The effect of protein provision and exercise therapy on patient-reported and clinical outcomes in intensive care unit survivors: A systematic review.

BACKGROUND: Intensive care unit (ICU) survivors deal with long-term health problems, which negatively affect their quality of life (QoL). Nutritional and exercise intervention could prevent the decline of muscle mass and physical functioning which occurs during critical illness. Despite the growing amount of research, robust evidence is lacking. METHODS: For this systematic review, Embase, PubMed and Cochrane Central Register of Controlled Trials databases were searched. The effect of protein provision (PP) or combined protein and exercise therapy (CPE) during or after ICU admission on QoL, physical functioning, muscle health, protein/energy intake and mortality was assessed compared to standard care. RESULTS: Four thousand nine hundred and fifty-seven records were identified. After screening, data were extracted for 15 articles (9 randomised controlled trials and 6 non-randomised studies). Two studies reported improvements in muscle mass, of which one found higher independency in activities of daily living. No significant effect was found on QoL. Overall, protein targets were seldom met and often below recommendations. CONCLUSION: Evidence for the effect of PP or CPE on patient-reported outcomes in ICU survivors is limited due to study heterogeneity and lack of high-quality studies. Future research and clinical practice should focus on adequate protein delivery with exercise interventions to improve long-term outcomes.

Plasma glutamine levels in patients after non-elective or elective ICU admission: an observational study.

BACKGROUND: A low plasma glutamine level at the time of acute admission to the intensive care unit (ICU) is an independent predictor of an unfavourable outcome in critically ill patients. The primary objective of this study was to determine whether there are differences in plasma glutamine levels upon non-elective or elective ICU admission. The secondary objective was to compare glutamine levels over time, and to determine correlations between glutamine levels and the severity of illness and presence of infection in ICU patients. METHODS: We performed a single-centre observational study in a closed-format, 22-bed, mixed ICU. Plasma glutamine levels were measured at admission and every morning at 6.00 a.m. during the ICU stay. We aimed to include at least 80 patients per group. The study was approved by the local Medical Ethics Committee. RESULTS: In 88 patients after elective surgery, the median plasma glutamine level at admission was significantly higher compared with that in 90 non-elective patients (0.43 mmol/l [0.33-0.55 mmol/l] versus 0.25 mmol/l [0.09-0.37 mmol/l], P = 0.001). During the ICU stay, plasma glutamine levels remained significantly higher in elective patients than in non-elective patients. There was a significant correlation between the APACHE IV score and glutamine levels (R = 0.52, P < 0.001). Moreover, backward linear regression analysis showed that this correlation was independently associated with the APACHE IV score and the presence of infection, but not with the type of admission. CONCLUSIONS: Plasma glutamine levels are significantly lower after non-elective admission compared with elective admission to the ICU. A considerable amount of elective and non-elective patients have decreased plasma glutamine levels, but this is not independently associated with the type of admission. In contrast to previous studies, we found that plasma glutamine levels were determined by the severity of illness and the presence of an infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02310035.

Protein and energy intake in intensive care unit survivors during the first year of recovery: A descriptive cohort study.

BACKGROUND: Many intensive care unit (ICU) survivors suffer long-term health issues that affect their quality of life. Nutrition inadequacy can limit their rehabilitation potential. This study investigates nutrition intake and support during ICU admission and recovery. METHODS: In this prospective cohort study, 81 adult ICU patients with stays ≥48 h were included. Data on dietary intake, feeding strategies, baseline and ICU characteristics, and 1-year outcomes (physical health and readmission rates) were collected. The number of patients achieving 1.2 gram per kilogram per day of protein and 25 kilocalories per kilogram per day at 3 months, 6 months, and 12 months after ICU admission was recorded. The impact of dietary supplementation during the year was assessed. Baseline characteristics, intake barriers, and rehabilitation's influence on nutrition intake at 12 months were evaluated, along with the effect of inadequate intake on outcomes. RESULTS: After 12 months, only 10% of 60 patients achieved 1.2 g/kg/day protein intake, whereas 28% reached the advised 25 kcal/kg/day energy target. Supplementary feeding significantly increased protein intake at 3, 6, and 12 months (P = 0.003, P = 0.012, and P = 0.033, respectively) and energy intake at 3 months (P = 0.003). A positive relation was found between female sex and energy intake at 12 months after ICU admission (ß = 4.145; P = 0.043) and taste issues were independently associated with higher protein intake (ß = 0.363; P = 0.036). However, achieving upper-quartile protein or energy intake did not translate into improved physical health outcomes. CONCLUSION: Continuous and improved nutrition care is urgently needed to support patients in reaching nutrition adequacy.

The prevalence of mental frailty in ICU survivors and informal caregiver strain: A 1-year retrospective study of the Frisian aftercare cohort.

Background: Intensive care unit (ICU) survivors often suffer from long-term mental problems and a reduced health-related quality of life (HRQoL). Symptoms of depression, anxiety, and post-traumatic stress disorder may render patients mentally frail post-ICU, resulting in impaired recovery and an increased informal caregiver burden. The aim of this study was to investigate the prevalence of mental frailty up to 12 months after ICU admission and pinpoint markers for early risk-assessment in clinical practice. Methods: A retrospective cohort study (2012-2018) in which clinical and post-ICU data of long-stay (⩾48 h) ICU-patients was used. Mental frailty was identified as clinically relevant symptoms of depression, anxiety, or post-traumatic distress disorder at 12 months after discharge. Results: The prevalence of mental frailty at 12 months post-ICU among the total group of 239 patients was 38%. Mental frailty was defined as clinically relevant symptoms of depression, anxiety, and/or trauma. To achieve this, previously validated cut off values were used for the HADS (HADS-Anxiety ⩾ 8; HADS-Depression ⩾ 8) and TSQ (⩾6), and CSI (⩾7). Conclusion: A significant proportion of ICU-survivors can be identified as mentally frail, which is associated with impaired HRQoL at baseline and post-ICU, and high caregiver strain. These findings emphasize the need for integrative aftercare programs for both the patient and their informal caregivers.

Long-term health-related quality of life, healthcare utilisation and back-to-work activities in intensive care unit survivors: Prospective confirmatory study from the Frisian aftercare cohort.

PURPOSE: More substantial information on recovery after Intensive Care Unit (ICU) admission is urgently needed. In a previous retrospective study, the proportion of non-recovery patients was 44%. The aim of this prospective follow-up study was to evaluate changes in Health-Related Quality of Life (HRQoL) in the first year after ICU-admission. METHODS: Long-stay adult ICU-patients (≥ 48 hours) were included. HRQoL was evaluated with the Dutch translation of the RAND-36 item Health Survey (RAND-36) at baseline via proxy measurement, and at three, six, and twelve months after ICU admission. Subsequently, the relation between physical functioning, healthcare utilisation, and work activities was explored. RESULTS: A total of 81 patients were included in this study. Fifty-five percent of patients did not meet criteria for full recovery and were allocated to the Non Recovery (NR)-group (Physical Functioning domain-score: 35 [15-55]). Baseline physical HRQoL differed significantly between the Recovery (R) and NR-group. Patients in the NR-group received home care more often and had higher healthcare utilisation (44 versus 17% in the first three months post-ICU, p = 0.013). Only fourteen percent of NR-patients were able to participate in work activities. Moreover, NR-patients persistently showed impaired overall HRQoL throughout the year after critical illness. CONCLUSIONS: Limited recovery in ICU survivors is reflected in overall impaired HRQoL, as well as in far-reaching consequences for patients' healthcare needs and their ability to reintegrate into society. In our study, baseline HRQoL appeared to be an important predictor of long-term outcomes, but not Clinical Frailty Scale (CFS) score. And, (proxy-derived) HRQoL may help to identify patients at risk of long-term non-recovery.

Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial.

OBJECTIVES: Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis. DESIGN: Prospective, single center, randomized, placebo-controlled, double-blind clinical trial. SETTING: Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital. PATIENTS: Patients > or =18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment. INTERVENTIONS: Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415. MEASUREMENTS AND MAIN RESULTS: Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09. CONCLUSIONS: In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.

Renal Function is a Major Determinant of ICU-acquired Hypernatremia: A Balance Study on Sodium Handling.

BACKGROUND AND OBJECTIVES: The development of ICU-acquired hypernatremia (IAH) is almost exclusively attributed to 'too much salt and too little water'. However, intrinsic mechanisms also have been suggested to play a role. To identify the determinants of IAH, we designed a prospective controlled study. METHODS: Patients with an anticipated length of stay ICU > 48 hours were included. Patients with hypernatremia on admission and/or on renal replacement therapy were excluded. Patients without IAH were compared with patients with borderline hypernatremia (≥ 143 mmol/L, IAH 143) and more severe hypernatremia (≥ 145 mmol/L, IAH 145). RESULTS: We included 89 patients, of which 51% developed IAH 143 and 29% IAH 145. Sodium intake was high in all patients. Fluid balances were slightly positive and comparable between the groups. Patients with IAH 145 were more severely ill on admission, and during admission, their sodium intake, cumulative sodium balances, serum creatinine and copeptin levels were higher. According to the free water clearance, all the patients conserved water. On multivariate analysis, the baseline serum creatinine was an independent risk factor for the development of IAH 143 and IAH 145. Also, the copeptin levels remained significant for IAH 143 and IAH 145. Sodium intake remained only significant for patients with IAH 145. CONCLUSIONS: Our data support the hypothesis that IAH is due to the combination of higher sodium intake and a urinary concentration deficit, as a manifestation of the renal impairment elicited by severe illness.

Patient-reported physical functioning is limited in almost half of critical illness survivors 1-year after ICU-admission: A retrospective single-centre study.

Post-intensive care unit (ICU) sequelae, including physical and mental health problems, are relatively unexplored. Characteristics commonly used to predict outcome lack prognostic value when it comes to long-term physical recovery. Therefore, the objective of this study was to assess the incidence of non-recovery in long-stay ICU-patients. In this single-centre study, retrospective data of adults with an ICU stay >48 hours who visited the specialized post-ICU clinic, and completed the Dutch RAND 36-item Short Form questionnaire at 3 and 12 months post-ICU, were retrieved from electronic patient records. In cases where physical functioning scores at 12 months were below reference values, patients were allocated to the physical non-recovery (NR) group. Significantly different baseline and (post-)ICU-characteristics were assessed for correlations with physical recovery at 12 months post-ICU. Of 250 patients, 110 (44%) fulfilled the criteria for the NR-group. Neither the severity of illness, type of admission, nor presence of sepsis did not differ between groups. However, NR-patients had a higher age, were more often female, and had a higher incidence of co-morbidities. Shorter LOS ICU, lower incidence of medical comorbidities, and better physical performance at 3 months were significantly correlated with 1-year physical recovery. Comorbidities and reduced physical functioning at 3 months were identified as independent risk-factors for long-term physical non-recovery. In conclusion, a substantial proportion of long-stay ICU-patients who visited the standard care post-ICU clinic did not fulfil the criteria for full physical recovery at 12 months post-ICU. Commonly used ICU-characteristics, such as severity of illness, do not have sufficient prognostic value when it comes to long-term recovery of health-related quality of life.

An observational study on intracutaneous sodium storage in intensive care patients and controls.

The development of ICU-acquired sodium disturbances is not fully understood. Alterations in non-osmotic skin sodium storage, hypothetically inflammation-driven, could play a role. To investigate this in critically ill patients we conducted a patient-control study with skin punch biopsies in patients with sepsis (n = 15), after coronary artery bypass grafting (CABG, n = 15) and undergoing total hip arthroplasty (THA-controls, n = 15) respectively, together representing a range in severity of systemic inflammation. Biopsies were taken within 24 hours (sepsis) and within 2 hours (CABG) after ICU-admission, and prior to arthroplasty. Biopsies were analysed for sodium content. In addition immunostainings and quantitative real time PCR were performed. The primary aim of this study was to detect possible differences in amounts of cutaneous sodium. The secondary aims were to quantify inflammation and lymphangiogenesis with concomitant markers. The highest amounts of both water and sodium were found in patients with sepsis, with slightly lower values after CABG and the lowest amounts in THA-controls. Correlation between water and sodium was 0.5 (p<0.01). In skin biopsies in all groups comparable amounts of macrophages, T-cells and lymph vessels were found. In all groups comparable expression of inflammation markers were found. However, higher mRNA transcript expression levels of markers of lymphangiogenesis were found in patients with sepsis and after CABG. The conjoint accumulation of water and sodium points towards oedema formation. However, the correlation coefficient of 0.5 leaves room for alternative explanations, including non-osmotic sodium storage. No signs of dermal inflammation were found, but upregulation of markers of lymphangiogenesis could indicate future lymphangiogenesis.

Phase angle is related to outcome after ICU admission; an observational study.

INTRODUCTION: Malnutrition at the time of ICU admission is associated with an increased morbidity and mortality. Malnutrition is most often assessed by a questionnaire but can also be determined with bio-impedance and measurement of phase angle. In a single-centre observational study we compared the percentage of malnutrition in patients admitted to our ICU, according to the Short Nutritional Assessment Questionnaire (SNAQ) with the phase angle measured with bio-impedance. Furthermore, we questioned whether malnutrition is related to outcome parameters. METHODS: In a 15 week period consecutive patients admitted to the ICU were included. Exclusion criteria included age <18 years, anatomical and/or neurological abnormalities of the limbs and an ICU stay less than 6 h. Bio-impedance measurements were performed shortly after admission, the SNAQ was obtained from the patient or legal representative. Malnutrition is considered with a SNAQ ≥2 or a phase angle of <5° for men and <4.6° for women. The study was approved by our local ethical committee (MCL, nWMO 77, April 18, 2015). RESULTS: 299 Patients were included (66% male, age 66 ± 12 year, BMI 27 ± 4 kg/m2 and APACHE II score 14 [11-17]), of which 64% elective and 36% acute admissions. Hospital mortality was 7.4%. Malnutrition was present in 16% according to the SNAQ and in 36% according to phase angle. There was a fair accordance between the SNAQ and phase angle. Phase angle was significantly higher in patients with a SNAQ score of 0-1 (5.5°±1.3) in comparison with patients with a SNAQ score ≥2 (4.4°± 1.1) (p < 0.001). Logistic regression analysis showed a significant relation between SNAQ and BMI, malignant disease and hospital length of stay and between phase angle and age, sex, BMI, malignant disease, hospital length of stay and hospital mortality. CONCLUSION: Malnutrition was present in 16% according to the SNAQ and in 36% according to phase angle in our IC population. Malnutrition was associated with prolonged hospital length of stay. In this small population of mixed ICU patients, a low phase angle was found to independently predict hospital mortality. CLINICAL TRIALS. GOV NUMBER: NCT02911181.

Strong ion difference and CVVH: Different response during nadroparin versus citrate anticoagulation.

PURPOSE: To determine the effect on strong ion difference of citrate as an anticoagulant during continuous veno-venous hemofiltration (CVVH). MATERIALS AND METHODS: ICU patients with renal failure and CVVH were included. Patients were treated with either nadroparin (N) or sodium citrate (C) as an anticoagulant. Strong ion difference (SID) apparent (SIDa) and SID effective (SIDe) and strong ion gap (SIG) were calculated at t = 0 and t = 24 h. Citrate concentration was measured in the citrate treated patients. RESULTS: Ten patients with N and nine with C were included. In both groups the SIDa did not change significantly. SIG decreased significantly with N (11.4 ±â€¯4.2 to 4.0 ±â€¯3.1 meq/l; p = 0.005) but not with C (9.3 ±â€¯1.9 to 8.1 ±â€¯2.4 meq/l; p = 0.097). The decrease was significantly greater for N compared to C; p = 0.014. This is reflected by the SIDe which increased significantly (p = 0.022) more from 24.7 ±â€¯4.5 to 32.9 ±â€¯3.9 (p = 0.005) for N and from 26.3 ±â€¯5.8 to 29.6 ±â€¯1.6 for C (p = 0.058). CONCLUSION: Citrate anticoagulation results in a persistently high SIG during CVVH compared to nadroparin. This is associated with the presence of unmeasured anions such as citrate in the systemic circulation.

Hydrochlorothiazide in intensive care unit-acquired hypernatremia: A randomized controlled trial.

PURPOSE: Thiazides are suggested as a treatment for intensive care unit (ICU)-acquired hypernatremia (IAH). The primary aim of the study was reducing serum sodium concentration (sNa) in patients with IAH with hydrochlorothiazide (HCT) in comparison to placebo. Secondary end points were a difference in urine sodium concentration (uNa) and duration of severe IAH. MATERIALS: A monocentric, double-blind, placebo-controlled trial was conducted in 50 patients with IAH and urine potassium + uNa less than sNa in a spot urine sample. Patients were randomized to HCT 25 mg or placebo 1 qd for maximal 7 days. Patients on renal replacement therapy, on medication inducing diabetes insipidus, or with recent use of diuretics were excluded. IAH was defined as sNa of at least 143 mmol/L. RESULTS: At baseline, sNa and uNa were comparable between groups. During the study period, sNa decreased significantly with median 4 mmol/L in both groups, with no significant difference between groups (P=.32). Median uNa increased significantly in both groups (46 [16-86] mmol/L in the HCT-group; 20 [10-66]mmol/L in the placebo group), with no difference between groups (P=.34). Median duration of sNa of at least 145 mmol/L was 3 days in both groups (P=.91). CONCLUSION: HCT 25 mg 1 qd did not significantly affect sNa or uNa in patients with IAH.

Plasma glutamine levels before cardiac surgery are related to post-surgery infections; an observational study.

BACKGROUND: A low plasma glutamine level was found in 34% of patients after elective cardiothoracic surgery. This could be a result of the inflammation caused by surgical stress or the use of extracorporeal circulation (ECC). But it is also possible that plasma glutamine levels were already lowered before surgery and reflect an impaired metabolic state and a higher likelihood to develop complications. In the present study plasma glutamine levels were measured before and after cardiac surgery and we questioned whether there is a relation between plasma glutamine levels and duration of ECC and the occurrence of postoperative infections. METHODS: We performed a single-centre prospective, observational study in a closed-format, 20-bed, mixed ICU in a tertiary teaching hospital. We included consecutive patients after elective cardiac surgery with use of extracorporeal circulation. Blood samples were collected on the day prior to surgery and at admission on the ICU. The study was approved by the local Medical Ethics Committee (Regional Review Committee Patient-related Research, Medical Centre Leeuwarden, nWMO 115, April 28th 2015). RESULTS: Ninety patients were included. Pre-operative plasma glutamine level was 0.42 ± 0.10 mmol/l and post-operative 0.38 ± 0.09 mmol/l (p < 0.001). There was no relation between duration of extracorporeal circulation or aortic occlusion time and changes in plasma glutamine levels. A logistic regression analysis showed a significant correlation between the presence of a positive culture during the post-operative course and pre-operative plasma glutamine levels (p = 0.04). CONCLUSION: Plasma glutamine levels are significantly lower just after cardiac surgery compared to pre-operative levels. We did not find a relation between the decrease in plasma glutamine levels and the duration of extracorporeal circulation or aortic clamp time. There was a correlation between pre-operative plasma glutamine levels and the presence of a positive culture after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02444780 .

The impact of a pulmonary-artery-catheter-based protocol on fluid and catecholamine administration in early sepsis.

Objective. The pulmonary artery catheter (PAC) remains topic of debate. Despite abundant data, it is of note that many trials did not incorporate a treatment protocol. Methods. We retrospectively evaluated fluid balances and catecholamine doses in septic patients after the introduction of a PAC-based treatment protocol in comparison to historic controls. Results. 2 × 70 patients were included. The first day the PAC group had a significantly higher positive fluid balance in comparison to controls (6.1 ± 2.6 versus 3.8 ± 2.4 litre, P < 0.001). After 7 days the cumulative fluid balance in the PAC group was significantly lower than in controls (9.4 ± 7.4 versus 13 ± 7.6 litre, P = 0.001). Maximum dose of norepinephrine was significantly higher in the PAC group. Compared to controls this was associated with a significant reduction in ventilator and ICU days. Conclusions. Introduction of a PAC-based treatment protocol in sepsis changed the administration of fluid and vasopressors significantly.