Danilo Radrizzani

Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial.

ObjectiveTo compare the mortality of critically ill patients given either enteral feeding with an immune-enhancing formula or parenteral nutrition (PN). We report the results of a planned interim analysis on patients with severe sepsis which was undertaken earlier than planned once a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition.DesignRandomised multicentre unblinded controlled clinical trial.SettingThirty-three General Intensive Care Units in Italy.Patients and participantsAmong the 237 recruited patients, 39 had severe sepsis or septic shock; 21 of them received PN.InterventionsEligible patients received either total PN or enteral nutrition, the latter containing extra L-arginine, omega-3 fatty acids, vitamin E, beta carotene, zinc, and selenium.Measurements and resultsThe primary endpoint for the subgroup analysis on patients with severe sepsis was mortality on Intensive Care Unit (ICU). The ICU mortality of patients with severe sepsis given enteral nutrition (EN) was higher than for those given PN (44.4% vs 14.3%; p=0.039). More patients given EN than patients given PN still had severe sepsis when they died (38.9% vs 9.5%, p=0.055). Recruitment of patients with severe sepsis was subsequently stopped.ConclusionsOur results show that enteral immunonutrition, compared to PN, may be associated with excess mortality in patients with severe sepsis.

The relationship between labour cost per patient and the size of intensive care units: a multicentre prospective study

ObjectiveWe examined the relationship between major ICU characteristics and labour cost per patient.DesignFour-week prospective data collection, in which the hours spent by each physician and nurse on both in-ICU and extra-ICU activities were collected.SettingEighty Italian adult ICUs.Measurements and resultsThe cost of the time actually spent by ICU staff on ICU patients (labour cost) was computed for each participating unit, by applying to the average annual salaries the proportions of in-ICU activity working time for physicians and nurses. Multiple regression analysis was used to identify ICU characteristics that predict labour costs per patient. Labour cost per patient was positively correlated with ICU mortality and patients average length of stay (slopes =0.67, p =0.048 and 0.09, p <0.0001, respectively). Labour cost per patient decreases almost linearly as the number of beds increases up to about eight, and it remains nearly constant above about twelve beds. The number of patients admitted per physician (not per nurse) increases with the number of beds (Spearman correlation coefficient =0.567, p <0.0001).ConclusionsOur findings suggest that ICUs with less than about 12 beds are not cost-effective.

Volume of activity and occupancy rate in intensive care units. Association with mortality

ObjectiveMortality after many procedures is lower in centers where more procedures are done. It is controversial whether this is true for intensive care units, too. We examined the relationship between the volume of activity of intensive care units (ICUs) and mortality by a measure of risk-adjusted volume of activity specific for ICUs.DesignProspective, multicenter, observational study.SettingEighty-nine ICUs in 12 European countries.PatientsDuring a 4-month study period, 12,615 patients were enrolled.InterventionsDemographic and clinical statistics, severity at admission and a score of nursing complexity and workload were collected.ResultsTotal volume of activity was defined as the number of patients admitted per bed per year, high-risk volume as the number of high-risk patients admitted per bed per year (selected combining of length of stay and severity of illness). A multi-step risk-adjustment process was planned. ICU volume corresponding both to overall [odds ratio (OR) 0.966] and 3,838 high-risk (OR 0.830) patients was negatively correlated with mortality. Relative mortality decreased by 3.4 and 17.0% for every five extra patients treated per bed per year in overall volume and high-risk volume, respectively. A direct relationship was found between mortality and the ICU occupancy rate (OR 1.324 and 1.351, respectively).ConclusionsIntensive care patients, whatever their level of risk, are best treated where more high-risk patients are treated. Moreover, the higher the ICU occupancy rate, the higher is the mortality.

Early enteral immunonutrition vs. parenteral nutrition in critically ill patients without severe sepsis: a randomized clinical trial

ObjectivesWe compared early parenteral nutrition (PN) and early enteral immunonutrition (iEN) in critically ill patients, distinguishing those with and without severe sepsis or septic shock (SS) on admission to intensive care units (ICUs).Design and settingMulticenter, randomized, unblinded clinical trial in 33 Italian general ICUs.Patients and participantsThe study included 326 patients, 287 of whom did not have SS on ICU admission. Eligibility criteria excluded the two tails in the spectrum of critical conditions, i.e., patients either too well or too ill. Of the patients recruited 160 were randomized to iEN (142 without SS) and 166 to PN (145 without SS).InterventionsPatients were randomized to two arms: early iEN or early PN.Measurements and resultsPrimary endpoint was 28-day mortality for all patients and the occurrence of SS during ICU stay for patients admitted without such condition. While 28-day mortality did not differ between iEN and PN (15.6% vs. 15.1%), patients without SS who received iEN had fewer episodes of severe sepsis or septic shock (4.9% vs. 13.1%). ICU length of stay was 4 days shorter in patients given iEN.ConclusionsCompared to parenteral nutrition iEN appears to be beneficial in critical patients without severe sepsis or septic shock. Parenteral nutrition in these patients should be abandoned, at least when enteral nutrition can be administered, even at an initial low caloric content.

Protein sparing and protein replacement in acutely injured patients during TPN with and without amino acid supply

The metabolic effects of TPN were studied in a selected group of trauma patients. Nineteen patients were randomly divided into two groups: the first was treated with glucose and insulin, the second with glucose, insulin and amino acids. Each patient in both groups received TPN isocaloric with respect to daily energy output and the treatment lasted five days. Each group was further divided into two subsets (severe or moderate catabolism) according to fasting energy output with respect to the expected energy expenditure. During the acute flow phase, both in moderate as well as in severe catabolism, glucose and insulin were effective for protein sparing; the maximum protein sparing effect was reached when giving a caloric intake equal to 130% of daily energy output. Glucose, insulin and amino acids were effective in replacement of nitrogen losses. In moderately catabolic patients nitrogen balance was significantly better than in severely catabolic patients. This study shows that early and short-term TPN is effective in controlling the flow phase of trauma. Glucose and insulin appear to be the determinants of the protein sparing effect when given in amounts equal to those needed; amino acids provided protein replacement when given in amounts equal to about 20% of energy output. Energy supply higher than 120–130% of daily energy output does not increase protein sparing and protein replacement, the only effect being a further increase in metabolism, which is possibly dangerous in critically ill patients.

External validation of the Simplified Acute Physiology Score (SAPS) 3 in a cohort of 28,357 patients from 147 Italian intensive care units

ObjectiveTo evaluate the SAPS 3 score predictive ability of hospital mortality in a large external validation cohort.DesignProspective observational study.Setting and patientsA total of 28,357 patients from 147 Italian ICUs joining the Project Margherita national database of the Gruppo italiano per la Valutazione degli interventi in Terapia Intensiva (GiViTI).InterventionsNone.MeasurementEvaluation of discrimination through ROC analysis and of overall goodness-of-fit through the Cox calibration test.Main resultsAlthough discrimination was good, calibration turned out to be poor. The general and the South-Europe Mediterranean countries equations overestimated hospital mortality overall (SMR values 0.73 with 95% CI 0.72–0.75 for both equations) and homogeneously across risk classes. Overprediction was confirmed among important subgroups, with SMR values ranging between 0.47 and 0.82.ConclusionsThe result strictly supported by our data is that the SAPS 3 score calibrates inadequately in a large sample of Italian ICU patients and thus should not be used for benchmarking, at least in Italian settings.

Daily classification of the level of care. A method to describe clinical course of illness, use of resources and quality of intensive care assistance

Objective: To develop a simple and comparable clinical method able to distinguish between higher and lower complexities of care in the ICU. Design: Retrospective analysis. Setting: Database of European ICUs Study I (Euricus-I: including 12,615 patients and 55,464 patient/days), prospectively collected in 89 ICUs of 12 European countries. Methods and results: A panel of experts developed the classification of the complexity of care. Six (in addition to monitoring, two levels of respiratory support – R and r – two levels of circulatory support – C and c – and dialysis) out of the nine items of Nine Equivalents of Nursing Manpower use Score (NEMS), a therapeutic index, were utilised. Two levels of care (LOCs) were defined according to a more (HT) and a less complex (LT) combination of common activities of care. The two LOCs were significantly related to mortality: higher in HT and they rose with increasing cumulative number of HT days. HT accounted for 31,976 NEMS days (57.7%) while 23,488 (42.3%) were LT. Major respiratory and cardiovascular support accounted for about 80% of the HT days. Respiratory assistance and monitoring were responsible for an equivalent percentage of LT days. The distribution of the clinical classification of LOCs coincided with that of the managerial scores of LOCs in the literature. Conclusions: The managerial instrument described uses simple and reliable clinical data. It is able to distinguish between patients with different severity and outcome, and shows that every additional consecutive day spent in ICU as HT increases the probability of death. Moreover, (1) it suggests the possibility of describing the clinical course of illness by relating the complexity/level of medical care to the available technology and staff; (2) using relevant markers of clinical activity, it might be useful to include in quality control programmes.

Influence of Total Parenteral Nutrition on Protein Metabolism following Acute Injury: Assessment by Urinary 3-Methylhistidine Excretion and Nitrogen Balance

The use of total parenteral nutrition after acute injury, either surgical or accidental, is widely accepted for its important benefits, although it is not yet completely understood whether a reduction of body protein catabolism can be effectively achieved. We applied total parenteral nutrition to 14 critically ill patients after either trauma or major surgery. Their daily nitrogen balance, urinary 3-methylhistidine and creatinine excretion, and molar 3-methylhistidine/creatinine ratio, during initial 24-hr fasting period, were respectively -0.19 +/- 0.01 (SEM) g kg-1, 5.46 +/- 0.47 mumol kg-1, 27 +/- 4 mg kg-1, and 0.030 +/- 0.005. Daily nonprotein calorie intake of 31.11 +/- 0.58 kcal kg-1, as glucose, and administration of nitrogen 0.350 +/- 0.004 g kg-1, as 10% crystalline L-aminoacids solution, and insulin 1 IU every 5.03 +/- 0.14 g of glucose, resulted in progressive decline of urinary 3-methylhistidine (4.21 +/- 0.43 mumol kg-1, p less than 0.001), creatinine (22 +/- 2 mg kg-1, NS), and their molar ratio (0.022 +/- 0.002, NS). Mean nitrogen balance resulted in 0.032 +/- 0.008 g kg-1. Since urinary 3-methylhistidine role as a marker of protein catabolism is well established, its decrease under total parenteral nutrition together with greatly improved nitrogen balance, demonstrates that our treatment can effectively quench protein catabolism, meanwhile enhancing protein synthesis.

The main determinants of nitrogen balance during total parenteral nutrition in critically ill injured patients

Factors influencing nitrogen balance during total parenteral nutrition have been investigated in 34 critically ill injured patients studied during the first 6 days after trauma. Basal nitrogen balance was severely negative (-0.26±0.12 (SD) g·kg-1), but improved consistently during treatment. Nitrogen intake proved to be the major determinant of a positive, or less negative, nitrogen balance, only secondarily followed by total energy intake corrected to predicted basal energy expenditure, according to multiple regression analysis. The amount of non-protein calories and the non-protein calorie to nitrogen ratio appeared to have little significance on nitrogen balance, when corrected for the two former variables.

Peripheral, visceral and body nitrogen balance of catabolic patients, without and with parenteral nutrition

The effect of major trauma and sepsis on skeletal muscle, central tissue and whole body nitrogen (N) metabolism was investigated in 5 patients before and during TPN (30 kcal, 0.30 g N kg-1 day-1). Fasting 3-methylhistidine (MEH) urinary excretion was elevated (407.9±67.6 μmol m-2 day-1), muscle and body N balances (NB) were markedly negative (-28.2±4.6 g m-2 day-1 and-15.7±3.1 g m-2 day-1), while central tissue NB was positive (13.0±2.4 g m-2 day-1). TPN effected a reduction in MEH excretion (261.8±27.5 mmol m-2 day-1-p<0.05) and decreased the release of almost all amino acids from muscle tissue, some of them acting as catabolic markers. Muscle (-7.2±1.2 g m-2 day-1-p<0.01) as well as body NB (-4.8±1.4 g m-2 day-1-p<0.01) improved, whilst central tissue NB worsened, even though still positive (3.1±1.6 g m-2 day-1-p<0.05). Gathering fasting and TPN data MEH excretion was significantly related to both body (r=0.89) and muscle (r=0.73) NB, that were highly related to each other (r=0.93), being muscle always worse than body NB. In conclusion, the anticatabolic activity of TPN is confirmed, although our setting did not achieve muscle NB, it was consistently improved and seems to be the major determinant of body NB, in contrast central NB and central N utilization (46.4%±5.4 vs 15.8%±8.4-p<0.05) worsened.