Incidence and importance of de novo diabetes mellitus after heart transplantation.

INTRODUCTION: Diabetes mellitus is one of the main metabolic complications after heart transplantation. The aims of our study were to determine the incidence and factors that determine the appearance of posttransplantation diabetes mellitus (PTDM) and its prognostic value. MATERIALS AND METHODS: We performed a retrospective study of all heart transplant recipients in our hospital from January 1993 to December 2005, including 116 patients with prolonged monitoring with 59-month median follow-up. We divided the patients into two groups, according to whether they had de novo diabetes (group 1) or no diabetes (group 2). RESULTS: Patients with PTDM were significantly older, with a median difference (MD) of 5.4 years (95% confidence interval [CI], 1.53-9.28) and a greater body mass index (MD, 3.37 kg/m(2); 95% CI, 1.68-5.06). Moreover, a greater percentage of patients in group 1 had ischemia compared to other etiologies. However, no significant differences were observed regarding other cardiovascular risk factors. PTDM was associated with a greater incidence of posttransplant hypertension (51.6% in group 1 vs 48.4% in group 2, P = .08) and posttransplant renal failure (59.5% in group 1 vs 40.5% in group 2, P = .001). However, no differences were observed in overall survival. CONCLUSIONS: Age, overweight, and ischemic origin of cardiopathy were the main risk factors for the development of PTDM in our population. Although no differences were observed in survival rates, PTDM was associated with a greater incidence of hypertension and renal insufficiency, which may have long-term influences on patient survival.

Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial.

We compared efficacy and safety of tacrolimus (Tac)-based vs. cyclosporine (CyA) microemulsion-based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade >/= 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade >/= 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new-onset diabetes mellitus (20.3% vs. 10.5%); post-transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

[Propranolol protects the myocardium and prevents arterial hypotension in an experimental organ donation model]. / El propranolol protege el miocardio y previene la hipotensión arterial en un modelo experimental de donante de órganos.

OBJECTIVE: To analyze the role that sympathetic nervous system hyperactivity immediately following brain death plays in the cardiovascular dysfunction of an organ donor. MATERIAL AND METHOD: Fifteen New Zealand white rabbits were placed in three groups: a control group, a brain-death group without propranolol and a brain-death group with propranolol. Brain death was caused by severe intracranial hypertension; in the third group propranolol was first perfused intravenously. We recorded hemodynamic (heart rate, number of extrasystoles, central venous pressure, systemic and pulmonary arterial pressure), biochemical (adrenaline, noradrenaline, dopamine and troponin T) and histologic data. RESULTS: Catecholamine levels rose significantly in both experimental groups after brain death, which coincided with clinical signs of sympathetic hyperactivity in the group not receiving propranolol but not in the group receiving the beta-blocker. The myocardium of animals not receiving the beta-blocker showed myocytolysis, edema, subendocardial bleeding and leukocyte infiltration. Such changes were practically absent in the animals that received beta-blockers. In the beta-blocker group, serum troponin, and index of myocytolysis, rose significantly less than in the non-premedicated group. Blood pressure in all the brain-dead animals was significantly lower than in the control group, but was more severe in animals that had not received propranolol. CONCLUSIONS: Sympathetic nervous system hyperactivity after brain death affects the histology and functioning of the myocardium in this experimental organ donor model. Pretreatment with propranolol prevents damage.

[Diagnosis of brain death using trancranial Doppler ultrasonography in an experimental model of organ donation for transplantation]. / Diagnóstico de la muerte encefálica mediante ultrasonografía Doppler transcraneal en un modelo experimental de donante de órganos para trasplante.

OBJECTIVE: To create an experimental organ donor model and validate it by ultrasound evaluation of intracranial blood flow velocity. MATERIAL AND METHOD: Ten white New Zealand rabbits were assigned to either a control group or an experimental group. Brain death was induced in the experimental group by way of severe cranial hypertension. A diagnosis of brain death was based on physical examination and velocity of intracranial blood flow determined by transcranial doppler ultrasonography. Physical and ultrasound examinations were performed on all animals at baseline and at the time of the experiment. RESULTS: Physical examination and intracranial blood flow velocity were normal in the control group animals at baseline and during the study. The findings were also normal for the experimental group animals at baseline. After provocation of intracranial hypertension, we observed signs of brain death (absence of response to pain stimulus in one cranial par absence of brainstem reflexes, and apnea) in the experimental animals, and the velocity of flow in arteries at the base of the skull acquired the waveform known as sharp systolic peaks, which are characteristic of cerebral circulation failure. CONCLUSIONS: The results of physical examination and ultrasonography in this study provide adequate validation of this experimental model of brain death and demonstrate that transcranial doppler ultrasonography is useful for diagnosing brain death in the rabbit.

Diagnóstico de la muerte encefálica mediante ultrasonografía Doppler transcraneal en un modelo experimental de donante de órganos para trasplante / Diagnosis of brain death by transcranial doppler ultrasonography in an experimental organ donor model

OBJETIVO: Crear un modelo experimental de donante de órganos para trasplante y validarlo mediante el estudio ultrasonográfico de la velocidad del flujo sanguíneo intracraneal. MATERIAL Y MÉTODO: Se emplearon 10 conejos blancos de Nueva Zelanda divididos en un grupo control y un grupo experimental. En el segundo se provocó la muerte encefálica (ME) por un mecanismo de hipertensión intracraneal (HTIC) severa. El diagnóstico de la ME se basó en la exploración clínica y en el estudio de la velocidad del flujo sanguíneo intracraneal mediante ultrasonografía Doppler transcraneal. Ambas exploraciones fueron realizadas en todos los animales en situación basal y experimental. RESULTADOS: La exploración clínica y la velocidad del flujo sanguíneo intracraneal fueron normales en los animales del grupo control tanto en situación basal como experimental. En el grupo experimental también se obtuvieron resultados normales en ambos casos en situación basal, pero tras provocar HTIC aparecieron los signos clínicos diagnósticos de la ME (ausencia de respuesta a estímulos dolorosos en el territorio de un par craneal, ausencia de reflejos troncoencefálicos y apnea) y la velocidad del flujo sanguíneo en las arterias de la base del cráneo adoptó un patrón denominado "espigas sistólicas", que es característico de la parada circulatoria cerebral. CONCLUSIONES: Los resultados obtenidos en la exploración clínica y ultrasonográfica en nuestro estudio suponen la validación adecuada de este modelo experimental de ME y demuestran que la ultrasonografía Doppler transcraneal es útil en el diagnóstico de la ME en el conejo. (AU)

El propranolol protege el miocardio y previene la hipotensión arterial en un modelo experimental de donante de órganos / Propranolol protects the myocardium and prevents arterial hypotension in an experimental organ donor model

OBJETIVO: Analizar el papel que desempeña la hiperactividad del sistema nervioso simpático (SNS) que tiene lugar inmediatamente después de producirse la muerte encefálica (ME) en la disfunción cardiovascular del donante de órganos. MATERIAL Y MÉTODO: Quince conejos blancos de Nueva Zelanda han sido divididos en tres grupos: grupo control, grupo de ME sin propranol y grupo de ME con propranolol. La ME se provocó por hipertensión intracraneal severa; en el tercer grupo, antes de hacerlo se administró propranolol IV. Se recogieron datos hemodinámicos (frecuencia cardiaca, número de extrasístoles, presión venosa central, presión arterial sistémica y pulmonar), bioquímicos (adrenalina, noradrenalina, dopamina y troponina T) e histológicos. RESULTADOS: En ambos grupos experimentales se elevaron significativamente las catecolaminas tras la ME. Este hecho coincidió con signos clínicos de hiperactividad simpática en el grupo sin propranolol, pero no en el betabloqueado. El miocardio de los animales no betabloqueados mostró miocitolisis, edema, hemorragia subendocárdica e infiltrado leucocitario, alteraciones que estuvieron prácticamente ausentes en los animales betabloqueados. En el grupo betabloqueado la troponina sérica, índice de miocitolisis, se elevó significativamente menos que en el no premedicado. En todos los animales en ME la presión arterial descendió significativamente respecto al grupo control, pero la hipotensión fue más severa en los animales que no recibieron propranolol. CONCLUSIONES: La hiperactividad de SNS posterior a la ME afecta histológica y funcionalmente al miocardio de este modelo experimental de donante de órganos. El pretratamiento con propranolol previene dicho daño. (AU)

Study of the reversibility of endothelial dysfunction in a rat model of diabetes mellitus: experimental treatment by transplantation of pancreatic islets.

OBJECTIVE: To study the endothelial dysfunction induced in a rat model of diabetes mellitus, and to find out if transplantation of islet cells is an effective treatment for the endothelial damage. DESIGN: Experimental study. SETTING: University hospital, Spain. ANIMALS: 24 Wistar rats in 3 groups of each: control, diabetic and transplanted. INTERVENTIONS: Diabetes was induced in the diabetic and transplanted animals by intravenous injection of streptozocin 45 mg/Kg. In the transplanted group fresh pancreatic islet from syngeneic donor rats (1200-1500/receptor) were injected intraportally 16 weeks after the induction of diabetes. The rats were killed at 18 weeks. Excision of rings of thoracic aorta, which were contracted with 0(-5) M phenylephrine. Once the maximum contraction had been reached relaxation was induced with 10(-5) M acetylcholine and then 10(-4) M independent nitroprusside endothelial vasodilator was added. MAIN OUTCOME MEASURES: Blood glucose concentrations throughout the experiment. Mean vasodilator response to acetylcholine as an indicator of recovery of endothelial function. RESULTS: The mean (SD) vasodilatation in the control group differed significantly from that in the diabetic group (27.6 (3.9) g compared with 20.1 (3.9) p = 0.002). The transplanted group also differed from the diabetic group (25.8 (3.6) g, p = 0.009). There was no significant difference between the transplanted group and the control group (p = 0.33). CONCLUSION: In rats diabetes mellitus causes considerable endothelial damage, which can be reversed by transplantation of pancreatic islets.

[Cardiac cryopreservation at subzero temperatures: study of systolic and diastolic function]. / Criopreservación cardíaca a temperatura subcero: estudio de la función sistólica y diastólica.

UNLABELLED: We studied the alterations produced in left ventricular systolic and diastolic function after applying a protocol of cryopreservation at subzero temperatures. Isolated rabbit hearts were used for the study with 5% polyethylene glycol (PM 4000) being the cryoprotective agent. MATERIALS AND METHODS: The cryoprotectant solution CP-16 was used on the explanted heart in three phases: induction, storage and thawing. After 60 minutes at -1.6 C and thawing at 2.7 C/min, the heart was connected to a Langendorff system and perfused anterogradely with Krebs-Henseleit buffer. We analyzed the systolic and diastolic parameters before and after cryopreservation, thereby establishing a comparative statistical study. RESULTS: Following cryopreservation we found a statistically significant increase (p < 0.05) in the peak and developed pressure of the left ventricle with an upward, left displacement of the ventricular function curve. This is indicative of improvement in systolic function. However, the diastolic function showed worsening, with a statistically significant increase (p < 0.05) in mean stiffness, decrease in differential stiffness (p < 0.05) and upward, left displacement of the diastolic pressure-volume curve. CONCLUSIONS: On the basis of our results we concluded that: a) PM 4000 polyethylene glycol maintains the heart biological viability during cryopreservation at subzero temperatures, and b) after an cryopreservation left ventricular diastolic function worsens with an increase in systolic function.

Coronary vasomotor disorders during hypoxia-reoxygenation: do calcium channel blockers play a protective role?

During heart surgery, myocardial dysfunction may occasionally appear when extracorporeal circulation is discontinued, causing serious haemodynamic disorders. Many mechanisms are involved in this hypoxia-reoxygenation syndrome. The aim of this experimental study was to characterize the vasomotor disorders that take place in the isolated porcine coronary artery during in vitro hypoxia-reoxygenation and to analyse the effect of nifedipine on them. Rings of porcine coronary artery were placed in an organ chamber connected to a system that recorded isometric forces. The vascular rings were divided into two groups: control group (no nifedipine) and study group (nifedipine, 10(-6) mol/l). The vascular rings were precontracted with 30 mmol/l KCl and then hypoxia-reoxygenation was induced. Control arterial rings showed important changes in coronary vasomotor tone: severe hypoxic contraction (from 14.48+/-1.16 g of stable contraction to 17.6+/-0.44 g after the imposition of hypoxia), and transient vasodilation during reoxygenation (69.9+/-10.1% of the maximum contraction achieved). The nifedipine group experienced a slow, progressive, vasodilation throughout the whole experiment (73+/-3.5% of the maximum contraction). Neither hypoxic vasospasm nor fluctuations of the coronary vascular tone occurred. Thus, at the end of the hypoxia, the control vessels presented a degree of contraction similar to the initial level. However, in the rings treated with nifedipine, the percentage of dilation was 73+/-3.5% (P<0.05). In the isolated porcine coronary artery with intact endothelium undergoing a situation of hypoxia-reoxygenation, we have detected transient vasoconstriction during the first period of hypoxia, followed by vasodilation during reoxygenation. The intracoronary administration of nifedipine prior to the imposition of hypoxia prevents hypoxic contraction, achieving a greater and more stable degree of coronary vasorelaxation during the complete process of hypoxia-reoxygenation.

Estudio de la reversibilidad de la disfunción endotelial en un modelo de diabetes mellitus. tratamiento experimental mediante trasplante de islotes pancreáticos / Study of the reversibility of endothelial dysfunction in a model of diabetes mellitus. Experimental treatment through transplant of pancreatic islets

La diabetes mellitus es una enfermedad endocrina metabólica crónica cuyo principal problema cardiológico es la afectación vascular coronaria, que constituye una de las principales causas de morbimortalidad en estos enfermos. La temprana disfunción endotelial que se produce en el enfermo constituye uno de los factores de riesgo para el desarrollo de la aterosclerosis difusa y grave que caracteriza a esta afección, así como de la enfermedad microvascular que es específica de la misma. Actualmente existen líneas de investigación en el trasplante de islotes pancreáticos como posible prevención de esta vasculopatía. Como objetivo de este estudio planteamos, por un lado, observar la disfunción endotelial inducida en un modelo experimental de diabetes mellitus y, por otro, valorar la eficacia del trasplante de islotes pancreáticos como tratamiento de la lesión endotelial producida. El modelo experimental ha sido la rata Wistar. La aorta torácica disecada y seccionada en anillos se estudió en una cámara de órganos. Se diferenciaron tres grupos experimentales: a) control; b) diabético, y c) diabético más trasplantado. Los anillos aórticos fueron colocados en una cámara de órganos. Se realizó un estudio estadístico comparativo de la función endotelial en los tres grupos según su respuesta vasodilatadora ante la acetilcolina. Nuestros resultados demuestran que existe una vasodilatación media a acetilcolina del 28,95 por ciento ñ 4,76 en el grupo control, siendo estadísticamente significativa con una p < 0,01 respecto al grupo diabético (19,80 por ciento ñ 3,87). En el grupo trasplantado (25,21 por ciento ñ 3,77), se alcanzó un valor significativo de recuperación de la función endotelial, con una p < 0,05 frente al grupo diabético. Por el contrario, no apareció ninguna significación estadística entre los valores de vasodilatación a acetilcolina obtenidos para los grupos control y trasplantadas. Concluimos que la diabetes mellitus produce un daño endotelial significativo en un modelo experimental de diabetes mellitus que revierte, en nuestro modelo, mediante trasplante de islotes pancreáticos (AU)

Nosocomial pneumonia in patients undergoing heart surgery.

OBJECTIVE: To determine the risk factors related to the presence of postsurgical nosocomial pneumonia (NP) in patients who had undergone cardiac surgery. DESIGN: A case-control study. SETTING: Postcardiac surgical intensive care unit at a university center. PATIENTS: A total of 45 patients with NP and 90 control patients collected during a 4-yr period. INTERVENTIONS: Pre-, intra-, and postoperative factors were collected and compared between two groups of patients (cases vs. controls) to determine their influence on the development of NP. The diagnosis of NP was always microbiologically confirmed as pulmonary specimen brush culture of > or =10(3) colony-forming units/mL or positive blood culture/pleural fluid culture by the growth of identical microorganisms isolated at the lung. For each patient diagnosed with NP, we selected control cases at a ratio of 1:2. MEASUREMENTS AND MAIN RESULTS: The incidence of NP was 6.5%. Multivariate analysis found a probable association of the following variables with a greater risk for the development of NP: reintubation (adjusted odds ratio [AOR], 62.5; 95% confidence interval [CI], 8.1-480; p = .01); nasogastric tube (AOR, 19.7; 95% CI, 3.5-109; p = .01), transfusion of > or =4 units of blood derivatives (AOR, 12.8; 95% CI, 2-82; p = .01) and empirical treatment with broad-spectrum antibiotics (AOR, 6.6; 95% CI, 1.2-36.8; p = .02). Culture results showed 13.3% of the NP to be of polymicrobial origin, whereas 77.3% of the microorganisms isolated were Gram-negative bacteria. The mortality (51 vs. 6.7%, p < .01) and the length of stay in the intensive care unit (25+/-14.8 days vs. 5+/-5 days, p < .01) were both greater in patients with NP. CONCLUSIONS: We conclude that the surgical risk factors, except the transfusion of blood derivatives, have little effect on the development of NP. Reintubation, nasogastric tubing, previous therapy with broad-spectrum antibiotics, and blood transfusion are factors most likely associated with NP acquisition.

[Infectious complications of heart transplantation. A prospective study for the first 6 years of a transplantation program]. / Complicaciones infecciosas de trasplante cardíaco. Estudio prospectivo durante los seis primeros años de programa de trasplante.

OBJECTIVE: To study the infectious complications, mortality, and associated factors in heart transplant recipients. METHODS: Prospective study of the first 69 heart transplantations performed from January 1991 until December 1996 in a university hospital. Description of clinical features of infectious complications during the first year after transplantation. Univariate and multivariate analyses of the risk factors associated with mortality and development of infectious complications. RESULTS: Seventy-three percent of patients had at least one infectious complication; the incidence was 1.13 episodes per patient-year. The etiology of complications was bacterial (50%), viral (31%), Pneumocystis carinii (5%), fungal (4%), and protozoal (4%). The opportunist organisms accounted for 42% of cases. Pneumonia was the most common complication (28%), followed by mucocutaneous herpetic reactivation (19%), bacteremia (13%), urinary tract infection (13%), cytomegalovirus disease (11.5%), pleural empyema (5%) and surgical wound infection (5%). Nosocomial pneumonia accounted for 50% of cases. Gram-negative rods accounted for 41% of pneumonia cases. A total of 62.5% of deaths were directly related to infectious complications. Factors independently associated with mortality were hospital origin at transplantation (RR = 4.5 [2-9], p = 0.034), development of infectious complications in the post-heart transplantation period (RR = 3.2 [1.2-12], p = 0.04) and a more prolonged hospital stay at ICU (p = 0.0004). The factor which was independently associated with the development of infectious complications was one or more severe episodes of acute rejection (RR = 1.5 [1.1-2.2], p = 0.04). Patients who developed infectious complications had a more prolonged accumulated annual hospital stay (p = 0.004) than those without infectious complications. CONCLUSIONS: Infectious complications are very common, prolong hospital stay, and are the first cause of mortality during the first year after transplantation. Bacteria are the most common etiology and pneumonia is the most common infection.

Alteration in diastolic function following cardiac cryopreservation at subzero temperatures.

BACKGROUND: We have studied the alterations produced in the diastolic function of the left ventricle after applying a protocol of cryopreservation at subzero temperatures. METHODS: Isolated rabbit hearts and 5% polyethylene glycol (PM 4000) as the cryoprotective agent were used for the study. RESULTS-CONCLUSIONS: Following cryopreservation we found a statistically significant increase in systolic function. However, the diastolic function shows worsening, with a statistically significant increase (p < 0.05) in mean stiffness, decrease in differential stiffness, (p < 0.05) and upward and leftward displacement of the diastolic pressure-volume curve.

The systemic vasodilatory action of protamine: is it inhibited or mediated by heparin?

UNLABELLED: The administration of protamine to neutralize the circulating heparin is common practice in cardiovascular surgery. The use of this drug is sometimes associated with hemodynamic alterations of varying degree and intensity (systemic hypotension, pulmonary hypertension and even cardiogenic shock). An intrinsic action of protamine has been suggested to be the cause of these vascular reactions. This action is blocked when protamine forms a complex with heparin, although in other cases it appears that the heparin-protamine complex is the factor responsible for these hemodynamic alterations. The aim of this experimental study was to characterize the vasodilatory action of protamine on the systemic circulation, determining whether or not it is dose-dependent; to analyze the role of endothelium; and to evaluate whether this vasodilatory effect is modified by the presence of heparin. MATERIALS AND METHODS: The abdominal aorta was dissected from eight New Zealand rabbits and then sectioned into vascular rings for study in an organ chamber. Mechanical disruption of endothelium was performed on some rings (n = 14). Once submaximal contraction was reached (ClK 80 mM), protamine sulfate with a final concentration in the organ chamber of 80-400 micrograms/ml was added to one of the groups (n = 12). In the second group (n = 12), equal concentrations of protamine were tested in the presence of heparin at a final concentration of 100 U/ml. RESULTS: The mean vasodilatation reached in the group of rings exposed only to protamine was 95.4 +/- 1.5% with respect to the submaximal contraction induced with ClK. In the second study group, the rings were exposed to protamine at equally increasing concentrations (80-400 micrograms/ml) but with the presence of heparin in the organ chamber. The mean vasodilatation in this group was 90 +/- 1.5. No statistically significant differences in vasodilatation were found between this group and the protamine without heparin group. On the other hand, in the endothelium-denuded rings (n = 14) exposed to isolated protamine and to protamine-heparin, no vasodilatory response was observed. CONCLUSION: Our results show that the administration in vitro of protamine induces endothelium-dependent vasodilatation of the systemic circulation. Likewise, this relaxing effect mediated through endothelium is not blocked when protamine forms a complex with heparin in comparable concentrations of both drugs. Based on these preliminary findings, we believe that in high-risk patients the prevention of systemic vasodilatation and cardiovascular collapse produced by protamine should move towards the use of other substances that can neutralize the anticoagulant effect of heparin or towards pre-medication guidelines that prevent these secondary effects in the case of protamine administration.