Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study.

Essentials Bleeding incidence as hemorrhagic risk factors are unknown in palliative care inpatients. We conducted a multicenter observational study (22 Palliative Care Units, 1199 patients). At three months, the cumulative incidence of clinically relevant bleeding was 9.8%. Cancer, recent bleeding, thromboprophylaxis and antiplatelet therapy were independent risk factors. SUMMARY: Background The value of primary thromboprophylaxis in patients admitted to palliative care units is debatable. Moreover, the risk of bleeding in these patients is unknown. Objectives Our primary aim was to assess the bleeding risk of patients in a real-world practice setting of hospital palliative care. Our secondary aim was to determine the incidence of symptomatic deep vein thrombosis and to identify risk factors for bleeding. Patients/Methods In this prospective, observational study in 22 French palliative care units, 1199 patients (median age, 71 years; male, 45.5%), admitted for the first time to a palliative care unit for advanced cancer or pulmonary, cardiac or neurologic disease were included. The primary outcome was adjudicated clinically relevant bleeding (i.e. a composite of major and clinically relevant non-major bleeding) at 3 months. The secondary outcome was symptomatic deep vein thrombosis. Results The most common reason for palliative care was cancer (90.7%). By 3 months, 1087 patients (91.3%) had died and 116 patients had presented at least one episode of clinically relevant bleeding (fatal in 23 patients). Taking into account the competing risk of death, the cumulative incidence of clinically relevant bleeding was 9.8% (95% confidence interval [CI], 8.3-11.6). Deep vein thrombosis occurred in six patients (cumulative incidence, 0.5%; 95% CI, 0.2-1.1). Cancer, recent bleeding, antithrombotic prophylaxis and antiplatelet therapy were independently associated with clinically relevant bleeding at 3 months. Conclusions Decisions regarding the use of thromboprophylaxis in palliative care patients should take into account the high risk of bleeding in these patients.

Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study.

OBJECTIVE: To investigate the effects of systemic administration of lidocaine on different components of neuropathic central pains by quantitative sensory testing. METHODS: The efficacy of systemic lidocaine (5 mg/kg IV over 30 minutes) was evaluated in a double-blind, placebo-controlled, and cross-over fashion, on both spontaneous ongoing pain and evoked pains (allodynia and hyperalgesia) in 16 patients with chronic poststroke (n = 6) or spinal cord injury (n = 10) related pain. RESULTS: Lidocaine was significantly superior to the placebo (saline) in reducing the intensity of spontaneous ongoing pain for up to 45 minutes after the injection: 10 of 16 patients (62.5%) receiving lidocaine showed a significant reduction in spontaneous pain, whereas only six patients showed this after the placebo. Lidocaine also significantly reduced the intensity of brush-induced allodynia and mechanical hyperalgesia, but was no better than the placebo against thermal allodynia and hyperalgesia. In general, the side effects were moderate and consisted mainly of lightheadedness (44%). CONCLUSIONS: Systemic lidocaine can induce a significant and selective reduction of several components of pain caused by CNS injuries. The observed preferential antihyperalgesic and antiallodynic effects of this drug suggest a selective central action on the mechanisms underlying these evoked pains.

Effects of IV morphine in central pain: a randomized placebo-controlled study.

OBJECTIVE: To investigate the effects of IV morphine on central pain syndromes through quantitative sensory testing and to assess the long-term benefit of oral morphine. METHODS: After an initial open titration phase aiming to determine the maximal tolerated dosage of IV morphine, the efficacy of morphine infusion (9-30 mg; mean dosage, 16 mg) was assessed in a double-blind, placebo-controlled and crossover fashion in 15 patients with poststroke- (6 patients) or spinal cord injury- (9 patients) related pain. All of the patients subsequently received sustained oral morphine. RESULTS: Morphine significantly reduced the intensity of brush-induced allodynia but had no effect on other evoked pains (i.e., static mechanical and thermal allodynia/hyperalgesia). The effects of morphine on ongoing pain were not significantly different from those of the placebo, but 7 patients (46%) responded to morphine. There was a correlation between the effects of morphine on spontaneous pain and the decrease of the responses to suprathreshold thermal stimuli on the nonpainful contralateral side, suggesting that these effects were related to the general antinociceptive activity of the drug. The effects of IV morphine were correlated with those of oral morphine at 1 month, but only 3 patients (20%) were still taking morphine after 1 year. CONCLUSIONS: IV morphine induces analgesic effects on some components of central neuropathic pain syndromes, but only a minority of patients may benefit from long-term opioid treatment.

Nefopam strongly depresses the nociceptive flexion (R(III)) reflex in humans.

Nefopam hydrochloride has been commercialized as an analgesic drug in most Western European countries for 20 years. It has been shown to possess analgesic activity with a profile distinct from that of opioids or anti-inflammatory drugs. In order to define the mechanisms of action of this pharmacological agent, we studied, in a double-blind and cross-over fashion, its effects on the nociceptive flexion (R(III)) reflex and the corresponding pain sensation in ten healthy volunteers. The R(III), reflex elicited by electrical stimulation of the sural nerve was recorded from the biceps femoris. Two experiments were performed on each volunteer at an interval of 7 days. On each experimental day, four recruitment (intensity-response) curves of the R(III) reflex were constructed: before (control period) and then 30, 60 and 90 min after the intravenous injection of nefopam (20 mg) or a placebo. Nefopam induced a powerful depression of the nociceptive R(III) reflex. It increased the threshold of the reflex and decreased the slope of the recruitment curve. At the same time, it decreased the painful sensations (as measured with a visual analogue scale(VAS)) elicited by the maximum stimulus intensity. These data suggest that nefopam probably produces its analgesic action through central (spinal and/or supraspinal) mechanisms. However, complementary peripheral mechanisms cannot be excluded on the basis of the present study. In view of these results, it seems that new clinical studies will have to be undertaken to revisit this potent analgesic agent and try to limit its adverse effects (i.e. nausea, vomiting, sweating). Its fast onset of action could clearly be an advantage, notably in the treatment of post-operative pain.

Effects of sufentanil and NMDA antagonists on a C-fibre reflex in the rat.

The effects of intravenous sufentanil and pre-administration of N-methyl-D-aspartate (NMDA) receptor antagonists were tested on a reflex triggered by C-fibre activation. The reflex was elicited by electrical stimulation of the sural nerve and recorded from the ipsilateral biceps femoris muscle in halothane anaesthetized rats either (1) with an intact neuraxis or (2) in which the brain had previously been transected at the level of the obex. All four doses of sufentanil (0.33, 0.6, 1 and 2 microg kg(-1)) elicited a depression of the reflex in a dose-dependent manner. However, following the expected depression, all doses of sufentanil elicited both facilitation of the reflex and tonic inter-stimulus discharges. The C-fibre reflex was not modified following intravenous ketamine (1 mg kg(-1)) or (+)-HA966 (5 or 10 mg kg(-1)) but, when administered 5 min before sufentanil, these drugs enhanced both the extent and the duration of the depression and strongly reduced the facilitations. In the obex-transected rats, the depressive effect of 1 microg kg(-1) sufentanil increased, while the facilitation of the C-fibre reflex and the tonic inter-stimulus discharges disappeared. Pre-administration of 10 mg kg(-1) (+)-HA966 reinforced and prolonged the depressive effect of sufentanil. These results extend previous studies suggesting the involvement of NMDA receptors in the spinal transmission of nociceptive signals. They illustrate the potential of spinal NMDA receptor blockade to both enhance the analgesic, and prevent the pro-nociceptive, effects of sufentanil.

Effects of intravenous and intrathecal sufentanil on a C-fibre reflex elicited by a wide range of stimulus intensities in the rat.

A C-fibre reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetised, intact rats, and in anaesthetised rats whose brains had been transected at the level of the obex. The temporal evolution of the response was studied by recording recruitment curves built with stimulus intensities from 0 to 10 times threshold. Both i.v. and i.t. sufentanil resulted in dose-dependent depressions of the reflex. Increasing the stimulus intensity from 1.5 to 10 times threshold resulted in an increase in the ED(50) from 0.58 (0.40-0.86) to 2.40 (1.87-3.31) microgram/kg for i.v. sufentanil and from 0.64 (0.46-0.79) to 1.63 (1.29-3.31) microgram/kg for i.t. sufentanil. With increasing stimulus intensity, the dose-response curves showed a progressive shift to the right, but this shift was only slight with the highest intensity stimuli. The ratios for the ED(50)s for i.v. to i.t. sufentanil were near 1. Following i.v. administration, sufentanil also facilitated the C-fibre reflex and produced tonic inter-stimulus discharges. They disappeared after the i.v. injection of naloxone. In the obex-transected rats, the depressive effect of sufentanil increased, while the facilitations and tonic inter-stimulus discharges disappeared. These findings suggest that the analgesic effects of i.v. ant i.t. sufentanil are similar, probably because sufentanil is highly soluble in lipids. Sufentanil-induced facilitations relate to supraspinal actions on motor controls and/or on the descending control of nociceptive transmission.

A sensitive test for studying the effects of opioids on a C-fibre reflex elicited by a wide range of stimulus intensities in the rat.

A C-fibre reflex elicited by electrical stimulation within the receptive field of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 50 mA and temporal evolution was studied by using a constant level of stimulation. At a constant level of stimulation, intrathecal administration of morphine resulted in a depressive effect on the C-fibre reflex in the 0.18-0.75 microgram range (ED50 = 0.2 microgram). Study of the recruitment curves showed that, in the 0.18-0.375 microgram range, morphine had little effect on the threshold, but induced significant decreases in the slopes. At doses above 0.75 microgram, morphine modified both the threshold and the slope of the recruitment curves. Systemic naloxone totally reversed these effects. It is concluded that intrathecal morphine not only produces a shift in the encoding functions of the spinal cord but also reduces the gain of these functions. It is suggested that this method is reliable for the pharmacological study of the spinal transmission of nociceptive signals.

Buprenorphine blocks diffuse noxious inhibitory controls in the rat.

A C-fibre reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetised rats. Such reflex responses can be inhibited by applying noxious conditioning stimuli to heterotopic areas of the body. These inhibitory processes have been termed diffuse noxious inhibitory controls. The responses were recorded before, during and after the immersion of the tail in a thermoregulated waterbath (at 50 degrees C) for 1 min. The C-fibre reflex responses were depressed by a maximum of 71 +/- 3% at 45 s after the start of such conditioning stimuli. A dose of 3 mu g/kg buprenorphine completely blocked the inhibition and post-stimulus effects triggered by the heterotopic noxious stimuli. In the 0.3-3 mu g/kg range, buprenorphine increased, in a dose-dependent manner, the magnitude of the inhibition. These doses did not produce any changes in the C-fibre reflex itself. The results are discussed in terms of the mechanisms underlying the analgesic properties of buprenorphine.

[Update on the pharmacologic approach to pain]. / Actualités de la prise en charge pharmacologique de la douleur.

Acute pain can be managed favourably by the use of paracetamol, non steroidal anti-inflammatory drugs, opioids and local anaesthetics, solely or in combination. Sophisticated methods of administration such as nerve blocks or patient-controlled analgesia will improve results. Chronic pain, on the other hand, presents a more complex situation and the pharmacological approach is only one aspect of bio-psycho-social management programmes. The role of opioids in the treatment of chronic non-cancer pain has still not been clarified. Adjuvant drugs are often required.

[Physiology of nociception]. / Physiologie de la nociception.

Nociception is related to the mechanisms elicited by stimuli threatening the integrity of the organism. At the peripheral level, unmyelinated C fibres (C polymodal nociceptores) or fine myelinated A delta fibres are excited by noxious stimulation, directly or indirectly by inflammatory processes. Nociceptive afferent fibres terminate in the superficial laminae of the dorsal horn of the spinal cord where informations are integrated and controlled. These first synapses are modulated by excitatory amino acids (glutamate and aspartate) and many peptides (substance P, CGRP, CCK, endogenous opiods). The majority of ascending pathways involved in nociception are located in the ventrolateral controlateral quadrant of the cord (spinorelicular and spinothalamic tracts). Many supraspinal sites are activated following nociceptive stimuli, with relays in the reticular formation of the brain stem (including the subnucleus reticularis dorsalis), the ponto-mesencephalic regions (periaqueducal gray matter and parabrachial area) and thalamic sites. Amygdala and hypothamic targets could be involved in motivational reactions and neuroendocrine adaptations to a noxious event. The cingular, insular and somatosensory cortices also receive nociceptive informations. Nociceptive signals are modulated at all levels of their transmission; the more extensively studied controls are located at the spinal level. Segmental controls are inhibitory effects produced by non-noxious mechanical stimuli. Spinal signals can also be inhibited following activation of bulbopinal descending inhibitor pathways and release of serotonin, norepinephrine and, indirectly, endogenous opiods. Inhibitory controls triggered by noxious stimuli could facilitate the extraction of the nociceptive tone of informations having priority over other stimuli.

[Periodic evaluation of practices in postoperative pain management] . / Intérêt d'une évaluation périodique des pratiques de prise en charge de la douleur postopératoire.

OBJECTIVE: Periodical assessment of practices as part of a quality assurance program: impact on postoperative pain. PATIENTS: All patients evaluated from the first postoperative day during a week. METHODS: Two surveys performed at a six month interval after establishment of some corrective measures. Different items were evaluated: pre-anaesthesia information for patients, pain severity and satisfaction with pain treatment. Medical data were consulted concerning postoperative analgesic prescriptions, their realization, pain assessment by nurses. Between the two surveys, first survey results were presented to anaesthesiologists. Then guidelines for prescriptions were suggested and new monitoring guidelines were proposed to nurses in surgical ward. RESULTS: 94 patients were evaluated during each survey. Patients had undergone orthopaedic, visceral, urology, ophthalmology and vascular surgery. Half of the patients did not receive information about pain before surgery. 43% of patients had a pain scores = 30/100 during movements; no difference was found between the two evaluations. Satisfaction graded as "moderate or insufficient" decreased from 22% (1rst survey) to 10 (2nd survey) (p < 0.05). Non steroidal anti-inflammatory drugs and nefopam prescriptions increased between the two surveys (p < 0.05). Association of three or four analgesics increased between the two surveys and monotherapies decreased (p < 0.05). Concordance of prescriptions with guidelines was 55% during first survey and 62% during the second (NS). Pain severity was not recorded for 36% of patients at first survey and in 18% at the second (p < 0.05). CONCLUSION: Although anaesthesiologists and nurses changed their practice due to a quality insurance program concerning postoperative pain, its consequence on the severity of postoperative pain was not significant.

[Use of halothane in a semi-closed circuit]. / Utilisation de l'halothane en circuit semi-fermé.

Halothane was administered to 10 ASA or 11 patients undergoing elective peripheral surgery. The vaporizer was included in the delivery gas line of the semiclosed system. Löwe's square root of time model of uptake was used to calculate the required doses of halothane. In order to reach an alveolar concentration corresponding to 1.3 MAC, 0.5 vol % of halothane (1.3 MAC) combined with 60 vol % of nitrous oxide (0.6 MAC) were administered at a fresh of 20 ml.kg-1. The ventilation controlled in order to maintain end-tidal CO2 partial pressure at a 5 vol %. Inspiratory halothane concentration was measured during the inspiratory plateau. The alveolar fraction was defined as being the mean end expiratory concentration. The latter was well above the theoretical values during the first 9 min of anaesthesia (0.85% at the 4 th min). This concentration then decreased progressively, becoming less than the expected value after 15 min (0.4% at the 30 th min). Löwe's model would therefore seem to lead to a gross overestimation of the amount of anaesthetic vapour to be delivered to a patient at the beginning of anaesthesia, and an underestimation thereafter.

[Carotid surgery under locoregional anesthesia]. / Chirurgie carotidienne sous anesthésie loco-régionale.

Eight-five carotid endarterectomies were performed in 77 patients, under regional anaesthesia using 2 different techniques: cervical epidural anaesthesia (35 cases) and cervical plexus block (50 cases). The patients' mean age was 71 years; 80 per cent had arterial hypertension and 41 per cent coronary disease. Transoperative cerebral ischaemia was detected by a 5-minute carotid clamping test, the occurrence of a neurological event indicating that shunting was required. In 62 patients this test was combined with measurement of carotid back pressure. None of the patients needed general anaesthesia. Intraoperative neurological events occurred more frequently (P less than 0.01) when the carotid back pressure was 25 mmHg or less, and 12 temporary shunts were installed for that reason (14.1 per cent). Three neurological events occurred at the end of endarterectomy: no shunt was installed and complete recovery was observed immediately after declamping. No complications ascribable to the anesthetic techniques were recorded. Mortality was nil, and the only neurological morbidity was a brachio-facial deficit which left few sequelae. The frequency of intra- or postoperative arterial hypertension was similar in both groups. Intraoperative hypotension, frequent under epidural anaesthesia, was observed in only one patient who had brachial plexus block (P less than 0.01). The analgesia obtained was equally good with both anaesthetic techniques, but cervical plexus block anaesthesia is easier to perform, had less haemodynamic repercussions and therefore tends to be preferred to cervical epidural anaesthesia. The lack of mortality, low morbidity and absence of systemic complications in this series despite the high number of patients at risk are in favour of this type of anaesthesia, notably for such patients. Moreover, because vigilance is preserved attention can be paid to the quality rather than the rapidity of endarterectomy, which is the best way of preventing embolism.

Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study.

Neurotoxicity represents a major complication of oxaliplatin. This study aimed to identify early clinical markers of oxaliplatin neurotoxicity, in comparison with cisplatin, and detect predictors of chronic neuropathy. Forty-eight patients with mainly colorectal cancer were evaluated prospectively before oxaliplatin (n=28) or cisplatin (n=20) administration and then 2 weeks after the third (C3), sixth (C6) and ninth (C9) cycles. Eighteen oxaliplatin patients were re-assessed at 12+/-2 months. Evaluation included quantitative sensory testing, i.e., detection/pain thresholds for mechanical, vibration, cold and heat stimuli; pain induced by suprathreshold cold (5-25 degrees C) and heat (38-48 degrees C) stimuli and quantified assessment of symptoms (neuropathic pain symptom inventory). Symptoms of oxaliplatin neurotoxicity (cold-triggered dysesthesia of the hands; 96% of the cases) were reversible between cycles for up to C6. In contrast, thermal testing identified sustained (irreversible between cycles) neurotoxicity two weeks after C3 in the oxaliplatin group only, characterized by hyperalgesia to cold (5-25 degrees C) (F=11.4; p=0.0002 relative to cisplatin patient responses in the hand) and heat stimuli (38-48 degrees C) (F=4.1; p=0.049 for the hand). Cold-evoked symptoms lasting 4 days or more after C3 predicted chronic neuropathy (OR: 22; 95% CI: 1.54-314.74; p=0.02) whereas enhanced pain in response to cold (20 degrees C stimulus on the hand) predicted severe neuropathy (OR: 39; 95% CI: 1.8-817.8 p=0.02). Thermal hyperalgesia is a relevant clinical marker of early oxaliplatin neurotoxicity and may predict severe neuropathy.

[Recent data on the physiology of pain]. / Physiologie de la douleur: données récentes.

Along the time, the relation between a painful stimulus and the created perception keeps on evolving. The distortion between stimulation and perception concerns all the steps of the painful messages transmission, from the peripheral level to the supraspinal sites. At the peripheral level, C or A delta fibres are excited by noxious stimuli. Involved molecules are released from cellular lysis, inflamed surrounding tissues and C or A delta fibres themselves. The progresses of molecular biology have once again enriched this peripheral inflammatory mix, which composition becomes more and more complicated: ATP and P2X3 purinergic receptor, bradykinin and B2 bradykinin receptor, H+ and ASIC proton receptor, vanilloïd receptor activated by heat, inflammation and increase in synthesis of sodic channels resistant to the tetradotoxine (TTXr).... The first synapses are modulated by excitatory amino-acids and many peptides, at the end of the peripheral nerves in the dorsal horn of the spinal cord A lot of supraspinal sites are activated: the brain stem, the pontomesencephalic regions, the thalamic sites and the cortex. Along the way, multiple mechanisms modulate the pain transmission: the painful perception depends on the balance between both exciting and inhibitory effects. Descending inhibitory controls triggered by noxious stimuli would play a decisive role in the extraction of the painful characteristic of information and would give it priority over other stimuli.