Publications by authors named "Stefan Kluge"

237 Publications

Liver transplantation for acute-on-chronic liver failure predicts post-transplant mortality and impaired long-term quality of life.

Liver Int 2021 Mar 19;41(3):574-584. Epub 2020 Dec 19.

Department of Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Among patients with cirrhosis, candidate selection and timing of liver transplantation (LT) remain problematic. Acute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis with excessive short-term mortality rates under conservative therapeutic measures. The role of LT in the management of ACLF is uncertain.

Objective: To assess the impact of ACLF on post-LT survival and long-term graft function, morbidity and quality of life (QoL).

Methods: We retrospectively analysed all cirrhosis patients undergoing LT at our institution between 01/2009 and 12/2014. Median follow-up was 8.7 years. Long-term LT survivors were interviewed with established QoL questionnaires.

Results: Of 250 LT recipients, 98 fulfilled the EASL diagnostic ACLF criteria before LT ('ACLF-LT'). ACLF associated with reduced post-LT survival (HR for 6-month survival compared to non-ACLF-LT: 0.18; HR for 10-year-survival: 0.47; both P < .001) depending on ACLF severity before LT, and mainly inferred by infections both in the early and late phases after LT. In ACLF patients, CLIFc-OFs was superior to MELD score in predicting post-LT mortality. Long-term follow-up revealed comparable graft functions and comorbidity burden in ACLF-LT and non-ACLF-LT survivors. ACLF-LT patients reported significantly impaired health and QoL, particularly with regards to anxiety/depression and physical and psychological health (all P < .05). LabMELD score, presence of ACLF at LT and duration of post-LT intensive care associated with poor long-term QoL.

Conclusion: ACLF predicts impaired post-LT survival. While long-term graft function and extrahepatic comorbidities are comparable in ACLF and non-ACLF LT survivors, the strikingly low QoL in many ACLF-LT recipients warrants consideration during follow-up patient care.
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http://dx.doi.org/10.1111/liv.14756DOI Listing
March 2021

[German S3 Guideline - Oxygen Therapy in the Acute Care of Adult Patients].

Pneumologie 2021 Sep 2. Epub 2021 Sep 2.

Krankenhaus Siloah, Klinik für Pneumologie und Beatmungsmedizin, Klinikum Region Hannover.

Background:  Oxygen (O) is a drug with specific biochemical and physiologic properties, a range of effective doses and may have side effects. In 2015, 14 % of over 55 000 hospital patients in the UK were using oxygen. 42 % of patients received this supplemental oxygen without a valid prescription. Healthcare professionals are frequently uncertain about the relevance of hypoxemia and have low awareness about the risks of hyperoxemia. Numerous randomized controlled trials about targets of oxygen therapy have been published in recent years. A national guideline is urgently needed.

Methods:  A S3-guideline was developed and published within the Program for National Disease Management Guidelines (AWMF) with participation of 10 medical associations. Literature search was performed until Feb 1st 2021 to answer 10 key questions. The Oxford Centre for Evidence-Based Medicine (CEBM) System ("The Oxford 2011 Levels of Evidence") was used to classify types of studies in terms of validity. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used and for assessing the quality of evidence and for grading guideline recommendation and a formal consensus-building process was performed.

Results:  The guideline includes 34 evidence-based recommendations about indications, prescription, monitoring and discontinuation of oxygen therapy in acute care. The main indication for O therapy is hypoxemia. In acute care both hypoxemia and hyperoxemia should be avoided. Hyperoxemia also seems to be associated with increased mortality, especially in patients with hypercapnia. The guideline provides recommended target oxygen saturation for acute medicine without differentiating between diagnoses. Target ranges for oxygen saturation are depending on ventilation status risk for hypercapnia. The guideline provides an overview of available oxygen delivery systems and includes recommendations for their selection based on patient safety and comfort.

Conclusion:  This is the first national guideline on the use of oxygen in acute care. It addresses healthcare professionals using oxygen in acute out-of-hospital and in-hospital settings. The guideline will be valid for 3 years until June 30, 2024.
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http://dx.doi.org/10.1055/a-1554-2625DOI Listing
September 2021

High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study.

Emerg Microbes Infect 2021 Dec;10(1):1807-1818

Department for Viral Zoonoses-One Health, Leibniz Institute for Experimental Virology, Hamburg, Germany.

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients ( = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU ( = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort ( = 39) and healthy individuals ( = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.
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http://dx.doi.org/10.1080/22221751.2021.1969869DOI Listing
December 2021

[Acute intoxications in the intensive care unit: A 10-year analysis].

Med Klin Intensivmed Notfmed 2021 Jul 23. Epub 2021 Jul 23.

Klinik für Intensivmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland.

Background: Acute intoxications play a special role in preclinical emergency medicine, in the emergency department, and in intensive care. This study characterizes cases of acute intoxications from an intensive care perspective.

Objectives: All cases of acute intoxications admitted to the intensive care units at the University Hospital Hamburg-Eppendorf between 01 January 2007 and 30 June 2017 were retrospectively analyzed.

Results: During the study period, 587 patients with acute intoxications were admitted to the university hospital's intensive care units. Median age was 45 years (interquartile range [IQR] 31 years); 83.1% of patients were younger than 70 years. The most common cause of intoxication in the younger patients was a suicide attempt (55.1%), while in older patients it was an iatrogenic event (47.5%). Cases involving intoxications with psychotropic medication (48.7%), alcohol (32.9%), analgesics (23.3%), and drugs (17.0%) were most frequent. In 50.6% of cases, intoxication was due to more than one substance. Intoxication-specific therapy was performed in 40.0% of cases and intensive care therapy in 42.4% of cases. The median length of intensive care unit stay was 2 days (IQR 3). Hospital mortality was 5.5%. In older patients (≥ 70 years) compared with younger patients, the need for intensive care treatment (56.6% vs. 39.5% of cases, p = 0.002), the length of intensive care unit stay (3 days [IQR 5] vs. 2 days [IQR 3], p = 0.0004) and in-hospital mortality (17.2% vs. 3.1%, p < 0.001) were significantly higher.

Conclusions: Acute intoxications are part of the spectrum of disorders treated in the intensive care unit. In older patients, iatrogenic causes are frequently found, which is associated with an increased risk of death.
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http://dx.doi.org/10.1007/s00063-021-00839-8DOI Listing
July 2021

Validation of a Prospective Urinalysis-Based Prediction Model for ICU Resources and Outcome of COVID-19 Disease: A Multicenter Cohort Study.

J Clin Med 2021 Jul 9;10(14). Epub 2021 Jul 9.

Emergency Department, University Medical Center Göttingen, 37075 Göttingen, Germany.

In COVID-19, guidelines recommend a urinalysis on hospital admission as SARS-CoV-2 renal tropism, post-mortem, was associated with disease severity and mortality. Following the hypothesis from our pilot study, we now validate an algorithm harnessing urinalysis to predict the outcome and the need for ICU resources on admission to hospital. Patients were screened for urinalysis, serum albumin (SA) and antithrombin III activity (AT-III) obtained prospectively on admission. The risk for an unfavorable course was categorized as (1) "low", (2) "intermediate" or (3) "high", depending on (1) normal urinalysis, (2) abnormal urinalysis with SA ≥ 2 g/dL and AT-III ≥ 70%, or (3) abnormal urinalysis with SA or AT-III abnormality. Time to ICU admission or death served as the primary endpoint. Among 223 screened patients, 145 were eligible for enrollment, 43 falling into the low, 84 intermediate, and 18 into high-risk categories. An abnormal urinalysis significantly elevated the risk for ICU admission or death (63.7% vs. 27.9%; HR 2.6; 95%-CI 1.4 to 4.9; = 0.0020) and was 100% in the high-risk group. Having an abnormal urinalysis was associated with mortality, a need for mechanical ventilation, extra-corporeal membrane oxygenation or renal replacement therapy. In conclusion, our data confirm that COVID-19-associated urine abnormalities on admission predict disease aggravation and the need for ICU (ClinicalTrials.gov number NCT04347824).
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http://dx.doi.org/10.3390/jcm10143049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306631PMC
July 2021

In Reply.

Authors:
Stefan Kluge

Dtsch Arztebl Int 2021 06;118(22):376-377

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http://dx.doi.org/10.3238/arztebl.m2021.0181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372771PMC
June 2021

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

Infection 2021 Jul 6. Epub 2021 Jul 6.

Department of Intensive Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19.

Methods: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation.

Results: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D should not be used in COVID-19 routine care.

Conclusion: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.
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http://dx.doi.org/10.1007/s15010-021-01645-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259552PMC
July 2021

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19.

iScience 2021 Jul 19;24(7):102752. Epub 2021 Jun 19.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical VID-19 everiy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients.
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http://dx.doi.org/10.1016/j.isci.2021.102752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213514PMC
July 2021

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

Eur J Heart Fail 2021 Jun 17. Epub 2021 Jun 17.

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Aims: Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials.

Methods And Results: Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility.

Conclusion: The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.
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http://dx.doi.org/10.1002/ejhf.2274DOI Listing
June 2021

Pharmacokinetics of meropenem during advanced organ support (ADVOS) and continuous renal replacement therapy.

Int J Artif Organs 2021 Oct 18;44(10):783-786. Epub 2021 Jun 18.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The advanced organ support (ADVOS) system allows to eliminate water-soluble as well as protein-bound molecules. Despite its clinical features, to date nothing is known about the elimination of clinically relevant drugs such as antiinfectives. Therefore, we report a case treated with ADVOS, continuous renal replacement therapy (CRRT), and meropenem (1 g 8-hourly) for empiric sepsis therapy monitored by meropenem drug levels. ADVOS showed more efficient elimination of meropenem compared to CRRT which has to be considered when evaluating dosing regimens.
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http://dx.doi.org/10.1177/03913988211021101DOI Listing
October 2021

Are muscle parameters obtained by computed tomography associated with outcome after esophagectomy for cancer?

Clin Nutr 2021 06 1;40(6):3729-3740. Epub 2021 May 1.

Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background & Aims: Esophageal cancer patients often suffer from cancer-related malnutrition and, as a result, sarcopenia. Whether sarcopenia worsens the outcome after esophagectomy is unclear. Inconsistent study results are partly caused by varying cut-off values used for defining sarcopenia. To overcome this challenge, a new statistical approach is proposed in this study: analyzing the linear association of computer tomography derived muscle parameters with important clinical short- and long-term outcomes post esophagectomy, regardless of cut-offs.

Methods: Skeletal muscle index (SMI), quantifying muscle mass, was assessed with computed tomography (CT) in 98 patients undergoing esophagectomy. Muscle radiation attenuation (MRA) was measured to evaluate muscle quality. To evaluate the influence of the SMI and MRA on post-surgery complications, logistic regression models were used. To analyze the relationship of lengths of stay to muscle parameters, the competing risk approach introduced by Fine and Gray was applied. For survival analysis, log-rank test and Cox proportional hazards regression modeling were used.

Results: Neither a relevant association of SMI nor MRA with pneumonia and esophagoenteric leak were observed. Furthermore, no relevant association to lengths of stay in intensive care or hospital were detected. If the SMI increased, the odds for pleural effusion and pleural empyema decreased, but the odds of a pulmonary embolism increased. Univariate, unadjusted long-term survival analysis revealed that lower MRA and lower SMI were associated with shorter survival (P = 0.03). However, if the analysis was adjusted for confounders, e.g., Charlson Comorbidity Index, no relevant association regarding long-term survival was detected.

Conclusion: Consequently, poor muscle status, determined by CT imaging, does not justify denying a patient an oncologic resection. The Charlson Comorbidity Index, however, was superior for preoperative risk stratification.
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http://dx.doi.org/10.1016/j.clnu.2021.04.040DOI Listing
June 2021

Urinary Levels of SARS-CoV-2 Nucleocapsid Protein Associate With Risk of AKI and COVID-19 Severity: A Single-Center Observational Study.

Front Med (Lausanne) 2021 25;8:644715. Epub 2021 May 25.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Acute kidney injury (AKI) is very common in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) and considered as a risk factor for COVID-19 severity. SARS-CoV-2 renal tropism has been observed in COVID-19 patients, suggesting that direct viral injury of the kidneys may contribute to AKI. We examined 20 adult cases with confirmed SARS-CoV-2 infection requiring ICU supportive care in a single-center prospective observational study and investigated whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19. The objective of the study was to evaluate whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19. Urinary SARS-CoV-2 N measured at ICU admission identified patients at risk for AKI in COVID-19 (HR 5.9, 95% CI 1.4-26, = ). In addition, the combination of urinary SARS-CoV-2 N and plasma albumin measurements further improved the association with AKI (HR 11.4, 95% CI 2.7-48, = ). Finally, combining urinary SARS-CoV-2 N and plasma albumin measurements associated with the length of ICU supportive care (HR 3.3, 95% CI 1.1-9.9, = ) and premature death (HR 7.6, 95% CI 1.3-44, = ). In contrast, urinary ACE2 and TMPRSS2 did not correlate with AKI in COVID-19. In conclusion, urinary SARS-CoV-2 N levels associate with risk for AKI and correlate with COVID-19 severity.
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http://dx.doi.org/10.3389/fmed.2021.644715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185060PMC
May 2021

Patient Characteristics and Clinical Course of COVID-19 Patients Treated at a German Tertiary Center during the First and Second Waves in the Year 2020.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

In this study, we directly compared coronavirus disease 2019 (COVID-19) patients hospitalized during the first (27 February-28 July 2020) and second (29 July-31 December 2020) wave of the pandemic at a large tertiary center in northern Germany. Patients who presented during the first ( = 174) and second ( = 331) wave did not differ in age (median [IQR], 59 years [46, 71] vs. 58 years [42, 73]; = 0.82) or age-adjusted Charlson Comorbidity Index (median [IQR], 2 [1, 4] vs. 2 [0, 4]; = 0.50). During the second wave, a higher proportion of patients were treated as outpatients (11% [ = 20] vs. 20% [ = 67]), fewer patients were admitted to the intensive care unit (43% [ = 75] vs. 29% [ = 96]), and duration of hospitalization was significantly shorter (median days [IQR], 14 [8, 34] vs. 11 [5, 19]; < 0.001). However, in-hospital mortality was high throughout the pandemic and did not differ between the two periods (16% [ = 27] vs. 16% [ = 54]; = 0.89). While novel treatment strategies and increased knowledge about the clinical management of COVID-19 may have resulted in a less severe disease course in some patients, in-hospital mortality remained unaltered at a high level. These findings highlight the unabated need for efforts to hamper severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission, to increase vaccination coverage, and to develop novel treatment strategies to prevent mortality and decrease morbidity.
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http://dx.doi.org/10.3390/jcm10112274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197386PMC
May 2021

Cefiderocol in Critically Ill Patients with Multi-Drug Resistant Pathogens: Real-Life Data on Pharmacokinetics and Microbiological Surveillance.

Antibiotics (Basel) 2021 May 28;10(6). Epub 2021 May 28.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Cefiderocol is a new siderophore-cephalosporin for the treatment of multi-drug resistant Gram-negative pathogens. As a reserve agent, it will and should be used primarily in critically ill patients in the upcoming years. Due to the novelty of the substance little data on the pharmacokinetics in critically ill patients with septic shock and renal failure (including continuous renal replacement therapy and cytokine adsorber therapy) is available. We performed therapeutic drug monitoring in a cohort of five patients treated with cefiderocol, to improve the knowledge on pharmacokinetics in this vulnerable patient population. As expected for a cephalosporin with predominantly renal elimination the maintenance dose could be reduced in patients with renal impairment or on continuous renal replacement therapy. The manufacturer's dosing instructions were sufficient to achieve a drug level well above the MIC. However, the addition of a cytokine adsorber might reduce serum levels substantially, so that in this context therapeutic drug monitoring and dose adjustment are recommended.
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http://dx.doi.org/10.3390/antibiotics10060649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226704PMC
May 2021

Characteristics and Risk Factors for Intensive Care Unit Cardiac Arrest in Critically Ill Patients with COVID-19-A Retrospective Study.

J Clin Med 2021 May 19;10(10). Epub 2021 May 19.

Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) led to an ongoing pandemic with a surge of critically ill patients. Very little is known about the occurrence and characteristic of cardiac arrest in critically ill patients with COVID-19 treated at the intensive care unit (ICU). The aim was to investigate the incidence and outcome of intensive care unit cardiac arrest (ICU-CA) in critically ill patients with COVID-19. This was a retrospective analysis of prospectively recorded data of all consecutive adult patients with COVID-19 admitted (27 February 2020-14 January 2021) at the University Medical Centre Hamburg-Eppendorf (Germany). Of 183 critically ill patients with COVID-19, 18% ( = 33) had ICU-CA. The median age of the study population was 63 (55-73) years and 66% ( = 120) were male. Demographic characteristics and comorbidities did not differ significantly between patients with and without ICU-CA. Simplified Acute Physiological Score II (SAPS II) (ICU-CA: median 44 points vs. no ICU-CA: 39 points) and Sequential Organ Failure Assessment (SOFA) score (median 12 points vs. 7 points) on admission were significantly higher in patients with ICU-CA. Acute respiratory distress syndrome (ARDS) was present in 91% ( = 30) with and in 63% ( = 94) without ICU-CA ( = 0.002). Mechanical ventilation was more common in patients with ICU-CA (97% vs. 67%). The median stay in ICU before CA was 6 (1-17) days. A total of 33% ( = 11) of ICU-CAs occurred during the first 24 h of ICU stay. The initial rhythm was non-shockable (pulseless electrical activity (PEA)/asystole) in 91% ( = 30); 94% ( = 31) had sustained return of spontaneous circulation (ROSC). The median time to ROSC was 3 (1-5) minutes. Patients with ICU-CA had significantly higher ICU mortality (61% vs. 37%). Multivariable logistic regression showed that the presence of ARDS (odds ratio (OR) 4.268, 95% confidence interval (CI) 1.211-15.036; = 0.024) and high SAPS II (OR 1.031, 95% CI 0.997-1.065; = 0.077) were independently associated with the occurrence of ICU-CA. A total of 18% of critically ill patients with COVID-19 suffered from a cardiac arrest within the intensive care unit. The occurrence of ICU-CA was associated with presence of ARDS and severity of illness.
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http://dx.doi.org/10.3390/jcm10102195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160993PMC
May 2021

[Novel aspects on causes of in-hospital cardiac arrest].

Dtsch Med Wochenschr 2021 06 1;146(11):733-737. Epub 2021 Jun 1.

Klinik für Intensivmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg.

Cardiac arrest is one of the most dramatic medical emergencies. The occurence of cardiac arrest in hospitalized patients, the so called in-hospital cardiac arrest, is common and associated with high mortality. However, in-hospital cardiac arrest has received quite little attention compared to cardiac arrest occuring outside the hospital. The present article reviews the recent literature of in-hospital cardiac arrest and outlines differences in characteristics and outcome compared to out of hospital cardiac arrest. Moreover, current literature regarding occurence and outcome of in-hospital cardiac arrest in hospitalized patients with COVID-19 is concisely summarized.
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http://dx.doi.org/10.1055/a-1258-5243DOI Listing
June 2021

Sepsis-Pathophysiology and Therapeutic Concepts.

Front Med (Lausanne) 2021 14;8:628302. Epub 2021 May 14.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Sepsis is a life-threatening condition and a global disease burden. Today, the heterogeneous syndrome is defined as severe organ dysfunction caused by a dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental and clinical research during the last three decades, the ability to positively influence course and outcome of the syndrome remains limited. Evidence-based therapy still consists of basic causal and supportive measures, while adjuvant interventions such as blood purification or targeted immunotherapy largely remain without proof of effectiveness so far. With this review, we aim to provide an overview of sepsis immune pathophysiology, to update the choice of therapeutic approaches targeting different immunological mechanisms in the course of sepsis and septic shock, and to call for a paradigm shift from the pathogen to the host response as a potentially more promising angle.
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http://dx.doi.org/10.3389/fmed.2021.628302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160230PMC
May 2021

Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.

EBioMedicine 2021 May 14;67:103382. Epub 2021 May 14.

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood.

Methods: We performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay.

Findings: FXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasmaaac acafajföeFXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro.

Interpretation: Collectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy.

Funding: This study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).
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http://dx.doi.org/10.1016/j.ebiom.2021.103382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120108PMC
May 2021

Endogenous vitamin E metabolites mediate allosteric PPARγ activation with unprecedented co-regulatory interactions.

Cell Chem Biol 2021 May 12. Epub 2021 May 12.

Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt 60438, Germany. Electronic address:

Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.
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http://dx.doi.org/10.1016/j.chembiol.2021.04.019DOI Listing
May 2021

Prognostic Value of Bioactive Adrenomedullin in Critically Ill Patients with COVID-19 in Germany: An Observational Cohort Study.

J Clin Med 2021 Apr 13;10(8). Epub 2021 Apr 13.

Department of Intensive and Intermediate Care, University Hospital RWTH Aachen, 52074 Aachen, Germany.

The coronavirus disease 2019 (COVID-19) pandemic has placed a significant burden on hospitals worldwide. Objective biomarkers for early risk stratification and clinical management are still lacking. The aim of this work was to determine whether bioactive adrenomedullin can assist in the risk stratification and clinical management of critically ill COVID-19 patients. Fifty-three patients with confirmed COVID-19 were included in this prospective observational cohort study between March and April 2020. Bioactive adrenomedullin (bio-ADM) plasma concentration was measured daily for seven days after admission. The prognostic value and clinical significance of bio-ADM plasma levels were evaluated for the severity of respiratory failure, the need for extracorporeal organ support and outcome (28-day mortality). Bio-ADM levels increased with the severity of acute respiratory distress syndrome (ARDS; < 0.001) and were significantly elevated in invasively ventilated patients ( = 0.006) and patients in need of extracorporeal membrane oxygenation ( = 0.040) or renal replacement therapy (RRT; < 0.001) compared to patients without these conditions. Non-survivors showed significantly higher bio-ADM levels than survivors ( = 0.010). Bio-ADM levels predicted 28-day mortality (C-index 0.72, 95% confidence interval 0.56-0.87, < 0.001). Bio-ADM plasma levels correlate with disease severity, the need for extracorporeal organ assistance, and outcome, and highlight the promising value of bio-ADM in the early risk stratification and management of patients with COVID-19.
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http://dx.doi.org/10.3390/jcm10081667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069401PMC
April 2021

Necrotizing Soft Tissue Infections in Intensive Care.

J Intensive Care Med 2021 Apr 26:8850666211010127. Epub 2021 Apr 26.

Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Background: Necrotizing soft tissue infections (NSTIs) are typically characterized by extensive soft tissue destruction with systemic signs of toxicity, ranging from sepsis to septic shock. Our aim was to analyze the clinical characteristics, microbiological results, laboratory data, therapies, and outcome of patients with NSTIs admitted to an intensive care unit (ICU).

Methods: A monocentric observational study of patients admitted to the ICU of a university hospital between January 2009 and December 2017. The demographic characteristics, comorbidities, clinical features, microbiology and laboratory results, organ dysfunctions, therapies, and outcome were retrospectively analyzed.

Results: There were 59 patients and 70% males. The mean age (± SD) was 55 ± 18; type II (monomicrobial) NSTI was present in 36 patients (61%); the most common isolated pathogen was in 28 patients (48%). Septic shock was diagnosed in 41 patients (70%). The most common organ dysfunctions were circulatory and renal in 42 (71%) and 38 patients (64%). The mean value (± SD) of serum lactate at admission to the ICU was 4.22 ± 5.42 mmol/l, the median SOFA score and SAPS II were 7 (IQR 4 - 10) and 46 (IQR 30.5 - 53). ICU mortality rate was 25%. Both SOFA score and serum lactate demonstrated a good prognostic value regarding ICU outcome (OR 1.29, 95%CI 1.07-1.57, < 0.007 and OR 1.53, 95%CI 1.19-1.98, < 0.001). A cut-off value for serum lactate of 6.55 mmol/L positively predicted mortality with 67% sensitivity and 97% specificity.

Conclusion: NSTIs carry a high risk of septic shock and multiple organ dysfunction syndrome and thus are still associated with high mortality. In our study, the value of serum lactate at admission to the ICU correlated well with mortality. This easy-to-measure parameter could play a role in the decision-making process regarding prognosis and continuation of care.
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http://dx.doi.org/10.1177/08850666211010127DOI Listing
April 2021

[Attitude towards vaccination against SARS-CoV-2 : Survey among employees in hospitals before and after the start of vaccinations in German hospitals].

Med Klin Intensivmed Notfmed 2021 Jun 20;116(5):421-430. Epub 2021 Apr 20.

ARDS und ECMO Zentrum Köln-Merheim, Kliniken der Stadt Köln und Universität Witten/Herdecke, Köln, Deutschland.

Background: The vaccinations against the "severe acute respiratory syndrome coronavirus type 2" (SARS-CoV‑2) play a decisive role in the global fight against the coronavirus pandemic. In the population, but also among health care workers (HCWs), there were concerns and skepticism about vaccinations even before the corona pandemic.

Methods: An online survey on the attitude of HCWs to vaccination against SARS-CoV‑2 was carried out in December (December 3rd-December 12th, 2020) before and in February (February 1st-February 10th, 2021) after the start of the vaccinations. Members of the German Society for Internal Intensive Care Medicine and Emergency Medicine (DGIIN) and the German Interdisciplinary Association for Intensive Care Medicine and Emergency Medicine (DIVI) were invited by email and on Facebook.

Results: In December 2305 and in February 3501 people took part. The approval rate for vaccination increased from 85.2% to 92.1% (p < 0.001). There was also an increase in willingness to vaccinate (63.8% vs. 75.9%; p < 0.001). The female gender, membership of the professional group nursing staff and age < 45 years were significantly associated with a restricted willingness to vaccinate. There was also a decrease in concerns about efficacy, side effects and long-term damage. There was clear skepticism about the vaccine from AstraZeneca (Cambridge, United Kingdom). Before and after the introduction of vaccinations against SARS-CoV‑2, an increase in the willingness to vaccinate against SARS-CoV-2 can be shown in German HCWs. Technical experts must bring objectivity into the currently controversial debate through precise and transparent information and thus counteract vaccination skepticism, not only among HCWs.
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http://dx.doi.org/10.1007/s00063-021-00821-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056372PMC
June 2021

Conservative management of COVID-19 associated hypoxaemia.

ERJ Open Res 2021 Apr 6;7(2). Epub 2021 Apr 6.

Dept of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany.

https://bit.ly/3qAn7la.
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http://dx.doi.org/10.1183/23120541.00113-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021801PMC
April 2021

MR-proAdrenomedullin as a predictor of renal replacement therapy in a cohort of critically ill patients with COVID-19.

Biomarkers 2021 Jul 5;26(5):417-424. Epub 2021 Apr 5.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: About 20% of ICU patients with COVID-19 require renal replacement therapy (RRT). Mid-regional pro-adrenomedullin (MR-proADM) might be used for risk assessment. This study investigates MR-proADM for RRT prediction in ICU patients with COVID-19.

Methods: We analysed data of consecutive patients with COVID-19, requiring ICU admission at a university hospital in Germany between March and September 2020. Clinical characteristics, details on AKI, and RRT were assessed. MR-proADM was measured on admission.

Results: 64 patients were included (49 (77%) males). Median age was 62.5y (54-73). 47 (73%) patients were ventilated and 50 (78%) needed vasopressors. 25 (39%) patients had severe ARDS, and 10 patients needed veno-venous extracorporeal membrane oxygenation. 29 (45%) patients required RRT; median time from admission to RRT start was 2 (1-9) days. MR-proADM on admission was higher in the RRT group (2.491 vs. 1.23 nmol/l;  = 0.002) and showed the highest correlation with renalSOFA. ROC curve analysis showed that MR-proADM predicts RRT with an AUC of 0.69 (95% CI: 0.543-0.828;  = 0.019). In multivariable logistic regression MR-proADM was an independent predictor (OR: 3.813, 95% CI 1.110-13.102, <0.05) for RRT requirement.

Conclusion: AKI requiring RRT is frequent in ICU patients with COVID-19. MR-proADM on admission was able to predict RRT requirement, which may be of interest for risk stratification and management.
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http://dx.doi.org/10.1080/1354750X.2021.1905067DOI Listing
July 2021

Cerebrovascular autoregulation and arterial carbon dioxide in patients with acute respiratory distress syndrome: a prospective observational cohort study.

Ann Intensive Care 2021 Mar 16;11(1):47. Epub 2021 Mar 16.

Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Background: Early hypercapnia is common in patients with acute respiratory distress syndrome (ARDS) and is associated with increased mortality. Fluctuations of carbon dioxide have been associated with adverse neurological outcome in patients with severe respiratory failure requiring extracorporeal organ support. The aim of this study was to investigate whether early hypercapnia is associated with impaired cerebrovascular autoregulation during the acute phase of ARDS.

Methods: Between December 2018 and November 2019, patients who fulfilled the Berlin criteria for ARDS, were enrolled. Patients with a history of central nervous system disorders, cerebrovascular disease, chronic hypercapnia, or a life expectancy of less than 24 h were excluded from study participation. During the acute phase of ARDS, cerebrovascular autoregulation was measured over two time periods for at least 60 min. Based on the values of mean arterial blood pressure and near-infrared spectroscopy, a cerebral autoregulation index (COx) was calculated. The time with impaired cerebral autoregulation was calculated for each measurement and was compared between patients with and without early hypercapnia [defined as an arterial partial pressure of carbon dioxide (PaCO) ≥ 50 mmHg with a corresponding arterial pH < 7.35 within the first 24 h of ARDS diagnosis].

Results: Of 66 patients included, 117 monitoring episodes were available. The mean age of the study population was 58.5 ± 16 years. 10 patients (15.2%) had mild, 28 (42.4%) moderate, and 28 (42.4%) severe ARDS. Nineteen patients (28.8%) required extracorporeal membrane oxygenation. Early hypercapnia was present in 39 patients (59.1%). Multivariable analysis did not show a significant association between early hypercapnia and impaired cerebrovascular autoregulation (B = 0.023 [95% CI - 0.054; 0.100], p = 0.556). Hypocapnia during the monitoring period was significantly associated with impaired cerebrovascular autoregulation [B = 0.155 (95% CI 0.014; 0.296), p = 0.032].

Conclusion: Our results suggest that moderate permissive hypercapnia during the acute phase of ARDS has no adverse effect on cerebrovascular autoregulation and may be tolerated to a certain extent to achieve low tidal volumes. In contrast, episodes of hypocapnia may compromise cerebral blood flow regulation. Trial registration ClinicalTrials.gov; registration number: NCT03949738; date of registration: May 14, 2019.
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http://dx.doi.org/10.1186/s13613-021-00831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962086PMC
March 2021

Severe liver dysfunction complicating course of COVID-19 in the critically ill: multifactorial cause or direct viral effect?

Ann Intensive Care 2021 Mar 15;11(1):44. Epub 2021 Mar 15.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Background: SARS-CoV-2 caused a pandemic and global threat for human health. Presence of liver injury was commonly reported in patients with coronavirus disease 2019 (COVID-19). However, reports on severe liver dysfunction (SLD) in critically ill with COVID-19 are lacking. We evaluated the occurrence, clinical characteristics and outcome of SLD in critically ill patients with COVID-19.

Methods: Clinical course and laboratory was analyzed from all patients with confirmed COVID-19 admitted to ICU of the university hospital. SLD was defined as: bilirubin ≥ 2 mg/dl or elevation of aminotransferase levels (> 20-fold ULN).

Results: 72 critically ill patients were identified, 22 (31%) patients developed SLD. Presenting characteristics including age, gender, comorbidities as well as clinical presentation regarding COVID-19 overlapped substantially in both groups. Patients with SLD had more severe respiratory failure (paO/FiO 82 (58-114) vs. 117 (83-155); p < 0.05). Thus, required more frequently mechanical ventilation (95% vs. 64%; p < 0.01), rescue therapies (ECMO) (27% vs. 12%; p = 0.106), vasopressor (95% vs. 72%; p < 0.05) and renal replacement therapy (86% vs. 30%; p < 0.001). Severity of illness was significantly higher (SAPS II: 48 (39-52) vs. 40 (32-45); p < 0.01). Patients with SLD and without presented viremic during ICU stay in 68% and 34%, respectively (p = 0.002). Occurrence of SLD was independently associated with presence of viremia [OR 6.359; 95% CI 1.336-30.253; p < 0.05] and severity of illness (SAPS II) [OR 1.078; 95% CI 1.004-1.157; p < 0.05]. Mortality was high in patients with SLD compared to other patients (68% vs. 16%, p < 0.001). After adjustment for confounders, SLD was independently associated with mortality [HR3.347; 95% CI 1.401-7.999; p < 0.01].

Conclusion: One-third of critically ill patients with COVID-19 suffer from SLD, which is associated with high mortality. Occurrence of viremia and severity of illness seem to contribute to occurrence of SLD and underline the multifactorial cause.
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http://dx.doi.org/10.1186/s13613-021-00835-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957439PMC
March 2021

Comparison of clinical characteristics and disease outcome of COVID-19 and seasonal influenza.

Sci Rep 2021 03 11;11(1):5803. Epub 2021 Mar 11.

I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

While several studies have described the clinical course of patients with coronavirus disease 2019 (COVID-19), direct comparisons with patients with seasonal influenza are scarce. We compared 166 patients with COVID-19 diagnosed between February 27 and June 14, 2020, and 255 patients with seasonal influenza diagnosed during the 2017-18 season at the same hospital to describe common features and differences in clinical characteristics and course of disease. Patients with COVID-19 were younger (median age [IQR], 59 [45-71] vs 66 [52-77]; P < 0001) and had fewer comorbidities at baseline with a lower mean overall age-adjusted Charlson Comorbidity Index (mean [SD], 3.0 [2.6] vs 4.0 [2.7]; P < 0.001) than patients with seasonal influenza. COVID-19 patients had a longer duration of hospitalization (mean [SD], 25.9 days [26.6 days] vs 17.2 days [21.0 days]; P = 0.002), a more frequent need for oxygen therapy (101 [60.8%] vs 103 [40.4%]; P < 0.001) and invasive ventilation (52 [31.3%] vs 32 [12.5%]; P < 0.001) and were more frequently admitted to the intensive care unit (70 [42.2%] vs 51 [20.0%]; P < 0.001) than seasonal influenza patients. Among immunocompromised patients, those in the COVID-19 group had a higher hospital mortality compared to those in the seasonal influenza group (13 [33.3%] vs 8 [11.6%], P = 0.01). In conclusion, we show that COVID-19 patients were younger and had fewer baseline comorbidities than seasonal influenza patients but were at increased risk for severe illness. The high mortality observed in immunocompromised COVID-19 patients emphasizes the importance of protecting these patient groups from SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41598-021-85081-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970952PMC
March 2021

Validation and Application of an HPLC-UV Method for Routine Therapeutic Drug Monitoring of Cefiderocol.

Antibiotics (Basel) 2021 Feb 28;10(3). Epub 2021 Feb 28.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Cefiderocol is a new siderophore cephalosporin approved for the treatment of multidrug resistant bacteria including activity against carbapenem-resistant Enterobacterales and . As cephalosporins are known for their high pharmacokinetic variability in critically ill patients, cefiderocol therapeutic drug monitoring might become a valuable tool. Therefore, we aimed to develop and validate a simple, rapid, cost-effective high performance liquid chromatography (HPLC) method for the quantification of cefiderocol in serum. Samples were treated for protein precipitation followed by chromatographic separation on a reverse phase column (HPLC C-18) with gradient elution of the mobile phase. Cefiderocol was detected via UV absorption and quantification was performed with the internal standard (metronidazole) method. The calibration range showed linearity from 4 to 160 mg/L. The intra and interday precision was less than 10% with a recovery rate of 81%. The method was successfully used for the analysis of subsequent serum samples of critically ill patients and showed good performance in monitoring serum levels and optimizing antibiotic therapy.
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http://dx.doi.org/10.3390/antibiotics10030242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997268PMC
February 2021
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