Wally Carlo, M.D. University of Alabama at Birmingham Randall Moorman, M.D. * Pam Griffin, M.D. *

1. Heart Rate Characteristics: A New Technique for Monitoring for Early Diagnosis of Neonatal Sepsis Wally Carlo, M.D. University of Alabama at Birmingham Randall Moorman, M.D. * Pam Griffin, M.D. * Doug Lake, Ph.D. * University of Virginia Dr. Griffin’s present address is MedImmune Corporation * Equity: Medical Predictive Science Corporation, Charlottesville

2. Is this baby septic? • The diagnosis of neonatal sepsis is difficult • The outcome of sepsis is potentially catastrophic • Leading physicians to: • obtain lab tests • administer antibiotics early and often

3. 3 days prior to sepsis Normal heart rate variability

4. Prior to sepsis we found reduced heart rate variability and transient decelerations 6 hours prior to sepsis

5. Prior to sepsis we found reduced heart rate variability and transient decelerations 3 hours prior to sepsis

6. Some infants had many decelerations but not below levels thought to be abnormal BW 1285 g, GA 29 weeks Day 18 of life 2 hours before Klebsiella sepsis BW 1005 g, GA 27 weeks Day 21 of life 7 hours before Pseudomonas sepsis

7. We developed new measures optimized to detect reduced variability and transient decelerations, and we tested the hypothesis: Heart rate characteristics (HRC) measures change prior to the clinical diagnosis of neonatal sepsis We took a standard, rigorous biostatistical approach. We developed a predictive model based on HRC measurements at one NICU, and asked if it successfully predicted neonatal sepsis at another NICU.

8. Predictive model – study design CRASH “Well” “Sick” 18 0 6 12 18 0 6 12 18 0 …. Blackout time of day in hours CRASH = Cultures, Resuscitation, & Antibiotics Started Here Epochs were defined as “well” (more than 24 hours prior to CRASH event), “sick”, or a 14-day “blackout” period that was not analyzed.

9. Predictive model - HRC index The HRC index is derived from regression modeling and uses HRC measures of standard deviation (S.D.), Sample Asymmetry (R1 and R2), and Sample Entropy (SampEn) to estimate the risk of upcoming proven or clinical sepsis. The formula for the HRC index is: HRC index = [exp(A) / 1+exp(A)] where: A = intercept + 1(S.D.) + 2(R1) + 3(R2) + 4(SampEn) We derived the intercept and coefficients  using UVa data, and then calculated the HRC index for WFU data.

10. HRC INDEX PREDICTS SEPSIS AT 2 NICUs TRAIN AT UVa: 316 infants; 155 events in 101 infants TEST AT WFU: 317 infants; 118 events in 93 infants result: formula for HRC index HRC index adds significantly to BW, GA and days of age p<0.0001 HRC index is associated with sepsis and sepsis-like illness p<0.0001

11. HRC index: goodness of fit HRC index 2 or more High risk – top 10% HRC index 1 or less Low risk – bottom 70%

12. 190 (+) blood cultures

13. All of this is sinus rhythm!!

14. Very early diagnosis of sepsis Labs: normal Signs: none BC: Serratia

15. HRC index rises prior to sepsis Term infant Premature infant risk risk

16. HRC and lab tests

21. Clinical illness score(Griffin and O’Shea) • Severe apnea • Increase in ventilatory support • Temperature instability • Lethargy or hypotonia • Feeding intolerance • Immature/total neutrophil (I:T) ratio • White blood cell count • Hyperglycemia

22. HRC rises before illness score

23. Q: Does HRC monitoring improve outcomes in the NICU? VLBW infants admitted to NICU randomize HRC display no HRC display Primary outcome measure: ventilator-free days during first 120 days of life • Other outcome measures: • days in hospital • days on antibiotics • in-hospital mortality 1 R01-HD 048562-04 NCT 00307333 @ ClinicalTrials.gov

24. A neonatal sepsis risk scorecard HRC index Clinical score

25. Frequently asked questions Q: What is the sensitivity, specificity and positive and negative predictive accuracies? A. We measured positive predictive accuracy for large and abrupt increase in HRC index as a level of 3- or more fold increase in risk of illness after a week of less than 1.5-fold increased risk.

27. 65 episodes of large, abrupt increases in HRC index SEPSIS 48% Major respiratory decompensation 16% Unexplained (usually mild respiratory decompensation) 31% Eye exam 5%

28. Fate of a single HeROscore >2

29. Frequently asked questions Q: Other than sepsis, what makes the HRC go up? A: UTI. Surgery. Eye exams. Other illnesses that (we think) make cytokine levels go up, like NEC, lung disease.

30. Frequently asked questions Q: At what HRC index does one act? A: There is no rule. At UVa, the M.D. is notified if: • If the value goes up by 1 or more in 24 hours • If the nurse feels uncomfortable with the HRC value • Usually the labs are normal. • They start antibiotics if the infant looks a little sick, or if labs are abnormal.

31. Frequently asked questions Q: What if HRC stays high and the blood and urine cultures stay (-)? A: There may be another reason for high HRC index, like respiratory illness

38. Clinical illness score • Severe apnea requiring positive pressure ventilation, or 50% increase in number of apneic episodes over a 24 hour period in an infant who had been extubated and stable for three days • Need for increase in ventilatory support and fio2 by 25% from baseline • Temperature instability (greater than 38 C or less than 36.2 C) twice within an eight-hour period • Lethargy or hypotonia • Feeding intolerance (feedings held for greater than 24 hours) in an infant who had been tolerating advancing or full feeds for three days • Immature/total neutrophil (I:T) ratio greater than 0.2 • White blood cell count > 25,000 or <5000 per mm3 • Hyperglycemia (> 180 mg/dl)

39. 0 points 0 points 1 point 1 point 2 points 2 points 6 5 4 3 2 1 HRC index rises prior to sepsis Ventilator Other O2 Blood culture Antibiotics Apnea Feeding intolerance Hypotonia Temp instability WBC I:T ratio Hyperglycemia HRC index (fold-increase) Clinical score Days of age

40. HRC index and development

41. Multivariate analysis of HRC Index Addison et al. J Perinatol 29:750, 2009

42. Summary • An increase in HRC Index is due to reduced heart rate variability and transient decelerations • HRC Index increases up to a day before clinical signs of sepsis are evident • HRC Index adds information independent of other laboratory tests or clinical signs