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There are concerns about the stability of meropenem in plasma samples, even when frozen at -20 °C. Previous smaller studies suggested significant degradation of meropenem at -20 °C after 3-20 days. However, in several recent clinical studies, meropenem plasma samples were still stored at -20 °C, or the storage temperature and/or time were not mentioned in the paper. The aim of this study was to describe and model meropenem degradation in human plasma at -20 °C over 1 year. Stability of meropenem in human plasma at -20 °C was investigated at seven concentrations (0.44, 4.38, 17.5, 35.1, 52.6, 70.1, and 87.6 mg/L) representative for the range of relevant concentrations encountered in clinical practice. For each concentration, samples were stored for 0, 7, 14, 21, 28, 42, 56, 70, 84, 112, 140, 168, 196, 224, 252, 280, 308, 336, and 364 days at -20 °C before being transferred to -80 °C until analysis. Degradation was modeled using polynomial regression analysis and artificial neural network (ANN). Meropenem showed significant degradation over time in human plasma when stored at -20 °C. Degradation was present over the whole concentration range and increased with higher concentrations until a concentration of 35.1 mg/L. Both models showed accurate prediction of meropenem degradation. In conclusion, this study provides detailed insights into the concentration-dependent degradation of meropenem in human plasma stored at -20 °C over 1 year. Meropenem in human plasma is shown to be stable at least up to approximately 80 days when stored at -20 °C. The polynomial model allows calculating original meropenem concentrations in samples stored for a known period of time at -20 °C. ispartof: ANTIBIOTICS-BASEL vol:10 issue:4 ispartof: location:Switzerland status: published

Although endocrine pathology is usually treated in an outpatient clinic, intensive care may be required when endocrinopathies are associated with other medical illnesses or reach a state of decompensation. Although endocrine emergencies are quite rare, they are potentially life-threatening if not recognised promptly and managed effectively. Therefore, every clinician should always be attentive to a possible diagnosis of these complex disorders. The three major diabetic emergencies comprise diabetic ketoacidosis, hyperglycaemic hyperosmolar state, and prolonged hypoglycaemia. Hyperglycaemic crises are characterised by hypovolaemia and electrolyte disturbances, and may be triggered by potentially life-threatening conditions. Hence, airway-breathing-circulation securement, early fluid resuscitation, and adequate diagnosis and treatment of the underlying condition are the cornerstones of acute management. Subsequently, monitoring and correction of electrolyte disturbances and insulin treatment are initiated. Profound hypoglycaemia should be suspected in every patient with coma of unclear etiology, especially if the patient has an indistinct history or was treated with insulin or sulfonylurea/meglitinide. This condition warrants an immediate administration of glucose, followed by regular blood glucose monitoring. Alternatively, glucagon may be injected subcutaneously, or preferably intramuscularly. Hyperglycaemia in critically ill patients is associated with adverse outcome. The optimal blood glucose target for critically ill patients remains unclear, however. In any case, clinicians should prevent severe hyperglycaemia, hypoglycaemia and large glucose fluctuations. The classical non-diabetic endocrine emergencies comprise thyroid storm, myxoedema coma, acute adrenal crisis, and phaeochromocytoma. They all pose diagnostic and therapeutic challenges and require specific treatment such as endocrine replacement or blockage therapy, apart from supportive care and treatment of the inciting event. It is important to note that such conditions are occasionally the first manifestation of an endocrine disorder. This chapter also briefly discusses amiodarone-induced thyroid dysfunction.

Background: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. Methods: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. Results: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0–1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7–5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (&lt, 1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. Conclusion: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously.

Item does not contain fulltext BACKGROUND: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolised by CYP3A4 and CYP3A5, and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450 inducers is contraindicated, although it is known that some CYP450 inducers are less potent in comparison with rifampin. OBJECTIVES: We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction effect has never been studied in combination with the patient's CYP3A genotype. PATIENTS: We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations. RESULTS: These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450 induction interaction. CONCLUSIONS: CYP3A inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low-isavuconazole exposure was observed in the extensive metaboliser with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.

Background Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. Objectives To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. Methods Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2–3) and a late (Day 4–7) sampling day. Daily trough concentrations were measured. Results The median (IQR) AUC0–24, CL and Vd were 34.3 (28.3–37.7) mg·h/L, 8.7 (8.0–10.6) L/h and 389 (314–740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. Conclusions ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.

Dear Editor, Infection with the SARS-CoV-2 virus may lead to hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). ARDS is frequently complicated by intensive care unit acquired weakness (ICUAW) [1], which is associated with poor outcomes [2]. Critically ill patients affected with coronavirus disease 2019 (COVID-19) may differ from typical ARDS-patients in baseline factors [3] and ICU exposures associated with ICUAW [4]. Of particular concern may be the need for deep sedation to avoid patient-ventilator dyssynchrony and ventilator-induced/self-inflicted lung-injury because of high respiratory drive [5]. We aimed to assess the incidence of ICUAW in critically ill COVID-19 patients, to identify factors associated with its occurrence, and to describe its short-term outcomes. This single-center, retrospective, observational study involved adult critically ill COVID-19 patients admitted to the University Hospitals Leuven, from March 13th until June 8th 2020. After April 1st, physiotherapists were re-engaged in patient care and performed daily strength-assessment when appropriate. Records of eligible patients were searched for baseline characteristics, ICU exposures and outcomes. The primary outcome was the incidence of ICUAW, assessed with the MRC-sum score [2], at awakening, at ICU and hospital discharge in patients requiring invasive mechanical ventilation (IMV). In addition, we evaluated factors and short-term outcomes associated with weakness at ICU discharge. To assess bias, we compared characteristics and outcomes for patients with and without MRC-sum score, and studied patients without IMV. Of 486 hospitalized COVID-19 patients, 114 required intensive care of whom 74 (64.9%) needed IMV (Supplemental Fig. 1). Admission and ICU characteristics are provided in the Online Supplement. Total hospital mortality was 60/486 (12.3%), ICU mortality was 11/114 (9.6%). All deaths occurred in IMV patients [11/74 (14.9%)]. In 50/74 (67.6%) assessed IMV patients, the incidences of ICUAW at awakening, ICU, and hospital discharge were 72%, 52% and 27% (Fig. 1). Those without MRC-sum-score were older as compared to those with MRC-sum-score [67 (60–76) versus 60 (53–67), p = 0.044] and comprised nine patients who died before awakening, possibly introducing selection bias. Admission characteristics were similar between patients with and without ICUAW, but weak patients had prolonged ventilation (days) [24 (15–29) versus 12 (8–17), p

Background For amoxicillin-clavulanic acid and meropenem to be effective, concentrations must exceed the minimum inhibitory concentration of infecting pathogens. Objective To retrospectively evaluate time windows between both scheduled prescription and administration and reconstitution-preparation and end of administration of intravenous amoxicillin-clavulanic acid and meropenem prescriptions. Setting 37 hospital wards at a tertiary hospital, Belgium. Method All adult hospital stays with at least one amoxicillin-clavulanic acid or meropenem administration in 2018 were reviewed. Time windows were deemed acceptable if

Objectives Augmented renal clearance might lead to subtherapeutic plasma levels of drugs with predominant renal clearance. Early identification of augmented renal clearance remains challenging for the ICU physician. We developed and validated our augmented renal clearance predictor, a clinical prediction model for augmented renal clearance on the next day during ICU stay, and made it available via an online calculator. We compared its predictive performance with that of two existing models for augmented renal clearance. Design Multicenter retrospective registry-based cohort study. Setting Three Belgian tertiary care academic hospitals. Patients Adult medical, surgical, and cardiac surgery ICU patients. Interventions None. Measurements and main results Development of the prediction model was based on clinical information available during ICU stay. Out of 33,258 ICU days, we found augmented renal clearance on 19.6% of all ICU days in the development cohort. We retained six clinical variables in our augmented renal clearance predictor: day from ICU admission, age, sex, serum creatinine, trauma, and cardiac surgery. We assessed performance by measuring discrimination, calibration, and net benefit. We externally validated the final model in a single-center population (n = 10,259 ICU days). External validation confirmed good performance with an area under the curve of 0.88 (95% CI 0.87-0.88) and a sensitivity and specificity of 84.1 (95% CI 82.5-85.7) and 76.3 (95% CI 75.4-77.2) at the default threshold probability of 0.2, respectively. Conclusions Augmented renal clearance on the next day can be predicted with good performance during ICU stay, using routinely collected clinical information that is readily available at bedside. Our augmented renal clearance predictor is available at www.arcpredictor.com.

Despite organ shortage, organs from donors with listeria infections have been discarded for transplantation. We present the first-reported case of liver transplantation following listeria encephalitis. The patient was admitted with progressing neurological symptoms after an episode of gastroenteritis. Rhombo-encephalitis was diagnosed, and Listeria monocytogenes was found to be the causative pathogen. Despite proper antibiotic treatment and rapid clearance of bacteremia, he continued to deteriorate and became brain dead, after which organ donation was performed. At procurement, he had been treated with amoxicillin for 9 days. The recipient was treated with pipercillin/tazobactam for 21 days. Besides an anastomotic biliary stricture, necessitating endoscopic dilatation and stenting, further clinical course was uneventful and she is doing well eleven months post-transplant. Our case suggests that listeria encephalitis is not an absolute contra-indication to solid organ donation. We suggest that donors should be treated with adequate antibiotics for at least 48h prior to procurement and advocate confirmation of sterile blood cultures as a prerequisite for donation. According to listeriosis guidelines, we suggest that the recipient should be treated with targeted antibiotics for at least 2 weeks. The risk of transmission should, however, always be balanced carefully against the suspected waiting list mortality.

Background Therapeutic drug monitoring for cefepime is increasingly being performed because of the potential relation between exposure and neurotoxicity. An in vitro pilot study suggested significant carryover of cefepime from central venous catheters when blood sampling is carried out via the same catheter used for administration of cefepime. Therefore, the aim of this study was to evaluate carryover of cefepime in a real-life clinical setting. Methods A prospective single-center study was conducted at the hematology department of the University Hospitals Leuven. Patients treated with cefepime, and having a central venous catheter, were included. Cefepime trough samples were taken simultaneously via the central venous catheter and peripheral venepuncture. Results Twenty-four patients were included in this study, resulting in 28, 11 and 5 paired samples for tunnelled catheters, implantable port catheters and peripherally inserted central catheters, respectively. No statistically nor clinically significant difference was found between cefepime concentrations measured in centrally versus peripherally obtained blood samples, overall and for all three types of central venous catheters separately. Of note, four paired samples showed a difference larger than 10%, with lower central concentrations probably reflecting a dilution error. Conclusion There was no significant carryover of cefepime from long-term central venous catheters. Cefepime samples can be drawn reliably via the central venous catheter, after flushing and discarding the first blood sample. Although, flushing and discard volumes should be standardized to avoid potential dilution errors.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m2 and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P 1 mg/L.

Purpose Low plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition. Methods This randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 µg IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3–6), subacute (ICU-day 7–16) or prolonged phase (ICU-day 17–28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135 min and AUC responses to placebo were subtracted from those to CRH. Results Patients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 µg/dl in healthy subjects, P

BackgroundAugmented renal clearance (ARC) might lead to subtherapeutic plasma levels of drugs with predominant renal clearance. Early identification of ARC remains challenging for the intensive care unit (ICU) physician. We developed and validated the ARC predictor, a clinical prediction model for ARC on the next day during ICU stay, and made it available via an online calculator. Its predictive performance was compared with that of two existing models for ARC.MethodsA large multicenter database including medical, surgical and cardiac ICU patients (n = 33258 ICU days) from three Belgian tertiary care academic hospitals was used for the development of the prediction model. Development was based on clinical information available during ICU stay. We assessed performance by measuring discrimination, calibration and net benefit. The final model was externally validated (n = 10259 ICU days) in a single-center population.ResultsARC was found on 19.6% of all ICU days in the development cohort. Six clinical variables were retained in the ARC predictor: day from ICU admission, age, sex, serum creatinine, trauma and cardiac surgery. External validation confirmed good performance with an area under the curve of 0.88 (95% CI 0.87 – 0.88), and a sensitivity and specificity of 84.1 (95% CI 82.5 – 85.7) and 76.3 (95% CI 75.4 – 77.2) at the default threshold probability of 0.2, respectively.ConclusionARC on the next day can be predicted with good performance during ICU stay, using routinely collected clinical information that is readily available at bedside. The ARC predictor is available at www.arcpredictor.com.

ispartof: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY vol:75 issue:12 pages:3696-3697 ispartof: location:England status: published

PURPOSE: To assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council (MRC) sum score, assessing weakness, for the prediction of 5-year outcomes. METHODS: Sub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score ('MRC-cohort', N = 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential ('CMAP-cohort', N = 689), or both ('MRC&CMAP-cohort', N = 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity). RESULTS: Both lower MRC sum score at ICU discharge, indicating less strength [HR, per-point-increase: 0.946 (95% CI 0.928-0.968), p = 0.001], and abnormal CMAP, indicating nerve/muscle dysfunction [HR: 1.568 (95% CI 1.165-2.186), p = 0.004], independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC [HR: 0.956 (95% CI 0.934-0.980), p = 0.001] but not CMAP [HR: 1.478 (95% CI 0.875-2.838), p = 0.088] independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF [0.866 (95% CI 0.237-1.527), p = 0.004], low 6-MWD [105.1 (95% CI 12.1-212.9), p = 0.043] and low PF-SF-36 [- 0.119 (95% CI - 0.186 to - 0.057), p = 0.002], whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC ≤ 55 best predicted poor long-term morbidity and mortality. Both MRC ≤ 55 and abnormal CMAP independently associated with 5-year mortality. CONCLUSIONS: ICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality. ispartof: INTENSIVE CARE MEDICINE vol:46 issue:6 pages:1184-1193 ispartof: location:United States status: published

Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently lacking. We present the first steps towards the establishment of a &ldquo, multidisciplinary phage task force&rdquo, (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.

Background Invasive fungal infections (IFI) are difficult to diagnose, especially in critically ill patients. As the mannose receptor (MR) is shed from macrophage cell surfaces after exposure to fungi, we investigate whether its soluble serum form (sMR) can serve as a biomarker of IFI. Methods This is a secondary analysis of the multicentre randomised controlled trial (EPaNIC, n = 4640) that investigated the impact of initiating supplemental parenteral nutrition (PN) early during critical illness (Early-PN) as compared to withholding it in the first week of intensive care (Late-PN). Serum sMR concentrations were measured in three matched patient groups (proven/probable IFI, n = 82; bacterial infection, n = 80; non-infectious inflammation, n = 77) on the day of antimicrobial initiation or matched intensive care unit day and the five preceding days, as well as in matched healthy controls (n = 59). Independent determinants of sMR concentration were identified via multivariable linear regression. Serum sMR time profiles were analysed with repeated-measures ANOVA. Predictive properties were assessed via area under the receiver operating curve (aROC). Results Serum sMR was higher in IFI patients than in all other groups (all p

Rapid pathogen identification (ID) and antimicrobial susceptibility testing (AST) of bacteria-causing bloodstream infections can improve patients' outcome. In this study, we evaluated the performance of Alfred60

PurposeLong-term outcomes of critical illness may be affected by duration of critical illness and intensive care. We aimed to investigate differences in mortality and morbidity after short (MethodsFormer EPaNIC-trial patients were included in this preplanned prospective cohort, 5-year follow-up study. Mortality was assessed in all. For morbidity analyses, all long-stay and—for feasibility—a random sample (30%) of short-stay survivors were contacted. Primary outcomes were total and post-28-day 5-year mortality. Secondary outcomes comprised handgrip strength (HGF, %pred), 6-minute-walking distance (6MWD, %pred) and SF-36 Physical Function score (PF SF-36). One-to-one propensity-score matching of short-stay and long-stay patients was performed for nutritional strategy, demographics, comorbidities, illness severity and admission diagnosis. Multivariable regression analyses were performed to explore ICU factors possibly explaining any post-ICU observed outcome differences.ResultsAfter matching, total and post-28-day 5-year mortality were higher for long-stayers (48.2% (95%CI: 43.9% to 52.6%) and 40.8% (95%CI: 36.4% to 45.1%)) versus short-stayers (36.2% (95%CI: 32.4% to 40.0%) and 29.7% (95%CI: 26.0% to 33.5%), pConclusionLonger duration of intensive care is associated with excess 5-year mortality and morbidity, partially explained by potentially modifiable ICU factors.Trail registration numberNCT00512122.

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., &lt, 90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear.We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided.Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006).In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.).

PURPOSE: For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus-pituitary-adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival. METHODS: Patients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward. RESULTS: In all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol. CONCLUSIONS: Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test. ispartof: INTENSIVE CARE MEDICINE vol:44 issue:10 pages:1720-1729 ispartof: location:United States status: published

OBJECTIVE: In the EPaNIC RCT (N=4640), postponing the administration of parenteral nutrition (PN) to beyond 1 week in the intensive care unit (ICU) (late-PN) reduced the number of ICU-acquired infections and the costs for antimicrobial drugs compared with initiation of PN within 24-48 hours of admission (early-PN). In a secondary analysis, we hypothesize that late-PN reduces the odds to acquire an invasive fungal infection (IFI) in the ICU. METHODS: The impact of late-PN (N=2328) versus early-PN (N=2312) on acquired IFI and on the likelihood to acquire an IFI over time was assessed in univariable and multivariable analyses. Subsequently, we performed multivariable analyses to assess the effect of the mean total daily administered calories from admission until day 3, day 5, and day 7 on the likelihood over time of acquiring an IFI. RESULTS: Fewer late-PN patients acquired an IFI compared with early-PN patients (77/2328 versus 112/2312) (p 0.008). After adjusting for risk factors, the odds to acquire an IFI and the likelihood of acquiring an IFI at any time were lower in late-PN (adjusted odds ratio 0.66, 95% CI 0.48-0.90, p 0.009; adjusted hazard ratio (HRadj) 0.70, 95% CI 0.52-0.93, p 0.02). Larger caloric amounts from admission until day 7 were associated with a higher likelihood to acquire an IFI over time (HRadj 1.09, 95% CI 1.02-1.16, p 0.009). CONCLUSION: Postponing PN to beyond 1 week and smaller caloric amounts until day 7 in the ICU reduced ICU-acquired IFIs and the likelihood to develop an IFI over time. ispartof: Clinical Microbiology And Infection vol:25 issue:3 pages:359-364 ispartof: location:England status: Published online

INTRODUCTION: Around 0.1-0.2% of all pregnancies are complicated by respiratory failure. The altered physiology of pregnancy predisposes mother and child to develop hypoxia and respiratory failure more easily than a non-pregnant patient. Respiratory failure in pregnancy may have detrimental fetal complications, therefore extensive knowledge of the range of therapeutic options is necessary. If conventional lung-protective mechanical ventilation strategies fail, alternative approaches such as veno-venous extracorporeal membrane oxygenation (VV-ECMO) should be considered. CASE PRESENTATION: A previously healthy 30-year-old P1G2 at 26 weeks and 6 days of gestation was admitted to the emergency department because of a severe respiratory infection. She suffered of severe hypoxic respiratory failure due to an overwhelming pneumonia (influenza type A) with acute respiratory distress syndrome (ARDS). Because long protective ventilation strategies and ventilation in prone positioning were inadequate, and further respiratory deterioration occurred, VV-ECMO was initiated. CONCLUSION: In a pregnant patient with severe respiratory failure, when other interventions fail, initiation of VV-ECMO should not be delayed. The use of VV-ECMO in pregnancy is a multi-disciplinary team approach. ispartof: TURKISH JOURNAL OF EMERGENCY MEDICINE vol:19 issue:3 pages:111-112 ispartof: location:India status: published

UNLABELLED: Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in the intensive care unit (ICU) (late PN) accelerated recovery as compared with early initiation of PN (early PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large randomized controlled trial of early PN versus late PN (n = 4,640). In all patients plasma bilirubin (daily) and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], twice weekly; n = 3,216) were quantified. In a random predefined subset of patients, plasma bile acids (BAs) were also quantified at baseline and on days 3, 5, and last ICU-day (n = 280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n = 776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late PN than in the early PN group (P < 0.001). In the late PN group, as soon as PN was started on day 8 bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP, and ALT were lower in the late PN group (P < 0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (P < 0.01), similarly for the two groups. Fewer patients in the late PN than in the early PN group developed biliary sludge on day 5 (37% versus 45%; P = 0.04). CONCLUSION: Tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP, and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early PN. ispartof: HEPATOLOGY vol:60 issue:1 pages:202-210 ispartof: location:United States status: published

The pituitary gland plays a predominant role in the endocrine system. Consequently, patients with pituitary diseases or after pituitary surgery present unique challenges to the intensivist. Failure of the anterior pituitary gland to secrete one or more pituitary hormones results in a clinical syndrome known as hypopituitarism. While hypopituitarism is mostly encountered in patients in whom the diagnosis has already been made, acute exacerbation of an undiagnosed insufficiency may occasionally occur. Acute decompensated patients with suspected hypopituitarism should be admitted to an intensive care unit for haemodynamic stabilization, replacement of missing hormones, and identification and treatment of the causative stressor. Prompt administration of hydrocortisone is the single most important acute medical intervention in hypopituitaric patients. Failure of the posterior pituitary to secrete antidiuretic hormone results in diabetes insipidus (DI). DI is characterized by excess volumes of severely diluted urine, which can lead to hyperosmolality and hypernatraemia as many critically-ill patients do not have free access to oral fluids due to obtundation or sedation. Management of DI includes the correction of free water deficit and the reduction of polyuria with desmopressin. The post-operative care following pituitary surgery focuses on vigilant observation for neurosurgical complications (visual loss, meningitis, and cerebrospinal fluid leakage) and monitoring of neuroendocrinological perturbations (hypopituitarism and disorders of water balance, such as DI and SIADH). SIADH presents with hyponatremia, hypo-osmolality, and inappropriately concentrated urine in a setting of euvolaemia and can be managed in most cases by fluid restriction. Potential disruption of the pituitary-adrenal function is covered with peri-operative glucocorticoids.

BACKGROUND: Augmented renal clearance in critically ill patients can result in underdosing of life-saving drugs, potentially leading to therapeutic failure. To detect this phenomenon, correct assessment of the kidney function is essential. Currently, little is known about the validity of mathematical formulas to estimate renal function in this subset of patients. OBJECTIVE: To evaluate the validity of different methods to estimate kidney function in critically ill patients with augmented renal clearance by comparing measured renal clearance with estimated clearance using different formulas. METHODS: An observational, retrospective, single-center study was conducted in a 34-bed surgical intensive care unit (SICU) of the University Hospitals Leuven, Leuven, Belgium. Adults admitted to the SICU in 2010 with a measured creatinine clearance (CrCl) of 120 mL/min or more (based on 24-hour urinary collection) were included. The measured clearance values were compared with estimated clearance values as calculated by the Cockcroft-Gault (CrClCG) method and the re-expressed 4-variable Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) formula. Spearman rank order correlation was performed to determine the relationship between measured and estimated clearances. Bland-Altman plots were evaluated to assess bias and limits of agreement between the 2 methods. RESULTS: Records on 1317 patients were screened. Augmented renal clearance was present in 390 patients. Spearman correlation showed fair correlation between measured and estimated clearances (rs = 0.343; p < 0.001 [CrClCG] and rs = 0.290; p < 0.001 [eGFR]). Bias was −11.2 mL/min with limits of agreement (–131.7; 109.3 mL/min [CrClCG]) and −19.9 mL/min with limits of agreement (–170.4; 130.7 mL/min [eGFR]). CONCLUSIONS: Estimated renal clearances, such as the eGFR estimated by the MDRD formula or CrCl estimated by CG, showed poor agreement with measured CrCl values in our critically ill population displaying augmented renal clearance. Clinicians should be cautious when interpreting kidney function based on estimating equations in this subset of patients. Instead, measured CrCl using urinary collection is recommended in patients suspected of displaying augmented renal clearance.

A b s t r ac t Background Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. Methods In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. Results Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = 0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P = 0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P = 0.008) and a lower incidence of cholestasis (P

Acute kidney injury frequently complicates critical illness and increases mortality; maintaining normoglycemia with insulin has been shown to reduce the incidence of intensive care unit (ICU)–acquired kidney injury. Here we tested the mechanisms by which this intervention might achieve its goal, using a rabbit model of burn-induced prolonged critical illness in which blood glucose and insulin were independently regulated at normal or elevated levels. Hyperglycemia caused elevated plasma creatinine and severe morphological kidney damage that correlated with elevated cortical glucose levels. Renal cortical perfusion and oxygen delivery were lower in hyperglycemic/hyperinsulinemic rabbits, compared to other groups, but this did not explain the elevated creatinine. Mitochondrial respiratory chain activities were severely reduced in the hyperglycemic groups (30–40% residual activity), and were inversely correlated with plasma creatinine and cortical glucose. These activities were much less affected by normoglycemia, and hyperinsulinemia was not directly protective. Mitochondrial damage, evident at day 3, preceded the structural injury evident at 7 days. Our study found that hyperglycemia evoked cellular glucose overload in the kidneys of critically ill rabbits, and this was associated with mitochondrial dysfunction and renal injury. Normoglycemia, independent of insulinemia, protected against this damage.

Objective: In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical Illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now Investigated the Impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity. Design: Prospective, randomized laboratory investigation. Setting: University laboratory. Subjects: Three-month-old male rabbits. Interventions. After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required alloxan administration, immediately followed by intravenous insulin and glucose infusions titrated to the respective targets. Measurements and Main Results. In liver, the reduced damage by glucose lowering was not explained by better perfusion/oxygen delivery. Abnormal mitochondrial ultrastructure and function was present in the two hyperglycemic groups, most pronounced with concomitant HI. Affected mitochondrial respiratory chain enzyme activities were reduced to 25% to 62% of values in healthy rabbits, In the presence of up to five-fold increased tissue levels of glucose. This was accompanied by elevated levels of dicarbonyls, which may mediate direct toxicity of cellular glucose overload and accelerated glycolysis. The abnormalities were also present in myocardium, although to a lesser extent and absent in skeletal muscle. Conclusions. In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage. (Crit Care Med 2009; 37:1355-1364)

Transient hyperglycemia is commonly observed in non-diabetic subjects during surgery. We undertook this study to investigate (1) insulin secretion pattern and glucose levels during elective surgery, and (2) the role of pre-operative fasting in the development of surgery-induced hyperglycemia.We examined 21 severely obese normal glucose tolerant patients, who underwent bariatric surgery. From the 21 operated subjects, 14 remained fasted while seven patients received 75 g glucose the preoperative night. They sampled at baseline and from the onset of operation frequently for 9 h thereafter, for measuring serum insulin and glucose.Hyperglycemia developed within 1 h from the onset of operation and lasted 9 h. The administration of 75 g glucose the preoperative night prevented surgery-induced hyperglycemia. Insulin profile analyzed by deconvolution analysis was similar between fasted patients and those who received 75 g glucose. Serum insulin was suppressed at the beginning of the surgery and reached baseline values 4 h thereafter.Hyperglycemia occurred within 1 h from the beginning of surgery and sustained for at least 9 h while insulin levels are suppressed or unaltered compared to baseline values in euglycemia. The administration of 75 g glucose the preoperative night prevents surgery-induced hyperglycemia without altering the profile of insulin secretion.

OBJECTIVE: Tight glycaemic control by intensive insulin therapy (IIT) reduces morbidity and mortality in critically ill patients. As potential mechanisms contributing to the clinical benefits we hypothesized that glycaemic control affects regional nitric oxide (NO) bioavailability by changing NO synthases (NOS) activity, NOS transcription, NOS substrate availability or the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) levels. DESIGN: Prospective, randomized experimental study. SETTING: University medical laboratory. INTERVENTIONS: In a rabbit model of prolonged critical illness we assessed the relative impact of maintaining normal insulin/normoglycaemia (n=8), high insulin/normoglycaemia (n=8), normal insulin/hyperglycaemia (n=9) and high insulin/hyperglycaemia (n=8) plasma levels over 7 days on activity and gene expression of endothelial and inducible NOS isoforms in muscle, liver and aorta biopsies, and on plasma levels of NO, arginine and ADMA. MEASUREMENTS AND RESULTS: Compared with normoglycaemic groups, both hyperglycaemic groups revealed 53% higher day-3 NO plasma levels (p

Although endocrine pathology is usually treated in outpatient clinic, intensive care may be required when endocrinopathies are associated with other medical illnesses or reach a state of decompensation. Although endocrine emergencies are quite rare, they are potentially life-threatening, if not recognized promptly and managed effectively. Therefore, every clinician should always be attentive to a possible diagnosis of these complex disorders. The three major diabetic emergencies comprise diabetic ketoacidosis, hyperglycaemic hyperosmolar state, and prolonged hypoglycaemia. Hyperglycaemic crises are characterized by hypovolaemia, electrolyte disturbances, and potentially life-threatening triggers. Hence, airway-breathing-circulation securement, diagnosis and treatment of the underlying condition, and fluid resuscitation are the cornerstones of acute diabetic ketoacidosis/hyperglycaemic hyperosmolar state management. Subsequently, monitoring and correction of electrolyte disturbances and insulin treatment are initiated. Profound hypoglycaemia should be suspected in every coma patient with an indistinct history or treated with insulin or sulfonylurea/meglitinide. This condition warrants an immediate and a sufficiently long administration of glucose, under blood glucose monitoring. Alternatively, glucagon may be injected subcutaneously, or preferably intramuscularly. Hyperglycaemia in intensive care unit patients is associated with adverse outcome which can be prevented via the implementation of glucose control with intravenous insulin. One should hereby target glucose levels to be as close to normal as possible, without evoking unacceptable glucose fluctuations and hypoglycaemia. The classical non-diabetic endocrine emergencies comprise thyroid storm, myxoedema coma, acute adrenal crisis, and phaeochromocytoma. They all pose diagnostic and therapeutic challenges and require specific treatment such as endocrine replacement or blockage therapy. It is important to note that they are occasionally the presenting manifestation in undiagnosed patients. This chapter also briefly discusses amiodarone-induced thyroid dysfunction.

Aims To document the impact of intensive insulin therapy during intensive care on long-term (4 years) outcome of high-risk cardiac surgery patients. Methods and results In this pre-planned sub-analysis and follow-up study of a large, randomized controlled trial on the effects of intensive insulin therapy during critical illness, we assessed long-term outcome in the 970 patients who had been admitted after high-risk cardiac surgery (mean±SD EuroSCORE of 6.0±3.7; EuroSCORE-predicted hospital mortality of 9.9%; observed hospital mortality of 7.5% in the conventional insulin group and 3.4% in the intensive insulin group). Long-term outcome was quantified as: (a) 4 years survival; (b) incidence of hospital re-admission; (c) level of activity and medical care requirements at 4 years as assessed by the Karnofsky score; and (d) perceived health-related quality-of-life at 4 years as assessed by the Nottingham Health Profile. Four years after ICU admission, the number of post-hospital discharge deaths was similar in the two study groups, reflecting maintenance of the acute survival benefit with intensive insulin therapy. Survivors who had been treated with intensive insulin during ICU stay revealed a similar risk for hospital re-admission and a comparable level of dependency on medical care. There was no effect on quality-of-life in the total group, whereas the increased survival of sicker patients with at least 3 days of insulin therapy evoked a more compromised perceived quality-of-life, in particular regarding social and family life. Conclusion The short-term survival benefit obtained with insulin-titrated glycaemic control during intensive care after cardiac surgery was maintained after 4 years, without inducing increased medical care requirements but possibly at the expense of compromised perceived quality of social and family life.

Tight blood glucose control with insulin reduces morbidity and mortality of critically ill patients. However, the relative impact of maintaining normoglycemia and of glycemia-independent actions of insulin remains unknown. We therefore independently manipulated blood glucose and plasma insulin levels in burn-injured, parentally fed rabbits over 7 days to obtain four study groups: two normoglycemic groups with either normal or elevated insulin levels and two hyperglycemic groups with either normal or elevated insulin levels. We studied the relative impact of glycemia and glycemia-independent effects of insulin on survival; myocardial contractility in an open chest preparation; endothelial function in isolated aortic rings; and liver, kidney, and leukocyte function in a rabbit model of critical illness. Mortality was significantly lower in the two normoglycemic groups independent of insulin levels. Maintaining normoglycemia, independent of insulin levels, prevented endothelial dysfunction as well as liver and kidney injury. To increase myocardial systolic function, elevated insulin levels and prevention of hyperglycemia were required concomitantly. Leukocyte dysfunction was present in the two hyperglycemic groups, which could in part be rescued by insulin. The results suggest that the observed benefits of intensive insulin therapy required mainly maintenance of normoglycemia; whereas glycemia-independent actions of insulin exerted only minor, organ-specific impact.

This article reviews the mechanisms behind the observed changes in plasma thyroid hormone levels in the acute phase and the prolonged phase of critical illness. It focuses on the neuroendocrinology of the low triiodothyronine syndrome and on thyroid hormone metabolism by deiodination and transport.

Prolonged critical illness is characterized by reduced pulsatile TSH secretion, causing reduced thyroid hormone release and profound changes in thyroid hormone metabolism, resulting in low circulating T(3) and elevated rT(3) levels. To further unravel the underlying mechanisms, we investigated the effects of exogenous TRH and GH-releasing peptide-2 (GHRP-2) in an in vivo model of prolonged critical illness. Burn-injured, parenterally fed rabbits were randomized to receive 4-d treatment with saline, 60 microg/kg.h GHRP-2, 60 microg/kg.h TRH, or 60 microg/kg.h TRH plus 60 microg/kg.h GHRP-2 started on d 4 of the illness (n = 8/group). The activities of the deiodinase 1 (D1), D2, and D3 in snap-frozen liver, kidney, and muscle as well as their impact on circulating thyroid hormone levels were studied. Compared with healthy controls, hepatic D1 activity in the saline-treated, ill animals was significantly down-regulated (P = 0.02), and D3 activity tended to be up-regulated (P = 0.06). Infusion of TRH and TRH plus GHRP-2 restored the catalytic activity of D1 (P = 0.02) and increased T(3) levels back within physiological range (P = 0.008). D3 activity was normalized by all three interventions, but only addition of GHRP-2 to TRH prevented the rise in rT(3) seen with TRH alone (P = 0.02). Liver D1 and D3 activity were correlated (respectively, positively and negatively) with the changes in circulating T(3) (r = 0.84 and r = -0.65) and the T(3)/rT(3) ratio (r = 0.71 and r = -0.60). We conclude that D1 activity during critical illness is suppressed and related to the alterations within the thyrotropic axis, whereas D3 activity tends to be increased and under the joint control of the somatotropic and thyrotropic axes.

Rationale: Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes. Objectives: To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge. Methods: Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis. Measurements and Main Results: A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549–0.888]; P = 0.009), live ICU (HR, 0.698 [0.553–0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514–0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001). Conclusions: After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122). ispartof: American Journal of Respiratory and Critical Care Medicine vol:190 issue:4 pages:410-20 ispartof: location:United States status: published

BACKGROUND: Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS: In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS: With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION: Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING: UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council. publisher: Elsevier articletitle: Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial journaltitle: The Lancet Respiratory Medicine articlelink: http://dx.doi.org/10.1016/S2213-2600(13)70183-8 associatedlink: http://dx.doi.org/10.1016/S2213-2600(13)70148-6 content_type: article copyright: Copyright © 2013 Elsevier Ltd. All rights reserved. ispartof: LANCET RESPIRATORY MEDICINE vol:1 issue:8 pages:621-629 ispartof: location:England status: published

Muscle weakness of critical illness is associated with prolonged dependency on ventilatory support and delayed rehabilitation. Muscle wasting related to poor nutrition has long been considered a major determinant, whereas the importance of myofiber integrity only recently emerged [1-4]. We hypothesized that nutrient restriction early during illness aggravates atrophy while preserving myofiber integrity by activating the crucial cellular quality control pathway autophagy. The latter could be important to preserve muscle function.

ObjectiveProlonged critically ill patients have low circulating thyroid hormone (TH) levels without a rise in TSH, a condition labeled ‘the low tri-iodothyronine (T3) syndrome’. Currently, it is not clear whether this represents an adaptive response. We examined the role of TH transporters monocarboxylate transporter 8 (MCT8, also known as SLC16A2) and MCT10 in the pathogenesis of the low T3 syndrome in prolonged critical illness.MethodsA clinical observational study in critically ill patients and an intervention study in an in vivo animal model of critical illness. Gene expression levels of MCT8 and MCT10 were measured by real-time PCR.ResultsIn prolonged critically ill patients, we measured increased MCT8 but not MCT10 gene expression levels in liver and skeletal muscle as compared with patients undergoing acute surgical stress. In a rabbit model of prolonged critical illness, gene expression levels of MCT8 in liver and of MCT10 in skeletal muscle were increased as compared with healthy controls. Treatment of prolonged critically ill rabbits with TH (thyroxine+T3) resulted in a downregulation of gene expression levels of MCT8 in liver and of MCT10 in muscle. Transporter expression levels correlated inversely with circulating TH parameters.ConclusionsThese data suggest that alterations in the expression of TH transporters do not play a major role in the pathogenesis of the ‘low T3 syndrome’ but rather reflect a compensatory effort in response to hypothyroidism.

The low plasma triiodothyronine (T3) observed during prolonged critical illness can be explained in part by suppressed hepatic deiodinase type I (D1) and increased D3 activity. Infusion of thyrotropin-releasing hormone (TRH) can restore D1 and D3 activity in critically ill rabbits, but it remains unknown whether this is a direct effect of TRH or the TRH-induced rise in circulating thyroxine (T4) and T3.To answer this specific question, burn-injured rabbits randomly received a 4-day treatment with saline, T4, T3, T4+T3, or TRH, started on day 4 of the illness. Plasma iodothyronine concentrations, D1 and D3 activity, and T3-responsive gene expression were quantified in liver and kidney.Infusion of T4, T3, or TRH increased circulating T3 levels and hepatic D1 activity. Co-infusion of T3 with T4 enhanced T4 to T3 conversion as demonstrated by lower T4, higher T3, and lower reverse T3 (rT3) levels and tended to further increase hepatic D1 activity. Hepatic D1 activity correlated positively with circulating T3 and the T3/rT3 ratio, but not with T4, rT3, or thyroid-stimulating hormone.During prolonged critical illness, D1 activity is primarily regulated via changes in circulating T3, suggesting that the low plasma T3 concentrations may be important in sustaining low D1 activity in this condition.

To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3'-diiodothyronine (T(2)) and T(4)S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5- fold higher dose of T(4) and T(3), either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T(3) (P=0.006), hepatic T(3) (P=0.02), and hepatic D1 activity (P=0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P=0.0006) and tissue T(4) (P=0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T(3) and tissue T(3)/reverse T(3) ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T(2). Plasma T(4)S was increased only by T(4) in high dose. We conclude that in prolonged critically ill rabbits, low plasma T(3) levels were associated with low liver and kidney T(3) levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.

In the context of the hypercatabolic response to stress, critically ill patients reveal hyperglycemia and elevated levels of asymmetrical-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases. Both hyperglycemia and elevated ADMA levels predict increased morbidity and mortality. Tight glycemic control by intensive insulin therapy lowers circulating ADMA levels, and improves morbidity and mortality. Methylarginines are released from proteins during catabolism. ADMA is predominantly cleared by the enzyme dimethylarginine-dimethylaminohydrolase (DDAH) in different tissues, whereas its symmetrical isoform (SDMA) is cleared via the kidneys. Therefore, glycemic control or glycemia-independent actions of insulin on protein breakdown and/or on DDAH activity resulting in augmented ADMA levels may explain part of the clinical benefit of intensive insulin therapy. Therefore, we investigated in our animal model of prolonged critical illness the relative impact of maintaining normoglycemia and of glycemia-independent action of insulin over 7 d in a four-arm design on plasma and tissue levels of ADMA and SDMA, on proteolysis as revealed by surrogate parameters as changes of body weight, plasma urea to creatinine ratio, and plasma levels of SDMA, and on tissue DDAH activity. We found that ADMA levels remained normal in the two normoglycemic groups and increased in hyperglycemic groups. SDMA levels in the investigated tissues remained largely unaffected. The urea to creatinine ratio indicated reduced proteolysis in all but normoglycemic/normal insulin animals. DDAH activity deteriorated in hyperglycemic compared with normoglycemic groups. Insulin did not affect this finding independent of glycemic control action. Conclusively, maintenance of normoglycemia and not glycemia-independent actions of insulin maintained physiological ADMA plasma and tissue levels by preserving physiological DDAH activity.