Journal of Perinatology (2014) 34, 292–295 & 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Cardiac troponin I concentrations as a marker of neurodevelopmental outcome at 18 months in newborns with perinatal asphyxia P Montaldo1, R Rosso2, G Chello2 and P Giliberti2 OBJECTIVE: To investigate whether creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) can be used to predict neurodevelopmental outcome at 18 months in infants with perinatal asphyxia (PA). The diagnostic value of cTnI to assess myocardial dysfunction was considered as well. STUDY DESIGN: Retrospective study of 178 neonates admitted with PA. cTnI concentrations measured within 12 h of birth were compared with medium-term outcome assessed with the Bayley Scales of Infant Development. cTnI concentrations measured within 12 h of birth were compared with clinical grade of hypoxic–ischemic encephalopathy (HIE) and with duration of inotropic support. Two-dimensional Doppler and color Doppler findings were recorded. Fractional shortening, tricuspid and mitral regurgitation were evaluated. RESULT: A statistically significant correlation between cTnI concentration and BSID-II score was found (mental development index r 0.69, Po0.05 and psychomotor development index r 0.39, Po0.05). There was no statistically significant correlation between CK-MB and BSID-II score (P40.05). Serum cTnI concentrations and duration of inotropic support were significantly greater with increasing severity of PA. cTnI was negatively correlated with fraction shortening (r 0.64; Po0.05). The severity of tricuspid regurgitation was correlated with the cTnI concentration (r 0.61; Po0.05). CONCLUSION: In asphyxiated neonates, cTnI concentrations within 12 h of birth correlate with medium-term outcome. Early cTnI concentration correlates with severity of HIE, myocardial dysfunction and with Bayley II scores at 18 months. Journal of Perinatology (2014) 34, 292–295; doi:10.1038/jp.2014.1; published online 30 January 2014 Keywords: troponin I; perinatal asphyxia; infant newborn; prognosis
INTRODUCTION Perinatal asphyxia (PA) or neonatal hypoxia–ischemia is a temporary interruption of oxygen availability that implies a risky metabolic challenge, even when the insult does not lead to a fatal outcome.1 The frequency of PA is approximately estimated to be 1 to 1.5% of live births in developed countries.2 A hypoxic–ischemic insult around the time of birth may result in an encephalopathic state characterized by the need for resuscitation at birth, neurological depression, electroencephalographic abnormalities and seizures.3 Although the myocardium in the newborn is preferentially perfused in case of asphyxia, when such compensatory mechanisms are compromised, the papillary muscles and subendocardial areas of the neonatal heart become particularly vulnerable4,5 with subsequent development of a low cardiac output, decreased myocardial contractility, pulmonary hypertension, systemic hypotension and multiorgan failure.6 Therefore, detecting myocardial injury is a useful tool to predict the mortality and morbidity in this group of patients. Clinical assessment alone, however, is inadequate to guide management or predict outcome.7 So far, some studies have shown the significance of cardiac enzymes to assess myocardial injury6,8 and a prospective study has been conducted to assess the predictive value of
these tests for mortality.9 However, the effect of cardiovascular dysfunction on neurodevelopmental outcome has not yet been investigated. The aim of this study was to investigate whether creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) can be used to predict medium-term neurodevelopmental outcome in infants with PA. The diagnostic value of cTnI to assess myocardial dysfunction was considered as well.
METHODS This retrospective study included all the patients admitted with PA and gestational age X37 weeks from 2002 to 2012 in the Unit of Neonatal Intensive Care of Monaldi Hospital in Naples, Italy. The Ethical Committee of Department of Pediatrics approved the study. PA was diagnosed if at least two of the following criteria were met:10 (i) Apgar score p5 at 5 min of life; (ii) an umbilical arterial cord blood base deficit of more than 12 mmol l 1 at birth or an arterial blood base deficit of greater than 10 mmol l 1 during the first hour of life; (iii) endotracheal intubation and intermittent positive pressure ventilation for persistent apnea of 410 min after birth; (iv) multiorgan failure within 24 h after birth; (v) evidence of fetal distress as indicated by thick meconiumstained liquor and/or abnormal cardiotocographic changes (sustained fetal bradycardia o100 beats per minute, late deceleration with loss of variability and/or severe recurrent deceleration with loss of variability).
1 Department of Pediatrics, Second University of Naples, Naples, Italy and 2Department of Neonatal Intensive Care, Monaldi Hospital, Naples, Italy. Correspondence: Dr P Montaldo, Department of Pediatrics, Second University of Naples, Via L. De Crecchio 4, Naples 80131, Italy. E-mail: [email protected] Received 31 August 2013; revised 26 December 2013; accepted 31 December 2013; published online 30 January 2014
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
293 RESULTS A total of 204 neonates were admitted with PA in the study period. Of these, 26 neonates were excluded (cTnI not measured in n ¼ 11; cTnI performed 448 h after birth in n ¼ 5; BSID-II outcome data at 18 months of age not available in n ¼ 10). A sample of 178 newborns with PA was therefore included in this study and, among these, 102 were diagnosed with PA but did not show any signs and symptoms of HIE. These infants were defined as hypoxic but not as HIE group. Baseline characteristics are shown in Table 1. CK-MB and cTnI concentrations are shown in Table 2. Patients with HIE grade 2 and 3 showed a higher cTnI concentration and a longer duration of inotropic support than those diagnosed with HIE grade 1 and PA. This difference was statistically significant (Po0.05). No statistically significant difference was found in the levels of CK-MB in the four groups (P40.05). Thirty-eight newborns were cooled. We found no differences in cTnI concentrations between cooled and non-cooled infants (P40.05). Twenty-one infants died. Their median cTnI concentration was 3.1 ng ml 1 (95% CI: 0.18 to 19.7 ng ml 1), significantly higher compared with that in the 157 overall survivors (median 0.18 ng ml 1 (95% CI: 0.06 to 0.25 ng ml 1); Po0.05). The optimal cTnI cutoff value for mortality was 8.1 ng ml 1 (area under the curve 0.95, 95% CI: 0.92 to 0.97). The median age at blood sampling for cTnI concentration was 8 h (range: 2 to 12 h). cTnI level did not correlate with birth weight (P40.05) and gestational age (P40.05), had a negative correlation with Apgar scores at 5 min (r 0.64; Po0.05) and showed a positive correlation with CK-MB levels (r 0.49; Po0.05). As many as 25 infants received cardiac compressions. Omitting these 25 infants from analysis did not alter the findings. A statistically significant correlation between cTnI concentration and BSID-II score was found (MDI 0.69, Po0.05 and PDI 0.39, Po0.05). There was no statistically significant correlation between CK-MB and BSID-II score (P40.05). Receiver operating characteristic curve analysis showed that the most suitable cTnI cutoff value for adverse neurodevelopmental outcome was 0.58 ng ml 1 (area under the curve 0.96, 95% CI: 0.93 to 0.98) (Figure 1). cTnI did not significantly differ between patients with clinical seizures (n ¼ 51) and patients without seizures (n ¼ 127) (P40.05). The results of echocardiographic analysis are shown in Table 3. Twenty-eight neonates were excluded from the echocardiographic
Cases with congenital heart diseases, major central nervous system malformations and neonatal sepsis were excluded. Since 2002, the routine clinical practice of our unit has been to measure cTnI, CK-MB concentration and perform an echocardiogram within the first 12 h for any baby admitted with suspected PA. A venous blood sample of 1 ml was obtained within the first 12 h of age. CK-MB was measured by quantitative determination based on immuneinhibition IFCC methodology (Agappe Diagnostics, Zurich, Switzerland) using semi auto-analyzer. The Calbiotech cTnI ELISA (Spring Valley, CA, USA) was used for the quantitative determination of cTnI from samples. The cTnI ELISA is based on the principal of a solid-phase ELISA. For this assay, the with-in-run coefficient of variations 6.6% and the manufacturer claims minimal cross-reactivity with cTnC (0.01%), cTnT (0.34%) and skeletal troponin I (0.04%) at a concentration of 1000 ng ml 1. The echocardiogram was obtained with a Toshiba 140 A scanner (Toshiba America Medical Systems, Tustin, CA, USA). Measurements were made using a 7.5-MHz probe, while a 5-MHz probe was used for Doppler examination. A complete two-dimensional and Doppler examination was performed to exclude structural heart diseases. In the functional echocardiographic study, left ventricular fractional shortening (LVFS) was obtained. The presence of mitral or tricuspid regurgitation was also evaluated. The severity of mitral or tricuspid regurgitation was estimated by the regurgitant jet area, which was measured as the largest clearly definable flow disturbance in the parasternal and apical views. A regurgitant jet area of 410 cm2 and 48 cm2 was considered as severe tricuspid regurgitation11 and as severe mitral regurgitation,12 respectively. The hypoxic–ischemic encephalopathy (HIE) grading had been designated by the designed clinician at the time of admission based on amplitude-integrated electroencephalogram13 and clinical examination, according to Sarnat and Sarnat classification.14 These data and the clinical evolution of the encephalopathy were recorded daily. Therapeutic hypothermia was available at study institution since 2009. All infants fulfilled the entry criteria for therapeutic hypothermia as used in the TOBY trials.15 For all infants, Apgar scores at 1 and 5 min, gestational age, birth weight, use and duration of inotropic support were recorded. Medium-term outcome was assessed in surviving infants at 18 months using the Bayley Scales of Infant Development.16 Adverse outcome was defined as an MDI (mental development index) and/or a PDI (psychomotor development index) o70 on the Bayley Scales of Infant Development-II (BSID-II); 70 is X2 s.d. below the mean of 100 in this test. The Pearson w2 test was used to evaluate the difference in prevalence. A Kruskal–Wallis test was used to assess differences between means and intergroup comparisons. Correlations were determined by Pearson’s correlation. Area under the curve (AUC) was obtained from receiver operating characteristic curves to assess the most suitable cTnI cutoff value for adverse neurodevelopmental outcome and for mortality. A P-value of o0.05 was considered as statistically significant. All analyses were conducted using Statgraphics Centurion XV.II (Warrenton, VA, USA).
Table 1.
Clinical variables of the sample PA, n ¼ 102
Male gender, n (%) Gestational age, mean (±s.d.) (weeks) Birthweight, mean (±s.d.) (g) 5-min Apgar score, median (range) Worst pH in first hour after birth, mean (±s.d.) Needed ventilation 412 h, n (%) Cardiac massage during resuscitation, n (%) Whole-body hypothermia therapy, n (%)
81 39.8 3040 5.87 7.20 25 7
(79) (1.5) (710) (2–10) (0.28) (24) (6) 0
HIE grade 1, n ¼ 15 11 39.4 2940 5.08 7.11 5 2 7
(73) (2.1) (810) (3–10) (0.15) (33) (13) (50)
HIE grade 2, n ¼ 37 28 39.2 3300 4.65 6.99 28 7 20
(75) (1.2) (685) (2–7) (0.24) (75) (18) (54)
HIE grade 3, n ¼ 24 18 39.6 3110 2.6 6.89 22 9 11
(79) (1.6) (750) (0–6) (0.42) (93) (37) (45)
P 40.05 40.05 40.05 o0.05 o0.05 o0.05 o0.05 40.05
Abbreviations: HIE, hypoxic–ischemic encephalopathy; PA, perinatal asphyxia.
Table 2.
CK-MB and cTnI concentrations
Duration of inotropic support (h) median (range) cTnI concentration (ng ml 1) median (range) CK-MB concentration(IU l 1) median (range)
16 (0–131) 0.19 (0.03–4.93) 122 (114–128)
0 (0–22) 0.09 (ND-0.12) 111 (107–120)
31 (0–122) 0.25 (0.09–1.69) 116 (105–118)
51 (0–137) 0.72 (0.11–19.7) 119 (102–124)
Abbreviations: CK-MB, creatine kinase-MB; cTnI, cardiac troponin I.
& 2014 Nature America, Inc.
Journal of Perinatology (2014), 292 – 295
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
294 analysis because not all the cardiac parameters had been assessed. cTnI was negatively correlated with LVFS (r 0.64; Po0.05). The severity of tricuspid regurgitation was correlated with the cTnI concentration (r 0.61; Po0.05). DISCUSSION This is the first study to report a strict correlation between cTnI concentration in the first 12 h of life and the medium-term outcome in perinatal asphyxiated newborn infants. In the clinical setting, several methods to predict outcomes in infants with PA are used. These include: neonatal clinical examination and clinical course, monitoring general movements,17 early electrophysiology testing, cranial ultrasound imaging and magnetic resonance imaging.18 The optimal window for intervention in infants with PA is not yet known, but reasonably the earlier the intervention of neuroprotection is carried out, the more effective. Recently, a small retrospective study showed plasma lactate dehydrogenase as a reliable biomarker to predict neurodevelopmental outcome in infants with HIE.19 Unfortunately, only at the end of 3-day hypothermic treatment, a significant difference in
1.0
Sensitivity
0.8
0.6
0.4
0.2
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1 - Specificity
Figure 1. Receiver operating characteristic (ROC) curves show the predictive value of cardiac troponin I (cTnI) (dotted line) together with reference line (solid) for prediction of adverse neurodevelopmental outcome.
Table 3.
lactate dehydrogenase activity was seen between the favorable group and the adverse outcome group. cTnT and cTnI are considered as useful markers to detect myocardial injury in the neonatal period.20,21 Serum troponin-T is reasonably sensitive, but not very specific in detecting myocardial injury presenting with heart failure and detecting myocardial injury with low ejection fraction in asphyxiated term infants.10 On the other hand, cord troponin-I is the marker with highest specificity (86%), sensitivity (88%), negative predictive value (85%), positive predictive value (88%) and area under receiver operator curve (0.929) for prediction of perinatal hypoxia21 and was identified as the most sensitive factor for predicting early death (area under receiver operator curve ¼ 0.956).22 Our results underline that cTnI is an early marker of severity of PA and mortality. Tu¨rker et al.22 identified cord cTnI concentration of 4.6 ng ml 1 as the optimal cutoff concentration for predicting serious risk of early mortality. Our findings identify cTnI concentration of 8.1 ng ml 1 as an optimal cutoff. The different cutoffs can be due to the different timings of sample collection. In fact, half life of cTnI is B2 h and levels of this marker in patients with hypoxic cardiac injury remain increased for 7 to 10 days.22 Furthermore, our findings show that cTnI is an early predictor of the neurodevelopmental outcome of the infants with PA as well. The statistically significant correlations between cTnI concentrations, duration of inotropes and clinical HIE grade imply that early cTnI concentrations may be a useful predictor of the severity of myocardial dysfunction which, in its turn, is strictly correlated with the severity of PA. Our findings suggest that when a cardiac involvement occurs during PA, a worse neurodevelopmental outcome can be expected. These data are in agreement with previous studies23,24 and show the efficiency and reliability of cTnI as a biochemical marker. Previous studies showed that cTnI concentrations are significantly elevated in PA.21,25,26 Trevisanuto et al.26 found that the optimal cutoff value of serum troponin-I for prediction of myocardial damage was 0.15 ng ml 1. They showed that among the asphyxiated infants, 77% had troponin-I concentrations over the decisional level for myocardial injury (40.15 ng ml 1). This is in agreement with our findings, which showed a median cTnI concentration of 0.26 and 0.72 ng ml 1 in grade 2 and grade 3 HIE, respectively. Furthermore, these data underline how hypoxia–ischemia severe enough to affect the brain will co-occur with a myocardial damage. In contrast to Trevisanuto et al.,26 we found a significant correlation between concentrations of troponin-I and 5-min Apgar score. This may be due to small sample size as Trevisanuto et al.26 enrolled only 13 asphyxiated neonates. Previous studies22,27 demonstrated that babies with moderateto-severe asphyxia had significantly higher cTnI levels compared to those with no or only mild asphyxia.
Echocardiographic parameters PA, n ¼ 80
% FS (s.d.) TI n (%) JA (cm2) mean (±s.d.) MI n (%) JA (cm2) mean (±s.d.)
30.1 (24±34)
HIE grade 1, n ¼ 13
HIE grade 2, n ¼ 35
HIE grade 3, n ¼ 22
36.4 (26±45)
27.3 (18±36)
22.5 (13±29)
P o0.05
25 (31) 6.2 (4.6)
4 (31) 5.1 (5.2)
13 (37) 8.2 (3.6)
11 (46) 13 (6.1)
o0.05 o0.05
3 (4) 4.9 (4.7)
2 (2) 5.1 (5.8)
2 (6) 5. 5 (2.9)
1 (4) 5.7 (2.1)
40.05 40.05
Abbreviations: FS, fractional shortening; HIE, hypoxic–ischemic encephalopathy; JA, regurgitant jet area; MI, mitral insufficiency; PA, perinatal asphyxia; TI, tricuspid insufficiency.
Journal of Perinatology (2014), 292 – 295
& 2014 Nature America, Inc.
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
295 Shastri et al.27 furthermore showed a correlation between cTnI concentration and duration of inotropic support as well. Nevertheless, a study limitation was the absence of any comparative cardiac function data from echocardiography. Our study confirmed these previous findings and showed that there is a negative correlation between LVFS and cTnI. These findings are in agreement with Barberi et al.6 and Wei et al.28 who demonstrated lower LVFS in infants with severe asphyxia compared with the mildly asphyxiated and control groups. Although mild tricuspid regurgitation can be detected in healthy infants, a severe insufficiency is often seen in moderate PA.8 This is also shown in our study where a statistically significant correlation between the severity of tricuspid regurgitation and the cTnI concentration was found. Levels of CK-MB, instead, do not appear to discriminate between mildly and severely asphyxiated newborns. These findings are in agreement with previous studies which showed that CK-MB is not helpful to identify infants with neonatal hypoxic ischemia.29 The main limit of this study lies in its retrospective design. Another limitation is that the left ventricular function has been studied by LVFS. Although LVFS is easily measured, it does not meet the assumptions of a round left ventricular cross section. In addition to this, this study included infants who underwent the cooling protocol that might reduce the correlation between cTnI and Bayley scores. Nevertheless, we found no statistical differences in cTnI concentrations between cooled and non-cooled infants as previously shown by Shastri et al.27 Our data show how the interplay of information provided by echocardiogram and serum enzymes can result in a reliable detection and grading of myocardial damage. Furthermore, these results may provide a biomarker in the assessment of the neurodevelopmental outcome of asphyxiated newborn infants.
CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Herrera-Marschitz M, Morales P, Leyton L, Bustamante D, Klawitter V, EspinaMarchant P et al. Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins. Neurotox Res 2011; 19: 603–627. 2 Hansen AR, Soul JS. Perinatal asphyxia. in Cloherty JP, Eichenwald EC, Stark AR (eds) Manual of Neonatal Care. 7th edn. Wolters Kluwer, Lippincott Williams and Wilkins: Philadelphia, pp 711–728, 2012. 3 Azzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M et al. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr 2008; 8: 17. 4 Donnelly WE, Bucciarelli RL, Nelson RM. Ischemic papillary muscle necrosis in stressed newborn infants. J Pediatr 1980; 96: 295–300. 5 Kilbride H, Way GL, Merenstein GB, Winfield JM. Myocardial infarction in the neonates with normal heart and coronary arteries. Am J Dis Child 1980; 134: 759–762. 6 Barberi I, Calabro` MP, Cordaro S, Gitto E, Sottile A, Prudente D et al. Myocardial ischaemia in neonates with perinatal asphyxia. Electrocardiographic, echocardiographic and enzymatic correlations. Eur J Pediatr 1999; 158: 742–747. 7 Evans N. Which inotrope for which baby? Arch Dis Child Fetal Neonatal Ed 2006; 91: 213–220.
& 2014 Nature America, Inc.
8 Szymankiewicz M, Matuszczak-Wleklak M, Hodgman JE, Gadzinowski J. Usefulness of cardiac troponin T and echocardiography in the diagnosis of hypoxic myocardial injury of full-term neonates. Biol Neonate 2005; 88: 19–23. 9 Kanik E, Ozer EA, Bakiler AR, Aydinlioglu H, Dorak C, Dogrusoz B et al. Assessment of myocardial dysfunction in neonates with hypoxic-ischemic encephalopathy: is it a significant predictor of mortality? J Matern Fetal Neonatal Med 2009; 22: 239–242. 10 Boo NY, Hafidz H, Nawawi HM, Cheah FC, Fadzil YJ, Abdul-Aziz BB et al. Comparison of serum cardiac troponin T and creatine kinase MB isoenzyme mass concentrations in asphyxiatedterm infants during the first 48 h of life. J Paediatr Child Health 2005; 41: 331–337. 11 Gonzalez-Vilchez F, Zarauza J, Vazquez de Prada JA, Martı´n Dura´n R, Ruano J, Delgado C et al. Assessment of tricuspid regurgitation by Doppler color flow imaging: angiographic correlation. Int J Cardiol 1994; 44: 275–283. 12 Spain MG, Smith MD, Grayburn PA, Harlamert EA, DeMaria AN. Quantitative assessment of mitral regurgitation by Doppler color flow imaging: angiographic and hemodynamic correlations. J Am Coll Cardiol 1989; 13: 585–590. 13 al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics 1999; 103: 1263–1271. 14 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress a clinical and electroencephalographic study. Arch Neurol 1976; 33: 696–705. 15 Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E et al. Moderate hypothermia to treat perinatal asphyxia encephalopathy. N Engl J Med 2009; 361: 1349–1358. 16 Bayley N. Bayley Scales of Infant Development. Harcourt, Brace & Co: San Antonio, 1993. 17 Ferrari F, Todeschini A, Guidotti I, Martinez-Biarge M, Roversi MF, Berardi A et al. General movements in full-term infants with perinatal asphyxia are related to basal ganglia and thalamic lesions. J Pediatr 2011; 158: 904–911. 18 Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86: 675–682. 19 Thoresen M, Liu X, Jary S, Brown E, Sabir H, Stone J et al. Lactate dehydrogenase in hypothermia-treated newborn infants with hypoxic ischaemic encephalopathy. Acta Paediatr 2012; 101: 1038–1044. 20 El-Khuffash A, Davis PG, Walsh K et al. Cardiac troponin T and N-terminal-pro-B type natriuretic peptide refl ect myocardial function in preterm infants. J Perinatol 2008; 28: 482–486. 21 Tu¨rker G, Babaog˘lu K, Duman C, Go¨kalp A, Zengin E, Arisoy AE. The effect of blood gas and Apgar score on cord blood cardiac troponin I. J Matern Fetal Neonatal Med 2004; 16: 315–319. 22 Tu¨rker G, Babaog˘lu K, Go¨kalp AS, Sarper N, Zengin E, Arisoy AE. Cord blood cardiac troponin I as an early predictor of short-term outcome in perinatal hypoxia. Biol Neonate 2004; 86: 131–137. 23 Karlsson M, Tooley JR, Satas S, Hobbs CE, Chakkarapani E, Stone J et al. Delayed hypothermia as selective head cooling or whole body cooling does not protect brain or body in newborn pig subjected to hypoxia-ischemia. Pediatr Res 2008; 64: 74–80. 24 Itskovitz J, LaGamma EF, Rudolph AM. Effects of cord compression on fetal blood flow distribution and O2 delivery. Am J Physiol 1987; 252: H100–H109. 25 El-Khuffash AF, Molloy EJ. Serum troponin in neonatal intensive care. Neonatology 2008; 94: 1–7. 26 Trevisanuto D, Picco G, Golin R, Doglioni N, Altinier S, Zaninotto M et al. Cardiac Troponin I in asphyxiated neonates. Biol Neonate 2006; 89: 190–193. 27 Shastri AT, Samarasekara S, Muniraman H, Clarke P. Cardiac troponin I concentrations in neonates with hypoxic-ischaemic encephalopathy. Acta Paediatr 2012; 101: 26–29. 28 Wei Y, Xu J, Xu T, Fan J, Tao S. Left ventricular systolic function of newborns with asphyxia evaluated by tissue Doppler imaging. Pediatr Cardiol 2009; 30: 741–746. 29 Mo¨ller JC, Thielsen B, Schaible TF, Reiss I, Kohl M, Welp T et al. Value of myocardial hypoxia markers (creatinine kinase and its MB-fraction, Troponin T, QT intervals) and serum creatinine for the retrospective diagnosis of perinatal asphyxia. Biol Neonate 1998; 73: 367–374.
Journal of Perinatology (2014), 292 – 295
ORIGINAL ARTICLE
Cardiac troponin I concentrations as a marker of neurodevelopmental outcome at 18 months in newborns with perinatal asphyxia P Montaldo1, R Rosso2, G Chello2 and P Giliberti2 OBJECTIVE: To investigate whether creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) can be used to predict neurodevelopmental outcome at 18 months in infants with perinatal asphyxia (PA). The diagnostic value of cTnI to assess myocardial dysfunction was considered as well. STUDY DESIGN: Retrospective study of 178 neonates admitted with PA. cTnI concentrations measured within 12 h of birth were compared with medium-term outcome assessed with the Bayley Scales of Infant Development. cTnI concentrations measured within 12 h of birth were compared with clinical grade of hypoxic–ischemic encephalopathy (HIE) and with duration of inotropic support. Two-dimensional Doppler and color Doppler findings were recorded. Fractional shortening, tricuspid and mitral regurgitation were evaluated. RESULT: A statistically significant correlation between cTnI concentration and BSID-II score was found (mental development index r 0.69, Po0.05 and psychomotor development index r 0.39, Po0.05). There was no statistically significant correlation between CK-MB and BSID-II score (P40.05). Serum cTnI concentrations and duration of inotropic support were significantly greater with increasing severity of PA. cTnI was negatively correlated with fraction shortening (r 0.64; Po0.05). The severity of tricuspid regurgitation was correlated with the cTnI concentration (r 0.61; Po0.05). CONCLUSION: In asphyxiated neonates, cTnI concentrations within 12 h of birth correlate with medium-term outcome. Early cTnI concentration correlates with severity of HIE, myocardial dysfunction and with Bayley II scores at 18 months. Journal of Perinatology (2014) 34, 292–295; doi:10.1038/jp.2014.1; published online 30 January 2014 Keywords: troponin I; perinatal asphyxia; infant newborn; prognosis
INTRODUCTION Perinatal asphyxia (PA) or neonatal hypoxia–ischemia is a temporary interruption of oxygen availability that implies a risky metabolic challenge, even when the insult does not lead to a fatal outcome.1 The frequency of PA is approximately estimated to be 1 to 1.5% of live births in developed countries.2 A hypoxic–ischemic insult around the time of birth may result in an encephalopathic state characterized by the need for resuscitation at birth, neurological depression, electroencephalographic abnormalities and seizures.3 Although the myocardium in the newborn is preferentially perfused in case of asphyxia, when such compensatory mechanisms are compromised, the papillary muscles and subendocardial areas of the neonatal heart become particularly vulnerable4,5 with subsequent development of a low cardiac output, decreased myocardial contractility, pulmonary hypertension, systemic hypotension and multiorgan failure.6 Therefore, detecting myocardial injury is a useful tool to predict the mortality and morbidity in this group of patients. Clinical assessment alone, however, is inadequate to guide management or predict outcome.7 So far, some studies have shown the significance of cardiac enzymes to assess myocardial injury6,8 and a prospective study has been conducted to assess the predictive value of
these tests for mortality.9 However, the effect of cardiovascular dysfunction on neurodevelopmental outcome has not yet been investigated. The aim of this study was to investigate whether creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) can be used to predict medium-term neurodevelopmental outcome in infants with PA. The diagnostic value of cTnI to assess myocardial dysfunction was considered as well.
METHODS This retrospective study included all the patients admitted with PA and gestational age X37 weeks from 2002 to 2012 in the Unit of Neonatal Intensive Care of Monaldi Hospital in Naples, Italy. The Ethical Committee of Department of Pediatrics approved the study. PA was diagnosed if at least two of the following criteria were met:10 (i) Apgar score p5 at 5 min of life; (ii) an umbilical arterial cord blood base deficit of more than 12 mmol l 1 at birth or an arterial blood base deficit of greater than 10 mmol l 1 during the first hour of life; (iii) endotracheal intubation and intermittent positive pressure ventilation for persistent apnea of 410 min after birth; (iv) multiorgan failure within 24 h after birth; (v) evidence of fetal distress as indicated by thick meconiumstained liquor and/or abnormal cardiotocographic changes (sustained fetal bradycardia o100 beats per minute, late deceleration with loss of variability and/or severe recurrent deceleration with loss of variability).
1 Department of Pediatrics, Second University of Naples, Naples, Italy and 2Department of Neonatal Intensive Care, Monaldi Hospital, Naples, Italy. Correspondence: Dr P Montaldo, Department of Pediatrics, Second University of Naples, Via L. De Crecchio 4, Naples 80131, Italy. E-mail: [email protected] Received 31 August 2013; revised 26 December 2013; accepted 31 December 2013; published online 30 January 2014
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
293 RESULTS A total of 204 neonates were admitted with PA in the study period. Of these, 26 neonates were excluded (cTnI not measured in n ¼ 11; cTnI performed 448 h after birth in n ¼ 5; BSID-II outcome data at 18 months of age not available in n ¼ 10). A sample of 178 newborns with PA was therefore included in this study and, among these, 102 were diagnosed with PA but did not show any signs and symptoms of HIE. These infants were defined as hypoxic but not as HIE group. Baseline characteristics are shown in Table 1. CK-MB and cTnI concentrations are shown in Table 2. Patients with HIE grade 2 and 3 showed a higher cTnI concentration and a longer duration of inotropic support than those diagnosed with HIE grade 1 and PA. This difference was statistically significant (Po0.05). No statistically significant difference was found in the levels of CK-MB in the four groups (P40.05). Thirty-eight newborns were cooled. We found no differences in cTnI concentrations between cooled and non-cooled infants (P40.05). Twenty-one infants died. Their median cTnI concentration was 3.1 ng ml 1 (95% CI: 0.18 to 19.7 ng ml 1), significantly higher compared with that in the 157 overall survivors (median 0.18 ng ml 1 (95% CI: 0.06 to 0.25 ng ml 1); Po0.05). The optimal cTnI cutoff value for mortality was 8.1 ng ml 1 (area under the curve 0.95, 95% CI: 0.92 to 0.97). The median age at blood sampling for cTnI concentration was 8 h (range: 2 to 12 h). cTnI level did not correlate with birth weight (P40.05) and gestational age (P40.05), had a negative correlation with Apgar scores at 5 min (r 0.64; Po0.05) and showed a positive correlation with CK-MB levels (r 0.49; Po0.05). As many as 25 infants received cardiac compressions. Omitting these 25 infants from analysis did not alter the findings. A statistically significant correlation between cTnI concentration and BSID-II score was found (MDI 0.69, Po0.05 and PDI 0.39, Po0.05). There was no statistically significant correlation between CK-MB and BSID-II score (P40.05). Receiver operating characteristic curve analysis showed that the most suitable cTnI cutoff value for adverse neurodevelopmental outcome was 0.58 ng ml 1 (area under the curve 0.96, 95% CI: 0.93 to 0.98) (Figure 1). cTnI did not significantly differ between patients with clinical seizures (n ¼ 51) and patients without seizures (n ¼ 127) (P40.05). The results of echocardiographic analysis are shown in Table 3. Twenty-eight neonates were excluded from the echocardiographic
Cases with congenital heart diseases, major central nervous system malformations and neonatal sepsis were excluded. Since 2002, the routine clinical practice of our unit has been to measure cTnI, CK-MB concentration and perform an echocardiogram within the first 12 h for any baby admitted with suspected PA. A venous blood sample of 1 ml was obtained within the first 12 h of age. CK-MB was measured by quantitative determination based on immuneinhibition IFCC methodology (Agappe Diagnostics, Zurich, Switzerland) using semi auto-analyzer. The Calbiotech cTnI ELISA (Spring Valley, CA, USA) was used for the quantitative determination of cTnI from samples. The cTnI ELISA is based on the principal of a solid-phase ELISA. For this assay, the with-in-run coefficient of variations 6.6% and the manufacturer claims minimal cross-reactivity with cTnC (0.01%), cTnT (0.34%) and skeletal troponin I (0.04%) at a concentration of 1000 ng ml 1. The echocardiogram was obtained with a Toshiba 140 A scanner (Toshiba America Medical Systems, Tustin, CA, USA). Measurements were made using a 7.5-MHz probe, while a 5-MHz probe was used for Doppler examination. A complete two-dimensional and Doppler examination was performed to exclude structural heart diseases. In the functional echocardiographic study, left ventricular fractional shortening (LVFS) was obtained. The presence of mitral or tricuspid regurgitation was also evaluated. The severity of mitral or tricuspid regurgitation was estimated by the regurgitant jet area, which was measured as the largest clearly definable flow disturbance in the parasternal and apical views. A regurgitant jet area of 410 cm2 and 48 cm2 was considered as severe tricuspid regurgitation11 and as severe mitral regurgitation,12 respectively. The hypoxic–ischemic encephalopathy (HIE) grading had been designated by the designed clinician at the time of admission based on amplitude-integrated electroencephalogram13 and clinical examination, according to Sarnat and Sarnat classification.14 These data and the clinical evolution of the encephalopathy were recorded daily. Therapeutic hypothermia was available at study institution since 2009. All infants fulfilled the entry criteria for therapeutic hypothermia as used in the TOBY trials.15 For all infants, Apgar scores at 1 and 5 min, gestational age, birth weight, use and duration of inotropic support were recorded. Medium-term outcome was assessed in surviving infants at 18 months using the Bayley Scales of Infant Development.16 Adverse outcome was defined as an MDI (mental development index) and/or a PDI (psychomotor development index) o70 on the Bayley Scales of Infant Development-II (BSID-II); 70 is X2 s.d. below the mean of 100 in this test. The Pearson w2 test was used to evaluate the difference in prevalence. A Kruskal–Wallis test was used to assess differences between means and intergroup comparisons. Correlations were determined by Pearson’s correlation. Area under the curve (AUC) was obtained from receiver operating characteristic curves to assess the most suitable cTnI cutoff value for adverse neurodevelopmental outcome and for mortality. A P-value of o0.05 was considered as statistically significant. All analyses were conducted using Statgraphics Centurion XV.II (Warrenton, VA, USA).
Table 1.
Clinical variables of the sample PA, n ¼ 102
Male gender, n (%) Gestational age, mean (±s.d.) (weeks) Birthweight, mean (±s.d.) (g) 5-min Apgar score, median (range) Worst pH in first hour after birth, mean (±s.d.) Needed ventilation 412 h, n (%) Cardiac massage during resuscitation, n (%) Whole-body hypothermia therapy, n (%)
81 39.8 3040 5.87 7.20 25 7
(79) (1.5) (710) (2–10) (0.28) (24) (6) 0
HIE grade 1, n ¼ 15 11 39.4 2940 5.08 7.11 5 2 7
(73) (2.1) (810) (3–10) (0.15) (33) (13) (50)
HIE grade 2, n ¼ 37 28 39.2 3300 4.65 6.99 28 7 20
(75) (1.2) (685) (2–7) (0.24) (75) (18) (54)
HIE grade 3, n ¼ 24 18 39.6 3110 2.6 6.89 22 9 11
(79) (1.6) (750) (0–6) (0.42) (93) (37) (45)
P 40.05 40.05 40.05 o0.05 o0.05 o0.05 o0.05 40.05
Abbreviations: HIE, hypoxic–ischemic encephalopathy; PA, perinatal asphyxia.
Table 2.
CK-MB and cTnI concentrations
Duration of inotropic support (h) median (range) cTnI concentration (ng ml 1) median (range) CK-MB concentration(IU l 1) median (range)
16 (0–131) 0.19 (0.03–4.93) 122 (114–128)
0 (0–22) 0.09 (ND-0.12) 111 (107–120)
31 (0–122) 0.25 (0.09–1.69) 116 (105–118)
51 (0–137) 0.72 (0.11–19.7) 119 (102–124)
Abbreviations: CK-MB, creatine kinase-MB; cTnI, cardiac troponin I.
& 2014 Nature America, Inc.
Journal of Perinatology (2014), 292 – 295
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
294 analysis because not all the cardiac parameters had been assessed. cTnI was negatively correlated with LVFS (r 0.64; Po0.05). The severity of tricuspid regurgitation was correlated with the cTnI concentration (r 0.61; Po0.05). DISCUSSION This is the first study to report a strict correlation between cTnI concentration in the first 12 h of life and the medium-term outcome in perinatal asphyxiated newborn infants. In the clinical setting, several methods to predict outcomes in infants with PA are used. These include: neonatal clinical examination and clinical course, monitoring general movements,17 early electrophysiology testing, cranial ultrasound imaging and magnetic resonance imaging.18 The optimal window for intervention in infants with PA is not yet known, but reasonably the earlier the intervention of neuroprotection is carried out, the more effective. Recently, a small retrospective study showed plasma lactate dehydrogenase as a reliable biomarker to predict neurodevelopmental outcome in infants with HIE.19 Unfortunately, only at the end of 3-day hypothermic treatment, a significant difference in
1.0
Sensitivity
0.8
0.6
0.4
0.2
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1 - Specificity
Figure 1. Receiver operating characteristic (ROC) curves show the predictive value of cardiac troponin I (cTnI) (dotted line) together with reference line (solid) for prediction of adverse neurodevelopmental outcome.
Table 3.
lactate dehydrogenase activity was seen between the favorable group and the adverse outcome group. cTnT and cTnI are considered as useful markers to detect myocardial injury in the neonatal period.20,21 Serum troponin-T is reasonably sensitive, but not very specific in detecting myocardial injury presenting with heart failure and detecting myocardial injury with low ejection fraction in asphyxiated term infants.10 On the other hand, cord troponin-I is the marker with highest specificity (86%), sensitivity (88%), negative predictive value (85%), positive predictive value (88%) and area under receiver operator curve (0.929) for prediction of perinatal hypoxia21 and was identified as the most sensitive factor for predicting early death (area under receiver operator curve ¼ 0.956).22 Our results underline that cTnI is an early marker of severity of PA and mortality. Tu¨rker et al.22 identified cord cTnI concentration of 4.6 ng ml 1 as the optimal cutoff concentration for predicting serious risk of early mortality. Our findings identify cTnI concentration of 8.1 ng ml 1 as an optimal cutoff. The different cutoffs can be due to the different timings of sample collection. In fact, half life of cTnI is B2 h and levels of this marker in patients with hypoxic cardiac injury remain increased for 7 to 10 days.22 Furthermore, our findings show that cTnI is an early predictor of the neurodevelopmental outcome of the infants with PA as well. The statistically significant correlations between cTnI concentrations, duration of inotropes and clinical HIE grade imply that early cTnI concentrations may be a useful predictor of the severity of myocardial dysfunction which, in its turn, is strictly correlated with the severity of PA. Our findings suggest that when a cardiac involvement occurs during PA, a worse neurodevelopmental outcome can be expected. These data are in agreement with previous studies23,24 and show the efficiency and reliability of cTnI as a biochemical marker. Previous studies showed that cTnI concentrations are significantly elevated in PA.21,25,26 Trevisanuto et al.26 found that the optimal cutoff value of serum troponin-I for prediction of myocardial damage was 0.15 ng ml 1. They showed that among the asphyxiated infants, 77% had troponin-I concentrations over the decisional level for myocardial injury (40.15 ng ml 1). This is in agreement with our findings, which showed a median cTnI concentration of 0.26 and 0.72 ng ml 1 in grade 2 and grade 3 HIE, respectively. Furthermore, these data underline how hypoxia–ischemia severe enough to affect the brain will co-occur with a myocardial damage. In contrast to Trevisanuto et al.,26 we found a significant correlation between concentrations of troponin-I and 5-min Apgar score. This may be due to small sample size as Trevisanuto et al.26 enrolled only 13 asphyxiated neonates. Previous studies22,27 demonstrated that babies with moderateto-severe asphyxia had significantly higher cTnI levels compared to those with no or only mild asphyxia.
Echocardiographic parameters PA, n ¼ 80
% FS (s.d.) TI n (%) JA (cm2) mean (±s.d.) MI n (%) JA (cm2) mean (±s.d.)
30.1 (24±34)
HIE grade 1, n ¼ 13
HIE grade 2, n ¼ 35
HIE grade 3, n ¼ 22
36.4 (26±45)
27.3 (18±36)
22.5 (13±29)
P o0.05
25 (31) 6.2 (4.6)
4 (31) 5.1 (5.2)
13 (37) 8.2 (3.6)
11 (46) 13 (6.1)
o0.05 o0.05
3 (4) 4.9 (4.7)
2 (2) 5.1 (5.8)
2 (6) 5. 5 (2.9)
1 (4) 5.7 (2.1)
40.05 40.05
Abbreviations: FS, fractional shortening; HIE, hypoxic–ischemic encephalopathy; JA, regurgitant jet area; MI, mitral insufficiency; PA, perinatal asphyxia; TI, tricuspid insufficiency.
Journal of Perinatology (2014), 292 – 295
& 2014 Nature America, Inc.
Cardiac troponin I concentrations in newborns with PA P Montaldo et al
295 Shastri et al.27 furthermore showed a correlation between cTnI concentration and duration of inotropic support as well. Nevertheless, a study limitation was the absence of any comparative cardiac function data from echocardiography. Our study confirmed these previous findings and showed that there is a negative correlation between LVFS and cTnI. These findings are in agreement with Barberi et al.6 and Wei et al.28 who demonstrated lower LVFS in infants with severe asphyxia compared with the mildly asphyxiated and control groups. Although mild tricuspid regurgitation can be detected in healthy infants, a severe insufficiency is often seen in moderate PA.8 This is also shown in our study where a statistically significant correlation between the severity of tricuspid regurgitation and the cTnI concentration was found. Levels of CK-MB, instead, do not appear to discriminate between mildly and severely asphyxiated newborns. These findings are in agreement with previous studies which showed that CK-MB is not helpful to identify infants with neonatal hypoxic ischemia.29 The main limit of this study lies in its retrospective design. Another limitation is that the left ventricular function has been studied by LVFS. Although LVFS is easily measured, it does not meet the assumptions of a round left ventricular cross section. In addition to this, this study included infants who underwent the cooling protocol that might reduce the correlation between cTnI and Bayley scores. Nevertheless, we found no statistical differences in cTnI concentrations between cooled and non-cooled infants as previously shown by Shastri et al.27 Our data show how the interplay of information provided by echocardiogram and serum enzymes can result in a reliable detection and grading of myocardial damage. Furthermore, these results may provide a biomarker in the assessment of the neurodevelopmental outcome of asphyxiated newborn infants.
CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Herrera-Marschitz M, Morales P, Leyton L, Bustamante D, Klawitter V, EspinaMarchant P et al. Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins. Neurotox Res 2011; 19: 603–627. 2 Hansen AR, Soul JS. Perinatal asphyxia. in Cloherty JP, Eichenwald EC, Stark AR (eds) Manual of Neonatal Care. 7th edn. Wolters Kluwer, Lippincott Williams and Wilkins: Philadelphia, pp 711–728, 2012. 3 Azzopardi D, Brocklehurst P, Edwards D, Halliday H, Levene M, Thoresen M et al. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr 2008; 8: 17. 4 Donnelly WE, Bucciarelli RL, Nelson RM. Ischemic papillary muscle necrosis in stressed newborn infants. J Pediatr 1980; 96: 295–300. 5 Kilbride H, Way GL, Merenstein GB, Winfield JM. Myocardial infarction in the neonates with normal heart and coronary arteries. Am J Dis Child 1980; 134: 759–762. 6 Barberi I, Calabro` MP, Cordaro S, Gitto E, Sottile A, Prudente D et al. Myocardial ischaemia in neonates with perinatal asphyxia. Electrocardiographic, echocardiographic and enzymatic correlations. Eur J Pediatr 1999; 158: 742–747. 7 Evans N. Which inotrope for which baby? Arch Dis Child Fetal Neonatal Ed 2006; 91: 213–220.
& 2014 Nature America, Inc.
8 Szymankiewicz M, Matuszczak-Wleklak M, Hodgman JE, Gadzinowski J. Usefulness of cardiac troponin T and echocardiography in the diagnosis of hypoxic myocardial injury of full-term neonates. Biol Neonate 2005; 88: 19–23. 9 Kanik E, Ozer EA, Bakiler AR, Aydinlioglu H, Dorak C, Dogrusoz B et al. Assessment of myocardial dysfunction in neonates with hypoxic-ischemic encephalopathy: is it a significant predictor of mortality? J Matern Fetal Neonatal Med 2009; 22: 239–242. 10 Boo NY, Hafidz H, Nawawi HM, Cheah FC, Fadzil YJ, Abdul-Aziz BB et al. Comparison of serum cardiac troponin T and creatine kinase MB isoenzyme mass concentrations in asphyxiatedterm infants during the first 48 h of life. J Paediatr Child Health 2005; 41: 331–337. 11 Gonzalez-Vilchez F, Zarauza J, Vazquez de Prada JA, Martı´n Dura´n R, Ruano J, Delgado C et al. Assessment of tricuspid regurgitation by Doppler color flow imaging: angiographic correlation. Int J Cardiol 1994; 44: 275–283. 12 Spain MG, Smith MD, Grayburn PA, Harlamert EA, DeMaria AN. Quantitative assessment of mitral regurgitation by Doppler color flow imaging: angiographic and hemodynamic correlations. J Am Coll Cardiol 1989; 13: 585–590. 13 al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics 1999; 103: 1263–1271. 14 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress a clinical and electroencephalographic study. Arch Neurol 1976; 33: 696–705. 15 Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E et al. Moderate hypothermia to treat perinatal asphyxia encephalopathy. N Engl J Med 2009; 361: 1349–1358. 16 Bayley N. Bayley Scales of Infant Development. Harcourt, Brace & Co: San Antonio, 1993. 17 Ferrari F, Todeschini A, Guidotti I, Martinez-Biarge M, Roversi MF, Berardi A et al. General movements in full-term infants with perinatal asphyxia are related to basal ganglia and thalamic lesions. J Pediatr 2011; 158: 904–911. 18 Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86: 675–682. 19 Thoresen M, Liu X, Jary S, Brown E, Sabir H, Stone J et al. Lactate dehydrogenase in hypothermia-treated newborn infants with hypoxic ischaemic encephalopathy. Acta Paediatr 2012; 101: 1038–1044. 20 El-Khuffash A, Davis PG, Walsh K et al. Cardiac troponin T and N-terminal-pro-B type natriuretic peptide refl ect myocardial function in preterm infants. J Perinatol 2008; 28: 482–486. 21 Tu¨rker G, Babaog˘lu K, Duman C, Go¨kalp A, Zengin E, Arisoy AE. The effect of blood gas and Apgar score on cord blood cardiac troponin I. J Matern Fetal Neonatal Med 2004; 16: 315–319. 22 Tu¨rker G, Babaog˘lu K, Go¨kalp AS, Sarper N, Zengin E, Arisoy AE. Cord blood cardiac troponin I as an early predictor of short-term outcome in perinatal hypoxia. Biol Neonate 2004; 86: 131–137. 23 Karlsson M, Tooley JR, Satas S, Hobbs CE, Chakkarapani E, Stone J et al. Delayed hypothermia as selective head cooling or whole body cooling does not protect brain or body in newborn pig subjected to hypoxia-ischemia. Pediatr Res 2008; 64: 74–80. 24 Itskovitz J, LaGamma EF, Rudolph AM. Effects of cord compression on fetal blood flow distribution and O2 delivery. Am J Physiol 1987; 252: H100–H109. 25 El-Khuffash AF, Molloy EJ. Serum troponin in neonatal intensive care. Neonatology 2008; 94: 1–7. 26 Trevisanuto D, Picco G, Golin R, Doglioni N, Altinier S, Zaninotto M et al. Cardiac Troponin I in asphyxiated neonates. Biol Neonate 2006; 89: 190–193. 27 Shastri AT, Samarasekara S, Muniraman H, Clarke P. Cardiac troponin I concentrations in neonates with hypoxic-ischaemic encephalopathy. Acta Paediatr 2012; 101: 26–29. 28 Wei Y, Xu J, Xu T, Fan J, Tao S. Left ventricular systolic function of newborns with asphyxia evaluated by tissue Doppler imaging. Pediatr Cardiol 2009; 30: 741–746. 29 Mo¨ller JC, Thielsen B, Schaible TF, Reiss I, Kohl M, Welp T et al. Value of myocardial hypoxia markers (creatinine kinase and its MB-fraction, Troponin T, QT intervals) and serum creatinine for the retrospective diagnosis of perinatal asphyxia. Biol Neonate 1998; 73: 367–374.
Journal of Perinatology (2014), 292 – 295
