Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock Brynne A. Sullivan a, *, Karen D. Fairchild b a b
Neonatal/Perinatal Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA Division of Neonatology, University of Virginia School of Medicine, Charlottesville, VA, USA
s u m m a r y Keywords: Heart rate characteristic monitoring Predictive monitoring Heart rate characteristics index Sepsis Necrotizing enterocolitis Systemic inflammatory response syndrome Shock
Despite vigilant clinical assessment of infants in the neonatal intensive care unit (NICU), diagnosis of sepsis and necrotizing enterocolitis often does not occur until an infant has significant hemodynamic compromise. Predictive monitoring involves analysis of vital signs and other clinical data to identify infants at highest risk and to detect early-stage illness, leading to timelier treatment and improved outcomes. The first vital-sign predictive monitoring device developed for sepsis detection in babies in the NICU is the heart rate characteristics index (HeRO) monitor, which continuously analyzes the electrocardiogram signal for low heart rate variability and transient decelerations. Use of this monitor in very low birth weight infants (300 VLBW infants with >100 episodes of sepsis. It represents the fold-increased risk that a baby will be diagnosed with culture-proven or clinical sepsis in the next 24 h, compared to the risk for all VLBW infants throughout the NICU stay. The index was externally validated at Wake Forest University in a similar number of infants and was again shown to be highly correlated with diagnosis of sepsis [33,34]. Subsequent studies showed that a high HRC index (“HeRO score”) is also correlated with mortality and with other infections and adds to laboratory values in the diagnosis of sepsis [35,36].
The HeRO (Heart Rate Observation) monitor (Medical Predictive Science Corporation, Charlottesville, VA, USA) received 510K clearance by the US Food and Drug Administration in 2003 for monitoring heart rate characteristics in infants and children and was CE-marked for use in Europe in 2012. The monitor analyzes the electrocardiogram data from standard NICU monitors in real time and continuously displays the HRC index, which is updated hourly and reflects heart rate variability and transient decelerations in previous 12 h. It displays the current HRC index, the trend over the last five days, and the last 30 min of heart rate (Fig. 2). Users may choose to view a display from an individual baby, multiple babies in a pod, or all babies in the unit. From 2004 to 2010, a multicenter randomized trial was conducted to determine the impact of heart rate characteristics monitoring on outcomes of very low birth weight infants (35 weeks of gestation who subsequently required intravenous fluids, respiratory support, and/or NICU admission [50]. Although none of these scores addresses early detection of sepsis in preterm infants in the NICU, they illustrate the concepts of combining analysis of vital signs and other parameters into a score that triggers closer evaluation of patients to prevent further deterioration. A “Preterm Sepsis/NEC Alert” could include some or all of the variables on the following list. Note that values out of normal range for gestational and postmenstrual age would be desirable and an acute change from an individual patient's baseline would be ideal. (1) A measure of abnormal respiratory rate (tachypnea, apnea). (2) A measure of abnormal heart rate (consistent tachycardia or consistent or repetitive transient bradycardia). (3) A measure of abnormal heart rate characteristics, such as the HRC index. (4) A measure of clinical signs such as new onset of feeding intolerance. (5) A measure of physical examination abnormalities such as absent bowel sounds. (6) A measure of poor perfusion such as delayed capillary refill time, low urine output, or low blood pressure. (7) A measure of abnormal laboratory values such as acute phase reactants, if these studies are available and clinically indicated. (8) A measure of abnormal radiographic findings, if studies are indicated.
new vital sign and hemodynamic metrics and integrating laboratory values, biomarkers, and clinical information could lead to even better algorithms for early sepsis detection. As new technologies or sepsis alerts are developed, training healthcare providers in how to interpret them and testing their impact on clinically meaningful outcomes should be a high priority toward improving outcomes of preterm infants.
Practice points The heart rate characteristics (HeRO) monitor analyzes bedside monitor electrocardiogram signal for decreased variability and transient decelerations and displays a score that is the fold-increased risk of sepsis in the next 24 h for VLBW infants. Heart rate characteristics monitoring reduced all-cause mortality by 22% and sepsis-associated mortality by 40% in a randomized clinical trial of 3003 VLBW infants. Abnormal heart rate characteristics are not specific to bloodstream infection and may occur in other infectious and non-infectious conditions. Implementing a system for alerting clinicians to abnormal vital signs or predictive monitoring scores may lead to earlier initiation of therapy for sepsis or NEC.
Research directions Test the ability of vital sign-based scores soon after birth to identify infants at highest risk for adverse outcomes such as late-onset septicemia or NEC. Add analysis of other vital signs including respiratory rate and oxygen saturation to heart rate characteristics analysis to determine optimum metrics for detection of earlystage sepsis or NEC.
Conflict of interest statement None declared. Funding sources None.
9. Advanced hemodynamic monitoring in preterm infants with sepsis and NEC Once preterm infants are diagnosed with suspected sepsis or NEC, advanced hemodynamic assessment tools, including nearinfrared spectroscopy (NIRS), electrical cardiometry, and functional echocardiography could be useful to monitor for clinical deterioration and guide fluid and vasopressor-inotrope therapy [51]. The role of these and other tools such as pulsatility index of the photoplethysmography (pulse oximeter) signal for risk assessment or early detection of sepsis and NEC deserves further study. 10. Conclusion Monitoring heart rate characteristics for signs of imminent sepsis was shown to reduce mortality among VLBW infants. Adding
References [1] Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2e8. [2] Hofer N, Zacharias E, Müller W, Resch B. Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates. J Perinat Med 2012;40:587e90. [3] Brierley J, Carcillo JA, Choong K, Cornell T, DeCaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009;37:666e88. [4] Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol 2010;37:439e79. [5] Anand R, Leaphart C, Mollen K, Hackam D. The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 2007;27:124e33. [6] Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285e91.
Please cite this article in press as: Sullivan BA, Fairchild KD, Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.006
B.A. Sullivan, K.D. Fairchild / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7 [7] Kermorvant-Duchemin E, Laborie S, Rabilloud M, Lapillonne A, Claris O. Outcome and prognostic factors in neonates with septic shock. Pediatr Crit Care Med 2008;9:186e91. [8] Verboon-Maciolek M. Clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a 12-year period. Pediatr Infect Dis J 2005;24:901e4. [9] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138e50. [10] Ng PC, Lam HS. Diagnostic markers for neonatal sepsis. Curr Opin Pediatr 2006;18:125e31. [11] Weitkamp J-H, Aschner JL. Diagnostic use of C-reactive protein (CRP) in assessment of neonatal sepsis. Neoreviews 2005;6:e508e15. [12] Person M, Esposito D. Risk factors for infectious disease death among infants in the United States. Pediatr Infect Dis J 2014;33:e280e5. [13] Gephart SM, Spitzer AR, Effken JA, Dodd E, Halpern M, McGrath JM. Discrimination of GutCheck(NEC): a clinical risk index for necrotizing enterocolitis. J Perinatol 2014;34:468e75. [14] Esposito S, Zampiero A, Pugni L, Tabano S. Genetic polymorphisms and sepsis in premature neonates. PLoS One 2014;9:e101248. [15] Abu-Maziad A, Schaa K, Bell EF, Dagle JM, Cooper M, Marazita ML, et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res 2010;68:323e9. [16] Maheshwari A, Schelonka RL, Dimmitt RA, Carlo WA, Munoz-Hernandez B, Das A, et al. Cytokines associated with necrotizing enterocolitis in extremelylow-birth-weight infants. Pediatr Res 2014;76:100e8. [17] Saria S, Rajani AK, Gould J, Koller D, Penn AA. Integration of early physiological responses predicts later illness severity in preterm infants. Sci Transl Med 2010;2:48e65. [18] Doheny KK, Palmer C, Browning KN, Jairath P, Liao D, He F. Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants. Neurogastroenterol Motil 2014;26:832e40. [19] Bravi A, Green G, Longtin A, Seely AJE. Monitoring and identification of sepsis development through a composite measure of heart rate variability. PLoS One 2012;7:e45666. [20] Fairchild KD. Predictive monitoring for early detection of sepsis in neonatal ICU patients. Curr Opin Pediatr 2013;25:172e9. [21] Griffin MP, Moorman JR. Toward the early diagnosis of neonatal sepsis and sepsis-like illness using novel heart rate analysis. Pediatrics 2001;107: 97e104. [22] Fairchild KD, O'Shea TM. Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010;37:581e98. [23] Fairchild KD, Saucerman JJ, Raynor LL, Sivak JA, Xiao Y, Lake DE, et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009;297:R1019e27. [24] Durosier LD, Cao M, Herry C, Batkin I, Seely A, Burns P, et al. A signature of fetal systemic inflammatory response in the pattern of heart rate variability measures matrix: a prospective study in fetal sheep model of lipopolysaccharide (LPS)-induced sepsis. FASEB J 2013;27:926.8. [25] Raynor LL, Saucerman JJ, Akinola MO, Lake DE, Moorman JR, Fairchild KD. Cytokine score identifies NICU patients with gram-negative bacteremia. Pediatr Res 2012;71:261e6. [26] Griffin MP, Lake DE, Bissonette EA, Harrell FE, O'Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005;116:1070e4. [27] Fairchild KD, Srinivasan V, Moorman JR, Gaykema RP, Goehler LE. Pathogeninduced heart rate changes associated with cholinergic nervous system activation. Am J Physiol Regul Integr Comp Physiol 2011;300:R330e9. [28] Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med 2011;269:45e53. [29] Kovatchev BP, Farhy LS, Cao H, Griffin MP, Lake DE, Moorman JR. Sample asymmetry analysis of heart rate characteristics with application to neonatal sepsis and systemic inflammatory response syndrome. Pediatr Res 2003;54: 892e8.
7
[30] Lake DE, Richman JS, Griffin MP, Moorman JR. Sample entropy analysis of neonatal heart rate variability. Am J Physiol Regul Integr Comp Physiol 2002;283:R789e97. [31] Moorman JR, Rusin CE, Lee H, Guin LE, Clark MT, Delos JB, et al. Predictive monitoring for early detection of subacute potentially catastrophic illnesses in critical care. Conf Proc IEEE Engng Med Biol Soc 2011;2011:5515e8. [32] Moorman JR, Delos JB, Flower AA, Cao H, Kovatchev BP, Richman JS, et al. Cardiovascular oscillations at the bedside: early diagnosis of neonatal sepsis using heart rate characteristics monitoring. Physiol Meas 2011;32:1821e32. [33] Griffin MP, O'Shea TM, Bissonette EA, Harrell FE, Lake DE, Moorman JR. Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness. Pediatr Res 2003;53:920e6. [34] Griffin MP, Lake DE, O'Shea TM, Moorman JR. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007;61:222e7. [35] Griffin MP, O'Shea TM, Bissonette EA, Harrell FE, Lake DE, Moorman JR. Abnormal heart rate characteristics are associated with neonatal mortality. Pediatr Res 2004;55:782e8. [36] Griffin MP, Lake DE, Moorman JR. Heart rate characteristics and laboratory tests in neonatal sepsis. Pediatrics 2005;115:937e41. [37] Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011;159:900e6. e1. [38] Fairchild K, Schelonka R, Kaufman D. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74: 570e5. [39] Stone ML, Tatum PM, Weitkamp J-H, Mukherjee AB, Attridge J, McGahren ED, et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J Perinatol 2013;33:847e50. [40] Sullivan BA, Grice SM, Lake DE, Moorman JR, Fairchild KD. Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants. J Pediatr 2014;164:775e80. [41] Fairchild KD, Sinkin RA, Davalian F, Blackman AE, Swanson JR, Matsumoto JA, et al. Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants. J Perinatol 2014;34:375e9. [42] Balan KV, Kc P, Hoxha Z, Mayer CA, Wilson CG, Martin RJ. Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata. Respir Physiol Neurobiol 2011;178:458e64. [43] Lee H, Rusin CG, Lake DE, Clark MT, Guin L, Smoot TJ, et al. A new algorithm for detecting central apnea in neonates. Physiol Meas 2012;33:1e17. [44] Clark MT, Vergales BD, Paget-Brown AO, Smoot TJ, Lake DE, Hudson JL, et al. Predictive monitoring for respiratory decompensation leading to urgent unplanned intubation in the neonatal intensive care unit. Pediatr Res 2013;73: 104e10. [45] Pearson G, Duncan H. Early warning systems for identifying sick children. Paediatr Child Health (Oxford) 2011;21:230e3. [46] Nguyen SQ, Mwakalindile E, Booth JS, Hogan V, Morgan J, Prickett CT, et al. Automated electronic medical record sepsis detection in the emergency department. PeerJ 2014;2:e343. [47] Sawyer A, Deal E, Labelle A. Implementation of a real-time computerized sepsis alert in nonintensive care unit patients. Crit Care Med 2011;39:469e73. [48] Arnold R, Sherwin R. Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department. Acad Emerg Med 2013;20: 433e40. [49] Duncan H, Hutchison J, Parshuram CS. The Pediatric Early Warning System score: a severity of illness score to predict urgent medical need in hospitalized children. J Crit Care 2006;21:271e8. [50] Holme H, Bhatt R, Koumettou M, Griffin MA, Winckworth LC. Retrospective evaluation of a new neonatal trigger score. Pediatrics 2013;131:e837e42. [51] Azhibekov T, Noori S, Soleymani S, Seri I. Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care. Semin Fetal Neonatal Med 2014;19:45e53.
Please cite this article in press as: Sullivan BA, Fairchild KD, Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.006
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock Brynne A. Sullivan a, *, Karen D. Fairchild b a b
Neonatal/Perinatal Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA Division of Neonatology, University of Virginia School of Medicine, Charlottesville, VA, USA
s u m m a r y Keywords: Heart rate characteristic monitoring Predictive monitoring Heart rate characteristics index Sepsis Necrotizing enterocolitis Systemic inflammatory response syndrome Shock
Despite vigilant clinical assessment of infants in the neonatal intensive care unit (NICU), diagnosis of sepsis and necrotizing enterocolitis often does not occur until an infant has significant hemodynamic compromise. Predictive monitoring involves analysis of vital signs and other clinical data to identify infants at highest risk and to detect early-stage illness, leading to timelier treatment and improved outcomes. The first vital-sign predictive monitoring device developed for sepsis detection in babies in the NICU is the heart rate characteristics index (HeRO) monitor, which continuously analyzes the electrocardiogram signal for low heart rate variability and transient decelerations. Use of this monitor in very low birth weight infants (300 VLBW infants with >100 episodes of sepsis. It represents the fold-increased risk that a baby will be diagnosed with culture-proven or clinical sepsis in the next 24 h, compared to the risk for all VLBW infants throughout the NICU stay. The index was externally validated at Wake Forest University in a similar number of infants and was again shown to be highly correlated with diagnosis of sepsis [33,34]. Subsequent studies showed that a high HRC index (“HeRO score”) is also correlated with mortality and with other infections and adds to laboratory values in the diagnosis of sepsis [35,36].
The HeRO (Heart Rate Observation) monitor (Medical Predictive Science Corporation, Charlottesville, VA, USA) received 510K clearance by the US Food and Drug Administration in 2003 for monitoring heart rate characteristics in infants and children and was CE-marked for use in Europe in 2012. The monitor analyzes the electrocardiogram data from standard NICU monitors in real time and continuously displays the HRC index, which is updated hourly and reflects heart rate variability and transient decelerations in previous 12 h. It displays the current HRC index, the trend over the last five days, and the last 30 min of heart rate (Fig. 2). Users may choose to view a display from an individual baby, multiple babies in a pod, or all babies in the unit. From 2004 to 2010, a multicenter randomized trial was conducted to determine the impact of heart rate characteristics monitoring on outcomes of very low birth weight infants (35 weeks of gestation who subsequently required intravenous fluids, respiratory support, and/or NICU admission [50]. Although none of these scores addresses early detection of sepsis in preterm infants in the NICU, they illustrate the concepts of combining analysis of vital signs and other parameters into a score that triggers closer evaluation of patients to prevent further deterioration. A “Preterm Sepsis/NEC Alert” could include some or all of the variables on the following list. Note that values out of normal range for gestational and postmenstrual age would be desirable and an acute change from an individual patient's baseline would be ideal. (1) A measure of abnormal respiratory rate (tachypnea, apnea). (2) A measure of abnormal heart rate (consistent tachycardia or consistent or repetitive transient bradycardia). (3) A measure of abnormal heart rate characteristics, such as the HRC index. (4) A measure of clinical signs such as new onset of feeding intolerance. (5) A measure of physical examination abnormalities such as absent bowel sounds. (6) A measure of poor perfusion such as delayed capillary refill time, low urine output, or low blood pressure. (7) A measure of abnormal laboratory values such as acute phase reactants, if these studies are available and clinically indicated. (8) A measure of abnormal radiographic findings, if studies are indicated.
new vital sign and hemodynamic metrics and integrating laboratory values, biomarkers, and clinical information could lead to even better algorithms for early sepsis detection. As new technologies or sepsis alerts are developed, training healthcare providers in how to interpret them and testing their impact on clinically meaningful outcomes should be a high priority toward improving outcomes of preterm infants.
Practice points The heart rate characteristics (HeRO) monitor analyzes bedside monitor electrocardiogram signal for decreased variability and transient decelerations and displays a score that is the fold-increased risk of sepsis in the next 24 h for VLBW infants. Heart rate characteristics monitoring reduced all-cause mortality by 22% and sepsis-associated mortality by 40% in a randomized clinical trial of 3003 VLBW infants. Abnormal heart rate characteristics are not specific to bloodstream infection and may occur in other infectious and non-infectious conditions. Implementing a system for alerting clinicians to abnormal vital signs or predictive monitoring scores may lead to earlier initiation of therapy for sepsis or NEC.
Research directions Test the ability of vital sign-based scores soon after birth to identify infants at highest risk for adverse outcomes such as late-onset septicemia or NEC. Add analysis of other vital signs including respiratory rate and oxygen saturation to heart rate characteristics analysis to determine optimum metrics for detection of earlystage sepsis or NEC.
Conflict of interest statement None declared. Funding sources None.
9. Advanced hemodynamic monitoring in preterm infants with sepsis and NEC Once preterm infants are diagnosed with suspected sepsis or NEC, advanced hemodynamic assessment tools, including nearinfrared spectroscopy (NIRS), electrical cardiometry, and functional echocardiography could be useful to monitor for clinical deterioration and guide fluid and vasopressor-inotrope therapy [51]. The role of these and other tools such as pulsatility index of the photoplethysmography (pulse oximeter) signal for risk assessment or early detection of sepsis and NEC deserves further study. 10. Conclusion Monitoring heart rate characteristics for signs of imminent sepsis was shown to reduce mortality among VLBW infants. Adding
References [1] Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2e8. [2] Hofer N, Zacharias E, Müller W, Resch B. Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates. J Perinat Med 2012;40:587e90. [3] Brierley J, Carcillo JA, Choong K, Cornell T, DeCaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009;37:666e88. [4] Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol 2010;37:439e79. [5] Anand R, Leaphart C, Mollen K, Hackam D. The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 2007;27:124e33. [6] Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285e91.
Please cite this article in press as: Sullivan BA, Fairchild KD, Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.006
B.A. Sullivan, K.D. Fairchild / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7 [7] Kermorvant-Duchemin E, Laborie S, Rabilloud M, Lapillonne A, Claris O. Outcome and prognostic factors in neonates with septic shock. Pediatr Crit Care Med 2008;9:186e91. [8] Verboon-Maciolek M. Clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a 12-year period. Pediatr Infect Dis J 2005;24:901e4. [9] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138e50. [10] Ng PC, Lam HS. Diagnostic markers for neonatal sepsis. Curr Opin Pediatr 2006;18:125e31. [11] Weitkamp J-H, Aschner JL. Diagnostic use of C-reactive protein (CRP) in assessment of neonatal sepsis. Neoreviews 2005;6:e508e15. [12] Person M, Esposito D. Risk factors for infectious disease death among infants in the United States. Pediatr Infect Dis J 2014;33:e280e5. [13] Gephart SM, Spitzer AR, Effken JA, Dodd E, Halpern M, McGrath JM. Discrimination of GutCheck(NEC): a clinical risk index for necrotizing enterocolitis. J Perinatol 2014;34:468e75. [14] Esposito S, Zampiero A, Pugni L, Tabano S. Genetic polymorphisms and sepsis in premature neonates. PLoS One 2014;9:e101248. [15] Abu-Maziad A, Schaa K, Bell EF, Dagle JM, Cooper M, Marazita ML, et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res 2010;68:323e9. [16] Maheshwari A, Schelonka RL, Dimmitt RA, Carlo WA, Munoz-Hernandez B, Das A, et al. Cytokines associated with necrotizing enterocolitis in extremelylow-birth-weight infants. Pediatr Res 2014;76:100e8. [17] Saria S, Rajani AK, Gould J, Koller D, Penn AA. Integration of early physiological responses predicts later illness severity in preterm infants. Sci Transl Med 2010;2:48e65. [18] Doheny KK, Palmer C, Browning KN, Jairath P, Liao D, He F. Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants. Neurogastroenterol Motil 2014;26:832e40. [19] Bravi A, Green G, Longtin A, Seely AJE. Monitoring and identification of sepsis development through a composite measure of heart rate variability. PLoS One 2012;7:e45666. [20] Fairchild KD. Predictive monitoring for early detection of sepsis in neonatal ICU patients. Curr Opin Pediatr 2013;25:172e9. [21] Griffin MP, Moorman JR. Toward the early diagnosis of neonatal sepsis and sepsis-like illness using novel heart rate analysis. Pediatrics 2001;107: 97e104. [22] Fairchild KD, O'Shea TM. Heart rate characteristics: physiomarkers for detection of late-onset neonatal sepsis. Clin Perinatol 2010;37:581e98. [23] Fairchild KD, Saucerman JJ, Raynor LL, Sivak JA, Xiao Y, Lake DE, et al. Endotoxin depresses heart rate variability in mice: cytokine and steroid effects. Am J Physiol Regul Integr Comp Physiol 2009;297:R1019e27. [24] Durosier LD, Cao M, Herry C, Batkin I, Seely A, Burns P, et al. A signature of fetal systemic inflammatory response in the pattern of heart rate variability measures matrix: a prospective study in fetal sheep model of lipopolysaccharide (LPS)-induced sepsis. FASEB J 2013;27:926.8. [25] Raynor LL, Saucerman JJ, Akinola MO, Lake DE, Moorman JR, Fairchild KD. Cytokine score identifies NICU patients with gram-negative bacteremia. Pediatr Res 2012;71:261e6. [26] Griffin MP, Lake DE, Bissonette EA, Harrell FE, O'Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005;116:1070e4. [27] Fairchild KD, Srinivasan V, Moorman JR, Gaykema RP, Goehler LE. Pathogeninduced heart rate changes associated with cholinergic nervous system activation. Am J Physiol Regul Integr Comp Physiol 2011;300:R330e9. [28] Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med 2011;269:45e53. [29] Kovatchev BP, Farhy LS, Cao H, Griffin MP, Lake DE, Moorman JR. Sample asymmetry analysis of heart rate characteristics with application to neonatal sepsis and systemic inflammatory response syndrome. Pediatr Res 2003;54: 892e8.
7
[30] Lake DE, Richman JS, Griffin MP, Moorman JR. Sample entropy analysis of neonatal heart rate variability. Am J Physiol Regul Integr Comp Physiol 2002;283:R789e97. [31] Moorman JR, Rusin CE, Lee H, Guin LE, Clark MT, Delos JB, et al. Predictive monitoring for early detection of subacute potentially catastrophic illnesses in critical care. Conf Proc IEEE Engng Med Biol Soc 2011;2011:5515e8. [32] Moorman JR, Delos JB, Flower AA, Cao H, Kovatchev BP, Richman JS, et al. Cardiovascular oscillations at the bedside: early diagnosis of neonatal sepsis using heart rate characteristics monitoring. Physiol Meas 2011;32:1821e32. [33] Griffin MP, O'Shea TM, Bissonette EA, Harrell FE, Lake DE, Moorman JR. Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness. Pediatr Res 2003;53:920e6. [34] Griffin MP, Lake DE, O'Shea TM, Moorman JR. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007;61:222e7. [35] Griffin MP, O'Shea TM, Bissonette EA, Harrell FE, Lake DE, Moorman JR. Abnormal heart rate characteristics are associated with neonatal mortality. Pediatr Res 2004;55:782e8. [36] Griffin MP, Lake DE, Moorman JR. Heart rate characteristics and laboratory tests in neonatal sepsis. Pediatrics 2005;115:937e41. [37] Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011;159:900e6. e1. [38] Fairchild K, Schelonka R, Kaufman D. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74: 570e5. [39] Stone ML, Tatum PM, Weitkamp J-H, Mukherjee AB, Attridge J, McGahren ED, et al. Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis. J Perinatol 2013;33:847e50. [40] Sullivan BA, Grice SM, Lake DE, Moorman JR, Fairchild KD. Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants. J Pediatr 2014;164:775e80. [41] Fairchild KD, Sinkin RA, Davalian F, Blackman AE, Swanson JR, Matsumoto JA, et al. Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants. J Perinatol 2014;34:375e9. [42] Balan KV, Kc P, Hoxha Z, Mayer CA, Wilson CG, Martin RJ. Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata. Respir Physiol Neurobiol 2011;178:458e64. [43] Lee H, Rusin CG, Lake DE, Clark MT, Guin L, Smoot TJ, et al. A new algorithm for detecting central apnea in neonates. Physiol Meas 2012;33:1e17. [44] Clark MT, Vergales BD, Paget-Brown AO, Smoot TJ, Lake DE, Hudson JL, et al. Predictive monitoring for respiratory decompensation leading to urgent unplanned intubation in the neonatal intensive care unit. Pediatr Res 2013;73: 104e10. [45] Pearson G, Duncan H. Early warning systems for identifying sick children. Paediatr Child Health (Oxford) 2011;21:230e3. [46] Nguyen SQ, Mwakalindile E, Booth JS, Hogan V, Morgan J, Prickett CT, et al. Automated electronic medical record sepsis detection in the emergency department. PeerJ 2014;2:e343. [47] Sawyer A, Deal E, Labelle A. Implementation of a real-time computerized sepsis alert in nonintensive care unit patients. Crit Care Med 2011;39:469e73. [48] Arnold R, Sherwin R. Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department. Acad Emerg Med 2013;20: 433e40. [49] Duncan H, Hutchison J, Parshuram CS. The Pediatric Early Warning System score: a severity of illness score to predict urgent medical need in hospitalized children. J Crit Care 2006;21:271e8. [50] Holme H, Bhatt R, Koumettou M, Griffin MA, Winckworth LC. Retrospective evaluation of a new neonatal trigger score. Pediatrics 2013;131:e837e42. [51] Azhibekov T, Noori S, Soleymani S, Seri I. Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care. Semin Fetal Neonatal Med 2014;19:45e53.
Please cite this article in press as: Sullivan BA, Fairchild KD, Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock, Seminars in Fetal & Neonatal Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.006
