Lionel Trueb

Augmented vasoreactivity in adult life associated with perinatal vascular insult.

BACKGROUND Adverse environmental events occurring early in life have received little attention as predictors of disease in the later stages of life. At birth, the transition from gas exchange by the placenta to gas exchange by the lungs requires dramatic changes in the pulmonary circulation, which during this period is particularly vulnerable to noxious stimuli. We measured pulmonary-artery pressure responses to high-altitude exposure, a stimulus that causes pronounced pulmonary vasoconstriction, in young adults who had had transient perinatal hypoxic pulmonary hypertension and in controls of similar age and sex distribution. METHODS Review of neonatal-care records at the Lausanne University Hospital for Children identified 15 individuals who met the eligibility criteria (birth at > or = 34 weeks of gestation, persistence of hypoxaemia during ventilation with oxygen during the first week of life, and persistence of fetal circulation). Ten of these individuals agreed to take part; the control group was ten volunteers without any history of perinatal complications. Systolic pulmonary-artery pressure (by echocardiography) and arterial oxygen saturation were measured at baseline and at high altitude (4559 m). FINDINGS The mean increase in pulmonary-artery pressure at high altitude was significantly greater (p=0.01) in the participants who had had perinatal pulmonary hypertension (from 26.2 mm Hg [SD 2.1] to 62.3 mm Hg [7.3]) than in the controls (from 25.8 mm Hg [2.3] to 49.7 mm Hg [11.3]). The fall in arterial oxygen saturation was similar in the two groups. INTERPRETATION These findings suggest that a transient perinatal insult to the pulmonary circulation leaves a persistent and potentially fatal imprint, which when activated in adult life predisposes to a pathological response. Survivors of perinatal pulmonary hypertension may be at risk of developing this disorder in later life.

Cardiovascular and Sympathetic Effects of Nitric Oxide Inhibition at Rest and During Static Exercise in Humans

BACKGROUND Nitric oxide (NO) regulates vascular tone and blood pressure, and studies in animals suggest that it does so, at least in part, by modulating sympathetic neural outflow. Loss of NO-induced vasodilator tone and restraint on sympathetic vasoconstrictor outflow could lead to exaggerated vasoconstrictor and pressor responses to physical stress in humans. METHODS AND RESULTS To determine the role of NO in the modulation of central sympathetic outflow and vascular tone at rest and during a physical stress, we tested effects of systemic inhibition of NO synthase by N(G)-monomethyl-L-arginine (L-NMMA) infusion (a stereospecific inhibitor of NO synthase) on sympathetic nerve activity (microneurography), regional vascular resistance, and blood pressure at rest and during static handgrip. The major new findings are that (1) under resting conditions, L-NMMA infusion, which increased mean arterial pressure by approximately 10%, did not have any detectable effect on muscle sympathetic nerve activity, whereas a similar increase in arterial pressure evoked by phenylephrine infusion (an NO-independent vasoconstrictor) decreased the rate of sympathetic nerve firing by approximately 50%; (2) during static handgrip, the exercise-induced sympathetic nerve responses were preserved during L-NMMA infusion but markedly attenuated during phenylephrine infusion; and (3) the L-NMMA-induced loss of vasodilator tone did not result in exaggerated exercise-induced pressor and calf vasoconstrictor responses. CONCLUSIONS These findings indicate that NO is involved in the central regulation of sympathetic outflow in humans and suggest that both neuronal and endothelial NO synthesis may contribute to the regulation of vasomotor tone.

High-Altitude Pulmonary Edema: From Exaggerated Pulmonary Hypertension to a Defect in Transepithelial Sodium Transport

High-altitude pulmonary edema (HAPE) is a form of lung edema which occurs in otherwise healthy subjects, thereby allowing the study of underlying mechanisms of pulmonary edema in the absence of confounding factors. Exaggerated pulmonary hypertension is a hallmark of HAPE and is thought to play an important part in its pathogenesis. Pulmonary vascular endothelial dysfunction and augmented hypoxia-induced sympathetic activation may be underlying mechanisms contributing to exaggerated pulmonary vasoconstriction in HAPE. Recent observations by our group suggest, however, that pulmonary hypertension itself may not be sufficient to trigger HAPE. Based on studies in rats, indicating that perinatal exposure to hypoxia predisposes to exaggerated hypoxic pulmonary vasoconstriction in adulthood, we examined effects of high-altitude exposure on pulmonary-artery pressure in a group of young adults who had suffered from transient perinatal pulmonary hypertension. We found that these young adults had exaggerated pulmonary vasoconstriction of similar magnitude to that observed in HAPE-susceptible subjects. Surprisingly, however, none of the subjects developed lung edema. These findings strongly suggest that additional mechanisms are needed to trigger pulmonary edema at high-altitude. Observations in vitro, and in vivo suggest that a defect of the alveolar transepithelial sodium transport could act as a sensitizer to pulmonary edema. The aim of this article is to review very recent experimental evidence consistent with this concept. We will discuss data gathered in mice with targeted disruption of the gene of the alpha subunit of the amiloride-sensitive epithelial sodium channel (alpha ENaC), and present preliminary data on measurements of transepithelial sodium transport in vivo in HAPE-susceptible and HAPE-resistant mountaineers.

Effects of Sympathectomy and Nitric Oxide Synthase Inhibition on Vascular Actions of Insulin in Humans

Insulin exerts cardiovascular actions by stimulating nitric oxide (NO) release and sympathetic neural outflow. It is unclear, however, whether insulin stimulates muscle blood flow (and NO release) by a direct action at the vasculature and/or by stimulating neural vasodilator mechanisms. In these studies we used patients with regional sympathectomy to examine the vascular actions of insulin in the presence and absence of sympathetic vasoconstrictor and vasodilator innervation. A 2-hour insulin (6 pmol/kg per minute)/glucose clamp increased muscle blood flow in both innervated and denervated limbs by roughly 40% (P<0.01 versus baseline for both limbs). The vasodilation reached its maximum within the first 30 to 45 minutes of insulin/glucose infusion in sympathetically denervated limbs, but only at the end of the infusion in innervated limbs (P<0. 01, denervated versus innervated limb). Infusion of a NO synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]) increased baseline arterial pressure, abolished the vasodilation in the denervated limb, and led to a significant additional increase in arterial pressure during the clamp, but did not alter whole body glucose uptake. Our data indicate that insulin stimulates blood flow in sympathectomized limbs by a direct action at the vasculature. This effect is mediated by stimulation of NO release and appears to be masked by the sympathetic vasoconstrictor tone in innervated limbs.

Social and Medical Vulnerability Factors of Emergency Department Frequent Users in a Universal Health Insurance System

OBJECTIVES The objectives were to identify the social and medical factors associated with emergency department (ED) frequent use and to determine if frequent users were more likely to have a combination of these factors in a universal health insurance system. METHODS This was a retrospective chart review case-control study comparing randomized samples of frequent users and nonfrequent users at the Lausanne University Hospital, Switzerland. The authors defined frequent users as patients with four or more ED visits within the previous 12 months. Adult patients who visited the ED between April 2008 and March 2009 (study period) were included, and patients leaving the ED without medical discharge were excluded. For each patient, the first ED electronic record within the study period was considered for data extraction. Along with basic demographics, variables of interest included social (employment or housing status) and medical (ED primary diagnosis) characteristics. Significant social and medical factors were used to construct a logistic regression model, to determine factors associated with frequent ED use. In addition, comparison of the combination of social and medical factors was examined. RESULTS A total of 359 of 1,591 frequent and 360 of 34,263 nonfrequent users were selected. Frequent users accounted for less than a 20th of all ED patients (4.4%), but for 12.1% of all visits (5,813 of 48,117), with a maximum of 73 ED visits. No difference in terms of age or sex occurred, but more frequent users had a nationality other than Swiss or European (n = 117 [32.6%] vs. n = 83 [23.1%], p = 0.003). Adjusted multivariate analysis showed that social and specific medical vulnerability factors most increased the risk of frequent ED use: being under guardianship (adjusted odds ratio [OR] = 15.8; 95% confidence interval [CI] = 1.7 to 147.3), living closer to the ED (adjusted OR = 4.6; 95% CI = 2.8 to 7.6), being uninsured (adjusted OR = 2.5; 95% CI = 1.1 to 5.8), being unemployed or dependent on government welfare (adjusted OR = 2.1; 95% CI = 1.3 to 3.4), the number of psychiatric hospitalizations (adjusted OR = 4.6; 95% CI = 1.5 to 14.1), and the use of five or more clinical departments over 12 months (adjusted OR = 4.5; 95% CI = 2.5 to 8.1). Having two of four social factors increased the odds of frequent ED use (adjusted = OR 5.4; 95% CI = 2.9 to 9.9), and similar results were found for medical factors (adjusted OR = 7.9; 95% CI = 4.6 to 13.4). A combination of social and medical factors was markedly associated with ED frequent use, as frequent users were 10 times more likely to have three of them (on a total of eight factors; 95% CI = 5.1 to 19.6). CONCLUSIONS Frequent users accounted for a moderate proportion of visits at the Lausanne ED. Social and medical vulnerability factors were associated with frequent ED use. In addition, frequent users were more likely to have both social and medical vulnerabilities than were other patients. Case management strategies might address the vulnerability factors of frequent users to prevent inequities in health care and related costs.

Haemodynamic and sympathetic effects of inhibition of nitric oxide synthase by systemic infusion of NG-monomethyl-L-arginine into humans are dose dependent

Background In several animal species, nitric oxide (NO) buffers central neural sympathetic outflow, but data concerning humans are sparse and conflicting. We hypothesized that these conflicting results could be related to large differences in the dose of NG-monomethyl-L-arginine, a stereospecific inhibitor of NO synthase, infused in these human studies. Objective To investigate the haemodynamic and sympathetic effects of systemic inhibition of NO synthase by intravenous infusion of two different doses of NG-monomethyl-L-arginine into healthy humans and compare these effects with those of an equipressor dose of the non-endothelium-dependent vasoconstrictor phenylephrine. Methods Muscle sympathetic nerve activity was measured by microneurography and blood flow by venous occlusion plethysmography. NG-monomethyl-L-arginine was infused over 15 min at a rate of 50 μg/kg per min into members of one group (n = 8) and at a rate of 450 μg/kg per min into members of another group (n = 7). An equipressor dose of phenylephrine was infused into four subjects from each group. Results Infusions of NG-monomethyl-L-arginine and of phenylephrine at the higher dose similarly suppressed sympathetic activity. In contrast, infusions of NG-monomethyl-L-arginine and of an equipressor dose of phenylephrine at the lower dose had different sympathetic effects. Burst frequency of muscle sympathetic nerve activity remained unchanged during infusion of NG-monomethyl-L-arginine but decreased by roughly 50% during infusion of phenylephrine. Infusion of NG-monomethyl-L-arginine at both doses did not alter forearm blood flow. Only infusion of NG-monomethyl-L-arginine at the higher dose increased forearm vascular resistance. Conclusions Haemodynamic and sympathetic effects of inhibition of NO synthase by infusion of NG-monomethyl-L-arginine into humans are dose dependent. At higher doses, NG-monomethyl-L-arginine exerts sympatho-inhibitory effects that are comparable to those evoked by a non-specific vasoconstrictor drug, whereas at lower doses, it exerts sympatho-excitatory effects.

High-fidelity simulation in the nonmedical domain: practices and potential transferable competencies for the medical field.

Simulation is a promising pedagogical tool in the area of medical education. High- fidelity simulators can reproduce realistic environments or clinical situations. This allows for the practice of teamwork and communication skills, thereby enhancing reflective reasoning and experiential learning. Use of high-fidelity simulators is not limited to the medical and aeronautical fields, but has developed in a large number of nonmedical organizations as well. The techniques and pedagogical tools which have evolved through the use of nonmedical simulations serve not only as teaching examples but also as avenues which can help further the evolution of the concept of high-fidelity simulation in the field of medicine. This paper presents examples of high-fidelity simulations in the military, maritime, and aeronautical fields. We compare the implementation of high-fidelity simulation in the medical and nonmedical domains, and discuss the possibilities and limitations of simulators in medicine, based on recent nonmedical applications.

Characteristics of highly frequent users of a Swiss academic emergency department: a retrospective consecutive case series

Objectives The aim of this study was to describe the demographic, social and medical characteristics, and healthcare use of highly frequent users of a university hospital emergency department (ED) in Switzerland. Methods A retrospective consecutive case series was performed. We included all highly frequent users, defined as patients attending the ED 12 times or more within a calendar year (1 January 2009 to 31 December 2009). We collected their characteristics and calculated a score of accumulation of risk factors of vulnerability. Results Highly frequent users comprised 0.1% of ED patients, and they accounted for 0.8% of all ED attendances (23 patients, 425 attendances). Of all highly frequent users, 87% had a primary care practitioner, 82.6% were unemployed, 73.9% were socially isolated, and 60.9% had a mental health or substance use primary diagnosis. One-third had attempted suicide during study period, all of them being women. They were often admitted (24.0% of attendances), and only 8.7% were uninsured. On average, they cumulated 3.3 different risk factors of vulnerability (SD 1.4). Conclusion Highly frequent users of a Swiss academic ED are a highly vulnerable population. They are in poor health and accumulate several risk factors of being even in poorer health. The small number of patients and their high level of insurance coverage make it particularly feasible to design a specific intervention to approach their needs, in close collaboration with their primary care practitioner. Elaboration of the intervention should focus on social reinsertion and risk-reduction strategies with regard to substance use, hospital admissions and suicide.

Missed Opportunities: Evolution of Patients Leaving without Being Seen or against Medical Advice during a Six-Year Period in a Swiss Tertiary Hospital Emergency Department

Aim. The study aimed at describing the evolution over a 6-year period of patients leaving the emergency department (ED) before being seen (“left without being seen” or LWBS) or against medical advice (“left against medical advice” or LAMA) and at describing their characteristics. Methods. A retrospective database analysis of all adult patients who are admitted to the ED, between 2005 and 2010, and who left before being evaluated or against medical advice, in a tertiary university hospital. Results. During the study period, among the 307,716 patients who were registered in the ED, 1,157 LWBS (0.4%) and 1,853 LAMA (0.9%) patients were identified. These proportions remained stable over the period. The patients had an average age of 38.5 ± 15.9 years for LWBS and 41.9 ± 17.4 years for LAMA. The median time spent in the ED before leaving was 102.4 minutes for the LWBS patients and 226 minutes for LAMA patients. The most frequent reason for LAMA was related to the excessive length of stay. Conclusion. The rates of LWBS and LAMA patients were low and remained stable. The patients shared similar characteristics and reasons for leaving were largely related to the length of stay or waiting time.

Nitric oxide mediates the blood pressure response to mental stress in humans

OBJECTIVE Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress. METHODS We, therefore, compared the sympathetic (muscle sympathetic nerve activity) and haemodynamic responses to mental stress performed during saline infusion and systemic inhibition of NO-synthase by NG-monomethyl-L-arginine (L-NMMA) infusion. RESULTS The major finding was that mental stress which during saline infusion increased sympathetic nerve activity by ~50 percent and mean arterial pressure by ~15 percent had no detectable sympathoexcitatory and pressor effect during L-NMMA infusion. These findings were not related to a generalised impairment of the haemodynamic and/or sympathetic responsiveness by L-NMMA, since the pressor and sympathetic nerve responses to immersion of the hand in ice water were preserved during L-NMMA infusion. CONCLUSION Mental stress causes pressor and sympathoexcitatory effects in humans that are mediated by NO. These findings are consistent with the new concept that, in contrast to what has been generally assumed, under some circumstances, NO has a blood pressure raising action in vivo.