Withholding parenteral nutrition until one week after intensive care unit (ICU) admission
(late-PN) was previously shown to accelerate recovery and reduce infections in critically
ill adults and children, as compared to early supplementing insufficient enteral feeding
with parenteral nutrition (early-PN) [1, 2]. In a detailed secondary analysis of the
pediatric PEPaNIC randomized controlled trial (RCT), we previously identified enhanced
ketogenesis as potential mediator of part of this outcome benefit. Indeed, late-PN
increased plasma concentrations of the ketone 3-hydroxybutyrate (3HB) up to sixfold,
with a peak effect on day 2 [3]. Increased 3HB independently associated with an accelerated
weaning from mechanical ventilation and a shorter time to live ICU discharge. These
associations remained significant after adjusting for ketogenic regulators, suggesting
a direct mediator role [3].
In this secondary analysis of patients included in the EPaNIC RCT (n = 4640), we studied
whether late-PN had a similar impact on ketones in critically ill adults as compared
with early-PN, and whether this may have mediated its outcome benefits. To this purpose,
we quantified plasma 3HB with an enzymatic assay [3] in the predefined subgroup of
patients with a surgical contraindication to enteral nutrition [1]. In this subgroup
(509/517 patients with available plasma), there was a larger difference in caloric
intake than in the total study population (Fig. 1a), and the outcome benefits of late-PN
appeared to be more pronounced [1] (Table1).
Fig. 1
Total caloric intake (a) and plasma 3HB (b) from admission/day 1 until day 7 in a
matched subset of early-PN patients (n = 55) and late-PN patients (n = 55) with a
surgical contraindication to enteral nutrition, an ICU stay of at least 7 days, and
available plasma sample on each day. The groups were propensity score-matched for
age, BMI, malignancy, APACHEII score, NRS score, diagnostic group. c Plasma 3HB concentration
on day 2 in ICU (or day 1 for 65 patients with a shorter ICU stay) in the total cohort
of patients with surgical contraindication to enteral nutrition (n = 509). Plasma
3HB concentrations were significantly higher (P < 0.0001) in late-PN than in early-PN
patients. Data are shown as means ± standard errors
Table 1
Baseline characteristics and outcome of the study patients
EPaNIC patients with surgical contraindication to enteral nutrition and available
plasma
Early-PN
Late-PN
P-value
Baseline characteristics time cohort (n = 110)
n = 55
n = 55
Age (years)—median (IQR)
68.1 (55.9–77.8)
66.1 (55.5–73.6)
0.45
BMI—median (IQR)a
25.3 (22.2–29.2)
25.7 (22.4–33.7)
0.61
Malignancy—no. (%)
31 (56.3)
32 (58.1)
1.00
APACHEII score—median (IQR)b
36 (28–39)
35 (31–39)
0.75
NRS score—median (IQR)c
4 (3–6)
4 (4–6)
0.49
Diagnostic categories
0.69
(Complications after) abdominal/pelvic surgery—no. (%)
36 (65.4)
33 (60.0)
(Complications after) thoracic surgery—no. (%)
19 (34.5)
22 (40.0)
Baseline characteristics total cohort (n = 509)
n = 252
n = 257
Age (years)—median (IQR)
64.4 (54.4–73.5)
64.4 (53.7–73.0)
0.99
BMI—median (IQR)a
24.5 (22.2–28.3)
24.6 (22.0–28.7)
0.89
Malignancy—no. (%)
161 (63.8)
154 (59.9)
0.36
APACHEII score—median (IQR)b
27 (16–37)
28 (18–36)
0.86
NRS score—median (IQR)c
4 (3–6)
4 (3–5)
0.34
Diagnostic categories
0.70
(Complications after) abdominal/pelvic surgery—no. (%)
168 (66.6)
177 (68.8)
(Complications after) thoracic surgery—no. (%)
84 (33.3)
80 (31.1)
Outcome of total cohort (n = 509)
n = 252
n = 257
Hazard ratio (95% CI) for time to live ICU discharge
1.23 (1.02–1.48)
0.024
Alive ICU discharge within 8 days—no. (%)
125 (49.6)
151 (58.7)
0.041
New infection—no. (%)
103 (40.2)
78 (29.8)
0.009
Data are presented as frequencies and percentages or medians with interquartile ranges.
Fisher’s exact test and Kruskal–Wallis test were used to analyze univariable differences
between patient groups, as appropriate. Hazard ratio and 95% confidence interval (CI)
was calculated with the use of Cox proportional-hazard analysis of the effect of late-PN,
with adjustment for age, BMI, malignancy, APACHEII score, NRS score, and diagnostic
category
aThe body-mass index is the weight in kilograms divided by the square of the height
in meters
bScores on the Acute Physiology and Chronic Health Evaluation II (APACHE II) range
from 0 to 71, with higher scores indicating a greater severity of illness
cScores on Nutritional Risk Screening (NRS) range from 0 to 7, with higher scores
indicating a higher risk of malnutrition
We first performed a time course analysis in a propensity-score-matched subset of
110 patients (Table 1), to study whether late-PN enhanced ketogenesis and to identify
the day of maximal effect (if any) (Fig. 1b). In the matched subset, late-PN significantly
increased plasma 3HB from day 1 until day 7 (all P ≤ 0.0013), with a maximal effect
on day 2. Subsequently, we quantified plasma 3HB on this day of maximal effect in
all patients with a surgical contraindication to enteral nutrition. In these patients,
late-PN significantly (P < 0.0001) increased plasma 3HB. Thereafter, we studied a
potential mediator role of this 3HB effect on time to live ICU discharge, live ICU
discharge within 8 days, and incidence of new infection through multivariable Cox,
respectively logistic regression analysis, adjusted for baseline risk factors (age,
BMI, malignancy, APACHEII score, NRS score, diagnostic group). Plasma 3HB did not
independently associate with time to live ICU discharge (P = 0.54), live ICU discharge
within 8 days (P = 0.23) or incidence of new infection (P = 0.71).
We demonstrated that withholding early parenteral nutrition induced ketogenesis in
adult ICU patients with a surgical contraindication to enteral nutrition [3]. However,
ketone concentrations were only modestly elevated as compared to the much larger effect
in critically ill children, and in contrast to critically ill children, plasma 3HB
did not independently associate with enhanced recovery. Also in health, the ketogenic
response is known to be more pronounced in children than in adults [4]. Although speculative,
this may explain why critically ill children had a more pronounced outcome benefit
than adults [1, 2]. Also in critically ill children, however, there was no independent
association of 3HB with incidence of infections, which suggests that other mechanisms
are involved in outcome protection through late-PN. In this regard, we previously
identified increased autophagy as one potential mediator [5]. Of note, especially
in early-PN adult patients, a considerable number of 3HB measurements were assigned
the detection limit (0.04 mmol/L) due to lower concentrations, which may have obscured
detecting a mediating role of ketones on outcome.
In conclusion, withholding early parenteral nutrition enhanced ketogenesis in critically
ill adults, but in contrast to children, increased ketones did not explain the improved
outcome. This suggests clinical benefits of omitting early-PN were mediated through
other mechanisms.