Veränderungen von Lungenmorphologie, regionaler Ventilation und Perfusion nach Ein-Lungen-Ventilation : eine tierexperimentelle Studie

Magdeburg, Univ., Med. Fak., Diss., 2015

New measurements of energy expenditure and physical activity in chronic kidney disease.

The accurate estimation of total daily energy expenditure (TEE) in chronic kidney patients is essential to allow the provision of nutritional requirements; however, it remains a challenge to collect actual physical activity and resting energy expenditure in maintenance dialysis patients. The direct measurement of TEE by direct calorimetry or doubly labeled water cannot be used easily so that, in clinical practice, TEE is usually estimated from resting energy expenditure and physical activity. Prediction equations may also be used to estimate resting energy expenditure; however, their use has been poorly documented in dialysis patients. Recently, a new system called SenseWear Armband (BodyMedia, Pittsburgh, PA) was developed to assess TEE, but so far no data have been published in chronic kidney disease patients. The aim of this review is to describe new measurements of energy expenditure and physical activity in chronic kidney disease patients.

Giant warts in a kidney transplant patient: regression with sirolimus.

Purpose: Recent reports have suggested that intraabdominal postoperative infection is associated with higher rates of overall and local recurrence and cancer-specific mortality. However, the mechanisms responsible for this association are unknown. We hypothesized that the greater inflammatory response in patients with postoperative intraabdominal infection is associated to an increase in local and systemic angiogenesis. Methods: We designed a prospective cohorts study with matched controls. Patients with postoperative intra-abdominal infection (abscess and/or anastomotic leakage) (group 1; n=17) after elective colorectal cancer resection operated on for cure were compared to patients with an uncomplicated postoperative course (group 2; n=17). IL-6 and VEGF levels were determined by ELISA in serum and peritoneal fluid at baseline, 48 hours and postoperative day 4 or at the time the peritoneal infection occurred. Results: No differences were observed in age, gender, preoperative CEA, tumor stage and location and type of procedure performed. Although there were no differences in serum IL-6 levels at 48 hours, this pro-inflammatory cytokine was higher in group 1 on postoperative day 4 (group 1: 21533 + 27900 vs. group 2: 1130 + 3563 pg/ml; p < 0.001). Serum VEGF levels were higher in group 1 on postoperative day 4 (group 1: 1212 + 1025 vs. group 2: 408 + 407 pg/ml; p < 0.01). Peritoneal fluid VEGF levels were also higher in group 1 at 48 hours (group 1: 4857 + 4384 vs. group 2: 630 + 461 pg/ml; p < 0.001) and postoperative day 4 (group 1: 32807 + 98486 vs. group 2: 1002 + 1229 pg/ml; p < 0.001). A positive correlation between serum IL-6 and VEGF serum levels was observed on postoperative day 4 (r=0.7; p<0.01). Conclusions: These results suggest that not only the inflammatory response but also the angiogenic pathways are stimulated in patients with intra-abdominal infection after surgery for colorectal cancer. The implications of this finding on long-term follow-up need to be evaluated.

Transport of methotrexate by the in vitro isolated rabbit proximal tubule.

The tubular transport of [3H]methotrexate was studied in isolated nonperfused and perfused superficial proximal tubular segments of rabbit kidneys. Reabsorption represented only 5% of perfused methotrexate, and appeared to be mostly of passive nature inasmuch as it was not modified by reducing the temperature or by ouabain. Cellular accumulation in nonperfused segments and secretion in perfused tubules were highest in the S2 segment and lower in the S3 and S1 segments. Secretion against a bath-to-lumen concentration gradient was observed only in S2 segments (with a maximum methotrexate secretory rate of 478 +/- 48 fmol/mm.min and an apparent Km of transport of 363 +/- 32 microM), and was inhibited by probenecid and folate. The low capacity for methotrexate secretion may be explained by a low capacity of transport across the basolateral membrane of the proximal cell as methotrexate was accumulated only to a low extent in nonperfused tubules (tissue water to medium concentration ratio of 8.2 +/- 1 in S2 segments). During secretion a small amount of methotrexate was metabolized; the nature of the metabolite(s) remains to be defined.

Intraoperative cerebral perfusion and postoperative cognitive dysfunction in geriatric patients

Background: Inadequate intraoperative cerebral perfusion has been suggested as a possible cause of postoperative cognitive dysfunction (POCD). Methods: We investigated 35 patients aged 65 or older undergoing elective major non-cardiac surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Intraoperative cerebral perfusion was monitored with transcranial Doppler, and near-infrared spectroscopy (NIRS). Arterial blood pressure was monitored continuously with a Finapres device. Mx, an index allowing continuous monitoring of cerebrovascular autoregulation based on the changes in mean arterial blood pressure (MAP) and cerebral blood flow velocity was calculated. Mx >0.5 was defined as disturbed cerebrovascular autoregulation. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-NAB Plus test battery. A postoperative decline >1 z-score in at least two of the tested domains was defined as POCD. Data are shown as mean } SD. Results: Mean age was 75 } 7 yrs. Sixteen patients (46%) developed POCD. These patients were older (77 } 8 vs 73 } 7 yrs), had lower MAP (77 } 12 vs 81 } 11 mm Hg), lower cerebral tissue oxygenation indices measured by NIRS (66.8 } 6.0 vs 68.6 } 4.3%) and less efficient cerebrovascular autoregulation (Mx 0.54 } 0.17 and 0.44 } 0.22) than patients without POCD. Disturbed intraoperative cerebrovascular autoregulation was found more often (56 vs 37%) in patients with POCD. However, none of these differences reached statistical significance. Conclusions: Our data show a trend towards subtle changes in intraoperative cerebral perfusion in elderly patients who develop POCD. However, a cause effect relationship must not be assumed and a greater number of patients needs to be investigated patients. However, more patients need to be investigated to confirm and characterize these differences.

Establishing an association between a peri-operative perfusion score system (PerfSCORE) and post-operative patient morbidity/mortality during CPB cardiac surgery.

BACKGROUND: To date, there is no quality assurance program that correlates patient outcome to perfusion service provided during cardiopulmonary bypass (CPB). A score was devised, incorporating objective parameters that would reflect the likelihood to influence patient outcome. The purpose was to create a new method for evaluating the quality of care the perfusionist provides during CPB procedures and to deduce whether it predicts patient morbidity and mortality. METHODS: We analysed 295 consecutive elective patients. We chose 10 parameters: fluid balance, blood transfused, Hct, ACT, PaO2, PaCO2, pH, BE, potassium and CPB time. Distribution analysis was performed using the Shapiro-Wilcoxon test. This made up the PerfSCORE and we tried to find a correlation to mortality rate, patient stay in the ICU and length of mechanical ventilation. Univariate analysis (UA) using linear regression was established for each parameter. Statistical significance was established when p < 0.05. Multivariate analysis (MA) was performed with the same parameters. RESULTS: The mean age was 63.8 +/- 12.6 years with 70% males. There were 180 CABG, 88 valves, and 27 combined CABG/valve procedures. The PerfSCORE of 6.6 +/- 2.4 (0-20), mortality of 2.7% (8/295), CPB time 100 +/- 41 min (19-313), ICU stay 52 +/- 62 hrs (7-564) and mechanical ventilation of 10.5 +/- 14.8 hrs (0-564) was calculated. CPB time, fluid balance, PaO2, PerfSCORE and blood transfused were significantly correlated to mortality (UA, p < 0.05). Also, CPB time, blood transfused and PaO2 were parameters predicting mortality (MA, p < 0.01). Only pH was significantly correlated for predicting ICU stay (UA). Ultrafiltration (UF) and CPB time were significantly correlated (UA, p < 0.01) while UF (p < 0.05) was the only parameter predicting mechanical ventilation duration (MA). CONCLUSIONS: CPB time, blood transfused and PaO2 are independent risk factors of mortality. Fluid balance, blood transfusion, PaO2, PerfSCORE and CPB time are independent parameters for predicting morbidity. PerfSCORE is a quality of perfusion measure that objectively quantifies perfusion performance.

La lithiase rénale: un marqueur du risque cardiovasculaire [Kidney stone as a cardiovascular risk marker].

Si le passage d'un calcul rénal est souvent considéré comme un événement médical mineur, quoique très douloureux, de plus en plus d'études indiquent qu'il doit être pris au sérieux puisqu'il peut indiquer un risque cardiovasculaire augmenté. Nous revoyons ici les études qui associent risque cardiovasculaire et calcul rénal et les liens physiopathologiques qui les unissent. Nous montrons que la lithiase est un événement intervenant tôt dans la vie d'un individu à risque de développer des complications cardiovasculaires. Ainsi, la lithiase ne doit pas être banalisée, mais doit être considérée comme une première alerte devant inciter le médecin traitant à recenser précocement les facteurs de risque cardiovasculaires et à mettre en place une stratégie de prévention. Cette approche pourrait permettre de diminuer l'incidence d'événements cardiovasculaires chez les patients formeurs de lithiases. Most of the time, kidney stones are considered as minor, but painful events. However, several studies have recently shown an association between kidney stone and an increased cardio-vascular risk. We review here these studies and explore the underlying pathophysiological hypotheses. At the end, we propose that lithiasis should be considered as a red flag intervening early during life-time and allowing a check of cardiovascular risk factors and early preventive intervention. Such approach may be successful in reducing the incidence of cardio-vascular events in stone formers.

Cerebral perfusion CT: Current state of the art : P44

Purpose: The aim of this educational poster is to introduce the technical principles of cerebral perfusion CT and to provide examples of its clinical applications and potential limitations in the everyday emergency practice. Methods and materials: Cerebral perfusion CT is a well established investigatory tool for many vascular and parenchymal brain dysfunctions. CT perfusion maps allow a semiquantitative assessment of cerebral perfusion. Results: Currently, cerebral perfusion CT has a pivotal role in differentiating reversible from irreversible ischemic parenchymal insult besides its integral role in grading vasospasm after subarachnoid hemorrhage. Furthermore, cerebral perfusion CT can be coupled to acetazolamide administration in order to assess the cerebrovascular reserve capacity before performing extra-/intra-cranial bypass surgery in patients with cerebral vascular insufficiency. Cerebral perfusion CT can also identify diffuse abnormalities of cerebral perfusion in children with traumatic brain injury showing a low initial GCS in order to predict the final outcome regarding the late occurrence of irreversible parenchymal damage. Cerebral Perfusion CT is also able to detect focal parenchymal perfusion abnormalities in acute epileptic seizures. Conclusion: Cerebral perfusion CT can be integrated in the management of many vascular, traumatic and functional disorders of the brain.

Treatment-dependent loss of polyfunctional CD8+ T-cell responses in HIV-infected kidney transplant recipients is associated with herpesvirus reactivation.

Antiretroviral-therapy has dramatically changed the course of HIV infection and HIV-infected (HIV(+)) individuals are becoming more frequently eligible for solid-organ transplantation. However, only scarce data are available on how immunosuppressive (IS) strategies relate to transplantation outcome and immune function. We determined the impact of transplantation and immune-depleting treatment on CD4+ T-cell counts, HIV-, EBV-, and Cytomegalovirus (CMV)-viral loads and virus-specific T-cell immunity in a 1-year prospective cohort of 27 HIV(+) kidney transplant recipients. While the results show an increasing breadth and magnitude of the herpesvirus-specific cytotoxic T-cell (CTL) response over-time, they also revealed a significant depletion of polyfunctional virus-specific CTL in individuals receiving thymoglobulin as a lymphocyte-depleting treatment. The disappearance of polyfunctional CTL was accompanied by virologic EBV-reactivation events, directly linking the absence of specific polyfunctional CTL to viral reactivation. The data provide first insights into the immune-reserve in HIV+ infected transplant recipients and highlight new immunological effects of thymoglobulin treatment. Long-term studies will be needed to assess the clinical risk associated with thymoglobulin treatment, in particular with regards to EBV-associated lymphoproliferative diseases.

Photodynamic therapy enhances liposomal doxorubicin distribution in tumors during isolated perfusion of rodent lungs.

BACKGROUND: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 μg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm(2) and 35 mW/cm(2)) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm(2) and 35 mW/cm(2)) followed by ILP (400 μg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. RESULTS: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. CONCLUSIONS: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

Angiotensinergic innervation of the kidney: present knowledge and its significance.

Intrarenal neurotransmission implies the co-release of neuropeptides at the neuro-effector junction with direct influence on parameters of kidney function. The presence of an angiotensin (Ang) II-containing phenotype in catecholaminergic postganglionic and sensory fibers of the kidney, based on immunocytological investigations, has only recently been reported. These angiotensinergic fibers display a distinct morphology and intrarenal distribution, suggesting anatomical and functional subspecialization linked to neuronal Ang II-expression. This review discusses the present knowledge concerning these fibers, and their significance for renal physiology and the pathogenesis of hypertension in light of established mechanisms. The data suggest a new role of Ang II as a co-transmitter stimulating renal target cells or modulating nerve traffic from or to the kidney. Neuronal Ang II is likely to be an independent source of intrarenal Ang II. Further physiological experimentation will have to explore the role of the angiotensinergic renal innervation and integrate it into existing concepts.

Effect of angiotensin converting enzyme inhibition in renovascular hypertension.

The unique ability of angiotensin converting enzyme (ACE) inhibitors to inhibit the generation of angiotensin II has made them very useful agents for treating patients with renovascular hypertension. Their efficacy in lowering blood pressure in this type of secondary hypertension is now well established. However, episodes of acute renal failure may occur during ACE inhibition, particularly when renal perfusion is compromised. This is often the case in patients with renal artery stenosis and a single kidney or with bilateral renal artery stenosis. In recent years, investigators have shown concern at the long-term fate of the stenotic kidney in patients with unilateral renal artery stenosis who are treated with ACE inhibitors. Although overall renal function remained stable, a decrease in glomerular filtration was demonstrated in the stenotic kidney under ACE inhibition. The long-term implications of this observation merit further investigations.

Evaluation of tumour vascularisation in two rat sarcoma models for studying isolated lung perfusion. Injection route determines the origin of tumour vessels.

Isolated cytostatic lung perfusion (ILP) is an attractive technique allowing delivery of a high-dose of cytostatic agents to the lungs while limiting systemic toxicity. In developing a rat model of ILP, we have analysed the effect of the route of tumour cell injection on the source of tumour vessels. Pulmonary sarcomas were established by injecting a sarcoma cell suspension either by the intravenous (i.v.) route or directly into the lung parenchyma. Ink perfusion through either pulmonary artery (PA) or bronchial arteries (BA) was performed and the characteristics of the tumour deposits defined. i.v. and direct injection methods induced pulmonary sarcoma nodules, with similar histological features. The intraparenchymal injection of tumour cells resulted in more reliable and reproducible tumour growth and was associated with a longer survival of the animals. i.v. injected tumours developed a PA-derived vascular tree whereas directly injected tumours developed a BA-derived vasculature.

Oral valganciclovir prophylaxis in kidney transplant recipients

Background: Immunosuppressive and antivira[ prophy[ actic drugs are needed to prevent acute rejection and infection after organ transplantation. We assessed the effectiveness of a new combined regimen introduced at our transplantation center. Methods: We reviewed at[ consecutive patients who underwent kidney transplantation at our institution over a 5.5-year period, with a follow-up of at [east 6 months. Patients transplanted from 1/2000 to 3/2003 (Period 1) were compared to patients transplanted from 4/2003 to 7/2005 (Period 2). In period 1, patients were treated with Basi[iximab, Cic[osporin, steroids and Mycophenotate or Azathioprine. Prophylaxis with Va[acic[ ovir was prescribed in CMV D+/R- patients; otherwise, a preemptive antivira[ approach was used. In period 2, immunosuppressive drugs were Basi[- iximab, Tacro[imus, steroids and Mycopheno[ate. A 3-month CMV prophylaxis with Va[gancic[ovir was used, except in D-/R- patients. Results: Sixty-three patients were transplanted in period 1 and 70 patients in period 2. Baseline characteristics of both groups were comparable; in particular 17% of patients were CMV D+/R- in period 1 compared to 23% in period 2 (p=0.67). Acute rejection was more frequent in period 1 than in period 2 (40% of patients vs 7%, respectively p<0.001). Nineteen patients (30%) in period 1 were diagnosed with CMV infection/disease that required treatment, compared with 8 patients (11.4%) in period 2 (p = 0.003). Of these 8 patients, at[ had CMV infection/disease after discontinuation of Va[gancic[ovir prophylaxis, 6 were D+/R- (75%), and at[ were treated with oral Va[gancic[ovir. There was no difference between periods in terms of incidence of BK nephropathy, post-transplant [ymphopro[ iferative disease, graft toss, and mortality. Conclusions: These results indicate that a 3-month course of oral Va[gancic[ovir is very effective to prevent CMV infection/disease in kidney transplantation. Late-onset CMV disease is a residual problem in D+/R- patients receiving VGC prophylaxis.

An adapted model of ex vivo vein perfusion: the key to understand vessel wall remodeling

Objective: Saphenous vein graft bypass remains the salvage option when¦endovascular procedure has failed or was contraindicated due to extensive¦occlusive lesions. However, pathological wall remodeling leading leading to¦graft failure is one of the most limiting factors of this therapy. Therefore, the¦understanding of this remodeling process of human vein is essential to the design¦of future effective therapeutics and it requires an adapted model of ex-vivo vein¦perfusion.¦Methods: We have developed an ex vivo vein support system (EVVSS), which¦uses standardized and controlled hemodynamic parameters for the pulsatile¦perfusion of saphenous vein segments. The morphological and molecular¦parameters involved in the remodeling process under an arterial shear stress¦associated to low (7 mm Hg) or high (70 mm Hg) pressure conditions can be¦analyzed.¦Results: Histomorphometric analysis showed that the vein segments perfused¦during 7 days under high pressure undergo a significant neointima development¦compared to veins exposed to low pressure conditions. The application of an¦arterial shear stress in the vein under low pressure induced an elevation of the¦MMP-2 and MMP-9 expression, activity and transcription. The application of¦higher pressure is associated to increased MMP2 expression and transcription¦and MMP9 transcription. TIMP1 expression and transcription were initiated by¦the application of an arterial shear stress but not modified by the modification¦of the pressure. However, TIMP2 expression was increased under high¦pressure conditions but its transcription was inhibited by arterial shear stress,¦independently of the pressure. The values of transcription and expression of¦PAI-1 were not modified by high pressure. Eph-B4 transcription and expression¦were significantly decreased under arterial shear stress.¦Conclusion: These data show that our EVVSS is a valuable setting to study¦ex vivo remodeling of human saphenous veins submitted to arterial conditions.¦The intimal hyperplasia as well as MMP 2, 9 and TIMP 2 seem to be influenced¦by the pressure.