Table 3.
A 3-step approach to investigate a potential mediation role of the effect on 3HB for the outcome benefits of late-PN
| Likelihood of live weaning from mechanical ventilatory support | Likelihood of live discharge from the PICU | Acquisition of a new infection in the PICU | ||||
|---|---|---|---|---|---|---|
| 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 |
| Demographics | ||||||
| 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 |
| Characteristics of type and severity of illness | ||||||
| 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 |
| Demographics | ||||||
| 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 |
| Characteristics of type and severity of illness | ||||||
| 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 |
| Demographics | ||||||
| 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 |
| Characteristics of type and severity of illness | ||||||
| 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 |
| Late-PN-affected regulators of ketogenesis | ||||||
| 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 |
1Plasma 3HB was quantified for all study patients with an available plasma sample on day 2 (n = 822) or day 1 (n = 320) for patients with a shorter PICU stay