Publications by authors named "Jan G Zijlstra"

158 Publications

Comparison of renal histopathology and gene expression profiles between severe COVID-19 and bacterial sepsis in critically ill patients.

Crit Care 2021 06 10;25(1):202. Epub 2021 Jun 10.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.

Methods: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients.

Results: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19.

Conclusions: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.
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http://dx.doi.org/10.1186/s13054-021-03631-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190989PMC
June 2021

Plasma neutrophil gelatinase-associated lipocalin at intensive care unit admission as a predictor of acute kidney injury progression.

Clin Kidney J 2020 Dec 17;13(6):994-1002. Epub 2020 Feb 17.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Acute kidney injury (AKI) is a common complication in patients during intensive care unit (ICU) admission. AKI is defined as an increase in serum creatinine (SCr) and/or a reduction in urine output. SCr is a marker of renal function with several limitations, which led to the search for biomarkers for earlier AKI detection. Our aim was to study the predictive value of plasma neutrophil gelatinase-associated lipocalin (NGAL) at admission as a biomarker for AKI progression during the first 48 h of ICU admission in an unselected, heterogeneous ICU patient population.

Methods: We conducted a prospective observational study in an academic tertiary referral ICU population. We recorded AKI progression in all ICU patients during the first 48 h of ICU admission in a 6-week period. Plasma NGAL was measured at admission but levels were not reported to the attending clinicians. As possible predictors of AKI progression, pre-existing AKI risk factors were recorded. We examined the association of clinical parameters and plasma NGAL levels at ICU admission with the incidence and progression of AKI within the first 48 h of the ICU stay.

Results: A total of 361 patients were included. Patients without AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 115 ng/mL [interquartile range (IQR) 81-201]. Patients with AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 156 ng/mL (IQR 97-267). To predict AKI progression, a multivariant model with age, sex, diabetes mellitus, body mass index, admission type, Acute Physiology and Chronic Health Evaluation score and SCr at admission had an area under the receiver operating characteristics (ROC) curve of 0.765. Adding NGAL to this model showed a small increase in the area under the ROC curve to 0.783 (95% confidence interval 0.714-0.853).

Conclusions: NGAL levels at admission were higher in patients with progression of AKI during the first 48 h of ICU admission, but adding NGAL levels at admission to a model predicting this AKI progression showed no significant additive value.
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http://dx.doi.org/10.1093/ckj/sfaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769547PMC
December 2020

Acute Kidney Injury is Associated with Lowered Plasma-Free Thiol Levels.

Antioxidants (Basel) 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands.

Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH) are crucial components of the extracellular antioxidant machinery and reliably reflect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this preliminary study, we hypothesized that plasma-free thiols are associated with AKI upon admission to the intensive care unit (ICU). In this study, 301 critically ill patients were included. Plasma samples were taken upon admission, and albumin-adjusted plasma-free thiols were determined. Albumin-adjusted plasma-free thiols were lower in patients with AKI (n = 43, median (interquartile range) 7.28 µmol/g (3.52, 8.95)) compared to patients without AKI (8.50 μmol/g (5.82, 11.28); < 0.05) upon admission to the ICU. Higher age (B = -0.72), higher levels of neutrophil gelatinase-associated lipocalin (B = -0.002), creatinine (B = -0.01) and lower serum albumin (B = 0.47) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were significantly reduced in patients with sepsis (8.30 (5.52-10.64) µmol/g) compared to patients without sepsis (6.95 (3.72-8.92) µmol/g; < 0.05). Together, albumin-adjusted plasma-free thiols were significantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis.
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http://dx.doi.org/10.3390/antiox9111135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696918PMC
November 2020

Post-Mortem Diagnostics in COVID-19 AKI, More Often but Timely.

J Am Soc Nephrol 2021 01 5;32(1):255. Epub 2020 Nov 5.

Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1681/ASN.2020091263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894667PMC
January 2021

Intra-abdominal hypertension and abdominal compartment syndrome in patients admitted to the ICU.

Ann Intensive Care 2020 Oct 1;10(1):130. Epub 2020 Oct 1.

Department of Critical Care (BA 49), University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.

Background: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. Risk factors for intra-abdominal hypertension and abdominal compartment syndrome have been widely investigated. However, data are lacking on prevalence and outcome in high-risk patients. Our objectives in this study were to investigate prevalence and outcome of intra-abdominal hypertension and abdominal compartment syndrome in high-risk patients in a prospective, observational, single-center cohort study.

Results: Between March 2014 and March 2016, we included 503 patients, 307 males (61%) and 196 females (39%). Patients admitted to the intensive care unit with a diagnosis of pancreatitis, elective or emergency open abdominal aorta surgery, orthotopic liver transplantation, other elective or emergency major abdominal surgery and trauma were enrolled. One hundred and sixty four (33%) patients developed intra-abdominal hypertension and 18 (3.6%) patients developed abdominal compartment syndrome. Highest prevalence of abdominal compartment syndrome occurred in pancreatitis (57%) followed by orthotopic liver transplantation (7%) and abdominal aorta surgery (5%). Length of intensive care stay increased by a factor 4 in patients with intra-abdominal hypertension and a factor 9 in abdominal compartment syndrome, compared to patients with normal intra-abdominal pressure. Rate of renal replacement therapy was higher in abdominal compartment syndrome (38.9%) and intra-abdominal hypertension (8.2%) compared to patients with normal intra-abdominal pressure (1.2%). Both intensive care mortality and 90-day mortality were significantly higher in intra-abdominal hypertension (4.8% and 15.2%) and abdominal compartment syndrome (16.7% and 38.9%) compared to normal intra-abdominal pressure (1.2% and 7.1%). Body mass index (odds ratio 1.08, 95% confidence interval 1.03-1.13), mechanical ventilation at admission (OR 3.52, 95% CI 2.08-5.96) and Apache IV score (OR 1.03, 95% CI 1.02-1.04) were independent risk factors for the development of intra-abdominal hypertension or abdominal compartment syndrome.

Conclusions: The prevalence of abdominal compartment syndrome was 3.6% and the prevalence of intra-abdominal hypertension was 33% in this cohort of high-risk patients. Morbidity and mortality increased when intra-abdominal hypertension or abdominal compartment syndrome was present. The patient most at risk of IAH or ACS in this high-risk cohort has a BMI > 30 kg/m and was admitted to the ICU after emergency abdominal surgery or with a diagnosis of pancreatitis.
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http://dx.doi.org/10.1186/s13613-020-00746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530150PMC
October 2020

Bundled care in acute kidney injury in critically ill patients, a before-after educational intervention study.

BMC Nephrol 2020 09 3;21(1):381. Epub 2020 Sep 3.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Postbus 30.001, 9700, RB, Groningen, The Netherlands.

Background: Acute kidney injury (AKI) often occurs in critically ill patients. AKI is associated with mortality and morbidity. Interventions focusing on the reduction of AKI are suggested by the Kidney Disease: Improving Global Outcomes guideline. We hypothesized that these educational interventions would improve outcome in patients admitted to the Intensive Care Unit (ICU).

Methods: This was a pragmatic single-centre prospective observational before-after study design in an ICU in a tertiary referral hospital. All consecutive patients admitted to the ICU irrespective their illness were included. A 'Save the Kidney' (STK) bundle was encouraged via an educational intervention targeting health care providers. The educational STK bundle consisted of optimizing the fluid balance (based on urine output, serum lactate levels and/or central venous oxygen saturation), discontinuation of diuretics, maintaining a mean arterial pressure of at least 65 mmHg with the potential use of vasopressors and critical evaluation of the indication and dose of nephrotoxic drugs. The primary outcome was the composite of mortality, renal replacement therapy (RRT), and progression of AKI. Secondary outcomes were the components of the composite outcome the severity of AKI, ICU length of stay and in-hospital mortality.

Main Results: The primary outcome occurred in 451 patients (33%) in the STK group versus 375 patients (29%) in the usual care group, relative risk (RR) 1.16, 95% confidence interval (CI) 1.03-1.3, p < 0.001. Secondary outcomes were, ICU mortality in 6.8% versus 5.6%, (RR 1.22, 95% CI 0.90-1.64, p = 0.068), RRT in 1.6% versus 3.6% (RR 0.46, 95% CI 0.28-0.76, p = 0.002), and AKI progression in 28% versus 24% (RR 1.18, 95% CI 1.04-1.35, p = 0.001).

Conclusions: Providing education to uniformly apply an AKI care bundle, without measurement of the implementation in a non-selected ICU population, targeted at prevention of AKI progression was not beneficial.
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http://dx.doi.org/10.1186/s12882-020-02029-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469422PMC
September 2020

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for , , and , respectively. The final 2-compartment model included weight as a covariate on volume of distribution (). The mean of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant ( ) was 0.09 (SD, 0.04) h, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.
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http://dx.doi.org/10.1128/AAC.00905-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449215PMC
August 2020

AKI: an enlightening acronym with a shadow side.

Kidney Int 2020 06;97(6):1301

Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.kint.2020.03.016DOI Listing
June 2020

Heterogenous Renal Injury Biomarker Production Reveals Human Sepsis-Associated Acute Kidney Injury Subtypes.

Crit Care Explor 2019 Oct 14;1(10):e0047. Epub 2019 Oct 14.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

To identify mechanisms associated with sepsis-acute kidney injury based on the expression levels of renal injury biomarkers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 in renal biopsies which may allow the identification of sepsis-acute kidney injury patient subtypes.

Design: Prospective, clinical laboratory study using "warm" human postmortem sepsis-acute kidney injury kidney biopsies.

Setting: Research laboratory at university teaching hospital.

Subjects: Adult patients who died of sepsis in the ICU and control patients undergoing tumor nephrectomy.

Measurements And Main Results: Reverse transcription quantitative polymerase chain reaction and immunohistochemical staining were used to quantify messenger RNA and protein expression levels of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in the kidney of sepsis-acute kidney injury patients and control subjects. Morphometric analysis was used to quantify renal and glomerular neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels. Neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 messenger RNA and protein levels were increased in kidneys of sepsis-acute kidney injury patients compared with control kidney tissue. Neutrophil gelatinase-associated lipocalin was localized in the distal tubules, collecting ducts, the adventitia of the renal arterioles, and in the glomerular tufts of renal biopsies from sepsis-acute kidney injury patients. In contrast, kidney injury molecule-1 was localized at the brush border of the proximal tubules. There was no correlation between neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels. Furthermore, renal neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels were not associated with the extent of renal injury, the severity of critical illness, or serum creatinine levels at either ICU admission or day of expiration. By laser microdissecting glomeruli, followed by reverse transcription quantitative polymerase chain reaction, we identified heterogenous glomerular neutrophil gelatinase-associated lipocalin production in the kidney of sepsis-acute kidney injury patients.

Conclusion: We found differences in the expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in patients with the same syndrome "sepsis-acute kidney injury" meaning there is no single pathway leading to sepsis-acute kidney injury. This underscores the beliefs that there are many/different pathophysiological pathways that can cause sepsis-acute kidney injury. Hence, patients with criteria that meet the definitions of both acute kidney injury and sepsis can be divided into subtypes based on pathophysiological features.
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http://dx.doi.org/10.1097/CCE.0000000000000047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063889PMC
October 2019

Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations.

J Antimicrob Chemother 2020 02;75(2):441-448

University of Groningen, University Medical Center Groningen, Department of Critical Care, Groningen, The Netherlands.

Background: In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population.

Objectives: To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime.

Methods: Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207.

Results: Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission.

Conclusions: These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.
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http://dx.doi.org/10.1093/jac/dkz463DOI Listing
February 2020

Identifying Sepsis Phenotypes.

JAMA 2019 10;322(14):1416

Department of Critical Care, University Medical Center Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1001/jama.2019.12587DOI Listing
October 2019

Commentary: Precision Immunotherapy for Sepsis.

Front Immunol 2019;10:20. Epub 2019 Jan 31.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

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http://dx.doi.org/10.3389/fimmu.2019.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365442PMC
July 2019

Kidney histopathology in lethal human sepsis.

Crit Care 2018 12 27;22(1):359. Epub 2018 Dec 27.

Department of Critical Care, University of Groningen, University Medical Center Groningen, P.O. 30.001, Hanzeplein 1, 9700 RB, Groningen, Netherlands.

Purpose: The histopathology of sepsis-associated acute kidney injury (AKI) in critically ill patients remains an understudied area. Previous studies have identified that acute tubular necrosis (ATN) is not the only driver of sepsis-AKI. The focus of this study was to identify additional candidate processes that may drive sepsis-AKI. To do this we immunohistochemically characterized the histopathological and cellular features in various compartments of human septic kidneys.

Methods: We studied the following histopathological features: leukocyte subsets, fibroblast activation, cellular proliferation, apoptosis, and fibrin deposition in the glomerulus and the tubulointerstitium in human post-mortem kidney biopsy tissue. Biopsy tissue samples from 27 patients with sepsis-AKI were collected 33 min (range 24-150) after death in the ICU. The unaffected part of the kidneys from 12 patients undergoing total nephrectomy as a result of renal carcinoma served as controls.

Results: Immunohistochemical analysis revealed the presence of more neutrophils and macrophages in the glomeruli and more neutrophils in the tubulointerstitium of renal tissue from patients with sepsis compared to control renal tissue. Type II macrophages were predominant, with some macrophages expressing both type I and type II markers. In contrast, there were almost no macrophages found in control kidneys. The number of activated (myo)fibroblasts was low in the glomeruli of sepsis-AKI kidneys, yet this was not observed in the tubulointerstitium. Cell proliferation and fibrin deposition were more pronounced in the glomeruli and tubulointerstitium of sepsis-AKI than in control kidneys.

Conclusions: The extensive heterogeneity of observations among and within patients emphasizes the need to thoroughly characterize patients with sepsis-AKI in a large sample of renal biopsy tissue from patients with sepsis.
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http://dx.doi.org/10.1186/s13054-018-2287-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307291PMC
December 2018

Partial Deletion of Tie2 Affects Microvascular Endothelial Responses to Critical Illness in A Vascular Bed and Organ-Specific Way.

Shock 2019 06;51(6):757-769

Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Tyrosine kinase receptor (Tie2) is mainly expressed by endothelial cells. In animal models mimicking critical illness, Tie2 levels in organs are temporarily reduced. Functional consequences of these reduced Tie2 levels on microvascular endothelial behavior are unknown. We investigated the effect of partial deletion of Tie2 on the inflammatory status of endothelial cells in different organs. Newly generated heterozygous Tie2 knockout mice (exon 9 deletion, ΔE9/Tie2) exhibiting 50% reduction in Tie2 mRNA and protein, and wild-type littermate controls (Tie2), were subjected to hemorrhagic shock and resuscitation (HS + R), or challenged with i.p. lipopolysaccharide (LPS). Kidney, liver, lung, heart, brain, and intestine were analyzed for mRNA levels of adhesion molecules E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule 1 (ICAM-1), and CD45. Exposure to HS + R did not result in different expression responses of these molecules between organs from Tie2 or Tie2 mice and sham-operated mice. In contrast, the LPS-induced mRNA expression levels of E-selectin, VCAM-1, and ICAM-1, and CD45 in organs were attenuated in Tie2 mice when compared with Tie2 mice in kidney and liver, but not in the other organs studied. Furthermore, reduced expression of E-selectin and VCAM-1 protein, and reduced influx of CD45 cells upon LPS exposure, was visible in a microvascular bed-specific pattern in kidney and liver of Tie2 mice compared with controls. In contrast to the hypothesis that a disbalance in the Ang/Tie2 system leads to increased microvascular inflammation, heterozygous deletion of Tie2 is associated with an organ-restricted, microvascular bed-specific attenuation of endothelial inflammatory response to LPS.
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http://dx.doi.org/10.1097/SHK.0000000000001226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511431PMC
June 2019

Identifying improvement opportunities for patient- and family-centered care in the ICU: Using qualitative methods to understand family perspectives.

J Crit Care 2019 02 12;49:33-37. Epub 2018 Oct 12.

Department of Anaesthesiology and Intensive Care, Vejle and Middelfart Hospitals, Beriderbakken 4, 7100 Vejle, Denmark; Institute of Regional Health Research, University of Southern Denmark, J.B.Winsløwsvej 19, 5000 Odense, Denmark. Electronic address:

Purpose: The purposes of the study were to provide richer context for families' quantitative assessments of the quality of ICU care, and to describe further quality areas of importance for family members.

Materials And Methods: Free-text comments from 1077 family members of 920 patients focusing on family evaluation of ICU quality of care were analyzed using content analysis. Twenty-one Danish and Dutch ICUs participated from October 2014 to June 2015.

Results: Four themes emerged as important to families: information, clinician skills, ICU environment, and discharge from the ICU. Families highlighted the importance of receiving information that was accessible, understandable and honest. They indicated that quality care was ensured by having clinicians who were both technically and interpersonally competent. The ICU environment and the circumstances of the transfer out of the ICU were described as contributing to quality of care. The comments identified room for improvement within all themes.

Conclusions: The study highlights the importance of including both technical and emotional care for patients and families and the consequent need to focus on clinicians' mastery of interpersonal skills.
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http://dx.doi.org/10.1016/j.jcrc.2018.10.008DOI Listing
February 2019

Renal Klotho is Reduced in Septic Patients and Pretreatment With Recombinant Klotho Attenuates Organ Injury in Lipopolysaccharide-Challenged Mice.

Crit Care Med 2018 12;46(12):e1196-e1203

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: To determine the applicability of recombinant Klotho to prevent inflammation and organ injury in sepsis in man and mice.

Design: Prospective, clinical laboratory study using "warm" human postmortem sepsis-acute kidney injury biopsies. Laboratory study using a mouse model of endotoxemia.

Setting: Research laboratory at a university teaching hospital.

Subjects: Adult patients who died of sepsis in the ICU and control patients undergoing total nephrectomy secondary to renal cancer; male C57BL/6 and Klotho haploinsufficient mice.

Interventions: Lipopolysaccharide (0.05 mg/kg) injection and kill after 4, 8, and 24 hours. Mice received recombinant Klotho (0.05 mg/kg) 30 minutes prior to lipopolysaccharide (1 mg/kg) injection. Mice treated with saline were included as controls.

Measurements And Main Results: Quantitative reverse transcription polymerase chain reaction and immunohistochemical staining were used to quantify Klotho messenger RNA and protein expression in the kidney of sepsis-acute kidney injury patients and the kidney and brain of mice. The messenger RNA and protein expression of damage markers, inflammatory cytokine, chemokines, and endothelial adhesion molecules were also determined in mice. Renal neutrophil influx was quantified. We found significantly lower renal Klotho messenger RNA and protein levels in sepsis-acute kidney injury biopsies than in control subjects. These findings were recapitulated in the kidney and brain of lipopolysaccharide-challenged mice. Decreased Klotho expression paralleled an increase in kidney damage markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Administration of recombinant Klotho prior to lipopolysaccharide injection attenuated organ damage, inflammation and endothelial activation in the kidney and brain of mice. Furthermore, less neutrophils infiltrated into the kidneys of recombinant Klotho mice compared with lipopolysaccharide only treated mice.

Conclusions: Renal Klotho expression in human sepsis-acute kidney injury and in mouse models of sepsis was significantly decreased and correlated with renal damage. Recombinant Klotho intervention diminished organ damage, inflammation, and endothelial activation in the kidney and brain of lipopolysaccharide-challenged mice. Systemic Klotho replacement may potentially be an organ-protective therapy for septic patients to halt acute, inflammatory organ injury.
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http://dx.doi.org/10.1097/CCM.0000000000003427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250245PMC
December 2018

Invalid methods lead to inappropriate conclusions.

Int J Qual Health Care 2019 Feb;31(1):72

Department of Anesthesiology and Intensive Care, Hillerød Hospital, Aarhus University, Aarhus, Denmark.

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http://dx.doi.org/10.1093/intqhc/mzy165DOI Listing
February 2019

Molecular Regulation of Acute Tie2 Suppression in Sepsis.

Crit Care Med 2018 09;46(9):e928-e936

Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Objectives: Tie2 is a tyrosine kinase receptor expressed by endothelial cells that maintains vascular barrier function. We recently reported that diverse critical illnesses acutely decrease Tie2 expression and that experimental Tie2 reduction suffices to recapitulate cardinal features of the septic vasculature. Here we investigated molecular mechanisms driving Tie2 suppression in settings of critical illness.

Design: Laboratory and animal research, postmortem kidney biopsies from acute kidney injury patients and serum from septic shock patients.

Setting: Research laboratories and ICU of Hannover Medical School, Harvard Medical School, and University of Groningen.

Patients: Deceased septic acute kidney injury patients (n = 16) and controls (n = 12) and septic shock patients (n = 57) and controls (n = 22).

Interventions: Molecular biology assays (Western blot, quantitative polymerase chain reaction) + in vitro models of flow and transendothelial electrical resistance experiments in human umbilical vein endothelial cells; murine cecal ligation and puncture and lipopolysaccharide administration.

Measurements And Main Results: We observed rapid reduction of both Tie2 messenger RNA and protein in mice following cecal ligation and puncture. In cultured endothelial cells exposed to tumor necrosis factor-α, suppression of Tie2 protein was more severe than Tie2 messenger RNA, suggesting distinct regulatory mechanisms. Evidence of protein-level regulation was found in tumor necrosis factor-α-treated endothelial cells, septic mice, and septic humans, all three of which displayed elevation of the soluble N-terminal fragment of Tie2. The matrix metalloprotease 14 was both necessary and sufficient for N-terminal Tie2 shedding. Since clinical settings of Tie2 suppression are often characterized by shock, we next investigated the effects of laminar flow on Tie2 expression. Compared with absence of flow, laminar flow induced both Tie2 messenger RNA and the expression of GATA binding protein 3. Conversely, septic lungs exhibited reduced GATA binding protein 3, and knockdown of GATA binding protein 3 in flow-exposed endothelial cells reduced Tie2 messenger RNA. Postmortem tissue from septic patients showed a trend toward reduced GATA binding protein 3 expression that was associated with Tie2 messenger RNA levels (p < 0.005).

Conclusions: Tie2 suppression is a pivotal event in sepsis that may be regulated both by matrix metalloprotease 14-driven Tie2 protein cleavage and GATA binding protein 3-driven flow regulation of Tie2 transcript.
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http://dx.doi.org/10.1097/CCM.0000000000003269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095816PMC
September 2018

Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia.

PLoS One 2018 15;13(5):e0196976. Epub 2018 May 15.

Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis-induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-κB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953446PMC
July 2018

Early Heterogenic Response of Renal Microvasculature to Hemorrhagic Shock/Resuscitation and the Influence of NF-κB Pathway Blockade.

Shock 2019 02;51(2):200-212

Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Hemorrhagic shock (HS) is associated with low blood pressure due to excessive loss of circulating blood and causes both macrocirculatory and microcirculatory dysfunction. Fluid resuscitation after HS is used in the clinic to restore tissue perfusion. The persistent microcirculatory damage caused by HS and/or resuscitation can result in multiple organ damage, with the kidney being one of the involved organs. The kidney microvasculature consists of different segments that possess a remarkable heterogeneity in functional properties. The aim of this study was to investigate the inflammatory responses of these different renal microvascular segments, i.e., arterioles, glomeruli, and postcapillary venules, to HS and resuscitation (HS/R) in mice and to explore the effects of intervention with a nuclear factor-kappa B (NF-κB) inhibitor on these responses. We found that HS/R disturbed the balance of the angiopoietin-Tie2 ligand-receptor system, especially in the glomeruli. Furthermore, endothelial adhesion molecules, proinflammatory cytokines, and chemokines were markedly upregulated by HS/R, with the strongest responses occurring in the glomerular and postcapillary venous segments. Blockade of NF-κB signaling during the resuscitation period only slightly inhibited HS/R-induced inflammatory activation, possibly because NF-κB p65 nuclear translocation already occurred during the HS period. In summary, although all three renal microvascular segments were activated upon HS/R, responses of endothelial cells in glomeruli and postcapillary venules to HS/R, as well as to NF-κB inhibition were stronger than those in arterioles. NF-κB inhibition during the resuscitation phase does not effectively counteract NF-κB p65 nuclear translocation initiating inflammatory gene transcription.
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http://dx.doi.org/10.1097/SHK.0000000000001126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319598PMC
February 2019

Quality of dying and death in the ICU. The euroQ2 project.

J Crit Care 2018 04 26;44:376-382. Epub 2017 Dec 26.

Department of Intensive Care, 9713 GZ Groningen, University Medical Center, University of Groningen, The Netherlands. Electronic address:

Purpose: Knowledge of families' perspective of quality of intensive care unit (ICU) care is important, especially with regard to end-of-life (EOL) care. Adaptation of the US-developed "Quality of dying and death questionnaire" (QODD) to a European setting is lacking. The primary aim of this study is to examine the euroQODD's usability and its assessments of EOL care in a cohort of Danish and Dutch family members.

Methods: Family members of patients dying in an ICU after a stay of at least 48h were sent the euroQODD three weeks after the patient died. Selected patient characteristics were obtained from hospital records. A total of 11 Danish and 10 Dutch ICU's participated.

Results: 217 family members completed the euroQODD part of the euroQ2 questionnaire. Overall rating of care was high, a median of 9 in Netherlands and 10 in Denmark on a 0-10 scale (p<0.001). The Danish were more likely to report adequate pain control all or most of the time (95% vs 73%; p<0.001). When decisions were made to limit treatment, the majority of family members agreed (93%). Most (92%) reported some participation in the decision-making, with half (50%) making the decision jointly with the doctor. About 18% would have preferred greater involvement. Factor analysis identified a six-indicator unidimensional quality of dying and death construct with between-country measurement invariance. However, in its current form the euroQODD instrument requires modeling the six items as reflective (or effect) indicators, when they are more accurately conceived as causal indicators.

Conclusions: The majority of family members were satisfied with the quality of EOL care and quality of dying and death. They agreed with decisions made to limit treatment and most felt they had participated to some extent in decision-making, although some would have preferred greater participation. Addition of items that can be accurately treated as effect indicators will improve the instrument's usefulness in measuring the overall quality of dying and death.
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http://dx.doi.org/10.1016/j.jcrc.2017.12.015DOI Listing
April 2018

Satisfaction with quality of ICU care for patients and families: the euroQ2 project.

Crit Care 2017 09 7;21(1):239. Epub 2017 Sep 7.

Department of Anaesthesiology and Intensive Care, Vejle and Middelfart Hospitals, Beriderbakken 4, 7100, Vejle, Denmark.

Background: Families' perspectives are of great importance in evaluating quality of care in the intensive care unit (ICU). This Danish-Dutch study tested a European adaptation of the "Family Satisfaction in the ICU" (euroFS-ICU). The aim of the study was to examine assessments of satisfaction with care in a large cohort of Danish and Dutch family members and to examine the measurement characteristics of the euroFS-ICU.

Methods: Data were from 11 Danish and 10 Dutch ICUs and included family members of patients admitted to the ICU for 48 hours or more. Surveys were mailed 3 weeks after patient discharge from the ICU. Selected patient characteristics were retrieved from hospital records.

Results: A total of 1077 family members of 920 ICU patients participated. The response rate among family members who were approached was 72%. "Excellent" or "Very good" ratings on all items ranged from 58% to 96%. Items with the highest ratings were concern toward patients, ICU atmosphere, opportunities to be present at the bedside, and ease of getting information. Items with room for improvement were management of patient agitation, emotional support of the family, consistency of information, and inclusion in and support during decision-making processes. Exploratory factor analysis suggested four underlying factors, but confirmatory factor analysis failed to yield a multi-factor model with between-country measurement invariance. A hypothesis that this failure was due to misspecification of causal indicators as reflective indicators was supported by analysis of a factor representing satisfaction with communication, measured with a combination of causal and reflective indicators.

Conclusions: Most family members were moderately or very satisfied with patient care, family care, information and decision-making, but areas with room for improvement were also identified. Psychometric assessments suggest that composite scores constructed from these items as representations of either overall satisfaction or satisfaction with specific sub-domains do not meet rigorous measurement standards. The euroFS-ICU and other similar instruments may benefit from adding reflective indicators.
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http://dx.doi.org/10.1186/s13054-017-1826-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590143PMC
September 2017

Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB.

J Innate Immun 2017 29;9(6):546-560. Epub 2017 Jun 29.

Medical Biology Section, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-α-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF-1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFκB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFκB.
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http://dx.doi.org/10.1159/000477211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738826PMC
July 2018

There Are More Things in Heaven and Earth, Horatio, Than Are Dreamt of in Our Philosophy.

Crit Care Med 2017 07;45(7):e740

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1097/CCM.0000000000002426DOI Listing
July 2017

Target attainment with continuous dosing of piperacillin/tazobactam in critical illness: a prospective observational study.

Int J Antimicrob Agents 2017 Jul 10;50(1):68-73. Epub 2017 May 10.

Department of Critical Care, University Medical Center Groningen, Groningen, The Netherlands.

Optimal dosing of β-lactam antibiotics in critically ill patients is a challenge given the unpredictable pharmacokinetic profile of this patient population. Several studies have shown intermittent dosing to often yield inadequate drug concentrations. Continuous dosing is an attractive alternative from a pharmacodynamic point of view. This study evaluated whether, during continuous dosing, piperacillin concentrations reached and maintained a pre-defined target in critically ill patients. Adult patients treated with piperacillin by continuous dosing in the intensive care unit of a university medical centre in The Netherlands were prospectively studied. Total and unbound piperacillin concentrations drawn at fixed time points throughout the entire treatment course were determined by liquid chromatography-tandem mass spectrometry. A pharmacokinetic combined target of a piperacillin concentration ≥80 mg/L, reached within 1 h of starting study treatment and maintained throughout the treatment course, was set. Eighteen patients were analysed. The median duration of monitored piperacillin treatment was 60 h (interquartile range, 33-96 h). Of the 18 patients, 5 (27.8%) reached the combined target; 15 (83.3%) reached and maintained a less strict target of >16 mg/L. In this patient cohort, this dosing schedule was insufficient to reach the pre-defined target. Depending on which target is to be met, a larger initial cumulative dose is desirable, combined with therapeutic drug monitoring.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.02.020DOI Listing
July 2017

Naming and Blaming, SIRS-UO.

Chest 2017 03;151(3):723-724

Department of Critical Care, University of Groningen, Groningen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2016.10.062DOI Listing
March 2017

Organ-Specific Differences in Endothelial Permeability-Regulating Molecular Responses in Mouse and Human Sepsis.

Shock 2017 07;48(1):69-77

*Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands †Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands ‡Department of Anaesthesiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

In patients with sepsis-induced multi-organ dysfunction syndrome, diverging patterns of oedema formation and loss of function in organs such as lung and kidney suggest that endothelial permeability-regulating molecular responses are differentially regulated. This potential differential regulation has been insufficiently studied at the level of components of adherens and tight junctions. We hypothesized that such a regulation by endothelial cells in sepsis takes place in an organ-specific manner. We addressed our hypothesis by studying by quantitative real time polymerase chain reaction the expression of a predefined subset of EC permeability-related molecules (occludin, claudin-5, PV-1, CD-31, endomucin, Angiopoietin-1, Angiopoietin-2, Tie2, VEGFA, VEGFR1, VEGFR2, and VE-cadherin) in kidney and lung after systemic lipopolysacharide injection in mice, and in kidneys of patients who died of sepsis. We showed that baseline endothelial expression of permeability-related molecules differs in mouse kidney and lung. Moreover, we showed differential regulation of these molecules after lipopolysacharide injection in the two mouse organs. In lung we found a decrease in expression levels of molecules of the adherence and tight junctions complex and related signaling systems, compatible with increased permeability. In contrast, in kidney we found expression patterns of these molecules compatible with decreased permeability. Finally, we partially corroborated our findings in mouse kidney in human kidneys from septic patients. These findings may help to understand the clinical difference in the extent of oedema formation in kidney and lung in sepsis-associated organ failure.
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http://dx.doi.org/10.1097/SHK.0000000000000841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457831PMC
July 2017

Bioavailability of voriconazole in hospitalised patients.

Int J Antimicrob Agents 2017 Feb 23;49(2):243-246. Epub 2016 Nov 23.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address:

An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90% in healthy volunteers, making this drug a suitable candidate for such a transition. Recently, two studies have shown that the bioavailability of voriconazole is substantially lower in patients. However, for both studies various factors that could influence the voriconazole serum concentration, such as inflammation, concomitant intake of food with oral voriconazole, and gastrointestinal complications, were not included in the evaluation. Therefore, in this study a retrospective chart review was performed in adult patients treated with both oral and i.v. voriconazole at the same dose and within a limited (≤5 days) time interval in order to evaluate the effect of switching the route of administration on voriconazole serum concentrations. A total of 13 patients were included. The mean voriconazole trough concentration was 2.28 mg/L [95% confidence interval (CI) 1.29-3.26 mg/L] for i.v. voriconazole administration and 2.04 mg/L (95% CI 0.78-3.30 mg/L) for oral administration. No significant difference was found in the mean oral and i.v. trough concentrations of voriconazole (P = 0.390). The mean bioavailability was 83.0% (95% CI 59.0-107.0%). These findings suggest that factors other than bioavailability may cause the observed difference in voriconazole trough concentrations between oral and i.v. administration in the earlier studies and stress the need for an antimicrobial stewardship team to guide voriconazole dosing.
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http://dx.doi.org/10.1016/j.ijantimicag.2016.10.010DOI Listing
February 2017

Low Caspofungin Exposure in Patients in Intensive Care Units.

Antimicrob Agents Chemother 2017 02 24;61(2). Epub 2017 Jan 24.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., <79 mg · h/liter, a ≥20% lower AUC), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC (<79 mg · h/liter) was seen in 10 patients. The AUC was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.).
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http://dx.doi.org/10.1128/AAC.01582-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278683PMC
February 2017

Interhospital critical care transports: have a safe trip!

Intensive Care Med 2016 Nov 12;42(11):1836. Epub 2016 Sep 12.

Universitair Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1007/s00134-016-4499-9DOI Listing
November 2016
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