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ABSTRACT: To explore dendritic cells (DCs) multiple functions in immune modulation.
We used bone-marrow derived dendritic cells from BALB/c mice pulsed with pseudo particles from the hepatitis C virus to vaccinate naive BALB/c mice. Hepatitis C virus (HCV) pseudo particles consist of the genotype 1b derived envelope proteins E1 and E2, covering a non-HCV core structure. Thus, not a single epitope, but the whole "viral surface" induces immunogenicity. For vaccination, mature and activated DC were injected subcutaneously twice.
Humoral and cellular immune responses measured by enzyme-linked immunosorbent assay and interferon-gamma enzyme-linked immunosorbent spot test showed antibody production as well as T-cells directed against HCV. Furthermore, T-cell responses confirmed two highly immunogenic regions in E1 and E2 outside the hypervariable region 1.
Our results indicate dendritic cells as a promising vaccination model for HCV infection that should be evaluated further.
World Journal of Gastroenterology 02/2012; 18(8):785-93. · 2.47 Impact Factor
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ABSTRACT: Chronic kidney disease has become increasingly prevalent after liver transplantation (LTPL) because outcome and survival rates have improved. Chronic kidney insufficiency is most likely associated with increased morbidity and mortality. The challenge is to identify patients who will be in need of long-term renal replacement therapy (RRT) after LTPL. We analyzed 208 liver transplant recipients with respect to mortality, associated laboratory values, underlying liver disease, immunosuppressive protocol and the need for RRT. Long-term RRT was defined by the need for RRT 3 months after LTPL. Altogether, 5.8% of the surviving study patients remained in need of RRT 3 months after LTPL. All of these patients continued to need RRT throughout the study period (2 years). The need for RRT significantly increased the 2-year mortality rate 4.3-fold, from 15.4 to 66.7% (p = 0.004). Comparison of laboratory and clinical parameters at the time of LTPL revealed no significant differences for creatinine, albumin and MDRD between patients undergoing hemodialysis 3 months after LTPL and patients without RRT. Comparing mean urea, a difference was observed. However, multivariate regression analyses using easy-to-observe demographic or laboratory parameters failed to generate a model to predict the need for RRT after LTPL. In addition, a comparison of underlying liver disease and immunosuppressive regimes identified no significant differences. Taken together, patients who were on hemodialysis 3 months after LTPL were also on hemodialysis 2 years after LTPL or until death. RRT 3 months after LTPL may predict the risk for chronic renal insufficiency and is associated with significantly increased mortality.
Nephron Clinical Practice 01/2011; 119(4):c342-7. · 2.04 Impact Factor
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ABSTRACT: Eradication of chronic Hepatitis B virus (HBV) infection, marked by HBs seroconversion, is very rarely achieved by treatment with nucleoside and nucleotide analogs. Therapeutic cell based approaches, like interferon therapy, have a higher chance of seroconversion. Dendritic cells (DC) are key players in the cellular immune response and have been shown to play an important role in controlling HBV infection. In this study, the potential of ex vivo activated DC to induce specific immune responses against HBV was examined. DC derived from bone-marrow of BALB/c or C56BL/6 mice were pulsed with HBV subviral particles (HBVsvp), derived from the HepG2.2.15 cell line. HepG2.2.15 produces subviral particles consisting of the HBc and HBs proteins. Thus, the entire "viral surface" is presented to DC to induce an immune reaction. In vitro pulsation with HBVsvp successfully activated bone-marrow derived DC, demonstrated by FACS analysis showing increased MHCII, CD 86 and CCR-7. Immunization of mice, via subcutaneous injection of the activated DC, induced HBV specific immune reactions which were measured by ELISA, ELISPOT and T-cell proliferation analysis. Vaccination with ex vivo activated DC may be a promising tool for therapeutic or prophylactic approaches against the Hepatitis B virus.
Vaccine 11/2010; 29(2):200-6. · 3.77 Impact Factor
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ABSTRACT: We investigated the effect of written drug information for senior clinicians on the incidence of drug-drug interactions (DDIs) and DDI-related adverse events in intensive care patients.
A prospective controlled intervention cohort study was conducted in a medical intensive and intermediate care unit in a university hospital. From 1,062 consecutive intensive care patients, those 265 (control: 136, intervention: 129) with > or =8 concurrently prescribed drugs were included in the study (to include high-risk patients with polypharmacy). The DDI information for senior clinicians during an intervention period of 3 months was based on a computerised clinical decision support system (CDSS) containing information on risk and management of 9,453 drug combinations.
The number of patients with at least one DDI at the end of the respective study phase decreased by 18% (relative risk reduction) from 90 (66%) patients in controls to 70 (54%) in the intervention group (p = 0.02). The relative risk of a patient suffering from at least one DDI-related adverse event decreased by 43% from 60 (44%) patients in controls to 32 (25%) in the intervention group (p < 0.01). Among these events, the incidence of QT(C) prolongation was reduced by 64% from 15 (11%) patients in the control group to 5 (4%) in the intervention group (p = 0.04), and the incidence of hypokalemia by 80% from 14 (10%) to 2 (2%, p < 0.01).
Written drug information based on a CDSS considerably decreased DDIs and DDI-related adverse events in routine practice.
European Journal of Intensive Care Medicine 02/2010; 36(4):665-72. · 5.17 Impact Factor
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ABSTRACT: In patients presenting with acute liver failure (ALF) prediction of prognosis is vital to determine the need of transplantation. Based on the evidence that plasma disappearance rate of indocyanine green (ICG-PDR) correlates with liver cell function, we evaluated the ability of ICG-PDR measured by pulse dye densitometry to predict outcome in patients with acute liver failure.
Prospectively markers of hepatocellular injury, synthesis and excretion, including ICG-PDR were measured daily until liver transplantation, death, discharge from intensive care unit, or up to 7 days in 25 patients with acute liver failure. Receiver operating curve (ROC) analysis was performed to assess the value of ICG-PDR to predict outcome in ALF.
The 25 patients analyzed included 18 that recovered spontaneously and 7 that underwent liver transplantation (n = 6) or died (n = 1). Causes of ALF included viral hepatitis (n = 4), toxic liver injury (n = 15), ischemic liver injury (n = 2), and cryptogenic liver failure (n = 4). King's college criteria were fulfilled in 85.7% of patients not recovering spontaneously and in 16.7% of patients recovering spontaneously. The mean ICG-PDR measured on day 1 in patients recovering spontaneously was 12.0 +/- 7.8%/min and in patients not recovering spontaneously 4.3 +/- 2.0%/min (P = 0.002). By ROC analysis the sensitivity and specificity of an ICG-PDR value <or= 6.3%/min on study day 1 were 85.7% and 88.9%, respectively, for predicting a non spontaneous outcome in ALF.
ICG-PDR allows early and sensitive bedside assessment of liver dysfunction in ALF. Measurement of ICG-PDR might be helpful in predicting the outcome in acute liver failure.
Clinicaltrials.gov, NCT 00245310.
BMC Gastroenterology 12/2009; 9:91. · 2.42 Impact Factor
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ABSTRACT: Death from end-stage liver disease (ESLD) because of chronic hepatitis B and C has become an increasing problem in human immunodeficiency virus (HIV)-infected patients in the last years. This is mainly because of the dramatic decrease of HIV-related morbidity and mortality since the introduction of highly active antiretroviral therapy (HAART). Although the data on the outcome of liver transplantation in HIV-infected recipients with ESLD is limited, overall results seem comparable to non-HIV-infected recipients. Therefore, liver transplant centres around the world are increasingly accepting HIV-infected individuals as organ recipients. Post-transplantation control of HIV replication is achieved by continuing HAART. As in non-HIV-infected patients, hepatitis B virus recurrence is efficiently prevented by hepatitis B immunoglobulin and antiviral therapy. Re-infection of the allograft with hepatitis C virus, however, remains an important problem, and progress to allograft cirrhosis may even be more rapid than in HIV-negative patients. Interactions in drug metabolism between the HAART components and the immunosuppressive drugs are difficult to predict and require close monitoring of drug levels and dose adjustments. The complexity in this setting makes close cooperation between transplant surgeons, hepatologists, HIV-clinicians and pharmacologists mandatory. As experience on liver transplantation in HIV-infected individuals is still limited, to date results from large prospective trials addressing key issues are needed.
Clinical Transplantation 12/2009; 23 Suppl 21:68-74. · 1.67 Impact Factor
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ABSTRACT: Moxifloxacin, the newest fourth-generation fluoroquinolone, has a broad spectrum of antibacterial activity covering both Gram-positive and Gram-negative aerobic and anaerobic bacteria and is therefore very well suited for the treatment of biliary tract infections. The present study aimed to determine the penetration of moxifloxacin into gallbladder tissue to evaluate its antibiotic potential in this indication.
Hospitalized patients with acute cholecystitis received a single, 1 h infusion of 400 mg of moxifloxacin before cholecystectomy. Serum and gallbladder wall tissue samples were collected during surgery, and the moxifloxacin concentrations were measured by HPLC.
Sixteen patients (eight men and eight women) were included between January 2007 and April 2008. The time between start of infusion and gallbladder removal ranged from 50 min to 21 h 10 min. The serum concentration at the time of cholecystectomy was between 0.39 and 4.37 mg/L, and the tissue concentration between 1.73 and 17.08 mg/kg. The tissue-to-serum concentration ratio ranged from 1.72 to 6.33.
The results show that moxifloxacin penetrates well into gallbladder tissue and is therefore a therapeutic option for biliary tract infection. The highest concentrations in serum and gallbladder tissue were measured shortly after the end of a 1 h infusion. As perioperative prophylaxis, moxifloxacin should therefore be administered 30-60 min before the first surgical incision.
Journal of Antimicrobial Chemotherapy 10/2009; 64(5):1091-5. · 5.07 Impact Factor
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American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 08/2009; 66(14):1250, 1253. · 2.10 Impact Factor
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ABSTRACT: Central venous catheters are frequently placed in intensive care medicine for multiple indications. The risk of severe bleeding after cannulation is considered to be increased in patients with abnormal coagulation, common in critically ill patients.
This open prospective trial, performed at two medical intensive care units and one hematology intermediate care ward, investigated whether insertion of a central venous catheter in patients with coagulopathy (prothrombin time <or= 50% [International Normalized Ratio, INR, >or= 1.5] and/or platelets <or= 50 x 10(9)/l) bears an increased risk of bleeding.
In 196 patients with and without severe disorders of hemostasis, no significant difference in decrease of hemoglobin after catheter placement was observed. In addition, no correlation between a significant drop in hemoglobin and increased levels of creatinine or urea was seen. Mechanical complications were similar in frequency compared to previous publications.
These findings demonstrate that coagulation disorders with altered prothrombin time (INR) or platelets do not increase the risk of significant bleeding when inserting a central venous catheter. Therefore, the prophylactic correction of coagulation by transfusion of blood products or coagulation factors is not necessary before central venous catheter insertion.
Medizinische Klinik 06/2009; 104(5):331-5. · 0.34 Impact Factor
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ABSTRACT: Over the past 4 decades, the surgical techniques of liver transplantation (LTx) have permanently evolved and been modified. Among these, the modified piggyback (MPB) technique by Belghiti offers specific advantages. The objective of this study was to present our single-center experience with the MPB technique in 500 cases. Recipients' perioperative data were prospectively collected and evaluated. Postoperative and specific complications, stay in the intensive and intermediate care unit, and the mortality rate with cause of death were analyzed. Most recipients were classified as Child C (49.1%). For the patients who underwent LTx for the first time, alcoholic (23.9%) and viral (22.2%) cirrhosis and hepatocellular carcinoma (15.1%) were the prevalent indications. The overall median warm ischemia time, anastomosis duration, and operative time were 45, 108, and 320 minutes, respectively. The median intraoperative blood loss was 1500 mL. A venovenous bypass was never needed to maintain hemodynamic stability. Only in a few cases was temporary inferior vena cava clamping necessary. Most prominent surgical complications were hemorrhage, hematoma, and wound dehiscence. Renal failure occurred in 6.2% of patients. The overall median stay in the intensive and intermediate care unit was 14 days. The mortality rates within 30 and 90 days were 6.3% and 13.3%, respectively. No technique-related death occurred. The MPB technique by Belghiti is a feasible and simple LTx technique. The caval flow is preserved during the anhepatic phase, and this minimizes the need for venovenous bypass or portocaval shunt. This technique requires only 1 caval anastomosis, which is easy to perform with a short anhepatic phase. To minimize the risk of outflow obstruction, attention should be paid by doing a wide cavocavostomy cranially to the donor inferior vena cava in a door-lock manner. This technique can be applied in almost all patients undergoing LTx for the first time and liver retransplantation as well.
Liver Transplantation 05/2009; 15(5):466-74. · 3.39 Impact Factor
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ABSTRACT: To correct overdosing of drugs requiring adjustment based on renal function in intensive-care patients.
In a prospective intervention study, we estimated individual glomerular filtration rate and assessed whether medication required dose adjustment based on renal function. Senior clinicians received a structured report containing recommendations as to whether and how to adjust dosage in the individual patient (intervention). Prevalence of overdosed drugs (primary outcome), extent of overdoses, and reasons for nonacceptance of recommendations (secondary outcomes) were assessed.
Of 138 screened intensive-care patients, 68 (49%) had renal impairment, and 110 (14%) of the 805 prescribed drugs required consideration of renal function. A potential overdose was found in 53/110 drugs (48%) and this rate decreased to 26/110 (24%, P < 0.001) after the intervention. The average extent of overdose was reduced from 54% before to 31% after the intervention (P < 0.001). The main reasons expressed by the physicians for nonacceptance of recommendations were a large therapeutic index or minor overdoses of the involved drugs.
In intensive-care patients, overdosing of drugs requiring adjustment based on renal function is still very common. Drug information counselling significantly decreased the prevalence and extent of overdose.
European Journal of Clinical Pharmacology 04/2009; 65(8):823-9. · 2.85 Impact Factor
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ABSTRACT: The aim of this study was to characterize patients after self-poisoning with suicidal intent regarding age, sex and type of substances ingested, as well as to identify temporal variations of attempted suicides and associations with climate variables and the lunar cycle. During the years 2002-2004, a total of 691 patients were admitted for self-poisoning parasuicides. The male to female ratio was 1:1.65 with mean ages of 39 and 37 years, respectively. Benzodiazepines and antidepressants were the most frequently taken substances. A significant variation with the time of the day with a peak before midnight was observed for both sexes. Variation with the day of the week was less clear and showed a peak incidence for parasuicides on Mondays. There was no significant variation with the monthly or annual cycle. The frequency of parasuicides was associated with "bad weather" (precipitation). No association of parasuicide incidences to the lunar cycle was observed.
Psychiatry Research 11/2008; 161(2):177-84. · 2.52 Impact Factor
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ABSTRACT: The frequency of drug administration errors and incompatibilities between intravenous drugs before and after an intervention in an intensive care unit (ICU) is discussed.
Critically ill adult patients with intoxications, multiorgan failure, and serious infections were included in a retrospective analysis and in a prospective two-period, one-sequence study. In the retrospective analysis, the most frequent brands of i.v. medications used in the ICU of a gastroenterologic department in a teaching hospital were identified. All possible combinations and resulting incompatibilities were defined. Based on the results, a standard operating procedure (SOP) was established to prevent frequent and well-documented incompatibilities among i.v. medications. In the prospective study, trained pharmacy students assessed incompatible coinfusions before and after SOP implementation.
In the retrospective analysis of 100 patients, 3617 brands of drug pairs were potentially given concurrently through one i.v. line and 7.2% of the drug pairs were incompatible. Antibiotics, such as piperacillin-tazobactam and imipenem-cilastatin, were the most frequent incompatible drug pairs. The newly developed SOP mandated that administration of these drugs be separated from all other drugs and suggested the use of an idle i.v. line for infusion whenever possible. In the prospective study of 50 patients, the frequency of incompatible drug pairs was reduced by the time of intervention from 5.8% to 2.4%. Incompatible drug pairs that were governed by the new SOP were reduced from 1.9% to 0.5%.
Administration of incompatible i.v. drugs in critically ill patients was frequent but significantly reduced by procedural interventions with SOPs.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 11/2008; 65(19):1834-40. · 2.10 Impact Factor
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ABSTRACT: The aim of the present study was (1) to determine the prevalence of intensive care unit (ICU) admissions due to an adverse drug reaction (ADR), and (2) to compare affected patients with patients admitted to the ICU for the treatment of deliberate self-poisoning using medical drugs.
Prospective observational cohort study.
Fourteen bed medical ICU including an integrated intermediate care (IMC) section at a tertiary referral center.
A total of 1,554 patients admitted on 1 January 2003 to 31 December 2003.
Ninety-nine patients were admitted to the ICU with a diagnosis of ADR (6.4% of all admissions), 269 admissions (17.3%) were caused by deliberate self-poisoning. Patients admitted for treatment of ADR had a significantly higher age, a longer treatment duration in the ICU, a higher SAPS II score, and a higher 6-month mortality than those with deliberate self-poisoning. Most patients (71.7%) suffering from ADR required advanced supportive care in the ICU while the majority of patients (90.7%) with deliberate self-poisoning could be sufficiently treated in the IMC area. All diagnostic and therapeutic procedures in the ICU except mechanical ventilation were significantly more often performed in patients with ADR.
This study provides further evidence that ADR is a frequent cause of admission to medical ICUs resulting in a considerable use of ICU capacities. In the present setting patients with ADR required longer and more intense medical treatment in the ICU than those with deliberate self-poisoning.
European Journal of Intensive Care Medicine 09/2008; 35(2):266-74. · 5.17 Impact Factor
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ABSTRACT: Imported falciparum malaria is characterized by a broad spectrum of potentially life-threatening complications that may arise even after initiation of appropriate antimalarial drug therapy. Hence, at Heidelberg University Hospital, all patients with newly diagnosed falciparum malaria are initially treated in the intermediate care unit (IMC) or intensive care unit (ICU). The present study was undertaken to evaluate critically the benefit of this strategy, which includes daily consultation with senior specialists in tropical medicine.
We conducted a retrospective cohort study at the 14-bed combined IMC/ICU of a 1,685-bed university hospital. A cohort of 122 patients with imported falciparum malaria admitted from 1 January 1996 to 31 December 2003 was included.
Thirty-four patients (27.9%) developed complications, defined according to the current World Health Organization classification. Most patients (80.3%) studied did not take the recommended chemoprophylaxis against malaria. The majority of patients (89.3% [n = 109]) could be adequately treated in the IMC. Life-threatening complications requiring ICU support occurred in 13 patients (10.7%). All complications were successfully managed. Fifty-five patients (45.1%) fulfilling recently published criteria for outpatient treatment had an excellent therapeutic response and did not require ICU support.
This retrospective evaluation demonstrated favourable therapeutic results in hospitalized patients with imported falciparum malaria. Both initial treatment in the medical IMC/ICU and close collaboration between intensivists and specialists in tropical medicine may improve disease outcome among affected patients. Prospective studies are needed to confirm these preliminary findings.
Critical care (London, England) 02/2008; 12(1):R22. · 4.61 Impact Factor
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Stefan Hofer,
Christoph Eisenbach,
Ivan K Lukic,
Lutz Schneider,
Konrad Bode,
Martina Brueckmann,
Sven Mautner,
Moritz N Wente, Jens Encke,
Jens Werner,
Alexander H Dalpke,
Wolfgang Stremmel,
Peter P Nawroth,
Eike Martin,
Peter H Krammer,
Angelika Bierhaus,
Markus A Weigand
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ABSTRACT: Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo.
Prospective, randomized laboratory investigation that used an established murine sepsis model.
Research laboratory in a university hospital.
Female C57BL/6 mice.
Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days.
Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals.
Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.
Critical care medicine 02/2008; 36(2):404-8. · 6.37 Impact Factor
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Christoph Lichtenstern,
Jan Schmidt, Jens Encke, Markus Weigand
Intensivmedizin up2date 01/2008; 4(1):61-84.
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ABSTRACT: Fulminant hepatic failure is characterized by the development of severe liver injury with impaired synthetic capacity and encephalopathy in patients with previous normal liver or at least well compensated liver disease. The etiology of fulminant hepatic failure refers to a wide variety of causes, of which toxin-induced or viral hepatitis are most common. In spite of specific therapeutic options in distinctive etiologies, orthotopic liver transplantation is the only therapy proven to improve patient survival in the majority of patients. The outcome is determined by the complications like severe coagulopathy, infections, renal impairment or increased intracranial pressure. The decision for transplantation depends on the possibility of spontaneous hepatic recovery, which may be estimated by several factors. The most important variables for predicting the need of transplantation in fulminant hepatic failure are the degree of encephalopathy, patients age and the underlying cause of liver failure.
Nephrology Dialysis Transplantation 10/2007; 22 Suppl 8:viii5-viii8. · 3.40 Impact Factor
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ABSTRACT: Orthotopic liver transplantation is the preferred treatment for many patients with complications of end-stage liver disease. For metabolic liver diseases liver transplantation does not only replace the diseased organ, but also can potentially correct the metabolic defect. Results of liver transplantation for metabolic diseases have been encouraging. In Wilson's disease liver transplantation is considered an effective treatment for the fulminant form and for end-stage liver disease, associated with an excellent long-term outcome. However, it is still a matter of controversy whether liver transplantation should be considered in Wilson's disease patients with severe neurological impairment. Liver transplantation for hereditary haemochromatosis is relatively uncommon and is associated with a decreased post-transplantation patient survival, most likely due to infections and cardiac complications. Reduction of iron overload prior to liver transplantation in patients with hereditary haemochromatosis might be associated with a better outcome.
Nephrology Dialysis Transplantation 10/2007; 22 Suppl 8:viii9-viii12. · 3.40 Impact Factor
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ABSTRACT: Organ shortage has driven many transplant programs to extend their criteria to accept donors. The goal of the present work is to further characterize the most important extended donor criteria (EDC) in liver transplantation and to identify factors that impact outcomes for this type of grafts through a comprehensive review of the most recent findings and current opinions. Age, steatosis, positive viral hepatitis serology, intensive care unit stay, and history of malignancy in donor have been the matter of substantial debate in recent years and are therefore discussed in further detail here. Cold and warm ischemic times have also been discussed separately as they have been identified as important independent risk factors for mortality. The use of grafts with EDC provides an immediate expansion of the donor pool. However, in order to optimize effective utilization of EDC, attempts should be made to carefully match the most appropriate graft-recipient pair.
Nephrology Dialysis Transplantation 10/2007; 22 Suppl 8:viii29-viii36. · 3.40 Impact Factor
