A systematic review and meta-analysis of the clinimetric properties of the core outcome measurement instruments for clinical effectiveness trials of nutritional and metabolic interventions in critical illness (CONCISE).

BACKGROUND: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE. METHODS: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted. RESULTS: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high. CONCLUSIONS: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness. TRIAL REGISTRATION: PROSPERO (CRD42023438187). Registered 21/06/2023.

Core outcome measures for clinical effectiveness trials of nutritional and metabolic interventions in critical illness: an international modified Delphi consensus study evaluation (CONCISE).

BACKGROUND: Clinical research on nutritional and metabolic interventions in critically ill patients is heterogenous regarding time points, outcomes and measurement instruments used, impeding intervention development and data syntheses, and ultimately worsening clinical outcomes. We aimed to identify and develop a set of core outcome domains and associated measurement instruments to include in all research in critically ill patients. METHODS: An updated systematic review informed a two-stage modified Delphi consensus process (domains followed by instruments). Measurement instruments for domains considered 'essential' were taken through the second stage of the Delphi and a subsequent consensus meeting. RESULTS: In total, 213 participants (41 patients/caregivers, 50 clinical researchers and 122 healthcare professionals) from 24 countries contributed. Consensus was reached on time points (30 and 90 days post-randomisation). Three domains were considered 'essential' at 30 days (survival, physical function and Infection) and five at 90 days (survival, physical function, activities of daily living, nutritional status and muscle/nerve function). Core 'essential' measurement instruments reached consensus for survival and activities of daily living, and 'recommended' measurement instruments for physical function, nutritional status and muscle/nerve function. No consensus was reached for a measurement instrument for Infection. Four further domains met criteria for 'recommended,' but not 'essential,' to measure at 30 days post-randomisation (organ dysfunction, muscle/nerve function, nutritional status and wound healing) and three at 90 days (frailty, body composition and organ dysfunction). CONCLUSION: The CONCISE core outcome set is an internationally agreed minimum set of outcomes for use at 30 and 90 days post-randomisation, in nutritional and metabolic clinical research in critically ill adults.

Anterior pituitary morphology and hormone production during sustained critical illness in a rabbit model.

Prolonged critical illness is hallmarked by striking alterations in the somatrope, thyrotrope, and lactotrope axes, the severity of which is associated with the risk of morbidity and mortality. The exact role of the pituitary gland in these alterations is unknown. We studied the impact of sustained critical illness on pituitary morphology and hormone production in a standardized rabbit model of prolonged (7 days) burn injury-induced critical illness. In healthy and prolonged critically ill rabbits, we determined pituitary weight, size, morphology and orientation of the somatrope, lactotrope and thyrotrope cells and the pituitary expression of GH, PRL, and TSH at gene and protein level. The weight of the pituitary gland was unaltered by 7 days of critical illness. Also, spatial orientation and morphology of the GH, PRL, and TSH producing cells remained normal. In prolonged critically ill rabbits GH mRNA levels were higher and PRL mRNA levels were lower than in healthy controls, whereas TSH mRNA was not affected. The sizes of GH, PRL, or TSH producing cells and the pituitary content of GH, PRL, and TSH proteins were unaltered. In conclusion, in this rabbit model of prolonged critical illness, the morphology of the pituitary gland and the pituitary GH, PRL, and TSH content was normal. The alterations in pituitary hormone mRNA levels with sustained critical illness are compatible with altered hypothalamic and peripheral regulation of pituitary hormone release as previously suggested indirectly by responses to exogenous releasing factors.

Enhanced immunoreceptor tyrosine-based activation motif signaling is related to pathological bone resorption during critical illness.

Prolonged critically ill patients present with distinct alterations in calcium and bone metabolism. Circulating bone formation markers are reduced and bone resorption markers are substantially elevated, indicating an uncoupling between osteoclast and osteoblast activity, possibly resulting in pronounced bone loss, impaired traumatic or surgical fracture healing, and osteoporosis. In addition, we have previously shown that increased circulating osteoclast precursors in critically ill patients result in increased osteoclastogenesis in vitro, possibly through FcγRIII signaling. In the current study, we investigated the effects of sustained critical illness on bone metabolism at the tissue level in a standardized rabbit model of prolonged (7 days), burn injury-induced critical illness. This in vivo model showed a reduction in serum ionized calcium and osteocalcin levels, as is seen in humans. Trabecular area, bone mineral content, and -density were decreased in sick rabbits [by 43% (p<0.01), 31% (p<0.01), and 29% (p<0.05), respectively], as was the trabecular gene expression of osteoblast and angiogenesis markers, indicating decreased bone formation and impaired vascularization. There was no change in the expression of osteoclast differentiation markers from the canonical RANK/RANKL/OPG pathway, however, there was an increase in expression of markers from the non-canonical, immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway, FcγRIII, and DAP12 (148% and 59%, respectively; p<0.01). The current study has shown a detrimental effect of prolonged critical illness on trabecular bone integrity, possibly explained by reduced osteoblast differentiation and angiogenesis, coupled with increased osteoclastogenesis signaling that may be mediated via the non-canonical immunoreceptor tyrosine-based activation motif signaling pathway.

Early hypophosphatemia in critically ill children and the effect of parenteral nutrition: A secondary analysis of the PEPaNIC RCT.

BACKGROUND & AIMS: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. METHODS: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. RESULTS: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). CONCLUSIONS: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH.

Prevalence of hypophosphatemia in the ICU - Results of an international one-day point prevalence survey.

BACKGROUND & AIMS: Hypophosphatemia (HypoP) is associated with organ dysfunction and mortality. Despite its potential severe consequences, HypoP remains poorly characterized in terms of real prevalence and timing of onset. The primary objective was to determine the prevalence of HypoP defined as blood phosphate <0.8 and < 0.65 mmol/l on one particular day at international level. METHODS: One-day point prevalence survey conducted by the Section of Metabolism, Endocrinology and Nutrition (MEN) of the European Society of Intensive Care Medicine (ESICM) during week 11-2020. RESULTS: In total, 56 adult and 4 paediatric ICUs, from 22 countries participated: 41 ICUs were mixed medico surgical, the 19 others being cardiac, medical or surgical. Phosphate measurements were performed daily in 21 ICUs, and 1-3 times per week in 39 ICUs. On D-Day 909 patients (883 adults) were present and 668/883 (75.7%) had serum/plasma phosphate determined, revealing a HypoP in 103 (15.4%) patients aged 62 [18 to 85] years. Of those, 49 patients presented phosphate <0.65 mmol/l: cases of hypophosphatemia were detected at any time of patient's ICU stay. No HypoP was observed in children. A treatment protocol existed only in 41.1% of adult ICUs, independently of ICU type, or size. Only 41/98 of the HypoP patients (29/41 of patients with phosphate <0.65 mmol/l) were receiving phosphate. CONCLUSION: HypoP is present at least in 15.4% of ICU patients, and may occur at any time during the ICU stay. The absence of phosphate repletion protocols in 60% of participating ICUs is an unexpected finding, and confirms the necessity for the development of ICU phosphate protocols and guidelines. CLINICALTRIALS IDENTIFIER: NCT04201899.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Managing atypical and typical herpetic central nervous system infections: results of a multinational study.

There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection.

Recovery from AKI in the critically ill: potential confounders in the evaluation.

PURPOSE: Studies on recovery from acute kidney injury (AKI) in ICU patients yield variable results. We assessed the impact of different recovery definitions, of different exclusion criteria, and of imputing missing baseline creatinine on AKI recovery in a heterogeneous ICU population. METHODS: Secondary analysis of the EPaNIC database. Recovery of kidney function in patients who developed AKI in ICU was assessed at hospital discharge. We studied recovery rates of different AKI stages with different definitions of recovery after inclusion or exclusion of non-survivors and in patients with or without chronic kidney disease (CKD). In addition, the impact of imputing missing baseline creatinine was investigated. RESULTS: A total of 1310 AKI patients were studied of which 977 were discharged alive from hospital. Rate of complete recovery (absence of KDIGO criteria) was markedly higher in survivors than in all AKI patients (79.5 vs 67.0%), especially for more severe forms of AKI. For patients with CKD, only the need for renal replacement therapy worsened kidney outcome as compared with no-CKD patients. Using stricter definitions of complete recovery significantly reduced its occurrence. New or worsening CKD occurred in 30% of AKI survivors. In no-CKD patients with available baseline creatinine, using an imputed baseline did not affect recovery. Patients with unavailable baseline creatinine were different from those with known baseline and revealed different recovery patterns. CONCLUSION: These results indicate the need for rigorous description of AKI severity, the included population, definitions, and baseline creatinine handling in reports on AKI recovery.

Prostaglandin E1 inhibits acute cell dehydration thirst.

Intraperitoneally injected PGE1 (100 micrograms/Kg) inhibits specifically the drinking induced by both IP and IV 2 M NaCl (6 ml/Kg) and compound 48/80 (100 micrograms/Kg, IP). Probenecid (150 mg/Kg, IP) which is not a dipsogen, has no effect on the PGE1 induced inhibition of acute cell dehydration thirst. It is concluded the PGE1 acts upon the peripheral mast cells, inhibiting their secretion and thus affecting the water intake associated with the activation of these cells either by hypertonicity or specific stimulants of amine release. These results raise the possibility that endogenous prostaglandins might be involved in the modulation of some of the signals which convey to the brain information on the tonicity of the body fluids.

[Prolonged apnea after suxamethonium administration during staphylococcal toxic shock]. / Apnée prolongée après administration suxaméthonium au cours d'un choc toxique staphylococcique.

A toxic shock syndrome occurred after a femoral nail removal requiring revision surgery. After administration of suxamethonium (1 mg.kg-1), an apnoea prolonged over 45 minutes was observed. The trachea was extubated 105 minutes after suxamethonium administration. For the nail removal, two days before, the anaesthetic had been given by the same anaesthesiologist, with a similar protocol. Apnoea extended over 20 minutes. The day of the revision surgery, plasma cholinesterase activity was 410 UI.L-1 and reached 910 UI.L-1, 9 months later. Dibucaine number was 20 and fluorure number 17. The apnoea was in relation with a genetic plasma cholinesterase deficiency increased by the toxic shock syndrome. Shock and hepatic insufficiency were suspected to contribute to the decrease in plasma cholinesterase. Suxamethonium should be avoided in case of toxic shock syndrome.

[Hemodynamic effects of flunitrazepam in cardiac patients during anesthetic induction]. / Effets hémodynamiques du flunitrazépam chez le malade cardiaque lors de l'induction anesthésique.

The hemodynamic effects of flunitrazepam were studied in eight coronary patients (group I) and in six patients with compensated cardiac failure (group II) during the induction of anesthesia with droperidol 5 mg and fentanyl 4 micrograms . kg-1. A right sided cardiac catheterization was performed to measure cardiac output by thermodilution. In coronary patients, the hemodynamic parameters were only slightly modified (NS). Cardiac output (-12.7%) and oxygen consumption (-20.4%) decreased; Pvo2 increased from 6.4 +/- 0.1 to 7.3 +/- 0.3 kPa. In patients with cardiac failure, significant cardiovascular changes were not observed. Arterial pressure (-13%), cardiac output (-2.6%), oxygen consumption (-6%) and systemic vascular resistance (-13.4%) decreased; Pvo2 increased from 6.4 +/- 0.5 to 6.8 +/- 0.7 kPa. In both groups, heart rate and pulmonary capillary wedge pressure were unchanged. There was only a significant difference (p less than 0.05) between the decrease in systemic resistance in group II and in the absence of change in systemic resistance in group I. Decrease in oxygen consumption be decrease in oxygen demand could explain the slight decrease in cardiac output. Flunitrazepam was a good hypnotic for the induction of anesthesia in normovolaemic coronary patients and in patients with compensated cardiac failure.

[Hemodynamic study during the postoperative period in coronary patients undergoing non-cardiac surgery. The role of mechanical ventilation and sedation]. / Etude hémodynamique au cours de la période postopératoire chez le coronarien en chirurgie non-cardiaque. Intérêt de la ventilation mécanique et de la sédation.

The initial period of postoperative rewarming is frequently marked by rapid increases in metabolic rate and myocardial work leading to haemodynamic instability. In order to test the beneficial effect of mechanical respiratory support with sedation in the postoperative period, 18 patients with coronary artery disease operated upon for abdominal or orthopedic surgery were submitted to a hemodynamic study. The patients were divided in two groups. In group II intravenous nitrates were administered perioperatively. Postoperative hemodynamic profiles were similar in both group. No perioperative signs of myocardial ischemia were detected. Prolonged ventilation with sedation can prevent the hemodynamic stress of recovery.

[Lung infection and acute adult respiratory distress syndrome during surgical resuscitation]. / Infections pulmonaires et syndrome de détresse respiratoire aiguë de l'adulte en réanimation chirurgicale.

Non cardiogenic pulmonary edema (PE) is frequently observed during the postoperative period. 56 patients with postoperative PE were divided into two groups: ARDS, acute respiratory distress syndrom and NHPE, non hemodynamic PE. The incidence of primary pulmonary infection and pulmonary superinfection were investigated. Both groups were not different except for the level of PaO2 lower in ARDS. Mortality was higher in ARDS (80%) than in NHPE (42%). Pulmonary primary infection and superinfection were respectively observed in 33 and 10%, and 23 and 15% of ARDS and NHPE. Blood cultures were more frequently positive during abdominal sepsis than during pneumonia. Viral etiology was thrice noted in 13 pneumonitis. Value of diagnostic methods for respiratory infections is discussed.

[Hemodynamic effects of flunitrazepam in coronary patients. Postoperative study immediately after digestive tract and orthopedic surgery]. / Effets hémodynamiques du flunitrazépam chez le coronarien. Etude en période postopératoire immédiate après chirurgie digestive et orthopédique.

The present study was designed to evaluate the haemodynamic effects of flunitrazepam used for sedation in the post operative period after abdominal or orthopedic surgery. Patients with coronary artery disease (C.A.D.) were divided in two groups; in group II stable cardiac failure was present. Results did not show any significant haemodynamic changes after flunitrazepam in both groups. Flunitrazepam is a haemodynamic secure and valuable agent for sedation during recovery for patients with C.A.D. even in stable cardiac failure.

The impact of using estimated GFR versus creatinine clearance on the evaluation of recovery from acute kidney injury in the ICU.

PURPOSE: To quantify the error in evaluating recovery from acute kidney injury (AKI) with estimated GFR (eGFR) in relation to ICU stay. METHODS: Secondary analysis performed on the database of the EPaNIC trial. In a cohort of patients who developed AKI during ICU stay we compared eGFR with measured creatinine clearance (Clcr) at ICU discharge. Recovery of kidney function was assessed by comparison with baseline eGFR and the accuracy of eGFR to detect "potential CKD status" defined by Clcr was quantified. The same analysis was performed in subgroups with different ICU stay. Multivariate regression was performed to determine independent predictors of the eGFR-Clcr difference. RESULTS: A total of 757 patients were included. The bias (limits of agreement (LOA)) between eGFR and Clcr at ICU discharge related to ICU stay, increasing from +1.3 (-37.4/+40) ml/min/1.73 m(2) in patients with short stay to +34.7 (-54.4/+123.8) ml/min/1.73 m(2) in patients with ICU stay of more than 14 days. This resulted in a significantly different incidence of complete recovery with the two evaluation methods and reduced sensitivity to detect "potential CKD status" with eGFR in patients with prolonged ICU stay. Independent predictors of the bias included creatinine excretion on the last day in ICU, baseline eGFR, ICU stay, gender, and age. CONCLUSION: Compared to Clcr, discharge eGFR results in overestimation of renal recovery in patients with prolonged ICU stay and in reduced accuracy of "CKD staging". Since age, gender and race do not change during ICU stay the same conclusion can be drawn with regard to plasma creatinine.