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.
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 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.
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
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.
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
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 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).
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
(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.
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
κ 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 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
Mantel-Haenszel37 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.
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, 0.75-1.71) 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%
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, 0.69-1.34). 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 reported median stay and 9 reported means. In 8 studies, the
duration of stay was shorter in the control group. Due to 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.
In the last 2 decades, 26 randomized trials have examined the
effect of TPN on the morbidity and mortality of hospitalized 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
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.
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