leoni 4 ventilation premature infants children with mother

Premature birth ‒ a global problem.

Inequality of opportunity in the first phase of life.

The WHO estimates worldwide premature births at 15 million annually. Preterm births are therefore a global problem. In all countries of the world, the rate of preterm births is between 5 and 18 % of all infants born. The majority of preterm births take place in Africa and South Asia1. In Germany, around 60,000 infants are born prematurely every year, making one in 11 infants a “preemie.” Accordingly, preterm babies are the largest group of patients in the country2.

The less developed a premature baby is, the greater the risk of complications and of healthy survival. Preterm births can have many different causes, such as infections, multiple pregnancies, chronic diseases of the mother or complications during pregnancy, including diabetes or high blood pressure. Often though no precise cause can be identified. Complications surrounding preterm births are the most common cause of death among infants under five years old and were responsible for around one million deaths in 20154.

Survival rates vary enormously worldwide.

There is a dramatic difference in survival rates for preterm babies depending on where they are born. For instance, more than 90 % of preterm babies born before the 28th week of pregnancy in low-income countries die within the first days of life. Compare that with less than 10 % of these infants that die in high-income regions.

Lack of affordable (primary) care.

The causes of high mortality rates in low-income countries include a lack of practical, affordable (primary) care such as heat supply/heat management, support with breastfeeding, basic care of infections and respiratory problems and no respiratory support. In high-income countries, almost all infants born after the 32nd week of pregnancy survive. In middle-income countries preterm infants who survive the neonatal period suffer a high burden of disability when the use of more advanced technology is suboptimal.

Skin contact and CPAP to provide support.

Besides avoiding known factors that may lead to preterm births, and therapeutic options before the imminent premature birth (e.g., steroid therapy for the mother to help the baby’s lungs mature or tocolytic therapy to inhibit labor), the WHO published new recommendations in November 2022 on the care of preterm babies. They reflect new insights that simple interventions such as kangaroo mother care straight after the birth, early commencement of breastfeeding, the use of continuous positive airway pressure (CPAP), and medication such as caffeine in response to respiratory problems can significantly reduce the mortality among preterm babies and babies with low birth weight.

Generally, preterm babies with an expected birth weight of under 1,500 grams (irrespective of the week of pregnancy) should receive care in specialized perinatal centers, on the basis of the relevant requirements5, 6. Especially extremely premterm infants whose lives are hanging by a thread need access to professional, experienced intensive and care7. These centers are fitted out with appropriate specialist equipment and technically trained staff. Here, preterm babies receive appropriate (usually intensive medicine) care, with the relevant care preventing possible complications due to the particularly immature babies. As an example, there were just under 10,000 infants in Germany in 2020 with a birth weight of under 1,500 grams needing care in these specialized centers8.

Infants aren’t little adults.

Lifelong consequences possible.

Classic problems of premature birth affect almost all organs due to their immaturity: e.g., respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and not least intraventricular hemorrhage (IVH), to name but a few. As already mentioned, the general supposition is that the lower the birth weight and the shorter the pregnancy, the higher the risk of complications9. Many of the infants that survive suffer the consequences of complications of premature birth the rest of their lives in the form of disability, including learning disability, sight and hearing problems. Preterm births are not such a rare event as some would think, and are relevant to society as a whole not just due to the potential long-term consequences. To draw attention to this global problem, World Prematurity Day has been held every year on November 17 since 2008. Through this day, parent representatives and associations aim to raise awareness of the concerns and problems of preterm babies and their families10.

Intensive medical care.

Here invasive and noninvasive respiratory support plays a major role. Particularly the group of extreme preterm babies (<28th week of pregnancy) normally requires intensive medical care. Around 80% of these preterm babies receive invasive mechanical ventilation in highly developed countries11. Even if new therapy approaches and strategies try to avoid invasive mechanical ventilation12 or to reduce usage time, and noninvasive ventilation of preterm babies has increased steadily over the past few years13, invasive ventilation therapy is still indispensable in neonatology and is associated with high morbidity and mortality despite general medical progress and is accompanied by acute and chronic lung damage (such as bronchopulmonary dysplasia, see above)14.

In times of progressive digitalization and automation, not just in medicine (e.g., autonomous driving and assistance systems), there is particularly in this vulnerable area a desire to further optimize therapy, tailor it to the needs of the particular patients, and, due to the increasing shortage of personnel and lack of time, also a desire for increasing automation, not least in the area of ventilation.

CLAC® respiratory support.

There are already approaches to automating the ventilation strategy for premature babies: Most preterm infants who require respiratory support also often require supplemental oxygen in the process, and thus frequently experience or are at higher risk for intermittent episodes of both hypoxaemia and hyperoxaemia15. Hypoxaemic episodes and exposure to inadequately high oxygen concentrations are known to increase the incidence of lung and eye damage16, 17 and are accordingly connected with an increased risk of retinopathy of prematurity (ROP)18, chronic lung disease (BPD), necrotising enterocolitis (NEC), neurodevelopmental disorders (NDI) and increased mortality19.

Manually adjusting oxygen settings is time-consuming.

The oxygen requirement and, in turn, the FiO2 settings change almost regularly over the course of the day, entailing many manual adjustments of the oxygen supply. These have normally been made by the healthcare staff in the intensive care unit. Depending on the patient group, these adjustments can be difficult and time-consuming. In the face of notable staff shortages, particularly in these specialized areas, increasing automation of the FiO2 settings can help improve patient care for certain infants. CLAC® – closed-loop automatic oxygen control – was developed with this goal in mind. The CLAC® algorithm adjusts the FiO2 value according to preselected settings by the user to the prevailing SpO2 value and assists the user with the FiO2 settings.

Automation brings benefits for healthcare staff and infants.

The principle of automated FiO2 control based on the SpO2 value is not new but has been used for several years and has been proven to be effective and safe20, 21, 22. For instance, Hallenberger et al. showed in their multicenter randomized, controlled crossover study that CLAC® can significantly improve SpO2 therapy with preterm babies with mechanical ventilation or nCPAP: The SpO2 values for the CLAC® infants were 10 % more in the SpO2 target range than for the infants that received purely manual control. The workload of the healthcare staff was also reduced as fewer SpO2 adjustments were required than with conventional therapy23.

In summary, it is evident that automatic control of the inspiratory oxygen fraction increases the proportion of time in which the oxygen saturation (SpO2) is in the target range, thereby reducing the number and duration of hypo- and hyperoxemic episodes and the workload of caregivers. Effects on clinically important endpoints of infants (such as ROP, BPD, NEC, NDI, and mortality) and the long-term development of the preterm babies were not yet investigated in long-term studies in particular24, 25.

FiO₂-C study.

It is precisely here where the FiO2-C study (closed-loop automatic control of FiO2) starts. A randomized, controlled parallel group study with observer-blinded recording of outcomes aims to investigate the effectiveness of automatically adjusted FiO2 usage compared with the manual control in terms of serious complications relating to hypoxemia and hyperoxemia. The study includes and investigates more than 2,300 preterm babies with a maturity between 23+0 and 27+7 weeks of pregnancy at 75 European sites with the highest levels of neonatal care.

The LEONI plus with CLAC® is also used here. The project aims to verify safety and the clinically significant impact of this technology with very immature preterm babies in a multicenter study26. This study differs in that the preemies are examined twice. The first takes place at a PMA of 36 weeks, i.e., normally just before being discharged from hospital, for indications of the previously mentioned complications and again at a corrected age of 24 months. In the follow-up, infants are examined for secondary outcome variables (death, speech and cognitive developmental delay, motor impairments and visual and hearing disabilities).

The study is currently underway and the results are eagerly anticipated. It will be interesting to see whether the partial automation of neonatal ventilation reduces the workload of medical staff and whether long-term results show a better outcome for premature babies and effective, lasting protection by reducing the complications of prematurity.

CLAC® further development.

Existing systems can still be improved: Löwenstein Medical is constantly working to keep its neonatology products up to date to guarantee the best possible patient safety and high levels of user comfort. The CLAC® system is therefore constantly being further developed and is currently being tested and improved, for example, in collaboration with the Neonatal Department at Tübingen University Hospital under the guidance of PD Dr. Axel Franz27. The aim is to optimize the system to further reduce the hypoxemic and hyperoxemic periods of the ventilated child. In addition, the team is also looking to reduce system alerts to improve comfort for users and to avoid “alarm fatigue,” i.e., users becoming desensitized to alarms.

Innovation through research.

Another innovative approach to automation in neonatal ventilation comes in the shape of the NANNI® project funded by the German Federal Ministry for Education and Research (BMBF): The funding initiative “Tiny Patients, Huge Need – Medical Technology Solutions for Child-Oriented Healthcare” supported the project to develop an innovative ventilation system for preterm babies designed to reduce the therapeutic effort and improve diagnosis quality. As described in detail above, the invasive ventilation of preterm babies is a life-saving therapy, which unfortunately can also entail complications. As a rule it is a time-consuming, labor-intensive therapy that has to be adjusted frequently as the medical condition of the child can vary wildly in no time at all. Here the response is often time-critical.

This project aims to extend automatic functions. Additional sensor technology also optimize the ventilation quality and allow conclusions to be drawn about the neonate’s physiological condition. This procedure is designed to improve ventilation quality and outcomes while reducing ventilation-associated complications28.

The initial phase of the project is complete and results have been published. We managed to get the paper’s authors to provide a short guest article that you can read below. Essentially, it focuses on automated CO2 control29, which is even more complicated than automated oxygen control. However, it is no less effective, as paCO2 extremes and fluctuations of the paCO2 within a short period of time are associated with severe intracranial bleeding in preterm babies30. This constitutes a serious and feared complication of prematurity and can cause serious lasting damage for the child.

Lots of potential but major challenges too.

Even if this constitutes a good initial approach to upgrading automation, other problems arise, such as measuring the relevant parameters. In the past, continuous monitoring of paCO2 or continuous regular mainstream measurement of the etCO2 has not been possible in preterm babies, as the current sensors are poorly suited to this specific group of patients due to often large amounts of dead space. Certain obstacles therefore need to be overcome in the search for ventilation automation.

1 Preterm birth (who.int), accessed 12/22.
2 Press kit – Bundesverband „das frühgeborene Kind“ e.V., last revised April 1, 2022.  
3 Checkliste Neonatologie – 5th Edition, Geznel-Boroviczény, Ross et al.; 2015 Georg Thieme Verlag KG.  
4 Perin, J.; Mulick, A.; Yeung D.; Villavicencio, F; Lopez, G.; Strong, K.L. et al.: Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/S2352-4642(21)00311-4.  
5perinatalzentren.org/informationen/faq/, accessed on January 17, 2023.  
6 Guideline of the Joint Federal Committee concerning Quality Assurance Measures of the Care of Premature and Term Babies as per § 136 (1) number 2 SGB V (Social Security Code V) in conjunction with § 92 (1) sentence 2 number 13, SGB V; (Quality Assurance Guideline Premature and Term Babies/QFRRL), in the version dated September 20, 2005, published in the Federal Gazette 2005 (p. 15 684), entered into force on January 1, 2006, last amended on October 20, 2022 published in the Federal Gazette (BAnz AT December 1, 2022 B3), entered into force on January 1, 2023.   
7 Press kit – Bundesverband „das frühgeborene Kind“ e.V., last revised April 1, 2022, accessed December 22, 2022.   
8 IQTIG – Institute for Quality Assurance and Transparency in Healthcare – National Analysis 2020 – Neonatologie, last revised August 10, 2021.   
9 Das neugeborene Kind – Wissen @ AMBOSS (accessed on January 12, 2023).
10 Warum ein solcher Tag? – World Prematurity Day (welt-fruehgeborenen-tag.de), accessed 12/22.
11 Stoll, B.J.; Hansen, N.I.; Bell, E.F. et al.: Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012. JAMA. 2015;314(10):1039-1051. doi:10.1001/ jama.2015.10244.
12 Göpel, W. et al.: Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. The Lancet. 2011 Nov; 378, 9803:1627–34.
13 Subramaniam, P.; Ho, J.J.; Davis, P.G.: Prophylactic or very early initiation of continuous positive airway pressure (CPAP) for preterm infants. Cochrane Database Syst Rev. 2021;10(10):CD001243. Published 2021 Oct 18. doi:10.1002/14651858.CD001243.pub4.
14 Thébaud, B.; Goss, K.N.; Laughon, M. et al.: Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019;5(1):78. Published 2019 Nov 14. doi:10.1038/s41572-019-0127-7.
15 Martin, R.J.; Di Fiore, J.M.; Macfarlane, P.M.; Wilson, C.G.: Physiologic basis for intermittent hypoxic episodes in preterm infants. Adv Exp Med Biol. 2012; 758:351–8.
16 Saugstad, O.D.: Bronchopulmonary dysplasia: oxidative stress and oxidants. Semin Neonatol.2003;8(1):39–49.
17 McColm, J.R.; Fleck, B.W.: Retinopathy of prematurity: causation. Semin Neonatol. 2001; 6(6):453–460.
18 Chow, L.C.; Wright, K.W.; Sola, A.: CSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics. 2003 Feb;111(2):339-45. doi: 10.1542/peds.111.2.339. PMID: 12563061.
19 Maiwald, C.A.; Niemarkt, H.J.; Poets, C.F. et al.: Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO₂-C) on outcome of extremely preterm infants – study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy. BMC Pediatr. 2019;19(1):363. Published 2019 Oct 21. doi:10.1186/s12887-019- 1735-9.
20 Claure, N.; Bancalari, E.; D’Ugard, C.; Nelin, L.; Stein, M.; Ramanathan, R.; Hernandez, R.; Donn, S.M.; Becker, M.; Bachman, T.: Multicenter crossover study of automated control of inspired oxygen in ventilated preterm infants. Pediatrics. 2011 Jan;127(1):e76-83. doi: 10.1542/peds.2010-0939. Epub 2010 Dec 27. PMID: 21187305.
21 Poets, C.F.; Franz, A.R.: Automated FiO₂ control: nice to have, or an essential addition to neonatal intensive care? Arch Dis Child-Fetal. 2017;102(1):F5–6.
22 Mitra, S.; Singh, B.; El-Naggar, W.; McMillan, D.D.: Automated versus manual control of inspired oxygen to target oxygen saturation in preterm infants: a systematic review and meta-analysis. J Perinatol. 2018;38(4):351–60.
23 Hallenberger, A.; Poets, C.F.; Horn, W.; Seyfang, A.; Urschitz, M.S.; CLAC Study Group: Closed-loop automatic oxygen control (CLAC) in preterm infants: a randomized controlled trial. Pediatrics. 2014 Feb;133(2):e379-85. doi: 10.1542/peds.2013-1834. Epub 2014 Jan 27. PMID: 24470641.
24 Maiwald, C.A.; Niemarkt, H.J.; Poets, C.F. et al.: Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO₂-C) on outcome of extremely preterm infants – study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy. BMC Pediatr. 2019;19(1):363. Published 2019 Oct 21. doi:10.1186/s12887-019- 1735-9.
25 FIT Project (uni-tuebingen.de) accessed December 22, 2022.
26 FIT Project (uni-tuebingen.de) accessed December 22, 2022.

A look into the future.

Besides special and ideally “smart” ventilation devices and tools with automation algorithms, neonatology will require automation algorithms and more tailored applications and sensor systems in the future if it is to address the needs of these tiny patients more effectively.

leoni 4 ventilation premature infants children with mother nurse
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