The cholinergic system in joint health and osteoarthritis: a narrative-review.

Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed.

Comparison of the effects of intrathecal administration of levobupivacaine and lidocaine on the prostaglandin E2 and glutamate increases in cerebrospinal fluid: a microdialysis study in freely moving rats.

BACKGROUND: Bupivacaine has a lower incidence of transient neurological symptoms than lidocaine after intrathecal (i.t.) injection. The increased toxic potential of lidocaine does not support its use in the clinical setting and could be related to augmented levels of spinal prostaglandin E(2) (PGE(2)). We tested whether levobupivacaine leads to lower PGE(2) levels than lidocaine. Moreover, we compared the release of PGE(2) and glutamate after i.t. injections of levobupivacaine or lidocaine. METHODS: Rats were anaesthetized for implantation of an i.t. dialysis catheter. This allowed sampling dialysates of cerebrospinal fluid (CSF) for measuring PGE(2) and glutamate levels. The microdialysis setting included baseline sampling and was followed by an i.t. injection of levobupivacaine 250 microg, 100 microg, or saline. PGE(2) and glutamate levels in CSF were analysed for 4 h. In addition, the residual effect of a second i.t. injection on, respectively, of PGE(2) and glutamate changes was compared after injection of either 250 or 100 microg levobupivacaine, 1000 or 400 microg lidocaine, or saline. RESULTS: Prolonged spinal PGE(2) increases lasting 50-120 min were observed after levobupivacaine injection. Higher PGE(2) concentrations were observed after the second lidocaine 1000 microg injection. Glutamate release after the second injection did not vary between the local anaesthetic groups. CONCLUSIONS: Spinal PGE(2) levels are similarly increased after i.t. levobupivacaine injection of 250 and 100 microg. A higher PGE(2) response was observed after a second i.t. injection in the animals receiving 1000 microg lidocaine than those receiving 400 mg lidocaine or either dose of levobupivacaine.

Intrathecal lidocaine elevates prostaglandin E2 levels in cerebrospinal fluid: a microdialysis study in freely moving rats.

BACKGROUND: In this study, we have investigated whether intrathecal (i.t.) lidocaine administration is accompanied with changes of cerebrospinal fluid (CSF) prostaglandin E(2) (PGE(2)) levels. METHODS: Rats were anaesthetized for i.t. implantation of a triple-lumen spinal loop dialysis catheter. CSF changes in PGE(2) after i.t. injection of saline, 400, or 1000 microg of lidocaine were measured. The impact of i.t. pretreatment with 5 microg MK801 (N-methyl-D-aspartate glutamate antagonist) or 10 microg SC76309A (COX-2 inhibitor) was also investigated. CSF dialysates for measurement of PGE(2) were collected for 4 h. During the whole procedure, motor and sensory blocks were evaluated. A separate group receiving i.t. lidocaine 400 microg (without dialysate sampling) was assessed for mechanical (Von Frey) and radiant heat pain. RESULTS: PGE(2) levels increased to 400% of baseline and remained elevated for 90-120 min after i.t. lidocaine at both doses. Pretreatment with SC76309A and MK801 attenuated this increase. A 40 min period of enhanced pain response was observed after Von Frey filament stimulation during and after sensory and motor block recovery. CONCLUSIONS: I.T. lidocaine (400 or 1000 microg) increases PGE(2) levels in the CSF for 90-120 min along with a transient period of mechanical hyperalgesia after sensory and motor block recovery.

Endometrial ossification and infertility: the diagnostic value of different imaging techniques.

We present a case of longstanding secondary subfertility caused by endometrial ossification. Of all diagnostic techniques performed, magnetic resonance imaging and hysterosalpingography did not detect the abnormality. Transvaginal ultrasound and computed tomography clearly showed the endometrial pathology. After successful operative hysteroscopy with removal of the osseous tissue, the patient became pregnant spontaneously within 2 months.

Remifentanil sedation compared with propofol during regional anaesthesia.

BACKGROUND: The short onset and offset of remifentanil may allow for accurate dosing of sedative effect with few side-effects and rapid recovery. In this study remifentanil is compared with propofol for sedation during successful regional anaesthetic blocks. METHODS: After informed consent was given, 125 patients undergoing surgery under spinal or brachial plexus anaesthesia were randomized to receive, either propofol: bolus 500 microg/kg plus initial infusion 50 microgkg/min or remifentanil: bolus 0.5 microg/kg plus initial infusion 0.1 microgkg/min. Study drug infusion rate was titrated throughout the procedure according to level of sedation and side-effects. Pain, discomfort, sedation level and side-effects were recorded at regular intervals until discharge from the post operative care unit (PACU). RESULTS: Two patients in the remifentanil group versus ten in the propofol group were treated for discomfort or pain during surgery (P<0.02). Due to a significantly higher rate of respiratory depression (46% vs. 19% with propofol, P<0.01) the mean remifentanil infusion rate was decreased to 0.078 +/- 0.028 microgkg/min, whereas it was kept stable with propofol. Propofol patients had significantly higher (P<0.05) sedation levels and experienced more frequent amnesia of the procedure. Eleven propofol patients experienced pain at injection site, versus two remifentanil patients (P<0.02). Nausea and vomiting were more frequent in the remifentanil patients during infusion (27% vs. 2% in the propofol group, P<0.001) but similar postoperatively. Time to discharge from PACU was similar in the two groups. CONCLUSION: Propofol results in less respiratory depression and nausea when sedation is needed during a case with a successful regional block. Remifentanil may be considered as an alternative if pain during the procedure is a major concern or if amnesia is contraindicated.

The safety and effectiveness of remifentanil as an adjunct sedative for regional anesthesia.

UNLABELLED: We assessed the sedative potential of continuous infusions of remifentanil with a validated composite alertness scale in 160 patients (ASA physical status I or II) undergoing hip replacement surgery with spinal block (n = 61) or hand surgery using brachial plexus block (n = 93). They were randomized to receive one of the following initial dose regimens in double-blinded fashion: placebo or 0.04, 0.07, or 0.1 microg x kg(-1) x min(-1) remifentanil subsequently titrated to effect. Additional midazolam IV was allowed for adequate sedation as required. The combined analysis of both surgery groups revealed a dose-related increase in achievement of sedation level > or =2 within 15 min of the start of the study drug infusion; all remifentanil dose comparisons with placebo reached significance (P < 0.001). The remifentanil 50% effective dose for a composite sedation level > or =2 within 15 min of the start of drug infusion was estimated as 0.043 microg x kg(-1) x min(-1) (95% confidence interval 0.01, 0.059). The requirement for midazolam decreased with increasing remifentanil dose compared with placebo (P < 0.001). The median time to return to alertness after the end of infusion was 10-12 min in the remifentanil groups and 5 min in the placebo group. Significant incidences of nausea, pruritus, sweating, and respiratory depression were reported during remifentanil infusions compared with placebo. The data suggest that remifentanil may be useful for supplementation of regional anesthesia, provided that ventilation is carefully monitored. IMPLICATIONS: In this dose-finding, placebo-controlled study, remifentanil infusions were used to provide sedation during spinal and brachial plexus regional anesthesia. The 50% effective dose for achievement of sedation was 0.043 microg x kg(-1) x min(-1). Return to alertness occurred after 10-12 min (median time). Remifentanil infusions can be used to supplement regional anesthesia, but this requires careful monitoring of ventilation.

Comparison of remifentanil and propofol infusions for sedation during regional anesthesia.

BACKGROUND AND OBJECTIVES: Patients treated with regional anesthesia often require concomitant medication for comfort and sedation. Propofol is widely used for this purpose. Remifentanil, a new ultra-short-acting opioid, exhibits at low doses distinct sedative properties that may be useful for supplementation of regional anesthesia. This study compared the effectiveness of remifentanil and propofol infusions for providing sedation during regional block placement and surgery. METHODS: In an open, prospective trial, 28 patients were randomly allocated to receive continuous infusions of remifentanil (6 microg/kg/h) or propofol (3 mg/kg/h) for sedation during spinal or axillary regional anesthesia. Infusion rates were titrated to maintain a sedation level > or = 2 as assessed with the Observer's Assessment of Alertness Scale. Vital signs were measured continuously, during and for 2 hours after ending study drug infusion. RESULTS: Similar scores for comfort and sedation were obtained in both groups during placement of the regional block and during surgery. Degree of sedation correlated with drug infusion rate of remifentanil (P < .002) but not for propofol. Respiratory rate decreased in the remifentanil group in absence of surgery (P < .05). Mean arterial pressure and heart rate were 20% lower in the propofol group (P < .05). Return to alertness occurred after 10 +/- 6 minutes in the remifentanil group and after 16 +/- 15 minutes in the propofol group. Similar incidences of hypotension, bradycardia, and nausea and vomiting were found in both groups, but intraoperative respiratory depression and nausea were more prominent in the remifentanil group. CONCLUSIONS: When titrated to the same sedation level, remifentanil provided a smoother hemodynamic profile than propofol during regional anesthesia. The frequent occurrence of remifentanil-induced respiratory depression requires cautious administration of this agent. The incidence of adverse reactions seen with both agents during and after their administration makes the management of such sedative infusion techniques difficult.

Preoperative ketorolac administration has no preemptive analgesic effect for minor orthopaedic surgery.

The utility of preoperative ketorolac administration to reduce the intensity and duration of postoperative pain was compared with placebo in a randomized double-blind design of 60 ASA 1-2 patients scheduled for minor orthopaedic surgery. No opioids nor local anaesthetic blocks were used during surgery. The patients received either 30 mg ketorolac IV before surgery followed by a placebo injection after surgery or the reverse. Postoperative pain intensity was assessed repeatedly for 6 h using a visual analogue scale. No differences in pain intensity were observed between the two groups except for the initial 15-min postoperative assessments in the ketorolac group. The time to first rescue morphine administration and the total morphine consumption during the 6-h observation period were similar. It is concluded that the preoperative administration of ketorolac did not provide a significant preemptive analgesic benefit with regard to postoperative pain relief and opioid dose-sparing effect.

Timing of perioperative non-steroidal anti-inflammatory drug treatment.

The time of non-steroidal antiinflammatory drug (NSAID) administration may be clinically important because their onset of effect may be delayed by 30-60 minutes while their opioid sparing effect is not apparent until 4 hours after administration. These findings can be explained by the pharmacokinetic behavior of these agents. Numerous studies addressing the short-term benefit of preemptive administration of NSAIDs gave inconclusive results, in part due to the study design. But if a preemptive analgesic effect of NSAIDs was demonstrated in some studies, it was of short duration and had no significant clinical benefit. Also, the risks associated with preoperative NSAID administration, such as operative site bleeding, should be considered against the potential benefits in establishing a treatment regimen.

Side effects of NSAIDs and dosing recommendations for ketorolac.

We reviewed the pathogenesis of the most important side effects of non-steroidal antiinflammatory drugs (NSAIDs). Short-term treatments for postoperative pain are not generally associated with gastric damage. Pharmacoepidemiological studies have shown that for ketorolac the risk of gastrointestinal bleeding was only important in older patients and when doses > 90 mg/day were used. Although NSAIDs cause platelet dysfunction resulting in prolonged bleeding time, these drugs do not affect clot formation. Therefore, NSAIDs should be used with caution in surgical procedures involving considerable dissection of tissues and where any reduction in hemostatic function could be hazardous. Acute reversible renal dysfunction may occur when volume depletion or reduced renal function are present, in particular in elderly patients. NSAIDs should also be used with great caution in asthmatic patients. In general, the adverse events associated with ketorolac are similar to other NSAIDs. Provided the current European Community label prescription of ketorolac is not exceeded and with due observation of the contra-indications for use of NSAIDs, this agent is not likely to induce an increased risk of adverse events.

Influence of sufentanil on propofol anesthesia using a target controlled infusion system.

We assessed the effect of three different dosings of sufentanil on induction, maintenance and recovery characteristics of a propofol target controlled infusion anesthesia in twenty-four patients scheduled for laparoscopic cholecystectomy. The patients were allocated randomly to receive a sufentanil bolus of 15, 30 or 45 micrograms followed by a continuous infusion of sufentanil of 15, 30 or 45 micrograms/h respectively. The maintenance propofol anesthesia was titrated to achieve hemodynamic stability. Recovery was assessed by noting the times at which patients opened their eyes and correctly gave their birth date. The predicted propofol blood concentration was noted at loss of consciousness, at different times of surgery and at the recovery events. A threefold increase of sufentanil dosing did not significantly affect the induction times nor recovery times following propofol anesthesia. The recovery parameters were determined by the total amount of propofol administered. The mean predicted propofol blood concentrations measured at induction, during maintenance and recovery (opening of eyes) were 3.4-3.9 micrograms/ml, 4.0-4.8 micrograms/ml and 1.1-1.4 micrograms/ml respectively and were not significantly influenced by the sufentanil dosing.

Inhalation anaesthesia and the Kearns-Sayre syndrome.

Kearns-Sayre syndrome is an extremely rare mitochondrial myopathy, characterised by retinitis pigmentosa associated with progressive external ophthalmoplegia. Cardiac conduction abnormalities are common and range from bundle branch block to third degree atrioventricular block. Generalised degeneration of the central nervous system has also been reported. We describe the anaesthetic management of a child afflicted by this syndrome. The major anaesthetic complication in this disease is sudden third degree atrioventricular block which may lead to death in the absence of an artificial cardiac pacemaker.

Incidence and aetiology of postoperative nausea and vomiting.

The reported incidence of emetic symptoms in surgical patients varies from 8-92%. Intractable postoperative nausea and vomiting remains one of the most unpleasant side-effects experienced by patients postoperatively, both in ambulatory and non-ambulatory care, and has potential risks for severe postoperative complications. Multiple factors are associated with an increased risk of developing postoperative nausea and vomiting: age, gender, pre-existing disease, premedication, operative procedure, anaesthetic and analgesic drugs, anaesthetic procedure, and postoperative symptoms. Prophylactic use of anti-emetic premedication is not currently routine practice because not all patients are at serious risk of postoperative nausea and vomiting, and currently available anti-emetics carry undesirable side-effects. However, anti-emetic prophylaxis is very valuable for patients at increased risk. If symptoms do develop in the recovery room, several factors need to be considered in order for anti-emetic treatment to be successful. Adequate hydration and pain control should be ensured, tight-fitting oxygen masks avoided, and patients should be encouraged to take slow, deep breaths to decrease the sensation of nausea. To avoid side-effects, anti-emetics should be administered in minimally effective doses. If the administration of anti-emetics is initially unsuccessful, it may be useful to try a combination of anti-emetic drugs with different mechanisms of action.

Prostaglandin synthetase inhibitor treatment and the regulatory role of prostaglandins on organ perfusion.

Prostaglandin synthetase inhibitors (PGIs) are increasingly used in anesthetic practice and postoperative care. The influence of these agents on the hemodynamics and organ perfusion control remains largely unknown. This review attempts to assess the role of endogenous prostaglandins on the regulation of the microcirculation in different organs and to identify disease states in which PGIs may have deleterious effects. Prostanoids participate to the regulation of blood pressure as vascular tone is subject to the continuous relaxing influence from endogenous vasodilating prostaglandins or related substances. Prostacyclin (PGI2), probably the most important physiologic modulator, decreases blood pressure with concomitant increase in cardiac output and reduction of systemic vascular resistance related to the peripheral vasodilation. Also splanchnic, pulmonary and coronary vasodilation are observed with increased blood flows in the mesenteric, renal and coronary beds. These changes in regional blood flows have been linked to the inhibition by PGI2 of the vasoconstrictor response to sympathetic stimulation and pressor hormones (noradrenaline, angiotensin II). Other prostaglandins exert their effects by inhibiting the release of noradrenaline at the noradrenergic terminals of the sympathetic system. PGIs appear to provide hemodynamic stability during intra-abdominal surgery. Data suggest that the underlying mechanism is an increase in systemic vascular resistance. PGIs have beneficial effects in hemorrhagic shock models in animals and humans but can also exacerbate hemodynamic and metabolic derangements in acute hypovolemic hypotension. In animal models these agents reduce regional blood flow in the ischemic myocardium and may increase infarct size.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular risks and benefits of perioperative nonsteroidal anti-inflammatory drug treatment.

Prostaglandins participate in the regulation of blood pressure in normotensive and hypertensive subjects; vascular tone is subject to the continuous relaxing influence of endogenous vasodilating prostaglandins. Prostaglandin I2 (PGI2; prostacyclin), probably the most important physiological modulator of vascular tone, decreases blood pressure together with a concomitant increase in cardiac output and a reduction in systemic vascular resistance secondary to peripheral vasodilation. In addition, vasodilation within the splanchnic, pulmonary and coronary vascular beds has been observed, with increased blood flow through the mesenteric, renal and coronary vascular beds. These changes in regional blood flow have been associated with the inhibition, by PGI2, of the vasoconstrictor response to sympathetic nervous stimulation and pressor hormones [noradrenaline (norepinephrine), angiotensin II]. However, other prostaglandins, such as prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha), induce coronary vasoconstriction and have different effects on pulmonary artery blood pressure because of their effect on pulmonary vascular resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. indomethacin) have been reported to induce hypertension parallel to a fall in cardiac output, suggesting that the underlying mechanism is an increase in systemic vascular resistance. In animal models these agents reduced regional blood flow in the ischaemic myocardium, with a corresponding increase in infarct size. Ibuprofen, which inhibits prostaglandin synthesis to a lesser extent than indomethacin, did not exert systemic or coronary haemodynamic effects. NSAIDs also provide protection in shock models but may exacerbate haemodynamic derangements and decrease survival in acute hypovolaemic hypotension. To what extent do NSAIDs and opioids influence cardiovascular status during the postoperative course and analgesic therapy? Continuous infusion of NSAIDs for analgesia had no major haemodynamic effects. Also, there were insignificant changes in indices of left heart function (cardiac output, stroke volume) and the systemic circulation (mean arterial pressure, systemic vascular resistance) following intravenous ketorolac injections, whereas cardiac output and mean arterial pressure decreased after administration of morphine. The pulmonary circulation was unaffected by ketorolac administration, whereas morphine administration induced an increase in pulmonary vascular resistance. Indices of right and left cardiac work were decreased by morphine. Thus, ketorolac produces fewer haemodynamic effects than morphine, although it is possible that some of the effects of morphine may result from morphine-induced histamine release. NSAIDs may be seen as a worthwhile gain with respect to morphine in clinical situations when hypotension is disadvantageous or when reduction in afterload is not a specific therapeutic aim.

Thrombolytic treatment of pulmonary embolism with APSAC.

BRL 26921 (Eminase registered trade mark in Belgium, Germany and The Netherlands) is the p-anisoyl derivative of the primary (human) lys plasminogen-streptokinase activator complex (APSAC). The acyl-enzyme has the theoretical advantage of causing fibrinolysis in situ in the presence of fibrin clotbound plasminogen. It was administered to 34 patients with severe pulmonary embolism (PE) in an open multicentre study. PE was suspected on clinical, blood gas, ECG, and radiographic data. Pulmonary angiograms performed pre- and post-treatment confirmed the diagnosis and were assessed using the Miller Index (MI). Fibrinogen, plasminogen, alpha-2-antiplasmin, fibrinogen degradation products (FDP), activated partial thromboplastin time (APTT), partial thromboplastin time (PTT) were closely monitored before and after each administration of APSAC. Median angiographic improvement was 50% (range 0-94%). The following adverse events were reported: bleeding at puncture sites (n = 12), haematuria (n = 1), epistaxis (n = 3), fever (n = 2). A blood transfusion was given in one patient with an inguinal haematoma. Systemic fibrinogenolysis occurred in 20/28 patients.

Evaluation of the role of pre- and postsynaptic serotonergic receptors in electroconvulsive shock therapy.

Despite the well-established clinical efficacy of electroconvulsive therapy (ECT) in the treatment of affective disorders, there is no generally accepted theory regarding its mode of action. Pre- and postsynaptic serotonin (5-hydroxytryptamine, 5-HT) receptors were studied following treatment of rabbits with electroconvulsive therapy (8 shocks). No change was observed in the binding at the postsynaptic 5-HT2 receptor in frontoparietal cortex, as indicated by an unchanged affinity and by the total number of receptors. In control rabbits, exogenously added serotonin and metitepin modulated the electrically evoked 3H-serotonin release, probably by acting on a presynaptic serotonin autoreceptor. Following electroconvulsive therapy, exogenous serotonin still inhibited the 3H-serotonin release, whereas metitepin had lost its enhancing effect. This observation provides evidence for a decreased amount of endogenous neurotransmitter present in the synaptic cleft at stimulation. The results indicate that postsynaptic receptor changes following antidepressant treatments are related to the presynaptic autoreceptor changes.

Comparison of biometric data of children with high and low levels of lead in the blood.

This paper deals with a biometric study of 312 boys and girls, aged 2.5-16 years, living in an area with a long history of pollution by lead. The aim was to search for eventual relationships between ten biometric variables and measures of lead absorption in the bodies, i.e. the amount of lead in the blood (PbB), of these children. Standardized values of the biometric variables were compared in the high-PbB and low-PbB categories, by multivariate analysis of variance. Comparison of the vectors of the ten biometric variables reveals a significant difference between the two categories of PbB levels. We found some evidence that the younger children (below 8 years of age) are more likely to absorb lead in the body and are more vulnerable to the effects of subclinical lead intoxication than their older counterparts. The differences between the averages of biometric variables in the two PbB categories are consistently (although not significantly) greater among younger children. This trend disappeared in the older age group. These results confirm data from the literature that young children are especially at risk. It can be concluded that there is a subtle, but significant, influence of lead absorption on the biometric profiles of children and that this effect is probably more important in children below 8 years of age.