Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome

Kelen, D; Andorka, Csilla; Szabó, Miklós; Alafuzoff, Aleksander; Kaila, Kai; Summanen, Milla

doi:10.1371/journal.pone.0184593

Cited by 29 publications

(29 citation statements)

References 29 publications

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“…Thus, the various actions of AVP, including the adaptive ones described in the Introduction, do not end abruptly after the asphyxic insult. Moreover, it is important to note that the post-asphyxia levels of copeptin seen in the present model are analogous to those measured in neonatal blood samples after birth (Kelen et al, 2017 ). In our previous work on copeptin as a diagnostic and prognostic biomarker of HIE, the median copeptin concentration 1 week after birth in infants diagnosed with HIE was 17.8 pmol/l (Kelen et al, 2017 ), which is still above the normal range for healthy volunteers (Struck et al, 2005 ; Morgenthaler et al, 2006 ).…”

Section: Discussionsupporting

confidence: 81%

Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

Summanen

Bäck

Voipio

et al. 2018

Front. Cell. Neurosci.

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Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding −11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia.

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Section: Discussionsupporting

confidence: 81%

Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

Summanen

Bäck

Voipio

et al. 2018

Front. Cell. Neurosci.

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“…Notably, both asphyxia protocols led to changes in blood gas parameters which fulfill the main diagnostic criteria of human BA: an acidemia with a decrease in pH below 7.0, coupled to a fall in base excess by 20 mmol/l and elevation of lactate by about 10 mmol/l. The massive release of copeptin (a stable fragment of prepro-AVP) to blood, which is triggered by the hypoxia component of asphyxia (Summanen et al, 2018), provides further support for the validity of our present model (Kelen et al, 2017;Schlapbach et al, 2011).…”

Section: Post-asphyxia Seizure Generation Depends On the Rate Of Ph Rsupporting

confidence: 72%

“…1C). In addition, the levels of plasma copeptin, a relevant biomarker of asphyxia (Kelen et al, 2017;Schlapbach et al, 2011), were highly elevated by the end of both asphyxia protocols (4.41 [1. 64 -11.15] nM and 6.32 [4.48 -7.74] nM for steady and intermittent, respectively vs. 0.22 [0.1 -2.5] nM in the control group; Fig 1D).…”

Section: Changes In Blood Ph Base Excess and Lactate And Plasma Copementioning

confidence: 99%

“…As shown here, the present model fulfills the main diagnostic criteria of BA in terms of blood acid-base parameters (American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2014). Moreover, a large release of copeptin, which is a stable fragment of pre-proAVP and a tell-tale blood biomarker of BA (Kelen et al, 2017;Schlapbach et al, 2011; see also Wellmann et al, 2010), was seen in response to asphyxia. In sharp contrast to all BA models based on hypoxia only, seizures were never observed during the profound brain hypoxia which takes place during exposure to asphyxia with 5 % O 2 .…”

Section: Introductionmentioning

confidence: 99%

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A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Ala-Kurikka

Pospelov

Summanen

et al. 2020

Preprint

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Birth asphyxia (BA) is a pathologic condition that arises from severe perinatal hypoxia and hypercapnia.Recovery following BA is often associated with seizures which may exacerbate the ensuing hypoxicischemic encephalopathy (HIE). Drugs used to treat post-BA seizures are often ineffective and there are concerns over their safety. Therefore, novel seizure-suppressing therapies are urgently needed. Most rodent models of BA-induced seizures are based on exposing neonatal rats or mice to hypoxia (or hypoxiaischemia), and overlook the fact that the hypercapnic acidosis linked to asphyxia has brain-sparing effects by suppressing neuronal excitability and enhancing cerebral blood flow. Thus, the aim of the present study was to investigate the dependence of asphyxia-induced seizures on brain pH and oxygen (Po 2 ) levels in a rodent model of term BA based on postnatal day 11-12 rat pups. Cortical activity and electrographic seizures were recorded in freely-behaving animals using epidural electrodes. Simultaneous measurements of cortical local field potentials as well as intracortical pH and Po 2 were made using microelectrodes and microsensors in urethane-anesthesized animals. The pups were exposed either to steady asphyxia (duration 15 min; with ambient air containing 5 % O 2 plus 20 % CO 2 ) or to intermittent asphyxia (30 min; with repetitive 5 min steps from 9 % to 5 % O 2 at constant 20 % CO 2 ). Both protocols led to acidemia (blood pH <7.0) coupled to a fall in base excess by 20 mmol/l, and to a large increase in plasma copeptin (from 0.2 nM to about 5 nM), a biomarker of BA. Brain pH decreased from 7.3 to 6.7 by the end of intermittent asphyxia.Brain Po 2 was only transiently affected by 9% ambient O 2 , but it fell below the level of detection with steps to 5 % O 2 , during which neuronal activity was near-abolished. The Po 2 steps to 9% were associated with a moderate increase in pH (0.12 units) and a slight recovery (~10 % of baseline) in ongoing neuronal activity.Behavioral seizures spanning the entire Racine scale were triggered after intermittent but not steady asphyxia, and they were tightly associated with neocortical electrographic seizures. The seizures were strongly suppressed when the post-asphyxia brain pH recovery was slowed down by a low level (5 %) of ambient CO 2 . The post-asphyxia overshoot in brain Po 2 (from 30 to 85 mmHg) had no discernible effect on neuronal activity. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures once the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one where, consistent with the clinical picture of BA, robust behavioral and electrographic seizures are triggered after and not during the asphyxic insult. HIGHLIGHTS Experimental asphyxia induced severe acidemia and abolished most cortical activity. Cortical activity during asphyxia was closely linked with changes in brai...

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“…It is synthesized within 5-20 minutes after the development of acute myocardial damage and remains stable for several days [10]. There is evidence of the use of copeptin as a marker of the development of various pathological conditions in newborns [11][12][13][14], but its role in the prediction of neonatal arrhythmias in newborns together with troponin I has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Prognosis of Individual Risk of Heart Rhythm Disturbances and Conductivity in Newborns in the Early Neonatal Period

Гончарь¹,

Ivanova²,

Кондратова³

et al. 2020

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Background. In the majority of cases neonatal arrhythmias have a good prognosis for recovery. However, they can also have an adverse course and lead to development of lifethreatening conditions. Therefore, it is important to search for earlier markers of myocardial lesion, diagnostic criteria and predictors of arrhythmias. Purpose. Improvement of diagnosis and prediction of the risk of cardiac arrhythmias and conduction in newborns in the early neonatal period by identifying factors that play a role in the prediction of neonatal arrhythmias. Subjects and Methods. The study involved 76 newborns. Group 1 included 57 infants with arrhythmias according to Holter monitoring, Group 2 included 19 infants without arrhythmias. The history data, laboratory and instrumental findings, levels of troponin I and copeptin were compared. To predict development of neonatal arrhythmias, logistic regression analysis was performed. The quality of the model was tested using the Percent Concordant (PC). Quality Score was evaluated by R2 Nigelkerke. Model adequacy was estimated using the Hosmer-Lemeshow test. Results. The study showed that the factors that can influence development of arrhythmias in the early neonatal period are the level of umbilical cord blood, the levels of troponin I, copeptin, GGT, assessment of Apgar scale in the 1 st and 5 th minutes, asphyxia at birth, indices of wave R amplitude in V3 and V5 of chest leads, ST segment deviation from the isoline according to standard surface ECG, QTc levels and mean daily maximum, minimum heart rate according to Holter monitoring. Conclusions. Predictors of neonatal arrhythmias development are indicators of laboratory-instrumental parameters of cardiovascular system status, troponin I level above 0.29 ng/ml and copeptin level above 0.1 ng/ml.

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Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome

Cited by 29 publications

References 29 publications

Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Prognosis of Individual Risk of Heart Rhythm Disturbances and Conductivity in Newborns in the Early Neonatal Period

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