The effect of blood glucose on the vasculature in young patients with type 1 diabetes

Background. Patients with type 1 diabetes are at markedly increased risk of vascular complications. In this respect it is noteworthy that hyperglycaemia that is shown to cause endothelial dysfunction, has clearly been shown to be a risk factor for diabetic microvascular disease. However, the role of hyperglycaemia as a predictor of macrovascular disease is not as clear as for microvascular disease, although type 1 diabetes itself increases the risk of cardiovascular disease substantially. Furthermore, it is not known whether it is the short-term or the long-term hyperglycaemia that confers possible risk. In addition, the role of glucose variability as a predictor of complications is to a large extent unexplored. Interestingly, although hyperglycaemia increases the risk of pre-eclampsia in women with type 1 diabetes, it is unclear whether pre-eclampsia, a condition characterized by endothelial dysfunction, is also a risk factor for microvascular complication, diabetic nephropathy. Aims. This doctoral thesis investigated the role of acute hyperglycaemia and glucose variability on arterial stiffness and cardiac ventricular repolarisation in male patients with type 1 diabetes as well as in healthy male volunteers. The thesis also explored whether acute hyperglycaemia leads to an inflammatory response, endothelial dysfunction and oxidative stress. Finally, the role of pre-eclampsia, as a predictor of diabetic nephropathy in type 1 diabetes was examined. Subjects and methods. In order to study glucose variability and the daily glycaemic control, 22 male patients with type 1 diabetes, without any diabetic complications, were monitored for 72-h with a continuous glucose monitoring system. At the end of the 72-h glucose monitoring period a 2-h hyperglycaemic clamp was performed both in the patients with type 1 diabetes and in the 13 healthy age-matched male volunteers. Blood pressure, arterial stiffness and QT time were measured to detect vascular changes during acute hyperglycaemia. Blood samples were drawn at baseline (normoglycaemia) and during acute hyperglycaemia. In another patient sample, women with type 1 diabetes were followed during their pregnancy and restudied eleven years later to elucidate the role of pre-eclampsia and pregnancy-induced hypertension as potential risk factors for diabetic nephropathy. Results and conclusions. Acute hyperglycaemia increased arterial stiffness as well as caused a disturbance in the myocardial ventricular repolarisation, emphasizing the importance of a strict daily glycaemic control in male patients with type 1 diabetes. An inflammatory response was also observed during acute hyperglycaemia. Furthermore, a high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness. While glucose variability in turn correlated with central blood pressure, the results suggest that the glucose metabolism is closely linked to the haemodynamic changes in male patients with uncomplicated type 1 diabetes. Notably, the results are not directly applicable to females. Finally, a history of a pre-eclamptic pregnancy, but not pregnancy-induced hypertension was associated with increased risk of diabetic nephropathy.

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to pro-inflammatory changes, leucostasis and vaso-occlusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy.

A double-blind cross-over study of nifedipine retard in patients with Raynaud's phenomenon

The effectiveness of nifedipine retard as a treatment for Raynaud's phenomenon was assessed in 15 patients in a placebo controlled double blind study. An associated connective tissue disease was evident in 7 patients. Changes in finger and forearm blood flow (venous occlusion plethysmography), digital skin temperature and digital systolic pressure were measured acutely before and after a 2-week treatment period. Subjective assessment of efficacy was based on patient diary data. In addition alpha 2-adrenoceptor density on platelets was measured before and after chronic nifedipine therapy in both the patient group and in an age-and-sex-matched control group. No significant haemodynamic changes were observed. Nifedipine retard significantly reduced the frequency (p less than 0.05) with no change in either the duration or severity of vasospastic attacks. Side effects were common following nifedipine retard. A reduction in alpha 2-adrenoceptor density on platelets was observed in patients compared to a control group (p less than 0.05). Alpha 2-adrenoceptor density was unchanged following a 2-week treatment period with nifedipine retard. This study concludes that nifedipine retard is not effective in the treatment of Raynaud's phenomenon over a short time course. Patients with Raynaud's phenomenon have reduced alpha 2-adrenoceptor densities on their platelets.

High-volume haemofiltration for sepsis.

Background: Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU.

Objectives: This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites.

Selection criteria: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units.

Data collection and analysis: Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists.

Main results: We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias.

Authors' conclusions: There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi-centred and have clinically relevant outcome measures. Financial implications should also be assessed.

Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity

New Findings

What is the central question of this study?Exercise performance is limited during hypoxia by a critical reduction in cerebral and skeletal tissue oxygenation. To what extent an elevation in systemic free radical accumulation contributes to microvascular deoxygenation and the corresponding reduction in maximal aerobic capacity remains unknown.What is the main finding and its importance?We show that altered free radical metabolism is not a limiting factor for exercise performance in hypoxia, providing important insight into the fundamental mechanisms involved in the control of vascular oxygen transport.

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine  in both normoxia (21% O_{2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at  to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower  (P < 0.05 versus normoxia). Despite an exercise-induced increase in oxidative–nitrosative–inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower  in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia.}

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients

Background: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification.

Methods: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices.

Results: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(-1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel.

Conclusion: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population.

Atrial natriuretic peptides: reproducibility of renal effects and response of liver blood flow.

To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 microgram/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 microgram/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p less than 0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.

Transcatheter aortic valve implantation (TAVI): state of the art techniques and future perspectives.

Transcatheter aortic valve therapies are the newest established techniques for the treatment of high risk patients affected by severe symptomatic aortic valve stenosis. The transapical approach requires a left anterolateral mini-thoracotomy, whereas the transfemoral method requires an adequate peripheral vascular access and can be performed fully percutaneously. Alternatively, the trans-subclavian access has been recently proposed as a third promising approach. Depending on the technique, the fine stent-valve positioning can be performed with or without contrast injections. The transapical echo-guided stent-valve implantation without angiography (the Lausanne technique) relies entirely on transoesophageal echocardiogramme imaging for the fine stent-valve positioning and it has been proved that this technique prevents the onset of postoperative contrast-related acute kidney failure. Recent published reports have shown good hospital outcomes and short-term results after transcatheter aortic valve implantation, but there are no proven advantages in using the transfemoral or the transapical technique. In particular, the transapical series have a higher mean logistic Euroscore of 27-35%, a procedural success rate above 95% and a mean 30-day mortality between 7.5 and 17.5%, whereas the transfemoral results show a lower logistic Euroscore of 23-25.5%, a procedural success rate above 90% and a 30-day mortality of 7-10.8%. Nevertheless, further clinical trials and long-term results are mandatory to confirm this positive trend. Future perspectives in transcatheter aortic valve therapies would be the development of intravascular devices for the ablation of the diseased valve leaflets and the launch of new stent-valves with improved haemodynamic, different sizes and smaller delivery systems.

Atrial assist device, a new alternative to lifelong anticoagulation?

OBJECTIVE: Atrial fibrillation is a very common heart arrhythmia, associated with a five-fold increase in the risk of embolic strokes. Treatment strategies encompass palliative drugs or surgical procedures all of which can restore sinus rhythm. Unfortunately, atria often fail to recover their mechanical function and patients therefore require lifelong anticoagulation therapy. A motorless volume displacing device (Atripump) based on artificial muscle technology, positioned on the external surface of atrium could avoid the need of oral anticoagulation and its haemorrhagic complications. An animal study was conducted in order to assess the haemodynamic effects that such a pump could provide. METHODS: Atripump is a dome-shape siliconecoated nitinol actuator sewn on the external surface of the atrium. It is driven by a pacemaker-like control unit. Five non-anticoagulated sheep were selected for this experiment. The right atrium was surgically exposed, the device sutured and connected. Haemodynamic parameters and intracardiac ultrasound (ICUS) data were recorded in each animal and under three conditions; baseline; atrial fibrillation (AF); atripump assisted AF (aaAF). RESULTS: In two animals, after 20 min of AF, small thrombi appeared in the right atrial appendix and were washed out once the pump was turned on. Assistance also enhanced atrial ejection fraction. 31% baseline; 5% during AF; 20% under aaAF. Right atrial systolic surfaces (cm2) were; 5.2 +/- 0.3 baseline; 6.2 +/- 0.1 AF; 5.4 +/- 0.3 aaAF. CONCLUSION: This compact and reliable pump seems to restore the atrial "kick" and prevents embolic events. It could avoid long-term anticoagulation therapy and open new hopes in the care of end-stage heart failure.

Cardiovascular effects of a medetomidine constant rate infusion at different dose levels in anaesthetized dogs

Les effets cardiovasculaires des alpha-2 agonistes, particulièrement importants chez les chiens, limitent leur utilisation en pratique vétérinaire. La perfusion à débit constant (PDC) de ces drogues, comme la médétomidine (MED) permettrait un contrôle plus précis de ces effets. Les effets hémodynamiques de plusieurs doses de MED en PDC ont été évalués chez le chien. Lors de cette étude prospective, réalisée en double aveugle, 24 chiens en santé, ont reçu de façon aléatoire une des 6 doses de MED PDC (4 chiens par groupe). Les chiens ont été ventilés mécaniquement pendant une anesthésie minimale standardisée avec de l’isoflurane dans de l’oxygène. Une dose de charge (DC) de médétomidine a été administrée aux doses de 0.2, 0.5, 1.0, 1.7, 4.0 ou 12.0 µg/kg pendant 10 minutes, après laquelle la MED PDC a été injectée à une dose identique à celle de la DC pendant 60 minutes. L’isoflurane a été administré seul pendant une heure après l’administration d’une combinaison d’ISO et de MED PDC pendant 70 minutes. La fréquence cardiaque (FC), la pression artérielle moyenne (PAM) et l’index du débit cardiaque (IC) ont été mesurés. Des prélèvements sanguins ont permis d’évaluer le profil pharmacocinétique. D’après ces études, les effets hémodynamiques de la MED PDC pendant une anesthésie à l’isoflurane ont été doses-dépendants. L’IC a diminué progressivement alors que la dose de MED augmentait avec: 14.9 (12.7), 21.7 (17.9), 27.1 (13.2), 44.2 (9.7), 47.9 (8.1), and 61.2 (14.1) % respectivement. Les quatre doses les plus basses n’ont provoqué que des changements minimes et transitoires de la FC, de la PAM et de l’IC. La pharmacocinétique apparaît clairement dose-dépendante. De nouvelles expériences seront nécessaires afin d’étudier l’utilisation clinique de la MED PDC.

Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis.

OBJECTIVE: Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis. MATERIAL AND METHODS: Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data. RESULTS: In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances. CONCLUSIONS: The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.

Contractile response of femoral arteries in pigs with acute liver failure.

BACKGROUND: Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. METHODS: Norwegian Landrace pigs weighing 27.1 +/- 0.5 kg (mean +/- sx (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10(-13) - 10(-5) mol/L) or norepinephrine (10(-13) - 10(-3) mol/L). RESULTS: Pigs suffering from ALF developed a hyperdynamic circulation with an increased ca^rdiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 +/- 7 versus 56 +/- 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 +/- 8 versus 93 +/- 16 mN, P = 0.55). CONCLUSIONS: This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.

Effets de la perfusion pulsatile durant une circulation extra-corporelle

INTRODUCTION : L’utilisation de la circulation extracorporelle durant la chirurgie cardiaque est associée à des problèmes pulmonaires chez certains patients. L’utilisation d’une pression pulsatile induite par un ballon intra-aortique (BIA) pourrait diminuer la dysfonction endothéliale et la survenue de tels événements. MATÉRIEL ET MÉTHODE : 12 porcs Landrace-Yorkshire ont subi une circulation extracorporelle et ont été divisés en deux groupes et 4 porcs ont servi de contrôles sans CEC. Le premier groupe (n=6) a bénéficié d’un flot pulsatile créé par un BIA en mode interne à 80 battements par minute durant les 90 minutes de l’opération alors que le second groupe (n=6) a subi une CEC standard. Après 60 minutes de reperfusion suivant la CEC, les valeurs hémodynamiques ont été évaluées dont les pressions artérielles, les pressions pulmonaires, l’index cardiaque et la concentration de glucose et de lactate. Les artères pulmonaires sont ensuite montées en chambre d’organe pour évaluer la fonction endothéliale. RÉSULTATS : Les porcs avec pression pulsatile ont tendance à produire moins de lactate sanguin après 60 minutes de reperfusion. Les autres valeurs hémodynamiques sont semblables. Finalement, la relaxation à la bradykinine est significativement meilleure dans le groupe pression pulsatile alors que la relaxation à l’acétylcholine n’est pas significativement différente. CONCLUSION : Ces résultats démontrent que la perfusion pulsatile produite par un BIA protège l’endothélium pulmonaire lors d'une CEC. Cet effet pourrait être dû à une augmentation du flot bronchique qui diminuerait l’ischémie pulmonaire ou à une diminution de la libération de cytokines et de bradykinine qui réduirait les dommages de reperfusion.

Selected Cardiovascular Studies Based on Photoplethysmography Technique

Photoplethysmography (PPG) is a simple and inexpensive optical technique that can be used to detect blood volume changes in the microvascular bed of tissues. There has been a resurgence of interest in the technique in recent years, driven by the demand for low cost, simple and portable technology for the primary care and community based clinical settings and the wide availability of low cost and small semiconductor components, and the advancement of computer-based pulse wave analysis techniques. The present research work deals with the design of a PPG sensor for recording the blood volume pulse signals and carry out selected cardiovascular studies based on these signals. The interaction of light with tissue, early and recent history of PPG, instrumentation, measurement protocol and pulse wave analysis are also discussed in this study. The effect of aging, mild cold exposure, and variation in the body posture on the PPG signal have been experimentally studied.

Hipotensión arterial y variabilidad de la frecuencia cardiaca en pacientes embarazadas llevadas a cesarea bajo anestesia raquídea

INTRODUCCION La hipotensión arterial por anestesia raquídea en embarazadas llevadas a cesárea es frecuente y deletérea para la madre y el feto, sin que a la fecha exista una herramienta clínicamente útil para predecirla. La variabilidad de la frecuencia cardiaca es una medida que estima la actividad del sistema nervioso autónomo y algunos estudio iniciales indican una posible utilidad como herramienta predictiva de hipotensión arterial en esta población. METODOLOGIA Se realizó un estudio observacional descriptivo para examinar el comportamiento de la variabilidad de la frecuencia cardiaca, medida como razón de Baja frecuencia/Alta frecuencia, con un punto de corte de 2.5 tomada con un reloj POLAR RS800CX, en una población de pacientes con embarazo a término llevadas a cesárea, en un hospital de tercer nivel en Bogotá- Colombia entre Febrero y Abril del 2015. RESULTADOS El estudio incluyó 82 pacientes. Se determinó que la razón Baja frecuencia/Alta frecuencia mayor a 2,5 era poco frecuente en nuestra población (15.85%), y su asociación no fue significativa. DISCUSION El presente estudio demostró que la asociación entre la presencia de hipotensión y un índice Baja frecuencia/Alta frecuencia con punto de corte de 2.5 no es significativo para nuestra población de mujeres con embarazo a término llevadas a cesárea con anestesia espinal. Según los resultados se sugieres un punto de corte de 1.6 como punto de partida para la realización de nuevos estudios que permitan validar este valor.