Implication of dipeptidylpeptidase IV activity in human bronchial inflammation and in bronchoconstriction evaluated in anesthetized rabbits.

BACKGROUND: Decreased dipeptidylpeptidase IV (DPPIV) activity within the human nasal mucosa has previously been shown to contribute to the severity of chronic inflammatory rhinosinusitis. OBJECTIVE: To investigate and correlate the role of DPPIV activity with regard to bronchial inflammation. METHODS: DPPIV/CD26 activity/concentration was investigated in the bronchial tissue of human subjects suffering from chronic bronchial inflammation. In addition, the effect of a recombinant Aspergillus fumigatus DPPIV (fuDPPIV) was investigated on histamine-induced bronchoconstriction in anesthetized rabbits. RESULTS AND CONCLUSIONS: DPPIV/CD26 was present in submucosal seromucous glands, in leukocytes and to a very low degree in endothelial cells of human bronchi. DPPIV activity was correlated with tissue CD26 content measured by immunoassay. As previously reported for the nasal mucosa, DPPIV/CD26 activity was inversely correlated with the degree of airway inflammation. Systemic pretreatment with recombinant fuDPPIV markedly reduced the increase in histamine-induced airway resistance in rabbits. In conclusion, DPPIV activity modulates lower airway tone by degrading unknown peptidic substrates released by histamine in response to an allergen. Contrasting with our observations in the nose, this modulation is apparently not mediated via a neurokinin (NK1) receptor.

TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria.

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found up-regulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 up-regulation was detected in the brain of Tnfr2 knockout mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 up-regulation in the brain. Our results in ARDS and CM indicate a specific up-regulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.

Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury.

BACKGROUND: Matrix metalloproteinases (MMPs) are able to degrade the endothelial basal lamina and increase vascular permeability. METHODS: In a porcine model of isolated-reperfused lung, we studied the alveolar-capillary permeability and the zymographic expression of MMP-9 and MMP-2 in the bronchoalveolar lavage fluid of lungs submitted ex vivo to ischemia in three preservation solutions [modified Euro-Collins (EC), low-potassium-dextran, modified-blood]. Twenty-two pigs were randomly divided into three groups according to the preservation solution used. One lung of each pig was rapidly reperfused and analyzed (control lung) although the other lung was reperfused and analyzed after 8 hr of ischemia (ischemic lung). RESULTS: Alveolar-capillary permeability, evaluated by the transferrin leak index, was increased after 8 hr of ischemia compared with controls in the three groups, but was significantly higher in the modified EC group. In the EC group, after 8 hr of ischemia, both proMMP-9 and MMP-9 increased significantly (8.8- and 22-fold, respectively) compared with controls and this increase correlated with the transferrin leak index. Neither proMMP-9 nor MMP-9 increased with the other two preservation solutions. The MMP-2 increase after ischemia was smaller and was also restricted to the EC group. CONCLUSION: MMP expression is enhanced during lung ischemia-reperfusion, especially in the presence of EC and this phenomenon correlates with the alteration of alveolar-capillary permeability.

Haemostatic properties of human pulmonary and cerebral microvascular endothelial cells.

Little is known on the haemostatic profiles of human microvascular endothelial cells (MVEC) from different tissues. In addition it is not known whether MVEC from patients display the same haemostatic pattern as MVEC coming from healthy controls. To address these questions MVEC from human lung and brain were isolated and stimulated with tumour necrosis factor alpha (TNF) and E. coli lipopolysaccharide (LPS) for 24 h. The level and the kinetics of procoagulant activity (PCA) and thrombomodulin (TM) expression were found to be different depending on the tissue of origin and on the agonist used. In particular, the inducible PCA was higher in lung than in brain MVEC, an observation that may be related to the frequency of lung involvement in septic shock. Differences were also observed for tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) with MVEC supernatants or cell lysates. These variables were then measured in lung MVEC purified from patients with acute respiratory distress syndrome (ARDS) and compared to controls. Cells from ARDS patients constitutively expressed more PCA and PAI-1 than controls. The fibrinolytic potential, expressed as t-PA/PAI-1 ratio, was lower in ARDS than in lung MVEC. It is concluded that MVEC display different haemostatic features depending on the tissue they come from and that lung MVEC from ARDS patients present a procoagulant profile when compared with those from controls.

Influence of TASP-V, a novel neuropeptide Y (NPY) Y2 agonist, on nasal and bronchial responses evoked by histamine in anaesthetized pigs and in humans.

1. In nine anaesthetized pigs we have studied the influence of intranasal or intrabronchial pretreatment with TASP-V, a neuropeptide Y (NPY) Y2 agonist formed by the attachment of NPY 21-36 to a template-assembled synthetic peptide (TASP), on the functional responses to subsequent intranasal or intrabronchial histamine challenge. 2. In a parallel study, subjective and objective nasal airway resistance (NAR) increase following intranasal histamine challenge was evaluated in 11 healthy volunteers after TASP-V or placebo pretreatment. 3. In pigs, increase in sphenopalatine blood flow induced by histamine dihydrochloride nasal spray (0.25 mg kg(-1) in 3 ml of saline) was significantly reduced by 65% (P<0.05) following intranasal pretreatment with 10 microg kg(-1) of TASP-V. Bronchoconstriction induced by histamine dihydrochloride nebulization (0.5 mg kg(-1) in 3 ml of saline) was significantly attenuated by 25 and 55% following aerosolized pretreatment with TASP-V analogue at 10 and 20 microg kg(-1), respectively. 4. In healthy volunteers, objective increase in NAR and reduction in nasal minimal cross section area (MCSA) induced by intranasal spray of histamine dihydrochloride (15 microg kg(-1) in 200 microl of saline) were significantly attenuated by 50% following local pretreatment with 1.275 microg kg(-1) of TASP-V when compared with saline. 5. It is concluded that intranasal or intrabronchial pretreatment with TASP-V reduced nasal obstruction and bronchoconstriction evoked by histamine challenge in the pig. In healthy human volunteers, this agent attenuated NAR increase and MCSA reduction induced by intranasal application of histamine.

Prostacyclin but not phentolamine increases oxygen consumption and skin microvascular blood flow in patients with sepsis and respiratory failure.

Inadequate tissue oxygenation may occur in critically ill patients with sepsis despite an apparently adequate O2 transport (QO2), and this may contribute to the development of an O2 debt and also to multiple organ failure. It has been shown that increasing QO2 by infusing a vasodilator may reveal this O2 debt in septic patients. To investigate whether the site of action of vasodilators may be of importance in unmasking such an O2 debt, we administered prostacyclin, a prostaglandin with a preferential effect on the microcirculation, and phentolamine, an arteriolar vasodilator, in 11 patients studied during the first 48 hours after the onset of sepsis, and compared their effect on whole body oxygen consumption (VO2) and skin microvascular blood flow. The results demonstrated that increasing QO2 by prostacyclin but not by phentolamine significantly increases VO2 in critically ill patients with sepsis. The site of action of vasodilators may therefore play an important role in their ability to unmask an O2 debt.

Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging.

RATIONALE AND OBJECTIVES: To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound. METHODS: The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection. RESULTS: The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. CONCLUSIONS: SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.

Evaluation of I.V. labetalol for treatment of posttraumatic hyperdynamic state.

A hyperdynamic state, characterized by an elevated blood pressure and tachycardia is frequently seen during the first few days following severe multiple trauma. We examined the cardiovascular effects of the alpha and beta adrenoceptor blocking agent labetalol in patients presenting a hyperdynamic cardiovascular state some days after major trauma. Ten patients with a heart rate-systolic blood pressure product (RPP) of more than 2000 during 6 consecutive hours, despite normovolaemia, adequate ventilation, analgesia and sedation were investigated. After a mean dose of 2.1 +/- 1.2 mg X kg-1 (mean +/- SD) of labetalol injected intravenously over a 10-min period, heart rate decreased from 117 +/- 28 to 102 +/- 19 beats X min-1, systolic arterial pressure from 25 +/- 3.5 to 18.5 +/- 2.7 kPa, diastolic pressure from 11 +/- 1.7 to 9.5 +/- 1.7 kPa, mean arterial blood pressure from 15.5 +/- 2.1 to 12.4 +/- 2.1 kPa, and the RPP from 2880 +/- 867 to 1853 +/- 373. The beneficial effect of this dose lasted 24 h in 8 of 10 patients without additional administration. No important side effects such as cardiac arrhythmias, hypotension, or bronchospasm were noted. We conclude that labetalol used in fractional intravenous doses permits an adequate treatment of a "hypertension-tachycardia syndrome" in severely injured patients.

Effects of fenoldopam on systemic and splanchnic haemodynamics and oxygen delivery/consumption relationship during hyperdynamic ovine endotoxaemia.

OBJECTIVE: To evaluate the use of a selective dopamine-1 agonist (fenoldopam) to provide selective splanchnic vasodilatation during sustained hypotensive endotoxaemia in sheep. DESIGN: Randomised, controlled, experimental study. SETTING: Animal research laboratory. SUBJECTS: 12 adult instrumented, midazolam-sedated sheep. INTERVENTIONS: The animals were randomised to receive a 20-min continuous infusion of dopamine (10 microg x kg(-1) x min(-1), fenoldopam (10 microg x kg(-1) x min(-1) and noradrenaline (1 microg x kg(-1) x min(-1)) under control conditions and 12 h after endotoxaemia was induced by a continuous infusion of Escherichia coli endotoxin producing a stable hyperdynamic state simulating human septic shock. This drug dosage was selected to produce a 25-30% increase in cardiac output by all three drugs during control conditions. MEASUREMENTS AND RESULTS: Systemic and splanchnic haemodynamic data were continuously obtained and systemic and splanchnic oxygen delivery (DO2) and consumption (VO2) were calculated. Hyperdynamic hypotensive endotoxaemia did not modify the splanchnic and renal reduction in DO2 and the vasoconstrictive reactivity to noradrenaline observed during control conditions. In contrast, endotoxaemia abolished the fenoldopam and dopamine-induced increase in splanchnic DO2 (especially in the coeliac trunk) observed during control conditions. CONCLUSIONS: During sustained hyperdynamic endotoxaemia, the dopaminergic-induced selective increase in coeliac trunk blood flow is abolished, most probably because of an already maximally vasodilated splanchnic circulation which prevented dopamine or fenoldopam to vasodilate this area further. Contrary to common belief, selective dopamine-1 agonist administration under these conditions may therefore not be beneficial to the splanchnic organs, though it improves whole body DO2 and VO2.

Lung mechanics and pulmonary but not systemic vascular responses to ET-1 are Tx and infusion rate dependent.

The role of cyclooxygenase metabolites formation in the systemic and pulmonary vascular and airway responses to different intravenous infusion rates of endothelin-1 (ET-1) was investigated in eight barbiturate-anesthetized mechanically ventilated adult sheep. ET-1 (20, 200, and 400 pmol/kg) was infused into the femoral vein over either 1, 10, or 180 s before and after pretreatment with indomethacin (1.5 mg/kg i.v.). ET-1 infusion produced a dose-dependent systemic vasoconstriction that was similar with all three infusion rates. In contrast, the pulmonary vascular and airways responses to ET-1 were not only dose dependent but also infusion rate dependent so that consistent effects on the pulmonary vasculature and airways were observed only when the peptide was injected over 1 s. At the highest dosage and at the fastest rate of administration, ET-1 produced a fivefold rise in pulmonary vascular resistance, a twofold rise in airway resistance, and a 45% decrease in dynamic pulmonary compliance, whereas no changes were observed when the peptide was injected over 180 s. Plasma levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) increased 20-fold when ET-1 was administered over 1 s but only 5-fold when it was administered over 180 s. Thromboxane B2 (TxB2) increased 5-fold when ET-1 was administered over 1 s and did not increase when ET-1 was given over 180 s. Plasma TxB2 levels were linearly correlated with pulmonary vascular or airway resistance during the bolus ET-1 infusion. Pretreatment with indomethacin completely prevented the ET-1-induced rise in TxB2 and 6-keto-PGF1 alpha and blocked pulmonary vaso- and bronchoconstriction observed, whereas it enhanced systemic vasoconstriction. These results demonstrate that in adult sheep intravenous ET-1 produces pulmonary vaso- and bronchoconstriction that is infusion rate dependent and is associated with the rate-dependent production of thromboxane. In contrast, the increase in systemic vascular tone elicited by ET-1 is not affected by its rate of infusion and does not depend on the secondary generation of cyclooxygenase metabolites.

Vascular control of the pig nasal mucosa: distribution and effect of somatostatin in relation to noradrenaline and neuropeptide Y.

By means of immunohistochemistry and radioimmunoassay (RIA), we have investigated the possible occurrence of somatostatin (SOM)-like immunoreactivity (-LI) in the autonomic innervation of the pig nasal mucosa. SOM-immunoreactive (-IR) fibres were present around nasal arteries, arterioles and venous sinusoids. Double-labelling experiments revealed that SOM-LI was co-localized with the noradrenaline (NA) markers tyrosine hydroxylase and dopamine-beta-hydroxylase as well as with neuropeptide Y (NPY) in a subpopulation of neurons in the superior cervical sympathetic ganglion and in perivascular nerve terminals. Furthermore, SOM-LI was also present in perivascular fibres containing vasoactive intestinal polypeptide (VIP) and NPY of presumably parasympathetic origin. The parasympathetic fibres that were associated with glands contained peptide histidine isoleucine (PHI), VIP and NPY but not SOM, suggesting that in the nasal mucosa SOM-IR is restricted to perivascular nerves. As revealed by RIA, the content of SOM-LI in biopsies of both nasal mucosa and superior cervical sympathetic ganglion was about 12 pmol/g and the reverse phase HPLC characterisation of SOM-LI shown two separate peaks for SOM-28 and SOM-14. In thiopentone anaesthetized pigs (n = 10), local intra-arterial (i.a.) infusion of SOM (1-14) induced dose-dependent, long lasting and parallel reduction of the nasal arterial blood flow, the volume of the nasal mucosa (reflecting capacitance vessel function) and decrease of the laser Doppler flowmeter signal (reflecting superficial nasal mucosal blood flow). These functional responses were not modified after pretreatment with the alpha-adrenoceptor antagonist phenoxybenzamine (1 mg kg-1 i.a.) whereas the effects of NA were almost abolished. SOM (6.10(-6) mol, i.a.) did not influence the nasal vascular responses to single impulse stimulation of the nasal sympathetic nerve supply providing no evidence for prejunctional activity in spite of clear-cut vascular effects. It is concluded that SOM-LI is co-localized with NA and NPY in sympathetic nerves and with VIP/NPY in parasympathetic perivascular nerves of the pig nasal mucosa. Since SOM evokes vasoconstriction via non-adrenergic mechanisms, this peptide should also be considered when discussing mediator candidates for the neural regulation of the nasal vascular bed.

Modulatory effect of two novel CGRP receptor antagonists on nasal vasodilatatory responses to exogenous CGRP, capsaicin, bradykinin and histamine in anaesthetised pigs.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and potent vasodilatator agent located in sensory C fibres. Several functional studies suggest that CGRP could be involved in the vasodilatation of different vascular beds during neurogenic inflammation. We have studied, in pentobarbital anaesthetised pigs, the antagonistic effect of local intra-arterial (i.a.) pretreatment with the analogues CGRP 8-37, [D31, P34, F35]CGRP 27-37 and [N31, P34, F35]CGRP 27-37 on the vasodilatation of the nasal vascular bed induced by exogenous CGRP, capsaicin, bradykinin (BK) and histamine. The attenuating effect of CGRP 8-37 analogue on exogenous CGRP-induced vasodilatation, previously described in other in vivo animal models, was confirmed in the pig nasal mucosa. It also interfered with BK-and, to a lesser extent, with capsaicin-and histamine-induced decrease in vascular resistance. CGRP 27-37 analogues reduced the duration of CGRP-, capsaicin- and BK-induced vasodilatation by more than 50%. Peak values of vasodilatation were attenuated by more than 25% overall. Attenuation of histamine-induced decrease in vascular resistance was less pronounced. It is concluded that CGRP 27-37 analogues antagonise the action of exogenous CGRP, capsaicin, BK and histamine by attenuating their vasodilatation effect, both in intensity and duration. These results strongly suggest that BK- and histamine-induced vasodilatation is partly mediated by CGRP. CGRP 8-37 and 27-37 appear to be potential contributors to the study of CGRP and its physiological role in neurogenic inflammation. In addition, they may have putative therapeutic applications in the treatment of rhinitic patients suffering from chronic nasal obstruction.

Systemic and splanchnic oxygen supply-demand relationship with fenoldopam, dopamine and noradrenaline in sheep.

The effects of intravenous administration of fenoldopam (0.3-10 micrograms.kg-1.min-1), dopamine (1-10 micrograms.kg-1.min-1) and noradrenaline (0.1-1 micrograms.kg-1.min-1) on systemic and splanchnic haemodynamics and oxygen supply-demand relationship were studied in 12 chronically instrumented, sedated sheep. Fenoldopam produced dose-dependent peripheral and splanchnic vasodilatation without change in arterial blood pressure. The coeliac trunk and portal vein blood flows were particularly sensitive to fenoldopam, whereas dopamine vasodilated these vascular beds only at high doses. Renal blood flow was not influenced by dopamine or fenoldopam, but decreased by noradrenaline. Fenoldopam maintained systemic oxygen extraction constant by increasing both oxygen supply and demand, while noradrenaline and dopamine increased oxygen supply more than demand, thus decreasing oxygen extraction. Both dopamine and fenoldopam increased oxygen delivery to the splanchnic organs while noradrenaline reduced it. Splanchnic oxygen consumption decreased with noradrenaline and increased with dopamine, resulting in a conserved oxygen extraction with both drugs, whereas oxygen consumption remained constant at all doses of fenoldopam infusion (i.e. dose-dependent decreased oxygen extraction). Both noradrenaline and fenoldopam, but not dopamine, were accompanied by increased portal lactataemia. We conclude that in sheep fenoldopam is a potent and selective splanchnic vasodilator but without vasodilatator effect on the renal circulation. The portal lactataemia associated with a decreased splanchnic oxygen extraction may present a significant limitation for some clinical applications of this drug.

An improved method for isolation of microvascular endothelial cells from normal and inflamed human lung.

Microvascular endothelial cells (MVEC), which differ from large vessel endothelial cells, have been isolated successfully from lungs of various species, including man. However, contamination by nonendothelial cells remains a major problem in spite of several technical improvements. In view of the organ specificity of MVEC, endothelial cells should be derived from the tissue involved in the diseases one wishes to study. Therefore, to investigate some of the immunopathological mechanisms leading to acute respiratory distress syndrome (ARDS), we have attempted to isolate lung MVEC from patients undergoing thoracic surgery for lung carcinoma and patients dying of ARDS. The method described here includes four main steps: (1) full digestion of pulmonary tissue with trypsin and collagenase, (2) aggregation of MVEC induced by human plasma, (3) Percoll density centrifugation, and (4) selection and transfer of MVEC after local digestion with trypsin/EDTA under light microscopy. Normal and ARDS-derived lung MVEC purified by this technique presented contact inhibition (i.e., grew in monolayer), and expressed classical endothelial markers, including von Willebrand factor (vWF), platelet endothelial cell adhesion molecule 1(PECAM-1, CD31), and transcripts for the angiotensin converting enzyme (ACE). The cells also formed capillarylike structures, took up high levels of acetylated low-density lipoprotein (Ac-LDL), and exhibited ELAM-1 inducibility in response to TNF. Contaminant cells, such as fibroblasts, smooth muscle cells, or pericytes, were easily recognized on the basis of morphology and were eliminated by selection of plasma-aggregated cells under light microscopy. The technique presented here allows one to study the specific involvement and contribution of pulmonary endothelium in various lung diseases.

A new imaging approach to quantitative evaluation of pulmonary vascular endothelial metabolism.

There has been no noninvasive, readily available method for clinically evaluating changes in pulmonary metabolism of biogenic aminelike substances. Such metabolic changes, which almost surely take place on the surface or within the endothelial cells that line the pulmonary vasculature, are likely to be significant components of the overall clinical response of the lung to many disorders. Radioiodinated metaiodobenzylguanidine (MIBG) shows properties in isolated, perfused lung preparations that simulate those of biogenic amines (eg, its uptake is sodium-dependent and virtually abolished by ouabain). New data from studies in sheep and humans indicate that changes in first transit pulmonary extraction of this compound can easily be monitored externally using conventional gamma camera-computer systems. MIBG labeled with iodine 123 may provide an important new means for clinical assessment of changes in pulmonary endothelial metabolism.

Postoperative fatal intestinal necrosis after enalapril treatment in a patient with rheumatoid arthritis.

The inappropriate use of antihypertensive medications may cause hypotensive responses associated with organ failure. We describe a patient who developed nonocclusive splanchnic ischemia leading to death following the administration of enalapril to treat postoperative hypertension. The mechanisms and consequences of refractory hypotension induced by angiotensin-converting enzyme inhibitors are discussed.

Pharmacokinetics of atracurium besylate in the pig after a single i.v. injection.

A pharmacokinetic study of atracurium besylate was performed in the pig after a single i.v. bolus injection of 2 mg/kg, the dose needed to produce surgical neuromuscular blockade. The plasma concentration values were obtained by high performance liquid chromatography. Using a two-compartment pharmacokinetic model, the elimination half life was found to be 28.6 +/- 6.3 min (mean +/- SEM), the total volume of distribution 341 +/- 56 ml/kg and the plasma clearance 8.7 +/- 1.1 ml/min/kg. Although the doses required to obtain a satisfactory neuromuscular blockade as well as the plasma level, volume of distribution and plasma clearance values were higher in the pig than in man, the distribution and elimination half-lives were similar to those recently reported.

Pharmacokinetics of pipecuronium in infants, children and adults.

In order to explain the reported shorter clinical duration of action of cumulative ED95 of pipecuronium in infants as compared to children or adults, the pharmacokinetic profiles of pipecuronium were compared in infants (n = 6; mean age 6.8 months; mean weight 7.3 kg) in children (n = 6; mean age 4.6 years; mean weight 19.2 kg) and in adults (n = 7; mean age 42 years; mean weight 58.2 kg). Equipotent doses (2 x ED95) of pipecuronium were injected i.v. as single bolus and arterial blood was sampled for 4-5 h. Pipecuronium was quantified by complex formation with [125I]-labelled rose bengal. Pharmacokinetic parameters were calculated using a two-compartment open model. The median for the distribution half-life of pipecuronium was 2.54 min (interquartile range: 1.0-2.5 min) in infants and 2.04 min (0.26-2.04 min) in children; both were significantly shorter than in adults (5.75 [3.7-9.7] min). The plasma clearance of pipecuronium was significantly decreased in infants (1.50 [0.6-1.5] ml.min-1.kg-1; P < 0.05) as compared to children and adults (2.27 [0.88-2.27] and 2.45 [1.7-3.2] ml.min-1.kg-1, respectively). The total volume of distribution was similar in all three groups. We conclude that the pharmacokinetic features of pipecuronium are age-dependent: differences as compared to adults consisted of a faster distribution in both infants and children and a slower elimination in infants. The pharmacokinetic profile of pipecuronium does not explain the faster recovery from neuromuscular blockade in infants as compared to children. Because of the low total plasma clearance in infants, pipecuronium dosage should be carefully monitored to avoid accumulation and prolonged paralysis.

[Studying pulmonary mechanics in intensive care]. / Exploration de la mécanique pulmonaire en soins intensifs.

Assessing pulmonary function in critically ill patients is difficult, mainly because of lack of cooperation, artificial ventilation and jeopardized vital functions. We describe bedside methods and mobile equipment used to measure lung volumes, static pulmonary and thoracic compliance. The analysis of single and multiple-breath nitrogen washout curves allows an estimation of closing volume and an assessment of the inhomogeneity of ventilation. The use of a microcomputer facilitates recording, calculation, reproduction and classification of the data; it also permits the collection of more information in a shorter time, allowing the adjustment of mechanical ventilation to the underlying pulmonary disease.