Download Total Parenteral Nutrition in the Critically Ill Patient

Caring for the Critically Ill Patient
Total Parenteral Nutrition
in the Critically Ill Patient
A Meta-analysis
Daren K. Heyland, MD, FRCPC, MSc; Shaun MacDonald MD, FRCSC;
Laurie Keefe, RD; John W. Drover, MD, FRCSC
JAMA. 1998;280:2013-2019
barrier structure and function, augmenting the inflammatory response to
illness and resulting in greater infectious
morbidity.3-5 As a consequence, nutritional support has become a standard of
care for hospitalized patients.
Because intestinal stimulation from
luminal nutrients helps maintain gastrointestinal mucosal structure and function,6-9 enteral nutrition may have some
advantage over total parenteral nutrition (TPN). Compared with TPN, randomized trials of critically ill patients
have demonstrated that enteral nutrition administered within the first 24
hours of admission to the intensive care
unit (ICU) results in better wound healing,10 a decrease in gastrointestinal tract
mucosal permeability,11 and lower infection rates.12-14 Where possible, enteral
feeding is preferred to parenteral feeding.15 However, some patients with an
intact gastrointestinal tract do not tolerate enteral feeds or do not receive sufficient intake enterally or orally to meet
their energy and protein requirements.
Total parenteral nutrition is used as a
supplement or as the sole source of nutrition in these patients16,17; however,
previous evidence supporting this practice seems to be lacking.18,19 Since these
studies were reviewed in 1987,19 additional randomized trials have been published. The purpose of this article is to
review systematically, appraise critically, and aggregate statistically studies
evaluating the effect of TPN in critically
ill patients.
MALNUTRITION among hospitalized
patients has been associated with increased morbidity, prolonged hospital
stay, and increased costs to the health
care system.1,2 Several studies have
documented that “bowel rest” is associated with a disruption of the mucosal
METHODS
Search Strategy
We conducted a computerized bibliographic search of MEDLINE (including
pre-MEDLINE) for studies from 1980
to April 1998 to locate all relevant articles. The terms randomized controlled
Context.—Nutritional support has become a standard of care for hospitalized
patients, but whether total parenteral nutrition (TPN) affects morbidity and mortality
is unclear.
Objective.—To examine the relationship between TPN and complication and
mortality rates in critically ill patients.
Data Sources.—Computerized search of published research on MEDLINE from
1980 to 1998, personal files, and review of relevant reference lists.
Study Selection.—We reviewed 210 titles, abstracts, and papers. Primary
studies were included if they were randomized clinical trials of critically ill or surgical patients that evaluated the effect of TPN (compared with standard care) on
complication and mortality rates. We excluded studies comparing TPN with enteral
nutrition.
Data Extraction.—Relevant data were abstracted on the methodology and outcomes of primary studies. Data were abstracted in duplicate, independently.
Data Synthesis.—There were 26 randomized trials of 2211 patients comparing
the use of TPN with standard care (usual oral diet plus intravenous dextrose) in
surgical and critically ill patients. When the results of these trials were aggregated,
TPN had no effect on mortality (risk ratio [RR], 1.03; 95% confidence interval [CI],
0.81-1.31). Patients who received TPN tended to have a lower complication rate,
but this result was not statistically significant (RR, 0.84; 95% CI, 0.64-1.09). We examined several a priori hypotheses and found that studies including only malnourished patients were associated with lower complication rates but no difference in
mortality when compared with studies of nonmalnourished patients. Studies published since 1989 and studies with a higher methods score showed no treatment
effect, while studies published in 1988 or before and studies with a lower methods
score demonstrated a significant treatment effect. Complication rates were lower
in studies that did not use lipids; however, there was no difference in mortality rates
between studies that did not use lipids and those studies that did. Studies limited
to critically ill patients demonstrated a significant increase in complication and mortality rates compared with studies of surgical patients.
Conclusions.—Total parenteral nutrition does not influence the overall mortality rate of surgical or critically ill patients. It may reduce the complication rate, especially in malnourished patients, but study results are influenced by patient population, use of lipids, methodological quality, and year of publication.
From the Departments of Medicine (Drs Heyland and
MacDonald) and Surgery (Dr Drover), Queen’s University and Nutritional Services, Kingston General Hospital
(Ms Keefe), Kingston, Ontario.
Dr Heyland is a Career Scientist of the Ontario Ministry of Health.
Reprints: Daren K. Heyland, MD, FRCPC, MSc, Angada
3, Kingston General Hospital, 76 Stuart St, Kingston, Ontario, Canada K7L 2V7 (e-mail: [email protected]).
JAMA, December 16, 1998—Vol 280, No. 23
Total Parenteral Nutrition in the Critically Ill Patient—Heyland et al
©1998 American Medical Association. All rights reserved.
2013
Table 1.—Criteria Used to Assess Methodologic Quality*
Score
0
Randomization
1
...
Not concealed
or not sure
...
...
2
Concealed randomization
Blinding
Analysis
Not blinded
Other
Adjudicators blinded
Intention to treat
Patient selection
Selected patients or
unable to tell
Consecutive eligible
patients
...
Comparability of groups
at baseline
Extent of follow-up
No or not sure
Yes
...
,100%
100%
...
Treatment protocol
Cointerventions†
Poorly described
Not described
Outcomes
Not described
Reproducibly described
Described but not equal
or not sure
Partially described
...
Well described and
all equal
Objectively defined
*The first 3 questions and the last 2 questions had a possible score of 0, 1, or 2. The middle 3 questions had a
possible score of 0 or 1. The highest possible score was 14. Ellipses indicate data not applicable.
†The extent to which antibiotics, enteral nutrition, ventilation, oxygen, and transfusions were applied equally across
groups.
trial, double blind method, clinical trial,
placebo, and comparative study were
combined with explode parenteral nutrition, total. Citations were limited to
English-language studies reporting on
adult patients. Reference lists of relevant review articles and personal files
were also searched.
Study Selection Criteria
Initially, 2 of us (D.K.H. and S.M.)
screened all citations and classified them
as primary studies, review articles, or
other. We then retrieved and reviewed
independently all primary studies. Primary studies were selected for inclusion
in this overview if the study’s (1) research design was a randomized clinical
trial; (2) population consisted of surgical
or critically ill human adult subjects; (3)
intervention included any form of TPN
(protein, source of nonprotein energy
with or without lipids) compared with
standard care (oral diet plus intravenous
fluids); and (4) outcome measures included complications, length of stay, and
mortality.
Because studies in which treatment is
allocated in any method other than randomization tend to show larger (and frequently false-positive) treatment effects
than do randomized trials,20 we elected
to include only randomized trials in this
review. We defined critically ill patients
as those who would routinely be cared
for in a critical care environment. Patients undergoing major surgery may
not always be cared for in a critical care
environment but share similarities in
their response to illness, a hypercatabolic state characterized by weight loss,
loss of body fat, and accelerated breakdown of body proteins.21 Previous systematic reviews have incorporated data
from surgical patients and critically ill
patients.15,22 Therefore, we opted to combine studies of surgical patients and
critically ill patients and to explore any
2014
differences that might exist between
these patients in the subgroup analysis.
We excluded studies of pediatric or neonatal patients.
We included only studies that evaluated the use of supplemental TPN in patients receiving enteral feeds or studies
evaluating the use of TPN in patients
who were not receiving TPN or enteral
nutrition. There are several randomized
trials of surgical patients that examine
the effect of amino acid infusion (without
additional nonprotein energy or lipids)
on clinical outcomes. Such therapy is not
a standard of care in the critically ill patient, whereas TPN (with or without lipids) is commonly administered to critically ill patients. For the purpose of this
review, we excluded studies that used
only amino acid infusions as the intervention. As the scope of our review was
defined by our research question, we also
excluded studies that compared TPN
with enteral nutrition or other forms of
TPN. Finally, studies that evaluated the
impact of TPN only on nutritional outcomes (ie, nitrogen balance, amino acid
profile) were not included in this article.
While these end points may explain underlying pathophysiology, we considered these as surrogate end points23 and
we only included articles that reported
on clinically important outcomes (morbidity and mortality).
Methodologic Quality
of Primary Studies
We assessed the methodologic quality
of all selected articles in duplicate, independently, using a scoring system that
we have used previously24 (Table 1).
Even in randomized trials, failure to prevent foreknowledge of treatment assignment can lead to an overestimation
of treatment effect.25 Accordingly, we
scored higher those studies that reported that their randomization schema
was concealed. Given the difficulties of
JAMA, December 16, 1998—Vol 280, No. 23
blinding the administration of TPN, we
only awarded points for studies that
blinded the adjudication of study end
points. We also evaluated the extent to
which consecutive, eligible patients
were enrolled in the trial, whether
groups were equal at baseline, if cointerventions were adequately described,
whether objective definitions of infectious outcomes were used, and whether
all patients were properly accounted for
in the analysis (intention-to-treat analysis) (Table 1).
Data Extraction
Two of us (D.K.H. and S.M.) extracted
data for analysis and assessment of the
methodologic quality; we resolved disagreement by consensus. Not all studies
reported complication rates. Some studies reported total complications per
group but not on a per-patient basis.
When data were missing, unclear, or not
reported on a per-patient basis, we attempted to contact the primary investigators and requested them to provide
further information if the article had
been published in the last 5 years.
Prior Hypotheses Regarding Sources
of Heterogeneity
When conducting a systematic review, heterogeneity (major differences
in the apparent effect of the interventions across studies) is often found.
When heterogeneity is present, it weakens inferences that can be made from the
results. The possible sources of variation in study results include the role of
chance or differences across studies in
population, intervention, outcome, and
methods. We developed several hypotheses that might explain heterogeneity of
study results.
First, we considered that the premorbid nutritional status of study patients
was a possible cause of variation in results. Where possible, we grouped the
results of studies that included only patients who were malnourished and compared them with the results of studies
that included patients who were not malnourished at entrance into the study.
When possible, we used the definition of
malnourished provided in each study. If
none was provided, we assumed patients
who had greater than 10% weight loss to
be malnourished.
Second, we hypothesized that study
results may be related to the methodologic quality of the study. We planned a
separate analysis comparing the effect
of studies with an overall methodologic
quality score to those with a score less
than 7 (median score, 7).
Third, since the practice of providing
nutritional support and managing critically ill patients has evolved over time
Total Parenteral Nutrition in the Critically Ill Patient—Heyland et al
©1998 American Medical Association. All rights reserved.
(included studies range from 1976 to
1997), we divided the studies into equal
groups comparing studies published in
1988 or earlier with studies published
since 1989 (halfway point of the study
range).
Fourth, since some studies administered amino acids and a carbohydrate
source of energy while others administered amino acids, carbohydrates, and
lipids, we separated trials into those that
included lipids and those without. We
hypothesized that there may be adverse
effects caused by lipid use.26
Finally, we speculated that differences in patient populations (surgical vs
critically ill) may account for different
results. To test this hypothesis, we
planned a separate analysis comparing
studies of surgical patients with studies
of critically ill patients.
Analysis
The primary outcome was perioperative mortality (death within 30 days of operation) or mortality reported at discharge from hospital. The secondary
outcome was the rate of major complications. We defined major complications as
pneumonia, intra-abdominal abscess, sepsis, line sepsis, myocardial infarction, pulmonary emboli, heart failure, stroke, renal failure, liver failure, and anastomotic
leak. Minor complications were defined as
wound infection, phlebitis, urinary tract
infection, and atelectasis. In 4 studies, the
data were not portrayed in a fashion that
allowed us to report major complication
rates, so we reported total complications27-29 and total infectious complications.30 Reporting methods of individual
studies did not allow us to disaggregate
infectious from noninfectious complications. One study31 randomized patients to
3 groups (control vs standard TPN vs
TPN with branch-chain amino acids). We
only included data from the control group
and the standard TPN group. Two other
studies randomized patients to 3 groups
(control vs TPN without lipids vs TPN
with lipids), and we included both experimental groups in the analysis.32-34 One
study included reports of 2 trials.34 The
second trial was presumed to include patients from the first trial and was therefore excluded. We also reported on duration of hospital stay, although these data
were not aggregated because of infrequent and variable reporting methods.
Agreement between reviewers on inclusion of articles was measured by k
with quadratic weights.
We combined data from all studies to
estimate the common relative risk of
mortality and complications and associated 95% confidence intervals (CIs). We
summarized the treatment effect using
risk ratios (RRs). To avoid the problem
JAMA, December 16, 1998—Vol 280, No. 23
with bias and instability associated with
RR estimation in sparse data, we added
one half to each cell.35 In the meta-analysis, we used maximum likelihood methods of combining RR across all trials and
examined the data for evidence of heterogeneity within groups.36 The MantelHaenszel37 method was used to test the
significance of treatment effect. We used
a random effects model to estimate the
overall RR.38,39 For the test of heterogeneity across subgroups, we used the t
test for the difference between the 2 subgroups. We considered P,.05 to be statistically significant.
RESULTS
Study Identification and Selection
A total of 153 citations were identified
through a computerized bibliographic
database search. Our personal files and
review of reference lists yielded 57 additional articles for consideration. Initial
eligibility screening resulted in 46 articles selected for further evaluation. Of
these potentially eligible studies, 26 met
the inclusion criteria.
We reached 100% agreement on the inclusion of articles for this systematic review. Reasons for excluding relevant randomized studies included studies not
generalizable to critically ill patients40;
studies that evaluated different kinds of
TPN41-43; studies that evaluated amino acids only44-47; pseudorandomized studies
(not true randomization)48-52; studies duplicated in other publications34,53,54; studies not reporting clinically important outcomes55-57; studies available in abstract
form only58; and a study that also randomized patients to anabolic steroids.59
Impact of TPN on Mortality
and Complications Rates
There are 26 randomized trials involving 2211 patients that compare the use of
TPN with standard care (usual oral diet
plus intravenous fluids) in patients undergoing surgery,27-34,60-74 patients with pancreatitis,75 patients in an intensive care
unit,76 and patients with severe burns.77
The details of each study, including the
methodologic quality score, are described
in Table 2. When the results of these trials
were aggregated, there was no effect on
mortality (RR, 1.03; 95% CI, 0.81-1.31)
(Figure 1). The test for heterogeneity was
not significant (P = .59), although a visual
inspection of Figure 1 suggests that the
treatment effects are variable.
Twenty-two studies reported major
complications in study patients. Aggregation of these results revealed a trend
toward reducing complication rates in
patients receiving TPN (RR, 0.84; 95%
CI, 0.64-1.09) (Figure 2). The test for heterogeneity was significant (P = .003).
To better understand our findings, we
proceeded to examine our a priori hypotheses. We compared trials that included only malnourished patients with
other trials. No difference in mortality
existed (Figure 3) for studies of malnourished patients (RR, 1.13; 95% CI, 0.751.71) or in studies that included adequately nourished patients (RR, 1.00;
95% CI, 0.71-1.39; P = .64 for differences
between subgroups). The rate of major
complications was significantly lower
among malnourished patients receiving
TPN (RR, 0.52; 95% CI, 0.30-0.91). No
difference existed in complication rates
among studies of adequately nourished
patients (RR, 1.02; 95% CI, 0.75-1.40).
The difference in complication rates between these subgroups was of borderline significance (P = .05).
We compared trials with a methodologic quality score of less than 7 with trials with a score of 7 or better (Figure 3).
Trials with the higher methods score
demonstrated no effect of TPN on mortality (RR, 1.17; 95% CI, 0.88-1.56). We
noted a trend toward a lower mortality
rate in studies with a lower methods
score (RR, 0.76; 95% CI, 0.49-1.19). The
difference between these 2 subgroups
was short of conventional levels of significance (P = .12). With respect to complication rates, studies with a higher
methods score demonstrated no treatment effect (RR, 1.13; 95% CI, 0.86-1.50).
Studies with a lower methods score
showed a significant reduction in complication rates associated with TPN
(RR, 0.54; 95% CI, 0.33-0.87). The difference in complication rates between these
subgroups was significant (P = .02).
We next compared trials published in
1988 or earlier with trials published in
1989 or later (Figure 3). Trials published
in 1988 or earlier demonstrated a trend
toward a lower mortality rate associated
with TPN (RR, 0.70; 95% CI, 0.44-1.13).
Trials published since 1989 demonstrated no treatment effect (RR, 1.18;
95% CI, 0.89-1.57). Differences between
these 2 subgroups were short of conventional levels of statistical significance
(P = .07). There were significantly fewer
major complications associated with
TPN reported in studies that were published in 1988 or earlier (RR, 0.49; 95%
CI, 0.29-0.81), while in studies published
since 1989 there was no effect of TPN on
complication rates (RR, 1.19; 95% CI,
0.93-1.53). The P value for the difference
between these subgroups was significant (P = .005).
We then compared studies that provided intravenous lipids as a component
of TPN administration with studies that
did not include lipids. In studies that
used lipids (RR, 1.03; 95% CI, 0.78-1.36)
and studies that did not (RR, 0.98; 95%
Total Parenteral Nutrition in the Critically Ill Patient—Heyland et al
©1998 American Medical Association. All rights reserved.
2015
Table 2.—Randomized Studies Evaluating Total Parenteral Nutrition (TPN) in Critically Ill Patients*
Source, y
Methods
Score
Patient Population (No.)
% of
Malnourished
Patients
Intervention
Veterans Affairs,27 1991
Fan et al,28 1989
10
10
Thoracoabdominal surgery (395)
Esophageal cancer surgery (40)
100
75
TPN with lipids 14 d before surgery
TPN with lipids 7-15 d before surgery
Figueras et al,29 1988
7
10
7
5
Gastrointestinal surgery (49)
Major surgery/trauma (300)
Liver transplant (18)
Gastric surgery (42)
0
22
100
...
TPN
TPN
TPN
TPN
Hwang et al,32 1993b§
Muller et al,33 1982
5
3
Gastric surgery (42)
Gastrointestinal surgery (125)
...
60
TPN without lipids after surgery
TPN without lipids 10 d before surgery
Muller et al,34 1986
Jimenez et al,60 1986
4
5
Gastrointestinal surgery (105)
Gastrointestinal surgery (75)
...
100
TPN with lipids 10 d before surgery
TPN without lipids after surgery
Brennan et al,61 1994
8
3
4
7
4
6
7
5
4
10
7
3
7
8
8
6
Pancreatic resection (117)
Radical cystectomy (35)
Gastrointestinal surgery (21)
Hepatocellular cancer surgery (124)
Cardiac surgery (44)
Gastrointestinal surgery (100)
Gastrointestinal surgery (34)
Gastrointestinal surgery (56)
Gastrointestinal surgery (64)
Thoracoabdominal surgery (122)
Gastrointestinal surgery (101)
Gastric surgery (62)
Colorectal surgery (20)
Gastrointestinal surgery (35)
Pancreatitis (54)
Neurology ICU (24)
...
...
100
26
100
100
100
100
100
...
29
...
0
0
...
...
Burns on .50% of body (49)
...
TPN with lipids after surgery
TPN with lipids after surgery
TPN without lipids 5 d before surgery
TPN with lipids 7 d before surgery
TPN without lipids after surgery
TPN with lipids 7 d before surgery
TPN without lipids 10 d before surgery
TPN without lipids 3 d before surgery
TPN with lipids 9 d before surgery
TPN with lipids after surgery
TPN with lipids 10 d before surgery
TPN with lipids after surgery
TPN with lipids after surgery
TPN without lipids after surgery
TPN with lipids after admission
TPN after admission; both groups received EN
(unknown lipids)
TPN without lipids after admission; both groups
received EN
Sandstrom et al,30 1993
Reilly et al,31 1990
Hwang et al,32 1993a§
Askanazi et al,62 1986
Thompson et al,63 1981
Fan et al,64 1994
Abel et al,65 1976
Bellatone et al,66 1988
Smith and Hartemink,67 1988
Holter and Fischer,68 1977
Meguid et al,69 1988
Woolfson and Smith,70 1989
Von Meyenfeldt et al,71 1992
Yamada et al,72 1983
Gys et al,73 1990
Freund et al,74 1979
Sax et al,75 1987
Chiarelli et al,76 1996
Herndon et al,77 1989
7
without lipids after surgery
with lipids after surgery
with lipids after surgery
with lipids after surgery
*Ellipses indicate data not available; EN, enteral nutrition; ICU, intensive care unit.
†Presented as mean ± SD or (range).
‡No range was specified.
§Control group is the same for both criteria.
CI, 0.49-1.95), there was no difference in
mortality. (P value for the difference between subgroups = .89). Complication
rates in studies that used lipids demonstrated no effect (RR, 0.96; 95% CI, 0.691.34). In studies that did not use lipids,
the complication rate was significantly
lower (RR, 0.59; 95% CI, 0.38-0.90). The
P value for the difference between these
subgroups was just short of significance
(P = .09).
Finally, we compared studies of critically ill patients with studies of primarily
surgical patients. The mortality rate of
critically ill patients was higher among
those receiving TPN (RR, 1.78; 95% CI,
1.11-2.85), while studies of surgical patients showed no treatment effect (RR,
0.91; 95% CI, 0.68-1.21). The difference between these subgroups was statistically
significant (P = .03). The complication rates
in the studies of critically ill patients (only
2 studies reported complication rates)
showed a trend toward an increase in complications (RR, 2.40; 95% CI, 0.88-6.58),
while studies of surgical patients were associated with lower complication rates
(RR, 0.76; 95% CI, 0.48-1.0). The P value
for the difference between these subgroups was significant (P = .05).
Only 14 studies reported the effect of
TPN on duration of hospital stay; 5 re2016
Holter and Fischer,68 1977
Freund et al,74 1979
Thompson et al,63 1981
Muller et al,33 1982
Yamada et al,72 1983
Brennan et al,61 1994
Askanazi et al,62 1986
Muller et al,34 1986
Sax et al,75 1987
Bellatone et al,66 1988
Smith and Hartemink,67 1988
Fan et al,28 1989
Figueras et al,29 1988
Woolfson and Smith,70 1989
Gys et al,73 1990
Veterans Affairs,27 1991
Von Meyenfeldt et al,71 1992
Hwang et al,32 1993a
Hwang et al,32 1993b
Fan et al,64 1994
Jimenez et al,60 1995
Chiarelli et al,76 1996
Abel et al,65 1976
Holter and Fischer,68 1977
Freund et al,74 1979
Thompson et al,63 1981
Muller et al,33 1982
Yamada et al,72 1983
Brennan et al,61 1994
Askanazi et al,62 1986
Muller et al,34 1986
Sax et al,75 1987
Bellatone et al,66 1988
Meguid et al,69 1988
Smith and Hartemink,67 1988
Fan et al,28 1989
Figueras et al,29 1988
Herndon et al,77 1989
Woolfson and Smith,70 1989
Gys et al,73 1990
Reilly et al,31 1990
Veterans Affairs,27 1991
Von Meyenfeldt et al,71 1992
Hwang et al,32 1993a
Hwang et al,32 1993b
Sandstrom et al,30 1993
Fan et al,64 1994
Jimenez et al,60 1995
Chiarelli et al,76 1996
Overall Risk Ratio
0.001 0.01 0.1
TPN
Beneficial
Overall Risk Ratio
0.001 0.01 0.1
TPN
Beneficial
1
Risk Ratio (Log Scale)
10 100
TPN
Harmful
Risk Ratio (Log Scale)
10 100
TPN
Harmful
1
Figure 2.—Risk ratios and associated 95% confidence intervals for the effect of total parenteral nutrition (TPN) on major complications.
Figure 1.—Risk ratios and associated 95% confidence intervals for effect of total parenteral nutrition
(TPN) on mortality.
ported median stay and 9 reported
means. In 8 studies, the duration of stay
was shorter in the control group. Due to
JAMA, December 16, 1998—Vol 280, No. 23
the variability in duration of stay and
variability of reporting methods, we did
not statistically aggregate these results,
but they are displayed in Table 2.
Total Parenteral Nutrition in the Critically Ill Patient—Heyland et al
©1998 American Medical Association. All rights reserved.
Major Complications, No. (%)
Mortality, No. (%)
Mean Hospital Stay, d†
TPN
Control
TPN
Control
TPN
Control
49/192 (25.5)
17/20 (85.0)
50/203 (24.6)
15/20 (75)
31/231 (13.4)
6/20 (30)
24/228 (10.5)
6/20 (30)
...
15
...
16‡
4/25 (16)
5/24 (20.8)
...
...
...
...
0/12 (0)
0/14 (0)
0/16 (0)
0/16 (0)
0/25 (0)
12/150 (8)
0/8 (0)
0/12 (0)
0/14 (0)
0/24 (0)
13 ± 6
11 ± 3
10/150 (6.7)
2/10 (20)
...
67 ± 29
...
47 ± 19
0/16 (0)
0/16 (0)
...
...
...
...
11/66 (16.6)
19/59 (32.2)
3/66 (4.5)
11/59 (18.6)
...
...
17/46 (37)
6/60 (10)
19/59 (32.2)
3/15 (20)
10/46 (21.7)
4/60 (6.7)
11/59 (18.6)
1/15 (6.7)
...
9±6
...
12 ± 8
27/60 (45)
13/57 (22.8)
4/60 (6.7)
1/57 (1.8)
16 (7-72)
14 (6-88)
0/22 (0)
0/12 (0)
2/13 (15.4)
0/9 (0)
17
...
24‡
...
1/22 (4.5)
2/12 (16.7)
22/64 (34.4)
2/13 (15.4)
1/9 (11.1)
33/60 (55)
5/64 (7.8)
9/60 (15.0)
...
...
...
8/54 (14.8)
...
22/46 (47.8)
4/20 (20)
1/54 (1.9)
3/24 (12.5)
1/46 (2.2)
19 ± 6
...
18 ± 6
...
3/17 (17.6)
4/30 (13.3)
6/17 (35.3)
5/26 (19.2)
1/17 (5.9)
2/30 (6.7)
3/17 (17.6)
2/6 (7.7)
44 ± 13
...
38 ± 10
...
1/32 (3.1)
0/34 (0)
10 (6-30)
13 (9-30)
6/62 (9.7)
6/51 (11.8)
0/29 (0)
...
4/60 (6.7)
7/50 (14.0)
5/28 (17.9)
...
8/62 (12.9)
2/51 (3.9)
0/29 (0)
8/60 (13.3)
2/50 (4.0)
1/28 (3.6)
14 (9-64)
36 ± 17
...
13 (9-95)
32 ± 22
...
1/10 (10)
0/25 (0)
4/29 (13.8)
1/10 (10)
0/10 (0)
1/29 (3.4)
0/10 (0)
0/25 (0)
1/29 (3.4)
0/10 (0)
0/10 (0)
1/26 (3.8)
...
17 ± 2.3
15 ± 4
...
19 ± 2.9
10 ± 3
6/12 (50)
3/12 (25)
3/12 (25)
4/12 (33.3)
37 ± 13
41 ± 23
...
...
10/16 (62.5)
6/23 (26.1)
...
...
Complications
Malnourished
Nonmalnourished
Quality Score <7
Quality Score ≥7
Published 1988 or Earlier
Published 1989 or Later
Lipids
No Lipids
Critically Ill
Surgical
Overall Effect
P = .05
P = .02
P = .005
P = .09
P = .05
Mortality
Malnourished
Nonmalnourished
Quality Score <7
Quality Score ≥7
Published 1988 or Earlier
Published 1989 or Later
Lipids
No Lipids
Critically Ill
Surgical
Overall Effect
P = .12
P = .07
P = .03
0.1
TPN
Beneficial
1
10
TPN
Harmful
Risk Ratio (Log Scale)
Figure 3.—Results of subgroup analysis examining
the effect on total parenteral nutrition (TPN) on
mortality and complication rates.
COMMENT
In the last 2 decades, 26 randomized
trials have examined the effect of TPN
on the morbidity and mortality of hospiJAMA, December 16, 1998—Vol 280, No. 23
talized patients. These studies ranged in
size from 18 to 395 patients with the majority of studies including fewer than 100
patients. The mortality event rate in
these studies ranged from 0% to 41%
with an overall average mortality rate of
8.9%. Individually, the majority of these
studies were underpowered to demonstrate a significant effect of TPN on major complications or mortality. The advantage of a meta-analysis is that it provides a method of aggregating similar
studies to determine the best estimate
of the treatment effect.
For this meta-analysis, we defined a
specific research question, conducted a
comprehensive literature search, and
used explicit criteria for study selection
and methodologic quality assessment.78
In the overall analysis, we found no effect of supplemental TPN on mortality,
and we found a trend toward lower complication rates associated with TPN.
However, the degree of heterogeneity
of the results weakens the inferences we
can make from the overall results.
We performed several subgroup analyses in our attempt to explain the heterogeneity present and to understand which
subgroups might benefit the most. Total
parenteral nutrition was associated with
significantly lower complication rates in
studies of malnourished patients, although there was no mortality benefit observed. Mortality and complication rates
of studies published in 1988 or earlier and
studies with a lower methodologic quality score showed greater treatment effect than did later studies or studies with
a higher methods score. Studies published in 1989 or later and those with a
higher methods score suggest that TPN
may be associated with increased mortality and no effect on complication rates.
The similarity of the subgroup results
based on year of publication and methods
score may be partially explained by the
fact that 9 of the 13 studies that had a
methods score of less than 7 also were
published in 1988 or earlier. The differences between these subgroups (methods score ,7 and $7 and published in 1988
or earlier vs later) was significant or close
to conventional levels of significance, suggesting that these subgroup results are
systematically different from each other
and, therefore, may explain a portion of
the heterogeneity in the overall results.
Indeed, if the results of studies published
in 1989 or later with a methods score of
more than 7 are considered the best estimate of treatment effect, then TPN may
do more harm than good in seriously ill
patients.
There are several reports that demonstrate that lipids may adversely affect immune status and clinical outcomes.26,79,80
The results of our meta-analysis suggest
that the adverse effects of lipids may negate any beneficial effect of nonlipid nutritional supplementation. This is consistent with the findings of a recent
randomized trial of TPN with lipids compared with TPN without lipids in critically ill trauma patients that demonstrated a lower complication rate in the
group that did not receive lipids.81
While we set out to summarize the experimental evidence of the effect of TPN
on critically ill patients, only 6 studies
included patients that would routinely
be admitted to the ICU as part of their
care.30,31,65,75-77 Two of these trials76,77
evaluated the use of supplemental TPN
in patients already receiving enteral nutrition, while the other 4 trials30,31,65,75
studied the use of TPN compared with
patients not receiving any nutritional
support. These 6 trials studied very narrowly defined ICU patient populations;
there were no studies of medical ICU
patients or patients with sepsis and only
a limited assessment of patients with
trauma. Since surgical patients and ICU
patients have a similar stress response
to illness, we assumed it reasonable to
aggregate such studies. However, the
results of our subgroup analysis suggest
that both mortality and complication
rates may be increased in critically ill
Total Parenteral Nutrition in the Critically Ill Patient—Heyland et al
©1998 American Medical Association. All rights reserved.
2017
patients receiving TPN and these treatment effects may differ from the results
in surgical patients. The results of studies evaluating the effect of TPN in surgical patients, therefore, may not be generalizable to all types of critically ill patients. This leaves a very limited data
set on which to base the practice of providing TPN to critically ill patients.
Because some evidence shows that enteral nutrition is superior to TPN, enteral nutrition may be the preferred
method of nutritional support for critically ill patients.15 Although the results
of our meta-analysis do not support the
use of TPN in critically ill patients, prolonged starvation (more than 14 days) is
associated with poor outcomes. In a
study of 300 patients undergoing major
general surgical procedures, TPN was
compared with prolonged glucose administration. There was no difference in
complication rates or mortality.30 However, patients in the control group who
were unable to take food by mouth for
more than 14 days had a much higher
complication and mortality rate than patients receiving TPN or patients receiving short-term glucose administration.
While one can only make weak inferences from such a post-hoc analysis, it
does suggest that patients who cannot
tolerate enteral nutrition for more than
2 weeks may benefit from intravenous
supplementation.
In conclusion, while TPN may have a
positive effect on nutritional end points
and on even minor complications, the
overall results of our meta-analysis fail
to support a benefit of TPN on mortality
or major complication rates, particularly
in critically ill patients. Our a priori subgroup analyses suggest that there may
be a treatment benefit in studies of malnourished patients. However, treatment
benefit was limited to those studies with
a lower methodologic quality score, studies published in 1988 or earlier, studies
that did not use lipids, and studies of surgical patients. Future research needs to
define the role of supplemental TPN in
critically ill patients who cannot tolerate
sufficient energy intake and protein via
the enteral route and the timing of TPN
in critically ill patients who cannot tolerate any enteral intake. Finally, the
economics of providing TPN to critically
ill patients needs to be carefully studied
to facilitate future practice guidelines.
We would like to thank the anonymous reviewers
for their helpful comments and Xiangyao Su, PhD,
for his help with the statistical analysis.
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