Enteral versus parenteral nutrition and enteral versus a combination of enteral and parenteral nutrition for adults in the intensive care unit

Sharon R Lewis; Oliver J Schofield‐Robinson; Phil Alderson; Andrew F Smith

doi:10.1002/14651858.CD012276.pub2

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Figure 1

Flow diagram of search strategy.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Blank spaces in tables indicated that study authors did not report the review outcome.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Blank spaces in tables indicate that study authors did not report the review outcome.

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Analysis 1.1

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 1 In‐hospital mortality.

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Analysis 1.2

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 2 Mortality at 30 days.

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Analysis 1.3

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 3 Mortality at 90 days.

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Analysis 1.4

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 4 Aspiration.

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Analysis 1.5

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 5 Pneumothorax.

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Analysis 1.6

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 6 Hyperglycaemia.

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Analysis 1.7

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 7 Vomiting.

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Analysis 1.8

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 8 Diarrhoea.

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Analysis 1.9

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 9 Abdominal distension.

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Analysis 1.10

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 10 Sepsis.

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Analysis 1.11

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 11 Pneumonia.

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Analysis 1.12

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 12 Intra‐abdominal infection.

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Analysis 1.13

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 13 Wound infection.

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Analysis 1.14

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 14 Urinary tract infection.

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Analysis 1.15

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 15 In‐hospital mortality: gastrointestinal (GI) medical/surgical vs non‐GI medical/surgical.

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Analysis 1.16

Comparison 1 Enteral (EN) versus parenteral nutrition (PN), Outcome 16 Mortality at 30 days: GI medical/surgical vs non‐GI medical/surgical.

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Analysis 2.1

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 1 In‐hospital mortality.

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Analysis 2.2

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 2 Mortality at 30 days.

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Analysis 2.3

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 3 Mortality at 90 days.

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Analysis 2.4

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 4 Feeding tube obstruction.

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Analysis 2.5

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 5 Diarrhoea.

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Analysis 2.6

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 6 Pneumonia.

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Analysis 2.7

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 7 Wound infection.

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Analysis 2.8

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 8 Bloodstream infection.

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Analysis 2.9

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 9 Urinary tract infection.

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Analysis 2.10

Comparison 2 Enteral (EN) versus combined EN and parenteral nutrition (PN), Outcome 10 Airway infection.

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Summary of findings for the main comparison. Enteral versus parenteral nutrition for adults in the intensive care unit

Enteral versus parenteral nutrition for adults in the intensive care unit
Patient or population: critically ill adults admitted to the ICU for trauma, emergency, or surgical care; population excluded people with acute pancreatitis Setting: intensive care units in: Brazil, China, Germany, Iran, Italy, Turkey, UK, and USA Intervention: EN Comparison: PN
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)
	Risk with EN	Risk with PN
Mortality	In‐hospital mortality		RR 1.19 (0.80 to 1.77)	361 (6 studies)	⊕⊕⊝⊝ Low^a
	Study population
	229 per 1000 (154 to 340)	192 per 1000
	Mortality within 30 days		RR 1.02 (0.92 to 1.13)	3148 (11 studies)	⊕⊕⊝⊝ Low^b
	Study population
	304 per 1000 (274 to 336)	298 per 1000
	Mortality within 90 days		RR 1.06 (0.95 to 1.17)	2461 (3 studies)	⊕⊝⊝⊝ Very low^c
	Study population
	393 per 1000 (352 to 434)	371 per 1000
	Mortality within 180 days		RR 0.33 (0.04 to 2.97)	46 (1 study)	⊕⊝⊝⊝ Very low^d
	Study population
	130 per 1000	43 per 1000 (5 in 387)
Number of ICU‐free days up to day 28	–	–	–	–	Not measured
Number of ventilator‐free days up to day 28	Mean number of ventilator‐free days: 14.2 (SD ± 12.2)	Mean difference 0 days (0.97 fewer to 0.97 more)	N/A	2388 (1 study)	⊕⊝⊝⊝ Very low^d
Adverse events: aspiration (as reported by study authors at end of study follow‐up period)	Study population		RR 1.53 (0.46 to 5.03)	2437 (2 studies)	⊕⊝⊝⊝ Very low^e
	5 per 1000 (2 to 17)	3 per 1000
Adverse events: sepsis (as reported by study authors at end of study follow‐up period)	Study population		RR 0.59 (0.37 to 0.95)	361 (7 studies)	⊕⊕⊝⊝ Low^f
	123 per 1000 (77 to 199)	209 per 1000
Adverse events: pneumonia (as reported by study authors at end of study follow‐up period)	Study population		RR 1.10 (0.82 to 1.48)	415 (7 studies)	⊕⊕⊝⊝ Low^f
	314 per 1000 (234 to 423)	268 per 1000
Adverse events: vomiting (as reported by study authors at end of study follow‐up period)	Study population		RR 3.42 (1.15 to 10.16)	2525 (3 studies)	⊕⊝⊝⊝ Very low^g
	11 per 1000 (4 to 32)	3 per 1000
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EN: enteral nutrition; ICU: intensive care unit; N/A: not applicable; PN: parenteral nutrition; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence High: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. ^bAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and study designs and evidence were less direct; downgraded one level for indirectness. ^cAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and study designs and evidence were less direct; downgraded one level for indirectness. Few studies and one included study had a large number of participants relative to other included studies; downgraded one level for imprecision. ^dData from only one study that had a high risk of performance bias; downgraded one level for study limitations and two levels for imprecision. ^eAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. Few studies and one included study had a large number of participants relative to other included studies; downgraded one level for imprecision. ^fAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. ^gAll studies had a high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and study designs and evidence were less direct; downgraded one level for indirectness. Few studies, with very few events, and one included study had a large number of participants relative to other included studies; downgraded one level for imprecision.

Summary of findings for the main comparison. Enteral versus parenteral nutrition for adults in the intensive care unit

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Summary of findings 2. Enteral versus enteral and parenteral nutrition for adults in the intensive care unit

Enteral versus enteral and parenteral nutrition for adults in the intensive care unit
Patient or population: critically ill adults admitted to the ICU for trauma, emergency, or post‐surgical care; population excludes participants with acute pancreatitis Setting: intensive care units in: France, Italy, Switzerland, Turkey, and USA Intervention: EN Comparison: EN + PN
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)
	Risk with EN	Risk with EN + PN
Mortality	In‐hospital mortality		RR 0.99 (0.84 to 1.16)	5111 (5 studies)	⊕⊕⊝⊝ Low^a
	Study population
	106 per 1000 (90 to 124)	107 per 1000
	Mortality within 30 days		RR 1.64 (1.06 to 2.54)	409 (3 studies)	⊕⊝⊝⊝ Very low^b
	Study population
	216 per 1000 (140 to 335)	132 per 1000
	Mortality within 90 days		RR 1.00 (0.86 to 1.18)	4760 (2 studies)	⊕⊕⊝⊝ Low^c
	Study population
	115 per 1000 (99 to 135)	115 per 1000
	Mortality within 180 days		RR 1.00 (0.65 to 1.55)	120 (1 RCT)	⊕⊝⊝⊝ Very low^d
	Study population
	400 per 1000 (260 to 620)	400 per 1000
Number of ICU‐free days up to day 28	–	–	–	–	Not measured
Number of ventilator‐free days up to day 28	–	–	–	–	Not measured
Adverse events: aspiration (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
Adverse events: sepsis (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
Adverse events: pneumonia (as reported by study authors at end of study follow‐up period)	350 per 1000 (228 to 538)	250 per 1000	RR 1.40 (0.91 to 2.15)	205 (2 studies)	⊕⊝⊝⊝ Very low^d
Adverse events: vomiting (as reported by study authors at end of study follow‐up period)	–	–	–	–	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EN: enteral nutrition; ICU: intensive care unit; PN: parenteral nutrition; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aAll studies had high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. ^bAll studies had high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. Few studies with increased risk of imprecision; downgraded one level. ^cBoth studies had high risk of performance bias; downgraded one level for study limitations. Studies included a variety of primary diagnoses and evidence was less direct; downgraded one level for indirectness. ^dData from only one study that had a high risk of performance bias; downgraded one level for study limitations and two levels for imprecision.

Summary of findings 2. Enteral versus enteral and parenteral nutrition for adults in the intensive care unit

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Table 1. Adverse events for single studies: enteral nutrition versus parenteral nutrition

Study ID	Description of event	EN group (n/N)	PN group (n/N)
Mechanical events
Adams 1986	Clogged jejunostomy tube	9/23	N/A
	Disconnected line	N/A	1/23
	Line eroded into right upper lobe bronchus	N/A	1/23
	Malfunctioned line	N/A	7/23
Dunham 1994	Transpyloric tube occlusion	2/12	0/15
	Failure to intubate	0/12	0/15
	Withdrawal of tube by participant	1/12	N/A
Metabolic events
Adams 1986	Hepatic failure	1/23	1/23
	Acute renal failure	1/23	1/23
	Pancreatitis	2/23	1/23
Fan 2016	Hypoproteinaemia	22/40	32/40
Harvey 2014	Electrolyte disturbance	5/1197	8/1191
Gastrointestinal events
Adams 1986	Nausea, cramps, bloating	19/23	16/23
Adams 1986	Gastrointestinal bleeding	0/23	0/23
Dunham 1994	Gastric reflux	0/12	0/15
	Ileus	1/12	0/15
	Small bowel ileus	0/12	1/15
Fan 2016	Stress ulcer	7/40	19/40
Harvey 2014	Elevated liver enzymes	7/1197	3/1191
	Jaundice	1/1197	1/1191
	Ischaemic bowel	0/1197	1/1191
Xi 2014	Anastomotic leak	2/22	6/23
Infective events
Adams 1986	Persistent fever without obvious cause	1/23	5/23
Altintas 2011	Catheter infection	2/30	4/41
Borzotta 1994	Meningitis	2/28	0/21
	Sinusitis	3/28	6/21
	Bronchitis	6/28	6/28
	Clostridium difficile	2/28	4/21
	Peritonitis	0/28	1/21
Fan 2016	Intracranial infection	7/40	13/40
Fan 2016	Pyaemia	3/40	19/40
Gencer 2010	Pulmonary infection	2/30	2/30
Kudsk 1992	Empyema	1/51	4/45
Young 1987	Aspiration pneumonia	9/28	3/23
Young 1987	Infection (type of infection not described)	5/28	4/23
EN: enteral nutrition; n: number of participants with an event; N: total number randomized to group; N/A: not applicable; PN: parenteral nutrition.

Table 1. Adverse events for single studies: enteral nutrition versus parenteral nutrition

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Table 2. Adverse events for single studies: enteral nutrition versus enteral nutrition and parenteral nutrition

Study ID	Description of event	EN group (n/N)	EN + PN group (n/N)
Mechanical events
Casaer 2011	CVC obstruction	9/2328	15/2312
	Nasal bleeding	18/2328	14/2312
	Pneumohaemothorax after CVC placement	0/2328	2/2312
	Subclavian artery puncture	0/2328	2/2312
Dunham 1994	Withdrawal of tube	1/12	0/10
Dunham 1994	Failure to intubate	0/12	2/10
Metabolic events
Fan 2016	Hypoproteinaemia	22/40	7/40
Gastrointestinal events
Casaer 2011	Vomiting or aspiration	284/2328	295/2312
Dunham 1994	Gastric reflux	0/12	2/10
Fan 2016	Stress ulcer	7/40	9/40
infective events
Fan 2016	Pyemia	3/40	10/40
Fan 2016	Intracranial infection	7/40	5/40
Wischmeyer 2017	Catheter bloodstream infection	0/73	7/52
	Intra‐abdominal infection	0/73	4/52
	Upper urinary tract infection	0/73	1/52
	Surgical deep infection	0/73	1/52
CVC: central venous catheter; EN: enteral nutrition; EN + PN: combined enteral and parenteral nutrition; n: number of participants with an event; N: total number randomized to group.

Table 2. Adverse events for single studies: enteral nutrition versus enteral nutrition and parenteral nutrition

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Comparison 1. Enteral (EN) versus parenteral nutrition (PN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 In‐hospital mortality Show forest plot	6	361	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.80, 1.77]

2 Mortality at 30 days Show forest plot	11	3148	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.92, 1.13]

3 Mortality at 90 days Show forest plot	3	2461	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.95, 1.17]

4 Aspiration Show forest plot	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.46, 5.03]

5 Pneumothorax Show forest plot	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.19, 11.22]

6 Hyperglycaemia Show forest plot	2	2437	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.35, 0.93]

7 Vomiting Show forest plot	3	2525	Risk Ratio (M‐H, Fixed, 95% CI)	3.42 [1.15, 10.16]

8 Diarrhoea Show forest plot	6	363	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [1.72, 2.75]

9 Abdominal distension Show forest plot	3	2505	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.34, 6.96]

10 Sepsis Show forest plot	7	361	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.37, 0.95]

11 Pneumonia Show forest plot	7	415	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.82, 1.48]

12 Intra‐abdominal infection Show forest plot	3	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.07, 0.89]

13 Wound infection Show forest plot	3	155	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.55, 3.82]

14 Urinary tract infection Show forest plot	3	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.65, 3.40]

15 In‐hospital mortality: gastrointestinal (GI) medical/surgical vs non‐GI medical/surgical Show forest plot	6	361	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.80, 1.77]

15.1 GI medical/surgical	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.06, 13.74]
15.2 Non‐GI medical/surgical	5	263	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.80, 1.79]
16 Mortality at 30 days: GI medical/surgical vs non‐GI medical/surgical Show forest plot	10	3068	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.93, 1.14]

16.1 GI medical/surgical	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.71]
16.2 Non‐GI medical/surgical	9	3008	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.93, 1.15]

Comparison 1. Enteral (EN) versus parenteral nutrition (PN)

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Comparison 2. Enteral (EN) versus combined EN and parenteral nutrition (PN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 In‐hospital mortality Show forest plot	5	5111	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.84, 1.16]

2 Mortality at 30 days Show forest plot	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.06, 2.54]

3 Mortality at 90 days Show forest plot	2	4760	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.86, 1.18]

4 Feeding tube obstruction Show forest plot	2	4662	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.70, 1.32]

5 Diarrhoea Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Pneumonia Show forest plot	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.91, 2.15]

7 Wound infection Show forest plot	2	4765	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.50, 0.92]

8 Bloodstream infection Show forest plot	2	4765	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.66, 1.01]

9 Urinary tract infection Show forest plot	3	4885	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.65, 1.17]

10 Airway infection Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Enteral (EN) versus combined EN and parenteral nutrition (PN)

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