Published online June 1, 2005
PEDIATRICS Vol. 115 No. 6 June 2005, pp. 1501-1512 (doi:10.1542/peds.2004-1396)
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Cardiovascular Support for Low Birth Weight Infants and Cerebral Hemodynamics: A Randomized, Blinded, Clinical Trial

Adelina Pellicer, MD*, Eva Valverde, MD*, María Dolores Elorza, MD*, Rosario Madero, MD{ddagger}, Francisco Gayá, EE{ddagger}, José Quero, MD, PhD* and Fernando Cabañas, MD, PhD*

* Department of Neonatology
{ddagger} Biostatistics Unit, La Paz University Hospital, Madrid, Spain


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. Maintaining adequate organ blood flow is the target of vasopressor treatment, but the impact of these measures on cerebral perfusion has not yet been evaluated systematically in a randomized, blinded, clinical trial.

Objectives. To explore the effects on brain hemodynamics of 2 different inotropic agents used to treat systemic hypotension among low birth weight (LBW) infants.

Design and Methods. Newborns of <1501 g birth weight or <32 weeks' gestational age, with a mean blood pressure (MBP) lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (DP) (2.5, 5, 7.5, or 10 µg/kg per minute; n = 28) or epinephrine (EP) (0.125, 0.250, 0.375, or 0.5 µg/kg per minute; n = 32), at doses that were increased in a stepwise manner every 20 minutes until the optimal MBP (MBP-OP) was attained and maintained.

Outcome Measures. Continuous monitoring of quantitative changes in cerebral concentrations of oxyhemoglobin and deoxyhemoglobin, cerebral intravascular oxygenation (HbD) (the difference between oxyhemoglobin and deoxyhemoglobin), and cerebral blood volume (CBV) were assessed with near-infrared spectroscopy. MBP, heart rate, transcutaneous PCO2 and PO2, and peripheral oxygen saturation were recorded continuously and analyzed at baseline, 20 minutes after each dose increase (T1, T2, T3, and T4) until MBP-OP was reached, and then every 20 minutes up to 1 hour of stable MBP-OP.

Results. Fifty-nine infants were considered for analysis. Patients did not differ in birth weight or gestational age (1008 ± 286 g and 28.3 ± 2.3 weeks, respectively, in the DP group and 944 ± 281 g and 27.7 ± 2.4 weeks in the EP group). Studies were performed at a mean age of 5.3 ± 3.7 hours of life (range: 2–16 hours). MBP-OP was attained for 96.3% of patients with DP and 93.7% with EP (responders). For those patients, MBP, heart rate, CBV, and HbD increased from baseline throughout the study period, with no differences between groups except for a higher heart rate with EP. Changes in MBP were correlated significantly with changes in HbD. Dose escalation of drugs produced no differences between groups in the behavior of the variables, except for a greater heart rate with EP from 20 minutes after dose 2 (T2) onward. Drug-induced changes in cerebral hemodynamics varied with gestational age; the EP-induced increase in CBV was greater among less mature patients (<28 weeks), whereas the DP-induced increase in CBV was greater among patients of ≥28 weeks.

Conclusions. Among hypotensive LBW infants, cardiovascular support with low/moderate-dose DP or low-dose EP increased cerebral perfusion, as indicated by the increase in both CBV and HbD. Low-dose EP was as effective as low/moderate-dose DP in increasing MBP among LBW infants.

Key Words: near-infrared spectroscopy • hypotension • cerebral hemodynamics • dopamine • epinephrine • low birth weight infants

Abbreviations: LBW, low birth weight • MBP, mean arterial blood pressure • MBP-OP, optimal mean arterial blood pressure • O2Hb, oxyhemoglobin • RHb, deoxyhemoglobin • THb, total hemoglobin • HbD, cerebral intravascular oxygenation • CBV, cerebral blood volume • DP, dopamine • EP, epinephrine • NIRS, near-infrared spectroscopy • 60-OP, 1 hour of stable optimal mean arterial blood pressure • IVH, intraventricular hemorrhage

The normal range of physiologic blood pressure among low birth weight (LBW) infants is still a matter of debate. Although the lack of consensus regarding the definition of hypotension among premature infants may result in marked differences in the threshold for treatment, most clinicians base the decision to provide cardiovascular support on empirical blood pressure standards.1–4 These blood pressure limits depend on gestational and postnatal age, with the lower limits of mean blood pressure during the first 24 hours of life being similar to the infant's gestational age.

The rationale for treating systemic hypotension among LBW infants is to maintain adequate organ perfusion. Several studies showed an association between hypotension and adverse neurologic outcomes.5–8 Alterations in cerebral blood flow patterns could be the link between cardiovascular instability and the development of hemorrhagic and ischemic brain injury among sick preterm infants.9–13

Dopamine (DP) is the inotropic agent most often used to treat hemodynamic instability among LBW infants, because it has been found to be superior in improving blood pressure.14–17 However, some studies have suggested that DP exerts its effect on blood pressure by increasing systemic vascular resistance,14,18 which would be counterproductive for the myocardium. Alternative strategies, such as low-dose epinephrine (EP), were shown to increase cardiac contractility and blood pressure and to decrease systemic and pulmonary vascular resistance in acutely instrumented, anesthetized piglets, probably because of a predominant ß-effect.19 Studies on regional blood flow reported no vasoconstriction of the renal20,21 and mesenteric21 circulation when low-dose EP was used in a neonatal pig model. These effects seem to be reproducible among sick newborn infants.22,23

Whatever drug is selected, ensuring stable, appropriate, cerebral blood flow should be one of the aims of treatment. Although it is still uncertain whether its major determinant is blood pressure or cardiac output, emerging evidence suggests that cerebral blood flow and oxygenation depend on systemic blood pressure among sick preterm infants.13 However, empirical research on the effects of vasopressor treatment of LBW infants on cerebral tissue perfusion has not been conducted systematically in randomized, blinded, controlled trials.

Therefore, we designed a study to explore the effects on brain hemodynamics of 2 different inotropic agents, DP and EP, used to treat systemic hypotension among LBW infants. We tested the hypothesis of the equivalence of low/moderate-dose DP and low-dose EP in increasing blood pressure, cerebral perfusion, and tissue oxygenation among hypotensive preterm infants.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design
The study was conducted at the La Paz University Hospital NICU between June 2002 and November 2003. Infants <24 hours of age with a birth weight of <1501 g and/or a gestational age of <32 weeks were eligible for study. Informed consent was obtained shortly after birth, at the time of admission. Infants were enrolled in the trial if they developed arterial systemic hypotension, defined as mean arterial blood pressure (MBP) lower than the infant's gestational age, that persisted at least 60 minutes at any time in the first day of life. Exclusion criteria were life-threatening congenital defects, congenital hydrops, frank hypovolemia (perinatal history consistent with decreased circulating blood volume plus clinical signs of hypovolemia), or other unresolved causes of hypotension (air leaks, lung overdistention, or metabolic abnormalities). The study was approved by the Ethics Committee for Human Studies at the La Paz University Hospital and the Spanish Drug Agency at the National Ministry of Health.

Cerebral Hemodynamic Monitoring
Changes in cerebral hemodynamics were assessed with near-infrared spectroscopy (NIRS). The technique is based on continuous spectrophotometric measurement of oxygen-dependent changes in the absorption properties of hemoglobin in the near-infrared range.24 With a modification of the Beer-Lambert law, changes in hemoglobin concentrations can be calculated from changes in light absorption.25,26 The sum of the changes in oxyhemoglobin (O2Hb) and deoxyhemoglobin (RHb) indicate the changes in total hemoglobin (THb) concentrations.

The NIRS equipment used was the commercial prototype Critikon cerebral redox monitor, with a sensor head containing a photodiode separated 3.5 cm from a light detector. The sensor is connected to the monitor through an electro-optic cable that contains electrical wires and a flexible fiber-optic core consisting of a bundle of individual glass fibers. Light pulses from a laser in the monitor are transmitted through the fiber bundle to the sensor head (emission window). Light pulses emerging from the tissue are detected by a single photodiode housed in the sensor head. The signals from the sensor head are carried to the monitor by a shielded pair of electrical cores within the electro-optic cable. The laser diodes produce sequential pulses of monochromatic light, maintaining precise spectral performance at 4 factory-calibrated wavelengths. A detailed description of the equipment can be found elsewhere.27,28 Changes in O2Hb and RHb concentrations were calculated from changes in light absorption at each of these wavelengths and are given in micromolar units. A fixed path-length factor of 4.4 was used to correct the path length of the light for the degree of scattering in brain tissue.29 The sensor was placed on the midline of the infant's forehead and attached firmly to the head with stretch bandages for all patients, to prevent displacement.

Changes in cerebral blood volume (CBV) can be estimated continuously at the bedside with NIRS, because the change in THb (in micromoles per liter) is proportional to the change in CBV (in milliliters per 100 g), with the following equation30: {Delta}CBV = K · {Delta}THb/H, where the value of the constant K is obtained from the molecular weight of hemoglobin (64500), brain tissue density (1.05 g/mL), and the large-vessel/tissue ratio, which is assumed to be equal to 0.69,31 and H represents the hemoglobin concentration in a large-vessel blood sample.

Changes in cerebral intravascular oxygenation (HbD), equivalent to the difference between O2Hb and RHb, reflect changes in cerebral perfusion, according to previous experimental studies.32,33 In the present study, baseline THb and its components O2Hb and RHb were related to an arbitrary zero. Changes in THb, O2Hb, and RHb were calculated as the average value of all samples obtained in the 20-second period at each measurement time point defined in the study protocol. Therefore, changes in both CBV and HbD are relative changes from baseline values.

Clinical and Physiologic Data
Patients were monitored continuously for heart rate, peripheral oxygen saturation (Fastrac; Critikon, Tampa, FL), and transcutaneous PCO2 (Microgas 7650; Kontron Instruments, Zurich, Switzerland). In addition, several patients also had continuous transcutaneous PO2 monitoring (Microgas 7650; Kontron Instruments). Invasive arterial monitoring with umbilical artery catheters or oscillometry (V24C; Hewlett Packard, Palo Alto, CA) was used to measure blood pressure changes. Blood arterial and/or venous samples were obtained through umbilical lines. Central venous catheters were positioned at midatrial level or at the transition between the inferior vena cava and right atrium. Ventilatory settings, oxygen requirements, and all medications other than the study drugs were recorded.

Study Protocol
Intervention
After consent and enrollment, hypotensive patients were allocated randomly to receive either DP or EP. The study drug was increased in a stepwise manner every 20 minutes until the optimal MBP (MBP-OP) was attained and maintained for 60 minutes (treatment success or responders). MBP-OP was defined as a 15% increase over the corresponding lower limit of MBP established for each infant according to gestational age. The inotrope was delivered by continuous infusion through a peripheral cannula or central venous line (inserted peripherally or through the umbilical vein) with calibrated infusion pumps. Double blinding was performed by preparing trial packs containing 2 identical opaque syringes labeled 1 and 2, supplied by the pharmacy as a transparent solution. Concentrations of DP or EP were adjusted so that each 0.6 mL/kg per hour increase in flow rate would deliver the corresponding step-increase in the drug infusion dose. Dose increments were 2.5, 5, 7.5, and 10 µg/kg per minute for DP and 0.125, 0.250, 0.375, and 0.5 µg/kg per minute for EP.

Main Outcome Measures
Changes in systemic MBP and in cerebral hemodynamic parameters (CBV, O2Hb, RHb, and HbD) were measured at baseline, 20 minutes after each increase in dose (T1, T2, T3, and T4) until MBP-OP was reached, and then every 20 minutes up to 1 hour of stable blood pressure (60-OP). If the inotrope failed to normalize blood pressure (nonresponders), then the study was finished 20 minutes after the last increase in dose (T4) and other treatment strategies were started to standardize drug interventions after completion of the protocol, for additional analysis of the study groups (see below).

Secondary Outcomes
Blood arterial and/or venous samples were obtained at the beginning and end of the studies, for analyses of blood gases, acid-base status, lactate and glucose concentrations, hematocrit, and central venous oxygen saturation. Before every NIRS study, a complete cerebral ultrasound scan was performed to detect white matter damage or germinal matrix intraventricular hemorrhage (IVH), according to a standardized cerebral ultrasound reporting system published elsewhere.34,35 Posthemorrhagic hydrocephalus was diagnosed in the presence of progressive ventricular dilation.36 Persistent periventricular echogenicity was considered if abnormal parenchymal hyperechogenicity lasted >14 days.34 All early deaths and patients who developed posthemorrhagic hydrocephalus before 14 days of age were excluded from this analysis. Serial ultrasound scans were repeated weekly for every patient up to 40 weeks' postconceptional age or death. The final cerebral ultrasound study for each patient was defined as the ultrasound study showing the most severe damage for each diagnosis before death or 40 weeks' postconceptional age. The initial and final cerebral ultrasound diagnoses are given in this study. All cerebral ultrasound studies were performed by the same investigator (F.C.), who did not know what intervention drug was being given.

NIRS data, peripheral oxygen saturation, heart rate, blood pressure, and transcutaneous blood gas monitoring results were recorded simultaneously and stored on a magnetic disk for later analysis. The same investigators (A.P. and E.V.) performed all NIRS studies. Analyses of the NIRS curves, including the quality check of raw data and rejection of measurements or calculations, were performed off-line with a custom-made computer program.27,28

During the study, patients lay supine, with the head of the bed tilted 30° upward. The position of the head was either midline or turned 45° to the right or left. Patients remained undisturbed, with no change in position, throughout the study.28 Surfactant therapy was always administered before the study when indicated by the attending physician. Lung volume (8 or 9 ribs above diaphragm) and the position of the endotracheal tube and intravascular catheters were optimized with clinical and radiographic criteria before study entry. Oxygenation, ventilation, and the adaptation to mechanical ventilation were adequate and stable; therefore, respiratory settings, apart from FIO2, and sedatives given in continuous infusion (fentanyl or midazolam) remained unchanged during the study period.

At the end of the study, inotropic drugs were reconstituted at a higher concentration. Infants who responded to a study inotrope continued to receive the infusion at the clinician's discretion. If a maximal rate was reached and hypotension persisted (failure criteria) or responders failed to maintain the desired MBP in the subsequent hours, then the other drug was added with the same escalation protocol. Infants with pressor-resistant hypotension received hydrocortisone (1 mg/kg per dose).37

Sample Size and Statistical Analyses
We estimated that a change difference in CBV of 0.3 mL/100 g brain tissue between the 2 inotropes could be clinically relevant, representing a 15% increase in the reported absolute CBV values for these patients.27,38 In a pilot study that included the first 10 patients enrolled in the trial (5 per group), it was calculated that a sample size of 25 in each group would produce a 2-group t test with a significance level of (1 side) of .025 with 80% power to reject the null hypothesis of nonequivalence in favor of the alternative hypothesis of equivalent means of the 2 groups. To compensate for possible missing cases after randomization, the sample size was increased to 60 patients. Random assignment was performed by one investigator (R.M.), by means of sealed envelopes, according to random number tables (Trial Run 1.0; SPSS Inc, Chicago, IL), after stratification according to gestational age (<28 or ≥28 weeks) to ensure population homogeneity.

Data were analyzed with SPSS for Windows software (release 9.0; SPSS Inc). Quantitative data are given as means ± SD and qualitative data as counts or percentages. Comparisons between groups were tested with the Mann-Whitney rank-sum test and Fisher's exact test or {chi}2 test, for quantitative and qualitative data, respectively. Correlations between quantitative data were explored with the Pearson's correlation coefficient. The mean values of changes in CBV, O2Hb, and RHb, at different measurement time points defined in the study protocol, including both positive and negative values, were calculated for each individual.

To explore the effect of inotropes on cerebral and systemic hemodynamic variables and transcutaneous blood gas monitoring results, a 2-way analysis of variance for repeated measurements was performed, factoring for group (DP or EP) and measurement time point (baseline, T1, MBP-OP, or 60-OP). We studied the main effect and interaction between factors (a significant interaction indicated that the profiles of the groups had different shapes). When there was a significant interaction, we studied the simple effects of each factor, that is, the behavior of the average values obtained for each inotrope group and/or the average value of the inotrope group at each time point. Posthoc analysis was performed with the Bonferroni adjustment for multiple comparisons. Partial {eta}2 was used to calculate the effect size for the evolution of variables according to drug allocation. This analysis was also used to test the evolution of PaO2, hematocrit, acid-base status, central venous saturation, and lactate and glucose concentrations at baseline and at the end of the study. A 2-way analysis of variance, factoring for drug and gestational age, was used to analyze the effects on systemic and cerebral hemodynamic variables at 60-OP.

The population considered in the analysis of primary and secondary outcomes (intention-to-treat) included responders and nonresponders, except for cerebral ultrasound comparisons. Missing data were completed by using the last observation carried forward principle.

All statistical analyses were considered bilateral. Values of P < .05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Groups
In the 17-month duration of the study, 206 infants of <32 weeks' gestational age and/or <1501 g, <24 hours of age, were admitted consecutively to the NICU. Figure 1 represents the flow of participants through each stage of the trial. Sixty of the 86 patients who did not meet any exclusion criteria and developed systemic hypotension during the first day of life were enrolled in the study, representing 70% of eligible infants. The parents of 3 infants withheld consent. Twenty-three hypotensive infants were not randomized because of unavailability of investigators, NIRS equipment, or parents to sign consent forms when the infants were admitted. The mean gestational age (28 ± 2.3 vs 28.2 ± 2.3 weeks) and birth weight (978 ± 282 vs 1050 ± 313 g) did not differ between the infants who were enrolled or not enrolled. Other clinical variables, such as gender, multiple-birth rate, prenatal steroids, surfactant, and type of ventilatory support, were also comparable.


Figure 1
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  		Fig 1. Flow of participants through each stage of the trial. Other reasons for exclusion were unavailability of investigators, NIRS equipment, or parents to sign consent forms when infants were admitted.

 
The 60 randomized patients were assigned to receive DP (n = 28) or EP (n = 32) as pressor therapy. However, 1 patient in the DP group was excluded from the analysis because of the poor quality of the NIRS tracings. Patients in the 2 groups did not differ with respect to birth weight or gestational age. Studies were performed at a mean age of 5.3 ± 3.7 hours of life. Twenty-one patients (10 in the DP group and 11 in the EP group) had received volume expanders (10–15 mL/kg), at a mean time of 3.5 ± 2.4 hours before randomization. None of the enrolled infants had received indomethacin before the inotrope. No differences were found in the infants' clinical condition at the time of randomization. Relevant clinical data at the time of entry into the study are shown in Table 1.


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  		TABLE 1. Clinical Data at Study Entry

 
Invasive arterial monitoring was used for 52 patients (26 in the DP group and 26 in the EP group). Arterial (n = 52) and/or venous (n = 22) blood samples were obtained at the beginning and end of the studies. Continuous transcutaneous PO2 monitoring was conducted for 27 patients, including all infants without arterial lines.

Primary Outcomes
Rate of MBP Response to Vasopressor Therapy
Treatment was successful for 95% of patients according to the protocol. The percentage of MBP-OP achieved at different time points, according to treatment allocation, is shown in Table 2. Although trends indicated a greater escalation in EP doses, differences were not statistically significant. No differences were found in the rate of treatment failure between the groups.


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  		TABLE 2. Rate of MBP Response to Vasopressor Therapy

 
In follow-up evaluations, we found 18 patients (8 in the DP group and 10 in the EP group) who reached MBP-OP initially but then decreased below the desired MBP after the study was completed. Consequently, 36% of patients (21 of 59 patients) required rescue therapy in the first 11 ± 8 hours after the first inotropic agent was started (Table 2). No differences were found in the rate of delayed or total treatment failure between the groups.

Evolution of Systemic and Cerebral Hemodynamic Variables
The evolution of systemic and cerebral hemodynamic variables and the effect size according to drug allocation of the study population are shown in Table 3. There were significant increases in MBP from baseline throughout the study period (P < .001), with no differences between groups. Both groups showed significant increases from baseline at T1, MBP-OP, and 60-OP (P < .05). Heart rate also increased throughout the study (P < .001), although this increase was significantly higher in the EP group than in the DP group (P = .03). Posthoc analysis revealed differences between groups at both MBP-OP and 60-OP (P < .05). Significant increases were found at MBP-OP and 60-OP in the DP group (P < .05) and at T1, MBP-OP, and 60-OP in the EP group (P < .05).


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  		TABLE 3. Systemic and Cerebral Hemodynamic Variables and Transcutaneous Blood Gas Results Throughout the Study (DP: n = 27; EP: n = 32)

 
With respect to cerebral hemodynamic parameters, changes in CBV showed significant increases from baseline at every time point (P < .001), with no difference depending on treatment allocation. Significant increases were found at T1, MBP-OP, and 60-OP in the DP group (P < .05) and at MBP-OP and 60-OP in the EP group (P < .05). These increases in CBV were coupled with significant increases in HbD (P < .001). Significant increases were found at MBP-OP and 60-OP in the DP group (P < .05) and at 60-OP in the EP group (P < .05).

Individual changes in MBP, heart rate, CBV, and HbD of responders and nonresponders, considering baseline and end-of-study values (60-OP and T4, respectively), are shown in Fig 2. A large scatter was observed in the range of response for changes in CBV (–1.3–3.8 mL/100 g) and HbD (–26–45 µmol/L). Drug-induced changes in HbD were correlated with changes in MBP at MBP-OP (r = 0.28; P = .03) and at 60-OP (r = 0.32; P = .013). Transcutaneous PCO2 and PO2 values remained unchanged throughout the study (Table 3).


Figure 2
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  		Fig 2. Changes in systemic (A and B) and cerebral (C and D) hemodynamic parameters of responders and nonresponders. Individual changes, considering values at baseline and at the end of the study (60-OP and T4, respectively), are shown. HR indicates heart rate.

 
MBP or heart rate as a result of pressor support did not differ between extremely immature (<28 weeks) and more mature preterm infants (28–32 weeks), when end-of-study values (60-OP) were considered. However, CBV changes showed an interaction (P = .013), indicating that drug effects varied with gestational age; the EP-induced increase in CBV was greater among less mature patients (<28 weeks) (DP: 0.34 ± 0.5 mL/100 g; EP: 1.2 ± 1.1 mL/100 g), whereas the DP-induced increase in CBV was greater among patients of ≥28 weeks' gestational age (DP: 0.62 ± 0.6 mL/100 g; EP: 0.28 ± 1.02 mL/100 g). For HbD, trends showed a similar profile but it was not significant.

An exploratory analysis of the evolution of systemic and cerebral hemodynamic variables with dose escalation is shown in Fig 3. Groups did not differ in behavior between baseline and the first step in dose (T1). However, from 20 minutes onward after the second step in dose (T2), trends pointed to a higher heart rate in the EP group (P < .05 at T2) (Fig 3B). Nevertheless, no differences between groups were found in the profiles of the cerebral hemodynamic parameters with increased dose titration (Fig 3 C and D).


Figure 3
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  		Fig 3. Evolution of systemic (A and B) and cerebral (C and D) hemodynamic variables with dose escalation (dose 4 not represented), from baseline (BL) to T1 (DP: n = 26; EP: n = 30), from baseline to T2 (DP: n = 20; EP: n = 24), and from baseline to T3 (DP: n = 11; EP: n = 15). The profile of the variables did not differ with increasing titration in dose between groups (A, C, and D), except for heart rate (HR) (B), for which, from 20 minutes after the second step in dose (T2) onward, the trends pointed to higher values for the EP group (P < .05 at T2).

 
Other Clinical Outcomes
Metabolic and Hematologic Parameters
The evolution of arterial blood gas findings, acid-base status and blood lactate concentrations, glycemia, and hematocrit among patients who responded to inotropic treatment between baseline and the end of the study is shown in Table 4. Arterial PO2 and PCO2 did not change. The behavior of the remaining variables differed according to treatment. Thus, pH did not vary, although base excess showed a different profile (P = .03), decreasing in the EP group but remaining unchanged in the DP group (P = .05). Blood lactate levels showed an inverted trend (P = .001), with final lactate levels decreasing with DP and increasing with EP. Blood glucose levels increased significantly after the inotrope was started, although we also found an interaction (P = .004), with the increase among EP-treated patients being significantly higher (P < .05). Hematocrit levels remained within physiologic ranges, but significant increases were observed and the patterns differed between groups (P = .003). Posthoc analysis showed an increase in the DP group but not in the EP group. Finally, the 22 patients with umbilical venous catheters (11 in the DP group and 11 in the EP group) showed similar baseline venous oxygen saturation values, which did not vary between baseline and the end of the study (Table 4).


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  		TABLE 4. Blood Gases, Acid-Base Status, Lactate, and Glucose Concentrations, Hematocrit, and Central Venous Oxygen Saturation at Baseline and the End of the Study (60-OP)

 
Cerebral Ultrasound Studies
Cerebral ultrasound diagnoses before administration of the inotrope did not differ between groups. Moderate/severe periventricular hyperechogenicity was present for 18 patients and grade 1 or 2 IVH for 12 patients. Some patients had both sonographic findings. Thirty-two infants had normal sonograms in the initial cerebral ultrasound evaluations (Table 5). In follow-up evaluations, the final cerebral ultrasound diagnoses were as follows: grade 1 or 2 IVH, 18 cases; grade 3 IVH, 8 cases; periventricular hemorrhagic infarction, 4 cases; posthemorrhagic hydrocephalus, 5 cases; persistent periventricular echogenicity, 13 cases; cystic periventricular leukomalacia, 2 cases. Some infants had >1 cerebral ultrasound finding. Twenty-six infants showed normal sonograms in follow-up evaluations (Table 5). No differences were found between groups in final cerebral ultrasound diagnoses. Considering the overall study population, comparisons between responders and nonresponders in either the initial or final cerebral ultrasound diagnoses revealed no statistically significant differences.


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  		TABLE 5. Cerebral Ultrasound Diagnoses

 
Mortality Rates
The overall mortality rate was 15% (3 deaths in the DP group and 6 deaths in the EP group), with no differences between groups. Seven of the 9 deceased patients were infants with treatment failure who received rescue therapy. All deaths occurred during the neonatal period (1–21 days of life), except for 1 infant (3 months of age).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The main goals of our study were to investigate differences in organ-specific (brain) blood flow in response to inotropic treatment among hypotensive preterm infants during the first hours of life. The lack of information about the effects of inotropic agents on the cerebral circulation in human newborns is remarkable, with the only reports being small observational studies.18,39–41 The present study is the first randomized, blinded, controlled trial exploring the effects of 2 different inotropes, DP and EP, titrated to optimize individual patient responses, with continuous measurement of systemic and cerebral hemodynamic parameters. A randomized, nonblinded trial42 compared the effects of volume expansion, DP, or no treatment on absolute cerebral blood flow, left ventricular output, and blood pressure. However, important methodologic differences between that study and our study make the results difficult to compare. In fact, in that trial,42 MBP enrollment criteria differed considerably, only the effects of a single dose of DP (5 µg/kg per minute) were evaluated, and mean postnatal ages (and ranges) also differed; our population was considerably younger and more uniform.

The behavior of the 2 inotropic agents was generally quite similar in this study. The significant and sustained increase in blood pressure was coupled with an increase in heart rate. It is noteworthy, however, that the effect on heart rate depended on drug allocation. EP produced a greater increase in heart rate, a difference that was evident not only in the average mean heart rate value when the highest dose was given to individual patients (MBP-OP and 60-OP) (Table 3) but also from the second step onward in dose titration, independent of whether the target blood pressure was achieved (Fig 3). In neonatal animal models, low-dose EP produced an increase in both heart rate and stroke volume, resulting in an increase in cardiac output.19 Previous studies also demonstrated increases in both parameters among preterm infants weighing >1750 g.22 It is interesting that the pattern of inotrope-induced changes in MBP and heart rate does not seem to depend on gestational age, because no differences in behavior were found between more immature and more mature infants in this study.

In view of the main goal of this study, ie, to evaluate the effects on cerebral perfusion and oxygenation of vasopressor support while attempting to reach the MBP-OP, we found significant increases in CBV and HbD throughout the study. Pressor support was accompanied by a mean increase in CBV of 0.70 mL/100 g, which, according to the absolute CBV reference values for this population,27,38 could represent up to a 33% increase in absolute CBV. We did not measure absolute cerebral blood flow, to avoid fluctuations in intravascular oxygenation influencing results; cerebral blood flow calculations with NIRS require manipulation of the FIO2, causing abrupt changes in peripheral oxygen saturation.27,38 However, we evaluated relative changes in cerebral blood flow, as indicated by changes in HbD, which showed a trend similar to that of changes in CBV, indicating a real increase in cerebral blood flow. The magnitude of this increase could not be ascertained with the methods used in this study. The results also indicate that our treatment protocol with either DP or EP does not cause cerebral vasoconstriction. In fact, we think that the observed increases in cerebral perfusion and oxygenation are attributable to a selective vasodilatory effect on the cerebral vasculature that is mediated through recruitment of unperfused capillaries, rather than an increase in linear flow rates,43 because CBV and HbD showed parallel changes in this study.

A limitation of this study was that we enrolled infants with low blood pressure, which showed poor correlation with measures of systemic blood flow in some studies.16 Therefore, it may be a matter of debate whether the increase in MBP is accompanied by an improvement in systemic blood flow, because other measurements, such as cardiac output14 and superior vena cava flow,16 were not evaluated in this study. However, only cerebral blood flow changes in relation to MBP variations have been evaluated in autoregulation studies, and studies on the relationship between brain damage and hemodynamic instability among preterm infants used blood pressure changes as the main outcome measure of systemic hemodynamics, rather than cardiac output.5–7,11

A recent study that used NIRS for the continuous monitoring of cerebrovascular autoregulation among premature infants found concordant changes in cerebral perfusion and oxygenation and mean blood pressure, with impaired autoregulation being associated with an increased likelihood of occurrence of severe ischemic or hemorrhagic brain lesions.13 It is important to note that we found a significant positive correlation between drug-induced changes in MBP and HbD. There are 2 possible explanations for these findings. First, the MBP threshold for initiating pressor support in this study was at the lower limit of the autoregulatory plateau, reinforcing the early use of cardiovascular support in such circumstances to ensure stable cerebral blood flow. Second, it is possible that the infants had impaired cerebral autoregulation. In fact, although none of our patients had severe degrees of IVH or periventricular hemorrhagic infarction before inotrope administration, 30% showed abnormal parenchymal echogenicity on the initial cerebral ultrasound scans (Table 5). Because a pressor-passive cerebral circulation was established for most of our patients, careful monitoring to optimize individual patient responses to treatment with dose titration is recommended strongly. In our understanding, these findings provide additional support for the use of MBP changes as a consistent outcome measure of systemic organ blood flow, at least in cerebral hemodynamic studies among sick preterm infants. It should also be noted that, whatever method is used to correlate systemic and organ-specific blood flow, continuous changes in both parameters should be documented. This was the case in this study, in which the responses to vasopressor treatment of blood pressure, as an estimate of systemic blood flow, and of CBV and oxygenation, representing changes in cerebral blood flow, were assessed with continuous data collection.

Despite the significant correlation between the MBP and HbD changes, the correlation coefficient was low, probably indicating that changes in MBP were not the only determinants of changes in cerebral perfusion pressure in this study. With coherence analysis, Tsuji et al13 found that, among patients with concordant MBP and HbD changes, not all records exhibited high coherence values, indicating that cerebral blood flow regulation in response to MBP changes varies at different times for a given patient. However, the inotropic regimen used in this study could have worked preferentially by improving cardiac contractility and effective circulatory volume,39,41,44 resulting in increases in organ blood flow that might not necessarily be mirrored by equivalent changes in blood pressure.16

The pattern of changes in cerebral hemodynamic parameters as a result of pressor support showed an interaction, indicating that drug effects varied with gestational age; EP had a greater effect among more immature patients and DP exerted a greater effect among more mature ones. We do not have a clear explanation for this, unless a lower myocardial reserve of endogenous catecholamines in the more immature heart may benefit more from direct stimulation by EP, rather than DP.44 Studies should be conducted to address this important question.

The effects of dose escalation within the ranges used in this study showed similar profiles in the 2 groups; sustained increases in CBV and HbD were observed with increasing dose titration, regardless of whether MBP-OP was achieved (Fig 3). This effect was also observed among patients for whom inotropic treatment failed to normalize blood pressure (Fig 2). We must keep in mind, however, that the MBP threshold for initiation of pressor therapy in our study was very low and that, even with significant increments in MBP, such as ≥25% with respect to baseline values, the target MBP established by the protocol was not reached for some patients. In such cases, it is reasonable to observe significant increases in cerebral hemodynamic parameters, as in this study.

It is interesting to note that physiologic variables that could have influenced the response of the cerebral vasculature to drug infusion remained unchanged throughout the study period. This was the case for PO2, which could influence HbD changes, and, more importantly, PCO2, which could influence both CBV and HbD changes (Tables 3 and 4). We observed, however, a significant increase in glycemia (Table 4). However, it is noteworthy that the trends observed for this parameter (increase) would have had the opposite effect (decrease) on organ blood flow and oxygenation.43 Hematocrit levels remained within the normal range, although a significant increase was observed. The comment about glycemia is also applicable to hematocrit.

Finally, the increase in plasma lactate levels among EP-treated patients is independent of the effects on oxygen transport and probably is the result of ß2-adrenoceptor stimulation, contributing to the hyperglycemic response to catecholamines as a result of gluconeogenesis and the subsequent conversion of lactate to glucose.45 Central venous oxygen saturation reflects residual oxygen after tissue oxygen extraction and is influenced by the hemoglobin concentration, cardiac output, and local tissue blood flow and oxygen consumption.46,47 In this study, we assumed that central venous oxygen saturation represents mixed venous blood, because it has been demonstrated that, even in shock states, oxygen saturation in the right atrium is correlated with oxygen saturation in the pulmonary artery.48 Therefore, we think that the trends in central venous oxygen saturation observed in this study, with end-of study measurements being similar to or higher than those at baseline, indicate adequate systemic blood flow and oxygen supply as a result of pressor support.

We report a prevalence of hypotension during the first 24 hours of life among LBW infants of 43%. In this population of hypotensive LBW infants, the 2 drugs showed similarly high rates of treatment success. However, the relatively brief duration of the study drug protocol precluded the demonstration of delayed failure. In fact, up to 36% of our patients needed rescue therapy hours after pressor support began, which is similar to findings reported in previous studies.16 This delayed failure after initial stabilization may be attributed to different clinical conditions. In fact, a hemodynamically significant patent ductus arteriosus or differences in catecholamine metabolism or clearance with advancing age or disease stage could play a pivotal role in this delayed failure.

The dosage regimens used in our study were based on previous studies in which the effectiveness and side effects of the drugs within the ranges used in this study were evaluated among neonates22,23,41 and in neonatal animal models.19–21 In the case of DP, several studies suggested that increasing the dose to >10 µg/kg per minute did not show any additional beneficial effects on either systemic blood flow16 or blood pressure,15,41 probably because of developmentally regulated, enhanced adrenergic sensitivity of the more immature cardiovascular system in this population of preterm infants. In the case EP, the dose regimen used in this study was reported to produce promising improvements in blood pressure and cardiac contractility, although the experience reported was limited to a population of preterm infants with higher birth weights.22

Another methodologic consideration is that, although the present study was designed to include 50 patients (25 per group), to achieve a power of 80%, the limitations of the technique for obtaining appropriate NIRS tracings for every patient moved us to increase the sample size to compensate for possible missing cases after randomization. We note that the conditions of the present study, with 59 analyzed cases (27 and 32 cases in the 2 groups), yielded an actual power of 86%.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The results of this study showed that hypotensive preterm infants treated with low/moderate-dose DP or low-dose EP experienced increased cerebral perfusion and oxygenation, as indicated by the increases in both CBV and HbD. The observed interaction that showed that drug effects varied with gestational age merits additional research. In view of the nearly uniform response among our patients, cerebral circulation appeared to be pressure-passive at the blood pressure threshold used to signal the start of inotropic treatment in this study, which must be close to the lower limit of the autoregulatory plateau. However, trials to compare treatment of infants at different thresholds are required. Finally, EP was as effective as DP in increasing blood pressure among LBW infants.


   ACKNOWLEDGMENTS
 
This work was supported by Instituto de Salud Carlos III grant FIS 02/1110, Arbora & Ausonia Dodot, and the Neonatal Spanish Society.

We thank Dr Keith J. Barrington for contribution to the report as scientific adviser. We also thank Dr Jesús Frías for technical help.


   FOOTNOTES
 
Accepted Sep 27, 2004.

Address correspondence to Adelina Pellicer, MD, Department of Neonatology, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain. E-mail: apellicer.hulp{at}salud.madrid.org

This work was presented in part at the annual meeting of the Pediatric Academic Societies/Society for Pediatric Research; May 1–4, 2004; San Francisco, CA.

No conflict of interest declared.


   REFERENCES
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 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
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