A model for procalcitonin concentrations following birth in non infected preterm neonates

Background: Procalcitonin (PCT) may be used to monitor infection and guide antibiotic therapy (1). However its usefulness in neonates is hampered due to changes following birth and events such as surgery.

Methods: PCT concentrations measured in 282 non-infected pre-term and term neonates (22 and 41 weeks gestation) were provided for analysis (2). A turnover model was used to describe PCT production and first-order elimination. Variability in clearance was predicted using theory based allometry with mass predicted from birth weight. The influence of birth and maturation on model parameters was explored. Simulation was used to propose reference ranges for PCT following birth. Covariate distributions for 1000 term, preterm and very preterm subjects (each) were sampled with replacement from a database of 5031 subjects (3). Median and 90% prediction intervals were generated.

Results: A two compartment turnover model best described PCT kinetics with CL= 29.4 L/day/70kg (population parameter variability, PPV 26.2%, CI ), V1=21.6 L/70kg (PPV 68.0%), Q=4.2 L/day/70kg (PPV 95.8%) and V2=108.0 L/70kg (PPV 78.5%). The effect of birth was predicted from a hypothetical birth event substance (CB) stimulating PCT production (RateIn) via an EMAX model, i.e. RateIn*SYN where SYN=1 + (Emax* CB /(CB + T50), Emax=45.7 mcg/L and T50=0.7 days. PCT production was parameterised as RateIn=CL*BASE, where BASE (baseline PCT concentration) decreased with increasing postmenstrual age according to an inhibitory EMAX model (TM50=31.9 weeks, Hill fixed at 1).  Figure 1 shows VPCs for 7 days after birth. PCT concentrations peaked on day 1 post birth with 90th prediction percentile of 60.4 mcg/L in very preterm neonates (< 33 weeks PMAW at birth), 39.3 mcg/L in preterm (between 33 and 38 PMAW at birth) and 31.3 mcg/L in term neonates.

Conclusions: We provide a physiokinetic model for PCT concentration in non-infected term and preterm neonates. Between subject variability was large despite accounting for maturity, body size and the impact of birth. The 90th prediction interval for peak concentrations in very preterm neonates is nearly twice that of term neonates and suggests a large portion of uninfected neonates would give PCT concentrations above commonly set diagnostic thresholds (e.g. 2-2.5 mcg/L for sepsis) if measured 24 h after birth. Visual Predictive Check for PCT concentrations for 0-7 post-natal days. A: very preterm (delivered before 33 weeks), B: preterm (delivered at 33 weeks to before 38 weeks) and C: term non-infected neonates. Percentiles (10%, 50%, and 90%) for observations=black dashed lines, predictions=pink dashed lines, with 95% confidence intervals for prediction percentiles (median, pink shading; 5th and 95th blue shading).

Acknowledgement: We are grateful to Professor Fukuzumi for providing the PCT data.

References: 1. Schuetz, P., et al., Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane database of systematic reviews; 2017(10): CD007498.
2.  Fukuzumi, N., et al., Age-specific percentile-based reference curve of serum procalcitonin concentrations in Japanese preterm infants. Sci Rep, 2016. 6: p. 23871.
3.  Sumpter, A.L. and N.H. Holford, Predicting weight using postmenstrual age–neonates to adults. Paediatr Anaesth, 2011. 21(3): p. 309-15.