The Proteome of Extracellular Vesicles Released from Pulmonary Microvascular Endothelium Reveals Impact of Oxygen Conditions on Biotrauma.

The lung can experience different oxygen concentrations, low as in hypoxia, high as under supplemental oxygen therapy, or oscillating during intermittent hypoxia as in obstructive sleep apnea or intermittent hypoxia/hyperoxia due to cyclic atelectasis in the ventilated patient. This study aimed to characterize the oxygen-condition-specific protein composition of extracellular vesicles (EVs) released from human pulmonary microvascular endothelial cells in vitro to decipher their potential role in biotrauma using quantitative proteomics with bioinformatic evaluation, transmission electron microscopy, flow cytometry, and non-activated thromboelastometry (NATEM). The release of vesicles enriched in markers CD9/CD63/CD81 was enhanced under intermittent hypoxia, strong hyperoxia and intermittent hypoxia/hyperoxia. Particles with exposed phosphatidylserine were increased under intermittent hypoxia. A small portion of vesicles were tissue factor-positive, which was enhanced under intermittent hypoxia and intermittent hypoxia/hyperoxia. EVs from treatment with intermittent hypoxia induced a significant reduction of Clotting Time in NATEM analysis compared to EVs isolated after normoxic exposure, while after intermittent hypoxia/hyperoxia, tissue factor in EVs seems to be inactive. Gene set enrichment analysis of differentially expressed genes revealed that EVs from individual oxygen conditions potentially induce different biological processes such as an inflammatory response under strong hyperoxia and intermittent hypoxia/hyperoxia and enhancement of tumor invasiveness under intermittent hypoxia.

Brief High Oxygen Concentration Induces Oxidative Stress in Leukocytes and Platelets: A Randomized Cross-over Pilot Study in Healthy Male Volunteers.

BACKGROUND: Supplemental oxygen is administered routinely in the clinical setting to relieve or prevent tissue hypoxia, but excessive exposure may induce oxidative damage or disrupt essential homeostatic functions. It is speculated that oxidative stress in leukocytes and platelets may contribute to vascular diseases by promoting inflammation and cell aggregation. METHODS: In this pilot study 30 healthy male volunteers (18-65 years) were exposed to high oxygen concentration (non-rebreather mask, 8 L/min, 100% O2) and synthetic air (non-rebreather mask, 8 L/min, 21% O2) in a cross-over design for 20 min at a 3-week interval. Venous blood samples were obtained at baseline and 1, 3, and 6 h postintervention. Primary outcome was generation of reactive oxygen species in leukocytes as measured by the redox-sensitive fluorescent dye dihydrorhodamine 123. Additional outcomes were oxidative stress in platelets and platelet aggregation as measured by thromboelastography (ROTEM) and Multiplate analyses. FINDINGS: High oxygen exposure induced oxidative stress in leukocytes as evidenced by significantly higher mean fluorescence intensity (MFI) compared with synthetic air at 3 h postintervention (47% higher, P = 0.015) and 6 h postintervention (37% higher, P = 0.133). Oxidative stress was also detectable in platelets (33% higher MFI in comparison with synthetic air at 6 h, P = 0.024; MFI 20% above baseline at 3 h, P  = 0.036; 37% above baseline at 6 h, P = 0.002). ROTEM analyses demonstrated reduced mean clotting time 1 h postintervention compared with baseline (-4%, P = 0.049), whereas there were no significant effects on other surrogate coagulation parameters. CONCLUSION: Clinically relevant oxygen exposure induces oxidative stress in leukocytes and platelets, which may influence the immune and clotting functions of these cells.

Iron deficiency-induced thrombocytosis increases thrombotic tendency in rats.

Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naive rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma P-selectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.

Comparison of patient intake of ticagrelor, prasugrel, or clopidogrel on restoring platelet function by donor platelets.

BACKGROUND: Bleeding complications are a common side effect in patients under dual antiplatelet (anti-PLT) therapy. PLT transfusion provides a treatment option for these patients. However it is currently unclear if, and to what extent, P2Y12 inhibitors influence PLT function of donor PLTs and if patients taking these medications are likely to benefit from PLT transfusions. STUDY DESIGN AND METHODS: We investigated the effect of blood and plasma of clopidogrel-, prasugrel-, and ticagrelor-treated patients on PLT function of blood from healthy volunteers in flow cytometry, light transmission aggregometry, and multiple electrode aggregometry (MEA). RESULTS: Our results demonstrate that clopidogrel had no and prasugrel had only mild effects on donor PLT function, but the reversible P2Y12 inhibitor ticagrelor completely abolished adenosine diphosphate-mediated PLT activation in all assays tested. We further show that ticagrelor itself and not elevated adenosine concentrations in patient plasma were responsible for the observed effects. Moreover, we show that a modified MEA assay could provide a simple and rapid tool to allow determination of whether patients are likely to benefit from PLT transfusions. CONCLUSION: Our results provide novel insights into potential differences between the P2Y12 inhibitors on donor PLT function in an in vitro setting, which may provide implications for future PLT transfusion strategies in these patients.

Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry.

BACKGROUND: Routine drug monitoring is not required for the two novel direct factor Xa inhibitors apixaban and rivaroxaban. Rapidly available test results might be beneficial in case of bleeding or prior to urgent surgery. OBJECTIVES: The aim of this study was to evaluate the applicability of the two rotational thrombelastometry (ROTEM®) -modifications Low-tissue factor activated ROTEM® (LowTF-ROTEM®) and Prothrombinase induced clotting time - activated ROTEM® (PiCT®-ROTEM®) for determination of apixaban and rivaroxaban in vitro and ex vivo. METHODS: Blood samples from 20 volunteers were spiked with apixaban / rivaroxaban to yield samples with ascending drug concentrations ranging from 50 - 400ng/mL. LowTF - and PiCT® modified ROTEM® tests and determination of the corresponding antifactor Xa activity were performed in duplicate in 280 samples. LowTF-ROTEM® tests were performed in samples from 20 patients on apixaban or rivaroxaban therapy and 20 controls. RESULTS: There was a strong correlation between apixaban / rivaroxaban plasma concentrations and the LowTF-ROTEM® parameters Clotting time (CT; spearman correlation coefficient (SCC) 0.81 and 0.81, respectively) and Time to maximum velocity (t,MaxVel; SCC: 0.81 and 0.80, resp.) and a low to moderate correlation for the PiCT®-ROTEM® parameters CT (SCC: 0.38 and 0.59, resp.) and t,MaxVel. (0.51 and 0.69, resp.) in the in vitro experiments. LowTF-ROTEM CT was significantly prolonged in patients on apxiaban or rivaroxaban therapy compared to controls. CONCLUSIONS: LowTF-ROTEM® could be a valuable diagnostic tool for rapid determination of the effect of apixaban and rivaroxaban at the point of care.

Posttraumatic stress disorder after high-dose-rate brachytherapy for cervical cancer with 2 fractions in 1 application under spinal/epidural anesthesia: incidence and risk factors.

PURPOSE: To investigate the psychological consequences of high-dose-rate brachytherapy with 2 fractions in 1 application under spinal/epidural anesthesia in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: In 50 patients with locally advanced cervical cancer, validated questionnaires were used for prospective assessment of acute and posttraumatic stress disorder (ASD/PTSD) (Impact of Event Scale-Revision), anxiety/depression (Hospital Anxiety and Depression Scale), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/Cervical Cancer 24), physical functioning (World Health Organization performance status), and pain (visual analogue scale), before and during treatment and 1 week and 3 months after treatment. Qualitative interviews were recorded in open format for content analysis. RESULTS: Symptoms of ASD occurred in 30% of patients 1 week after treatment; and of PTSD in 41% 3 months after treatment in association with this specific brachytherapy procedure. Pretreatment predictive variables explain 82% of the variance of PTSD symptoms. Helpful experiences were the support of the treatment team, psychological support, and a positive attitude. Stressful factors were pain, organizational problems during treatment, and immobility between brachytherapy fractions. CONCLUSIONS: The specific brachytherapy procedure, as performed in the investigated mono-institutional setting with 2 fractions in 1 application under spinal/epidural anesthesia, bears a considerable risk of traumatization. The source of stress seems to be not the brachytherapy application itself but the maintenance of the applicator under epidural anesthesia in the time between fractions. Patients at risk may be identified before treatment, to offer targeted psycho-social support. The patients' open reports regarding helpful experiences are an encouraging feedback for the treatment team; the reported stressful factors serve as a basis for improvement of patient management, especially regarding pain control.

Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: a crossover, randomised, double-blinded, placebo-controlled study.

BACKGROUND: Addition of nonopioid analgesic drugs reduces pain and opioid requirements in acute low back pain. In noncancer chronic low back pain (CLBP), the efficacy of a combined regimen to reduce breakthrough pain has not been proven so far. OBJECTIVE: Evaluation of the effects of intravenous (i.v.) nonopioid analgesic drugs on pain intensity and lumbar mobility in CLBP patients on chronic opioid therapy. DESIGN: Randomised, placebo-controlled, double blinded, crossover study. SETTING: Vienna General Hospital, Austria, from December 2002 to May 2004. PATIENTS: Thirty-six adults with CLBP on chronic opioid therapy. Inclusion criteria are as follows: American Society of Anesthesiologists' physical status less than 3, visual analogue scale (VAS) more than 4 and no known allergy to any of the used drugs. INTERVENTION: After written informed consent and VAS assessment, any oral nonopioid analgesic drug (NSAIDs, metamizol, paracetamol) was replaced by placebo 10 days before the first test infusion as a washout period. Coanalgesics (anticonvulsants, antidepressants) were maintained. Each patient received randomly four i.v. test infusions of diclofenac 75 mg (and orphenadrine 30 mg), parecoxib 40 mg, paracetamol 1 g and isotonic saline. A washout time of 72 h was allowed between each infusion. MAIN OUTCOME MEASURES: Primary outcome was as follows: VAS pain intensity (0 to 100 mm) at inclusion, before and within 30 min after infusion. Secondary outcomes were as follows: Roland-Morris questionnaire, McGill pain questionnaire and a test panel of physical functioning for spinal mobility, muscular endurance, balance and coordination. The differences in means of the above assessments among the groups were analysed. RESULTS: We found an improvement in VAS from the day of inclusion to the day of each appointment. We observed no improvement in pain intensity (VAS) or in any of the physical functioning tests immediately before versus after administration of the four i.v. drugs. Reductions in sensory, affective and cognitive dimensions of the McGill pain questionnaire were statistically significant in the diclofenac group. A trend of McGill pain questionnaire improvement existed in the other groups. CONCLUSION: The present data show that the anticipation of an i.v. infusion of nonopioid analgesic drug improves VAS significantly, probably through expectation-related mechanisms. However, single dose i.v. infusions of nonopioid analgesic drugs fail to improve pain intensity and spinal mobility in CLBP patients on chronic opioid treatment, even immediately after the infusion.

Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study.

Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20°C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 ± 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 ± 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 ± 3.6 vs 4.8 ± 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 ± 2.8 (ENF/mm ± SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20°C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling.

Heparin-induced effects of prothrombin complex concentrates in thromboelastometry.

BACKGROUND: Prothrombin complex concentrates (PCC) are currently used to treat congenital or acquired coagulation factor deficiency. In case of serious bleeding caused by new oral anticoagulant agents, reversing treatment with PCC is under debate. PCC preparations mostly contain heparin to prevent thromboembolic events. In factor VIII and IX deficient plasma, Takeyama et al. observed in vitro a heparin effect at appropriate concentrations of PCCs. The aim of the present experiment was to investigate the heparin effect of four factor-PCC at clinically relevant concentrations in whole blood. In an in vitro experiment, we compared the PCC preparation used in the experiments of Takeyama with a high heparin content to a new heparin-free PCC preparation. METHOD: After ethics committee approval and written informed consent, the citrated whole blood was obtained from ten healthy volunteers. We tested heparin-containing Prothromplex(®) and heparin-free Cofact(®) at concentrations of 0.31, 0.63, and 1.25 IU/ml. Protamine was added to another set of samples (1:1 heparin:protamine). We used the NATEM test in the rotational thromboelastometer ROTEM(®). RESULTS: In the heparin PCC preparation, we observed a significant (p < 0.001) concentration-dependent prolongation in CT and CFT, even at the lowest concentration. MCF was also significantly reduced. The heparin effect was reversible by protamine. The heparin-free PCC did not affect the onset of coagulation. The interpretation of the alpha-angle showed no increased thrombus formation in heparin-free PCC preparation. CONCLUSION: Our results extend the report of Takeyama et al. At clinically relevant PCC concentrations, the heparin effect was significant in thromboelastometry. The heparin content of PCCs should be considered in clinical routine.

Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate.

INTRODUCTION: The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates. METHODS: This retrospective analysis included trauma patients who received >or= 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score. RESULTS: Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014). CONCLUSIONS: ROTEM-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.

The effect of ex vivo anticoagulants on whole blood platelet aggregation.

Pre- and intraoperative platelet function monitoring is increasingly recommended in order to detect risk factors for bleeding and to target coagulation management. The ideal anticoagulant for accurate platelet aggregometry remains controversial. The aim of this experimental trial was to compare platelet aggregability in whole blood stored in citrate, heparin and direct thrombin inhibitors. Whole blood was drawn from 11 healthy adult volunteers who had not taken any medication in the previous 14 days. Blood was stored in trisodium citrate, unfractionated heparin, melagatran, lepirudin and argatroban. Platelet aggregation was performed using the impedance aggregometer Multiplate (Dynabyte, Munich, Germany) with adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP), collagen, arachidonic acid and ristocetin as agonists. Samples were analysed immediately after blood sampling (baseline), as well as 30 and 120 min afterwards. At baseline there were no significant differences in aggregability between samples containing direct thrombin inhibitors and heparin. In contrast, aggregation in response to all agonists except for ristocetin was significantly impaired in citrated blood. During storage the response to arachidonic acid and collagen was maintained by direct thrombin inhibitors and heparin, whereas ADP-, TRAP- and ristocetin-induced aggregation varied considerably over time in all ex vivo anticoagulants tested. Pre-analytical procedures should be standardized because storage duration and anticoagulants significantly affect platelet aggregability in whole blood. For point-of-care monitoring with immediate analysis after blood withdrawal all tested direct thrombin inhibitors as well as unfractionated heparin can be used as anticoagulants whereas citrate is not recommended.

Point-of-care platelet function tests: detection of platelet inhibition induced by nonopioid analgesic drugs.

Detection of platelet inhibition is of clinical relevance in the preinterventional risk-benefit assessment in chronic low-back-pain patients scheduled for invasive pain therapy. We evaluated the sensitivity of various point-of-care platelet function tests for the detection of platelet inhibition induced by nonopioid analgesic drugs. After Institutional Review Board approval and informed consent, citrated whole blood from 40 patients with chronic unspecific low back pain was investigated before and 30 min after intravenous infusion of the study medication consisting of diclofenac 75 mg (plus orphenadrin 30 mg; Neodolpasse; Fresenius Kabi Austria GmbH, Austria), parecoxib 40 mg (Dynastat; Pharmacia Europe EEIG, UK), paracetamol 1 g (Perfalgan; Bieffe Medital S.P.A., Italy), or normal saline in a randomized, cross-over, double-blinded, placebo-controlled study. Platelet function was assessed using the PFA-100 platelet function analyzer and thromboelastometry, as well as impedance aggregometry (in the last 17 patients recruited after it became commercially available). Sensitivity for detecting diclofenac-induced platelet inhibition was 85% for the PFA-100 using epinephrine as agonist and 94% for arachidonic acid-induced impedance aggregometry. ADP-induced platelet function tests, as well as cytochalasin D-modified thromboelastometry were unreliable. All tests had a low incidence of false-positive test results after normal saline. Paracetamol and parecoxib had no significant platelet inhibiting effect. The PFA-100 using epinephrine as agonist and arachidonic acid-induced impedance aggregometry are recommended for the detection of cyclooxygenase-I-inhibiting effects of nonsteroidal anti-inflammatory drugs such as diclofenac. Our findings confirm that a single rescue dose of paracetamol and parecoxib has no antiplatelet effect.

Garlic at dietary doses does not impair platelet function.

BACKGROUND: In vitro studies suggest that various bioactive constituents of Allium sativum (garlic) inhibit platelet function. The extent, however, to which dietary doses of garlic influence platelet function remains unknown. Therefore, we tested the effect of raw garlic on platelet function using point-of-care monitoring devices sensitive for cyclooxygenase I-inhibition and platelet adhesion. METHODS: Whole blood from 18 healthy volunteers was investigated before and 5 h after ingestion of the study medication consisting of Greek tsatsiki with 4.2 g raw garlic (verum), or Greek tsatsiki without garlic (placebo), in a randomized, crossover, observer-blinded, placebo-controlled study. The potential long-term effects of garlic were investigated in five volunteers after daily ingestion of 4.2 g of raw garlic over 1 wk. Platelet function was assessed with the Platelet Function Analyzer (PFA-100), impedance aggregometry (Multiplate), and thrombelastographic Platelet Mappingtrade mark. In vitro experiments were performed to prove the sensitivity of the assays to garlic-induced platelet inhibition. RESULTS: Baseline values of platelet function were within normal range in all volunteers. Platelet function was not impaired by single and repeated oral consumption of Greek tsatsiki containing raw garlic in any point-of-care monitoring test used. CONCLUSIONS: Platelet function is not impaired by single and repeated oral consumption of a dietary dose of garlic in healthy volunteers. Dishes containing socially acceptable doses of raw garlic are unlikely to increase the risk of perioperative bleeding. Further studies are warranted to determine the potential additive effects of platelet-inhibiting drugs combined with garlic and other herbs.

The effects of test temperature and storage temperature on platelet aggregation: a whole blood in vitro study.

We systematically evaluated the effects of test temperature and storage temperature on platelet aggregation using flow cytometry and impedance aggregometry. Aliquots of citrated whole blood from 27 healthy adult male volunteers were stored at 37 degrees C and 22 degrees C. Aliquots were subjected to impedance aggregometry in response to collagen, adenosine diphosphate, ristocetin, and arachidonic acid performed at 22 degrees C, 34 degrees C, 37 degrees C, and 40 degrees C. The expression of activated fibrinogen receptor was determined on adenosine diphosphate-activated platelets at 22 degrees C and 37 degrees C by whole blood flow cytometry using PAC-1 for fluorescent staining. Aggregation induced by collagen, ristocetin, and arachidonic acid was not significantly different at the test temperatures of 34 degrees C and 37 degrees C but was significantly impaired at 22 degrees C. In contrast, adenosine diphosphate-induced aggregation was significantly increased at both 34 degrees C and 22 degrees C. Hyperthermia exclusively impaired collagen-induced aggregation. Storage temperature of 22 degrees C exclusively enhanced adenosine diphosphate- and collagen-induced aggregation compared with storage at 37 degrees C. The binding of PAC-1 was enhanced at test temperatures below 37 degrees C. Prewarming the antibody above 22 degrees C significantly decreased binding. Our results suggest that mild hypothermic test conditions have no relevant effect, whereas profound hypothermia induces defects in adhesion, thromboxane generation, and activation. The pathomechanism for the increased response to adenosine diphosphate at mild and profound hypothermia remains unclear. Storage temperature considerably affects the aggregation response to the agonists adenosine diphosphate and collagen but not to arachidonic acid and ristocetin. Flow cytometry using the temperature-labile antibody PAC-1 fails to assess temperature effects on platelet aggregability.

Chronic pelvic pain treated with gabapentin and amitriptyline: a randomized controlled pilot study.

BACKGROUND: The aim of this study was to compare the efficacy and side effects of gabapentin, amitriptyline, and their combination in women with chronic pelvic pain. METHODS: In this open-label, prospective, randomized trial, 56 women with chronic pelvic pain were investigated with a two-year follow-up at the Vienna Medical University Hospital. If pain intensity assessed by a visual analog scale (VAS) was 5 or more (0, no pain; 10, maximal pain), despite analgesic therapy using the nonopioid drug metamizol together with weak opioids, patients were randomized to receive gabapentin (n = 20), amitriptyline (n = 20), or a combination of both drugs (n = 16). Doses of gabapentin and amitriptyline were increased to maximum daily doses of 3600 mg and 150 mg, respectively, until sufficient pain relief or the occurrence of side effects. VAS and side effects were evaluated before treatment and at 1, 3, 6, 12 and 24 months afterwards. RESULTS: All patients experienced significant pain relief during the observation period. However, after 6, 12 and 24 months, pain relief was significantly better in patients receiving gabapentin either alone or in combination with amitriptyline than in patients receiving monotherapy with amitriptyline (gabapentin: 0 months, 7.7 +/- 1.5; 6 months, 1.6 +/- 0.9; 12 months, 1.5 +/- 0.9; 24 months, 1.9 +/- 0.9; amitriptyline: 0 months, 7.3 +/- 1.5; 6 months, 2.2 +/- 1.6; 12 months, 2.2 +/- 1.6; 24 months; 3.4 +/- 0.9; amitriptyline-gabapentin: 0 months, 7.6 +/- 0.8; 6 months, 1.3 +/- 0.9; 12 months, 1.7 +/- 1.0; 24 months, 2.3 +/- 0.9). Side effects were lower in the gabapentin group than in the two other groups, the difference reaching statistical significance after three months (P < 0.05). CONCLUSION: Gabapentin alone or in combination with amitriptyline is better than amitriptyline alone in the treatment of female chronic pelvic pain.

Ultrasound-guided lumbar facet nerve block: a sonoanatomic study of a new methodologic approach.

BACKGROUND: Lumbar facet nerve (medial branch) block for pain relief in facet syndrome is currently performed under fluoroscopic or computed tomography scan guidance. In this three-part study, the authors developed a new ultrasound-guided methodology, described the necessary landmarks and views, assessed ultrasound-derived distances, and tested the clinical feasibility. METHODS: (1) A paravertebral cross-axis view and long-axis view were defined under high-resolution ultrasound (15 MHz). Three needles were guided to the target point at L3-L5 in a fresh, nonembalmed cadaver under ultrasound (2-6 MHz) and were subsequently traced by means of dissection. (2) The lumbar regions of 20 volunteers (9 women, 11 men; median age, 36 yr [23-67 yr]; median body mass index, 23 kg/m2 [19-36 kg/m2]) were studied with ultrasound (3.5 MHz) to assess visibility of landmarks and relevant distances at L3-L5 in a total of 240 views. (3) Twenty-eight ultrasound-guided blocks were performed in five patients (two women, three men; median age, 51 yr [31-68 yr]) and controlled under fluoroscopy. RESULTS: In the cadaver, needle positions were correct as revealed by dissection at all three levels. In the volunteers, ultrasound landmarks were delineated as good in 19 and of sufficient quality in one (body mass index, 36 kg/m2). Skin-target distances increased from L3 to L5, reaching statistical significance (*, **P < 0.05) between these levels on both sides: L3r, 45+/-6 mm*; L4r, 48+/-7 mm; L5r, 50+/-6 mm*; L3l, 44+/-5 mm**; L4l, 47+/-6 mm; L5l, 50+/-6 mm**. In patients, 25 of 28 ultrasound-guided needles were placed accurately, with the remaining three closer than 5 mm to the radiologically defined target point. CONCLUSION: Ultrasound guidance seems to be a promising new technique with clinical relevance and the potential to increase practicability while avoiding radiation in lumbar facet nerve block.

The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture.

UNLABELLED: Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain. Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia. In this prospective, randomized, double-blind, controlled study we tested the hypothesis that auricular electroacupuncture (EA) relieves pain more effectively than conventional manual auricular acupuncture (CO) in chronic low back pain patients with insufficient pain relief (visual analogue scale [VAS] > or = 5) treated with standardized analgesic therapy. Disposable acupuncture needles were inserted in the auricular acupuncture points 29, 40, and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear. Patients were randomized into group EA (n = 31) with continuous low-frequency auricular EA (1 Hz biphasic constant current of 2 mA) and group CO (n = 30) without electrical stimulation (sham-electroacupuncture). Treatment was performed once weekly for 6 wk, and in each group needles were withdrawn 48 h after insertion. During the study period and a 3-mo follow-up, patients were asked to complete the McGill questionnaire. Psychological well being, activity level, quality of sleep, and pain intensity were assessed by means of VAS; moreover, analgesic drug consumption was documented. Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO. Similarly, psychological well-being, activity, and sleep were significantly improved in group EA versus group CO, the consumption of analgesic rescue medication was less, and more patients returned to full-time employment. Neuropathic pain in particular improved in patients treated with EA. There were no adverse side effects. These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population. IMPLICATIONS: Continuous electrical stimulation of auricular acupuncture points using the new point stimulation device P-stim significantly decreases pain intensity and improves psychological well-being, activity, and sleep in chronic low back pain patients.

Electrical stimulation of auricular acupuncture points is more effective than conventional manual auricular acupuncture in chronic cervical pain: a pilot study.

UNLABELLED: In this prospective, randomized, double-blinded, controlled study, we tested the hypothesis that auricular electroacupuncture relieves pain more effectively than conventional manual auricular acupuncture. We studied 21 chronic cervical pain patients without radicular symptoms with insufficient pain relief (visual analogue scale >5) treated with standardized analgesic therapy. All patients received disposable acupuncture needles on the dominant side on the following acupuncture points: cervical spine, shen men, and cushion. In 10 patients, needles were continuously stimulated (2-mA constant current, 1 Hz monophasic) by using the electrical point stimulation device P-STIM. In 11 control patients, no electrical stimulation was administered. All needles were withdrawn 48 h after insertion. Acupuncture was performed once a week for 6 wk. Patients had to complete a questionnaire assessing pain intensity, psychological well-being, activity, sleep, and demand for rescue medication (lornoxicam and tramadol). The reduction in pain scores was significant in the electrical acupuncture group. Similarly, psychological well-being, activity, and sleep were significantly improved in patients receiving electrical acupuncture, and consumption of rescue medication was significantly less. These results demonstrate that continuous electrical stimulation of auricular acupuncture points by using the new point stimulation device P-STIM improves the treatment of chronic cervical pain in an outpatient population. IMPLICATIONS: Continuous electrical stimulation of auricular acupuncture points by using the new point stimulation device P-STIM significantly decreases pain intensity and significantly improves psychological well-being, activity, and sleep in chronic cervical pain patients.