How to cite this article: García-Pasquel MJ, Iglesias-Leboreiro J, Bernardez-Zapata I. Correlation between the use of sodium bicarbonate and intraventricular hemorrhage in preterms. Rev Med Inst Mex Seguro Soc. 2015 Jul-Aug;53(4):512-7.
CLINICAL AND SURGICAL PRACTICE
Received: March 28th 2014
Accepted: August 11th 2014
María José García-Pasquel,a José Iglesias-Leboreiro,a Isabel Bernardez-Zapataa
aServicio de Neonatologia, División de Pediatría, Hospital Español de México, Distrito Federal, México
Communication with: María José García-Pasquel
Telephone: (55) 5543 6318
Background: Being born preterm implies comorbidities, among them the risk of intraventricular hemorrhage (IVH). The use of sodium bicarbonate has been linked to the presence of IVH. The main purpose of this study was to determine if the infusion of sodium bicarbonate during the first 24 hours increases the risk of IVH in preterm infants.
Methods: Our study is a cohort; we analyzed the files of 160 patients and divided them into two groups: one in which sodium bicarbonate was not used and another in which it was; this latter group was subdivided into two considering if the use was therapeutic of prophylactic.
Results: In our total group of patients 10 % presented IVH; had a mean weight of 1500 g and 31 weeks of gestational age. The incidence of IVH was identical between both groups, although patients in which bicarbonate was used were more premature, unstable, and in worse clinical conditions.
Conclusions: Our data indicate the need of large scale studies to determine if the clinical benefits of the use of sodium bicarbonate outweigh the risk of IVH.
Keywords: Premature infant; Sodium bicarbonate; Hemorrhage
Premature birth carries a risk of comorbidities in almost all organs and systems; proof of this is the presence of intraventricular hemorrhage at a neurological level. In the 80s of last century, when description was made of intraventricular hemorrhage, it was estimated that this disease was present in 50% of those born at less than 34 weeks gestation; currently, there is talk of 45% in extremely low weight preterms, and 20-25% in those under 1500 grams.1,2 In a study by the National Institute of Child Health and Human Development (NICHD) in the United States in 1990, an incidence is reported, by weeks of gestation, of 36% at 24 weeks; 21% at 25 weeks; 14% at 26 weeks; 11% at 27 weeks, and 7% at 28 weeks.3
Approximately 90% of intraventricular hemorrhages appear within the first 4-7 days of life, about 70% were evident within 72 hours after birth, 30-50% occurred in the first 12 hours of life, and it is estimated that 40% occur in the first hour.4,5 As expected, the presence of intraventricular hemorrhage increases the likelihood of neurologic sequelae and death.2
Intraventricular hemorrhage begins in the germinal matrix, which actively produces neurons that migrate to the cerebral cortex.6 The number of vessels in the germinal matrix is greater than in the other regions of brain.2 The subependymal region of the germinal matrix is the main site of bleeding, and it begins to decrease in thickness at 24 weeks of gestation to be undetectable at the end.1,6,7 The way to detect these hemorrhages is transfontanellar ultrasound, which has a sensitivity of 91% and specificity of 81%.8 In 1978, Papile described 4 degrees of intraventricular hemorrhage using this tool. Grade I corresponds to mild hemorrhage, II to moderate, and III-IV to severe,8 as follows:
The pathogenesis of intraventricular hemorrhage is multifactorial, and has been associated with both the inherent fragility of the germinal matrix, and with changes in coagulation, quantity and quality of platelets, changes in cerebral blood flow, vaginal delivery, low APGAR, respiratory distress, pneumothorax, hypercapnia, seizures and infections, hyper and hipocapnia.1,2,6,9-11 In 1978 Papile et al.12 described the correlation between rapid infusions of bicarbonate and the presence of intraventricular hemorrhage, and recommend the use of bicarbonate in slow infusions. In another study, published in 2010 by Barnette et al,1 no correlation between the use of sodium bicarbonate was found (at doses <4 mEq/kg/day) during the first week of life; however, a greater intake of sodium bicarbonate was associated with a higher incidence of intraventricular bleeding. The incidence of bleeding presented in this study correlated with the intake of sodium in the first 48 hours of life.
It has been shown that rapid infusion of sodium bicarbonate (less than 5 minutes) affects the cerebral vasculature.13,14 In a meta-analysis of the organization, Cochrane,15 found no sufficient evidence to claim that the use of bicarbonate for metabolic acidosis in first 24 hours of life is harmful to the newborn; another study published by Murki et al.16 mentions that the use of bicarbonate in the first hours of life did not involve harm to newborns.
A study published by Levene et al. (1982)4 and another of Berg et al. (2010)17 mentioned an increase in the presence of higher grade intraventricular hemorrhage and mortality in infants treated with bicarbonate; however, they clarify that newborns who had this treatment were in more serious condition and had greater comorbidities.
The purpose of the use of bicarbonate in a newborn is to bring them to an acid-base state suitable for their age. Studies have been done to determine the normal pH of a newborn at term in the average range between 7.33 and 7.26 and base deficit averaging -2.5 to -4.5 mmol/L.17,18
In the Hospital Español the use of sodium bicarbonate is variable according to the judgment of the treating physician, so there are patients in whom it is used and others not.
A retrospective cohort study was done, where the records of children born in the Hospital Español January 2012 to August 2013 were reviewed. The inclusion criterion was preterm birth at 34 weeks or less, and they were divided according to the use or non-use of sodium bicarbonate in continuous infusion during the first 24 hours of life. To avoid recall bias, exposure to sodium bicarbonate was determined based on patient chart and corroborated with nursing notes. Exclusion criteria included:
An elimination criteria also was also if they had chromosomopathies or hydrops fetalis. 170 records were collected, of which 9 were excluded and one removed. Of the excluded, three left the hospital before 1 week of life, 5 for not having all the necessary studies, one child for having been transferred from another hospital, and the patient excluded was a newborn with non-immune hydrops fetalis.
With the remaining 160 infants, two groups were formed, one of administration of bicarbonate within the first 24 hours of life, and one without. The use of bicarbonate group was divided into two subgroups according to the indication for the administration of bicarbonate. The first group, which we will call prophylactic use, includes preterm who were administered sodium bicarbonate infusion for 24 hours, having arterial blood gas analysis showing a base deficit less than -5 mmol/L; this group had 42 members. The second group, which we call therapeutic use, includes those who were given continuous bicarbonate infusion for 24 hours after arterial blood gas analysis with a base deficit of more than -5 mmol/L. This group had 58 children. The dependent variable is the presence or absence of intraventricular hemorrhage according to the written report of the transfontanellar ultrasound; this study was performed in all cases by the same certified radiologist, a test being done at least at birth and one week of life.
In order to know if the populations were the same in each variable studied, ANOVA tests, Kruskal-Wallis tests, chi-square, Pearson and Fisher's exact tests were performed. In all tests p <0.05 was taken as statistically significant. To determine whether the independent variables represented a risk to the presence of intraventricular hemorrhage (YES/NO dichotomous variable), logistic regression was done taking as output the presence or lack thereof within the first week of life.
Of the 160 cases examined, 2 groups were formed, one with use (n = 100, 62.5%) and one without use of bicarbonate (n = 60, 37.5%) in the first 24 hours of life. The first subgroup of prophylactic use consists of 42 preterms (42% bicarbonate group and 26.25% of the total).
In the second group, therapeutic use cases were 58 infants (58% of the bicarbonate group and 36.25% of the total). The majority of patients were male with 82 infants (51.2%). Importantly, 10% (16 patients) of all our children had some type of intraventricular hemorrhage. The infants had an average weight of 1,500 grams (± 415.7 g) and a mean gestational age of 31 weeks (± 2.2); the general characteristics of our population are described in Table I.
|Table I Clinical features of the population analyzed (N = 160)|
|Variable||Average (% SD)|
|Gestational age (weeks)||31.4 (2.2)|
|Type of birth|
|Caesarean section||157 (98.1%)|
|< 6||5 (3.1%)|
|Birth weight (grams)||1531.3 (415.7)|
|Rupture of membranes (h)||4.8 (15.2)|
|pH in arterial gas analysis||7.32 (0.07)|
|pCO2 in arterial gas analysis (mmHg)||38.5 (9.5)|
|HCO3 in arterial gas analysis (mmHg)||19.33 (3.21)|
|Base deficit in arterial gases (mmHg)||-5.5 (3.5)|
|Leukocytes (x 103UL)||9.57 (4.7)|
|Hemoglobin (g/dL)||16 (1.8)|
|Platelets (x 103UL)||210.77 (62.1)|
|Amines in the first 24 hours of life
|23 (14.3 ) %)|
|Type of ventilatory support|
|Indirect oxygen||2 (1.2%)|
|Nasal CPAP||19 (11.8%)|
|Mechanical ventilation||50 (31.2%)|
|No support||3 (1.8%)|
|Intraventricular hemorrhage (grade)
|1st week of life||5 (3.1%)|
|After first week of life||4 (2.5%)|
The distribution of sex, mode of delivery, APGAR score at 5 minutes, number of hours post membrane rupture, serum sodium at 24 hours of life, and platelet counts are comparable between the 3 groups, i.e. there is no statistically significant difference. After analysis, the data reveal that there is no difference between the groups regarding the presence or absence of intraventricular hemorrhage in the first week of life. That is, regardless of belonging to any of the groups that were administered bicarbonate, the presence of some degree of intraventricular hemorrhage is equal for all groups (Table II).
|Table II Description of variables by group|
|Without sodium bicarbonate
|Birth weight (grams)||1577.7 ± 419.9||1397.1 * ± 424.4||1628.5 ± 374.5|
|Weeks of gestation||31.3 ± 2.2||30.6** ± 2.5||32.3 ± 1.1|
|Rupture of membranes (h)||7.5 ± 20.0||5.6 ± 15.8||2 ± 9.1|
|Arterial blood gas pH||7.33 ± 0.06||7.29** ± 0.07||7.35 ± 0.08|
|Bicarbonate at intake||21.8 ± 1.5||16.8** ± 2.7||19.9 ± 2.7|
|Serum sodium at 24 hours of life||134.3 ± 6.1||132.7 ± 15||132.5 ± 3.9|
|Leukocytes intake biometrics||10.6 ± 5.6||8.6 * ± 5.1||9.7 ± 3.4|
|Hemoglobin in intake biometrics||16 ± 1.6||15.5 * ± 1.9||16.4 ± 1.8|
|Platelets in intake biometrics||213.4 ± 52.1||201.8 ± 54.9||217.5 ± 73.8||*p ≤ 0.05; **p≤ 0.001|
Among the variables that were significantly different between groups (p <0.05) are: birth weight, weeks of pregnancy, arterial blood gas pH, and the amount of bicarbonate in arterial gases; all these variables were lower in newborns of groups in which bicarbonate was administered. Other variables that were different between groups are the use of pressor amines and type of respiratory support given to infants. It was observed that infants in the therapeutic use subgroup had increased use of pressor amines and a higher percentage of mechanical ventilation.
To determine whether our independent variables pose a risk of intraventricular hemorrhage, a logistic regression was done with its presence or absence as outcome. Two variables associated with intraventricular hemorrhage were observed; the first is birth weight, where an odds ratio of 0.99 was observed, with a confidence interval of 95% between 0.997-0.998 and p <0.001. The second variable associated with intraventricular hemorrhage was the administration of sodium bicarbonate/ kg weight/ 24 h, where an odds ratio of 1.22 was observed, with 95% CI 1.02-1.47 and p <0.05.
In our population, the percentage of intraventricular hemorrhage was 10%, considering the average weeks of gestation (31 weeks) and the average weight of 1,500 grams, this value is similar to that reported in international series;1 that is, our premature population has this condition similarly to that reported in relation to birth weight and gestational weeks, being only slightly higher than those reported by the NICHD.3
Noting our two populations and subgroups with their behavior, we can conclude that our groups are not homogeneous. Those infants who were given bicarbonate, especially those for whom it was therapeutic, were clearly lower birth weight and smaller in weeks of gestation; also they behaved less favorably because they required more assisted ventilation and hemodynamics. With this information we might dare to conclude that they were newborns in generally more severe condition. Importantly, despite this difference in severity, presence of intraventricular hemorrhage (taking as presence or absence without stratifying by degrees,) was the same in all three groups.
However, when doing logistic regression to establish whether any of our variables meant by itself a risk of intraventricular hemorrhage, we note that birth weight has a huge impact, with p <0.01. It was determined that for every gram of weight for patient, (compared with another of the same characteristics) the risk of intraventricular hemorrhage decreases by 1%. This finding in our population reaffirms observations by international studies.1,2
On the other hand, taking as independent variable bicarbonate administration, we observed that there is a 1.22 fold risk of presenting IVH for every mEq/kg/24 h bicarbonate used, comparing two infants with the same birth weight. That is, eliminating another factor associated with observed bleeding (birthweight) for two infants, one who is administered bicarbonate and another who is not, the patient receiving the measure will have a risk 1.2 times that of the other patient. With these data we can take the therapeutic or prophylactic use of bicarbonate as confounding factors. For the authors of this work it is very important to individualize each case and determine whether the average benefits of the clinical intervention outweigh the risk of raising the probability of intraventricular hemorrhage brought by prematurity. It is clear that studies of large numbers of infants are required to devise a general policy for neonatologists.
Our study has limitations, since it is a single hospital. However, internationally most are single-center studies with small samples. In our study a broader sample of infants was achieved. No similar studies have been published in this country. We attempted to reduce bias especially of memory, by having all the data logged on the record in writing, corroborating bicarbonate administration with medical records (indications) and nursing records. Patient follow-up was strict, reviewing all documents within the first week of life. They were classified strictly based on the use or non-use of bicarbonate and arterial blood gas data with written results. Importantly, the meta-analysis by Cochrane15 indicates the need for many more studies, with larger samples to reach a formal recommendation. Our work makes a contribution in this regard. We believe that the treating physician should take into account the possibility of cerebral hemorrhage associated with the use of bicarbonate when making the balance between risk and reward, which is not a trivial consideration.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.