Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

BACKGROUND: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. METHODS: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. DISCUSSION: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. TRIAL REGISTRATION: ClinicalTrials.gov NCT02384876 . Registered on March 2015.

[Radiation-related heart toxicity: Update in women]. / Lésions cardiaques radio-induites chez la femme : mise au point.

Breast cancer is a common diagnosis in women and thus women are at risk of radiation-induced heart disease, in particular during radiotherapy for left breast cancer and when the internal mammary chain is included. Rates of major cardiac events increase with younger age at the time of irradiation, diagnosis before 1990s, higher radiation doses, coexisting cardiovascular risk factors and adjuvant cardiotoxic chemotherapy. Radiation-induced heart disease comprises a spectrum of cardiac pathologies, including pericardial disease, cardiomyopathy, coronary artery disease and valvular disease. The cardiac injury can appear a long time after radiotherapy and can consist of complex lesions with poor prognosis. The disciplines of cardiology and oncology have increasingly recognized the benefits of collaborating in the care of cancer patients with cardiac disease, developing guidelines for the assessment and management of radiation-related cardiovascular disease. We could consider screening patients with previous chest radiation every 5 years with transthoracic echocardiography and functional imaging. However, prevention remains the primary goal, using cardiac sparing doses and avoidance techniques in radiotherapy to improve patient survival.

[French residents' training in instrumental deliveries: A national survey]. / Évaluation nationale de la formation des internes de gynécologie-obstétrique à l'accouchement instrumental.

OBJECTIVES: To evaluate French residents in Obstetrics and Gynaecology's training in instrumental deliveries in 2015. PATIENTS AND METHODS: We conducted a national descriptive survey among 758 residents between December 2014 and January 2015. Respondents were invited by email to specify their University Hospital, their current university term, the number of instrumental deliveries performed by vacuum extractor, forceps or spatulas, and whether they made systematic ultrasound exams before performing the extraction. RESULTS: Response rate was 34.7 % (n=263). There were important differences between regions in terms of type of instruments used. Vacuum extractor was the most commonly used instrument for instrumental deliveries by French residents (56.9 %), more than forceps (25.2 %) and spatulas (17.9 %). At the end of the residency, all the residents had been trained in instrumental deliveries with at least two instruments. CONCLUSION: The training of difficult techniques as well as their perfect control is required for instrumental deliveries. Yet, we are forced to note that there are substantial differences in the French residents' training in instrumental deliveries depending on their region. So, teaching at least two techniques seems essential as well as improving the training capacities and standardizing practices. A greater systematization of the teaching of the mechanics and obstetric techniques might be a solution to be considered too.

[Thoracoabdominal CT scan: a useful tool for the diagnosis of air embolism during an endoscopic retrograde cholangiopancreatography]. / Intérêt d'un scanner corps entier pour le diagnostic d'embolie gazeuse au cours d'une cholangiopancréatographie rétrograde endoscopique.

We report the case of an 82-year-old woman treated with biliary stents for an ampulloma of Vater's papilla, with recurrent stenosis of the common bile duct. She was hospitalized with a cholestasis. An endoscopic retrograde cholangiopancreatography (ERCP) was scheduled to change the biliary stent for a metallic one, under general anaesthesia, with oral intubation. The ERCP was performed initially without any complication, but as the metallic biliary stent was placed, an air embolism occurred and a cardiac arrest happened immediately. The etiologic diagnosis was quickly confirmed by an injected multislice body-scan, which showed liver, right heart and brain gas embolism. Cardiopulmonary resuscitation allowed a complete haemodynamic recovery but a poor neurological recovery. The patient was transferred in intensive care unit, were she died 12 days after, despite hyperbaric oxygen therapy and the disappearance of the air embolism on the following computed tomography scan. This case may be useful to recall the utility of a body-scan for the diagnosis, treatment and follow-up of an air embolism during ERCP.

Volume dependence of respiratory system resistance during artificial ventilation in rabbits.

The volume dependence of respiratory resistance (Rrs), usually observed during normal breathing, is expected to be accentuated during expiratory flow limitation (EFL). In order to quantify this dependence we studied the pressure, flow, and volume data obtained from eight New Zealand rabbits, artificially ventilated at different levels of applied expiratory pressure (0-10 hPa), before and during histamine i. v. infusion. EFL was provoked by lowering the expiratory pressure and was detected by the application of an additional negative expiratory pressure and by forced oscillations. The analysis of respiratory system mechanics was performed by multiple regression, using the classical linear first-order model and also a nonlinear model, accounting for volume dependence of Rrs. Both models satisfactorily fitted the data in the absence of EFL. The nonlinear model proved to be more appropriate in the presence of EFL. The coefficient expressing the volume dependence of Rrs (Rvd) was significantly more negative during EFL. Rvd values were highly correlated with the fraction of the tidal volume left to be expired at the onset of EFL. A threshold Rvd value of -1,000 (hPa x s x l(-2)) detected EFL with high sensitivity and specificity. We conclude that a strongly negative volume dependence of Rrs is a reliable and noninvasive index of EFL during artificial ventilation.

Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs.

Because hypoxic pulmonary vasoconstriction occurs mainly in the small pulmonary arteries, the authors investigated the effects of drugs acting on the nitric oxide (NO) pathway and the calcium and potassium channels in the peripheral pulmonary circulation, without interference with the overall pulmonary or systemic circulation. Mixed venous blood was infused in wedged areas to study the pressure/flow relationship and to compute peripheral pulmonary vascular resistance (PPVR). The authors studied the effects of Nomega-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, sodium nitroprusside (SNP, an NO donor), the calcium channel blockers verapamil, nifedipine and nicardipine, and the potassium channel opener levcromakalim, during normoxia and acute mild normocapnic hypoxia. In the peripheral pulmonary circulation, L-NAME caused an increase in PPVR during normoxia (+95%; p<0.001) and hypoxia (+60%; p<0.01). Following the increase by L-NAME, SNP decreased PPVR during normoxia (-24%; p<0.05) and hypoxia (-23%; p<0.05). Verapamil, nifedipine and nicardipine did not modify PPVR during normoxia but during hypoxia they decreased PPVR (-28%, nonsignificant; -27%, p<0.01 and -33%, p<0.05, respectively). Levcromakalim did not modify PPVR during normoxia or hypoxia. In conclusion, the nitric oxide pathway and voltage-dependent calcium channels, and not adenosine triphosphate sensitive potassium channels, play an important role in the control of peripheral pulmonary circulation in dogs.

Effect of the H1 blocker d-chlorpheniramine on cerebral blood flow in the conscious dog during normocapnic hypoxia.

The mechanism causing cerebral vasodilatation during hypoxia remains unclear. A role for histamine is suspected because H2 receptor-blocking drugs blunt the hypoxia-induced increase in cerebral blood flow (CBF). Moreover, in vitro blockade of H1 receptors by chlorpheniramine decreases the vasodilatation of cerebral arteries that is induced by histamine. The present study tested the hypothesis that an H1 receptor blocker (d-chlorpheniramine) would have a similar effect in vivo during hypoxia. Isocapnic hypoxia (inspired oxygen fraction, FIO2 = 0.10; inspired carbon dioxide fraction, FICO2 = 0.035) was induced in 16 conscious dogs randomly divided into two groups: eight dogs received saline intravenously (controls) at time 0 (normoxia) and after 2 h and 4 h hypoxia, and the other eight dogs received d-chlorpheniramine intravenously (0.5 mg kg-1) to block the H1 receptors. Regional CBF was measured by the radioactive microspheres technique 15 min after each injection of d-chlorpheniramine or saline. In the control group, CBF increased during hypoxia in all regions of the brain. In the d-chlorpheniramine group, total CBF increased similarly after 2 h of hypoxia. After 4 h of hypoxia, the increase was limited, especially in the pons, cerebral peduncles, hippocampus, hypothalamus, thalamus, and occipital lobes (six out of 12 studied regions). It is concluded that the H1 blocker d-chlorpheniramine did not strongly inhibit the increase in CBF during hypoxia. After cumulative doses, however, as in the fourth hour of hypoxia, the increase in total CBF was limited.

Effect of the inhibitor of NO synthase, NG-nitro-L-arginine methyl ester, on histamine-induced bronchospasm in the rabbit.

New Zealand male rabbits were anaesthetized with thiopental, tracheotomized, curarized by vecuronium bromide and mechanically ventilated. Six rabbits received L-NAME 10 mg kg-1 i.v., six rabbits L-NAME 15 mg kg-1 iv, and six rabbits received saline i.v. (controls), 5 min before a histamine aerosol (2% solution during 5 min). Six others rabbits received an injection of L-NAME 15 mg kg-1 iv, 5 min before the histamine aerosol, followed by an infusion of L-arginine over a 60- min period. Total respiratory resistance (Rrs) and elastance (Ers) were derived by least square analysis of the relationship between tracheal pressure and flow, and computed every minute before and over a 1-h period after the histamine aerosol. Oxygen free radicals (OFR) were measured with a luminometer, in microsomes from lung homogenates at the end of the experiment. Compared with the histamine response of the control group, the Rrs response in the L-NAME 10 group was slightly less, while Ers changes were the same in the two groups. In contrast, L-NAME 15 was responsible for an increased Rrs response, the difference being significant (P < 0.05) only between 15 and 40 min after the aerosol (+114% vs. +85% in controls at the 20th min). The increase in Ers with L-NAME 15 was stronger and significantly larger (+71% vs. +42% in controls at the 20th min after the histamine aerosol, P < 0.001). The relatively greater effect of L-NAME on Ers than on Rrs suggests that NO predominantly modulates the response to histamine of the peripheral lung rather than that of the large airways. Furthermore, the effect of L-NAME on Rrs was completely abolished by L-arginine, while its effect on Ers was only partially reversed. This suggests that the changes in Ers are partly related to a hardly reversible phenomenon. Possibly, the mechanical changes are linked with the rise of OFR in the lung parenchyma, which were significantly higher in the L-NAME 15 group compared to the control group (P < 0.05).

Changes in peripheral pulmonary vascular resistance after ioxaglate infusion in anesthetized dogs.

The pulmonary vascular resistance in a peripheral portion of the pulmonary vascular bed can be determined with a catheter wedged in a peripheral branch of the pulmonary artery, from the pressure increase induced by infusion of mixed venous blood at known flow rates. The volume of the wedged vascular bed can be estimated during fluoroscopy, from the volume of a contrast agent infused until the corresponding pulmonary vein can be seen. The present work was undertaken to determine the possible influence of this maneuver on the peripheral pulmonary vascular resistance (PPVR). In anesthetized dogs, after a control flow run, Hexabrix (meglumine ioxaglate and sodium ioxaglate) was infused, then the catheter was flushed with saline, and another flow run was performed. There was no significant difference between two consecutive control runs in the same site (n = 14). Before Hexabrix (n = 23), PPVR was 162 (+/-24) x 10(3) dyn.s.cm-5 (1 dyn = 10 microN) during the control run; it increased to 339 (+/-33) x 10(3) dyn.s.cm-5 after Hexabrix (p < 0.001). These results show that care should be taken to avoid interference between Hexabrix and the results of physiological or pharmacological interventions with this technique.

Expiratory flow limitation during mechanical ventilation detected by the forced oscillation method.

We have previously observed large phasic variations of respiratory mechanical impedance in chronic obstructive pulmonary disease (COPD) patients mechanically-ventilated for acute respiratory failure, and postulated that they were due to expiratory flow limitation (EFL). The aim of this study was to test that assumption experimentally and to assess the value of impedance for automatic and noninvasive detection of EFL during mechanical ventilation. The study was performed: 1) in a mechanical analogue, including a flow-limiting element; and 2) in eight anaesthetized and paralysed rabbits, before and during histamine infusion. In both instances, EFL was obtained by lowering the expiratory pressure, using a computer-controlled ventilator; the absence of flow increase when expiratory pressure was further lowered was taken as evidence of EFL. Impedance was measured by applying 15 Hz oscillations at the airway opening. Its real (Re) and imaginary (Im) parts were measured separately during the inspiratory and the expiratory phases, and their differences were related to the mean inspiratory modulus. With the analogue, EFL was accompanied by large decreases both of Re and Im during the expiratory phase. In the rabbits, phasic variations of Re were variable in sign and were not significantly different with and without EFL. In contrast, EFL systematically and specifically decreased Im during the expiratory phase. A threshold of -50% provided a sensitivity of 96% and a specificity of 100% for detecting EFL. The observed phasic variations may be explained by airway wall shunt properties. The study suggests that a large decrease of the imaginary part of impedance during the expiratory phase is a sensitive and specific index of expiratory flow limitation during artificial ventilation.

Effect of the inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester, on cerebral and myocardial blood flows during hypoxia in the awake dog.

The increase in cerebral blood flow (CBF) elicited by moderate hypoxia in anesthetized animals is little attenuated by nitric oxide (NO) synthase inhibitors. However, in previous studies, the effects of NO synthase inhibitors may have been altered by anesthetics. Consequently, we studied the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on cerebral and myocardial blood flows during hypoxia in the awake dog. Regional CBF and myocardial blood flows (MBF) were measured under normoxia and hypoxia in 16 beagle dogs after an intravenous (IV) injection of either saline (control, n = 8) or L-NAME 20 mg/kg (n = 8). One week after thoracotomy for catheter insertion, awake dogs were studied during three periods: normoxia and after 2 and 4 h of normocapanic hypoxia in an environmental chamber (FIO2 = 0.10, FICO2 = 0.035, balance N2). At each stage, a bolus injection of L-NAME or saline was followed 15 min later by left atrial injection of radiolabeled microspheres (141Ce, 103Ru, 46Sc) for regional CBF and MBF. After the dogs were killed, the brain and the heart were fixed in 10% formaldehyde, dissected by region and weighed, and radioactivity was measured in a gamma counter. During hypoxia, Pao2 was approximately 45 mm Hg with normal Paco2. In the control group, CBF increased by 45% after 2 h and 48% after 4 h of hypoxia; MBF increased by 69% and 60%, respectively. L-NAME prevented the CBF increase during hypoxia and the MBF increase after 2 h of hypoxia; after 4 h of hypoxia the measurement of MBF was confounded by cardiac dysfunction. These results suggest that NO plays a role in cerebral vasodilation during hypoxia in the awake animal.

Analysis of low-frequency lung impedance in rabbits with nonlinear models.

Lung mechanics was studied in six paralyzed tracheotomized rabbits ventilated with a specially devised computer-controlled ventilator. The target flow waveform contained noninteger multiple frequencies ranging from 0.83 to 6-10 Hz and met a neither-sum-nor-difference criterion to minimize the effects of nonlinearity (B. Suki and K. Lutchen. IEEE Trans. Biomed. Eng. 39: 1142-1151, 1992). The actual flow, however, contained harmonics of the two lowest frequencies. Measurements were performed at mean airway pressure (Paw) levels of 8 and 12 hPa and during histamine-induced bronchoconstriction. Smooth impedance curves were observed in unchallenged rabbits at low mean Paw levels. In contrast, unrealistic impedance fluctuations, suggestive of cross talk from the unwanted frequency components in the flow input, were seen at high mean Paw levels and during acute bronchoconstriction. Model analysis was performed by using the actual flow signal as an input to various nonlinear models. The impedance fluctuations observed at high mean Paw levels were well simulated by a model featuring a volume-dependent elastance, and those observed after histamine were almost perfectly reproduced by a model where resistance increased with the reciprocal of lung volume. We conclude that impedance data biased by cross talk may provide useful information on the presence and nature of respiratory system nonlinearities.

Influence of hypoxia and hypercapnia on the kinetics and hypokaliaemic effect of salbutamol in the rabbit.

1. The aims were to document the influence of moderate hypoxia or hypercapnia on salbutamol kinetics and its hypokaliaemic effect, following its administration through the intravenous (60 micrograms/kg), intratracheal (60 micrograms/kg), and oral (2400 micrograms/kg) routes (n = 5). In control animals, PaO2 was around 85 mmHg and PaCO2 20 mmHg; in hypoxic animals PaO2 was around 40 mmHg and in the hypercapnic rabbit PaCO2 was 50 mmHg. 2. Following the intravenous administration of salbutamol, the apparent volume of distribution increased two-fold (p < 0.05) in animals with hypoxia and hypercapnia. Consequently, its half life was enhanced (p < 0.05). Given via the trachea, salbutamol bioavailability was decreased by hypoxia. 3. When salbutamol was given orally, hypoxia or hypercapnia increased the area under salbutamol plasma concentration as a function of time (p < 0.05). 4. In control animals, the salbutamol hypokaliaemic effect was greater when administered orally than through the other routes. Compared with control animals, the experimental conditions reduced the hypokaliaemic effect of salbutamol only when given orally. 5. It is concluded that salbutamol kinetics and dynamics can be altered by hypoxia and hypercapnia.

Effect of acute hypercapnia on alpha atrial natriuretic peptide, renin, angiotensin II, aldosterone, and vasopressin plasma levels in patients with COPD.

Disturbances in hormonal systems involved in sodium and water homeostasis are common during respiratory insufficiency. To investigate the role of hypercapnia, we designed a study to examine the hormonal response to acute hypercapnia induced at constant cardiac filling pressures and without hypoxemia. Seven sedated patients with COPD receiving mechanical ventilation were studied during five successive periods. Hemodynamics, arterial blood gases, and plasma hormone levels (atrial natriuretic peptide, renin, angiotensin II, aldosterone, vasopressin) were measured three times during 60 min of acute hypercapnia (52 +/- 5 mm Hg) and at control periods, before (36 +/- 4 mm Hg) and after (42 +/- 3 mm Hg) acute hypercapnia. During acute hypercapnia, mean pulmonary arterial pressure and cardiac output were increased without variation of other measured cardiorespiratory data and hormonal levels when compared with control values. After acute hypercapnia, cardiorespiratory variables returned to control values without variations of hormonal levels. Our results show that moderate acute hypercapnia does not significantly influence the hormonal levels when cardiac filling pressures and sympathetic tone remain stable. We suggest that changes in those plasma hormones involved in salt and water homeostasis during acute hypercapnia are secondary to hemodynamic changes induced by acute respiratory failure and not to acute hypercapnia per se.

Fourier analysis versus multiple linear regression to analyse pressure-flow data during artificial ventilation.

Respiratory resistance (Rrs) and elastance (Ers) are commonly measured in artificially-ventilated patients or animals by multiple linear regression of airway opening pressure (Pao) versus flow (V') and volume (V), according to the first order model: Pao = P0 + Ers.V + Rrs.V', where P0 is the static recoil pressure at end-expiration. An alternative way to obtain Rrs and Ers is to derive them from the Fourier coefficients of Pao and V' at the breathing frequency. A potential advantage of the second approach over the first is that it should be insensitive to a zero offset on V' and to the corresponding volume drift. The two methods were assessed comparatively in six tracheotomized, paralysed and artificially ventilated rabbits with and without adding to V' an offset equal to 5% of the mean unsigned flow. The 5% flow offset did not modify the results of Fourier analysis, but increased Rrs and Ers from linear regression by 15.8 +/- 4.6% and 4.55 +/- 0.64%, respectively. Without additional offset, differences between the two methods averaged 30.2 +/- 14.0% for Rrs and 9.3 +/- 6.2% for Ers. The differences almost completely disappeared (2.47 and 0.61%, respectively) when the flow signal was zero-corrected using the assumption that inspired and expired volumes were the same. After induced bronchoconstriction, however, Ers was still slightly larger by linear regression than by Fourier analysis, which may result from nonlinearities and/or frequency dependence of the parameters. We conclude that the regression method requires zero flow correction and that Fourier analysis is an attractive alternative.

Influence of chronic hypoxia on salbutamol tissular concentrations and on respiratory resistance in anesthetized rabbits.

Salbutamol is a potent beta 2-adrenoceptor agonist given to patients with bronchial asthma who are frequently hypoxemic. The aims of this study were to document the influence of chronic hypoxia on salbutamol tissue concentrations and on salbutamol effect on total respiratory resistance. To this purpose, salbutamol (60 micrograms/kg) was administered intravenously to four groups of six rabbits exposed to four experimental conditions: (1) control rabbits breathing air, (2) histamine-induced bronchoconstriction in rabbits breathing air, (3) animals with chronic hypoxia, (4) histamine-induced bronchoconstriction in animals with chronic hypoxia. The area under salbutamol plasma concentration time curve (0 to 45 min) was not affected by these experimental conditions. Compared with control rabbits breathing air, following histamine-induced bronchoconstriction, salbutamol concentrations rose by 40 to 50% in lung and heart (p < 0.05). Hypoxia did not affect salbutamol distribution in these organs; however, in hypoxic animals, histamine-induced bronchoconstriction increased salbutamol concentrations only in the heart (p < 0.05), without affecting those in the lung. Compared with rabbits breathing air and with histamine-induced bronchoconstriction, the effect of salbutamol was reduced in rabbits under chronic hypoxia and histamine-induced bronchoconstriction (p < 0.05). We conclude that chronic hypoxia reduces salbutamol effect on pulmonary resistance, possibly by decreasing salbutamol lung concentrations.

Two-frequency analysis of respiratory mechanics in artificially ventilated rabbits.

The frequency dependence of respiratory mechanical properties was studied in 10 paralyzed, artificially ventilated rabbits, by superimposing a single sinusoidal signal with a frequency of 10, 20 or 30 Hz upon the ventilator waveform. The tracheal pressure and flow signals were analyzed both with the usual first order model, which provided total respiratory elastance (Ers) and resistance (Rrs), and by Fourier analysis, which provided respiratory impedance (Zrs) at the breathing frequency (0.85 Hz) and at the superimposed oscillation frequency. The real part of Zrs (Re(Zrs)) decreased by 30% from 0.85 to 10 Hz (P < 0.001), but did not vary significantly from 10 to 30 Hz. This finding is satisfactorily explained by tissue viscoelasticity. Following a histamine aerosol, the frequency dependence of Re(Zrs) changed very little in three out of four rabbits, but increased substantially in the fourth. In that instance, assuming that lung hysteresivity was not markedly modified by histamine, the results suggest inhomogeneous airway obstruction and/or airway wall shunting.