Intrauterine and neonatal period asphyxia; what can be hidden behind heart rhythm disturbances in asphyxiated newborns?
Heart starts to work at the end of the third week of gestational age. By its own activity heart can support and maintain the circulation in the fetal part of the placenta. The cardiovascular system in cooperation with other organ systems also supports the adaptation to extrauterine life. The consequences of asphyxia on the cardiovascular system can be manifested before or after delivery as rhythm disturbances, syndrome of myocardial dysfunction as well as transient myocardial ischemia with tricuspid insufficiency. (1-3)
Fetal rhythm disturbances comprise potentially life-threatening situations. Heart frequency of fetus is an indirect parameter of the fetal central nervous system activity, oxygenation status and acid balance. Basic fetal heart frequency is between 110-160 beats per minute. Normal variability is 5-10 beats per minute. One of the reversible reasons of intrauterine as well as postnatal paroxysmal tachycardia can be asphyxia and adnate infection. (4) In some cases clinical symptoms during unknown paroxysm of tachycardia during intrauterine development can overlap or amplify the symptoms of acute asphyxia. Most frequent is reentry tachycardia close to various forms of Wolf-Parkinson-White (WPW) syndrome. (5-10)
Reentry fetal and newborn tachycardia are categorized in one common group of tachycardias of various etiology, clinical signs and prognosis range. The basic characteristic of supraventricular paroxysmal tachycardia (SPT) is a presence of tachycardia with narrow QRS complex. An exact incidence is not known. SPT can originate from a defective impulse formation (focal mechanism), defective nervous impulse transfer (reentry mechanism) or the combination of both. According to the place of origin, reentry tachycardia can be divided into several groups. Sinus reentry tachycardia is formed when the pathological pathway is located in nodus sinuatrialis. If it is located in atrial myocardium, atrial flutter is formed. An impulse can circle in nodus atrioventricularis and cause atrioventricular nodal reentry tachycardia. Various forms of WPW syndrome are described (exact WPW syndrome, latent ventricular preexcitation, permanent junctional reciprocating tachycardia) in a presence of aberrant atrioventricular pathways in heart.
Bradycardia during the intrauterine development (less than 100 beats per minute during 1-2 seconds) reflects longstanding distress of the fetus, direct damage of the myocardium or systemic disease of the mother. (11) Postnatally, bradycardia is an indirect sign of overcome asphyxia (decreased heart frequency under 80 beats per minute). In the most severe cases a heart failure is confirmed. Fasting during first days of life can trigger disorder in [beta] oxidation of fatty acids--deficiency of carnitine palmitoyltransferase II. Congenital disease of the electrical conduction system of the heart or a congenital heart disease can also be a reason of intrauterine rhythm disturbances. (12)
Syndrome of myocardial dysfunction or syndrome of low systemic perfusion can be observed in both premature newborns and full term newborns. The involvement of myocardium leads to decreased contractility of the left ventricular muscle, increased end-diastolic pressure and acute decrease of cardiac output (systemic hypoperfusion). Decreased systemic perfusion leads to development of metabolic acidosis. Beside these changes insufficiency of both atrioventricular valves (tricuspid valve, mitral valve) may occur. This extent of insufficiency lies beneath cases of severe asphyxia.
Transient myocardial ischemia with the involvement of tricuspid valve may be clinically presented with asphyxia, and comprises potential damage of the papillary muscles of the heart. The result is the insufficiency of the valve. (3)
Syndrome of latent ventricular preexcitation in Wolf-Parkinson-White syndrome Patient 1
This case is a newborn with birth weight 3140 grams, child of first pregnancy. In the 35th week of gestation, the mother did not feel the movement activity of the fetus. Cardiotocography revealed the silent type of curve and ultrasonic investigation of fetus confirmed the diagnosis of ventricular fibrillation. The pregnancy was acutely interrupted at the 35th week of gestation by caesarian section. The Apgar score was 1/4/6. The newborn was resuscitated just after delivery. Because of damage in heart, lungs, liver and kidneys, the newborn was transported to our intensive care unit for observation. Mechanical ventilation was needed for eight days. Hibernation was indicated for 72 hours. At the age of eight days, paroxysms of tachycardia with a good response to adenosine occurred. Consequently, the patient was treated with an anti-arrhythmic drug (Rytmonorm). By the neurological assessment, a central muscle tonus disability was diagnosed, indicating a hypotonic syndrome.
The second patient was a child from the 2nd risk pregnancy. During regular gynecological control at the 31st week of gestation a rhythm disturbance (fibrillation) was detected. The mother was treated with digoxine, the heart frequency was transiently stabilized, but because of the development of fetal hydrops (induced by arrhythmia) the pregnancy was after 24 hours interrupted by caesarian section. The newborn after delivery was asphyxiated with concomitant signs of hydrops. The birth weight was 1880 grams and the value of Apgar score was 7/9. The patient had recurrent paroxysms of tachycardia with a good response to adenosine. At the age of four days of life the patient was admitted to our intensive care unit after exclusion of congenital heart disease with anti-arrhythmic therapy (rytmonorm, metoprolol). The patient needed twelve days of mechanical ventilation with maximal O2 concentration 0.4 and inotropic support (Dopamine). The newborn had clinical manifestations of hydrops, fluid accumulation in the thorax cavity (3 days of bilateral fluid drainage were needed), signs of acute renal insufficiency (urea 11.5 [micro]mol/l, creatinine 150 [micro]mol/l) and hypocoagulation (Quick 2.31, PTT not detected). The antiarrhythmic therapy was changed to digoxine and sotalol due to recurrent paroxysms of tachycardia and the status of patient was then stabilized. A normal status of central nervous system was observed using ultrasonic investigation. The aforementioned clinical picture was accompanied with central muscle disability--hypotonic syndrome. The patient was treated with nootropic drugs and mild rehabilitation treatment was started.
The third patient was the child from first pregnancy, which ended in spontaneous delivery at the 37th week of gestation, in head position and with a birth weight of 2760 grams. The postnatal adaptation was without complications. At the age of 13th days a shock occured, the child was pale, dyspneic and tachypneic. The patient was admitted with a suspicion of right-sided bronchopneumonia. At the time of admission the child was extremely hypothermic with irregular respiratory activity and mechanical ventilation was necessary. An extreme metabolic acidosis (pH 7.02, HCO3 9.5, BE -21.4) and hypoglycemia (1.3 mmol/l) were adjusted to physiological values. The status of the patient was slowly stabilized. The suspicion of septic shock was not confirmed while inflammatory parameters and results of microbiological analysis were negative. Echocardiography excluded the structural congenital heart disease. In the differential diagnosis we suspected a metabolic disease, which was finally negative. On the 20th days of life a paroxysm of tachycardia, with a good response to vagal maneuver (application of ice to the face), was observed. Later the patient was treated with Rytmonorm. The neurological examination and the ultrasonic findings of the central nervous system confirmed physiological findings.
The fourth patient was the child from the 1st pregnancy and delivery at full term by head position. The birth weight was 4650 grams and the value of Apgar score was 7/8. The child had many somatic stigmata, the most dominant on the 3rd day of life were convulsions on upper extremities. Ultrasonic investigation of the central nervous system showed multifocal hyperechogenic areas. The patient had inclination to tachycardia. A tumor behind the left atrium which was detected by echocardiography was not confirmed by the computer tomography. The patient was admitted to our intensive care unit on the 16th day of life because of convulsions and suspicion of metabolic disease. Four days after admission the patient had signs of SPT, with a good response to adenosine and rytmonorm. Neurological investigation confirmed a central muscle tonus disability--hypotonic syndrome, which gradually led to areflexia, fault of muscle perception and tonic convulsions. Ultrasonic investigation revealed multifocal brain damage characterized by brain tissue disintegration after severe hypoxic-ischemic encephalopathy. Deficiency of molybdenum cofactor was confirmed. (13)
The fifth patient was the child from the 6th risk pregnancy. At the 40th week of gestation paroxysmus of tachycardia were detected (240 beats per minute). The pregnancy was ended by an emergency caesarian section. The birth weight was 4050 grams, the amniotic fluid was green and the umbilical cord was wrapped around the newborn's neck. The value of Apgar score was 6/9/9. Many infarcts of the placenta were present. The ultrasonic investigation of the heart was negative. Laboratory findings confirmed elevated values of C-reactive protein and microbiological analysis of the tonsils were positive for Klebsiella and Pseudomonas aeruginosa. After antibiotic therapy the patient presented a good clinical response. Postnatal tachycardia was shortly treated using digoxine. (4)
The sixth patient was a child from the 1st pregnancy, which ended by caesarean section because of the detection of severe fetal bradycardia (50 beats per minute). The birth weight was 2300 grams and the value of Apgar score was 1/2. We confirmed congenital complete heart block. Laboratory results revealed positive antinuclear antibodies anti Ro (SSA) 133.6 (normal range less than 15), anti La (SS-B) with values of 38.5 (normal range less than 15) and ANA/IF (+++). During the first day of life a pacemaker was implanted. Complete investigation of the mother confirmed autoimmune systemic disease of connective tissue--Sjogren syndrome. (11)
The patient was the 1st term male newborn of unrelated parents of Caucasian origin, delivered spontaneously with birth weight 3450 grams, values of Apgar score 10/10, with good direct postnatal adaptation. On the 2nd day of life, after recurrent vomiting, bradycardia and severe asphyxia status was diagnosed induced by rhythm disturbances, cardiorespiratory insufficiency and circulatory failure. The final diagnosis, inherited metabolic disease (carnitine palmitoyltransferase type II deficiency) was based on the measurement of free carnitine in blood serum and of long-chain acylcarnitines by tandem mass spectrometry. The reduced activity of carnitine palmitoyltransferase II (CPT II) in leucocytes was confirmed. (12)
Fetal and newborn reentry tachycardia belongs to life threatening situations. Development of new examination approaches and strategies of prenatal and postnatal treatment improved neonatal survival and overall prognosis in cases of rhythm disturbances. The therapy of a such a patient in emergency depends on the gestational age, the status of mother, but mainly on the severity of the fetal status. Treatment can be pharmacological (transfer of drug through placenta, direct admission to fetus), non-pharmacological (interruption of pregnancy) or observational. (6-8)
Termination of the pregnancy is indicated in a premature fetus with signs of hydrops. Pregnancy is terminated also in a case of failure to detect the movement activity of the fetus or accelerated diastolic dysfunction with unsuccessful treatment. (9) In the present case series, which was partially presented in 2006 by our team with four patients only and with preliminary data (10), the pregnancy was interrupted prematurely by caesarean section; the emergency status of the fetus(patient 1) and the unsuccessful therapy of fetal tachycardia (patient 2) made us to decide the pregnancy interruption. In the first case, we were unable to exactly determine the extent of the asphyxia caused by tachycardia and the development of atrophic hydrocephalus. In the second case the pregnancy was interrupted because of hydrops diagnosis; consequently, complete management was unable to avoid a damage of nervous tissue. In the cases of the patient 3 and 4, with postnatal manifestations of asphyxia paroxysms (with hydrops/without hydrops) the early establishment of diagnosis, the continuing monitoring and tailored treatment was crucial. Trigger mechanism for the patient 3 was the metabolic disbalance. The reason of paroxysm of tachycardia in the patient 4 was the neurodegenerative disease and the deficit of molybdenum cofactor. The termination of pregnancy is the method of choice in full term newborns with paroxysms of tachycardia since the maturity of the lung parenchyma allows the initiation of the operation depending on the fetal condition. (5)
Autoimmune systemic disease of connective tissue of the mother has a negative influence on the development of the fetus and newborn. In most severe cases an irreversible congenital atrioventricular block of 3rd degree is manifested due to influence of transplacental antibodies IgG which damage the cells of the electrical conduction system of the heart. Confirmation of the diagnosis needs teamwork among specialists and long-term follow up. Prognosis depends on the underlying disease however in many cases there is a poor outcome.
Not all metabolic diseases are joined with rhythm disturbances. (14) In the case of mitochondrial dysfunction there are some typical clinical and laboratory findings. Mitochondrial fatty acid oxidation constitutes the main energy supply for liver, heart, and skeletal muscle in situations that require mobilization of endogenous glucose, such as fasting, prolonged exercise, and in early neonatal period. (12,15) The movement of long chain fatty acids into mitochondria requires the use of a specific carnitine transport system referred to as carnitine palmitoyltransferase (CPT). CPT system consists of three enzymes located in the outer (carnitine palmitoyltransferase I) and in the inner (translocase and carnitine palmitoyltransferase II, CPT II) mitochondrial membranes. Deficiency of CPT II is the most common autosomal recessive disorder of mitochondrial beta-oxidation of long chain fatty acids. Deficiency of CPT II has a fascinating phenotypic variability. The clinical manifestation of CPT II deficiency has three forms (neonatal form, early onset/infantile form, late onset/ adult muscular form).
In our case report (patient 7) we analysed clinical and laboratory findings in a full term newborn with bradycardia on the second day of life after recurrent vomiting. Bradycardia was followed by severe asphyxia due to dysrhythmia. Afterwards the cardio-respiratory insufficiency with circulatory failure was observed and prolonged resuscitation was performed, reaching the three hours. (12)
Fetal asphyxia can be often a consequence of a severe arrhythmia, but also the asphyxia alone could be a trigger of SPT. The next cause of SPT could be the metabolic disbalance. Damage of the electrical conduction system of the heart in case of neurodegenerative disease like deficiency of molybdenum cofactor, is due to the accumulation of toxic sulfite. In these cases therapy is controversial and prognosis is very poor.
Molybdenum is essential for the function of xanthine dehydrogenase, sulfite oxidase and aldehyde oxidase. Molybdenum cofactor deficiency with the sequential accumulation of toxic sulfite in brain and in heart produces the convulsions refractive to therapy and reentry tachycardia. (16)
Cardiac problems in neonatal form of CPT II deficiency are not detectable during the prenatal period even if it is a kind of congenital metabolic disease. The neonatal form of CPT II deficiency is the most severe form and is considered invariably fatal. Fasting in the early newborn period is a main trigger of CPT II deficiency manifestations. Investigation of acylcarnitine profiles and free carnitine in the serum in all cases of severe postnatal asphyxia and in cases of unusual newborn arrhythmias is useful, because some forms of disturbances in [beta] oxidation of fatty acids are partially treatable.
Hopefully, in the future we will be able to apply knowledge achieved from animal experimentation and extrapolate findings into new treatment strategies or protect patients against accumulation of toxic substrates using specific therapy as it is used in cardiovascular surgery. (17-21)
Clinical manifestations in a case of unknown paroxysm of tachycardia during intrauterine development can cause or accompany the signs of acute asphyxia. Differential diagnosis in newborn age is necessary to exclude severe sepsis, metabolic disbalance, metabolic disease and heart failure in structural congenital heart disease.
This work was supported by the grant VEGA 2/0083/08.
CPT II--carnitine palmitoyltransferase II
SPT--supraventricular paroxysmal tachycardia
Conflict of interest: None declared.
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Address correspondence to: Assoc. Prof. Ingrid Brucknerova, MD, PhD, 1st Department of Pediatrics, Medical School, Comenius University, Limbova 1,833 40 Bratislava, Slovakia E-mail: firstname.lastname@example.org
1st Department of Pediatrics, Medical School, Comenius University, Bratislava, Slovakia
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|Title Annotation:||CASE SERIES|
|Publication:||Archives: The International Journal of Medicine|
|Date:||Apr 1, 2009|
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