Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype.

ABSTRACT: It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

Documented nutritional therapy in relation to nutritional guidelines post burn injury - a retrospective observational study.

BACKGROUND & AIMS: Intensive nutritional therapy is an essential component of burn care. Regarding post-minor burn injuries, the literature is lacking. The aim of this study was to evaluate documented nutritional therapy in relation to international guidelines after both minor and major burn injuries. The secondary aim of this study was to evaluate the adequacy of energy and protein intake compared to individual nutritional goals post-burn injury. METHODS: A retrospective observational single-centre study including patients admitted between 2017 and 2019 at a burn centre in Sweden was performed. The patients included in the study were ≥18 years old and in need of hospital care for ≥72 h post-burn injury. Information about patients' demographics, nutritional therapy, and clinical characteristics of burn injury was collected. The patients were divided according to total body surface area burnt (TBSA %) into minor burn injuries (TBSA <20%) and major burn injuries (TBSA ≥20%). Descriptive statistics were used to analyse data. Adherence to guidelines was established by comparing 24 nutritional therapy recommendations to documented treatment. If documented nutritional treatment were in accordance with guidelines, adherence was considered high (≥80%), moderate (60-79.9%) or low (<59.9%). RESULTS: One hundred thirty-four patients were included, 90 patients with minor burn injuries and 44 patients with major burn injuries. Documented adherence to the nutritional guideline was overall low. After minor burn injury, 8% (2/24) of nutritional therapy recommendations had a high adherence (fat intake <35% of total energy intake and enteral nutrition as prioritized feeding route), 17% (4/24) a moderate adherence, and 75% (18/24) a low adherence. In patients treated after a major burn injury, there were two recommendations with documented high adherence (Vitamin C and Zinc); 25% (6/24) had moderate adherence, and 67% (16/24) had low adherence. In addition, quite a large amount of missing data was found. Adequacy of documented nutritional intake, compared to the individual documented goal, was 78% (±23%) for energy and 66% (±22%) for protein after minor burn injury. After major burn injury, the adequacy was 89% (±21%) for energy and 78% (±19%) for protein, respectively. CONCLUSIONS: This study revealed low adherence to nutritional guidelines in patients treated for minor and major burn injuries. Compared to major burn injuries, lower documented adequacy for both energy and proteins was found in minor burn injuries. Given the disparity between guidelines and documented nutritional therapy, and the lack of specific guidelines for minor burn injuries, there could be a considerable risk of inadequate nutritional therapy post-burn injury.

Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries.

OBJECTIVES: Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities. METHODS: One hundred and thirty-one subjects [69 with neuropathic pain, NP; 62 with painless neuropathy, nP] underwent a conditioned pain modulation (CPM) test that included a cold pressor task (CPT) conducted with the non-injured hand submerged in cold water (4 °C) until pain was intolerable. CPM was assessed by pain ratings to pressure stimuli before and after applying the CPT. Efficient CPM effect was defined as the ability of the individual's CS to inhibit at least 29% of pain (eCPM). The subjects were assigned to one of two subgroups: pain sensitive (PS) and pain tolerant (PT) after the time they could tolerate their hand in cold water (PS<40 s and PT=60 s) . Plasma samples were analyzed for 92 proteins incorporated in the inflammation panel using multiplex Protein Extension Array Technology (PEA). Differentially expressed proteins were investigated using both univariate and multivariate analysis (principal component analysis-PCA and orthogonal partial least-squares discriminant analysis-OPLS-DA). RESULTS: Significant differences in all protein levels were found between PS and PT subgroups (CV-ANOVA p<0.001), but not between NP and nP groups (p=0.09) or between inefficient CPM (iCPM) and eCPM (p=0.53) subgroups. Several top proteins associated with NP could be detected using multivariate regression analysis such as stromelysin 2 (MMPs), interleukin-2 receptor subunit beta (IL2RB), chemokine (C-X-C motif) ligand 3 (CXCL3), fibroblast growth factor 5 (FGF5), chemokine (C-C motif) ligand 28 (CCL28), CCL25, CCL11, hepatocyte growth factor (HGF), interleukin 4 (IL4), IL13. After adjusting for multiple testing, none of these proteins correlated significantly with pain. Higher levels of CCL20 (p=0.049) and CUB domain-containing protein (CDCP-1; p=0.047) were found to correlate significantly with cold pain sensitivity. CDCP-1 was highly associated with both PS and iCPM (p=0.042). CONCLUSIONS: No significant alterations in systemic proteins were found comparing subjects with neuropathic pain and painless neuropathy. An expression of predominant proinflammatory proteins was associated with experimental cold pain sensitivity in both subjects with pain and painless neuropathy. One these proteins, CDC-1 acted as "molecular fingerprint" overlapping both CPM and CPT. This observation might have implications for the study of pain in general and should be addressed in more detail in future experiments.

Sex-related differences in experimental pain sensitivity in subjects with painful or painless neuropathy after surgical repair of traumatic nerve injuries.

Introduction: Sex-related influences represent a contributor to greater pain sensitivity and have a higher prevalence of many chronic pain conditions, including neuropathic pain (NP), among women. Objectives: The aim was to analyze how differences in ongoing pain, experimental pain intensity, and conditioned pain modulation (CPM) relate to sex in subjects with neuropathy after traumatic nerve injuries. Methods: Endogenous pain modulation was compared between male (n = 77) and female (n = 55) subjects and between subjects with NP (female = 31, male = 39) and pain-free subjects with posttraumatic neuropathy (female = 24, male = 38). Conditioned pain modulation was assessed by pain ratings to pressure stimuli before and after a noxious conditioning stimulus (CS) conducted with one arm submerged in cold water (4°C) for 1 minute. Time of recovery (Time off) of pain intensity from peak VASmaxc after CS was recorded and compared between male and female patients. Results: Greater ongoing pain intensity was found among female patients compared with male patients and more experimental pain after pressure and cold induced pain. Summing all groups together, women had 0.8 times higher odds (20%) of recovering sooner than men after CS (95% CI = 0.65-2.9). No differences in CPM, time off, and psychosocial variables were seen between female and male patients (P < 0.05). Conclusion: Our hypothesis for sex differences in endogenous pain modulation was only supported by a shorter after-sensation time after cold CS in female patients. No sex differences in the magnitude of CPM effect were identified. Increased pain intensity for experimental pain, in both neuropathic pain and neuropathy without pain, was found in female patients.

Prolonged time of after-sensation after experimental pain stimuli despite efficient conditioned pain modulation in patients with chronic neuropathic pain after traumatic nerve injuries in upper extremity.

BACKGROUND: As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities. METHODS: Subjects in both groups (pain, n = 69; painless, n = 62) underwent clinical assessment of sensory nerve function and psychophysical tests: quantitative sensory testing and conditioned pain modulation (CPM). Conditioned pain modulation was assessed by pain ratings to 120 seconds pressure stimuli administered before and after a 60 seconds noxious 4°C cold conditioning stimulus (CS). Time of recovery (time off) of pain intensity from peak VASmaxc after CS was recorded. Questionnaires about the quality of life (RAND-36) and disability of the extremity (QuickDash) were completed. RESULTS: There were no significant differences between groups for CPM (P = 0.19). Time off was 42 seconds in subjects with pain in comparison with 28 seconds in those without pain (P < 0.0001). Compared with individuals reporting no pain, participants with neuropathic pain after nerve injuries had 1.8 times the odds of recovering later after CS, gain of function findings at sensory examination (P < 0.0001), lower scores of the physical component of RAND-36 (P < 0.0001), and increase arm disability (P < 0.0001). Hyperesthesia to cold pain stimulation (P = 0.03) and lowered pain pressure threshold (P = 0.01) were found in the pain group. CONCLUSION: Recovery after the pain induced by cold CS indicates changes in central processing of pain and provides a potential measurement of endogenous pain modulation in individuals with chronic neuropathic pain.

Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication.

Background and aims Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed. Methods A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors. Results More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019). Conclusions A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

Chronic pain patient and anaesthesia.

Severe chronic pain is often devastating for the affected individuals causing substantial suffering, health impairment, and a very low quality of life, including significant negative consequences for the patient and for society. Patients with complex pain disorders are seen often in relation to anaesthesia. They deserve special attention and require long time hospitalization and multiple contacts with health-care providers after discharge from hospital. A wider adoption of best perioperative and intraoperative pain management practice is required. This paper reviews current knowledge of perioperative and intraoperative pain management and anaesthetic care of the chronic pain patient. The individual topics covered include the magnitude of the problem created by chronic pain, the management of the patients taking various types of opioids, tolerance and opioid induced hyperalgesia and the multidisciplinary approach to pain management. The preventive and preemptive strategies for reducing the opioid needs and chronic pain after surgery are reviewed. The last section includes the role of acute pain services and an example of the implementation of a transitional pain service with the various benefits it offers; for example, the decrease of the opioid dose after discharge from the hospital. Patients also receive the continuity of care, with not only pain relief but also improvements in physical functioning, quality of life and emotional stress.

Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue.

The present investigation is an expansion of previous studies which all share a basic experimental protocol of a porcine-induced cardiac arrest (CA) of 12 min followed by 8 min of cardiopulmonary resuscitation (CPR), different experimental treatments (immediate as well as postponed induced mild hypothermia and administration of much or less cool intravenous fluids), and a follow-up period of 3 h after which the animals were sacrificed. Another group of animals was studied according to the same protocol after 12-min CA and "standard CPR." After death (within 1 min), the brains were harvested and frozen in liquid nitrogen awaiting analysis. Control brains of animals were collected in the same way after short periods of untreated CA (0 min, 5 min, and 15-30 min). Previous studies concerning chiefly neuropathological changes were now expanded with analyses of different tissue indicators (glutathione, luminol, leucigenin, malonialdehyde, and myeloperoxidase) of cerebral oxidative injury. The results indicate that a great part of oxidative injury occurs within the first 5 min after CA. Immediate cooling by administration of much intravenous fluid results in less cerebral oxidative injury compared to less intravenous fluid administration. A 30-min postponement of induction of hypothermia results in a cerebral oxidative injury comparable to that of "standard CPR" or the oxidative injury found after 5 min of untreated CA. Intravenous administration of methylene blue (MB) during and immediately after CPR in combination with postponed cooling resulted in no statistical difference in any of the indicators of oxidative injury, except myeloperoxidase, and glutathione, when this treatment was compared with the negative controls, i.e., animals subjected to anesthesia alone.

The changing face of acute pain services.

BACKGROUND AND AIMS: Acute Pain Services have been implemented initially to treat inadequate postoperative pain. This study was undertaken to prospectively review the current challenges of the APS team in an academic hospital assessing the effects of its activity on both surgical and medical pain intensity. It also define the characteristics of the patients and the risk factors influencing the multiple visits from the APS team. METHOD: This prospective cohort study was conducted at Uppsala University Hospital (a Swedish tertiary and quaternary care hospital) during one year. All the patients referred to the APS team were enrolled. A standardized data collection template of demographic data, medical history, pain diagnosis, associated diseases, duration of treatment, number of visits by the APS team and type of treatment was employed. The primary outcomes were pain scores before, after treatment and the number of follow-ups. The patients were visited by APS at regular intervals and divided by the number of visits by APS team into several groups: group 1 (one visit and up to 2 follow ups); group 2 (3 to 4 follow-ups); group 3 (5 to 9 follow-ups); group 4 (10 to 19 follow-ups); group 5 (>20 followups). The difference between groups were analyzed with ordinal logistic regression analyses. RESULTS: Patients (n=730) (mean age 56±4, female 58%, men 42%) were distributed by service to medical (41%) and surgical (58%). Of these, 48% of patients reported a pain score of moderate to severe pain and 27% reported severe pain on the first assessment. On the last examination before discharge, they reported 25-30% less pain (P=0.002). The median NRS (numerical rating scores) decreased significantly from 9.6 (95% confidence interval, 8.7-9.9) to 6.3 (6.1-7.4) for the severe pain (P<0.0001), from 3.8 (3.2-4.3) to 2.4 (1.8-2.9) for the moderate pain. The odds ratio for frequent follow-ups of the patients between 18 and 85 years (n=609) was 2.33 (95% CI: 1.35-4.02) if the patient had a history of chronic neuropathic pain, 1.80(1.25-2.60) in case the patient had a history of chronic nociceptive pain, 2.06(1.30-3.26) if he had mental diseases, and 3.35(2.21-5.08) if he had opioid dependency at the time of consultation from APS. Strong predictors of frequent visits included female gender (P=0.04). CONCLUSIONS: Beside the benefits of APS in reducing pain intensity, this study demonstrates that the focus of APS has been shifted from the traditional treatment of acute surgical pain to the clinical challenges of treating hospitalized patients with a high comorbidity of psychiatric diseases, opioid dependency and chronic pain. IMPLICATIONS: The concept of an APS will ultimately be redefined according to the new clinical variables. In the light of the increasing number of patients with complex pain states and chronic pain, opioid dependency and psychiatric comorbidities it is mandatory that the interdisciplinary APS team should include other specialties besides the "classical interdisciplinary APS team", as psychiatry, psychology, rehabilitation and physiotherapy with experience in treating chronic pain patients.

The switch from buprenorphine to tapentadol: is it worth?

Opioid analgesia continues to be the primary pharmacologic intervention for managing acute pain and malignant pain in both hospitalized and ambulatory patients. The increasing use of opioids in chronic nonmalignant pain is more problematic. Opioid treatment is complicated with the risks raised by adverse effects, especially cognitive disturbance, respiratory depression but also the risk of tolerance, opioid abuse and drug-disease interactions. Despite the growing number of available opioids within the last years, adequate trials of opioid rotation are lacking and most of the information is anecdotal. This article reviews the clinical evidence surrounding the switch from transdermal buprenorphine to tapentadol in malignant and non-malignant pain. Tapentadol acts on both the µ-opioid receptors (MOR) and on the neuronal reuptake of noradrenaline with a limited usefulness in acute pain management while buprenorphine is a mixed agonist-antagonist, and both present some advantages over other opioids. Both drugs show particular pharmacodynamic and pharmacokinetic properties which reduce the risks of development of tolerance, opioid abuse, diversion and determine fewer hormone changes than the "classical opioids" making these opioids more attractive than other opioids in long term opioid treatment. However, in the absence of powered clinical trials, the evidence to support the method used for transdermal buprenorphine rotation to tapentadol is weak.

Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study.

AIM: This study was carried out in patients with neuropathic pain in order to assess the analgesic effects and changes in protein biomarkers after the administration of methylene blue (MB), a diaminophenothiazine with antioxidant and anti-inflammatory properties, and with inhibitory effects on nitric oxide. MATERIALS AND METHODS: Ten patients with chronic refractory neuropathic pain were randomized to receive either MB (10 mg/mL Methylthioninium chloride) 2 mg/kg (MB group) or MB 0.02 mg/kg (control group) infused over 60 minutes. Sensory function and pain (Numerical Rating Scale) were evaluated at baseline and at 60 minutes after the start of the infusion. The patients kept a pain diary during the next 24 hours and for the following 4 days. Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) and plasma protein biomarkers prior to and after the infusions were measured with radioimmunoassay and with proximity extension assay. RESULTS: A decrease of the Numerical Rating Scale at 60 minutes in comparison with baseline was observed in the MB (P=0.047) group. The decrease was significant between the MB and the control group on the day of and day after MB infusion (P=0.04 and P=0.008, respectively). There was no difference in systemic protein expressions between groups except for prolactin (PRL) (P=0.02). Three patients demonstrated diminished dynamic mechanical allodynia. CONCLUSION: MB decreased the pain levels in patients with chronic therapy-resistant neuropathic pain on the first 2 days after administration. Known as an endocrine modulator on the anterior pituitary gland, MB infusion produced a decrease of PRL. The detailed role of PRL effects in chronic neuropathic pain remains undetermined.

Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood-Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain.

The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier.

Differential analgesic effects of subanesthetic concentrations of lidocaine on spontaneous and evoked pain in human painful neuroma: A randomized, double blind study.

Background Both peripheral nerve injury and neuroma pain are the result of changes in sodium channel expression. Lidocaine selectively inhibits the spontaneous ectopic activity by binding to sodium channels. Subanesthetics concentrations of lidocaine are able to produce a differential block of the ectopic discharges, but not propagation of impulses, suppressing differentially the associated neuropathic pain symptoms. The aim of this study was to investigate the differences between the analgesic effects of lidocaine 0.5% and a control group of lidocaine 0.1% on several neuroma related pain modalities. Methods Sixteen patients with neuropathic pain due to painful neuromas caused by nerve injury participated in this randomized, double-blind experiment. The patterns of sensory changes were compared before and after injection of 1ml lidocaine 0.5% and 0.1% close to the neuroma, the sessions being 1-2 weeks apart. Spontaneous and evoked pains were assessed using a visual analogue scale (VAS), quantitative and qualitative sensory testing. The primary end-point measure was defined as the change in pain score measured from baseline until 60min after injection. Assessments of spontaneous pain and evoked pain were done post injection at 15s, 30s, 1min, and at 5-min intervals for the first 30-min post injection and then every 10-min to 1 hr post injection. The assessments of pain were performed between the limbs in the following order: spontaneous pain, then assessment of dynamic mechanical allodynia and then hyperalgesia. Results Lidocaine dose-dependently reduced spontaneous and evoked pain scores by more than 80% with maximum effects between 1 and 5min for evoked pain and between 3 and 15min for spontaneous pain. While evoked pain normalized rapidly reaching about 50% of the control level 20min after the injection, spontaneous pain levels continue to be lower in comparison with baseline values for more than 60min. When comparing the time course of analgesia between spontaneous and evoked pain, lidocaine-induced a greater reduction of evoked pain, but with shorter duration than spontaneous pain. The differences between evoked pain and spontaneous pain were statistically significant in both groups (lidocaine 0.5% group; p = 0.02 and lidocaine 0.1% group; p = 0.01). Reproducibility was high for all assessed variables. Surprisingly, both lidocaine concentrations produced a sensory loss within the area with hyperalgesia and allodynia: hypoesthesia occurred earlier and lasted longer with lidocaine 0.5% (between 30s and 5min) in comparison with lidocaine 0.1% (p = 0.018). Conclusion Differential analgesic effects of subanesthetic concentrations of local lidocaineon evoked and spontaneous pain in human neuroma suggest that different mechanisms underlie these two key clinical symptoms. Spontaneous pain and evoked pain need an ongoing peripheral drive and any possible CNS amplification change is temporally closely related to this peripheral input. Implications Painful neuroma represents a clinical model of peripheral neuropathic pain that could lead to a significant step forward in the understanding of pain pathophysiology providing the opportunity to study spontaneous and evoked pain and the underlying mechanisms of neuropathic pain. The proposed model of neuropathic pain allows testing new substances by administration of analgesics directly where the pain is generated.

Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation.

Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34 °C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

Targeting oxidative injury and cytokines' activity in the treatment with anti-tumor necrosis factor-α antibody for complex regional pain syndrome 1.

Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2 -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

Effectiveness of multidisciplinary rehabilitation treatment for patients with chronic pain in a primary health care unit.

Background In recent years, multidisciplinary rehabilitation (MDR) became an alternative treatment option for chronic non-cancer pain. MDR is mostly available in specialized pain units, usually at rehabilitation centers where the level of knowledge and therapeutically options to treat pain conditions are considered to be high. There is strong evidence that MDR in specialized pain units is affecting pain and improves the quality of life in a sustainable manner. There are few studies about MDR outcome in primary health care, especially in those units situated in rural areas and with a different population than that encountered in specialized hospitals. That, in spite of the fact that the prevalence of pain in the patients treated in primary care practice is about 30%. The aim of this study is to analyze the effectiveness of MDR for chronic non-cancer patients in a primary health care unit. Methods This study included a total of 51 patients with chronic pain conditions who were admitted and completed the local MDR-program at the primary health care unit in Arvika, Sweden. The major complaint categories were fibromyalgia (53%), pain from neck and shoulder (28%) or low back pain (12%). The inclusion criteria were age between 16 and 67 years and chronic non-cancer pain with at least 3 months duration. The multidisciplinary team consisted of a general practitioner, two physiotherapists, two psychologists and one occupational therapist. The 6-week treatment took place in group sessions with 6-8 members each and included cognitive-behavioral treatment, education on pain physiology, ergonomics, physical exercises and relaxation techniques. Primary outcomes included pain intensity, pain severity, anxiety and depression scores, social and physical activity, and secondary outcomes were sick leave, opioid consumption and health care utilization assessed in the beginning of the treatment and at one year follow-up. Data was taken from the Swedish Quality Register for Pain Rehabilitation (SQRP) and the patients' medical journal. Results One year after MDR treatment, sick leave decreased from 75.6% to 61.5% (p <0.05). Utilization of health-care during one year decreased significantly from 27.4 to 20.1 contacts (p = 0.02). There were significant improvements concerning social activity (p = 0.03) and depression (p <0.05), but not in anxiety (p = 0.1) and physical activity (p = 0.08). Although not statistically significant, some numerical decrease in the mean levels of pain intensity, pain severity and opioid consumption were reported one year after MDR (p > 0.05). Conclusions The results obtained one year after rehabilitation indicated that patients with chronic noncancer pain might benefit from MDR in primary health care settings. Implications This study suggests that MDR in primary care settings as well as MDR at specialized pain units may lead to better coping in chronic non-cancer pain conditions with lower depression scores and higher social activity, leading to lower sick leave. This study demonstrated that there is a place for MDR in primary health care units with the given advantage of local intervention in rural areas allowing the patients to achieve rehabilitation in their home environment.

Crystalloid vs. hypertonic crystalloid-colloid solutions for induction of mild therapeutic hypothermia after experimental cardiac arrest.

PURPOSE: To compare cerebral and hemodynamic consequences of different volumes of cold acetated Ringer's solution or cold hypertonic saline dextran administered in order to achieve mild hypothermia after cardiac arrest (CA) in a pig model of experimental cardiopulmonary resuscitation (CPR). METHODS: Using an experimental pig model of 12 min CA (followed by 8 min CPR or no resuscitation) we compared four groups of piglets: a control group, a normothermic group and two groups with different solutions administered for induction of hypothermia. The control group of 5 piglets underwent 12 min CA without subsequent CPR, after which the brain of the animals was removed immediately. After restoration of spontaneous circulation (ROSC) the resuscitated piglets were randomized into a normothermic group (NT group=10), and two hypothermic groups that received cold infusions of either 30 mL/kg acetated Ringer's solution (Much fluid group, M, n=10) or 3mL/kg hypertonic saline dextran solution (Less fluid group, L, n=10), respectively, administered during 30 min. Additional external cooling with ice packs was used in hypothermic groups. Sixty or 180min after ROSC the experiment was terminated. Immediately after arrest the brain was removed for histological analyses. RESULTS: The median time to reach the target core temperature of 34 °C after ROSC was 51.5±7.8 min in L group and 48.8±8.6 min in M group. Less cerebral tissue content of water (p<0.001), sodium (p<0.0001), potassium (p<0.0001) and less central venous pressure (CVP) at 5 and 15 min after ROSC were demonstrated in L group. Increased brain damage was demonstrated over time in NT group (p<0.001). Less neurologic damage and BBB disruptions (albumin leakage) was observed at 180min in M group in comparison with both NT and L groups (p<0.001). CONCLUSION: No statistical differences were observed between the hypothermic groups in the time to achieve mild hypothermia. Although inclusion of cold hypertonic crystalloid-colloidal solutions in the early resuscitation after ROSC may be more effective than cold crystalloids in reducing brain edema, this study demonstrates that mild hypothermia induced with small volumes of cold hypertonic crystalloid-colloids is less as effective as crystalloid's induced hypothermia in mitigating brain injury after cardiac arrest.

Central nervous tissue damage after hypoxia and reperfusion in conjunction with cardiac arrest and cardiopulmonary resuscitation: mechanisms of action and possibilities for mitigation.

Only approximately 10% of patients encountering a cardiac arrest (CA) and subsequent cardiopulmonary resuscitation survive to a meaningful life. One of the most important causes for this low survival rate is the ischemia-reperfusion injury that hits the brain. This review summarizes some of the more important mechanisms causing cerebral injury. Thus, we describe some of our findings when performing genome-wide transcriptional profiling as well as histological and immunohistological staining of cerebral cortical areas. In order to shed some light on therapeutic opportunities, our findings relating to the use of induced mild hypothermia and methylene blue as neuroprotective agents are reviewed. Furthermore, we would like to share some interesting data on gender differences and effects of estrogen on the ensuing cerebral injury occurring after hypovolemic CA.

Propofol mitigates systemic oxidative injury during experimental cardiopulmonary cerebral resuscitation.

Effects of propofol, an intravenous anesthetic agent that exerts potent antioxidant properties, were investigated in an experimental model of cardiac arrest and cardiopulmonary resuscitation. An extended cardiac arrest with 15 randomized piglets was studied to assess the effect of propofol or its solvent intralipid as the control group. Oxidative stress (as measured by a major F(2)-isoprostane) and inflammation (a major metabolite of PGF(2α)) were evaluated in addition to the hemodynamic evaluation, protein S-100ß and in situ tissue brain damage by immunochemistry at sacrifice after 3h of reperfusion following cardiac arrest and restoration of spontaneous circulation (ROSC). ROSC increased jugular bulb plasma levels of F(2)-isoprostane and PGF(2α) metabolite significantly more in controls than in the propofol-treated group. In situ tissue damage after ischemia-reperfusion was variable among the pigs at sacrifice, but tended to be greater in the control than the propofol-treated group. Propofol significantly reduced an ROSC-mediated oxidative stress in the brain.

Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain.

Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.