Hemodynamic Changes in Anemic Premature Infants: Are We Allowing the Hematocrits to Fall Too Low?
* Divisions of Neonatology
Cardiology, Department of Pediatrics, Ahmanson Pediatric Center, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California
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ABSTRACT |
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Objective. Currently, many nurseries allow hematocrits to fall to <21% in apparently "stable" premature infants before considering a blood transfusion. We evaluated clinical changes and hemodynamic changes by echocardiogram in "stable" anemic premature infants before, during, and after transfusion.
Methods. "Stable" premature infants (
32 weeks’ gestation) who were to receive transfusions (2 aliquots of 10 mL/kg packed red blood cells, 12 hours apart) were eligible for prospective enrollment. Cardiac function by echocardiography and vital signs were measured 4 times: 1 to 3 hours before and 2 to 4 hours after the initial aliquot and 4 to 7 hours and 27 to 34 hours after the second aliquot. Infants were grouped prospectively according to pretransfusion hematocrit ranges for analysis: 21% (low), 22% to 26% (mid), and 
27% (high).
Results. Thirty-two infants were enrolled. No differences were observed between the groups in sex, birth weight, postconceptional age, or postnatal weight at enrollment. Before transfusion, low- and mid-range groups had higher left ventricular end systolic and diastolic diameters, in comparison with high range. Low range had increased stroke volume in comparison with the high-range group. These changes persisted after transfusion. Mean diastolic blood pressure rose and peak velocity in the aorta fell in the low-range group after transfusion. Pretransfusion hematocrit was correlated with but poorly predictive of echocardiographic measurements. Infants with inappropriate weight gain had increased ventricular end diastolic diameters, consistent with congestive heart failure.
Conclusions. Apparently "stable" anemic premature infants may be in a clinically unrecognized high cardiac output state, and some echocardiographic measurements do not improve within 48 hours after transfusion. The benefits of transfusion practices guided by measures of cardiac function should be evaluated.
Key Words: anemia of prematurity • heart failure • transfusion criteria • echocardiogram • hematocrit
Abbreviations: PRBC, packed red blood cell • NICU, neonatal intensive care unit • echo, echocardiographic • HR, heart rate • RR, respiratory rate • SBP, systolic blood pressure • DBP, diastolic blood pressure • MBP, mean arterial blood pressure • PP, pulse pressure • LVESD, left ventricular end-systolic diameter • LVEDD, left ventricular end-diastolic diameter • LVO, left ventricular output • SV, stroke volume • FS%, percentage of fractional shortening • Vcfc, velocity of circumferential fiber shortening • PVA, peak velocity of the systolic blood flow in the ascending aorta
No objective criteria exist for packed red blood cell (PRBC) transfusion in premature infants. It has been estimated that 38 000 premature neonates receive annually >300 000 transfusions.1 Transfusion practices range from waiting for signs and symptoms of anemia to develop to transfusing at a predetermined hematocrit level.2–4 So far, studies that have attempted to establish indications for transfusions on the basis of clinical signs and symptoms have been equivocal.3,5,6 Since the 1980s, a progressive decline in frequency of PRBC transfusions has taken place as a result in part of the institution of transfusion guidelines and in part of the acceptance of lower hematocrits. In very low birth weight infants, transfusions per infant (mean ± standard deviation) declined from 7.0 ± 7.4 in 1982 to 2.3 ± 2.7 in 1993 (P < .001). This decline was associated with a decrease in pretransfusion hematocrits from 33.6 ± 2.8% in 1982 to 29.8 ± 5.1% in 1993.7 In 1995, although the safe lower limit of pretransfusion hematocrits was not determined, recommendations for pretransfusion hematocrit levels in asymptomatic infants declined even further to <20% to 21%.4,8
Attempts have been made to formulate objective criteria for when to transfuse anemic infants. These criteria, although based on "best guess" estimates of hemoglobin needs for optimal tissue oxygenation under various clinical circumstances, have never been shown to improve any measurable outcome variable (eg, length of stay, growth). Although neonatal intensive care units (NICUs) may have rigorous practice guidelines, it is believed that commonly the final decision to transfuse is based on the clinical judgment of the practitioner.
One clinical consequence of long-standing anemia in fetuses is fetal hydrops as a result of congestive heart failure. Several previous studies have reported measurements of cardiac function in neonates with anemia.9–17 Previous studies have shown increases in cardiac output in anemic preterm infants, which decreased after transfusion,9,10 but no long-standing changes in cardiac function were noted. However, these studies were small, enrolling only 12 and 14 infants, respectively, and the hemoglobin ranges studied (65–78 g/L and 65–88 g/L, respectively, with estimated hematocrits ranging from 20% to 23% and 20% to 26%, respectively) were higher than current recommended transfusion levels (hematocrit <20%–21%). Therefore, it is conceivable that decreasing the lower limit of pretransfusion hematocrits may cause these infants to be in an inapparent state of high cardiac output. This is likely an undesirable clinical condition. This study evaluated hemodynamic parameters in "stable" anemic premature infants before, during, and after PRBC transfusion, as a step toward developing objective criteria for transfusion.
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METHODS |
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Patient Eligibility and Enrollment
The Institutional Review Board approved the study. Eligibility criteria for the study were as follows: estimated gestational age
32 weeks (determined by best obstetric estimate); postnatal age 60 days; absence of ventilator support; and no evidence of infection, patent ductus arteriosus, congenital heart disease, or major congenital anomalies. Infants were considered "stable" when they were extubated, with no need for fraction of inspired oxygen 0.24, and if in the 24 hours before transfusion, they did not have tachypnea (70 breaths/min), tachycardia (180 beats/min), or frequent apneas (10 episodes of self-resolving apneas in 12 hours). The decision for PRBC transfusion was made at the discretion of the attending neonatologist. Two aliquots of 10 mL/kg leukocyte-depleted, irradiated PRBC from cytomegalovirus seronegative donors were used. Each aliquot was transfused over a period of 4 hours at 12-hour intervals.
Data Measurement and Collection
Each infant had 4 sets of vital signs and echocardiographic (echo) evaluations: at 1 to 2 hours (T1) before and 2 to 4 hours (T2) after initial transfusion and at 4 to 7 hours (T3) and 27 to 34 hours (T4) after the second transfusion. The following data were collected: clinical indications for transfusion; resolution of those signs and symptoms; average daily weight gain for the week before transfusion; average daily calorie intake for the week before transfusion; central hematocrit (%) by venipuncture or arterial puncture; heart rate (HR) in beats/min; respiratory rate (RR) in breaths/min; systolic, diastolic, and mean arterial blood pressures (SBP, DBP, and MBP) in mm Hg; pulse pressure (PP = SBP – DBP) in mm Hg; left ventricular end-systolic diameter (LVESD) in mm; left ventricular end-diastolic diameter (LVEDD) in mm; left ventricular output (LVO) in ml/min/kg; stroke volume (SV) in ml/kg; percentage of fractional shortening (FS%); corrected velocity of circumferential fiber shortening (Vcfc) in circumference/sec; and peak velocity of the systolic blood flow in the ascending aorta (PVA) in cm/sec. FS% = [(LVEDD – LVESD)/LVEDD x 100].18 The Vcfc was calculated and normalized to the LVEDD by dividing FS% by the ejection time.19 Left ventricular ejection time was measured from the Doppler flow pattern in the ascending aorta and taken as an average of 5 sequential beats. The ejection time was rate-corrected to an HR of 60 beats/min and was divided by the square root of the RR interval. A single echo technician performed all echo studies on sleeping or quietly resting infants, and a single cardiologist (D.A.F.) verified the measurements. Both were blinded to the infant’s hematocrit and indications for transfusion.
The echo M-mode measurements were obtained from standard precordial views on an Acuson echocardiograph (model 128 XP) with a 7.5-MHz transducer (Acuson Computed Sonography, Mountain View, CA). The blood pressure measurements were done by Critikon Dinamap vital signs monitor (model 8100) with a 120-V/60-Hz 0.5 A (Critikon INC, Tampa, FL).
Statistical Analysis
For evaluating the relationship between different hematocrits levels and echo and vital signs data, patients were blocked prospectively into 3 subgroups on the basis of their pretransfusion hematocrits: low range (21%), mid-range (22%–26%), and high range (27%). For detecting shifts of >10% in the echo variables across the 4 sets of measurements in each infant, a sample of >20 infants in all groups combined was required to achieve a power of 90%. Continuous data were analyzed either by analysis of variance (multigroup comparison) for repeated measurements (
= 0.05) with Bonferroni post hoc analysis for between-group comparison or by linear regression. Categorical data were analyzed by 
2. Continuous data are reported as median and interquartile range (25th percentile, 75th percentile).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Demographics
A total of 32 premature infants were enrolled prospectively. Demographic information for these patients is presented in Table 1. Among the 3 subgroups, there was a difference noted for gestational age, but the subgroups did not differ in sex, birth weight, postconceptional age, or postnatal weight on the day of study. The indications for PRBC transfusion in study infants and resolution of those symptoms after transfusion are listed in Table 2.
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Analysis of Changes in Clinical and Echo Measurements After Transfusion
A total of 128 echo studies were performed (4 per infant). Clinical and echo data of study patients are depicted in Table 3. Statistical analysis of study patients revealed that DBP, MBP, and hematocrit levels increased significantly after PRBC transfusion. However, there were no differences in echo data before and after PRBC transfusion when analyzed on aggregate.
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Subgroup Analysis
Table 4 shows the baseline echo data of the 3 groups. The low- and mid-range groups had significantly larger baseline LVEDD and LVESD, in comparison with the high-range group (Table 4). The low-range group had significantly higher baseline SV in comparison with the high-range group (Table 4). There was a trend for the low-range group toward a lower baseline DBP, higher PVA, wider PP, and higher LVO, in comparison with the mid- and high-range groups.
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In the low-range hematocrit group, in comparison with mid- and high-range groups, the DBP increased and PVA decreased after PRBC transfusion (Table 5, low-range group). In the low-range group, DBP at T1 was significantly different from both T3 and T4, and PVA at T1 was statistically different from T2. LVEDD, LVESD, and SV did not change during the study period despite the PRBC transfusion in any group (Table 5). The high-range hematocrit group showed a significant increase in RR after PRBC transfusion (Table 5, high-range group).
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Correlation of Echo and Clinical Findings
No initial echo parameter or clinical parameter (HR, RR, SBP, DBP, MBP, PP, or hematocrit) correlated with resolution of the symptoms cited as the indications for transfusion (results not shown). Also, no clinical parameter correlated with initial hematocrit (results not shown). However, 4 echo parameters (LVEDD, LVESD, LVO, and SV) correlated with the initial hematocrit (Fig 1). Although the correlation between these echo parameters and the initial hematocrits was statistically significant (P < .05), the initial hematocrits were poorly predictive of echo parameters (low R2).
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Patients in congestive failure secondary to sustained high cardiac output may be expected to have inappropriate weight gain. Weight gain (averaged over the 7 days before transfusion) was correlated but poorly predictive of LVEDD before transfusion (Fig 2). Furthermore, 10 (31.3%) patients gained
30 g/d (average: 36 g/d; range: 30–42 g/d) for the week before transfusion, despite receiving only an average of 105 kcal/kg/d during that week (range: 58–121 kcal/kg/d). Several of these patients were noted to be edematous before transfusion. Pretransfusion hematocrit ranged from 17% to 27% in these 10 patients (3 from low-range group, 6 from mid-range group, and 1 from high-range group). Nine of these ten had a LVEDD at T1 greater than the mean LVEDD at T1 for the high-range group, and 6 of 10 were >1 standard deviation above that mean. Data on the average weight gain over the week after transfusion was not collected, as some patients in this study were discharged within that week.
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Figure 3 depicts percentiles for the baseline (T1) echo parameters for the 4 measurements that have been found to be significantly affected in this study (ie, either at baseline [LVEDD, LVESD, and SV] or that correlate with initial hematocrit [LVO]). Using the 75th percentile for the high-range group as an arbitrary value for each parameter, Table 6 describes the number in each subgroup that have values above that percentile. In this cohort of stable patients, deemed by their attending neonatologist to require blood transfusion for clinical indications, only <16% had normal echo measurement and >62% had 3 or more abnormal measurements.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Infants with symptomatic anemia have increased cardiac output, which may lead to left ventricular dysfunction if the anemia is not treated.20 In the present study, apparently "stable" infants with hematocrits
21% show hemodynamic signs of a high cardiac-output state as demonstrated by their high baseline SV and large LVEDD and LVESD. To a lesser extent, infants with hematocrits between 22% and 26% also showed increased LVEDD and LVESD (Table 4). Although not significant, infants with hematocrits 21% tended to have lower baseline DBP, higher PVA, wider PP, and higher LVO, in comparison with the other groups. After PRBC transfusion, parameters such as DBP and PVA improved immediately in the low-range group, whereas other parameters, such as SV, LVEDD, and LVESD, did not improve immediately. In a previous pilot study, we noted no hemodynamic changes, by echo studies, after PRBC transfusion in premature infants who had hematocrit levels between 25% and 33%.15 This previous study includes fewer children with higher hematocrits. Two previous studies that examined cardiac function in anemic preterm infants also looked at fewer infants, with no infant who would have been in the low-range group.9,10 For eliminating interobserver variability, a single echo technician performed all echo studies and a single cardiologist verified the measurements. Both were blinded to the infants’ hematocrits and indications for transfusion. All children were sleeping or quietly resting during the study to reduce intraobserver variability. We could not control for feedings as transfusions were not coordinated with feeding schedules, and different infants were fed differently (some continuous, some bolus).
We did observe a trend toward a decrease in baseline HR after transfusion, but it did not reach statistical significance in aggregate or in any subgroup (Tables 3 and 5). It is interesting that although not reaching statistical significance, the baseline HR for the low-range group was lower than for the mid-range group, which was lower than for the high-range group (P = .13; Table 4). As baseline LVEDD, LVESD, and SV are increased (and LVO trends to be increased), we speculate that the HR tends to be lower in infants with compensated anemia, to permit adequate time for ventricular filling and ejection. A corollary speculation is that compensated anemic infants might decompensate more rapidly if HR were increased under circumstances such as handling, phlebotomy, surgery, or intercurrent illness. Although increased baseline HR is frequently included in guidelines for transfusion in the NICU,4 our data suggest that this is unsupported.
In 1995, Alverson12 wrote, "Clinically useful indicators of physiologically significant anemia requiring intervention have yet to be defined in the newborn." To date, there is still no clinical or laboratory "gold standard" for transfusing premature infants, and attempts to define such standards have been unsuccessful.17,21–23 For the study, we enrolled infants who were 32 weeks’ gestation and 60 postnatal days because these infants compose the overwhelming majority of infants with anemia of prematurity.24 Signs and symptoms such as tachycardia, tachypnea, and poor weight gain may not be attributable to anemia only but to other causes as well.4,6,21–23,25–28 If children are in heart failure, then they may have inappropriate excessive weight gain. Again, although guidelines include inadequate weight gain as an indication for transfusion,4 our data suggest that this is unsupported. Many clinical signs of anemia in preterm infants, particularly apnea, have been previously debunked.12,25
Our study is consistent with the hypothesis that the primary consequence of adaptation to anemia is to augment tissue oxygenation by increasing cardiac output. In fetuses with anemia as a result of nonimmune hydrops, prenatal echo findings of enlarged biventricular outer dimensions in diastole had 100% predictive value for mortality.29 In fetuses, the measurement of peak velocity of systolic blood flow in the middle cerebral artery by Doppler ultrasonography as an indication of the severity of anemia was well documented.14,16 It is not clear, however, whether preterm infants can compensate adequately. It is likely that some infants would be better able to compensate than others and that some may not be able to compensate at all. This would be difficult to assess in an individual patient by any means other than echocardiography.
Our data suggest that there is correlation between anemia and LVEDD, LVESD, LVO, and SV. It is extremely important to note that these do not improve within 48 hours of transfusion, which suggests that there is chronic adaptation to anemia. Whether these adapted hearts would be compromised by volume expansion from a transfusion remains to be seen. We did not investigate whether these changes persisted beyond 48 hours. Table 6 and Fig 3 complement each other. Table 6 refers to the total number measurements that were greater than the >75th percentile per patient. Figure 3 shows the overall percentiles for each subgroup. We arbitrarily chose to include patients whose echo parameters were >75th percentile for the highest range group as the measure for determining abnormal echo findings. If the 90th percentile (as depicted by the dashed line in Fig 3) is used, then all patients in the low-range group and >70% of the mid-range group meet that criterion for at least 1 echo parameter. As the high-range group patients were deemed to require transfusion on the basis of clinical symptoms, perhaps the mean value for this group may be the value above which one should consider transfusion. However, this would need to be tested prospectively in a trial to determine whether this would improve outcome in preterm patients. Previous authors have suggested that preterm infants’ ability to compensate is extremely limited.11,12
Early signs of heart failure may be able to be assessed by measuring urinary catecholamine or plasma renin levels. However, normal values for these have not been firmly established in this population and can be affected by intercurrent illness or diuretic use, both common in patients in the NICU. Furthermore, laboratory evaluation may take longer than would be preferable when considering a transfusion for a patient with anemia. Although echocardiography should not be considered a noninvasive procedure in preterm or ill newborn infants,30 it is readily available in the NICU and was well tolerated 4 times by the "stable" preterm infants in our study. A single echocardiogram and interpretation may be able to be performed for approximately the cost of an avoided transfusion. Furthermore, trained neonatologists may be able to perform this procedure at little if any additional cost.
In study infants, "symptoms and signs" of anemia that precipitated PRBC transfusions resolved only in part after transfusions (Table 2). PRBC transfusion in infants with hematocrit 27% (high-range group) resulted in an increase in the RR and the work of breathing. The explanation for increasing RR may be that PRBC transfusion in these infants may decrease minute ventilation, worsen lung compliance, and increase pulmonary resistance, presumably as a result of the expanding circulating blood volume and increasing lung water.20
Study results suggest that some apparently hemodynamically "stable" preterm infants with hematocrits 21% and, to a lesser extent, infants with hematocrits between 22% and 26% may be in a high cardiac-output state. This condition may not be desirable and may be potentially dangerous. We suggest that this needs to be addressed by the clinician when balancing the risks and the benefits of PRBC transfusion. The treatment options for asymptomatic infants in a high cardiac-output state would be to give a PRBC transfusion or to initiate erythropoietin therapy, if transfusion seems to be less urgent,4 and/or to follow the infant closely until the resolution of the condition. However, there have recently been concerns raised about the use of hemopoietic growth factors in neonates,31,32 such as red-cell aplasia and the formation of antierythropoietin antibodies.
As current "traditional" criteria for PRBC transfusion are not sensitive, objective relatively noninvasive echo criteria may guide the clinician as to when PRBC transfusion is necessary or when it can be postponed. Echo measurements may help to indicate the reason for excessive weight gain in an anemic infant. Furthermore, it remains to be seen whether these chronic adaptations to anemia have long-term impact in these patients regarding chronic health problems, such as hypertension. Testing these criteria using a prospective, randomized, control trial is important to validate their clinical applicability.
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ACKNOWLEDGMENTS |
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This work was supported by a grant from the Ahmanson Pediatric Endowment.
We thank Dr Gil Wernovsky and Dr Sandra Juul for expertise in reviewing this manuscript during preparation. We are indebted to Al Nasrat for expert echocardiographic measurements.
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FOOTNOTES |
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Received for publication Nov 4, 2002; Accepted Feb 7, 2003.
Reprint requests to (A.L.A.) Neonatology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Rm 4310, Los Angeles, CA 90048. E-mail: arie.alkalay{at}cshs.org
Part of this work was presented as a pilot study at APS/SPR in 1999. Pediatric Research 1999;45:1622A.
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