Denis R. Morel

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.

Increased plasma and pulmonary lymph levels of endothelin during endotoxin shock.

Arterial and mixed venous blood and pulmonary lymph samples were collected, together with continuous measurement of pulmonary and systemic haemodynamics in six awake sheep receiving a constant rate intravenous infusion of Escherichia coli endotoxin dissolved in sterile normal saline

Long-term Angiotensin-converting Enzyme Inhibitor Treatment Attenuates Adrenergic Responsiveness without Altering Hemodynamic Control in Patients Undergoing Cardiac Surgery

Background The sympathoadrenal and the renin-angiotensin systems are involved in blood pressure regulation and are known to be markedly activated during cardiac surgery. Because unexpected hypotensive events have been reported repeatedly during anesthesia in patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors, the authors questioned whether renin-angiotensin system blockade would alter the hemodynamic control through attenuation of the endocrine response to surgery and/or through attenuation of the pressor effects of exogenous catecholamines. Methods Patients with preserved left ventricular function undergoing mitral valve replacement or coronary revascularization were divided into two groups according to preoperative drug therapy: patients receiving ACE inhibitors for at least 3 months (ACEI group, n = 22) and those receiving other cardiovascular drug therapy (control group, n = 19). Anesthesia was induced using fentanyl and midazolam. Systemic hemodynamic variables were recorded before surgery, after anesthesia induction, during sternotomy, after aortic cross-clamping, after aortic unclamping, as well as after separation from cardiopulmonary bypass (CPB) and during skin closure. Blood was sampled repeatedly up to 24 h after surgery for hormone analysis. To test adrenergic responsiveness, incremental doses of norepinephrine were infused intravenously during hypothermic CPB and after separation from CPB. From the dose-response curves, pressor (defined as mean arterial pressure changes), and vasoconstrictor (defined as systemic vascular resistance changes) effects were analyzed, and the slopes and the dose of norepinephrine required to increase mean arterial pressure by 20% were calculated (PD20). Results At no time did the systemic hemodynamics and the need for vasopressor support differ between the two treatment groups. However, for anesthesia induction, significantly less fentanyl and midazolam were given in the ACEI group. Although plasma renin activity was significantly greater in the ACEI group throughout the whole 24-h study period, plasma concentrations of angiotensin II did not differ between the two groups. Similar changes in catecholamines, angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB. The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group: the dose-response curves were shifted to the right and the slopes were decreased at the two study periods; PD20 was significantly greater during hypothermic CPB (0.08 micro gram/kg in the ACEI group vs. 0.03 micro gram/kg in the control group; P < 0.05) and after separation from CPB (0.52 micro gram/kg in the ACEI group vs. 0.13 micro gram/kg in the control group; P < 0.05). In both groups, PD20 was significantly less during hypothermic CPB than in the period immediately after CPB. Conclusions Long-term ACE inhibitor treatment in patients with preserved left ventricular function alters neither the endocrine response nor the hemodynamic stability during cardiac surgery. However, a significantly attenuated adrenergic responsiveness associated with incomplete blockade of the plasma renin-angiotensin system supports the hypothesis that inhibition of angiotensin II generation and of bradykinin degradation within the vascular wall mediates some of the vasodilatory effects of ACE inhibitors.

Adverse effects of methylene blue on the central nervous system

Background:An increasing number of clinical observations suggest adverse neurologic outcome after methylene blue (MB) infusion in the setting of parathyroid surgery. Hence, the aim of the current study was to investigate the potentially neurotoxic effects of MB using a combination of in vivo and in vitro experimental approaches. Methods:Isoflurane-anesthetized adult rats were used to evaluate the impact of a single bolus intravascular administration of MB on systemic hemodynamic responses and on the minimum alveolar concentration (MAC) of isoflurane using the tail clamp test. In vivo, MB-induced cell death was evaluated 24 h after MB administration using Fluoro-Jade B staining and activated caspase-3 immunohistochemistry. In vitro, neurotoxic effects of MB were examined in hippocampal slice cultures by measuring excitatory field potentials as well as propidium iodide incorporation after MB exposure. The impact of MB on dendritic arbor was evaluated in differentiated single cell neuronal cultures. Results:Bolus injections of MB significantly reduced isoflurane MAC and initiated widespread neuronal apoptosis. Electrophysiologic recordings in hippocampal slices revealed a rapid suppression of evoked excitatory field potentials by MB, and this was associated with a dose-dependent effect of this drug on cell death. Dose–response experiments in single cell neuronal cultures revealed that a 2-h-long exposure to MB at non–cell-death-inducing concentrations could still induce significant retraction of dendritic arbor. Conclusions:These results suggest that MB exerts neurotoxic effects on the central nervous system and raise questions regarding the safety of using this drug at high doses during parathyroid gland surgery.

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 upregulated 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 upregulation was detected in the brain of Tnfr2° mice, indicating a close correlation between protection against CM‐associated brain damage, absence of TNFR2, and absence of ICAM‐1 upregulation in the brain. Our results in ARDS and CM indicate a specific upregulation 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. J. Leukoc. Biol. 61: 551–558; 1997.

Cardiac output by Modelflow® method from intra-arterial and fingertip pulse pressure profiles

Modelflow, when applied to non-invasive fingertip pulse pressure recordings, is a poor predictor of cardiac output (Q, litre x min(-1)). The use of constants established from the aortic elastic characteristics, which differ from those of finger arteries, may introduce signal distortions, leading to errors in computing Q. We therefore hypothesized that peripheral recording of pulse pressure profiles undermines the measurement of Q with Modelflow, so we compared Modelflow beat-by-beat Q values obtained simultaneously non-invasively from the finger and invasively from the radial artery at rest and during exercise. Seven subjects (age, 24.0 +/- 2.9 years; weight, 81.2 +/- 12.6 kg) rested, then exercised at 50 and 100 W, carrying a catheter with a pressure head in the left radial artery and the photoplethysmographic cuff of a finger pressure device on the third and fourth fingers of the contralateral hand. Pulse pressure from both devices was recorded simultaneously and stored on a PC for subsequent Q computation. The mean values of systolic, diastolic and mean arterial pressure at rest and exercise steady state were significantly ( P < 0.05) lower from the finger than the intra-arterial catheter. The corresponding mean steady-state Q obtained from the finger (Qporta) was significantly ( P < 0.05) higher than that computed from the intra-arterial recordings (Qpia). The line relating beat-by-beat Qporta and Qpia was y =1.55 x -3.02 ( r2 = 0.640). The bias was 1.44 litre x min(-1) and the precision was 2.84 litre x min(-1). The slope of this line was significantly higher than 1, implying a systematic overestimate of Q by Qporta with respect to Qpia. Consistent with the tested hypothesis, these results demonstrate that pulse pressure profiles from the finger provide inaccurate absolute Q values with respect to the radial artery, and therefore cannot be used without correction with a calibration factor calculated previously by measuring Q with an independent method.

Respiratory depressant effects of different doses of midazolam and lack of reversal with naloxone--a double-blind randomized study.

Conflicting data concerning the ventilatory effects of benzodiazepines may be caused by the large variability in investigational conditions. Respiratory effects of three different intravenous doses of midazolam (0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg) and placebo were measured in a double-blind and randomized fashion in eight healthy volunteers. The respiratory variables were analyzed by means of a noninvasive method, thereby avoiding interferences associated with the stimulating effects of mouthpiece and nose clip. After injection of midazolam, tidal volume decreased by 40% with the three doses and respiratory frequency increased to the same extent, minute ventilation remained constant. Only the largest dose of the drug produced a significant decrease (P < 0.05) in O2 saturation that was related to the longer duration of apnea. Intravenous naloxone (0.015 mg/kg) injected 5 min after midazolam did not change any measured respiratory or hemodynamic variable. We conclude that the respiratory effects of midazolam are poorly dose related and not reversed by naloxone. The observed compensatory increase in respiratory frequency which is not noted in other studies, is probably related to the noninvasive measurement technique used.

Loss of dipeptidylpeptidase IV activity in chronic rhinosinusitis contributes to the neurogenic inflammation induced by substance P in the nasal mucosa

In this study, we have found that dipeptidylpeptidase IV (DPPIV) plays in vivo an active role in the modulation of the inflammatory response of chronic rhinosinusitis. Human nasal mucosa expresses DPPIV‐like immunoreactivity in submucosal seromucus glands, leukocytes, and endothelial cells of blood vessels. DPPIV enzymatic activity in nasal tissue biopsies taken from patients suffering from chronic rhinosinusitis was correlated inversely with the density of inflammatory cells in the nasal mucosa, and the DPPIV activity rose when chronic rhinosinusitis was treated. By using a pig animal model, we have shown that the intranasal administration of recombinant DPPIV decreased the vasodilatation induced by exogenous substance P (SP), a proinflammatory peptide released by sensory nerves. In contrast, an inhibitor of DPPIV enhanced the vasodilatatory effect at low doses of SP. SP5–11 was 100‐ to 1000‐fold less potent than SP as a vasodilator of the nasal mucosa. The vasodilatatory effect of SP was abolished by a NK1 receptor antagonist. In conclusion, these results suggest a new pathophysiological pathway for rhinitis based on clinical observations in humans, indicating the involvement of an enzyme to modulate non‐adrenergic and non‐cholinergicnon‐cholinergic substrate that occurred during nasal dysfunctions.

Cardiovascular responses to anesthetic induction in patients chronically treated with angiotensin-converting enzyme inhibitors

Purpose: To investigate the effects of chronic ACE inhibition on cardiac neural function following induction of general anesthesia in patients with underlying coronary artery disease.Method: In a prospective case-control study, heart rate variability (HRV) and baroreflex control were compared preoperatively and 30 min after anesthesia induction in patients receiving, or not, ACEI (n=16, control group and n=16, ACEI group). All patients had normal cardiac function and anesthesia consisted of a fixed dose regimen of fentanyl and midazolam. Anesthesia-related hypotension was defined by systolic blood pressure<90 mmHg. Spectral density of HRV was calculated for low frequency and high frequency bands (LF, from 0.05 to 0.15 Hz and HF, from >0.15 to 0.6 Hz). Baroreflex sensitivity was estimated after blood pressure changes induced by injections of phenylephrine (PHE) and nitroglycerin (NTG).Results: The HRV parameters and baroreflex sensitivity were not different between groups, during the awake and anesthesia periods. Anesthesia produced similar reduction in total HRV in the Control and ACEI groups (−93±28% vs −89±32%,) and in baroreflex sensitivity during NTG (−64±21% vs −54±17%) or PHE tests (−74±25% vs −72±22%). Anesthesia-related hypotension occurred in nine patients in the ACEI group (vs two controls). Although the hypertensive response to phenylephrine was greater after anesthesia in both groups, the sensitivity to phenyle-phrine was attenuated in those patients experiencing hypotension in the ACEI group.Conclusions: Chronic preoperative treatment with ACEIs does not influence cardiac autonomic regulation and anesthetic- induced hypotensive episodes are mainly attributed to decreased-adrenergic vasoconstrictive response.RésuméObjectif: Rechercher les effets d’une inhibition chronique de l’ECA sur la fonction neurale cardiaque à la suite de l’induction d’une anesthésie générale chez des patients qui présentent une cardiopathie ischémique sous-jacente.Méthode: Lors d’une étude prospective cas-témoins, la variabilité de la fréquence cardiaque (VFC) et le contrôle baroréflexe ont été comparés avant l’opération et 30 min après l’induction de l’anesthésie chez des patients qui reçoivent, ou non, un IECA (groupe témoin: n=16, groupe IECA: n=16). Tous les patients présentaient une fonction cardiaque normale et l’anesthésie comprenait un schéma posologique fixe de fentanyl et de midazolam. On a défini l’hypotension reliée à l’anesthésie comme la tension artérielle systolique<90 mmHg. La densité spectrale de la VFC a été calculée pour des bandes de basses et de hautes fréquences (BF, de 0,05 à 0,15 Hz et HF, de >0,15 à 0,6 Hz). La sensibilité baroréflexe a été évaluée après les changements de pression sanguine induits par les injections de phényléphrine (PHE) et de nitroglycérine (NTG).Résultats: Les paramètres de la VFC et la sensibilité baroréflexe n’ont pas présenté de différence intergroupe pendant les périodes d’éveil et d’anesthésie. L’anesthésie a produit une réduction similaire de la VFC totale dans les groupes témoin et IECA (−93±28 % vs −89±32%,), et de la sensibilité baroréflexe pendant les tests avec la NTG (−64±21 % vs −54±17 %) ou la PHE (−74±25 % vs −72±22 %). L’hypotension reliée à l’anesthésie est survenue chez neuf patients du groupe IECA (vs deux témoins). Bien que la réponse hypertensive à la phényléphrine ait été plus grande après l’anesthésie dans les deux groupes, la sensibilité à la phényléphrine a été atténuée chez les patients qui ont présenté de l’hypotension dans le groupe IECA.Conclusion: Le traitement préopératoire prolongé avec l’IECA n’influence pas la régulation autonomique cardiaque et l’hypotension induite par l’anesthésique est principalement causée par la diminution de la réponse vasoconstrictive α-adrénergique.

Dichotomal role of TNF in experimental pulmonary edema reabsorption

Distinct from its receptor binding sites, TNF carries a lectin-like domain, situated at the tip of the molecule, which specifically binds oligosaccharides, such as N,N′-diacetylchitobiose. In view of the apparently conflicting data concerning TNF actions in pulmonary edema, we investigated the contribution of, on the one hand, the receptor binding sites and, in contrast, the lectin-like domain of the cytokine on pulmonary fluid reabsorption in in situ and in vivo flooded rat lungs. Receptor binding sites were blocked with the human soluble TNFR type 1 construct (sTNFR1), whereas the lectin-like domain was blunted with the oligosaccharide N,N′-diacetylchitobiose. We observed that in situ, TNF failed to stimulate alveolar liquid clearance, but did so together with the sTNFR1, and this activity was neutralized by N,N′-diacetylchitobiose. In vivo TNF inhibited liquid clearance, but activated it when complexed with the sTNFR1. A TNF-derived peptide mimic of the lectin-like domain activated fluid reabsorption in flooded lungs, and this activity was blunted by cotreatment with TNF. Our results thus indicate that in these models the receptor binding sites of TNF inhibit, whereas its lectin-like domain activates, edema reabsorption.