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Ahmed S, Rehman AU, Bibi Z, Iftikhar S, Raza M, Yousuf HMA, Naz F, Shah SAM, Mir SL, Bibi A, Khan WA, Salat MS, Ambreen G, Hussain K. Predictors for poor daily weight gain in preterm neonates exposed to different dose regimens of caffeine in ICU- a retrospective cohort study. BMC Pediatr 2024; 24:401. [PMID: 38898410 PMCID: PMC11188204 DOI: 10.1186/s12887-024-04850-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU. METHOD This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG. RESULTS Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (β=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (β=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (β=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (β=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods. CONCLUSION In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.
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Affiliation(s)
- Saeed Ahmed
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Ayaz Ur Rehman
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Zainab Bibi
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Sundus Iftikhar
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Maleeha Raza
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | | | - Fizzah Naz
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | | | | | - Ayesha Bibi
- Dow University of Health Sciences, Karachi, Pakistan
| | - Wasif Ahmed Khan
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Muhammad Sohail Salat
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan
| | - Gul Ambreen
- Department of Pediatrics & Child Health, Aga Khan University Hospital, Karachi, Pakistan.
| | - Kashif Hussain
- Department of Pharmacy , Aga Khan University Hospital, Karachi, Pakistan
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Hussain I, Kumar M, Ali A, Naz F, Khan WA, Salat MS, Rauf S, Ambreen G, Hussain K. Dose-Response Study of Caffeine on Postnatal Weight Gain in Premature Neonates-A Retrospective Cohort Study. Dose Response 2024; 22:15593258241247185. [PMID: 38617389 PMCID: PMC11016235 DOI: 10.1177/15593258241247185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 03/27/2024] [Indexed: 04/16/2024] Open
Abstract
Background Caffeine citrate (CC)-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side effects (CC-APSEs) result in lower daily weight gain (WG) in premature neonates. This study aimed to assess higher CC-doses' effect on the mean daily-WG (MD-WG) and CC-APSE development, considering 5 mg/kg/day as the standard regimen. Method This retrospective cohort study included neonates of ≤36 weeks gestational age and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I=(5 mg/kg/day), group-II=(>5-7 mg/kg/day), and group-III=(>7 mg/kg/day). Data was analyzed separately for group-II and group-III using group-I as the standard. Results The study included 284 neonates. During phase-I, the MD-WG was significantly higher in group-I than group-II (19.9 ± .88 g/kg/d vs 17.5 ± .49, P = .031) and group-III (19.9 ± .88 g/kg/d vs 16.7 ± .71, P < .001). During 29-42 DOL, the MD-WG of group-I was only significantly higher than group-III (21.5 ± .42 g/kg/d vs 18.1 ± .39 g/kg/d, P = .003) and comparable with group-II. During 15-28 DOL, CC-APSEs were significantly higher in group-II and group-III but during 29-42 DOL was significant only in group-III. Conclusion Exposure to higher caffeine doses in this study cohort is associated with lower postnatal WG in preterm neonates than standard daily doses may be due to its catabolic effects and CC-APSEs.
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Affiliation(s)
- Ijaz Hussain
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Manoj Kumar
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Amin Ali
- Department of Neonatology & Paediatrics, Dow University of Health Sciences, Karachi, Pakistan
| | - Fizzah Naz
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Wasif Ahmed Khan
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | | | - Shahzad Rauf
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Gul Ambreen
- Department of Pharmacy, Aga Khan University Hospital, Karachi, Pakistan
| | - Kashif Hussain
- Department of Pharmacy, Aga Khan University Hospital, Karachi, Pakistan
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Rauf S, Shah S, Bibi Z, Munir R, Jiskani H, Ahmad S, Mir Shah SA, Bibi A, Fasih Ahmad H, Hussain K, Ariff S, Ambreen G. Association of Caffeine Daily Dose With Respiratory Outcomes in Preterm Neonates: A Retrospective Cohort Study. INQUIRY : A JOURNAL OF MEDICAL CARE ORGANIZATION, PROVISION AND FINANCING 2024; 61:469580241248098. [PMID: 38666733 PMCID: PMC11055476 DOI: 10.1177/00469580241248098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024]
Abstract
Apnea and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in preterm neonates (pre-nates) with respiratory distress. Caffeine citrate (CC) is often prescribed for pre-nates in doses of 5-10 mg/kg in 24 h. This study aimed to evaluate the most effective dosage regimen (5 mg/kg/day vs >5-10 mg/kg/day) to prevent apnea and EF with minimal caffeine-associated potential side effects (CC-APSEs) in pre-nates. This one-year retrospective cohort study included all the eligible neonates admitted to NICU and received CC-therapy till 28 days of life (DOL) or discharge. Based on CC-daily dose formed LD-caffeine-group (5 mg/kg/day) and HD-caffeine-group (>5-10 mg/kg/day). Antenatal, prenatal, and postnatal characteristics, CC-regimen, comorbidities, and CC-APSEs were compared between the groups. Predictors of apnea and EF were analyzed through logistic regression. There were 181 and 72 neonates in the LD and HD-caffeine-groups respectively. In HD-caffeine-group daily CC-dose was 7 to 7.5 mg/kg/day in 93% of neonates and >7.5 to 10 mg/kg/day in only 7%. Significantly fewer neonates experienced apnea and EF in the HD-caffeine-group till 28DOL or discharge. This difference was even greater in the subgroup of ≤28 weeks GA (15.6% vs 40.0%; P < .01). In HD-caffeine-group the incidence of severe/moderate-BPD was significantly lower and the frequency of CC-APSEs was higher. Multivariate analysis showed that; the smaller the GA higher the risk of apnea (AOR = 0.510, 95% CI 0.483-0.999) and EF (AOR = 0.787, 95% CI 0.411-0.997). The HD-caffeine was inversely associated with developing apnea (AOR = 0.244, 95% CI 0.053-0.291) and EF (AOR = 0.103, 95% CI 0.098-2.976). IMV-duration before extubation (AOR = 2.229, 95% CI 1.672-2.498) and severe/moderate-BPD (AOR = 2.410, 95%CI 1.104-2.952) had a high risk of EF. Initiating early HD-caffeine may prevent apnea and extubation failure in preterm neonates. Optimization of caffeine initiation time and dosages can be a safe and feasible approach to decrease the burden of neonatal respiratory morbidities.
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Affiliation(s)
| | - Samar Shah
- Naseer Teaching Hospital PESHAWAR, Peshawar, Pakistan
| | - Zainab Bibi
- Aga Khan University Hospital, Karachi, Pakistan
| | | | | | - Saeed Ahmad
- Aga Khan University Hospital, Karachi, Pakistan
| | | | - Aysha Bibi
- Dow University of Health Sciences, Karachi, Pakistan
| | | | | | | | - Gul Ambreen
- Aga Khan University Hospital, Karachi, Pakistan
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Ambalavanan N, Weese-Mayer DE, Hibbs AM, Claure N, Carroll JL, Moorman JR, Bancalari E, Hamvas A, Martin RJ, Di Fiore JM, Indic P, Kemp JS, Dormishian A, Krahn KN, Qiu J, Dennery PA, Ratcliffe SJ, Troendle JF, Lake DE. Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants. Am J Respir Crit Care Med 2023; 208:79-97. [PMID: 37219236 PMCID: PMC10870840 DOI: 10.1164/rccm.202210-1971oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 05/01/2023] [Indexed: 05/24/2023] Open
Abstract
Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.
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Affiliation(s)
| | - Debra E. Weese-Mayer
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Stanley Manne Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anna Maria Hibbs
- University Hospitals Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
| | | | - John L. Carroll
- University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | | | | | - Aaron Hamvas
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Stanley Manne Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Richard J. Martin
- University Hospitals Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
| | - Juliann M. Di Fiore
- University Hospitals Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
| | | | - James S. Kemp
- Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | | | | | - Jiaxing Qiu
- University of Virginia, Charlottesville, Virginia
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Ambreen G, Kumar M, Ali A, Shah SAA, Saleem SM, Tahir A, Salat MS, Aslam MS, Hussain K. Evaluation of pharmaceutically compounded oral caffeine on the impact of medication adherence and risk of readmission among preterm neonates: A single-center quasi-experimental study. PLoS One 2022; 17:e0275655. [PMID: 36350877 PMCID: PMC9645656 DOI: 10.1371/journal.pone.0275655] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 09/21/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Caffeine is available in an ampoule, used via parenteral and enteral routes in preterm neonates to treat apnea of prematurity (AOP) in neonates of gestational age ≥ 35-40 weeks. A longer duration of therapy has a higher risk of medication non-adherence due to higher costs and inappropriate dosage forms. Pharmaceutically compounded oral caffeine (PCC) could be an appropriate alternate dosage form. The researchers aimed to determine the impact of PCC on medication-related factors influencing medication adherence (MA) and the frequency of hospital readmission with apnea (HRA) in preterm neonates. METHODS We conducted a single-center quasi-experimental study for this quality improvement project using PCC among the preterm neonates admitted in a tertiary care level-III NICU at the Aga Khan University Hospital Karachi, Pakistan, received caffeine therapy, and survived at discharge. The researchers compared pre-PCC data (April-December 2017) with post-PCC data (April-Dec 2018) each for nine months, with three months intervals (January-March 2018) of PCC formulation and implementation phase. The study was conducted according to the SQUIRE2.0 guidelines. The Data were collated on factors influencing MA, including the cost of therapy, medication refill rates, and parental complaints as primary outcome measures. The Risk factors of HRA were included as secondary outcomes. RESULTS After PCC implementation cost of therapy was reduced significantly from Rs. 97000.0 (729.0 USD) to Rs. 24500.0 (185.0 USD) (p<0.001), significantly higher (p<0.001) number of patients completed remaining refills (77.6% pre-phase vs 97.5% post-phase). The number of parental complaints about cost, ampoule usage, medication drawing issue, wastage, inappropriate dosage form, and longer duration of therapy reduced significantly in post-phase. HRA reduced from 25% to 6.6% (p<0.001). Post-implementation of PCC (RR 0.14; 95% CI: 0.07-0.27) was a significant independent risk factor for reducing HRA using a multivariate analysis model. Longer duration of caffeine therapy after discharge (RR 1.05; 95% CI: 1.04-1.04), those who were born in multiple births (RR 1.15; 95% CI: 1.15-1.15), and those who had higher number of siblings were other significant independent risk factors for HRA. CONCLUSIONS PCC dispensation in the appropriate dosage form at discharge effectively reduced cost, non-adherence to therapy, and risk of hospital readmissions. This neonatal clinical and compounding pharmacist-led model can be replicated in other resource-limiting setting.
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Affiliation(s)
- Gul Ambreen
- Department of Pharmacy, Aga Khan University Hospital, Karachi, Pakistan
| | - Manoj Kumar
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Amin Ali
- Department of Neonatology & Paediatrics, Dow University of Health Sciences, Karachi, Pakistan
| | - Syed Akbar Ali Shah
- Department of Neonatology, Dr. Ruth K. M. Pfau, Civil Hospital Karachi, Karachi, Pakistan
| | - Syed Muzafar Saleem
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | - Ayesha Tahir
- Department of Paediatrics & Child Health, Aga Khan University, Karachi, Pakistan
| | | | | | - Kashif Hussain
- Department of Pharmacy, Aga Khan University Hospital, Karachi, Pakistan
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AIM in Neonatal and Pediatric Intensive Care. Artif Intell Med 2022. [DOI: 10.1007/978-3-030-64573-1_309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Camacho-Hernández P, Lorea-Hernández JJ, Pinedo-Vargas L, Peña-Ortega F. Perinatal inflammation and gestational intermittent hypoxia disturbs respiratory rhythm generation and long-term facilitation in vitro: partial protection by acute minocycline. Respir Physiol Neurobiol 2021; 297:103829. [PMID: 34921999 DOI: 10.1016/j.resp.2021.103829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 10/31/2021] [Accepted: 12/13/2021] [Indexed: 01/04/2023]
Abstract
Perinatal inflammation triggers breathing disturbances early in life and affects the respiratory adaptations to challenging conditions, including the generation of amplitude long-term facilitation (LTF) by acute intermittent hypoxia (AIH). Some of these effects can be avoided by anti-inflammatory treatments like minocycline. Since little is known about the effects of perinatal inflammation on the inspiratory rhythm generator, located in the preBötzinger complex (preBötC), we tested the impact of acute lipopolysaccharide (LPS) systemic administration (sLPS), as well as gestational LPS (gLPS) and gestational chronic IH (gCIH), on respiratory rhythm generation and its long-term response to AIH in a brainstem slice preparation from neonatal mice. We also evaluated whether acute minocycline administration could influence these effects. We found that perinatal inflammation induced by sLPS or gLPS, as well as gCIH, modulate the frequency, signal-to-noise ratio and/or amplitude (and their regularity) of the respiratory rhythm recorded from the preBötC in the brainstem slice. Moreover, all these perinatal conditions inhibited frequency LTF and amplitude long-term depression (LTD); gCIH even induced frequency LTD of the respiratory rhythm after AIH. Some of the alterations were not observed in slices pre-treated in vitro with minocycline, when compared with slices obtained from naïve pups, suggesting that ongoing inflammatory conditions affect respiratory rhythm generation and its plasticity. Thus, it is likely that alterations in the inspiratory rhythm generator and its adaptive responses could contribute to the respiratory disturbances observed in neonates that suffered from perinatal inflammatory challenges.
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Affiliation(s)
- Polet Camacho-Hernández
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico
| | - Jonathan Julio Lorea-Hernández
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico
| | - Laura Pinedo-Vargas
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico
| | - Fernando Peña-Ortega
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico.
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AlRyalat SA, Al Oweidat K, Al-Amer A, Khader A, Ajaj A, Alessa Z, Roto A. Perinatal events predicting retinopathy of prematurity in extremely pre-term infants. J Neonatal Perinatal Med 2021; 13:261-266. [PMID: 32250325 DOI: 10.3233/npm-190336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Extremely preterm infants are peculiar in regard to their risk of retinopathy of prematurity (ROP). In this study, we aim to study insults that may affect extremely preterm infants, including prenatal, at birth, and postnatal insults and their effect on the development of ROP. METHODS This study used the data from Prematurity and Respiratory Outcomes Program (PROP). All included infants with a gestational age of 23 0/7 to 28 6/7 weeks using best obstetrical estimate. We included stressful events and/or modifiable variables that may affect the normal development. We used multiple regression analysis in our statistical analysis. RESULTS We included a total of 751 infants in our study. The mean birth weight for the included sample was 915.1 (±232.94) grams. 391 (52.1%) Infants were diagnosed with ROP. We found a significant negative correlation between ROP development and birth weight (p < 0.001), with a correlation coefficient of - 0.374. We found that the need for prophylactic indomethacin (OR 1.67), the occurrence of air leaks (OR: 2.35), ventilator-associated pneumonia (OR: 2.01), isolated bowel perforations (OR: 3.7), blood culture-proven sepsis (OR: 1.5), other infections (OR: 1.44), and receiving ventricular shunt (OR: 2.9) are significantly associated with the development of ROP. CONCLUSIONS We believe this study included the largest number of factors studied in the largest sample of extremely premature infants. We recommend a screening program for extremely preterm infants that takes into account a scoring system with higher scores for complicated condition.
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AIM in Neonatal and Paediatric Intensive Care. Artif Intell Med 2021. [DOI: 10.1007/978-3-030-58080-3_309-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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O'Connor KM, Lucking EF, Cryan JF, O'Halloran KD. Bugs, breathing and blood pressure: microbiota-gut-brain axis signalling in cardiorespiratory control in health and disease. J Physiol 2020; 598:4159-4179. [PMID: 32652603 DOI: 10.1113/jp280279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
There is clear evidence of physiological effects of the gut microbiota on whole-body function in health and disease. Microbiota-gut-brain axis signalling is recognised as a key player in behavioural disorders such as depression and anxiety. Recent evidence suggests that the gut microbiota affects neurocontrol networks responsible for homeostatic functions that are essential for life. We consider the evidence suggesting the potential for the gut microbiota to shape cardiorespiratory homeostasis. In various animal models of disease, there is an association between cardiorespiratory morbidity and perturbed gut microbiota, with strong evidence in support of a role of the gut microbiota in the control of blood pressure. Interventions that target the gut microbiota or manipulate the gut-brain axis, such as short-chain fatty acid supplementation, prevent hypertension in models of obstructive sleep apnoea. Emerging evidence points to a role for the microbiota-gut-brain axis in the control of breathing and ventilatory responsiveness, relevant to cardiorespiratory disease. There is also evidence for an association between the gut microbiota and disease severity in people with asthma and cystic fibrosis. There are many gaps in the knowledge base and an urgent need to better understand the mechanisms by which gut health and dysbiosis contribute to cardiorespiratory control. Nevertheless, there is a growing consensus that manipulation of the gut microbiota could prove an efficacious adjunctive strategy in the treatment of common cardiorespiratory diseases, which are the leading causes of morbidity and mortality.
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Affiliation(s)
- Karen M O'Connor
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,Department of Anatomy & Neuroscience, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Eric F Lucking
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland
| | - John F Cryan
- Department of Anatomy & Neuroscience, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
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Gravina G, Svedin P, Ardalan M, Levy O, Ek CJ, Mallard C, Lai JCY. Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice. Front Immunol 2020; 11:516. [PMID: 32373108 PMCID: PMC7186320 DOI: 10.3389/fimmu.2020.00516] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/06/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice. Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 107 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O2. White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling. Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro- and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection. Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.
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Affiliation(s)
- Giacomo Gravina
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pernilla Svedin
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maryam Ardalan
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ofer Levy
- Precision Vaccines Program, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States.,Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - C Joakim Ek
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jacqueline C Y Lai
- Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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12
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Beyeler SA, Hodges MR, Huxtable AG. Impact of inflammation on developing respiratory control networks: rhythm generation, chemoreception and plasticity. Respir Physiol Neurobiol 2020; 274:103357. [PMID: 31899353 DOI: 10.1016/j.resp.2019.103357] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/17/2019] [Accepted: 12/02/2019] [Indexed: 10/25/2022]
Abstract
The respiratory control network in the central nervous system undergoes critical developmental events early in life to ensure adequate breathing at birth. There are at least three "critical windows" in development of respiratory control networks: 1) in utero, 2) newborn (postnatal day 0-4 in rodents), and 3) neonatal (P10-13 in rodents, 2-4 months in humans). During these critical windows, developmental processes required for normal maturation of the respiratory control network occur, thereby increasing vulnerability of the network to insults, such as inflammation. Early life inflammation (induced by LPS, chronic intermittent hypoxia, sustained hypoxia, or neonatal maternal separation) acutely impairs respiratory rhythm generation, chemoreception and increases neonatal risk of mortality. These early life impairments are also greater in young males, suggesting sex-specific impairments in respiratory control. Further, neonatal inflammation has a lasting impact on respiratory control by impairing adult respiratory plasticity. This review focuses on how inflammation alters respiratory rhythm generation, chemoreception and plasticity during each of the three critical windows. We also highlight the need for additional mechanistic studies and increased investigation into how glia (such as microglia and astrocytes) play a role in impaired respiratory control after inflammation. Understanding how inflammation during critical windows of development disrupt respiratory control networks is essential for developing better treatments for vulnerable neonates and preventing adult ventilatory control disorders.
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Affiliation(s)
- Sarah A Beyeler
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States
| | - Matthew R Hodges
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Adrianne G Huxtable
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States.
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13
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Continuous vital sign analysis for predicting and preventing neonatal diseases in the twenty-first century: big data to the forefront. Pediatr Res 2020; 87:210-220. [PMID: 31377752 PMCID: PMC6962536 DOI: 10.1038/s41390-019-0527-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/20/2019] [Accepted: 07/25/2019] [Indexed: 01/03/2023]
Abstract
In the neonatal intensive care unit (NICU), heart rate, respiratory rate, and oxygen saturation are vital signs (VS) that are continuously monitored in infants, while blood pressure is often monitored continuously immediately after birth, or during critical illness. Although changes in VS can reflect infant physiology or circadian rhythms, persistent deviations in absolute values or complex changes in variability can indicate acute or chronic pathology. Recent studies demonstrate that analysis of continuous VS trends can predict sepsis, necrotizing enterocolitis, brain injury, bronchopulmonary dysplasia, cardiorespiratory decompensation, and mortality. Subtle changes in continuous VS patterns may not be discerned even by experienced clinicians reviewing spot VS data or VS trends captured in the monitor. In contrast, objective analysis of continuous VS data can improve neonatal outcomes by allowing heightened vigilance or preemptive interventions. In this review, we provide an overview of the studies that have used continuous analysis of single or multiple VS, their interactions, and combined VS and clinical analytic tools, to predict or detect neonatal pathophysiology. We make the case that big-data analytics are promising, and with continued improvements, can become a powerful tool to mitigate neonatal diseases in the twenty-first century.
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14
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McDonald FB, Dempsey EM, O'Halloran KD. The impact of preterm adversity on cardiorespiratory function. Exp Physiol 2019; 105:17-43. [PMID: 31626357 DOI: 10.1113/ep087490] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/15/2019] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS What is the topic of this review? We review the influence of prematurity on the cardiorespiratory system and examine the common sequel of alterations in oxygen tension, and immune activation in preterm infants. What advances does it highlight? The review highlights neonatal animal models of intermittent hypoxia, hyperoxia and infection that contribute to our understanding of the effect of stress on neurodevelopment and cardiorespiratory homeostasis. We also focus on some of the important physiological pathways that have a modulatory role on the cardiorespiratory system in early life. ABSTRACT Preterm birth is one of the leading causes of neonatal mortality. Babies that survive early-life stress associated with immaturity have significant prevailing short- and long-term morbidities. Oxygen dysregulation in the first few days and weeks after birth is a primary concern as the cardiorespiratory system slowly adjusts to extrauterine life. Infants exposed to rapid alterations in oxygen tension, including exposures to hypoxia and hyperoxia, have altered redox balance and active immune signalling, leading to altered stress responses that impinge on neurodevelopment and cardiorespiratory homeostasis. In this review, we explore the clinical challenges posed by preterm birth, followed by an examination of the literature on animal models of oxygen dysregulation and immune activation in the context of early-life stress.
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Affiliation(s)
- Fiona B McDonald
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland
| | - Eugene M Dempsey
- Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland.,Department of Paediatrics & Child Health, School of Medicine, College of Medicine & Health, Cork University Hospital, Wilton, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland
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15
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Bittencourt‐Silva PG, Menezes MF, Mendonça‐Junior BA, Karlen‐Amarante M, Zoccal DB. Postnatal intermittent hypoxia enhances phrenic and reduces vagal upper airway motor activities in rats by epigenetic mechanisms. Exp Physiol 2019; 105:148-159. [DOI: 10.1113/ep087928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 10/08/2019] [Indexed: 11/08/2022]
Affiliation(s)
- Paloma G. Bittencourt‐Silva
- Department of Physiology and Pathology School of Dentistry of Araraquara São Paulo State University (UNESP) Araraquara Brazil
| | - Miguel Furtado Menezes
- Department of Physiology and Pathology School of Dentistry of Araraquara São Paulo State University (UNESP) Araraquara Brazil
| | - Bolival A. Mendonça‐Junior
- Department of Physiology and Pathology School of Dentistry of Araraquara São Paulo State University (UNESP) Araraquara Brazil
| | - Marlusa Karlen‐Amarante
- Department of Physiology and Pathology School of Dentistry of Araraquara São Paulo State University (UNESP) Araraquara Brazil
| | - Daniel B. Zoccal
- Department of Physiology and Pathology School of Dentistry of Araraquara São Paulo State University (UNESP) Araraquara Brazil
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16
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Gauda EB, McLemore GL. Premature birth, homeostatic plasticity and respiratory consequences of inflammation. Respir Physiol Neurobiol 2019; 274:103337. [PMID: 31733340 DOI: 10.1016/j.resp.2019.103337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/11/2019] [Accepted: 11/10/2019] [Indexed: 12/23/2022]
Abstract
Infants who are born premature can have persistent apnea beyond term gestation, reemergence of apnea associated with inflammation during infancy, increased risk of sudden unexplained death, and sleep disorder breathing during infancy and childhood. The autonomic nervous system, particularly the central neural networks that control breathing and peripheral and central chemoreceptors and mechanoreceptors that modulate the activity of the central respiratory network, are rapidly developing during the last trimester (22-37 weeks gestation) of fetal life. With advances in neonatology, in well-resourced, developed countries, infants born as young as 23 weeks gestation can survive. Thus, a substantial part of maturation of central and peripheral systems that control breathing occurs ex-utero in infants born at the limit of viability. The balance of excitatory and inhibitory influences dictates the ultimate output from the central respiratory network. We propose in this review that simply being born early in the last trimester can trigger homeostatic plasticity within the respiratory network tipping the balance toward inhibition that persists in infancy. We discuss the intersection of premature birth, homeostatic plasticity and biological mechanisms leading to respiratory depression during inflammation in former premature infants.
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Affiliation(s)
- Estelle B Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, M5G 1X8, Canada.
| | - Gabrielle L McLemore
- Department of Biology, School of Computer, Mathematics and Natural Sciences (SCMNS), Morgan State University, Baltimore, MD, 21251, United States
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17
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Morrison NR, Johnson SM, Hocker AD, Kimyon RS, Watters JJ, Huxtable AG. Time and dose-dependent impairment of neonatal respiratory motor activity after systemic inflammation. Respir Physiol Neurobiol 2019; 272:103314. [PMID: 31614211 DOI: 10.1016/j.resp.2019.103314] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 09/07/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
Abstract
Neonatal respiratory impairment during infection is common, yet its effects on respiratory neural circuitry are not fully understood. We hypothesized that the timing and severity of systemic inflammation is positively correlated with impairment in neonatal respiratory activity. To test this, we evaluated time- and dose-dependent impairment of in vitro fictive respiratory activity. Systemic inflammation (induced by lipopolysaccharide, LPS, 5 mg/kg, i.p.) impaired burst amplitude during the early (1 h) inflammatory response. The greatest impairment in respiratory activity (decreased amplitude, frequency, and increased rhythm disturbances) occurred during the peak (3 h) inflammatory response in brainstem-spinal cord preparations. Surprisingly, isolated medullary respiratory circuitry within rhythmic slices showed decreased baseline frequency and delayed onset of rhythm only after higher systemic inflammation (LPS 10 mg/kg) early in the inflammatory response (1 h), with no impairments at the peak inflammatory response (3 h). Thus, different components of neonatal respiratory circuitry have differential temporal and dose sensitivities to systemic inflammation, creating multiple windows of vulnerability for neonates after systemic inflammation.
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Affiliation(s)
- Nina R Morrison
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States
| | - Stephen M Johnson
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Austin D Hocker
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States
| | - Rebecca S Kimyon
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Jyoti J Watters
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, United States
| | - Adrianne G Huxtable
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States.
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18
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Johnson SM, Randhawa KS, Baker TL, Watters JJ. Respiratory frequency plasticity during development. Respir Physiol Neurobiol 2019; 266:54-65. [PMID: 31055188 DOI: 10.1016/j.resp.2019.04.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/22/2019] [Accepted: 04/26/2019] [Indexed: 01/20/2023]
Abstract
Respiratory frequency plasticity is a long-lasting increase in breathing frequency due to a perturbation. Mechanisms underlying respiratory frequency are poorly understood, and there is little evidence of frequency plasticity in neonates. This hybrid review/research article discusses available literature regarding frequency plasticity and highlights potential research opportunities. Also, we include data demonstrating a model of frequency plasticity using isolated neonatal rat brainstem-spinal cord preparations. Specifically, substance P (SubP) application induced a long-lasting (>60 min) increase in spontaneous respiratory motor burst frequency, particularly in brainstem-spinal cords with the pons attached; there were no male/female differences. SubP-induced frequency plasticity is dependent on the application pattern, such that intermittent (rather than sustained) SubP applications induce more frequency plasticity. SubP-induced frequency plasticity was blocked by a neurokinin-1 receptor antagonist. Thus, the newborn rat respiratory control system has the capacity to express frequency plasticity. Identifying mechanisms that induce frequency plasticity may lead to novel methods to safely treat breathing disorders in premature and newborn infants.
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Affiliation(s)
- Stephen M Johnson
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, United States.
| | - Karanbir S Randhawa
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, United States
| | - Tracy L Baker
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, United States
| | - Jyoti J Watters
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, United States
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19
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Stålnacke SR, Tessma M, Böhm B, Herlenius E. Cognitive Development Trajectories in Preterm Children With Very Low Birth Weight Longitudinally Followed Until 11 Years of Age. Front Physiol 2019; 10:307. [PMID: 31001126 PMCID: PMC6454032 DOI: 10.3389/fphys.2019.00307] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/07/2019] [Indexed: 11/13/2022] Open
Abstract
Background: There is a high prevalence of cognitive dysfunction in very low birthweight (500–1250 g) infants (VLBW). Understanding long-term risk factors associated with cognitive development in preterm children requires longitudinal characterization. Thus, follow-up evaluations, including identification of risks and resilience influences–are important to promote health and cognitive abilities of children born preterm. Aim: To examine changes in cognitive development from birth until 11 years of age in preterm children with very low birthweight. Methods: 24 VLBW infants, at the Karolinska University Hospital, Stockholm, were assessed with regards to cognitive functioning at three times during development at 18 months, 5 and 11 years of age using standardized tests. Longitudinal data were analyzed using Generalized Estimating Equation (GEE) univariate and multivariate models. Results: The follow-up rate was 100%. Level of cognitive functioning at 18 months and at 11 years was similar. Females had higher cognitive scores than males at all three timepoints. We found that intraventricular hemorrhage (IVH) and prolonged invasive ventilatory support (>7 days) had a negative effect on cognitive functioning. Higher levels of parental education had a favorable influence on cognitive functioning over time. Conclusion: Level of cognitive development at 18 months was highly predictive of level of cognitive function at 11 years of age and differences in assessment scores between male and female VLBW infants persisted. Additional longitudinal studies, performed before school entry and across childhood, are needed to further elucidate the cognitive trajectories of preterm children.
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Affiliation(s)
- Sofia Ryytty Stålnacke
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Mesfin Tessma
- Department of Learning, Informatics, Management and Ethics - LIME, Karolinska Institutet, Stockholm, Sweden
| | - Birgitta Böhm
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Eric Herlenius
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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20
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Peña-Ortega F. Clinical and experimental aspects of breathing modulation by inflammation. Auton Neurosci 2018; 216:72-86. [PMID: 30503161 DOI: 10.1016/j.autneu.2018.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 11/06/2018] [Accepted: 11/07/2018] [Indexed: 12/19/2022]
Abstract
Neuroinflammation is produced by local or systemic alterations and mediated mainly by glia, affecting the activity of various neural circuits including those involved in breathing rhythm generation and control. Several pathological conditions, such as sudden infant death syndrome, obstructive sleep apnea and asthma exert an inflammatory influence on breathing-related circuits. Consequently breathing (both resting and ventilatory responses to physiological challenges), is affected; e.g., responses to hypoxia and hypercapnia are compromised. Moreover, inflammation can induce long-lasting changes in breathing and affect adaptive plasticity; e.g., hypoxic acclimatization or long-term facilitation. Mediators of the influences of inflammation on breathing are most likely proinflammatory molecules such as cytokines and prostaglandins. The focus of this review is to summarize the available information concerning the modulation of the breathing function by inflammation and the cellular and molecular aspects of this process. I will consider: 1) some clinical and experimental conditions in which inflammation influences breathing; 2) the variety of experimental approaches used to understand this inflammatory modulation; 3) the likely cellular and molecular mechanisms.
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Affiliation(s)
- Fernando Peña-Ortega
- Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, QRO 76230, México.
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21
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Monteiro J, Alves MG, Oliveira PF, Silva BM. Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Crit Rev Food Sci Nutr 2018; 59:2597-2625. [PMID: 29624433 DOI: 10.1080/10408398.2018.1461607] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Methylated xanthines (methylxanthines) are available from a significant number of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compounds through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacologic applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come.
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Affiliation(s)
- João Monteiro
- Mass Spectrometry Centre, Department of Chemistry & CESAM, University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal
| | - Marco G Alves
- Department of Microscopy, Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto , Porto , Portugal
| | - Pedro F Oliveira
- Department of Microscopy, Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto , Porto , Portugal.,Institute of Health Research an Innovation (i3S), University of Porto , Porto , Portugal
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22
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MacFarlane PM, Di Fiore JM. Myo-inositol Effects on the Developing Respiratory Neural Control System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1071:159-166. [PMID: 30357747 DOI: 10.1007/978-3-319-91137-3_20] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Myo-inositol is a highly abundant stereoisomer of the inositol family of sugar alcohols and forms the structural basis for a variety of polyphosphate derivatives including second messengers and membrane phospholipids. These derivatives regulate numerous cell processes including gene transcription, membrane excitability, vesicular trafficking, intracellular calcium signaling, and neuronal growth and development. Myo-inositol can be formed endogenously from the breakdown of glucose, is found in a variety of foods including breastmilk and is commercially available as a nutritional supplement. Abnormal myo-inositol metabolism has been shown to underlie the pathophysiology of a variety of clinical conditions including Down Syndrome, traumatic brain injury, bronchopulmonary dysplasia (BPD), and respiratory distress syndrome (RDS). Several animal studies have shown that myo-inositol may play a critical role in development of both the central and peripheral respiratory neural control system; a notable example is the neonatal apnea and respiratory insufficiency that manifests in a mouse model of myo-inositol depletion, an effect that is also postnatally lethal. This review focuses on myo-inositol (and some of its derivatives) and how it may play a role in respiratory neural control; we also discuss clinical evidence demonstrating a link between serum myo-inositol levels and the incidence of intermittent hypoxemia (IH) events (a surrogate measure of apnea of prematurity (AOP)) in preterm infants. Further, there are both animal and human infant studies that have demonstrated respiratory benefits following supplementation with myo-inositol, which highlights the prospects that nutritional requirements are important for appropriate development and maturation of the respiratory system.
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Affiliation(s)
- Peter M MacFarlane
- Case Western Reserve University, Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
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23
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Ribeiro A, Mayer C, Wilson C, Martin R, MacFarlane P. Intratracheal LPS administration attenuates the acute hypoxic ventilatory response: Role of brainstem IL-1β receptors. Respir Physiol Neurobiol 2017; 242:45-51. [DOI: 10.1016/j.resp.2017.03.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 03/08/2017] [Accepted: 03/09/2017] [Indexed: 01/01/2023]
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24
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Master ZR, Porzionato A, Kesavan K, Mason A, Chavez-Valdez R, Shirahata M, Gauda EB. Lipopolysaccharide exposure during the early postnatal period adversely affects the structure and function of the developing rat carotid body. J Appl Physiol (1985) 2016; 121:816-827. [PMID: 27418689 DOI: 10.1152/japplphysiol.01094.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 07/12/2016] [Indexed: 12/15/2022] Open
Abstract
The carotid body (CB) substantially influences breathing in premature infants by affecting the frequency of apnea and periodic breathing. In adult animals, inflammation alters the structure and chemosensitivity of the CB, yet it is not known if this pertains to neonates. We hypothesized that early postnatal inflammation leads to morphological and functional changes in the developing rat CB, which persists for 1 wk after the initial provoking insult. To test our hypothesis, we exposed rat pups at postnatal day 2 (P2) to lipopolysaccharide (LPS; 100 μg/kg) or saline (SAL) intraperitoneally. At P9-10 (1 wk after treatment), LPS-exposed animals had significantly more spontaneous intermittent hypoxic (IH) events, attenuated ventilatory responses to changes in oxygen tension (measured by whole body plethysmography), and attenuated hypoxic chemosensitivity of the carotid sinus nerve (measured in vitro), compared with SAL-exposed controls. These functional changes were associated with the following: 1) increased inflammatory cytokine mRNA levels; 2) decreased volume of supportive type II cells; and 3) elevated dopamine levels (a major inhibitory neuromodulator) within the CB. These findings suggest that early postnatal inflammation in newborn rats adversely affects the structure and function of the CB and is associated with increased frequency of intermittent desaturations, similar to the phenomenon observed in premature infants. Furthermore, this is the first newborn model of spontaneous intermittent desaturations that may be used to understand the mechanisms contributing to IH events in newborns.
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Affiliation(s)
- Zankhana R Master
- Department of Pediatrics, Division of Neonatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrea Porzionato
- Department of Molecular Medicine, University of Padova, Padova, Italy; and
| | - Kalpashri Kesavan
- Department of Pediatrics, Division of Neonatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ariel Mason
- Department of Pediatrics, Division of Neonatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Raul Chavez-Valdez
- Department of Pediatrics, Division of Neonatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Machiko Shirahata
- Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Estelle B Gauda
- Department of Pediatrics, Division of Neonatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
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25
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Forsberg D, Horn Z, Tserga E, Smedler E, Silberberg G, Shvarev Y, Kaila K, Uhlén P, Herlenius E. CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture. eLife 2016; 5. [PMID: 27377173 PMCID: PMC4974055 DOI: 10.7554/elife.14170] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 06/21/2016] [Indexed: 12/20/2022] Open
Abstract
Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+ cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails. DOI:http://dx.doi.org/10.7554/eLife.14170.001 Humans and other mammals breathe air to absorb oxygen into the body and to remove carbon dioxide. We know that in a part of the brain called the brainstem, several regions work together to create breaths, but it is not clear precisely how this works. These regions adjust our breathing to the demands placed on the body by different activities, such as sleeping or exercising. Sometimes, especially in newborn babies, the brainstem’s monitoring of oxygen and carbon dioxide does not work properly, which can lead to abnormal breathing and possibly death. In the brain, cells called neurons form networks that can rapidly transfer information via electrical signals. Here, Forsberg et al. investigated the neural networks in the brainstem that generate and control breathing in mice. They used slices of mouse brainstem that had been kept alive in a dish in the laboratory. The slice contained an arrangement of neurons and supporting cells that allowed it to continue to produce patterns of electrical activity that are associated with breathing. Over a three-week period, Forsberg et al. monitored the activity of the cells and calculated how they were connected to each other. The experiments show that the neurons responsible for breathing were organized in a “small-world” network, in which the neurons are connected to each other directly or via small numbers of other neurons. Further experiments tested how various factors affect the behavior of the network. For example, carbon dioxide triggered the release of a small molecule called prostaglandin E2 from cells. This molecule is known to play a role in inflammation and fever. However, in the carbon dioxide sensing region of the brainstem it acted as a signaling molecule that increased activity. Therefore, inflammation could interfere with the body’s normal response to carbon dioxide and lead to potentially life-threatening breathing problems. Furthermore, prostaglandin E2 induced deeper breaths known as sighs, which may be vital for newborn babies to be able to take their first deep breaths of life. Future challenges include understanding how the brainstem neural networks generate breathing and translate this knowledge to improve the treatment of breathing difficulties in babies. DOI:http://dx.doi.org/10.7554/eLife.14170.002
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Affiliation(s)
- David Forsberg
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Stockholm, Sweden
| | - Zachi Horn
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Stockholm, Sweden
| | - Evangelia Tserga
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Stockholm, Sweden
| | - Erik Smedler
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Gilad Silberberg
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Yuri Shvarev
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Stockholm, Sweden
| | - Kai Kaila
- Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland
| | - Per Uhlén
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Eric Herlenius
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Stockholm, Sweden
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Clinical associations with immature breathing in preterm infants: part 2-periodic breathing. Pediatr Res 2016; 80:28-34. [PMID: 27002984 PMCID: PMC4929034 DOI: 10.1038/pr.2016.58] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 01/19/2016] [Indexed: 11/13/2022]
Abstract
BACKGROUND Periodic breathing (PB) is a normal immature breathing pattern in neonates that, if extreme, may be associated with pathologic conditions. METHODS We used our automated PB detection system to analyze all bedside monitor chest impedance data on all infants <35 wk' gestation in the University of Virginia Neonatal Intensive Care Unit from 2009-2014 (n = 1,211). Percent time spent in PB was calculated hourly (>50 infant-years' data). Extreme PB was identified as a 12-h period with PB >6 SDs above the mean for gestational age (GA) and postmenstrual age and >10% time in PB. RESULTS PB increased with GA, with the highest amount in infants 30-33 wk' GA at about 2 wk' chronologic age. Extreme PB was identified in 76 infants and in 45% was temporally associated with clinical events including infection or necrotizing enterocolitis (NEC), immunizations, or caffeine discontinuation. In 8 out of 28 cases of septicemia and 10 out of 21 cases of NEC, there was a >2-fold increase in %PB over baseline on the day prior to diagnosis. CONCLUSION Infants <35 wk GA spend, on average, <6% of the time in PB. An acute increase in PB may reflect illness or physiological stressors or may occur without any apparent clinical event.
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Clinical associations of immature breathing in preterm infants: part 1-central apnea. Pediatr Res 2016; 80:21-7. [PMID: 26959485 PMCID: PMC5015591 DOI: 10.1038/pr.2016.43] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/15/2015] [Indexed: 11/08/2022]
Abstract
BACKGROUND Apnea of prematurity (AOP) is nearly universal among very preterm infants, but neither the apnea burden nor its clinical associations have been systematically studied in a large consecutive cohort. METHODS We analyzed continuous bedside monitor chest impedance and electrocardiographic waveforms and oxygen saturation data collected on all neonatal intensive care unit (NICU) patients <35 wk gestation from 2009 to 2014 (n = 1,211; >50 infant-years of data). Apneas, with bradycardia and desaturation (ABDs), defined as central apnea ≥10 s associated with both bradycardia <100 bpm and oxygen desaturation <80%, were identified using a validated automated algorithm. RESULTS Number and duration of apnea events decreased with increasing gestational age (GA) and postmenstrual age (PMA). ABDs were more frequent in infants <31 wk GA at birth but were not more frequent in those with severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or severe intraventricular hemorrhage (IVH) after accounting for GA. In the day before diagnosis of late-onset septicemia and necrotizing enterocolitis, ABD events were increased in some infants. Many infants continued to experience short ABD events in the week prior to discharge home. CONCLUSION Frequency of apnea events is a function of GA and PMA in infants born preterm, and increased apnea is associated with acute but not with chronic pathologic conditions.
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Siljehav V, Hofstetter AM, Leifsdottir K, Herlenius E. Prostaglandin E2 Mediates Cardiorespiratory Disturbances during Infection in Neonates. J Pediatr 2015; 167:1207-13.e3. [PMID: 26434370 DOI: 10.1016/j.jpeds.2015.08.053] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 07/06/2015] [Accepted: 08/25/2015] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To determine whether infection, with associated eicosanoid release, is a main cause of respiratory disruption in neonates, by measuring levels of prostaglandin E2 (PGE2) and its metabolite (PGEM) in cerebrospinal fluid (CSF). STUDY DESIGN Of 59 eligible infants, 25 preterm infants (mean gestational age, 28 ± 0.5 weeks) and 22 full-term infants (mean gestational age, 40 ± 0.5 weeks) from a level 3 neonatal intensive care unit and the general maternity neonatal ward were enrolled prospectively. Infants with a condition that can cause secondary apnea were excluded. Cardiorespiratory disturbances, such as apnea, bradycardia, and desaturation (ABD) events, were quantified. All infants were subjected to standard laboratory analysis of blood and CSF concentrations of biomarkers, including PGE2 and PGEM, within 24 hours of lumbar puncture, which were correlated with ABD events and culture-verified infections. RESULTS PGEM levels were highest in infants with culture-verified sepsis and meningitis (P < .01). In infants without culture-verified bacterial infections, PGEM levels were higher in preterm infants compared with term infants (P < .05). The numbers of desaturation events and apnea events in neonates were positively associated with PGE2 levels in CSF (P < .05). CONCLUSION PGE2 and PGEM are rapidly elevated in CSF during an infectious event and may explain cardiorespiratory disturbances, which are the major presenting symptoms of neonatal infections. PGE2 and PGEM are released during bacterial infections and could serve as biomarkers for sepsis and autonomic dysfunction in neonates.
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Affiliation(s)
- Veronica Siljehav
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Annika M Hofstetter
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Kristin Leifsdottir
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Eric Herlenius
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
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Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Caffeine therapy in preterm infants. World J Clin Pediatr 2015; 4:81-93. [PMID: 26566480 PMCID: PMC4637812 DOI: 10.5409/wjcp.v4.i4.81] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 07/11/2015] [Accepted: 08/21/2015] [Indexed: 02/06/2023] Open
Abstract
Caffeine is the most commonly used medication for treatment of apnea of prematurity. Its effect has been well established in reducing the frequency of apnea, intermittent hypoxemia, and extubation failure in mechanically ventilated preterm infants. Evidence for additional short-term benefits on reducing the incidence of bronchopulmonary dysplasia and patent ductus arteriosus has also been suggested. Controversies exist among various neonatal intensive care units in terms of drug efficacy compared to other methylxanthines, dosage regimen, time of initiation, duration of therapy, drug safety and value of therapeutic drug monitoring. In the current review, we will summarize the available evidence for the best practice in using caffeine therapy in preterm infants.
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Bang SR. Neonatal anesthesia: how we manage our most vulnerable patients. Korean J Anesthesiol 2015; 68:434-41. [PMID: 26495052 PMCID: PMC4610921 DOI: 10.4097/kjae.2015.68.5.434] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/31/2015] [Accepted: 08/18/2015] [Indexed: 12/12/2022] Open
Abstract
Neonates undergoing surgery are at higher risk than older children for anesthesia-related adverse events. During the perioperative period, the maintenance of optimal hemodynamics in these patients is challenging and requires a thorough understanding of neonatal physiology and pharmacology. Data from animals and human cohort studies have shown relation of the currently used anesthetics may associate with neurotoxic brain injury that lead to later neurodevelopmental impairment in the developing brain. In this review, the unique neonatal physiologic and pharmacologic features and anesthesia-related neurotoxicity will be discussed.
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Affiliation(s)
- Si Ra Bang
- Department of Anesthesiology and Pain Medicine, Seoul Paik Hospital, Inje University School of Medicine, Seoul, Korea
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31
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Mohammed S, Nour I, Shabaan AE, Shouman B, Abdel-Hady H, Nasef N. High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial. Eur J Pediatr 2015; 174:949-56. [PMID: 25644724 DOI: 10.1007/s00431-015-2494-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 01/09/2015] [Accepted: 01/16/2015] [Indexed: 01/10/2023]
Abstract
UNLABELLED The optimum caffeine dose in preterm infants has not been well investigated. We aimed to compare the efficacy and safety of high versus low-dose caffeine citrate on apnea of prematurity (AOP) and successful extubation of preterm infants from mechanical ventilation. We compared high-dose (loading 40 mg/kg/day and maintenance of 20 mg/kg/day) versus low-dose (loading 20 mg/kg/day and maintenance of 10 mg/kg/day) caffeine citrate in preterm infants <32 weeks gestation, presented with AOP within the first 10 days of life. A total of 120 neonates (60 in each group) were enrolled. High-dose caffeine was associated with a significant reduction in extubation failure in mechanically ventilated preterm infants (p<0.05), the frequency of apnea (p<0.001), and days of documented apnea (p<0.001). High-dose caffeine was associated with significant increase in episodes of tachycardia (p<0.05) without a significant impact on physician decision to withhold caffeine. CONCLUSION The use of higher, than current standard, dose of caffeine may decrease the chance of extubation failure in mechanically ventilated preterm infants and frequency of AOP without significant side effects. WHAT IS KNOWN • Caffeine therapy for treatment of apnea of prematurity has been well established over the past few years. The optimal loading and maintenance dose of caffeine in preterm infants is not well-studied. What is New: • This double blind randomized controlled trial demonstrated that using a higher, than current standard, loading and maintenance doses of caffeine for treatment of apnea in preterm infants is well tolerated and significantly decrease the frequency of apnea.
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Affiliation(s)
- Sameh Mohammed
- Neonatal Intensive Care Unit, Mansoura University Children's Hospital, Mansoura, Egypt,
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32
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Cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia by interleukin-1β in rats. Respir Physiol Neurobiol 2015; 209:85-90. [DOI: 10.1016/j.resp.2014.12.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 12/07/2014] [Accepted: 12/07/2014] [Indexed: 01/08/2023]
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Idborg H, Pawelzik SC, Perez-Manso M, Björk L, Hamrin J, Herlenius E, Jakobsson PJ. Evaluation of urinary prostaglandin E2 metabolite as a biomarker in infants with fever due to viral infection. Prostaglandins Leukot Essent Fatty Acids 2014; 91:269-75. [PMID: 25305792 DOI: 10.1016/j.plefa.2014.09.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 08/19/2014] [Accepted: 09/16/2014] [Indexed: 01/25/2023]
Abstract
We have investigated the clinical feasibility of the major urinary metabolite of prostaglandin (PG) E2, tetranor-PGEM, as a biomarker of inflammation in infants with fever. We tested two different and clinically relevant sampling methods, using self-adhesive urinary bags or gauze pads, with respect to stability of tetranor-PGEM and ease of sampling from infants. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was used to quantify tetranor-PGEM in urine, and different normalization parameters, i.e., urinary creatinine and body surface area, were investigated. To study inflammation, infants (1 month-1 year) that were hospitalized with fever of unknown origin at admittance (n=14) were compared to age-matched healthy controls (n=14). Levels of urinary tetranor-PGEM in infants with viral induced fever were increased compared to controls (102.4±56.2 vs. 37.0±21.6pmol/ml/m(2) body surface area, p<0.001). We conclude that urinary tetranor-PGEM is a potential non-invasive biomarker of inflammation in infants.
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Affiliation(s)
- Helena Idborg
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Sweden
| | | | - Monica Perez-Manso
- Neonatal Research Unit, Department of Women's and Children׳s Health, Astrid Lindgren Children׳s Hospital both at Karolinska Institutet, S-171 76, Stockholm, Sweden
| | - Lars Björk
- Neonatal Research Unit, Department of Women's and Children׳s Health, Astrid Lindgren Children׳s Hospital both at Karolinska Institutet, S-171 76, Stockholm, Sweden
| | - Johan Hamrin
- Neonatal Research Unit, Department of Women's and Children׳s Health, Astrid Lindgren Children׳s Hospital both at Karolinska Institutet, S-171 76, Stockholm, Sweden
| | - Eric Herlenius
- Neonatal Research Unit, Department of Women's and Children׳s Health, Astrid Lindgren Children׳s Hospital both at Karolinska Institutet, S-171 76, Stockholm, Sweden.
| | - Per-Johan Jakobsson
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Sweden
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Siljehav V, Shvarev Y, Herlenius E. Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice. J Appl Physiol (1985) 2014; 117:1027-36. [DOI: 10.1152/japplphysiol.00542.2014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R−/− mice ( P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R−/− preparations ( P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R−/− mice. Moreover, during severe hypoxic stress EP3R−/− mice had an increased gasping duration ( P < 0.01) as well as number of gasps ( P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R−/− mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia ( P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R−/− mice ( P < 0.05). In vitro, EP3R−/− brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium ( P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates.
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Affiliation(s)
- Veronica Siljehav
- Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and
| | - Yuri Shvarev
- Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and
- Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Eric Herlenius
- Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; and
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Mosca E, Ciechanski P, Roy A, Scheibli E, Ballanyi K, Wilson R. Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action. Respir Physiol Neurobiol 2014; 200:80-9. [DOI: 10.1016/j.resp.2014.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 06/03/2014] [Accepted: 06/03/2014] [Indexed: 02/02/2023]
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Apnea of prematurity--perfect storm. Respir Physiol Neurobiol 2013; 189:213-22. [PMID: 23727228 DOI: 10.1016/j.resp.2013.05.026] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 05/17/2013] [Accepted: 05/21/2013] [Indexed: 12/23/2022]
Abstract
With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate respiration and corresponding oxygenation represents a clinical challenge in this unique patient cohort. Respiratory instability characterized by apnea and periodic breathing occurs in premature infants because of immature development of the respiratory network. While short respiratory pauses and apnea may be of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this population concurrent with respiratory instability creates the perfect storm leading to frequent episodes of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and long term co-morbidities that occur in this population. In this review we discuss the pathophysiology leading to the perfect storm, diagnostic assessment of breathing instability in this unique population and therapeutic interventions that aim to stabilize breathing without contributing to tissue injury.
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Mayer CA, Ao J, Di Fiore JM, Martin RJ, MacFarlane PM. Impaired hypoxic ventilatory response following neonatal sustained and subsequent chronic intermittent hypoxia in rats. Respir Physiol Neurobiol 2013; 187:167-75. [PMID: 23562917 DOI: 10.1016/j.resp.2013.03.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 03/20/2013] [Accepted: 03/21/2013] [Indexed: 11/15/2022]
Abstract
Neonatal chronic intermittent hypoxia (CIH) enhances the ventilatory sensitivity to acute hypoxia (acute hypoxic ventilatory response, HVR), whereas sustained hypoxia (SH) can have the opposite effect. Therefore, we investigated whether neonatal rats pre-treated with SH prior to CIH exhibit a modified HVR. Rat pups were exposed to CIH (5% O2/5min, 8h/day) between 6 and 15 days of postnatal age (P6-15) after pre-treatment with either normoxia or SH (11% O2; P1-5). Using whole-body plethysmography, the acute (5min, 10% O2) HVR at P16 (1 day post-CIH) was unchanged following CIH (67.9±6.7% above baseline) and also SH (58.8±10.5%) compared to age-matched normoxic rats (54.7±6.3%). In contrast, the HVR was attenuated (16.5±6.0%) in CIH exposed rats pre-treated with SH. These data suggest that while neonatal SH and CIH alone have little effect on the magnitude of the acute HVR, their combined effects impose a synergistic disturbance to postnatal development of the HVR. These data could provide important insight into the consequences of not maintaining adequate levels of oxygen saturation during the early neonatal period, especially in vulnerable preterm infants susceptible to frequent bouts of hypoxemic events (CIH) that are commonly associated with apnea of prematurity.
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Affiliation(s)
- C A Mayer
- Department of Pediatrics, Case Western Reserve University, Rainbow Babies & Children's Hospital, Cleveland, OH 44106, USA
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Gauda EB, Shirahata M, Mason A, Pichard LE, Kostuk EW, Chavez-Valdez R. Inflammation in the carotid body during development and its contribution to apnea of prematurity. Respir Physiol Neurobiol 2013; 185:120-31. [DOI: 10.1016/j.resp.2012.08.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 07/20/2012] [Accepted: 08/02/2012] [Indexed: 01/09/2023]
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Abstract
BACKGROUND Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E(2) (PGE(2)) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE(2) pathway influences respiratory control and response to hypoxia. METHODS Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1(+/-)), and mPGES-1 knockout (mPGES-1(-/-)) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp). RESULTS IL-1β worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE(2) was not dependent on mPGES-1 expression. CONCLUSION Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.
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An inflammatory pathway to apnea and autonomic dysregulation. Respir Physiol Neurobiol 2011; 178:449-57. [DOI: 10.1016/j.resp.2011.06.026] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 06/29/2011] [Accepted: 06/29/2011] [Indexed: 01/04/2023]
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Lorch SA, Srinivasan L, Escobar GJ. Epidemiology of apnea and bradycardia resolution in premature infants. Pediatrics 2011; 128:e366-73. [PMID: 21746726 PMCID: PMC3387856 DOI: 10.1542/peds.2010-1567] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND There is little epidemiologic evidence to assess the maturation of respiratory control in premature infants. OBJECTIVE To measure the success rate or the percentage of infants who have no additional events of various apnea- or bradycardia-free intervals after correcting for gestational age, postmenstrual age of the last apnea or bradycardia event, and the severity of the event. METHODS This was a retrospective cohort study of infants born at 34 weeks' gestational age or earlier at 1 of 5 Kaiser Permanente Medical Care Program hospitals between 1998 and 2001. The success rates of various apnea- or bradycardia-free intervals were calculated after stratifying according to gestational age, postmenstrual age of the last event, or event severity. RESULTS Among the 1403 infants identified in this study, 84.2% did not have an apnea event and 78.5% did not have a bradycardia event after they were otherwise ready for discharge. For the entire cohort, a 95% success rate was statistically reached, with a 7-day apnea- or bradycardia-free interval. Infants with a gestational age of 30 weeks or less had a 5% to 15% lower success rate than infants with a gestational age more than 30 weeks for any given apnea- or bradycardia-free interval. The success rate was reduced by an additional 5% to 10% if the last apnea or bradycardia event occurred at a postmenstrual age of more than 36 weeks. Including only the most severe events slightly improved the success rate of a given interval. CONCLUSIONS The risk of recurrence for apnea or bradycardia differs depending on the gestational age of the infant and the postmenstrual age of the last apnea or bradycardia event.
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Affiliation(s)
- Scott A. Lorch
- Division of Neonatology, Department of Pediatrics, and ,Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ,Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Gabriel J. Escobar
- Systems Research Initiative and Perinatal Research Unit, Kaiser Permanente Division of Research, Oakland, California; and ,Department of Inpatient Pediatrics, Kaiser Permanente Medical Centers, Walnut Creek and Antioch, California
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Lee DS, Zahari M, Russell G, Darlow BA, Scarrott CJ, Reale M. An exploratory investigation of some statistical summaries of oximeter oxygen saturation data from preterm babies. ISRN PEDIATRICS 2011; 2011:296418. [PMID: 22389774 PMCID: PMC3263575 DOI: 10.5402/2011/296418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 03/30/2011] [Indexed: 05/31/2023]
Abstract
Aim. To explore the potential usefulness of the mean, standard deviation (SD), and coefficient of variation (CV = SD/mean) of oximeter oxygen saturations in the clinical care of preterm babies. Methods. This was an exploratory investigation involving 31 preterm babies at 36 weeks postmenstrual age. All babies were healthy, but two were considered to be clinically unstable and required greater attention. Each baby's oxygen saturations were recorded using an oximeter and summarized by the mean, SD, and CV. The potential usefulness of each measure was assessed by its ability to distinguish the two unstable babies from the others. This was achieved using box plots and hierarchical clustering together with the Calinski-Harabasz (CH) index to quantify clustering performance (higher CH index indicates stronger clustering outcome). Results. The box plots flagged both unstable babies as outliers and none of the other babies. Successful clustering of the stable and unstable babies was achieved using the CV (CH = 72.8) and SD (CH = 63.3) but not with the mean. Conclusion. Taking the box plots and clustering results together, it seems plausible that variability might be more effective than mean level for detecting instability in oxygen saturation in preterm babies and that the combination of variability and level through the CV might be even better.
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Affiliation(s)
- Dominic S. Lee
- Department of Mathematics and Statistics, University of Canterbury, Christchurch 8140, New Zealand
| | - Marina Zahari
- Department of Mathematics and Statistics, University of Canterbury, Christchurch 8140, New Zealand
| | - Glynn Russell
- Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Brian A. Darlow
- Department of Paediatrics, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch 8140, New Zealand
| | - Carl J. Scarrott
- Department of Mathematics and Statistics, University of Canterbury, Christchurch 8140, New Zealand
| | - Marco Reale
- Department of Mathematics and Statistics, University of Canterbury, Christchurch 8140, New Zealand
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Elder DE, Whale J, Galletly D, Campbell AJ. Respiratory events in preterm infants prior to discharge: with and without clinically concerning apnoea. Sleep Breath 2010; 15:867-73. [PMID: 21191656 DOI: 10.1007/s11325-010-0457-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Revised: 10/13/2010] [Accepted: 11/26/2010] [Indexed: 11/24/2022]
Abstract
PURPOSE This study aimed to determine the characteristics of respiratory events in preterm infants with clinically concerning apnoea at or beyond 35 weeks postmenstrual age and to compare these findings with a group of preterm infants ready for discharge, without clinically concerning apnoea. METHODS Infants born at <32 weeks of gestation and who underwent nap polysomnography at or beyond 35 weeks corrected age prior to discharge were included. Cases were preterm infants with clinically concerning apnoea, and control infants were preterm infants asymptomatic for apnoea. Infants with upper airway obstruction, congenital malformations or apnoea associated with sepsis were excluded. Studies were retrospectively reviewed for length, type and frequency of apnoea. The relationship between sleep state and changes in oxygen saturation was compared between groups. Peri-natal and demographic data were also compared. RESULTS Data were complete for 16 case and 18 control infants. Gestational age was similar at birth and at time of study, but cases had a lower birth weight (p = 0.04) and higher weight at study (p = 0.04). There were no group differences in the mean duration, type or numbers of apnoea. The duration of the longest apnoea was greater in case infants (17.4 s vs. 12.3 s, p = 0.02). Lowest oxygen saturation (p < 0.05) and average minimum oxygen saturation (p < 0.05) were lower in case infants. CONCLUSIONS Preterm infants with clinically concerning apnoea have similar amounts and types of apnoea but lower oxygen saturation after apnoea compared with controls. The use of oxygen saturation monitoring is more useful than respiratory monitoring alone in recognising these events.
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Affiliation(s)
- Dawn E Elder
- Department of Paediatrics, University of Otago Wellington, Wellington, New Zealand.
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Bloch-Salisbury E, Hall MH, Sharma P, Boyd T, Bednarek F, Paydarfar D. Heritability of apnea of prematurity: a retrospective twin study. Pediatrics 2010; 126:e779-87. [PMID: 20837586 DOI: 10.1542/peds.2010-0084] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Apnea of prematurity (AOP) is a disturbance in respiratory rhythm defined by idiopathic pauses in breathing that reduce blood oxygen levels and/or heart rate. It is a major clinical problem among preterm infants. OBJECTIVES The primary goal of this study was to estimate the genetic susceptibility to AOP in a cohort of preterm twins. A secondary aim was to identify risk factors associated with AOP in this cohort. METHODS A single-center, retrospective study (2000-2008) was performed by using data from 317 premature twin pairs (<36 weeks' gestational age). Heritability estimates were determined by comparing intrapair AOP concordance between 56 monozygotic and 161 dizygotic twin pairs by using structural equation modeling. Risk factors of AOP among a cohort of 543 premature twins were assessed by using mixed-effects logistic regression. RESULTS The heritability of AOP was 87% (95% confidence interval [CI]: 0.64-0.97) among same-gender twins. A gender-dependent model revealed that genetic factors accounted for 99% of the variance in male twins (95% CI: 0.89-1.00) and 78% of the variance in female twins (95% CI: 0.49-0.94). Significant risk factors for AOP were low gestational age (P<.001), cesarean delivery (P=.017), and conception through assisted reproductive technologies (P=.008). CONCLUSIONS These findings suggest that AOP has an important genetic basis underlying this developmental-related disorder of respiratory control. Future genomic studies may provide information on pathophysiological mechanisms that underlie AOP.
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Affiliation(s)
- Elisabeth Bloch-Salisbury
- Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01655, USA.
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