods: A novel interdisciplinary simulation and web-based training course was developed to teach the use of BB for forearm fracture reduction at a tertiary PED. Participants were surveyed pre/post training, and at 2- and 6-months regarding their comfort with and willingness to use BB. In parallel, we prospectively assessed the clinical utilization of BB in the PED during the 24-month period immediately following course completion. Results: Course participation included 38 members of the PED (N = 26 physicians, 12 nurses), and survey response rate was 100% at all time points. Respondents reported that course participation increased both their comfort (10% pre vs. 89% post-training, p&lt;0.001) and willingness (51% pre vs. 95% post-training, p&lt;0.001) to use BB for forearm fracture reduction, an effect that was sustained at 6-months following course completion (66% and 92%, respectively, p&lt;0.001 for both). Before course attendance, only 6% of respondents indicated that they had ever used BB in a PED setting, and all participants indicated that the course addressed their learning objectives. In clinical practice, there were no BB performed prior to course administration. We observed a consistent and sustained increase in the clinical utilization of BB, with 39% of all PED forearm reductions performed using BB at 24-months post-course completion (114 BB, 17 unique physicians). Conclusion: A combined simulation and web-based training course increased comfort and willingness to use BB and was associated with increased utilization of this technique for forearm fracture reduction in the PED.

LO065: Reduced length of stay and adverse events using Bier block for forearm fracture reduction in the pediatric emergency department

Introduction: Distal forearm fractures are one of the most common injuries presenting to the pediatric emergency department. Procedural sedation (PS) is commonly used to provide analgesia during fracture reduction, but requires a prolonged recovery period and can be associated with adverse respiratory events. Bier block (BB) regional anesthesia is a safe alternative to PS for fracture reduction analgesia. We sought to assess the impact of BB on length of stay (LOS) and adverse events following forearm fracture reduction compared to PS. Methods: We performed a retrospective study of patients aged 6 to 18 years, presenting with forearm fractures requiring closed reduction from June 2012 to March 2014. The primary outcome measure was emergency department LOS; secondary outcomes included reduction success rates, adverse events and unscheduled return visits. Results: Two-hundred and seventy-four patients were included for analysis; 109 treated with BB, 165 underwent PS. Overall, mean LOS was 82 min shorter for patients treated in the BB group (279 min vs. 361 min, p&lt;0.05). Sub-analysis revealed a reduced LOS among patients treated with BB for fractures involving a single bone (286 min vs. 388 min, p&lt;0.001) and both-bones of the forearm (259 min vs. 321 min, p&lt;0.05). Both BB and PS resulted in comparable rates of successful reduction (98.2% vs. 97.6%, p=0.74). There were no major adverse events in either group. Patients who received BB experienced significantly fewer minor adverse events (2.7% vs. 14.5%, p&lt;0.05). Return visit rates were similar in the BB and PS groups (17.6% vs. 17.1%, p&lt;0.05). Conclusion: Compared to PS, forearm fracture reduction performed with BB was associated with a reduced emergency department LOS and fewer adverse events, with no difference in reduction success or return visits.

A double-blind trial of the combination effect of lidocaine, ketamine and verapamil in intravenous regional anesthesia

BackgroundThe aim of this study was to evaluate the effects of adding two different doses (2.5 mg or 5 mg) of verapamil to lidocaine ketamine (0.5 mg/kg) during Intravenous Regional Anesthesia (IVRA) compared with lidocaine with ketamine alone.MethodsSeventy-five patients, aged 18–50 years, ASA physical status I and II undergoing elective hand or forearm surgery under Bier’s Block lasting one to one and half hours were included in this randomized controlled double-blind study. Patients were divided into three groups, 25 each to receive either group (I, control group) received 40 ml of 0.5% Lidocaine plus ketamine (0.5 mg/kg), group (II) received as group I plus verapamil 2.5 mg or group (III) received as group I plus verapamil 5 mg for IVRA. Postoperative assessment of block characteristics, sedation, pain, first time for rescue analgesia, hemodynamic changes and side effects were evaluated over a period of 12 h.ResultsBlock characteristics were significant in groups II and III compared with group I. There were significant hemodynamic changes, sedation score, pain score and delayed first request for analgesics postoperatively in groups (II) and (III) compared to group (I) postoperatively. There was no significant difference in group (III) compared to group (II) postoperatively. The incidence of postoperative side effects were more in group (III).ConclusionAdding verapamil 2.5 mg to Lidocaine plus ketamine (0.5 mg/kg) for IVRA was effective and safe adjuvant for acute pain after surgery.

A randomized controlled study of the effects of adding ultra-low dose naloxone to lidocaine for intravenous regional anesthesia

ObjectiveThis study was designed to evaluate the effect of adding ultra-low dose of naloxone as an adjuvant to lidocaine for intravenous regional anesthesia (IVRA).MethodForty patients undergoing elective short procedures in the upper limb were randomly and blindly divided into two groups of twenty patients each. Group L (n = 20) received 3 mg/kg of 2% lidocaine diluted with normal saline to 30 ml. Group LN (n = 20) received 3 mg/kg of 2% lidocaine and naloxone 100 ng (1 ml) diluted with normal saline to 30 ml. Onset and recovery time of sensory and motor block, intraoperative and post-operative pain were measured by visual analog score (VAS), and also intraoperative analgesic requirement, time of first requirement of diclofenac postoperatively, total amount of diclofenac needed in 24 h, patient’s satisfaction and surgeon’s satisfaction scores were measured.ResultsRecovery of sensory block was significantly longer in group LN (26.7 ± 2.8 min) compared to group L (16.3 ± 0.6 min); p value (0.000). Also the recovery of motor block was significantly longer in group LN (19.1 ± 1.0 min) compared to group L (17.9 ± 1.2 min), p value (0.002). Intraoperative fentanyl requirement was significantly less in group LN (15.8 ± 5.0 mcg) compared to group L (40.0 ± 10.5 mcg), p value (0.000). 1st fentanyl requirement time was significantly longer in group LN (22.4 ± 3.1 min) than in group L (14.5 ± 6.1 min), p value (0.000). Time of first analgesic requirement post-operative was longer in group LN (78.5 ± 6.8 min) compared to group L (40.5 ± 2.0 min), p value (0.000). Total amount of diclofenac needed in 24 h was significantly less in group LN (57 ± 50 mg) compared to group L (120 ± 45 mg), p value (0.000).ConclusionThe addition of ultra-low-dose naloxone 100 ng to lidocaine for IVRA in upper limb surgery, prolonged the duration of sensory and motor block, and reduced tourniquet pain, as well as intraoperative and postoperative analgesic consumption.

Effect of preoperative gabapentin on pain intensity and development of chronic pain after carpal tunnel syndrome surgical treatment in women: randomized, double-blind, placebo-controlled study.

Effective postoperative analgesia is important for reducing the incidence of chronic pain. This study evaluated the effect of preoperative gabapentin on postoperative analgesia and the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgical treatment. Randomized, double-blind controlled trial, Federal University of São Paulo Pain Clinic. Forty patients aged 18 years or over were randomized into two groups: Gabapentin Group received 600 mg of gabapentin preoperatively, one hour prior to surgery, and Control Group received placebo. All the patients received intravenous regional anesthesia comprising 1% lidocaine. Midazolam was used for sedation if needed. Paracetamol was administered for postoperative analgesia as needed. Codeine was used additionally if the paracetamol was insufficient. The following were evaluated: postoperative pain intensity (over a six-month period), incidence of postoperative neuropathic pain (over a six-month period), need for intraoperative sedation, and use of postoperative paracetamol and codeine. The presence of neuropathic pain was established using the DN4 (Douleur Neuropathique 4) questionnaire. Complex regional pain syndrome was diagnosed using the Budapest questionnaire. No differences in the need for sedation, control over postoperative pain or incidence of chronic pain syndromes (neuropathic or complex regional pain syndrome) were observed. No differences in postoperative paracetamol and codeine consumption were observed. Preoperative gabapentin (600 mg) did not improve postoperative pain control, and did not reduce the incidence of chronic pain among patients undergoing carpal tunnel syndrome surgery.

Comparative study of ketorolac versus butorphanol as an adjuvant in Intravenous regional anaesthesia (IVRA)

Background: Intravenous regional anaesthesia (IVRA) is simple, effective technique for upper limb orthopaedic surgeries specifically in developing countries like India because of cost- effectiveness. IVRA is also called Bier’s block after the name of its inventor August Bier. Aim: Present study was carried out to evaluate the effects of adding either butorphanol or ketorolac to lignocaine during Bier’s block. Materials and Methods: In a prospective randomized double blind study, 60 patients of age group 18-65 years of either sex with weight range of 65-70 kg of ASA grade I- III were randomly allocated into two groups of 30 each. Group I received butorphanol 1mg added to 3mg/kg lignocaine and group II received ketorolac 30 mg added to 3mg/kg lignocaine. Sensory and motor block onset, regression time, intraoperative and postoperative VAS score, duration of analgesia, total analgesic consumption in first 24 hr and side effects were noted. Statistical analysis of data was based on chi square test and post hoc test. Results: Demographic profile in both the groups was same. Duration of analgesia was significantly prolonged in group II(10.8 ±6.42) as compared to group I(3.02±1.52). In both the groups, patients remained haemodynamically stable and side effects and complications were also comparable. Conclusion: Ketorolac with lignocaine in IVRA provides prolonged post-operative analgesia as compared to butorphanol and lesser number of patients require rescue analgesia intraoperatively as well as postoperatively without any significant side effects.