Table 3 A 3-step approach to investigate a potential mediation role of the effect on 3HB for the outcome benefits of late-PN

A. Impact of randomization (n = 1142)

Risk ratio (95% CI)

P value

Risk ratio (95% CI)

P value

Odds ratio (95% CI)

P value

 Randomization to late-PN (n = 562) vs. early-PN (n = 580)

1.14 (1.01–1.29)

0.02

1.19 (1.06–1.35)

0.003

0.49 (0.34–0.70)

< 0.0001

  Age per year added

1.02 (0.98–1.05)

0.18

1.02 (0.99–1.06)

0.11

1.02 (0.93–1.13)

0.59

  Weight per kg added

0.99 (0.98–1.00)

0.65

0.99 (0.98–1.00)

0.34

0.99 (0.96–1.02)

0.72

  Male gender

0.98 (0.85–1.11)

0.85

0.94 (0.83–1.07)

0.39

1.11 (0.78–1.58)

0.52

  Emergency vs. planned admission

0.74 (0.61–0.90)

0.003

0.77 (0.63–0.93)

0.008

1.74 (1.03–2.92)

0.03

  Diagnostic group

0.22

0.40

0.06

  PIM2 score per point added

0.70 (0.66–0.74)

< 0.0001

0.72 (0.68–0.76)

< 0.0001

1.41 (1.25–1.60)

< 0.0001

  High vs. medium risk of malnutrition (STRONGkids risk level 4–5 vs. 1–3)

0.86 (0.68–1.06)

0.17

0.83 (0.67–1.03)

0.1

1.15 (0.65–2.02)

0.62

  Presence of infection on admission

0.72 (0.61–0.84)

< 0.0001

0.71 (0.61–0.84)

< 0.0001

0.52 (0.32–0.83)

0.005

  Need for hemodynamic assist device on admission

0.51 (0.34–0.76)

0.001

0.48 (0.32–0.73)

0.0005

1.71 (0.80–3.64)

0.16

B. Mediation role for plasma 3HB (n = 1142)

Risk ratio (95% CI)

P value

Risk ratio (95% CI)

P value

Odds ratio (95% CI)

P value

 Plasma 3HB on day 2 (per mmol/l)¹

1.12 (1.05–1.20)

0.0002

1.10 (1.03–1.17)

0.004

0.85 (0.68–1.06)

0.14

 Randomization to late-PN (n = 562) vs. early-PN (n = 580)

1.01 (0.88–1.16)

0.79

1.08 (0.94–1.24)

0.26

0.56 (0.38–0.84)

0.004

  Age per year added

1.02 (0.99–1.06)

0.11

1.03 (0.99–1.06)

0.06

1.02 (0.92–1.12)

0.64

  Weight per kg added

0.99 (0.98–1.00)

0.55

0.99 (0.98–1.00)

0.28

0.99 (0.96–1.02)

0.72

  Male gender

0.99 (0.88–1.12)

0.95

0.95 (0.84–1.07)

0.44

1.11 (0.78–1.57)

0.55

  Emergency vs. planned admission

0.77 (0.63–0.94)

0.01

0.79 (0.65–0.96)

0.02

1.65 (0.98–2.79)

0.05

  Diagnostic group

0.27

0.32

0.07

 PIM2 score per point added

0.70 (0.66–0.74)

< 0.0001

0.72 (0.68–0.76)

< 0.0001

1.41 (1.24–1.60)

< 0.0001

  High vs. medium risk of malnutrition

0.85 (0.68–1.05)

0.14

0.83 (0.67–1.03)

0.09

1.16 (0.66–2.05)

0.59

  Presence of infection on admission

0.72 (0.61–0.85)

< 0.0001

0.72 (0.61–0.84)

< 0.0001

0.51 (0.32–0.82)

0.004

  Need for hemodynamic assist device on admission

0.50 (0.33–0.76)

0.001

0.48 (0.32–0.73)

0.0001

1.66 (0.78–3.55)

0.19

C. Sensitivity analysis (direct/indirect 3HB effect) (n = 1142)

Risk ratio (95% CI)

P value

Risk ratio (95% CI)

P value

Odds ratio (95% CI)

P value

 Plasma 3HB on day 2 (per mmol/l)¹

1.12 (1.05–1.19)

0.0005

1.09 (1.02–1.17)

0.007

0.80 (0.63–1.02)

0.06

 Randomization to late-PN (n = 562) vs. early-PN (n = 580)

0.97 (0.83–1.12)

0.70

1.04 (0.89–1.21)

0.60

0.62 (0.40–0.94)

0.02

  Age per year added

1.03 (0.99–1.06)

0.08

1.03 (0.99–1.06)

0.06

1.03 (0.93–1.14)

0.50

  Weight per kg added

0.99 (0.98–1.00)

0.67

0.99 (0.98–1.00)

0.36

0.99 (0.96–1.02)

0.54

  Male gender

0.97 (0.86–1.11)

0.74

0.94 (0.83–1.06)

0.34

1.19 (0.83–1.72)

0.33

  Emergency vs. planned admission

0.72 (0.59–0.89)

0.002

0.76 (0.62–0.93)

0.01

1.62 (0.94–2.79)

0.07

  Diagnostic group

0.28

0.42

0.03

  PIM2 score per point added

0.69 (0.65–0.73)

< 0.0001

0.72 (0.68–0.75)

< 0.0001

1.45 (1.27–1.65)

< 0.0001

  High vs. medium risk of malnutrition

0.84 (0.67–1.04)

0.12

0.82 (0.65–1.02)

0.07

1.15 (0.64–2.06)

0.63

  Presence of infection on admission

0.72 (0.61–0.85)

0.0001

0.72 (0.62–0.85)

0.0001

0.49 (0.30–0.81)

0.004

  Need for hemodynamic assist device on admission

0.51 (0.34–0.78)

0.002

0.48 (0.32–0.74)

0.0008

1.44 (0.66–3.13)

0.36

  Plasma insulin at time of 3HB assessment (per μIU/l)

1.00 (0.99–1.00)

0.93

0.99 (0.99–1.00)

0.52

0.80 (0.63–1.02)

0.76

  Blood glucose at time of 3HB assessment (per mg/dl)

0.99 (0.99–0.99)

0.02

0.99 (0.99–1.00)

0.46

0.99 (0.99–1.00)

0.49