Fernando Cabañas

Dopamine Versus Epinephrine for Cardiovascular Support in Low Birth Weight Infants: Analysis of Systemic Effects and Neonatal Clinical Outcomes

BACKGROUND. Early postnatal adaptation to transitional circulation in low birth weight infants frequently is associated with low blood pressure and decreased blood flow to organs. Catecholamines have been used widely as treatment, despite remarkably little empirical evidence on the effects of vasopressor/inotropic support on circulation and on clinically important outcomes in sick newborn infants. AIMS. To explore the effectiveness of low/moderate-dose dopamine and epinephrine in the treatment of early systemic hypotension in low birth weight infants, evaluate the frequency of adverse drug effects, and examine neonatal clinical outcomes of patients in relation to treatment. DESIGN/METHODS. Newborns of <1501-g birth weight or <32 weeks of gestational age, with a mean blood pressure lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (2.5, 5, 7.5, and 10 μg/kg per minute; n = 28) or epinephrine (0.125, 0.250, 0.375, and 0.5 μg/kg per minute; n = 32) at doses that were increased stepwise every 20 minutes until optimal mean blood pressure was attained and maintained (responders). If this treatment was unsuccessful (nonresponders), sequential rescue therapy was started, consisting first of the addition of the second study drug and then hydrocortisone. OUTCOME MEASURES. These included: (1) short-term changes (first 96 hours, only responders) in heart rate, mean blood pressure, acid-base status, lactate, glycemia, urine output, and fluid-carbohydrate debit; and (2) medium-term morbidity, enteral nutrition tolerance, gastrointestinal complications, severity of lung disease, patent ductus arteriosus, cerebral ultrasound diagnoses, retinopathy of prematurity, and mortality. RESULTS. Patients enrolled in this trial did not differ in birth weight or gestational age (1008 ± 286 g and 28.3 ± 2.3 weeks in the dopamine group; 944 ± 281 g and 27.7 ± 2.4 weeks in the epinephrine group). Other main antenatal variables were also comparable. However, responders and nonresponders differed significantly with respect to the need for cardiorespiratory resuscitation at birth (3% vs 23%), Critical Risk Index for Babies score (3.8 ± 3 vs 7 ± 5), and premature rupture of membranes >24 hours (39.5% vs 13.6%), respectively. No differences were found in the rate of treatment failure (dopamine: 36%; epinephrine: 37%) or need for rescue therapy according to treatment allocation. Groups did not differ in age at initiation of therapy (dopamine: 5.3 ± 3.9 hours; epinephrine: 5.2 ± 3.3 hours), but withdrawal was significantly later in the dopamine group. For short-term changes, mean blood pressure showed a significant increase from baseline throughout the first 96 hours with no differences between groups. However, epinephrine produced a greater increase in heart rate than dopamine. After treatment began, epinephrine patients showed higher plasma lactate (first 36 hours) and lower bicarbonate and base excess (first 6 hours) and received more bicarbonate. Patients in the epinephrine group also had higher glycemia (first 24 hours) and needed insulin therapy more often. Groups did not differ in urine output or fluid-carbohydrate supply during the first 96 hours. For medium-term morbidity, there were no differences in neonatal clinical outcomes in responders. However, significant differences were found in the incidence of patent ductus arteriosus, bronchopulmonary dysplasia, need for high-frequency ventilation, occurrence of necrotizing enterocolitis, and death between responders and nonresponders. CONCLUSIONS. Low/moderate-dose epinephrine is as effective as low/moderate-dose dopamine for the treatment of hypotension in low birth weight infants, although it is associated with more transitory adverse effects.

Early Systemic Hypotension and Vasopressor Support in Low Birth Weight Infants: Impact on Neurodevelopment

BACKGROUND. The duration and severity of systemic hypotension have been related with altered neurodevelopment. Cerebral circulation is pressure-passive in low birth weight infants with early systemic hypotension who receive cardiovascular support. The treatment of early systemic hypotension is controversial, because it has been associated with short-term and long-term morbidity in retrospective studies. However, there has been no prospective information on cardiovascular support for hypotension and morbidity. OBJECTIVE. Our goal for this prospective study was to evaluate the effect on neurodevelopment resulting from the use of vasopressors/inotropes for early systemic hypotension. METHODS. Low birth weight infants with early systemic hypotension (<24 hours of life; study group) were assigned randomly to receive dopamine (2.5–10 μg/kg per minute) or epinephrine (0.125–0.5 μg/kg per minute) in progressively larger doses until target blood pressure was attained (treatment-success subgroup). Hemodynamically stable patients who did not receive cardiovascular support were the control group. Outcome measures were serial cranial ultrasound up to 40 weeks, structured neurologic evaluation (every 3 months), and neurodevelopmental test at 2 to 3 years of age. RESULTS. One hundred thirty patients were included (study = 60; treatment success = 38; controls = 70). Study-group patients had lower birth weight, gestational age, and 5-minute Apgar score, higher rates of premature rupture of membranes, need for cardiorespiratory resuscitation at birth, and sickness shortly after birth than the control group. The patients in the study group also had significantly higher serum troponin I levels at birth. Initial cranial ultrasound findings did not differ between groups, but the final cranial ultrasounds revealed higher rates of severe periventricular hemorrhage in the study group and higher rates of normal cranial ultrasounds in the control group. Only the latter remained when the treatment-success subgroup and control group were compared. Multivariate analysis did not detect any association between final cranial ultrasounds and the use of vasopressors/inotropes. Sixteen infants died and 103 were followed up (90% survival rate). No differences between groups were found in the rates of abnormal neurologic status, developmental delay, or combined adverse outcome (death or cerebral palsy or severe neurodevelopmental delay). CONCLUSIONS. Cautious use of cardiovascular support to treat early systemic hypotension in low birth weight infants seems to be safe. The question of whether raising systemic blood pressure to within a normal range will improve outcome should be examined by using appropriate study designs.

Central nervous system vasculopathy in neonatal lupus erythematosus

Central nervous system involvement in neonatal lupus erythematosus (NLE) has not been previously reported. We report four patients with NLE, all with complete congenital heart block and three with cerebral ultrasound and color Doppler flow imaging (CDFI) studies demonstrating evidence of associated vasculopathy in the gangliothalamic vasculature. CDFI confirmed blood flow through the affected vessels, indicating that blood flow was not compromised at this early stage. Short-term follow-up revealed no signs of progression of the vasculopathy, focal ischemia, gangliothalamic atrophy, or neurological impairment. Nevertheless, the implications of this finding with respect to the natural history of NLE remain to be defined, particularly in cases in which the disease develops into systemic lupus erythematosus later in life. Besides specific diagnostic studies for NLE, cerebral ultrasound, and CDFI studies are mandatory in all cases of complete congenital heart block, regardless of whether mothers are diagnosed as having connective-tissue disease or not. Neonates with signs of vasculopathy in the gangliothalamic region should be examined for NLE.

Stroke in neonates with cardiac right-to-left shunt

Neonatal focal cerebral arterial infarction has been rarely reported in the literature, in contrast to the watershed infarctions, which are common entities among asphyxiated infants. In neonatal postmortem series, thromboembolism was the commonest cause of cerebral arterial occlusion; the source of emboli was associated to different risk factors. Our four cases are the first alive patients reported with congenital heart disease and right-to-left shunt, who suffered a cerebral infarct with its clinical neurological correlates in the neonatal period. We assume that the most probable mechanism was paradoxical embolism, once pulmonary filter is obviated as a result of the altered hemodynamics in these patients. Our data demonstrate the value of ultrasound scanning for assessment of focal cerebral ischemic lesions. Thus, although abnormal neurological signs in this particular group of infants could be attributed to hypoxemia or specific treatments as prostaglandins, we suggest routine cerebral ultrasounds in neonates with congenital heart disease and neurological disabilities, as early complications could be not so infrequent.

New pattern of hyperechogenicity in thalamus and basal ganglia studied by color Doppler flow imaging

Thirty-seven infants whose cerebral real-time B-mode ultrasound (CUS) documented hyperechogenic areas in the thalamus and basal ganglia (HTBG) either of linear or fine punctate pattern, were studied prospectively by color Doppler imaging (CDI). This study aimed to establish a relationship between these areas and the regional vasculature, to analyze associated disorders to establish pathogenesis, and to determine clinical significance. HTBG were diagnosed in the first 4 days of life in all but 7 infants. Different patterns of HTBG were observed: punctate in 11 infants, linear in 12, and mixed in 14. The basal ganglia were affected in all patients, 9 also had involvement of the thalamus. CDI confirmed that HTBG were allocated along the gangliothalamic vessels. Blood flow velocity waves were obtained at this level in all patients. Real-time spectral analyses were performed in 35 patients and compared with a control group of 20 healthy neonates. Differences were not significant. Computed tomography and magnetic resonance imaging failed to indicate this abnormality. Necropsy revealed basophilic deposits in the walls of involved arteries. Congenital infections manifested in 5 patients, chromosomal abnormality in 1, dysmorphic syndromes in 9 (3 unidentified), isolated congenital defects in 5, and diverse congenital disorders in 3. In the remaining 14, no congenital disorders nor infections were found. This CDI study demonstrates the vascular location of these HTBG. Supported by early CUS diagnosis, it is speculated that vascular injury in that region has a prenatal origin. This abnormality does not appear to alter regional blood flow. HTBG are associated with very heterogeneous disorders and in most patients the etiology and pathogenesis remain unclear.

Postnatal adaptation of brain circulation in preterm infants.

Global and regional postnatal cerebral circulatory changes in stable preterm infants were studied, and their relation to brain injury was assessed. Thirty-five preterm infants were studied on the first and second days of age. Cerebral blood flow (CBF) (mL/hg per min) and cerebral blood volume (CBV) (mL/hg) were measured using near-infrared spectroscopy. The cerebral blood flow velocity (cm/second) (peak systolic, diastolic flow, mean flow) and resistance index (RI) were determined in the internal carotid, anterior cerebral, and striate arteries by color Doppler flow imaging. Serial cerebral ultrasound studies were performed to detect changes in brain parenchymal echogenicity or intraventricular hemorrhage (IVH); the maximum severity of these findings was considered. CBF and cerebral blood flow velocity increased significantly with time, and such changes were independent of mean blood pressure, PO(2), PCO(2), hematocrit, or glycemia. In contrast, CBV and RI remained unchanged. According to the results of sonograms, no differences were found in postnatal CBF and cerebral blood flow velocity changes, regardless of whether patients had or did not have parenchymal lesions or IVH. However, higher CBV values were found on the second day in infants with IVH compared with infants without IVH. Early coupling of CBF and metabolic demands is independent of blood pressure. Improved venous return, instead of vasodilation, could be important in this adaptation.

Cerebral abnormalities in congenital myotonic dystrophy

The brain structure of 14 infants born with congenital myotonic dystrophy at 2 hospitals was evaluated by cranial ultrasonography, and the findings were correlated with clinical and neuropathologic data. Ventricular dilation was diagnosed in 11 infants (78%). Seven infants died during the neonatal period; all had ventricular dilation which remained essentially static. In the ultrasound scans of the 5 infants with ventricular dilation. Of the 7 survivors, 4 had ventricular dilation born at 1 hospital, 4 had widening of the interhemispheric fissure. Macrocephaly, a previously unrecognized finding in congenital myotonic dystrophy, was present in 10 infants (71%), 8 of whom presented with ventricular dilation. None had clinical evidence of increased intracranial pressure. There was no ventricular obstruction in the 4 brains examined pathologically. Histologic examination revealed minor expression of neuronal migrational disturbances in each patient. Macrocephaly together with the ultrasonographic and neuropathologic findings in our patients suggest that these abnormalities may originate in an external hydrocephalus.

Ultrasonographic findings in thalamus and basal ganglia in term asphyxiated infants

Three severely asphyxiated term neonates demonstrated bilateral hyperechogenicity in the thalamus and basal ganglia. During evolution, areas of attenuated echogenicity appeared in these structures at the same time as periventricular cysts were evident in 2 patients with coexistent periventricular leukomalacia. All 3 patients developed ventricular dilatation; in the 2 patients with periventricular leukomalacia, the ventricular border was irregular in the outer (dorsal) margin, and interhemispheric fissures were widened as a manifestation of cerebral atrophy. Furthermore, the thalamic inner (ventral) margins of the lateral ventricles were irregular in all 3 patients. This previously unrecognized finding points to a particular form of cerebral atrophy localized in the gangliothalamic region that contributes to the development of ventriculomegaly. The reported sonographic sequence implies profound damage in the thalamus and basal ganglia in asphyxiated infants which undoubtedly has contributed to the poor outcomes of our patients.

Neural migration disorders studied by cerebral ultrasound and colour Doppler flow imaging.

Cerebral ultrasound and colour Doppler flow imaging (CDFI) were used to diagnose a wide spectrum of anomalies of cell migration (17 patients): presumed lissencephaly (n = 12); schizencephaly of both fused (n = 2) and open lips (n = 2); hemimegalencephaly (n = 1); and subependymal type grey matter heterotopia (n = 12). The patients with grey matter heterotopia had irregular ventricular margins (n = 10), periventricular hyperechogenic bands (n = 12), and/or periventricular hyperechogenic nodules (n = 7). Some patients had more than one type of migration disorder as well as other central nervous system malformations. Cerebral ultrasound diagnoses were confirmed by magnetic resonance imaging (MRI) or necropsy. It is concluded that colour Doppler flow imaging is a worthwhile addition to the assessment of brain surface anomalies.

Natural history of ventricular dilatation in preterm infants: prognostic significance

Cerebral ultrasounds were prospectively performed in 100 infants weighing 1,500 gm or less in order to evaluate the prognostic significance of ventricular dilatations and their associated findings. There was no difference in the incidence of ventricular dilatation (24%) between patients with or without periventricular hemorrhage (PVH). Although patients with PVH developed ventricular dilatation significantly earlier than infants without PVH, no differences were observed in severity, location, head circumference growth, or intracranial pressure between the groups. Ventricular dilatation was statistically related to PVH grade III and PVH with parenchymal involvement; grades moderate-to-severe of periventricular echogenicity; and cystic periventricular leukomalacia (PVL). Ventricular dilatation persisted longer than 6 weeks in 61% of infants and had irregular margins in 62%. The latter were significantly related to cystic PVL. Seventy-seven of 100 infants examined were followed until 20 months corrected age. Ventricular dilatation mainly when persistent and with irregular margins was associated with handicaps. We conclude that ventricular dilatation is frequent in very low-birth weight infants. Furthermore, its occurrence may be independent of PVH. Persistent ventricular dilatation with irregular margins, even in its mild forms, suggests a parenchymal lesion and guarded prognosis.