J. Schüttler

Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans.

Background Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the &mgr;-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the &agr;2-receptor agonist clonidine. Methods Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 ± 16.8 mA, mean ± SD) induced acute pain (numerical 11-point rating scale: 5–6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 &mgr;g · kg−1 · min−1 and S-ketamine at 5 &mgr;g · kg−1 · min−1 over a period of 30 min, respectively; clonidine infusion at 2 &mgr;g/kg for 5 min). Results Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings. Conclusions Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the &agr;2-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.

A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine.

Background The authors used the analgesics alfentanil, S (+)-ketamine, and systemic lidocaine to examine a new human model of experimental pain and hyperalgesia. Methods Transcutaneous electrical stimulation at a high current density (5 Hz, 67.5 ± 6.6 mA) was used to provoke acute pain (numeric rating scale, 5 of 10), stable areas of secondary mechanical hyperalgesia to pin prick (43.6 ± 32.1 cm2), and light touch (27.5 ± 16.2 cm2) for 2 h. Alfentanil, S (+)-ketamine, and lidocaine were applied for 20 min in a double-blind, placebo-controlled, crossover design in 12 subjects using target controlled infusions. Results In the placebo session, pain ratings and areas of hyperalgesia were stable during the stimulation period, which facilitated the assessment of analgesic effects. Alfentanil effectively inhibited electrically evoked pain and reduced pin prick hyperalgesia and allodynia during its infusion. S (+)-ketamine–induced inhibition of secondary hyperalgesia was more pronounced and lasted for the whole experimental protocol. Therapeutic levels of systemic lidocaine showed only marginal analgesic effects, but lasting antihyperalgesic effects. Conclusions A new model of electrically induced pain and hyperalgesia was established, which enabled assessment of the time course of analgesic and antihyperalgesic effects with high temporal resolution and minimum tissue damage and which was further validated by use of common intravenous anesthetics.

One-year survival after out-of-hospital cardiac arrest in Bonn city: outcome report according to the 'Utstein style'.

Outcome after prehospital cardiac arrest was examined in the EMS system of Bonn, a midsized urban community, and presented according to the Utstein style. The data were collected from January 1st, 1989 to December 31st, 1992 by the Bonn-north ALS unit, which serves 240,000 residents. Fifty-six patients suffered from cardiac arrest of non-cardiac aetiology and were excluded; 464 patients were resuscitated after cardiac arrest of presumed cardiac aetiology (incidence of CPR attempts: 48.33 per year/100,000 population). The collapse was unwitnessed, bystander witnessed or EMS personnel witnessed in 178, 214 or 72 patients, respectively. In these subgroups discharge rates and 1-year survival accounted for 7.3% (4.5%), 22.9% (15.9%) and 16.7% (11.1%), respectively. Thirty-four patients were discharged without neurological deficits (cerebral performance category 1: CPC 1), 22 and nine patients scored CPC 2 or CPC 3, respectively. Nine patients were comatose (CPC 4) when they were discharged and remained in this state until they died. Of the 50 1-year survivors 35 lived without neurological deficit, eight demonstrated mild (CPC 2) and five severe (CPC 3) cerebral disability at 1-year after resuscitation, and, finally, two patients remained comatose for more than 1 year. The Utstein template recommends the selection of patients who were found in VF after bystander witnessed collapse. In our cohort 118 patients met these criteria. Of them 41 (35%) could be discharged from hospital and 28 (24%) lived more than 1 year. The comparison of our data with those from double-response EMS systems of other communities revealed that, in midsized urban and suburban communities the highest discharging rates could be achieved. Our study demonstrated that survival depends crucially on short response intervals and life support which will be performed by well-trained emergency technicians, paramedics and physicians.

Spinal Endocannabinoids and CB1 Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization

Plastic Pain Perception Drugs and endocannabinoids acting on cannabinoid (CB) receptors have potential in the treatment of certain types of pain. In the spinal cord they are believed to suppress nociception, the perception of pain and noxious stimuli. Pernia-Andrade et al. (p. 760) now find that endocannabinoids, which are released in spinal cord by noxious stimulation, may promote rather than inhibit nociception by acting on CB1 receptors. Endocannabinoids not only depress transmission at excitatory synapses in the spinal cord, but also block the release of inhibitory neurotransmitters, thereby facilitating nociception. Noxious stimulation releases endocannabinoids in the spinal cord that may promote, rather than inhibit, the perception of pain. Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways that reduce synaptic inhibition in inflammatory and neuropathic pain states have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C-fiber) input to the spinal dorsal horn. We found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB1) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of γ-aminobutyric acid and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Our results suggest that spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits.

Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care--short version.

Targeted monitoring of analgesia, sedation and delirium, as well as their appropriate management in critically ill patients is a standard of care in intensive care medicine. With the undisputed advantages of goal-oriented therapy established, there was a need to develop our own guidelines on analgesia and sedation in intensive care in Germany and these were published as 2nd Generation Guidelines in 2005. Through the dissemination of these guidelines in 2006, use of monitoring was shown to have improved from 8 to 51% and the use of protocol-based approaches increased to 46% (from 21%). Between 2006–2009, the existing guidelines from the DGAI (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) were developed into 3rd Generation Guidelines for the securing and optimization of quality of analgesia, sedation and delirium management in the intensive care unit (ICU). In collaboration with another 10 professional societies, the literature has been reviewed using the criteria of the Oxford Center of Evidence Based Medicine. Using data from 671 reference works, text, diagrams and recommendations were drawn up. In the recommendations, Grade “A” (very strong recommendation), Grade “B” (strong recommendation) and Grade “0” (open recommendation) were agreed. As a result of this process we now have an interdisciplinary and consensus-based set of 3rd Generation Guidelines that take into account all critically illness patient populations. The use of protocols for analgesia, sedation and treatment of delirium are repeatedly demonstrated. These guidelines offer treatment recommendations for the ICU team. The implementation of scores and protocols into routine ICU practice is necessary for their success.

The cyclooxygenase isozyme inhibitors parecoxib and paracetamol reduce central hyperalgesia in humans.

&NA; Non‐steroidal antiinflammatory drugs (NSAIDs) are known to induce analgesia mainly via inhibition of cyclooxygenase (COX). Although the inhibition of COX in the periphery is commonly accepted as the primary mechanism, experimental and clinical data suggest a potential role for spinal COX‐inhibition to produce antinociception and reduce hypersensitivity. We used an experimental model of electrically evoked pain and hyperalgesia in human skin to determine the time course of central analgesic and antihyperalgesic effects of intravenous parecoxib and paracetamol (acetaminophen). Fourteen subjects were enrolled in this randomized, double blind, and placebo controlled cross‐over study. In three sessions, separated by 2‐week wash‐out periods, the subjects received intravenous infusions of 40 mg parecoxib, 1000 mg paracetamol, or placebo. The magnitude of pain and areas of pinprick‐hyperalgesia and touch evoked allodynia were repeatedly assessed before, and for 150 min after the infusion. While pain ratings were not affected, parecoxib as well as paracetamol significantly reduced the areas of secondary hyperalgesia to pinprick and touch. In conclusion, our results provide clear experimental evidence for the existence of central antihyperalgesia induced by intravenous infusion of two COX inhibitors, parecoxib and paracetamol. Since the electrical current directly stimulated the axons, peripheral effects of the COX inhibitors on nociceptive nerve endings cannot account for the reduction of hyperalgesia. Thus, besides its well‐known effects on inflamed peripheral tissues, inhibition of central COX provides an important mechanism of NSAID‐mediated antihyperalgesia in humans.

Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by Parecoxib in Humans

Background:Numerous experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. It is suggested that spinal cyclooxygenase activity may contribute to the development and expression of opioid tolerance. The aim of the investigation was to determine analgesic and antihyperalgesic properties of the cyclooxygenase-2 inhibitor parecoxib on remifentanil-induced hypersensitivity in humans. Methods:Fifteen healthy male volunteers were enrolled in this randomized, double-blind, placebo-controlled study in a crossover design. Transcutaneous electrical stimulation at high current densities was used to induce spontaneous acute pain (numeric rating scale 6 of 10) and stable areas of pinprick hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during, and after a 30-min intravenous infusion of remifentanil (0.1 &mgr;g · kg−1 · min−1) or placebo (saline). Parecoxib (40 mg) was administered intravenously either with onset of electrical stimulation (preventive) or in parallel to the remifentanil infusion. Results:Remifentanil reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level. Preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion (71.3 ± 7 vs. 46.4 ± 17% of control) and significantly diminished the hyperalgesic response after withdrawal. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanil-induced hyperalgesia. Conclusion:The results confirm clinically relevant interaction of &mgr; opioids and prostaglandins in humans. Adequate timing seems to be of particular importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors.

Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans

&NA; In contrast to an expected preventive analgesic effect, clinical observations suggest that intraoperatively applied opioids can induce postoperative hyperalgesia. We tested the development of post‐infusion hyperalgesia in a newly developed experimental model of electrically induced pain and secondary mechanical hyperalgesia. In a double‐blind, placebo controlled, cross‐over study, 13 subjects received either saline placebo, remifentanil (0.05 or 0.1 &mgr;g/kg/min) or naloxone (0.01 mg/kg). Remifentanil dose‐dependently reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level (p<0.01 and p<0.05, respectively). Naloxone infusion similarly resulted in increased pain (anti‐analgesia) (p<0.001) and mechanical hyperalgesia (p<0.01). Increased pain ratings following withdrawal of remifentanil significantly correlated to anti‐analgesia evoked by the &mgr;‐opioid antagonist naloxone (p<0.01) and was of similar magnitude, suggesting inhibition of endogenous opioids as an underlying mechanism. In contrast, hyperalgesia after remifentanil was more pronounced than hyperalgesia after naloxone administration and did not correlate to the observed anti‐analgesic effects, suggesting the involvement of additional receptors systems other than the endorphin system.

Precision and accuracy of a new device (CNAP™) for continuous non-invasive arterial pressure monitoring: assessment during general anaesthesia

BACKGROUND Continuous non-invasive arterial pressure measured with CNAP (CNAP) has been shown to be superior to intermittent oscillometric measurements during procedural sedation and spinal anaesthesia. We assessed the performance of CNAP during general anaesthesia by analysis of agreement with invasive measurements of arterial pressure (AP). METHODS Eighty-eight patients undergoing elective abdominal surgery, cardio-, or neurosurgery were included in the study. Systolic, diastolic, and mean AP measured by an intra-arterial catheter in the radial artery (IAP) were compared with those obtained by CNAP from the same arm. Data were analysed to determine the precision (i.e. measurement error) and accuracy (i.e. systematic error) of beat-to-beat CNAP values with respect to IAP. Also, we compared the frequency of fast changes in AP (FCAP) and hypotension (IOH) by both methods. RESULTS CNAP precision of 4.5, 3.1, and 3.2 mm Hg (systolic, diastolic, and mean AP, respectively) was not significantly different from IAP precision, and CNAP accuracy was +6.7, -5.6, and -1.6 mm Hg. The frequency of AP pairs having a difference within the calculated limits of agreement was 81%, 64%, and 76% for systolic, diastolic, and mean AP, respectively. The calculated limits of agreement were +/-17.6, +/-11.4, and +/-12.0 mm, Hg, respectively. CNAP and IAP detected simultaneously to 82.1% FCAP and to 84.6% IOH. CONCLUSIONS CNAP provides real-time estimates of arterial pressure comparable with those generated by an invasive intra-arterial catheter system during general anaesthesia.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients

BACKGROUND Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.