Methods

Study design: prospective, randomized controlled trial.

Study dates: “study dates not available"

Setting: level‐1 trauma centre. Department of Surgery, Detroit Receiving Hospital, Wayne State University, Detroit, Michigan

Country: USA

Participants

Inclusion criteria

1. Surgical patients, ≥ 18 years old, with requirement for parenteral nutrition by a central catheter due to contraindication or intolerance to enteral nutrition

Exclusion criteria

1. Baseline blood glucose level > 200 mg/dl

2. Expectation of receiving parenteral nutrition for < 4 days

3. Severily underweight (< 75% of ideal body weight)

4. Morbid obesity (> twice their ideal body weight

5. Currently receiving corticosteroid therapy

6. Admitting diagnosis of burn

7. Receiving parenteral nutrition on admission

8. Not able to provide informed consent

Sample size: calculated sample size of 26 participants to detect an absolute difference in glucose area under the curve of 50 mg hr/dl with 80% power (P = 0.05). 40 participants were randomized: 20 to each group. Only 18 were ICU participants (8 of the low caloric and 10 of the standard group). At baseline both groups were well matched, with exception of lower creatinine clearance in the standard group.

Age (years mean ± SD) group 1: 45.3 ± 17.2; group 2: 53.1 ± 17.9

Sex (male, %) group 1: 75; group 2: 80

Most frequent admitting diagnosis (groups 1 and 2 respectively): pancreatitis 6 & 6, trauma 7 & 3, bowel obstruction 4 & 5.

ICU participants (n). group 1: 8; S group 2: 10

APACHE II score (mean ± SD of participants in ICU). Group 1: 20.1 ± 9.1; Group 2: 18.6 ± 11.1

Mechanical ventilation (n). 8 participants in each group

Baseline nutrition status No major differences between ideal and actual body weight in both groups

Duration of parenteral nutrition (days; median (interquartile range)). group 1 6 (4 to 10); group 2 7 (5 to 10)

Interventions

Group 1, low caloric parenteral nutrition (n = 20)

1. 20 non‐protein calories/kg ideal body weight/day

Group 2, standard parenteral nutrition (n = 20)

1. 30 non protein calories/kg ideal body weight/day

In both groups, parenteral nutrition was administered by a multiple‐bottle system. Lipids administration was standardized to 1000 kcal 3 times weekly. Proteins administered according the levels of estimated metabolic stress of the disease (mild 1.2 ‐ 1.4; moderate 1.5 ‐ 1.7; or severe 1.8 ‐ 2.2 gr/kg/day)

Outcomes

Primary outcomes

1. Incidence and severity of hyperglycaemia and daily insulin requirements during parenteral nutrition

Incidence of hyperglycaemia was calculated as the number of assessments of glycaemia ≥ 200 mg/dl divided by the total number of assessments

Severity of hyperglycaemia was assessed by measuring the area under the curve

Secondary outcomes

1. Infectious complications (new‐onset infections according to established criteria)

2. Hospital charges (charges for hospital room, diagnostic services, medication, nursing services, direct expenses)

Funding sources

Not available

Declarations of interest

The authors have no financial interests to disclose

Notes

Total calories administered/kg (median (interquartile range)) were: 26.6 (26.2 to 27.5) and 37.0 (36.6 to 38.4); the amount of protein administered and the duration of PN therapy were similar. The first author sent the data of continuous outcomes expressed as mean and standard deviation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly assigned by means of a computer‐generated random‐numbers

Allocation concealment (selection bias)

Low risk

Central allocation (pharmacist)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Clinicians were blinded to which caloric group participants were randomized to, with the exception of the critical care pharmacist who calculated the formula.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Clinicians were blinded to which caloric group participants were randomized to, with the exception of the critical care pharmacist who calculated the formula.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants.

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: April 2006 to January 2008

Setting: 1 tertiary care academic hospital

Country: Saudi Arabia

Participants

Inclusion criteria

1. Participants aged 18 to 80 years, admitted to an ICU, blood glucose concentration of > 110 mg/dl, expected to remain in ICU ≥ 48 hours

Exclusion criteria

1. Type 1 diabetes

2. Diabetic ketoacidosis

3. Hypoglycaemia

4. Brain death

5. Do‐not‐resuscitate status

6. Terminal illness

7. Pregnancy

8. Postcardiac arrest

9. Burns

10. Seizures within the past 6 months

11. Liver transplant

12. Readmission to the ICU within the same hospitalization

13. Enrollment in a competing trial

14. Oral feeding

15. Total parenteral nutrition

Sample size: authors estimated a relative difference of 50% in ICU mortality between participants receiving .90% of caloric requirements and those receiving 60% to70% of caloric requirements (28% compared with 14%). Quote: “on the basis of an estimated 28‐d mortality rate of 25%, a power of 0.8, and an α of 0.05, the number of subjects needed to show a reduction in mortality was 120 in each group.”

Age (years): intervention group: 50.3 ± 21.3; Control group: 51.9 ± 22.1

Sex (male, %): intervention group: 71.1; Control group: 65

Primary disease of the participants Intervention; Control group

Admission category (n (%))

Nonoperative 95 (79.2); 103 (85.8)

Postoperative 25 (20.8); 17 (14.2)

Traumatic brain injury 35 (29.2); 31 (25.8)

Disease severity score: APACHE II Intervention group: 25.2 ± 7.5; Control group: 25.3 ± 8.2

Mechanical ventilation n (%) Intervention group: 119 (99.2); Control group: 119 (99.2)

Comorbidities: not available

Nutrition status: intervention group; Control group: Not available

Level of inflammation: not available

Interventions

Intervention Group 1 (n = 120)

1. Permissive‐underfeeding group: caloric goal 60% to 70% of caloric requirements

Control Group 2 (n = 120)

1. Target‐feeding group: 90% to 100% of caloric requirements

Quote: “for both groups, caloric requirement was estimated by the dietitian using the Harris‐Benedict equations and adjusting for stress factors. The selection of formula was left to discretion of the attending physician as long as it satisfied the total caloric intake criteria and was not enriched with immunonutrients. Calculation of caloric intake took into account intravenous dextrose and propofol infusions.”

Quote: “the patients were followed until discharge from the ICU, except if the patient tolerated oral feeding, had a do‐not‐resuscitate order written (after enrolment), or became brain dead (after enrolment). In the latter situations, the intervention was stopped but the outcome data were collected.”

Co‐interventions

Quote:“The protein requirement was calculated as 0.8–1.5 g/kg on the basis of patient condition and underlying diseases. To avoid protein malnutrition in the permissive underfeeding group, additional protein (Resource Beneprotein; Nestle Healthcare Nutrition Inc, Minneapolis, MN) was added to maintain the full protein requirement without affecting the assigned caloric intake.”

Outcomes

Primary outcome

1. 28‐day all‐cause mortality

Secondary outcomes

1. 180‐day mortality

2. ICU mortality

3. Hospital mortality

4. ICU length of stay

5. Hospital length of stay

6. Mechanical ventilation duration

7. Hypoglycaemic episodes

8. Packed red blood cell transfusion

9. Renal replacement therapy

10. Hypokalaemic episodes

11. Health care–associated infections: bacteraemia, catheter‐related bloodstream infection, urinary tract infection, ventilator‐associated pneumonia, and skin and soft tissue

How measured or definition and time point measured

1. 28‐day mortality: mortality rate at 28 days of ICU admission

2. 180‐day all‐cause mortality: mortality rate at 180 days of ICU admission

3. ICU mortality: mortality rate at ICU discharge

4. Hospital mortality: mortality rate at hospital discharge

5. Health care–associated infections:according to the National Nosocomial Infection Surveillance (NNIS) System (Emori 1991)

6. Hypoglycaemia: defined as a blood glucose concentration ≤ 2.2 mmol/L or 40 mg/dL

7. Hypokalaemia: defined as a potassium concentration < 2.8 mmol/L

8. Health care–associated infections: according to Nosocomial Infection Surveillance (NNIS) System

Subgroups

1. Not available/not performed

Funding sources

Funded by King Abdulaziz City for Science and Technology (LG 10‐30).

Declarations of interest

No potential conflict of interest relevant to this article was reported.

Notes

As it was a 2 x 2 factorial trial, the enrolled participants were randomly assigned by using concealed envelops to 1 of the 4 study groups: 1‐permissive underfeeding with intensive insulin therapy (IIT), 2‐permissive underfeeding with conventional insulin therapy (CIT), 3‐target feeding with IIT, and 4‐target feeding with CIT. We grouped 1 and 2; 3 and 4.

Blood glucose concentration target was 4.4 – 6.1 mmol/L (80 – 110 mg/dL) in the IIT group and 10 – 11.1 mmol/L (180 – 200 mg/dL) in the CIT group. The frequency of blood glucose monitoring increased to every 20 mins when blood glucose concentrations decreased to > 3.2 mmol/L (58 mg/dL) and reduced to every 2 – 4 hrs when measurements were stable.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

On the basis of (quote:) "computer‐generated random permuted blocks"

Allocation concealment (selection bias)

Low risk

The enrolled participants were randomly assigned by using concealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Unblinded study. Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Not blinded but main and secondary outcomes well‐defined. We judge that the outcome measurement was probably not influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants.

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: November 2009 to September 2014

Setting: 7 tertiary care centres

Country: Saudi Arabia and Canada

Participants

Inclusion criteria

1. Age 18 to 80 years, admitted to ICU and starting enteral feeding within 48 hours of ICU admission; expected to remain in ICU ≥ 72 hours

Exclusion criteria

1. Lack of commitment to ongoing life support

2. Brain death

3. A pre‐existing condition with expected 6‐month mortality > 50%

4. Post‐cardiac arrest

5. Use of total parenteral nutrition

6. Previous enrolment in this study

7. Pregnancy

8. Liver transplantation

9. Burns

10. Receipt of high‐dose vasopressors (norepinephrine > 0.4 μg/ kg/min, epinephrine > 0.4 μg/kg/min, dopamine > 20 μg/kg/min, phenylephrine > 300 μg/min, vasopressin > 0.04 unit/min, or 50% of these doses for participants who received 2 or more vasopressors)

Sample size

With 432 participants in each group; with an estimated 3% loss to follow‐up, the final calculated sample size was 892 participants. Permissive underfeeding would be associated with an absolute risk reduction in mortality of 8 percentage points. Assuming an estimated 90‐day mortality of 25% with standard feeding, they estimated that enrolment of 432 participants in each group would give the study 80% power.

Age (years): intervention group: 50.2 ± 19.5; Control group: 50.9 ± 19.4

Sex (male, %): intervention group: 65.2; Control group: 63.2

Primary disease of the participants Intervention; Control group

Medical no. (%) 336 (75.0); 335 (75.1)

Surgical no. (%) 19 (4.2); 12 (2.7)

Nonoperative trauma no. (%) 93 (20.8); 99 (22.2)

Severe sepsis at admission no. (%) 159 (35.5); 133 (29.8)

Traumatic brain injury no. (%) 55 (12.3); 63 (14.1)

Disease severity score: APACHE II

Intervention group: 21.0 ± 7.9; Control group: 21.0 ± 8.2

Mechanical ventilation no. (%)

Intervention group: 436 (97.3); Control group: 429 (96.2)

Comorbidities: not available

Nutrition status: intervention group; Control group

Albumin g/litre 28 ± 7; 28 ± 6

Prealbumin g/litre 0.15 ± 0.13; 0.14 ± 0.12

Transferrin g/litre 1.36 ± 0.49; 1.38 ± 0.50

24‐hour urinary nitrogen excretion mmol 284 ± 176; 303 ± 219

Level of inflammation : not available

Interventions

Intervention Group (n = 448)

1. Permissive‐underfeeding group: caloric goal 40% to 60% of caloric requirements

Control group (n = 446)

1. Standard‐feeding group: 70% to 100% of caloric requirements

For both groups, the calculation of caloric requirements was using the Penn State equation for mechanically‐ventilated participants who had a BMI < 30 and using the 1992 Ireton‐Jones equation for mechanically‐ventilated participants who had a BMI of 30 or higher and for spontaneously‐breathing participants. Protein requirements were calculated at 1.2 to1.5 g per kilogram of body weight a day, in accordance with clinical practice guidelines.

Co‐interventions

Quote. "to ensure that enteral protein and volume delivery in the permissive‐underfeeding group would be similar to those in the standard‐feeding group, the permissive‐underfeeding group received additional protein (Beneprotein, Nestlé Nutrition) and normal saline or water at a dose of 2 ml per kilogram every 4 hours unless otherwise specified by the clinical team. The assigned intervention was continued for up to 14 days or until ICU discharge, initiation of oral feeding, death, or withholding of nutrition as part of palliation."

The study protocol provided suggestions on the selection of enteral formulas on the basis of published guidelines; however, the decision was left to the clinical team. Study centres used their own insulin protocols, with a target blood glucose level of 4.4 to 10 mmol.

Outcomes

Primary outcome

1. 90‐day all‐cause mortality.

Secondary outcomes

1. Mortality in the ICU

2. 28‐day mortality

3. In‐hospital mortality

4. 180‐day mortality

5. Serial SOFA scores.

Tertiary outcomes

1. Days free from mechanical ventilation

2. ICU‐free days

3. Hospital length of stay

4. Hypoglycaemia

5. Hypokalaemia

6. Hypomagnesaemia

7. Hypophosphataemia

8. Transfusions of packed red cells

9. Infectious complications (ICU‐associated infections documented by the research co‐ordinator according to published definitions)

10. Non‐infectious complications (feeding intolerance: vomiting, abdominal distention, or a gastric residual volume of more than 200 ml and diarrhoea)

How measured or definition and time point measured

1. 90‐day all‐cause mortality: mortality rate at 90 days from ICU admission

2. ICU mortality: mortality rate at ICU discharge

3. 28‐day mortality: mortality rate at 28 days from ICU admission

4. In‐hospital mortality: mortality rate at hospital discharge

5. 180‐day mortality: mortality rate at 180 days from ICU admission

Subgroups

1. Non‐surgical admission /surgical admission

2. Diabetic/non‐diabetic

3. APACHE II ≤ 18 /APACHE II > 18

4. Admitted with severe sepsis/admitted with no severe sepsis

5. Traumatic brain injury/no traumatic brain injury

6. Vasopressors/no vasopressors

7. Randomization blood glucose ≤ 9.2 mmol/L/ > 9.2 mmol/L

Funding sources

Funded by the King Abdullah International Medical Research Center

Declarations of interest

No potential conflict of interest relevant to this article was reported.

Notes

The total caloric intake included calories from propofol, intravenous dextrose and parenteral nutrition.

The author provided additional information about mean and standard deviation values of length of hospital and ICU stay and of mechanical ventilation.

In 2017, the researchers published a subgroup analysis using a Nutrition Risk In Critically ill (NUTRIC) score. However these subgroup analyses did not contribute to our review objectives.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "the randomization list was computer‐generated"

Allocation concealment (selection bias)

Low risk

Quote: "enrolled patients were randomly assigned to the permissive‐underfeeding group or the standard‐feeding group with the use of opaque, sealed, sequentially numbered envelopes."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

PermiT was a multicentre, pragmatic, open‐label international randomized clinical trial.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

There was no blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for 445/448 and 440/446 participants in the intervention and control group respectively.

Selective reporting (reporting bias)

Low risk

Authors reported all protocol outcomes.

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: September 1992 to July 1994

Setting: Trauma surgery service. University of California, Davis, Medical Center

Country: USA

Participants

Inclusion criteria

1. Polytrauma participants,18 to 50 years old, requiring total parenteral nutrition at the 5th post‐injury day

Exclusion criteria

1. If able to tolerate > 10% of their caloric requirement as enteral feeding at the time of randomization

2. If clinical evidence of fatty acid deficiency, hepatic cirrhosis, HIV, malignancy

3. If receiving steroids or nonsteroidal anti‐inflammatory agents.

Sample size: 60 participants randomized, data analysed of 57 participants

Age (years; mean ± SD). Group 1: 32 ± 9; Group 2: 33 ± 10

Sex (male, %). Group 1: 85%; Group 2: 80%

Type of injury (blunt trauma %): Group 1: 85%; Group 2: 80%

APACHE II score (mean ± SD). Group 1: 22 ± 5; Group 2: 23 ± 6

Injury severity score (mean ± SD). Group 1: 30 ± 9; Group 2: 27 ± 8

Nutrition status. On admission no participants weighted less than ideal body weight

Interventions

Participants randomized at the 5th post‐injury day. 10 days study period with parenteral nutrition.

No lipid group (Group 1) (n = 27)

1. Parenteral nutrition without lipid emulsion. Same formulation but without lipids during 10 days (no added calories to replace the fat calories), so the formulae were isonitrogenous but hypocaloric in relation to the control (lipid) group.

Lipid group (Group 2) (n = 30)

1. Standard total parenteral nutrition: goal of 30 nonprotein kcal/kg ideal body weight/day (25% provided by lipids) and 1.5 grams amino acids/kg/day, during 10 days

Outcomes

1. Length of ICU stay

2. Length of hospital stay

3. Length of mechanical ventilation

4. Infectious complications: total infectious complications (pneumonia, line sepsis, wound infections, acalculous cholecystitis, intra‐abdominal abscess, empyaema, bacteraemia)

Outcomes evaluated after 10 days of parenteral nutrition

Other outcomes

1. Clinical signs of fatty acid deficiency; immune function assays (T‐cell function: lymphokine activated killer cell activity and natural killer cell activity; T‐cell phenotype: CD₄/CD₈)

Funding sources

Study supported in part by National Institutes of Health Grant P30 DK‐35747

Declarations of interest

Not reported

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not described.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Reasonable explanation: quote: "Of the 60 patients enrolled, only 57 had data that could be analysed. One patient was ineligible for the study because he had been admitted for management of an entero‐cutaneous fistula that had resulted as a complication of a remote trauma and two patients died before being randomized (before the fifth post injury day)".

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No evidence of other bias.

Methods

Study design: prospective, randomized controlled trial

Study dates: March 2008 to November 2011

Setting: Surgical/trauma ICU at a tertiary‐care hospital. Department of Surgery, University of Virginia Health System. Charlottesville, Virginia

Country: USA

Participants

Inclusion criteria

1. Age ≥ 18 years; projected need for nutrition support > 48 hrs and for ICU stay > 48 hrs according to the attending intensivist

Exclusion criteria

1. Participants aged < 18 years, expected to die or ICU discharge within 48 hours, pregnancy and primary diagnosis of burn

Sample size: From 2892 admissions to the ICU 83 participants were enrolled and randomized: 41 to the hypocaloric group and 42 to the eucaloric group (detailed flow diagram given of the randomization, exclusion and study end)

Age (years; mean ± SD). Hypocaloric group 50.4 ± 2.8; Eucaloric group 53.4 ± 2.7

Sex (male, %). Group 1: 58.3; Group 2: 73.8

Primary disease. Trauma admission (%). Group 1: 68.3; Group 2: 59.5. The other participants in the surgical ICU were abdominal, vascular, orthopaedic and liver transplant surgery.

Disease severity, APACHE II score (mean ± SD) Group 1: 16.6 ± 0.9; Group 2: 17.3 ± 0.8

Mechanical‐ventilation dependence (%). Group 1: 68.3; Group 2: 57.1

Comorbidities. Diabetes mellitus and coronary artery disease (%). Group 1. 19.5 and 17.1 respectively; Group 2: 14.3 and 11.9 respectively

Nutrition status BMI (kg/m², mean ± SD). Group 1: 32.9 ± 2.0; Group 2: 28.1 ± 0.9

Risk of refeeding syndrome at admission (due to weigh loss, poor caloric intake or alcohol abuse) (%). Group 1: 31.7; Group 2: 54.8

Level of inflammation: not available

Interventions

Group 1 hypocaloric (n = 41)

1. The hypocaloric target was 50% of the calculated daily caloric requirement: 12.5 to 15 kcal/kg actual weight/day

Group 2 eucaloric (n = 42)

1. The goal was 100% of the calculated caloric requirements: 25 to 30 kcal/kg actual weight/day

Co‐interventions: the protein goal of the 2 groups was 1.5 grams protein/kg/day. If the participant’s actual weight was > 130% of ideal weight, adjusted weight was used. Participants with severe malnutrition not able to receive enteral nutrition were considered for parenteral nutrition, all others received enteral nutrition. In cases of enteral feeding intolerance, parenteral nutrition was started after 5 to 7 days.

Outcomes

Primary outcome

1. Development of hospital‐acquired infectious complications. The diagnosis of all the infections was done according to the criteria of US Centers for Disease Control and Prevention.

Secondary outcomes

1. Glucose control during the study period: mean overall glucose values, mean morning glycaemia at 06.00 hours and mean daily insulin requirements

2. Length of stay in ICU

3. Length of stay in hospital

4. Hospital mortality: all causes of in‐hospital mortality

5. The study protocol was followed during 10 to 12 days

6. The analysis of participants was done on an intention‐to‐treat basis

Subgroups

1. The authors analysed but did not report subgroups of trauma and non‐trauma participants, and men versus women

Funding sources

Supported by grant 5‐T32‐AI‐078875‐03 from the National Institute of Health, USA

Declarations of interest

The authors stated that “No conflicts of interest were reported”

Notes

Due to slow enrolment, the study was closed before the planned enrolment of 116 participants.

Enteral nutrition was given initially. Participants were considered for parenteral nutrition if they were severely malnourished and could not receive enteral feeding, or in case of continuous intolerance of enteral nutrition lasting more than 5 to 7 days.

The author provided additional information: mean and standard deviation of the length of mechanical ventilation and to complete the 'Risk of bias' table.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated 1:1 by using a computer‐based random number generator

Allocation concealment (selection bias)

Low risk

Quote: "investigators were blinded to the preparation of the randomization envelopes, and the randomization assignment was determined by opening sequential opaque security envelopes containing the randomization assignment."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

There was no blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessment was blinded (written information provided by the author).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants.

Selective reporting (reporting bias)

Low risk

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified.

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: Not stated

Setting: participants referred to the Nutrition Support Service of the Ohio State University Hospital. Departments of Surgery and Medical Dietetics. College of Medicine. Ohio State University. Columbus, Ohio

Country: USA

Participants

Inclusion criteria

1. Participants weighing > 130% of ideal body weight (formula of Hamwi) and requiring PN.

Exclusion criteria

1. Pre‐existing renal disease

2. Hepatic disease

3. Adrenal disease

4. Receiving exogenous steroids

5. Minors, prisoners, pregnant women, mental or physical retardation

Sample size: 30 participants, stratified according their hospitalization in ICU (n = 13) or regular floor (n = 17) (randomized with separate randomization tables)

Age (years; mean ± SD; whole sample): Group 1: 52 ± 19; Group 2: 52 ± 15

Sex (male, %: whole sample): Group 1: 31.25; Group 2: 14.29

Primary disease of the participants, surgical diseases. 70% of the whole‐sample diagnosis were cancer with or without enterocutaneous fistulae and pancreatic disease.

Nutrition status. Body weight/BMI (kg and kg/m² respectively; mean ± SD; whole sample). Group 1: 97 ± 19 and 36 ± 5. Group 2: 90 ± 17 and 34 ± 6

Comorbidities. Diabetes type 1 and 2 (n of ICU participants) Group 1: 2 and 1; Group 2: 2 and 2

Disease severity score. APACHE II score at the time of enrolment (mean ± SD of the ICU participants). Group 1: 13 ± 5; Group 2: 15 ± 5

Level of inflammation Initial urinary urea nitrogen (grams/24 hours; mean ± SD of the ICU participants). Group 1: 10.1 ± 9.0; Group 2: 10.0 ± 4.2

Duration of PN (days; mean ± SD). Group 1: 10 ± 3; Group 2: 12 ± 2

Interventions

Group 1 hypocaloric PN (whole sample n = 16; n of ICU participants = 6) has 50% of the carbohydrate and lipid compared with the standard PN.

Group 2 standard PN (whole sample n = 14; n of ICU participants = 7)

Co‐interventions: both PN solutions were isonitrogenous, providing 2 grams of protein/kg ideal body weight/day, added with electrolytes, vitamins and trace elements, administered during ≤ 14 days or until they could receive enteral or oral feeding.

Outcomes

1. Mortality at hospital (events)

2. Hospital length of stay (days; mean ± SD)

3. Carbohydrate metabolic outcomes: glucose control (glycaemia and glycosuria) and insulin requirements (mean daily IU insulin dose ± SD)

4. Protein metabolic outcome:overall nitrogen balance (grams/day; mean ± SD )

5. Nutrition status: weigh (kg) and albumin change (gr/L) during hospital stay

Time points reported

1. Results during the administration of PN

Subgroups

1. The authors reported most of the results for the whole sample populations. Some results of both intervention groups were reported separately for the ICU and regular‐care participants.

Funding sources

Supported by funds from the Bremer Foundation, Department of Surgery Medical Research Development Fund, and Surgical Research, Inc.

Declarations of interest

Not available

Notes

Both groups of participants in ICU had moderate severity of diseases by APACHE II scores, the initial urinary urea nitrogen and the mortality rate (15%).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were then randomly assigned to receive either the control parenteral nutrition (PN) formula or the hypoenergetic PN formula by using separate randomization tables by the investigational pharmacist in the research pharmacy of the hospital.

Allocation concealment (selection bias)

Low risk

Participants randomly assigned to receive either the control PN formula or the hypoenergetic PN formula by using separate randomization tables (ICU or regular floor) by the research pharmacist of the hospital (Central allocation)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All care providers as well as participants were blinded to the nutrient composition of the parenteral formulas.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Double‐blinded. All care providers as well as participants were blinded to the nutrient composition of the parenteral formulas.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants.

Selective reporting (reporting bias)

Low risk

Not clearly described research outcomes, although: (quote:) "this study was designed to determine whether a restricted energy parenteral formulation providing 2 gr protein/kg ideal body weight could be administered to acutely ill obese participants with the same degree of efficacy as a standard parenteral nutrition solution provided to a comparable group of patients". Participants located in the intensive care unit and those with diabetes mellitus were included in the study population to determine the efficacy of this treatment in critically‐ill participants and to assess the effect on glycaemic control in obese diabetic participants. Results were reported regarding this description and more detailed measurement methods described in the appropriate section.

Other bias

Unclear risk

Not clear if any bias could have been introduced by some of the funders

Methods

Study design: prospective, randomized controlled trial

Study dates: May 1999 to December 2000

Setting: Medical ICU, Barnes‐Jewish Hospital, affiliated to Washington University School of Medicine. St. Louis, Missouri

Country: USA.

Participants

Inclusion criteria

1. ICU participants > 18 years, expected to require mechanical ventilation for > 24 hrs

Exclusion criteria

1. Transferred to the medical ICU for lack of beds in the other hospital ICUs

2. Expected to die or extubated within 24 hours of ICU admission

3. With prior mechanical ventilation during the same hospitalization

4. With contraindication of enteral feeding (e.g. pancreatitis, short gut, malabsorption)

5. Classified as malnourished at hospital admission

6. With enteral or parenteral nutrition prior to admission to the medical ICU

7. Different strategy of nutrition support according to the prescription of the attending physician

8. Refusal to give informed consent to participate in the study

9. Without tolerance of the placement of oral or naso‐gastric tube (e.g. severe coagulopathy, oesophageal varices)

Sample size

189 consecutive participants were evaluated for enrolment, with 39 not included for different reasons, and 150 finally included and analysed. 75 participants were randomized to each study group. The estimated sample size for a significant reduction of the incidence of pneumonia (primary outcome) was 82 participants in each study group.

Age (years, mean ± SD). Group 1: 59.1 ± 19.0; Group 2: 56.5 ± 15.6

Sex (% of male). Group 1: 46.7; Group 2: 37.3

Primary reason for ICU admission. Respiratory diseases (%). Group 1: 58.7; Group 2: 64.0

Disease severity: APACHE II score. Group 1: 25.6 ± 8.3; Group 2: 24.7 ± 8.4

P_aO₂/FiO₂ (mean ± SD). Group 1: 204 ± 108; Group 2: 207 ± 126

Predicted mortality based on APACHE II score (%, mean ± SD). Group 1: 48.7 ± 24.9; Group 2: 49.6 ± 23.9

Process of care variables: with 2 exceptions, all of them had statistically non‐significant differences between the study groups: Duration of enteral nutrition and of mechanical ventilation (days, mean ± SD respectively). Group 1: 5.2 ± 5.9 and 8.1 ± 7.4; Group 2: 9.9 ± 12.3 and 12.9 ± 15.7 respectively.

Comorbidities, nutrition status and level of inflammation: not reported

Interventions

Group 1 late feeding‐hypocaloric (n = 75)

1. Participants scheduled to receive 20% of their estimated daily requirements for the first 4 days of mechanical ventilation (to prevent atrophy of the intestinal mucosa) and full requirements beginning at day 5 of mechanical ventilation.

Group 2 early feeding‐normocaloric (n = 75)

1. Participants scheduled to receive their estimated total daily enteral nutrition requirements starting on day 1 of mechanical ventilation.

Co‐interventions

The goal for enteral nutrition daily requirements were defined as 25 kcal/kg ideal body weight/day and 1 to 1.3 grams of protein/kg ideal body weight/day. The enteral nutrition, with a polymeric iso‐osmolar formula, was administered in the stomach by bolus feeding, through an orogastric tube inserted on day 1 of mechanical ventilation. In case of 3 consecutive gastric residual volumes > 150 ml, a post‐pyloric enteral tube was inserted for continuous drop enteral nutrition.

Outcomes

Primary outcome

1. Occurrence of ventilator‐associated pneumonia. Diagnosis of pneumonia done by one of the investigators blinded to the group assignment, based on predetermined and well‐defined clinical diagnostic criteria of pneumonia; they also registered several described potential risk factors for the development of ventilator‐associated pneumonia.

Secondary outcomes

1. Hospital mortality

2. Length of stay in ICU

3. Length of stay in hospital

4. Length of mechanical ventilation

5. Diarrhoea associated with clostridium difficile infection (rectal swab for culture of the clostridium difficile)

6. 6. Need for a gastrostomy tube

7. Total number of antibiotic days in the ICU

How measured or defined

1. The authors defined most of the study items.

Time of measurements

1. During the first 5 days of mechanical ventilation

Subgroups

1. No subgroups were analysed in the study.

Funding sources

Supported in part by a grant from the Barnes‐Jewish‐Christian Health Care Innovations Program

Declarations of interest

Information not available

Notes

The total calories and protein received by the participants showed a statistically significant difference between the study groups, but participants in each group only received a percentage of the defined goals during the first 5 days of mechanical ventilation: in the hypocaloric group the participants received 7% of their estimated caloric requirements and 7.7% of the estimated protein requirements, and in the control group they received 27.9% and 26.9% respectively.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

The study allocated participants to treatment groups based on the date of their ICU admission using a quasi‐randomized design (odd/even‐numbered days).

Allocation concealment (selection bias)

High risk

The study allocated participants to treatment groups based on the date of their ICU admission using a quasi‐randomized design.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Unblinded study. Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Not blinded but main and secondary outcomes well‐defined. We judge that the outcome measurement was probably not influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants.

Selective reporting (reporting bias)

High risk

Some prespecified secondary outcomes (duration of mechanical ventilation, need for gastrostomy tube) not reported

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized, controlled non‐blinded trial

Study dates: Not stated

Setting: single‐centre, university‐affiliated teaching hospital with a dedicated total parenteral nutrition (TPN) service. Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Country: USA

Participants

Inclusion criteria

1. Sequential participants requiring TPN according to standard hospital criteria

Exclusion criteria

1. Severely underweight (< 50 kg)

2. Home TPN

3. Malnutrition requiring specific pre‐operative TPN

4. Reinstitution of TPN for a setback of the current illness

Sample size

48 participants were initially included, but 4 in each group were excluded from the analysis because of PN duration ≤ 4 days, leaving 21 participants in the hypocaloric group and 19 in the control group

Age (years; mean ± SD). Group 1 hypocaloric: 57.5 ± 14.9; Group 2 control: 56.6 ± 20.4

Sex (% male): Group 1: 57; Group: 53

Primary disease of the participants. Mainly surgical participants with different types of complications. Major differences between groups: Group 1 acute pancreatitis and bowel surgery/postoperative ileus: n = 6 and 3 participants respectively; Group 2 n = 1 and 6 respectively.

Mechanically‐ventilated participants (n). Hypocaloric group: 11; Control group: 6

Comorbidities. Diabetes (n). Group 1: 5 participants; Group 2: 2 participants. Obesity: 4 participants in each group

Nutrition status. BMI (mean ± SD). Group 1: 27.6 ± 8.1; Group 2: 25.7 ± 6.2

Interventions

Group 1 hypocaloric (n = 21)

1. Administration of 1 litre of fat‐free TPN, providing 70 grams protein, 210 grams of dextrose and ˜ 1000 kcal when maximally concentrated

Group 2 control (n = 19)

1. Standard TPN regimen with a maximum of 25 total kcal/kg actual weight/day (adjusted weight in obese participants). Goal of 20 to 25 kcal/kg/day with 1.5 gr protein/kg/day. Fat could account for up to ⅓ of the calories.

Co‐interventions

1. After 10 days the participants were removed from the experimental protocol and fed in the traditional manner.

Outcomes

1. Reduction of hyperglycaemia: frequency rate of glycaemia > 220 mg/d (measured by fingerstick and confirmed in the laboratory), average capillary glycaemia during the TPN administration

2. Incidence of in‐hospital infections: pneumonia, venous catheter infection, wound infection, abdominal collection/abscess. Infection diagnoses were done by well‐defined common clinical objective methods

3. Nitrogen balance at day 5 of TPN (difference of measured 24‐hr urinary urea nitrogen plus 4 gr/day and TPN nitrogen)

Time points of measurements

1. The outcomes were evaluated during the time of TPN.

2. Nitrogen balance was measured in only 12 participants (57%) in the hypocaloric and 10 (53%) of the control group, usually because of an error during collection.

Funding sources

Not available

Declarations of interest

Not available

Notes

Due to a protocol violation, fat was given to 1 participant in the hypocaloric group.

Some results associated with hospital rules to avoid iatrogenic hyperglycaemia by gradual increase of nutrients to avoid complications.The hypocaloric group also received less protein than the control group.

More participants in the hypocaloric group had acute pancreatitis and mechanical ventilatory support than in the control group.

The hypocaloric group received 14 ± 3 kcal/kg/day and the control group 18 ± 4 kcal/kg/day (also hypocaloric). The hypocaloric group not only received significantly fewer calories than the control group (due to fewer dextrose and fat calories), but also less protein (1.1 ± 0.2 versus 1.3 ± 0.2 in the control group).

If the infection rate trend observed were to persist, they calculated the study would have required ˜174 participants to see a statistical difference between the 2 groups.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not mentioned

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding: the standard group received parenteral nutrition as 3‐in‐1 bags, and the hypocaloric group received 1 litre of fat‐free parenteral nutrition. Outcomes could have been influenced by different performance of clinical personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding and not clearly‐defined and objective outcomes that would warrant a low risk of detection bias

Incomplete outcome data (attrition bias)
All outcomes

High risk

4 participants in each group were excluded from the data analysis because of a TPN duration of ≤ 4 days (not prespecified exclusion criteria).

Selective reporting (reporting bias)

High risk

Nitrogen balance was only measured in 12 participants (57%) in the hypocaloric and 10 (53%) of the control group, usually because of an error during collection.

Other bias

Unclear risk

The lack of detail in the description of the Methods section could not warrant a low risk of other sources of bias.

Methods

Study design: prospective, randomized controlled trial

Study dates: January 2008 to April 2011

Setting: 44 ICUs of the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network

Country: USA

Participants

Inclusion criteria

1. participants within 48 hours of Acute Lung Injury onset who had received mechanical ventilation < 72 hours and indication for enteral nutrition

Exclusion criteria

1. Chronic lung disease

2. Unable to provide consent

3. Outside acute lung injury time window

4. Outside mechanical ventilation time window

5. Fatal underlying disease

6. Severe liver disease

7. Moribund

8. Refractory shock

9. Physician refusal

10. Intracranial haemorrhage

11. Total parenteral nutrition

12. Not committed to full support

13. Refused consent

14. Severe neuromuscular disease

15. Severe malnutrition

16. Other

Sample size

500 participants for each arm, to detect a 2¼‐day difference in ventilator‐free days (VFDs), assuming a mean of 14 ± 10.5 VFDs. power: 91% α: 0.05

Age (years): intervention group: 52 ± 17; Control group: 52 ± 16

Sex (male, %): intervention group: 53; Control group: 49

Primary disease of the participants

Diagnosis:% intervention group/% control group

Medical ICU: 61; 63

Primary lung injury category % intervention group/control group

Pneumonia 67; 63

Sepsis 16; 13

Aspiration 8; 11

Trauma 3; 4

Transfusion 1; 2

Disease severity score: APACHE III Intervention group: 92 ± 28; Control group: 90 ± 27

Mechanical ventilation 100% in each group (inclusion criterion)

Comorbidities: % intervention group; % control group Diabetes: 27; 29

No other data available

Nutrition status: not available

Level of inflammation: not available

Interventions

Intervention (trophic) Group 1 (n = 508)

1. Initial feeding at 10 ml/hr (10 to 20 kcal/hr for the first 272 participants who also received the omega‐3 or control supplement (240 ml volume a day)

2. After the Data and Safety Monitoring Board stopped the OMEGA portion of the factorial design, the initial trophic feeding rate was changed to 20 kcal/hr to approximate the calories that had been delivered in the OMEGA study

3. Enteral nutrition was advanced to full‐energy feeding rates following the same protocol used for the full‐feeding group if they were still receiving mechanical ventilation at 144 hrs

Control Group 2 (n = 492)

1. Enteral nutrition was initiated at 25 mL/hr and advanced to goal rates as quickly as possible

2. Full feeding rates were calculated with goals of 25 to 30 kcal/kg a day of nonprotein calories and 1.2 to 1.6 g/kg a day of protein

Co‐interventions

1. Both feeding strategies specified when and for how long to hold enteral nutrition for GRVs greater than 400 mL and for other gastrointestinal intolerances. As in usual ICU practice, participants were maintained in the semirecumbent position whenever possible.

2. Blood glucose control was accomplished using institution‐specific insulin protocols targeting ranges of 80 to 150 mg/dL (to convert to mmol/L, multiply by 0.0555), with tighter control allowed.

Outcomes

Primary outcome

1. Ventilator‐free days (VFDs) through day 28

Secondary outcomes

1. Failure‐free days: cardiovascular, renal, hepatic, coagulation

2. ICU‐free days

3. 60‐day mortality

4. Development of infections: ventilator‐associated pneumonia, clostridium difficile colitis, bacteraemia

How measured or definition

1. VFDs: defined as the number of days from the time of initiating UAB to day 28 after randomization

2. ICU‐free days: calculated similarly to VFDs

3. 60‐day mortality: mortality rate at 60 days

Subgroups

1. Not available

Funding sources

Supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268200536165C and HHSN268200536179C

Declarations of interest

Authors have not disclosed any potential conflicts of interest.

Notes

The initial 272 participants were also simultaneously randomized to a separate trial (the OMEGA study) comparing a nutritional supplement containing omega‐3 fatty acids and antioxidants with an isocaloric, isovolemic control in a 2 x 2 factorial design. After the Data and Safety Monitoring Board stopped the OMEGA portion of the factorial design, participants randomized to the initial trophic‐feeding group received additional calories to compensate for the calories that had been received in the OMEGA study (240 ml volume a day).

We asked the first author for some data not reported in the manuscript or reported differently. He gave us the data we used in the meta‐analysis for the following outcomes: 28‐day mortality, length of ICU stay (days from randomization to first ICU discharge); length of mechanical ventilation (ventilator days up to day 28); hyperglycaemia (participants with any on‐study glucose > 200 mg/dl); incidence of total infectious complications and of diarrhoea, and the amount of calories received by both groups of participants. The author also informed they did not have duplicate participants with the Rice 2011 study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomized by a web‐based randomization system, stratified by site and presence of shock at enrolment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation.

Allocation concealment (selection bias)

Low risk

Participants were randomized by a web‐based randomization system, stratified by site and presence of shock at enrolment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Unblinded study. Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessment was not blinded but most outcomes were objective.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 participant lost, from the control group. All analyses were by intention‐to‐treat.

Selective reporting (reporting bias)

Low risk

All planned outcomes were reported. All analyses were by intention‐to‐treat.

Other bias

Low risk

No evidence of other bias

Methods

Study design: single‐centre double‐blind, randomized controlled trial

Study dates: Not stated

Setting: Nutrition and neurosurgery departments. Mashad University of Medical Sciences. Mashad

Country: Islamic Republic of Iran

Participants

Inclusion criteria

1. Adults head trauma participants admitted to the ICU

Exclusion criteria

1. Not reported

Sample size

60 participants randomized

Age: not reported

Sex: not reported

Primary disease: head trauma

Disease severity: not reported

Mechanical ventilation: number of participants not reported

Comorbidities: not reported

Nutrition status: not reported

Level of inflammation: not reported

Interventions

Group 1 permissive underfeeding (n = not reported )

1. Initial caloric goal of 30% to 50% of calculated requirements (not defined)

Group 2 standard full calorie (n = not reported)

1. Initial caloric goal of 90% to 100% of calculated requirements (not defined)

All participants received enteral nutrition

Outcomes

Primary outcome

1. 28 day all‐cause mortality.

Secondary outcomes

1. Hyperglycaemia

2. Length of hospital stay

3. Duration of mechanical ventilation

4. Gastro intestinal intolerance

5. Diarrhoea

6. Liver enzymes

No information about measures or definition of the outcomes

The participants in the permissive‐underfeeding group received full enteral feeding after the 7th day of the study.

No subgroups reported

Funding sources

Not available

Declarations of interest

None declared

Notes

Available only in abstract form. Poster presentation in the 35th ESPEN Congress (Leipzig, Germany, August 2013)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Only mentioned in the abstract (quote:) "head trauma randomly assigned to a double‐blind randomized controlled clinical trial"

Allocation concealment (selection bias)

Unclear risk

Same as above

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Mentioned that was double‐blind, but did not report the methodology

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Mentioned that was double‐blind, but did not report the methodology

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not mentioned in the abstract

Selective reporting (reporting bias)

Unclear risk

Not mentioned in the abstract

Other bias

Unclear risk

Insuficient information to make judgement (abstract only)

Methods

Study design: prospective, randomized controlled trial

Study dates: July 2008 to December 2010

Setting: 1 tertiary medical ICU

Country: Germany

Participants

Inclusion criteria

1. Participants with presumed need for artificial nutrition support for at least 3 days and informed consent

Exclusion criteria

1. Pre‐existent malnutrition (BMI < 18.5 kg/m²)

2. Age < 18 years or > 80 years

3. Pregnancy

4. Active malignant disease

5. Current immunosuppressive therapy

6. Readmission to the ICU liver transplantation

7. Do‐not‐resuscitate decision

8. Refusal of study inclusion by the participant or the guardian, or consent given too late for study inclusion

Sample size: not available

Age (years): intervention group: 67.6 ± 11.5; Control group: 64.3 ± 11.5

Sex (male, %): intervention group: 70; Control group: 63

Primary disease of the participants

Diagnosis: % intervention group; % control group

Sepsis: 25; 28

Acute cardiovascular dysfunction: 30; 46

Acute respiratory insufficiency: 22; 33

Other: 9; 11

Disease severity score: APACHE II

Intervention group: 28.6 ± 6.5; Control group: 27.7 ± 8.4

Mechanical ventilation: not available

Comorbidities: % intervention group; % control group

Underlying chronic disease:

None: 26; 43

Diabetes mellitus: 33; 20

Respiratory: 31; 22

Cardiovascular: 19; 20

Neuropsychiatric: 0; 20

Other: 9; 13

Nutrition status: not available

Level of inflammation: not available

Interventions

Intervention group 1 (n = 54)

1. Hypocaloric group: 50% of daily energy expenditure during the 1st week of ICU admission

Control group 2 (n = 46)

1. Normocaloric group: 100% of daily energy expenditure

For both groups, energy expenditure was measured with an indirect calorimeter (Deltatrac II, Datex Ohmeda, Helsinki, Finland). If this was not possible, the Ireton‐Jones prediction equation was used.

Co‐interventions

Quote: “artificial nutrition support was started within 24 hours of ICU admission. Enteral feeding was favoured in every case if there was no sign of gastrointestinal intolerance (defined as gastric aspirate > 300 mL/d) and/or diarrhoea. Diarrhoea was defined as at least 3 watery bowel movements per day or continuous watery stool. In case of enteral feeding, the target energy supply was to be achieved on day 3 at the latest. A commercially available standard solution with a caloric concentration of 1 kcal/mL was used in every case. If at least 70% of the target caloric supply was considered not to be achieved on day 3 via the enteral route based on gastrointestinal tolerance and the consensus of the managing physicians together with members of the trial group, participants received supplementary parenteral nutrition. The expected deficit was calculated everyday during the morning hours by one of the study authors and supplementary PN prescribed as required. If enteral nutrition (EN) was to be interrupted for unforeseen reasons during the course of the day (diagnostic or therapeutic procedures), adjustment of the supply rate was carried out depending on clinical judgment as to whether an increased rate would be tolerated by the participant. In such cases, possible caloric deficits were not compensated with PN. Causes of the feeding interruptions were recorded if the interruption lasted at least an hour. The blood glucose level was monitored every 3 hours. The insulin dose was adjusted to a target blood glucose level of 6–8 mmol/L.”

Outcomes

Primary end point

1. Rate of nosocomial infections during the ICU stay

Secondary end points

1. Insulin demand

2. ICU mortality rate

3. Hospital mortality rate

4. 28‐day mortality rate

Funding sources

None declared

Declarations of interest

None declared

Notes

Study originally published as a congress abstract with few results. The first author answered several questions, so some of the results originally included in the review came from the information provided by him. During the editorial process the study was published (Petros 2016). All the published data were the same as the first author had originally reported to us.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Electronic randomization list

Allocation concealment (selection bias)

Low risk

Quote: "yes, the allocation was concealed. The electronic randomization was managed by coauthors not directly involved in the management of the patients” (written information provided by the author)

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study was single‐blinded (participants were blinded, the ICU personnel were not). Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessment was not blinded but outcomes were objective (written information provided by the author).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcomes: outcome data were available for all participants (written information provided by the author)

Selective reporting (reporting bias)

Low risk

All outcome assessed were reported (written information provided by the author).

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: August 2003 to July 2009

Setting: 2 ICUs at a single academic centre

Country: USA

Participants

Inclusion criteria

1. Participants expected to require mechanical ventilation ≥ 72 hrs and indication for enteral nutrition

Exclusion criteria

1. > 48 hours elapsed since inclusion criteria met

2. Participant, legal representative, or physician refuses consent or is unavailable to provide consent

3. Participant, legal representative, or physician not committed to full support

4. Presence of malignant or irreversible condition and estimated 28‐day mortality > 50%

5. Severe or refractory shock

6. Chronic respiratory disease that requires home oxygen or results in severe exercise restriction

7. Moribund participants not expected to survive 24 hours from start of enteral nutrition (as decided by primary medical team)

8. Child‐Pugh score > 9

9. Presence of partial or complete mechanical bowel obstruction, or ischaemia, or infarction

10. Current parenteral nutrition use or intention to use within 7 days

11. Severe malnutrition with BMI < 18.5 and/or loss of > 30% total body weight in the previous 6 months

12. Neuromuscular disease impairing the ability to ventilate spontaneously

13. Laparotomy expected within 7 days

14. Unable to raise head of bed 45 °

15. > 30% total body surface area burns

16. Absence of GI tract/short‐bowel syndrome (defined as entire length of small bowel totaling 4 feet or less)

17. Presence of high‐output (> 500 cc/day) enterocutaneous fistula

18. Age < 13 years

19. Allergy to enteral formula

Sample size

94 participants were randomized in each arm. An independent sample t test, designed to demonstrate a 15% relative increase of 3.0 VFDs with 80% power and a 2‐sided P value of 0.05. The study enrolled 200 to allow for a 5% withdrawal rate and compensate for the single interim analysis.

Age (years): intervention group: 53 ± 19; Control group: 53 ± 19

Sex (male, %): intervention group: 39.8; Control group: 46.1

Primary disease of the participants: 100% medical diagnosis

Acute lung injury: 21; 20

Pneumonia: 15; 19

Altered mental status/neurologic: 14; 15

Sepsis: 10; 12

Overdose: 10; 7

Disease severity score: APACHE II

Intervention group: 26.9 ± 8.1; Control group: 26.9 ± 6.6

Mechanical ventilation 100% in each group (inclusion criteria)

Comorbidities:% intervention group/ % control group

Hypertension 42; 37

Cardiac disease 24; 23

Diabetes 22; 23

Chronic renal insufficiency 18; 12

Chronic obstructive pulmonary disease 16; 18

Immunosuppression 14; 16

Peptic ulcer disease 4; 4

Gastroesophageal reflux 4; 4

Nutrition status : not available

Albumin concentration (g/dL) 2.8± 0.6; 2.8± 0.7

Level of inflammation: not available

Interventions

Group 1 (n = 98): trophic group

1. Initial feeding at 10ml/hr; the same feeding rate for 6 days. In participants still ventilated after 6 days, enteral nutrition was advanced to full‐energy target feeding rates using the same protocol as for the full‐energy feeding group. Most participants received a commercially‐available standard formula containing 1 to 1.2 kcal/cm³.

Group 2 (n = 102): control group

1. Full feeding rate targeting 25 to 30 kcal/kg ideal body weight/day of non‐protein energy and 1.2 to 1.6 g/kg ideal body weight/day of protein. Most participants received a commercially‐available standard formula containing 1 to 1.2 kcal/cm³. Initial feeding at 25 ml/hr; feeding rate increased by 25 ml/hr every 6 hrs until full‐energy feeding rate was reached.

Co‐interventions

For both groups, in participants who were extubated and then required re‐intubation, enteral nutrition was started and managed according to the study protocol through study day 28.

Elevated gastric residual volumes (GRV) were defined as > 300 cc of gastric contents withdrawn from the gastric tube at one time. GRVs were checked every 6 hours while feeding rates were being increased to full‐energy rates and every 12 hours if the participant was receiving trophic rates or once full‐energy rate was achieved. Gastric residuals were only measured in participants with post‐pyloric feeding tubes if a separate gastric port on the feeding tube or separate gastric tube was in place. Since a single, isolated elevated GRV has been shown to be a poor predictor of enteral nutrition intolerance, feeding rates were not adjusted after a single elevated GRV. After the first episode of elevated GRV, 300 cc was replaced and the feeding rate was maintained. GRV was rechecked in 2 hours. If this recheck was also above 300 cc, feeds were held until GRV decreased below 300 cc and restarted at a rate of 25 cc/hr < the previous rate in the full‐energy group and at 10 cc/hr in the trophic group.

Outcomes

1. Length of mechanical ventilation

2. Ventilator‐free days (VFDs)

How measured or definition

1. Defined as the number of days from the time of initiating UAB to day 28 after randomization, assuming survival for at least 48 consecutive hours of UAB

Time points measured and time points reported

1. If a participant survived for > 48 hours after UAB, but required assisted breathing again (for any reason) before day 28, only the number of days of UAB prior to day 28 were included. Participants who died prior to the earlier of 28 days or hospital discharge were counted as having zero VFDs, regardless of whether or not they ever achieved UAB

2. Length of stay (ICU): ICU‐free days: calculated similarly to VFDs

3. Hospital mortality: hospital mortality: mortality rate at hospital discharge

Subgroups

1. Subgroup: acute lung injury, sepsis, or pneumonia

2. Subgroup: BMI of ≥ 35

Funding sources

Supported, in part, by grants K23HL81431(TWR), P30DK058404 (TWR), and 1 UL1 RR024975 (TWR, GRB) from the National Institutes of Health (Bethesda, MD)

Declarations of interest

Dr Rice, Dr Bernard, and Dr Wheeler received funding from the National Institutes of Health. The remaining authors have not disclosed any potential conflicts of interest.

Notes

Variables were assessed by intention‐to‐treat analyses. Upon our request, the data for the following outcomes was provided by the first author: hospital and 28‐day mortality, length of mechanical ventilation, length of ICU stay and incidence of infectious complications. None of the participants included in this study was included in NHLBI 2012.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Permuted block scheme with a random block size of 2, 4 or 6 participants.

Allocation concealment (selection bias)

Low risk

Assignments were placed in consecutively‐numbered, opaque envelopes that were sealed before the start of the study by personnel not associated with the trial.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Unblinded study. Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Open‐label study but most outcomes were objective. The number of ventilator‐free days to study day 28 was the primary efficacy measure. Secondary end points included 28‐day and hospital all‐cause mortality, organ‐failure‐free days, ICU‐free days, and hospital‐free days to study day 28. Only gastrointestinal intolerance and infections are more subjective.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants had complete follow‐up to death or hospital discharge.

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: August 2011 to July 2012

Setting: 30‐bed ICU of a tertiary‐level university hospital

Country: Colombia

Participants

Inclusion criteria

1. Age ≥18 years

2. Admission to an ICU

3. Expected to require EN through nasoenteric tube for at least 96 hours

Exclusion criteria

1. Participants with previous nutritional support in the same hospitalization

2. Participants with concomitant parenteral nutrition

3. Participants in transplantation programme

4. Pregnancy

5. Chronic renal failure

6. Uraemic encephalopathy

7. Diabetes

8. Morbid obesity

9. Do‐not‐resuscitate orders

Sample size

80 participants: 40 participants in each group to detect an absolute difference in the SOFA score between the 2 measurements of 15% (8.0 expected total score and 1.2 for expected delta SOFA) and a SD between the difference of the means of 3.0. 80% power α error of 0.05

Age (years): intervention group: 53.3 (19.5); Control group: 55.7 (19.5)

Sex (male, %): intervention group: 55; Control group: 60

Primary disease of the participants

Reasons for admission‐ Intervention/Control group n (%)

Respiratory disease 16 (40); 14 (35)

CNS disorder 13 (33); 12 (30)

Cardiac disease 2 (5); 4 (10)

Gastrointestinal disease 0 (0); 3 (8)

Other 9 (23); 7 (18)

Disease severity score: APACHE II

Intervention group: 13.9 ± 4.8; Control group: 15.1 ± 6.2

Mechanical ventilation no. (%) Not available

Comorbidities: not available

Nutrition status: not available

Level of inflammation: not available

Interventions

Intervention Group 1 (n = 40)

1. Hypocaloric group: 15 kcal/kg/day, with more than 1.5 g of protein per kg of body weight

Control Group 2 (n = 40)

1. Control group: received standard nutritional regimen with a goal of 25 kcal/kg/day

Co‐interventions

"for both groups, it was used an enteral formula in continuous feeding. To reach the protein goal, the study group regimen was enriched with additional protein modules, based on soy protein diluted in water and administered in two daily boluses. Participants in the study group received hyperproteic regimen until day 7, if they needed any further enteral nutrition they were switched to standard nutritional regimen with a goal of 25 kcal/kg/day without protein boluses."

Outcomes

Primary outcome

1. Delta SOFA at 48 hours

Secondary outcomes

1. SOFA score at baseline

2. SOFA score at 48 hours

3. SOFA score at 96 hours

4. Participants achieving a delta SOFA of 2 or more

5. Insulin requirements

6. Hyperglycaemic events per day

7. ICU length of stay, days

8. Ventilator requirement (days)

Subgroups

Not available

Funding sources

This research was supported by an unrestricted grant from Lafrancol Colombia.

Declarations of interest

No potential conflict of interest relevant to this article was reported.

Notes

The first author sent us the final manuscript of the study before publication, and answered our questions about the average time of the participants on enteral nutrition, the standard deviation of the calories and proteins received by both groups, why they did not report mortality and the way they gave the protein supplements to achieve the double blinding.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was performed using dark sealed envelopes with computer‐generated random allocations.

Allocation concealment (selection bias)

Low risk

Randomization was performed using dark sealed envelopes with computer‐generated random allocations.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind clinical trial. Although one of the investigators was not blind: (quote:) "only one of the members of the team (JDR) knew patient allocation, prescribed the formulations, and supervised the administration of the regimens; but ICU staff, who decided on daily care patient, was blind to patient allocation". The authors, upon request, gave further explanations about how there was low risk of blinding being broken.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Double‐blind clinical trial. Although one of the investigators was not blind (quote:) "only one of the members of the team (JDR) knew patient allocation, prescribed the formulations, and supervised the administration of the regimens; but ICU staff, who decided on daily care patient, was blind to patient allocation". The authors, upon request, gave further explanations about how there was low risk of blinding being broken.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "only patients who completed 96 hours of follow‐up were considered for the analysis; patients who did not fulfil the follow‐up period were excluded, and the envelope was returned to the sequence for patient replacement, until completion of the sample size (40 in each group)". Although the inclusion criteria stated that "Study population consisted of adult patients (18 years or older) admitted in the ICU, who were expected to require enteral nutrition through nasoenteric tube for at least 96 hours.", having participants randomized, intervened, and then excluded if they did not have 96 hours of enteral feeding could lead to a high risk of selection bias. Especially if the primary endpoint was "change in SOFA score at 48 hours". The number of excluded participants was significant: "In total, 115 potential patients met the initial inclusion criteria for enrolment, but only 80 completed the follow‐up and were included in the per protocol analysis".

Selective reporting (reporting bias)

High risk

Mortality, a secondary outcome, was not reported. Nevertheless, upon request, the authors responded that given that they excluded participants that did not fulfil the 96 hours of enteral nutrition requirement, they did not report mortality because this result would have been biased (they only measured mortality in participants who completed the 96 hours). This is why they did not report it. This is correct, although the best thing would have been to perform an intention‐to‐treat analysis and also report premature deaths.

Other bias

Low risk

No evidence of other bias

Methods

Study design: prospective, randomized controlled trial

Study dates: December 2013 to July 2015

Setting: 30‐bed ICU of a tertiary‐level university hospital

Country: Colombia

Participants

Inclusion criteria

1. age ≥18 years

2. admission to an ICU

3. expected to require EN through nasoenteric tube for at least 96 hours

Exclusion criteria

1. participants with previous nutritional support in the same hospitalization

2. participants with concomitant parenteral nutrition

3. participants in transplantation programme

4. pregnancy

5. chronic renal failure

6. uraemic encephalopathy

7. diabetes

8. morbid obesity

9. do‐not‐resuscitate orders

Sample size

60 participants in each group to detect a 15% (1.7 points) difference in SOFA at 48 hours between the 2 groups with an SD of 1.9 with a 2‐tailed t test. 80% power α error of 0.05

Age (years): intervention group: 53.8 ± 19.0; Control group: 51.8 ± 20.3

Sex (male, %): intervention group: 45; Control group: 55

Primary disease of the participants

Reasons for admission‐ Intervention/Control group n (%)

Cardiovascular 7 (12%); 7 (12%)

Gastrointestinal 4 (7%); 6 (10%)

Hematology 4 (7%); 1 (2%)

Orthopaedics 0 (0%); 1 (2%)

Respiratory 31 (52%); 22 (37%)

Central nervous system 8 (13%); 18 (30%)

Trauma 1 (2%); 1 (2%)

Urology 1 (2%); 0 (0%)

Other 4 (7%); 4 (7%)

Disease severity score: APACHE II Intervention group: 13.5 ± 6.4; Control group: 13.7 ± 6.8

Mechanical ventilation no. (%) Not available

Comorbidities: not available

Nutrition status: intervention group; Control group

Subjective global assessment nutritional status, n (%) b

A 4 (7%); 4 (7%)

B 36 (60%); 43 (72%)

C 20 (33%); 13 (22%)

Level of inflammation: not available

Interventions

Intervention Group 1 (n = 60)

1. Hypocaloric group: 15 kcal/kg per day of total calories and high protein intake (1.7 g of protein/kg a day)

1. Control Group 2 (n = 60)

1. Normocaloric group: 25 kcal/kg per day with high protein intake (1.7 g of protein/kg a day).

For both groups, ideal body weight was used to calculate caloric and protein requirements. A commercial enteral formula was adjusted to achieve caloric goals and was enriched with additional modules of whey and soy protein diluted in water, given in 3 or 4 daily boluses. All participants received allocated nutritional regimen until day 7. If further EN was necessary, all participants received normocaloric nutrition.

Co‐interventions

1. Not available

Outcomes

Primary outcome

1. Change in SOFA score from baseline at 48 hours.

Secondary outcomes

1. SOFA at 96 hours

2. Insulin requirements (mean daily units of insulin)

3. Frequency of hyperglycaemia episodes (glycaemic measurements ˃ 180 mg/dL) or hypoglycaemia episodes (glycaemic measurements < 45 mg/dL)

4. Length of ICU stay

5. Days on ventilator

6. Days to start nutrition

7. Mortality within 28 days of randomization

Subgroups

1. Not available

Funding sources

This research was supported by an unrestricted grant from Lafrancol Colombia and Hospital Universitario San Ignacio.

Declarations of interest

No potential conflict of interest relevant to this article was reported.

Notes

The study sponsor (Lafrancol S.A) provided an unrestricted grant and was not involved in any of the stages of the study.

The authors sent us the full paper of this clinical trial before it was indexed in MEDLINE (registered in clinicaltrials.gov with the Identifier: NCT02577211). They gave us the mean and SD values for length of ICU stay and of mechanical ventilation, and also some additional information to complete the 'Risk of bias' table.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was performed using dark sealed envelopes with computer‐generated random allocations.

Allocation concealment (selection bias)

Low risk

Randomization was performed using dark sealed envelopes with computer‐generated random allocations

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The authors considered 1 limitation of the study could be lack of proper blinding of ICU staff. One investigator knew participant allocation and prescribed and supervised the administration of nutritional regimens after randomization. Participants and ICU staff deciding on the rest of medical care were blinded to participant allocation. Nutritional information and regimen formulation were not registered in clinical records, except for general information such as total liquids administered.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

It is not clear if outcome assessors were blinded to participant allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All outcome data were reported for non‐excluded participants.

Selective reporting (reporting bias)

Low risk

All the outcomes were registered and reported (written information provided by the author)

Other bias

Low risk

No other bias (written information provided by the author)

Methods

Study design: prospective, randomized controlled trial

Study dates: period of one year, but study dates not available

Setting: single centre. ICU at Attikon University Hospital. Athens. Greece

Participants

Inclusion criteria

1. Mechanically‐ventilated septic participants

Exclusion criteria

1. Obese patients

Sample size

Total number of participants enrolled: 74

Age (years): whole group age of 68.4 ± 18.4 years

Sex (male, %): 38 men included (100%)

Primary disease of the participants: all participants met the consensus criteria for sepsis.

Disease severity score: at entry overall APACHE II score 22 ± 4. etc. and SOFA score 8 ± 4

Mechanical ventilation: 100% of the participants were mechanically ventilated

Comorbidities: not reported

Nutrition status: non‐obese participants. Overall BMI ≈ 21.5 ± 3.4 kg/m²

Interventions

Permisive underfeeding group (n = not available )

1. Caloric goal 50% to 70% of calculated caloric requirements. During the study period the participants received 962 ± 314 kcal/day or 51 ± 14% of the caloric requirements, and 57 ± 24 grams protein day.

Standar protocol feeding group (n = not available)

1. 80% to 100% of calculated caloric requirement. During the study period the participants received 1308 ± 513 kcal/day or 82 ± 14% of the caloric requirements, and 59 ± 25 grams of protein day.

Same protein intake for both groups: 1.5 gr protein/kg/day

Each participant monitored for 14 days

Outcomes

Primary outcome

1. 28‐day mortality

Funding sources

Not available.

Declarations of interest

Not available

Notes

This information was extracted from an abstract. We contacted Dr. Maria Theodorakoupoulou to request the missing data (including outcome data).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information for judgement (abstract only)

Allocation concealment (selection bias)

Unclear risk

Insufficient information for judgement (abstract only)

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information for judgement (abstract only)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information for judgement (abstract only)

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information for judgement (abstract only)

Selective reporting (reporting bias)

Unclear risk

Insufficient information for judgement (abstract only)

Other bias

Unclear risk

Insufficient information for judgement (abstract only)