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Association of inotrope use with neurodevelopmental outcomes in infants
The Journal of Maternal-Fetal & Neonatal Medicine
Abstract
Objective
The primary objective was to compare neurodevelopmental (ND) outcomes at 18–24 months in preterm infants <29 weeks gestational age (GA) who received versus those who did not receive inotropes in the first week of life. The secondary objective was to assess ND outcomes according to the duration of inotropic support in the first week of life (≤3 or >3 days).
Study design
Retrospective population-based cohort study of preterm infants <29 weeks GA admitted to participating neonatal intensive care units (NICUs) of the Canadian Neonatal Network (CNN) from January 2010 to September 2011 with follow-up data available at 18–24 months. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Long-term outcomes were categorized as neurodevelopmental impairment (NDI) and significant neurodevelopmental impairment (sNDI), and effect modification due to other neonatal morbidities including receipt of antenatal steroids, GA, small for gestational age (SGA) status, sex, score for neonatal acute physiology (SNAP-II) >20, postnatal steroids, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) grade ≥3/periventricular leukomalacia (PVL), early- and late-onset sepsis, retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC) was assessed. Maternal and infant demographic characteristics and short- and long-term outcomes were compared using Pearson’s Chi-square test for categorical variables and Student’s t-test or the Wilcoxon rank test for continuous variables. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analysis.
Results
Of the 491 (18.7%) eligible preterm infants who received inotropes during the first week of life, 314 (64%) survived to NICU discharge and 245 (78%) had ND outcome data available. A total of 1775 eligible preterm infants did not receive inotropes in the first week of life; 1647 (92.7%) survived to NICU discharge and 1149 (70%) had ND outcome data. Maternal and infant characteristics associated with infants receiving inotropes included: younger maternal age, clinical chorioamnionitis, no antenatal steroids, outborn, lower GA, BW and Apgar scores at both one and five minutes; and higher SNAP-II scores (p < .05). Infants who received inotropes in the first week of life were more likely to be require postnatal steroids, had higher rates of BPD, IVH grade ≥3/PVL, early- and late-onset sepsis, ROP, NEC and mortality (p < .05). Infants who received inotropes in the first week of life also had higher rates of sensorineural or mixed hearing loss with an AOR (95% CI) of 1.99 (1.13, 3.49). After adjusting for confounding variables, there was no difference in the risk of NDI or sNDI between infants who did and did not receive inotropes in the first week of life. Of the infants with neurodevelopmental outcome data available, 186 received inotropes for ≤3 days and 59 for >3 days. After adjusting for confounding variables there was no difference in the risk of NDI or sNDI. Infants who received inotropes for >3 days were more likely to have lower BSID-III cognitive [AOR 2.43 95% CI (1.03, 5.76)] and motor scores <85 [AOR 2.38 95% CI (1.07, 5.30)] respectively.
Conclusions
In this large, population-based cohort, infants who received inotropes in the first week of life were at increased risk for sensorineural or mixed hearing loss. There was no difference in NDI or sNDI after adjusting for confounding variables. A longer duration of inotrope use in the first week of life was associated with lower BSID-III cognitive and motor scores, but no difference in overall NDI or sNDI.
... Inotropic score (IS) is a standard formula based on dopamine, dobutamine, and epinephrine dosages that was first described in the Boston Circulatory Arrest Study [14] and later used as a measure of postoperative pharmacologic cardiac support. As IS was adopted into clinical use, many studies showed that myocardial dysfunction could be a marker of disease severity, morbidities, and mortality after heart surgery; however, current knowledge is scarce about its use in HIE-associated mortality [14][15][16][17][18]. ...
... Türker et al. [13] identified cord cardiac troponin I as the most sensitive factor in predicting early death, with a cut-off value of 4.6 ng/mL; however, unlike our results, they found that CK-MB was also significant in predicting mortality. In another study, the troponin I cut-off value for predicting mortality was 8.1 mg/ml [16]. The different cut-off values reported in the literature may be due to differences Our results confirmed previous studies however, to our knowledge, it has the largest sample size, which includes 141 moderate to severe HIE infants. ...
... There are no data regarding the measurement of inotropic support using a standard formula based on dose and drug potency and its association with prognosis. In pediatric heart surgery patients, low cardiac output syndrome and maximum IS were strongly correlated with mortality, mechanical ventilation time, and length of hospital stay [14][15][16][17]. Our study demonstrated that maximum IS increased by the HIE stage and changed significantly with troponin I in surviving and non-surviving HIE infants. ...
Purpose
Cardiovascular dysfunction is common in hypoxic-ischemic encephalopathy (HIE), which is one of the leading causes of multi-organ failure in neonates. We aimed to assess troponin I and creatine kinase myocardial band (CK-MB) levels, inotropic score (IS) in HIE patients, and their associations with HIE staging and mortality.
Method
The medical records of all HIE infants admitted to our unit between 2016 and 2018 were retrospectively analyzed. Demographic characteristics of the infants, seizures, anticonvulsive therapies, maximum inotrope doses, and the derived IS (dopamine dose [µg/kg/min] + dobutamine dose [µg/kg/min] + 100 × epinephrine dose [µg/kg/min]) and CK-MB and troponin-I levels obtained in the first six hours of life were compared according to HIE staging. Comparisons between survivors and non-survivors were made.
Results
The study included data from 195 patients. Twenty-five patients were classified as stage 3, 116 as stage 2, and 54 as stage 1 HIE. Median Troponin-I, CK-MB level, and IS significantly differed by HIE staging (p < 0.01). The deceased infants had significantly higher median troponin I level [0.36 (0.02-3) vs. 0.16 (0.01–1.1) ng/ml; p = 0.006], median IS [20 (5-120) vs. 5 (5–10); p < 0.001], however, CK-MB values were comparable with survivors [129 (51–300) vs. 60.7 (31–300) ng/ml; p = 0.57]. The area under the curve was 0.93 for IS and 0.81 for Troponin I to predict mortality.
Conclusion
Troponin I, CK-MB, and IS could be successfully used as disease severity markers in HIE furthermore, troponin I and IS, are good predictors of mortality. These results need to be confirmed with larger prospective multi-center studies.
... Recent epidemiologic studies have shown that every day of antibiotic exposure in neonates increases mortality and risk of bronchopulmonary dysplasia. 20,21 In addition, neonatal EOS and LOS may lead to long-term neurodevelopmental impairments in survivors, both in humans and in animal models of disease. 22,23,24 This is one of the few studies to report the factors associated with the composite outcome of mortality or severe illness from E. coli sepsis. ...
... However, studies show that hypotension and the need for inotropes are associated with neurodevelopmental impairment (NDI) in preterm infants. 20,37 This study adds to the current wealth of knowledge of E. coli sepsis in the neonatal population and the relationship between various host and pathogen factors contributing to poor outcomes. ...
Background: Neonatal Escherichia coli (E. coli) sepsis is increasing. There is limited data on the factors which contribute to increased mortality and severity of illness in neonatal E. colisepsis.
Methods: Retrospective review of neonates (<30 days) admitted to a Level IV NICU in the United States from 2008 to 2022 with a diagnosis of E. coli bloodstream or cerebrospinal fluid infection was conducted. Primary outcome was defined as mortality from or severe illness during E. coliinfection (defined as need for inotropic support or metabolic acidosis).
Results: E. coli neonatal sepsis rate increased from 2008-2022 (average of 1.12 per 1,000 live births). The primary outcome, which occurred in 50% of cases, was independently associated with prematurity, neutropenia, and thrombocytopenia. Ampicillin resistance was not associated with the primary outcome.
Conclusion: GA, neutropenia, and thrombocytopenia but not ampicillin resistance, are associated with mortality or severe illness from E. colisepsis.
... [9,10] On the other hand, the use of vasoactive drugs, specially dopamine, has been associated with increased morbimortality. [11][12][13][14] As a consequence, the use of inotropes to treat LSBF or even measuring SVCf in clinical practice remain controversial. [9,10,[15][16][17] Our prede ned hypothesis was that attaining a normal and stable SBF during the transitional period may preserve brain perfusion and contribute to prevent ischemic brain injury. ...
Purpose:To determine whether the application of a protocolized early echocardiographic screening for low systemic blood flow and guided inotropic therapy is associated with reduced intraventricular hemorrhage in preterm infants.
Methods: Prospective, observational multicenter study between September 2020 and September 2021 in nine neonatal intensive care units. Preterm infants below 33 weeks of gestational age were eligible. The exposure variable was early targeted neonatal echocardiography screening for low systemic blood flow. Five of the centers performed early screening and guided inotrope therapy (intervention group), and 4 centers did not (control group). Our main outcome was >grade II intraventricular hemorrhage or death within the first 7 days of life. Inverse probability of treatment weighting based on the propensity score accounting for the clustered nature of data was used for the main analysis.
Results: 332 preterm infants (131 in the intervention group and 201 in thecontrol group) were included. Protocolized early echocardiography screening for low systemic blood flow and guided inotropic treatment was associated with a significant reduction in > grade II intraventricular hemorrhage or early death (odds ratio 0.285 (95% CI: 0.133-0.611); p=0.001)
Conclusions: Early echocardiography screening for low systemic blood flow and guided inotropic treatment may reduce the incidence of intraventricular hemorrhage in preterm infants.
... Concerning clinical practice, a survey of 60 Spanish NICUs unveils that 100% delay enteral feeding when there is a hemodynamic failure (52). Considering that we analyzed data from a purely observational cohort, our findings do not allow at this stage to suggest different approaches to minimize inotrope treatments with uncertain cognitive outcomes (53). However, this study contributes evidence on the potential role of very early HM feeding in improving the quality of care of newborn infants with signs of shock and might boost further research on the most effective feeding practices for this group of neonates. ...
Background
Regarding neonatal hypotension, there is no certainty as to whether inotrope properties are beneficial or whether they may be harmful. However, given that the antioxidant content of human milk plays a compensatory role in neonatal sepsis and that human milk feeding has direct effects in modulating the cardiovascular function of sick neonates, this research hypothesized that human milk feeds might predict lower requirements of vasopressors in the management of neonatal septic shock.
Method
Between January 2002 and December 2017, all late preterm and full-term infants attending a neonatal intensive care unit, with clinical and laboratory findings of bacterial or viral sepsis, were identified in a retrospective study. During their first month of life, data on feeding type and early clinical characteristics were collected. A multivariable logistic regression model was constructed to determine the impact of human milk on the use of vasoactive drugs in septic newborns.
Results
322 newborn infants were eligible to participate in this analysis. Exclusively formula-fed infants were more likely to be delivered via C-section, to have a lower birth weight and a lower 1-minute Apgar score than their counterparts. Human milk-fed newborns had 77% (adjusted OR = 0.231; 95% CI: 0.07–0.75) lower odds of receiving vasopressors than exclusively formula-fed newborns.
Conclusion
We report that any human milk feeding is associated with a decrease in the need for vasoactive medications in sepsis-affected newborns. This observation encourages us to undertake further research to determine whether human milk feeds mitigate the use of vasopressors in neonates with sepsis.
Background
We conducted a nationwide population-based case-control study to analyse potential predisposing factors for hearing loss (HL) that present during the fetal, perinatal, and postnatal periods in prematurely born children.
Design
This study enrolled 21,576 children born at < 37 weeks of gestation; 3,596 with HL and 17,980 with normal hearing born between 2002 and 2015, matched for sex, age at diagnosis, and enrollment time. Data were abstracted from the concatenation of three nationwide databases for overall risk factors till the diagnosis of HL.
Results
Maternal HL, maternal diabetes, particularly type 1 diabetes mellitus, and at or before 32 weeks of gestation were the major obstetric risk factors for HL. Prematurely born children who were born via cesarean section and received a combination of antenatal steroids and magnesium sulfate exhibited a significantly reduced risk of developing HL. Ear malformation was a critical predictor for HL. The major postnatal risk factors included seizure and ototoxic drugs use. Premature infants diagnosed with more than 1 diagnosis of bronchopulmonary dysplasia, necrotizing enterocolitis, and intracerebral hemorrhage were at an increased risk of developing HL. Congenital CMV infection and recurrent acute otitis were also independent postnatal factors for HL in prematurely born children.
Conclusions
To reduce the incidence of childhood HL in prematurely born children, aggressive management of premature birth-related consequences and treatable causes and longitudinal audiological follow-up with early detection and adequate intervention are crucial.
Anti-hypotensive treatment, which includes dopamine, dobutamine, epinephrine, norepinephrine, milrinone, vasopressin, terlipressin, levosimendan, and glucocorticoids, is a long-established intervention in neonates with arterial hypotension (AH). However, there are still gaps in knowledge and issues that need clarification. The main questions and challenges that neonatologists face relate to the reference ranges of arterial blood pressure in presumably healthy neonates in relation to gestational and postnatal age; the arterial blood pressure level that potentially affects perfusion of critical organs; the incorporation of targeted echocardiography and near-infrared spectroscopy for assessing heart function and cerebral perfusion in clinical practice; the indication, timing, and choice of medication for each individual patient; the limited randomized clinical trials in neonates with sometimes conflicting results; and the sparse data regarding the potential effect of early hypotension or anti-hypotensive medications on long-term neurodevelopment. In this review, after a short review of AH definitions used in neonates and existing data on pathophysiology of AH, we discuss currently available data on pharmacokinetic and hemodynamic effects, as well as the effectiveness and safety of anti-hypotensive medications in neonates. In addition, data on the comparisons between anti-hypotensive medications and current suggestions for the main indications of each medication are discussed.
Objective:
To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct).
Methods:
A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age.
Results:
VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs.
Conclusion:
High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.
Background
There is little evidence regarding the outcome of the inotropes accepted for treating neonatal hypotension. Even more, there is no certainty as to whether inotrope properties are beneficial or whether they may be harmful. However, given that the antioxidant content of human milk plays a compensatory role in neonatal sepsis and that human milk feeding has direct effects in modulating the cardiovascular function of sick neonates, this research hypothesized that human milk feeds might predict lower requirements of vasopressors in the management of neonatal septic shock.
Method
Between January 2002 and December 2017, all late preterm and full-term infants attending a neonatal intensive care unit, with clinical and laboratory findings of bacterial or viral sepsis, were identified in a retrospective study. During their first month of life, data on feeding type and early clinical characteristics were collected. A multivariable logistic regression model was constructed to determine the impact of human milk on the use of vasoactive drugs in septic newborns.
Results
322 newborn infants were eligible to participate in this analysis. Exclusively formula-fed infants were more likely to be delivered via C-section, to have a lower birth weight and a lower 1-minute Apgar score than their counterparts. Human milk-fed newborns had 77% (adjusted OR = 0.231;95%CI 0.07 to 0.75) lower odds of receiving vasopressors than exclusively formula-fed newborns.
Conclusion
We report that any human milk feeding is associated with a decrease in the need for vasoactive medications in sepsis-affected newborns. This observation encourages us to undertake further research to determine whether human milk feeds mitigate the use of vasopressors in neonates with sepsis.
Umbilical venous catheters (UVCs) are routinely inserted in preterm infants for total parenteral nutrition, medications, and blood sampling. The unique course of the umbilical vein, and the associated hemodynamic instability during sampling or infusion via UVCs place preterm infants at a higher risk of intraventricular hemorrhage (IVH). Alternative central line placement would theoretically avoid the swinging of cerebral blood flow and reduce chances of IVH development.
PURPOSE To examine whether the rates of severe IVH or death vary among preterm infants receiving UVCs compared to peripherally inserted central catheters (PICCs).
METHODS This randomized, controlled unmasked trial was conducted at the neonatal intensive care unit of Dubai Hospital between January 2018 and December 2021. A total of 280 preterm infants (born at 23-30 weeks gestation) were randomly assigned after birth to either the UVC placement group or the PICC group.
MAIN OUTCOMES AND MEASURES The primary outcome was a composite of severe IVH or death among preterm infants less than 30 weeks gestation with UVC vs PICC. The secondary outcomes were the incidence of neonatal sepsis, necrotizing enterocolitis, any grade of IVH, and feeding intolerance.
RESULTS Among the 223 preterm infants randomized (median gestational age, 27 weeks [interquartile range, 26-29]; male: UVC group, 59 [49%]; PICC group, 63 [61%]), 120 (53%) were randomized to the UVC group and 103 infants (47%) were randomized to the PICC group. Severe IVH occurred in 16 infants (13.3%) in the UVC group and 11(10.7%) in the PICC group (risk difference [RD], 2.6% [95% CI, -5.9 to 11.1]; P = 0.55). The incidence of death before 28 days of life did not differ significantly between groups (10 [8.3%] in UVC vs 6 [5.8%] in PICC; RD, 2.5% [95% CI, −4.1% to 9.1%]; P = 0.47). Sixteen percent (20/120) of the UVC group died or developed severe IVH compared with 13% (14/103) of the PICC group (risk difference, 1.7% [95% CI, −7.3% to 10.9%]; P = 0.57). Logistic regression analysis showed that gestational age rather than birth weight and early inotropic support were significant risk factors for severe IVH occurrence in preterm infants [OR= 0.75, (95% CI, 0.58-0.99); p=0.042], and [OR= 3.15, (95% CI, 1.18-8.38); p=0.022]. The incidence of necrotizing enterocolitis was significantly higher in the UVC group infants than in the PICC group infants (7.5% vs. 2%); p = 0.04.
CONCLUSION This study found that the incidence of severe IVH or death did not differ significantly among preterm infants <30 weeks gestation subjected to UVC or PICC placement. Gestational age rather than birth weight and early inotropic support were significant risk factors for the development of severe IVH. Umbilical venous catheter is an additional risk factor for the development of NEC, but further research is required to validate this finding.
TRIAL REGISTRATION ANZCTR Identifier: ACTRN12617001049369.
Objective
To compare outcomes at hospital discharge for preterm infants born before 29 weeks of gestation who had at least one episode of isolated hypotension during their first 72 hours of life for which they did or did not receive antihypotensive treatment.
Design
Etude Epidémiologique sur les Petits Ages Gestationnels 2 (EPIPAGE 2) French national prospective population-based cohort study in 2011.
Setting
60 neonatal intensive care units.
Patients
All infants with a minimum mean arterial blood pressure less than gestational age (in weeks) (minMAP<GA) within 72 hours of birth. Infants whose reason for receiving antihypotensive treatments was isolated hypotension only were compared with untreated hypotensive infants by propensity score matching.
Treatments
Fluid bolus and/or inotropes and/or corticosteroids.
Main outcomes and measures
The primary outcome was survival at hospital discharge without major morbidity, defined as any of necrotising enterocolitis, severe cerebral abnormalities, severe bronchopulmonary dysplasia or severe retinopathy of prematurity.
Results
Among the 1532 infants with available data, 662 had a minMAP<GA; 206 were treated for unknown or other reasons than isolated hypotension, 131 were treated for isolated hypotension only and 325 were untreated; 119 infants from each of these last two groups were matched. Treated infants had a significantly higher survival rate without major morbidity (61.3% vs 48.7%; OR, 1.67, 95% CI 1.00 to 2.78, p=0.049) and a lower rate of severe cerebral abnormalities (10.1% vs 26.5%, p=0.002).
Conclusions
In this population, antihypotensive treatment was associated with improved short-term outcomes. Therapeutic abstention should be cautiously considered for early isolated hypotension in extremely premature infants.
Objective To investigate the relationships between early blood pressure (BP) changes, receipt of antihypotensive therapy and 18–22 months’ corrected age (CA) outcomes for extremely preterm infants.
Design Prospective observational study of infants 230/7–266/7 weeks’ gestational age (GA). Hourly BP values and antihypotensive therapy exposure in the first 24 h were recorded. Four groups were defined: infants who did or did not receive antihypotensive therapy in whom BP did or did not rise at the expected rate (defined as an increase in the mean arterial BP of ≥5 mm Hg/day). Random-intercept logistic modelling controlling for centre clustering, GA and illness severity was used to investigate the relationship between BP, antihypotensive therapies and infant outcomes.
Setting Sixteen academic centres of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
Main outcome measures Death or neurodevelopmental impairment/developmental delay (NIDD) at 18–22 months’ CA.
Results Of 367 infants, 203 (55%) received an antihypotensive therapy, 272 (74%) survived to discharge and 331 (90%) had a known outcome at 18–22 months’ CA. With logistic regression, there was an increased risk of death/NIDD with antihypotensive therapy versus no treatment (OR 1.836, 95% CI 1.092 to 3.086), but not NIDD alone (OR 1.53, 95% CI 0.708 to 3.307).
Conclusions Independent of early BP changes, antihypotensive therapy exposure was associated with an increased risk of death/NIDD at 18–22 months’ CA when controlling for risk factors known to affect survival and neurodevelopment.
Clinical trial registration number clinicaltrials.gov #NCT00874393.
Introduction:
A number of illness severity scores have evolved which would predict mortality and morbidity in intensive care units. One such scoring system developed by Richardson was SNAPPE-II (Score for Neonatal Acute Physiology with Perinatal extension-II).
Aim:
The present study was conducted to assess the validity of SNAPPE-II score as a predictor of mortality and morbidity.
Materials and methods:
A total of 248 neonates who met the inclusion criteria were included in the study and SNAPPE-II score was calculated. Receiver Operating Characteristic (ROC) curve was constructed to derive the best cut-off score and SPSS package (Statistical Package for the Social Sciences) was used for statistical analysis.
Results:
SNAPPE-II score was higher among expired neonates compared to survived ones. A mean score of 37 was associated with higher mortality. However, it didn't accurately predict the length of stay.
Conclusion:
SNAPPE II score is a better predictor of mortality irrespective of gestational ages and it is not a good predictor of morbidity.
Objective
To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants.
Study Design
Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 hours.
Results
A cohort of 367 infants had 18,709 ABP measurements recorded. ABP decreased for the first three hours, reached a nadir at 4 – 5 hours, then increased at an average rate of 0.2 mmHg / hour. The rise in ABP from hour 4 – 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135), or dopamine (n=92). GA specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA.
Conclusion
Arterial blood pressure increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.
Many practitioners routinely treat infants whose mean arterial blood pressure in mm Hg is less than their gestational age in weeks (GA).
To assess the effectiveness of utilising a combined approach of clinical signs, metabolic acidosis and absolute blood pressure (BP) values when deciding to treat hypotension in the extremely low birthweight (ELBW) infant.
Retrospective cohort study of all live born ELBW infants admitted to our neonatal intensive care unit over a 4-year period. Patients were grouped as either normotensive (BP never less than GA), hypotensive and not treated (BP<GA but signs of good perfusion; we termed this permissive hypotension) and hypotensive treated (BP<GA with signs of poor perfusion).
118 patients were admitted during this period. Blood pressure data were available on 108 patients. 53% of patients were hypotensive (mean BP in mm Hg less than GA in weeks). Treated patients had lower birth weight and GA, and significantly lower blood pressure at 6, 12, 18 and 24 h. Normotensive patients and patients designated as having permissive hypotension had similar outcomes. Mean blood pressure in the permissive group increased from 26 mm Hg at 6 h to 31 mm Hg at 24 h. In a logistic regression model, treated hypotension is independently associated with mortality, odds ratio 8.0 (95% CI 2.3 to 28, p<0.001).
Blood pressure spontaneously improves in ELBW infants during the first 24 h. Infants hypotensive on GA criteria but with clinical evidence of good perfusion had as good an outcome as normotensive patients. Treated low blood pressure was associated with adverse outcome.
Very low birth weight infants are vulnerable to hypotension and its associated complications. Vasopressors are used to raise blood pressure (BP), but indications for use are uncertain. Our objectives were (1) to study variations in BP stability among NICUs, (2) to investigate inter-NICU differences in vasopressor use, and (3) to address the association between intraventricular hemorrhage (IVH) and abnormal BPs.
A total of 1288 infants with birth weight <1500 g were admitted to six NICUs in Massachusetts and Rhode Island over 21 months. The lowest and highest mean BPs were collected within the first 12 hours. Also recorded were the use of vasopressors within the first 24 hours and the occurrence of IVH. Logistic regressions were used to model outcomes, controlling for gestational age and illness severity using the Score for Neonatal Acute Physiology.
Two of the six NICUs had significantly higher percentages of infants with at least one hypotensive BP, with prevalences of 24% to 45%. Percentages of infants treated with vasopressors ranged from 4% to 39%. This range of vasopressor use could not be explained by inter-NICU differences in birth weight, illness severity, or rates of hypotension. We found a borderline association between severe IVH and hypotension (odds ratio 1.6, p=0.055), but not between severe IVH and hypertension.
Wide differences exist in the prevalence of hypotension, hypertension, and vasopressor use among NICUs. We also found an association between hypotension and IVH, but not between hypertension and IVH.
Volume expansion is used commonly in preterm infants to treat presumed hypovolaemia. However, the amount that should be given is uncertain. We present data that were obtained from anonymised regional case notes of Project 27/28, a national case-controlled study run by the Confidential Enquiry into Stillbirths and Deaths in Infancy. Various clinical parameters were analysed, including the volume expansion administered during the first 48 h of life. All deaths in the first year of the study in the West Midlands (cases, n = 22) and matched regional controls (survivors, n = 29) were included. The primary outcome was death within 28 days. Sixteen of the 22 deaths were considered 'not inevitable' on the basis of the neonates' condition at birth. These newborns received on average more than twice the volume expansion compared with controls in the first 48 h of life (38.2 vs. 18.2 mL/kg, P = 0.007). There were no significant differences between the groups in lowest blood pressure or base deficit within the first 12 h of life. Newborns who received >or= 30 mL/kg volume expansion in the first 48 h of life were more likely to die than those who received < 30 mL/kg (OR 4.5 [95% CI 1.2, 17.2]). Our data suggest that administration of >or= 30 mL/kg volume expansion is associated with increased mortality in neonates of 27-28 weeks' gestation. Unless there is clear evidence of hypovolaemia, clinicians should exercise caution when prescribing volume expansion.
Whether extremely low birth weight (ELBW) infants are at risk of cerebral hypoperfusion is uncertain because key issues concerning their cerebral blood flow (CBF) and mean arterial pressure (MAP) are unresolved: (1) whether CBF is pressure-passive or autoregulated; (2) the normal level of MAP; and (3) whether inotropic drugs used to increase MAP might inadvertently impair CBF. We addressed these issues in ELBW infants undergoing intensive care.
CBF (measured by near-infrared spectroscopy) and MAP were measured in 17 infants aged 1.5 to 40.5 hours.
Five infants remained normotensive (MAP 37 +/- 2 mm Hg, [mean +/- SEM]); twelve became hypotensive (MAP 25 +/- 1 mm Hg) and were treated with dopamine (10-30 mug x kg(-1) per min). CBF of hypotensive infants (14 +/- 1 mL x 100 g(-1) per min) was lower than the CBF of normotensive infants (19 +/- mL x 100 g(-1) per min). After commencement of dopamine in hypotensive infants, MAP increased (29 +/- 1 mm Hg) and CBF also increased (18 +/- 1 mL x 100g(-1) per min). CBF was correlated with MAP in hypotensive infants before (R = 0.62) and during (R = 0.67) dopamine, but not in normotensive infants. A breakpoint was identified in the CBF versus MAP autoregulation curve of untreated infants at MAP = 29 mm Hg; no breakpoint was evident in dopamine-treated infants.
In ELBW infants (1) cerebral autoregulation is functional in normotensive but not hypotensive infants; (2) a breakpoint exists at approximately 30 mm Hg in the CBF-MAP autoregulation curve; and (3) dopamine improves both MAP and CBF.
The goals were to identify the blood pressures of extremely low gestational age newborns that prompt intervention, to identify other infant characteristics associated with receipt of therapies intended to increase blood pressure, and to assess the interinstitutional variability in the use of these therapies.
The cohort included 1507 extremely low gestational age newborns born at 23 weeks to 27 weeks of gestation, at 14 institutions, between March 2002 and August 2004; 1387 survived the first postnatal week. Blood pressures were measured as clinically indicated. Interventions were grouped as any treatment (ie, vasopressor and/or fluid boluses of >10 mL/kg) and vasopressor treatment, and logistic regression analyses were performed.
At each gestational age, the lowest mean arterial pressures in treated and untreated infants tended to increase with advancing postnatal age. Infants who received any therapy tended to have lower mean arterial pressures than infants who did not, but uniform thresholds for treatment were not apparent. The proportion of infants receiving any treatment decreased with increasing gestational age from 93% at 23 weeks to 73% at 27 weeks. Treatment nearly always began during the first 24 hours of life. Lower gestational age, lower birth weight, male gender, and higher Score for Neonatal Acute Physiology-II values were associated with any treatment and vasopressor treatment. Institutions varied greatly in their tendency to offer any treatment and vasopressor treatment. Neither the lowest mean arterial pressure on the day of treatment nor other characteristics of the infants accounted for center differences in treatment.
Blood pressure in extremely premature infants not treated for hypotension increased directly with both increasing gestational age and postnatal age. The decision to provide treatment was associated more strongly with the center where care was provided than with infant attributes.
Background Neonatal databases worldwide have become a prominent tool for benchmarking, evaluation of outcomes, and quality improvement initiatives. We aimed to assess the precision of the Canadian Neonatal Network (CNN) database by conducting an internal audit of data extraction.
Methods An audit was conducted in all 31 neonatal units participating in the CNN. Ninety-five data items selected for reabstraction were classified into categories (critical, important, less important) based on predefined agreement rates. Five records were randomly selected at each site for reabstraction, including one short (3–7 days), two medium (8–12 days), and two long (18–22 days) stay cases. Agreement rates for each data item were calculated for individual units and across the network.
Results A total of 155 cases and 14,725 data fields were reabstracted. The overall agreement rates for critical, important, and less important data items were 98.0, 96.1, and 96.3%, respectively. Individual site variation for discrepancies ranged between 0.2 and 12.8% for all collected data items.
Conclusion Neonatal data extraction within the CNN database structure exhibited high precision; thereby, revealing the reliability of our data abstraction for neonatal demographic, processes of care, and outcomes information. An independent external audit of data extraction would be beneficial.
Objectives
Identify determinants of neurodevelopmental outcome in preterm children.
Methods
Prospective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death.
Results
Of the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38%–51%) had a NDI, 17% (11%–23%) had a sNDI, 6.4% (3.1%–8.6%) had CP, 2.6% (2.5%–13.3%) had hearing aids or cochlear implants and 1.6% (0%–3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3–4.3, 0.04–3.5 and 0.12–1.96, respectively.
Conclusion
Most preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes.
Objective:
To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.
Methods:
Prospective observational study of infants 23(0/7) to 26(6/7) weeks' gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.
Results:
Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.
Conclusions:
Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.
Objective:
To compare neonatal outcomes between infants who received inotropes and those who did not, and identify variation in inotrope use.
Study design:
Retrospective review of data from neonates < 29 weeks gestation collected by the Canadian Neonatal Network during 2003 to 2010. After controlling for confounders and maternal/infant characteristics, rates of mortality and major morbidity were compared between those who received inotropes on days 1 and 3 of admission and those who did not. Rate of inotrope use was compared between sites.
Results:
Inotropes were administered to 772 (10%) of the 7,913 neonates. Infants who received inotropes had significantly higher illness severity, surfactant use, and need for mechanical ventilation. Inotrope use was also associated with significantly higher rates of mortality (adjusted odds ratio [AOR] = 2.05 [1.64, 2.57]), retinopathy of prematurity (AOR = 2.04 [1.54, 2.71]), intraventricular hemorrhage (AOR = 1.59 [1.29, 1.93]), bronchopulmonary dysplasia (AOR = 1.38 [1.11, 1.72]), and necrotizing enterocolitis (AOR = 2.06 [1.59, 2.67]). Rates of inotrope use varied significantly between participating sites (0-36%; AOR = 0 [0, 0.1]-7.7 [2.9, 21]).
Conclusion:
Risk of mortality and major morbidities were significantly higher in neonates who received inotropes. Inotrope use varied significantly among Canadian neonatal intensive care units.
Despite substantial progress in prevention of perinatal group B streptococcal (GBS) disease since the 1990s, GBS remains the leading cause of early-onset neonatal sepsis in the United States. In 1996, CDC, in collaboration with relevant professional societies, published guidelines for the prevention of perinatal group B streptococcal disease (CDC. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR 1996;45[No. RR-7]); those guidelines were updated and republished in 2002 (CDC. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC. MMWR 2002;51[No. RR-11]). In June 2009, a meeting of clinical and public health representatives was held to reevaluate prevention strategies on the basis of data collected after the issuance of the 2002 guidelines. This report presents CDC's updated guidelines, which have been endorsed by the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the American College of Nurse-Midwives, the American Academy of Family Physicians, and the American Society for Microbiology. The recommendations were made on the basis of available evidence when such evidence was sufficient and on expert opinion when available evidence was insufficient. The key changes in the 2010 guidelines include the following: • expanded recommendations on laboratory methods for the identification of GBS, • clarification of the colony-count threshold required for reporting GBS detected in the urine of pregnant women, • updated algorithms for GBS screening and intrapartum chemoprophylaxis for women with preterm labor or preterm premature rupture of membranes, • a change in the recommended dose of penicillin-G for chemoprophylaxis, • updated prophylaxis regimens for women with penicillin allergy, and • a revised algorithm for management of newborns with respect to risk for early-onset GBS disease. Universal screening at 35-37 weeks' gestation for maternal GBS colonization and use of intrapartum antibiotic prophylaxis has resulted in substantial reductions in the burden of early-onset GBS disease among newborns. Although early-onset GBS disease has become relatively uncommon in recent years, the rates of maternal GBS colonization (and therefore the risk for early-onset GBS disease in the absence of intrapartum antibiotic prophylaxis) remain unchanged since the 1970s. Continued efforts are needed to sustain and improve on the progress achieved in the prevention of GBS disease. There also is a need to monitor for potential adverse consequences of intrapartum antibiotic prophylaxis (e.g., emergence of bacterial antimicrobial resistance or increased incidence or severity of non-GBS neonatal pathogens). In the absence of a licensed GBS vaccine, universal screening and intrapartum antibiotic prophylaxis continue to be the cornerstones of early-onset GBS disease prevention.
To evaluate in extremely low gestational age newborns, relationships between indicators of hypotension during the first 24 postnatal hours and developmental delay at 24 months of age.
The 945 infants in this prospective study were born at <28 weeks, were assessed for three indicators of hypotension in the first 24 postnatal hours, and were evaluated with the Bayley Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 24 months corrected age. Indicators of hypotension included: (1) mean arterial pressure in the lowest quartile for gestational age; (2) treatment with a vasopressor; and (3) blood pressure lability, defined as the upper quartile for the difference between the lowest and highest mean arterial pressure. Logistic regression was used to evaluate relationships between hypotension and developmental outcomes, adjusting for potential confounders.
78% of infants in this cohort received volume expansion or vasopressor; all who received a vasopressor were treated with volume expansion. 26% had an MDI <70 and 32% had a PDI <70. Low MDI and PDI were associated with low gestational age, which in turn, was associated with receipt of vasopressor treatment. Blood pressure in the lowest quartile for gestational age was associated with vasopressor treatment and labile blood pressure. After adjusting for potential confounders, none of the indicators of hypotension were associated with MDI <70 or PDI <70.
In this large cohort of extremely low gestational age newborns, we found little evidence that early postnatal hypotension indicators are associated with developmental delay at 24 months corrected gestational age.
A large proportion of very preterm infants receive treatment for hypotension. The definition of hypotension is unclear, and, currently, there is no evidence that treating it improves outcomes or, indeed, which treatment to choose among the available alternatives. Assessment of circulatory adequacy of the preterm infant requires a careful clinical assessment and may also require ancillary investigations. The most commonly used interventions, fluid boluses and dopamine, are problematic: fluid boluses are statistically associated with worse clinical outcomes and may not even increase blood pressure, whereas dopamine increases blood pressure mostly by causing vasoconstriction and may decrease perfusion. For neither intervention is there any reliable data showing clinical benefit. Prospective trials of intervention for hypotension and circulatory compromise are urgently required.
To compare neurodevelopment (ND) in 3 cohorts of extremely preterm infants: untreated with normal blood pressure (BP), untreated with low BP, and treated with low BP.
We conducted a retrospective study of infants 23 to 25 weeks gestation. Low BP was defined as >or=3 mean arterial pressures <or=25 mm Hg in the first 72 hours of life. Treatment included fluids, inotropes, and corticosteroids.
We examined 67 infants with normal BP, 31 infants with untreated low BP, and 70 infants with treated low BP. A total of 75% survived to be discharged from the hospital, and 95% of survivors had ND assessment. Perinatal variables differed between treated infants with low BP and the other groups. Untreated infants with low BP had similar survival rates, but more cerebral palsy, deafness, or any ND impairment when compared with infants with normal BP. Treated infants with low BP had more mortality, worse ND, and less survival without ND impairment compared with infants who had normal BP. Results were unchanged after logistic regression adjusting for prenatal steroids, maternal education, race, sex, bronchopulmonary dysplasia, and postnatal dexamethasone exposure.
Infants with low BP-regardless of treatment-had worse ND than infants with normal BP. Early low BP may be independently associated with a poor outcome.
We have performed brain scanning by computed tomography on 46 consecutive live-born infants whose birth weights were less than 1,500 gm; 20 of them had evidence of cerebral intraventricular hemorrhage. Nine of the 29 infants who survived had IVH. Four grades of IVH were identified. Grade I and II lesions resolved spontaneously, but there was prominence of the interhemispheric fissue on CT of the infants at six months of age. Hydrocephalus developed in infants with Grade III and IV lesions. Seven of the surviving infants with IVH did not have clinical evidence of hemorrhage. There were no significant differences between the infants with and without IVH in birth weight, gestational age, one- and five-minute Apgar scores, or the need for resuscitation at birth or for subsequent respiratory assistance.
A method of clinical staging for infants with necrotizing enterocolitis (NEC) is proposed. On the basis of assigned stage at the time of diagnosis, 48 infants were treated with graded intervention. For Stage I infants, vigorous diagnostic and supportive measures are appropriate. Stage II infants are treated medically, including parenteral and gavage aminoglycoside antibiotic, and Stage III patients require operation. All Stage I patients survived, and 32 of 38 Stage II and III patients (85%) survived the acute episode of NEC. Bacteriologic evaluation of the gastrointestinal microflora in these neonates has revealed a wide range of enteric organisms including anaerobes. Enteric organisms were cultured from the blood of four infants dying of NEC. Sequential cultures of enteric organisms reveal an alteration of flora during gavage antibiotic therapy. These studies support the use of combination antimicrobial therapy in the treatment of infants with NEC.
We conducted a case-control study of antecedents of bronchopulmonary dysplasia (BPD) in 223 infants enrolled in a prospective, randomized clinical trial of phenobarbital prophylaxis for intracranial hemorrhage. The trial took place at three Boston neonatal intensive care units between June 1981 and April 1984. The 76 babies with BPD had radiographic evidence of the condition and required oxygen therapy for 28 days or more. All 147 control babies survived until day 28 of life without meeting either of these criteria for BPD. Compared with control infants, those with BPD received greater quantities of total, crystalloid, and colloid fluids per kilogram per day in the first 4 days of life. In addition, infants with BPD generally had a net weight gain in the first 4 days of life in contrast to the normal pattern of weight loss seen in control infants. Finally, the infants with BPD were more likely to be given a clinical diagnosis of patent ductus arteriosus and to have received furosemide on days 3 and 4 of life. From these observations we infer that early postnatal phenomena such as excessive fluid therapy may be important in the pathogenesis of BPD.
Neonatal hypotension may be a risk factor for neurologic impairment. Few studies have examined the impact of low blood pressure in extremely low birth weight (ELBW) infants weighing 400 to 999 g on neurodevelopmental outcome.
We set out to explore the relationship between treated hypotension in the first 72 hours of life and perinatal factors, morbidity, and mortality in ELBW infants and then to compare neurosensory outcome in ELBW infants with treated hypotension and those who never received treatment for hypotension.
We performed chart review of all 156 ELBW infants admitted to our level III NICU in 1998-1999. Infants had "treated hypotension" if they received fluid pushes, corticosteroids, and/or vasopressors during the first 72 hours of life in an attempt to increase blood pressure. Follow-up included neurologic examination, Bayley Scales of Infant Development, vision and hearing evaluation. Statistical analysis was performed by using SPSS 11.0. Univariate and multivariate analyses were conducted to determine morbidities associated with treated hypotension.
Fifty-nine infants received treatment for hypotension. Ninety-seven infants did not. The groups had similar race, gender, delivery mode, chorioamnionitis, and maternal socioeconomic status. Thirty-eight (24%) infants expired, including 20 who received treatment for hypotension. Of the 156 infants in the study group, 110 underwent neurodevelopment testing, and 103 were able to undergo complete neurodevelopment testing and Bayley examination. Multivariate analysis controlling for socioeconomic status and neonatal morbidity revealed that treated hypotension is associated with delayed motor development and hearing loss.
Treated hypotension in ELBW infants in the first 72 hours of life is associated with significant short-term and long-term morbidity. Infants with treated hypotension are more likely to have delayed motor development, hearing loss, and death.
Our aims were to identify the range of blood pressure values during the first postnatal week in infants born between 23 and 25 weeks postmenstrual age who were not considered in need of treatment for hypotension, and to describe the clinical course of these untreated infants compared with those who were treated for hypotension. We reviewed retrospectively the charts of 142 consecutive inborn infants over a 6-year period. For 86 infants who survived the first postnatal week without being treated for hypotension, the mean arterial pressure (MAP) increased 0.3 mm Hg/h during the first 24 hours, 0.1 mm Hg/h from the 25th to the 48th hour, and then stabilized for the remainder of the week. MAP values < or = 25 mm Hg were not uncommon and were not associated with apparent consequences. Thirty-five infants treated for hypotension differed significantly from untreated infants in several clinical variables present at birth, suggesting a different degree of fetal compromise. Treated infants were less likely to survive (43 versus 85%; P < 0.001) or survive without a major morbidity (29 versus 53%; P = 0.013) than untreated infants. It was not apparent from our data that the treatment of hypotension was helpful.
Report of a Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians
An international classification of retinopathy of prematurity
Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm
- L A Papile
- J Burstein
- R Burstein