Bolus dispersal through the lungs in surfactant replacement therapy

A model is presented of surfactant replacement therapy. An instilled bolus is pushed into the lungs on the first inspiration, coating the airways with a layer of surfactant and depositing some in the alveoli. Layer thickness depends on the capillary number (muU/gamma, where mu, U, and gamma are bolus viscosity, advancing meniscus velocity, and surface tension, respectively). Larger capillary number leads to thicker layers, reducing alveolar delivery. Subsequently, surface tension gradients sweep surfactant into alveoli not receiving surfactant during the first inspiration. The effects on spreading of sorption kinetics, bolus viscosity, initial layer thickness, initial penetration of surfactant, gravity, and shear stress are examined. Sorption nearly eliminates surface tension gradients in central airways but produces a sharp transition at the leading edge of the exogenous layer. Local thinning of the liquid layer results, trapping 95% of the surfactant in the airways. Gravity and ventilation augment transport somewhat. Transport to the periphery takes 4-170 s for the leading edge but considerably longer for the bulk of the surfactant. The model demonstrates how the various physical parameters governing surfactant distribution might alter the response to surfactant replacement therapy.     

Surfactant decreases pulmonary vascular resistance and increases pulmonary blood flow in the fetal lamb model of congenital diaphragmatic hernia

INTRODUCTION: Experiments using animal models of neonatal respiratory distress syndrome have shown a decrease in pulmonary vascular resistance (PVR) with surfactant replacement, whereas studies with the lamb model of congenital diaphragmatic hernia (CDH) have demonstrated improvement in oxygenation and lung mechanics with this therapy. The aim of the present study was to measure the effects of surfactant replacement therapy on the pulmonary hemodynamics of the lamb model of CDH. METHODS: Ten lambs with surgically created CDH and five control lambs were instrumented at term, with the placental circulation intact. Ultrasonic flow probes were positioned around the main pulmonary artery and the common origin of the left and right pulmonary arteries to record total lung and main pulmonary artery blood flow. Catheters were inserted to record systemic, pulmonary, and left atrial pressure. Five CDH animals received 50 mg/kg of surfactant by tracheal instillation just before delivery. All 15 animals were then ventilated for 4 hours. RESULTS: Correcting the surfactant deficiency in the CDH lamb resulted in a significant increase in pulmonary blood flow, a decrease in PVR, and a reduction in right-to-left shunting. These improvements in hemodynamics were associated with a significant improvement in gas exchange over 4 hours. CONCLUSION: The fetal lamb model of CDH has elevated PVR in comparison to controls. Prophylactic surfactant therapy reduces this resistance and dramatically increases pulmonary blood flow while reducing extrapulmonary shunt. A surfactant deficiency may be partially responsible for the persistent pulmonary hypertension in neonates with CDH.     

Inhibition by pulmonary surfactant Curosurf of secretory phospholipase A2 expression in guinea-pig alveolar macrophages

Replacement therapy with exogenous surfactant has been proven successful in animal models of acute respiratory distress syndrome (ARDS). Here, we investigated the effect of seminatural surfactant Curosurf on the expression of secretory phospholipase A2 (sPLA2) in guinea-pig alveolar macrophages (AM). The latter produced an sPLA2 activity whose level was markedly reduced when culture medium was supplemented with Curosurf. This effect was concentration-dependent and was accompanied by a decrease in sPLA2 mRNA levels. By contrast, when AM were first cultured for 20 hr and then incubated with Curosurf, no significant change was observed in their sPLA2 activity. Finally, f-Met-Leu-Phe (FMLP)-induced thromboxane B2 release from AM was not altered by Curosurf, indicating that the inhibition of sPLA2 expression cannot be attributed to a nonspecific membraneous effect of Curosurf. These findings show that pulmonary surfactant modulates the expression of sPLA2 in AM and suggest that this effect may account for the clinical efficacy of surfactant replacement therapy in ARDS.     

Cerebral hemodynamics and oxygenation in preterm infants after low-vs. high-dose surfactant replacement therapy

In thirteen preterm infants receiving surfactant (Curosurf) replacement therapy, changes in cerebral hemodynamics and oxygenation were investigated by near infrared spectroscopy. Surfactant instillation led to an instantaneous increase in cerebral blood volume (CBV) in all infants, which was primarily due to an increase in deoxygenated hemoglobin. Five infants received a low dose (100 mg/kg = 1.25 ml/kg) of surfactant and 8 a high dose (200 mg/kg = 2.50 ml/kg). A significantly larger increase in CBV was observed in the infants receiving a high dose compared to those receiving a low dose of surfactant. We conclude that cerebral perfusion is affected more after the instillation of a high dose compared to a low dose of surfactant.     

Adjuncts to mechanical ventilation

Adjunctive ventilatory strategies have been developed to improve oxygenation and carbon dioxide (CO2) removal during mechanical ventilation of critically ill patients. These techniques allow clinicians to attain their clinical goals at lower levels of ventilatory support. In this article, the authors discuss extracorporeal CO2 removal, venovenous intravena caval oxygenator, and tracheal gas insufflation as adjuncts to CO2 removal and nitric oxide, surfactant replacement therapy, perfluorocarbon-associated gas exchange, and prone positioning as adjuncts to oxygenation.     

Women's decisions about hormone replacement therapy after education and bone densitometry

BACKGROUND: The decisions that postmenopausal women make about whether to start hormone replacement therapy may depend on the potential risks and benefits of such therapy as well as their risk for osteoporosis-related fractures. This study examined the decisions made by women at risk for osteoporosis-related fractures who were educated about hormone replacement therapy and who were given information about their bone mineral density. METHODS: The study employed a prospective cohort design. Thirty-seven post--menopausal women with risk factors for osteoporosis-related fractures were recruited from an orthopedic clinic at a teaching hospital in Hamilton, Ont. The women were given an education kit (consisting of an audio tape and a work-book) to clarify the benefits and risks of hormone replacement therapy. Two to 4 weeks later, densitometry of the hip and the lumbar spine was performed. A summary of the risks, the densitometry findings and decisions about hormone replacement therapy were given to the women's family physicians for follow-up. Outcome measures included decisions about hormone replacement therapy, as well as use of such therapy and other medications at 12 months. RESULTS: After the education component alone, 10 (27%) of the women requested hormone replacement therapy. After densitometry testing, 4 more requested hormone replacement therapy (for a total of 14 women [38%]). At 12 months, 2 (5%) of the women had been lost to follow-up. Of the remaining 35, 6 (17%) were receiving hormone replacement therapy, 7 (20%) were using bisphosphonates, and 24 (68%) were taking calcium supplements. INTERPRETATION: These preliminary findings suggest that the combination of education about hormone therapy and feedback about bone density is associated with an increase in the use of hormone replacement therapy and other preventive medications by women at risk for osteoporosis-related fractures. However, the observed increase was small and so the clinical significance must be confirmed and clarified.     

Effect of surfactant replacement therapy on the outcome of premature infants with respiratory distress syndrome

Lung surfactant replacement has been tested clinically in recent years. In this study the outcome of 31 premature infants with moderate to severe neonatal respiratory distress syndrome (RDS) treated with surfactant was compared to that of 74 prematures with RDS treated conventionally by positive pressure ventilation and supportive care. The groups were well matched for gestational age, birthweight, sex, and Apgar scores at 1 and 5 min. Surfactant treatment resulted in a significant decrease in mortality--from 36.6% in the untreated group to 12.9% in the surfactant-treated group (P < 0.04). This improvement in survival was seen also in prematures with a birthweight < 1,000 g; in the untreated group mortality was 57.6% compared to 23.5% in the treated group (P < 0.05). The incidence of pneumothorax was lower in the treated group--42% vs. 13% (P < 0.01). Surfactant treatment resulted in a trend of more survivors without bronchopulmonary dysplasia or intraventricular hemorrhage, even though surfactant therapy did not change the incidence of either.     

Principles of surfactant replacement

Surfactant therapy is an established part of routine clinical management of babies with respiratory distress syndrome. An initial dose of about 100 mg/kg is usually needed to compensate for the well documented deficiency of alveolar surfactant in these babies, and repeated treatment is required in many cases. Recent experimental and clinical data indicate that large doses of exogenous surfactant may be beneficial also in conditions characterized by inactivation of surfactant, caused by, for example, aspiration of meconium, infection, or disturbed alveolar permeability with leakage of plasma proteins into the airspaces. The acute response to surfactant therapy depends on the quality of the exogenous material (modified natural surfactants are generally more effective than protein-free synthetic surfactants), timing of treatment in relation to the clinical course (treatment at an early stage of the disease is better than late treatment, and may reduce the subsequent need for mechanical ventilation), and mode of delivery (rapid instillation via a tracheal tube leads to more uniform distribution and is more effective than slow airway infusion). Treatment with aerosolized surfactant improves lung function in animal models of surfactant deficiency or depletion, but is usually associated with large losses of the nebulized material in the delivery system. Furthermore, data from experiments on immature newborn lambs indicate that treatment response may depend on the mode of resuscitation at birth, and that manual ventilation with just a few large breaths may compromise the effect of subsequent surfactant therapy. The widespread clinical use of surfactant has reduced neonatal mortality and lowered costs for intensive care in developed countries. The hydrophobic surfactant proteins SP-B and SP-C are probably essential for optimal biophysical and physiological activity of exogenous surfactants isolated from mammalian lungs, and the dose-effectiveness (in part reflecting resistance to inactivation) can be further improved by enrichment with SP-A. The development of new artificial surfactant substitutes, based on synthetic analogues of the native surfactant proteins, is an important challenge for future research.     

Hormone replacement therapy and risk of hip fracture: population based case-control study. The Swedish Hip Fracture Study Group

OBJECTIVE: To determine the relative risk of hip fracture associated with postmenopausal hormone replacement therapy including the effect of duration and recency of treatment, the addition of progestins, route of administration, and dose. DESIGN: Population based case-control study. Setting: Six counties in Sweden. SUBJECTS: 1327 women aged 50-81 years with hip fracture and 3262 randomly selected controls. MAIN OUTCOME MEASURE: Use of hormone replacement therapy. RESULTS: Compared with women who had never used hormone replacement therapy, current users had an odds ratio of 0.35 (95 % confidence interval 0.24 to 0.53) for hip fracture and former users had an odds ratio of 0.76 (0.57 to 1.01). For every year of therapy, the overall risk decreased by 6% (3% to 9%): 4% (1% to 8%) for regimens without progestin and 11% (6% to 16%) for those with progestin. Last use between one and five years previously, with a duration of use more than five years, was associated with an odds ratio of 0.27 (0.08 to 0.94). After five years without hormone replacement therapy the protective effect was substantially diminished (-7% to 48%). With current use, an initiation of therapy nine or more years after the menopause gave equally strong reduction in risk for hip fracture as an earlier start. Oestrogen treatment with skin patches gave similar risk estimates as oral regimens. CONCLUSIONS: Recent use of hormone replacement therapy is required for optimum fracture protection, but therapy can be started several years after the menopause. The protective effect increases with duration of use, and an oestrogen-sparing effect is achieved when progestins are included in the regimen.     

Effects of hormone replacement therapy in bone resorption, in post-menopausal women

BACKGROUND: The effects of different therapies on bone loss rate can be measured using biochemical markers of bone resorption such as urinary hydroxyproline. AIM: To study the effects of hormone replacement therapy on urinary hydroxyproline in postmenopausal women. PATIENTS AND METHODS: Eighty three postmenopausal women without hormone replacement therapy, 54 postmenopausal women receiving hormone replacement therapy and 16 premenopausal women (considered as the control group) were studied. Hydroxyproline was measured in an early morning urine sample, after one day of diet without meat or gelatin. RESULTS: Urinary hydroxyproline in premenopausal women was 33.7 +/- 7.9 mg/g creatinine. The figure for postmenopausal women with hormonal replacement therapy was 33.7 +/- 5.9 mg/g creatinine. Postmenopausal women without replacement therapy had an urinary hydroxyproline of 47.4 +/- 8.5 mg/g creatinine, significantly higher than that of premenopausal and supplemented women. In 21 postmenopausal women, hydroxyproline was measured before and after three months of replacement therapy, values decreased 35.5 +/- 11% in this period and there was a direct correlation between initial values and the degree of reduction (r = 0.69, p < 0.001). CONCLUSIONS: Postmenopausal women receiving hormone replacement therapy have a urinary hydroxyproline excretion similar to that of premenopausal women.     

Surfactant replacement increases compliance in premature lamb lungs during partial liquid ventilation in situ

Treatments available to improve compliance in surfactant-deficient states include exogenous surfactant (ES) and either partial (PLV) or total liquid ventilation (TLV) with perfluorochemical (PFC). Because of the additional air-lung and air-PFC interfaces introduced during PLV compared with TLV, we hypothesized that compliance would be worse during PLV than during TLV. Because surfactant is able to reduce interfacial tension between air and lung as well as between PFC and lung, we further hypothesized that compliance would improve with surfactant treatment before PLV. In excised preterm lamb lungs, we used Survanta for surfactant replacement and perflubron as the PFC. Compliance during PLV was intermediate between TLV and gas inflation, both with and without surfactant. Surfactant improved compliance during PLV, compared with PLV alone. Because of the force-balance equation governing the behavior of immiscible droplets on liquid surfaces, we predict that PFC droplets spread during PLV to cover the alveolar surface in surfactant-deficient lungs during most of lung inflation and deflation but that the PFC would retract into droplets in surfactant-sufficient lungs, except at end inspiration.     

Breast reconstruction through tissue expansion

In this article the pathophysiology and diagnosis of neonatal respiratory distress syndrome as a primarily form of surfactant deficiency is disclosed. Attention is paid to surfactant composition, productive and secretion in the alveoli and metabolic turnover as well. From clinical point the view basic principles concerning the surfactant replacement is discussed. Surfactant minimizes the surface tension and friction between the gas molecules and lung tissues during breathing. It also helps keep lung tissues dry and alveoli patent. At 26 to 28 weeks of gestation alveolar ducts and bronchioles are present but pulmonary capillaries are not in close contact with them. Alveoli may not even be distinguishable. Surfactant develops all through gestation but does not surge until about the 34th week. Infants born before 35 weeks of gestation are at risk for respiratory distress syndrome which is at first characterised by decrease of lung compliance. It leads to progressive respiratory failure.     

The use of hormone replacement therapy in women with acute myocardial infarction: an audit of current practice

We undertook criterion-based audit of the current practice of prescribing hormone replacement therapy for women with acute myocardial infarction; the audit included 181 consecutive women admitted to one hospital with this diagnosis in one calendar year. The set standard was that, barring any contraindication, all postmenopausal women with acute myocardial infarction should be prescribed hormone replacement therapy before discharge from hospital. The evidence base of this standard derives from more than 30 epidemiological and clinical studies and a large body of biological data. Only 4.7% of the women were current users of hormone replacement therapy and the set standard was met in only 3% of eligible nonusers. Professionals caring for women who have had a myocardial infarction need to consider hormone replacement therapy as a secondary prophylaxis of myocardial infarction. Gynaecologists should liaise with colleagues in other specialties and general practice to ensure that information on the nongynaecological benefits of hormone replacement therapy is widely disseminated.     

Liquid assisted ventilation: an alternative ventilatory strategy for acute meconium aspiration injury

Evidence of surfactant inactivation by meconium has led to the use of exogenous surfactant therapy in the management of meconium aspiration syndrome (MAS). Liquid assisted ventilation has been shown to improve the cardiopulmonary function in lungs with high surface tension. We compared exogenous surfactant therapy with liquid assisted ventilation in the management of experimental acute meconium aspiration injury. Thirty-two newborn lambs were ventilated at peak inspiratory pressures of 13-16 cm H2O, positive end expiratory pressure of 3-4 cm H2O, fractional inspired oxygen concentration (FiO2) of 1.0, and a respiratory frequency range between 30 and 35 breaths/min. Baseline arterial blood gases, pulmonary function, and arterial blood pressure measurements were taken. All lambs were given 2-3 ml/kg of an unfiltered 25% meconium solution. Lambs were then randomized into either gas-ventilated meconium control, or one of three treatment groups: 1) surfactant; 2) partial liquid ventilation (PLV); or 3) total liquid ventilation (TLV) for 4 hours after meconium injury. All treated groups demonstrated a significant increase in arterial oxygenation (P < 0.05); surfactant and PLV-treated lambs demonstrated significantly decreased arterial PCO2 (P < 0.05). Compliance in all groups increased compared with injury values; compliance of the TLV group increased more than in all other treatment groups (P < 0.05). In addition, lung histology of the TLV group demonstrated clear, intact alveolar epithelium and homogeneously expanded alveoli, while no such improvement was evident in the other groups. These data suggest roles for both exogenous surfactant therapy and liquid assisted ventilation techniques in the management of MAS.     

Estrogen replacement in surgical stage I and II endometrial cancer survivors

OBJECTIVE: Our purpose was to evaluate our experience with estrogen replacement in women with a history of early-stage endometrial cancer and to determine whether it increased the risk for recurrence or death. STUDY DESIGN: A retrospective review was performed of 123 women with surgical stage I and II endometrial adenocarcinoma treated between 1984 and 1994; 62 had received estrogen replacement therapy after cancer therapy. Sixty-one women received no estrogen. Variables analyzed included age parity, surgical stage, grade, depth of myometrial invasion, presence of intercurrent illnesses, duration of follow-up, and duration of estrogen replacement, if applicable. Outcome variables assessed included recurrence rate, time to recurrence, and disease-free interval. RESULTS: The estrogen replacement therapy group had earlier stage disease (p = 0.04) and less severe depth of invasion (p = 0.003); however, the total number of deaths in each group was not significantly different. The disease-free survival in the estrogen replacement therapy group did not differ significantly compared with those not receiving estrogen replacement therapy. The data are suggestive of improved disease-free survival in the estrogen replacement therapy group, which may be related to differences in age, stage, grade, and depth of invasion. The overall recurrence rate was 6.5%, with an overall death rate of 1.6%. CONCLUSIONS: There is no evidence to suggest that estrogen decreased the disease-free interval or increased the risk for recurrence in early-stage disease.     

Transfusion-related acute lung injury treated with surfactant in a neonate

A term, male neonate suddenly developed respiratory distress and severe cyanosis while undergoing exchange transfusion for hyperbilirubinaemia. Transfusion-related acute lung injury was diagnosed. Because of persistent hypoxaemia despite aggressive treatment, two doses of surfactant were administered, resulting in marked improvement. Conclusion: Transfusion-related acute lung injury may occur in neonates, and may be successfully treated by surfactant replacement.     

A comparative study of human immunodeficiency virus culture, polymerase chain reaction and anti-human immunodeficiency virus immunoglobulin A antibody detection in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection

Asynchrony of delivered and spontaneous breaths in mechanically ventilated infants may impair gas exchange and prolong the need for assisted ventilation. We conducted a randomized, controlled trial of a patient-triggered, flow-synchronized ventilator on 30 preterm infants with respiratory distress syndrome who weighed between 1100 and 1500 gm at birth. Entry criteria included radiographic evidence of respiratory distress syndrome and the need for mechanical ventilation and surfactant replacement therapy. Patients were assigned to either conventional time-cycled, pressure-limited ventilation or patient-triggered, flow-synchronized ventilation in an assist/control mode. Otherwise clinical management was identical. Time to extubation was the primary outcome measure. Patients treated with flow-synchronized ventilation were weaned more rapidly and had a significantly shorter mean time to extubation than those treated with time-cycled, pressure-limited ventilation, 119 versus 271 hours, p = 0.0152. In addition, there was no difference in the rate of complications between the two groups. There were, however, considerable reductions in patient charges of $4344 per patient in the flow-synchronized ventilation group.     

Sudden cardiac death in hypertrophic cardiomyopathy: risk evaluation

The pathophysiology of the lamb model of congenital diaphragmatic hernia (CDH) involves pulmonary hypoplasia, pulmonary hypertension, and surfactant deficiency. Inhaled nitric oxide (NO) is a highly selective pulmonary vasodilator. The aim of this study was to determine the effects of inhaled NO on pulmonary gas exchange, acid-base balance, and pulmonary pressures in a lamb model of CDH with or without exogenous surfactant therapy. At the gestational age of 78 days (full term, 145 days) 11 lamb fetuses had a diaphragmatic hernia created via a left thoracotomy and then were allowed to continue development in utero. After cesarean section, performed at term, six lambs received exogenous surfactant therapy (50 mg/kg, Infasurf) and five served as controls. All animals were pressure-ventilated for 30 minutes and then received 80 ppm of inhaled NO at an F1O2 of .9 for a 10-minute interval. Compared with the control lambs, the lambs with exogenous surfactant therapy had higher pH (7.17 +/- .06 v 6.96 +/- .07; P < .05), lower PCO2 (73 +/- 8 v 122 +/- 20, p < .05), and higher PO2 (153 +/- 38 v 50 +/- 23; P < .05). In control CDH lambs (without surfactant), inhaled NO did not improve pH, PCO2, or PO2, or decrease pulmonary artery pressure. In CDH lambs given exogenous surfactant, NO decreased pulmonary artery pressures (42 +/- 4 v 53 +/- 5; P < .005) and further improved PCO2 and PO2. NO also made the difference between pulmonary and systemic artery pressures more negative in the surfactant-treated lambs (-15 +/- 4 v -2.3 +/- 2.4; P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen replacement in women treated for breast cancer

Oestrogen replacement therapy in women with a history of breast cancer has long been considered contraindicated. However, the literature does not indicate an increased risk of recurrent breast cancer in postmenopausal women receiving oestrogen replacement therapy. We advocate that women with a history of breast cancer without nodal involvement could be offered oestrogen replacement therapy and thereby benefit from prevention of cardiovascular disease and osteoporosis. But the patients must accept a potentially increased risk of recurrence. We emphasize the need for randomized prospective studies.     

Islet transplantation as a treatment for diabetes

BACKGROUND: The microvascular complications of diabetes are directly linked to hyperglycemia. Beta-cell failure is a critical factor in regulation of blood sugar levels. However, only a small proportion of persons with type 1 and type 2 diabetes obtain sufficient glycemic control to avoid complications. METHODS: There are two routes for beta-cell replacement, transplantation, and a mechanical beta cell equivalent. Beta-cell replacement therapy is a potential treatment modality, since diabetes is caused by beta-cell failure. RESULTS: An obvious path for glycemic control is some form of beta-cell replacement therapy. Successful islet transplantation is a difficult challenge, but current achievements with human pancreas transplants and islet allografts may greatly improve glycemic control. CONCLUSION: Beta-cell replacement therapy is an accepted treatment modality for diabetes.