This randomized clinical trial aimed to compare the preparation time and severity of postoperative pain between HyFlex Electric Discharge Machine (EDM) glide path file (GPF) and PathFile.P ≤ 0.05).Eighty patients whose molar teeth had at least one severely curved canal were treated by the same specialist. After access cavity preparation, the patients were randomly assigned to receive glide path enlargement with either HyFlex EDM GPF or PathFile. ProTaper Next X1 and X2 files were used to prepare the canals. The time of preparation was assessed and the severity of postoperative pain over the next 7 days was recorded. The preparation time and the postoperative pain scores were compared using the Linear Mixed Models (P < 0.001). The highest postoperative pain score was recorded on the first day and the pain decreased over time in both groups. HyFlex EDM GPF group patients reported significantly less postoperative pain than PathFile group patients overall (P < 0.001).Glide path enlargement time was significantly shorter with HyFlex EDM GPF (27.828 ± 2.345 s) than with PathFile (48.942 ± 2.864 s) (Postoperative pain and glide path preparation time could be reduced by using HyFlex EDM GPF system.Trial registration PKUSSNCT, PKUSSNCT-17B12, Registered 24 October 2017. Endodontic postoperative pain is a sensation of discomfort experienced by 25–40% of patients after root canal treatment , 2. PostThe endodontic glide path is the smooth tunnel created from the orifice of the root canal to the physiological terminus of the root apex, which facilitates cleaning and shaping during root canal treatment . PrelimiThe HyFlex EDM  NiTi GPF is a GPF file system produced using an innovative manufacturing process called Electrical Discharge Machine with a controlled memory (CM) wire. In EDM, instead of conventional grinding, electric discharges are used to shape the file via melting and vaporization of the material . This meThe PathFile  NiTi rotary system consists of three file systems, which are made of conventional NiTi alloy with different tip sizes such as 13#, 16#, and 19#. The files have square cross-sections, with four cutting edges and a 2% taper. Glide path preparation with PathFile promotes less deviation from the original canal anatomy when compared with hand-operated instruments .The effect of GPFs on postoperative pain has not been adequately investigated. Therefore, the aim of this study was to compare the preparation time and severity of postoperative pain with two glide path preparation systems—HyFlex EDM GPF versus PathFile.The study was approved by the local university clinical research ethics committee with vide letter no. PKUSSIRB-201735063. Prior to this clinical trial, we did an in vitro simulated root canal study. We compared the shaping ability and preparation time of HyFlex EDM GPF with PathFile in simulated root canals. Using PASS software, the required sample size in this study was determined by comparing the mean preparation time for HyFlex EDM GPF and PathFile. In this study, two-tailed hypothesis test was used, with a test level of 0.05 and a power of 90%.According to existing literatures on evaluation preparation time, the mean of HyFlex EDM GPF in the experimental group was 196.825 s, with standard deviation of 10.328 s, and the mean of the control group was 229.633 s, with standard deviation of 16.870 s. The sample size of each group was calculated according to 1:1 matching. Further stratified comparison of samples was considered in the analysis, and the sample size should be at least 8–10 times the number of variables in the multi-factor analysis. Therefore, appropriately increasing the sample size was considered, and the sample size of 40 people in each group designed in this study can basically meet the needs of analysis.The sample consisted of 80 patients who were treated at the Second Dental Center of Peking University School of Stomatology between June 2018 and February 2019. The following inclusion criteria had to be fulfilled by the patients to be enrolled in the study: (1) More than 18 years old. (2) No previous history of systemic diseases. (3) Selected for root canal treatment for asymptomatic or symptomatic irreversible pulpitis in the maxillary or mandibular first or second molars with at least one severely curved canal . The diagnosis of symptomatic irreversible pulpitis was based on positive pulp sensibility test results of a cold test and an electric pulp test, presence of spontaneous pain, and deep caries or extensive restorations exposing the pulp. The diagnosis of asymptomatic irreversible pulpitis was based on no clinical symptoms and presence of a deep caries that will result in a pulp exposure following removal. The diagnosis was recorded after access cavity preparation with the presence of bleeding. Periapical radiographs were taken for each patient using a digital radiologic system . Curvatures of the curved canals were analysed by 2 blinded examiners who were specialists in endodontics. If conflicts existed, a third opinion was obtained from another endodontist. Kappa test using a case series of interexaminer reliability above 0.90, was reached prior to the trial.The exclusion criteria were (1) Pulp necrosis, with or without apical periodontitis, based on negative pulp cold and electirc tests and periradicular radiographic feature, diagnosis recorded after access cavity preparation without bleeding. (2) Acute or chronic apical abscess with signs of systemic infection. (3) Allergic to local anesthetic agents. (4) Progressive periodontal disease at any stage . (5) Taking analgesic, antibiotic or anti-inflammatory drugs during the 7 days prior to the treatment.Before the procedure, pulpal and periradicular status was evaluated by means of a cold test and an electric pulp tester , reactions to palpation and percussion also recorded. Periodontal probing was performed and periradicular radiographic image was taken and analysed. These datas were recorded on each patient’s clinical note, together with baselined emographic information Table . At thisThe working length (WL) was determined using the Root ZX apex locator  by inserting a size 10 K-file into the root canal up to the apical foramen. The WL was confirmed radio-graphically and was also repeatedly checked during the treatment procedure. The HyFlex EDM GPF (size 10/0.05) was operated with an endomotor  in continuous rotation at a speed of 300 rpm and 1.8 N·cm of torque, according to the manufacturer’s instructions. Irrigation with 5.25% NaOCl and 17% EDTA was carried out during the glide path enlargement and the preparation time was recorded from the insertion of the GPF till the completion of the enlargement, including irrigation time during the enlargement. After the instrumentation was completed, the root canal was irrigated with 5 mL of 5.25% NaOCl and 5 mL of 17% EDTA.The WL was determined as described above in the HyFlex EDM GPF group. The PathFile (size 13/0.02 and 16/0.02) instruments were operated using the same endomotor (X-SMART) at a speed of 300 rpm and 5 N·cm of torque. Irrigation with 5.25% NaOCl and 17% EDTA was carried out during the glide path enlargement and the preparation time was recorded from the insertion of the PathFile 13/0.02 till the completion of the PathFile 16/0.02 enlargement, including the irrigation time during the enlargement and the time required to change files. After enlargement, the root canal was irrigated with 5 mL of 5.25% NaOCl and 5 mL of 17% EDTA.After glide path creation, subsequent endodontic procedures were standardized as per the protocol. The root canals were then prepared with X1 and X2 instruments by using the ProTaper Next  rotary instrumentation system and then irrigated with 5.25% NaOCl and 17% EDTA.The preparation time of the severely curved canal for the GPFs and ProTaper Next was recorded. Only the time used for active instrumentation such as checking the WL, cleaning the flutes of the instruments, and irrigation were included. The time taken to change files was not considered. The preparation time was recorded by a nurse and other canals for the same molar were prepared using only the ProTaper Next.2) was placed in the canals, temporary filling was performed, and an appointment was scheduled to complete the subsequent root canal procedure. Finally, all patients were informed about the possible pain and were instructed how to complete a visual analog scale (VAS) to determine their postoperative pain scores. The pain score was recorded on a scale of 0–10. Pain intensity was categorized as no pain (0), mild pain (1–3), moderate pain (4–6), and severe pain (7–10). The patients were instructed to record postoperative pain intensity twice daily (morning and evening) for 1 week using a visual analog scale (VAS) on paper. They were recommended to take ibuprofen 600 mg when required. All patients returned the original copies of the VAS form on the next visit.Accordingly, the prepared root canals were irrigated again with 10 mL of 5.25% NaOCl with a 30-gauge needle syringe and then dried with sterile paper points. Calcium hydroxide (Ca(OH)P ≤ 0.05 (two-tailed). Considering that multiple pain measurements were performed for the same individual within 7 days after the preparation of the curved root canal, the Linear Mixed Models was used to analyze the differences between groups and the trend of pain changes over time in different groups.SPSS version 20.0  was used for statistical analysis. The distributions of age, sex, the tooth treated, and the angle of root canal curvature in the two treatment groups were compared by using the chi-square test or t test. The preparation time and the postoperative pain scores were compared using the Linear Mixed Models. Statistical significance was recognized at P > 0.05, Table The age of the patients was between 23 and 73 years old, 48.1 ± 14.1 (12 men and 28 women) in the HyFlex EDM GPF group compared to 45.5 ± 14.4 (11 men and 29 women) in the PathFile group. Regarding the tooth type, 19 first molars and 21 second molars were included in each group. The angle of the root canal was 28.8° ± 6.8° in the HyFlex EDM GPF group and 26.5° ± 8.3° in the PathFile group. Demographic variables such as age and sex and clinical variables such as the tooth type and the angle of the root canal curvature were similarly distributed in the two treatment groups .Table No patients reported endodontic interappointment emergencies and analgesics intake. There was no severe pain in both groups during the first week after the procedure. The highest postoperative pain score was recorded on the first day. All of the patients had mild or moderate pain on the first day, but the pain decreased over time in both groups Table .Table 3DP value of less than 0.05  for 1 week after root canal preparation. The vertical axis consisted of the mean VAS scores. HyFlex EDM GPF group patients reported significantly less postoperative pain than PathFile group patients overall, with a significant F = 91.223, P < 0.001). There were statistically significant differences in pain scores at 14 different time after root canal instrumentation . The HyFlex EDM GPF group had an average pain score 0.54 lower than the PathFile group .The results of the Linear Mixed Models showed that there were statistically significant differences in pain scores between the HyFlex EDM GPF group and the PathFile group  of the HyFlex EDM GPF creates a larger canal at the coronal and middle portions.Postoperative pain is considered to have an important impact on the quality of life, so the proper management of pain is very important. Although postoperative pain is multifactorial, root canal preparation technique is considered to play a major role in the pain , 20, 21.In the present study, the highest postoperative pain score was recorded on the first day. All patients had mild or moderate pain on the first day and the pain decreased over time in both groups. Postoperative pain can occur within a few hours or a few days after endodontic treatment . In systGlide path preparation minimizes the possibility of extrusion debris and bacteria into the periapical area, which further reduces postoperative pain, regardless of the type of instrument used for root canal shaping , 24. In Glide path preparation prior to mechanical enlargement is helpful to reduce the operation errors in the follow-up root canal procedures. Apical transportation and foramen widening may lead to the loss of apical stop, which further causes more postoperative discomfort . In thisThe HyFlex EDM GPF has significantly greater cyclic fatigue resistance and flexibility than PathFile . The cycThe limitation of this study was that the endodontic dentist was not blinded to the grouping information. Additionally, the type of teeth was not standardized in the study and there was no differentiation between maxillary and mandibular molars or between first and second molars.Glide path preparation time is shorter and postoperative pain severity is lower with the HyFlex EDM GPF than with PathFile. Glide path preparation with HyFlex EDM GPF is advantageous to the subsequent NiTi instruments and can reduce postoperative pain. The highest postoperative pain score was recorded on the first day.


To test the feasibility of a randomized controlled study design comparing epidural analgesia (EDA) with continuous wound infiltration (CWI) in respect to postoperative complications and mobility to design a future multicentre randomized controlled trial.CWI has been developed to address drawbacks of EDA. Previous studies have established the equivalent analgesic potential of CWI compared to EDA. This is a single centre, non-blinded pilot randomized controlled trial at a tertiary surgical centre. Patients undergoing elective non-colorectal surgery via a midline laparotomy were randomized to EDA or CWI. Endpoints included recruitment, feasibility of assessing postoperative mobility with a pedometer and morbidity. No primary endpoint was defined and all analyses were explorative.CWI with local anaesthetics  vs. thoracic EDA (control).Of 846 patients screened within 14 months, 71 were randomized and 62 (31 per group) included in the intention-to-treat analysis. Mobility was assessed in 44 of 62 patients and revealed no differences within the first 3 postoperative days. Overall morbidity did not differ between the two groups (measured via the comprehensive complication index). Median pain scores at rest were comparable between the two groups, while EDA was superior in pain treatment during movement on the first, but not on the second and third postoperative day. Duration of preoperative induction of anaesthesia was shorter with CWI than with EDA. Of 17 serious adverse events, 3 were potentially related to EDA, while none was related to CWI.This trial confirmed the feasibility of a randomized trial design to compare CWI and EDA regarding morbidity. Improvements in the education and training of team members are necessary to improve recruitment.DRKS00008023. Sufficient analgesia is a prerequisite for the successful perioperative management of patients undergoing surgery and reduces postoperative complications and the development of chronic pain ,2. In maSpecifically, EDA has been criticised for causing rare, but serious adverse events, its multiple contraindications, high failure rates , associaCWI could potentially circumvent EDA-associated problems as placement into the laparotomy wound is fast and simple and the technique does not carry the risk of potentially detrimental epidural hematoma or infection. Also, CWI has already been shown to successfully treat postoperative pain and a number of trials have established the equivalent analgesic potential of CWI vs. EDA following abdominal surgery ,15.Until now, however, no study has compared the overall postoperative morbidity of CWI versus EDA directly. This is important, as postoperative morbidity and mortality in conjunction with pain control are arguably the most patient-relevant outcomes. Also, the widespread implementation of EDA has been justified by its supporters because of its potential beneficial effect on postoperative recovery and pain . TherefoTherefore, our current study was designed as a randomized-controlled pilot trial (RCT) comparing EDA vs. CWI in patients undergoing major upper gastrointestinal surgery with the focus on assessing feasibility of recruitment and feasibility of assessing postoperative patient mobility via a pedometer Immobility has been associated with adverse outcomes like pulmonary and thrombotic complications and is discouraged in all current enhanced recovery from surgery (ERAS) guidelines . Therefost August 2015 except the planned inclusion date of the first patient (first-patient-in), which was correct in the DRKS registry on 1st December 2015. Confirmation of registration occurred on 4th December 2015. The first patient was recruited and randomized into the study on 20th October 2015. Until 4th December 2015 eight patients were randomized into the trial. The authors confirm that all ongoing and related trials for this drug/intervention are registered.The Painless-Pilot trial was a randomized, controlled, non-blinded, single centre pilot trial with two parallel study groups performed at the Department of General, Visceral and Transplantation Surgery at Heidelberg University Hospital. The trial was performed according to the IDEAL recommendations (step 2b exploration)  and the All patients aged 18 years or more scheduled for elective upper abdominal surgery  via a midline laparotomy with an indication for EDA were screened for eligibility. Rectal surgeries were excluded, because of the frequent need for stoma placement, which creates an abdominal incision not reached by the CWI catheter. Furthermore, patients with chronic pain and/or regular consumption of opioid analgesics were excluded due to potential confounding. Patients unable to walk unaided were not admitted as postoperative mobility could not be evaluated in these patients. Further exclusion criteria were a contraindication for EDA or CWI, planned stoma placement, pregnancy or breast-feeding and participation in another interventional trial with interference with the intervention or endpoint of this trial. Only patients able to understand the character and all relevant aspects of the trial including aims, methods, risks and individual consequences of this trial who provided written informed consent were included.In order to achieve comparable intervention groups for known and unknown risk factors, patients were allocated randomly to the two treatment groups using randomizer.at, a web-based tool from university Graz ). A block-randomization with a block length of four was implemented. Randomization was performed block wise (permuted blocks) the day before or at the day of surgery at the Study Centre of the Department of General, Visceral, and Transplantation Surgery by the responsible study nurse. Blinding of patients, anaesthesiologists and outcome assessors to the intervention was not implemented as the insertion of the epidural catheter is performed when the patient is awake. Moreover, the difference between CWI and EDA will be obvious to patients and observers postoperatively. Given the pilot aspect of this trial and the objective nature of most endpoints a non-blinded design of the trial seemed justifiable.Patients in the intervention group received a CWI catheter, which was placed suprafascially in the surgical site of the midline laparotomy at the end of surgery after closure of the abdominal fascia and before closure of the subcutaneous tissue and skin. The catheter covered the complete length of the incision  Figs. IfIn the control group patients received a thoracic EDA  during preoperative induction of anaesthesia at Th 7/8 for upper GI procedures and hepatobiliary surgery or Th 8/9 for pancreatic surgery according to internal standard operating procedures. The catheter was inserted 5–6 cm into the epidural space. 5 mL Lidocain 2% were injected as a testing dose to exclude intrathecal placement. Before surgical incision, 10mL Ropivacaine 0.5% supplemented with 4mL Sufenta (R) epidural (20μg sufentanil) were injected as a loading dose to facilitate epidural analgesia. To maintain epidural analgesia during surgery a continuous infusion of 8 mL/h 0.2% Ropivacain was established until skin closure. In the postoperative period EDA was achieved with ropivacain 0.2% with sufentanil at 6-10ml/h administered for 3 days according to the following scheme: on postoperative day 1 0.5μg/ml were administered, on day 2 the sufentanil dose was reduced to 0.25μg/ml. From day 3 on 0.2% ropivacaine was given without additional sufentanil.All patients were seen by a dedicated acute pain service on a daily basis. A physician and a pain nurse evaluate the puncture side for signs of infection or catheter dislocation. During every visit pain level at rest and during movement were assessed and cold sensations were tested to confirm sufficient pain control. In addition, all patients were screened for neurologic deficits including assessment of muscle tone and strength.29 via a running suture with Monomax® . No subcutaneous drains were placed in both groups with the exception of the CWI in the intervention group. Overall postoperative management was performed identically in both intervention groups according to hospital standard.Abdominal wound closure was performed in a standardized manner in small-stitches techniqueBoth, CWI and EDA catheters were set to be removed at the third postoperative day. In both groups, patients received a standardized additional pain medication with fixed-dose 1g metamizole four times daily, and intravenous oxycodone 5mg up every 4 hours on demand. In case of treatment failure defined as uncontrollable pain with a numeric rating scale of ≥5 despite the above-mentioned treatment regime a systemic oxycodon (1 mG/mL) PCA with no baseline rate, 1.5 mG oxcycodon bolus given over 3 minutes and a 20-minute hold-off period was initiated. Other analgesic medication was not routinely given.The outcome assessors were study nurses and physicians of the clinical study center of the Department of Surgery. Pain was evaluated by our interprofessional acute-pain team. All outcome assessors were independent of the research team and were well trained before the start of the study. The following postoperative outcome measures were assessed and no changes to the outcome measures occurred after commencement of the trial:A. Trial feasibility outcome measures1Accomplished recruitment of n = 70 patients within 6 months2Feasibility of assessing the postoperative mobility of patients via a digital pedometer  placed at patients’ right hip bone using adhesive bandage at the end of surgery in at least two thirds of all patients. During the first three postoperative days distance (in meters) and the number of steps were measured.B. Analgesia-associated outcome measures3Pain scores at rest and during movement recorded on postoperative day 1–3 via a numeric rating scale (NRS).4Amount of systemic opioid consumption in both groups within the first 3 postoperative days in morphine equivalents. In order to compare different opioids, the following rules were applied: a.) 1 mg oxycodone i.v. equals 1.3 mg morphine i.v., b.) 1 mg oxycodone oral equals 0.5mg morphine i.v., c.) For the conversion of epidural opioids to i.v. opioids we assumed that 1 mg epidural sufentanil equals 1 mg sufentanil i.v. which in turn equals 0.001 mg morphine i.v. based on the studies by Miguel et al.  and Tave5Treatment-failure rate defined as uncontrollable pain with a numeric rating scale of ≥5 despite the randomized treatment regime with the need for an i.v. PCA (see above).6Duration of EDA /CWI therapy (in days).7Length of preoperative induction of anaesthesia and length of surgery (in minutes).8Length of hospital stay (in days)9Time to first flatus/bowel movement.C. Morbidity endpoints10The overall postoperative morbidity of patients in the study was evaluated based on the comprehensive complication index (CCI) ,25.D. Safety parameters11Frequency and severity of serious adverse events (SAE).12Rate of catheter-related complications in both groups. In the EDA group the rate of catheter infections, dislodgement, neuroaxial hematoma, bleeding into the vertebral canal confirmed by MRI and/or CT scan was assessed. In the CWI group, the rate of surgical side infection (SSI) according to the definition of the Centre for Disease Control and Prevention was applied .Demographic and baseline data were documented during visit 1. Patients were randomized the day before or at the day of surgery (visit 2). Intraoperative parameters were recorded during visit 2. Patients were planned for clinical follow-up at postoperative day 1, 2, 3, 7 and 30–35 (visit 3–7) for evaluation of postoperative outcome measures and SAEs. Items assessed during visits are listed in No formal sample size calculation was performed as this was a pilot trial. However, 60 patients (30 patients in each group) were deemed necessary to draw valid conclusions about recruitment rates, to achieve preliminary pedometer data and to confirm an expected median CCI of approximately 20 in our mixed patient cohort, as has been reported previously in patients undergoing pancreaticoduodenectomy (20.9 (0–29.6)) ,27. FollAs this was a pilot trial without confirmative character, no primary endpoint was defined and all analyses were strictly explorative. We describe our data as median values along with minimum and maximum values for ordinal or continuous, and relative and absolute frequencies for categorical endpoints, stratified for treatment groups. We used nonparametric estimation methods as the outcomes are either ordinal distributed or, in case of continuous outcomes, because our pilot trial has a small sample size and normality cannot be assumed. We further report Wilcoxon-Mann-Whitney odds (WMWodds) and their confidence intervals as discussed by Franklin Dexter as an effect estimator . All anaPatients and the public were not involved in the development of the protocol.th, 2015 to Dec 15th, 2016 (14 months) 846 patients were screened for eligibility of which 71 patients were randomly assigned to CWI (n = 36) or EDA (n = 35)  . A totalBaseline characters revealed no difference between the two study groups . More maAs pointed out above, 14 months were required to include the planned number of 70 patients (5 patients/ month). Thus, our goal of recruiting 70 patients in 6 months (11.7 patients/ month) was not met. However, the second feasibility parameter (measurement of postoperative mobilization via a pedometer in ≥ 2/3 of patients) was successfully accomplished as 44 patients out of 62 in the ITT group received pedometers and data read-out. Reasons for failure were . Steps and distance covered by patients in the first postoperative days did not differ between groups in explorative analysis . Number Explorative analysis of median pain scores at rest during the first three postoperative days according to the NRS revealed no differences between the two groups . Median The total amount of opioid consumption  within the first three postoperative days was lower on exploratory analysis in the CWI group than in the EDA group who received a continuous infusion of ropivacaine plus sufentanil  EDA: 216  mg vs. CWI: 102  mg; Wilcoxon-Mann-Whitney odds (WMWodds): 3.35 CI ).Treatment failure, defined as uncontrollable pain despite the randomized treatment regime with a numeric rating scale of ≥5 with the need of instalment of an i.v. PCA, occurred in 3 patients in the EDA group and 4 patients in the CWI group. Additional PCAs could be implemented on the discretion of the treating physician. Therefore, the total number of PCA placements was high in both groups: seven out of 31 patients in the EDA group received a PCA (23%). Reasons were pain (n = 3), failure of EDA insertion (n = 3) or catheter dislocation (n = 1). Out of 31 patients in the CWI group, 22 received an i.v. PCA (71%) because of pain (n = 8), leakage of local anaesthetic from the wound (n = 1), failed CWI insertion (n = 2) or following relaparotomy (n = 1). An additional 10 patients received a “prophylactic” PCA in the recovery room on the day of surgery, when recovery room physicians not acquainted with the study protocol, assumed potential future inadequate pain control by the CWI, despite patients reporting adequate pain scores in the recovery room with CWI alone.Explorative analysis revealed that pain-catheter therapy was significantly longer with EDA than with CWI median  EDA: 4  days versus CWI: 2  days, WMWodds: 2.95 ). Catheters were removed prematurely (before postoperative day 3 (POD)) in 11 and 4 cases in the CWI and EDA group, respectively.Duration of preoperative induction of anaesthesia was shorter (about 17 minutes) with CWI compared to EDA, which were placed during induction of anaesthesia . HoweverExplorative analysis of the CCI revealed no difference between groups  versus CWI 15  WMWodds: 1.31 ) with an overall CCI of 19.8 +/-15.7 and single scores between 0 and 60.8. Overall, 13 major complications (defined as Clavien Dindo >II) occurred in 10 patients .Safety analyses in terms of SAEs did not show any difference between groups. Overall six patients experienced 17 SAEs with overall ten SAEs in the EDA group and seven SAEs in the CWI group. Three SAEs in patients with an EDA were classified as potentially related to the intervention . No SAE was associated with CWI use.Regarding catheter-related complications, three patients in the EDA group suffered from paraesthesia, one had focal motor deficits, one had a superficial hematoma at the puncture side, one had pain at the puncture side after multiple punctures and one suffered from hypotension. No catheter related complications were recorded for the CWI group. Only one superficial surgical site infection occurred in the EDA group and none in the CWI group.The main objectives of our pilot study were to inform the decision whether or not to conduct a confirmatory trial comparing EDA with CWI in a multicenter setting and to inform the design of such a potential trial. To this end, 70 patients undergoing elective open upper gastrointestinal surgery were randomly assigned to epidural analgesia (EDA) or continuous wound infiltration (CWI) in the Painless Pilot trial and underwent a broad set of exploratory outcome assessments including trial feasibility-, safety-, morbidity and analgesia-associated endpoints. Recruitment took longer than expected (14 months instead of 6 months). Postoperative mobility was successfully measured via pedometers and showed no difference between the two groups on exploratory analysis. Similarly, morbidity assessment via the comprehensive complication index, pain and safety assessment were successfully established in the study.Valuable information can be drawn from the results of the PAINLESS Pilot trial for a multicentre RCT comparing EDA vs. CWI following upper gastrointestinal surgery, thus confirming the importance of pilot trials for the planning of high-quality trials in surgery . While tFirst, recruitment was difficult in our trial and only 71 out of 555 eligible patients were eventually randomized during a 14-month period. This is less than has been reported in other RCTs ,30. ReasSecond, based on the preliminary data from our pilot trial a sample size of roughly 712 patients would be necessary to detect the observed mean difference of CCI between EDA and CWI when applying a two-sided t-test with a power of 80% and chosen level of significance of 5% . Consequently, in a future multicenter trial 10 sites could recruit the necessary number of patients in around 15 months.Third, lack of sufficient information and training likely explains two other problems we encountered during our pilot study, namely the high rate of “prophylactic” PCA placements in the recovery room in the CWI group and the loss of pedometers in about one third of patients. “Prophylactic” placement occurred when recovery room physicians not acquainted with the study protocol, assumed potential future inadequate pain control by the CWI, despite patients reporting adequate pain scores in the recovery room with CWI alone. Similarly, pedometers were frequently removed by nursing personnel not acquainted with the specifics of our study. Pedometer bracelets, rather than attaching the pedometer to the patients’ hip with adhesive tape, might circumvent this problem in future trials.Fourth, as in previous trials CWI was not inferior to EDA in pain control on explorative analysis  with excFifth, several CWI catheters were also removed early (and PCA placed) because of leakage of local anaesthetics from the wound. This problem was caused by the subcutaneous placement of the catheter, the relatively high flow rate of the CWI in our study compared to previous trials ,15 and tOur pilot study established the feasibility of measuring the CCI ,25 in a A limitation of our trial was the unblinded trial design. Blinding EDA and CWI procedures would require significant efforts. EDA catheters are placed when the patient is awake making blinding impractical. A potential way of blinding would be to place sham EDA or CWI catheters. However, this not only raises ethical concerns, but also contradicts the pragmatic nature of the trial as it would create an artificial intervention with two catheters in each patient. Furthermore, it is still unclear if such blinding measures really reduce performance and detection bias . AlthougIt was crucial to establish that the CWI does not inflict any potential harm on patients. Although postoperative overall morbidity in the CWI group evaluated via the CCI, SAEs, rate of catheter related complications and surgical side infections were not different in the two groups, the rate of SAEs in the EDA group was high. This is in line with recent reports that have shed a more critical light on EDA-associated adverse events ,40.As expected, duration of induction of anaesthesia was shorter with CWI in our trial, which is a relevant economic advantage for our health care system compared to EDA. This supports recent studies that have outlined the high costs associated with EDA .Our findings support the increasing recognition of CWI as a useful and safe technique within a multimodal approach to postoperative pain management . Based oS1 Checklist(DOC)Click here for additional data file.S1 FigReprinted with permission from Mann V. et al. Chirurg. 2011 Oct;82(10):906–12.(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Table(CSV)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Protocol(DOC)Click here for additional data file.


Background: Botulinum toxin is an injectable neuromodulator that inhibits transmission between peripheral nerve endings and muscle fibers, resulting in muscle paralysis. Botulinum toxin type A is the most common form of botulinum toxin used in clinical practice.Methods: In this review, we examine the mechanism of action, formulations, common clinical use in the genital-urinary tract, and potential clinical use in pelvic floor disorders of botulinum toxin type A.Results: Several aspects of botulinum toxin A make it a favorable therapeutic tool, including its accessibility, its longevity, and its impermanence and reversibility of resultant chemodenervation in a relatively short and safe manner. Although botulinum toxin A has well-established efficacy in treating refractory overactive bladder and neurogenic detrusor overactivity, its use in pelvic floor disorders is still in its infancy.Conclusion: The efficacy of botulinum toxin A for treating pelvic pain, voiding dysfunction, muscle pain and dysfunction, and certain colorectal-related pain issues shows promise but requires additional rigorous evaluation. Clostridium botulinum, a gram-positive, rod-shaped anaerobic bacterium responsible for the production of the botulism-inducing neurotoxin. This neurotoxin inhibits transmission between peripheral nerve endings and muscle fibers, resulting in weakness or flaccid paralysis of skeletal muscle. The clinical potential of C botulinum was recognized initially in 1897 when the toxin produced by the organism was identified as the etiologic agent of botulism.2 Since then, 7 serotypes of botulinum toxin , produced by different strains of the bacterium, have been identified. Although the pharmacologic properties of the serotypes differ, suggesting differences in clinical efficacy, only serotypes A and B are available for clinical use. Several aspects of botulinum toxin A make it a favorable therapeutic tool, such as injection longevity  and impermanence and reversibility (recovery of resultant chemodenervation after 3 to 6 months because of synaptic turnover).4 Botulinum toxin type A is the most common form of botulinum toxin used in clinical practice7 and is the primary focus of this review in which we examine its mechanism of action, formulations, common clinical use in the genital-urinary tract, and potential clinical use in pelvic floor disorders.Botulinum toxin is an injectable neuromodulator derived from neurotoxins produced by 8 As a result of cleavage, acetylcholine remains within the neuron where it is unable to bind to receptors on muscle fibers and stimulate muscle contraction (chemodenervation).The clinical utility of botulinum toxin stems from its ability to prevent muscular contraction through inhibiting the release of acetylcholine from peripheral nerve cells into their neuromuscular junctions. In short, release of acetylcholine is suppressed sequentially as follows: toxin receptor binding and internalization, followed by cleaving and inhibition of acetylcholine. Botulinum toxins are peptides composed of one heavy chain and one light chain. After the heavy chain of the injected toxin binds to the terminal ends of a neuron, the peptide enters the cytoplasm through endocytosis. Once within the cytoplasm, the light chain cleaves components of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE), a complex of proteins necessary for the exocytosis of acetylcholine. The sites of cleavage within the SNARE protein complex differ among the serotypes; while botulinum toxin types A, C1, and E cleave synaptosome-associated protein of 25kDa (SNAP-25), serotypes B, D, F, and G cleave vesicle-associated membrane protein (VAMP), also known as synaptobrevin .8 As a r10The inhibitory effect of botulinum toxin is temporary; recovery of muscular function often becomes clinically evident approximately 3 to 6 months after treatment as the neuromuscular junction begins to recover. The development of new collateral nerve endings may be partially responsible for this recovery. However, these terminal buds appear to be transient, and recovery of the original nerve terminal eventually occurs, resulting in reversal of the toxin's effect.11 Of the formulations of botulinum toxin type A that are available in 2020 or in development, onabotulinumtoxinA has been studied most extensively.As stated previously, 2 serotypes of botulinum toxin have been formulated for clinical use: type A (the most common serotype used for cosmetic applications) and type B. Commercially available formulations of botulinum toxin type A in North America include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. RimabotulinumtoxinB is the established name for botulinum toxin type B.12 Botox (onabotulinumtoxinA) has been FDA approved for treatment of neurogenic detrusor overactivity since 2011 and for refractory overactive bladder symptoms since 2013,13 increasing the likelihood of insurance coverage, and thus the affordability of and access to this treatment for pelvic floor indications. Additionally, studies have shown Botox to be cost effective relative to nonselective anticholinergics, advocating for consideration as a first-line treatment for overactive bladder.14Botulinum toxin is US Food and Drug Administration (FDA)-indicated for multiple purposes, but with regard to urogenital and pelvic floor disorders , in 202017 every 6 to 12 months, with most clinicians administering 100-IU doses to minimize side effects.4 Compelling evidence from a 2011 meta-analysis noted significant reduction in urinary frequency and urge incontinence at 6 and 12 weeks compared with placebo treatment.18 Multiple studies have also shown that this treatment regimen has some duration, although time of efficacy after each injection has been variable.20 In initial trials, time to retreatment after injection of 100 IU of injected onabotulinumtoxinA was 19 to 24 weeks, leading the manufacturer to recommend passage of at least 12 weeks between injections.12 Predictors of treatment success have been assessed, although also with inconsistent results. Female participants  with low overactive bladder symptom scores on preoperative questionnaires, subjects with wet overactive bladder, and subjects who stopped other treatments before undergoing Botox injection have all been found to have higher success rates with treatment.23Botox has been effective in treating refractory overactive bladder and is usually given at doses of 100 to 300 IU24 In a large meta-analysis, subjects receiving treatment experienced a reduction in urinary urge incontinence episodes per week and maximum detrusor voiding pressure, while increasing maximum cystometric capacity.25 Although doses of 200 to 300 IU have been studied, injection of 200 IU has been found to have optimized efficacy while minimizing potential side effects.26Botox injections have also been useful in the treatment of neurogenic detrusor overactivity, while protecting the upper urinary tract and improving quality of life through decreasing overall urge incontinence episodes.28 A European consensus report includes some discussion about the efficacy of suburothelial vs intradetrusor injections.29Injection of Botox for urinary symptoms is generally through a rigid or flexible cystoscope, with the total dose divided and administered in 10 to 20 small injections into the detrusor muscle of the bladder. The specifics about injection technique, such as the optimal intravesical anatomic location and the number of injections, are still topics of debate, although limited studies have not demonstrated increased rates of urinary retention, frequency of urinary tract infections, or vesicoureteral reflux after trigonal injection.29 and life-threatening toxicity, similar to typical botulism, resulting in issuance of an FDA warning in 2009.13 More commonly, Botox injections for urinary issues can result in increased rates of urinary retention and increased frequency of urinary tract infections.12Although Botox treatment is typically considered safe for use in the treatment of overactive bladder and neurogenic detrusor overactivity, the potential for adverse effects exists. Most significantly, high injection doses  have (rarely) been associated with generalized weaknessAs of 2020, Botox is not FDA approved for the pelvic floor disorders discussed in this section; however, data show that the use of Botox in these areas is promising.Pelvic pain in women, which is a major cause of morbidity and disability for patients and results in significant costs to health services, is a complex and challenging dilemma. When the cause of pain can be defined, the majority of women experiencing acute pain can be effectively treated with medical and surgical interventions. However, in a subset of patients, diagnosing the cause of pain can be evasive, and these patients often have decreased success and dissatisfaction with treatment. As a further complication, chronic pelvic pain is not only influenced by multiple systems , but a growing body of evidence also shows a strong behavioral and psychological component. Given its potential analgesic effects, Botox may be a potential treatment modality for pelvic pain. These analgesic effects are likely attributable to secondary effects achieved from muscle paralysis, which leads to improved blood flow, decompression of nerve fibers by abnormally contracting muscle, and downregulation of nociceptive neurons.30Sacral roots S2 to S4 coalesce to form the pudendal nerve. Typically, the pudendal nerve courses underneath the piriformis muscle and between the sacrospinous and sacrotuberous ligaments at the level of the ischial spine. The pudendal nerve then travels through the Alcock canal between the obturator internus and levator ani muscles and divides into 3 branches: the dorsal nerve of the clitoris (or penis), the perineal nerve, and the inferior rectal nerve. The 2 most common areas of nerve entrapment occur at the level of the ischial spine and the Alcock canal. Damage to the pudendal nerve can result in unilateral or bilateral pelvic pain in females, involving the vulva, vagina, clitoris, or bladder. Pudendal nerve dysfunction because of entrapment or compression has been postulated to not only lead to chronic pain but also to negatively impact the afferent, efferent, and autonomic signals between pelvic organs that are essential for maintaining their proper functions.30 Visual analog scale (VAS) scores and muscle manometry showed improvement at 4 weeks, which was maintained at the 12-week assessment. Abbott et al conducted a double-blind randomized controlled trial in which women received pelvic floor injections of 80 IU of Botox (n=30) vs saline (n=30).31 Significant improvement in VAS scores and muscle manometry was noted in the Botox recipients. Adelowo et al published a retrospective review of 31 subjects who received Botox injections of 100 to 300 IU for myofascial pain.32 Primary outcomes were self-reported pain on muscle palpation and symptom improvement. The median pain noted with levator palpation was significantly lower at 6 weeks (P<0.0001) postinjection and remained significantly decreased at 12 weeks (P<0.0001). Within the cohort, 58% opted to have a repeat injection, with a median time to repeat injection of 4 months. Adverse side effects included de novo urinary retention (10.3%), fecal incontinence (6.9%), and constipation and/or rectal pain (10.3%), all of which resolved spontaneously. In 2013, a prospective study by Nesbitt-Hawes et al assessed successive botulinum toxin A injections in women with pelvic floor disorders.33 Thirty-seven patients received injections of 100 IU of botulinum toxin A into the puborectalis and pubococcygeus muscles, with 30% receiving 2 or more injections. The VAS scores and vaginal pressure measured by manometry were evaluated at 0, 4, 12, and 26 weeks. Both single and repeated injections demonstrated a statistically significant reduction in dyspareunia (P=0.001) as measured by VAS scores, but vaginal pressure improvement was only noted in the multiple injection group (P=0.02). No differences in dysmenorrhea or dyschezia rates were observed. In 2015, Morrissey et al selected subjects with chronic pelvic pain and high muscle tone pelvic floor dysfunction who had failed conventional therapy to receive Botox injections (maximum dose 300 IU) through electromyography guidance, allowing specific localization of spasticity in pelvic floor muscles.34 Posttreatment vaginal manometry demonstrated significant decreases in resting pressure and maximum contraction pressures (P<0.05). Adverse effects after injections included constipation (28%), stress urinary incontinence (4.8%), and fecal incontinence (4.8%).Levator myalgia is a condition characterized by burning pain or tenesmus of the perineum or rectum. In a 2004 study by Jarvis et al, 12 patients with a minimum 2-year history of chronic pelvic pain and pelvic floor hypertonicity underwent injection of 40 IU of botulinum toxin A into bilateral levator ani muscles.36 Postulated efficacy in this subset of patients with pelvic pain is based on the effect of Botox at the neuromuscular junction and within parasympathetic and sympathetic neural synapses. The first report of Botox used to treat vulvovaginal pain was in 1997, when Brin and Vapnek published their data on successful treatment of vaginismus with Botox.37 In 2000, after injection of Botox vs saline in a small population, Shafik and El-Sibai found superiority in pain control for the Botox group.38 In 2004, Gunter et al described successful management of refractory vulvodynia with a combination of surgery and Botox.39 Since that time, other studies have reported improvement in vulvodynia,45 while others have found no change in symptoms.46 In 2017, Halder et al reported improved VAS scores after treatment with combined Botox and physical therapist–mediated myofascial release.47 Posttreatment complications included constipation (8%), urinary retention (2%), and urinary tract infections (4%). In an effort to improve injection success, Nesbitt-Hawes et al developed a technique using 4-dimensional sonogram guidance to aid injection.48 Their findings have shown good feasibility while allowing accurate placement of the injection within the target muscle in women with pelvic floor muscle overactivity.Vulvodynia is characterized by burning pain in the vulvar area, persistent for at least 3 months, in the absence of other relevant dermatologic or neurologic findings. Vulvodynia negatively impacts quality of life, and various treatment modalities, including surgery and yttrium aluminum garnet (YAG) lasers, have been useful in reducing this type of pain.49 Chuang and Kuo evaluated the use of intravesical instillation of a liposomal lipotoxin form of Botox in patients with interstitial cystitis/bladder pain syndrome.50 Significant improvement was noted at 4 weeks; however, no differences in endpoints were appreciated among the groups at 12 weeks. In 2018, Pinto et al also found a significant reduction in VAS scores in the subjects receiving botulinum toxin A vs placebo.51 Studies by Rappaport et al and Jiang et al assessed hydrogel-based delivery systems and trigonal intravesical injections, respectively, and the studies demonstrated safety and at least short-term efficacy with both techniques.53 In 2020, no consensus exists regarding the efficacy of treating interstitial cystitis/bladder pain syndrome with botulinum toxin A. However, studies suggest a trend toward improvement in symptoms. Well-designed studies are needed to further evaluate this trend, as well as to define ideal dosage, injection location, and alternate delivery systems.Now more commonly termed bladder pain syndrome, interstitial cystitis is a type of chronic pain that affects the bladder and pelvic floor. Symptoms vary but often include persistent urinary urgency and frequency, dyspareunia, bladder base tenderness, and levator myalgia. Interstitial cystitis/bladder pain syndrome also has strong associations with depression and anxiety, irritable bowel syndrome, and fibromyalgia. Although the exact pathophysiology of interstitial cystitis/bladder pain syndrome is unknown, several theories exist; the most common faults disruption in the glycosaminoglycan of the basement membrane of the bladder that leads to greater infiltration of irritating substances. Generally, glomerulations, petechial hemorrhages, or other signs of inflammation can be seen on cystoscopy, but the identification of a Hunner ulceration has greater specificity for interstitial cystitis/bladder pain syndrome diagnosis and is usually associated with more severe symptoms. To date, 3 double-blind randomized controlled studies have evaluated the use of botulinum toxin A in the treatment of interstitial cystitis/bladder pain syndrome. Kuo and Kuo compared 100 IU Botox vs saline, and the botulinum toxin A group showed a significantly greater reduction in VAS scores and global improvement response assessment at 3 months.45 More research is needed to fully define the role of Botox in the treatment of postoperative pelvic pain.Postoperative pelvic pain is complex in its presentation and treatment. Studies concerning the utility of Botox injections in treating this type of pain are limited, but Park and Paraiso reported successfully treating a patient presenting with de novo refractory dyspareunia after pelvic floor reconstructive surgery.As the discussion in this section has demonstrated, the indications for Botox treatment are not entirely clear for patients experiencing different types of pelvic pain. However, treatment of such pain with Botox shows promise in conditions such as chronic pelvic floor muscle spasm (primary or etiology) and interstitial cystitis/bladder pain syndrome. Botox should be considered for patients with refractory cases who have received proper counseling about the use of Botox in treating their condition. The clinician should proceed with caution before considering using Botox to treat a patient with pelvic pain, as Botox is only FDA approved for pain related to cervical dystonia. When treating different types of pelvic pain with botulinum toxin A, patients should be closely monitored within the bounds of ethical research standards.54 Subjects were randomized to intrasphincteric injection of Botox vs placebo. No significant difference in postvoid residual between the 2 groups was found. However, compared to placebo, Botox significantly increased voiding volume (P=0.02) and reduced premicturition (P=0.02) and maximal detrusor pressures (P=0.02). Overall, female-specific data are lacking because many studies included either male-only or combined male/female populations, and additional studies are needed to fully understand the efficacy of botulinum toxin A in treating detrusor sphincter dyssynergia in female patients.Evidence suggesting decreased postvoid residual, maximum urethral closure pressure, and maximum voiding detrusor pressure after treatment with Botox—while still protecting the upper urinary tract—indicates that patients with detrusor sphincter dyssynergia may benefit from treatment with botulinum toxin A. Gallien et al published one of the largest trials evaluating the effectiveness and safety of Botox in 86 patients, 58 of whom were women, with detrusor sphincter dyssynergia secondary to multiple sclerosis.55 Notably, no difference in narcotic use was seen between groups, and no anal incontinence or other complications were reported for the treatment group. Similarly, a study by Patti et al in 2005 showed improved wound healing after hemorrhoidectomy for third- and fourth-degree piles in patients who received intrasphincteric botulinum toxin injection.56 Anorectal manometry was also evaluated preoperatively and postoperatively at intervals, with significant postoperative improvement noted in mean rectal pressure and decreased wound healing time in the Botox treatment group. Anal incontinence was reported for 9 patients, although cases were almost evenly distributed between Botox (n=4) vs placebo (n=5) recipients. A 2008 study by Patti et al assessed the utility of Botox injections for pain relief in the setting of thrombosed external hemorrhoids.57 Patients who refused surgical intervention were randomized to receive Botox vs placebo injection. Anorectal manometry was performed before the procedure and 5 days posttreatment. Anal resting pressure, pain, and time to return to work or normal activity were all decreased in the Botox group, while the placebo group had increased analgesic consumption. No patients in either group reported anal incontinence.Treatment of hemorrhoids, especially with traditional hemorrhoidectomy, can cause significant postoperative pain. As postoperative pain for these cases can often be refractory to standard treatment options, development of new methods for pain control is paramount. In 2003, Davies et al reported decreased VAS scores in subjects who received internal anal sphincter injections of botulinum toxin A status post Milligan-Morgan hemorrhoidectomy compared with those who received placebo.An anal fissure is a tear in the lining of the distal anal canal caudal to the dentate line that most commonly occurs along the posterior midline. The incidence is comparable in both sexes and affects people of varying ages. Clinical symptoms include anal pain during and after defecation, often accompanied by bright red rectal bleeding, and pruritus ani. Acute fissures typically have sharply demarcated fresh mucosal edges and may have granulation tissue along their bases. Chronic fissures typically have rolled edges, characteristically exposing the horizontal fibers of the internal anal sphincter muscle at their bases, and are often accompanied by external skin tags, hypertrophied anal papillae, elevated resting anal pressures, and, rarely, anal stenosis.New England Journal of Medicine.58 The Botox group demonstrated higher fissure healing rates (73% vs 13%), with only one subject experiencing transient incontinence of flatus. Botulinum toxin A injection has also been compared with topical glyceryl trinitrate 0.2% for the treatment of patients with chronic anal fissures.59 Healing rates were significantly higher (96% vs 60%), and resting anal pressures were decreased (29% vs 14%) in the botulinum toxin A group vs the glyceryl trinitrate group. No side effects were noted in the Botox group, while 20% of the glyceryl trinitrate group complained of headaches. While surgical intervention for anal fissures, particularly with lateral internal sphincterotomy, is considered the therapeutic gold standard, multiple reports have compared lateral internal sphincterotomy to Botox treatment. Although Botox is inferior to lateral internal sphincterotomy when given alone, studies have shown Botox to be less invasive and repeatable and to have a decreased risk of long-term fecal or flatal incontinence compared with lateral internal sphincterotomy.61 Of note, a study from 2015 showed that treatment with topical diltiazem combined with Botox injection had similar success rates to partial lateral internal sphincterotomy, and the botulinum toxin A + topical diltiazem group had lower rates of fecal incontinence.62 In subjects with chronic anal fissures however, the healing rate was significantly higher in the partial lateral internal sphincterotomy group.Studies assessing botulinum toxin A for treating anal fissures are limited. As early as 1998, Maria et al published a comparison of Botox and saline for the treatment of chronic anal fissures in the Despite demonstrating much utility in treating pelvic floor disorders, especially with regard to evolving therapies, the use of botulinum toxin A is not without challenges. Researchers continue to investigate ideal dosing, injection placement, and administration technique reproducibility, all contributing to the likelihood that recipients will have successful outcomes while minimizing side effects.64 Although immunogenicity does not signify conclusive formation of neutralizing antibodies, this type of antibody has been specifically associated with a secondary nonresponse or loss of response after a period of successful therapy.65 Laboratory tests (mouse diaphragm assay and mouse protection assay) and clinical tests  have been developed to detect the presence of Botox antibodies, but not all tests have good sensitivity and specificity.Patients who receive multiple doses can potentially develop immunogenicity to Botox . As Boto66 Injecting the smallest effective dose of Botox and waiting the longest possible time interval between treatments may decrease the potential for immunogenicity.67 Refractory cases may warrant revisiting other standard treatment modalities for the specific pelvic floor condition being treated.If ascertainable, treatment of immunogenicity with specific immunoglobulins, immunosuppressants, or plasmapheresis would be ideal, although implementation of each is not without risks and logistic considerations. Prevention of immunogenicity remains the ultimate goal. Minimizing modifiable risk factors , while acknowledging fixed genetic predisposition, could help reduce the certainty and impact of antigen formation.Although botulinum toxin A has well-confirmed efficacy in treating certain urogenital conditions, such as refractory overactive bladder and neurogenic detrusor overactivity, use of Botox to treat different types of pelvic pain, muscle dysfunction, and certain colorectal-related pain issues is promising. Research is needed to provide justification to broaden FDA-approved indications for Botox in treating such conditions and thereby facilitate access to robust, affordable treatment options for patients with these ailments.


This is a case series of six emergency department (ED) patients who received an ultrasound-guided serratus anterior plane block (SAPB) for a variety of painful conditions. Our cases illustrate the feasibility and analgesic efficacy of the SAPB in providing pain management in ED patients with a variety of painful syndromes, including those with severe pain from multiple rib fractures, herpes zoster, and tube thoracostomy placement. In addition, we found no adverse events in our case series. The serratus anterior plane block (SAPB) is a relatively new compartment block described in the anesthesia literature for the treatment of thoracic wall pain.The SAPB is a sensory nerve block that provides analgesia to the hemithorax from second thoracic (T2) to T9 dermatomes. Anesthetic, usually 25–30 milliliters (mL), is injected under ultrasound-guidance into the serratus anterior plane, either superficial or deep to the serratus anterior muscle (SAM). Within this fascial plane are the lateral cutaneous branches of the thoracic intercostal nerves.The most common indication for SAPB in the emergency department (ED) is for treatment of rib fracture pain. However, we also report a novel ED indication including treatment of herpes zoster pain and periprocedural pain from tube thoracostomy. Contraindications include local infection or allergy to the local anesthetic. Complications may result in local anesthetic toxicity, pneumothorax, and block failure.7Patients with rib fractures have an increased risk of developing pneumonia, respiratory failure, and death, with mortality ranging from 4–20%.The evidence supporting the use of SAPB in the ED is limited to one prior case report in two ED patients for rib fracture pain.An 85-year-old female with a medical history of meningioma, seizures, and hypertension, presented to the ED after a ground-level fall. On physical examination, the patient was uncomfortable and tender to her right flank. Chest radiography (CXR) and computed tomography (CT) demonstrated six posterior rib fractures (T4 to T9). The patient had pain with an intensity rating of 10/10, and reported minimal improvement despite administration of intravenous (IV) morphine sulfate at 8 milligrams (mg). The SAPB was performed using 30 mL of 0.25% bupivacaine deposited superficial to the SAM, with complete relief of pain 10 minutes after the block. The patient did not require any further pain medication in the ED, and received only acetaminophen during her inpatient stay. She was discharged without any use of opioids.What do we already know about this clinical entity?One prior case series found that emergency physician (EP)-performed serratus anterior plane block (SAPB) can provide analgesia for rib fracture pain.What makes this presentation of disease reportable?There is limited literature describing the effects of EP-performed SAPB on a range of different, painful thoracic processes.What is the major learning point?SAPB can be an effective analgesic modality for thoracic diseases and injuries including rib fractures, herpes zoster, and thoracostomy placement.How might this improve emergency medicine practice?EPs may decide to use SAPB as a method for pain control, especially in patients for whom nonsteroidal anti-inflammatory drugs or opioids may have suboptimal side effects.A 72-year-old male with medical history of diabetes and hypertension, and daily use of ticagrelor presented to the ED after a fall from standing that day. On physical examination, he was not in any respiratory distress and had tenderness to the left lateral chest wall. CXR showed displaced overriding, left-sided posterolateral fractures of ribs 8 to 11 that was confirmed on CT. SAPB was performed using 30 mL of 0.25% bupivacaine deposited superficial to the SAM. No other analgesics besides the SAPB were given. The patient reported complete pain relief after the procedure, required no further pain medication in the ED, and was admitted to the trauma service.A 78-year-old female with a history of diabetes and hypertension presented to the ED with six days of “pimples” to her right chest with pain intensity rating of 10/10. On physical examination she had a classic zoster rash localized to lateral chest within the distribution of T5 to T8 dermatomes. The patient had a SAPB performed with 20 mL of 0.5% bupivacaine mixed with 60 mg of solumedrol deposited superficial to the SAM. The patient did not require any other pain medicine during her ED stay and reported significant pain relief. She was discharged on gabapentin 100 mg three times per day upon discharge, and did not have any return visits to the ED.An 89-year-old female with history of atrial fibrillation on aspirin, hypertension, congestive heart failure (CHF), and chronic obstructive pulmonary disease presented to the ED, after being found on the floor by family, complaining of left-sided chest wall pain. On physical examination, the patient was tachypneic with a respiratory rate of 25 breaths per minute, and had left lateral chest wall tenderness. She was placed on bi-level positive airway pressure (BIPAP). Her CXR demonstrated left-sided rib fractures of indeterminate age with prominence of interstitial lung markings bilaterally. Her CT was remarkable for left-sided rib fractures 2 to 11 with a segmental fracture of rib seven and trace left-pleural effusion. Her venous blood gas showed a pH of 7.29 (7.320–7.430) and PCO2 of 71 millimeters of mercury (mm Hg) (38–50 mm Hg).She and the family did not want intubation. Despite administration of 650 mg of oral acetaminophen, 10 mg of IV ketorolac, and 25 micrograms of IV fentanyl, the patient continued to complain of severe pain. There was concern that more opioids would worsen her sedation, hypercarbia and respiratory acidosis. Thus, the SAPB was performed with 30 mL of 0.25% bupivacaine with epinephrine deposited deep to the SAM. After the procedure, the patient reported numbness to her left chest wall and complete relief of her pain. She was discharged two days later with a prescription for acetaminophen and lidocaine patch.A 94-year-old female with history of CHF and atrial fibrillation not on anticoagulation presented to the ED in respiratory distress. On arrival, her respiratory rate was 32 breaths per minute and oxygen saturation was 94% on non-rebreather. Her physical examination was significant for a chronically ill-appearing female in respiratory distress with decreased bibasilar breath sounds and poor air movement. Her B-type natriuretic peptide was 1180 picograms (pg) per mL (<100 pg/mL) and CXR showed new bilateral moderate-sized pleural effusions. She was placed on BIPAP without improvement. The patient and family did not want intubation, so the decision was made to insert a pigtail catheter for drainage of the pleural effusion. Pre-procedurally, a SAPB was performed using 30 mL of 0.25% bupivacaine deposited deep to the SAM. The patient tolerated the procedure well and did not require any pain medication besides the SAPB in the ED.A 60-year-old female with no past medical history presented to the ED with severe, left-sided chest pain two days after a mechanical fall down a flight of stairs. She went to an urgent care center and had a CXR showing five displaced rib fractures and was sent to the ED. On arrival to the ED, the patient was tachypneic with a respiratory rate of 25 breaths per minute. On physical examination, she was uncomfortable appearing with tenderness to palpation over the left lateral ribs. In the ED she was given 4 mg of IV morphine but still could not tolerate lying flat for a chest CT due to worsening pain. A SAPB was performed with 20 mL of 0.25% bupivacaine deposited superficial to the SAM. The patient had significant relief of pain and was able to lie flat almost immediately after the block, which allowed her to tolerate lying supine for a CT that showed anterior rib fractures T5 to T9 and posterior rib fractures T8 to T10. The patient was admitted to the trauma service.Our case series reports on the positive efficacy of the SAPB performed in a series of six patients in the ED either as an alternative or as an adjunct to opioid and non-opioid analgesia. There was no evidence of SAPB-related adverse events.SAPB was most commonly performed for rib fractures in our case series. Effective analgesia in patients with rib fractures is necessary for the prevention of reduced inspiratory volume and pneumonia.13SAPB was also performed for pain control in the treatment of acute herpes zoster pain as well as for procedural pain, ie, from tube thoracostomy, which has not been previously reported in the ED literature, although a few case reports in the anesthesiology literature exist.This case series is limited due to its small size, and as this was not a retrospective chart review, data was not systematically collected. There is the possibility that the physician may not have documented all side effects. These findings do not evaluate the efficacy of the nerve block for all patients and does not identify instances of failed SAPB. In addition, the findings from this case series may not be generalizable. The dosing of parenteral pain medication was not standardized prior to the administration of the SAPB and, therefore, patients may have been underdosed, which could have exaggerated the impact of the nerve block on pain relief. All patients, except those from Cases 2 and 5, received an SAPB that was performed by an ultrasound fellowship-trained EP. The extra training and skill level required for performing this nerve block may limit the generalizability of this case series.While this case series highlights the benefits of using SAPB in the patients described, further investigation must be pursued to determine the efficacy of and indications for all ED patients receiving a SAPB. Prospective studies evaluating the effectiveness of SAPB compared to traditional treatment for rib fracture pain, thoracostomy pain, and herpes zoster-related pain may further support the use of SAPB in these conditions.This case series found that SAPB was an effective treatment of pain secondary to rib fractures, herpes zoster, and tube thoracostomy with no adverse events. Based on our report, we believe that the SAPB can be an effective tool for the treatment of the aforementioned painful conditions and has several advantages over opioids that may make it an ideal treatment for specific patient populations. Further investigation is still needed to determine the role of SAPB in the management of a variety of patients with acutely painful conditions.Video.Serratus anterior plane block video. Yellow line = target plane; Purple-dotted line = needle.SAM, serratus anterior muscle; LDM, latissimus dorsi muscle; ICM, intercostal muscle.


The results of clinical trials should be assessed for both statistical significance and importance of observed effects to patients. Minimal important difference (MID) is a threshold denoting a difference that is important to patients. Patient acceptable symptom state (PASS) is a threshold above which patients feel well.To determine MID and PASS for common outcome instruments in patients with subacromial pain syndrome (SAPS).We used data from the FIMPACT trial, a randomised controlled trial of treatment for SAPS that included 193 patients. The outcomes were shoulder pain at rest and on arm activity, both measured with the 0–100 mm visual analogue scale (VAS), the Constant-Murley score (CS), and the Simple Shoulder Test (SST). The transition question was a five-point global rating of change. We used three anchor-based methods to determine the MID for improvement: the receiver operating characteristic (ROC) curve, the mean difference of change and the mean change methods. For the PASS, we used the ROC and 75th percentile methods and calculated estimates using two different anchor question thresholds.Different MID methods yielded different estimates. The ROC method yielded the smallest estimates for MID: 20 mm for shoulder pain on arm activity, 10 points for CS and 1.5 points for SST, with good to excellent discrimination (areas under curve (AUCs) from 0.86 to 0.94). We could not establish a reliable MID for pain at rest. The PASS estimates were consistent between methods. The ROC method PASS thresholds using a conservative anchor question threshold were 2 mm for pain at rest, 9 mm for pain on activity, 80 points for CS and 11 points for SST, with AUCs from 0.74 to 0.83.We recommend the smallest estimate from different methods as the MID, because it is very unlikely that changes smaller than the smallest MID estimate are important to patients: 20 mm for pain VAS on arm activity, 10 points for CS and 1.5 points for SST. We recommend PASS estimates of 9 mm for pain on arm activity, 80 points for CS, and 11 points for SST.ClinicalTrials.gov NCT00428870 .The online version contains supplementary material available at 10.1186/s12874-021-01241-w. The efficacy of interventions is often measured as the mean difference between intervention and control groups, or the differences in proportions of patients who achieve a desired state. It is important to judge whether a difference is important to patients, instead of relying on statistical significance testing to draw conclusions about the importance of research results. To assess whether a desired state has been achieved for an individual patient, continuous outcomes must be dichotomised to “success” and “non-success”. In most orthopaedic conditions, the outcomes most important to patients are assessed with patient-reported outcome measures (PROMs), which measure pain, function or (disease-related) quality of life. Important questions remain about their interpretation. In particular, how a certain change in PROM score is perceived by the patients, or at what level of a PROM patients consider themselves well. Concepts like MID and PASS have been developed to better understand how PROM scores reflect patients’ perceptions of their pain or disability.The minimal important difference, MID , reflectAnother measure that can help to interpret study results is the patient acceptable symptom state (PASS). The PASS is the highest symptom level at which patients consider themselves well . ImproviSubacromial pain syndrome (SAPS) is the most common shoulder condition –10. DespWe used the 2-year follow-up data from the FIMPACT trial  to estimFIMPACT is a randomised, placebo-surgery controlled three-arm efficacy trial of subacromial decompression for treating SAPS. The trial was conducted at three orthopaedic clinics in Finland. One hundred ninety-three patients aged 35 to 65 years with SAPS were randomised to arthroscopic subacromial decompression (ASD), diagnostic arthroscopy (DA) or exercise therapy (ET), and followed for 24 months. At the eligibility screening visit, an experienced shoulder surgeon examined the patients to rule out shoulder instability, rotator cuff rupture, frozen shoulder or other causes of shoulder symptoms. All potentially eligible participants had standard x-rays and MRI to rule out rotator cuff rupture and other shoulder pathology. Baseline characteristics of participants are presented in Table SPain and global rating of change (GRC) were collected at baseline, 6-, 12- and 24-month follow-ups; SST and Constant-Murley score were measured at baseline, 6- and 24-month follow-ups.Shoulder pain intensity during the previous 24 h was assessed on a 100 mm visual analogue scale (VAS) ranging from 0 (no pain) to 100 (extreme pain)  , consistParticipants were asked their subjective satisfaction to treatment outcome relative to baseline at the 6-, 12- and 24-month follow-up visits on a five-point global rating of change (GRC) scale  . The corWe used three approaches to determine the MID for improvement: 1) the ROC method, 2) the mean difference of change (MDoC) method and 3) the mean change (MC) method.For the ROC method , we dichTo evaluate how well each measure could discriminate between those who were improved and those who were not improved, we calculated the area under the ROC curve (AUC). We determined the confidence intervals for AUC using DeLong’s method . The areIn the MDoC method, we calculated the mean difference of the change scores of each outcome from baseline to the follow-up time point (with 95% CIs) between the participants who answered” Somewhat satisfied” and” Dissatisfied”  and used the whole dataset irrespective of treatment for analyses to provide an estimate derived from a larger number of GRC-outcome pairs. We explored the ROC curves, and MID and PASS estimates at different time points and found them to be very similar, supporting our decision to pool data for our primary analysis. To explore whether the different treatments affected the MIDs, we performed sensitivity analyses and calculated MIDs for patients who underwent surgery (ASD and DA groups combined) and for patients who received exercise therapy. In the FIMPACT trial, the blinding between ASD and DA held well, and the patients in both ASD and DA groups subjectively underwent “surgical treatment”.For PASS, we used the ROC and the 75th percentile  methods This study was conducted in compliance with good clinical practice, and the Declaration of Helsinki.We analysed data from 193 patients. Due to missing data items, the number of available GRC-outcome pairs varied at each time point Table .Table 2To test the adequacy of our transition anchor, we calculated the correlations to the baseline values and outcomes at each time point. The correlations between the GRC and baseline values were close to zero  or excellent (Constant-Murley score) discrimination between patients who considered themselves improved or not improved. The correlations to change scores were adequate for these three outcomes, but the correlations to post scores were slightly larger than the correlations to change scores. MID values derived for pain at rest do not appear useful in this patient population. When interpreting trial results, the smallest credible estimate from different methods for MID sets the low limit for the MID, as changes smaller than the smallest MID estimate are very unlikely to be important to patients. The likely best MID estimates were 20 mm for pain VAS on arm activity, 10 points for Constant-Murley score and 1.5 points for Simple Shoulder Test.The PASS estimates using GRC 1 answer only for pain on arm activity (9 mm), Constant-Murley score (81 points), and Simple Shoulder Test (11 points) were consistent between methods and showed good discrimination. Using GRC answers 1 + 2, the PASS estimates were also consistent between methods and the AUCs were better or similar to the analysis using answer option 1 only. The PASS estimates with GRC 1 + 2 were 8 for pain at rest, 26 for pain on arm activity, 69 for the Constant-Murley score and 9 for the Simple Shoulder Test. We recommend using more conservative of the estimates for PASS values, which we think certainly represents a state of being well.In line with previous findings , 4, our We used multiple established methods to estimate the MID and PASS values in a relatively large patient sample with high adherence to follow-up (92% at 24 months). Our study population was exceptionally well established and uniform: a robust clinical examination by highly experienced orthopaedic surgeons ensured that participants had clinical findings consistent with SAPS, and magnetic resonance imaging with intra-articular contrast agent (MRA) was used to exclude other shoulder pathology. The strict inclusion criteria may limit the generalisability of our results to other shoulder conditions.The anchor question we used for determining the PASS was not verbatim the recommended PASS question . The FIMGiven the relatively long interval between the baseline and first follow-up, risk of recall bias is obvious. This notion is supported by very low correlations between the transition item and baseline and lower correlations to change scores than to the post scores , 22. ThiThe method of determining MID affected the values in our study , 4. The A recent systematic review of anchor-based MIDs for improvement in patient-reported outcomes provided MID estimates for mixed shoulder conditions . There wWe identified two studies that attempted to determine PASS estimates for VAS or numeric pain rating scale (NPRS) of patients treated for subacromial pain. Tubach et al.  reportedWe were not able to identify studies reporting PASS estimates for Constant-Murley score or Simple Shoulder Test in patients with subacromial pain syndrome.The smallest trustworthy estimate from different methods for MID can be used because anything less than the smallest MID estimate should be interpreted as unimportant to the patient. There may be settings where using the highest estimate is useful, for example, in a superiority trial where there is a large difference between treatments the higher limit for MID might be a good choice as a threshold for “unequivocal effectiveness.”. In our study, the ROC method provided the smallest estimates and discriminated well between those who considered themselves improved from those not improved. Pain at rest showed poor correlation with the anchor question and change score and low ability to discriminate, reflecting its low usefulness in this patient population.Our PASS estimates for pain at rest and pain on arm activity, Constant-Murley score, and Simple Shoulder Test were consistent across methods and showed good to excellent discrimination between those who considered themselves well from those who did not. We chose to recommend using the estimates derived from analysis using GRC answer 1 only, but it is likely to be conservative, as the acceptable symptoms state may include some minor symptoms also. When the PASS estimates are used to interpret study results, depending on the study setting and characteristics of the patient population, the estimates derived using GRC 1 + 2 can be applicable as well.The MID estimates vary widely, depending on assessment methods and patient populations . Change Different methods provided different estimates for MIDs. We recommend MID estimates for patients with subacromial pain as follows: 20 mm for pain VAS on arm activity, 10 points for Constant-Murley score and 1.5 points for Simple Shoulder Test. We could not establish a reliable MID for changes in pain at rest in this patient population. We recommend PASS estimates of 9 mm for pain on arm activity, 80 points for Constant-Murley score, and 11 points for Simple Shoulder Test.Additional file 1: Table S1. Baseline characteristics of the participants according to study group. Table S2 Correlations between GRC and baseline, post scores and change scores*. Table S3 MID estimates from the ROC analysis at 6, 12, 24 months. Table S4 MID values calculated by the mean difference of change (MDoC) and the mean change (MC) methods and their respective 95% confidence intervals (CI). Fig. S1 VAS figure from the original questionnaire (translated from Finnish to English). Fig. S2 MID ROC curves. Fig. S3 PASS ROC curves.