RESUMO
BACKGROUND: Acute kidney injury (AKI) treated with continuous renal replacement therapy (CRRT) may deplete micronutrient levels. Patients are also at risk for micronutrient depletion due to underlying illness(s), poor nutrient intake prior to intensive care unit (ICU) admission and/or increased requirements. We determined vitamin and trace element status before, during and after CRRT in critically ill patients. METHODS: This prospective observational study performed in mixed medical and surgical ICU patients. Serial serum vitamin B6 and vitamin C concentrations were measured by HPLC and folic acid by ECLIA. Serum chromium, copper, selenium, and zinc were measured using ICP-MS. Serum ceruloplasmin was measured by the Erel method. RESULTS: Fifty adult ICU patients with AKI were recruited. The median APACHE II score on ICU admission was high at 24.0 (6.0-33.0). The median days on CRRT was 2.0 (2.0-4.0) days. At baseline (within 10-15 minutes of CRRT initiation), serum vitamin C, selenium and zinc were below normal. Serum vitamin B6 levels at 72 hours on CRRT were significantly lower than at 24 hours (p = 0.011). Serum vitamin C values fell significantly at 24 and 72 hours during CRRT (p = 0.030 and p = 0.001), respectively, and remained low 24 and 48 hours after CRRT was stopped (p = 0.021). At baseline and during CRRT, 96% of participants had at least two or more micronutrient levels below the normal range. CONCLUSION: Serum vitamin C, selenium and zinc concentrations were below the normal range at baseline. CRRT was associated with a significant further decrease in levels of vitamin C, selenium and zinc.
Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Selênio , Oligoelementos , Injúria Renal Aguda/terapia , Adulto , Ácido Ascórbico , Estado Terminal/terapia , Humanos , Unidades de Terapia Intensiva , Micronutrientes , Estudos Prospectivos , Terapia de Substituição Renal/métodos , Estudos Retrospectivos , Vitamina B 6 , Vitaminas , ZincoRESUMO
BACKGROUND: The use of central venous catheter (CVC) access for home parenteral nutrition (HPN) is associated with catheter-related bloodstream infections (CRBSIs). There are limited data on the use of ethanol lock therapy (ELT) to prevent CRBSI in adult HPN patients. Our aim was to determine whether the routine institution of ELT decreased the incidence of CRBSI compared with historic controls at Emory University Hospital (EUH) in Atlanta, Georgia, USA. METHODS: EUH medical records of adult HPN patients discharged with a tunneled, silicone CVC on ELT were retrospectively studied during a pre-hoc determined 14-month observation period (n = 87; 13,386 catheter days) and compared with clinically similar HPN patients from the same institution before institution of the ELT protocol for all appropriate patients. The ELT protocol involved instilling 2 mL of 70% ethanol into each catheter lumen daily after the HPN cycle, following initial flushing with normal saline. RESULTS: Only 5 of 87 patients (5.7%) who received ELT were diagnosed with a CRBSI (0.45/1000 catheter days) during observation. We compared these data with our previously published clinically matched patient population from EUH (n = 22) receiving HPN via a silicone CVC without ELT. Of these historical controls, 45.5% were diagnosed with 1 or more CRBSIs (8.7/1000 catheter days) during observation (P < .001 vs the current ELT cohort). CONCLUSIONS: In this retrospective study with historical controls from the same academic center, institution of ELT in adults requiring HPN via a silicone CVC was associated with a marked (19-fold) reduction in CRBSI.
Assuntos
Bacteriemia , Infecções Relacionadas a Cateter , Etanol , Nutrição Parenteral no Domicílio , Adulto , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo Venoso Central , Cateteres Venosos Centrais/efeitos adversos , Feminino , Humanos , Masculino , Nutrição Parenteral no Domicílio/efeitos adversos , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
BACKGROUND: Continuous renal replacement therapy (CRRT) is commonly used to provide renal replacement therapy in the intensive care unit. Limited published data suggest that CRRT may lead to depletion of water-soluble vitamins and trace elements. The goal of this study was to identify the incidence of trace element and vitamin deficiencies in critically ill patients during CRRT. MATERIALS AND METHODS: This study is based on a retrospective chart review of patients who were referred to Emory University Hospital's nutrition support services and had at least 1 serum micronutrient level measured during CRRT (thiamin, pyridoxine, ascorbic acid, folate, zinc, and copper) between April 1, 2009, and June 1, 2012. RESULTS: Seventy-five patients were included in the study. Nine of 56 patients (16%) had below-normal whole blood thiamin concentrations, and 38 of 57 patients (67%) had below-normal serum pyridoxine levels. Serum ascorbic acid and folate deficiencies were identified among 87% (13 of 15) and 33% (3 of 9) of the study patients, respectively. Nine of 24 patients had zinc deficiency (38%), and 41 of 68 patients had copper deficiency (60%). Of the 75 total subjects, 60 patients (80%) had below-normal levels of at least 1 of the micronutrients measured. CONCLUSIONS: The incidence of various micronutrient deficiencies in critically ill patients who required CRRT was higher than previously reported. Prospective studies are needed to determine the impact of CRRT on micronutrient status and the potential clinical and metabolic efficacy of supplementation in the intensive care unit setting.
Assuntos
Estado Terminal/terapia , Micronutrientes/sangue , Diálise Renal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácido Ascórbico/sangue , Índice de Massa Corporal , Cobre/sangue , Cobre/deficiência , Feminino , Ácido Fólico/sangue , Humanos , Unidades de Terapia Intensiva , Masculino , Micronutrientes/deficiência , Pessoa de Meia-Idade , Piridoxina/sangue , Piridoxina/deficiência , Terapia de Substituição Renal , Estudos Retrospectivos , Tiamina/sangue , Adulto Jovem , Zinco/sangue , Zinco/deficiênciaRESUMO
OBJECTIVE: To determine whether glutamine (GLN)-supplemented parenteral nutrition (PN) improves clinical outcomes in surgical intensive care unit (SICU) patients. SUMMARY BACKGROUND DATA: GLN requirements may increase with critical illness. GLN-supplemented PN may improve clinical outcomes in SICU patients. METHODS: A parallel-group, multicenter, double-blind, randomized, controlled clinical trial in 150 adults after gastrointestinal, vascular, or cardiac surgery requiring PN and SICU care. Patients were without significant renal or hepatic failure or shock at entry. All received isonitrogenous, isocaloric PN [1.5âg/kg/d amino acids (AAs) and energy at 1.3× estimated basal energy expenditure]. Controls (nâ=â75) received standard GLN-free PN (STD-PN); the GLN group (nâ=â75) received PN containing alanyl-GLN dipeptide (0.5âg/kg/d), proportionally replacing AA in PN (GLN-PN). Enteral nutrition (EN) was advanced and PN weaned as indicated. Hospital mortality and infections were primary endpoints. RESULTS: Baseline characteristics, days on study PN and daily macronutrient intakes via PN and EN, were similar between groups. There were 11 hospital deaths (14.7%) in the GLN-PN group and 13 deaths in the STD-PN group (17.3%; difference, -2.6%; 95% confidence interval, -14.6% to 9.3%; Pâ=â0.66). The 6-month cumulative mortality was 31.4% in the GLN-PN group and 29.7% in the STD-PN group (Pâ=â0.88). Incident bloodstream infection rate was 9.6 and 8.4 per 1000 hospital days in the GLN-PN and STD-PN groups, respectively (Pâ=â0.73). Other clinical outcomes and adverse events were similar. CONCLUSIONS: PN supplemented with GLN dipeptide was safe, but did not alter clinical outcomes among SICU patients.
Assuntos
Cuidados Críticos/métodos , Glutamina/administração & dosagem , Soluções de Nutrição Parenteral , Nutrição Parenteral/métodos , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/mortalidade , Estados Unidos , Adulto JovemRESUMO
Malabsorptive bariatric surgery is rapidly becoming a major cause of copper deficiency given the increasing prevalence of these procedures for morbid obesity. Acquired copper deficiency can present with clinically significant hematologic and neurological manifestations. Although hematologic manifestations of copper deficiency are rapidly reversible, significant neurological improvement after copper supplementation therapy is unusual and many patients remain debilitated and may only experience, at best, stabilization of the neurological manifestations. Here we present a case of an undiagnosed copper deficiency several years after bariatric gastric bypass surgery, in a patient who concomitantly used zinc-containing denture cream for several years, associated with anemia, neutropenia, myelopathy, respiratory failure, and bilateral optic neuropathy, which caused major vision loss. This patient was also a heterozygote carrier of the 5,10-methylenetetrahydrofolate reductase A1298C gene polymorphism, which may affect copper metabolism. Intravenous copper repletion resulted in rapid correction of hematologic indices. However, neurological manifestations, including vision loss responded only modestly to copper supplementation, despite achieving normal blood copper concentrations. Clinicians should consider copper deficiency in patients at risk, as in this case, as a delayed diagnosis can lead to irreversible disability due to neurological manifestations.
Assuntos
Anemia/etiologia , Cobre/deficiência , Deficiências Nutricionais/etiologia , Derivação Gástrica/efeitos adversos , Neutropenia/etiologia , Obesidade Mórbida/cirurgia , Doenças do Nervo Óptico/etiologia , Doenças da Medula Espinal/etiologia , Anemia/sangue , Anemia/diagnóstico , Anemia/terapia , Cobre/sangue , Cobre/uso terapêutico , Deficiências Nutricionais/sangue , Deficiências Nutricionais/diagnóstico , Deficiências Nutricionais/genética , Deficiências Nutricionais/terapia , Feminino , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/diagnóstico , Neutropenia/terapia , Doenças do Nervo Óptico/sangue , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/terapia , Polimorfismo Genético , Fatores de Risco , Doenças da Medula Espinal/sangue , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/terapia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.
Assuntos
Emulsões Gordurosas Intravenosas/administração & dosagem , Nutrição Parenteral/métodos , Óleos de Plantas/administração & dosagem , Óleo de Soja/administração & dosagem , Adulto , Idoso , Cuidados Críticos , Método Duplo-Cego , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Azeite de Oliva , Estudos Prospectivos , Procedimentos Cirúrgicos Operatórios , Resultado do TratamentoRESUMO
Copper is an essential cofactor in many enzymatic reactions vital to the normal function of the hematologic, vascular, skeletal, antioxidant, and neurologic systems. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation, myelodysplastic syndrome, use of parenteral nutrition and chronic tube feeding, and in various malabsorptive syndromes, including following gastrectomy and gastric bypass surgery. Features of copper deficiency include hematologic abnormalities (anemia, neutropenia, and leukopenia) and myeloneuropathy; the latter is a rarer and often unrecognized complication of copper deficiency. We here describe two patients who presented with severe gait abnormalities and anemia combined with neutropenia several years after roux-en-Y gastric bypass (RYGB) surgery for obesity who were found to be severely copper deficient. Intravenous copper repletion resulted in the rapid correction of hematologic indices; combined intravenous and oral copper supplementation and eventual oral copper supplements alone normalized serum copper levels in each patient, but resulted in only partial resolution of the neurologic deficits. This report serves to alert physicians of the association between RYGB procedures and subsequent copper deficiency in order to avoid diagnostic delays and to improve treatment outcomes.
Assuntos
Cobre/deficiência , Derivação Gástrica/efeitos adversos , Obesidade/cirurgia , Anemia/diagnóstico , Anemia/etiologia , Cobre/administração & dosagem , Cobre/uso terapêutico , Suplementos Nutricionais , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Nosocomial infections are an important cause of morbidity and mortality in the surgical intensive care unit (SICU). Clinical benefits of glutamine-supplemented parenteral nutrition may occur in hospitalized surgical patients, but efficacy data in different surgical subgroups are lacking. The objective was to determine whether glutamine-supplemented parenteral nutrition differentially affects nosocomial infection rates in selected subgroups of SICU patients. METHODS: This was a double-blind, randomized, controlled study of alanyl-glutamine dipeptide-supplemented parenteral nutrition in SICU patients requiring parenteral nutrition and SICU care after surgery for pancreatic necrosis, cardiac, vascular, or colonic surgery. Subjects (n = 59) received isocaloric/isonitrogenous parenteral nutrition, providing 1.5 g/kg/d standard glutamine-free amino acids (STD-PN) or 1.0 g/kg/d standard amino acids + 0.5 g/kg/d glutamine dipeptide (GLN-PN). Enteral feedings were advanced as tolerated. Nosocomial infections were determined until hospital discharge. RESULTS: Baseline clinical/metabolic data were similar between groups. Plasma glutamine concentrations were low in all groups and were increased by GLN-PN. GLN-PN did not alter infection rates after pancreatic necrosis surgery (17 STD-PN and 15 GLN-PN patients). In nonpancreatic surgery patients (12 STD-PN and 15 GLN-PN), GLN-PN was associated with significantly decreased total nosocomial infections (STD-PN 36 vs GLN-PN 13, P < .030), bloodstream infections (7 vs 0, P < .01), pneumonias (16 vs 6, P < .05), and infections attributed to Staphylococcus aureus (P < .01), fungi, and enteric Gram-negative bacteria (each P < .05). CONCLUSIONS: Glutamine dipeptide-supplemented parenteral nutrition did not alter infection rates following pancreatic necrosis surgery but significantly decreased infections in SICU patients after cardiac, vascular, and colonic surgery.
Assuntos
Estado Terminal/terapia , Infecção Hospitalar/prevenção & controle , Glutamina/farmacologia , Nutrição Parenteral/métodos , APACHE , Suplementos Nutricionais , Dipeptídeos/administração & dosagem , Dipeptídeos/farmacologia , Método Duplo-Cego , Feminino , Glutamina/administração & dosagem , Glutamina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/cirurgia , Período Pós-Operatório , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Glutamine (Gln) may become conditionally indispensable during critical illness. The short-term metabolic effects of enteral versus parenteral Gln supplementation are unknown in this clinical setting. OBJECTIVES: We studied metabolic effects of intravenous (i.v.) alanyl-Gln dipeptide (AG) supplementation and enteral (e.n.) AG supplementation on plasma Gln concentration, antioxidant status, plasma lymphocyte subset number, gut permeability and nitrogen balance in adult critically ill patients requiring tube feeding compared to a control group not receiving Gln supplementation. METHODS: In a double-blind, pilot clinical trial, 44 medical and surgical ICU patients received identical Gln-free tube feedings 24 h/day and were randomized to either isonitrogenous control (n=15), e.n. AG (n=15) or i.v. AG (n=14) groups (AG). Twelve patients were discontinued from the study. The goal AG dose was 0.5 g/kg/day. Biochemical and metabolic endpoints were measured at baseline and on day 9 (plasma Gln, antioxidant indices, lymphocyte subsets; serum IGF-1 and IGF-binding protein-3; intestinal permeability). Nitrogen balance was determined between study days 6 and 8. RESULTS: Illness severity indices, clinical demographics, enteral energy and nitrogen intake and major biochemical indices were similar between groups during study. Plasma Gln was higher in the i.v. AG (565+/-119 microM, mean+/-SEM) vs the e.n. AG (411+/-27 microM) group by day 9 (p=0.039); however, subjects in the i.v. AG group received a higher dose of AG (i.v. AG 0.50 versus e.n. AG 0.32+/-0.02 g/kg/day; p<0.001). E.n. AG subjects showed a significant increase in plasma alpha-tocopherol levels over time and maintained plasma gamma-tocopherol concentrations. There were no differences between groups for plasma concentrations of vitamin C, glutathione, malondialdehyde (MDA), T-lymphocyte subsets, intestinal permeability or nitrogen balance. CONCLUSIONS: This study showed that alanyl-Gln administration by enteral or parenteral routes did not appear to affect antioxidant capacity or oxidative stress markers, T-lymphocyte subset (CD-3, CD-4, CD-8) number, gut barrier function or whole-body protein metabolism compared to unsupplemented ICU patients requiring enteral tube feeding. Enteral Gln appeared to maintain plasma tocopherol levels in this pilot metabolic study.
Assuntos
Estado Terminal/terapia , Dipeptídeos/farmacologia , Nutrição Enteral , Glutamina/sangue , Nutrição Parenteral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/metabolismo , Cuidados Críticos , Dipeptídeos/imunologia , Método Duplo-Cego , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Nitrogênio/metabolismo , Projetos Piloto , Índice de Gravidade de Doença , Resultado do Tratamento , alfa-Tocoferol/sangue , gama-Tocoferol/sangueRESUMO
OBJECTIVES: Antioxidant depletion is common in critically ill patients. This study was designed to determine the effects of parenteral nutrition (PN), with or without glutamine (Gln) supplementation, on systemic antioxidant status in adult patients after major surgery who required PN in the surgical intensive care unit (SICU) setting. METHODS: Fifty-nine patients in the SICU who required PN after pancreatic surgery or cardiac, vascular, or colonic (non-pancreatic) surgery were randomized in a double-blinded study to receive standard PN (Gln-free) or Gln-supplemented PN (Gln-PN) in which Gln was provided as alanyl-Gln dipeptide. Conventional PN vitamin and mineral doses were administered to all subjects. Plasma concentrations of the antioxidant glutathione (GSH) and the antioxidant nutrients alpha-tocopherol, vitamin C, and zinc were determined at baseline (initiation of study PN) and again after 7 d of study PN. Data were analyzed for the total study cohort and within the pancreatic surgery and non-pancreatic (cardiac, vascular, and colonic) surgery patient subgroups. RESULTS: Mean plasma antioxidant concentrations were within or slightly below the normal ranges at baseline. However, a larger percentage of patients demonstrated below-normal baseline plasma concentrations of GSH (59%), vitamin C (59%), and zinc (68%), respectively. A smaller percentage of patients exhibited below-normal plasma alpha-tocopherol levels (21%). Study PN significantly improved plasma zinc levels in the entire study group and in each surgical subgroup. Gln-PN significantly improved the change in plasma levels of reduced GSH from baseline to day 7 in the non-pancreatic surgery patients (PN -0.27 microM versus Gln-PN +0.26 microM, P < 0.03). CONCLUSION: Low plasma levels of key antioxidants were common in this group of patients in the SICU despite administration of PN containing conventional micronutrients. Compared with standard PN, Gln-supplemented PN improved plasma GSH levels in patients in the SICU after cardiac, vascular, or colonic operations.
Assuntos
Antioxidantes/metabolismo , Cuidados Críticos , Suplementos Nutricionais , Dipeptídeos/farmacologia , Nutrição Parenteral/métodos , Adolescente , Adulto , Idoso , Ácido Ascórbico/sangue , Procedimentos Cirúrgicos Cardíacos , Estudos de Coortes , Colo/cirurgia , Estado Terminal/terapia , Dipeptídeos/administração & dosagem , Método Duplo-Cego , Feminino , Glutationa/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/cirurgia , Período Pós-Operatório , Fatores de Tempo , Procedimentos Cirúrgicos Vasculares , Zinco/sangue , alfa-Tocoferol/sangueRESUMO
OBJECTIVE: Heat shock protein 70 (HSP-70) is protective against cellular and tissue injury. Increased serum HSP-70 levels are associated with decreased mortality in trauma patients. Glutamine (Gln) administration increases serum and tissue HSP-70 expression in experimental models of sepsis. Gln has been safely administered to critically ill patients and can improve clinical outcomes, but the effect of Gln administration on HSP-70 expression in humans is unknown. We examined whether Gln-supplemented parenteral nutrition (PN) increases serum HSP-70 levels in critically ill patients. DESIGN AND SETTING: Randomized, controlled, double-blind study in surgical intensive care units (SICU) in a university hospital. PATIENTS: 29 patients admitted to the SICU and requiring PN for more than 7 days. INTERVENTIONS: Patients received either Gln-PN (containing alanyl-glutamine dipeptide; 0.5 g/kg per day; n=15) or standard Gln-free PN (control-PN) that was iso-nitrogenous to Gln-PN (n=14). Serum HSP-70 concentrations were measured at enrollment and at 7 days. Clinical outcome measures were also determined. RESULTS: HSP-70 concentrations were unchanged in control-PN subjects from baseline to day 7. In marked contrast, Gln-PN subjects demonstrated significantly higher (3.7-fold) serum HSP-70 concentrations than control subjects. In Gln-PN patients there was a significant correlation between increases in HSP-70 levels over baseline and decrease in ICU length of stay. CONCLUSIONS: Gln-PN significantly increases serum HSP-70 in critically ill patients. The magnitude of HSP-70 enhancement in Gln-treated patients was correlated with improved clinical outcomes. These data indicate the need for larger, randomized trials of the Gln effect on serum and tissue HSP-70 expression in critical illness and relationship to clinical outcomes.