The effect of higher versus lower protein delivery in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

Background: The optimal protein dose in critical illness is unknown. We aim to conduct a systematic review of randomized controlled trials (RCTs) to compare the effect of higher versus lower protein delivery (with similar energy delivery between groups) on clinical and patient-centered outcomes in critically ill patients. Methods: We searched MEDLINE, EMBASE, CENTRAL and CINAHL from database inception through April 1, 2021.We included RCTs of (1) adult (age ≥ 18) critically ill patients that (2) compared higher vs lower protein with (3) similar energy intake between groups, and (4) reported clinical and/or patient-centered outcomes. We excluded studies on immunonutrition. Two authors screened and conducted quality assessment independently and in duplicate. Random-effect meta-analyses were conducted to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Results: Nineteen RCTs were included (n = 1731). Sixteen studies used primarily the enteral route to deliver protein. Intervention was started within 72 h of ICU admission in sixteen studies. The intervention lasted between 3 and 28 days. In 11 studies that reported weight-based nutrition delivery, the pooled mean protein and energy received in higher and lower protein groups were 1.31 ± 0.48 vs 0.90 ± 0.30 g/kg and 19.9 ± 6.9 versus 20.1 ± 7.1 kcal/kg, respectively. Higher vs lower protein did not significantly affect overall mortality [risk ratio 0.91, 95% confidence interval (CI) 0.75-1.10, p = 0.34] or other clinical or patient-centered outcomes. In 5 small studies, higher protein significantly attenuated muscle loss (MD -3.44% per week, 95% CI -4.99 to -1.90; p < 0.0001). Conclusion: In critically ill patients, a higher daily protein delivery was not associated with any improvement in clinical or patient-centered outcomes. Larger, and more definitive RCTs are needed to confirm the effect of muscle loss attenuation associated with higher protein delivery. PROSPERO registration number: CRD42021237530

Association between ultrasound quadriceps muscle status with premorbid functional status and 60-day mortality in mechanically ventilated critically ill patient: a single-center prospective observational study

Background & aims: In critically ill patients, direct measurement of skeletal muscle using bedside ultrasound (US) may identify a patient population that might benefit more from optimal nutrition practices. When US is not available, survey measures of nutrition risk and functional status that are associated with muscle status may be used to identify patients with low muscularity. This study aims to determine the association between baseline and changing ultrasound quadriceps muscle status with premorbid functional status and 60-day mortality. Methods: This single-center prospective observational study was conducted in a general ICU. Mechanically ventilated critically ill adult patients (age ≥18 years) without pre-existing systemic neuromuscular diseases and expected to stay for ≥96 h in the ICU were included. US measurements were performed within 48 h of ICU admission (baseline), at day 7, day 14 of ICU stay and at ICU discharge (if stay >14 days). Quadriceps muscle layer thickness (QMLT), rectus femoris cross sectional area (RFCSA), vastus intermedius pennation angle (PA) and fascicle length (FL), and rectus femoris echogenicity (mean and standard deviation [SD]) were measured. Patients' next-of-kin were interviewed by using established questionnaires for their pre-hospitalization nutritional risk (nutrition risk screening-2002) and functional status (SARC-F, clinical frailty scale [CFS], Katz activities of daily living [ADL] and Lawton Instrumental ADL). Results: Ninety patients were recruited. A total of 86, 53, 24 and 10 US measures were analyzed, which were performed at a median of 1, 7, 14 and 22 days from ICU admission, respectively. QMLT, RFCSA and PA reduced significantly over time. The overall trend of change of FL was not significant. The only independent predictor of 60-day mortality was the change of QMLT from baseline to day 7 (adjusted odds ratio 0.95 for every 1% less QMLT loss, 95% confidence interval 0.91-0.99; p = 0.02). Baseline measures of high nutrition risk (modified nutrition risk in critically ill ≥5), sarcopenia (SARC-F ≥4) and frailty (CFS ≥5) were associated with lower baseline QMLT, RFCSA and PA and higher 60-day mortality. Conclusions: Every 1% loss of QMLT over the first week of critical illness was associated with 5% higher odds of 60-day mortality. SARC-F, CFS and mNUTRIC are associated with quadriceps muscle status and 60-day mortality and may serve as a potential simple and indirect measures of premorbid muscle status at ICU admission

Impact of Smoking and Brain Metastasis on Outcomes of Advanced <i>EGFR</i> Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

<div><p>Objectives</p><p>This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in <i>EGFR</i> mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.</p><p>Methods</p><p>A retrospective review of <i>EGFR</i> mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced <i>EGFR</i> M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.</p><p>Results</p><p>444/742 (59.8%) ADC reflex tested for <i>EGFR</i> mutations were <i>EGFR</i> M+. Amongst never-smokers (n=468), <i>EGFR</i> M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.</p><p>Conclusions</p><p>The high prevalence of <i>EGFR</i> M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.</p></div

Association between ultrasound quadriceps muscle status with premorbid functional status and 60-day mortality in mechanically ventilated critically ill patient: A single-center prospective observational study

Background & aims: In critically ill patients, direct measurement of skeletal muscle using bedside ultrasound (US) may identify a patient population that might benefit more from optimal nutrition practices. When US is not available, survey measures of nutrition risk and functional status that are associated with muscle status may be used to identify patients with low muscularity. This study aims to determine the association between baseline and changing ultrasound quadriceps muscle status with premorbid functional status and 60-day mortality. Methods: This single-center prospective observational study was conducted in a general ICU. Mechanically ventilated critically ill adult patients (age ≥18 years) without pre-existing systemic neuromuscular diseases and expected to stay for ≥96 h in the ICU were included. US measurements were performed within 48 h of ICU admission (baseline), at day 7, day 14 of ICU stay and at ICU discharge (if stay >14 days). Quadriceps muscle layer thickness (QMLT), rectus femoris cross sectional area (RFCSA), vastus intermedius pennation angle (PA) and fascicle length (FL), and rectus femoris echogenicity (mean and standard deviation [SD]) were measured. Patients' next-of-kin were interviewed by using established questionnaires for their pre-hospitalization nutritional risk (nutrition risk screening-2002) and functional status (SARC-F, clinical frailty scale [CFS], Katz activities of daily living [ADL] and Lawton Instrumental ADL). Results: Ninety patients were recruited. A total of 86, 53, 24 and 10 US measures were analyzed, which were performed at a median of 1, 7, 14 and 22 days from ICU admission, respectively. QMLT, RFCSA and PA reduced significantly over time. The overall trend of change of FL was not significant. The only independent predictor of 60-day mortality was the change of QMLT from baseline to day 7 (adjusted odds ratio 0.95 for every 1% less QMLT loss, 95% confidence interval 0.91-0.99; p = 0.02). Baseline measures of high nutrition risk (modified nutrition risk in critically ill ≥5), sarcopenia (SARC-F ≥4) and frailty (CFS ≥5) were associated with lower baseline QMLT, RFCSA and PA and higher 60-day mortality. Conclusions: Every 1% loss of QMLT over the first week of critical illness was associated with 5% higher odds of 60-day mortality. SARC-F, CFS and mNUTRIC are associated with quadriceps muscle status and 60-day mortality and may serve as a potential simple and indirect measures of premorbid muscle status at ICU admission

Kaplan-Meier plots of cohort of 211 patients treated with 1^st line EGFR TKI; (a) PFS by brain metastasis in ECOG 0–1 patients, (b) PFS by brain metastasis in ECOG 2–4 patients, (c) OS by brain metastasis in ECOG 0–1 patients, and (d) OS by brain metastasis in ECOG 2–4 patients.

<p>Kaplan-Meier plots of cohort of 211 patients treated with 1^st line EGFR TKI; (a) PFS by brain metastasis in ECOG 0–1 patients, (b) PFS by brain metastasis in ECOG 2–4 patients, (c) OS by brain metastasis in ECOG 0–1 patients, and (d) OS by brain metastasis in ECOG 2–4 patients.</p

Univariate analysis of progression free survival and overall survival.

<p>Univariate analysis of progression free survival and overall survival.</p

Sites of EGFR mutations amongst 461 patients.

<p>Sites of EGFR mutations amongst 461 patients.</p

Clinical characteristics and <i>EGFR</i> mutation status rates categorised by smoking status and sex.

<p>11 patients with unknown smoking status, and 6 who had samples indeterminate for <i>EGFR</i> mutational status were excluded. 464/762 (60.9%) tested positive for <i>EGFR</i> mutations (<i>EGFR</i> M+). The number of patients needed to test in order to pick up 1 <i>EGFR</i> mutant lung adenocarcinoma in any sub-population stratified by sex and smoking status, was less than 3 patients (male ES; 1/0.357 = 2.8).</p

<i>EGFR</i> mutation rates amongst ever smokers classified by pack years.

<p><i>EGFR</i> mutation rates amongst ever smokers classified by pack years.</p