IntroductionTourniquet pain may have cutaneous and ischemic components. It is questionable whether blockade of a sensory nerve will help reduce ischemic pain. In addition, complete anesthesia of the axilla in the intercostobrachial nerve (ICBN) distribution is challenging to execute, and ICBN blockade has an inherently higher failure rate because of its variable anatomic location and source of innervation. We sought to determine the utility of an ICBN block for the prevention of tourniquet pain.MethodsWe conducted a single-center randomized controlled trial at a major academic medical center involving patients scheduled to undergo distal upper extremity surgery under ultrasound-guided supraclavicular brachial plexus block. Forty patients were randomized to receive an additional ICBN block or no ICBN block, with 22 allocated to the intervention and 18 to control. We collected data on the incidence of tourniquet pain and systemic anesthetic requirements.Results2 analysis failed to show that tourniquet time was significantly related to the development of tourniquet pain.Initial contingency analysis examining the relationship between ICBN block placement and the development of pain using the two-tailed Fisher exact test failed to show that the presence or absence of ICBN block was associated with the development of tourniquet pain. χConclusionsThe overall incidence of tourniquet pain in the setting of a dense supraclavicular brachial plexus block for surgical anesthesia was low even without an ICBN block and even with tourniquet times greater than 90 min. Tourniquet pain was easily managed with small amounts of systemic analgesics. Traditional teaching suggests that the intercostobrachial nerve (ICBN) should be blocked to prevent tourniquet pain. Data that support this teaching include older studies incorporating non-ultrasound-guided and distal approaches to the brachial plexus -4. HowevFrom a mechanistic point of view, tourniquet pain described as a dull, pressured, and achy pain in the tissue underneath and distal to the tourniquet may have cutaneous and ischemic origins. However, if wrinkle-free padding is placed underneath the tourniquet to avoid skin folding and shear stresses to the skin, then the cutaneous component to tourniquet pain could be minimal. Additionally, blocking the ICBN, a cutaneous sensory nerve, should have minimal benefits in preventing tourniquet pain. Ischemic pain becomes progressively intolerable with the duration of ischemia and is much more difficult to blunt unless the regional anesthetic block results in dense anesthesia . Indeed,Our primary aim was to determine the utility of an ICBN block for the prevention of tourniquet pain. We randomized patients who were scheduled to undergo distal upper extremity surgery under an ultrasound-guided supraclavicular brachial plexus block to receive an ICBN block or a control group that did not receive the block.clinicaltrials.gov; NCT03797924; date of registration: 1/1/19; dates of patient enrollment: 4/25/2019 to 12/8/2020). Patients were included if they were 18 to 80 years old, American Society of Anesthesiologists status I to III, scheduled to undergo surgery of the upper extremity distal to the elbow with anticipated tourniquet use, and desiring regional anesthesia as the primary anesthetic. Patients were excluded if there was a contraindication to regional anesthesia, if they had primary block failure, or if they desired deep intraoperative sedation. As this is a pilot study, a sample size of 40 was chosen based on the potential availability of subjects and study completion within a period of 1 to 2 years.This single-center, prospective, randomized, single-blinded clinical trial was approved by the University of Florida Institutional Review Board (IRB201802525) and registered as a clinical trial  was placed on the arm over soft padding, according to local protocol. Exsanguination with an Esmarch bandage was performed before tourniquet inflation to 250 mm Hg. The intraoperative anesthesia team documented the tourniquet inflation and deflation time.Sedation, supplemental analgesia, and management of tourniquet painPatients were provided with midazolam (up to 2 mg) if requested and music via earphones for intraoperative anxiolysis. No opioids were administered before the incision. At the first patient complaint of pain, the intraoperative anesthesia team was asked to document the quality and location of pain, and 50 mcg of fentanyl was administered if the patient requested it. If pain persisted, the fentanyl dose could be repeated one additional time. If the pain persisted despite two doses of fentanyl, a propofol infusion was started at 50 mcg/kg/min and titrated at 10 mcg/kg/min every two to three minutes to achieve the lowest Richmond Agitation-Sedation Scale (RASS) score resulting in patient comfort.Outcome parametersThe primary aim of the study was to determine if the ICBN block affected the incidence, time to onset (in minutes), and severity of tourniquet pain, defined by the presence of dull, aching pain underneath the tourniquet. Secondary endpoints of the study were ICBN block effect on intraoperative opioid consumption and depth of anesthesia to alleviate tourniquet pain.Sample sizeBecause the incidence of tourniquet pain was not known before the commencement of the study, a retrospective power analysis was conducted. Having found that one of 25 participants in the ICBN block group developed pain and three of 25 in the non-blocked group  and using a null difference in the proportions of 0.2, the study had 95.4% power to detect such a difference.Statistical analysisData collected included patient demographic information , sensory/motor distributions of the musculocutaneous/radial/median/ulnar/ICBN blocks, time of tourniquet inflation and deflation, quality and location of intraoperative pain, use of intraoperative fentanyl or propofol, and RASS scores.Data were analyzed using the JMP Pro 15 statistical software package . Data were tested for normality. Initial contingency analysis was made by comparing the frequency of tourniquet pain in patients treated with the ICBN block and those not treated with the block. This was followed by comparing tourniquet inflation time in those who did and those who did not develop tourniquet pain with logistic fit models. First, the role of tourniquet inflation time was examined across all study participants. Subsequently, the role of tourniquet inflation time was examined in each of the treatment groups separately. Last, a mixed-models analysis of variance was undertaken in a model incorporating tourniquet time, treatment group, and the interaction between treatment group and tourniquet time. All data are presented as means ± SD for one-way analyses and parameter estimates and 95% confidence intervals for logistic fit analyses.Forty-six patients were enrolled; after the exclusion of six patients for various reasons, 40 patients completed the study, and data were collected for analysis Figure . PatientEighteen patients had tourniquet times of 90 min or longer. Four patients in the ICBN group failed to have sensory changes in the anteromedial and/or posteromedial aspect of their upper arm, representing an 18% incidence of failed ICBN blocks. None of these patients with failed ICBN blocks complained of tourniquet pain.Four patients complained of tourniquet pain, but two declined analgesia for management Table . The incOf the three patients who received intraoperative fentanyl, two complained of tourniquet pain. One patient in the no ICBN block group was given 50 mcg of fentanyl by the intraoperative anesthesia provider for anxiety.Initial contingency analysis examining the relationship between ICBN block placement and the development of pain using a two-tailed Fisher exact test failed to show the significance that the presence or absence of ICBN block was associated with the development of tourniquet pain (p = 0.31). When examined again using a one-tailed Fisher exact test to examine the probability that tourniquet pain was more likely in patients not receiving the ICBN block, the results remained statistically nonsignificant , treatment group (ICBN vs. no ICBN), and the interaction between tourniquet times and treatment group. Neither tourniquet times  nor presence of the ICBN block  was significantly associated with the development of tourniquet pain and there was no interaction effect between these two factors .In the setting of an effective ultrasound-guided supraclavicular block for surgical anesthesia, the incidence of tourniquet pain was low. Even when tourniquet times exceeded 1½ h, the incidence of tourniquet pain was low (approximately one in three patients without the ICBN block and one in five patients with the ICBN block). Furthermore, the number of systemic analgesics required to manage tourniquet pain when it manifested was minimal. Propofol infusion was not needed to manage tourniquet pain.One of the reasons for such effective brachial plexus blocks is the use of moderate volumes (20-30 mL) of a higher concentration of local anesthetic, 0.5% ropivacaine. The reason a supraclavicular block was performed instead of a more distal approach was twofold. When compared to an axillary block, the supraclavicular block more reliably covers the axillary nerve and musculocutaneous nerve, as well as the medial cutaneous nerve of the arm and forearm. In addition, the placement of an infraclavicular block theoretically more likely spills into the area where the ICBN traverses and results in an unanticipated spread in this distribution . In addiIt is notable that with tourniquet times exceeding two hours, the addition of an ICBN block to blunt tourniquet pain may be of some benefit. However, using a mixed-models logistic fit model, the ICBN block did not appear to reduce the likelihood of tourniquet pain. The effect of tourniquet time remained nonsignificant in terms of an effect on pain, although our sample size was too small to make definitive conclusions. Notably, the patient with the longest tourniquet time did not receive an ICBN block and did not complain of tourniquet pain. We used a chest wall approach to anesthetize the ICBN because we perceive that the reliability of anesthetizing this nerve is better, and the coverage is greater when targeted on the chest wall instead of in the axilla, where terminal branches may be missed. Numerous fascial plane block techniques have been proposed to anesthetize the lateral cutaneous branch of the T2 intercostal nerve, including PECS2, subpectoral intercostal plane, serratus anterior plane, and serratus-intercostal fascial plane blocks ,14. BecaSamerchua et al.  publisheWith the low reliability of success of an ICBN block, a low incidence of tourniquet pain in the setting of a successful brachial plexus block (even without anesthetizing the ICBN), and the ease of management of tourniquet pain with minimal systemic analgesics/sedatives, we do not believe that the addition of an ICBN block is warranted for the prevention of tourniquet pain, even with anticipated prolonged tourniquet times.LimitationsWe could not enroll patients in this study without the use of sedatives for block performance, given the surgical population at our institution. However, the time from block completion to initiation of surgery was as long as four hours; frequently, the sedative effects of the block procedure were minimal by that time.The overall incidence of tourniquet pain in the setting of an effectively dense supraclavicular brachial plexus block for surgical anesthesia was low, even without the addition of an ICBN block. This tourniquet pain can be easily managed with small increases in systemic analgesics.


Sciatica pain is a typical symptom of lumbar disc herniation (LDH), but some neurogenic and malignant tumours surrounding the sciatic nerve can also cause similar symptoms. These tumours are often misdiagnosed or even mistreated as LDH in clinical practice.In our clinical practice, we found two patients with malignant tumours who were misdiagnosed with LDH. One patient complained of pain and numbness in the right lower limb. The primary diagnosis was LDH, and the patient underwent posterior lumbar interbody fusion surgery. After the operation, the symptoms were not alleviated. Then, diffuse large B-cell lymphoma involving the soft tissue and the sciatic nerve was identified. Another patient who manifested with radiating pain in the right lower limb was diagnosed with LDH at Chengde Central Hospital. He received regular conservative treatment for approximately 6 months, but his symptoms were not relieved, and then he was referred to our hospital. A malignant peripheral nerve sheath tumour (MPNST) of the sciatic nerve was diagnosed, and he received cisplatin (DDP) chemohyperthermia.Descriptions of tumour lesions involving the sciatic nerve and misdiagnosed as LDH in the literature are rare. In the reported literature, 7 patients were misdiagnosed with LDH, and all patients presented with sciatica. Among them, 4 patients only received surgical treatment, 1 patient only underwent neurolysis, and 2 patients received both surgical and chemotherapy treatment. Their low incidence and similar clinical manifestations to LDH make malignant tumours involving the sciatic nerve easy to misdiagnose. When the clinical symptoms and signs are inconsistent with the imaging findings, we need to be aware of non-discogenic sciatica, including tumours involving the sciatic nerve. Furthermore, tumours that grow near the exit of the sciatic notch may be misdiagnosed because of their deeper location and because they are covered with gluteal muscles. Sometimes sciatica caused by sciatic nerve tumours is only distal, without any radicular distribution. This pain is more severe than that caused by LDH, and this pain is not related to the position of the lumbar spine. Thus, it is beneficial to perform a detailed physical examination of the sciatic nerve to avoid this kind of misdiagnosis. Lumbar disc herniation (LDH) often occurs because of intervertebral disc degeneration, and trauma is one of the important factors in its pathogenesis. In addition to degeneration and trauma, genetic and developmental abnormalities are also related to LDH , 2. TypiA 54-year-old man complained of pain and numbness in the right lower limb for 6 months. This intermittent intense pain and numbness could be slightly relieved by supine positioning and hip overextension and was aggravated after overuse. The visual analogue scale (VAS) score of pain was 6/10 at the first visit to the clinic, and the pain did not wake the patient up from sleep during the night. Physical examination revealed a decreased tingling sensation of the right hip, right posterolateral leg and foot skin, and there was slight tenderness in the lumbar 4-5 intervertebral space. In addition, a grade 3/5 weakness of the extensor hallucis longus and a positive straight leg raise test were found. The muscular tension, knee reflex and Achilles tendon reflex were normal, and the patient had a negative Babinski sign, Chaddock sign, Gordon sign and Oppenheim sign. Lumbar MRI examinations were performed in the clinic, and lumbar 4-5 intervertebral disc herniation were found Fig. . PET-CT A 37-year-old man who was diagnosed with LDH was referred to our hospital. He complained of radiating pain in the right lower limb for approximately 9 months. The pain radiated from the posterior aspect of the right thigh to the lateral aspect of the leg and right foot. The persistent and intense pain could be aggravated after hip flexion and slightly relieved after rest or hip overextension. The VAS score for pain was 7/10 at the first visit to the clinic, and the pain could wake the patient up from sleep during the night. Moreover, the pain was combined with numbness of the right lower limb. Physical examination revealed a decreased tingling sensation of the right dorsolateral foot and sole skin, grade 3/5 weakness of the quadriceps femoris, grade 2/5 weakness of the extensor hallucis longus and extensor digitorum longus and a positive straight leg raise test. The muscular tension, knee reflex and Achilles tendon reflex were normal, and he had a negative Babinski sign, Chaddock sign, Gordon sign and Oppenheim sign, and there was no tenderness in the lumbar spine. He had received conservative treatment, which included analgesic drugs, acupuncture treatment and local nerve blocks for approximately 6 months in Chengde Central Hospital. Thereafter, the symptoms were slightly alleviated (VAS = 6/10). The patient also underwent a lumbar MRI examination in Chengde Central Hospital that showed L4-5 intervertebral disc expansion. Although LDH was diagnosed in Chengde Central Hospital, the radiological imaging results were inconsistent with the symptoms and signs. To further explore the cause of the radiating pain in the lower limb radiation, the patient was transferred to our hospital and received a detailed physical examination. Fortunately, a soft tissue mass in the area where the sciatic nerve runs in the middle thigh was palpated. The tumour size was approximately 50 × 30 mm, the boundary was not clear, and there was a positive Tinel’s sign. Subsequently, the patient underwent an enhanced MRI scan that revealed a fusiform tumour in the femoral region. The T1-weighted image showed a nonuniform low-intensity signal, while the T2-weighted image showed a mixed low- and high-intensity signal (Fig. Common clinical manifestations of LDH include typical dermatomal pain, increased pain on coughing, leg coldness, sneezing, paresis, straining, absence of knee or ankle tendon reflex, a finger-floor distance of more than 25 cm and a positive straight leg raise test, mostly at the L4-5 or L5-S1 level . On rareTo date, the relevant reports on sciatic nerve tumours misdiagnosed as LDH are case reports , 20, 21.To avoid misdiagnosis, it is essential to recognize the clinical manifestations of non-discogenic sciatica causes. First and foremost, for people over 50 years old, if the clinical manifestation is progressive and if severe pain at night is present without remission, the acute sciatica syndrome must be suspected to be caused by a malignancy , 22. In In conclusion, we reported two cases of soft tissue masses that were misdiagnosed as LDH. Although diffuse large B-cell lymphoma and schwannoma are very rare in clinical work, they are of great significance in differentiating between discogenic and non-discogenic sciatica. When a patient with sciatica presents with pain while sitting, marked tenderness to deep intragluteal palpation, a positive Tinel’s sign, and imaging findings that seem inadequate for explaining the patient’s symptoms and signs, the patient should receive gluteal and/or pelvic MRI, even when no palpable mass is evident. In patients with both sciatic nerve tumours and LDH, when the symptoms gradually worsen after conservative treatment, we must consider that the cause of the pain is sciatic nerve tumours.


Functional near-infrared spectroscopy (fNIRS) has evaluated pain in awake and anesthetized states.We evaluated fNIRS signals under general anesthesia in patients undergoing knee surgery for anterior cruciate ligament repair.Patients were split into groups: those with regional nerve block (NB) and those without (non-NB). Continuous fNIRS measures came from three regions: the primary somatosensory cortex (S1), known to be involved in evaluation of nociception, the lateral prefrontal cortex (BA9), and the polar frontal cortex (BA10), both involved in higher cortical functions (such as cognition and emotion).Our results show three significant differences in fNIRS signals to incision procedures between groups: (1) NB compared with non-NB was associated with a greater net positive hemodynamic response to pain procedures in S1; (2) dynamic correlation between the prefrontal cortex (PreFC) and S1 within 1 min of painful procedures are anticorrelated in NB while positively correlated in non-NB; and (3) hemodynamic measures of activation were similar at two separate time points during surgery  in PreFC and S1 but showed significant differences in their overlap. Comparing pain levels immediately after surgery and during discharge from postoperative care revealed no significant differences in the pain levels between NB and non-NB.Our data suggest multiple pain events that occur during surgery using devised algorithms could potentially give a measure of “pain load.” This may allow for evaluation of central sensitization  to postoperative pain levels and the resulting analgesic consumption. This evaluation could potentially predict postsurgical chronic neuropathic pain. Exclusion criteria included inability to cooperate or understand the nature of the study, structural or genetic disorders that affect typical brain structure and function, significant medical disease, smoking history, inability to obtain reliable fNIRS measures in initial signal test, or inability to maintain head stillness for 200 continuous seconds. This protocol was approved by Boston Children’s Hospital’s institutional review board, and all participants and legal guardians assented/consented to participation in this study. This study conformed to the Declaration of Helsinki for experiments in patients related to pain.2.2Study personnel gathered data from 24 patients (ages 12 to 25 years) who underwent arthroscopic knee surgery under general anesthesia; however, five patients were excluded from analysis; one patient had unsaved data, one patient withdrew due to medical emergency, and three patients had incomplete pre- and/or postsurgical data. 2.3Supplementary Material. Drug dosages are presented here as median [range]. Briefly, all patients were premedicated with 2-mg midazolam IV and propofol (median 200 mg [150 to 300 mg]) used for induction of anesthesia in 18 patients (95%). In one patient (#13), the induction dose of propofol was not recorded. Fentanyl (median 100 g [100 to 250 mg]) was administered as part of the induction in all but one patient who was given sufentanil (#2). Anesthesia was maintained with an inhalational agent, predominantly sevoflurane, and supplemented with a propofol infusion in 12 patients (47%). The airway was managed with a laryngeal mask airway and spontaneous ventilation; neuromuscular blockade was not employed. For intraoperative analgesia, hydromorphone (median 0.6 mg [0.3 to 1.6 mg]) was the opioid of choice and acetaminophen (650 mg IV) was administered intraoperatively to all but one patient. Ketorolac (median 30 mg [18 to 30 mg]) and diazepam (median 2.5 mg [2.5 to 7.5 mg]) were each administered to approximately half the patients. The acetaminophen, ketorolac, and diazepam were generally given toward the end of the surgery. Antiemetic prophylaxis included ondansetron (4 mg) in all but one patient (#17), dexamethasone (median 4 [4 to 8] mg) in all but three patients , and a scopolamine patch (1.5 mg) was applied in two patients .All patients underwent general anesthesia according to routine practice. Anesthetic data for each patient are shown in Table S1 in the Supplementary Material. A catheter for infusion of local anesthetic was placed in one patient (#17) but the infusion was only started 6 h postoperatively. In one patient, a lateral femoral cutaneous nerve block was added to the adductor canal block. Dexmedetomidine and clonidine were added to the ropivacaine in one (#7) and two  patients, respectively.An adductor canal peripheral nerve block with ropivacaine (0.2% or 0.35%) was performed under ultrasound guidance on the ipsilateral limb in 11 (58%) patients. Nerve block was administered based on the clinical team’s recommendation following standard clinical evaluation and the patient’s consent. Details for the regional anesthesia are presented in Table S1 in the Local anesthetic  was injected by the surgeon in 16 patients (84%), either immediately prior to incision . The changes in hemoglobin concentration of oxygenated . A smaller EEG cap with the same probe layout was used for pediatric patients as needed. Data quality and optode positions were confirmed with a 10-min baseline scan in the preoperative setting. There were two steps of quality control, one during data acquisition and one during postprocessing. After setup and before the beginning of the scan, the channels were visually inspected. Good contact between the scalp and the optode was confirmed by (1) acceptable power intensity (as indicated by CW7 software) and (2) a visible heart rate in all the channels, including short-separation channels. After which, the fNIRS data were continuously collected, beginning at anesthetic induction, and concluding following final suturing at the end of surgery. During this period, one research personnel was responsible for monitoring fNIRS data acquisition quality, while another was responsible for noting the time and type of surgical procedures; for instance, the initial incision was noted as “incision,” arthroscopic scraping was noted as “scraping,”and so on. A summary of fNIRS signal acquisition and data analysis for a single patient is shown in Prior to entering the operating room, the probe-containing cap was securely placed on patients’ heads. The optodes were secured using custom designed washers to maintain contact  exhibited a visible heart rate component in the raw time series and a discernible peak at the cardiac frequency range of the power spectrum, that region qualified as “good” data. If the raw time series exhibited a heart rate component, but the data were noisy, it was classified as “average” data. If the raw time series did not show a visible heart rate, the data were too noisy, and the power spectrum did not show a discernable heart rate component, then that data were considered “poor” data. This classification was performed for every subject. Subjects with at least two cortical regions with “average” or more data were included in the next steps of the analysis. Raw fNIRS time series data were then preprocessed using scripts written by our group in the MATLAB R2018b platform. The raw fNIRS signal was converted to optical density and corrected for head-motion using a wavelet-based algorithm.This was performed for every long-separation channel , first incision (P1), and last incision (P2). P0 was defined as the 60-s intraoperative epoch in which patients did not receive any procedure. This metric was individually determined for each patient by selecting the longest possible lapse of time between any procedure . This was because there was not enough duration before any kind of surgical intervention was made. P1 was defined as the 60-s epoch following the first incision, and P2 was defined as the 60-s epoch following the last incision. All epochs were normalized to the mean at the time of observation. A timeline of the surgical procedures including the P0, P1, and P2 events in each patient is shown in trapz function in MATLAB. A mixed ANOVA approach was utilized to protect against type I errors due to multiple comparisons. This helps to identify significant differences in the area under the curve measure of P0, P1, and P2 procedures in NB versus non-NB groups. Statistically significant effects were obtained at the significance level of Next, a standardized 10-s sliding window with 1-s increments was calculated for the 60 s during P0, P1, and P2. The area for the absolute standardized rolling average curves was computed for the six ROIs in each patient using the 2.9Between the 15 unique ROI–ROI connections for a given epoch, we calculated Pearson’s 33.1The values of 3.1.1Supplementary Material.) No significant relationships are observed in the PreFC ROIs during any event, with all The time series graph in 3.1.2Supplementary Material, there are 10 relations between the NB and non-NB groups that are statistically significant under a mixed model ANOVA approach. Of these, eight of these are in the contralateral S1 region. Notably, all three observed time periods  are significant for contralateral Absolute areas between contralateral and ipsilateral Supplementary Material).–These significances provide crucial information for showing the presence of a nerve block within the patient based on the findings thus far, especially early on into surgery observing contralateral P1 CL 3.1.3Correlation analyses were performed to determine if interactions between ROIs could provide further insights to the cortical hemodynamic response to pain procedures. Correlations between ROIs were shown to be robustly positive in PreFC regions, weakly positive in S1 and very weakly negative in the PreFC/S1 overlap. Supplementary Material shows that observations (a) to (d) is repeated across the ipsilateral side for Table S3 in the 4,Our results in Sec. 4.1We obtained continuous bilateral recordings from three brain regions in patients under general anesthesia: S1, mPFC and LPFC as shown in Sec. Taken together, we have deduced a number of indicators (fNIRS response time) locked with incision presumed to activate nociceptor fibers with an incision. This is dependent on measures of 4.2Here, we discuss three aspects of why we consider our fNIRS measures to likely be measures of pain/nociception. We are careful to use the term “pain” here, since it normally refers to conscious perception .Tissue damage activates nociceptors via direct damage to pain fibers.As noted above, nociceptive activation of the central nervous system may occur with deep general anesthesia—although clinical responses may not be detected —and nociceptive activation persists under general anesthesia in healthy volunteers in the brain4.3,,,The primary somatosensory cortex is well defined to be involved following primary nociceptive activation in animal and human studies.,,Opioids are potent analgesics for acute pain,We observed an increase in the fNIRS response at the last incision. We suggest that there are two mechanisms that may be at play: (1) hyperalgesia induced by the incision as noted above due to inflammatory activation and also repetitive nociceptive barrages occurring as a result of the surgical repair; and (2) fentanyl produces rapid onset of hyperalgesic priming at both peripheral and central nociceptors as a result of prolongation of inflammatory-induced hyperalgesia.4.4There are a few salient issues related to pain in this paper that deserve further investigation. The first is the ability to measure pain/nociceptive events as discussed above, and the second relates to the efficacy of the nerve block. Based on postsurgical self-reported VRS pain scores in the PACU see , there aThe changes to hemoglobin concentrations as a response to pain can be measured in real time as a way to detect when the patient is feeling pain during surgery. From a series of repeatable results, an algorithm can be trained to receive previous time series values and foresee how the patient will respond to painful stimuli. Machine learning techniques practice on previous patient data where times of incision can be recorded.4.5There are a number of caveats that need to be considered.4.5.1Measures of nociception in a clinical setting do not allow for a paradigm that would allow for specific timing of anesthesia nor surgical interventions across all individuals. In our patients, measures are taken during routine procedures , this is consistent with our goal of developing a marker for uncontrolled nociception during surgery.4.5.2We have measures in a total of 19 subjects, 11 with nerve blockade procedure. The use of repeated measures adds to the fidelity of the results. Although the number of patients was relatively small, for NB versus non-NB, our data still showed significant differences; clearly larger datasets would allow us to distinguish and other categories of differences, e.g., sex differences, age differences, etc.4.5.3,Based on our data, there was no difference between the postoperative pain scores between the two groups see . This ma4.5.4,Opioids may depress cortical activity4.5.5,There are a number of technical concerns aside from This was mitigated by taking the period of time furthest from any record of surgical procedures being conducted (these were chosen on a patient-by-patient basis). Alternatively, recording a minute from the preoperative data would ensure that the patient had not experience prior pain, but this would not be consistent with previous recordings, and would not account for the presence of nerve block in the 11 patients who received it. (g) Only incisions were considered “painful” when other procedures elicit minor responses which can build up over time. Future work can be made more sensitive to small pain events than this paper.4.5.6While machine learning can train on existing patterns where pain does and does not occur, observing distinctions that clarify when a patient is undergoing a painful procedure without external interference, there are problems with these methods in their current incarnation. The current method pursued so far is based on time series analysis and the forecasting of future events. This is accomplished through looking at hemoglobin concentration levels in the two observed pain events P1 and P2 and comparing them with the control period P0. Typical time series models can incorporate known trends and cycles into the training cycle due to the large amount of accrued data; however, because of the nature of the experiments and the lack of a large sample size, these results are only based on the data that the 19 patients have been able to provide. Considerable work has gone into overcoming these deficiencies;5,Surgery, by its very nature, produces tissue damage and inflammatory processes that result in an afferent barrage of nociceptor activity.Click here for additional data file.


Hip osteoarthritis (HOA) leads to pain and reduced function. The use of intra-articular injections based on corticosteroids, platelet-rich plasma (PRP), or hyaluronic acid (HA) is becoming a common symptomatic therapy for HOA. For the first time, we compare the effectiveness of plasma with a high concentration of platelets and leukocytes (L-PRP) with PRP+HA in patients with mild to moderate HOA. A total of 26 patients in each group were administered with either L-PRP or PRP+HA. Outcomes were evaluated at baseline, 3 months, and 1 year after the injection. The mean visual analog scale (VAS) and Harris hip score (HHS) within and between groups among different time points were compared using repeated measures ANCOVA (age set as a covariate). Both treatments were effective in reducing VAS, but not in significantly increasing HHS. In the group treated with L-PRP, VAS showed interaction between time and treatment (in favor of L-PRP). Pairwise comparison for treatment and time point evidenced a significant difference at 1-year follow-up between L-PRP and PRP-HA. Outcomes support the idea that both treatments may be effective in reducing pain, with maximal pain reduction achieved after 3 months. L-PRP showed better results in reducing VAS over time. Both treatments are effective at reducing pain in the short to medium term. L-PRP could be the treatment of choice due to a more marked effect over time. Nevertheless, further research is needed to better describe the clinical outcome of these formulations. Like other chronic joint diseases, hip osteoarthritis (HOA) leads to reduced quality of life and disability, mainly due to hip pain and functional limitation. The rapid increase in the prevalence of HOA makes it one of the most common joint diseases: the global prevalence of HOA is approximately 0.85%, higher in females (0.98%) than in males (0.70%), and consistently increasing with age . ConservOn the other hand, as concerns HA, the delivery of this biomolecule in the arthritic joint is called viscosupplementation, and is considered crucial to restore the mechanical properties of synovial fluid, exerting an analgesic, anti-inflammatory, and chondroprotective effect . Pain control and improved joint function are the main aims of conservative therapy of osteoarthritis ,8,9,10. As regards HOA, this is the first study comparing clinical outcomes of PRP plus hyaluronic acid (PRP+HA)—which is relatively poor in leucocytes—with L-PRP, which conversely shows abundance of white cells. The primary aim of this study is to evaluate both L-PRP and PRP+HA treatments’ effectiveness to reduce pain and increase hip function. The secondary aim is to find out whether one of the two treatments could lead to better results: we hypothesized that, due to the viscosupplementation effect of HA, PRP+HA may show superior results in pain control in HOA with chronic pain.Among 89 patients treated with L-PRP or PRP+HA, 27 did not meet the inclusion criteria: 26 patients were excluded due to a previously mentioned clinical condition. A patient treated with PRP+HA underwent total hip surgery. No patient refused informed consent.We included 52 patients suffering from HOA treated with intra-articular injections of L-PRP or PRP+HA between December 2017 and December 2018, meeting the inclusion criteria. Among these, 26 were treated with L-PRP and 26 with PRP+HA; from this point, we will address two separate groups (L-PRP and PRP+HA). Participants included in the analysis received the treatment, and none of them noticed/complained of any harmful/unexpected effects. A disposition diagram summarizes patient selection .p = 0.001). At the baseline moment, 24 patients (46.2%) showed II KL grade, while 28 patients (56.8%) showed III grade. The study included 52 patients for the final analysis, 24 females (46.2%) and 28 males (56.8%). Study participants treated with PRP+HA showed higher age , but not for HHS (p > 0.05). Post hoc Bonferroni pairwise comparison highlighted significant improvement in VAS between baseline and 3 months’ follow-up, the improvement in both measures was not retained, and between 3 months’ follow-up and 1-year follow-up, a significant worsening (increased VAS and reduced HHS) was observed (p < 0.001).ANCOVA for VAS showed significant results  = 13.836, p = 0.040, ηp2 = 0.120). In PRP+HA,  = 10.732, p < 0.001, ηp2 = 0.309).In the L-PRP group, VAS showed significant changes  = 3.286, p > 0.001). As regards VAS scores, the interaction between time and treatment was significant (in favor of L-PRP), with a small effect size  = 5.392, p = 0.007, ηp2 = 0.099). Pairwise comparison for treatment and time point evidenced a significant difference at 1-year follow-up between L-PRP and PRP+HA (p = 0.020).In the VAS score, no main effect of treatment type was highlighted  undergoing two consecutive L-PRP or PRP+HA intra-articular injections 3 months and 1 year after treatment. A significant short-term reduction of pain of the osteoarthritic hip, as shown by the significant lowering of VAS, was the most important consequence of both treatments: on average, in the L-PRP group, the mean VAS decreased to 42.79 , while in the PRP+HA group, it decreased to 32.30 . Nevertheless, at the 1-year follow-up, the mean VAS worsened : it was worsening when compared with the score after 3 months, but at the same time, it was significantly lower than baseline; in other words, the analgesic effect partly persisted after 12 months, but it was weaker than in the first follow-up visit. The group treated with L-PRP showed a lower mean VAS at the last follow-up (−9.61): results of our statistical analysis confirmed that there was a significant interaction between time and treatment, with significantly lower scores in the L-PRP group at the last follow-up. This observation suggests that L-PRP could induce a more marked long-term pain reduction compared with PRP+HA; nevertheless, it is important to consider the small effect size of this result as a limit of this observation, especially considering the restricted sample size of this study.Our results do not support the effectiveness of L-PRP and PRP+HA to improve function , reduce movement restrictions , and improve ROM in flexion, abduction, adduction, and external rotation, measured using an orthopedic goniometer. It is worthy to note that, although the change in HHS in the two groups was found to be not significant, the evolution of this functional score in the two groups followed the same pattern of VAS: an initial (significant) improvement after 3 months, followed by a marked worsening between 3 months and 1 year . DespiteFurther evidence supporting the short-term efficacy of biological gel injections as a strong analgesic solution for HOA comes from a previous paper by Sante and colleagues: in a comparative study, either PRP or HA intra-articular injections were administered to a total of 43 patients suffering from severe monolateral HOA. PRP determined a 4-week pain reduction (assessed with VAS), which was not retained at the successive follow-up; conversely, the administration of HA determined a 16-week pain reduction . AnotherCurrently, scientific evidence is supporting the view that the administration of intra-articular PRP injections could exert an analgesic effect more markedly within 3 months, with several reports of effectiveness in short-/midterm evaluations. The superiority of PRP against other injective treatments is yet to be determined, while longer-term evaluations from 4 to 12 months show diverse results [de facto, a relatively cheap solution, and it is not burdened by the collateral effects of systemic treatments. It can be obtained with ease and in a restricted amount of time and can be eventually delivered in the synovial cavity a few minutes after blood sampling [Our work, with a major focus on the comparison between L-PRP and PRP+HA, shows substantial agreement with the evidence brought on by previous research. Furthermore, in our study no relevant adverse effects were observed, supporting the idea that intra-articular injections are a safe conservative local analgesic treatment when administered by physicians with expertise in eco-guided intra-articular injections. PRP is widely considered beneficial and safe for patients with HOA, and PRP has been demonstrated to improve HOA symptoms at midterm follow-up ,20; nevesampling ,19,20. IThe interpretation of the results must take in consideration several limitations: due to the retrospective design, the baseline scores are obtained from a singular assessment of a nonrandomized group. Herein, design and statistical analysis are not accounting for regression to the means. We can only obtain preliminary conclusions, while a randomized study carried out with a test–retest design would be more indicated to compare the two treatments. Furthermore, we enrolled participants not responding to analgesic/anti-inflammatory use. Nevertheless, we did not systematically collect concomitant treatment, and we interviewed patients about their drug consumption : we did not take into account the occasional assumption of analgesic/anti-inflammatory drugs .The absence of follow-up after 1 year is a limitation to this study, as at that time point, the pain reduction was observable, but we did not assess whether this effect lasted more with one of the two treatments.Being that this is a retrospective study, we did not compare the effects with other intra-articular treatments  or with saline solutions. PRP preparations could vary from different manufacturers, and our results might not be extrapolated to all commercially available PRP preparations, but only those that determine the production of a PRP of similar composition.We partially accounted for selection bias by adjusting for age; nevertheless, an analysis based on matching, if feasible , may have been superior.To summarize, what we exposed previously, the two formulations analyzed, showed a significant analgesic effect: 1 year after the infiltrative therapy, pain perception was still improved, but the analgesic effect reached a peak in the baseline at 3 months’ interval.In our opinion, these results encourage the adoption of PRP intra-articular administration as a safe, simple, and minimally invasive solution to mid- and long-term chronic pain management.The efficacy of these and similar biological treatments and the comparison (in terms of effectiveness) with other nonsurgical options, as well as their possible role in severe OA or in other degenerative joint diseases management, could be better described by further studies.Our result suggest that L-PRP may in fact determine, at a long-term follow-up, a superior pain reduction. Indeed, these results may not be enough to indicate a management choice, and more evidence is necessary to find out whether one, between L-PRP and PRP+HA, could be more indicated.This retrospective, comparative, observational study was conducted at the Policlinic “G. Martino” of Messina  to investigate outcome differences between PRP+HA and L-PRP. The study is under the authorization of the Comitato Etico di Messina, the local committee (registration number: 0014580). Participants were selected among patients suffering from HOA, treated with L-PRP or PRP+HA injections between December and November 2017 and December 2018. Standard follow-up for patients lasted 12 months, so data collection for the last patient enrolled in the study ended in December 2019.Diagnosis was based on clinical history, physical examination, and weight-bearing anteroposterior radiographs of both knees in full extension, graded by adopting the Kellgren and Lawrence (KL) grading system  by two e3). Patients were considered eligible if they reported no pain relief after the repetitive administration of NSAIDs. Therefore, patients enrolled in this study were informed to avoid cortisone/NSAIDs for analgesic–anti-inflammatory purposes.Injective treatment was indicated in patients suffering from HOA, with physiological hematocrit and coagulation profile  of drugs, or physical therapy  for analgesic/anti-inflammatory purposes—were excluded due to their influence on pain and function.We included in our revision patients with a mild–moderate grade of HOA.All patients received an ultrasonography-guided injection in the most symptomatic hip, followed by another one after 14 days for a total of two injections (one on the 1st day and another on the 15th day). Physiotherapy and gradual muscle strengthening have been prescribed since the second infiltration of the treatment.Due to the retrospective nature of the study, patients were aware of the treatment received; thus, this can be considered an open-label work. Questionnaires were administered and collected by physicians external to the context of the study. Patients were asked for permission to use data collected in the study time after questionnaire administration, so the filling of questionnaires was not performed under research—but only clinical regime.Statistical analysis was performed without any possible identifier of the groups (only named groups A and B).With the patient in supine position , the physician sits on the side of the patient’s symptomatic hip.The first step of the procedure is a survey sonography of the hip joint  to identify the anterior rim of the acetabulum, femoral head, femoral neck, and joint capsule, with Doppler imaging to identify femoral vessels.The injection must be performed using aseptic technique. The patient’s groin area and anterior hip are sterilized with a chlorhexidine swab, and sterile ultrasound gel is applied over the injection site.After cleaning the transducer using a germicidal cloth wipe, the hip joint is visualized in a long-axis view. Then a 3.5-inch 22-gauge sterile spinal needle is inserted 1 cm from the distal portion of the ultrasound transducer. The needle can be inserted, under visualization, in plane with the transducer until it enters the joint capsule.The needle enters the hip joint near the anterolateral surface of the femoral neck, at the femoral head–neck junction. Injection is performed as lateral as possible to avoid lesion of femoral vessels.Holding the needle in the correct position, L-PRP or PRP+HA can eventually be injected . ®-THT-3/RegenCell®  we obtained L-PRP, after centrifugation of venous blood for 9 min at 3400 rpm/1500× g.For each PRP injection, 8 mL of venous blood from the cubital vein was collected in a sterile tube. Subsequently, with RegenKitg). The volume obtained from each tube stood at 5 mL .Using Cellular Matrix A-CP-HA, we obtained PRP+HA with centrifugation . The Regen THT concentration factor was 1.7×. Platelet recovery was approximately 95%. L-PRP had a mean concentration of 370,000 platelets/mm3 and 4000 leukocytes/mm3.Performance tests were carried out by Regen Lab SA . Cellular Matrix A-CP-HA had a platelet concentration factor of 1.6×, with a platelet recovery of approximately 80%. PRP+HA reached a mean concentration of 310.000 platelets/mm3 and 290.000 platelets/mm3, while L-PRP contains 3600 leukocytes/mm3 and 340.000 platelets/mm3. The mean concentrations were calculated by an automatic cell counter .Functionality tests performed in our hospital  revealed that PRP+HA contains, on average, 800 leukocytes/mmTo assess the effectiveness of the treatment on hip function and pain, we evaluated the patients with the Harris hip score (HHS) and the visual analog scale (VAS). The HHS consists of four subscales: pain severity (44 points); function, evaluating daily activities and gait (47 points); deformity, which measures hip flexion, adduction, internal rotation, leg length discrepancy, and range of motion measures (4 points); and range of motion (5 points). Scores range from 0 to 100. A score of <70 is considered a poor result, 70–80 is fair, 80–90 is good, and a score of 90–100 is excellent ,23. The We proposed to the patients the visual analog scale (VAS) on a segment of 100 mm, with “no pain” and “worst pain imaginable” as anchor descriptions. The patient was invited to place a sign to indicate the level of pain perception: the outcome is represented by the distance between the left (no pain) endpoint and the sign, measured in mm.Participants were evaluated with VAS and HHS before injection  and 3 months (T1) and 12 months (T2) after intra-articular injections. Treatment and outcome assessment were performed in outpatient regime by an orthopedic surgeon not involved in other procedures (PR).Sample size was assessed by G*Power software . A minimal sample size of 44 subjects (22 per group) was adopted, with α level = 0.05, power (1-β) = 0.95, and effect size of 0.25 (medium effect size) .t-test) were analyzed. The two groups were compared for baseline HHS and VAS using independent-samples t-test. A general linear model (repeated measures ANCOVA) was adopted, based on the mean values of the outcome variables  between the levels of a within-subject and a between-subject factor , with simple main effects and interaction assessment. Post hoc Bonferroni pairwise comparison was performed. Age was set as a covariate. The differences between the two groups for gender, K-L grade (χ2 test), and mean age (independent-sample


Although single-incision laparoscopic appendectomy (SILA) was introduced decades ago, it is still considered a difficult technique to perform compared to conventional laparoscopic appendectomy (CLA). In addition, controversy about the benefits of SILA compared to CLA abound and no definite criteria for choosing SILA over CLA in patients with appendicitis currently exist. Therefore, we have planned a multi-center randomized controlled trial to compare SILA with CLA in terms of cosmetic satisfaction and pain reduction.Patients diagnosed with appendicitis at the participating centers will be recruited and allocated into either a CLA or an SILA groups using a 1:1 randomization. Patients in the CLA group will receive a conventional 3-port laparoscopic appendectomy and patients in the SILA group will receive a laparoscopic appendectomy using a single-incision at the umbilicus. The primary trial endpoint is cosmetic satisfaction assessed using the Patients and Observer Scar Assessment Scale (POSAS) administered 6 weeks post-surgery. Secondary trial endpoints include cosmetic satisfaction assessed via the Body Image Questionnaire, pain levels assessed via the Visual Analog Scale and International Pain Outcomes questionnaire, and the presence of postoperative complications. The target sample size of this superiority trial is 120 patients, as this will provide 80% power at the 2.5% level of significance to detect a 3-point difference in POSAS.The results of this planned multi-center randomized controlled trial will provide substantive evidence to help surgeons choose when to use SILA over CLA in patients with appendicitis.This trial was approved by the institutional review board at Daegu joint on February 27, 2020 (No: 19-12-001-001) and registered with the clinical research information service (CRIS) (KCT0005048). The results of the study will be published and presented at appropriate conferences.To investigate the clinical benefits comparing between single incision laparoscopic appendectomy and conventional laparoscopic appendectomyTo assess the pain and cosmetic satisfaction through quantitative scales, Patient-Reported Outcomes Measures (PROMs), International Pain Outcome (IPO) Questionnaire, the Patient and Observer Scar Assessment Scale (POSAS), and the Body Image Questionnaire (BIQ)To help surgeons choose when to use single incision laparoscopic appendectomy in patients with appendicitis. Acute appendicitis is one of the most common causes of emergency gastrointestinal surgery worldwide. Even though controversy regarding the medical management of acute appendicitis using antibiotics exists, appendectomy is currently considered the gold standard treatment.Open appendectomy rather than laparoscopic appendectomy was performed universally until the 1990s, even though Kurt Semm, a German gynecologist, first introduced laparoscopic appendectomy firstly in 1983 .A conventional laparoscopic appendectomy (CLA) usually requires insertion of three port trocars with two working ports and one camera port. Additionally, single-incision laparoscopic appendectomy (SILA) has become popular since it was first introduced in 1992 . Recent 45Theoretically, SILA would be expected to produce less pain, encourage faster recovery, and result in better cosmetic satisfaction than CLA. However, several previous reports comparing SILA and CLA have yielded conflicting results and only a few studies have reported that SILA is superior to CLA with respect to pain and/or cosmesis 891011. O8910514Previous RCTs compared between SILA and CLA used simple visual analog score (VAS) for the assessment of both pain and cosmetic satisfaction. Results originated from this type of assessment have limitations with regard to their objectiveness.There are several patient-reported outcomes measures (PROMs) used for assessing the pain and cosmetic satisfaction after surgery including the International Pain Outcome (IPO) Questionnaire , the PatTherefore, our trial aims to investigate the clinical benefits of SILA over CLA using these more objective PROMs for pain and cosmetic satisfaction.Figure 1.This study is a multi-center, prospective, open-label, randomized trial. Patients diagnosed with acute appendicitis at participating centers will be screened for study enrollment. Enrolled participants will be randomly allocated to either the SILA group or the CLA group. This study follows the recommendations of the SPIRIT  guidelines. The study flowchart is shown in Patients 19–75 years of age diagnosed with acute appendicitis who will receive a laparoscopic appendectomy will be recruited. Diagnosis of acute appendicitis is confirmed by abdominopelvic CT or ultrasonography performed on patients with clinically suspected appendicitis, and is defined by appendiceal diameter exceeding 6 mm with thickened and enhancing wall, and periappendiceal edema or fluid collection.Patients who have one or more of the following will be excluded from this study: (1) patients with a suspected abscess or appendiceal perforation; (2) patients with symptoms of pan-peritonitis symptom; (3) patients with a history of major abdominal surgery; (4) patients who have an inability to express themselves due to conditions such as dementia or intellectual disability; (5) patients with chronic pain who need to take analgesics; (6) patients with severe medical disease such as pulmonary, cardiovascular, hepatic, or renal insufficiency; (7) Pregnancy; and (8) patients unable to provide consent.A single 2cm incision will be made at the umbilical area and a custom multi-channel single port  will be inserted into the incision site. There will be no restrictions placed on the type of laparoscopic instruments used, and all such decisions will be left to the discretion of the surgeon. The mesoappendix and appendiceal artery will be ligated and resected with an energy device or bipolar cauterization. The appendiceal base will be ligated with a loop tie or clip as per the surgeon’s preference. After the appendectomy, the facia will be closed with an absorbable suture and the skin will be closed using a nylon suture, an absorbable subcuticular suture, or a topical skin adhesive as per the surgeon’s preference.Additional port insertion or conversion to an open surgery will be possible at the surgeon’s discretion to ensure patient safety.A standard three-trocar technique will be used with incisions made at the peri-umbilical, left lower quadrant, and supra-pubic sites. All other techniques for the appendectomy will be similar to those used in the SILA procedure.All participants will be randomized to either the SILA group or the CLA group in a 1:1 ratio. The randomization allocation will occur just to surgery using a computerized randomization system.The target sample size will be 120 participants, as this will provide 80% power at the 2.5% (two-sided) level of significance to detect a three-point difference in the POSAS score between the SILA group and the CLA group at 6 weeks after surgery. Our target sample size allows for 10% attrition.The primary trial endpoint is cosmetic satisfaction at 6 weeks after surgery as measured by POSAS. The secondary endpoints are cosmetic satisfaction assessed via BIQ, pain assessed via the IPO questionnaire and VAS, and the presence of general postoperative complications.Figure 3).All data for this RCT will be collected after obtaining consent from the participants prior to surgery. All data will be recorded on a paper case report form as well as a digital record form. A participating surgeon or trained researching nurse will perform the postoperative interview to collect the necessary PROMs data  and statistical significance will be declared for tests with p values < 0.05.Laparoscopic abdominal surgery is generally regarded as a minimally invasive surgery with advantages such as less pain, faster recovery and better cosmetic results compared with open surgery. Many types of laparoscopic abdominal surgeries are currently used including single-incision procedure and conventional multi-port procedures 2021. Sin2022Surgeons and patients believe that reduced port surgery has advantages in terms of cosmetic satisfaction and pain reduction. This belief is based on the results of previous studies comparing open and laparoscopic surgery. In addition, among laparoscopic surgical techniques, SILA would be expected to outperform CLA with regard to cosmetic satisfaction and pain reduction because of further reductions in invasiveness. However, it has been difficult to prove the superiority of SILA over CLA because patient expectations are raised.In this context, as mentioned above, there are controversies about the efficacy of SILA with respect to cosmetic satisfaction and pain reduction compare to CLA. However, previous studies including RCTs have used only a simple VAS and/or analgesic usage as indicators for pain reduction 102425. A1024For evaluation of cosmetic satisfaction, most previous studies used a subjective numeric rating from 5 to 100 242627. T24268This study has some limitations even though it was designed as a prospective multi-center RCT. First, there are no Korean validated versions of the PROMs which will be used. However, investigators discussed the bases of clinical similarity and significance of the original version and translated the PROMs into Korean. In addition, all PROMS will be administered under the guidance of investigators or trained clinical nurses. Second, we will not be specifying which appendiceal base ligation or wound closer method must be used and instead will leave these decisions to the surgeon’s preference. This may act as a source of bias affecting the results. However, all the participating surgeons are colorectal surgery specialists who have performed hundreds of laparoscopic colorectal resections including SILA and CLA techniques. As a result, surgical skill should have a minimal impact on postoperative morbidities between surgeons.In summary, this study is a prospective multi-center RCT designed to compare SILA and CLA with regard to cosmetic satisfaction and postoperative pain. We believe that the results of this study will clarify the efficacy of SILA for the treatment of acute appendicitis and will be helpful for determining which patients would benefit from SILA instead of CLA.Data sharing is not applicable to this paper as no datasets were generated or analysed during the current study.


Background: Inadequately controlled sternotomy pain after cardiac surgery can lead to delayed recovery and patient suffering. Preoperative intravenous methadone is effective for reducing both postoperative pain and opioid consumption. Despite ease of administration, the effects of preoperative oral methadone are not well described in the literature.Aims: This pilot study investigated the effect of preoperative oral methadone on pain scores, analgesia requirements, and opioid-induced side effects.Methods: A randomized double-blind placebo-controlled model was used with sampling of patients undergoing sternotomy for isolated coronary artery bypass graft (CABG) surgery . Participants were randomized to receive oral methadone (0.3 mg/kg) or oral placebo prior to entering the operating room. The primary outcome was pain scores on a 0–10 Verbal Rating Scale. Secondary outcomes included morphine requirements using patient-controlled analgesia (PCA), time to extubation, level of sedation, and side effects such as nausea, vomiting, pruritus, hypoventilation, and hypoxia over a 72-h monitoring time.Results: Twenty-one patients completed the study. Oral methadone did not reduce pain scores in the methadone group (P = 0.08). However, postoperative morphine requirement during the first 24 h was reduced by a mean of 23 mg in the methadone group . No reduction in pain scores or PCA morphine was observed beyond 24 h postoperatively. There was no difference in incidence of opioid-related side effects between groups throughout the postoperative period.Conclusions: Though preoperative oral methadone did not reduce pain scores, morphine requirements were reduced in the first 24 h post-CABG. Approximately 30% of patients will develop chronic, noncardiac pain poststernotomy, independent of the type of cardiac surgery.14Moderate to severe postoperative pain is common in cardiac surgery patients, particularly during the first 48 h after surgery, even with potent opioids.15 Repeated doses or boluses of analgesic medications result in fluctuating plasma opioid concentrations that can be avoided by the use of a single adequate dose of methadone (20–30 mg) that provides analgesia for approximately 24 to 36 h.During early recovery, intravenous opioids are often administered for analgesia, either intermittently by nursing staff or by a patient-controlled analgesia (PCA) device.ethadone –30 mg thWe conducted a randomized blinded placebo-controlled parallel design pilot study with one-to-one allocation and allocation concealment. This trial was registered at ClinicalTrials.gov (NCT02774499).Included were patients undergoing sternotomy for elective, isolated coronary artery bypass graft (CABG) surgery. Participants were recruited by reviewing operating room schedules and were seen in the pre-assessment clinic (if outpatient) or on the wards (if inpatient) prior to surgery. If a patient was missed in the pre-assessment clinic, a researcher called the patient at home to explain the study in advance, to answer any questions, and to allow the patient time to consider his or her participation on the day of surgery. Signed informed consent was obtained.21 Other exclusion criteria included pulmonary disease necessitating home oxygen therapy, preoperative requirement for inotropic agents or intra-aortic balloon pump to maintain hemodynamic stability, emergency surgery, allergy to methadone, use of preoperative opioids, or recent history of opioid abuse. Opioid-tolerant patients were excluded according to the U.S. Food and Drug Administration definition: those taking at least oral morphine 60 mg daily or equianalgesic dose of another opioid for 1 week or longer.22Exclusion criteria included the following: <18 years of age, concomitant valve replacement, preoperative renal failure requiring dialysis or serum creatinine greater than 176 µmol/L, significant hepatic dysfunction , ejection fraction less than 30%, corrected QT interval (QTc) on ECG >440 ms for men and 450 ms for women. Many medications have interactions with methadone; though we did not exclude participants based on other medications they were taking, an already prolonged QTc was used for exclusion because of the known possibility of methadone further prolonging QT interval and subsequently inducing torsades de pointes.23The study was conducted in the Regina General Hospital in Regina, Saskatchewan, Canada. The trial received ethical approval from the research ethics boards of the University of Saskatchewan and the Regina Qu’Appelle Health Region and was conducted in compliance with good clinical practice.24 For convenience and safety, our conversion ratio was 1:1.Participants received oral liquid methadone or an equal volume of sweetened syrup prepared as described below. This dose was consistently given when the patient was called to the operating room, just prior to transport. When used at doses of 0.2 to 0.3 mg/kg, intravenous methadone has not been associated with a higher incidence of opioid-related adverse events (compared with short-acting opioids).Patients received midazolam (2 mg) before being transported to the operating room. Standard Canadian Anesthesiologists' Society (CAS) monitors were applied, including a five-lead electrocardiogram and bispectral index monitoring. A radial arterial line and central venous catheter were inserted for invasive monitoring and access. Transesophageal echocardiography was used at the discretion of the anesthesiologist. Anesthesia was induced with midazolam (0–4 mg), sufentanil (0.5 μg/kg), propofol titrated to loss of lash reflex, and rocuronium (0.6–1 mg/kg). Sufentanil (0.5 μg/kg) was given as an infusion over 2 h. Additional sufentanil was given as clinically indicated, which was recorded and accounted for in the data analysis. Rocuronium was given to maintain paralysis and monitored with a nerve stimulator. Sevoflurane (0.4%–2.3%) and propofol (0–50 mcg/kg/min) were used to maintain anesthesia and were titrated to the bispectral index  and to mean arterial pressures no less than 20% of baseline. Sevoflurane titration, nitroglycerin, phenylephrine, ephedrine, norepinephrine infusion, dobutamine, epinephrine, milrinone, or fluid boluses were used to control hemodynamics as clinically indicated. No steroids or antiemetic agents were given perioperatively. A propofol infusion (10–60 μg/kg/min) was initiated at sternal closure and maintained until the patient was transported to the intensive care unit (ICU).As is normal ICU care at our institution, morphine (2–5 mg) intravenously up to every 5 min as needed was given for pain until extubated. Propofol was infused as per weaning protocol at a rate of 10–60 μg/kg/min for sedation until extubated. Once extubated, if analgesia was required, intravenous morphine (0.05 mg/kg) was given every 10 min until either the patient appeared to be resting comfortably or a maximum of five doses had been given. Once the patient’s base level of analgesia was established, he or she was provided with a PCA pump programmed to administer morphine (0.015 mg/kg), with a lockout interval of 6 min.Gastrointestinal prophylaxis was maintained with ranitidine 50 mg intravenously (IV) every 8 h for 5 days, as well as pantoprazole 40 mg daily by mouth or IV, and was reassessed upon discharge from ICU. Acetaminophen 650 mg was given by mouth every 6 h while awake for 96 h and then 325–650 mg by mouth every 4 h as needed (not to exceed 4000 mg/24 h). Metoclopramide 10 mg by mouth or intravenously every 6 h as needed was ordered for nausea. Normal cardiovascular parameters were maintained using a combination of the following where clinically indicated: epinephrine, norepinephrine, dopamine, nitroprusside, milrinone, hydralazine, labetalol, and nitroglycerin. Fluid maintenance was achieved with Ringer’s lactate. Cardiopulmonary bypass was used in all cases. Patients were discharged from ICU and transferred to the Cardiac Surveillance Unit and then to the Cardiosciences ward once standard transfer criteria were met.25 Secondary outcomes included 24-h postoperative morphine requirements, time to extubation, level of sedation, and opioid-related side effects, specifically nausea, vomiting, pruritus, hypoventilation, and hypoxia during a 72-h monitoring period. The following baseline preoperative data were recorded: age, sex, weight, height, previous heart surgery, previous stroke, peripheral vascular disease, congestive heart failure, diabetes mellitus, lung disease, obstructive sleep apnea, chronic pain, hypertension, smoking, preoperative pain at rest and with cough, preoperative vital signs, and American Society of Anesthesiologists physical status classification. Total operating room time, total sufentanil, and total midazolam were also recorded.Postoperative pain scores were measured and reported for 72 h postoperatively using a validated 0- to 10-point Verbal Rating Scale (VRS).2 < 90% or needing supplemental oxygen), confusion/delirium as assessd by the validated Richmond Agitation–Sedation Scale (RASS), and hypoventilation (respiratory rate <8).26The following postoperative data were collected: total time until extubation, total midazolam in ICU, total morphine given pre-PCA establishment, pain with cough postextubation, VRS pain scale (0–10) at rest and with cough, number of PCA requests, total morphine (mg), and number of incidents of nausea, vomiting, pruritus, constipation, urinary retention, hypoxia  was used with 1:1 allocation.A computer-generated simple randomization  to mask any potential bitter taste. The 5-mL syringe containing either methadone plus diluent or placebo plus diluent was self-administered by the participant by mouth in the holding area prior to entering the operating room. The researchers were not present at the time of administration. A dose of 0.3 mg/kg was given (to a maximum of 30 mg).The study design ensured concealment because recruiters and outcome assessors could not know the allocation of any participant. All of the researchers and members of the participants’ care team were blinded, including researchers, anesthesiologists, surgeons, and all other members of the operating room, ICU, and ward team.t test if normally distributed and with a Mann-Whitney rank sum test if nonnormally distributed. The secondary outcomes with continuous data were similarly dealt with; secondary outcomes with categorical data were analyzed by chi-square test. Secondary outcomes were intended to have alpha levels corrected for multiple comparisons by the Sidak correction, but there were no significant differences in secondary outcomes. Numbers were insufficient for subgroup analysis.We used a modified intent-to-treat analysis that removed participants who for any reason received no drug or placebo. The primary outcome, pain scores, and the secondary endpoint, total postoperative morphine consumption in the first 24 h as measured by total Patient-Controlled Analgesia (PCA) morphine, were assessed for normality of distribution by the Kolmogorov-Smirnov test and compared between groups with a Recruitment was conducted from February to August 2016. Twenty-four patients consented to the study and were randomized. One patient was excluded because of significant intraoperative complications requiring prolonged ICU stay and abandonment of the protocol. One patient withdrew due to inability to tolerate the PCA. One patient was removed because of anesthesia protocol violation (high-dose ketamine). Twenty-one patients were included in a modified intent-to-treat analysis according to group allocation of either placebo or methadone. Twelve patients received placebo and nine received methadone .10.1080Of 21 participants, 9 participants were analyzed in the intervention group and 12 were in the placebo group . AnalysiP = 0.08; P < 0.005; P = 0.007). No statistically significant difference in pain scores or PCA morphine was observed beyond 24 h postoperatively. The incidence of opioid-related side effects was not different between groups throughout the postoperative period (P = 0.09). Conversion between morphine and methadone is nuanced because of the differences between their respective pharmacokinetics and pharmacodynamics. Single-dose equianalgesic conversions of morphine to methadone have been reported from 1:1 to 1428; however, more recently, the mathematical relationship between methadone and morphine has been described as nonlinear, approaching a parabola29:Baseline demographic and medical comorbidities were comparable between the groups . Howevere period . Total iUsing this mathematical relationship, at the mean dose of oral methadone given (24 mg), the conversion ratio approaches 1:1.5 and gives an oral morphine-equivalent dose of 35.2 mg. If we consider oral : parenteral morphine conversion to be 2:1 or 3:1, the equianalgesic dose given would be in the range of 11.7 to 17.6 mg of IV morphine, with a mean of 14 mg.Though a single dose of preoperative oral methadone prior to CABG surgery did not reduce postoperative pain scores, it resulted in a significant reduction in morphine consumption in the first 24 h with similar rates of opioid-related side effects in both groups. This is the first prospective, randomized study using oral methadone in this population.An obvious limitation of our study is its small size; despite this, the data showed a reduction of morphine consumption postoperatively. A second limitation is that high-risk patients and opioid-tolerant patients were excluded from enrollment. It is unclear what effect preoperative oral methadone would have in this group; however, one could speculate that it might show a similar benefit. Due to our small sample size, we only captured two patients with chronic pain and, due to randomization, they both received placebo; however, they did not use significantly more morphine than other patients in the placebo group and therefore did not skew the results. Extracorporeal circulation was used for every patient undergoing coronary artery bypass grafting. Although we know that initiation of cardiopulmonary bypass decreases the plasma concentration of other lipophilic opioids, such as fentanyl (by 53%) and sufentanil (by 34%), separation from cardiopulmonary bypass returns these sequestered narcotics into the systemic circulation of the patientPsychological data such as history of depression, anxiety, and posttraumatic stress disorder were not collected on our patient population but could have been another factor contributing to our participants’ perceptions of their postoperative pain. The effect of methadone on long-term chronic pain development was not investigated in this study.PCAs are not routinely used in our institution for postoperative pain control in sternotomy. We used PCA to measure morphine requirements as accurately as possible. Though our pilot study was underpowered to demonstrate superiority of methadone, equianalgesic conversion suggests that morphine was not merely replaced one-to-one by methadone.Our sample was made up of patients with symptomatic coronary artery disease requiring CABG. Though we excluded patients receiving valve replacements to maintain a homogeneous study population, we likely could have included these procedures without compromising homogeneity.33 Several analgesic regimens have been utilized for cardiac surgery, including neuraxial analgesia, local anesthetic infusion, and peripheral nerve blocks.Perioperative pain control is critical for good patient outcomes, because it enables early mobilization and may prevent chronic pain.The literature offers little evidence regarding the utility of oral methadone; only recently have studies been published suggesting the utility of intravenous methadone.37Possible mechanisms for our positive signal likely include a combination of methadone’s long duration of action (24–36 h) as well as its dual mu agonist and NMDA antagonist effect.Our study was not adequately powered to show that preoperative oral methadone is superior to placebo for reducing postoperative morphine consumption; however, a larger trial should be carried out to further elucidate the clinical significance of this result.Currently there are only a small number of studies that have investigated the utility of perioperative intravenous methadone. Our study is unique in its route of administration, which has obvious clinical implications. Oral methadone could be given easily in the preoperative setting for many surgeries, although further research is required, including a larger multicenter trial, investigation of other surgical types, direct comparison of oral versus intravenous methadone, and impacts on the incidence of chronic pain following surgery. In summary, our pilot study suggests that a single administration of preoperative oral methadone prior to sternotomy results in equianalgesic reduction in morphine consumption in the first 24 h with equivalent rates of opioid-related side effects compared to placebo.


The management of pain in patients undergoing total knee arthroplasty (TKA) for chronic knee osteoarthritis (OA) has remained a challenge for the anesthesiologist regarding regional anesthesia as no single regional technique is adequate with regard to balancing effective analgesia with minimal muscle weakness. Severe postoperative pain following TKA has been shown to negatively impact patient outcomes and mortality. The genicular nerve block has recently been demonstrated to provide effective analgesia to the anterior and posterior knee capsule in recent studies. In this retrospective case series, we compare the efficacy of combined genicular nerve block (GNB) and adductor canal block (ACB) to only ACB in both primary and revision TKA patients. This combined novel approach for TKA patients can be utilized to improve patient pain scores and early ambulation, limiting the use of opioids and early discharge. Chronic knee osteoarthritis (OA), an epidemic among aging populations, is a leading source of chronic pain in the United States and other developed countries . The risSevere postoperative pain following TKA has been shown to negatively affect early mobilization, physical rehabilitation, time to discharge, and overall post-op recovery ,8,9. BalSuccessful postoperative analgesia for TKA requires careful consideration of knee innervation, with an emphasis placed on branches of the femoral nerve innervating the anterior and medical aspects of the knee and branches of the sciatic nerve innervating the posterior aspects of the knee capsule . In the However, patients do not achieve adequate posterior knee analgesia as ACB pain relief is primarily limited to the anterior capsule of the knee. Infiltration between the popliteal artery and capsule of the posterior knee (IPACK) block is a relatively new regional anesthesia technique and has been shown to be a potentially superior method of motor-sparing pain control compared to prior techniques, providing analgesia to the posterior compartment of the knee without causing any motor weakness affecting ambulation ,10. The The comparison of combined GNB and ACB analgesia for TKA is currently lacking in the anesthesia literature. This retrospective case series investigates the efficacy of treating patients with a combined GNB and ACB approach compared to ACB alone in both primary and revision TKA patients. The authors hypothesize that the combination of GNB with ACB would provide superior analgesia, while also limiting motor weakness and improving postoperative pain score, ambulation, and oral morphine equivalents (OME) use in patients undergoing TKA for chronic knee OA.This retrospective case series included patients undergoing primary or revision TKA at a tertiary academic medical center between July 1, 2019, and April 23, 2021. Eighty-two patients undergoing TKA provided written consent for the nerve block(s). Of these 82 patients, 52 (63.4%) underwent primary procedures, while 30 (36.6%) underwent revision procedures. Of the 52 primary TKA patients, 26 (50%) received only an ACB, while 26 (50%) received both an ACB plus genicular nerve blocks. Of the 30 revision TKA patients, 20 (66.7%) received only an ACB, while 10 (33.3%) received both an adductor canal and genicular nerve blocks. All nerve blocks were performed preoperatively with the patient in the supine position. The blocks were performed by a regional anesthesia fellow or senior resident under the direct supervision of an experienced regional anesthesia faculty. The primary or revision TKA was performed either under spinal or general anesthesia based on patient preference and medical indications. The visual analog scores of pain in the post-anesthesia care unit (PACU) and at 6, 12, 24, and 28 hours after surgery stop time were obtained. Cumulative OME were also calculated for 0-6 hours, 6-12 hours, and 12-24 hours postoperatively. In addition, ambulation distances were obtained for postoperative days 0, 1, and 2. SAS version 9.4  was used to conduct all statistical analyses. Data are expressed as means and standard errors (for continuous variables) or counts and percentages . The Wilcoxon rank-sum test was used to compare OME, pain scores, and ambulation distance. Analyses were stratified by procedure type (primary vs revision). All tests of statistical significance were two-sided and used a significance level of 5%.Ultrasound-guided technique for genicular blockThe patient was positioned in the supine position, and a high-frequency linear transducer was used to target the superomedial, superolateral, and inferomedial genicular nerves. For the superomedial genicular nerve, a linear transducer was placed along the longitudinal plane of the femur to visualize vastus medialis, the distal femur, and the genicular artery Figures , 2. UsinWhen considering only primary TKA patients, average pain scores for the genicular plus ACB group were lower across all recorded time points during the study Table , with a When comparing primary versus revision procedures for patients receiving genicular blocks, the average OME requirement was decreased in all time periods considered in the study for the primary procedure group, with a statistically significant reduction in OMEs at 0-6 hours postoperatively p = 0.042) Figure , Table 2 Figure ,Revision TKA patients showed no statistically significant difference in OME requirements, pain scores, or ambulation distance with the addition of genicular nerve blocks as compared to ACB only Figure , Table 3When considering both primary and revision TKA, ambulation distance on postoperative day 1 (POD1) was significantly greater for patients receiving genicular nerve blocks, 126.55 feet SD 17.91 ft), as compared to those who did not receive genicular nerve blocks, 82.55 feet (SD 11.03 ft) (p = 0.028). There were no statistically significant differences in ambulation distances for either POD0 or POD2 , we performed superolateral, superomedial, and inferomedial genicular blocks. The rationale to abandon inferolateral genicular block was to avoid any unwanted motor weakness or potential foot drop by inadvertently blocking the branch of the common peroneal nerve. The mid-thigh approach of the ACB targets the saphenous nerve, medial cutaneous femoral nerve, nerve to vastus medialis, and possibly the articular branches of the obturator nerve. The ACB has become widely popular, given its motor-sparing analgesia, but it does not provide a complete block of the knee . The comIn this study, for the primary TKA group, average pain scores for the genicular plus ACB group were lower across all recorded time points during the study Table , with a When comparing primary versus revision procedures for patients receiving genicular blocks with ACB, the average OME requirement was decreased in all time periods considered in the study for the primary procedure group, with a statistically significant reduction in OMEs at 0-6 hours postoperatively p = 0.042) (Table  Table 2.There are some limitations to this case series such as small sample size, retrospective design, and publication bias . The comThe ideal regional technique for postoperative TKA management should provide effective analgesia with minimal muscle weakness to augment early functional recovery. At the same time, this case series explores a new combination approach for TKA patients, which can be utilized to provide effective analgesia and early ambulation. Large sample size studies are warranted to further understand this new technique and also to compare its efficacy with traditional blocks for knee analgesia. Also, cadaveric and magnetic resonance imaging studies are required for a better understanding of the anatomical spread of LA and nerves covered with various genicular blocks.The ACB plus genicular block provided adequate analgesia for patients undergoing primary TKA during the early postoperative period. This combination block for primary TKA reduced pain scores and had opioid-sparing effects postoperatively. The addition of genicular blocks helped improve early ambulation for both primary and revision TKA patients. The genicular block is an easy ultrasound-guided regional technique, which can be performed in the supine position for patient comfort. Further prospective randomized studies are warranted to determine the efficacy of genicular blocks for analgesia and quality of recovery after knee surgery. Also, the safety of genicular blocks alone or in combination with other blocks needs further investigation.