Relevance of Protein Intake for Weaning in the Mechanically Ventilated Critically Ill: Analysis of a Large International Database.

OBJECTIVES: The association between protein intake and the need for mechanical ventilation (MV) is controversial. We aimed to investigate the associations between protein intake and outcomes in ventilated critically ill patients. DESIGN: Analysis of a subset of a large international point prevalence survey of nutritional practice in ICUs. SETTING: A total of 785 international ICUs. PATIENTS: A total of 12,930 patients had been in the ICU for at least 96 hours and required MV by the fourth day after ICU admission at the latest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We modeled associations between the adjusted hazard rate (aHR) of death in patients requiring MV and successful weaning (competing risks), and three categories of protein intake (low: < 0.8 g/kg/d, standard: 0.8-1.2 g/kg/d, high: > 1.2 g/kg/d). We compared five different hypothetical protein diets (an exclusively low protein intake, a standard protein intake given early (days 1-4) or late (days 5-11) after ICU admission, and an early or late high protein intake). There was no evidence that the level of protein intake was associated with time to weaning. However, compared with an exclusively low protein intake, a standard protein intake was associated with a lower hazard of death in MV: minimum aHR 0.60 (95% CI, 0.45-0.80). With an early high intake, there was a trend to a higher risk of death in patients requiring MV: maximum aHR 1.35 (95% CI, 0.99-1.85) compared with a standard diet. CONCLUSIONS: The duration of MV does not appear to depend on protein intake, whereas mortality in patients requiring MV may be improved by a standard protein intake. Adverse effects of a high protein intake cannot be excluded.

Long-Term Trends in the Protection Against Severe Courses of COVID-19 by Vaccination.

BACKGROUND: The long-term course of protection against severe COVID-19 courses by vaccine-induced or hybrid immunity in Germany is unclear. METHODS: We studied 146 457 cases aged 60-99 years in the German federal state of Bavaria who were immunized against COVID-19 and tested positive for it from February 2022 to January 2023. We calculated adjusted hazard ratios for a severe course (hospitalization or death due to COVID-19) for different intervals between the onset of full primary or booster immunity and the date of the infection. RESULTS: 3342 (2.3%) severe courses of COVID-19 were observed in the first 60 days after the infection. The risk of a severe course rose with the interval between the onset of immune protection and the infection (adjusted hazard ratios and 95% confidence intervals at 6, 9, 12, and 15 months: 1.14 [1.08; 1.20]; 1.33 [1.24; 1.42]; 1.39 [1.25; 1.54]; 1.61 [1.35; 1.93]). The risk rose more slowly when mRNA-based vaccines were used exclusively. In a previous study, we observed 82% initial efficacy in cases aged 60 and above who received a booster vaccination (compared to unvaccinated cases) and an absolute risk reduction of 2.1%. If one extrapolates these findings to the current study, the residual efficacy and absolute risk reduction are found to be approximately 71% and 1.8% (respectively) at 6 months, and 32% and 0.8% at 15 months. CONCLUSION: These results indicate that, during the Omicron wave, the protection of older persons against a severe COVID-19 course gradually declined from six months after vaccination onward. The limitations of this study include confounders that could not be taken into account, possible misclassification of the cause of death, and selection bias due to missing information about vaccination status and severe COVID-19 courses.

[Laboratory and calorimetric monitoring of medical nutrition therapy in intensive and intermediate care units : Second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI)]. / Laborchemisches und kalorimetrisches Monitoring der medizinischen Ernährungstherapie auf der Intensiv- und Intermediate Care Station : Zweites Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

This second position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) provides recommendations on the laboratory monitoring of macro- and micronutrient intake as well as the use of indirect calorimetry in the context of medical nutrition therapy of critically ill adult patients. In addition, recommendations are given for disease-related or individual (level determination) substitution and (high-dose) pharmacotherapy of vitamins and trace elements.

Medical nutrition therapy and clinical outcomes in critically ill adults: a European multinational, prospective observational cohort study (EuroPN).

BACKGROUND: Medical nutrition therapy may be associated with clinical outcomes in critically ill patients with prolonged intensive care unit (ICU) stay. We wanted to assess nutrition practices in European intensive care units (ICU) and their importance for clinical outcomes. METHODS: Prospective multinational cohort study in patients staying in ICU ≥ 5 days with outcome recorded until day 90. Macronutrient intake from enteral and parenteral nutrition and non-nutritional sources during the first 15 days after ICU admission was compared with targets recommended by ESPEN guidelines. We modeled associations between three categories of daily calorie and protein intake (low: < 10 kcal/kg, < 0.8 g/kg; moderate: 10-20 kcal/kg, 0.8-1.2 g/kg, high: > 20 kcal/kg; > 1.2 g/kg) and the time-varying hazard rates of 90-day mortality or successful weaning from invasive mechanical ventilation (IMV). RESULTS: A total of 1172 patients with median [Q1;Q3] APACHE II score of 18.5 [13.0;26.0] were included, and 24% died within 90 days. Median length of ICU stay was 10.0 [7.0;16.0] days, and 74% of patients could be weaned from invasive mechanical ventilation. Patients reached on average 83% [59;107] and 65% [41;91] of ESPEN calorie and protein recommended targets, respectively. Whereas specific reasons for ICU admission (especially respiratory diseases requiring IMV) were associated with higher intakes (estimate 2.43 [95% CI: 1.60;3.25] for calorie intake, 0.14 [0.09;0.20] for protein intake), a lack of nutrition on the preceding day was associated with lower calorie and protein intakes (- 2.74 [- 3.28; - 2.21] and - 0.12 [- 0.15; - 0.09], respectively). Compared to a lower intake, a daily moderate intake was associated with higher probability of successful weaning (for calories: maximum HR 4.59 [95% CI: 1.5;14.09] on day 12; for protein: maximum HR 2.60 [1.09;6.23] on day 12), and with a lower hazard of death (for calories only: minimum HR 0.15, [0.05;0.39] on day 19). There was no evidence that a high calorie or protein intake was associated with further outcome improvements. CONCLUSIONS: Calorie intake was mainly provided according to the targets recommended by the active ESPEN guideline, but protein intake was lower. In patients staying in ICU ≥ 5 days, early moderate daily calorie and protein intakes were associated with improved clinical outcomes. Trial registration NCT04143503 , registered on October 25, 2019.

[Assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units : Position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI)]. / Erfassung und apparatives Monitoring des Ernährungsstatus von Patient*innen auf der Intensiv- und Intermediate Care Station : Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

At the time of admission to an intensive or intermediate care unit, assessment of the patients' nutritional status may have both prognostic and therapeutic relevance with regard to the planning of individualized medical nutrition therapy (MNT). MNT has definitely no priority in the initial treatment of a critically ill patient, but is often also neglected during the course of the disease. Especially with prolonged length of stay, there is an increasing risk of malnutrition with considerable prognostic macro- and/or micronutrient deficit. So far, there are no structured, evidence-based recommendations for assessing nutritional status in intensive or intermediate care patients. This position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI) presents consensus-based recommendations for the assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units. These recommendations supplement the current S2k guideline "Clinical Nutrition in Intensive Care Medicine" of the German Society for Nutritional Medicine (DGEM) and the DIVI.

Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models.

BACKGROUND: Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use. METHODS: Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: < 0.8 g/kg per day, standard: 0.8-1.2 g/kg per day, high: > 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet). RESULTS: Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27-0.66], standard intake 0.99 g/kg [IQR 0.89- 1.09], and high intake 1.41 g/kg [IQR 1.29-1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome. CONCLUSIONS: Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198.

[The New DGEM Guideline - All the Clinician Needs to Know]. / Die neue DGEM-Leitlinie ­ alles, was der Kliniker wissen muss.

The German Society for Nutritional Medicine has recently updated its guideline on clinical nutrition in critically ill patients thereby cooperating with seven other national medical societies. This article provides readers with a concise overview on selected key aspects of this guideline relevant for clinical practice. We will discuss some issues in detail such as the determination of energy expenditure and of calorie and protein intake, the choice of the route of administration (enteral or parenteral), and the handling of micronutrients.

Clinical Nutrition in Critical Care Medicine - Guideline of the German Society for Nutritional Medicine (DGEM).

PURPOSE: Enteral and parenteral nutrition of adult critically ill patients varies in terms of the route of nutrient delivery, the amount and composition of macro- and micronutrients, and the choice of specific, immune-modulating substrates. Variations of clinical nutrition may affect clinical outcomes. The present guideline provides clinicians with updated consensus-based recommendations for clinical nutrition in adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. METHODS: The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. According to the S2k-guideline classification, no systematic review of the available evidence was required to make recommendations, which, therefore, do not state evidence- or recommendation grades. Nevertheless, we considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of other societies. The liability of each recommendation was described linguistically. Each recommendation was finally validated and consented through a Delphi process. RESULTS: In the introduction the guideline describes a) the pathophysiological consequences of critical illness possibly affecting metabolism and nutrition of critically ill patients, b) potential definitions for different disease phases during the course of illness, and c) methodological shortcomings of clinical trials on nutrition. Then, we make 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in critically ill patients. Among others, recommendations include the assessment of nutrition status, the indication for clinical nutrition, the timing and route of nutrient delivery, and the amount and composition of substrates (macro- and micronutrients); furthermore, we discuss distinctive aspects of nutrition therapy in obese critically ill patients and those treated with extracorporeal support devices. CONCLUSION: The current guideline provides clinicians with up-to-date recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. The period of validity of the guideline is approximately fixed at five years (2018-2023).

Enteral vs. parenteral nutrition in septic shock: are they equivalent?

PURPOSE OF REVIEW: The current review focuses on recent clinical evidence and updated guideline recommendations on the effects of enteral vs. parenteral nutrition in adult critically ill patients with (septic) shock. RECENT FINDIGS: The largest multicenter randomized-controlled trial showed that the route of nutrient supply was unimportant for 28-day and 90-day mortality, infectious morbidity and length of stay in mechanically ventilated patients with shock. The enteral route, however, was associated with lower macronutrient intake and significantly higher frequency of hypoglycemia and moderate-to-severe gastrointestinal complications. Integrating these findings into recent meta-analyses confirmed that the route per se has no effect on mortality and that interactions with (infectious) morbidity are inconsistent or questionable. SUMMARY: The strong paradigm of favoring the enteral over the parenteral route in critically ill patients has been challenged. As a consequence, updated guidelines recommend withholding enteral nutrition in patients with uncontrolled shock. It is still unclear, however, whether parenteral nutrition is advantageous in patients with shock although benefits are conceivable in light of less gastrointestinal complications. Thus far, no guideline has addressed indications for parenteral nutrition in these patients. By considering recent scientific evidence, specific guideline recommendations, and expert opinions, we present a clinical algorithm that may facilitate decision-making when feeding critically ill patients with shock.

[DGEM Guideline "Clinical Nutrition in Critical Care Medicine" - short version]. / DGEM-Leitlinie: Klinische Ernährung in der Intensivmedizin ­ Kurzversion.

PURPOSE: Variations of clinical nutrition may affect outcome of critically ill patients. Here we present the short version of the updated consenus-based guideline (S2k classification) "Clinical nutrition in critical care medicine" of the German Society for Nutritional Medicine (DGEM) in cooperation with 7 other national societies. The target population of the guideline was defined as critically ill adult patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g. mechanical ventilation) to maintain organ function. METHODS: The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. We considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of international societies. The liability of each recommendation was indicated using linguistic terms. Each recommendation was finally validated and consented by a Delphi process. RESULTS: The short version presents a summary of all 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in the target population. A specific focus is the adjustment of nutrition according to the phases of critical illness, and to the individual tolerance to exogenous substrates. Among others, recommendations include the assessment of nutritional status, the indication for clinical nutrition, the timing, route, magnitude and composition of nutrition (macro- and micronutrients) as well as distinctive aspects of nutrition therapy in obese critically ill patients and those with extracorporeal support devices. CONCLUSION: The current short version of the guideline provides a concise summary of the updated recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring pharmacological and/or mechanical support. The validity of the guideline is approximately fixed at five years (2018 - 2023).

Calorie intake and short-term survival of critically ill patients.

BACKGROUND & AIMS: The association between calorie supply and outcome of critically ill patients is unclear. Results from observational studies contradict findings of randomized studies, and have been questioned because of unrecognized confounding by indication. The present study wanted to re-examine the associations between the daily amount of calorie intake and short-term survival of critically ill patients using several novel statistical approaches. METHODS: 9661 critically ill patients from 451 ICUs were extracted from an international database. We examined associations between survival time and three pragmatic nutritional categories (I: <30% of target, II: 30-70%, III: >70%) reflecting different amounts of total daily calorie intake. We compared hazard ratios for the 30-day risk of dying estimated for different hypothetical nutrition support plans (different categories of daily calorie intake during the first 11 days after ICU admission). To minimize indication bias, we used a lag time between nutrition and outcome, we particularly considered daily amounts of calorie intake, and we adjusted results to the route of calorie supply (enteral, parenteral, oral). RESULTS: 1974 patients (20.4%) died in hospital before day 30. Median of daily artificial calorie intake was 1.0 kcal/kg [IQR 0.0-4.1] in category I, 12.3 kcal/kg [9.4-15.4] in category II, and 23.5 kcal/kg [19.5-27.8] in category III. When compared to a plan providing daily minimal amounts of calories (category I), the adjusted minimal hazard ratios for a delayed (from day 5-11) or an early (from day 1-11) mildly hypocaloric nutrition (category II) were 0.71 (95% confidence interval [CI], 0.54 to 0.94) and 0.56 (95% CI, 0.38 to 0.82), respectively. No substantial hazard change could be detected, when a delayed or an early, near target calorie intake (category III) was compared to an early, mildly hypocaloric nutrition. CONCLUSIONS: Compared to a severely hypocaloric nutrition, a mildly hypocaloric nutrition is associated with a decreased risk of death. In unselected critically ill patients, this risk cannot be reduced further by providing amounts of calories close to the calculated target. STUDY REGISTRATION: ID number ISRCTN17829198, website http://www.isrctn.org.

Penalized estimation of complex, non-linear exposure-lag-response associations.

We propose a novel approach for the flexible modeling of complex exposure-lag-response associations in time-to-event data, where multiple past exposures within a defined time window are cumulatively associated with the hazard. Our method allows for the estimation of a wide variety of effects, including potentially smooth and smoothly time-varying effects as well as cumulative effects with leads and lags, taking advantage of the inference methods that have recently been developed for generalized additive mixed models. We apply our method to data from a large observational study of intensive care patients in order to analyze the association of both the timing and the amount of artificial nutrition with the short term survival of critically ill patients. We evaluate the properties of the proposed method by performing extensive simulation studies and provide a systematic comparison with related approaches.

Nonparametric change point estimation for survival distributions with a partially constant hazard rate.

We present a new method for estimating a change point in the hazard function of a survival distribution assuming a constant hazard rate after the change point and a decreasing hazard rate before the change point. Our method is based on fitting a stump regression to p values for testing hazard rates in small time intervals. We present three real data examples describing survival patterns of severely ill patients, whose excess mortality rates are known to persist far beyond hospital discharge. For designing survival studies in these patients and for the definition of hospital performance metrics (e.g. mortality), it is essential to define adequate and objective end points. The reliable estimation of a change point will help researchers to identify such end points. By precisely knowing this change point, clinicians can distinguish between the acute phase with high hazard (time elapsed after admission and before the change point was reached), and the chronic phase (time elapsed after the change point) in which hazard is fairly constant. We show in an extensive simulation study that maximum likelihood estimation is not robust in this setting, and we evaluate our new estimation strategy including bootstrap confidence intervals and finite sample bias correction.

Long-term changes of patient-reported quality of life after major trauma: The importance of the time elapsed after injury.

BACKGROUND: Numerous studies have identified various risk factors for a poor health-related quality of life (HRQOL) after severe trauma. The relative importance of the time elapsed after injury, however, is unknown and results of clinical studies have been conflicting. METHODS: A cross-sectional study was performed in two trauma centres using data from the German TraumaRegister DGU®, which contained prospectively collected information on the type and severity of the injury, on critical care, and on outcome. To evaluate HRQOL in patients surviving more than 500days after the injury, we used a self-rating instrument, the EQ-5D which contains a visual analogue scale (EQ-VAS), and which allows the calculation of a global outcome indicator, the EQ-D5 index value. Complex statistical models were used to evaluate independent associations between the time elapsed after injury and a poor HRQOL. RESULTS: Of 380 contacted patients, follow-up assessments could be obtained in 168 patients (44.2%) 3.6±1.6 (SD) years after the injury. There was a linear association between the time elapsed after the injury and the% of contacted patients not participating in the study (p=0.013). In participating subjects, average EQ-5D index value was 0.599±0.299, and average EQ-VAS rating 67.8±22.0. A very poor quality of life (EQ-5D index value<0.6, EQ-VAS rating≤50) could be found in 43.5% and 28.0% of the patients, respectively. After adjusting for multiple confounders, the number of days elapsed after injury showed a complex non-linear and independent association with a poor HRQOL (low EQ-5D index value: p=0.027; low EQ-VAS rating: p=0.008). Frequencies of a poor HRQOL reached their minimum about four to five years after the injury and increased thereafter. CONCLUSIONS: There is an independent, U-shaped association between the frequency of extreme values of HRQOL and the time elapsed after injury. Time patterns of HRQOL may be sensitive to increasing rates of attrition since patients with a good outcome are less likely to respond to questionnaires. Time from injury should be incorporated into all future cross sectional studies trying to identify predictors of HRQOL.