There was no statistically significant difference between pain reduction in both groups (p = 0.347). The decrease differences of the pain effect upon general activities, sleeping, socializing, walking, and enjoying life in the follow-up period between the two groups were not statistically significant. No complications were noted in both groups. Results from the current study report that intradiscal injection of a gelified ethanol and tubular discectomy were equally effective on terms of efficacy and safety for the treatment of symptomatic lumbar intervertebral disc herniation regarding the 12-month mean leg pain improvement. Both achieved similar rapid significant clinical improvement persisting throughout follow-up period.The purpose of this study was to retrospectively compare efficacy and safety between intradiscal injection of a gelified ethanol product and tubular discectomy in the treatment of intervertebral disk herniation. A bi-central institutional database research identified forty (40) patients suffering from symptomatic contained disc herniation. Nucleolysis Group included 20 patients [mean 50.05 ± 9.27 years-of-age ] and Surgery Group included 20 patients . Primary outcome was overall 12-month improvement over baseline in leg pain (NVS units). Procedural technical outcomes were recorded, and adverse events were evaluated at all follow-up intervals. CIRSE classification system was used for complications’ reporting. Mean pre-operative pain score in Nucleolysis Group was 7.95 ± 0.94 reduced to 1.25 ± 1.11 at month 1 and 0.45 ± 0.75 NVS units at year 1. Mean pre-operative pain score in Surgery Group was 7.65 ± 1.13 reduced to 1.55 ± 1.79 at month 1 and 0.70 ± 1.38 NVS units at year 1. Pain decrease was statistically significant after both procedures ( Intervertebral disc herniation constitutes the most frequent reason for visits to an orthopedic or neurosurgeon and the fifth most common cause of hospitalization due to severe pain resulting in absence from work or daily activities . At presWhen compared to conservative therapy, percutaneous decompression techniques were shown to provide significantly better and longer lasting effects; in addition, various comparative studies and systematic reviews of the literature focusing mainly on mechanical, thermal, and ozone chemical decompression showed non-inferiority when compared to surgical options ,10,11,12The purpose of the present study was to retrospectively compare efficacy (in terms of pain reduction) and safety between Discogel injection and tubular discectomy in the treatment of intervertebral disk herniation.All patients were informed about the technique itself as well as possible benefits and complications and signed a relevant written informed consent form prior to the procedure. This bi-institutional retrospective cohort study received institutional review board approval. Clinical data were abstracted from prospectively maintained registries. The need for written informed consent for this study was waived.A bi-central institutional database study, conducted from 1 January 2020 to 31 December 2020, identified 40 patients suffering from pain due to single intervertebral disk herniation with no neurologic deficit. All patients in the Nucleolysis Group were treated in the same center (Center 1); all patients in the Surgery Group were also treated in the same center (Center 2). All patients complained of leg pain with or without back pain and described a lancinating, burning, stabbing, or electrical sensation of pain. When leg and back pain coexisted, symptoms in the lower extremity were always of greater intensity. In each patient, symptoms were consistent to the segmental level and side of the herniation . Clinical evaluation included Laseque, Slump, and Wasermann tests. All patients included in the study had undergone electromyography testing to avoid uncertainty of the disc to be treated . InclusiPrior to any therapeutic procedure, each patient underwent a thorough clinical examination, review of his or her medical records, and evaluation of previous imaging studies. Preprocedural imaging included lumbar spine face and lateral x rays  and multiplanar MR imaging .Intervertebral disk nucleolysis was performed by intradiscal injection of Discogel  under fluoroscopic imaging guidance, local anesthesia in accordance with the Cardiovascular and Interventional Radiological Society of Europe Standards of Practice for percutaneous treatment of intervertebral disks ; treated disc levels in the Nucleolysis Group included L3–L4 (decrease  was stat< 0.001) . There w 0.347), . There w 0.347), .p < 0.005). All therapeutic sessions in the Nucleolysis Group were performed as outpatient procedures. Patients in the Surgery Group were hospitalized overnight and exited the hospital the morning after the discectomy. In the Nucleolysis Group, minor extradiscal leakages (Grade 1) were depicted in the CBCT scan performed immediately post injection in 5/19 patients; all fi cases of extradiscal leakages were without any clinical significance and none of the patients reported any symptoms. There were no allergic reactions to RGE or other drugs. Transient back or lower extremity  pain was noted in 3/20 patients of the Nucleolysis Group recovering spontaneously within minutes after treatment; these temporary symptoms were attributed most probably to the trocar’s route of approach being either close to a nerve root or during its passage from the annulus fibrosus of the target intervertebral disc. No complications were noted in the Surgery Group. There were no cases of local or systemic iatrogenic infection. During the follow-up period, there were no deaths related to the procedure.In the Nucleolysis Group, the mean procedure time from patient’s entry to exit of the angiography suite was 42.55 ± 2.34 min, whilst in the Surgery Group, the mean procedure time from patient’s entry to exit of the operating theater was 95.6 ± 3.35, . Both nucleolysis and tubular discectomy resulted in significant pain reduction from week 1, which was sustained throughout the 12-month follow-up period (p < 0.005). The rapid and significant effectiveness of both intervertebral disc nucleolysis and tubular discectomy was consistent with clinical outcome improvement, as reported in numerous systematic reviews and clinical studies [The present retrospective comparative study added to the growing number of case series and comparative reports showing that percutaneous decompressive approaches for the management of primary single-level intervertebral disc herniation with refractory radicular leg pain meet non-inferiority criteria and constitute comparable treatments to surgical approaches ,23,24,25 studies ,23,24. SIntradiscal injection of RGE during percutaneous nucleolysis seemed to work in two ways: the gelling effect engaged the herniation breach, thus preventing a greater discal excursion under axial loading, whilst ethanol contributed to reduction in local inflammatory mechanisms generated by the herniation itself . The funAlthough not shown in the current study , another advantage for the patients is the lower complication rate of percutaneous approaches when compared to the 7.6% of surgical approaches . No clinLocal anesthesia was performed only at the skin surface, aiming to avoid any potential interference of anesthetic application at the nerve level. To perform a valid assessment of therapeutic effectiveness, the current study focused upon proper selection of patients with the best chance for a successful procedure; this is also essential not only for decision-making in everyday clinical practice. Since magnetic resonance imaging is considered as the gold standard for the diagnosis of intervertebral disc herniation, all patients included in the current study were evaluated for rigorous quantitative MRI criteria that were used to select candidates eligible for the study ,31. ThesThere were several limitations of the present study apart from its retrospective character and the short follow-up that should be considered, and which could introduce selection and results’ biases; the small sample size along with the mixed levels of the treated disc hernias rendered difficult the evaluation of site-specific complications. No data regarding function improvement through specific scales were recorded; however, such questions were included and evaluated from the questionnaire used in the current study. This study did not provide a comparison with open surgery, nevertheless, our findings suggest that minimally invasive percutaneous or endoscopic approaches constitute a safe and effective technique for the management of intervertebral disc herniation. Discography was not performed to avoid the limited visualization of the RGE by the injected iodinated contrast medium and the immediate gelling effect that occurs when the product meets any fluid increasing the risk of trocar occlusion. Although technically two or three levels can be treated in the same session, only single-level intervertebral disc herniations were treated in the current study.The results of the current study showed that intradiscal injection of a gelified ethanol and tubular discectomy were equally effective in terms of efficacy and safety for the treatment of symptomatic lumbar intervertebral disc herniation regarding the 12-month mean leg pain improvement. Both treatment arms achieved similar rapid significant clinical improvement, which persisted throughout the follow-up period.


Breakthrough cancer pain (BTcP) is a complex and variegate phenomenon that may change its presentation during the course of patients’ disease in the same individual. An appropriate assessment is fundamental for depicting the pattern of BTcP. This information is determinant for a personalized management of BTcP. The use of opioids as needed is recommended for the management of BTcP. There are several options which should be chosen according to the individual pattern of BTcP. In general, a drug with a short onset and offset should be preferred. Although oral opioids may still have specific indications, fentanyl products have been found to be more rapid and effective. The most controversial point regards the opioid dose to be used. The presence of opioid tolerance suggests to use a dose proportional to the dose used for background analgesia. In contrast, regulatory studies have suggested to use the minimal available dose to be titrated until the effective dose. Further large studies should definitely settle this never ended question. Breakthrough cancer pain is a complex and variegate phenomenon.An appropriate assessment is fundamental for defining the characteristics.Opioids still remain the pharmacological option for treating breakthrough pain.Management is based on the individual characteristics of breakthrough pain.The choice of opioid doses should be based on the level of tolerance. In the last 30 years, physicians have paid more and more attention to the phenomenon of breakthrough cancer pain (BTcP) . CliniciIn the 1990s, the definition of BTcP focused on some characteristics to better characterize this phenomenon, providing more insights on this phenomenon –9. The rStudies published in the last 10 years confirmed that BTcP is a variegate phenomenon, with different presentations that may change during the course of patients’ disease , 12. In This narrative review will explore some aspects regarding the assessment and the management of BTcP to give an updated overview of this phenomenon.To depict the pattern of BTcP in individuals and to provide accordingly a specific treatment, an appropriate assessment is of paramount importance. Thus, a proper definition should be given a priori. BTcP has been defined as transitory increase in pain to greater than moderate intensity, which occurs on a baseline pain of moderate intensity or less. This definition resulted to be a little bit ambiguous in literature, as many studies included different patterns of patients, for example, receiving or not opioids, having or not controlled background pain, and experiencing severe or less severe episodes of BTcP. In literature, studies of BTcP often included patients with mild-moderate pain having BTcP episodes of moderate-severe pain, resulting in a gray area which included a relatively high background pain intensity and a low BTcP intensity –18. The First, to define BTcP, patients must be receiving a stable and effective analgesic regimen, providing well-controlled background pain for most hours of the day. Indeed, the peak of BTcP should be moderate-severe in intensity and should be clearly distinguishable from the background pain intensity. It has been reported that at least 3 points of differences on the numerical pain scale give the input to request a medication .Interestingly, patients receiving lower doses of opioids with an adequate background analgesia develop episodes of BTcP with a prevalence similar to that reported in general population of cancer patients. This group of patients was on an early stage of disease and had less aggressive pain syndromes and less interference with daily activity, probably due to a lower number of episodes with a lower intensity. It is likely that for this reason, this subgroup of patients was less frequently prescribed a BTcP medication. Of interest, patients showed a longer time to meaningful pain relief and were less satisfied with BTcP medications which were mainly oral morphine . This asSecondly, the temporal pattern should be taken into consideration. The onset of BTcP is relatively short, reaching a peak within 10 min in about 2/3 of cases. The offset is variable, 45 min on average, ranging from minutes to 1–2 h. Most of these episodes vanish spontaneously , 8. The Spontaneous or idiopathic BTcP lacks an recognizable cause or a precipitating event. These peaks of pain intensity are characterized by a gradual onset, prolonged duration, and slow offset. In the incident-type BTcP, pain is triggered by an identifiable factor that can be predictable or not. In contrast, this type of BTcP often has a rapid onset and short duration. The most common types of incident BTcP are movement-induced bone pain, frequently due to bone disease, and swallow-induced pain, due to oral mucositis [Third, BTcP may be spontaneous or incident, due to a precipitating event. ucositis , 8. In aucositis .Fourth, the number of episodes per day in another element is to be considered. The occurrence of 3–4 BTcP episodes per day is commonly considered acceptable when pain is controlled during the rest of the day , 6. In tFifth, pain mechanisms should be considered. For example, some forms of neuropathic pain may produce BTcP episodes with an onset and an offset of few seconds or minutes. In this case, no drug will have such temporal pattern. In this case, BTcP events should be prevented with the preemptive use of adjuvant drugs, rather than treating the single BTcP event .Sixth, some tumors may have some peculiarities. Patients with head and neck cancer report a higher number of episodes of BTcP, which were predictable, particularly with the ingestion of food, which was the main precipitating event. This may be explained by the prevalence of mucositis of severe intensity, inducing pain on swallowing . SimilarSeventh, BTcP is often a sentinel event of a pain that is not well controlled as previous analgesic treatment loses efficacy, meaning that BTcP is related to insufficient opioid therapy. The development of more frequent episodes of BTcP is a marker of poor analgesia. This distinction is fundamental, because the relative intervention is much different (see below).Finally, the characteristics of BTcP may change during the course of disease. Different studies have shown that advanced cancer patients having a lower Karnofsky level and followed by a palliative care team, and possibly severely ill, experience a lower number of BTcP episodes/day, with a slower onset, and less predictability than patients evaluated in a pain clinic or oncologic ward, possibly visited in an early phase of disease , 12, 25.The knowledge of the different types of BTcP may allow an individualized care planning and a global better outcome. Pain characteristics, optimization of background pain, disease status, and patient preference should be the basis for the treatment of BTcP, which is likely to change over time.Although different non-pharmacological methods have been proposed, the evidence for efficacy is very poor . The useVarying recommendations from different organizations have been published. Current guidelines agree on many aspects of the management of BTcP. However, the evidence regarding such guidelines remains low grade [. For example, the European Association for Palliative Care (EAPC) guidelines suggest oral opioids as the first-line treatment, with the use of ROOs recommended only for episodes with rapid onset and shorter duration of effect [. The National Institute for Clinical Excellence (NICE) guidelines suggested that morphine should be considered the first-choice drug for BTcP [. Indeed, the European Society for Medical Oncology (ESMO) recommends the use of ROOs as a first-line treatment [.ow grade . For exaf effect . The Natfor BTcP . Indeed,reatment .NICE recommendations were mainly based on an economic criterion rather than on effectiveness, reflecting concerns about the higher cost of fentanyl preparations. In contrast to the suggestion of prescribing oral morphine as first choice for treating breakthrough pain episodes, a recent double blind randomized study confirmed the inadequacy of oral morphine. Different doses of oral morphine were compared with placebo were ineffective for relieving BTcP, and some pain relief was observed only after about 2 h, just when any “typical” BTcP event spontaneously evanishes [Oral opioids have been used for years, possibly because there were no alternatives for a rapid analgesic effect, unless the injectable formulations are given parenterally. From a pharmacological point of view, there is a mismatch between the time course of a BTcP episode and the typical time-action relationship of oral opioids. Oral opioids have a slow onset of effect, ranging 30–45 min, providing a late initial analgesia when the majority of BTcP episodes are resolved spontaneously. In addition, the duration of effect is much longer than the typical BTcP temporal wave. It is likely that an eventual benefit reported after taking an oral opioid for BTcP is expectational, rather than pharmacological . On the vanishes . This tavanishes . This stvanishes .Various transmucosal fentanyl formulations provide a fast analgesic effect, within 5–10 min. All controlled studies of transmucosal fentanyl preparations demonstrated superiority over oral opioids and placebo, with a time-action relationship supporting a faster onset than oral opioids and yielded more favorable outcomes , 34.Transmucosal fentanyl provides fast analgesia as it rapidly pass the mucosa and then the blood–brain barrier due to its potency and lipophilicity. Transmucosal fentanyl preparations belong to n heterogeneous group of delivery systems. The availability ranges from 50%  to 90% . Fentanyl pectin nasal spray (FPNS), buccal fentanyl (FBT), and sublingual fentanyl (SLF) have an availability of 60–65%. Each formulation has its peculiarity and could be chosen according to the clinical condition of nasal and oral cavities, ease of use, and patient’s preference.These fentanyl formulations all have been tested in opioid-tolerant patients receiving at least daily doses of 60 mg or greater of oral morphine equivalents (OME). This approach was proposed to improve safety and prevent any risk of respiratory depression.On the other hand, some patients may receive doses of OME for background pain lower than 60 mg/day of OME. For these reasons, oral morphine was more frequently used, likely due to prescription requirements for patients with relatively low opioid exposure , resultiAnother controversial point regards the choice of the dose of fentanyl products to be prescribed for BTcP episodes. Early clinical trials of the transmucosal fentanyl formulations provided data for regulatory approval and safety issues. These studies used a paradigm of a dose-finding approach, suggesting to start with the lowest existing dose of the formulation and then to increase until the effective dose was reached. This statement, however, was passed off as evidence based, because the subsequent part of the study design, which is the comparison of the successful dose with oral opioids or placebo, was double blind and controlled according to the best evidence studies. However, the part of dose finding was open label, resulting in an enrichment study recruiting only patients responsive to dose-finding protocol, and excluding patients who did not respond or not achieved the effective dose. According to this data, no relationship between the effective transmucosal dose and the daily dose of the opioid taken for baseline pain was found in a secondary analysis. Thus, the approval of the formulations incorporated instructions was incorporated to approve the formulations and give instructions to start therapy at the lowest doses available for each product and then titrate to the effective dose .This approach, however, is pharmacologically contrary to the dose–effect proportionality typical of opioid drugs. Although dose titration increases early safety overall, it could result to be problematic for some patients, resulting in prolonged periods of unsuccessful treated events , 38. TheThere are other aspects deserving a deeper evaluation of early randomized trials regarding the finding of a lack of association between the fentanyl dose and the opioid dose used for background pain. In these studies, patient selection was not based on modern criteria of BTcP definition, as levels of background pain were unexpectedly high while BTcP intensity was not too high. This observation explains the amplification of the placebo effect , 38. EveThe proportional approach has been assessed in several studies, also including patients receiving high doses of opioids and older patients –46.In comparison studies, the use of FBT and FPNS in doses proportional to those used for background analgesia was substantially superior over oral morphine during the first 30 min of administration , 45.In the real world, the prescription of opioid dose used for BTcP was based on the proportionality , 48. A sThus, patients with distressing BTcP episodes, who are highly tolerant to opioids and do not have serious comorbidities or frailty, should be given a dose roughly proportionate to the dose used for background pain. A possible compromise between the two different methods should be skipping some steps of dose titration for patients receiving high doses of opioids for background analgesia.Indeed, when taking into consideration the dose-finding and proportional methods, there is a need of a greater flexibility when prescribing opioid for BTcP. Low doses of transmucosal fentanyl could not be optimal in an opioid-tolerant patient receiving high opioid doses for their background analgesia. As these patients are highly opioid tolerant, the titration process would be time-consuming and frustrating. comparing the different available substances in different conditions and providing more solid data regarding dosing.BTcP is a variegate phenomenon which requires a careful assessment for the different clinical presentations, which are variable in individuals and often changing in the same individual. The clinical pattern will help in finding the most appropriate management. A personalized approach is of paramount importance when prescribing a medication for BTcP, and careful attention should be given to drug choice, doses, and route of administration, considering both pain- and patient-related factors. Further studies should investigate on alternative treatments,


Persistent hypotension is a rare complication of celiac plexus neurolysis. It is important to know what are the main and rare complications and how to treat these in patients who undergo CPN.Celiac plexus neurolysis is an effective treatment for visceral abdominal pain in oncological patients. Although it rarely has complications, some side effects may occur. A patient with visceral abdominal pain who developed long‐lasting orthostatic hypotension and was treated with the use of corticosteroids after a neurolytic celiac plexus block for intractable pain. We describe a rare complication and its treatment and we emphasize the importance of having a guide for the management and treatment of rare complications. We also suggest that every patient be informed about complications, from the most common to the rarest.  Pain can be controlled with conventional analgesics, such as acetaminophen, nonsteroidal anti‐inflammatory drugs, and opioids, in majority of oncological patients. However, some patients may experience refractory pain or report adverse effects that prevent their further use. In these patients, interventional pain procedures may be indicated. The commonly indicated procedures are morphine intrathecal delivery, midline myelotomy, and celiac plexus neurolysis (CPN). Intrathecal drug delivery systems are expensive and pose a risk of infection. Patients who undergo midline myelotomy may suffer from bowel and bladder dysfunction and loss of proprioception and vibratory sensation. Neurolysis, however, is a very effective and minimally invasive procedure and is commonly chosen as the initial therapy for the treatment of visceral abdominal pain in cancer patients.Celiac plexus innervates the liver, pancreas, diaphragm, spleen, stomach, small bowel, ascending and proximal transverse colon, adrenal glands, kidneys, aorta, and mesentery; hence, CPN can be performed to treat upper abdominal pain. Surgical techniques for celiac plexus blockade and neurolysis using both the anterior and posterior approaches to the plexus have been published in the literature. CPN is performed by injecting ethanol into or by radiofrequency ablation of the celiac plexus, leading to permanent disruption of pain transmission.Although CPN is a low‐risk procedure, some adverse effects have been documented. Most of the effects are transient, and serious complications occur only in less than 2% of cases. The most common adverse effects are diarrhea, hypotension, constipation, nausea and vomiting, pain, and neurological adverse events. Some symptoms are less common after CPN, such as persistent hypotension.We describe the case of a patient with intractable, visceral abdominal pain who developed long‐lasting postural hypotension after a neurolytic celiac plexus block. This article aims to review the main complications involved in the surgical technique of CPN and discuss the treatment of each of these complications.2A 41‐year‐old woman diagnosed with breast cancer received neoadjuvant chemotherapy (doxorubicin + cyclophosphamide + paclitaxel) and underwent right breast radical mastectomy. Despite the treatment, the patient developed brain metastases, which were treated by radiosurgery, and lymph‐node metastases . Subsequently, the patient developed deep, constant upper abdominal pain. The pain was not adequately relieved even with the prescription of dyprione, pregabalin, and opioids such as morphine, methadone, and oxycodone. The oncology team decided to perform CPN for the treatment of her refractory abdominal pain.CPN was performed under general anesthesia by injecting 60 mL of absolute alcohol into the celiac plexus ganglia, guided by fluoroscopy Figure . There w3Persistent hypotension is a rare complication of celiac plexus neurolysis. In this case, the hypotension was refractory to intravenous hydration and a sodium‐rich diet and improved only with the use of corticosteroids. Although the occurrence of transient post‐procedural hypotension has been well documented in the literature, chronic postural hypotension after CPN remains a rare and poorly documented entity.Yousefshahi and Tahmasebi (2018)The reported patient also experienced an initial worsening of the abdominal pain. This event is not uncommon after CPN and usually resolves spontaneously.Neurological complications such as paraplegia, paraparesis, sensory deficits, and paresthesia are rare symptoms that occur in only 1% of cases. The probable causes of neurological deficits are direct irritation of the lumbar nerve roots by alcohol and spasms of radicular lumbar arteries, the anterior spinal artery, or the artery of Adamkiewicz. Permanent paraplegia has been reported in only 0.15% of cases, and the attributed cause was ischemia of the spinal cord secondary to damage or spasm of the artery of Adamkiewicz.Physiotherapy plays an important role in the treatment of patients with paralytic episodes during the procedure and in those with postoperative paraplegia or paresthesia. As the vast majority of cases occur due to lumbar root irritation or temporary arterial spasm, physiotherapy can help restore lower limb function.Vascular complications are rare after CPN. Anterior transaortic CPN is performed in some hospitals but should be avoided in patients with mural calcification or aortic aneurysms. Kaplan et al.Another rare complication of CPN is alcohol intoxication. The intravenous hydration and elevation of the lower limbs apparent to be an effective treatment for acute alcohol intoxication. Many authors had described patients with signs of alcohol intoxication and who developed acetaldehyde syndrome‐like reactions. All patients recovered within a few days with no lasting effects.Although post‐procedural diarrhea is quite common, severe and prolonged diarrhea rarely occurs. Persistent diarrhea can be life‐threatening if it is not recognized early and treated. Diarrhea can be treated using somatostatin analogs, such as ocreotide. Ocreotide is effective in controlling diarrhea, with its dosage titrated to effect (0.05–0.2 mg daily over a period of 1 week). The cessation of ocreotide therapy may cause the symptoms to reappear.4The main limitation of this study is that it is a single case study. However, it was important to draw attention to this rare complication that may occur after CPN and discuss the most appropriate treatment modalities. This paper was also designed to serve as a guide in the management of complications in patients who undergo CPN. We recommend that every patient undergoing a procedure should be informed about all its complications, and we recommend that all authors report complications so that we can know the actual number of complications related to the procedure.Rhuann Pontes dos Santos Silva: Conceptualization; data curation; software; writing – original draft; writing – review and editing. Arthur José Maia Lopes: Data curation; formal analysis; writing – review and editing. Roberto Borges Bezerra: Formal analysis; funding acquisition; investigation. Rafael Albanez Andrade: Investigation; methodology; project administration; validation. Rebeca Gonelli Andrade: Formal analysis; investigation; software; visualization; writing – original draft; writing – review and editing. Larissa Monteiro Ferreira da Costa: Investigation; methodology; project administration; visualization; writing – original draft. Carolina Albanez de Albuquerque da Cunha Andrade: Methodology; software; supervision; writing – original draft; writing – review and editing.Not applicable.Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.


Outside the United States, bromelain-based enzymatic debridement (BBED) has become an effective tool for removal of burn eschar. BBED can be performed at bedside and allows for complete eschar removal with maximal dermal preservation and markedly reduced blood loss. It may also decrease the need for autografting or the amount of autograft required. A primary concern with BBED is that it is a painful procedure requiring appropriate analgesia. Experience with BBED in the U.S. has been gained through a multicenter phase 3 clinical trial (DETECT) and an expanded access treatment protocol (NEXT). In this retrospective study, we describe our experience using BBED, with particular focus on pain management.A retrospective review was conducted on 29 adult burn patients enrolled in the DETECT or NEXT trials who underwent BBED of acute deep partial- and full-thickness thermal burn wounds at a major burn center between November 2016 and July 2022. Patient demographics and procedural characteristics, including pain management strategies and Numerical Pain Rating Scale (NPRS) scores before, during, and after debridement, were analyzed and described.Twenty-nine patients with an average age of 41.2 years  and an average TBSA of 6.3%  underwent a total of 29 BBED. For pain control during debridement, 6 patients required conscious sedation (CS), 7 a regional block (RB), 5 a local block (LB), and 9 only IV and oral (IVPO) medications. Two patients were intubated and sedated prior to the procedure. No patient required additional BBED treatment and all patients achieved >95% eschar removal. The average NPRS pain score 24 hours before treatment, during treatment, and 24 hours after treatment was 4.0, 4.6, & 4.4, respectively (P=0.65). Sixteen patients (55%) healed without the need for autografting. The average number of days from debridement to wound closure for all patients was 34.9 days (SD=11.9) and for patients who underwent autografting was 40.1 days (SD=12.3).With appropriate analgesia, it is possible to perform BBED of acute deep partial- and full-thickness thermal burns without significant changes in patient-reported pain scores. Prior to debridement, it is critical to establish procedure logistics and reasonable patient expectations.The authors review their experience controlling pain associated with BBED.


Intrathyroidal injection using an insulin pen filled with a mixture of lidocaine and triamcinolone acetonide is a therapy for subacute thyroiditis (SAT) reported by us previously. We aimed to evaluate the clinical efficacy of ultrasound-guided intrathyroidal injection in the treatment of SAT.A total of 93 patients with SAT completed the study. All patients were evaluated via a history and clinical examination followed by thyroid function tests and ultrasonography of the thyroid. After ultrasound-guided intrathyroidal injection, the patients were followed up with respect to the injection frequency, treatment duration, and patient satisfaction. The visual numerical rating scale was used as a pain questionnaire for a given interval.Thyroid pain instantly decreased to scores below 3.0 following the first injection. Sixty-three patients (67.74%) avoided relapse of thyroid pain within 3 injections, which occurred within only 3 days after the first injection. The pain in 27 patients (29.03%) disappeared completely after 4-6 injections. Only 3 patients (3.23%) were found to need more than 6 injections, with 10 cited as the maximum number of injections, the injection took only 17 days altogether. The mean treatment cycle of the intrathyroidal injection was 3.98 days. There were no other associated complications with the novel therapy except infrequent small subcutaneous hematomas, which could be prevented with skilled practice. The average patient satisfaction score was as high as 9.0.Intrathyroidal injection of lidocaine and triamcinolone acetonide using an insulin pen was found to be an advantageous and satisfactory treatment for SAT. Subacute thyroiditis (SAT), a transient and self-limiting inflammatory thyroid disease, has gradually increased, and its etiology remains unclear. According to statistical analysis, the incidence of SAT is 4.9/100,000 persons, accounting for 5% of all thyroid diseases ,3. The dThe initial use of nonsteroidal anti-inflammatory drugs (NSAIDs) was recommend, particularly for mild SAT cases. Oral glucocorticoids (GCs) are suggested when patients fail to respond to treatment or initially present with moderate to severe pain and/or thyrotoxic symptoms ,8. SymptIn our previous report, a total of 18 patients who underwent intrathyroidal injection reported rapid pain relief and significant neck relaxation within 1 week compared with the oral prednisone group . The freA total of 126 Chinese patients with newly diagnosed painful SAT  who underwent treatment at Huai'an Second People's Hospital from June 2014 to July 2019 were included in this study. The diagnosis of SAT was based on laboratory findings that revealed elevated ESR (>20 mm/hour) or at least C-reactive protein (>10 mg/L) and hypoechoic areas/areas with blurred margins and decreased vascularization on ultrasound.Meanwhile, at least one of the following criteria should be met: 1. Hard and swollen thyroid. 2. Pain and tenderness of the thyroid gland/lobe. 3. Elevated serum FT4 and suppressed TSH. 4. Decreased radioiodine uptake. 5. Typical FNAB result for SAT . All 126The study was approved by the ethics committee of Huai'an Second People's Hospital, and the code of approval is No. 20141209. Informed consent was obtained from all of the participants who were informed about the study, procedure, outcomes and complications. The exclusion criteria were as follows: pregnancy, severe heart disease, end-stage renal and liver diseases and a history of allergy to lidocaine and glucocorticoids.At study entry, all participants received a clinical evaluation for the collection of experimental data. The treatment adopted in this study was intrathyroid injection with an insulin pen under ultrasound guidance. Due to expansion and compression of the thyroid parenchyma swelling toward the skin, the distance from the skin to the thyroid capsule was shortened to 2-3 mm in the isthmus and 3-5 mm in the lateral lobes of SAT patients. Based on the distance from the skin to the thyroid capsule in SAT patients, the thyroid isthmus was injected with a 4-mm needle (32 G), and the lobe was injected with a 6-8 mm needle (32 or 30 G). The thyroid was scanned via ultrasound before the operation to understand the location, boundary, morphology, and internal echo of the pathological tissue in both lobes. The injection was administered in the pathological tissue of the lobe of the thyroid (low-echo region). The injection needle was perpendicular to the skin at the angle of 90°. Target the low echo area  for injection and pause for at least 5 seconds after pressing the injection button. After the injection, the injection sites needs to be pressed for about 10 seconds. If bleeding occurs, press a sterile cotton ball on the skin for about 30 seconds or longer.The insulin penfills were rinsed and recycled after the insulin was injected. The insulin refill that was used was removed , and approximately 3 mL of sterile normal saline was injected into it with a 5 mL syringe. Drain and inject the sterile normal saline repeatedly (five to ten times). To achieve the effect of repeated washing, the syringe needle would not be pulled out, except when replacing new sterile normal saline three times.The penfills were filled with 3.0 mL (300 units) solution that contained 2 mL lidocaine solution (drug concentration 5 mL: 0.1 g), 1 mL triamcinolone acetonide solution (drug concentration 5 mL:50 mg). The doses of lidocaine and triamcinolone were 40 mg and 10 mg, respectively. The painful lobe was injected with 20 to 80 Units , which was divided into five locations of the inflammatory site (low-echo region in the ultrasound): up, down, left and right, and the center. The initial dose of injected drugs depended on the size of the low echo region. It required 40 units of the injection drugs when the region of low echo area is 1 to 1.5 cm in diameter. It required 60 units of the injection drugs when the region of low echo area is 1.5 to 2 cm in diameter. It required 80 units of the injection drugs when the region of low echo area is more than 2 cm in diameter.A total of 3 injections were administered daily for the first three days and then every other day, wherein the injections were given for at least three days until the patients were satisfied with the level of pain relief. After symptom relief or disappearance for more than one day, ultrasound examination was performed. Therapy was discontinued as soon as the thyroid morphology returned to normal. If it recurred anytime during hospitalization, the treatment was continued. Thyroid function, routine blood count, and the ESR were reviewed to observe the safety and efficacy of the treatment. At the end of the first week, if the patients receiving injections continued to complain of significant pain in the thyroid region after five injections, oral ibuprofen was added to the regimen. At the beginning of the third week, if SAT persisted or recurred, prednisone or ibuprofen was administered orally.By verbally administered numerical rating scales (NRSs), patients verbally rated pain intensity as an integer from 0 to 10  and marked their pain intensity on a 10-cm horizontal visual analog scale (VAS) bounded by these descriptors . The thyVerbally administered numerical rating scales were also used to measure satisfaction with the therapy. Patients verbally graded satisfaction as an integer from 0 to 10  and marked their satisfaction on a 10-cm horizontal visual analog scale (VAS) bounded by these descriptors.The clinical features and laboratory measurements before and after treatment were recorded and compared, such as body temperature, swelling with pain , tenderness in the thyroid gland, neck pain, thyroid function, routine blood count, and ESR and CRP levels. The duration of the treatment, the injection times and the patient satisfaction were observed and analyzed.Evaluation of clinical efficacy: 1. Recovery: the body temperature returned to normal, the symptoms of neck pain disappeared (VAS < 3’), and the goiter returned to normal expected characteristics. ESR decreased to below 20 mm/h, and thyroid function returned to normal. 2. Effective: body temperature returned to normal, neck pain significantly improved, thyroid enlargement was smaller than before but not completely normal, ESR was close to normal (20-25 mm/h) when any of the above conditions were met, and thyroid function was improved. 3. Ineffective: fever, symptoms of neck pain were still evident (VAS > 4 points), ESR was still very fast, the goiter did not change, and thyroid function was higher than normal, in accordance with any of the above. 4. Worsening: fever, aggravated thyroid pain (VAS > 7 points), the sense of distension was not relieved, ESR was faster than before, and thyroid function was considered hyperactive.The following adverse reactions and complications were evaluated whether to occur: patients were observed whether to have pain and local congestion caused by percutaneous intrathyroid injection or whether to have symptoms of nerve injury, such as hoarseness, a choking cough when drinking water, abnormal breathing, tracheal perforation, or serious adverse events such as syncope, shock or loss of consciousness.After the therapy was discontinued, follow-up visits were performed every 1 month until half a year later. In addition, patients were reviewed immediately if they felt they might be suffering from disease relapse.9/L, neutrophils (1.80-6.30)×109/L, ESR 0-20.0 mm/h, and CRP 0-5.0 mg/L. In addition, the distance between the skin surface and the thyroid capsule for all the patients was obtained by thyroid ultrasound. The anti-TSH receptor antibody (TSHR-Ab) titer and I-131 uptake was measured to confirm the diagnosis. Laboratory tests, including the white blood cell count, the ESR, and other routine tests, were obtained by routine clinical assays in the hospital laboratory.Blood samples were drawn from the subjects by venipuncture into vacutainer tubes. The serum levels of TSH, FT3, FT4, and anti-thyroid antibodies were determined by electrochemiluminescence immunoassays . The reference ranges were as follows: TSH 0.34-5.44 mIU/mL, FT3 2.92-5.93 pmol/L, FT4 7.91-20.59 pmol/L, WBCs (4.0-10.0) × 10p value < 0.05 was considered statistically significant.Statistical analyses were conducted with the SPSS 18.0 software . The normally distributed measurement data are represented as the mean ± standard deviation. The skewed measurement data are expressed as the median (minimum - maximum). And count data are expressed as a percentage (%). The Student's paired t test was used to compare the mean values before and after treatment. A two-tailed 9/L, neutrophils was (5.02 ± 1.92) × 109/L and ESR was 68.88 ± 18.08 mm per hour at the time of presentation. FT3 (4.64 ± 1.09 pmol/L) and FT4 (13.82 ± 5.38 pmol/L) after the treatment were significantly lower than before the treatment (p < 0.01). TNF after the treatment was higher compared with before the treatment (p = 0.022). Compared with the value at the time of presentation, WBCs (6.59 ± 1.84) × 109/L, neutrophils (3.12 ± 1.68) × 109/L, ESR (14.04 ± 6.04 mL/hour) and CRP (4.10 ± 2.61 mg/L) were significantly lower after the treatment (p < 0.05 or p < 0.001).The clinical and biochemical characteristics of the SAT patients are presented in None of the patients reported worsening of symptoms after starting the treatment. Thyroid pain instantly decreased, with scores below 3.0 following the administration of an injection. Approximately 92 out of the 93 patients, i.e., more than 99%, showed “recovery” results (VAS < 3 points) with no pain within two weeks. One patient (1%) showed an “ineffective” result (VAS > 4 points) with neck pain within two weeks, with up to ten injections, which took only 17 days altogether when the patient achieved a “recovery” therapeutic effect (VAS < 3 points). As shown in The changes in the patients’ pain scale scores during treatment are shown in Adverse reactions from the intrathyroidal injections were mild, and none of the patients were removed from the study because of side effects. Most of the patients complained of mild pain and swelling at the injection site, and these sensations usually lasted only for a few minutes. No cases of severe bleeding, such as hematoma, infection at the injection site or anaphylactic reactions, were observed after the injection. There were no reports of impaired blood sugar levels in patients following triamcinolone injection.Surprisingly, there were no reports of relapse following the intrathyroidal injection of GCs using an insulin pen.In this study, we evaluated the efficacy and safety of ultrasound-guided intrathyroidal injection in the treatment of SAT. The simple injection could reduce local inflammation and easily improve symptoms via an insulin pen device. We devised a new way to ameliorate the symptoms, allow the disease to run its spontaneous course in an asymptomatic manner and avoid the systemic side effects of corticosteroids even using them. The results of this study indicate that our treatment is effective and safe.Over 95% of people with SAT often present with moderate-to-severe pain . Once paOral corticosteroids are important in the treatment of subacute thyroiditis. However, numerous adverse effects have been attributed to oral corticosteroids. Several retrospective reports have shown that long-term use of corticosteroids orally, even in low doses, is a significant independent predictor of adverse effects, such as increased appetite and weight, exacerbated insomnia, osteoporosis, and abnormal glucose regulation –17. The Fortunately, in our study, the patients immediately achieved neck pain relief through local injections. Compared with oral administration (systemic administration), local administration (percutaneous intrathyroid injection) has a direct effect on the gland, which can increase local drug concentrations rapidly, inhibit local inflammatory responses effectively, reduce the size of pathological tissues in the thyroid gland, and promote the recovery of the structure and function of thyroid follicles. Furthermore, compared with oral corticosteroid therapy, ultrasound-guided percutaneous corticosteroid injection for subacute thyroiditis is relatively safe and has less impact on patients’ body shape as well as glucose and lipid metabolism. The long-term recurrence rate during follow-up was significantly low.Locally administered corticosteroids are already used as a common therapy in many hand and wrist disorders, representing a low risk to patients . IntrathSurprisingly, different from previous study, we have some innovations and improvements. The insulin pen device relieves pain perception of injection because the device uses tiny needles and improves the accuracy of the injection . We haveThe injection drugs in the present study are fast-acting and effective. The mixture of lidocaine and triamcinolone was critical for this effect. Locally administered the mixture of corticosteroids and lidocaine are more effective than lidocaine or corticosteroids alone for pain control . These tIn our present study, the administration of lidocaine and triamcinolone via an insulin pen device has many advantages over conventional oral therapy or injection with conventional syringes. First, this method was as simple and easy to perform as an insulin pen injection, with the microneedle inserted into the edge of the pathological tissue stably and precisely under ultrasound guidance. The injection itself was almost painless and less likely to cause damage. However, the operation should be handled with care to avoid small hematomas. Complications can be avoided by improving the technique. Second, the accurate microdosing of lidocaine and triamcinolone by local injection had no obvious side effects compared to systemic administration. Third, the new technique shortened the duration of treatment and relieved pain immediately, rapidly and effectively in the appropriate clinical setting compared to conventional oral therapy.In conclusion, we provide an innovative approach to the treatment of SAT. Ultrasound-guided intrathyroidal injection of glucocorticoids and lidocaine with an insulin pen is an effective and safe therapy. Injection is an ideal method of administration with respect to its rapid delivery, short duration, microdosing capacity, lack of obvious side effects, painlessness, ease of operation, and safety in patients with SAT. In future, we should designed a controlled trial compared with oral therapy.


Pecto-intercostal fascial block (PIFB) provides analgesia for cardiac median sternotomy, but many patients complain of severe drainage pain that cannot be covered by PIFB. Rectus sheath block (RSB) has been attempted to solve this problem, but whether PIFB combined with RSB can achieve better analgesia is uncertain.This was a single-center randomized controlled trial at Peking University People’s Hospital from September 22, 2022 to December 21, 2022. Patients undergoing elective cardiac surgery with a median sternotomy were randomized at a 1:1 ratio to receive either bilateral PIFB and RSB (PIFB + RSB group) or PIFB (PIFB group). The primary outcome was intravenous opioid consumption within 24 h after surgery. Secondary outcomes included opioid consumption within 48 h, postoperative pain scores, time to extubation, and length of stay in the hospital. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α before and the first 24 h after surgery were measured.p = 0.010). Opioid consumption within 48 h after surgery was also reduced in the PIFB + RSB group . There was no significant difference in pain scores, time to extubation, length of stay in hospital, or the levels of IL-6, IL-10 and TNF-α between the two groups.A total of 54 patients were analyzed (27 in each group). Intravenous opioid consumption within 24 h after surgery was 2.33 ± 1.77 mg in the PIFB + RSB group vs 3.81 ± 2.24 mg in the PIFB group  on 19/07/2022.This trial is registered at the Chinese Clinical Trial Registry ( Acute postoperative pain is severe in cardiac patients undergoing sternotomy, and pain intensity is more severe than expected . Poorly We conducted a single-center randomized controlled trial to explore the hypothesis that PIFB combined with RSB, covering more surgical area, could reduce opioid consumption and achieve better analgesia after sternotomy.This trial was conducted at the Peking University People’s Hospital from September 22, 2022, to December 21, 2022. The study was approved by the Ethical Review Committee of Peking University People’s Hospital (#2022PHB179-001). Then, it was registered in the Chinese Clinical Trial Registry (ChiCTR2200062017) on 19/07/2022.Inclusion criteria included 1) elective cardiac surgery with a median sternotomy; 2) American Society of Anesthesiologists (ASA) II ~ III; and 3) adult patients (18 to 75 years of age). Exclusion criteria included 1) known allergy to ropivacaine; 2) platelet count < 100*10^9/L; 3) infection at the puncture site; 4) a history of opioid abuse; and 5) cognitive dysfunction and communication difficulties. Written informed consent was obtained from all participants.Eligible patients were randomized at a 1:1 ratio to be allocated to the PIFB + RSB group (20 ml 0.3% ropivacaine plus 2.5 mg dexamethasone on each side for PIFB and 15 ml 0.3% ropivacaine plus 2.5 mg dexamethasone on each side for RSB) and PIFB group  after induction of general anesthesia before incision. A randomization sequence was generated using a personal computer with a block size of 6 before recruitment by a biostatistician. Concealment was conducted using opaque, sealed envelopes. The envelopes were delivered to another researcher, and he prepared ropivacaine or normal saline. All nerve block procedures were performed by an appointed researcher, and he did not learn about what the fluid was. Anesthesiologists, patients and follow-up nurses were blinded to the group allocation. Statistical analysis was performed by another researcher who was blinded to allocation.Anesthesia was induced with 0.02–0.04 mg/kg midazolam, 0.2–0.4 mg/kg etomidate, 1–1.5 μg/kg sufentanil and 0.2–0.3 mg/kg cisatracurium. The bispectral index was maintained at 40–55 with propofol, sevoflurane, dexmedetomidine and cisatracurium. Bolus sufentanil (0.3–0.5 μg/kg) and vasoactive drugs were given by supervising anesthesiologists according to hemodynamic changes. After surgery, patients were transferred to the intensive care unit (ICU) for extubation and further medical care.Bilateral PIFB was conducted in the supine position under ultrasound guidance after anesthesia induction. A high-frequency linear ultrasound probe  was placed 2–3 cm lateral to the edge of the sternum at the fourth intercostal space to identify anatomic landmarks Fig. . A 21-gaBilateral RSB was conducted after the PIFB was performed with the same position and probe. The probe was placed 2–3 cm next to the xiphoid in the epigastric region Fig. . The neeAll patients received patient-controlled intravenous analgesia (PCIA) with a standard regimen of hydromorphone . Patients were educated on how to evaluate pain intensity and use PCIA properly by professional staff the day before surgery. Postoperative pain was assessed using a 10-point numeric rating scale (NRS) at rest and cough at 12, 24 and 48 h after surgery. An oral polypill consisting of oxycodone (5 mg) and acetaminophen (325 mg) was given as rescue analgesia for moderate to severe pain (pain score of 4 or greater at any time within 48 h). Intravenous tropisetron (5 mg) was used to treat postoperative nausea and vomiting (PONV).The primary outcome was intravenous opioid consumption at 24 h after surgery. Secondary outcomes included intravenous opioid consumption within 48 h, intraoperative opioid consumption, pain score at rest and upon coughing at 12, 24 and 48 h, moderate-to-severe pain, pain at the drainage within 48 h, creatine kinase-MB and cardiac troponin I at 24 h, time to extubation, time to drainage removal, time to catheter removal, ability to ambulate after surgery, length of stay (LOS) in the ICU and hospital, mortality within 30 days and incidence of chronic pain at three months after surgery. Opioid-related adverse events included PONV, urinary retention, dizziness and pruritus within 48 h. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α were measured before the induction of anesthesia and 0 and 24 h after surgery. Opioid consumption within 48 h after surgery only included hydromorphone in the PCIA. Whole blood was immediately centrifuged at 3000 rpm for 10 min to separate the plasma. Then, it was frozen at -80 °C for subsequent analysis.n = 7 in each group); 2) α at 0.05 and β at 0.20; and 3) dropout rate of 10%. The calculation yielded 60 subjects (30 in each group). Continuous variables other than pain score were analyzed using Student’s t test. The pain score was analyzed using analysis of variance for repeated measures with Geisser-Greenhouse correction and Sidak’s test for comparisons at each time point. Categorical variables were analyzed using Fisher’s exact test. Statistical significance was defined as p < 0.05 (2-sided). All statistical analyses were performed using GraphPad Prism version 9.0.Sample size estimation was based on our pilot trial: 1) opioid consumption at 24 h after surgery was 2.1 ± 1.4 mg in the PIFB + RSB group and 3.4 ± 1.9 mg in the PIFB group  were randomized, and 54 were analyzed (27 in each group). Six patients  were excluded because of late extubation, as they did not use opioids within 48 h after surgery . Intravenous opioid consumption at 48 h after surgery was 4.71 ± 2.71 mg in the PIFB + RSB group vs 7.25 ± 3.76 mg in the PIFB group (p = 0.006). The pain score did not differ between the two groups at rest  or cough  at 12, 24 and 48 h . There was no difference in adverse events with opioids . The incidence of pain at the chest tube within 48 h was 14.8% in the PIFB + RSB group and 29.6% in the PIFB group (p = 0.190). The incidence of chronic pain at three months was 18.5% and 25.9% in the PIFB + RSB group and PIFB group, respectively (p = 0.513). . Opioid consumption within 48 h was also significantly decreased . The application of RSB reduced opioid consumption by nearly 35%. From the view of opioid consumption, we can conclude that combined PIFB with RSB could provide better analgesia, although pain scores were similar  at 12, 24, 48 h between the two groups. As all participants were educated by professional staff on how to use analgesic devices according to their own pain intensity and demands. There was no significant difference in the incidence of pain at the chest tube within 48 h , only a higher trend in the PIFB group. There was no difference in the adverse events with opioids, perhaps hydromorphone is a kind of improved opioid subtype with fewer adverse events.Intravenous opioid consumption within 24 h after surgery was significantly decreased in the PIFB + RSB group (2.33 ± 1.77 mg vs 3.81 ± 2.24 mg, Cardiac surgery is commonly performed via median sternotomy, which causes catastrophic pain, particularly sternal splitting. Full heparinization and hemodynamic instability make the use of epidural analgesia or paravertebral block controversial. Transverse thoracic muscle plane block and PIFB, aiming at the anterior chest wall innervated by branches of intercostal nerves, can achieve the same analgesia for sternotomy in cardiac surgery , but PIFThe duration of a single shot for regional anesthesia is limited, even for long-acting local anesthetics. Surprisingly, a single shot of PIFB combined with RSB in our trial decreased opioid consumption until 48 h after surgery. The long duration of combined regional techniques can be explained as follows. The addition of dexamethasone, as a safe and effective adjunct, can further prolong the duration of long-acting local anesthetics . Its eff1-T10, has been attempted with good analgesia in cardiac surgery. [There was no difference in time to drainage removal, ability to ambulate, or LOS in the ICU and hospital between the two groups. Although opioid consumption was decreased in our trial, the effect on early recovery was mild. Actually, the process of recovery is related to a series of programs, including adequate postoperative analgesia, surgeon-based preferences, and protocols for system perioperative care . The impsurgery.  More resSawing the sternum and cardiopulmonary bypass in cardiac surgery made patients experience severe systemic inflammation associated with poor outcomes. IL-6, IL-10 and TNF-α are important cytokines that are related to surgical trauma and the degree of tissue damage, and the levels of these cytokines reflect the systemic inflammatory response to some extent –21. In oChest tube-related pain has been recognized gradually, and this pain is described as piercing and occurring upon breathing and coughing. In addition, the pain related to chest tubes is severe and persistent, and many protocols have been administered to address this problem. Injection of bupivacaine into the pleural and mediastinal drains has been concluded to relieve pain after cardiac surgery . IntraplThere are some limitations in this trial. First, PIFB and RSB were conducted after anesthesia induction to maximize patient comfort, so we cannot check the spread range of regional blocks according to the patients’ sense. Successful nerve block was uncertain merely from total intraoperative opioid consumption and hemodynamics. However, all regional blocks were guided under ultrasound, and the spread of the drug was definitely observed. Second, our sample size was based on the primary outcome, and it was small to detect the differences in postoperative early outcomes. However, we conducted a randomized controlled trial to explore the efficacy of PIFB combined with RSB. Combined regional techniques could provide adequate analgesia for median sternotomy in cardiac surgery.PIFB combined with RSB decreased intravenous opioid consumption and provided better analgesia after cardiac surgery.


Fentanyl transdermal therapy is a suitable treatment for moderate-to-severe cancer-related pain. The inter-individual variability of the patients leads to different therapy responses. This study aims to determine the effect of physiological features on the achieved pain relief. Therefore, a set of virtual patients was developed by using Markov chain Monte Carlo (MCMC) based on actual patient data. The members of this virtual population differ by age, weight, gender, and height. Tailored digital twins were developed using these correlated, individualized parameters to propose a personalized therapy for each patient. It was shown that patients of different ages, weights, and gender have significantly different fentanyl blood uptake, plasma fentanyl concentration, pain relief, and ventilation rate. In the digital twins, we included the virtual patients’ response to the treatment, namely, pain relief. Therefore, the digital twin was able to adjust the therapy in silico to have more efficient pain relief. By implementing digital-twin-assisted therapy, the average pain intensity decreased by 16% compared to conventional therapy. The median time without pain increased by 23 h over 72 h. Therefore, the digital twin can be successfully used in individual control of transdermal therapy to reach higher pain relief and maintain steady pain relief.(Created with BioRender.com) Fentanyl is a strong synthetic opioid that is 50 to 100 times more potent than morphine and 30 to 50 times more potent than heroin . FentanyBy implementing the experimental and clinical data, and involving physics, physics-based modeling of the drug uptake can predict the patient’s plasma concentration and clinical response to different therapies. Via this approach, we are able to examine different approaches to modify them based on the patient’s needs in a shorter time without putting the patient in danger or discomfort. The aim of applying in silico study is providing additional and key information that is not possible or too complicated to gain by in vivo and in vitro studies. Numerous studies were conducted in order to develop a mathematical or computational model to predict the outcome of therapies for the patient –13. ThesIn this study, a virtual population containing 3000 virtual cancer patients was generated based on sample data. This sample data was obtained from the available data in the literature , which i® fentanyl patches. The Duragesic® fentanyl patches provide a different flux of fentanyl to the body based on their surface area. The surface area of these patches varies between 5.25 and 42 cm2. In this model, the chosen section of skin and the patch have a square shape. We considered the skin block has the same length and width as the transdermal patch. We assumed that there was perfect contact between the patch and the skin. The implemented geometry in this study is shown in Fig. The drug uptake model simulates the drug diffusion in the transdermal patch and skin layers . The thickness of the skin layer was modified for each patient, as this was dependent on patient physiology, such as gender, weight, and age. The geometric dimensions for the patch were based on Duragesic2/s] of fentanyl in domain The drug penetration from the patch through the skin was modeled by transient diffusion which is described by Fick’s second law Eq. .1\documeentclass1pt{minimad in Eq. , it was Fentanyl penetrates through the epidermis and reaches the dermis. In the dermis layer, the drug will be taken up by capillary vessels at different lengths of the dermis. Besides diffusion, other physical mechanisms, such as advection, will play a role. In this study, we only modeled the diffusion process. Additionally, the capillaries will absorb the fentanyl in the upper part of the dermis, and all of the drug or part of it will be absorbed before reaching its bottom. To obtain the same drug uptake through the skin as the clinical studies, we used an equivalent dermis thickness, which is smaller than the real dermis thickness. The details of this assumption and modification and validation of drug uptake model are mentioned in our previous studies , 28, 29.At the top boundaries Fig. , b1 and In this study, a physiologically based pharmacokinetic model was used to predict the concentration of fentanyl in the blood plasma. Due to the complexity of the human body, different organs were lumped together into PK compartments . We consThe parameters of these equations are mentioned in Table alidated .There is a delay between the concentration of fentanyl in the blood plasma and the corresponding clinical effects on pain relief and breathing rate . To accoAs fentanyl is a small lipid-soluble drug, it will rapidly penetrate through the blood–brain barrier from the blood circulation system and bind to opioid receptors in the central nervous system . Throughtal data .Ten women and ten men with age 40 to 68 with different tumor sites were studied by Zech et al. . All theN = 20) as a likelihood function. The prior distribution for age, weight, and height is considered normal, and gender is considered a uniform distribution. By using the Gibbs sampling method, the posterior distribution  was evaluated. The demographic characterization of virtual patients of the generated population (N = 3000) was obtained from this joint distribution. In Fig. In this study, we developed a virtual population of patients from sample data to examine the performance of digital twins for patients with a wider range of physiological features. Members of this population differ from each other based on their age, gender, weight, and height. In reality, these physiological features of patients are correlated, as shown in Fig. The patient’s physiology changes the skin properties, volume of the organs, blood flow, glomerular filtration rate, metabolization, and opioid tolerance of the patient. By using the patient’s individual physiological features, we can predict the input parameters for the model. It should be noted that despite these equations being obtained from experimental data, as a result of inter-individual variability, different values for these parameters correspond to patients with the same age, gender, weight, and height. To account for this inter-individual variability, the calculated value was modified by the exponential of a normal random number with mean = 0 and SD = 0.1. By including this random factor, 95% of the evaluated parameters are in the range of entclass1pt{minimaBased on Table The grid sensitivity analysis by using Richardson extrapolation was done over the skin layers and fentanyl patch based on the flux out of the dermis, in which spatial discretization error was considered 0.1%. As a result of this grid sensitivity analysis, about 900 quadrilateral grids were built. However, this number varies from case to case as the thickness of the skin’s layer differs between cases. In some cases, almost 100 quadrilateral grids were sufficient. In order to increase the numerical accuracy, the accumulation of grids near the interfaces is more. To define the time steps, sensitivity analysis based on maximum fentanyl concentration was done, which defined a maximum time step of 6 h; however, to reach a higher temporal resolution, time steps were assigned as 1 h.COMSOL Multiphysics version 5.4 was used in this study to solve the diffusion process of fentanyl from the patch through the skin in the mechanistic model, the distribution of fentanyl in the human body in the pharmacokinetics model, and the drug’s effect in the pharmacodynamics model. The MUMPS  was chosen as the solver scheme in this set of simulations. The partial differential equation (PDE) interface was implemented to solve the diffusion process of fentanyl in the mechanistic model. To take to account the distribution, elimination, and metabolization of fentanyl, the boundary ordinary differential equation (ODE) was used. In the pharmacodynamics model, the concentration of fentanyl in the effect compartment was calculated by the PDE interface, and the boundary probe calculated the drug’s effect. To apply the change of the patch and skin location during the therapy, the event interface was used. The population generation was done in RStudio by using the “mixAK” package. Analyzing the sample data, calculating the posterior distribution, generating the virtual patients’ characteristics, calculating the model parameters, and analyzing the result of digital twins are done in RStudio.The tailored physics-based digital twin predicts the outcome of fentanyl transdermal therapy for the patient at any moment of the treatment. Based on the summary of product characteristics (SmPC), which we will call “® fentanyl patch with a nominal flux of 75 µg h−1 over 72 h based on the SmPC. The outcome of therapy was evaluated based on three output parameters: fentanyl concentration in plasma, pain intensity, and ventilation rate. This result is shown in Fig. The conventional therapy was applied to all virtual patients over 3 days. Three thousand virtual patients implemented a DuragesicAs mentioned in "−1 [−1 [The concentration of fentanyl in plasma for all the virtual patients during conventional therapy versus time is shown in Fig. −1  is an av−1 [−1 . This thBesides reducing the overall pain intensity, the aim of digital-twin-assisted therapy is to keep the pain below the target. In this study, we defined a parameter for the duration that the patient experiences pain lower than VAS pain score 3, called the time without pain. By implementing digital-twin-assisted therapy, the median time without pain for the population increases by 23 h compared to conventional therapy, which is shown in Fig. Through digital-twin-assisted therapy, each patient will use an individualized number of patches for 72 h based on their pain intensity experience. Figure p value = 0.45). However, for weight distribution, there is a shift in the mean of the distribution (by + 6 kg), and with a p value of 2.2 * 10−5, these two distributions are different. For height distribution, the mean of the distribution is shifted by 3 cm, and the two distributions are significantly different . The ratio of females to males in the population is 1.02; however, in the subgroup, this ratio is 0.29. Based on this result, patients of the male gender and with higher body mass need to change the fentanyl patch more frequently to reach the target pain relief.In the next step, we analyzed the patients that needed to change the patch more frequently. We separated the part of the population that they need more than one patch per day. We compare the patient physiology distribution between the population and this subgroup in a density graph. The result in Fig. In order to reduce the error in the calculation and prediction of the digital twin, the model parameters should be calculated based on the outcome of fentanyl therapy on the patient, such as fentanyl concentration in plasma and pain intensity.Liver enzyme activity and kidney filtration rate greatly impact the plasma concentration level as they determine the elimination and metabolism rate of fentanyl . These pIn this study, only pain intensity was considered the main factor in modifying the therapy. However, in order to reach a safer therapy, it is important to consider adverse effects such as hypoventilation in decision-making.Besides respiratory depression, fentanyl transdermal therapy can cause other side effects such as nausea, skin dryness, muscle spasms, confusion, and anxiety . Taking This study analyzed the patient characteristics that affect fentanyl transdermal therapy. These characteristics were age, weight, gender, and height. Based on patient physiological features and published experimental studies, model parameters for drug uptake, pharmacokinetics, and pharmacodynamics model were calculated. In the next step, the tailored digital twin for each patient proposed a modification of the therapy based on the pain intensity. Digital-twin-assisted therapy successfully reduced the pain intensity and the variation in therapy outcomes for virtual patients. However, there are approaches to increase the compatibility to the real-world and higher efficiency and safety in the therapy. These approaches are mentioned below:−1. Additionally, the minimum VAS pain score varied in the range of 0–5, and the minimum minute ventilation rate was in the range of 2.5–10 L min−1 for the virtual patients. This result shows that the outcome of therapy has a high variation between patients as some patients receive excessive amounts of fentanyl, while some of the virtual patients could not reach the target pain relief.In this study, we tailored a physics-based digital twin of transdermal fentanyl therapy for 3000 virtual patients. By implementing a set of sample data and Markov chain Monte Carlo (MCMC), these virtual patients that were different from each other based on age, gender, weight, and height were developed. The model parameters for each patient were calculated based on these physiological features and applied inter-individual variability. Conventional SmPC-based therapy of fentanyl transdermal patch, which is implementing fentanyl patch and replacing it every 72 h, was studied. Based on the outcome of conventional therapy, the maximum fentanyl concentration varied in the range of 1.3–3.2 ng mlIn order to reach the target pain relief for each patient, we designed a new therapy by digital twin. In this digital-twin-assisted therapy, the patient’s pain intensity will be checked every 8 h, and if it is higher than the target, the patient implements a new patch of the same size. As a result of modifying the treatment based on the patient feedback, the average pain intensity decreased by 16%, and the standard deviation among the population decreased by 54%. Based on the result, the digital twin successfully kept the pain intensity for 98.8% of the patients below 3 for more than half of the treatment duration. However, this number is only 57.1% for conventional therapy. Digital-twin-assisted therapy increased the median time without pain (VAS pain score under 3) by 23 h in 3 days and reduced its interquartile range (IQR) by 70%. Based on this result, digital-twin-assisted therapy reduces the overall pain intensity for the whole virtual population and reduces the variation of the outcome of therapy between the patients. Therefore, the tailored digital twin can predict the patient’s needs and conditions, propose a therapy, monitor the endpoint of therapy, and update when the patient needs it. In this way, all patients suitable for fentanyl transdermal therapy can receive suitable pain relief.


There was no change in needling pain scores in patients with an increased number of acupuncture sessions (p = 0.776). Patients experience minimal needling pain during acupuncture needling and are highly satisfied with acupuncture. Those with more treatment sessions report feeling increased satisfaction and relaxation.Previous studies have shown the benefit and safety of pediatric acupuncture, but it is often rejected by patients and their caregivers due to the perception of needling pain associated with acupuncture. A retrospective cohort study of 230 unique patients (1380 sessions) aged 8 to 21 underwent Kiiko Matsumoto Style acupuncture in an outpatient pain clinic. Patients completed a post-acupuncture survey, including the Faces Pain Scale-Revised and Likert-like scales about overall satisfaction, relaxation, and anxiolysis. Univariate analyses were conducted on all outcomes of interest. The mean needling pain score was 1.3 out of 10 with 57.7% of patients reporting no needling pain during their first acupuncture session. The mean score for overall satisfaction was 8.4 out of 10, relaxation was 8.2 out of 10, and anxiety reduction was 7.7 out of 10. The overall satisfaction, relaxation, and anxiolytic effect of acupuncture was increased in patients with more sessions ( Integrative approaches to pediatric pain management have been gaining attention and popularity, as they have the potential to help children manage symptoms  associated with chronic pain, as well as decrease the usage of addictive opioid medications . While aDespite evidence on the safety and efficacy of pediatric acupuncture for different pain pathologies, acupuncture is often rejected by pediatric patients and their caregivers due to the perception of needling pain associated with acupuncture . SimilarThe purpose of this study is to explore pediatric patients’ self-reported experiences with acupuncture with a primary focus on needling pain, anxiolysis, acupuncture satisfaction, and relaxation. A secondary aim of this study is to investigate whether the number of acupuncture sessions is related to any changes in patient-reported needling pain, anxiolysis, satisfaction, and relaxation. A large sample of outpatients were enrolled from a pain medicine clinic with varying pain conditions, severity, and symptomology. It was hypothesized that acupuncture would be a minimally painful, anxiety-reducing, satisfying, and relaxing experience. It was also hypothesized that the experience would be more favorable in patients who attended more acupuncture sessions. The main clinical implication of the current study is to demonstrate that acupuncture is minimally painful and that patients report positive outcomes associated with acupuncture. The hope is that the results can aid in educating healthcare providers, patients, and caregivers on the relatively pain-free nature of acupuncture and allow all parties to make an informed decision on the role of acupuncture as an acceptable integrative medicine practice for pediatric patients and part of a comprehensive treatment paradigm that focuses on whole person health.The current retrospective cohort study focuses on an outpatient pain clinic convenience sample of pediatric patients receiving acupuncture for chronic pain complaints. Patients were assessed and referred for acupuncture after their intake visit by the pain clinic team. Routine surveys were collected after acupuncture sessions as part of the acupuncture clinic visit to assess acupuncture needling pain and overall satisfaction with the acupuncture experience. Patient medical records from the pain clinic were accessed to review the routine surveys and data collected under the standard of care procedure for non-research purposes. Patient data was collected and analyzed from the first 5 years (January 2009 to December 2013) of this inaugural acupuncture program. All the acupuncture sessions and data collection were conducted at an urban, pediatric, and academic medical center in the western US. This manuscript adheres to applicable STROBE guidelines. The study was reviewed and approved by the local hospital Institutional Review Board (IRB) committee.A total of 236 unique pediatric patients were identified with completed surveys. Data was reviewed from all patients who attended an acupuncture session at least once and completed the self-report acupuncture questionnaire as part of the standard of care procedure. Caregivers were also given the opportunity to leave a comment at the end of the questionnaire. Six patients who were younger than 8 years old at the time of survey completion only had caregiver-completed surveys and were excluded from the analysis. This study includes data from 230 unique pediatric patients  from patients aged 8 to 21 (mean age = 15.9 years old). The study was set at a pediatric hospital that treats patients from 0 to 21, and as a result, our population will be referred to as pediatric. The number of acupuncture sessions attended was not controlled, with a range of 1 to 71 sessions. There was a total of 1380 completed questionnaires included in the analysis with a median of 3 acupuncture sessions per patient. This retrospective convenience cohort reflected the ethnic diversity of the medical center with 67% Latinx, 24% White, 4% Black, 3% Asian, and 2% Other. The patient population was comprised of a heterogeneous patient population with a combination of primary/functional pain disorders  and comorbid musculoskeletal chronic pain conditions to another primary  medical condition. All patients were English-speaking.The acupuncturists, employed at the pain clinic, used Kiiko Matsumoto Style (KMS), a type of Japanese acupuncture to treat all patients who agreed to receive treatments ,10. EachThe needles used were sterile, single-use, disposable, Seirin (brand) 40-gauge (0.16 mm wide) needles inserted at depths from 5 to 15 mm depending on the location of the point and the size of the patient. The total number of needles used was dependent on the number of identified positive, KMS reflexes. The needle retention time, which increased with age, was at least one minute but did not exceed twenty minutes.After each acupuncture session, patients completed an acupuncture questionnaire as part of the standard of care procedure. To avoid observer bias, the questionnaire was completed in the front office of the clinic during checkout, away from the acupuncturist. The acupuncture questionnaire is a 6-item Likert-like measure used to assess overall satisfaction, relaxation, anxiety reduction, and satisfaction with the acupuncturist. The questionnaire also includes an acupuncture pain score measured with the Faces Pain Scale-Revised, which is a validated measure of pain in children . The quePower analyses based on preliminary data from the principal investigator’s previous acupuncture studies determined that 200 patients were needed for this study. Baseline pain characteristics were not collected as part of the standard of care procedure and were not available to analyze.Primary outcomes include pain associated with needling, anxiety reduction, pain reduction, relaxation, and satisfaction scores. The variables were analyzed both individually and across treatment cohorts. For the grouped data analysis, patients were split into 4 groups; A: patients who had only gone to 1 acupuncture session, B: patients who had gone to 2 or 3 sessions, C: patients who had gone to 4 to 6 sessions, D: patients who had gone to 7 or more sessions. Treatment group criteria/assignments were delineated based on the acupuncturist’s recommendation on the number of treatments that would yield incremental increases in treatment response.p-values were assessed at the 0.05 significance level.Univariate analyses of primary outcomes were conducted through IBM SPSS Statistics 28.0. The distribution  of needling pain, anxiety reduction, relaxation, and satisfaction scores across all patients in their first acupuncture session and final acupuncture session were calculated. Due to the skewed distribution of the primary outcomes, nonparametric statistical analyses were applied. Kruskal-Wallis and Dunn’s post-hoc test with Bonferroni correction analyses were conducted to analyze intergroup comparisons of needling pain, anxiety reduction, relaxation, and satisfaction scores across each cohort. Wilcoxon Signed Rank tests were conducted to analyze inter-session differences between the first and final sessions, if applicable. All A total of 230 unique patients  and 1380 completed acupuncture questionnaires were analyzed with an overall mean age of 15.9 years old . Resultsp = 0.777), relaxation (p = 0.096), anxiety reduction (p = 0.733), needling pain (p = 0.642), and acupuncturist satisfaction (p = 0.220). The presenting pain type  did not influence the mean first session acupuncture score for overall satisfaction (p = 0.096), relaxation (p = 0.260), anxiety reduction (p = 0.671), needling pain (p = 0.712), and acupuncturist satisfaction (p = 0.902). Further, there were no differences in sex (p = 0.491), gender (p = 0.682), and presenting pain type (p = 0.804) between cohorts.The sex of the patient had no impact on overall satisfaction , relaxation (p = 0.042), and anxiolysis (p = 0.009) [p = 0.776) and acupuncturist satisfaction (p = 0.832) [p = 0.035) and anxiolysis (p = 0.030) scores on average compared to their initial session [Patients reported high scores during their final acupuncture treatment session for overall satisfaction , relaxation , anxiety reduction , and satisfaction with the acupuncturist  and low scores on pain associated with acupuncture needling . While the overall satisfaction with acupuncture and its anxiolytic effect has increased mean scores when compared to the initial acupuncture session, needling pain and acupuncturist satisfaction remain positive and relatively unchanged. When separated by cohort (A through D), there appears to be a trend of higher scores in the most recent acupuncture session when patients attended more acupuncture sessions, as seen in = 0.009) . No sign= 0.832) . A post- session .One patient had one adverse effect during one acupuncture session. The patient’s mild facial redness and swelling resolved on its own with no impact on breathing or eating at the conclusion of the session. No other adverse events were reported or observed.The current findings support the hypothesis that KMS acupuncture is relatively pain-free and well-liked in a pediatric patient population. Acupuncture-related pain from needling remains low to none irrespective of whether it is an initial acupuncture treatment session or a follow-up treatment session. While pain and fear of acupuncture is a commonly held perceptions among patients, caregivers, and healthcare providers, the current study shows that acupuncture is relatively pain-free. The majority (87%) of patients report experiencing minimal to no needling pain during acupuncture. Given the current findings paired with the literature on the benefits of acupuncture, healthcare providers can feel more confident that KMS acupuncture does not hurt, is well received, and has evidence supporting a variety of positive health outcomes. Healthcare providers can also educate and dispel the commonly held perception that acupuncture is painful. Additionally, patients and their caregivers reported high overall satisfaction, relaxation, and reductions in anxiety. Moreover, most patients report a reduction of their self-reported pain symptoms immediately following acupuncture, regardless of their presenting pain problem.The results indicate a significant change in primary outcomes, reflecting higher levels of overall satisfaction, relaxation, and anxiety reduction in cohorts that participate in more acupuncture sessions. Although patients experienced significantly greater relaxation and anxiety reduction between their initial and final acupuncture sessions , the curThe current findings contribute to the growing evidence on pediatric acupuncture reflecting zero to minimal self-reported pain associated with needling, acceptability and satisfaction, and the effectiveness of acupuncture in patients with chronic pain. While most studies examine pain ratings before and after acupuncture sessions related to the patient’s presenting health condition, the current study uniquely and primarily examines the self-reported pain experience of the acupuncture needling itself, while also investigating satisfaction and other therapeutic benefits. Kemper and colleagues in a smaller cohort previously found that acupuncture was helpful and acceptable in patients with severe chronic pain as reported by the patient’s guardians over a telephone interview . The curThe study also gathers favorable qualitative comments from patients and their caregivers, such as a 16-year-old patient stating, “I was scared at first, but I found it to be an enjoyable experience. I was very relaxed as the result with it (acupuncture)”. Another 16-year-old patient reports, “It always helps me to feel better and relaxed. I never feel any pain or discomfort either”. A mother of a 15-year-old patient claims, “Acupuncture has helped my son tremendously. No pain meds are needed at all”. Overall, the acupuncture service is received with overwhelmingly positive feedback and satisfaction.The present study has some limitations. First, the study only examines patient data from children aged 8 or older because that is the age at which they could self-report on the acupuncture questionnaire. Thus, results cannot be applied to children younger than 8 years. Second, patients are more likely to attend more acupuncture sessions if they are satisfied with the initial sessions, which may influence the ratings of sequential acupuncture sessions. Further, our study is subject to self-selection bias as participants who were unsatisfied with acupuncture are less likely to continue with treatment. Lastly, Kiiko Matsumoto Style acupuncture, a known gentler acupuncture technique, was used for all patients, therefore the findings may not generalize to all forms of acupuncture, like other Traditional Chinese Medicine acupuncture practices.Future investigations examining the effects of acupuncture for chronic pain in children would benefit from randomized-controlled clinical trials with younger cohorts, comparisons to other integrative medicine practices, like massage or yoga, and pharmacological treatment options. Integrative care is what is required to manage chronic pain and the associated health and co-morbid mental health issues. Ultimately conducting clinical trials that take a more pragmatic control trial (PCT) approach, may have greater generalizability to real-life struggles and solutions for patients with complex pain and associated medical symptoms. In the end, patients require multi-modal therapies to tackle the complexities associated with chronic pain, therefore engaging in PCT may ultimately shed light on the necessary treatment combinations for doing exactly what we’ve named our pain management clinics, pain “management”.Overall, acupuncture is a promising and relatively pain-free strategy that can be used to treat patients with chronic pain, focus on pain and anxiety reduction, and help patients feel more relaxed and satisfied with their treatment. Mixed method data collection, reflecting quantitative and qualitative data, strongly suggests that patients are highly satisfied with their acupuncture treatment experience. The data dispels the belief that acupuncture needling is painful and should signal physicians, caregivers, and patients to recommend/try acupuncture for the management of pediatric pain symptoms and other pain-associated concerns. The mandate to hoist integrative medicine practices to the highest level for patients suffering from chronic pain has never been greater, given the complexities of their medical problems and the co-morbidity of mental health concerns. It is upon all healthcare providers to recognize the debilitating nature of chronic pain, embrace a multi-modal integrative treatment approach, and confidently recommend acupuncture in an effort to reduce patient suffering, increase quality of life, and improve other pediatric health outcomes.