Frédéric Duflo

Alveolar and Serum procalcitonin. Diagnostic and prognostic value in ventilator-associated pneumonia

Background The potential role of serum and alveolar procalcitonin as early markers of ventilator-associated pneumonia (VAP) and its prognostic value were investigated. Methods Ninety-six patients with a strong suspicion of VAP were prospectively enrolled. VAP diagnosis was based on a positive quantitative culture obtained via a mini–bronchoalveolar lavage of 103 colony-forming units/ml or more. Blood and alveolar samples were collected for procalcitonin measurement and analyzed for diagnostic and prognostic evaluation on days 0, 3, and 6. Sensitivity, specificity, positive likelihood ratio, and receiver-operating characteristic curves were analyzed to define ideal cutoff values and approach the decision analysis. Results Serum procalcitonin was significantly increased in the VAP group (n = 44) compared with the non-VAP group (n = 52): 11.5 ng/ml (95% confidence interval, 5.9–17.0) versus 1.5 ng/ml (1.1–1.9). A serum procalcitonin concentration greater than 3.9 ng/ml (best cutoff value) was considered positive for the VAP diagnosis (sensitivity, 41%; specificity, 100%). Serum procalcitonin was significantly increased in the non-survivors compared with the survivors for the VAP group: 16.5 ng/ml (95% confidence interval, 8.1–24.9) versus 2.9 ng/ml (1.2–4.7). The best cutoff value for serum procalcitonin of the nonsurvivors in the VAP group was 2.6 ng/ml (sensitivity, 74%; specificity, 75%; positive likelihood ratio, 2.96). Regarding VAP diagnosis and prognosis, no significant differences were found for alveolar procalcitonin in all groups. Conclusions Serum but not alveolar procalcitonin seems to be a helpful parameter in the early VAP diagnosis and an appropriate marker for predicting mortality.

Steady-state plasma and intrapulmonary concentrations of cefepime administered in continuous infusion in critically ill patients with severe nosocomial pneumonia.

ObjectiveTo determine the steady-state plasma and epithelial lining fluid concentrations of cefepime administered in continuous infusion in critically ill patients with severe bacterial pneumonia. DesignProspective, open-label study. SettingAn intensive care unit and research ward in a university hospital. PatientsTwenty adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled. InterventionsAll subjects received a 30-min intravenous infusion of cefepime 2 g followed by a continuous infusion of 4 g over 24 hrs. The concentrations of cefepime in plasma and epithelial lining fluid were determined at steady state after 48 hrs of therapy with high performance liquid chromatography. Measurements and Main ResultsThe mean ± sd steady-state plasma and epithelial lining fluid concentrations of cefepime 4 g in continuous infusion were 13.5 ± 3.3 &mgr;g/mL and 14.1 ± 2.8 &mgr;g/mL, respectively, with a mean percentage penetration of cefepime into epithelial lining fluid of about 100%. ConclusionsThe administration of 4 g of cefepime in continuous infusion in critically ill patients with severe nosocomial pneumonia appears to optimize the pharmacodynamic profile of this &bgr;-lactam by constantly providing concentrations in excess of minimal inhibitory concentration of most of susceptible organisms over the course of therapy in both serum and epithelial lining fluid.

Oxidative Stress Status During Exposure to Propofol, Sevoflurane and Desflurane

We evaluated the circulating and lung oxidative status during general anesthesia established with propofol, sevoflurane, or desflurane in mechanically ventilated swines. Blood samples and bronchoalveolar lavage fluid (BAL) specimens were respectively performed via an internal jugular vein catheter and a nonbronchoscopic BAL for baseline oxidative activity measurements: malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPX). A 4-h general anesthesia was then performed in the three groups of 10 swine: the Propofol group received 8 mg · kg−1 · h−1 of IV propofol as the sole anesthetic; the Desflurane group received 1.0 minimum alveolar concentration of desflurane; and the Sevoflurane group received 1.0 minimum alveolar concentration of sevoflurane. We observed significantly larger levels of MDA in plasma and BAL during desflurane exposure than with the other anesthetics. We also observed smaller concentrations of circulating GPX and alveolar GPX. We found a significant decrease for MDA measurements in the plasma and the pulmonary lavage during propofol anesthesia. We also found larger values of GPX measurements in the serum and the pulmonary lavage. No significant changes were observed when animals were exposed to sevoflurane. No significant changes were found for circulating concentrations of SOD during exposure to all anesthetics. In this mechanically ventilated swine model, desflurane seemed to induce a local and systemic oxidative stress, whereas propofol and sevoflurane were more likely to have antioxidant properties.

Spinal nerve ligation increases α2-adrenergic receptor G-protein coupling in the spinal cord

Intrathecal and epidural administration of the alpha2-adrenergic receptor agonist clonidine in humans results in analgesia to both acute nociceptive and chronic neuropathic pain. The potency of clonidine increases with hypersensitivity to mechanical stimuli after nerve injury, although the reasons for this change are unknown. In the present study, we tested the hypothesis that peripheral nerve injury alters either spinal alpha2-adrenergic receptor-mediated G-protein activity or alpha2-adrenergic receptor number. Rats were randomized to left spinal nerve ligation (SNL) or sham surgery. Tactile hypersensitivity in the hindpaw was confirmed and lumbar spinal cords were removed for binding assays. To examine agonist-induced G-protein coupling, [35S]GTP gamma S binding experiments were performed in spinal cord membranes and sections using norepinephrine as an alpha2-adrenergic agonist. SNL was associated with an increase in maximal efficacy, but not potency, of norepinephrine-stimulated [35S]GTP gamma S binding in dorsal horn. SNL had no effect on basal [35S]GTP gamma S binding or on muscarinic cholinergic-stimulated [35S]GTP gamma S binding. [35S]GTP gamma S autoradiography showed that this increase in alpha2-adrenergic-activated G-proteins occurred both ipsilateral and contralateral to SNL surgery. SNL did not alter total alpha2-adrenergic receptor number or affinity to [3H]-rauwolscine binding, and displacement studies with the alpha2A-adrenergic antagonist BRL44408 revealed that most of the binding was associated with the alpha2A-adrenergic subtype. These data suggest that the increased potency of clonidine in neuropathic pain could reflect increased efficiency of G-protein coupling from spinal alpha2-adrenergic receptors.

Peripheral nerve injury alters the α2 adrenoceptor subtype activated by clonidine for analgesia

BACKGROUND Previous studies suggest that the alpha adrenoceptor subtype is the target for spinally administered alpha -adrenergic agonists, clonidine, for pain relief. However, ST 91, a preferential alpha adrenoceptor subtype agonist, induces antinociception, and intrathecally administered alpha antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of alpha adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity. METHODS The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated with vehicle, BRL 44408 (an alpha subtype-preferring antagonist), and ARC 239 (an alpha subtype-preferring antagonist). RESULTS In normal animals, clonidines effect was diminished by pretreatment with either antagonist, whereas ST 91s antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective. CONCLUSIONS These data agree with previous studies supporting that the alpha adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on alpha adrenoceptors.

Chronobiology of epidural ropivacaine: variations in the duration of action related to the hour of administration.

Background A temporal pattern of the kinetics of local anesthetics is demonstrated in dental and skin anesthesia, with an important variation in the duration of action related to the hour of administration. The aim of this study is to determine whether the hour of injection influences the duration of epidurally administered ropivacaine during labor. Methods One hundred ninety-four women in the first stage of labor were assigned to one of four groups throughout the day period: group 1 (night: from 1:01 to 7:00 am), group 2 (morning: from 7:01 am to 1:00 pm), group 3 (afternoon: from 1:01 to 7:00 pm), and group 4 (evening: from 7:01 pm to 1:00 am). Each patient received 14 ml ropivacaine, 0.17%, epidurally, and analgesia duration was measured. Results Pain assessed by a visual analog score was not differ-ent among groups before the first injection of local anesthetic. Analgesia duration was greater in the diurnal period (group 2: 110 ± 25 min and group 3: 117 ± 23 min) compared with the nocturnal period (group 1: 94 ± 23 min and group 4: 91 ± 23 min) (P < 0.01). The largest intraday variation of analgesia duration among groups reached 28%. Conclusions Epidural analgesia duration exhibits a temporal pattern with important differences among diurnal and nocturnal phases. The authors emphasize that the lack of consideration of the chronobiologic conditions in epidural analgesia studies may create significant statistical bias. Future studies dealing with epidural local anesthetics should consider the time of drug administration.

Chronobiology and anaesthesia

Purpose of review It has been shown that biological rhythms influence the pharmacology and effects of anaesthetic agents such as local anaesthetics, hypnotics and muscle relaxants. This review discusses the latest findings and their consequences for anaesthesiological practice. Recents findings Opioids and new local anaesthetics exhibit circadian changes when they are injected into spinal or epidural spaces for labour pain analgesia. Other studies have demonstrated that propofol and ketamine have maximal duration of action when they are injected during a period of rest in animals (at night in humans). It has been also shown that propofol can perturb the central circadian pacemaker and so cause a phase-shifted advance in effect on activity in rats. Summary Although studies are lacking for most newer anaesthetic agents used in humans, recent findings emphasize once again that chronobiology should be considered in studies of anaesthetic drugs. Circadian rhythms should be considered in pharmacokinetic and pharmacodynamic analyses so that proper research protocols can be designed. The implications of chronobiology for the practice of clinical anaesthesia are probably of lesser importance because of the use of patient-controlled devices for pain management, monitoring of muscle paralysis and depth of anaesthesia monitors.

Spinal adrenergic and cholinergic receptor interactions activated by clonidine in postincisional pain.

Background Previous pharmacologic and molecular studies suggest that the &agr;2-adrenoceptor subtype A is the target for spinally administered &agr;2-adrenergic agonists, i.e., clonidine, for pain relief. However, intrathecally administered &agr;2 C antisense oligodeoxynucleotide was recently reported to decrease antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. The current study sought to determine the subtype of &agr;2 adrenoceptors activated by clonidine in a rodent model for human postoperative pain, and to examine its interaction with spinal cholinergic receptors. Methods Postoperative hypersensitivity was produced in rats by plantar incision of the hind paw and punctuate mechanical stimuli were applied around the wound 24 h after surgery. Effects of intrathecal clonidine and 2-(2,6-diethylphenylamino)-2-imidazoline (ST91) on withdrawal thresholds to the stimulus were determined. To examine the adrenoceptor subtype and its interaction with spinal cholinergic receptors, animals were intrathecally pretreated with vehicles BRL44408 (an &agr;2 A subtype–preferring antagonist), ARC239 (an &agr;2 non-A subtype–preferring antagonist), atropine (a muscarinic antagonist), and mecamylamine (a nicotinic antagonist). Results Intrathecal ST91 showed a significantly greater efficacy when compared with clonidine. The analgesic effect of clonidine was diminished by pretreatment with either adrenoceptor antagonist, whereas the effect of ST91 was solely blocked by ARC239 pretreatment. Atropine and mecamylamine abolished the effect of clonidine effect but not the effect of ST91. Conclusions Both &agr;2 A and &agr;2 non-A adrenoceptors, as well as spinal cholinergic activation, are important to the antihypersensitivity effect of clonidine after surgery. ST91 is more efficacious in this model than clonidine and relies entirely on &agr;2 non-A adrenoceptors.

α2-adrenoceptors inhibit the intracellular Ca2+ response to electrical stimulation in normal and injured sensory neurons, with increased inhibition of calcitonin gene-related peptide expressing neurons after injury

Nerve injury resulting in chronic pain is associated with novel excitatory effects of norepinephrine on injured peripheral nerve terminals and their cell bodies, due to actions on alpha2-adrenoceptors. Paradoxically, alpha2-adrenoceptor agonists administered near peripheral terminals or their cell bodies results in analgesia, not pain. This study tested, using intracellular Ca2+ response to stimulation, the effects of alpha2-adrenoceptor agonists on injured sensory neurons and classified their neuronal phenotype. Dorsal root ganglion cells from normal and spinal nerve-ligated rats were dissociated and activated twice with electrical field stimulation, while measuring Fura-2 fluorescence. Cells were perfused between stimulations with vehicle or alpha2-adrenoceptor agonists alone or with antagonists. Cells were considered inhibited if the ratio of their peak Ca2+ response to the second stimulus divided by the first was less than the 2.5th percentile for vehicle controls. alpha2-, But not alpha1-adrenoceptor agonists inhibited the Ca2+ response in a concentration related fashion, and this inhibition was blocked by alpha2-adrenoceptor antagonists. Clonidine inhibited a similar percentage of cells in the normal and spinal nerve-ligated group. In both groups, the large majority of clonidine-inhibited cells stained for isolectin B4. Spinal nerve ligation resulted in a 4-10-fold increase in the percentage of clonidine inhibited cells which immunostained for calcitonin gene-related peptide. These data are consistent with the known inhibition of Ca2+ currents by alpha2-adrenoceptors and suggest that, at the level of intracellular Ca2+, the key determinant of neurotransmitter release, alpha2-adrenoceptors are inhibitory after nerve injury, not excitatory. There is a shift in phenotype of sensory neurons which are inhibited by clonidine after nerve injury, which may explain clonidines increased potency in the treatment of neuropathic compared with acute pain.

Erythromycin promotes gastric emptying during acute pain in volunteers

In this double-blind cross-over study, we assessed whether erythromycin infusion is effective as a prokinetic drug against gastroparesis from acute pain. The effect of erythromycin on gastric emptying (GE) was measured in seven volunteers subjected to a standardized acute painful stimulus. The GE rate for solids was measured using the octanoic acid breath test. An acetaminophen absorption test measured the GE rate for liquids. Five minutes after ingestion of a 13C-labeled meal, the subjects received in randomized order either a test (placebo and erythromycin groups) or a control (control group) stimulus consisting of repeated 1-min immersion of a hand into 4°C (test) or 37°C (control) water, with 15 s for recovery between immersions, for a total of 20 min. While the stimulus was applied, 250 mL saline (control and placebo groups) or 250 mg erythromycin (erythromycin group) was infused. Pain and stress were evaluated using visual analog scales, and standard hemodynamic values were recorded throughout the study. Our results show that acute stress decreased GE for solids, which was significantly accelerated in the erythromycin group in comparison with the placebo group. GE for liquids was similar in the three groups. We conclude that erythromycin is effective as a prokinetic drug for solids in acute painful situations.