We thank Dr Duffin for his reply to our letter (Teppema & Berendsen, 2012). In reading the manuscript by (Battisti- Charbonney et al. 2011), our attention was drawn by the intermediate phase of the rebreathing manoeuver during which the cerebrovascular response to CO2 saturated, however, without disregarding the subsequent phase of the blood pressure-related rise in cerebral blood flow (CBF). The mass balance for CO2 of the brain shows that in a non-steady-state situation is determined by brain metabolism and blood flow density, the arterial , the slopes of the brain tissue and blood CO2 dissociation curves, the Haldane parameter and a parameter that locates brain tissue () between the of blood entering the brainstem and the cerebral venous (Read & Leigh, 1967; Berkenbosch et al. 1989). During the rebreathing manoeuver, we consider the circulation the vehicle that removes CO2 from the brain, rather than transporting CO2 into the tissues as stated by Duffin. The question raised by us refers to the dynamic change in during the rebreathing phase with a more or less constant CBF. During this phase the relative influence of the slopes of the CO2 dissociation curves on will increase and this raises the question as to how this would affect the – relationship. What we clearly would need here is simultaneous measurement of the arterial, cerebral venous and tissue during the entire rebreathing procedure but for obvious reasons in humans this is elusive. With regard to the CO2-induced vasodilatation and the slope of the blood CO2 dissociation curve during the rebreathing procedure, it would be interesting to induce maximum vasodilatation with acetazolamide (which in humans requires an i.v. dose of 13–18 mg kg−1, Grossmann & Koeberle, 2000); note that Fan and coworkers used 10 mg kg−1, Fan et al. 2012). In this condition, red cell carbonic anhydrase is completely inhibited (Maren, 1967) and the steady-state CO2 response slope diminished due to a reduction in slope of the blood CO2 dissociation curve (Teppema et al. 1995). A complication, however, would be that in this situation rises considerably (Teppema et al. 1995), making it more difficult to lower it below the central CO2 threshold by voluntary hyperventilation. In addition, by the chemical disequilibrium in vivo, blood leaving the lungs has a lower than when it enters the brain and the brain tissue-to-arterial gradient may not be uniform. And then the issue regarding the mode of peripheral–central interaction. Duffin refers to a recent study designed to compare the hypoxic response at low (subthreshold) and high central , from which the authors concluded that there is no more than a simple additive peripheral–central interaction (Cui et al. 2012). Starting from a subthreshold central (induced by voluntary hyperventilation) subjects were exposed to a brief step increase in end-tidal () to 45 mmHg during which the ventilatory response was measured (test 1). Subsequently, again starting from subthreshold central , the response to a brief hypercapnic/hypoxic stimulus (= 45 mmHg, = 50 mmHg) was determined (test 2). Finally, they measured the response to a brief hypoxic stimulus (= 50 mmHg) at suprathreshold central resulting from a constant of 45 mmHg (test 3; Cui et al. 2012). This is a very elegant approach to study the mode of peripheral–central interaction, but for the following reason we arrive at another conclusion than the authors did. To estimate the contribution of the hypoxic component to the response in test 2, the authors subtracted the hypercapnic response obtained in test 1 from the composite response in test 2, compared the result with the response in test 3 and concluded that there is no more than simple additive interaction since the result of this subtraction (considered the isolated peripheral hypoxic response at subthreshold central ) yielded a result that was no different from the response in test 3 obtained at suprathreshold central . However, by assuming equal peripheral hypercapnic responses in the normoxic test 1 and the hypoxic test 2, the authors disregarded the O2–CO2 interaction in the carotid bodies implying that in the hypoxic test 2 the magnitude of the hypercapnic component of the response must have been greater than the response obtained in the normoxic test 1. In other words, the hypoxic component in test 2 was overestimated (and the hypercapnic component underestimated), and could well have been smaller than the hypoxic response obtained from test 3. So, if anything, in our opinion the results of the study by Cui et al. may suggest the presence of a hyperadditive peripheral–central interaction rather than a simple additive one. Recent studies in both humans and animals also support a hyperadditive peripheral–central interaction. We refer to studies in humans with resected carotid bodies showing a (considerably) lower central CO2 sensitivity (Dahan et al. 2007; Fatemian et al. 2003; further references in Teppema & Dahan, 2010) and in dogs with separated perfusion of the carotid bodies and brainstem that showed a dramatically low central CO2 response when the carotid bodies were kept hypocapnic (Blain et al. 2010). Also, in the rat, an anatomical substrate for peripheral–central crosstalk has convincingly been demonstrated (Takakura et al. 2006). Finally, concerning the study by Cui et al. (2012), we have the impression from their Figure 1 that the responses in tests 1 and 2 may comprise both a fast and slow component and we wonder if it would have been appropriate to analyse the data with a two-compartment model and compare the results with those estimated from a single-compartment model. The source of a potential slow compartment remains unknown, but as the authors have discussed, it cannot be excluded that it may find its origin in a central contribution. Finally, the issue of whether hyperventilation down to a of 17 mmHg and a of 63 mmHg (with a normal A–a gradient resulting in a below 55 mmHg) is sufficient to silence the sensitized carotid bodies in acclimatized subjects remains to be proven. What remains, however, is that in the study by Fan et al. (2012) modified rebreathing was performed in different conditions at sea level and high altitude, i.e. a sudden transient from hypoxia to hyperoxia at high altitude.
Three women aged 25, 34 and 22 years respectively, experienced high-altitude pulmonary oedema during a climbing holiday. The first patient presented with complaints arising from a fast ascent to high altitude and was treated with acetazolamide and rapid descent. She recovered without any complications. The second patient developed symptoms during the night, which were not recognised as high-altitude pulmonary oedema. The next morning she died while being transported down on a stretcher without having received any medication or oxygen. The third case was not a specific presentation of high-altitude pulmonary oedema but autopsy revealed pulmonary oedema. This woman had already been higher up on the mountain before she developed complications. The cases illustrate the seriousness of this avoidable form of high altitude illness. The current Dutch national guidelines advise against the use of medication by lay people. A revision is warranted: travellers to high altitude should be encouraged to carry acetazolamide, nifedipine and corticosteroids on the trip. Travel guides ought to be trained to use these drugs. In addition climbing travellers should be encouraged to adopt appropriate preventive behaviour and to start descending as soon as signs of high-altitude pulmonary oedema develop.
To evaluate four factors essential in the preparation of high-altitude expeditions and of the performance during these expeditions, the Manaslu 2016 Medical Team, as part of the medical team of the Royal Netherlands Marine Corps (RNLMC), developed the Military Expedition Performance Environment (MEPE) concept. The scope of this concept is intended to cover (1) selection of a team, (2) medical planning and support, (3) competencies in the field (team work and human factors), and (4) and chain of command.
What is the central question of this study? Does a clinically relevant intravenous dose of erythropoeitin affect the hypoxic ventilatory response and/or hypoxic pulmonary vasoconstriction in healthy humans? What is the main finding and its importance? Erythropoeitin does not influence the ventilatory and pulmonary vascular responses to acute hypoxia in men or women. Sustained and chronic hypoxia lead to an increase in pulmonary ventilation (hypoxic ventilatory response, HVR) and to an increase in pulmonary vascular resistance (hypoxic pulmonary vasoconstriction, HPV). In this study, we examined the effect of a clinical i.v. dose of recombinant human erythropoietin (50 IU kg-1 ) on the isocapnic HVR and HPV in seven male and seven female subjects by exposing them to hypoxia for 20 min (end-tidal PO2 ∼50 mmHg) while measuring their ventilation and estimating pulmonary arterial pressure from the maximal velocity of the regurgitant jet over the tricuspid valve during systole (ΔPmax ) with echocardiography. In the placebo session, after 5 and 20 min men responded with an increase in ventilation by 0.0056 and 0.0023 l min-1 kg-1 %SpO2-1 , respectively, indicating the presence of hypoxic ventilatory depression. In women, the increase in ventilation was 0.0067 and 0.0047 l min-1 kg-1 %SpO2-1 , respectively. In both sexes, erythropoietin did not alter these responses significantly. In the placebo session, mean ΔPmax increased by 6.1 ± 0.7 mmHg in men (P = 0.035) and by 8.4 ± 1.4 mmHg in women (P = 0.020) during the hypoxic exposure, whereby women had a ∼5 mmHg lower end-tidal PCO2 . Erythropoietin did not alter these responses; in men, ΔPmax increased by 7.5 ± 1.1 mmHg (n.s. versus placebo) and in women by 9.7 ± 2.2 mmHg (n.s. versus placebo). We conclude that women tended to have a greater HPV in placebo conditions and that a clinical dose of erythropoietin has no effect on the HVR and HPV in either sex.
• In Nederland zijn bevriezingsletsels in de gezonde populatie zeldzaam. Door een groeiend aantal winter- en buitensporters en reizigers naar hooggelegen gebieden, neemt het risico op bevriezingsletsel wel toe. • Bevriezing is een koudegeinduceerd letsel veroorzaakt door 2 processen: bevriezing en microvasculaire occlusie. • Een goede eerste opvang, bestaande uit voorkoming van opnieuw bevriezen en van mechanisch letsel in combinatie met snel opwarmen en ibuprofen, is de belangrijkste factor die de uiteindelijke weefselschade kan beperken. • Als een patient zich presenteert binnen 24 uur nadat het bevroren lichaamsdeel is ontdooid en de ernst van het letsel van dien aard is dat ernstige morbiditeit verwacht kan worden, is behandeling met iloprost en eventueel recombinant weefselplasminogeenactivator geindiceerd. • Als een patient zich later presenteert, is hyperbare-zuurstofbehandeling te overwegen; het bewijs hiervoor is echter beperkt.
Abstract Background Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved. Methods This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with ( N = 12) and without heart failure (N = 12). Discussion Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome. Trial registration The Netherlands Trial Register (NTR), NTR5647 . Registered 26 January 2016.
