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Purpose: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models., Methods: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision., Results: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE| median_all_models 45.1/67.5%; MAPE median_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models., Conclusion: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM., (© 2023. The Author(s).)

Purpose: This case-control study investigated the long-term evolution of multidrug-resistant bacteria (MDRB) over a 5-year period associated with the use of selective oropharyngeal decontamination (SOD) in the intensive care unit (ICU). In addition, effects on health care-associated infections and ICU mortality were analysed., Methods: We investigated patients undergoing mechanical ventilation > 48 h in 11 adult ICUs located at 3 campuses of a university hospital. Administrative, clinical, and microbiological data which were routinely recorded electronically served as the basis. We analysed differences in the rates and incidence densities (ID, cases per 1000 patient-days) of MDRB associated with SOD use in all patients and stratified by patient origin (outpatient or inpatient). After propensity score matching, health-care infections and ICU mortality were compared., Results: 5034 patients were eligible for the study. 1694 patients were not given SOD. There were no differences in the incidence density of MDRB when SOD was used, except for more vancomycin-resistant Enterococcus faecium (0.72/1000 days vs. 0.31/1000 days, p < 0.01), and fewer ESBL-producing Klebsiella pneumoniae (0.22/1000 days vs. 0.56/1000 days, p < 0.01). After propensity score matching, SOD was associated with lower incidence rates of ventilator-associated pneumonia and death in the ICU but not with ICU-acquired bacteremia or urinary tract infection., Conclusions: Comparisons of the ICU-acquired MDRB over a 5-year period revealed no differences in incidence density, except for lower rate of ESBL-producing Klebsiella pneumoniae and higher rate of vancomycin-resistant Enterococcus faecium with SOD. Incidence rates of ventilator-associated pneumonia and death in the ICU were lower in patients receiving SOD., (© 2022. The Author(s).)

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI)., Participants: A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)., Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews., Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity., Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.

Objective: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients., Participants: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine., Design/methods: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members., Results: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO 2 /FiO 2  < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence)., Conclusions: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Introduction: Corticosteroids have been proposed to decrease morbidity and mortality in patients with septic shock. An impact on morbidity should be anticipated to be earlier and more easily detected than the impact on mortality., Methods: Prospective, randomized, double-blind, placebo-controlled study of 28-day mortality in patients with septic shock for <72 h who underwent a short high-dose ACTH test in 52 centers in 9 European countries. Patients received 11-day treatment with hydrocortisone or placebo. Organ dysfunction/failure was quantified by the use of the sequential organ failure assessment (SOFA) score., Results: From March 2002 to November 2005, 499 patients were enrolled (hydrocortisone 251, placebo 248). Both groups presented a similar SOFA score at baseline (hydrocortisone 10.8 ± 3.2 vs. placebo 10.7 ± 3.1 points). There was no difference in 28-day mortality between the two treatment groups (hydrocortisone 34.3% vs. placebo 31.5%). There was a decrease in the SOFA score of hydrocortisone-treated patients from day 0 to day 7 compared to the placebo-treated patients (p = 0.0027), driven by an improvement in cardiovascular organ dysfunction/failure (p = 0.0005) and in liver failure (p < 0.0001) in the hydrocortisone-treated patients., Conclusion: Patients randomized to treatment with hydrocortisone demonstrated a faster decrease in total organ dysfunction/failure determined by the SOFA score, primarily driven by a faster improvement in cardiovascular organ dysfunction/failure. This organ dysfunction/failure improvement was not accompanied by a decreased mortality.

Purpose: To compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock., Methods: In the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a 'gold standard' reference method in a subset of samples., Results: A total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratory immunoassay and local hospital assays was 0.98 (CI 0.97-0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54-0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases., Conclusion: In samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.

Objective: To assess the effects of stress doses of hydrocortisone (HC) on clinical parameters and neutrophil functions in patients with septic shock., Design: Prospective, double-blind, randomized, placebo-controlled study., Setting: Intensive care units of a university hospital., Patients and Participants: 30 adult patients with septic shock., Interventions: Patients were allocated to receive either HC (intravenous bolus of 100 mg preceding a continuous infusion 10 mg/h, n = 15) or placebo (n = 15), respectively. The effects of HC were assessed at baseline and after 24 h., Measurements and Results: As compared with placebo-treated patients, administration of HC significantly decreased norepinephrine requirements (from 1.5 to 0.8 mg/h; p < 0.001), interleukin-6 serum concentrations (from 388.8 to 88.8 pg/ml; p < 0.02), and the spontaneous release of hydrogen peroxide (H2O2) by neutrophils (-33.0%; p < 0.05). Additionally, HC treatment preserved the autologous plasma-induced amplification of phagocytosis of zymosan particles [factor of opsonin-induced amplification of phagocytosis of unopsonized particles: 1.80 for placebo vs. 1.75 for HC at baseline (not significant between groups) and 0.50 for placebo vs. 1.75 for HC after 24 h of treatment (p < 0.05)]. These effects were paralleled by respective changes in the phagocytosis-associated H2O2 production., Conclusions: In patients with septic shock stress doses of HC exert beneficial effects in terms of improvements in hemodynamics, decrease in pro-inflammatory mediators, and oxidative stress without the compromise of opsonization-dependent phagocytic neutrophil functions; thus, HC treatment does not aggravate non-specific immunosuppression but instead improves innate immunity in the early stage of septic shock.

Objective: We performed a follow-up cohort analysis in order to delineate the correlation between pulmonary function (PF) and health-related quality of life (HRQL) in patients after ARDS., Design: Follow-up cohort study., Setting: A 20-bed ICU of a university teaching hospital., Patients: A cohort of 50 long-term survivors of ARDS., Measurements and Results: Measurements of PF (FVC, FEV1, TLC, D(LCO)) and HRQL (SF-36 Health Status Questionnaire) were made 5.5 years (median value) after discharge from the ICU. Impairments in PF (defined as PF results below 80% of the predicted value) were frequent but generally mild. Twenty patients had a single PF impairment (with limitations in FEV1/FVC ratio in 12 patients being the most common), four patients had two (with D(LCO) and FEV1/FVC ratio impairment the most common) and three patients had pathologic results in three PF tests (FEV1/FVC ratio, TLC and capillary pO2 during exercise in one case, FVC, TLC and capillary pO2 during exercise in the second patient and FVC, TLC and D(LCO) in the third). Compared to normal controls, survivors of ARDS showed impairments in all SF-36 health dimensions (p < 0.001). Patients with multiple (> 1) PF impairments described the lowest HRQL with major limitations in all SF-36 categories (p < 0.037) including physical and mental summary scores (36.5 vs 46.9, p = 0.037 and 31.3 vs 51.4, p = 0.003) when compared to patients with no or only one PF impairment., Conclusions: Long-term survivors of ARDS have a significant reduction in HRQL and the presence of multiple PF impairments is associated with maximal decrements in HRQL.

Introduction: Liver transplantation is the method of choice for metabolic diseases and end-stage liver failure., Methods: At the Klinikum Grosshadern we have performed liver transplantation for inborn errors of metabolism in 24 patients (5.3% of all transplantations, 16 adults, age 39 +/- 13 years; 8 children, age 9 +/- 3 years); 19 patients received a transplant for end-stage liver disease, and in 5 cases because of fulminant hepatic failure., Results: Twenty-four patients received 27 transplants. In 3 cases, a split-liver transplantation was performed; one patient received a combined lung-liver graft. The 5-year survival rate for children is 100% and for adults 68%., Conclusions: Liver transplantation for inborn errors of metabolism not only replaces the diseased organ, but also leads to complete reversal of the metabolic defect.

Objective: To investigate the effects of noninvasive positive pressure ventilation (NPPV) on pulmonary gas exchange, breathing pattern, intrapulmonary shunt fraction, oxygen consumption, and resting energy expenditure in patients with persistent acute respiratory failure but without chronic obstructive pulmonary disease (COPD) after early extubation., Design: Prospective study., Setting: Multidisciplinary intensive care unit of a university hospital., Patients: 15 patients after prolonged mechanical ventilation (> 72 h) with acute respiratory insufficiency after early extubation., Interventions: Criteria for early extubation were arterial oxygen tension (PaO2) > or = 40 mm Hg (fractional inspired oxygen 0.21), arterial carbon dioxide tension (PaCO2) < or = 55 mm Hg, pH > 7.32, respiratory rate < or = 40 breaths per min, tidal volume (VT) > or = 3 ml/kg, rapid shallow breathing index < or = 190 and negative inspiratory force > or = 20 cmH2O. After extubation, two modes of NPPV were applied [continuous positive airway pressure (CPAP) of 5 cmH2O and pressure support ventilation (PSV) with 15 cmH2O pressure support]., Measurements and Main Results: Oxygenation and ventilatory parameters improved during both modes of NPPV (p < 0.05): increase in PaO2 of 11 mm Hg during CPAP and 21 mm Hg during PSV; decrease in intrapulmonary shunt fraction of 7% during CPAP and 12% during PSV; increase in tidal volume of 1 ml/kg during CPAP and 4 ml/kg during PSV; decrease in respiratory rate 6 breaths/min during CPAP and 9 breaths/min during PSV. Oxygen consumption (15% during CPAP, 22% during PSV) and resting energy expenditure (12% during CPAP, 20% during PSV) were reduced (p < 0.05). PaCO2 decreased, whereas minute ventilation and pH increased during PSV (p < 0.05). The median duration of NPPV was 2 days. Two patients had to be reintubated., Conclusions: In non-COPD patients with persistent acute respiratory failure after early extubation, NPPV improved pulmonary gas exchange and breathing pattern, decreased intrapulmonary shunt fraction, and reduced the work of breathing.

Objective: Many survivors of critical illness and intensive care unit (ICU) treatment have traumatic memories such as nightmares, panic or pain which can be associated with the development of posttraumatic stress disorder (PTSD). In order to simplify the rapid and early detection of PTSD in such patients, we modified an existing questionnaire for diagnosis of PTSD and validated the instrument in a cohort of ARDS patients after long-term ICU therapy., Design: Follow-up cohort study., Setting: The 20-bed ICU of a university teaching hospital., Patients: A cohort of 52 long-term survivors of the acute respiratory distress syndrome (ARDS)., Interventions and Measurements: The questionnaire was administered to the study cohort at two time points 2 years apart. At the second evaluation, the patients underwent a structured interview with two trained psychiatrists to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria. The reliability and validity of the questionnaire was then estimated and its specificity, sensitivity and optimal decision threshold determined using receiver operating characteristic (ROC) curve analyses., Results: The questionnaire showed a high internal consistency (Crohnbach's alpha = 0.93) and a high test-retest reliability (intraclass correlation coefficient alpha = 0.89). There was evidence of construct validity by a linear relationship between scores and the number of traumatic memories from the ICU the patients described (Spearman's rho = 0.48, p < 0.01). Criterion validity was demonstrated by ROC curve analyses resulting in a sensitivity of 77.0% and a specificity of 97.5% for the diagnosis of PTSD., Conclusions: The questionnaire was found to be a responsive, valid and reliable instrument to screen survivors of intensive care for PTSD.

Objective: To review five sedation scoring systems and to determine their correlation with an objective method for assessing the level of sedation by means of auditory evoked potentials (AEP) in critically ill patients., Design: Prospective clinical study., Setting: Multidisciplinary intensive care unit in a university hospital., Patients: Ninety-five consecutive patients requiring sedation during intensive care therapy., Measurements and Results: Previous studies have shown that auditory evoked potentials, especially latencies of the midlatency component N(b), could serve as an indicator of depth of anaesthesia. In the present study we used this electrophysiological method to evaluate sedation during intensive care therapy. Changes in latency of peak N(b) were compared with various levels of sedation assessed by five established sedation scoring systems. As in anaesthesia, latencies of N(b) increased with increasing depth of sedation. Among the scoring systems, the one developed by Ramsay correlated best with changes in N(b) latency (r2=0.68). The coefficient of determination, r2, of the other scores ranged from 0.56 to 0.61., Conclusion: For the assessment of sedation, several scoring systems have been introduced into clinical practice, but the differentiation of deeper sedation levels, especially, remains poor. In this study we compared auditory evoked potentials, as an objective method with which to assess the level of sedation, with five different sedation scoring systems. In comparison with changes in latency of the midlatency component N(b), Ramsay's sedation score showed the closest correlation. Objective electrophysiological monitoring is desirable during long-term sedation.

Objective: Inhalation of high concentrations of nitric oxide (NO) has been shown to improve gas exchange and to reduce pulmonary vascular resistance in individuals with ischemia-reperfusion injury following orthotopic lung transplantation. We assessed the cardiopulmonary effects of low doses of NO in early allograft dysfunction following lung transplantation., Design: Prospective clinical dose-response study., Setting: Anesthesiological intensive care unit of a university hospital., Patients and Participants: 8 patients following a single or double lung transplantation who had a mean pulmonary arterial pressure (PAP) in excess of 4.7 kPa (35 mmHg) or an arterial oxygen tension/fractional inspired oxygen ratio (PaO2/FIO2) of less than 13.3 kPa (100 mmHg)., Interventions: Gaseous NO was inhaled in increasing concentrations (1, 4 and 8 parts per million, each for 15 min) via a Siemens Servo 300 ventilator., Measurements and Results: Cardiorespiratory parameters were assessed at baseline, after each concentration of NO, and 15 min after withdrawal of the agent [statistics: median (25th/75th percentiles: Q1/Q3), rANOVA, Dunnett's test, p < 0.05]. Inhaled NO resulted in a significant, reversible, dose-dependent, selective reduction in PAP from 5.5(5.2/6.0) kPa at control to 5.1(4.7/5.6) kPa at 1 ppm, 4.9(4.3/5.3) kPa at 4 ppm, and to 4.7(4.1/5.1) kPa at 8 ppm. PaO2 increased from 12.7(10.4/17.1) to 19.2(12.4/26.0) kPa at 1 ppm NO, to 23.9(4.67/26.7) kPa at 4 ppm NO and to 24.5(11.9/28.7) kPa at 8 ppm NO. All patients responded to NO inhalation (either with PAP or PaO2), all were subject to long-term inhalation (1-19 days). All were successfully weaned from NO and were discharged from the intensive care unit., Conclusion: The present study demonstrates that low-dose inhaled NO may be an effective drug for symptomatic treatment of hypoxemia and/or pulmonary hypertension due to allograft dysfunction subsequent to lung transplantation.

In the last 10 years an increasing number of cases of group A streptococcal toxic shock syndrome have appeared in various clinical settings. The manifestation of this syndrome includes rapidly progressive multiorgan failure and soft-tissue necrosis. This report presents a case of streptococcal toxic shock syndrome caused by Streptococcus pyogenes with severe necrotizing fasciitis of the abdominal wall following hysterectomy. Aggressive surgical intervention with debridement of all necrotic tissue necessitated resection of the complete abdominal wall (skin, subcutaneous tissue, muscle and peritoneum). The abdominal wall defect was covered with free myocutaneous flaps and split-skin grafts. Optimal treatment, including adequate antibiotic therapy and radical surgical intervention, is an indispensable prerequisite of successful outcome.

Objective: To compare the adrenocortical response to corticotropin during septic shock and after complete recovery., Design: Prospective clinical study., Setting: Multidisciplinary intensive care unit in a university hospital., Patients: 20 consecutive patients surviving septic shock. All patients met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock. In addition, the presence of high-output circulatory failure with a cardiac index > 41/min per m2 was a criterion for enrollment in the study. Complete recovery from septic shock was defined as discontinuation of any supportive therapies. Severity of illness during septic shock and after recovery was graded using the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system., Interventions: In each patient, two short corticotropin stimulation tests were done during septic shock and after recovery., Measurements and Results: Basal cortisol levels recorded during septic shock and after recovery did not differ (medians: 18.8 vs 18.9 micrograms/dl). However, the response to corticotropin was significantly attenuated during septic shock when compared with the response after recovery (medians: 7.7 vs 14.7 micrograms/dl; p = 0.02). After recovery, patients' stress response was less, as indicated by a reduction in APACHE II scores (medians: 21 vs 5 points; p < 0.01)., Conclusions: Adrenocortical response to corticotropin is attenuated in patients with septic shock and high-output circulatory failure compared to the response in the much less stressful condition after recovery. The attenuated adrenocortical responsiveness may be explained by effects of circulating mediators from the systemic inflammatory response.