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MEDICINA HOJE - Chiesi Special Issue • january, 2007
p u b licação i n dep en dente di r igi da
à classe médica
1st International Simposium of Neonatal Respiratory Distress
Dr. Ola D. Saugstad (Norway)
“It´s possible to resuscitate a newborn with room air only.”
New protocols for oxygen use in Neonatology
pAGE 2
Dr. Henry L. Halliday (United Kingdom)
Corticosteroids should be used in lower dose in a shortest length of time as possible after birth and be avoided in the first four days of life.” pAGE 6
Dr. Christian Speer (Germany)
“The current guideline is to keep the oxygen concentration between 85% and 92% for the first week of life, to avoid O2 fluctuation and to perform resuscitation which needs urgency.” pAGE 7
From left to right: Dr. Rangasamy Ramanathan (USA), Dr. Christian Speer (Germany), Dr. Edna Diniz (Brazil), Dr. Ola D. Saugstad (Norway), Dr. Renato Fiori (Brazil), Dr. Henry L. Halliday (United Kingdom), Dr. Tore Curstedt (Sweden).
The 1st International Simposium of Neonatal Respiratory Distress, 3rd and 4th of November, has brought together some of the most known researchers worldwide of the neonatal intensive care field. The main topics of the symposium were questions on how to use better the oxygen, the most used method in newborn resuscitation, as well as the surfactant therapy which, according to controlled trials, is recommended in infants with less than 27 or 28 weeks, always in the
first three hours. The specialists have also concluded that the new synthetic surfactants generation still need more controlled trials to be done. All conclusion taken in this symposium have shown that this “young” field of medicine has been changing very fast in the last two decades. The event was run by Chiesi Pharmaceuticals and sponsored by Fiocruz (Osvaldo Cruz Foundation), UFRJ (Federal University of Rio de Janeiro) and UERJ (Estate University of Rio de Janeiro).
Over 200 pediatrician and neonatal intensive care specialist have taken part in the Symposium.
Bronchopulmonary dysplasia A simple test to evaluate the pulmonary maturity prevention and therapy Dr. Renato Fiori (PUCRS, Porto Alegre, Brazil) has developed a simple test, quick and inexpensive: the stable micro bubble test which is to evaluate the newborn pulmonary maturity and then to determine the surfactant administration.
Dr. Tore Curstedt (Sweden)
“Rare genetic mutations are responsible for serious deficiencies which usually lead to death.”
pAGE 5
pAGE 3
Other surfactant recommendation Dr. Rangasamy Ramanathan (USA)
“Between 400 and 600 babies become blind every year due to ROP in the USA.” pAGE 4
According to Dr. Jose Muniz Duarte Bandeira (Pedro Ernesto Hospital-University, Rio de Janeiro) fight infection, mal-nutrition and promote a stress free environment are essential to prevent infants from developing BPD. pAGE 3
The surfactant may have a wider use in many newborns diseases such as in the meconium aspiration syndrome, in the pulmonary infections or in the congenital diaphragmatic hernia according to researches led by Dr. Edna Diniz (Sao Paulo University, Sao Paulo, Brazil). pAGE 4
MEDICINA HOJE - Chiesi Special Issue • january, 2007
Resuscitation
Using room air
According to Dr. Ola Saugstad, the room air is initially the best choice for newborn resuscitation and in case of using oxygen, the amount administration should be between 21 to 40% and not 100% as it has been recommended in the main guidelines. Instead of using the recommended 100% of oxygen by the previous guidelines for newborn resuscitation, the current one gives the doctor the option to choose which concentration is more adequate. If such change could be already regarded as an improvement, and show the new tendency to lower rates of oxygen use in resuscitation. In the Dr. Ola Saugstad opinion, there is not even the need to use extra oxygen in the first step for the resuscitation procedure. “In the majority of the cases, it is possible to resuscitate a new-
Differences between countries Dr. Ola Saugstad says that one big challenge now is to find out how much oxygen concentration for resuscitation should be use in the first place in cases where room air is not possible. “Many research for an oxygen concentration rate between 21% and 40%. However, in my opinion even 40% rate is too high. I am convinced that the guidelines will take on concentrations lower and lower. And maybe the next guideline will recommend the room air first and, if it is necessary, an extra oxygen
“
In the majority of the cases, it is possible to resuscitate a newborn only with the use of room air.
born only with the use of room air” says the scientist. In his opinion, the choice for using room air only is related to low-rate mortality and a faster recovery. “The newborn breaths faster when they are resuscitated with room air. It is also known that the inflammation caused by oxygen happened not only in the lung but also in the heart and in the brain”.
amount – which I think it is the best recommendation” he said. He said that there is no guideline on this topic in Norway but the oxygen use has been reduced to exceptional cases. “And if the oxygen is necessary, it should be given a concentration which is similar to the room air. In the neighbor country Sweden, as well in Canada, the room air has to be administered first”, he pointed out.
For Ola Saugstad, the main advantage of the current recommendation is that allows doctors to use lower concentration than 100%. The change is considered essential especially for the American doctors who were forced to use pure oxygen to prevent facing legal actions in case they didn’t follow the usual procedures – despite all the published researches have been proving otherwise. “And currently more and more neonatologists are taken the room air or lower oxygen concentration as the first step in the newborn resuscitation procedure”, he pointed out. Saving live According to the specialist, the last trials, carried out between 2000 and 2006 have shown that the risk of oxidative stress is higher in the brain, lungs and intestines and also lung, heart and brain damages when the pure oxygen procedure is applied. It also causes brain damage-related necrosis; increase the activation of transcription factors, MMPs and of proinflamatory cytokines, causing damage in the DNA and in the genes regulation. The researcher pointed out that previous studies focusing global hy-
Ola Saugstad, Norway: “the preterm infant start to breath faster when we use room air as the resuscitation procedure”.
poxemia, carried out between 1990 and 1999, had already shown that the room air was as efficient as pure oxygen in restoring the metabolism, the high pressure, the cardiac debit and cerebral and pulmonary bloodstream. In addition, a meta-analyses outcome which included five studies carried out between 1991 and 2003 by Ola Saugstad team shows a decrease in the mortality rate from 13% to 8% and reaching a lower rate from 3,5% to 0,5%, in a trial carried out in Spain. Overall, the five studies included in the meta-analyses had 1.737 children enrolled. He said that “only a 5% reduction in the mortality rates of four million newborns that need resuscitation worldwide would save 200.000 lives a year”, he added The Pediatrics magazine published, in 2003, an article where the researcher compares the outcome of a room air resuscitation study involving 91 children and a second one where children received oxygen. Ac-
Oxidative stress
Oxygenation vs. antioxidants Although the oxidative stress is associated to several newborn pathology, “there is no evidence neither for its pathogenic importance nor for the therapeutic efficacy with antioxidant, despite 25 years of clinical trials on the subject”, concluded Dr. Ola Ditrik Saugstad, Norway. Anyhow, the understanding of the newborn oxidative stress mechanism may support researchers who are looking for either etiological or even therapeutical answers to the problem. On the other hand, the infant delivery by itself is an entering process, for the newborn, into a room with a bigger oxigen supply comparing to what they used to be provided in the intra-uterine gestation and which they will have to deal with. In fact, “it is about the moment when the human being received the strongest hyporaxic discharge in their lifetime”, said Ola. He declared that “we need oxygen to produce energy, and in order to fight the oxygen radicals generated in the break process of energy we need antioxidant enzymes which is only available to the embryo in the end of the gestational period”. Therefore, for the preterm infants the situation becomes more complicated “since their antioxidant
defense mechanism is very low”. Besides that, the oxidative stress marker is more likely to be observed in pregnant than in non-pregnant and appears to be associated to pregnancy-related disease such as eclampsia and to the infant low weight. He also declared that it is possible that the oxidative stress plays a role on the “programmed embryo” of the adult disease. In addition to that, high free iron and inflammation also contribute to release reactive oxygen substances, and can be found in high conditions in preterms. It is the fact that they show a low level of antioxidant factors such as superoxide dismutase (SOD), catalase and glutathione peroxidases, bilirubin, ascorbic acid, tocopherol, uric acid etc. According to articles of Suzuki, Saugstad and Jankov, “the oxidative stress is related to the inflammation process, hypoxia-reoxygenation injury, persistence of arterial duct and others carcinogenesis, atherosclerosis, signal transduction, growth and cellular differentiation, apoptosis and genetic expression”, said Ola Saugstad. Hypoxantine and hypoxia Ola Saugstad spent a lot of time researching about hyperoxigena-
tion process in the cardiac resuscitation in newborn babies after the hypoxia of cardiac failure has taken place. “I have been studying the hypoxantine which is high during the hypoxia”, he said, adding that in dogs experiment the hypoxantine increases rapidly in cardiac failure and resuscitation.
“
The preterms infants develop a so-called “oxygen radical disease”, responsable for eyes, lung, intestines and brain injuries.
case worsens the radical condition because release iron radical and worsen the oxidative stress while the high concentration oxygen supply release xantines increasing the oxygen radicals production which induce the citocines, worsening the inflamatory process” said Dr. Saugstad On the other hand, the debate on the possible tamponment of those
I have been studying the hypoxantine which is high during the hypoxia.
Radical Oxygen Disease “Preterms tend to show eyes, lungs, intestines and, mainly, brain injuries. Is it possible to be many sides of the same disease?”, questioned the researcher. “I called it Radical Oxygen Disease in newborns”, he answered. He shows an article published in JAMA in 2003 by Schmidt and team que calculated the bad prognostic (35%) to late death or chronic pulmonar dysplasia newborns incapacity, brain injury and retinopathy of prematurity, syndromes which in his opinion could be part of the same disease, and could be cause and even consequence of the peroxidation. The therapeutic for preterm infants with low weight define a vicious circle in the situation. “For instance, blood transfusion in hemorrhagic
oxygen radicals with antioxidant is at least controversial. He has pointed out the ascorbic acid ineffectiveness, and even though questioned by many researchers, he considered that the vitamin A only has good outcome “in one out of 15 treated patient”, according to Tyson on article published in 1999 in NEJM. However, “multivitamins protect against light which causes peroxidation, the aminoacids nutricional content provides glutathione and should be stimulated, but the ascorbic acid should be avoided in the first days of life”, he said. In short, roughly, in the therapeutic point of view, facing the difficulties generated to an infant by the increase of oxigen free radicals, “the best option is rather to reduce the oxigenation than to supply antioxidants”, he declared.
cording to him, no differences were identified neither in the somatic growth nor in the psychomotor development. Insufficient information Considering all the studies carried out to the date, Saugstad has pointed out some of his conclusion on how to proceed with newborns. The main one, in his opinion, is that “there is not enough information to determine how much oxygen should be use in the resuscitation initially”. The other change, pointed out by the specialist, is “that the intrapartum oropharyngeal and nasopharyngeal suction for newborn with meconiated fluid is no longer recommended Although there is no records on human, Ola Saugstad believes to be reasonable to carry on administering epinephrine/adrenaline when ventilation and massage failed to increase the heart rate over 60bpm. The recommended dose is 0, 01-0,03mg/kg. This dosage should not exceed in epinephrine administration. There is no research on safety level for higher endotracheal doses”, justify. He reminds the fact that the use of tracheal tube should be evaluated, especially in children with low heart rate which remains low despite the use of alternative procedures. “Detecting CO2 exhalation may help on the tracheal tube fitting”, he emphasized. The specialist pointed out to the fact that 10% of newborns need some assistance to star breathing after being delivery which represents about 1,3 millions every year worldwide, and about 1%, 1,4 million need extensive interventions.
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MEDICINA HOJE - Chiesi Special Issue • january, 2007
Pulmonary complications
Prevention and treatment of chronic pulmonary dysplasia in preterm infants The prevention for pulmonary complication requires a range of care, which goes from fighting infection and malnutrition to an adequate oxygen concentration and surfactant administration. Christian Speer, University Children’s Hospital, Würzburg, Germany and José Luiz Muniz Duarte Bandeira do university Hospital Pedro Ernesto, Uerj, Rio de Janeiro, Brazil, have discussed about all researches and the different realities among countries in relation to treatment and prevention for preterm infant with BPD. They all have come to a mutual agreement on one statement: the oxygen concentration needs to be administered carefully, either on the syndrome therapeutic procedure or when avoiding or minimizing the administration They also have reached a consensus statement on how the surfactant should be administered: “within the three first hours after birth, the pulmonary surfactant should be given” said José Luiz Bandeira. Christian Speer recalled in his lecture the physiopathology of intra-uterine and postnatal events that contribute to the development of the so-called new BPD in preterm infants, having in mind that they are those which have to be inhibited in order to proceed with the prophylaxis mode. Before birth, the chorioamnionitis along with postnatal resuscitation, oxygen toxicity, mechanical ventilation, pulmonary infection or arterial duct systemic and persistence lead to the new BPD, which is pathologically characterized by a sequence of inflammatory pulmonary response and the abnormal wound healing, with alveolarisation and vascular development inhibition. Anyhow, the developed disease treatment mixes up with prophylactic attempts, since the preterm infants’ dysplasia incidence – the most common pathology – worsens the lower is the weight and gestational age. In face of that, Speer and Bandeira have analyzed the therapeutic possibilities accordingly with clinical trials and evidences, emphasizing geographical differences. “When I found only 5% for BPD in the Neonatology Department Newborn records, under my direction, compared with the 10% and 15% rates found in the worldwide literature, I found peculiar such a low rates compared to developed centers”, Bandeira said. There is an objective explanation: “this is due here to the high mortality rate of low-weight preterm infants as they never develop BPD”. Infection and mal-nutrition prevention in preterm infants is, in the UERJ professor opinion, the main issue for BPD prevention in Brazil. “Preterm infants need to be dealt only once together with physicians, physiotherapists and nurses clinical procedures, contrary to the current practice. Besides that, it is necessary to avoid the use of ventilators, looking out for CPAP nasal use. On the other hand, it is necessary to extent to the maximum the pregnancy term in order to obtain a better ponderal gain Once the infant is born, the focus is on the nourishment, which should be the maternal milk added with fortifiers,
premature-prescribed milk and antioxidant substances such as vitamin A, E, selenium and zinc”, he said. According to Bandeira, it is the infection itself that, sometimes, contribute to trigger PDA development which, in Speer´s opinion, in lowweight preterm infants with severe respiratory failure “can reach 80% incidence rate”, as observed before in a study published by Bancalari and team in Biology of the Neonate. The study, as stated by the German speaker, investigates the PDA incidence in severe low-weight infants after being delivered and in those with severe dysplasia being born between 1996 and 2002. “The canal treatment, including pharmacologically, is in this case fundamental condition for those infants since the longer is the therapeutic length, the worst is the BPD condition”, he said. Another study published 10 years ago in the Journal of Pediatrics by Gonzales et al. has already shown infection and PDA as determinants factors for severe dysplasia in newborns. Oxygen: lower levels The main target of the whole symposium, the oxygen and the abrupt gradient which settle in infant blood mainstream when they are subject to high room air concentrations or by nasal catheter or artificial respirator, have led Speer to reveal the evidences of observational study which had taken place in the north of England involving 295 infants, with less than 28 weeks gestational age, who had survived in the first year. The study aimed, published in the Archives of Disease in Childhood, 2001, at investigating whether differences in the oxygen saturation control policies would have any impact in the development of the retinopathy. “what has been verified is that the interval saturation between 88 and 98, the damage in children with less than 28 weeks was higher, comparing to saturation intervals between 70 and 90, modifying the artificial ventilation for 27 days in the first case, and 14 days in the second one”, he said. Besides that, at intervals with lower numbers, the infants have undergone an average of 44 days of oxygen and, in a higher interval, the average was 78 days. However, it is important to have in mind the fact that, according to Speer, researchers agree with the statement that “attempts to keep saturation in physiological levels may cause more damage than being beneficial for infants being born before 28 weeks and controlled trials would be necessary”. Another controlled, randomized, double-blind trial called BOOST has revealed, according to Speer, that the oxygen saturation was lower than 95% or the same comparing to the higher concentration than 95%, of which results were 46% and 64% for pulmonary dysplasia, respectively. Finally, “results of 5 observational tri-
José Luiz Muniz Duarte Bandeira (Brazil) (left) and Christian Speer (Germany).
als has indicated that oxygen concentration higher than 92% increase the retinopathy risks and dysplasia in preterm infants with very low weight, and suggest a recommendation of oxygen saturation between 85 and 92% during the first weeks of life, avoidance of oxygen fluctuation and carry out resuscitation in emergency situation”. Carefully, Bandeira extend the saturation to 95% and has pointed out to the procedures routine: “the difficult is to make the people who work at the neonatology unit to keep the oxygen levels unaltered”.
Caffeine: potential therapeutic effects Both researchers agree that the nitric oxide use may be effective in some severe insufficiency cases, and Speer recommend for BPD with severe pulmonary hypertension. On the other hand, while the German scientist has criticized the dexamethasone administration, saying that the medication “has no effect on severe preterm infants”, Bandeira use the corticoid with doses for 6 days “to ‘wean’ the little preterm infant out of the ventilator”.
Besides the vitamin A which, in studies, has shown a reduction – considered tiny for some pediatricians when its administration is considered – of 7% in BPD in relation to the control, indomethacin (don’t prevent BPD, according to studies), diuretic (the administration is controversial, with specific prescription), eritromicina and other inflammatory substance were introduced but as research routes. Interesting information, stated by Speer, was about caffeine. The Recent Advances in Neonatal Medicine has published in 2005 a study by Schmidt showing the results of research with the substance and placebo. The loading citrate of caffeine dose of 20mg/kg and of maintenance between 5 and 10mg/kg every 24h have reduced BPD and PDA but also have decreased the weight gain in the 3 first weeks. “However, Schmidt had point out that an evaluation in long term of caffeine effects is necessary before the substance could be administered routinely in the pulmonary dysplasia prevention”, considered Speer.
Inflammatory mechanisms in BPD Prenatal factors such as chorioamnionitis and postnatal factors, like longer ventilation and infection, trigger severe inflammatory infection causing pulmonary disease. The bronchopulmonary dysplasia (BPD) in preterm infants it is a consequence of an imbalance between proinflammatory and anti-inflammatory mechanisms favoring the pro-inflammatory mechanisms, explain Dr. Speer, Professor of Pediatrics and Director of University Children’s Hospital, Würzburg, Germany. The researches carried out in the last year allow them to understand better the complex events cascade which ends up in BPD, but Speer realized that the exact pathogenetic sequence of acute and chronic pulmonary inflammation is far from clear and has only partially been elucidated yet. The first evidence is that the bronchoalveolar fluids in preterm infants with BPD contain many inflammatory factors such as TNF-α, TGF-β1, interleukins 1 and 8 (IL-1 e IL-8), mediators of lipids, oxygen radicals, fibronectin, elastin fragments, etc. Several trials involving animals have proved the relation between postnatal factors, as ventilation and the oxygen use, to the increasing lung inflammatory factors. The oxygen, for instance, involving preterm rats, increases the TNF-α, MCP-1, IL-6 rates, ventilation and the oxygen exposure are also responsible for the increase of the macrophages numbers. The CPAP (continu-
ous positive airway pressure) to 4 cmH2O is significantly responsible for pulmonary injuries in rats, according to study led by Tsuchida et al. (Am J Ohysiol Lung Cell 2005). The pulmonary expansion caused by concentrations which exceed the total pulmonary capacity induce the alveolar and vascular structures elements break, the leucocytes influx, increase the alveolar and interstitial permeability, consequently resulting in edema. The infant is exposed to prenatal factors such as sepses, SIRS (Systemic inflammatory response syndrome), and mainly the chorioamnionitis, the fetus maternal-derivate membranes infection, damaging the chorioamniotic membrane, the amniotic fluid and the umbilical cord. One of the consequences of this infection is the increasing of pro-inflammatory cytokines in the amniotic fluid. Gene therapy To those prenatal events we can add the postnatal events such as the resuscitation, oxygen toxicity, mechanical ventilation and the possible pulmonary infections. They are together responsible for a pulmonary inflammatory response, and inhibition of the alveolarisation and vascular development.
Prof. Dr. Christian Speer
According to Speer, chorioamnionitis, mechanical ventilation and postnatal infection are the main factors for pulmonary disease. The exposure to the chorioamnionnitis and mechanical ventilation over 7 days or postnatal infection are enough to define what is called the “new” BPD. Those events are responsible for the inflammatory reaction progression, with specific preterm infants’ characteristics: despite some deficits well-defined in the neutrophils supply and in the phagocyte role, “the preterm infants apparently are able to show a considerable and sustained neutrophil response to a variety of inflammatory mediators”, explains Speer. The prolonged survival of neonatal neutrophils in inflammatory areas may contribute to devastating and injurious effects of these cells to pulmonary tissues and airways. New therapeutic perspectives exist with the gene therapy: the postnatal administration of VEGF factor (vascular growth factor), mediate by adenovirus, and have demonstrated improvement in the survival, in the vascular capillary formation and also in the alveolar development among
MEDICINA HOJE - Chiesi Special Issue • january, 2007
Retinopathy of prematurity
The importance in decreasing oxygen saturation
Oxygen concentration used in resuscitation worsens retinopathy and the risk of blindness. The number of cases increases currently when low-weight preterm infants survive, justifying the strict control of oxygen concentration administration. between 1990 and 1994 a incidence ROP taken place in a English town which last from 1990 to 1999, out of 203 preterm infants weighing less than 1250g, nine (4,4%) have developed Retinopathy of prematurity (ROP) in equal or over stage III. In the remaining period, between 1995 and 1999, among 302 preterm infants, the ROP percentage increased to 11, 9%. “There is a strong evidence that the severity of ROP in children weighing less than 1.250g is getting worse and it is irrespective of the improvement in the survival rate, said the American professor. “Between 400 and 600 children become blind due to ROP in the USA, every year”. Besides that, mature newborn are developing ROP, “which is particularly a problem in developing countries comparing to developed world.
“
There are three epidemic of retinopathy of prematurity in history (ROP): first one took place from 1942 to 1950, the second one from 1970 to 2000 and currently we are experiencing the third one. When lecturing on “Oxygen saturation and ROP”, Rangasamy Ramanatham, researcher and Pediatric professor of University of Southern Califórnia, Los Angeles, CA demonstrated that in the first multicenter randomized controlled trial of oxygen saturation and ROP, the preterms infants who survived and administered with a lower oxygen concentration have developed less ROP and blindness. “The Archives of Ophthalmology in 1956, in articles published by Klynney and team, shows that, at those days, out of 22% of preterm infants weighing less than 1.500g who had survived and had been administered with conventional oxygen, 72% have developed ROP, 23% between stage III and IV and 11% have become blind”, the professor said. On the other hand, out of 25% who have survived using a reduced concentration of oxygen, 33%, 6% and 2% have developed ROP, III and IV stages and blindness respectively.
together in the second HDI group”, he said. Those information were based on Gilbert and team report, International No-ROP Group, published in the Pediatrics, May, 2005. USA: from 400 to 600 blinds a year Anyway, the truth is that in USA, specifically in California, another study, by Tomkins, published in 2002 in Pediatrics, shows increasing rates of blindness by ROP between 1995 and 1999. The infants born in 1995, 1996, 1997, 1998 and 1999 have shown, respectively, 12%, 8%, 14%, 15% and 22% cause by the pathology. The concern is that in USA, “12,3% of newborn are preterm infants, which of 40.000, a year, with weigh lower than 1220g; 2000 develop, a year,
Between 400 and 600 children become blind due to ROP in the USA, every year.
Developing world: higher risk of ROP
Randomized, controlled trials in England
In Argentine, Cuba, Paraguay and Colombia, ranging from 31 to 100 in the Human Development Index, shows percentages of 60%, 38,6%, 33,3% and 23,9% for blindness caused by ROP comparing the 13% in USA. In any case, the American blindness rate is much righer comparing to the British 3% and Sweden 4%, countries that together with USA are placed in a privileged position, between 1 and 30 in HDI. “The Brazilian blindness rate caused by ROP, according to this trial, is 14, 2% coming close to the 16% of Peru,
The first ROP epidemic reported by Terry in 1942, according to Rangasamy Ramanathan was related to hyperoxy, the second one was also related to hyperoxy and normoxia in extremely premature babies and the current epidemic is about extremely small preterm infants who had an improvement in the survival rate and are subjected to all those factors”, he declared. The Pediatrics in 2004 published an study by Hameed and team which shows that the in the period
cicatricial ROP, between 400 and 600 become blind and 2000 show other type of anomalies such as myopia, amblyopic, strabismus and late retinal detachment”, said Rangasamy. Causing factors: IGF-1 and VEGF The scientist has reminded in the Symposium the main ROP pathophysiological factors. “In the phase 1 of the disease the vascular growth stops and also vascular loss occurs, with consequently, hypoxia of vascular retina; in the phase 2 neovascularization occurs” he said. In regular physiological
Rangasamy Ramanathan (USA): “a protocol of low physiological oxygen reduces significantly the beginning of ROP in preterm infants with severe low weight at birth”.
terms, the activation of kinase B protein occurs(critical factor to the endothelial cells growth) under the VEGF action (oxygen-regulated growth factor) and lead by IGF-1 (non oxygen-regulated growth factor such as the COX2 – which are induced by cytokines and inflammatory mediators- and the growth hormones). “VEGF is induced by hypoxia, therefore, if the hyperoxia occurs, VEGF is suppressed, which cause the phase 1 of ROP”, said Rangasamy. In the phase 2, the VEGF overproduction is important for the retina neovascularization and, obviously is stimulated by hypoxia which develops in this phase. On the other hand, preterm infants show IGF-1 low which is aggravated by malnutrition and infection, therefore, “preterm infants with malnutrition and infection have low IGF-1, according study by Smith in May, 2001, in Proceeding of the National Academy of Sciences (PNAS), said in his lecture, making the audience to think about the main ROP etiology in poorer countries where malnutrition and neonatal infection are serious issues. Risk factors summary Finally, according to the professor, several studies show that
the risk factors for the ROP developing are “low weigh (lower than 1000g), hyperoxia, hypoxia, sepsis (fungal infections), PDA, NEC (necrotizing enterocolitis), IVH (intra-ventricular hemorrhage), renal insufficiency, arterial catheters (endothelia), low selenium, room light, transfusion, steroids, low antioxidant concentration and, mainly, oxygen”. In the face of that and years of research, the lecturer and his colleagues of Good Samaritan Hospital, of Cedar-Sinai Medical Center and of the Singapore National University Hospital propose in article published by the Biology of the Neonate in 2006 that “a protocol of low physiological oxygen reduce significantly the developing of ROP in preterm infants with severe low weight at birth”. In the hospital, Rangasamy has hung a board, near the babies under his care, saying: “my birthweigh is less than 1000g or over and I am 28 weeks or less at birth. Please, keep my oxygen saturation between 85% and 89% until I become 33 weeks PMA (Post Menstrual). Keep me out of 90%! If you think I have PPHN (Persistent Pulmonary Hypertension of the newborn), ask Dr Rangasamy about my saturation limits”. Here is my advice to all neonatologists.
Others exogenous surfactant therapy use The surfactant therapy has positive results in bacterial or viral pneumonia cases in newborns. It could also be indicated in congenital diaphragmatic hernia cases.
Edna Maria de Albuquerque Diniz, USP.
The surfactant replacement therapy in the Respiratory Distress Syndrome (RDS) is part of clinical routine in newborn treatment with immature lungs. There are several randomized controlled trials of surfactant use and the meta-analysis has shown
clearly that the surfactant administration reduces significantly the pneumothorax and the perinatal mortality. The chronic pulmonary disease and the intracranial hemorrhage decrease is less substantial, still needing more comparative trials between different surfactants, explain Edna Maria de Albuquerque Diniz, University of São Paulo – Medicine, Department of Pediatrics, Neonatology Unit. The surfactant deficiency may or may not coexist with others pulmonary diseases. The surfactant can be either inactive or deficient in diseases other than RDS, such as: meconium aspiration syndrome, bacterial or viral diffuse pneumonia, sepsis, perinatal asphyxia, pulmonary hypoplasy (congenital diaphragmatic hernia), congenital deficiency SP-B, pulmonary hemorrhage, and trauma. Plasmatic protein (in particular, fibrogenic, hemoglobin and albu-
min) and meconium are the main biological substances which may inhibit the surfactant. The meconium is responsible for the atelectasias, stretch of the airways and chemical pneumonite but researches show that they may have a specific action of the surfactant inactivation. In order to the treatment succeed it is important that the administered surfactant resist to the inactivation by these different substances. In trials involving animal models (rabbit), Herting et al. has shown that infected animals, which have been given surfactants, have shown significantly less bacterial development than the animal which have been given placebo. Also adult rats with pneumonia E Coli have improved the PaO2 after receiving Curosurf. In the contrary, animals with SP-A and SP-D deficiency have shown that signs of inflammation
and inflammatory cells in the lungs have worsened after infection. Study of Diniz et al. (International Workshop on Surfactant Replacement, 2002), involving 26 infants with severe bacterial or viral pneumonia, has shown a significant improvement after administering surfactant via endotracheal tube (Curosurf). The majority of newborns have been given one dose and the improvement has remained for the following 6 and 12 hours. The surfactant therapy was also administered in congenital diaphragmatic hernia where surfactant deficiency is usually found despite the trials in infants remain limited. According to Edna Diniz, “any neonatal pulmonary disease which occurs with surfactant dysfunction constitutes a potential target for surfactant therapy”.
MEDICINA HOJE - Chiesi Special Issue • january, 2007
Nitric oxide is controversial
Stable micro bubbles
Inhaled Nitric Oxide should not be used neither in preterm infants with less than 34 weeks nor with health complication.
Renato Fiori, titular professor of Pediatric Department, Medicine School of PUCRS, specialized in intensive neonate care, has developed a simple test, quick, and not expensive to evaluate the pulmonary maturity in preterm infants and then to make a decision on the surfactant administration.
An expensive treatment is not necessarily a good option and the use of Nitric Oxide in preterm infants is one of them, according to Professor Rangasamy Ramanathan, Pediatric Department of University of Southern Califórnia, LA. “There have been many studies carried out with animals which show that Nitric Oxide may promote lung development, pressure and inflammation decrease and that is why all therapeutic units are holding experiment with Nitric Oxide in preterm infants. However, the results in infants are not as good as those observed in animal models”, said Ramanathan. In his opinion, the inhaled Nitric Oxide (iNO) should not be used in the following cases: preterm infants with less than 34 weeks; patient with Pulmonary Veno Occlusive Disease; dependent neonates on Right to Left shunting of Blood; severe Left Ventricular Failure, patient with significant bleeding diathesis, with severe thrombocytopenia and also with known “severe” IVH. On the other hand, the iNO appears to be effective in less sick infants, Non-Caucasian infants and in more mature (over 1000g) infants and the gas may be “neuroprotec-
chopulmonary dysplasia in patients who have been given either iNO or placebo (71,6% vs 75,3%, P=0.24). “It appears that for preterm infants with a birth weight less than 1000g there is no difference in the incidence death or bronchopulmonary dysplasia” Ramanathan said. He also concluded the overall risk of brain injury is not yet reduced. The second randomized trial, carried out by Roberta Ballard and team of the Children’s Hospital of Philadelphia, Ramanathan pointed out the difference in outcomes when comparing the therapy starting day and the ethnic aspect of the infant. When the iNO therapy started between 7 and 14 days of age, among infants with bronchopulmonary dyspalsia (BPD), the survival rate was 49,1% against 27,8% of placebo group – with a rate variation of 40,7% and 42,8%, respectively, for the therapy starting between 15 and 21 days of age. The comments on the ethnic group pointed out the difference in the survival rates among infants without BPD. “While the Afro-Americans and Hispanics had 56,6% and 65,6%, respectively, receiving iNO against 35,6% and 39,5% on the placebo
“
The results in infants are not as good as those observed in animal models.
tive” in a subset of preterm infants, Ramanathan specified. Positive outcomes on AfroAmerican and Hispanic The researchers´ statement is supported on several clinical trials. The New England Journal of Medicine published in the last July two articles, where professor John Kinsella and team of University of Colorado, School of Medicine, have performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749g, 750 to 999g, or 1.000 to 1.250g). According to the outcome, for infants with a birth weight between 1.000 and 1.250g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent) but, overall, the results have shown no significant difference neither in the incidence of death nor in the bron-
group, the white infants group has shown almost no difference for both therapeutic methods: 34,7% (iNO) and 34,5% (placebo%)”, Ramanathan said. Hypoxemic Respiratory Failure Rangasamy Ramanathan also has pointed out that seven randomized trials carried out before have shown no difference neither in the mortality nor BPD rates and there was no improvement in oxygenation in the short term for preterm infants who had received iNO with respiratory failure (Cochrane Reviews, 2006). Finally, a third randomized, controlled, double-blind trial, published by John Kinsella, in 1999 in the Lancet (354:1061-5), has involved 80 premature neonates with severe hypoxemic respiratory failure with gestational age of 34 weeks or less in 12 perinatal centres which provide tertiary care. “Having analyzed the use of early iNO therapy for preterm infants with severe hypoxemic respiratory failure, there was no improvement in the survival rate – 52% for infants in the iNO group against 47% for the placebo group”, the researcher concluded.
A simple test to evaluate the pulmonary maturity in newborn
Renato Fiori (Brazil) (left) and Christian Speer (Germany).
The surfactant, when needed, should be administered as soon as possible right after the delivery in order to prevent the Respiratory Distress Syndrome (RDS) in newborns babies. For that reason, several tests were developed in the last decades, particularly, since the surfactant therapy has been brought into use. The first tests were the biochemical ones, such as the lecithin/ sphingomyelin relation, protein surfactant A, the saturated phosphatidylcholine and phosphatidylglycerol dosage and furthermore the overall phospholipids. All those tests are slow, expensive and they are not suitable to be performed in the patient room. The biophysical tests, because of their practicality, the quick performance and low cost, are more promising: the most performed one are the clic test and the stable micro bubbles lamellar bodies count. The surfactant is administered in the rescue or therapeutic mode, after the RDS diagnosis, and in the prophylactic mode, usual for preterm infant within 28-32 weeks, when the surfactant is use straight away after the birth. The surfactant therapy helps to prevent pneumothorax interstitial emphysema and mortality. Therefore, for the last mode, the risk of medicine misuse in preterm infants who have not developed the disease exist, especially there is the need of intubation and ventilation, with afferent risk. The ideal, explains Dr. Fiori, “is to do the selective prophylactic only in the high risk preterm infant who shows pulmonary immaturity evidences”. That is the reason why, the tests most carried out currently, are, for instance, the lamellar bodies count which are found in many fluids such as the amniotic or in the inhaled gastric. The count is a simple technique and can be made using a blood count machine. The amniotic fluid is difficult to obtain, especially when the baby is trans-
ferred and the gastric fluid may show problems for being viscous and lack homogeneity. The clic test The clic test is based on an event that occurs within the bubbles produced in the pulmonary surfactants. The bubbles flatten gradually and suddenly they turn back to the spherical shape again and again (the clic phenomenon). The process can be observed on the microscope which shows the tensioactive substance (surfactant). According to studies, such as Osborn et al., the clic test reduces the surfactant administration time and the treated newborn number. After the Clic test had been applied, the surfactant administration has occurred within 50 minutes against 159 minutes when the diagnosis is based in clinical and radiological criteria. The stable micro bubbles test correlates the bubbles number, with
less than 15 micrometer, to the surfactant presence in the fluid (inhaled gastric or inhaled tracheal, which is better but needs intubation). The test is a simple and a quick procedure: it needs a drop of the fluid in a Pasteur pipette and shake it followed by the micro bubbles count on the microscope. The more bubble is found the more is the surfactant existent in the secretion. In Porto Alegre, the test is carried out in a daily basis in the Neonate Unit of the São Lucas Hospital. The test is applied on inhaled gastric among patients with 23-32 weeks. In the situation where the bubbles number is less than 25/ mm2, the prophylactic mode using surfactant is applied. If it is not the case, the rescue therapy is applied in accordance with clinical and radiological signals (figure 1). In recent published study by Fiori et al. (J. Perinatal Medicine, Jan 2006), a section point of 25 microbubbles/mm2 was used, corresponding to a sensibility over than 90%. Using a section point between 10 and 15 microbubbles/mm2, the accuracy remains between 80-85%, similar to biochemical tests such as lecithin/sphingomyelin. In this study involving 98 preterm infants, 55% showed the bubble count lower than 25 micro bubbles/mm2 and then received surfactants treatment immediately. Only newborns with high bubbles count, have developed the hyaline, membrane disease. The average time to surfactant administration was 20 minutes. Comparing with USA outcomes, 80% of infants with less than 30 weeks have received surfactant and average procedure time is 50 minutes. We can conclude that a not expensive and quick test is available which allows to select the preterm infants subset with higher RDS risk and give the surfactant, when necessary, in less than 30 minutes after delivery.
Figure 1 – The micro bubbles observed on the microscope. Source: Renato Fiori
MEDICINA HOJE - Chiesi Special Issue • january, 2007
New trends
Is there still a role for postnatal steroids in BPD?
According to Henry Halliday, the corticosteroids have currently a very limited role and should be used very carefully.
The corticosteroids have a limited role in the neonatal: they should be avoided in the first 4 days and be reserved to infants at high risk of developing chronic lung disease. The corticosteroids use in newborns was welcome enthusiastically and was criticized very little 10 years ago until the American Association of
Pediatrics guidelines started having doubts on their effects. According to Henry Holliday, director of the Royal Maternity Hospital Neonatal unit,
Belfast, North Ireland and editor of the Biology of Neonate magazine, the corticosteroids have currently a very limited role and should be administered very carefully. Besides that, they should not be administered in the first days of birth and only in infants at high risk of developing BPD. The Halliday statement is supported by meta-analyses of several recent randomized controlled trials, which will help to develop guidelines based on evidences for corticosteroids postnatal treatment in infant at risk of developing chronic pulmonary disease. The results show that corticosteroids given at any time in the neonatal period reduce the BPD risk, especially before 36 weeks but the risk of adverse effects in the central nervous system are likely to happen. The cerebral palsy is more frequent in infants treated before 4 days. The results of meta-analysis of randomized controlled trials involving 4000 infants show that the corticosteroids use in infants who are at pulmonary disease low risk are more likely to develop cerebral palsy. “In fact this
explain the reason for the cerebral palsy risk is worsening only in preterm infants being treated prematurely and that is why they show lower risk of developing BPD”, said Halliday. The conclusion is that the corticosteroids should be avoided in the first four days of life and reserved to infants at risk of developing CLD or in those who already have CLD. The corticosteroids should be prescribed at lowest dose for the shortest possible duration. The corticosteroids have a direct toxic effect on the neurons, on the growth factors, the neuronal migration, myelinization and reduce the defense mechanism effectiveness against hypoxia, hypoglycemia, hyperoxia and hypocarbia. The corticosteroids most administered are the dexamethasone on the 0,5mg/kg/day dose for 3 days, lasting overall 12 days. The dexamethasone was compared to methylprednisolone which appears to be as effective as the dexamethasone, but there have been no randomized, controlled trials carried
out yet. Hydrocortisone low doses (1mg/kg/day) have reduced the risk of dysplasia but two trials have showed the high risk of intestine perforations which explain the trials interruption. Halliday and his team have carried out randomized controlled trials (Halliday et al., OSECT trial, Pediatrics 2001) in order to compare the effectiveness of systemic dexamethasone (started with 0,5mg/ kg/day) and the inhaled budesonide (800µg/kg/day). The results have shown similar effectiveness despite the adverse effects a little bit higher in the budesonide. In 110 newborns receiving corticosteroids in the first 96 hours of life, 9 will prevent from developing BPD but further 6 had gastrointestinal hemorrhage and further 6 cerebral palsy. In a near future, follow-up studies are needed as well as randomized trials to observe better the lower doses effects, in a short period of time, to compare different products and to study better the inhaled corticosteroids effects.
poractante vs. beractante
Natural vs. synthetic surfactants
Randomized trials with a large number of infants are necessary in order to corroborate the interest in a new class of synthetic surfactants. Neonatologists seek to develop a protocol which will work as a guide to therapy for Respiratory Distress Syndrome with surfactant administration. The protocol, according to Henry Halliday, Queen’s University, Belfast, will be based upon evidences from systemic reviews of randomized and controlled trials which have been carried out since 1980 when was reported the wellsucceeded therapy with a modified bovine surfactant. The trials aim at evaluating the efficiency, timing, number of doses, methods of administration and other aspect of surfactant therapy. Surfactants tested in controlled trials The natural and synthetic surfactants used as replacement in Respiratory Distress Syndrome treatment are divided in four groups: the old synthetic without protein, the new synthetic with analogue protein, the natural from minced lung extracts and the natural lung lavage extracts. A third natural surfactant type, the amniotic fluid extract has been banned because of the risk of HIV contamination. The randomized, controlled trials systemic reviews, obtained from the Cochrane Library and Pub med, comparing synthetic and natural surfactants either for the prophylactic mode or therapeutic mode have shown that the natural surfactants are more effective than the synthetic at reducing air leak,
mortality and death combined with BPD. Trials based on the criteria of relative risk (RR), numbers needed to treat (NNT) and 95% confidence intervals (CI) have shown that multiple doses (up to three) are better than a single dose for infants who relapse. The natural surfactants are not similar, showing different makeup which has been revealed in several comparative trials. Studies comparing Curosurf, Infasurf, Alveofact and Survanta were carried out between 1995 and 2004 involving over 3000 infants. In a trial led by Rangasamy Ramanathan comparing 200mg/kg of Curosurf (Poractant), 100mg/kg of Curosurf and 100mg/kg of Survanta (Beractante) in newborns with developed respiratory failure was shown a reduction in the neonatal mortality rate and also a improvement in the oxygenation for infants treated with Poractant, especially with the 200mg/kg administration (3% against 8% of beractante). That could mean a beneficial aspect for the survival in the initial dose administration of 200mg/kg in rescue studies. Prophylactic comparative trials with these surfactants have not been performed to date. For the prophylaxis, the treatment before RDS development, 100mg/kg may be enough since the surfactant inactivation is unlikely to occur in this situation. The Pediatrics, last year, has published two prospective ran-
domized controlled trials comparing calafactante (Infasurf 105mg/ kg) and beractante (Survanta, 100mg/kg) in the prophylactic study involving infants with gestational age between 23 and 29 weeks and weighing between 401 and 2000g, using mechanical ventilation and a oxygen concentration of 40%. Three treatments could have been administered at 6h apart in case the infant need a higher oxygen concentration than 30% and still intubated. The primary outcome for both trials was a survival up to 36 weeks without oxygen. With calafactante a sudden decline in inhaled oxygen has taken place comparing to beractante. The study was discontinuous as there were not sufficient infants in order to show the difference in these surfactants and, according to authors of those studies, issues related to safety and effectiveness will remain unanswered until clinical researchers will get involved more seriously in complicated tasks linked to clinical randomized trial in large scale. The problem with trials with equally efficient surfactants is that is necessary to have a huge number of infants involved in order to obtain satisfactory outcomes. The study combining surfactant and CPAP has revealed effectiveness in the reduction of length and need of mechanical ventilation and should therefore reduce CLD but prospective study is essential to obtain more conclusive results. A new synthetic surfactant genera-
tion protein analogue SP-B or SPC have been researched but there is no evidence that they are more effective than the existent surfactant. An evidence-based protocol for surfactant therapy, according to Halliday, should have as a proposal the prophylaxis for infants with less than 27 or 28 weeks, early rescue for gestational age between 28 and 31 weeks and over 31 weeks, the CPAP in respiratory distress. The evidences favor the natural surfactant use and about the synthetics there is insufficient
information to a conclusion. The dosage depends on the most appropriate length of treatment and the prenatal corticosteroids administration. The new randomized trials should have in mind the early use of CPAP and the prophylaxis with surfactant, comparative studies on new synthetic, available surfactant supply in developing world, avoidance of intubation (inhalation or nebulization, laryngeal mask and pharyngeal deposition), a wide recommendation of tailored surfactants and prevention of CLD (budesonite and Survanta).
CUROSURF vs. SURVANTA Effect on neonatal mortality 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0%
CUROSURF 200mg/kg
CUROSURF 100mg/kg
SURVANTA 100mg/kg
Figure 1 – Comparative studies with 2 dosage of Curosurf against 1 dosage of Survanta in newborns with Respiratory Distress Syndrome, severely ill need a 40% oxygen concentration. It proved more beneficial with Curosurf, especially with a higher dose.
MEDICINA HOJE - Chiesi Special Issue • january, 2007
Oxygen
Specialists stand up for room air in the resuscitation process
From left to right: José Roberto de Morais Ramos (Fiocruz), José Maria de A. Lopes (Laranjeiras Perinatal Clinic, Rio de Janeiro), José Luiz Muniz D. Bandeira (UERJ).
Brazilian and international neonatologists agree with the promotion of room air in the neonatal intensive medicine in order to decrease either the chronic pulmonary dysplasia or retinopathy of prematurity. Near the event enclosure, Jose Maria de Andrade Lopes, Director of Laranjeiras Perinatal Clinic, Rio de Janeiro, in his lecture: “Oxygen: 50 years of uncertainty”, has stated a right historic dimension of the reality which the neonatologists worldwide have been undertaking on how to use oxygen in preterm infants. Jose Maria de Andrade Lopes, PHD in McGill University, Canada, and physician and researcher of Fernandes Figueira Institute, Fiocruz, has been studied the relation between the oxygen saturation and the PaO2, in other words, the relation between what is measured in the peripheral haemoglobin and the existent oxygen real concentration, in that moment, in the arterial blood and the choices made in the Neonatal Intensive Care Unit linked to the ox-
ygen supplied to the preterm infant. Besides, the researcher has shown the existent experience with resuscitation using room air and with the oxygen supply and the chronic pulmonary dysplasia and retinopathy of prematurity incidences. Room air Taking in consideration that all possibilities of oxygen dosage in the infants, in the mixture and the room have been beneficial for the neonatal intensive therapy, Lopes has pointed out the continuous arterial oxygen dosage, the transcutaneous screening and the saturation measure device, working as important artefacts of good quality in the health care and the possibility of having PaO2 follow-up in re-
lation to SaO2. On the other hand, it has brought up the discussion on air room resuscitation. According to him, European resuscitation randomised trials involving 134 newborns with medium Apgar of 3,4 with room air or oxygen supply, “have shown that the resuscitation with air has led to a faster recovery of the cardiac frequency and needed less ventilation with ambu and mask than resuscitation with 100% O2 concentration”. Lopes also has quoted another randomised trial, exactly the same one quoted by the Norwegian scientist Ola Saugstad which has compared among 119 preterm infants the resuscitation with 20% oxygen concentration and 100%, with a follow-up between 18 and 24 months. In the study, for instance, the somatic growth and infants development in the follow-up, the information were absolutely compared, suggesting that the 100% oxygen concentration is unnecessary. Safety in the asphyxia Another randomised trial quoted by José Lopes, carried out by Maximo Vento and team, Valencia University, Spain, has studied 1.315 infants who were resuscitated between 1993 and 2004. The outcome of the Spanish physicians has stated that “the room air is safe for infants resuscitation with asphyxia. Therefore, the recovery time decreases and the mortality rate is lower”. He also added that “the room air-derived oxidative stress is low and of short term which causes less damage to the tissue”. The results have
shown better Apgar, shorter crying and recovery time, better laboratory exams and lower mortalility rate in room air comparing to 100% oxygen supply. “The study has indicated 11,1 against 29,0% of mortality rates in room air and 100% oxygen concentration respectively, said Lopes who was sorry about the American Pediatric Association which has not changed its recommendation on the resuscitation procedure although four meta-analyses have shown the beneficial role of room air resuscitation. Routine and conduct code Pointing out the need of a defined routine and care when evaluating the oxygen saturation, having in mind that it doesn’t show the accurate oxygen concentration in the arterial blood, Jose Maria has corroborated with his Brazilian and international colleagues who have attended the Symposium about the options of keeping the saturation levels raging between 85% and 95% for the pulmonary dysplasia prophylaxis and retinopathy of prematurity. The physician has demonstrated the routine based on experience of his practice and a comparative table of perinatal results with the Vermont Oxford Network 2002-2003 which are satisfactory enough. However, the researcher is not fully happy with the incidence. “In infants weighing less than 1,5kg, international practices show results 1% and 2% of retinopathy of prematurity, less than the 6% in my unit. I have to find a way to reduce my rates”, he said.
genetic
Mutations may cause lack of surfactant In another study, quoted by Curstedt, scientists from the Paediatrics Department, Washington University, have identified 33 SPB-deficient infants between 1993 and 2005 and have concluded that the results, in long term after the infants’ lung transplant for SPB deficient, are similar to those in transplanted infants for other indications. According to the article, in the Journal of Pediatrics, October, 2006 (149[4]:548-53), the results are important to make a decision of undertaking the lung transplantation for infants with alveolar homeostasis disorders. Curstedt has pointed out that, in general, the SP-B deficiency occurs in preterm infants and the average age of those, by the time they die, is three months. About the SP-C deficiency, the researcher has said that is not well understood which has been identified more than 25 mutations. He has recalled that the disease, in general, shows only between childhood and adult life. In his opinion, one of the possible advantages with the studies development would be to identify the genetics markers for the respiratory distress, “which could be used in the clinical practice and also would allow to develop strategies for genetic pulmonary disorders treatment”.
Synthetic surfactant has not proved effective yet limited to two or three as they are currently. It would be synthetic surfactants more complex than the ones currently available”, he said. He also pointed out that there are no records of real analogue SP-B surfactants. In his opinion, to obtain more positive outcome, it is fundamental to take in consideration the alveolar stabilization. “The synthetic surfactant has to prevent the alveolar failure in the expiration, which doesn’t happen with the current ones”, he pointed out. Curstedt emphasized that the evidences suggested that even with the synthetic surfactants therapy, PEEP is necessary to keep the alveolar stabilization appropriated. He explains that because the alveolus surface is too large, when the surfactant is applied it would spread faster. “In the inspiration, the alveolar surface enlarges and the surface to be covered consequently is bigger. It is fundamental to stabilize the alveolus in the expiration”, he said.
According to the specialist, “the idea to produce a synthetic surfactant is to try to simplify its composition”. “The ideal synthetic surfactant make-up would be the same as the natural one but the phospholipids composition of the natural one is too complex”, he reinforced. For him, the synthetic peptide – containing surfactants
and others with different SP-B fragments. According to him, the more promising outcome was obtained with the 34-residue peptide Mini-B, corresponding to the SPB 8-25 and SP-B63-78. On the other hand, besides the alveolar stabilization, there is the surface activity as a fundamental surfactant characteristic – among them the low-tension surface and the quick respreading after com-
From three to five years, I believe we will have an effective synthetic surfactant. currently available seek to imitate the SP-B, but its make-up is too simple. He has given as an example the KL4 (Lucinactant) made up of 21 amino acids residues only, while the SP-B has 158. He has also pointed out that the lucinactant is a gel, with high viscosity, that requires heating at 44oC for at least 15min before being administered to the infant. He has emphasized the fact that there are 4 different SP-B-fragmented surfactants: the monomeric SP-B125; dimeric SP-B1-25; the Mini-B
pression – and its resistance to the inactivation. In Curstedt opinion, it will take few years until adequate synthetic surfactants reach the market. “Many years ago, I used to think that in the late 90s a synthetic surfactant would be introduced into the market which did not happened due to many difficulties faced”, he said. However, the researcher remains optimistic. “From three to five years, I believe we will have in the market an effective synthetic surfactant”, he said.
09010761 H-MED HOJE NEO INGLE 2007
Tore Curstedt (Sweden) was one of the scientists who has developed in the 80s the animal-derived surfactant poractant alfa which was used in treatment involving 600.000 newborns worldwide.
The animal-produced surfactant has to undergo a time-consuming purification process before applied in human being. The similar synthetic type could reduce the cost and consequently the supply would be increased. However, the production process faces objective difficulties such as: how to repeat synthetically the natural substance, even if partially, reaching the same outcome? “To obtain the synthetic surfactant is very difficult as the phospholipids make-up is too complex and its proteins are not stable”, Tore Curstedt, Clinical Chemistry, Karolinsca University Hospital, Stockholm, Sweden, summarized. According to Curstedt, in order to be as effective as the natural surfactant, currently in use, the synthetic type should have in its makeup more than one peptide. “I think they have to be analogue to the hydrophobic proteins SP-C and SP-B and they should be more complex in their phospholipids make-up; not
The phospholipids make-up
“
The animal-derived natural surfactants use is effective for preterm infants but the production is limited and expensive. A new generation of synthetic surfactants developing, started in the 90s, is showing more complicated than expected and more controlled trials are needed.