Publications by authors named "Ben van der Hoven"

20 Publications

  • Page 1 of 1

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

Intensive Care Med 2021 Jun 29;47(6):674-686. Epub 2021 May 29.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Purpose: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.

Methods: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).

Results: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.

Conclusion: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.
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http://dx.doi.org/10.1007/s00134-021-06431-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164057PMC
June 2021

Relation between intra-abdominal pressure and early intestinal ischemia in rats.

Trauma Surg Acute Care Open 2020 1;5(1):e000595. Epub 2020 Dec 1.

Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Little is known on early irreversible effects of increased intra-abdominal pressure (IAP). Therefore, timing of abdominal decompression among patients with abdominal compartment syndrome remains challenging. The study objective was to determine the relation between IAP and respiratory parameters, hemodynamic parameters, and early intestinal ischemia.

Methods: Twenty-five anesthetized and ventilated male Sprague-Dawley rats were randomly assigned to five groups exposed to IAPs of 0, 5, 10, 15, or 20 mm Hg for 3 hours. Respiratory parameters, hemodynamic parameters, and serum albumin-cobalt binding (ACB) capacity as measure for systemic ischemia were determined. Intestines were processed for histopathology.

Results: IAP was negatively associated with mean arterial pressure at 90 (Spearman correlation coefficient; Rs=-0.446, p=0.025) and 180 min (Rs=-0.466, p=0.019), oxygen saturation at 90 min (Rs=-0.673, p<0.001) and 180 min (Rs=-0.882, p<0.001), and pH value at 90 (Rs=-0.819, p<0.001) and 180 min (Rs=-0.934, p<0.001). There were no associations between IAP and lactate level or ACB capacity. No histological signs for intestinal ischemia were found.

Discussion: Although increasing IAP was associated with respiratory and hemodynamic difficulties, no signs for intestinal ischemia were found.

Level Of Evidence: Prognostic and epidemiologic study, level II.
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http://dx.doi.org/10.1136/tsaco-2020-000595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709516PMC
December 2020

Intestinal fatty acid binding protein as a predictor for intra-abdominal pressure-related complications in patients admitted to the intensive care unit; a prospective cohort study (I-Fabulous study).

J Crit Care 2021 Jun 10;63:211-217. Epub 2020 Sep 10.

Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Purpose: Critically ill patients are at risk for intra-abdominal hypertension (IAH) and related complications such as organ failure, abdominal compartment syndrome (ACS), and death. This study aimed to determine the value of urinary and serum intestinal fatty acid binding protein (I-FABP) levels as early marker for IAH-associated complications.

Methods: A prospective observational study was conducted in two academic institutional mixed medical-surgical ICUs in the Netherlands. Adult patients admitted to the ICU with two or more risk factors for IAH (198) were included. Urinary and serum I-FABP and intra-abdominal pressure (IAP) were measured every six hours during 72 h.

Results: Fifteen (8%) patients developed ACS and 74 (37%) developed new organ failure. I-FABP and IAP were positively correlated. Patients who developed ACS had higher median baseline levels of urinary I-FABP (235(P-P 85-1747)μg/g creat) than patients with IAH who did not develop ACS (87(P-P 33-246)μg/g, p = 0.037). With an odds ratio of 1.00, neither urinary nor serum I-FABP indicated increased risk for developing new organ failure or ACS.

Conclusions: A relevant diagnostic value of I-FABP levels for identifying individual patients at risk for intra-abdominal pressure related complications could not be demonstrated.
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http://dx.doi.org/10.1016/j.jcrc.2020.08.023DOI Listing
June 2021

Successful Reduction of Creatine Kinase and Myoglobin Levels in Severe Rhabdomyolysis Using Extracorporeal Blood Purification (CytoSorb®).

Blood Purif 2020 28;49(6):743-747. Epub 2020 Feb 28.

Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.

Rhabdomyolysis, if severe, can lead to acute kidney injury (AKI). Myoglobin is an iron and oxygen-binding protein that is freely filtered by the glomerulus. Precipitation of myoglobin in the nephrons' distal parts is responsible for tubular damage with AKI as a consequence. Extracorporeal clearance of myoglobin is conventionally attempted by the use of continuous renal replacement therapy (CRRT) with high cut-off dialysis membranes to limit the extent of the damage. We describe a case of a 56-year-old man with traumatic crush injury and a persistent source of muscle ischaemia unresponsive to high dose CRRT with EMiC-2 filter. Due to therapy failure, he was subsequently treated with the addition of a haemoadsorber (CytoSorb®) to the circuit. This reduced myoglobin and creatine kinase levels successfully despite ongoing tissue ischaemia. However, CytoSorb® was not enough to maintain microcirculatory perfusion, resulting in the eventual demise of the patient due to severity of the injury. Our report indicates that myoglobin was efficiently removed with CytoSorb® following exchange with the conventional high cut-off filter in continuous venovenous haemodialysis in severe traumatic rhabdomyolysis.
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http://dx.doi.org/10.1159/000505899DOI Listing
June 2021

Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study.

Clin Infect Dis 2019 04;68(9):1463-1471

Department of Medical Microbiology, Radboud University Medical Center.

Background: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking.

Methods: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated.

Results: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days.

Conclusions: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.
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http://dx.doi.org/10.1093/cid/ciy859DOI Listing
April 2019

Assessment of paravalvular leakage after transcatheter aortic valve implantation: add clinical signs to echocardiographic data.

Echo Res Pract 2017 Dec 11;4(4):I15-I16. Epub 2017 Sep 11.

Department of Intensive Care Medicine, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1530/ERP-17-0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633051PMC
December 2017

Effectiveness of insertion and maintenance bundles to prevent central-line-associated bloodstream infections in critically ill patients of all ages: a systematic review and meta-analysis.

Lancet Infect Dis 2016 Jun 18;16(6):724-734. Epub 2016 Feb 18.

Department of Paediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.

Background: Central-line-associated bloodstream infections (CLABSIs) are a major problem in intensive care units (ICUs) worldwide. We aimed to quantify the effectiveness of central-line bundles (insertion or maintenance or both) to prevent these infections.

Methods: We searched Embase, MEDLINE OvidSP, Web-of-Science, and Cochrane Library to identify studies reporting the implementation of central-line bundles in adult ICU, paediatric ICU (PICU), or neonatal ICU (NICU) patients. We searched for studies published between Jan 1, 1990, and June 30, 2015. For the meta-analysis, crude estimates of infections were pooled by use of a DerSimonian and Laird random effect model. The primary outcome was the number of CLABSIs per 1000 catheter-days before and after implementation. Incidence risk ratios (IRRs) were obtained by use of random-effects models.

Findings: We initially identified 4337 records, and after excluding duplicates and those ineligible, 96 studies met the eligibility criteria, 79 of which contained sufficient information for a meta-analysis. Median CLABSIs incidence were 5·7 per 1000 catheter-days (range 1·2-46·3; IQR 3·1-9·5) on adult ICUs; 5·9 per 1000 catheter-days (range 2·6-31·1; 4·8-9·4) on PICUs; and 8·4 per 1000 catheter-days (range 2·6-24·1; 3·7-16·0) on NICUs. After implementation of central-line bundles the CLABSI incidence ranged from 0 to 19·5 per 1000 catheter-days (median 2·6, IQR 1·2-4·4) in all types of ICUs. In our meta-analysis the incidence of infections decreased significantly from median 6·4 per 1000 catheter-days (IQR 3·8-10·9) to 2·5 per 1000 catheter-days (1·4-4·8) after implementation of bundles (IRR 0·44, 95% CI 0·39-0·50, p<0·0001; I(2)=89%).

Interpretation: Implementation of central-line bundles has the potential to reduce the incidence of CLABSIs.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(15)00409-0DOI Listing
June 2016

Intestinal fatty acid binding protein as a marker for intra-abdominal pressure-related complications in patients admitted to the intensive care unit; study protocol for a prospective cohort study (I-Fabulous study).

Scand J Trauma Resusc Emerg Med 2015 Jan 16;23. Epub 2015 Jan 16.

Background: Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) have detrimental effects on all organ systems and are associated with increased morbidity and mortality in critically ill patients admitted to an intensive care unit. Intra-bladder measurement of the intra-abdominal pressure (IAP) is currently the gold standard. However, IAH is not always indicative of intestinal ischemia, which is an early and rapidly developing complication. Sensitive biomarkers for intestinal ischemia are needed to be able to intervene before damage becomes irreversible. Gut wall integrity loss, including epithelial cell disruption and tight junctions breakdown, is an early event in intestinal damage. Intestinal Fatty Acid Binding Protein (I-FABP) is excreted in urine and blood specifically from damaged intestinal epithelial cells. Claudin-3 is a specific protein which is excreted in urine following disruption of intercellular tight junctions. This study aims to investigate if I-FABP and Claudin-3 can be used as a diagnostic tool for identifying patients at risk for IAP-related complications.

Methods/design: In a multicenter, prospective cohort study 200 adult patients admitted to the intensive care unit with at least two risk factors for IAH as defined by the World Society of the Abdominal Compartment Syndrome (WSACS) will be included. Patients in whom an intra-bladder IAP measurement is contra-indicated or impossible and patients with inflammatory bowel diseases that may affect I-FABP levels will be excluded. The IAP will be measured using an intra-bladder technique. During the subsequent 72 hours, the IAP measurement will be repeated every six hours. At these time points, a urine and serum sample will be collected for measurement of I-FABP and Claudin-3 levels. Clinical outcome of patients during their stay at the intensive care unit will be monitored using the Sequential Organ Failure Assessment (SOFA) score.

Discussion: Successful completion of this trial will provide evidence on the eventual role of the biomarkers I-FABP and Claudin-3 in predicting the risk of IAP-associated adverse outcome. This may aid early (surgical) intervention.

Trial Registration: The trial is registered at the Netherlands Trial Register (NTR4638).
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http://dx.doi.org/10.1186/s13049-015-0088-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324026PMC
January 2015

Immature granulocytes predict microbial infection and its adverse sequelae in the intensive care unit.

J Crit Care 2014 Aug 5;29(4):523-7. Epub 2014 Apr 5.

Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: We evaluated the predictive value of immature granulocyte (IG) percentage in comparison with white blood cell counts (WBC) and C-reactive protein (CRP), for infection, its invasiveness, and severity in critically ill patients.

Methods: In 46 consecutive patients, blood samples were collected at the day (0) of a clinical suspicion of microbial infection and at days 1 and 3 thereafter. We defined infections, bloodstream infection, and septic shock within 7 days after enrollment.

Results: Of the 46 patients, 31 patients had infection, 15 patients developed bloodstream infection, and 13 patients septic shock. C-reactive protein and IG percentage increased with increasing invasiveness and severity of infection, from day 0 onwards. Receiver operating characteristic analysis to predict infection showed an area under the curve of 0.66 (P=.10) for WBC vs 0.74 (P=.01) for CRP and 0.73 (P=.02) for IG percentage on day 0. Comparing WBC and CRP to WBC and IG percentage results in comparable prediction of microbial infection. Comparing WBC and CRP with WBC, CRP, and IG percentage suggests an additional early value of IG percentage, when not elevated, in ruling out infection.

Conclusion: Immature granulocyte percentage is a useful marker, as CRP, to predict infection, its invasiveness, and severity, in critically ill patients. However, the IG percentage adds to WBC and CRP in the early exclusion of infection and can be obtained routinely without extra blood sampling or costs.
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http://dx.doi.org/10.1016/j.jcrc.2014.03.033DOI Listing
August 2014

Routine use of the confusion assessment method for the intensive care unit: a multicenter study.

Am J Respir Crit Care Med 2011 Aug 11;184(3):340-4. Epub 2011 May 11.

Department of Intensive Care Medicine, University Medical Center Utrecht, The Netherlands.

Rationale: Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear.

Objectives: To investigate the diagnostic value of the CAM-ICU in daily practice.

Methods: Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each other's conclusions.

Measurements And Main Results: Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8).

Conclusions: Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.
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http://dx.doi.org/10.1164/rccm.201101-0065OCDOI Listing
August 2011

What to do when a competent ICU patient does not want to live anymore but is dependent on life-sustaining treatment? Experience from The Netherlands.

Intensive Care Med 2010 Dec 6;36(12):2145-8. Epub 2010 Aug 6.

Department of Intensive Care, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

If patients on the intensive care unit (ICU) are awake and life-sustaining treatment is suspended because of the patients' request, because of recovering from the disease, or because independence from organ function supportive or replacement therapy outside the ICU can no longer be achieved, these patients can suffer before they inevitably die. In The Netherlands, two scenarios are possible for these patients: (1) deep palliative (terminal) sedation through ongoing administration of barbiturates or benzodiazepines before withdrawal of treatment, or (2) deliberate termination of life (euthanasia) before termination of treatment. In this article we describe two awake patients who asked for withdrawal of life-sustaining measures, but who were dependent on mechanical ventilation. We discuss the doctrine of double effect in relation to palliative sedation on the ICU. Administration of sedatives and analgesics before withdrawal of treatment is seen as normal palliative care. We conclude that the doctrine of the double effect is not applicable in this situation, and mentioning it criminalised the practice unnecessarily and wrongfully.
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http://dx.doi.org/10.1007/s00134-010-1953-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981744PMC
December 2010

Noninvasive functional liver blood flow measurement: comparison between bolus dose and steady-state clearance of sorbitol in a small-rodent model.

Am J Physiol Gastrointest Liver Physiol 2010 Feb 25;298(2):G177-81. Epub 2009 Nov 25.

Department of Intensive Care, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Plasma clearance of D-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma D-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 +/- 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously (Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% D-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between (T(1/2,sorbitol) = 9 min), a crossover was done. The hepatic clearance of D-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) (r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance (r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF (r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of D-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.
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http://dx.doi.org/10.1152/ajpgi.90688.2008DOI Listing
February 2010

"Flatus profuse present in the muscles": subcutaneous emphysema of the lower abdominal wall and thighs, described in 1593 by fabricius hildanus.

Surg Infect (Larchmt) 2009 Aug;10(4):349-51

Department of Intensive Care, Erasmus MC University Medical Center Rotterdam, The Netherlands.

Background: Between 1598 and 1641, 600 medical and surgical observations made by the famous German surgeon Guilhelmius Fabricius Hildanus (1560-1634) were published in his Observationum et curationum chirurgicarum centuriae I-VI.

Methods: Review of the extant document for evidence of infection-related cases.

Results: One of the case reports, published as Observatio LXX in the fifth Centuria, bears the title (in translation) Of flatus, profuse present in the muscles. This case report probably is the earliest accurate description of subcutaneous emphysema of the lower abdomen and thighs secondary to a retroperitoneal abscess.

Conclusion: The presence of gas in the superficial tissues of the abdominal wall or thighs is a rare feature and can be a late sign of an otherwise-obscure intra-abdominal abscess with gas-producing bacteria. Fabricius Hildanus almost certainly was the first to document this rare feature in 1593, and judged it important enough to describe in his Centuriae.
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http://dx.doi.org/10.1089/sur.2008.075DOI Listing
August 2009

Prognostic value of blood lactate levels: does the clinical diagnosis at admission matter?

J Trauma 2009 Feb;66(2):377-85

Department of Intensive Care, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Hyperlactatemia and its reduction after admission in the intensive care unit (ICU) have been related to survival. Because it is unknown whether this equally applies to different groups of critically ill patients, we compared the prognostic value of repeated lactate levels (a) in septic patients versus patients with hemorrhage or other conditions generally associated with low-oxygen transport (LT) (b) in hemodynamically stable versus unstable patients.

Methods: In this prospective observational two-center study (n = 394 patients), blood lactate levels at admission to the ICU (Lac(T0)) and the reduction of lactate levels from T = 0 to T = 12 hours (DeltaLac(T0-12)) and from T = 12 to T = 24 hours (DeltaLac(T12-24)), were related to in-hospital mortality.

Results: Reduction of lactate was associated with a lower mortality only in the sepsis group (DeltaLac(T0-12): hazard ratio [HR] 0.34, p = 0.004 and DeltaLac(T12-24): HR 0.24, p = 0.003), but not in the LT group (DeltaLac(T0-12); HR 0.78, p = 0.52 and DeltaLac(T12-24); HR 1.30, p = 0.61). The prognostic values of Lac(T0), DeltaLac(T0-12), and DeltaLac(T12-24) were similar in hemodynamically stable and unstable patients (p = 0.43).

Conclusions: Regardless of the hemodynamic status, lactate reduction during the first 24 hours of ICU stay is associated with improved outcome only in septic patients, but not in patients with hemorrhage or other conditions generally associated with LT. We hypothesize that in this particular group a reduction in lactate is not associated with improved outcome due to irreversible damage at ICU admission.
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http://dx.doi.org/10.1097/TA.0b013e3181648e2fDOI Listing
February 2009

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis.

Clin Infect Dis 2006 May 12;42(10):1404-13. Epub 2006 Apr 12.

Charles University, Prague, Czech Republic.

Background: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species.

Methods: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10.

Results: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated.

Conclusions: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.
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http://dx.doi.org/10.1086/503428DOI Listing
May 2006

No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia.

Gynecol Obstet Invest 2006 27;62(1):7-13. Epub 2006 Feb 27.

Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Background/aims: Placental dysfunction of the asymmetric dimethylarginine (ADMA) degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) has been suggested as one of the initiating events in the development of preeclampsia (PE). Our primary aim was to investigate the role of the placenta in the metabolism of ADMA during normal pregnancy and PE.

Methods: We studied 27 nonpregnant healthy women (C), 15 normotensive pregnant females (P), 16 patients with PE, and 7 patients with the 'hemolysis, elevated liver enzymes and low platelets' syndrome (H).

Results: There were no significant differences between P and PE with respect to fetomaternal gradient of ADMA, placental DDAH activity and placental ADMA content. During the first stage of labour, mean (+/-SD) plasma ADMA (micromol/l) was higher in H (0.69 +/- 0.22; p < 0.05) compared with C (0.44 +/- 0.07), P (0.37 +/- 0.06), and PE (0.40 +/- 0.06). ADMA was significantly associated with laboratory parameters of hepatic and renal function and with clinical parameters, including systolic and diastolic blood pressure, gestational age, birth weight, and placenta weight.

Conclusions: A compensatory upregulation of placental DDAH activity is absent in patients suffering from PE and levels of ADMA in plasma and placenta are normal in patients suffering from PE. However, when the course of PE deteriorates and organ dysfunction (especially liver and kidney) becomes involved, such as during the hemolysis, elevated liver enzymes and low platelets syndrome, ADMA levels increase.
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http://dx.doi.org/10.1159/000091752DOI Listing
December 2006

Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy.

JPEN J Parenter Enteral Nutr 2004 Nov-Dec;28(6):382-7

Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the arginine-nitric oxide pathway. It is conceivable that its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver. In rats, we showed a high net hepatic uptake of ADMA. Therefore, we aimed to confirm the role of the liver in humans and hypothesized elevated ADMA levels after major liver resection by a reduction of functional liver mass and injury to the remnant liver.

Methods: Patients undergoing a major hepatic resection (HEP, n = 17) or major abdominal surgery (MAS, n = 12) were included and followed in time. In addition, ADMA levels were measured in 4 patients having severe hepatic failure after a liver resection. Plasma ADMA concentration was measured by high-performance liquid chromatography.

Results: Preoperatively and on days 1, 3, and 5, plasma levels of ADMA were higher in HEP patients when compared with MAS patients. In HEP patients with prolonged (>7 days) hepatic injury, ADMA levels were especially elevated. On the first postoperative day, ADMA significantly correlated to bilirubin concentration (r = .528, p < .05) as a marker of postoperative hepatic function. Besides, in patients with severe hepatic failure, ADMA levels were highly elevated.

Conclusions: In the present study, evidence was found for the role of the liver in the elimination of ADMA in humans. Increased levels of ADMA occur in the postoperative course after a major hepatic resection, especially when liver function is severely impaired. Further studies need to assess the role of ADMA in the development of complications after liver surgery.
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http://dx.doi.org/10.1177/0148607104028006382DOI Listing
April 2005

The transplanted liver graft is capable of clearing asymmetric dimethylarginine.

Liver Transpl 2004 Dec;10(12):1524-30

Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation. The aim of the present study was to investigate the role of the liver in the metabolism of ADMA in patients undergoing liver transplantation. In this prospective study, we investigated the course of ADMA concentrations in 42 patients undergoing liver transplantation and results showed that preoperative ADMA concentrations were higher in patients with acute (1.26 micromol/L, P < .001) and in patients with chronic (.69 micromol/L, P < .001) hepatic failure compared with healthy volunteers (.41 micromol/L). In addition, ADMA concentrations decreased from the preoperative day to the first postoperative day in both the acute (Delta(ADMA): -.63 micromol/L, P = .005) and the chronic hepatic failure group (Delta(ADMA): -0.15 micromol/L, P < .001). Furthermore, in patients who experienced acute rejection, ADMA concentrations were higher during the whole first postoperative month compared with nonrejectors (P = .012). Moreover, in 11 of 13 rejectors (85%) a clear increase in ADMA concentration preceded the onset of the first episode of rejection, which was confirmed by liver biopsy. In conclusion, our results indicate that the transplanted liver graft is quickly capable of clearing ADMA, suggesting preservation of DDAH. In addition, increased ADMA concentrations in the posttransplantation period reflect serious dysfunction of the liver graft during acute rejection.
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http://dx.doi.org/10.1002/lt.20286DOI Listing
December 2004

Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers.

Br J Clin Pharmacol 2002 Feb;53(2):133-9

Department of Pharmacy and Medical Intensive Care Unit, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, the Netherlands.

Aims: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics.

Methods: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam.

Results: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively.

Conclusions: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874292PMC
http://dx.doi.org/10.1046/j.0306-5251.2001.01182.xDOI Listing
February 2002