Pain detection and treatment is a major challenge in the care of critically ill patients, rendered more complex by the need to take into consideration the risk of insufficient or excessive analgesia. The nociceptive flexion reflex threshold (NFRT) has become the established basis for measuring the level of analgesia in the perioperative context. However, it remains unclear whether NFRT measurement can be usefully applied to mechanically ventilated, analgosedated critically ill patients who are unable to communicate. Therefore, the aim of the present study was to investigate whether there is an association between the NFRT measurement and the Behavioral Pain Scale (BPS) in critically ill, analgosedated, and mechanically ventilated patients and whether the NFRT measurement can also detect potential excessive analgesia.This prospective, observational, randomized single-center pilot study included patients admitted to the surgical Intensive Care Unit of University Hospital Ulm, Germany, all of whom were analgosedated and intubated. Major exclusion criteria were defined as the need for the administration of neuromuscular blocking agents or neurological diseases associated with peripheral nerve conduction restriction. Initial NFRT and BPS measurements were conducted within 12 h after admission. A structured pain assessment was performed at least twice daily until extubation throughout the observation period thereafter .114 patients were included in the study. NFRT is associated negatively with BPS. NFRT was almost twice as high in patients with a Richmond Agitation Sedation Scale (RASS) score of -5 than in patients with a RASS score ≥ -4 .NFRT measurement is associated negatively with the BPS in critically ill patients. NFRT measurement provides guidance for the evaluation of nociceptive processes in patients with RASS scores ≤ −4, in whom analgesia level is often difficult to assess. However, in order to identify excessive analgesia and derive therapeutic consequences, it is necessary to gradually decrease analgesics and sedatives until a stimulus threshold is reached at which the patient does not feel pain.https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021149.Retrospectively registered in the German Clinical Trials Register, registration number DRKS00021149, date of registration: March 26, 2020. The online version contains supplementary material available at 10.1186/s12871-021-01490-8. According to the International Association for the Study of Pain (IASP), Williams et al. describe pain as a “distressing experience associated with actual or potential tissue damage with sensory, emotional, cognitive and social components” . AlthougPain is not only important in the perioperative context, but is also of great significance in critically ill patients. Adequate pain management for critically ill patients is still a challenge, even in modern intensive care medicine. Mechanically ventilated patients in particular are at risk of excessive analgesia , 6. The Analgesia and sedation during general anesthesia are broadly similar in terms of dosage and drug type and differ from profound analgesia, which is sometimes required in mechanically ventilated, critically ill patients.At present, pain assessment in profoundly analgosedated, critically ill patients who are not able to self-assess their pain, e.g., using the Numeric Rating Scale (NRS), is predominantly limited to the interpretation of physiological parameters. The Behavioral Pain Scale (BPS)  is acknoMeasurement of the RIII-reflex threshold of the nociceptive flexor reflex (NFR) is a particularly interesting option for addressing the limitations of pain assessment in critically ill patients who are unable to communicate. “The reflex response of the nociceptive flexion reflex consists of three components. The RIII reflex component can be recorded 90 ms to 150 ms after a painful stimulus, which is mediated by Aδ- and C-fibers. The reflex responses preceding the RIII component are mediated primarily by fast-conducting Aβ fibers and correspond to the reflex response to non-painful stimuli.“ , 14. In Another equally important aspect in the context of pain assessment in critically ill patients is the quantification of adequate and appropriate analgesia. Analgesia is usually administered empirically, especially in profoundly sedated patients. The empirical approach carries the risk of excessive opioid use with adverse side effects such as respiratory depression, constipation, ileus, and pruritus .Therefore, the aim of the present pilot study was to examine whether measuring the stimulus threshold of the nociceptive flexion reflex can be a useful complement to pain assessment using the BPS.The present study was designed as a prospective, monocentric, randomized, observational pilot study. It was approved by the ethics committee of the University of Ulm, Germany  and registered retrospectively in the German Clinical Trials Register (DRKS ID: DRKS00021149). This study adhered to the STROBE  principles and was conducted between November 2018 and March 2020 in the interdisciplinary 12-bed surgical intensive care unit (ICU) at Ulm University Hospital, Germany. Cardiosurgical patients were treated in a different ICU and were only transferred to the interdisciplinary ICU in the event of capacity issues. Data were evaluated between 4/2020 and 11/2020.Figure The NFRT, which is determined using the Paintracker® device, essentially examines the excitability of the spinal component of the pain processing system. The afferent reflex arc is composed of A-delta and C-fibers. Electrodes on the medial plantar surface are used to stimulate the tibial nerve. The stimulated A-delta and C-fibers conduct the stimulus to the spinal cord, where the polysynaptic circuitry of the stimulus occurs. This, in turn, causes motor neuron activation. The activated motoneurons represent the efferent element of the reflex. The resulting stimulus response can be recorded via a surface electromyogram on the tibialis anterior muscle. A reduction in the excitability of the reflex arc is reflected as an increase in the reflex threshold. The threshold tracking, i.e., the automated determination of the reflex threshold, is calculated by delivering five single rectangular pulses, each lasting 1 ms duration, with a 4 ms interpulse interval 200 Hz). The stimulation threshold is determined by automatically varying the intensity of the stimulation current. This correlates with the subjective pain threshold in patients who are awake , 20, 21.0 Hz. TheThe interpretation of stimulus thresholds in different patients is critical because different surgical procedures are associated with different levels of pain intensity. For example, thoracic procedures are very painful and often require an epidural catheter technique for pain management. By contrast, patients with cerebral hemorrhage often have impaired central pain processing. NFRT measurement is particularly suitable for these patients, since this method records nociception, i.e., pain processing, rather than the subjective perception of “pain.“ The study protocol was in accordance with the Declaration of Helsinki ethical guidelines. All patients or their legal representatives signed written informed consent forms to take part in this study. Inclusion criteria were: (a) age ≥ 18 years, (b) need for intensive care treatment and intubation, (c) expected ICU stay of at least 24 h, (d) written informed consent of the patient’s legal representative and post-hoc verbal and written patient consent. Patients were excluded from the study based on the following criteria: (a) age < 18 years, (b) pregnancy, (c) neurological diseases associated with a restriction of peripheral nerve conduction, (d) pacemaker/implanted cardioverter defibrillator, (e) need for neuromuscular blocking agent, (f) local anesthesia and epidural analgesia.Prior to the first NFRT measurement, the anesthesia documentation was used for all patients admitted to the ICU to verify complete neuromuscular recovery by means of train-of-four (TOF) monitoring at the end of surgery (TOF ratio > 0.9). In emergency cases, we checked whether the patient had been given a muscle relaxant by the emergency physician. Similarly, it was ensured that neither neuromuscular blockade due to local anesthetics nor epidural anesthesia was present. Spontaneous activity of all extremities was observed in neurosurgical patients/patients with intracranial hemorrhage during the daily wake-up test to exclude the possibility that the motor response to the nociceptive stimulus was impaired.Potentially eligible patients were first evaluated on the basis of the inclusion and exclusion criteria. Then, simple, unrestricted randomization was performed by means of a random table generated using “Research Randomizer.“ Patients assigned even numbers were randomized to the group in which both BPS and NFRT were measured, referred to as Group A. Patients who were assigned odd numbers were randomized to the group where only BPS was measured, termed Group B.Since NFRT measurement was not part of routine clinical practice in the group of patients investigated, a comparison group was randomized by means of simple randomization in order to verify whether the measurement of the NFRT had an impact on the outcome or analgesic management of ICU patients. Due to the lack of evidence in this regard, the NFRT measurement in the present study was intended to be observational only rather than interventional.A structured pain assessment was conducted for all study patients within 12 h of admission to the intensive care unit. Pain assessments were conducted by two trained medical students throughout the entire study period.Both BPS and NFRT measurements were performed for Group A patients. In Group B, pain levels were measured using BPS only. During the subsequent observation period, a structured pain assessment was conducted at least twice daily until extubation .BPS and NFRT were measured in all patients at rest with a minimum interval of 30 min from the previous nursing or medical intervention. Repetitive measurements were performed whenever possible and are included in the data analysis. This explains the difference between the number of patients measured and the number of NFRT measurements as well as the difference in the number of BPS and RASS measurements.Patients received sufentanil (µg/h) or remifentanil (mg/h) as continuous intravenous infusions. The analgesic regimen was adapted according to the BPS scale with the aim of achieving BPS scores of 3–4 (mild pain). Remifentanil dosage was administered in the ICU in mg/h via a perfusor, in contrast to the dosing specification generally applied for intraoperative use (µg/kg body weight).During surgical procedures, metamizole was administered as a continuous infusion unless there were any contraindications. Metamizole is a prescription analgesic frequently used in the perioperative context in Germany, the mechanism of action of which is not yet fully understood. As a prodrug, it is hydrolyzed to the active N-methylaminoantipyrine and acts both centrally and peripherally. Indications include mild to moderate pain, postoperative pain, and tumor pain. The clinical duration of action is 4 to 6 h. The daily dosage is calculated as 10 to 15 mg/kg, with a maximum dose of 60 mg/kg . GeneralWhen a patient was already less deeply analgosedated (RASS ≥ -3), the opioid piritramide was administered intravenously to treat anticipated painful stimuli such as patient positioning. “As a 4-aminopiperidine derivative, it is a pure µ-agonist and the opioid most commonly used for postoperative analgesia in Germany. The potency is approximately 0.7 times that of parenteral morphine. The dosage is generally 0.1 mg/kg or 3.5 – 7.5 mg as an intravenous bolus. The clinical context half-time is 4 to 10 hours. Metabolization is almost entirely hepatic” .With regard to intravenous hypnotics, patients received either propofol (mg/h) or lormetazepam (mg/h) as a continuous infusion. The dosage was adjusted with respect to the previously determined RASS score.The objectives of the study were as follows:Is there a correlation between the NFRT and the BPS and the Richmond Agitation Sedation scale in critically ill, mechanically ventilated, analgosedated patients who are unable to communicate in Group A?Do the measured stimulus thresholds for the nociceptive flexion reflex differ between the various specialties in patients in Group A?Does NFRT measurement detect potential excessive analgesia in critically ill, analgosedated, mechanically ventilated patients who are unable to communicate in Group A?Measurement of a cohort of critically ill patients in whom pain is assessed using only the BPS (Group B) in order to demonstrate that Cohort A patients were not selected arbitrarily in favor of the measurement method.A sample size of 105 patients per group was calculated using GPower 3.1 to achieve a power of 80 % with a two-sided α-level < 0.05 and an effect size of d = 0.5.The following patient-related data were collected during patient stays in the ICU: (a) age upon registration & sex, (b) primary reason for ICU admission & length of ICU stay, (c) BPS & Richmond Agitation Sedation Scale (RASS), (d) Sequential Organ Failure Assessment Score (SOFA-Score), (e) Therapeutic Intervention Scoring System (TISS-28) and Simplified Acute Physiology Score (SAPS II), (f) vital signs, (g) analgesics and hypnotics. Data were collected in Microsoft EXCEL 2010®  and analyzed using Sigma Plot Version 14® for Windows  and SAS Version 9.4 . Quantitative data were expressed as median, minimum and maximum values and were compared for nonparametric distributions using the Wilcoxon Matched Pairs test. In the analysis of the independent samples, the Student’s t-test was used for normally distributed data (testing by Shapiro-Wilk). In the absence of normal distribution, the Mann-Whitney rank-sum test was performed. Due to the early cessation of the trial, all results reported must be interpreted in an exploratory manner. Thus, adjustment of the p-values for multiple testing was not required. A linear model (LM) was applied to evaluate possible associations between the measured NFRT and the key baseline characteristics which were not assessed in a time-dependent manner. We also used mixed linear regression modelling (MLM) to assess the possible association between NFRT and BPS measurements, which enabled us to account for the repeated-measures structure of the data. Specifically, the time of measurement was added as a further independent predictor alongside the BPS values. The repeated-measures structure was implemented by means of a random intercept. An explorative, two-sided type 1 error level of 5 % was applied to all analyses.All eligible patients were assessed based on the inclusion and exclusion criteria and then divided into two groups using simple randomization Fig. . The chaUnivariate LM analyses were performed to determine whether the NFRTs measured were affected by demographic factors such as age, sex, body height and weight, and length of ICU stay. We did not find that any of the aforementioned determinants had a statistically significant influence on the NFRT measurement, as shown in Table 1 in the Additional file We then investigated whether there was any association between the measured NFRTs and the BPS scores assessed for patients in Group A.With a total of 297 measurements in 57 patients, the NFRT was defined as the dependent variable and the BPS as the independent predictor in a mixed model. Corrections were made for the repeated-measures structure. The resulting regression line, which takes into account the data dependency effect, indicates that there is a negative association between the BPS and the NFRT Fig. .Figure A graphical analysis was performed to assign the determined stimulus thresholds in patients with BPS scores of 3 and 4 to the different operations/diseases, Fig. : Table 2Patients with neurosurgical intervention/intracranial hemorrhage had a statistically significantly higher NFRT at BPS 3 than at BPS 4 . Patients undergoing thoracic surgery had the highest NFRT at BPS 3 with 62.0 mA, IQR: 16.3 − 114.0 mA. Neurosurgical patients had the lowest NFRT at BPS 3 . Similarly, the highest NFRT at BPS 4 for patients with respiratory failure/ECMO was 92. 0 mA, (IQR: 28.0 − 99.0). The lowest NFRT at BPS 4 was recorded in patients with neurosurgery intervention/intracranial hemorrhage with 13.75 mA (IQR: 4.0 − 28.0 mA). For details of the NFRTs corresponding to the BPS scores, please see Additional file The amounts of analgesics administered in Group A patients in comparable pain conditions were analyzed with respect to the different stimulus thresholds resulting from different surgeries and diseases Table . PatientThe postoperative dosage of metamizole was almost the same in Group A and Group B. Here, the dose of 168 mg/h is equivalent to a continuous infusion rate of 2.1 ml/h at a standard dosage of 4 g metamizole to 50 ml NaCl 0.9 %. Metamizole was administered postoperatively in both groups. Piritramide was administered in a small number of patients in both groups as a single dose before a nursing intervention or planned wake-up attempt.Comparing the measured median NFRTs at different RASS values, it can be seen that the deeper the sedation, the higher the corresponding stimulus threshold. This is depicted in Fig. Patients with a RASS-Score of -5 have a median stimulus threshold of 59.40 mA (IQR: 32.95 – 91.00) which is higher to a statistically significant extent than less deeply sedated patients. .These results indicate that very deeply sedated patients are at a high risk of excessive analgesia. Stimulus thresholds of > 90 mA appear to be too high considering that patients sedated to a RASS of -4 showed much lower peak stimulus thresholds.Due to the outbreak of the SARS-CoV-2 pandemic in spring 2020, we decided to terminate the study prematurely with the current number of cases. Comparable studies include a patient population of between 40 and 100 patients , 23. NevThe primary objective of the present study was to demonstrate whether NFRT measurement is associated with the BPS and RASS scores in critically ill, mechanically ventilated, and analgosedated patients who are unable to communicate. We also investigated whether the measured stimulus thresholds differ between patient groups and whether the NFRT measurement can be used to detect potential excessive analgesia.Critically ill, mechanically ventilated patients who are unable to communicate need pain assessment that is as accurate as possible. However, established pain assessment scales such as the BPS reach their limits in patients under profound analgosedation (RASS score ≤ -4) , 24. As Furthermore, the results indicate that patients with presumed absence of pain have higher stimulus thresholds than patients with mild pain. Thus, NFRT measurement could help to better assess patient analgesia, especially in patients where clinically established pain assessment scales reach their limits. However, this also implies that the method will only be truly beneficial in a select few patients.There is a high risk of misinterpretation of analgesia by the treatment team in profoundly analgosedated patients. In a study by Whipple et al., a large proportion of the treatment team recorded freedom from pain in patients who retrospectively reported severe to extremely severe pain . TherefoMost patients in the present study with a RASS score ≤ -4 were excessively analgosedated. In the context of modern intensive care medicine and the credo “more analgesia, less sedation,“ such deep sedation can only be considered appropriate in exceptional cases , 31, 32.The study is subject to a number of limitations that need to be discussed.The chosen study design had to be modified to that of a pilot study due to its premature termination as a result of the SARS–CoV–2 pandemic. The reduction of the number of cases studied to half of the initially planned number does not allow for a statistically valid subgroup. The disparity observed between the two groups may have been due to the premature termination of the study, although the number of cases was balanced at the time of termination.Because NFRT measurement is not conducted regularly in critically ill patients, Group B (BPS measurements only) was created as a control group. Group B is thus descriptive in nature and does not contribute towards answering the primary research questions. BPS scores of 3 and 4 were recorded for almost all patients in Group A. Due to the very small number of measurements with BPS scores ≥5, it remains unclear which NFRTs can be recorded in critically ill patients with severe to very severe pain. Due to the lack of blinding for the clinicians, the possibility that the NFRT measurements had an impact, albeit unintended, on the analgosedation regimen of the patients in Group A cannot be excluded with certainty.Because the study was performed in a heterogeneous patient cohort of critically ill patients, it is not possible to extrapolate the results to internal medicine or cardiac surgery patients. The administration of analgesics and hypnotics must also be discussed as a major point of criticism. The study was conducted in a clinical practice. Therefore, some patients received remifentanil when the measurements were begun and sufentanil later on. This hampers the interpretation of the influence of the analgesics used on the measured NFRT stimulus thresholds considerably. Furthermore, the dosage of the analgesics and hypnotics administered was not adapted to each patient’s body weight.Because of the repeated NFRT measurements performed for each patient, it is not possible to perform any simple correlation analyses. Thus, no correlation coefficients can be provided for the association between BPS, NFRT, and RASS. This complicates the interpretation of our results.NFRT measurement is useful in detecting potentially excessive analgesia in critically ill, analgosedated, mechanically ventilated patients who are unable to communicate. In particular, very deeply sedated patients in whom pain assessment using the BPS method indicates that only patients with slight pain or freedom of pain would benefit from NFRT measurement. In these patients, a gradual reduction of analgesics and sedatives to the specific NFRT above which the patient perceives no pain could lead to more appropriate analgesia with a decrease in sedatives. Further studies are needed to systematically examine the use of NFRT measurement in a heterogenous group of critically ill, mechanically ventilated patients who are unable to communicate.Additional file 1.


A paucity of data exists centering on the pain experience of children following hemipelvectomy performed for primary bone and soft tissue sarcomas. In this study, we aimed to describe the incidence, severity, and evolution of perioperative pain and function in pediatric oncology patients undergoing hemipelvectomy, and, additionally, we sought to detail the analgesic regimens used for these patients perioperatively. A retrospective chart review was conducted, studying cancer patients, aged 21 years and under, who underwent hemipelvectomy at MD Anderson Cancer Center (MDACC) from 2018 to 2021. Primary outcomes included the evolution of pain throughout the perioperative course, as well as the route, type, dose, and duration of analgesic regimens. Eight patients were included in the analysis. The mean age at operation was 13 ± 2.93 years. All patients received opioids and acetaminophen. The mean pain scores were highest on post-operative day (POD)0, POD5, and POD 30. The mean opioid use was highest on POD5. A total of 75% of patients were noted to be ambulating after hemipelvectomy. The mean time to ambulation was 5.33 ± 2.94 days. The combination of acetaminophen with opioids, as well as adjunctive regional analgesia, non-steroidal anti-inflammatory drugs, gabapentin, and/or ketamine in select patients, appeared to be an effective analgesic regimen, and functional outcomes were excellent in 75% of patients. Hemipelvectomy is a complex surgical procedure performed for malignant or locally aggressive pelvic bone and soft tissue tumors, and it is less commonly performed for trauma or osteomyelitis ,2,3,4. RAlthough external hemipelvectomy (EH) was once the surgical approach of choice for the treatment of pelvic sarcomas, limb-sparing internal hemipelvectomy (IH), when possible, has now become the popular and more viable option ,10. TherPost-operative pain management in this patient population can be challenging; however, it is vital in order to obtain maximal functional outcome. Previous studies have described post-operative pain and analgesia after hemipelvectomy in adult patients ,16,17, aThis study was approved by the University of Texas, M.D. Anderson Cancer Center (MDACC) Institutional Review Board. We conducted a retrospective chart review of cancer patients, aged 21 years and under, who underwent hemipelvectomy at MDACC from 2018 to 2021. Patients were identified from a database maintained by the orthopedic oncology department, and they were screened to include only ages less than 21 years. We extracted demographic and clinical data from the electronic medical record (EMR).Primary outcome measures included the evolution of pain throughout the perioperative course, measured on post-operative days 0–7, day 30, and day of discharge, and the route, type, dose, and duration of analgesia regimens utilized during these same time points. Pain was assessed via Numeric Pain Rating Scale . AnalgesSecondary outcome measures included the measurement of perioperative functional status, assessed at the same time points by the Activity Measurement for Postacute Care (AM-PAC) score ,25, and Additional demographic and perioperative data collected included cancer diagnosis, age, sex, type of hemipelvectomy, surgical margins, necrosis percentage, adjuvant chemotherapy, perioperative labs, blood product transfusions, post-operative complications, PT, OT, nutrition and psychology consults, time to first ambulation, time to full diet, time to first bowel movement, time to tubes and drains removal, and 30-day readmission status.Patient demographics and clinical characteristics were described and analyzed using means and medians for continuous variables, and percentages for categorical variables. Baseline variables were summarized as means with standard deviations or as frequencies with percentages.Patient demographics are summarized in n = 7) and 100%, respectively; the 24-month EFS and OS were 75% (n = 6) and 87.5% (n = 7), respectively; and the 36-month EFS and OS were 62.5% (n = 5) and 75% (n = 6), respectively. The cause of death in the two deceased patients were related to metastatic disease progression.Hemipelvectomy characteristics are summarized in p = 0.5). The mean duration on analgesics was 31.63 ± 13.47 days. All patients were converted to oral opioids by day of discharge.Pain and analgesia data are summarized in Rehabilitation data are summarized in Hematologic and blood product data are summarized in This retrospective study assessed the evolution of pain, analgesia regimens, and functional status of pediatric cancer patients after hemipelvectomy. Our findings describe a pediatric oncologic cohort of hemipelvectomy patients with 100% free surgical margins, mean pain scores and opioid use that decreased throughout the post-operative course, and functional status that increased throughout the post-operative course, with 75% of patients ambulating and surviving post-operatively. The post-operative care of these patients at our institution involves collaboration amongst pediatric orthopedic oncology, pediatric oncology, pediatric anesthesia, pediatric supportive care, and pediatric critical care, as well as nursing, PT, OT, nutrition, and psychology.Acute pain is a hallmark of pediatric pelvic sarcoma patients, occurring both at presentation and in the post-operative period following hemipelvectomy ,19,27. PThe mean pain scores peaked on POD0, POD5, and POD30, while peak opioid administration peaked on POD5. Pain on POD0 is most likely due to hemipelvectomy surgical pain. It is striking to observe that both the mean pain score and opioid administration peaked on POD5, which coincides with the mean time to ambulation of 5.33 ± 2.94 days. Patients who underwent EH received a non-significant increased opioid dosage, but they displayed similar pain scores compared with IH patients across hospitalization. The small sample size may have precluded the detection of significant differences in opioid dose.Pain management was accomplished in all patients through a combination of opioid and non-opioid analgesic agents. Acetaminophen, given its well-tolerated side effect profile in the absence of hepatic insufficiency, is a safe medication that acts centrally, crossing the blood-brain barrier in large amounts, and satisfies all components of the WHO three-step ladder in the prevention and treatment of mild post-operative pain in our cohort ,31. BeyoThe majority of patients received gabapentin. While opioids target nociceptive pain, up to 90% of patients can develop peripheral neuropathy from neurotoxic chemotherapy . GabapenMost patients received ketamine, all of whom received ketamine intraoperatively, as well as one who remained on a ketamine infusion until POD3. Ketamine is a useful analgesic adjunct in the operative and critical care settings, functioning pharmacologically as an NMDA-receptor antagonist . It has One patient received NSAIDs. Previous studies have described the role of cyclooxygenase-2 (COX-2) in bone graft healing, and thus NSAIDs, which reversibly inhibit COX-2, are usually avoided in the perioperative period following hemipelvectomy ,37. The Apart from parenteral and enteral analgesics, most patients also received regional anesthesia. Regional anesthesia involves blockage of spinal and peripheral nerve transmission via afferent pain signaling pathways, potentially reducing post-operative pain and opioid consumption ,39. LocaA total of 75% of patients were ambulating post-operatively, and 50% of patients were discharged ambulating without assistance. There are several strengths to this study. Most importantly, this is the first study describing the evolution of pain, analgesic regimens, and functional status of pediatric cancer patients after hemipelvectomy in the perioperative period. We described a patient cohort with mean pain scores of 3 at their peak, most of whom were ambulating, with improved functional status on average, and all on oral analgesics by discharge. Consistent with the published experience, we use discharge criteria, regarding pediatric hemipelvectomy patients, that includes adequate pain control on oral analgesics, evidence of wound healing, bowel/bladder continence, and adequate functional performance for activities of daily living either independently or with the assistance of a caregiver ,41,43.While retrospective cohort studies can provide insight into the ideal management of pain, there are limitations. This was a single institution study with a small number of unique patients. Given the small cohort of patients, linear regression analysis was not substantially powered to derive associations between outcomes. In addition, the retrospective data extraction did not allow for collection of patient reported outcomes regarding health related quality of life.Further investigation at MDACC within this scope will focus on our prospective Enhanced Recovery Program , which aAcute pain is a hallmark of pediatric pelvic sarcoma patients, occurring both at presentation and in the post-operative period. The combination of perioperative acetaminophen with opioids, as well as adjunctive regional analgesia, non-steroidal anti-inflammatory drugs, gabapentin, and/or ketamine in select patients, appears to be an effective analgesic regimen for these patients. Early and frequent evaluation and treatment of pain is imperative in order to enable these patients to participate in essential physical and occupational therapy to reach their optimal goal of assistance free ambulation. In conclusion, this retrospective series suggests that hemipelvectomy for pediatric patients requiring local control for pelvic bone and soft tissue malignant neoplasms, when managed with multimodal pharmacologic analgesia, is associated with acceptable pain control and positive functional outcomes.


The aim of this study was to investigate if patients with temporomandibular disorders (TMD) prior to head and neck cancer (HNC) treatment are at higher risk of developing trismus after oncological treatment.Eighty‐three study patients underwent detailed dental examination prior oncological treatment and 6 months after radiotherapy completion, including evaluation of temporomandibular jaw function, palpation of the jaw muscles, and measurement of mouth opening capacity. TMD criteria were based on both clinical examination findings and patient‐reported symptoms. TMD at baseline was used in regression analysis in order to predict restricted mouth opening.p = 0.030]) and “During the last week, have you felt pain and tenderness in the muscles of mastication?” (OR [95% CI] 5.90 [1.19–29.40] [p = 0.030]).At the 6 months follow‐up more than a third of the patients (35%) were examined with reduced mouth opening of >20% compared to baseline. A majority of the patients had bilateral tenderness of both the temporal and the masseter muscle. At the 6 months follow‐up, 42% of the study patients reported mouth opening problems. About one‐third of the patients suffered from fatigue and stiffness of the jaw as well as pain when mowing the jaw. Two questions from the validated symptom‐specific Gothenburg Trismus Questionnaire were found to be related to a statistically significant increased risk of restricted mouth opening after radiotherapy; “During the last week, have you felt: Pain on moving the jaw?” (OR [95% CI] 5.9 (1.2–29.4) [TMD is common amongst HNC patients. Patients who suffer from pain in the jaw muscles and pain when moving the jaw before start of treatment are at higher risk of radiation‐induced trismus after 6 months. Clinicians should strive for optimizing the patients pain treatment and oral health before, during, and after radiotherapy. Disturbances in any of these structures can result in pain and dysfunction for the patient. Temporomandibular disorder (TMD) includes all functional disturbances in the masticatory system Okeson, .Most patients with head and neck cancer (HNC) are treated with external beam radiotherapy (RT). Even though RT has developed over the last decades, with higher precision and less toxicity, the treatment‐related side effects remain a heavy symptom burden for patients both short as well as long term  according to the study protocol. The study protocol included evaluation of temporomandibular jaw (TMJ) function, measurement of mouth opening , laterotrution capacity, horizontal overbite, vertical overbite, maximal protrusion capacity, mouth opening deviation, TMJ palpation , TMJ sounds or crepitation and, palpation of the jaw muscles assessing tenderness. Patients were assessed with regards to comorbidities according to adult comorbidity evaluation (ACE‐27)  receiving oncological treatment (RT ± chemotherapy) and age >18 years. Exclusion criteria were: surgical treatment only, trismus at baseline (MIO ≤35 mm), recurrent disease, poor general health, difficulties in filling out questionnaires, and edentulous patients. Furthermore, patients with tumors treated with RT where the muscles of mastication were not included in the radiation fields were excluded.3.2TMD criteria were based on both clinical examination findings and patient‐reported symptoms. For TMD diagnosis according to clinical examination, the presence of restricted mouth opening (MIO ≤35 mm) or tenderness in the temporomandibular joint or muscular tenderness in the jaw muscles was mandatory.For TMD diagnosis according to patient‐reported symptoms, the presence of facial pain or jaw‐related problems were required as follows:Mild to very severe problems in at least three of the following six items; stiffness/fatigue of the jaw, pain in the face or jaw, pain on moving the jaw, problems opening the mouth, pain or soreness in the jaw muscles, problems yawning. On the other hand, symptoms of facial pain according to the following items: (mild‐unbearable) facial pain right now, how strong pain during the last month (maximum and average), and additionally a reported impact of facial pain on daily activities. The definition of TMD has earlier been described in detail in the article TMD in HNC patients: Clinical findings and patient‐reported symptoms by Pauli et al. .Trismus was defined as MIO ≤35 mm  is presented. For continuous variables mean (SD)/median /n = is presented. For comparison between groups Fisher's Exact test  was used for dichotomous variables, the Mantel Haenszel χ2 test for ordered categorical variables, the χ2 test for non‐ordered categorical variables, and the Mann–Whitney U‐test was used for continuous variables.Potential predictors for trismus were used in regression analysis together with patient and treatments characteristics at baseline  stage). Furthermore, clinical examination findings and patient‐reported symptoms at baseline were used in regression analysis in order to predict restricted mouth opening. In the regression analysis, the investigated endpoint was any occurrence of trismus during the first 6 months of follow‐up. For categorical variables 4For this study, 89 patients with HNC were available for analysis. Six patients with trismus (MIO ≤35 mm) before oncological treatment were excluded from the analysis. Hence, 83 patients were included for the final analysis of the risk for future trismus. Mouth opening before oncological treatment varied from 37 to 68 mm with a mean (SD) of 50.5 mm . Chemotherapy was generally administered as inductive cisplatin‐fluorouracil therapy before RT or concomitant cisplatin throughout the treatment course.4.2Before the oncological treatment, 48% of the patients had clinical signs of TMD and 39% of the patients reported TMD symptoms. The corresponding figures at 6 months were 82% and 75% respectively. At the 6 months follow‐up, more than a third of the patients (35%) were examined with reduced mouth opening of >20% compared to baseline. A majority of the patients had bilateral tenderness of both the temporal and the masseter muscle on the same occasion, as per Table 4.3At the 6 months follow‐up, 42% of the study patients reported mouth opening problems. About one‐third of the patients suffered from fatigue and stiffness of the jaw as well as pain on mowing the jaw. Problems with eating solid food was reported in 50% of the patients, Table 4.4Logistic regression was performed in order to explore which risk factors can predict the development of trismus after RT in HNC. Univariable logistic regression analysis for MIO ≤35 mm explained by characteristics at baseline  was performed, where none of these factors were found to be significant risk factors for trismus. Analysis results showed a trend toward an increased risk for women to develop trismus and for patients with oropharyngeal tumors, albeit not significant, Table 4.5p = 0.054) Table p = 0.051) Table When analyzing TMD prior RT as risk factor for restricted mouth opening after RT, both according to clinical examination findings and using patient‐reported outcome in regression analysis, a tendency toward an increased risk of reduced mouth opening was seen but was not statistically significant, OR 4.7  and “During the last week, have you felt pain and tenderness in the muscles of mastication?”  Table In terms of TMD according to the patient‐reported outcome, two of the items of the GTQ were found to be related to a statistically significant increased risk of restricted mouth opening after RT. “During the last week, have you felt: Pain on moving the jaw?”   the statistical demands on sample size rises.6TMD is common amongst HNC patients. Patients who suffer from pain in the jaw muscles and pain when moving the jaw before start of oncological treatment are at higher risk of radiation‐induced trismus after 6 months. Clinicians should strive to optimize the patients' pain treatment and oral health before, during, and after RT.The authors have no other funding, financial relationships, or conflicts of interest to disclose.Nina Pauli: Conceived and designed the analysis; wrote the paper. Bodil Fagerberg Mohlin: Collected the data; contributed data or analysis tools. Christina Mejersjö: Conceived and designed the analysis; other contribution ; Caterina Finizia: Conceived and designed the analysis; contributed data or analysis tools; other contribution .


The current study sought to explore whether cancer pain (CP) already exists in patients at colorectal cancer (CRC) diagnosis before treatment compared with patients with colorectal cancer (CRC) after treatment and a healthy matched control group. The study also sought to examine whether factors related to physical health status could enhance pain processes.d and Hedge’s effect size, as appropriate.An observational cross-sectional study was conducted following the STROBE checklist. Twenty-nine newly diagnosed and forty post-treatment patients with CRC and 40 healthy age/sex-matched controls were included for comparison. Pain, local muscle function, and body composition outcomes were assessed by a physiotherapist with > 3 years of experience. ANCOVA and Kruskal–Wallis tests were performed, with Bonferroni and Dunn-Bonferroni post hoc analyses and Cohen’s p < 0.05). In the post-treatment and healthy matched control groups, positive associations were observed between the PPT lumbar dominant side points and abdominal isometric strength and lean mass, and negative associations were observed between the lumbar dominant side points and body fat (p < 0.05).The analysis detected lower values of pressure pain threshold (PPT) points, the PPT index, and abdominal strength and higher values of self-reported abdominal pain in newly diagnosed patients, with even more marked results observed in the post-treatment patients, where lower lean mass and skeletal muscle index values were also found than those in the healthy matched controls (Upon diagnosis, patients with CRC already show signs of hyperalgesia and central sensitization and deteriorated physical conditions and body composition, and this state could be aggravated by subsequent treatments. Cancer pain (CP) is one of the most prevalent and concerning aspects of the disease that patients with cancer must face, and it occurs in more than 60% of patients across all cancer stages , even frA systematic classification of chronic pain was developed by the International Association for the Study of Pain (IASP) that distinguishes chronic primary and chronic secondary pain syndromes. When pain persists or recurs for more than 3 months, it is considered chronic pain. In some conditions where pain may be considered a disease, the term chronic primary pain is used. However, in other cases, pain is secondary to an underlying disease, such as chronic cancer-related pain . AdditioThe presentation of chronic pain and central sensitization in patients with colorectal cancer (CRC) in the survival phase is well established , 8. ThisIn patients newly diagnosed with CRC who did not undergo cancer treatment, abdominal pain may already be present . Tumors Although cancer treatment may induce pain, how this may be already established from the moment of diagnosis is unclear. Therefore, it would be interesting to fully elucidate this early CP appearance to offer tailored interventions to prevent or mitigate CP. Therefore, the current study sought to explore whether CP already exists in patients with CRC upon diagnosis before cancer treatment compared with patients after treatment and a healthy matched control group. The study also sought to examine whether factors related to the physical health status could influence pain processes.n = 29; post-treatment n = 40) and 40 healthy age/sex-matched controls were included for comparison. Healthy age/gender-matched controls were recruited through announcements by the University of Granada on social networks. Both previous cohorts had the following inclusion criteria: (1) patients of legal age (> 18 years), (2) patients diagnosed with CRC (stage I to IIIa), (3) patients on a waiting list for surgery (newly diagnosed study), or (4) patients completed their medical treatment (post-treatment group). Patients with any medical contraindication or musculoskeletal condition to perform the assessments , any abdominal surgery, or any previous cancer treatment (newly diagnosed group) were excluded. After the first contact, the patients were contacted by telephone for an appointment at the Sport and Health Research Center or Physiotherapy Laboratory of the Health Science Faculty of the University of Granada. All the participants signed an informed consent form before participating in the study.We conducted an observational cross-sectional study following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist . For thiThe study protocols were approved by the Research Ethics Committee of the University of Granada (0572-M1–16 and 1087-N-16), and the study was performed in accordance with Law 14/2007 on Biomedical Research and the guidelines of the World Medical Association Declaration of Helsinki.The same evaluation protocols and assessment instruments (model and brand) were used in all the participants. Evaluations were made by a trained researcher with experience in the evaluation of patients with a CRC > 3 years. The patients were asked if they had taken any rescue analgesics in the last 24 h; if so, the assessment could be postponed. The demographic and clinical details were entered from the medical reports of the patients.Testing was performed using an electronic algometer  at the dominant and nondominant lumbar, supraumbilical, infraumbilical, and second metacarpal points, with a perpendicular diameter of 1 cm . At each point, the evaluation was performed three times with a rest of 30 s, and progressive increases in force (30 kPA/s) were applied until the first perception of change from pressure to pain, which was previously explained to the participants. The mean of three rounds was registered as a unidimensional variable with an intraclass correlation coefficient (ICC) of 0.91. SimilarPatients were asked to rate their pain intensity in the abdominal and lumbar areas using a horizontal visual analog scale (VAS) of 10 cm (cm), where 0 means “no pain” and 10 means “the worst pain.” This instrument has an ICC of 0.97 . The cutAbdominal isometric strength was assessed using the trunk curl test to evaluate a possible alteration of the lumbopelvic functional stability. From a supine position with flexion of the knees and hips, patients flexed their trunk to separate the lower angle of the scapula from the stretcher and then maintained this position, with their arms extended without touching their knees as long as they could. Time was recorded up to a maximum of 90 s. This test has a high reliability (ICC > 0.97) .Muscle images were captured using an ultrasound device  for the multifidus, transversus abdominis, and external and internal obliques (cm). A 12-MHz linear probe was used following a previous protocol . The ima2), and skeletal muscle mass index ) were obtained using an InBody 720 tetrapolar eight-point tactile electrode system . The patients were instructed to rest (no rigorous exercises in the previous 24 h) without a meal/water 3 h before measurement. The cutoff points related to a higher risk of CRC are a weight of 82 kg and a BMI of 31 kg/m2 [2 (men) or 5.76 and 6.75 kg/m2 (women) [Body composition, musculoskeletal mass (kg), body fat (%), body mass index  .Waist circumference (cm) was assessed using plastic tape at the end of exhalation at the midpoint between the lowest rib and iliac crest. A value of 87 cm is associated with a higher risk of CRC .p < 0.05 and a 95% confidence interval (CI). The results are expressed as means (m) ± standard deviation (SD) for continuous variables or numbers (n) and percentages (%) for category variables. The Shapiro–Wilk test was used to check the normal distribution of the outcomes (p > 0.05). Analysis of variance (ANOVA) was performed to assess the similarity between groups for continuous variables related to demographic and clinical characteristics. The chi-squared (χ2) test was used for category variables. Three-way analysis of covariance (ANCOVA) was used to evaluate the between-group difference in d effect size was calculated to quantify the between-group differences considered small (0.20), moderate (0.50), and large (0.80). The Kruskal–Wallis test was used when the outcomes did not reach normality, and post hoc comparisons were performed using the Dunn-Bonferroni post hoc method. Hedge’s effect size was calculated to quantify the between-group differences, which were considered small (0.20), moderate (0.50), and large (0.80). Additionally, Pearson’s test was used to analyze the bivariate correlation between the dominant lumbar side of the PPT and the remaining dependent outcomes in each group. A correlation from 0 to 0.25 indicates an absent or weak relationship, a correlation from 0.25 to 0.50 indicates a fair relationship, a correlation from 0.50 to 0.75 indicates a moderate to good relationship, and a correlation greater than 0.75 indicates a very good relationship [Analyses were performed using the SPSS statistical package for MacOS Sierra version 10.13 , with a level of significance of tionship . Missingn = 76), not meeting the inclusion or exclusion criteria (n = 46), and failure in the assessment instruments (n = 7). Finally, 29 patients (69.0% men) with an average age of 61.68 ± 12.78 years were included in the newly diagnosed group (NDG), 40 patients (65.0% men) with an average age of 60.80 ± 10.02 years were included in the post-treatment group (PTG), and 40 healthy matched people (52.5% men) with an average age of 59.54 ± 9.69 years were included in the HMCG. The demographic and clinical characteristics of each participant group are shown in Table Of the 239 screened patients, 110 were eligible to complete the assessment. The reasons for ineligibility included participation declination , supraumbilical side , infraumbilical side , and second metacarpal side . The NDG and PTG registered lower values than the HMCG and were always lower in the PTG. The intergroup effect size between the NDG and PTG was large for the supraumbilical dominant side  and moderate for the lumbar nondominant side , supraumbilical nondominant side , infraumbilical dominant side , and infraumbilical nondominant side . The intergroup effect size between the NDG and HMCG was moderate for the dominant lumbar side  and nondominant lumbar side . The intergroup effect sizes between the PTG and HMCG were large for the nondominant lumbar side , supraumbilical points , infraumbilical points , and second metacarpal nondominant side  and moderate for the lumbar dominant side  and second metacarpal nondominant side . ANCOVA with cancer stage as a covariate influenced the results on the lumbar side  and infraumbilical side .Figure n = 14, 50.0% in the NDG; n = 27, 67.5% in the PTG), lumbar nondominant side , supraumbilical dominant side , supraumbilical nondominant side , infraumbilical dominant side , infraumbilical nondominant side , second metacarpal dominant side , and second metacarpal nondominant side . Figure ANCOVA of the PPT index revealed the number of patients with significant clinical differences > 20%) relative to the HMCG values for the lumbar dominant side (0% relatip = 0.006). Figure p = 0.005). The intergroup effect size was moderate  between these groups .The Kruskal–Wallis test of self-reported spontaneous pain revealed a significant difference between groups in abdominal pain (p < 0.001) between groups for abdominal isometric strength, with lower values in the NDG and PTG than in the HMCG. Post hoc analysis identified significant differences between the NDG and HMCG (p = 0.011) and between the PTG and HMCG (p < 0.001). Table The Kruskal–Wallis test revealed a significant difference (p < 0.002) between groups, with lower values in the NDG and PTG than in the HMCG. Post hoc analysis identified significant differences between the NDG and HMCG (p = 0.011) and between the PTG and HMCG (p = 0.004). Table The Kruskal–Wallis test showed a significant difference in the width of the lumbar multifidus p < 0.00 between F = 3.14; p = 0.047), with lower values in the PTG than in the NDG and HMCG. Bonferroni post hoc analysis identified significant differences between the NDG and PTG . Additionally, the Kruskal–Wallis test showed a significant difference between groups for the skeletal muscle mass index (p = 0.038). Post hoc analysis identified significant differences between the NDG and PTG (p = 0.042). No significant differences were found for the remaining variables. Table ANCOVA of musculoskeletal mass data revealed a significant difference between groups ( p = 0.04. No signp < 0.001) between the dominant lumbar side point and remaining PPT points. In the PTG and HMCG, positive associations were observed between the dominant lumbar side points and abdominal isometric strength  and musculoskeletal mass . Additionally, negative associations were observed between the dominant lumbar side points and body fat . Figure In all groups, Pearson’s test showed a significant positive association  of the patients presented CP, and that only in 8% of those cases was due to cancer treatment. Also, they found that, among other reasons, pain prevalence correlated with patient socioeconomic characteristics  and pain severity with a more advanced stage of the disease and previous inadequate pain management. In another study by Kelsen et al. [Curiously, our findings of a reduction in PPT suggest that from the moment of diagnosis, patients with CRC had CP, indicating the possible onset of central sensitization without the presence of some of the factors that may enhance CP in the post-treatment group. Additionally, 1 of 2 patients in the NDG showed a minimal clinical difference (> 20%) in the PPT index compared with that in the HMCG. There are studies that address the issue of pain in newly diagnosed cancer patients, although their cohort is only partially treatment-naïve and it does not focus on patients with CRC. In the study by Ger et al. , a Taiwan et al. , they ann et al. , which aAdditionally, the isometric strength values were 30% lower in the NDG and almost 60% lower in the PTG than in the HMCG, findings that are consistent with other study findings from our research group on PTG patients , 35. TheRelated to general muscle mass, the skeletal muscle mass index indicated that only the PTG showed moderate sarcopenia, a prevalent problem in patients with cancer because it involves a higher risk of developing immediate postoperative complications and decreased tolerance to chemoradiotherapy because of side effects . HoweverCorrelation analysis revealed that the PTG and HMCG were unexpectedly similar, with reductions in the dominant lumbar side PPT correlated with the remaining PPT points, lower values of isometric abdominal strength, lean mass, and higher body fat in both groups. Better muscle function may mitigate pain perception , 50; addSome limitations of our study should be noted. First, not all the factors that influence the development of central sensitization from the biopsychosocial perspective were analyzed in these patients; secondly, analyses with different groups limit the results, and no longitudinal changes could be studied; also, the study did not examine the presence of background pain or record any analgesic treatment; therefore, these characteristics were not established as inclusion criteria to establish a representative sample of patients with CRC.This study also presents some strengths. Widespread pain, which is a crucial objective measure, was addressed. Also, this work attempts to respond to the limitations of a previous study in which prospective data from patients with CRC was needed to be obtained upon diagnosis . MoreoveBefore the start of cancer treatment, NDG patients with CRC show signs of primary hyperalgesia, central sensitization, and deterioration in physical condition and body composition. Such symptoms appear to be further aggravated following cancer treatment. Hence, addressing the health status of these patients at diagnosis is crucial.


Arthrogryposis multiplex congenita (AMC) is a rare congenital condition that leads to severe joint contractures and deformities. As painful joint dysplasia and degeneration might develop over time, total joint replacement (TJR) can be a potential treatment option for these patients. The aim of this study is to investigate functional results, implant survivorship and potential complications in patients with AMC who undergo hip or knee arthroplasty.t test. The level of significance was defined at < 0.05.We retrospectively identified six TJR in three patients at a single centre performed between 2006 and 2019. The median patient age at surgery was 23 years and the median follow-up period was 69 (IQR 55–99) months. We analysed surgical technique, implant survivorship and complications as well as functional outcome determined by pain reported on the Numerical Rating Scale (NRS), patient-reported outcome scores , range of motion and ambulatory status. Depending on data distribution means with ranges and median with interquartile range were compared with the Wilcoxon signed rank test or Student’s p = 0.014) and in rotation  as well as mean pain score on the NRS , OHS  and HHS  significantly improved. In knees, mean range of motion , mean pain score on the NRS (0 vs. 7) and the OKS (2 vs. 21) also improved. While the ambulatory status did not change, the patients who were wheelchair dependent reported less problems with transfers to a bed or chair and the patient who ambulated reported an improved walking distance. One total knee arthroplasty (TKA) underwent revision for an acute, late infection 155 months following the initial surgery.In hips, the mean range of motion in flexion/extension (52° vs. 85°, TJR is a safe procedure in patients with AMC that effectively improves function and reduces pain irrespective of preoperative ambulatory status. Arthrogryposis multiplex congenita (AMC) is a rare congenital symptom complex that describes a collection of aetiologies with several significant joint contractures and consequent deformities –3. WhileConsidering that a high percentage of patients with AMC has the potential to ambulate in adulthood and has a close to normal life expectancy , 7, surgConsidering the perpetual improvements in total hip arthroplasty (THA) and total knee arthroplasty (TKA) that allow for simultaneous correction of deformities and show excellent long-term survival –12, thesHowever, THA and TKA following deformity correction in patients with syndrome associated joint dysplasia are usually technically challenging procedures and only few solitary cases have been reported so far , 13, 14.The aim of the present study is to analyse the surgical treatment details, implant survivorship and functional results following THA or TKA in patients suffering from AMC and provide an overview of the current literature.We conducted a retrospective database search of a single institution’s electronic database and identified a total of 18 consecutive patients who underwent surgical treatment at our department for AMC between 2006 and 2019.Of these patients, three received total joint replacement (TJR). All of whom had tetramelic amyoplasia type 1 according to the Munich classification (disorders with mainly limb involvement) . Two patTJR surgery was indicated if pain and joint degeneration was present and conservative treatment with non-steroidal anti-inflammatory drugs and physical therapy had failed. All patients previously underwent multiple surgical interventions with soft tissue releases to address contractures and correction of clubfoot deformities in our department and in other hospitals. However, in only one patient to our knowledge a subtrochanteric varisation osteotomy and modified acetabuloplasty were performed  to treatThe THA  was diagnosed using the criteria as proposed by the musculoskeletal infection society (MSIS) published in 2018  and Oxfot test for paired, parametric data. Level of significance was defined at < 0.05; all p values were two sided.We conducted a descriptive statistical analysis and analysed the distribution of data using the Shapiro–Wilk test. For non-parametric data median and 25–75% interquartile ranges (IQR) were presented while for parametric data means and ranges were given. Differences in functional scores were compared using the Wilcoxon signed rank test for non-parametric data and the Student’s The median follow-up period amounted to 69 months (IQR 53–99) with all patients available for functional analysis.p = 0.014) and the range of motion in internal and external hip rotation improved from a mean of 28° (range 10–50) to 63° (range 40–80) postoperatively (p = 0.002).In the four THA performed pain, range of motion and functional scores all improved significantly. The preoperative hip flexion and extension range was at a mean of 52° (range 40–70) preoperatively and 85° (range 70–90) postoperatively (p = 0.001).The mean pain score as determined by the NRS fell to a mean value of 0 postoperatively from a preoperative mean pain score of 8.5 (range 7–10) (p = 0.031) and the HHS from a mean 17 (range 0–32) to 52 (range 40–74) postoperatively (p = 0.007).The preoperative OHS improved from a mean of 9 (range 3–13) to 26 (range 20–40) postoperatively (p = 0.403). The NRS fell from 7 to 0 and the OKS improved from a mean of 2 (range 1–2) to 21 (range 20–21). Testing of the significance was not possible because the difference in standard deviation was 0.The two TKA resulted in an improvement of knee flexion and extension from 55° (range 40–70) preoperatively to 93° (range 80–105) postoperatively  or mechanical complications such as dislocation or loosening, one patient developed a late acute PJI of the replaced knee joint 155 months following primary arthroplasty. Symptoms with newly onset knee pain and swelling occurred several weeks after a foot pressure ulcer due to an increasing ankle contracture on the same leg. Cultures yielded Patient 1 initially presented to our arthroplasty department at the age of 16 due pain and 30° of flexion contracture of the right knee. Prior to this, at age 9 he had undergone open arthrolysis that was initially successful but had recurred over the last 2 years prior and was associated with disabling pain despite the limited overall mobility with dependency on a wheelchair from early on. Additionally the patient had undergone complex corrective hind foot surgery to correct bilateral clubfoot deformities in early childhood and requires orthopaedic shoes since then. The patient was consulted for either re-arthrolysis or arthrolysis and joint replacement because of the fact that the primary issue was pain at mobilisation and transfers. The postoperative rehabilitation resulted in a range of motion at discharge of full extension with 50° of active flexion. Wheelchair transfers were consequently possible. At long-term follow-up, the range of motion improved to 110° of flexion. Unfortunately, the patient underwent treatment for PJI of this TKA later on as described above.After 5 years of uneventful follow-up visits at an outside orthopaedic practice, the patient presented at age 21 with a laterally dislocated patella and subluxated, stiff knee in 30° of flexion contracture on the left side. The patient complained of worsening pain at weight bearing and during transfers. Due to the arthritic changes and successful surgery on the right side, a primary rotating hinge knee was implanted resulting in a postoperative range of motion of 90° flexion with 10° of residual flexion contracture. The patient was able to perform transfers and short periods of standing 3 months after surgery.The patient presented again at age 23 with bilateral hip pain and was found to have dysplastic and arthritic hips. Once again, transfers were not possible independently and pain at rest was also reported. The patient had bilateral flexion contractures of 20° with maximum flexion of 60° and no rotatory motion due to pain. The left hip was replaced first using a cementless diaphyseal anchorage stem and a cementless primary hip cup. Due to the successful treatment with postoperative absence of pain and recovered motion and ability to do transfers over the left leg, the patient underwent replacement of the right hip using the same implants 8 months after the left side. After 6 weeks of non-weight bearing, the patient went on to full weight bearing and achieved improved flexion in both hips Table .Table 1PPatient 2 first presented to our arthroplasty department at age 27 due to progressive left hip pain, limited range of motion of 70° degrees of flexion with 10° flexion contractures with no pain-free rotatory motion and reduced walking distance of less than 100 m. She had previously undergone varisation of the proximal femur and acetabuloplasty on the same side at age 5 for teratogenic hip dislocation. Since then the hip has been reduced. She had previously undergone multiple tenotomies of the lower extremity flexors around both knees as well as triple arthrodeses of both feet for recurrent clubfoot deformity at age 12.The patient underwent primary THA using a cementless stem and cup through a lateral approach.Postoperatively the patient regained full extension with flexion to 90° and 20° of internal and external rotation without pain. Ambulation without aids is in the domestic environment, but she still requires a wheelchair for outside activities.The third patient presented at age 18 due to worsening hip pain on the left side with reduced range of motion of 70° of flexion with full extension and no rotatory motion. The patient had been ambulatory since childhood despite a teratogenically dislocated hip on the left. The maximum walking distance had been reduce to 500 m while it was almost unlimited before. The patient had previously undergone several soft tissue releases and arthrolysis of the knee and ankle using external fixation at an outside hospital during childhood. The hip had not been operated on previously.Due to the small femur configuration and reduced bone quality due to the teratogenic dislocation, a cemented dysplasia stem and a cemented dual-mobility cup was used. Additionally, a Harris plasty of the acetabulum was performed using the patient’s femoral head.After 6 weeks of partial weight bearing to allow the Harris plasty to achieve bony fixation, the patient assumed full weight bearing and returned to unassisted ambulation with no pain and unlimited walking distance.As for rehabilitation, the patients usually remained in the hospital for 1 week and went on to undergo conventional orthopaedic rehabilitation treatment when full weight bearing had been achieved.While AMC is a serious disease that leads to severe impairment of joint function and consequently may restrict the ability to ambulate, overall life expectancy is generally considered to be close to normal and the treatment goal is to enable patients to live an independent life , 7, 22. While this is the only case series in the literature that systematically investigates patients with AMC and patients were operated on in a single centre, this study has several limitations. First, it is a retrospective study that relies on the completeness of patient records and is prone to selection bias as patients might have undergone further treatment at other hospitals. However, probably due to the rarity of the disease all patients have returned to regular follow-up visits and the reported results came from very recent visits to our outpatient clinic. Second, while this is the largest collection of cases in the literature, it is still based on the results of only six TJR surgeries. Therefore, the presented results might not be applicable to every patient with AMC seeking advice on TJR. Third, while only one patient has developed a major complication and underwent reoperations, the limited number of patients that are available from our report and the overall literature make it difficult to identify risk factors for complications or assess the overall risk for revision surgeries following TJR. Fourth, while we report PROMS using several established scores to measure functional results in these patients, particularly in the Oxford scores, several questions were not addressed or scored with 0 out of 4 possible points (lowest possible results) by two of the patients who are still largely dependent on a wheelchair to handle the activities of daily living. In consequence, the test values were lower than expected despite both patients being subjectively very satisfied with the results. This must be considered when measuring function in patients who are not fully ambulatory.In four previous reports Table  9, 14, , 24, theConsidering the young age of the patients who underwent TJR surgery in the present study, long-term implant survivorship may become an issue. The Nordic arthroplasty registry recently reported a 10-year survival probability of 83% for THA in patients under 21 years of age with the most common indication being inflammatory arthritis and aseptic loosening being the main reason for revision . This isLastly, as dislocation in THA might be a particular risk in AMC patients due to the joint contractures and risk for recurrent contractures of the affected muscles after surgery, dual-mobility cups  may be uTo our knowledge, there are no comparable studies on TKA survival in very young patients; nonetheless, the same concerns might be transferred to TKA and instability could be addressed pre-emptively with the use of a constrained or hinged knee.In conclusion, based on the results from the present study and the limited evidence provided in the literature, we recommend joint replacement surgery in patients with painful joint deformities and osteoarthritic changes due to AMC independent of the ambulatory status. Implant selection as well as fixation techniques can be adapted to the local joint configuration, bone quality and severity of soft tissue contractures. Long-term studies should address implant survivorship and complications in patients with AMC.


The biopsychosocial paradigm contemplates the patient’s personality traits in physiotherapy treatments for chronic pain. Among these traits, the locus of control has a direct relationship with the person’s coping strategies in the face of their health problems. The objective of this systematic review was to assess the influence of locus of control on the efficacy of physiotherapy treatments in patients with chronic pain. A systematic review of the publications of the last ten years in Pubmed, Scopus, Science Direct and Web of Science databases was conducting with the terms physical therapy modalities, chronic pain, internal-external control, self-management, physical therapy and physiotherapy. The inclusion criteria were participants with chronic pain lasting at least three months who have received at least one session of physical therapy; the studies should have collected the patient’s locus of control as a prognostic factor at the beginning of physiotherapy treatment; the variables studied should include the pain intensity or clinical variables related to pain. A total of 13 articles were found, of which three were experimental studies and ten were observational studies. The included samples had chronic knee pain, nonspecific back pain, low back pain or neck pain; were people over 65 years of age or patients who had undergone hand surgery. In patients with chronic pain for more than three months, the locus of control construct participates as a predictor of the results of physiotherapy treatment. The presence of an internal locus of control favors better results. The personality traits of the subjects represent an important factor to take into account when planning physiotherapy treatments. Pain is considered chronic when it lasts for more than three to six months and/or persists beyond the expected tissue healing time . This tyChronic pain (CP) is a symptom that affects 20–40% of the world’s population  ,7. The pTraditionally, PT has assumed that the most appropriate techniques were to be chosen according to the clinical picture, and that successful treatment was based on the implementation of these techniques . The curThe LoC is a construct that defines how a person perceives events according to whether the person considers them to be a consequence of or modifiable by their own behavior  or by that of other people, or chance . Consequently, in relation to health, patients with internal LoC are those who consider that their health condition is a product of their own behavior or actions, and therefore they are also individuals who are capable of taking control of the events that happen to them. Conversely, an external LoC patient considers their health condition to be the result of chance and/or other factors outside of their control .Likewise, there seems to be a direct relationship between LoC and a person’s coping strategies when faced with health problems. The individual’s belief that there is nothing they can do to improve their condition produces a growing sense of threat and alarm, which facilitates the possible perpetuation of their painful state . The intThus, active physiotherapy treatments, where the patient must perform therapeutic exercises in the belief that these can improve their state of health, may be influenced by the person’s LoC type. In this case, PTs should pay attention to this personality variable when scheduling certain exercises, individualizing the treatment.Consequently, the efficacy of PT treatments in patients with chronic pain could be influenced by the patient’s LoC about their pain . TherefoThis study was registered on PROSPERO ID: CRD42021230088) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and the recommendations of the Cochrane Collaboration [21230088 The PICO question was chosen as follows: P—population: adults with chronic pain lasting at least three months and interna LoC; I—intervention: PT treatment; C—control: adults with chronic pain lasting at least three months and external LoC; O—outcome: pain intensity or clinical variables related to pain .; S—study designs: experimental and observational studies.A systematic search of publications published in the last ten years was conducted throughout the month of December 2020. The search was limited to the last ten years in order to provide novel and representative information on research in this area. The databases included were PubMed, Science Direct, Web of Science and Scopus. The search strategy included different combinations with the following medical subject headings (MeSH) terms: Physical therapy modalities, Chronic pain, internal-external control and self-management. In addition, they were also combined with the following free terms: physical therapy and physiotherapy. The search strategy is presented in The inclusion criteria were (a) participants had to be adults with chronic pain lasting at least three months, excluding patients with chronic pain of oncological origin, systemic diseases, infectious or inflammatory diseases diagnosed with a severe psychological disorder. (b) Participants must have received at least one session of PT , delivered by a physiotherapist and involving some direct clinical contact. (c) The studies should have collected the patient’s LoC as a prognostic factor at the beginning of PT treatment. (d) The variables studied should include the pain intensity or clinical variables related to pain .After screening the data, extracting, obtaining and screening the titles and abstracts for inclusion criteria, the full texts of the selected abstracts were obtained. The full texts of titles and abstracts lacking sufficient information regarding inclusion criteria were also obtained. Full text articles were selected by three reviewers , all physiotherapists with experience in conducting systematic reviews used, a data extraction form, provided that the studies met the inclusion criteria. The three authors independently collected the following data for further analysis: demographic information , characteristics of the sample , study-specific parameter  and results obtained. Furthermore, the Oxford 2011 levels of evidence  and the Out of 662 search results, 448 studies were considered eligible for inclusion after removing duplicates. Among the 448 papers screened, 400 were excluded after abstract and title screening. Kappa score of reviewers 1 and 2 was 0.397, indicating slight agreement. Of the 48 full-text articles assessed for eligibility, 13 were finally included in the synthesis, as depicted by the PRISMA flowchart in Regarding the experimental designs of the investigations analyzed, three were experimental studies ,25,26 anXu et al. , López-OIn another study, manual therapy was applied (passive mobilizations) ,33 and aOther studies failed to report the PT treatment applied ,33 and iFor the assessment of pain the studies used the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) ,34, PainFor the evaluation of the LoC, the studies used the LoC Questionnaire , the HeaXu et al.  found thAnother observational study  identifiFinally, another study found no significant association between LoC and pain intensity after hand surgery  and GroeThe aim of this review was to assess the influence of LoC as prognostic factor on the efficacy of PT treatments in patients with CP. The results obtained indicate that, irrespective of the treatment modalities chosen, LoC could act as a mediator in reducing pain intensity.Most of the studies reviewed identified a direct relationship between high levels of internal LoC and lower pain intensity than subjects with inverse LoC characteristics ,32,34,35The majority of PT interventions applied were successful for the reduction of pain intensity, degree of depression and perceived degree of disability, immediately after treatment ,25,29,32In the field of PT in patients with PC, high levels of anxiety and/or depression predispose to higher levels of disability and poorer quality of life . These aWhatever treatment modality is chosen, the ultimate goal is that it should be effective for the patient, avoiding side effects and unnecessary financial costs . ConsequIn relation to the previous hypothesis that the efficacy of physical therapy treatments in patients with chronic pain is influenced by the type of patient’s locus of control. The authors can affirm that this influence has been proven. As practical implications, it is important to bear in mind the psychosocial characteristics of CP patients when planning and implementing their treatment . In patiThe present study has methodological limitations that should be acknowledged, such as the inclusion of nonexperimental studies, research that involved data collection via questionnaires completed by patients without the direct control of a researcher, and the lack of long-term follow-up and control groups in most of the results. Furthermore, due to the small number of studies in the review, the conclusions drawn should be interpreted with caution. However, we must recognize the strengths of this research: such as that it is the first systematic review of the literature with this objective and that it covers research from the last ten years (which implies a wide space of time).Further research is necessary, with experimental designs and including a long-term follow-up after the intervention period, assessing the study variables with sensitive, objective, quantitative and reliable instruments (handled by trained researchers to avoid extraneous variables) and considering the attitudes and beliefs of the physiotherapist  (a variaIn patients with CP of more than three months’ duration, the LoC construct serves as a predictor value of PT treatment outcomes. The presence of a predominant internal LoC prior to the start of PT treatment favors improved outcomes, and vice versa.There is a relationship between LoC and pain-related variables, such as pain intensity and the degree of depression and disability.The personality traits of the subjects represent an important factor to consider when planning treatments for the management of patients with CP, therefore the psychosocial sphere must be considered in all cases. Therefore, physiotherapists and other healthcare professionals involved in the treatment of patients with CP should consider the psychosocial characteristics of their patients when planning and implementing their treatment.


Patients with lumbar disc herniation, who undergo spine surgery, occasionally complain of pain and functional disability. Fortunately, the concept of enhanced recovery after surgery has emerged recently. As a result, patients seek traditional Chinese medicine after spine surgery. This systematic review will thoroughly analyze and synthesize evidence on integrative traditional Chinese medicine therapy for lumbar disc herniation after surgery.The following databases will be utilized to search for pertinent studies: the Cochrane Central Register of Controlled Trials, MEDLINE/PubMed, EMBASE, Chinese National Knowledge Infrastructure, Japan Medical Abstracts Society, and 7 Korean databases . The risk of bias of the selected studies will be assessed according to the Cochrane assessment tool for risk of bias. For articles that used the same measurements, a meta-analysis will be conducted to synthesize the results of each trial. Pain severity will be the primary outcome, while the results of functional questionnaires and range of motion, etc, will be the secondary outcomes.Since this protocol does not include any data from patients, ethics approval is not required. The results of this review will be disseminated through a peer-reviewed journal.https://osf.io/kp47a)DOI 10.17605/OSF.IO/KP47A ( This has globally resulted in an increase in cases of low back pain. Additionally, the duration of low back pain increased by more than 50% between 1990 and 2015. Around 90% patients have reportedly recovered with conservative treatment. However, the presence of severe pain, regardless of the period of noninvasive care, progressive motor weakness, or cauda equina syndrome, may sometimes require surgical intervention.Lumbar disc herniation (LDH) is one of the main causes of low back and leg pain. Moreover, it can also manifest as sensory loss or muscle weakness. Nonetheless, midterm or long-term follow-up do result in better outcomes. Moreover, surgical intervention can sometimes lead to pain or dysfunction of the low back or leg in some patients. At this point, conservative treatment can be helpful for patients not undergoing additional surgery.Surgery for LDH has several advantages over conservative treatment. It provides fast pain relief. When appropriately applied to patients undergoing spine surgery, ERAS can result in fast pain relief, reduced hospital stay, fast return to everyday life, and low costs.,10Enhanced recovery after surgery (ERAS) is an emerging concept for good postoperative conditions in medical teams and patients. In clinical situations, TCM is usually administered in an integrative form of 2 or more TCM interventions, such as acupuncture, moxibustion, cupping, herbal medicine, and tuina. Various interventions can lead to diverse effects. Acupuncture has a positive effect on postoperative pain relief. Moxibustion enhances autophagy and reduces apoptosis, thereby providing beneficial effects to intervertebral disc degeneration. Spinal manipulation affects brain activity in patients with LDH. Therefore, it is hypothesized that a combination of TCM interventions may result in benefits in LDH patients who undergo surgery.Traditional Chinese medicine (TCM) is an effective treatment option for ERAS.No systematic review has investigated the effect of integrative TCM in patients with LDH after surgery. This systematic review will aim to thoroughly assess and analyze randomized controlled trials (RCTs) on integrative TCM for LDH after surgery.22.1 which have been uploaded and registered on the Open Science Framework (osf.io/kp47a).This protocol was written according to the preferred reporting items for systematic reviews and meta-analysis protocols,2.22.2.1RCTs in English, Chinese, Japanese, and Korean languages will be included in this systematic review. Crossover studies, quasi-RCTs, case reports, or laboratory studies will be excluded.2.2.2Patients who underwent disc surgery after being diagnosed with LDH will be included. The age, race, and sex will not be considered for discrimination.2.2.32.2.3.1Patients who underwent 2 or more TCM interventions, such as acupuncture, moxabustion, cupping, herbal medicine, and tuina will be included.2.2.3.2Patients who underwent conventional medical care will be included in the control group. It includes oral medications, physical therapy, electrical stimulation, and injections, etc.2.2.4The primary outcome will be the pain score, which will be quantified by pain scales, such as the visual analogue scale and numerical rating scale. The secondary outcomes will be measured using questionnaires for lumbar function, the quality of life, and the range of motion of the lumbar spine.2.32.3.1The Cochrane Central Register of Controlled Trials, MEDLINE/PubMed, EMBASE, Chinese National Knowledge Infrastructure, Japan Medical Abstracts Society, and 7 Korean databases  will be systematically searched for articles from their inception to May 2021. The search strategies are presented in Table 2.3.2Reviewers will check the references of the included papers in detail. Manual searches will also be conducted for articles that are not uploaded online.2.42.4.1Two independent researchers (HK and KK) will screen and select the studies. They will repeatedly review the data according to the selection criteria. If they do not agree on a certain issue, another third reviewer (WC) will take part in the decision. A flow diagram based on the preferred reporting items for systematic reviews and meta-analysis flowchart is presented in Figure 2.4.2An Excel file with vacant cells for the title, author name, number of participants, interventions, and outcomes will be provided to the 2 reviewers for data extraction.2.4.3The Cochrane risk of bias assessment tools will be used to assess included studies in seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias. One of the 3 evaluations will be written for each item: “high risk,” “low risk,” or “unclear risk.” Any discrepancies will be resolved by a third reviewer.2.4.4For continuous variables, the mean differences and the 95% confidence intervals will be used.2.4.5If any data are missing or ambiguous information is obtained during the review process, researchers will contact the corresponding author of the article for explanation and clarity.2.4.62 > 50%). Otherwise, a fixed-effects model will be used.When there are articles on the same kinds of TCM interventions, data synthesis will be conducted using the software distributed by the Cochrane Collaboration . A random-effects model will be employed when the heterogeneity is high (I2.4.7This is a protocol for a systematic review; therefore, ethical approval is waived. The findings of this systematic review will be disseminated through a peer-reviewed journal for publication.3 However, several patients still complain of symptoms of low back or leg pain or dysfunction after surgery. Increasing attention has been provided to patients who experience discomfort after surgical intervention since low back pain can result in long hospital stays and high medical costs. These patients seek noninvasive and safe treatment modalities. A systematic review analyzed the performance of acupuncture for postoperative pain in various operations and concluded that acupuncture improved postoperative pain and reduced opioid use. According to a report from a Korean hospital in 2012, 64% of patients who underwent spinal surgery sought TCM as a primary means of treatment. TCM is now widely used clinically. In particular, the combined type of TCM is common. This systematic review will search for RCTs to provide clinicians or patients with an accurate viewpoint of the treatment options for LDH after surgery.An increasing number of patients with LDH are treated with surgery.Conceptualization: Hyungsuk Kim, Won Seok Chung.Data curation: Koh-Woon Kim, Won Seok Chung.Formal analysis: Hyungsuk Kim, Koh-Woon Kim.Funding acquisition: Won-Seok Chung.Investigation: Koh-Woon Kim.Methodology: Hyungsuk Kim.Project administration: Hyungsuk Kim, Koh-Woon Kim.Resources: Koh-Woon Kim.Software: Koh-Woon Kim.Supervision: Koh-Woon Kim.Validation: Koh-Woon Kim.Visualization: Koh-Woon Kim, Won Seok Chung.Writing – original draft: Hyungsuk Kim, Won Seok Chung.Writing – review & editing: Hyungsuk Kim, Won Seok Chung.