To compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls.Sixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers.2) compared to their respective controls  and in the H-NCP group  compared to their respective controls . Alterations in DC density were similar between all groups .The mean pain intensity score for the last 24 h , last 2 weeks  for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5,702.4 ± 4,599.0 μm/mmNeuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease. NeuropaOur knowledge about NCP, including underlying etiology, pathophysiological mechanism, severity of pain, its effect on quality of life (QoL), treatment and prognosis is very limited ,6. AlterIn addition to many systemic etiologies of NCP –5,10–12,2.This is a cross-sectional, comparative, retrospective, case control study, with two comparison control groups, which was conducted at New England Eye Center, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA. The study was approved by Institutional Review Board/Ethics Committee of Tufts Medical Center/Tufts University Health Sciences and the study protocol conformed to the Declaration of Helsinki, and adhered to the Health Insurance Portability and Accountability Act (HIPAA).2.1.The medical records and in vivo confocal microscopy (IVCM) images of patients who were diagnosed as NCP by the same experienced clinician (PH) between January 2015 and April 2019 were evaluated retrospectively. Diagnosis of NCP was made based on presence of neuropathic ocular symptoms , absent or minimal slit-lamp findings to explain symptoms, corneal nerve abnormalities as detected by IVCM . Subjects with refractive surgery related NCP (RS-NCP) and herpetic eye disease-related NCP (H-NCP) were included in the analysis. Patients were excluded if they had any other ocular pathology that might have resulted in pain, such as active corneal infections, abrasions, angle-closure glaucoma, and anterior uveitis, or if they had NCP with a different etiology rather than refractive surgery or herpetic eye disease. Age- and sex-matched reference controls in this study were healthy, asymptomatic individuals, with no ocular pathology, absent ocular surface staining, and tear film break-up time of more than 10 s. All controls were drawn from an IRB-approved prospective normative study database that enrolled healthy subjects after having a complete history and ocular examination. Matching our control group to the other 2 groups in terms of age and sex resulted in the 37 participants from this database. Reference controls were classified as controls for the refractive surgery group (C-1) if their age was ≥ 20 and ≤ 50 and controls for the herpetic group (C-2) if they were > 50 years of age. This subgroup classification was needed for assessment of IVCM images, as the mean age of the population for the refractive surgery patients with NCP was different and less than NCP patients with a history of herpetic eye disease and due to the fact that nerve density may decrease with increasing age.2.2.Demographic features of the patients, time of insult, time between insult and pain onset, duration of pain (time between first consistent pain experience described by patient and the first visit date at our center. Duration of non-specific ocular symptoms and inconsistent pain was not included), Ocular Surface Disease Index (OSDI) , Ocular 2.3.Laser IVCM images were conducted on central corneas of all patients and controls, bilaterally, as previously described . Equippehttps://imagej.nih.gov/ij/) as previously described [Out of a total of six to eight sequence scans performed on the full thickness of the central cornea, resulting in a total of 50–100 images of the corneal subbasal layer, a masked observer (B.N.B.) selected the three most representative images  of the subbasal nerve plexus. Two masked observers  analyzed IVCM images for morphology and density of dendritiform cells (DCs) and subbasal nerve plexus (SNP). In case of any discrepancy, the images were analyzed and adjudicated by a third observer. The DC density was measured using Image J  were controlled by using a generalized linear model. P values lower than 0.05 were considered statistically significant.Statistical analyses were performed with SPSS software version 22.0 . Distribution of data was analyzed by Kolmogorov-Smirnov test. Mann Whitney 3.Sixty patients were included in the study. Sixteen patients  with post-refractive surgery neuropathic corneal pain (RS-NCP), 7 patients  with post-herpetic neuropathic corneal pain (H-NCP), and thirty-seven healthy  controls were enrolled to the study. The mean age of the patients was 39.7 ± 13.4 years (25.0–66.0 years), 70.7 ± 12.8 (56.0–89.0 years), 33.6 ± 9.5 (22.0–49.0 years) and 61.0 ± 6.8 (51.0–74.0 years) in RS-NCP, H-NCP, C-1 and C-2 controls, respectively . Demographic features of patients are summarized in 3.1.In the RS-NCP group, 1 patient had laser epithelial keratomileusis (LASER), 2 patients had photorefractive keratectomy (PRK) and 13 patients had laser assisted in-situ keratomileusis (LASIK) surgery prior to NCP. In the H-NCP group, 5 patients developed NCP after herpes zoster ophthalmicus and 2 patients developed NCP after herpes simplex keratitis.A history of DED prior to surgery was recorded in 3 (18.7%) of RS-NCP patients (2 of them developed DED after surgery and 1 had surgery with history of DED) and in 2 (28.5%) of H-NCP patients. In the RS-NCP group, there was no predominance for any systemic condition, but depression in 2 patients (12.5%), trigeminal neuralgia in 1 patient (6.2%), chronic inflammatory demyelinating polyneuropathy in 1 patient (6.2%), and small fiber neuropathy in 1 patient (6.2%) were recorded. The most common systemic disorder recorded in H-NCP group was hyperlipidemia  and in 1 patient (14.2%) depression was recorded. Detailed demographic and clinical features of patients were shown in The mean time between insult and pain was 9.4 ± 17.3 weeks (range: 0.1–68.0 weeks) in the RS-NCP and 45.0 ± 32.5 weeks (range: 2.0–96.0 weeks) in H-NCP group (p = 0.006). The mean duration of pain at the visit was 89.3 ± 75.3 weeks (range: 1.0–252.0 weeks) in RS-NCP and 172.0 ± 183.3 weeks (range: 6.0–416.0 weeks) in H-NCP and (p = 0.59) –3.Proparacaine challenge test results were recorded in 10 RS-NCP patients (55.5%) and in 3 H-NCP patients (42.8%). In the RS-NCP group, 4 patients (40.0%) had peripheral NCP, 4 patients (40.0%) had mixed NCP and 2 patients (20.0%) had central NCP, whereas, in the H-NCP group, 2 patients had mixed NCP (66.6%) and 1 patient had central NCP (33.3%) (p = 0.42).3.2.2  and 2,149.5 ± 2,985.9  in RS-NCP and H-NCP respectively, compared to 26,422.8 ± 4,491.0  in C-1 and 22,948.8 ± 3,169.0 , in C-2 groups.The mean total, trunk and branch subepithelial nerve plexus density are shown in The mean total (p < 0.001), trunk (p < 0.001) and branch (p < 0.001) nerve densities were lower in RS-NCP compared to C-1. The mean total (p < 0.001), trunk (p < 0.001) and branch (p < 0.001) nerve densities were lower in H-NCP compared to C-2. However, total (p = 0.30), trunk (p = 0.32) and branch (p = 0.97) nerve densities were similar in RS-NCP and H-NCP  and 2. T3.3.The mean DCs densities are shown in 3.4.The mean OSDI score and the mean pain intensity scores calculated from OPAS are presented in The mean effect of pain on reading and/or computer use (p = 0.53), driving and/or watching TV (p = 0.63), general activity  (p = 0.78), mood (p = 0.06), sleep (p = 0.18), enjoying life/relations with other people (p = 0.10), and time spent thinking about eye pain (p = 0.83) did not show statistical difference between RS-NCP and H-NCP patients . HoweverIn both groups, patients reported that they spent most of their time by thinking about their eye pain . Aggravating factors such as wind, dry air, heat and air conditioning (p=0.40) and volatile chemicals (p=0.75) had a similar effect on pain in both groups . Redness4.All NP disorders have a common denominator  with different underlying etiologies and pathogenesis ,26. PainIt is well-known that herpes simplex , herpes Herein, we present and compare clinical characteristics of post-refractive surgery NCP and post-herpetic neuralgia patients. Both refractive surgery and herpetic eye disease related NCP present with moderate to severe pain levels, which affect quality of life negatively and significantly. OSDI scores showed that RS-NCP and H-NCP patients suffered from ocular discomfort symptoms with a similar frequency. Further, pain intensity scores showed that pain following refractive surgery was at least as severe as H-NCP patients. Pain levels of patients were strong enough to have moderate impact on daily activities such as reading, computer use, driving, watching TV, walking, and doing house chores. The pain not only affects daily activities, but also mood, enjoying life, and relations with other people, particularly in the post-refractive surgery group.Although, QoL scores and the sub-questions  are similar in both groups, RS-NCP patients were affected more significantly. However, in contrast to QoL, RS-NCP patients were affected less by aggravating factors . Furthermore, RS-NCP patients’ symptoms were less likely to be associated with other ocular surface symptoms such as redness, burning, sensitivity to light and tearing compared to H-NCP. When comparisons have been made between other serious chronic conditions including cancer, cardiovascular or neuromuscular disorders and chronic pain, it has been showed that chronic pain conditions had at least as much impact on QoL as those conditions ,45. NCP Previous studies have shown that negative mood also might influence the experience of neuropathic pain ,51. DiarIn our NCP patients, peripheral nerve damage was detected in both groups by IVCM. The nerve densities were comparable in RS-NCP and H-NCP patients. However, both groups demonstrated significantly lower nerve densities than their respective age- and sex-matched healthy controls groups. Previous studies have shown that although corneal nerve regeneration occurs in patients with herpetic eye disease, it still remains low as compared to age-matched healthy individuals, even after 3 years of follow-up . FurtherThe goal of NCP treatment should be to reduce pain in the short term and to inhibit and/or resolve central sensitization in the long term. Therefore, treatment of NCP requires differentiation of peripheral and central component pain for adequate management ,3,12. InIn conclusion, despite the limitations of our study, including the retrospective design, relatively small sample size, and heterogeneity of the groups, our study suggests that RS-NCP patients may present with a wide spectrum of clinical features similar to post-herpetic neuralgia. However, pain severity, impaired quality of life and mood, severe nerve damage and the presence of central sensitization are dominant findings in these patients. Therefore, NCP should be kept in mind in refractive surgery patients with non-specific persistent symptoms, who are unresponsive to conventional dry eye treatments and additional evaluation, such as IVCM to assess nerve abnormalities, and the proparacaine challenge test to assess central component of symptoms, should be considered for diagnosis and management purposes. Early diagnosis prior to the development of central sensitization is thus of great importance.


Video-assisted thoracoscopic surgery (VATS) lobectomy is currently the recommended approach for treating early-stage non-small cell lung cancer (NSCLC). Different VATS approaches have been proposed so far, and the actual advantages of one technique over the other are still under debate. The aim of our study is to compare postoperative pain and analgesic drug consumption in uniportal VATS and triportal VATS for pulmonary lobectomy in early-stage lung cancer patients.This study is a single-center, prospective, two-arm, parallel-group, randomized controlled trial. It is designed to compare uniportal video-assisted thoracic surgery (u-VATS) and three-port video-assisted thoracic surgery (t-VATS) in terms of postoperative pain. The trial will enroll 120 patients with a 1:1 randomization. The primary outcome is the assessment of analgesic drug consumption. Secondary outcomes are postoperative pain measurement, evaluation of postoperative pulmonary function, and metabolic recovery after pulmonary lobectomy.The choice of which VATS approach to adopt for treating patients undergoing pulmonary resection mostly depends on the surgeon’s preferences; therefore, it is hard to prove whether one VATS technique is superior to the other. Moreover, postoperative analgesic protocols vary consistently among different centers. To date, only a few studies have evaluated the effects of the most popular VATS techniques. There is no evidence about the difference between multiport VATS and u-VATS in terms of postoperative pain. We hope that the results of our trial will provide valuable information on the outcomes of these different surgical approaches.NCT03240250. Registered on 07 August 2017; retrospectively registered.ClinicalTrials.gov The online version contains supplementary material available at 10.1186/s13063-021-05115-w. Currently, video-assisted thoracoscopic surgery (VATS) lobectomy is the recommended approach for treating early-stage non-small cell lung cancer (NSCLC). In 2013, the American College of Chest Physicians indicated VATS as their preferred technique over open surgery (grade 2C) . At presThe study was designed as a single-center, prospective, two-arm, parallel-group, randomized controlled trial.The protocol (version 1.0_13/12/2016) is reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines following the SPIRIT schedule , with a 1:1 randomization.We planned to perform an “interim analysis” once a total number of at least 60 randomized patients, dropouts excluded, is reached. The “interim analysis” will be performed to ensure the safety of the study and to evaluate any significant outcome-related differences between the two techniques that would make the study unnecessary. The surgical staff routinely analyzes the complication rates of every surgical procedure, in a dedicated monthly meeting. From this analysis, if a higher complication rate will be detected in one arm over the other, a data and safety monitoring board (DSMB) will be set up. Furthermore, to protect patients’ safety, the DSMB could be set up during the study, if necessary. All items from the WHO clinical trial registry can be found within the protocol.All consecutive patients referred to our center, the Thoracic Surgery Unit of the University Hospital Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan , will be screened by one of two designed members of our surgical staff, according to inclusion and exclusion criteria. Before enrolment, each patient will receive detailed information regarding the study protocol. A specific informed consent regarding the participation to the trial, the randomization, and the surgical incisions will be obtained by a staff surgeon from each participant, after an adequate explanation of the benefits and risks of the study.The study was approved by the Ethics Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, on 21 February 2017 (reference number 86_2017), before the trial registration on ClinicalTrials.gov.The study will be carried out in accordance with the Helsinki Declaration.Age between 30 and 80 yearsBoth gendersSurgically resectable (R0) non-small cell lung cancer (NSCLC), with cytological or histological diagnosis or clinically suspected, with a diameter lower than 5 cmClinical stage I and II NSCLCPatient with American Society of Anaesthesiologists (ASA) score I, II, or IIIWritten informed consent (ICF) signed by the patientInability to comply with the study procedureN2 or N3 clinical nodal involvement of diseaseInduction chemotherapy before surgeryChest wall involvementPrevious thoracic surgery (any type)High-grade pleural adhesionsRenal, liver, or cardiac failureSevere chronic obstructive pulmonary disease (COPD), bronchial asthma, or interstitial lung disease (ILD)Coagulation disordersAllergy to analgesic drugs included in the study protocolChronic use of analgesics, opioids, or steroidsWedge resection, sleeve lobectomy, or pneumonectomyRe-intervention after VATS lobectomyPostoperative pain after u-VATS and t-VATS, measured by means of total analgesic consumptions, normalized to morphine milligrams, recorded within the 7 days following the operationPostoperative pain measured by a numeric rating scale (NRS) after 2, 6, 12, and 24 h and on postoperative days (POD) 2, 3, 4, 5, and 30. A pain score will be assigned to each patient after the total amount of NRS is determined. A mean pain score will be calculated and compared between the two groups.Evaluation of respiratory function, measured by pulmonary function tests (PFTs) as basal spirometry on POD 7 and POD 30, compared with preoperative measures. Forced vital capacity (FVC) and forced expiratory volume at 1 s (FEV1) will be considered in liters and percentage as measured by PFTs. Preoperative and postoperative measurements will be weighted and normalized for the number of lung segments removed during each lobectomy. The mean differences between pre- and postoperative values will be calculated and compared between the two groups.Evaluation of functional and metabolic recovery, measured by metabolic Holter, a multidetection tool recording patients’ physiological data and energy consumption. We will measure physiological data at rest  and the level of physical activity of the patient, expressed in metabolic equivalents (METs). Means of METs will be calculated and compared between the two groups.Intraoperative time: measurement of time in minutes from skin incision to the closure of the chest (skin to skin)Intraoperative bleeding: measurement of the total amount of bleeding during the operation expressed in millilitersTotal number of resected lymph nodesConversion rate from VATS to open thoracotomy Intraoperative parameters, calculated by means and percentage:Postoperative air leaks (days of air leaks)Chest drain dwelling time (days)Infection of the surgical site Pulmonary complications, including pneumonia, pulmonary embolism, atelectasis Postoperative parameters, calculated by means and percentage:random allocation rule [An individual simple sequence randomization with 1:1 allocation will be generated by a person not involved in the enrolment, using the ion rule  by Randou-VATS: a single, lateral, muscle-sparing, 4- to5-cm minithoracotomy will be performed through the 4th or 5th intercostal space. No other intercostal incision will be made. All the instruments and camera will be inserted through the minithoracotomy. After pulmonary lobectomy and lymphadenectomy, one intercostal drainage will be inserted through the minithoracotomy [racotomy .t-VATS: a lateral, muscle-sparing, 4- to 5-cm minithoracotomy will be performed through the 4th or 5th intercostal space. Two additional thoracoscopy ports will be performed in the 7th or 8th intercostal space. The camera and the instrument will be inserted into the pleural space through the minithoracotomy or the thoracoscopy port according to the surgeon’s preference. After pulmonary lobectomy and lymphadenectomy, one intercostal drainage will be inserted through the anterior intercostal incision [Both surgical procedures, u-VATS and t-VATS, will be performed following the same anesthesiologic plan. General anesthesia will be administered, and a double-lumen endobronchial tube will be used to allow single-lung ventilation. Patients will be monitored by standard electrocardiogram (ECG), invasive arterial blood pressure, pulse oximeter, urine catheterization, and, if necessary, central venous catheterization. Patients will be positioned in lateral decubitus, contralaterally to the side of surgery and the bed will be flexed to get wide intercostal spaces.Preoperative assessment was performed according to the European Society of Anesthesiology guidelines for the evaluation of candidates to non-cardiac surgery .After routine monitoring as per the American Society of Anesthesiologists guidelines and peripheral venous cannulation (20–16 Ch PVC catheter), induction of general anesthesia with fentanyl (1–2 mcg/kg), midazolam (1–2 mg), and propofol (1–3 mg/kg), and muscle paralysis with rocuronium (0.6–1 mg/kg) is achieved. Patients are intubated with an appropriately sized left-sided double-lumen endotracheal tube under bronchoscopic guidance. General anesthesia is maintained with sevoflurane  to keep the Bispectral Index value between 40 and 60 during the whole surgical procedure, muscle paralysis with sequential rocuronium boluses (0.15 mg/kg), while analgesia is achieved by titrating remifentanil infusion between 0.05 and 0.15 mcg/kg/min according to autonomical responses to surgical stress. Whenever potential risk factors for malignant hyperthermia are identified, total intravenous anesthesia with propofol (4–6 mg/kg/h) is induced. Patients’ invasive arterial pressure is monitored with radial artery cannulation . Central venous cannulation is performed only if central venous pressure monitoring is required. A body surface heating device is applied, and pharyngeal temperature monitoring is established with a target temperature of 35.5–36.5 °C.Ahead skin incision, together with antibacterial prophylaxis, 30 mg ketorolac and either anti-H2 receptors or proton pump inhibitors are administered. About 1 h before surgery termination, 0.1–0.15 mg/kg, intravenous morphine is administered together with 1 g acetaminophen. For postoperative nausea and vomiting prevention, 4 mg ondansetron is given. Before suturing surgical incisions, an intercostal nerve block is performed by the surgeon on the surgical field by injecting 2–5 mL of 0.375% ropivacaine per intercostal space under thoracoscopic view. Up to 40 mL is administered with a maximum ropivacaine dose of 2 mg/kg. After anesthesia termination, the patient is extubated in the operating room, unless he or she needs protected weaning from mechanical ventilation in the Intensive Care Unit. Immediate postoperative monitoring is performed in the recovery room. If hemodynamic and respiratory function stability is achieved, the patient is transferred to the surgical ward; otherwise, if further monitoring or intensive medical treatment prove necessary, he or she will be transferred to the Intensive Care Unit. Postoperative analgesia is initiated in the recovery room as soon as full recovery of consciousness is observed: intravenous morphine is administered at a rate of 1 mg/h for the first 6 h postoperatively. Six hours after surgery completion and every 4 h thereafter, nurses record the dynamic NRS for pain evaluation. If at any evaluation timepoint the NRS value is below 4, morphine infusion is halved; if NRS value is between 4 and 6, morphine infusion rate is maintained, while, if NRS value is higher than 6, a bolus of 1–2 mg morphine is administered. Parallel administration of intravenous acetaminophen 1 g every 6 h and ketorolac 30 mg every 8 h is performed for the first 3 postoperative days.The patient will be treated during the postoperative course as the standard of care requires, including short-term intravenous antimicrobial prophylaxis, early mobilization, and respiratory physiotherapy. The chest tube will be removed when the total amount of pleural fluid will be < 300 mL/day and no air leaks are detectable.Patients will be followed up after discharge at POD 7 with clinical examination and PFTs (spirometry) and POD 30 with a clinical examination, NRS pain score, PFTs, and chest X-rays. During the study period, any relevant concomitant treatment will be authorized.Every patient has the opportunity to drop out of the study at any time. The participant’s choice will not compromise their medical treatment that he or she will receive as the standard of care requires. Patients who will drop out will not be displaced to other units. Due to the relatively short follow-up time required (30 days), we expect a small percentage of patients who will be lost at follow-up (about 1–2%), since patients are usually seen 1 month after the discharge. No specific plans are scheduled for participant retention and prevention of loss-to-follow-up. If the percentage of dropout will be < 5%, we will continue the recruitment and consider the study valid.t test for difference between two independent means, according to the following assumptions: normal distribution for the primary outcome, Choen’s d effect size = 0.55 , power (1-β) = 0.85, and α = 0.05 [All the statistical analyses will be performed by blinded analysts. Periodical checking of the input data will be performed in order to verify the completeness and consistency of the dataset. Checks on the consistency and plausibility of the reported data will be carried out before data analysis. The study is powered based on its primary outcome. The sample size was calculated considering a 2-sided α = 0.05 . The samα = 0.05 . We haveWe will propose two analysis sets: the intention-to-treat set, which would consider all patients randomized regardless of whether they received the randomized treatment, and the “per protocol” analysis set, excluding patients for intraoperative reasons . The rationale for a “per protocol” analysis is due to the fact that intraoperative complications have a significant impact on pain which is the primary outcome of our study.The effect that any missing data might have on results will be assessed via sensitivity analysis of augmented data sets. Dropouts  will be included in the analysis using Bayesian Multiple Imputation by Chained Equations (MICE).Patients will be enrolled by a team physician, and their data will be collected in a paper-based case report form (CRF) designed by study staff during pre- and postoperative courses and until 1 month after surgery.CRFs will be transferred in a password-protected Microsoft Excel® spreadsheet with an ID number assigned to every consecutive enrolled patient. The paper-based CRFs and the electronic database will be kept locked up at the Thoracic Surgery and Lung Transplant Unit of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan. The partial and final dataset will be available to the investigators at any time after a request submitted to the Principal Investigator. There are no plans for sharing data from the trial. The trial results will be disseminated in meeting communications and scientific publications. The authorship policies will be shared with the investigators.Since both surgical techniques (t-VATS and u-VATS) are used in the current clinical practice, patients will not be exposed to any risk besides those typically entailed in VATS lobectomy. For this reason, there are no additional adverse events that might be expected in the study. We will use the US National Cancer Institute Common Terminology Criteria for Adverse Events 4.1 (CTCAE version 4.1) in order to describe postoperative complications. All the complications will be registered on patient CRFs.The choice of one VATS approach over the others for patients undergoing pulmonary resection largely depends on the experience of each surgeon; therefore, it is hard to prove whether a technique is more efficient than the other, especially in terms of postoperative pain. Moreover, postoperative analgesic protocols vary considerably among different centers. So far, only a few studies have evaluated the effects of the most popular VATS techniques, the t-VATS and the u-VATS. In 2005, a paper by Jutley et al. retrospectively compared the postoperative pain scores in patients undergoing t-VATS or u-VATS for the treatment of spontaneous pneumothorax, using a visual analog scale (VAS) from 0 to 4. They concluded that postoperative pain and paraesthesia incidence was lower in the u-VATS group, despite the cohort of patients being limited .Recently, we have published an observational, retrospective, multicenter study on data collected in the Italian VATS Group Database, evaluating lobectomies performed for clinical stage I–II NSCLC, by u-VATS and t-VATS: u-VATS lobectomy seemed to entail a higher risk of moderate/severe pain on postoperative days 2 and 3 .The only randomized study comparing u-VATS with the “multiports” VATS lobectomy was a single monocentric trial published by Perna et al. No statistically significant difference between the two groups in terms of postoperative pain was recorded. Nevertheless, one might argue that the sample size was rather under-dimensioned, mainly because the “multiports” group included patients who underwent two different procedures: the Duke two-port technique and the Copenhagen t-VATS approach .The proposed trial will broaden current knowledge of this area by investigating the difference between the t-VATS and the u-VATS in terms of postoperative pain. We have based our hypothesis on a simple premise: u-VATS is less painful than t-VATS because “one incision is less painful than three.” From a strictly logistical point of view, manipulation of the intercostal space is inevitable while employing every VATS technique, as any additional access to the service minithoracotomy can only increase the patient’s amount of pain. Unlike other studies that compared multiport VATS  to u-VATS, our own study compared two single techniques: in our opinion, this is a methodological advantage, reducing possible confounding bias.A challenging aspect of any clinical trial is the evaluation of pain suffered by patients. Several clinically tested and validated pain scales have been proposed so far; these try to meet the criteria of objectivity, comprehensibility, and reproducibility. Among the most frequently used pain scales, the Verbal Rating Scale is based on patients’ answers to verbal questions of health care professionals; this scale measures pain intensity only and is subject to discrepancies depending on how each patient understands “mild,” “moderate,” and “severe” pain. Visual analog scale (VAS) is probably the most used pain assessment tool because it is simple to administer, rapid, and easy for patients to understand. However, the VAS likely undervalues pain as a “biopsychosocial” experience and furthermore only measures pain intensity in a specific moment. For our trial, we have decided to use analgesic drug consumption as an objective measure of the “entire pain” suffered by patients during the first postoperative week. By normalizing the amount of the different painkillers used during the first postoperative week to morphine milligrams, we will obtain cumulative morphine consumption, which is a numeric parameter that statistics can properly manage .A secondary endpoint of our study is the evaluation of early postoperative respiratory function, measured by pulmonary function tests. There is no doubt that the greatest impact on respiratory function is attributable to the parenchymal sacrifice following the pulmonary lobectomy itself; nevertheless, the type of surgical insult of the chest wall is significant as well . Hence, In conclusion, the results of this project will broaden current knowledge of the effects of two different VATS approaches to pulmonary lobectomy for lung cancer.The study started in February 2017. Patients have been enrolled since March 2017 and will be enrolled until September 2020. The study will be interrupted once the sample size of 120 patients enrolled is reached.Additional file 1. SPIRIT Checklist


In the setting of increasingly streamlined surgical techniques and perioperative care, the United States healthcare system is seeing a steady rise in the number of procedures being carried out at ambulatory surgery centers. Concurrently, awareness and diagnosis of both chronic pain conditions and substance use disorders have also improved in recent years. As a result of these two shifts, the demographic characteristics of patients undergoing procedures at ambulatory surgery centers are actively evolving. Chronic pain and substance use disorders are difficult to manage in both the outpatient and inpatient settings and present unique challenges in the context of perioperative planning. Both conditions are associated with worsened postoperative outcomes, including refractory pain, decreased functional status, increased length of stay, increased readmission rates, and increased economic costs. There has been a recent movement to include a preoperative risk stratification calculation for these patients, followed by the implementation of enhanced recovery after surgery (ERAS) protocols in these patient cohorts. Taking a step further, patients benefit when standard ERAS protocols are augmented by integrating designated pain specialists into the ambulatory surgery team. This multimodal and multidisciplinary approach must be assessed in the context of the human and financial resources of a given institution and surgery center, but has been shown to improve the quality and safety of perioperative care effectively.  Uncontrolled pain is the leading cause of disability in the United States, estimated to affect over 90 million people . Pain inThe decades in which we have observed a significant increase in opioid use have also seen a steady rise in the prevalence of ambulatory surgery , 6. As tThe Chronic Pain PatientChronic pain is highly prevalent and has historically been managed with daily opioid regimens . It is eOne of the other issues associated with the treatment of chronic pain patients in ambulatory surgery settings is the potentially overwhelming number of suggestions for pain management. In these patients, recommendations may be made by the patient’s outpatient pain specialist, primary care physician, anesthesiologist, and surgeon. Despite the many benefits offered by multidisciplinary teams, a large number of inputs may predispose to high risk. These recommendations can be especially difficult to manage and optimize during the nearly-universal fifteen-minute preoperative visit conducted by the surgeon or primary care provider . It has The other well-known issue posed by chronic pain patients when it comes to perioperative care is opioid tolerance. Opioid-tolerant patients have been shown to be at high risk for poor postoperative outcomes. A study comparing opioid-tolerant patients undergoing non-emergent major abdominal surgery to controls found that opioid-tolerant patients were less likely to be compliant with enhanced recovery after surgery (ERAS) protocols and were two times more likely to require readmission. In this study, a patient was deemed “opioid-tolerant” if he or she was taking an opioid regimen equivalent to 60 mg of daily oral morphine for at least one week prior to surgery. The consequences of opioid tolerance include poorly-controlled pain, which in itself, can lead to decreased compliance with ERAS protocols . Approach to CarePain as a symptom is inherently difficult to manage because it is a subjective phenomenon: the experience of pain is both physiologic and emotional. While the mechanism for sensing pain involves the action of nociceptors coupled with processing in the somatosensory cortex, individual patients have different thresholds for both perceiving and responding to the different components of pain . The notOne of the challenges associated with optimizing pain control in the setting of ambulatory surgery is understanding and anticipating the factors that can complicate postoperative pain. Studies of consecutive ambulatory surgical patients have shown that body mass index, the type of procedure, and the duration of anesthesia are especially helpful in predicting pain outcomes . OrthopeThe principles of perioperative pain management for patients with chronic pain or substance use disorder and the positive effects of these specialized techniques on morbidity and mortality are well-described in the literature. Unfortunately, it has been demonstrated that these evidence-based protocols are difficult to implement consistently . For thiRecommendations for ManagementOne of the major goals of ERAS guidelines is to reduce opioid consumption as much as possible , 18, 19.Anxiety associated with surgery can be a significant issue for patients with chronic or uncontrolled pain. For these patients, recommendations have been made for the use of gabapentinoids preoperatively or benzodiazepines perioperatively . Given tPatients chronically taking opioids as part of their pain regimen should be advised to take their daily dose on the day of surgery to prevent withdrawal. Studies have shown that since patients frequently underreport usage of medications for pain, care must be taken to gather accurate history . Given tChallengesWhile widely endorsed in the pain medicine community, the integration of a designated pain specialist into the flow of an ambulatory surgery center is practically challenging. It requires immense planning, assessment of human resources, and financial consideration on the part of the administration. The costs of full-time staffing of at least one fellowship-trained anesthesiologist are significant. Care must also be taken to ensure that this individual is well integrated into the team dynamic and that excellent communication is maintained between perioperative staff members, surgeons, and anesthesiologists. It is important to evaluate the implications of this recommendation critically and to look toward the future to anticipate potential hurdles. Given the increasing numbers of patients undergoing surgery at outpatient facilities, the feasibility that only one pain medicine specialist will be sufficient may be unlikely. There has been a continual increase in the number of procedures being carried out at ambulatory surgery centers. As the sheer number of patients undergoing ambulatory surgery increases, the number of patients who suffer from chronic pain conditions and those who struggle with substance use will follow suit. The management of these patients should include ERAS techniques that emphasize patient education and expectation management as well as the use of multimodal analgesia and regional anesthesia. Further, ambulatory surgery centers should employ pain specialists trained in anesthesia at ambulatory surgery centers to streamline the implementation of ERAS techniques. There is endorsement for the role of this designated physician to serve as a consultant for the surgeons and perioperative staff on site at the ambulatory surgery facility with the aim of increasing safety of both care and discharge.


Vaso‐occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD), with higher severity among hospitalized patients. Clustering hospitalizations with similar pain trajectories could identify vulnerable patient subgroups. Aims were to (a) identify clusters of hospitalizations based on pain trajectories; (b) identify factors associated with these clusters; and (c) determine the association between these clusters and 30‐day readmissions.We retrospectively included 350 VOC hospitalizations from 2013 to 2016 among 59 patients. Finite mixture modeling identified clusters of hospitalizations from intercepts and slopes of pain trajectories during the hospitalization. Generalized estimating equations for multinomial and logistic models were used to identify factors associated with clusters of hospitalizations and 30‐day readmissions, respectively, while accounting for multiple hospitalizations per patient.Three clusters of hospitalizations based on pain trajectories were identified: slow (n = 99), moderate (n = 207), and rapid (n = 44) decrease in pain scores. In multivariable analysis, SCD complications, female gender, and affective disorders were associated with clusters with slow or moderate decrease in pain scores (compared to rapid decrease). Although univariate analysis found that the cluster with moderate decrease in pain scores was associated with lower odds of 30‐day readmissions compared to the cluster with slow decrease, it was nonsignificant in multivariable analysis. SCD complications were associated with higher odds of 30‐day readmissions and older age was associated with lower odds of 30‐day readmissions.Our results highlight variability in pain trajectories among patients with SCD experiencing VOC and provide a novel approach for identifying subgroups of patients that could benefit from more intensive follow‐up. The halWhen patients with VOC present acutely to healthcare providers, they have usually exhausted home care options and require more aggressive pain management, typically delivered inpatient . Prior sGrowth mixture modeling and latent class growth analysis provides data‐driven approaches for identifying unobserved (“latent”) growth curves or trajectories, based on variables  collected over time . HoweverThe overall goal of our study was to use our proposed methods to identify clusters of hospitalizations with similar pain trajectories among patients with SCD hospitalized for VOC. We then assessed whether patient  and clinical characteristics  were associated with these clusters. Based on prior research, we hypothesized that hospitalizations among patients with more severe SCD, patients with affective disorders, and patients prescribed hydroxyurea would have worse pain trajectories , 19, 20.22.1+ thalassemia, and Hb Sβ0 thalassemia) were included. Only hospitalizations for VOC were included, which was determined by review of the EMR for documentation of VOC or pain crisis. VOC could be due to SCD complications , but hospitalizations for SCD complications without a documented VOC were not included. Hospitalizations for procedures  were excluded, as were hospitalizations during pregnancy or after stem cell transplant (SCT) where the pain experience and treatment may differ [We created a retrospective cohort of consecutive hospitalizations for VOC among adult patients ≥18 years) with SCD from 2013 to 2016 at Tufts Medical Center (Tufts MC), an academic medical center in Boston, MA. Hospital billing data were used to identify hospitalizations with ICD‐9 (282.6) or ICD‐10 D57) codes for SCD. Trained study staff then reviewed the electronic medical record (EMR) to determine eligibility for each patient and hospitalization .Hospitalization‐level data included patient characteristics at the time of admission and characteristics or events occurring during the hospitalization. This included admission and discharge date, discharge status, insurance, whether the patient received routine care for SCD (“established”) at Tufts MC, history of SCD complications, documented affective disorder from the EMR  in the prior 12 months, street address for calculating the Area Deprivation Index (ADI) , and homHospital day‐level data included pain scores from a numeric rating scale . The maximum and minimum pain scores were abstracted for each hospital day; our analysis focuses on maximum daily pain scores. Daily medications including opioids and nonopioid pain medications were abstracted. Standard inpatient treatment protocols were not used across all patients; instead, inpatient pain regimens were tailored to the individual patient, based on their standing home regimen and medical history.For each hospitalization, we calculated the 30‐day unplanned readmission rate for a VOC from the hospital billing data. Readmission rates were restricted to patients who were discharged home after that hospitalization  and who were discharged prior to December 1, 2016 (to ensure ≥30 days of follow‐up). VOC hospitalizations from outside hospitals that were documented in our EMR were included when calculating the 30‐day unplanned readmission rate.2.3Patient and hospitalization characteristics were described for the full sample at the patient and hospitalization level using means, standard deviations (SD), medians, 25th‐75th quartiles , frequencies, and percentages. For patient characteristics that could vary over time, characteristics at the first hospitalization were used for the patient‐level description. Data were analyzed using R (3.6.2 for Windows)/R Studio Desktop (1.2.5003) and SAS Software 9.4/SAS Enterprise Guide 7.1  and used a two‐sided alpha of .05.2.4We used a two‐step approach to identify clusters of VOC hospitalizations with similar pain trajectories: (a) estimate intercepts and slopes of maximum daily pain scores for each hospitalization and (b) estimate finite mixture models using these intercepts and slopes for each hospitalization to identify clusters . BrieflyTo plot the pain trajectories by cluster, predicted values and 95% confidence intervals were estimated using a mixed effects model with random intercepts and slopes for each hospitalization (proc mixed in SAS). Maximum daily pain score was regressed on cluster, hospitalization day, and their interaction, assuming an autoregressive covariance structure (based on Akaike information criteria). Pain trajectories by cluster were plotted from hospitalization day 1 to 7, with 7 representing the 75th percentile of LOS.When interpreting differences in pain scores, research suggests that 1‐point changes on the 0 to 10 pain scale represent minimally important change, whereas 2‐point changes represent more meaningful decreases in pain .2.5We identified patient and hospitalization characteristics that were associated with clusters of pain trajectories, while accounting for the correlation of hospitalizations within patients using generalized estimating equations (proc GEE in SAS) with a multinomial distribution (glogit link) and an independent covariance structure . The folWe hypothesized that daily use of opioids would be associated with clusters of pain trajectories. However, we were unable to assess for this relationship because nearly all hospitalization days (98%) involved opioid use and daily morphine equivalent dose (MED) was not available for all patients during the study period.2.6This analysis was restricted to patients who were established at Tufts MC because they would be expected to be readmitted at Tufts MC  based on the area under the receiver operator characteristic curve for the primary multivariable model and the models from the sensitivity analysis to determine which model better discriminated among those who had 30‐day readmissions. The c‐statistic ranges from 0.5 to 1, with higher scores indicating better predictive accuracy of the model.33.1Initially, 568 hospitalizations among 90 patients with SCD were identified as potentially eligible. After applying inclusion/exclusion criteria, the analytic cohort included 350 hospitalizations for VOC among 59 patients Figure . The medAmong the 59 patients, 55.9% were female, 76.3% were black, and Hb SS was the most common genotype Table . At thei3.2Across all hospitalizations, the mean intercept was 9.03 (SD = 1.06) and the mean slope was –0.43 (SD = 0.58). Three distinct clusters of hospitalizations with similar pain trajectories were identified using finite mixture models and were described based on the steepness of the pain slope over the course of hospitalization: (a) slow decrease ; 2) moderate decrease ; and rapid decrease in pain scores   had a 30‐day readmission. Univariate analysis found that hospitalizations in the cluster with moderate decrease in pain scores  had lower odds of 30‐day readmissions than hospitalizations in the cluster with slow decrease; and hospitalizations for patients with more SCD complications  had higher odds of readmission (Table 4). In multivariable analysis, hospitalizations among older patients had lower odds of 30‐day readmission , whereas hospitalizations for patients with more SCD complications had higher odds of 30‐day readmission .3.5Hospitalizations with longer LOS had higher odds of being in the cluster with moderate decrease  and the cluster with slow decrease  than the cluster with rapid decrease in pain scores. LOS was not associated with 30‐day readmission in univariate or multivariable  analysis. Clusters of pain trajectories  had a higher c‐statistic for the univariate relationship with 30‐day readmission than LOS ; the c‐statistic for the primary multivariable model for 30‐day readmission was 0.75 (SE = 0.03), which did not change after adding LOS .4Based on 350 VOC hospitalizations among 59 patients with SCD, we identified three clusters of hospitalizations with similar pain trajectories ; the cluster with moderate decrease in pain scores was the most common. Hospitalizations among females, patients with more SCD complications, or patients with affective disorders had higher odds of being in the cluster with worse pain trajectories . Although hospitalizations in the cluster with moderate decrease in pain scores had lower odds of 30‐day readmissions than the cluster with slow decrease, this was no longer significant in the multivariable model. Younger age and more SCD complications were associated with higher odds of 30‐day readmissions.This analysis provides an advancement over prior studies of pain trends during VOC hospitalizations, which were primarily descriptive , 8, 9. WAlthough a widely used and validated measure of SCD severity does not currently exist, frequent VOCs and more SCD‐related complications likely represent higher disease severity , 16, 17.Aside from SCD complications, we found that affective disorders and female gender were associated with less rapid resolution of pain trajectories. The relationship between affective disorders and the pain experience is complicated and bidirectional; pain may lead to an increase in anxiety or depression, whereas anxiety or depression may lead to differences in the pain experience , 19. PriAge was the only factor besides SCD complications that was associated with 30‐day readmissions. Older age was actually associated with lower 30‐day readmission rates, which has been observed in other studies of SCD . InteresResults from this study could be used in clinical care to help identify vulnerable subgroups of patients with SCD, such as those with more SCD complications or affective disorders, who are at risk for worse pain trajectories. Ideally, treatment with hydroxyurea, blood transfusions, and more recently approved therapies  would reduce the frequency and severity of VOC and associated SCD complications . HoweverWe acknowledge this study's limitations. Although the number of patients was not large, we included 350 hospitalizations and used methods to account for multiple hospitalizations per patient. This study was conducted at a single medical center, which may reduce generalizability based on patient characteristics or practice patterns. Patients’ pain treatment protocols, including their daily MED, could have influenced their pain trajectories, but daily MED was not available on all patients during the study period. Exclusions of hospitalizations based on LOS may also affect generalizability as these patients may reflect patients with more severe disease based on the number of SCD complications. Readmissions to outside hospitalizations could have been missed, but this is unlikely given that we restricted our analysis to established patients, we included outside hospitalizations that were documented in our EMR, and our readmission rate was comparable to other studies , 40.In conclusion, we identified three unique clusters of pain trajectories among VOC hospitalizations using a novel, data‐driven approach. SCD complications were associated with slower decreases in pain scores as well as increased 30‐day readmissions. These results highlight the variability in pain trajectories among patients with SCD experiencing VOC and provide a novel approach for identifying subgroups of patients who are most vulnerable and could benefit from interventions, such as more intensive follow‐up.National Institute on Minority Health and Health Disparities (R21 MD011455‐01) and National Center for Advancing Translational Sciences (1KL2TR002545).AMR conceptualized the study; acquired the data; analyzed the data and created the figures and tables; acquired funding support; and wrote and edited the paper. KSE contributed to the study design; helped acquire the data; and reviewed and edited the paper. NSS helped acquire the data and reviewed and edited the paper. SKP conceptualized the study; helped acquire the data; helped acquire funding support; and reviewed and edited the paper.The authors declare no conflict of interest.


Introduction: Cryoanalgesia has been recently described as alternative technique for immediate and persistent pain treatment after pectus excavatum repair. Cryoanalgesia has the potentiality to reduce analgesic consumption and length of hospitalization. However, cryoanalgesia has not been standardized yet: the previous reports describe different techniques and systems and include only small series. In Europe, no reports on cryoanalgesia for pectus repair have been published so far.Materials and Methods: This is a prospective single center pilot study performed in adolescents undergoing minimally invasive pectus excavatum repair with a new cryoanalgesia system, using a probe designed specifically for thoracoscopy. This new double lumen probe has the theoretical advantage of freezing only in its tip, so reducing the risk of complications.Results: Seven patients undergoing pectus excavatum repair were treated with cryoanalgesia performed with the new probe. No complications of cryoanalgesia were reported. Total consumption of morphine during hospital stay was between 0.1 and 0.35 mg/kg, with no side effects reported. Mean time to discharge was 2.4 days. All patients reported a good pain control with a fair need of rescue medications for pain relief during the first week after discharge, and a very good pain control without need of rescue medications during following weeks.Conclusions: Our pilot study showed that the new cryoanalgesia device is efficacious in terms of pain control, hospital stay and resumption of post-operative activities. The cryoprobe designed allowed an easy and safe maneuver. A prospective trial is needed to better define the risks and benefits of this technique. Mini-invasive repair of PE (MIRPE) has gradually become the preferred surgical approach to correct pectus excavatum (PE), the most common chest wall anomaly . During Cryoanalgesia has been recently described with promising results as alternative technique for immediate and persistent pain treatment after PE repair –6. CryoaAccording to the recent literature on cryoanalgesia in MIRPE, published from North and South America, cryoanalgesia has the potentiality to reduce analgesic consumption and length of hospitalization, but also to ameliorate persistent pain and facilitate return to normal activity –13. HoweCryoanalgesia has been introduced in our hospital, one of the referral center for MIRPE repair in our Country, with an average of 60 patients per year operated. However, before starting a proper trial it was decided to run a pilot to determine feasibility and efficacy of this approach, performed with the new probe, as well as potential limitations and side effects. Then, the aim of this article is to describe our preliminary experience and provide an input for future research on this field.This is a prospective single center pilot study performed between December 2019 to January 2020 in adolescents undergoing MIRPE with cryoanalgesia treatment.The study involving human participants was reviewed and approved by IRB (authorization n.31435/20). The participants  provided written informed consent to participate in this study.Anesthesia management consisted of total intravenous anesthesia with propofol and remifentanil titrated in order to obtain a bispectral index (BIS) range of 40–60 and muscle relaxation with rocuronium. A double lumen tracheal tube was inserted for lung one lung ventilation. When thoracoscopy was installed, the ventilation was temporarily suspended on the ipsilateral lung of the side for cryoanalgesia application. At the end of the cryoanalgesia, bilateral lung ventilation was started, and the MIRPE was performed.Post-operative analgesic protocol was based on PCA of morphine with no background infusion and ketorolac plus acetaminophen as rescue analgesia, plus oral benzodiazepine for muscle relaxation.2 at −70°C), without reaching CO2 boiling point (−79°C), hence ensuring the reversibility of the nerve injury and the lack of effect on the connective structures. The dedicated cryoprobes were specifically designed with a “double lumen,” differently from the “single lumen” probes, in which the gas flows toward the whole length of the probe, generating the freezing effect on the whole probe length. Cryo-S Painless device and double lumen cryoprobe manufactured by a Polish company Metrum Cryoflex consists of two cannulas. One of them is located along the external wall of the probe and the other one goes through the center of the probe for the gas to flow. Pressurized CO2 flowing between two cannulas provides probe dynamic isolation. The rapid expansion of the gas can only be observed at the tip of the probe (Joule–Thompson effect). As a result of the temperature drop, an ice ball is generated just at the tip of the cryoprobe, allowing a safe and precise treatment. CO2 is then vented through the inner cannula, no gas is released into the body. For the thoracoscopic use, a 12 G, 35 cm long blunt tip atraumatic probe was produced. The purpose was to treat 5 nerves (from T3 and T8) on each side in every patient undergoing MIRPE with cryoanalgesia. The probe was inserted on the same side of thoracoscopy  and kept in contact with the posterior aspect of the selected intercostal nerve for 2 min at −70°, under direct visual control. A small ice ball formation indicated that the probe was functioning properly  to evaluate ability in daily routine and activity limitations . Three mThis pilot study included seven patients undergoing MIRPE. Demographic data are summarized in In all patients cryoanalgesia was successfully performed before standard MIRPE. After the first 4 patients, it was decided with the manufacturer to additionally improve the cryo-performance, based on challenging situation generated by the core heat counteracting the generation of the freezing effect. The cryoprobe microchip was calibrated to obtain a gas flow able to adequately perform. The dedicated cryoprobe was designed to generate a 3 cm long ice ball providing the desired freezing effect at the very end of the probe only. The equipment allowed performing the procedure in both automatic or manual mode. Surgical approach was also slightly modified. In the first 4 patients, the probe was inserted into the thorax through a 5 mm port, placed at the level of skin incision . In the All patients reported a good pain control with a fair need of rescue medications for pain relief during the first week after discharge, and a very good pain control without need of rescue medications during following weeks.All patients came back to school and social activity within the first month after discharge and they all referred problems with the fast walking only during the first week.Results from this initial experience confirm cryoanalgesia is a promising technique for post-operative analgesia after MIRPE. The technique resulted in good post-operative analgesia and, as consequence, in reduced use of analgesics and early return to normal life. Comparing the patients treated with cryoanalgesia and the standard PE patients in our Institution, the first were discharged earlier [2.4 days with respect to 6 days of the standard group ].However, despite no relevant side effects, a well-performed prospective trial is needed to understand risks and benefits of this technique.Considering that time required for MIRPE was 82 min in our overall series of 600 patients , MIRPE oCryoanalgesia creates wallerian degeneration without interrupting the myelin sheath and endoneurium, so we prefer the term of “cryoanalgesia” to the term “cryoablation” often reported in the literature and suggesting the (wrong) idea of removing something. Cryoanalgesia proved to be useful in terms of reduction of opioid consumption and hospital stay in previous experiences in North and South America [US –12 and A2 as cryogenic gas, differently from previous reports , while the temperature needed for axonotmesis is between −15 and −35°C. Our data seem to demonstrate that CO2 is effective as well as N2O in order to achieve the result, but it could be interesting to compare in future the effects of the two gases.In our experience, we have been using CO reports –12, repoParrado et al.  comparedIn our experience, we did not find a 24 h (or more) delay of the peak cryoanalgesic effect, as reported by other Authors . Graves Another point to be clarified is the preferred approach for the cryonalagesia probe insertion. The first described was the transmediastinal, with the sternum elevated, mediastinal dissection performed, and the probe passed substernally toward the contralateral side . The traIn Europe, no reports of cryoanalgesia in MIRPE have been published yet. Our aim was to test MetrumCryoflex system and its efficacy on pain control, using special thoracoscopic probes created specifically for MIRPE cryoanalgesia. Some important technical details specific of these probes are worthy to be underlined. First, the length and the strength of the probe allowed a safe, precise, and easy surgical approach. The equipment can be used in both manual/automatic mode according to the clinicians need. In all cases we were able to reach 5 or 6 intercostal levels. The dimensions of the probe (length and diameter) were optimized for a thoracoscopic use, creating an ergonomic tool allowing a percutaneous approach and an easy approach to the selected nerves. In our experience, the improved probe used in the last three patients was more ergonomic than the first and the procedure resulted easier to perform. Moreover, the double lumen cannula allowed ice ball formation exclusively at the very end of the probe tip, with the probe sheath not freezing. This technical detail reduced the risks of complications related to tissue cold injury that are seldom reported with other types of cryoprobes (in particular pneumothorax and skin lesions)  and alloThe cryoprobe is atraumatic (blunt tip) and echogenic; the ice ball could be detectable also with ultrasound imaging if percutaneous approach will be preferred. Percutaneous cryoanalgesia ultrasound guided with paravertebral nerve blockade could be an attractive alternative in PE patients. We do not have experience of this alternative approach and in our opinion comparative studies between thoracoscopic and percutaneous approach are warranted.In conclusion, our pilot study showed that cryoanalgesia is efficacious in terms of pain control, hospital stay and resumption of post-operative activities. The cryoprobe designed allowed an easy and safe maneuver.We acknowledge there are many limitations with this preliminary results, mainly due to the small sample of patients and the heterogeneity of the technical details. However, our result confirms that cryoanalgesia is a promising tool to treat post-operative pain of MIRPE. A large prospective study with a strict follow-up will definitely clarify is cryoanalgesia is the technique of choice for MIRPE.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by IRB Gaslini Institute. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MT designed the study, performed the procedures, and wrote the main part of the paper. LM participated to the design of the study, participated to the procedures, and evaluated the pain level in the post-operative periods. RB participated to the procedures, evaluated the pain level during the post-operative and follow-up periods, and contributed to the drawing of the paper. LP and LD evaluated the pain level during the post-operative and follow-up periods and analyzed the data. ND participated to the design of the technique and reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Femoral nerve block (FNB) is considered the preferred analgesia after anterior cruciate ligament reconstruction (ACLR), but leads to weakness in the quadriceps muscles. Adductor canal block (ACB) is a new sensory block technique that effectively relieves postoperative pain while preserving quadriceps strength. The purpose of our study was to compare the efficacy of FNB vs ACB for pain control after ACLR.This prospective, randomized, double-blind, controlled, superiority clinical trial was approved by the institutional review board in our university hospital. We enrolled 120 patients set to undergo ACLR in this randomized therapeutic trial. Sixty patients received FNB and the other 60 received ACB for postoperative pain control. All ACB and FNB were performed using ultrasound-guided single-shot procedures. The primary outcomes included maximum voluntary isovolumetric contraction and postoperative pain score. Secondary outcomes included total opioid consumption, length of hospital stay, complication, and satisfaction score.This clinical trial might provide some insights to estimate and compare the safety and efficacy of ACB vs FNB following ACLR.This study protocol was registered in Research Registry (researchregistry5569). As peripheral nerve blocks provide effective analgesia, they are considered an essential part of the current multimodal pain management protocol following ACLR.,4Anterior cruciate ligament reconstruction (ACLR) has been increasingly employed in recent times to restore knee stability and optimize function and has been demonstrated as a safe, effective, and cost-saving procedure. However, patients often report moderate to severe postoperative pain requiring narcotic analgesia for pain control, especially within 24 to 48 hours after surgery.,6 Within this context, a growing body of evidence supports the use of an adductor canal block (ACB), which offers pure sensory block with minimal motor involvement in patients undergoing ACLR. An ACB can be expected to include the saphenous nerve, vastus medialis, medial femoral cutaneous, articular branches from the obturator, and the medial retinacular nerves. This distribution provides the innervation for the medial, anterior, and lateral portions of the knee.Given the excellent pain relief and synergistic analgesic effect, femoral nerve block (FNB) is commonly used as an analgesic modality and is considered the standard peripheral nerve block in patients undergoing ACLR. However, FNB is followed by a significant decrease in quadriceps muscle strength, resulting in delayed mobilization, which is associated with the potential risk of falling.–4 However, these studies suffer from several important methodologic shortcomings. Therefore, the question of potential analgesic and motor-sparing benefits of ACB in the setting of ACL reconstruction remains unanswered. Thus, this prospective randomized study was conducted to determine whether patients perceive a difference in pain level, and to investigate how different patients experience functional recovery of the quadriceps muscle with ACB and FNB after undergoing ACLR. Additionally, it was hypothesized that patients receiving ACB would exhibit similar postoperative outcomes compared with patients receiving FNB.Some of the high quality studies have confirmed that ACB and FNB, in ACLR, can achieve similar postoperative analgesic effect, but patients with ACB can obtain better early rehabilitation compared with those with FNB.2This blinded and randomized study was performed after approval of the institutional review board in our academic hospital QHC2020071). It was carried out in accordance with the principles of the Helsinki Declaration. Data are presented according to the CONSORT statement. This trial was also registered in Research Registry (researchregistry5569). The flowchart of this trial is shown in Figure . It was 2.1Eligible patients included those aged <75 years, with an American Society of Anesthesiologists (ASA) score of 1 or 2, and who were scheduled for elective unilateral ACLR. Patients were excluded in case of pregnancy; significant psychiatric or mental disorders precluding assessment; baseline neuropathy or neurologic deficits involving the lower extremities; chronic pain or requirement of 30 mg or greater oxycodone  daily; nerve block contraindications, including coagulopathy or bleeding diathesis, local skin infections, and allergy to local anesthetics; or any component of multimodal analgesia. Patients who declined to participate in this trial or who were unable to provide informed consent were also excluded.2.2www.randomization.com) by a research assistant. A unique randomization code was used with no restrictions to either of the 2 study groups: single dose or multiple doses dexamethasone. The results of the randomization were maintained in opaque envelopes and stored with the research coordinator. The patient, anesthesiologist, surgeon, physiotherapists, acute pain nurses, and outcome assessors were unaware of study group allocation.After written informed consent was taken, patients were randomly allocated to one of the 2 groups in a 1:1 ratio using a computer-generated list of random numbers with a block randomization technique . This test correlates well with the functional outcome. We placed the standard handheld dynamometer perpendicular to the tibial crest 5 cm proximal to the medial malleolus to make the measurement as previously described by Maffiuletti. The patients were told to “reach maximum force and hold for 3 seconds.” Three measurements were done, and the average was taken. The pain score was measured using visual analog scale (VAS) score . VAS scores were recorded by nursing staff, blinded to treatment group, every 6 hours throughout the hospital stay.The primary outcomes included maximum voluntary isovolumetric contraction and postoperative pain score. The maximum voluntary isovolumetric contraction, which measures quadriceps strength and is normalized to the body mass index ; Pearson Chi-squared test or Fisher exact test was used to analyze the qualitative variable . The nature of the hypothesis testing was 2-tailed, and a P-value <.05 was considered statistically significant.All the data were analyzed using SPSS v. 24 . We used the Kolmogorov–Smirnov test to assess whether variable distributions violated the assumption of normality. Data are presented as mean and standard deviation or with medians and 25th to 75th percentiles as appropriate. The normal distributed numerical variable  was analyzed by Student 2.6The sample size was determined for the primary endpoint. According to the results of our previous study, the postoperative VAS score for nausea was 2.16 in the control group. We anticipated a difference of 0.72 in the VAS score. With a power of 0.90 and significance level of 0.05, the required sample size was calculated as 50 in each arm. Considering possible exclusion, we decided to include 60 patients in each group.3 FNB is an effective analgesic technique for ambulatory ACL reconstruction; however, it weakens the quadriceps muscle, an outcome that is preferably avoided. In addition, recent evidence of persistent strength deficits in patients receiving FNB further underscores the need for effective alternatives.The ACLR is one of the most frequently performed orthopedic procedures. The ability to perform ACL reconstruction on outpatient basis is largely dependent on an effective analgesic regimen that minimizes the role of systemic analgesics yet provides adequate postoperative pain control and eliminates the need for overnight stay or readmission. Some of the high quality studies have confirmed that ACB and FNB, in total knee arthroplasty, can achieve similar postoperative analgesic effect, but patients with ACB can obtain better early rehabilitation compared with those with FNB.–9 Similarly, in a prospective randomized, controlled trial, patients who underwent ACLR were randomized to receive either FNB or ACB, ACB exhibited early relative sparing of quadriceps strength at 6 to 8 hours postanesthesia compared with FNB.,11–15The ACB, a regional analgesic technique, is successfully used for postoperative pain control after knee surgery. In a retrospective cohort study, Manickam et al have demonstrated effectiveness of the ACB plus LIA on early ambulation after TKA compared with LIA alone.The present research seeks to compare the effects of ACB and FNB on the postoperative analgesic area, analgesic effect, and early rehabilitation in patients undergoing ACLR. The main limitation is that the clinical effects and complications of ACB were compared with that of FNB without the control group in the present study. According to the beneficence principle for patients, no control group with placebo was designed in the protocol of the present study. We do not think this limitation would affect the results tremendously.Conceptualization: Qingpei Xue, Wei Jiang.Data curation: Qingpei Xue, Wei Jiang.Formal analysis: Qingpei Xue, Wei Jiang.Funding acquisition: Jinkui Sui.Investigation: Qingpei Xue, Wei Jiang.Methodology: Yiping Wang.Resources: Jinkui Sui.Software: Qingpei Xue, Wei Jiang.Supervision: Jinkui Sui.Validation: Qingpei Xue.Visualization: Qingpei Xue, Wei Jiang.Writing – original draft: Qingpei Xue, Wei JiangWriting – review & editing: Meng Wang.


In response to issues with timely access and high non-attendance rates for Emergency Department (ED) physiotherapy, a telephone assessment and advice service was evaluated as part of a quality improvement project. This telehealth option requires minimal resources, with the added benefit of allowing the healthcare professional streamline care. A primary aim was to investigate whether this service model can reduce wait times and non-attendance rates, compared to usual care. A secondary aim was to evaluate service user acceptability.n=36) contacting the service. 25 patients (22%) opted for the face-to-face service. Data on wait time and non-attendance rates was gathered using the hospital data reporting system. Satisfaction data was collected on discharge using a satisfaction survey adapted from the General Practice Assessment Questionnaire. Independent-samples t-test or Mann Whitney U Test was utilised depending on the distribution of the data. For categorical data, Chi-Square tests were performed. A level of significance of p ≤ 0.05 was set for this study.This was a single-site quality improvement cohort study that compares data on wait time to first physiotherapy contact, non-attendance rates and participant satisfaction between patients that opted for a service based on initial telephone assessment and advice, versus routine face-to-face appointments. 116 patients were referred for ED physiotherapy over the 3-month pilot at the ED and out-patient physiotherapy department, XMercy University Hospital, Cork, Ireland. 91 patients (78%) opted for the telephone assessment and advice service, with 40% (p ≤ 0.05). There was no significant between-group differences for non-attendance rates or satisfaction.Those that contacted the telephone assessment and advice service had a significantly reduced wait time  compared to those that opted for usual care  (A telephone assessment and advice service may be useful in minimising delays for advice for those referred to ED Physiotherapy for musculoskeleltal problems. This telehealth option appears to be broadly acceptable and since it can be introduced rapidly, it may be helpful in triaging referrals and minimising face-to-face consultations, in line with COVID-19 recommendations. However, a large scale randomised controlled trial is warranted to confirm these findings.The online version contains supplementary material available at 10.1186/s40945-020-00098-4. Musculoskeletal conditions make the most significant contribution to the global burden of disability, with more than 20% of the world’s population living with a painful musculoskeletal disorder . Given oTelehealth, a subcategory of eHealth , is becoAlthough robust research is lacking on the role of telephone assessment within the field of physiotherapy, evidence exists on the safety, clinical- and cost-effectiveness, along with patient acceptability within other clinical settings such as nurse telephone consultation for routine asthma review and in out of hours primary care –18. The This patient care pathway reflects the evidence about the effectiveness of different modalities within physiotherapy for various conditions. For example, trials have found that a single session of advice from a physiotherapist is as effective as a course of physiotherapy for patients with back pain , 21, witThis study was a single-site cohort study with two parallel groups with recruitment between May and August 2018. Data collection was complete in May 2019. The comparison was between patients that opted for a service based on initial telephone assessment and advice, versus routine face-to-face appointments. This study design was utilised due to a consistently high non-attendance rate (approx. Average 30%) and some qualitative research nested within the ‘PhysioDirect’ study  (AdditioAll adults (aged ≥ 18 years of age) were invited to participate in this study, if following their attendance at the X Hospital ED, physiotherapy was deemed appropriate by a member of the ED team . Inclusion criteria were deliberately broad to maximize generalizability. Participants were excluded if they were unable to communicate in English via telephone or were referred with non-musculoskeletal problems.All eligible participants were provided with a participant information leaflet in ED and the two treatment pathways were discussed by a member of the ED team, with the patient choosing based on their preference. The first treatment option was the physiotherapy telephone assessment and advice service, while the alternative was the usual care pathway i.e. appointment made for a face-to-face consultation. Patients that opted for the telephone assessment and advice service had their verbal consent noted during the first telephone consultation with another copy of the participant information leaflet, questionnaires, consent form and prepaid return envelope sent out in the post on discharge. Those who did not respond to the first mail out were sent a second mail-out approx. Two weeks later. Those that opted for a face-to-face consultation provided written informed consent during the first consultation if they wished to participate.Patients were invited to telephone a senior physiotherapist at specific times for initial assessment and advice. Generally, at the end of the consultation, the senior physiotherapist posted a relevant advice leaflet about exercises and self-management to the patient and invited them to phone back in approx 2–4 weeks to report progress if appropriate. At that point, they were given further advice or booked for a face-to-face appointment if necessary. If the initial call indicated more urgent face-to-face care was required, this was booked at the outset.Usual care generally involved an initial face-to-face physiotherapy assessment and then a series of follow-up treatment appointments over several weeks or months, according to therapist’s discretion.To characterize the study population, demographic information such as employment status, location of symptoms, age, gender etc. was recorded on a data collection form.The primary outcome measures were wait time to first physiotherapy contact, non-attendance rates and participant satisfaction. Wait time to first physiotherapy contact and non-attendance rates  was gathered using the hospital data reporting system, Implement Single Patient Administration System (iPIMS). Satisfaction data was collected using a satisfaction survey adapted from the General Practice Assessment Questionnaire, which has been utilised previously , with inp ≤ 0.05 was set for this study. Normality of the continuous variables was tested with the Shapiro-Wilk test and appropriate descriptive statistics were calculated. Where the normality assumption was violated, equivalent non-parametric tests were used. The Mann Whitney U Test was utilized to evaluate between-group differences in wait time and number of physiotherapy consultations given the non-normal distribution. Median and inter- quartile values (Q1 – Q3) are presented as these values are better represented by the median rather than the mean, with the median less sensitive to outliers [All data analysis was undertaken using the Statistical Package for the Social Sciences Version (SPSS) 23.0 . A leveloutliers . Chi-Squoutliers , 33, mean=91) opted for the telephone assessment and advice service. Of those deemed eligible at that stage, 40% (n=36) contacted the service; however three participants were excluded . Table Figure p ≤ 0.05).Those that contacted the telephone assessment and advice service had a significantly reduced wait time for consultation  compared to those that opted for the face to face care pathway  (Χ2(2) = 4.41, p > 0.05).For the telephone advice and assessment group, there was 99 appointments in total, with 10 ‘did-not-attends’ at subsequent face to face appointments, resulting in a 10% non-attendance rate. For the usual care group, there was 68 appointments in total, with 15 ‘did-not-attends’, resulting in a 22% non-attendance rate. This difference was non-significant between both groups (Χ2(3) = 3.44, p > 0.05)  = 3.00, p > 0.05)  were managed entirely by telephone consultation. Patients in the telephone assessment and advice service had a similar number of physiotherapy contacts overall (via telephone and face to face)  compared to the usual care group  (p > 0.05). No adverse events were reported in either the telephone assessment and advice service or face-to-face group.The purpose of this quality improvement cohort study was to evaluate whether a telephone assessment and advice service could reduce non-attendance rates and improve wait times within an ED Physiotherapy clinic. While text message  and teleThe main finding from this cohort study is that, compared with usual face-to-face care, the telephone assessment and advice service care provided faster access to ED physiotherapy without compromising on service user satisfaction. While no studies to date have assessed the impact of telehealth on wait times within an ED Physiotherapy clinic, these findings are consistent with research conducted within other physiotherapy settings , 37, aloThis telephone assessment and advice service operated via a ‘one-way’ system in general, where the senior physiotherapist waited for patients to call at specified times on a Monday, Wednesday and Friday morning. These times were chosen based on previous service provision and to minimise unnecessary delays to service access as much possible. Nevertheless, the median wait time was 6 days, in line with other literature evaluating a musculoskeletal physiotherapy telephone service, operating via a ‘one-way’ system , 50. TheFindings from this study suggest that more than a third of those suitable for an ED Physiotherapy service can be managed via telephone consultation alone. This figure is somewhat lower than figures reported in other studies (47–50%) , 15 althIt is worth noting that 78% (91/116) opted for the telephone assessment and advice service suggesting this eHealth solution is broadly acceptable to patients. Furthermore, there was no significant difference between groups with respect to the satisfaction survey results, with both groups demonstrating a similar response rate. This is consistent with qualitative findings from the PhysioDirect trial  along wiThis study utilised a global improvement score to crudely characterise clinical effectiveness, with no significant differences observed between groups. While this measure has good psychometric properties across a broad range of musculoskeletal conditions , it is iA number of limitations are acknowledged, with the high risk of confounding bias foremost. Secondly, a large proportion (60% or 55/91) that opted for the telephone assessment and advice service did not contact the service. While the ‘did not contact’ figure is similar to figures reported elsewhere , we did In conclusion, this study indicates that a telephone assessment and advice service may be a useful strategy of reducing delays for advice for musculoskeletal problems for patients referred by a member of an ED team for ED Physiotherapy. Furthermore, this eHealth option appeared to be broadly acceptable to patients with musculoskeletal disorders. However, further research involving a larger sample size and utilising a randomised controlled trial design is warranted to validate these findings.Additional file 1.