Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses.

Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics.

[Chronic pain patients and their expectations towards physician care. Results from the Austrian Patient Report]. / Schmerzpatienten und ihre Erwartungen an die ärztliche Versorgung. Ergebnisse aus dem Osterreichischen Patientenbericht.

BACKGROUND: The Austrian Patient Report illustrates the preferences of Austrian chronic disease patients for the first time. MATERIAL AND METHODS: A standardised, self-administered questionnaire was used with items in the fields of general information, information flow, medicine and health, social and societal aspects and statistics. RESULTS: The most important item for Austrian chronic pain patients is a comprehensive discussion with their physician, which is even more important than a reduction in pain intensity. CONCLUSIONS: More efforts have to be made to educate and inform chronic pain patients adequately from the doctor's side.

Antithrombin III in patients with severe sepsis: a pharmacokinetic study.

OBJECTIVES: To evaluate the safety, pharmacokinetics, and the practicability of two different antithrombin III (AT III) high-dose regimens in patients with severe sepsis. DESIGN: Prospective, open, randomized, 2 parallel groups, multinational clinical trial. SETTING: Eleven academic medical center intensive care units (ICU) in Austria, Belgium, Denmark, Germany, Norway and Sweden. PATIENTS: Thirty-three patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III. INTERVENTIONS: Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days, resulting in a total dose for both dosage regimens of 30,000 IU AT III. MEASUREMENTS: All patients were evaluated for safety and all but one for pharmacokinetics. RESULTS AND CONCLUSIONS: The administration of AT III was safe and well tolerated. The overall 28-day all-cause mortality was 30% (43% intermittent bolus infusions; 21% continuous infusion). The mean probability of dying according to the SAPS II was 48%. The difference in mortality between both groups was within the range of chance. AT III plasma levels were elevated from low baseline levels to above 120% soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days. Functional and immunologic levels of AT III corresponded very well. With an overall median volume of distribution of 4.5 l (range: 2.4-6.5 l), AT III only moderately extended beyond plasma. The overall median elimination half-life was 18.6 h (range: 5.1-37.4). Overall, median response was 1.75% per IU/kg (range: 1.14-2.8). The variability of elimination parameters was quite noteworthy (CV = 41-59%), whereas distribution-related parameters showed a moderate variability (CV = 24%). In spite of this variability, both high-dose IV regimens reliably provided AT III levels above 120% for all but one patient. An increased mortality was observed for patients with a distribution volume exceeding 4.5 l (or a response < 1.7% per IU/kg). AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon. The continuous infusion regimen was slightly preferred by the investigators with regard to practicability.

[Blood loss and absorption in TURP vs. TUVRP under low pressure and high pressure conditions]. / Blutverlust und Einschwemmung bei TURP vs. TUVRP unter Niederdruck- bzw. Hochdruckbedingungen.

This study analyzes the causes of different fluid absorption and loss of blood in TURP (transurethral resection of the prostate) and also compares TURP with TUVRP (transurethral vaporesection of the prostate). Continuous intraoperative, intravesical pressure measurement and registration of the extent of fluid absorption (measurement of C(2)H(5)OH in the patient's expiratory air) and precise intra- and postoperative analysis of serum and ASTRUP analysis made it possible to differentiate between high- and low-pressure TUR. In addition positive and negative characteristics of TUVRP could be examined. When fluid absorption was registered, a clear correlation between C(2)H(5)OH absorption and decrease in serum concentration of sodium could be seen, making sodium in serum a good marker of fluid absorption. Neither the duration of the operation nor the size of the adenoma had an influence on fluid absorption and loss of blood, but sinus bleeding and capsular lesions, especially in high-pressure TUR, had a significant influence. An advantage of low-pressure TUR, especially in "low compliance bladder," could be clearly seen. No benefit concerning fluid absorption and loss of blood was seen in cases of total resection by TUVRP. In cases of palliative, planned TUR (elderly patients with multiple risk factors) a TUVRP is recommended.

Guidelines for anaesthesiologist specialist training in pain medicine.

The Section and Board of Anaesthesiology of the European Union of Medical Specialists aims (EUMS/UEMS) at harmonization of training of anaesthesiologists and at improvement of patient care throughout Europe. Pain medicine is considered to be an area of expertise in anaesthesiology although exclusivity is not claimed. The Section and Board has approved both a core syllabus for pain medicine to be part of the specialist training in anaesthesiology and an additional qualification in pain medicine following the completion of a 5 yr basic specialty training in anaesthesiology. These proposals were prepared by the Working Party on Pain Medicine of the Section and Board. It considers a multidisciplinary approach to pain to contribute to quality in care and has taken the initiative to set up a Multidisciplinary Joint Committee on Pain Medicine within the EUMS/UEMS, for which these guidelines define the area of expertise of anaesthesiology.

[Importance of intrathecal pain therapy]. / Stellenwert der intrathekalen Schmerztherapie.

Intraspinal drug infusion using implantable pumps and catheter systems is a safe and effective therapy for selected pain patients with severe chronic pain. It improves pain relief, reduces drug-related side effects, decreases the need for oral analgesia and enhances quality of life in a segment of chronic pain patients whose pain has not been controlled with more conservative therapies. Intrathecal drug therapy has therefore established its role in the treatment of malignant pain, benign pain and severe spasticity.Careful patient selection and management as well as a multidisciplinary approach are determinants of successful treatment. Current practices for patient selection and management, screening, drug selection, dosing and implantation for intrathecal drug delivery systems are discussed.

Premedication administered to anesthesiologists as patients: their evaluations of its effect and its influence on premedication prescribing habits.

Inquiries were sent to practising Austrian anesthesiologists to ascertain their premedication-prescribing habits and their assessment of premedicants that they received as patients. The 143 replies received showed meperidine/promethazine (M/P) as most used n = 83 and received (n = 54) drug (combination), followed by fentanyl/droperidol (F/D) n = 33 (n = 21), benzodiazepines (BZ) n = 17 (n = 10) and several other drugs (combinations) n = 10 (n = 14). There was no significant difference in the premedication habits of the 82 anesthesiologists who had received premedication and those (61) who had no personal experience with premedicants. The former judged M/P to be significantly superior to F/D and other schemes; however there was no significant difference from the judgement of the BZ. Unpleasant side effects have been described in 9% of M/P, 10% of BZ, 24% of F/D and 21% of other premedicants. On future occasions 10% of BZ-, 13% of the M/P-, 24% F/D- and 21%-receivers of other combinations would reject the same drug. Seven F/D and five M/P users converted their prescription schemes after they had received the same drug for their own premedication. The prescription habits were not influenced by dependency on departmental or hospital orders. Of those who had received it 75% desired premedication and 25% accepted premedication, suggesting that anesthesiologists believe in the positive effects of premedication. However, the overall incidence of 10% unpleasant side effects, even in the better ranked drugs, shows that the available premedicants do not yet seem to be satisfactory.

[Plexus analgesia in childhood with special consideration of the "loss of resistance"-method and psychic care of children (author's transl)]. / Die Plexusanalgesie im Kindesalter unter besonderer Berücksichtigung der "Loss of Resistance"-Methode und psychischen Betreuung der Kinder.

The possibility of a brachial plexus block in children is discussed and presented as a relatively safer method than general anaesthesia. 10 cases aged between 4 and 13 years are reported. Intensive verbal communication with the child during the procedure is essential and sedation may have disadvantages. Prolonged post-operative pain prevention can be achieved by in an indwelling Venflon cannula.

[Can pathological changes in the upper arm and axilla prevent a successful axillary plexus block? A case report]. / Wie weit sind pathologische Veränderungen im Bereich des Oberarmes und der Axilla als Hemmnis für die axilläre Plexusblockade anzusehen? (Fallbericht).

Even if one can find in the literature many contra indications to nerve blocks, this case with a pseudarthrosis of the humerus and severe scars in the axilla shows that non-inflammatory pathologic-anatomical changes need not prevent a brachial plexus block. Prerequisites are the ability to palpate the axillary artery and a reliable technique.

Pain control after hysterectomy: an observer-blind, randomised trial of lornoxicam versus tramadol.

This 24-hour, randomised, double-blind, placebo-controlled study compared the efficacy and tolerability of intravenous injections of lornoxicam 4 mg and 8 mg with tramadol 50 mg in 78 female patients aged 20-65 years with moderate to intolerable postoperative pain following mainly hysterectomy. Patients who received lornoxicam 8 mg had a significantly (p < 0.05) longer time to first remedication than placebo recipients and tended to have a greater reduction in pain intensity and a longer time to withdrawal due to "non-response' than tramadol and placebo patients. Lornoxicam was well tolerated at both doses and was associated with a lower incidence of adverse events than tramadol. Thus, intravenous lornoxicam at a dose of 8 mg is superior to placebo and at least as effective as intravenous tramadol 50 mg in relieving moderate to intolerable post-hysterectomy pain. Furthermore, lornoxicam seems to possess a more favourable tolerability profile than tramadol.

[Interaction of the calcium antagonists nifedipine and nisoldipine with the nondepolarizing muscle relaxant vecuronium bromide in an vivo rat preparation]. / Zur Wechselwirkung der Ca-Antagonisten Nifedipin und Nisoldipin mit dem nichtdepolarisierenden Muskelrelaxans Vecuroniumbromid im "in vivo" Rattenpräparat.

The interaction of two orally administered Ca-channel blockers, the dihydropyridines nisoldipine and nifedipine, with the non-depolarizing muscle relaxant, vecuronium bromide, was tested in the indirectly stimulated tibialis anterior muscle of anesthetized and ventilated Sprague-Dawley rats. In both the nisoldipine and the nifedipine group, depression of twitch tension and duration of vecuronium-induced neuromuscular blockade was potentiated when compared with a control group. The possible clinical relevance of these findings is discussed.

Potentiation of pancuronium induced neuromuscular blockade by calcium channel blockers in vitro.

The calcium channel blockers verapamil, methoxyverapamil, diltiazem, and nisoldipine have been tested for interactions with the nondepolarizing muscle relaxant pancuronium bromide by using the indirectly stimulated in vitro preparation of the rat hemidiaphragm. Dose response curves of each calcium channel blocker, pancuronium bromide, and combinations of both were determined. Each of the four calcium channel blocking drugs showed agonistic interaction in potentiating pancuronium induced neuromuscular blockade.

[Nifedipine and vecuronium bromide. How does a patient treated with calcium antagonists react to nondepolarizing muscle relaxants? Brief scientific communication]. / Nifedipin und Vecuroniumbromid. Wie reagiert der mit Ca-Antagonisten behandelte Patient auf nichtdepolarisierende Muskelrelaxantien? Kurze wissenschaftliche Mitteilung.

The muscle-relaxation reactions of Ca-antagonist (nifedipine) pretreated patients and a control group (5 in each group) were observed after administration of vecuronium bromide using the "priming principle." Twitch depression induced by the "priming dose" of vecuronium bromide (20 micrograms/kg body weight and T4/T1 ratio in the Ca-antagonist-treated patients (35 +/- 13% and 0.42 +/- 0.14%, respectively), was significantly different (P less than 0.01) when compared with the control group (1.2 +/- 2.7% and 0.75 +/- 0.15%). Similarly, the onset time to maximum blockade after the intubating dose of vecuronium bromide (60 micrograms/kg body wt.) was significantly shorter in the nifedipine group (40 +/- 21 s) when compared with the controls (100 +/- 17 s). The duration of the effect observed clinically (until 25% recovery) in the nifedipine group 32.9 +/- 7.3 min versus 25 +/- 8.15 min was enhanced; however, the difference between the treated group and the control group was not significant.

[Modification of patients positions in operation table during regional anaesthesia (author's transl)]. / Modifikationen der Lagerung bei Patienten unter Regionalanästhesie (Plexus-axillaris-Blockade).

The comfort was improved by better positioning on the operating table in six patients undergoing extensive hand surgery with axillary plexus block. Opposite to that we could show in 16 similar cases with traditional position during surgery some pain, chills and discomfort despite optimal block technique.

Comparative investigations on the cardiovascular effects of Org NC45 and pancuronium in dogs.

Cardiovascular effects of Org NC 45 and pancuronium were examined in seven anaesthetized dogs. Systemic circulatory effects were measured after increasing doses administered as a single i.v. bolus. Cardiac effects were measured after intracoronary (i.c.) injection of the equivalent dose of the respective neuromuscular blocking agent, which produced 90% neuromuscular blockade. Org NC 45 i.v. did not cause any significant cardiovascular changes, whereas pancuronium i.v. produced significant and dose-related increases in heart rate, left ventricular (LV) dP/dtmax and cardiac output (CO). After i.c. injection of equipotent doses, neither drug induced any significant change in haemodynamic measurements. This implies that neither drug exerted a direct influence on cardiac contractility, the increases in LV dP/dt max and CO following pancuronium being dependent on heart rate.

[The intraoperative use of falipamil (AQ-A39), a new calcium antagonist with specific bradytropic properties]. / Zum intraoperativen Einsatz von Falipamil (AQ-A39), einem neuen Kalziumantagonisten mit spezifisch bradytropen Eigenschaften.

Tachycardia caused by surgical stimulation can compromise the myocardial oxygen balance and may also lead to a reduction of cardiac output. Conventional drugs with negative chronotropic effects also cause reduction of inotropy. Recent so-called specific bradytropic agents are expected to act merely upon chronotropy without affecting pressure of the systemic or coronary circulation. The goal of this study was to investigate the effects of a calcium channel blocker. Falipamil, on the circulation controlling excessive intraoperative tachycardia. PATIENTS AND METHODS. In this study 15 patients, aged 32 to 73 years, mean 55 +/- 12 were investigated. The cardiac risk classes included classification I-III, according to Goldman. The patients underwent major abdominal or thoracoabdominal operations. Monitoring consisted of a radial arterial cannula, as well as a 7 French Swan-Ganz catheter, which was introduced via the internal jugular vein. Determination of cardiac output was done using the thermodilution technique with a Kimray Medical Association Oklahoma City model 3500; related indexes were calculated. Electrophysiological data were read from the ECG. The recorded QT interval was corrected for heart rate according to the formula of Hegglin and Holzmann. Anesthesia consisted of premedication with diazepam, 0.1 mg/kg, 1 h preoperatively. Anesthesia was induced with thiopentone, 5 mg/kg, and fentanyl, 1.5 micrograms/kg. After giving 1 mg alcuronium, succinylcholine, 1 mg/kg, was used for intubation. Anesthesia was continued using ventilation with O2: N2O 1:2 and intermittent doses of fentanyl and alcuronium. When tachycardia occurred at a rate higher than 100 beats per minute, a dose of 2 micrograms/kg fentanyl was administered to deepen the anesthesia. If this had no influence, control readings were taken and subsequently falipamil 2 mg/kg was injected. After that the hemodynamic parameters were monitored for 1, 2, 3, 5, 10, and 20 min. Statistical analysis was performed using the analyses of variance, followed by the Newman-Keuls test. The level of significance was p less than 0.05. RESULTS. The means and standard deviations of the hemodynamic parameters following induction of anesthesia (0) and at the peak rate are shown in Table 1. The mean increase in heart rate at that time was 38 +/- 18% and the QT and RR interval were reduced concomitantly. Both times the QT measured and the QT corrected for rate did not significantly differ from each other. (ABSTRACT TRUNCATED AT 400 WORDS)

[Malignant hyperthermia in swine: a study of atracurium in MH-susceptible swine]. / Maligne Hyperthermie des Schweines: Untersuchung von Atracurium an MH-empfindlichen Schweinen.

Since muscle relaxants have been implicated in triggering malignant hyperthermia (MH) in MH-susceptible humans and animals, the potential of new muscle relaxants for triggering MH needs to be assessed in vivo in MH-susceptible pigs. The triggering potential of atracurium was evaluated in six MH-susceptible pigs during one hour infusion of a 90% blocking dose (0.4 mg/kg/h) of atracurium. The mean recovery time (25% to 75%) was 10.2 min and a slight increase in heart rate (142 to 170 beats per minute) was observed. Rectal temperature decreased slightly (36.4 to 35.6 degrees C) and end tidal CO2 was stable at 5.46 kpa. In this study atracurium did not trigger MH in susceptible pigs.

Continuous spinal anesthesia with a microcatheter and low-dose bupivacaine decreases the hemodynamic effects of centroneuraxis blocks in elderly patients.

This prospective randomized study was designed to investigate the hemodynamic effects and quality of continuous spinal anesthesia (CSA) after rapid injection of a low dose of 0.5% bupivacaine through a 32-gauge microcatheter. The method was compared with continuous epidural (CEA) and single-dose spinal anesthesia (SSA). Seventy-seven elderly patients (ASA II-III) ranging from 57 to 94 yr old and undergoing lower limb surgery were assigned to CSA (n = 26), CEA (n = 26), and SSA groups (n = 25). In all three groups, mean arterial pressure (MAP) and heart rate (HR) were assessed continuously for 30 min after initial injection, as well as after every reinjection of local anesthetic in the CSA and CEA groups. Bupivacaine (0.5%) was used as a local anesthetic. The initial doses were 1 mL of CSA, 10 mL of CEA, and 3 mL of SSA. The reinjection doses were 1 mL of CSA and 5 mL of CEA. In the CSA group, MAP did not decrease, whereas in the CEA group, the maximum decrease was 15% +/- 3% (mean +/- SEM) for the initial injection, 12% +/- 2% for the first repetition, and 13% +/- 2% for the second repetition. In the SSA group, the largest decrease of MAP was 19% +/- 2%. All changes of MAP in the CEA and SSA groups were significantly larger compared with CSA group (P < 0.05). A total of seven patients in these two groups needed vasopressors due to a decrease of MAP of more than 30% from baseline values. Heart rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

[X-ray control of position of subclavian catheter necessary or not? (author's transl)]. / Ist die angiographische Kontrolle eines Zentralvenekatheters erforderlich?

After subclavian vein cannulation of a 49 year old woman, the catheter was found within the pleural space by a special X-ray-technique. The rare complication stresses the importance of checking the position of a vena cava catheter by X-ray, using radio-opaque dye.