Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines

PURPOSE: To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness. METHODS: We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds. RESULTS: We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion. CONCLUSIONS: We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.

Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome-Based Analysis.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).

The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality.

BACKGROUND: Patients with cirrhosis are susceptible to sepsis, pre-disposing to the development of encephalopathy, bleeding and organ dysfunction with associated high mortality. AIM: To characterise circulating neutrophil function in a cirrhotic cohort as a determinant of 90-day and 1-year mortality. METHODS: Sixty-two patients with cirrhosis [49 stable (Child-Pugh A/B/C = 24%/39%/37%); 13 acute-on-chronic liver failure] were prospectively studied and compared with 11 healthy controls. Neutrophil function was evaluated at baseline and repeated at critical points during the course of the patient's illness until death/transplantation. Neutrophil phenotype was determined using fluorochrome-labelled antibodies to CD16/CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) and capacity (NPC) were determined using FITC-labelled opsonised Escherichia coli. Oxidative burst (OB) was quantified by the percentage of neutrophils producing reactive oxygen species (ROS) and mean fluorescence intensity at rest, and after stimulation with E. coli. Physiological variables, biochemistry, microbiology and outcomes were collected. Plasma pro- and anti-inflammatory cytokine profiles were performed by ELISA. RESULTS: NPA/NPC was impaired in cirrhosis with the most significant dysfunction being observed in those with advanced disease and in those treated with propranolol. NPC predicted survival in stable cirrhosis [AUROC 0.83 (95% CI 0.68-0.97); P = 0.021] and differentiated survivors from nonsurvivors (90-day P = 0.01; 1 year P < 0.001). Resting OB ≥12% predicted 90-day mortality with 80% sensitivity and 71% specificity [AUROC 0.81 (95% CI 0.64-0.97); P = 0.026 and differentiated survivors from nonsurvivors; P = 0.015]. CONCLUSION: Circulating neutrophils in patients with cirrhosis are dysfunctional and predict the development of infection, organ dysfunction and survival at 90 days and 1 year.

Comparison of scoring systems and outcome of patients admitted to a liver intensive care unit of a tertiary referral centre with severe variceal bleeding.

BACKGROUND: Acute variceal haemorrhage (AVH) is associated with significant mortality. AIMS: To determine outcome and factors associated with hospital mortality (HM) in patients with AVH admitted to intensive care unit (ICU) and to compare outcomes of patients requiring transfer to a tertiary ICU (transfer group, TG) to a local in-patient group (LG). METHODS: A retrospective study of all adult patients (N = 177) admitted to ICU with AVH from 2000-2008 was performed. RESULTS: Median age was 48 years (16-80). Male represented 58%. Median MELD score was 16 (6-39), SOFA score was 8 (6-11). HM was higher in patients who had severe liver disease or critical illness measured by MELD, SOFA, APACHE II scores and number of failed organs (NFO), P < 0.05. Patients with day-1 lactate ≥ 2 mmol/L had increased HM (P < 0.001). MELD score performed as well as APACHE II, SOFA and NFO (P < 0.001) in predicting HM (AUROC = 0.84, 0.81, 0.79 and 0.82, respectively P > 0.05 for pair wise comparisons). Re-bleeding was associated with increased HM (56.9% vs. 31.6%, P = 0.002). The TG (n = 124) had less severe liver disease and critical illness and consequently had lower HM than local patients (32% vs. 57%, P = 0.002). TG patients with ≥2 endoscopies prior to transfer had increased 6-week mortality (P = 0.03). Time from bleeding to transfer ≥3 days was associated with re-bleeding (OR = 2.290, P = 0.043). CONCLUSIONS: MELD score was comparable to ICU prognostic models in predicting mortality. Blood lactate was also predictive of hospital mortality. Delays in referrals and repeated endoscopy were associated with increased re-bleeding and mortality in this group.

Predicting the development of acute kidney injury in liver cirrhosis--an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.

BACKGROUND: The timely diagnosis of acute kidney injury (AKI) in liver cirrhosis is challenging. AIM: To evaluate whether quantification of glomerular filtration rate (GFR), proteinuria and kidney injury biomarkers can accurately predict the development of AKI. METHODS: A prospective cohort analysis of patients with cirrhosis was performed. Measures of baseline kidney function included serum creatinine, iohexol clearance and urine protein:creatinine ratio. Blood and urine samples were collected daily. A retrospective analysis of cystatin C GFR and neutrophil gelatinase-associated lipocalin (NGAL) measured 48 h prior to the diagnosis of AKI was undertaken to evaluate their ability to predict the development of AKI. RESULTS: Eighteen of the 34 cirrhosis patients studied developed AKI. A GFR <60 mL/min/1.73 m(2) was identified in 56% with Iohexol clearance compared to 8% using the four-variable modified diet in renal disease formula (P < 0.0001). Prediction of AKI, 48 h prior to the development of AKI with cystatin C GFR and serum NGAL concentration were similar; area under the receiver operating curve (AUROC) values 0.74 (0.51-0.97), P = 0.04 and 0.72 (0.52-0.92), P = 0.02 respectively. The development of AKI was strongly predicted by urine protein:creatinine ratio above the cut-off of >30 (equivalent to 300 mg/day of proteinuria) sensitivity 82% (57-96) and specificity 80% (52-96), AUROC 0.86 (0.73-0.98), P ≤ 0.0001. [OR 21 (3-133), P ≤ 0.002]. CONCLUSIONS: In patients with liver cirrhosis a urine protein:creatinine ratio >30 predicts AKI. Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI.

Complications related to less-invasive haemodynamic monitoring.

BACKGROUND: The aim of this study was to evaluate the type and incidence of complications during insertion, maintenance, and withdrawal of central arterial catheters used for transpulmonary thermodilution haemodynamic monitoring (PiCCO™). METHODS: We conducted a prospective, observational, multicentre study in 14 European intensive care units (six countries). A total of 514 consecutive patients in whom haemodynamic monitoring by PiCCO™ was indicated were studied. RESULTS: Five hundred and fourteen PiCCO catheters (475 in femoral, 26 in radial, nine in axillary, and four in brachial arteries) were inserted. Arterial access was obtained on the first attempt in 86.4% of the patients. Minor problems such as oozing after insertion (3.3%) or removal of the catheter (3.5%) were observed, but no episodes of serious bleeding (more than 50 ml) were recorded. Small local haematomas were observed after insertion (4.5%) and after removal (1.2%) of the catheter. These complications were not more frequent in patients with coagulation abnormalities. The incidence of site inflammation and catheter-related infection was 2% and 0.78%, respectively. Other complications such as ischaemia (0.4%), pulse loss (0.4%), or femoral artery thrombosis (0.2%) were rare, transient, and all resolved with catheter removal or embolectomy, respectively. CONCLUSIONS: In this series of patients, central arterial catheters used for PiCCO™ monitoring were demonstrated to be a safe alternative for advanced haemodynamic monitoring.

Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. METHODS: We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. RESULTS: 46% of patients had positive cultures taken within ± 48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. CONCLUSIONS: These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.

Outcomes of severe pregnancy-related liver disease: refining the role of transplantation.

Severe liver disease in pregnancy is generally considered to have a favorable prognosis. The limited data available have not yielded disease-specific prognostic criteria or guidance on who should undergo liver transplantation (LT). We retrospectively evaluated 54 admissions with pregnancy-related liver disease to (1) evaluate if any admission parameters were associated with death and/or transplantation and (2) identify maternal complications. Eighteen had acute fatty liver of pregnancy and 32 had hypertension/eclampsia related disease. Seven patients (13%) died and four (7%) underwent LT. Survival rates were 43/48 if not listed for LT and 4/6 if listed. Of the four transplanted, three survived. Patients who died and/or underwent LT were more likely to have encephalopathy (p = 0.04) and hyperlactaemia (p = 0.03). Serum lactate was the best discriminant (ROC AUC 0.84). An admission lactate greater than 2.8mg/dL had 73% sensitivity and 75% specificity for predicting death or LT. The addition of encephalopathy to this parameter increased sensitivity and specificity to 90% and 86%, respectively. The King's College criteria were not effective in predicting outcome. This study confirms the overall favorable prognosis in pregnancy-related liver failure but indicates that elevated lactate levels in the presence of encephalopathy best identify patients at greatest risk of death or LT.

Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis.

BACKGROUND & AIM: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti-inflammatory cytokine interleukin (IL)-10. We investigated the prognostic value of admission IL-10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF)-alpha. METHODS: We measured these cytokines within 48 h of admission in 51 ALF and 39 decompensated cirrhosis patients admitted to intensive care, and obtained follow-up measurement a median of 2 days later in 35 patients. RESULTS: Levels of all cytokines were higher in those with a poor outcome. IL-10 performed as well as TNF-alpha and IL-6 in the whole cohort (area under receiver operator curve 0.73 vs 0.66 and 0.72). However IL-10 outperfomed pro-inflammatory cytokines in the subgroups with ALF (0.80 vs 0.63 and 0.70) and acetaminophen-induced ALF (0.92 vs 0.67 and 0.81). Levels of all cytokines rose significantly in non-surviving patients (n=15); IL-10 by a factor of 2, TNF-alpha by 2.6 and IL-6 by 1.13. No significant changes were seen in the surviving patients. In ALF, IL-10 was an independent predictor of outcome in multivariate analysis. CONCLUSION: The magnitude of the compensatory anti-inflammatory response at admission, and its development during the early phase of treatment, predicts outcome as well as the pro-inflammatory response in acute hepatic syndromes and supports a vital role for this immunological phenomenon in the outcome of these patients.

Multiple organ failure and severe bone marrow dysfunction in two 18 year-old Caucasian patients: Epstein-Barr virus and the haemophagocytic syndrome.

Haemophagocytic lymphohistiocytosis secondary to viral infection is an unusual but well recognised cause of bone marrow dysfunction and multiple organ failure in young patients. Two 18 year-old patients were admitted to a tertiary liver unit with features of acute liver failure, cardio-respiratory collapse and pancytopenia. Serological tests and bone marrow examination with in-situ hybridisation revealed severe acquired haemophagocytic lymphohistiocytosis secondary to acute Epstein-Barr virus infection. Both patients died despite full supportive therapy; the first due to pulmonary haemorrhage, the second due to acute respiratory distress syndrome refractory to high frequency oscillatory ventilation. The clinical spectrum, diagnostic features and current evidence based recommendations for treatment of this condition are explored. The diagnosis of haemophagocytic lymphohistiocytosis should be considered in young patients with marked bone marrow dysfunction and multiple organ failure. Further research into appropriate therapy for patients with acute severe forms of the disease who require intensive organ support is required.

Hepatic function and non-invasive hepatosplanchnic monitoring in patients with abdominal hypertension.

A better understanding of intra-abdominal hypertension with relation to the liver is vital to the management of all forms of liver pathophysiology. Supporting good hepatic function within the critically ill patient is important not only in maintaining synthetic function, but also in avoiding the multi-organ complications of liver dysfunction. The resulting reduction in hepato-splanchnic blood flow (HSBF) observed with increasing intra-abdominal pressure has been clearly documented and seen to be exaggerated in animals with established liver disease. Unfortunately the tools required to measure this, remain difficult to apply routinely in the clinical setting and as such goal directed therapy to specifically improve the hepatosplanchnic circulation remains elusive. Given the documented effects of lAP on HSBF and the relatively high incidence of intra-abdominal hypertension and the abdominal compartment syndrome within "liver patients" as a whole, close attention to IAP and timely correction by appropriate medical or surgical means would appear to be essential.

Hepatic function and non-invasive hepatosplanchnic monitoring in patients with abdominal hypertension.

A better understanding of intra-abdominal hypertension with relation to the liver is vital to the management of all forms of liver pathophysiology. Supporting good hepatic function within the critically ill patient is important not only in maintaining synthetic function, but also in avoiding the multi-organ complications of liver dysfunction. The resulting reduction in hepato-splanchnic blood flow (HSBF) observed with increasing intra-abdominal pressure has been clearly documented and seen to be exaggerated in animals with established liver disease. Unfortunately the tools required to measure this, remain difficult to apply routinely in the clinical setting and as such goal directed therapy to specifically improve the hepatosplanchnic circulation remains elusive. Given the documented effects of IAP on HSBF and the relatively high incidence of intra-abdominal hypertension and the abdominal compartment syndrome within "liver patients" as a whole, close attention to IAP and timely correction by appropriate medical or surgical means would appear to be essential.

Myeloma associated amyloidosis presenting as subacute liver failure.

Multiple myeloma related amyloidosis is rare and its presentation with subacute liver failure (SALF) has not been reported. A case is described of a 46 year old woman presenting with a six week history of nausea, abdominal pain, and jaundice. Routine tests failed to establish a cause. Computed tomography showed a small volume liver consistent with SALF. Emergency liver transplantation was not undertaken because of the suspicion of underlying malignancy. At necropsy, liver biopsy showed amyloid deposition and bone marrow biopsy showed multiple myeloma. Thus, amyloidosis should be added to the list of potential causes of SALF.

Effects of serum from patients with acute liver failure due to paracetamol overdose on human hepatocytes in vitro.

OBJECTIVE: Our goal was to investigate the effects of serum from patients with acute liver failure due to paracetamol (acetaminophen) overdose on the function of human hepatocytes in vitro. METHODS: Freshly isolated human hepatocytes plated on collagen-coated culture plates were, incubated (24 hours 37 degrees C) in medium containing pooled human sera (0%-80%) obtained from normal individuals or from patients with acute liver failure due to paracetamol overdose. The effects of the sera on cell function were assessed using MTT, [14C]-leucine incorporation, and cytochrome P450 (CYP1A1/2) activity assays. RESULTS: The overall cellular metabolic activity was significantly greater at all concentrations after exposure to acute liver failure serum compared to normal serum. There were no significant differences in the decreases produced by pooled acute liver failure and normal sera at concentrations up to 80% on the [14C]-leucine incorporation or CYP1A1/2 activity. CONCLUSION: The overall cell function/activity of human hepatocytes was not impaired in vitro on exposure to serum from patients with acute liver failure due to paracetamol overdose.

Timing and aetiology of bacterial infections in a liver intensive care unit.

We undertook a prospective study of 887 consecutive adult patients admitted over an 11 year period to a liver intensive care unit. One or more bacterial infections occurred in 335 (37.8%) patients. Gram-positive cocci predominated. In relation to the date of admission these infections occurred in a statistically significant sequence. Streptococci infections were earliest (median time to infection two days), followed by Staphylococcus aureus (three days), coagulase-negative staphylococci (six days) and enterococci (eight days). Escherichia coli infections occurred earlier than those due to klebsiella-enterobacter (two vs seven days; P = 0.0001) and, overall, Enterobacteriaceae earlier than non-fermentative Gram-negatives (four vs. eight days; P = 0.0081). This study contributes to the management of high-dependency patients by confirming statistically the timing and sequence of infecting bacteria in patients with acute liver failure.

Severe hepatic dysfunction in pregnancy.

Acute liver disease in pregnancy may have fatal consequences. Pre-eclampsia, HELLP syndrome and acute fatty liver of pregnancy form a spectrum of disease that range from mild symptoms to severe life-threatening multi-organ dysfunction. Early recognition of signs and prognostic indicators may enable prompt referral to specialist centres providing the multidisciplinary support required to reduce maternal and perinatal morbidity and mortality. We review the common causes of acute hepatic failure associated with pregnancy, and current management practices.