Purpose
To evaluate aerobic exercise capacity in 5-year intensive care unit (ICU) survivors and to assess the association between severity of organ failure in ICU and exercise capacity up to 5-year ...follow-up.
Methods
Secondary analysis of the EPaNIC follow-up cohort (NCT00512122) including 433 patients screened with cardiopulmonary exercise testing (CPET) between 1 and 5 years following ICU admission. Exercise capacity in 5-year ICU survivors (
N
= 361) was referenced to a historic sedentary population and further compared to demographically matched controls (
N
= 49). In 5-year ICU survivors performing a maximal CPET (respiratory exchange ratio > 1.05,
N
= 313), abnormal exercise capacity was defined as peak oxygen consumption (VO
2
peak) < 85% of predicted peak oxygen consumption (%predVO
2
peak), based on the historic sedentary population. Exercise liming factors were identified. To study the association between severity of organ failure, quantified as the maximal Sequential Organ Failure Assessment score during ICU-stay (SOFA-max), and exercise capacity as assessed with VO
2
peak, a linear mixed model was built, adjusting for predefined confounders and including all follow-up CPET studies.
Results
Exercise capacity was abnormal in 118/313 (37.7%) 5-year survivors versus 1/48 (2.1%) controls with a maximal CPET,
p
< 0.001. Aerobic exercise capacity was lower in 5-year survivors than in controls (VO
2
peak: 24.0 ± 9.7 ml/min/kg versus 31.7 ± 8.4 ml/min/kg,
p
< 0.001; %predVO
2
peak: 94% ± 31% versus 123% ± 25%,
p
< 0.001). Muscular limitation frequently contributed to impaired exercise capacity at 5-year 71/118 (60.2%). SOFA-max independently associated with VO
2
peak throughout follow-up.
Conclusions
Critical illness survivors often display abnormal aerobic exercise capacity, frequently involving muscular limitation. Severity of organ failure throughout the ICU stay independently associates with these impairments.
Critically ill patients typically present with low or low-normal plasma thyroxine, low plasma triiodothyronine (T3), increased plasma reverse T3 (rT3) concentrations, in the absence of a rise in ...thyrotropin (TSH). This constellation is referred to as nonthyroidal illness syndrome (NTI). Although it is long known that the severity of NTI is associated with risk of poor outcomes of critical illness, the causality in this association has not been well investigated.
In this narrative review, the different faces of NTI during critical illness are highlighted. Acute alterations are dominated by changes in thyroid hormone binding, peripheral thyroid hormone uptake, and alterations in the expression and activity of the type-1 and type-3 deiodinases. It was recently shown that at least part of these acute changes are brought about by concomitant macronutrient restriction, and this part appears adaptive and beneficial. However, the face of the NTI in the prolonged phase of critical illness is different, when patients are fully fed but continue to depend on intensive medical care. In that prolonged phase of illness, hypothalamic thyrotropin releasing hormone (TRH) expression is suppressed and explains reduced TSH secretion and whereby reduced thyroidal hormone release. During prolonged critical illness, and in the presence of adequate nutrition, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level. Infusing hypothalamic releasing factors in these prolonged critically ill patients can reactivate the thyroid axis and induce an anabolic response.
It is clear that the name "NTI" during critical illness refers to a syndrome with different faces. Tolerating the early "fasting response" to critical illness and its concomitant changes in thyroid hormone parameters appears to be wise and beneficial. This thus applies to the NTI present in the majority of the patients treated in intensive care units. However, the NTI that occurs in prolonged critically ill patients appears different with regard to both its causes and consequences. Future studies should specifically target this selected population of prolonged critically ill patients, and, after excluding iatrogic drug interferences, investigate the effect on outcome of treatment with hypothalamic releasing factors in adequately powered randomized controlled trials.
Summary Background Critically ill infants and children often develop hyperglycaemia, which is associated with adverse outcome; however, whether lowering blood glucose concentrations to age-adjusted ...normal fasting values improves outcome is unknown. We investigated the effect of targeting age-adjusted normoglycaemia with insulin infusion in critically ill infants and children on outcome. Methods In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged ≥1 year), who were admitted to the paediatric intensive care unit (PICU) of the University Hospital of Leuven, Belgium. Patients were randomly assigned by blinded envelopes to target blood glucose concentrations of 2·8–4·4 mmol/L in infants and 3·9–5·6 mmol/L in children with insulin infusion throughout PICU stay (intensive group n=349), or to insulin infusion only to prevent blood glucose from exceeding 11·9 mmol/L (conventional group n=351). Patients and laboratory staff were blinded to treatment allocation. Primary endpoints were duration of PICU stay and inflammation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00214916. Findings Mean blood glucose concentrations were lower in the intensive group than in the conventional group (infants: 4·8 SD 1·2 mmol/L vs 6·4 1·2 mmol/L, p<0·0001; children: 5·3 1·1 mmol/L vs 8·2 3·3 mmol/L, p<0·0001). Hypoglycaemia (defined as blood glucose ≤2·2 mmol/L) occurred in 87 (25%) patients in the intensive group (p<0·0001) versus five (1%) patients in the conventional group; hypoglycaemia defined as blood glucose less than 1·7 mmol/L arose in 17 (5%) patients versus three (1%) (p=0·001). Duration of PICU stay was shortest in the intensively treated group (5·51 days 95% CI 4·65–6·37 vs 6·15 days 5·25–7·05, p=0·017). The inflammatory response was attenuated at day 5, as indicated by lower C-reactive protein in the intensive group compared with baseline (−9·75 mg/L 95% CI −19·93 to 0·43 vs 8·97 mg/L −0·9 to 18·84, p=0·007). The number of patients with extended (>median) stay in PICU was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (p=0·013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (p=0·038). Interpretation Targeting of blood glucose concentrations to age-adjusted normal fasting concentrations improved short-term outcome of patients in PICU. The effect on long-term survival, morbidity, and neurocognitive development needs to be investigated. Funding Research Foundation (Belgium); Research Fund of the University of Leuven (Belgium) and the EU Information Society Technologies Integrated project “CLINICIP”; and Institute for Science and Technology (Belgium).
Changes in the GH axis during critical illness resemble fasting in healthy adults and contribute to hypercatabolism, which potentially affects outcome. Accepting macronutrient deficits by withholding ...parenteral nutrition (PN) during the first week in the intensive care unit (ICU; late PN) reduced complications and accelerated recovery as compared with early use of PN (early PN).
To investigate how late PN affects the GH axis in relation to its clinical outcome benefits.
Preplanned subanalysis of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients randomized controlled trial.
A total of 1128 patients for time-course study, 20 patients investigated for nocturnal GH pulsatility, and 600 patients investigated for muscle weakness, with early PN and late PN patients having comparable baseline characteristics.
Withholding PN during the first ICU week (late PN) vs early PN.
Changes in serum GH, IGF-I, IGF-binding protein (IGFBP) 3, and IGFBP1 concentrations from ICU admission to day 4 or last ICU day for patients with a shorter ICU stay (d4/LD) and association in multivariable analyses with likelihood of earlier live ICU discharge, risk of new infection, and muscle weakness.
Late PN attenuated a rise in serum GH and IGF-I (P < 0.0001), did not affect IGFBP3, and attenuated a decrease in IGFBP1 concentrations from admission to d4/LD (P < 0.0001) as compared with early PN. Late PN decreased nonpulsatile (P = 0.005), but not pulsatile, GH secretion. Adjusting the multivariable models for the observed GH axis alterations increased the independent benefit of late PN for all outcomes. GH axis alterations induced by late PN were independently associated with adverse outcomes (P ≤ 0.03).
Accepting macronutrient deficits early during critical illness further suppressed the GH axis, which statistically attenuated its clinical outcome benefits.
Sepsis is hallmarked by hypercortisolemia, a stress response essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We ...demonstrate that a controlled downregulation of the hepatic glucocorticoid receptor (hepatic GR) is crucial. In a mouse model of fluid-resuscitated, antibiotic-treated abdominal sepsis and in human intensive care unit patients, sepsis reduced hepatic GR expression and signaling but increased (free) plasma cortisol/corticosterone, explained by suppressed cortisol/corticosterone-binding proteins and A-ring reductases. However, further experimental inhibition of hepatic GR with short hairpin RNA (shRNA) in septic mice increased mortality fivefold. Acutely, this further hepatic GR suppression prevented the rise in total corticosterone but further reduced binding proteins, resulting in elevated free corticosterone. After 3 days of shRNA-GR inhibition in sepsis, both total and free corticosterone levels were elevated, now explained by an additional reduction in A-ring reductase expression. Hepatic GR inhibition blunted the hyperglycemic stress response without causing hypoglycemia but also markedly increased circulating and hepatic inflammation markers and caused liver destruction, the severity of which explained increased mortality. In human sepsis, glucocorticoid treatment further suppressed hepatic GR expression, which could directly predispose to worse outcomes. In conclusion, sepsis partially suppressed hepatic GR expression, which appeared crucial to upregulate free cortisol/corticosterone availability. However, further sustained hepatic GR suppression evoked lethal excessive liver and systemic inflammation, independent of systemic cortisol/corticosterone availability.
Hyperglycaemia during critical illness unequivocally correlates with adverse outcome. Three proof-of-concept randomized controlled trials have shown that preventing hyperglycaemia in patients ...admitted to the intensive care unit (ICU) reduces organ failure and mortality. A subsequent multicentre, randomized controlled trial found that targeting normoglycaemia in this patient population does not affect organ function differently than targeting an intermediate glucose level (7.8-10.0 mmol/l). However, an intermediate glucose target evoked less hypoglycaemia and, for currently unexplained reasons, also fewer deaths than a normoglycaemic target. Moreover, tolerating a caloric deficit, rather than providing nutrients parenterally, accelerated recovery from critical illness in the presence of normoglycaemia. Whether macronutrient restriction renders moderate hyperglycaemia less harmful remains to be investigated. Hence, if adequate monitoring tools and expertise are available, normoglycaemia remains the only proven effective target for insulin treatment of hyperglycaemia in ICU patients. However, if these conditions are not fulfilled in clinical practice, is an intermediate target range preferable? In the absence of hard evidence, common sense supports such an intermediate blood glucose target.
Patients requiring prolonged intensive care are at high risk for multiple organ failure and death. Insulin resistance and hyperglycemia accompany critical illness, and the severity of this "diabetes ...of stress" reflects the risk of death. Recently it was shown that preventing hyperglycemia with insulin substantially improves outcome of critical illness. This article examines some potential mechanisms underlying prevention of glucose toxicity as well as the effects of insulin independent of glucose control. Unraveling the molecular mechanisms will provide new insights into the pathogenesis of multiple organ failure and open avenues for novel therapeutic strategies.
Large randomised controlled trials have shown that early supplemental parenteral nutrition in patients admitted to adult and paediatric intensive care units (PICUs) is harmful. Overdosing of energy ...with too little protein was suggested as a potential reason for this. This study analysed which macronutrient was associated with harm caused by early supplemental parenteral nutrition in the Paediatric Early versus Late Parenteral Nutrition In Critical Illness (PEPaNIC) randomised trial.
Patients in the initial randomised controlled trial were randomly assigned to receive suppplemental parenteral nutrition (PN) within 24 h of PICU admission (early PN) or to receive such PN after 1 week (late PN) when enteral nutrition was insufficient. In this post-randomisation, observational study, doses of glucose, lipids, and aminoacids administered during the first 7 days of PICU stay were expressed as % of reference doses from published clinical guidelines for age and weight. Independent associations between average macronutrient doses up to each of the first 7 days and likelihood of acquiring an infection in the PICU, of earlier live weaning from mechanical ventilation, and of earlier live PICU discharge were investigated using multivariable Cox proportional hazard analyses. The three macronutrients were included in the analysis simultaneously and baseline risk factors were adjusted for.
From June 18, 2012, to July 27, 2015, 7519 children aged between newborn and 17 years were assessed for eligibility. 6079 patients were excluded, and 1440 children were randomly assigned to receive either early PN (n=723) or late PN (n=717). With increasing doses of aminoacids, the likelihood of acquiring a new infection was higher (adjusted hazard ratios HRs per 10% increase between 1·043-1·134 for days 1-5, p≤0·029), while the likelihood of earlier live weaning from mechanical ventilation was lower (HRs 0·950-0·975 days 3-7, p≤0·045), and the likelihood of earlier live PICU discharge was lower (HRs 0·943-0·972 days 1-7, p≤0·030). By contrast, more glucose during the first 3 days of PICU stay was independently associated with fewer infections (HRs 0·870-0·913, p≤0·036), whereas more lipids was independently associated with earlier PICU discharge (HRs 1·027-1·050, p≤0·043 days 4-7). Risk of harm with aminoacids was also shown for low doses.
These associations suggest that early administration of aminoacids, but not glucose or lipids, could explain harm caused by early supplemental parenteral nutrition in critically ill children.
Flemish Agency for Innovation through Science and Technology; UZLeuven Clinical Research Fund; Research Foundation Flanders; Methusalem Programme Flemish Government; European Research Council; Fonds-NutsOhra; Erasmus-MC Research Grant; Erasmus Trustfonds.
Purpose
This study aimed to examine health-related quality of life (HRQoL) of children and their parents, 6 months after the child’s admission to the Pediatric Intensive Care Unit (PICU). ...Associations between parents’ reports regarding HRQoL of their child and of themselves were investigated, as well as associations between children’s baseline variables and their parent-reported HRQoL outcomes.
Methods
This is a secondary analysis of cross-sectional data collected in a group of children who participated in the PEPaNIC trial. Six months after discharge from the PICU, parents of critically ill children completed the Infant–Toddler Quality of Life Questionnaire (ITQOL, for age 0–3 years) or the Child Health Questionnaire-Parent Form 50 (CHQ-PF50, for age 4–18 years), which are parallel questionnaires. Parents completed the Short Form Health Survey (SF-12) regarding their own HRQoL. Results were compared with normative data.
Results
At 6 months’ follow-up, 86 children of the 1343 (6%) had died which resulted in 1257 eligible children. Parents of 576 surviving children (46%) completed the questionnaires. Children of responding parents had less often an acute reason for admission and differed in diagnosis compared with children of non-responders. PICU children scored lower on most ITQOL (
n
= 390) scales and CHQ-PF50 (
n
= 186) scales compared with normative data. Parents reported (
n
= 570) higher scores on the physical (
p
< 0.001) and lower scores on the mental SF-12 scale (
p
< 0.001) compared with normative data. Parents̕ mental HRQoL correlated with HRQoL they reported for their child (Pearson Correlations range 0.25–0.57,
p
< 0.001–0.002). Shorter length of stay, lower risk of mortality, younger age, and cardiac diagnosis were associated with higher parent-reported HRQoL outcomes for the child.
Conclusions
Six months after PICU discharge, critically ill children have lower HRQoL compared with normative data. The mental component of HRQoL is impaired in parents and is associated with lower overall parent-reported HRQoL of their child.
Purpose
Withholding parenteral nutrition (PN) early in critical illness, late-PN, has shown to prevent infections despite a higher peak C-reactive protein (CRP). We investigated whether the ...accentuated CRP rise was caused by a systemic inflammatory effect mediated by cytokines or arose as a consequence of the different feeding regimens, and whether it related to improved outcome with late-PN.
Methods
This secondary analysis of the EPaNIC-RCT first investigated, with multivariable linear regression analyses, determinants of late-PN-induced CRP rise and its association with cytokine responses (IL-6, IL-10, TNF-
α
) in matched early-PN and late-PN patients requiring intensive care for ≥ 3 days. Secondly, with multivariable logistic regression and Cox proportional-hazard analyses, we investigated whether late-PN-induced CRP rises mediated infection prevention and enhanced recovery or reflected an adverse effect counteracting such benefits of late-PN.
Results
CRP peaked on day 3, higher with late-PN 216(152–274)mg/l (
n
= 946) than with early-PN 181(122–239)mg/l (
n
= 946) (
p
< 0.0001). Independent determinants of higher CRP rise were lower carbohydrate and protein intakes (
p
≤ 0.04) with late-PN, besides higher blood glucose and serum insulin concentrations (
p
≤ 0.01). Late-PN did not affect cytokines. Higher CRP rises were independently associated with more infections and lower likelihood of early ICU discharge (
p
≤ 0.002), and the effect size of late-PN versus early-PN on these outcomes was increased rather than reduced after adjusting for CRP rise, not confirming a mediating role.
Conclusions
The higher CRP rise with late-PN, explained by the early macronutrient deficits, did not relate to cytokine responses and thus did not reflect more systemic inflammation. Instead of mediating clinical benefit on infection or recovery, the accentuated CRP rise appeared an adverse effect reducing such late-PN benefits.
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