Respiratory distress syndrome (RDS) happens when the lungs are damaged and cannot absorb enough oxygen into the blood. RDS occurs in premature babies but also in adults. Extensive research has led to treatments which have saved patients' lives, but more research is needed.
Respiratory distress syndrome (RDS) is a clinical syndrome for which no speciﬁc marker exists. It is characterised by insufﬁcient absorption of oxygen by the lungs, resulting in progressive hypoxaemia (low levels of oxygen in the blood). Oxygen cannot be absorbed by collapsed or fluid-ﬁlled lung sacs called alveoli. The syndrome is associated with decreased lung compliance, with intrapulmonary shunting and pulmonary oedema. RDS follows direct damage to the lung, e.g. infectious pneumonia, aspiration of contents of the stomach, near-drowning, smoke-inhalation and thermal lung-injury, or systemic damage such as septicaemia or haemorrhagic shock with multi-organ-failure, resulting in injury to the lining of the lung enabling it to absorb oxygen.
The course of the syndrome can be divided into three pathologic stages: (i) in the exudative stage, damage occurs to the cells lining the capillaries and to the cells covering the alveoli in the lung, resulting in pulmonary oedema and hyaline membrane formation. The exudative stage is associated with vascular occlusion and pulmonary hypertension; (ii) the proliferative stage follows between the ﬁrst and third week after the initial damage. It involves a complex host response by a series of immune mediators and is characterized by proliferation of various cells such as pneumocytes and ﬁbroblasts, resulting in conversion of intra-alveolar exudate into cellular granulation tissue; (iii) ﬁnally, in the ﬁbrotic stage, if the patient survives for three weeks, the lungs show some permanent damage.
RDS occurs in children as well as in adults. The annual incidence in Europe is ﬁve to ten per 100,000 population which corresponds to between 25,000 to 50,000 cases each year. It is observed in all locations where medical care enables patients to survive acute insults of a primary pulmonary or systemic nature. The time course after onset of the associated acute disease and onset of RDS varies from hours to days.
There is often a latent period in which the patient exhibits little respiratory distress, except for excessive breathing, with normal chest sounds and chest radiographs.
RDS is one of the most common lung disorders in premature infants and affects about ten per cent of all pre-term babies. The incidence of RDS declines with degree of maturity at birth. It occurs in 60 per cent of babies born at less than 28 weeks’ gestation, 30 per cent of those born at 28 to 34 weeks, and less than ﬁve per cent of those born after 34 weeks. RDS only rarely affects those children born at full-term.
In premature babies, the syndrome is caused by a lack of natural lung surfactant, a chemical that normally appears in mature lungs. Surfactant is produced by type II alveolar cells. Its function consists in reducing the work of breathing by lowering the surface tension of the fluid lining the alveolar membranes. Symptoms usually appear shortly after birth and become progressively more severe. Risk factors are prematurity, diabetes in the mother, and stress during delivery. As lung growth is not complete until the age of eight years, the effect of RDS on young children may be worse than in older children or adults.
Mortality rates are difﬁcult to determine due to the variety of triggering insults and underlying disease processes. It is estimated that, today, overall mortality rates are as high as 35 per cent despite modern standards of intensive care.
For RDS in adults, no speciﬁc medication exists. The patients are treated by general supportive therapy, such as the balanced administration of intravenous fluids. Intubation and application of mechanical ventilation to deliver both oxygen and pressure to keep the lungs inflated usually is required in cases with clinical and radiographic evidence suggestive of worsening lung disease.
Inhaled nitric oxide has produced physiological improvements in ventilation-perfusion matching and intrapulmonary shunting; however, no randomised clinical studies have documented improved patient outcome. There appears to be an association between improvement with inhaled nitric oxide and improved clinical outcome.
The increase in pulmonary vascular resistance in RDS results in increased work for the heart. Adequate output depends on the ability of the right ventricle to increase its pumping action. So-called inotropic agents often are given because they increase cardiac output without producing signiﬁcant constriction of pulmonary vessels.
Agents which have been found to modulate the inflammatory response, such as corticosteroids, prostaglandin E1, antioxidants, antifungals and phosphodiesterase inhibitors, have so far failed to demonstrate an improvement in mortality, although some studies were able to demonstrate an improved lung injury score, improved oxygenation and reduced new organ failure.
Standard surfactant replacement therapies are applied in premature infants and children with RDS. Different forms of replacement surfactant have been approved. One is derived from cattle; another is synthetic. The bovine-derived product contains surfactant proteins and relies on cetyl alcohol to act as the dispersing agent. The synthetic surfactant preparation contains surfactant proteins and humanised surfactant lung phospholipids which aid lipid adsorption.
Since RDS is a condition that may occur in a premature infant, every effort should be made to help mothers carry babies to term. Good prenatal care results in fewer premature births. If a mother goes into labour prematurely, medicines called beta2-mimetics are given to prolong the pregnancy to full term. Labour is halted until the foetus’s lung maturity ratio looks promising. Administration of corticosteroids to the mother two to three days prior to delivery may stimulate surfactant production and reduce the likelyhood of RDS.
Adult and infant animal models of RDS suggest that liquid ventilation with perfluoro-carbon liquids may prove to be clinically useful. Clinical trials are underway.
In late 2003, results of Phase 3 clinical trials showed that synthetic human surfactant replacement therapy is at least equivalent to pig-derived surfactant in the treatment of RDS in premature infants with birth weights of 600 to 1,200g. Humanised synthetic surfactant has the advantage of almost unlimited manufacturing quantities. In early 2004, the product has been ﬁled for approval in the US for the prevention of RDS in premature babies. In late 2004, the preparation was ﬁled in the EU for the prevention and treatment of RDS.
Future plans include the development of surfactants combined with novel antibiotics to target lung diseases. In addition, there have been proposals about the use of surfactants as a treatment for Severe Acute Respiratory Syndrome (SARS) which falls into the category of acute RDS. Other surfactants in development include a bovine-derived product and a pig-derived preparation which is being investigated in Phase 3 trials for acute lung injury and RDS in adults.
Active efforts to identify patients at high risk of mortality are underway. This will help to provide insight as to who might beneﬁt from alternative therapies, such as extracorporeal membrane oxygenation.
Improvements in the supportive care of patients suffering from RDS and a better understanding of the syndrome have contributed to the decline in its mortality rate.
In Europe, a decline in mortality rate from over 60 per cent in 1990 to about 35 per cent in 2000 was reported. Continuing research into the inflammatory response of RDS will direct therapy to be even more speciﬁc to the stage of the disease, thus reducing mortality further.