Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ±â€Š89 vs. 7 ±â€Š1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Effects of transcranial direct current stimulation of the primary sensory cortex on somatosensory perception.

BACKGROUND: Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and activity in humans. OBJECTIVE: The aim of the present study was to analyze the effects of tDCS of the primary sensory cortex (SI) on thermal and mechanical perception, assessed by quantitative sensory testing (QST). METHODS: The comprehensive QST protocol encompassing thermal and mechanical detection and pain thresholds as devised by the German Research Network on Neuropathic Pain (DFNS) was applied to skin areas innervated by the radial and median nerve of 12 healthy subjects, who were examined before and after each tDCS stimulation type. Anodal, cathodal, and sham tDCS was applied at a 1 mA current intensity with the active electrode placed over the left primary sensory cortex (SI) and the reference electrode above the right orbit for 15 minutes. RESULTS: After cathodal tDCS cold detection threshold (CDT) significantly increased in the contralateral (P < .01) and ipsilateral hand (P < .05) as compared to baseline condition and sham stimulation, after cathodal stimulation significantly increased warm detection threshold (WDT) was observed in the contralateral hand when compared with the baseline condition (P < .05) but not with sham stimulation. Thermal pain as well as mechanical detection and pain thresholds remained unaltered. CONCLUSIONS: Cathodal tDCS of the primary sensory cortex significantly reduced the sensitivity to Aδ-fiber-mediated cold sensation, C-fiber-mediated warm sensation was reduced only compared with baseline, whereas Aß-fiber-mediated somatosensory inputs were less affected. Our results correspond with our previous observations of primary motor cortex tDCS effects on QST parameters.

The role of quantitative sensory testing in the evaluation of musculoskeletal pain conditions.

Quantitative sensory testing (QST) is a noninvasive method of assessing sensory and pain perception that has been used in the past 30 years primarily for analysis of cutaneous and mucosal perception. In recent years, several published studies have demonstrated that QST may be useful in the analysis of painful musculoskeletal disorders as well. Based on the results of these studies, it can be postulated that QST may be useful in the analysis of the pathogenesis, classification, and differential diagnosis of musculoskeletal disorders. However, due to the diverse ethiopathogenetic basis of these disorders, a broad range of QST test batteries may be necessary to analyze the various musculoskeletal disease entities. This review analyzes published studies on this subject and summarizes current information on altered sensory and pain perception available for some of the most common musculoskeletal disorders. At present, QST remains primarily a research tool but may be useful in differential diagnosis in indicating the presence of central sensitization and for clinical monitoring of disease progression or treatment response.

Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome.

This study aimed to assess thermal and mechanical perception and pain thresholds in primary idiopathic restless legs syndrome and secondary restless legs syndrome associated with small fibre neuropathy. Twenty-one patients (age: 53.4 + or - 8.4, n = 3, male) with primary restless legs syndrome and 13 patients (age: 63.0 + or - 8.2, n = 1, male) with secondary restless legs syndrome associated with small fibre neuropathy were compared with 20 healthy subjects (age: 58.0 + or - 7.0; n = 2, male). Differential diagnosis of secondary restless legs syndrome associated with small fibre neuropathy was based on clinical symptoms and confirmed with skin biopsies in all patients. A comprehensive quantitative sensory testing protocol encompassing thermal and mechanical detection and pain thresholds, as devised by the German Research Network on Neuropathic Pain, was performed on the clinically more affected foot between 2 pm and 1 am when restless legs syndrome symptoms were present in all patients. Patients with primary restless legs syndrome showed hyperalgesia to blunt pressure (P < 0.001), pinprick (P < 0.001) and vibratory hyperaesthesia (P < 0.001). Patients with secondary restless legs syndrome associated with small fibre neuropathy showed thermal hypoaesthesia to cold (Adelta-fibre mediated) and warm (C-fibre mediated) (all P < 0.001) and hyperalgesia to pinprick (P < 0.001). Static mechanical hyperalgesia in primary and secondary restless legs syndrome is consistent with the concept of central disinhibition of nociceptive pathways, which might be induced by conditioning afferent input from damaged small fibre neurons in secondary restless legs syndrome.

How far can we go with positive end-expiratory pressure (PEEP) in liver transplant patients?

STUDY OBJECTIVE: To assess the effect of positive end-expiratory pressure (PEEP) up to 15 cm H(2)O on blood flow throughput of the liver and its effects on systemic hemodynamics in patients following liver transplantation. DESIGN: Prospective, interventional study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: 74 consecutive liver transplant recipients with a regular allocated cadaveric graft. INTERVENTION: The lungs of all study patients were postoperatively mechanically ventilated with biphasic positive airway pressure. Three different PEEP levels (5, 10, and 15 cm H(2)O) were randomly set within 4 hours of admission to the ICU. Systemic hemodynamic parameters were recorded using a pulmonary artery catheter and flow velocities were measured of the hepatic artery, portal vein, and right hepatic vein using a Doppler. MEASUREMENTS AND MAIN RESULTS: PEEP of 15 cm H(2)O induced a significant increase in central venous pressure and pulmonary capillary wedge pressure versus PEEP 5 cm H(2)O. Flow velocities of the right hepatic vein, portal vein, and hepatic artery were not influenced by PEEP. There also was no impact of increased PEEP on mean arterial pressure or cardiac index. CONCLUSION: PEEP up to 15 cm H(2)O does not impair liver outflow or systemic hemodynamics in liver transplant patients.

Is positive end-expiratory pressure suitable for liver recipients with a rescue organ offer?

PURPOSE: Rescue organ offers may help to overcome the organ shortage. However, because of initial poor liver function, the recipient may develop a severe lung injury with the requirement for higher positive end-expiratory pressure (PEEP) levels to achieve adequate oxygenation. Positive end-expiratory pressure has been associated with perfusion impairment in the hepatosplanchnic area. We assessed the effects of increased PEEP levels on systemic hemodynamic and liver perfusion in liver transplantation (LT) patients with a rescue organ. METHODS: Twenty-four LT recipients of a rescue organ offer were enrolled. All patients were postoperatively mechanically ventilated with biphasic positive airway pressure, and 3 different PEEP levels (0, 5, 10 mbar) were randomly set within 4 hours after admission at the intensive care unit. Systemic hemodynamic parameters were recorded using a pulmonary artery catheter; and flow velocities of the hepatic artery, portal vein, and right hepatic vein were measured using Doppler. RESULTS: Positive end-expiratory pressure of 10 mbar did not impair the systemic hemodynamic. Flow velocities in the right hepatic vein, the portal vein, and the hepatic artery were not influenced by PEEP. CONCLUSION: Our study demonstrates that PEEP up to 10 mbar did not impair the liver outflow in recipients with a rescue organ offer.

Neurologic complications in adult living donor liver transplant patients: an underestimated factor?

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Effect of buspirone on thermal sensory and pain thresholds in human volunteers.

BACKGROUND: Buspirone is a partial 5-HT1A receptor agonist. Animal studies have shown that modulation of serotoninergic transmission at the 5-HT1A receptor can induce analgesia in acute pain models. However, no studies have been published so far on the effects of serotonin receptor agonists on pain perception in humans. METHODS: The effects of buspirone (30 mg p.o.) on thermal sensory and pain thresholds were investigated in twelve female volunteers (26 +/- 2 yrs) in a prospective, randomized, double-blind, double-dummy, placebo-controlled study with morphine (10 mg i.v.) as positive control. RESULTS: Morphine significantly increased the heat pain detection threshold (DeltaT: placebo 1.0 degrees C and 1.3 degrees C, p < 0.05) at 60 minutes. Buspirone caused mild sedation in six participants at 60 minutes, but was without effect on any of the measured parameters. CONCLUSION: Buspirone in the maximal recommended dose was without significant effect on thermal pain. However, as it is only a partial agonist at the 5-HT1A receptor and also acts on other receptor types, the negative results of the present study do not rule out a possible analgesic effect of more specific 5-HT1A receptor agonists.

Effect of thermode application pressure on thermal threshold detection.

Studies using quantitative sensory testing (QST) often present incongruent results due to intra- and intersubject as well as interobserver variability which limit widespread use of the technique. Eliminating or reducing the factors responsible for this variability is of great interest, as it increases reliability and reproducibility of QST. Thermal sensory threshold determination is a crucial part of QST. It was previously suggested that the pressure of the thermode on the skin could influence measurements. To verify this, we developed a new thermode with a built-in pressure sensor. Thresholds obtained with this thermode were compared to those obtained with a commercially available thermotesting device (Medoc TSA-II). Heat detection and heat pain detection thresholds were higher, and cold detection thresholds were lower when measured with our thermode than they were with the Medoc thermode. Cold pain detection thresholds did not differ between the thermodes. Analysis of the heat transfer capacity of the thermodes indicated that the material of the skin contact surface of the thermode may play a role in these shifts in threshold values. Altering the thermode pressure on the skin did not affect the thermal thresholds. Furthermore, the intrasubject variability of the measurements (minimal-to-maximal range of measured threshold values in individual subjects) was also not influenced by the pressure with which the thermode was attached to the skin. Our results suggest that the pressure with which the thermode is attached to the skin does not significantly affect the intra- and intersubject reproducibility of the thermal sensory threshold measurements.

Pulmonary and blood stream infections in adult living donor and cadaveric liver transplant patients.

BACKGROUND: Infectious complications occur in approximately 50% of cadaveric liver transplant (CDLT) recipients. Living-donor liver transplantation (LDLT) is an established alternative to shorten the waiting time. Currently, the incidence of pulmonary infections after LDLT and the microbiologic causes are unknown. In the present cohort study, we compared the incidence and profiles of pulmonary and blood stream infections (BSI) between LDLT and CDLT recipients. We hypothesized a lower incidence in LDLT recipients. METHODS: The clinical course of 55 LDLT recipients consecutively transplanted between January 2003 and December 2006 was analyzed. The 173 CDLT recipients who were transplanted in the same period served as a control group. Patients were treated in a single Intensive Care Unit, applying standardized postoperative care. RESULTS: Mean model for end-stage liver disease score did not differ between LDLT and CDLT recipients (14.2 vs. 13.3). The overall incidence of pulmonary and BSI for both groups was 8% and 24%, respectively. Pulmonary infections were experienced by 18% of LDLT versus 5% of CDLT recipients (P=0.005) and BSI occurred in 33% of LDLT versus 21% of CDLT recipients (P=0.1). CONCLUSIONS: In contrast to our hypothesis, LDLT recipients experienced significantly more pulmonary infections and a trend toward increased higher incidence of BSI. These findings emphasize the need for future research on the causative agents and prevention of infection in LDLT recipients. The observation that patients with pulmonary infection had a significantly reduced 1-year survival rate underscores the importance of our observations.

Positive end-expiratory pressure induces liver congestion in living donor liver transplant patients: myth or fact.

Living-donated liver transplant (LDLT) patients may develop lung edema during reperfusion, requiring higher positive end-expiratory pressure (PEEP) levels, which may impair liver outflow. The aim of the study was to assess the effect of increased PEEP levels on venous liver outflow and systemic hemodynamics in patients after LDLT. Thirty-nine LDLT recipients were enrolled in this study. All patients were postoperatively pressure-controlled ventilated and three different PEEP levels (0, 5 and 10 mbar) were randomly set. Systemic hemodynamic parameters and flow velocities of the hepatic artery, portal vein, and right hepatic vein were recorded at each PEEP level. PEEP of 10 mbar increased significantly central venous and pulmonary capillary pressure. Flow velocities in the right hepatic vein, the portal vein, the hepatic artery, mean arterial pressure, pulmonary arterial pressure, and cardiac index were not influenced by PEEP. Our study demonstrated that PEEP up to 10 mbar did not impair liver outflow in LDLT recipients.

Portopulmonary hypertension in the early phase following liver transplantation.

BACKGROUND: Portopulmonary hypertension (PPH) is a severe complication of liver cirrhosis, which poses a high risk for postliver transplantation (LT) mortality. In most liver transplant centers, severe PPH is viewed as an absolute contraindication for LT, but recent reports challenge this. The purpose of our study was to determine the incidence of PPH, its influence on the 30-day mortality rate following LT and to determine the sensitivity and specificity of Doppler echocardiography and electrocardiography as noninvasive tools to determine PPH. METHODS: We studied 74 consecutive patients that underwent LT between February 2004 and November 2005. Pulmonary arterial pressure and cardiac index were repeatedly determined during surgery and postoperatively. PPH was defined as mild (mean pulmonary arterial pressure (MPAP) 25-35 mm Hg), moderate (MPAP of 35-45 mm Hg) and as severe (MPAP >45 mm Hg). RESULTS: The total incidence of PPH was 31% (16 mild, 5 moderate, and 2 severe). There was a tendency towards increased 30-day mortality rate in patients with PPH compared to controls (22% vs. 12%, P=0.1). However, the two patients with the most severe PPH survived. The duration of ventilation and total stay at the intensive care unit did not differ significantly between groups. The positive predictive value of Doppler echocardiography for PPH was 39% and the negative predictive value 90%. CONCLUSIONS: Mild pulmonary hypertension is common in patients with liver failure, whereas moderate and severe hypertension is not. Severe PPH should not be considered as absolute contraindication for LT.

Does PEEP impair the hepatic outflow in patients following liver transplantation?

OBJECTIVE: Evaluation of the impact of end-expiratory pressure (PEEP) ventilation on venous liver outflow, portal vein, and hepatic artery flows as well as systemic hemodynamics in patients following liver transplantation (LT). DESIGN: Prospective, interventional patient study. SETTING: University hospital intensive care unit. PATIENTS: 65 consecutive patients after LT. INTERVENTIONS: All patients were intubated and mechanically ventilated with biphasic positive airway pressure (BIPAP). The effects of three levels of PEEP (0, 5, and 10 mbar) applied at random order on hepatic inflow and outflow were studied in the immediate postoperative period. MEASUREMENT AND RESULTS: Central venous-, arterial pressure, and cardiac index was recorded from every patient at three different PEEP levels (0, 5, and 10 mbar). Simultaneously, flow velocities in the hepatic-, portal vein, and hepatic artery were determined by Doppler ultrasound. PEEP of 10 mbar significantly increased central venous pressure in comparison with zero PEEP. Mean arterial pressure and cardiac index was not influenced. Hepatic inflow and outflow of the transplanted livers were not impaired by any of the used PEEP levels. CONCLUSIONS: BIPAP ventilation with PEEP levels up to 10 mbar does not affect systemic hemodynamics. Furthermore, neither venous outflow nor portal venous or hepatic artery inflow of the liver are impaired at PEEP levels up to 10 mbar immediately following liver transplantation. Although these results suggest that PEEP ventilation up to 10 mbar does not affect liver hemodynamics, further studies are needed to determine whether these findings could be confirmed for a longer ventilation period with PEEP.

Both local anesthetics and salbutamol pretreatment affect reflex bronchoconstriction in volunteers with asthma undergoing awake fiberoptic intubation.

BACKGROUND: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a beta2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. STATISTICS: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD. RESULTS: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo inhalation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l; P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline. CONCLUSION: In asthmatics, awake fiberoptic intubation evokes a more than 50% decrease in FEV1 following dyclonine inhalation. Using lidocaine for topical anesthesia the decrease in FEV1 is significantly mitigated (35%) and can be even further attenuated by salbutamol pretreatment. Therefore, combined treatment with lidocaine and salbutamol can be recommended for awake intubation while the use of dyclonine, despite its excellent and longer lasting topical anesthesia, may be contraindicated in patients with bronchial hyperreactivity.

Lung function under high thoracic segmental epidural anesthesia with ropivacaine or bupivacaine in patients with severe obstructive pulmonary disease undergoing breast surgery.

BACKGROUND: Because general anesthesia with tracheal intubation can elicit life-threatening bronchospasm in patients with bronchial hyperreactivity, epidural anesthesia is often preferred. However, segmental high thoracic epidural anesthesia (sTEA) causes pulmonary sympathetic and respiratory motor blockade. Whether it can be safely used for chest wall surgery as a primary anesthetic technique in patients with chronic obstructive pulmonary disease or asthma is unclear. Furthermore, ropivacaine supposedly evokes less motor blockade than bupivacaine and might minimize side effects. To test the feasibility of the technique and the hypotheses that (1) sTEA with ropivacaine or bupivacaine does not change lung function and (2) there is no difference between sTEA with ropivacaine or bupivacaine, the authors studied 20 patients with severe chronic obstructive pulmonary disease (forced expiratory volume in 1 s [FEV1] = 52.1 +/- 17.3% of predicted [mean +/- SD]) or asthma who were undergoing breast surgery. METHODS: In a double-blind, randomized fashion, sTEA was performed with 6.6 +/- 0.5 ml of either ropivacaine, 0.75% (n = 10), or bupivacaine, 0.75% (n = 10). FEV1, vital capacity, FEV1 over vital capacity, spread of analgesia (pin prick), hand and foot skin temperatures, mean arterial pressure, heart rate, and local anesthetic plasma concentrations were measured with patients in the sitting and supine positions before and during sTEA. RESULTS: Segmental high thoracic epidural anesthesia (segmental spread C4-T8 [bupivacaine] and C5-T9 [ropivacaine]) significantly decreased FEV1 from 1.22 +/- 0.54 l (supine) to 1.09 +/- 0.56 l (ropivacaine) and from 1.23 +/- 0.49 l to 1.12 +/- 0.46 l (bupivacaine). In contrast, FEV1 over vital capacity increased from 64.6 +/- 13.5 to 68.2 +/- 14.5% (ropivacaine) and from 62.8 +/- 12.4 to 66.5 +/- 13.6% (bupivacaine). There was no difference between ropivacaine and bupivacaine. Skin temperatures increased significantly, whereas arterial pressure and heart rate significantly decreased indicating widespread sympathetic blockade. All 20 patients tolerated surgery well. CONCLUSIONS: Despite sympathetic blockade, sTEA does not increase airway obstruction and evokes only a small decrease in FEV1 as a sign of mild respiratory motor blockade with no difference between ropivacaine and bupivacaine. Therefore, sTEA can be used in patients with severe chronic obstructive pulmonary disease and asthma undergoing chest wall surgery as an alternative technique to general anesthesia.