Casaer, 2011

Type of study:

prospective, randomized, controlled,

parallel-group, multicenter trial

Setting and country:

ICUs of 7 hospitals in Belgium

Funding and conflicts of interest:

Funded by the Methusalem program of the Flemish government and others

Inclusion criteria:

a score of ≥3 on nutritional risk screening (NRS) (on a scale of 1 to 7, with a score ≥3 indicating that the patient was

nutritionally at risk

Exclusion criteria:

- <18 yr of age,
- moribund or coded

DNR
- enrolled in another trial

- Had short-bowel

Syndrome

- Had home ventilation

- Was in a diabetic coma

- Were referred with nutritional regimen

- pregnant or

lactating

- no central catheter

- taking oral

nutrition

- Were readmitted to ICU

- BMI <17

- NRS score <3

N total at baseline:

Intervention: 2312

Control: 2328

Important prognostic factors²:

For example

age ± SD:

I: 64±14

C: 64±15

Sex:

I: 1486 (64.3%) M

C: 1486 (63.8%) M

APACHE II score:
I: 23±11

C: 23±10

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

early initiation of parenteral nutrition (European guidelines)

day 1 and 2: intravenous 20% glucose solution.
Target for total energy intake:
day 1: 400 kcal; day 2: 800 kcal

day 3: parenteral nutrition (OliClinomel or Clinimix, Baxter) was initiated, with the dose targeted to 100% of the caloric goal through combined EN and PN (except when clinicians predicted that the patient would tolerate sufficient EN or oral feeding on day 3).

Maximum caloric goal: 2880 kcal per day.

When EN covered

80% of the calculated caloric goal or when the

patient was judged to be able to resume oral nutrition, PN was reduced and eventually stopped. PN was restarted whenever enteral or oral intake fell to less than 50% of the calculated caloric needs

Describe  control (treatment/procedure/test):

late initiation (American and Canadian guidelines)

5% glucose solution in a volume equal to that of the PN administered in the early-initiation group in order to provide adequate hydration, with the delivered volume

of EN taken into account. If EN was insufficient after 7 days in the ICU, PN was initiated on day 8 to reach the caloric goal.

Length of follow-up:

90 days

Loss-to-follow-up:

Intervention:

N (%) 0

Reason: -

Control:

N (%): 15 (0.65%)

Reason: Discontinued intervention

owing to protocol violation

Incomplete outcome data:

Intervention:

N (%): 44 (1.9%)

Reasons ?

Control:

N (%): 24 (1.0%)

Reasons ?

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality:

ICU

I: 146/2312 (6.3%)

C: 141/2328 (6.1%)

P = 0.76

Hospital

I: 251/2312 (10.9%)

C: 242/2328 (10.4%)

P=0.63

90 days

I: 255/2312 (11.2%)

C: 257/2328 (11.2%)

P=1.00

MV duration (median, IQR)

I: 2 (1-5)

C: 2 (1-5)

P=0.02

Functional status

Distance 6 min walk test

I: 283 (205–336)

C: 277 (210–345) 283

P=0.57

Independent in all activities

I: 752/2312 (75.5%)

C: 779/2328 (73.5%)

P=0.31

New infection

Any

I: 605/2312 (26.2%)

C: 531/2328 (22.8%)

P=0.008

Airway or lung

I: 447/2312 (19.3%)

C: 381/2328 (16.4%)

P=0.009

Bloodstream

I: 174/2312 (7.5%)

C: 142/2328 (6.1%)

P=0.05

Wound

I: 98/2312 (4.2%)

C: 64/2328 (2.7%)

P=0.006

UTI

I: 72/2312 (3.1%)

C: 60/2328 (2.6%)

P=0.28

Author’s conclusion:

“We found that there was no significant difference in mortality between late initiation and early initiation

of parenteral nutrition among patients in the ICU who were at risk for malnutrition, despite

the use of early enteral feeding plus micronutrients in a protocol that prevented hyperglycemia.

However, withholding of parenteral nutrition until

day 8 was associated with fewer ICU infections but a higher degree of acute inflammation. Late

initiation of parenteral nutrition was also associated

with a shorter duration of mechanical ventilation

and a shorter course of renal-replacement therapy, a shorter ICU stay despite a slight increase

in hypoglycemic episodes, a shorter hospital stay without a decrease in functional status, and reduced health care costs.”

Doig, 2013

Type of study:

Multicenter, randomized, single-blind clinical trial

Setting and country:

31 ICUs in Australia and New-Zealand

Funding and conflicts of interest:

academic grant from the Australian National

Health and Medical Research Council

(NH&MRC) and unrestricted academic grants from Fresenius

Kabi Deutschland and Baxter Healthcare. Fresenius Kabi Australia supplied the study parenteral nutrition.

Inclusion criteria:

within 24 hours of ICU admission, were expected to remain in the ICU on the calendar day after enrollment,

were considered ineligible for

enteral nutrition by the attending clinician due to a short-term relative contraindication

and were not expected to receive parenteral or oral nutrition on the day of enrollment or the day after

enrollment, and had a central venous line through which parenteral nutrition could be delivered

Exclusion criteria:

moribund and not expected to survive

24 hours, who were to receive palliative

care only, or who had a licensing/

labeling contraindication to the study

PN (eg, known pregnancy,

documented allergy, etc.)

N total at baseline:

Intervention: 681

Control: 682

Important prognostic factors²:

For example

age ± SD:

I: 68.4 (15.1)

C: 68.6 (14.3)

Sex:

I: 281 (41.3%) F

C: 262 (38.4%) F

APACHE II, mean (SD)

I: 20.5 (7.4)

C: 21.5 (7.8)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Standard parenteral nutrition from a readyto- mix 3-chamber bag containing amino acids, glucose, lipids, and electrolytes (Kabiven G19%, Fresenius Kabi Australia), with starting rates and rate

increases defined by study protocol and trace elements, minerals, and vitamins added as clinically appropriate.

Targets were to be achieved by study day 3.

Describe  control (treatment/procedure/test):

“Standard care was defined pragmatically and was not via protocol. The attending

clinician selected the route,

starting rate, metabolic targets, and composition of nutrition to be provided

to patients receiving standard care based on current practice in their ICU.”

Length of follow-up:

60 days

Loss-to-follow-up:

Intervention:

N (%): 8 (1.2%)

Reasons: withdrew consent (5), could not be contacted on day 60 (3)

Control:

N (%) 6 (0.9%)

Reasons: withdrew consent (4), could not be contacted on day 60 (2)

Incomplete outcome data:

Intervention:

N (%) -

Reasons

Control:

N (%) -

Reasons

Outcome measures and effect size (include 95%CI and p-value if available):

Death before hospital discharge

I: 140/681 (20.6%)

C: 151/682 (22.1%)

P=0.51

Day-60 mortality

I: 146/678 (21.5%)

C: 155/680 (22.8%)

P=0.60

New infections

Surgical wound:

I: 27/682 (3.96%)

C: 22/681 (3.23%)

P=0.56

Bloodstream

I: 39/681 (5.73%)

C: 33/682 (4.84%)

P=0.47

Abdominal

I: 6/681 (0.88%)

C: 3/682 (0.44%)

P=0.34

UTI

I: 2/681 (0.29%)

C: 1/682 (0.15%)

P=0.62

Airway or lung

I: 101/681 (14.83%)

C: 123/682 (18%)

P= 0.12

Any major infection

I: 74/681 (10.9%)

C: 78/682 (11.4%)

P=0.80

Quality of life and physical function, mean (SD)

RAND-36 general health status

I: 49.8 (27.6) (n = 525)

C: 45.5 (26.8) (n = 516)

P= 0.01

ECOG performance status

I: 1.51 (1.1) (n = 525)

C: 1.53 (1.1) (n = 516)

P=0.70

RAND-36 physical function

I: 42.5 (30.8) (n = 524)

C: 40.7 (29.6) (n = 513)

P=0.33

Days per 10 patient X ICU days, Mean (95% CI)

I: 7.26 (7.09 to 7.44)

C: 7.73 (7.55 to 7.92)

MD: -0.47 (-0.82 to -0.11)

P=0.01

ICU stay, mean days (95% CI)

I: 8.6 (8.2 to 9.0)

C: 9.3 (8.9 to 9.7)

MD: -0.75 (-1.47 to 0.04)

P=0.06

Author’s conclusion:

“The use of early parenteral nutrition did not result in significant differences in

day-60 mortality or infection rates.

Early parenteral nutrition resulted in a significant reduction in days of invasive

mechanical ventilation, but this did not result in a significant shortening of ICU or hospital length of stay.”

Heidegger, 2013

Type of study:

RCT

Setting and country:

mixed medical and surgical ICUs

of two tertiary care hospitals in Switzerland

Funding and conflicts of interest:

Funding by Foundation Nutrition 2000Plus, ICU Quality Funds, Baxter, and Fresenius Kabi.
Sponsor had no role in study design, data collection, data analysis, data interpretation, or

writing of the report.

Inclusion criteria:

received less than

60% of their energy target from EN at day 3 after admission to the ICU, were expected to stay for more

than 5 days, expected to survive for more than 7 days, and had a functional gastrointestinal tract.

Exclusion criteria:

receiving PN, had persistent gastrointestinal

dysfunction and ileus, were pregnant, refused

to consent, or had been readmitted to the ICU after

previous randomisation

N total at baseline:

Intervention: 152

Control: 153

Important prognostic factors²:

For example

age ± SD:

I: 60 (16)

C: 61 (16)

Sex:

I: 105 (69%) M

C: 110 (72%) M

APACHE II:

I: 23(7)

C: 22(7)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Day 1 onwards: all patients in the ICU who were unable to eat orally were given EN (20–30 mL/h up to

a maximum of 150 mL/h). EN was administered continuously by the primary care team according to routine protocols, in cluding the following items: semi-recumbent positioning, preferred use of nasogastric tubes, and the use of prokinetic agents if necessary (gastric residual

volume ≥300 mL). EN products consisted of polymeric, fibre-enriched formulas, routinely prescribed in both

hospitals, containing 1·05–1·62 kcal/mL of energy

(18% proteins, 29% lipids [8% medium-chain triglycerides], 53% carbohydrates).

On day 3 randomisation took place.

The intervention group continued with EN alone

Describe  control (treatment/procedure/test):

The control group received EN for the entire intervention period plus

Supplemental PN from day 4 onwards. This was administered by central or peripheral catheter for 5 days.

PN formulas consisted of 0·62–1·37 kcal/mL of energy

(20% proteins, 29% lipids [15% medium-chain triglycerides], and 51% carbo hydrates).

Length of follow-up:

28 days

Loss-to-follow-up:

Intervention:

N (%) 10

Reasons: protocol violation (10)

Control:

N (%) 20

Reasons: protocol violation (16), consent withdrawal (2), therapeutic withdrawal (2)

Incomplete outcome data:

Intervention:

N (%) -

Reasons

Control:

N (%) -

Reasons

Outcome measures and effect size (include 95%CI and p-value if available):

Infections during intervention period

Pneumonia

I: 28/152 (18.4%)

C:35/153 (22.9%)

Bloodstream

I: 6 /152 (3.9%)

C: 10/153 (6.5%)

Urogenital

I: 2 /152 (1.3%)

C: 4/153 (2.6%)

Abdominal

I: 4 /152 (2.6%)

C: 1/153 (0.7%)

Other

I: 3 /152 (2.0%)

C: 2/153 (1.3%)

ICU stay, mean (SD) days
I: 13 (11), 95% CI 12–14

C: 13 (10), 95% CI 11-14
p=0.2592

ICU mortality

I: 12/152 (7%)

C: 8/153 (5%)

28 day mortality

I: 28/152 (18%)

C: 20/153 (13%)

Hours on MV (day 1 to 28)

I: 166 (SD 160)

C: 153 (SD 163)

P=0.2912

Author’s conclusions

“Findings from this trial suggest the clinical usefulness of complementing the energy delivery of insufficient EN

with a parenteral booster between day 4 and day 8 after

ICU admission. The provision of close to 100% of energy

requirements reduced the risk of development of

nosocomial infections, the number of antibiotic days,

and the duration of mechanical ventilation in patients

without nosocomial infections up to day 28.”

Ridley, 2018

Type of study:

prospective, unblinded, parallel group,

block randomized phase II pilot trial

Setting and country:

Six ICUs in

Australia and New Zealand

Funding and conflicts of interest:

unrestricted research grant

from Baxter Healthcare Corporation. The interventional PN was manufactured

by Baxter Healthcare Corporation and provided at no charge. Baxter Healthcare

Corporation was not involved in the original development of the trial concept,

trial management, data collection, analysis or interpretation of the data

Inclusion criteria:

Patients aged ≥ 16 years, admitted to ICU in the previous

48–72 hours, who were receiving

MV and expected to continue until the day after

randomization, with central venous access and one or more defined organ system failure

Exclusion criteria:

could not receive EN and/or PN at

the time of randomization, were already receiving PN,

had a requirement for a specific PN solution (e.g.

glutamine containing), had received more than 80% of their estimated nutrition requirements from EN in the 24 hours prior to randomization, seemed not likely to survive the subsequent 96 hours, had a treatment limitation in place or a high likelihood of terminal illness,

were pregnant or the treating clinician denied

N total at baseline:

Intervention: 51

Control: 49

Important prognostic factors²:

For example

age ± SD:

I: 59 (17)

C: 60 (17)

Sex:

I: 35 (69%) M

C: 35 (73%) M

APACHE II

I: 18(7)

C: 19 (7)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

The intervention group received a supplemental PN

strategy, delivered for up to 7 days after randomization,

using Olimel N9-840/Triomel with added multi-trace elements and multi-vitamins (manufactured and supplied

by Baxter Healthcare Corporation, Sydney, Australia)

The intervention strategy was designed to increase average delivery towards 100% of the estimated energy requirement but avoid overfeeding by (1) using ideal body weight in those who were overweight or obese, (2) having variable PN rates which were individually titrated, reviewed daily and based on the percentage

estimated energy requirement delivered, (3) accounting for additional energy from EN, iv glucose

solutions ≥ 25% and propofol and (4) never providing more than 80% of the estimated energy requirement by the intervention PN.

Describe  control (treatment/procedure/test):

Nutrition therapy in the usual care group followed

clinical practice at the participating ICU. PN was only used when EN delivery remained insufficient despite

attempts to improve it with strategies recommended in

best practice guidelines. If PN was required

during the first 7 days of the study in the usual care

group, the same PN formulation used in the intervention group was provided. If PN was required in usual care after the first 7 days the usual hospital PN formulation was used.

Length of follow-up:

7 days or until ICU discharge or switch to oral nutrition

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%) 1

Reasons: withdrew consent (1)

Incomplete outcome data:

Intervention:

N (%)

Reasons

Control:

N (%)

Reasons

Outcome measures and effect size (include 95%CI and p-value if available):

Duration of ICU stay, days, median [IQR]

I: 11 [5-17]

C: 11 [6-17]

P=0.83

ICU mobility scale at hospital D/C, median [IQR]

I: 9 [5-10]

C: 8 [4-10]

P= 0.58

Duration of mechanical ventilation, days, median [IQR]

I: 10 [6-15]

C: 8 [5-18]

P=0.68

Mortality ICU

I: 15/51 (19%)

C: 11/48 (23%)

Mortality hospital

I: 16/51 (31%)

C: 11/48 (23%)

Mortality 90 days

I: 19/51 (37%)

C: 13/48 (27%)

Mortality 180 days

I: 19/51 (37%)

C: 13/48 (27%)

Author’s conclusions

“Our multicentre, pilot, randomized trial in 100 critically ill adults receiving EN, found that an individually titrated supplemental PN strategy was feasible and effective in delivering increased energy, closer to estimated requirements than usual care. There were no differences between our two groups in any clinical outcomes.”

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Casaer, 2011

Probably yes

Reason: stratified according

to 16 diagnostic categories, randomization tool is not defined

Definitely yes

Reason: Opaque, sealed envelopes were used

Probably no

Reason: investigators were blinded, patients and their ICU providers were not

Probably no

Reason: loss to follow up was infrequent and only appeared in the control group (<1%), however missing data was frequent and no reason was provided.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes

Reason: less than one third was funded by industry, but the company was not involved in any other part

Some concerns

(all outcomes except mortality)

Reason: lack of blinding, incomplete data

Doig, 2013

Probably yes

Reason: central randomization

web server

Probably yes

Reason: the web server maintained allocation concealment

Probably no

Reason: only the data monitoring was blinded, the site investigators, healthcare providers and outcome assessors were not

 Definitely yes

Reason: loss to follow-up was infrequent in both groups (1.2 and 0.9%) and reasons were provided

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes

Reason: the company that partially funded the study was not involved in any other part

Some concerns

(all outcomes except mortality)

Reason: lack of blinding

Heidegger, 2013

Probably yes

Reason: computer-generated randomization

sequence

Definitely yes

Reason: Allocation concealment was achieved with

sequentially numbered, sealed, opaque envelopes

Probably no

Reason: data collectors and analysts were blinded, patients and care providers were not

Probably no

Reason: loss to follow-up was somewhat frequent in the intervention (>5%) and the control (>10%) group.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes

Reason: the company that partially funded the study was not involved in any other part

Some concerns

(all outcomes except mortality)

Reason: lack of blinding,

Ridley, 2018

Probably yes

Reason: a web-based randomization system was used

Probably yes

Reason: a web-based randomization system was used, but details on allocation concealment lack

Definitely no

Reason: Open-label trial (patients and health care providers not blinded),

Definitely yes

Reason: no loss to follow-up

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes

Reason: the company that partially funded the study was not involved in any other part

Some concerns

(all outcomes except mortality)

Reason: lack of blinding