STOP Pain Project-Opioid Response in Pediatric Cancer Patients and Gene Polymorphisms of Cytokine Pathways.

Moderate to severe cancer pain treatment in children is based on the use of weak and strong opioids. Pharmacogenetics play a central role in developing personalized pain therapies, as well as avoiding treatment failure and/or intolerable adverse drug reactions. This observational study aimed to investigate the association between IL-6, IL-8, and TNFα genetic single nucleotide polymorphisms (SNPs) and response to opioid therapy in a cohort of pediatric cancer patients. Pain intensity before treatment (PIt0) significantly differed according to IL-6 rs1800797 SNP, with a higher PI for A/G and G/G individuals (p = 0.017), who required a higher dose of opioids (p = 0.047). Moreover, compared to G/G subjects, heterozygous or homozygous individuals for the A allele of IL-6 rs1800797 SNP had a lower risk of having a PIt0 > 4. Dose24h and Dosetot were both higher in G/G individuals for TNFα rs1800629 (p = 0.010 and p = 0.031, respectively), while risk of having a PIt0 > 4 and a ∆VAS > 2 was higher for G/G subjects for IL-6 rs1800795 SNP compared to carriers of the C allele. No statistically significant association between genotypes and safety outcomes was found. Thus, IL-6 and TNFα SNPs could be potential markers of baseline pain intensity and opioid dose requirements in pediatric cancer patients.

Doctors and Nurses' Knowledge and Attitudes Towards Pediatric Pain Management: An Exploratory Survey in a Children's Hospital.

Despite the existence of protocols for effective pain control, pediatric pain is still high, due to scarce knowledge of its treatment, especially regarding opioids. This study aimed to evaluate doctors and nurses' knowledge of pain treatment and the use of opioids in children, before and after the implementation of Law 38/2010, that represented an important step in guaranteeing patients' rights to gain access to appropriate services for pain control and palliative care in Italy and in establishing the obligation of specific training programs in this matter for health professionals. An ad hoc questionnaire was developed and administered before (investigation A) and after (investigation B) the issuance of the Law. In B both doctors and nurses showed a slight but significant increase in correct answers and a reduction in incorrect ones, mainly concerning the category Myths and Prejudices. In both investigations doctors and nurses showed adequate general knowledge, yet there were some gaps regarding the specific knowledge of opioid drugs. Most of the participants were not familiar with the Law and its provisions.Investigation B showed an improvement in health professionals' knowledge, perhaps due to a hospital environment that followed the provisions of Law 38/2010. Nevertheless, the establishment of training courses according to the Law is needed to improve the knowledge of opioids, as well as to dispel deeply rooted myths and prejudices on pediatric pain.

Relaxation-guided imagery reduces perioperative anxiety and pain in children: a randomized study.

Several studies have shown the efficacy of psychological interventions in reducing preoperative anxiety in children undergoing surgery. This study aims to investigate the effectiveness of a specific non-pharmacological technique, the relaxation-guided imagery, in reducing both preoperative anxiety and postoperative pain in a sample of 60 children (6-12 years old) undergoing minor surgery who were randomly assigned to the experimental group (N = 30) or the control group (N = 30). The first group received the relaxation-guided imagery, before the induction of general anesthesia; the second group received standard care. The levels of preoperative anxiety and postoperative pain were assessed using, respectively, the modified Yale Preoperative Anxiety Scale and the Face, Legs, Activity, Cry, and Consolability Scale. The results showed a statistically significant difference between groups, with less anxiety and less pain for children included in the experimental group (p < .001; p < .001).Conclusion: Results suggest that relaxation-guided imagery reduces preoperative anxiety and postoperative pain in children. Future studies should focus on developing protocols and studying the eventual reduction of administered drugs for anesthesia and pain. What is Known: • Literature suggests the usefulness of relaxation-guided imagery in reducing anxiety and pain in the perioperative period. • Stronger evidences are needed to support the application of relaxation-guided imagery as routine care in pediatric surgery. What is New: • To our knowledge, this is the first randomized study to investigate the efficacy of relaxation-guided imagery in reducing preoperative anxiety and postoperative pain within a single pediatric sample. • The present study provides stronger evidence in an area that is lacking in research.

The use of opioids in children receiving intrathecal baclofen therapy.

PURPOSE: We hypothesized that children on chronic intrathecal baclofen therapy (ITB) may require less analgesics for postoperative pain control and are at higher risk of developing opioid-induced respiratory depression postoperatively. The aims of this study are to review children on chronic intrathecal baclofen therapy receiving opioids after major surgery and to determine the incidence complications in this population. METHOD: We conducted a retrospective cohort study comparing 13 children on ITB, who underwent posterior spinal fusion surgery, to 17 children with spina bifida that received the same surgery. RESULTS: On postoperative day 0 (POD 0), four children (40%) had respiratory depression in the baclofen group compared to none in the control group. Desaturation was significantly more frequent in children in the ITB group compared to those of the control group on POD 0; oversedation was recorded in 8 (80%) children in the baclofen group vs. 3 (17.6%) in the control group. Desaturation, respiratory depression, and oversedation were significantly more frequent on POD 0 in children in the baclofen group compared with children in the control group. CONCLUSIONS: The findings of the current study suggest that children on chronic intrathecal baclofen therapy require lesser amounts of opioids for postoperative pain control and are at a greater risk of developing postoperative respiratory depression and excessive sedation compared to patients without baclofen therapy.

Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review.

BACKGROUND: Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings. METHODS: The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement. RESULTS: In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers. CONCLUSIONS: Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context. TRIAL REGISTRATION: Registration number: CRD42017057831 .

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study.

BACKGROUND: Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients. METHODS: We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol). CONCLUSIONS: Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory. TRIAL REGISTRATION: CRD42017057740 .

Virtual Reality Analgesia During Venipuncture in Pediatric Patients With Onco-Hematological Diseases.

Background: Venipuncture is described by children as one of the most painful and frightening medical procedures. Objective: To evaluate the effectiveness of Virtual Reality (VR) as a distraction technique to help control pain in children and adolescents undergoing venipuncture. Methods: Using a within-subjects design, fifteen patients (mean age 10.92, SD = 2.64) suffering from oncological or hematological diseases received one venipuncture with "No VR" and one venipuncture with "Yes VR" on two separate days (treatment order randomized). "Time spent thinking about pain", "Pain Unpleasantness", "Worst pain" the quality of VR experience, fun during the venipuncture and nausea were measured. Results: During VR, patients reported significant reductions in "Time spent thinking about pain," "Pain unpleasantness," and "Worst pain". Patients also reported significantly more fun during VR, and reported a "Strong sense of going inside the computer-generated world" during VR. No side effects were reported. Conclusion: VR can be considered an effective distraction technique for children and adolescents' pain management during venipuncture. Moreover, VR may elicit positive emotions, more than traditional distraction techniques. This could help patients cope with venipuncture in a non-stressful manner. Additional research and development is needed.

Occupational exposure to nitrous oxide during procedural pain control in children: a comparison of different inhalation techniques and scavenging systems.

BACKGROUND: Nitrous oxide (N2 O 50% in oxygen) is commonly used for painful procedures in children. Potential negative health effects associated with chronic workplace exposure limit its use. Safe occupational N2 O exposure concentrations are below 25 ppm environmental concentration as a time-weighted average (TWA) and below 200 ppm as a short-time exposure level (STEL) of 15 min. AIM: The aim was to assess occupational exposure of staff during nitrous oxide administration to children using different inhalation delivery devices and scavenging systems. METHODS: Staff nitrous oxide exposure during use of a double face mask (DFM) with or without a demand valve (DV) was compared with a conventional single face mask (FM). We also compared exposure using the hospital central scavenging system with a portable evacuation system. N2 O concentrations, representing exposure values, were monitored within proximity to staff. Urine N2 O concentration was measured in staff administering the N2 O at the end of the procedural session. RESULTS: The mean and median values of TWA and STEL within the working area were lower than recommended values in the DFM (10.8, 11.6 ppm for TWA; 13.9, 11.0 ppm for STEL) and DFM-DV groups (2.3, 2.8 ppm for TWA; 4.4, 3.5 ppm for STEL) using the portable evacuation system. The N2 O urine exposure in DFM-DV group was lower than DFM group: a mean difference of 9.56 ppm (95% CI 2.65-16.46). Staff N2 O urinary concentrations were within safe biological limits in both the DFM and DFM-DV groups. High exposure concentrations to N2 O were recorded in all FM and FM-DV environmental and biological samples. CONCLUSIONS: The DFM system, with or without a DV, connected to a portable evacuation system during N2 O administration to children for painful procedures kept N2 O levels within the local environment below recommended limits.

Parental presence, clowns or sedative premedication to treat preoperative anxiety in children: what could be the most promising option?

BACKGROUND AND OBJECTIVES: A significant number of children undergo surgery experience high levels of anxiety in the presurgical period. The aim of this study is to investigate which intervention is more effective in reducing preoperative anxiety. METHODS/MATERIALS: The sample was composed of 75 subjects (aged 5-12 years) who had to undergo minor day surgery. Children were randomly assigned to: the Clowns group (N = 25) accompanied to the preoperative room by the clowns and by a parent; Premedication group (N = 25) premedicated with oral midazolam and accompanied to the preoperative room by one parent; or the Control group (N = 25) only accompanied by one parent. Anxiety in the preoperative period was measured by using the Modified Yale Preoperative Anxiety Scale (m-YPAS). Parental anxiety was measured by using the State-Trait Anxiety Inventory (STAI Y-1/Y-2). RESULTS: The Clown group was significantly less anxious during the induction of anesthesia compared with Premedication group and Control group. There were not any significant differences between Control group and Premedication group. There was an increased level of anxiety in the induction room in comparison with the waiting room: this difference was statistically significant for Control group and Premedication group, whereas it was not significant in Clown group. CONCLUSIONS: PPIA+clown intervention is more effective in reducing anxiety in children during the preoperative period than PPIA alone or PPIA+oral midazolam.

Clown doctors as a treatment for preoperative anxiety in children: a randomized, prospective study.

BACKGROUND: The induction of anesthesia is one of the most stressful moments for a child who must undergo surgery: it is estimated that 60% of children suffer anxiety in the preoperative period. Preoperative anxiety is characterized by subjective feelings of tension, apprehension, nervousness, and worry. These reactions reflect the child's fear of separation from parents and home environment, as well as of loss of control, unfamiliar routines, surgical instruments, and hospital procedures. High levels of anxiety have been identified as predictors of postoperative troubles that can persist for 6 months after the procedure. Both behavioral and pharmacologic interventions are available to treat preoperative anxiety in children. OBJECTIVE: The aim of this study was to investigate the effects of the presence of clowns on a child's preoperative anxiety during the induction of anesthesia and on the parent who accompanies him/her until he/she is asleep. METHODS: The sample was composed of 40 subjects (5-12 years of age) who had to undergo minor day surgery and were assigned randomly to the clown group (N = 20), in which the children were accompanied in the preoperative room by the clowns and a parent, or the control group (N = 20), in which the children were accompanied by only 1 of his/her parents. The anxiety of the children in the preoperative period was measured through the Modified Yale Preoperative Anxiety Scale instrument (observational behavioral checklist to measure the state anxiety of young children), and the anxiety of the parents was measured with the State-Trait Anxiety Inventory (Y-1/Y-2) instrument (self-report anxiety behavioral instrument that measures trait/baseline and state/situational anxiety in adults). In addition, a questionnaire for health professionals was developed to obtain their opinion about the presence of clowns during the induction of anesthesia, and a self-evaluation form was developed to be filled out by the clowns themselves about their interactions with the child. RESULTS: The clown group was significantly less anxious during the induction of anesthesia compared with the control group. In the control group there was an increased level of anxiety in the induction room in comparison to in the waiting room; in the clown group anxiety was not significantly different in the 2 locations. The questionnaire for health professionals indicated that the clowns were a benefit to the child, but the majority of the staff was opposed to continuing the program because of perceived interference with the procedures of the operating room. The correlation between the scores of the form to self-evaluate the effectiveness of the clowns and of the Modified Yale Preoperative Anxiety Scale is significant for both the waiting room and induction room. CONCLUSIONS: This study shows that the presence of clowns during the induction of anesthesia, together with the child's parents, was an effective intervention for managing children's and parents' anxiety during the preoperative period. We would encourage the promotion of this form of distraction therapy in the treatment of children requiring surgery, but the resistance of medical personnel make it very difficult to insert this program in the activity of the operating room.

Painful procedures in children with cancer: comparison of moderate sedation and general anesthesia for lumbar puncture and bone marrow aspiration.

BACKGROUND: The study was conducted to compare moderate sedation (MS) with general anesthesia (GA) in the management of frequently performed lumbar puncture or bone marrow aspiration (BMA) during the treatment of childhood cancer. PROCEDURE: The MS (14 patients for 30 procedures) was managed by non-anesthesiologists (combined nitrous oxide-midazolam +/- non-pharmacological techniques). The GA was managed by anesthesiologists (17 patients for 30 procedures). A neutral observer recorded side effects, use of sedative antagonists, recovery time, oncologist's evaluation, procedure behaviors check list (PBCL); subjective perceptions during the procedure with a questionnaire administered to children (>6 years) and their parents; drugs costs and professional resources. P-values <0.05 were considered significant. RESULTS: We had two inadequate sedations in MS (6.6%) versus 0 in GA. We had no significant differences in side effects (7.10% MS vs. 8.6% in GA), use of antagonists (2.90% GA vs. 0 MS), PBCL, oncologist evaluation and questionnaire data or drugs costs. We observed significant differences in recovery times (MS, mean 43 +/- SD min vs. GA, mean 117 +/- SD min) and professional resources costs. The effects of non-pharmacological techniques on anxiety were perceived very positively by both children and parents (on 0-4 scale, mean scores 3.57 for the children; 3.53 for the parents). CONCLUSIONS: Our study suggests that MS compared favorably to GA with respect to both safety and efficacy. When performed by non-anesthesiologists, MS may be associated with better compliance and cost-effectiveness as it relies on the contribution of non-pharmacological techniques.

Anaesthesia induction in children: a psychological evaluation of the efficiency of parents' presence.

BACKGROUND: The induction of anaesthesia for surgery is a stressful time for both child and parents. To treat preoperative anxiety in children, pharmacological methods (premedication) and behavioural methods (the presence of parents during the induction of anaesthesia) have been used, both independently and in combination. The purpose of this investigation was to study the effect of both premedication and parental presence on preoperative anxiety in a homogeneous population. METHODS: In this study conducted between January and April 2001 in the Meyer Hospital in Florence (Anaesthesia Department and Surgical Department), we studied 39 Italian speaking children aged 2-14 years who were undergoing minor surgery. Before the surgical intervention the State Trait Anxiety Inventory (STAI) questionnaire and a questionnaire for the social-demographic characteristics were given to the parents. The stress of the children was evaluated during induction of anaesthesia. We also studied behavioural areas of both children and parents with two specific questionnaires administered after the surgery. RESULTS: The STAI scores showed that the mothers had a higher level of anxiety compared with the fathers. The induction of anaesthesia for surgery was a stressful time for 23% of children of our sample. The correlation between stress of the child at induction and state (P = 0.034) and trait (P = 0.049) anxiety of parents was statistically significant. The child's loss of consciousness was for the majority of parents (56%) the moment of greatest stress and 97% of parents did feel useful during the induction of anaesthesia. There was a significant difference, P = 0.032, in the presence or absence of stress depending on whether the mother or father accompanied the child to the operating room. There was no significant difference in the presence of stress between children who did and did not receive premedication. CONCLUSIONS: Maternal presence, compared with the father's presence, is fundamental in helping to overcome anxiety in a child receiving anaesthesia. If the parents are present during the induction, the addition of premedication does not offer further benefit. Parents themselves judged their presence during the induction of anaesthesia in their child as a positive event. We also found a statistical significant correlation between anxiety of the parents with the level of the stress of the child during induction of anaesthesia.

Thoracentesis in pericardial and pleural effusion caused by central venous catheterization: a less invasive neonatal approach.

An 840 g infant developed a rapid onset of shock-like symptoms. Pericardial and pleural effusions from an indwelling central catheter were diagnosed via echocardiography. A thoracentesis was promptly performed with immediate clinical improvement. The fluid withdrawn from the pleural space was analysed as hyperalimentation. The infant survived because of early diagnosis and aggressive therapeutic intervention. A pericardial effusion should be drained if there is cardiovascular compromise and because pericardiocentesis represents a high risk technique, attempts should be made to rectify the extravasation via thoracentesis.

Tumescent local anesthesia for the surgical treatment of burns and postburn sequelae in pediatric patients.

BACKGROUND: Tumescent local anesthesia is a technique for regional anesthesia of the skin and the subcutaneous tissue, using infiltration of large volumes of local anesthetic. The advantages of this technique are (1) simplicity, (2) prolonged postoperative analgesia, (3) low incidence of bleeding, and (4) anesthetization of a large area of the body. There are no reports on the use of tumescent local anesthesia in pediatric patients. METHODS: In 30 consecutive pediatric burn patients with American Society of Anesthesiologists physical status class I or II who were 1-120 months old (34 +/- 31.6 months), after induction of anesthesia with nitrous oxide-oxygen-sevoflurane, infiltration with 0.05% (14 ml/kg) or 0.1% (7 ml/kg) lidocaine solution was performed. Anesthesia was maintained with patients spontaneously breathing with 1.5% sevoflurane in nitrous oxide-oxygen (50%). The maximum dose of lidocaine used was 7 mg/kg. Postoperative pain was assessed by using the Children's Hospital of Eastern Ontario Pain Scale (for patients aged up to 5 yr) and by using a visual analog scale (for patients older than 5 yr). A comparison with a historic control group not treated with the tumescent local anesthesia technique was performed. RESULTS: No patients were excluded from the study, and no significant variations in the monitored intraoperative parameters were observed. Five patients had an increase in heart rate and respiratory rate at the beginning of surgery, and of these, two needed a temporary increase in sevoflurane concentration. After the initial incision, no response to painful stimulus was observed. No complications occurred. Six patients required postoperative acetaminophen administration, and 24 patients did not require analgesic treatment. CONCLUSIONS: Tumescent local anesthesia with maximum dose of 7 mg/kg lidocaine seems to be safe and the sole possible effective locoregional anesthesia technique for the surgical treatment of noncontiguous pediatric burns.

Analgesic efficacy and tolerability of ketoprofen lysine salt vs paracetamol in common paediatric surgery. A randomized, single-blind, parallel, multicentre trial.

BACKGROUND: In this study, we compared the analgesic efficacy of ketoprofen lysine salt (OKi) suppositories) vs paracetamol, in children undergoing minor surgery. We also studied the side-effects of the treatment. METHODS: Eighty-five children of both sexes, aged 6-14 years, were enrolled in a multicentre, randomized, single-blind, parallel-group study design. In all patients postsurgical pain was evaluated by visual analogue scale (VAS) and degree of distress (night-time awakening, crying, behaviour and defence posture). RESULTS: Ketoprofen lysine was more effective than paracetamol in reducing postoperative pain (P = 0.008) with earlier onset and longer duration (8 h) of the antinociceptive effect. Evaluation of area under the curve, an aggregated measure of VAS, and of distress, confirm the time profile of pain reduction. No adverse effects related to the treatment were observed. CONCLUSIONS: Ketoprofen lysine salt can be considered a potent therapeutic approach to control postsurgery pain in children, and an alternative to other established drug regimens.

Use of percutaneous radial artery catheter for peripheral blood progenitor cell collection in pediatric patients.

BACKGROUND: Leukapheresis procedures require adequate flow rates, which in children may frequently involve invasive vascular access placement. STUDY DESIGN AND METHODS: A minimally invasive peripheral radial artery catheter was used for drawing blood in 85 leukapheresis procedures performed in 33 pediatric patients. Blood return to the patients was provided by either a central Broviac-type catheter or a peripheral venous access. The patients' age range was 1 to 18 years (median, 9.5) and the weight range was 9 to 73 kg (median, 29 kg). Vasocan Braunüle Luer Lock IV cannulas (22 gauge in 78 and 20 gauge in 7) were placed percutaneously under local anesthesia, and in 8 patients, catheter placement was carried out during general anesthesia for other procedures. A continuous flow cell separator was used in all cases (Fresenius AS104 in 23 and AS204 in 62). RESULTS: Flow rates ranged from 18 to 45 mL per minute, the mean number of total blood volumes processed was 2.07 (range, 0.51-2.51), and the mean duration of the procedures was 150 minutes (range, 90-260). The 22-gauge cannulas provided adequate flow rates independently of patient age and weight. No significant thrombotic, embolic, hemorrhagic, ischemic, or infectious complications were observed. CONCLUSION: Peripheral radial artery catheters are safe, are minimally invasive, and provide steady, high-flow rates, and they should be considered for patients requiring leukapheresis and lacking a suitable vascular access for drawing blood.