Among the medical problems that may occur in the newborn period, perhaps none are more common or significant than respiratory problems. The range of disorders includes immaturity of the lungs in premature infants, retained fetal lung fluid in the immediate newborn period, meconium or amniotic fluid aspiration, and pneumonia. While each of these disorders has unique characteristics and requires specialized aspects of care, they share certain similarities in their underlying pathophysiology that make CPAP, or Continuous Positive Airway Pressure, an ideal therapy in developing countries.     What follows is a brief description of each of the major types of respiratory disease in newborns, an explanation of CPAP, and a discussion of how this therapy can be applied effectively.

Our views are heavily influenced by our direct clinical experience in Vietnam, which we have visited more than a dozen times over the last five-and-a-half years. We believe that the widespread availability of CPAPs in Vietnam could reduce the mortality of "moderately" premature infants (i.e. weighing more than 1,500 kg) from respiratory distress by as much as two-thirds, with the result of saving more than 15,000 lives annually. Our conclusion is based on research that we supervised directly on the efficacy of CPAPs when they were first introduced in 2002 at the National Hospital of Pediatrics (in Hanoi).  

From our perspective, the effective distribution of developing countries provides a unique opportunity to save children's lives at very little expense. In Vietnam, a new CPAP costs approximately $1,500. We extrapolate that the CPAPs used at the NHP have, on average, each save five or so infants' lives annually. Also, our experience so far is that CPAPs have a useful life of many years (the devices first built in 2002 are still going strong). Thus, CPAPs, if used in the correct places by health care personnel with adequate medical and technical training (which only requires several days, at most) can save children for no more than several hundred dollars--or less--per life saved. We believe that CPAPs may also provide other important benefits to the population of children treated, including a reduction in the incidence of brain damage due to respiratory distress.

Respiratory Distress Syndrome

Respiratory Distress Syndrome (RDS) also called Hyaline Membrane Disease is a very common disorder that primarily affects premature infants. The underlying cause is an absence or deficiency of surfactant, a complex compound that is made by special cells in the lungs (Type II cells).   Surfactant production normally occurs in the lungs beginning in the late phases of gestation, For example, at less than 28 weeks, production is rare, by 33 weeks about 2/3 of fetuses will produce it, and by term almost 100% of babies produce adequate amounts of this important factor.

Surfactant is a complex of lipids arranged in a bi-layer, with interspersed special proteins. The material lines the alveoli, or air sacs of the lung, and acts to reduce the surface tension within these sacs. As the alveoli expand and contract, the surfactant acts to equalize the pressures resulting from the surface tension. As a result, the pressures that cause the alveoli to contract are equalized across the lung, and between alveoli of different sizes. This means that the tendency of the alveoli to collapse each during expiration is minimized and stabilized, and all the alveoli remain open, even at end expiration.

In the absence of surfactant, it is very difficult to open alveoli during inspiration. The common analogy is the experience of blowing up a child's balloon. When the balloon is empty, it is very difficult to get the first breath into it, but as the balloon is inflated, it is easier and easier to do so. Surfactant reduces the difficulty of opening the balloon like alveoli, and equalizes the effort needed to inflate alveoli of different sizes.

Clinically, babies who lack surfactant struggle to open their lungs with each breath, and the cycle of struggle repeats ads the lung collapses to near empty between each breath. Manifestations of this include rapid respirations, and characteristic grunting efforts to open lungs, flaring nostrils, and retractions- deep tugging-in of the muscles between and below the ribs. Unable to breathe, the babies tire out and eventually will succumb to the disorder.

In some infants, the deficiency of surfactant is only partial; the compound is distributed unequally throughout the lung. The baby may have many of the same symptoms as a baby with total lack of surfactant, but these babies have the additional problem that parts of the lung are open, while others are not. In this circumstance, blood flows preferentially to the uninflated parts of the lung, where no gas exchange can occur. This worsens the degree of oxygen lack, and hastens the build up of carbon dioxide. Again the baby may tire out or suffer from the abnormally low oxygen. As the baby struggles to open their lungs, they may over expand the surfactant-replete areas as they work to open the closed areas, and these over expanded areas of the lung may rupture, causing collapse of the lungs and an emergency situation that can rapidly lead to death.

Overall, RDS is a disease of low compliance- meaning the lungs are difficult to inflate even when high pressures are given or generated by the baby. In addition, it is a disorder of atelectasis, or collapse. In infants of very low gestational age, the immature architecture of the lung contributes to the disease, but at gestational ages above about 30 weeks, most of the problem is surfactant deficiency alone. Importantly, the process of birth tends trigger the signals leading to surfactant synthesis, so that within a few days most babies begin to make surfactant and the RDS improves.

Surfactant replacement therapy is available that dramatically reduces the severity of RDS and decreases many of the complications of the disorder. This therapy is extremely expensive and not generally available outside the developed world. Use of surfactant replacement is also only effective when used with mechanical ventilation, another extremely expensive, technically complex therapy that is only rarely available in developing countries.   Another therapy is necessary.

Retained Fetal Lung Fluid

Retained fetal lung fluid is a disorder that occurs more commonly in term or near term infants. It is somewhat more common when labor is very rapid, or after Cesarean delivery, because normal labor promotes fluid absorption within the lung, and vaginal delivery accelerates the process of getting rid of the excess fluid. This fluid is normal- before birth the fetal lung is filled with fluid.   If some of the fluid is retained in the lung, it interferes with a normal transition to newborn life. The presence of fluid with in the lung tissue makes the lungs stiff, and therefore more difficult for normal inspiration and expiration to occur. As a result, the baby breathes rapidly, and may require additional oxygen to maintain a normal blood level.

In addition to disrupting lung function enough to interfere with normal oxygenation, this disorder has two additional aspects. Breathing rapidly makes it virtually impossible for the normal baby to breathe suck and swallow in a coordinated fashion, so eating becomes dangerous or impossible. Secondly, the condition is often difficult to distinguish from pneumonia, so babies get treated with antibiotics, IVs, etc.

Unlike RDS, the lungs in this condition may be of normal or even increased expansion. Similar to RDS, the stiffened lungs have poor compliance and may benefit from a therapy that accelerates fluid reabsorption.

Pneumonia

Bacterial pneumonia in the newborn can be a profoundly devastating disease that rapidly progresses to respiratory failure and death, even if promptly treated and supported. In part this is because it occurs as part of overwhelming systemic infection in a host, the newborn, which is immuno-compromised by definition.

In many cases of pneumonia, however, the patient is very ill but can recover with appropriate support and care. In these babies, the systemic infection can be controlled, and much of the problems revolve around the pulmonary aspects of the disease. One part of a lung infection is that the bacteria and debris create clogging in the alveoli, blocking normal gas exchange and function. In addition, this debris, the exuded fluid and other factors all act to inactivate surfactant, and to limit its function. Thus, many of the pulmonary consequences of pneumonia mimic RDS, with areas of collapse and other areas of over-expansion. The result is again a low compliance disease that can be treated with surfactant where available. However, even with surfactant, there is a need for therapy that works by maintaining lung expansion and aiding in the recruitment of collapsed alveoli into the group of functional air-sacs.

Aspiration Pneumonias

Newborns (fetuses) are at unique risk for aspiration during the process of labor and delivery. They live in a fluid environment, and this fluid may become contaminated by fecal material or blood. Fetal fecal material, or meconium, may be passes during a period of hypoxia or stress, and bleeding from placental separation or other sources can also occur. The fetus and newborn respond to hypoxic stress by gasping, so they may then aspirate the contaminated amniotic fluid. These disorders may be mild or severe, and they are also unique in being heterogeneous- i.e., they occur throughout the lung in a spotty fashion. . In the more severe forms, the blood or meconium inactivates surfactant, resulting in collapse of parts of the lung and overexpansion of others, similar to RDS due to partial surfactant deficiency. These disorders are characterized by their heterogeneous nature, and the fact that contaminated fluid may result in "ball-valve" obstruction of the airways, again resulting in areas of collapse and other areas of overexpansion. A therapy that gently distends airways and limits collapse is often the correct choice for these disorders.

Therapy

Is there a single therapy that works perfectly for all these disorders?   Without a doubt the answer is no, and in fact there is no therapy that works perfectly even for one of these disorders. However, there are therapeutic options that are very effective.

CPAP

CPAP, or Continuous Positive Airway Pressure, is a therapeutic modality of respiratory care that involved applying a continuous low distending pressure to the airways. While mechanical ventilators do provide a baseline level of pressure (usually called Positive End Expiratory Pressure, or PEEP) they also provide intermittent higher pressures to actively distend the lung (Peak Inspiratory Pressure, or PIP).   CPAP is based on the premise that low continuous pressure will maintain open alveoli, and as the baby's own respiratory drive opens additional alveoli, these will be maintained as well. Over time, the majority of the lung will gently be recruited, and be able to function in a near normal manner.

This therapy is successfully used every day in US Neonatal Intensive Care Units. In some, including most prominently Columbia Babies and Children's Hospital in New York (now Morgan Stanley Children's Hospital) this is the primary and predominant mode of respiratory support. It can be provided using relatively simple devices where the pressure is generated by flowing gas (air-oxygen) across a tube or prongs placed in the baby's airway. The end of the gas flow tube is submerged to a set depth into a bottle of dilute acetic acid. The depth of insertion determines the CPAP pressure applied, expressed as cm of water.

From the descriptions of the common disease processes above, one can see that CPAP is an excellent therapy or mode of support for these diseases. For RDS, CPAP maintains open alveoli, and permits the gentle recruitment of additional alveoli. It maintains and tends to even out expansion across the lung, contributing to more normal gas exchange. The risks of over distention or lung injury from the therapy are small and are usually manageable. Curiously perhaps, the greatest risk of over distention as a result of CPAP tends to be in near term babies who are strong enough to generate significant forces within their own lungs.

CPAP provides the same benefits in pneumonia and is often useful in aspiration syndromes. In this latter group of disorders, there is the greatest risk of the therapy increasing the "ball-valve obstruction" noted above, but in many babies it is just the ideal way to gently recruit alveoli and permit a return to more normal function.

CPAP also works well in the treatment of retained fetal lung fluid. In this disorder, the CPAP probably works to gently distend alveoli and help promote reabsorption of fluid. While the mechanism of action is different, the success of CPAP in this group is often quite significant.

CPAP has a long track record of safety and efficacy in the newborn and others. It was first used to provide pilots with oxygen in the 1940s, and Gregory and coworkers described its use in newborns in 1971, really at the birth of modern neonatal intensive care. The use of CPAP has waned and waxed as mechanical ventilation and surfactant therapy became available, but it is now once again a major modality in almost all Neonatal Intensive Care Units.

CPAP can be provided by a number of different devices. Some are simply settings on mechanical ventilators to provide a steady pressure at a set level. Other devices are simpler, and set the pressure by administering air-oxygen to a patient through a tubing circuit that is connected at one end to a gas source which then flows past the patient (who is connected to the circuit via small nasal prongs). The terminal end of the tubing is submerged in water (with a small amount of bacteriostatic agent). The depth to which the tubing is submerged creates the pressure, or CPAP. As the gas escapes into the water, it bubbles out, so this system is called "Bubble CPAP". Most US units use this modality to deliver CPAP. It is simpler and very safe, and the bubbling action may provide some additional benefits in terms of efficacy.

Mechanical Ventilation

The use of CPAP can not fully replace mechanical ventilation- there are some babies who do not adequately respond to CPAP or whose disease is so severe that additional support is needed. One value of CPAP is that it marked decreases the number of patients who would otherwise need mechanical ventilation.   This is important on all Neonatal units, but is particularly important in the developing world where the extremely expensive ventilators are rare.

The risks of mechanical ventilation are also much higher than those of CPAP. The use of distending pressures (PIP) increases the risk of over-distention and rupture of the lung. The skill and knowledge needed to effectively and safely use ventilators is much greater than for CPAP. The more prominent risks mean that using ventilators without adequate monitoring is potentially dangerous- including the maintenance of indwelling arterial lines and sophisticated electronic monitoring, both of which are rare in the developing world.

Is CPAP enough?

As noted above, there are babies for who CPAP alone is not adequate, and mechanical ventilation, including specialized modalities not discussed here, must be used to support and save the baby. There are other much less common respiratory disorders for which CPAP is of limited if any use. These are uncommon disorders, many of which include congenital malformations of the lung or other organs.

The intent of this question is really to highlight other therapies that reduce the severity and incidence of RDS, which is the major respiratory disorder in babies. The use of antenatal steroids (corticosteroids given to the mother before a threatened premature birth) dramatically accomplishes this goal. Treatment with two doses of betamethasone, given 24 hours apart, results in dramatically lower incidences of RDS and other complications of prematurity. This therapy is inexpensive and easy to administer. While it has its maximal efficacy if 48 hours have elapsed during therapy, it in fact starts to confer some benefit within hours of the first dose.   The major drawback to this therapy is in identifying the women at risk, and getting them to a healthcare facility early enough to make the therapy possible. These are non-trivial challenges in the developing world, but not insurmountable. The use of this therapy in conjunction with increased availability of CPAP makes it possible to dramatically impact respiratory disease in the newborn.

What is the optimal CPAP device for use in the developing world?

In the developing world, the use of CPAP as the major modality for respiratory support is the best choice. The therapy is safe and effective, and can be administered by most practitioners with a moderate degree of sophistication, following a discrete period of training. The optimal device must be simple to use, relatively inexpensive (to permit the most widespread implementation) and good local support and repair must be available. The device must be attractive and ergonomically designed, to ease use and hasten acceptance by physicians and caregivers. In addition, the use of the device must include a cleaning system that is not dependent on autoclaving, a sterilizing procedure not widely available. This system is key to ensuring that the use of the device will not inadvertently increase infections.

In Vietnam, the KSE CPAP device was developed with these criteria in mind. The device is manufactured using materials and equipment that is available within the country, so initial production is efficient and repair parts are available. The establishment of KSE Medical as a company within Vietnam means that advice phone calls are readily available, and on site service and repair are available. In addition, the machines was designed and modified with input and advice from Vietnamese neonatologists. As a result it is ergonomically designed for the Vietnamese physician, and has a finish that is attractive to the Vietnamese eye. Based on knowledge about the availability or lack of other cleaning systems, a cleaning system for the device was developed that ensures that each device can be adequately cleaned and prepared for use between patients and on a regular schedule, so the infectious risk from use is kept to a minimum. Finally, the device is inexpensive, costing roughly 10-20% of systems produced in the developed world.

All of these attributes would be of limited value if the device did not work. Extensive testing on animals was done using the device at the National Hospital of Pediatrics (Hanoi) that demonstrated safety. Use in humans in controlled studies at NHP (manuscript in preparation) demonstrated efficacy and safety equal to more expensive devices. Most importantly, installation of several CPAP devices at the NHP during the initial study period resulted in a 70% reduction in neonatal mortality from respiratory distress in the first 24 hours, from 35% to about 10%. When extrapolated to all of Vietnam based on the rates of prematurity and incidence of respiratory distress, this translates into more than 15,000 lives saved each year.

CPAP treatment may provide other important benefits in addition to mortlity reduction. Frequent consequences of inadequately treated respiratory distress syndrome in infants are hypoxia and blood pressure swings, both of which can result in significant brain damage among children who survive. While precise estimates are impossible, we are hopeful that CPAPs will reduce the incidence of brain damage in the population of babies that are treated.  

In summary, we believe that effective distribution of CPAPs, with the minimal training required of medical personnel, provides a virtually unprecedented opportunity to save and improve children's lives, with modest expenditure, in Vietnam, and quite likely other nations, throughout the developing world.

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