Mineo Konishi

Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant

Thirty preterm infants (birth weight < 1500 gm) treated with Surfactant TA for the respiratory distress syndrome, who had no complicating clinical problems other than ductal patency, were studied by serial Doppler flow examinations to determine the effects of early left-to-right shunt through the patent ductus arteriosus on the left ventricular output and organ blood flows. Doppler flow variables in 15 infants with a hemodynamically significant patent ductus arteriosus (hsPDA) were compared with those in 15 subjects without hsPDA matched for age, body weight, and gestational age. Infants with hsPDA had significantly higher left ventricular output and significantly lower blood flow volume in the abdominal aorta, and lower temporal mean blood flow velocities, with concomitant increases in the relative vascular resistance in the celiac artery, superior mesenteric artery, and renal artery. Pulsatility indexes of these vessels and the anterior cerebral artery were significantly higher in the hsPDA group, but the temporal mean blood flow velocities in the anterior cerebral artery and its vascular resistance were not significantly different between the two groups. After closure of the patent ductus arterious was achieved with mefenamic acid therapy, alterations in Doppler flow variables in the hsPDA group reverted to the levels seen in the group without hsPDA. These results suggest that despite large left-to-right ductal shunting, the heart of the preterm infant is capable of mounting a compensatory increase of cardiac output sufficient to maintain unchanged cerebral blood flow, but is unable to maintain postductal organ blood flows because of decreased perfusion pressure (ductal steal) and localized increase in vascular resistance.

Surfactant replacement therapy in neonatal respiratory distress syndrome

We conducted a prospective, randomized, controlled trial comparing the efficacy of two doses of a reconstituted bovine surfactant (Surfactant TA) in premature infants requiring mechanical ventilation shortly after birth for respiratory distress syndrome. Forty-six infants weighing 1000–1499 g were randomized into two groups: a low-dose group (23 infants given a single dose of 60 mg surfactant lipid/kg) and a high-dose group (23 infants given a single dose of 120 mg/kg). The mean (SD) age at which surfactant was given was 5.5 (±1.2) h in the low-dose group and 6.0 (±1.5) h in the high dose group. Both treatments improved oxygenation (increased arterial-alvcolar PO2 ratio) with decreased mean airway pressure, the high-dose surfactant having a more beneficial effect in prolonging the response. Infants in the high-dose group had significantly less (P<0.05) incidence of both intraventricular haemorrhage and bronchopulmonary dysplasia. This prospective trial documents that a greater benefit can be obtained by increasing the dose of surfactant (120 mg/kg) beyond 60 mg/kg in the treatment of premature infants with severe respiratory distress syndrome (RDS).

Stable microbubble test for predicting the risk of respiratory distress syndrome: II. Prospective evaluation of the test on amniotic fluid and gastric aspirate

We determined prospectively if the stable microbubble (SM) test on gastric aspirate obtained at birth was as useful as that on amniotic fluid in predicting respiratory distress syndrome (RDS). One hundred and five paired samples of amniotic fluid obtained at delivery from 105 consecutive women with gestation of 35 weeks or less and gastric aspirates from their neonates obtained within 30 min of birth were studied. The SM test with the predefined cut-off value of less than 5 bubbles/mm2 for amniotic fluid and less than 10 bubbles/mm2 for gastric aspirate signified the risk of RDS with the positive predictive value of 100% and 96% and with the negative predictive value of 91% and 84%, respectively. We conclude that the SM test on both amniotic fluid and gastric aspirate obtained at birth is a rapid (<10 min), simple and reliable procedure for predicting neonates who will develop RDS. It may be used as a bedside test to define a population of neonates with surfactant deficiency in clinical trials of prophylactic surfactant therapy.

A prospective, randomized trial of early versus late administration of a single dose of surfactant-TA

Thirty-two neonates weighing 500-1500 g with documented surfactant deficiency and without evidence of severe birth asphyxia, infection, prolonged rupture of membranes greater than or equal to 72 h, or oligohydramnios were randomly assigned to receive a single intratracheal dose of surfactant-TA (100 mg/kg) either within 30 min of birth (n = 16, early group) or at 6 h of age (n = 16, late group). By 6 h of age, all neonates of the late group had moderate/severe RDS, while none of the neonates of the early group had either clinical or radiological respiratory distress syndrome. The incidence of bronchopulmonary dysplasia was significantly lower in survivors of the early group than those of the late group (1/15 versus 7/14, a 43% reduction with a 95% confidence interval of 14-72%, P = 0.025). These beneficial effects of early surfactant treatment remained after controlling for the various confounding factors in the logistic models.

Surfactant Replacement Therapy in Premature Babies with Respiratory Distress Syndrome: Factors Affecting the Response to Surfactant and Comparison of Outcome from 1982–86 and 1987–91

The impact of surfactant therapy on chronic lung disease remains uncertain. During the past decade (1982–91), over 300 babies with respiratory distress syndrome (RDS) weighing 501–2,500 g at birth were consecutively treated with surfactant‐TA at our neonatal intensive care unit. Data on 95 RDS babies treated in the first 5 year period (Period 1, 1982–86) were compared with those on 158 RDS babies treated in the second 5 year period (Period 2, 1987–91). Overall respiratory improvement was better in Period 2 than in Period 1. In Period 2, surfactant therapy converted 98% of the babies with moderate/severe RDS to those with ‘near normal’ lung by 72 hr post‐treatment. In Period 2, 95% of the surfactant‐treated babies weighing 501–1,750 g at birth survived, 97% of which required no supplemental oxygen at 40 weeks corrected gestational age. Increased survival rate in the surfactant‐treated babies during the past decade has not been followed by a parallel increase in chronic lung disease. The severity of the initial pulmonary disease per se was not the significant risk factor for chronic lung disease. Several other variables affecting the response to surfactant therapy and outcome have been identified by stepwise logistic regression analysis and include factors related to perinatal events such as birth asphyxia and infection, and other complications of prematurity.

Surfactant proteins and stable microbubbles in tracheal aspirates of infants with respiratory distress syndrome: relation to the degree of respiratory failure and response to exogenous surfactant.

Abstract Surfactant proteins (SP-A and SP-BC), albumin (ALB), and stable microbubble (SM) count were measured in tracheal aspirates from infants with respiratory distress syndrome (RDS) receiving single-dose Surfactant-TA (surfactant group, n = 32) or no surfactant (control group, n = 12), and those without RDS (non-RDS group, n = 8) to determine biochemical and biophysical status of surfactant in the course of RDS after surfactant replacement. Surfactant therapy resulted in immediate and sustained elevations of SP-BC/ALB and SM count with a rapid fall in ventilatory index to levels measured in the non-RDS group, whereas these indices improved slowly in the control group. The SP-A/ALB was initially low in both RDS groups and increased to levels measured in the non-RDS group by age 48 h. Multiple regression analysis showed that SP-BC/ALB, postnatal age, SM count, SM count/SP-A plus SP-BC, and surfactant therapy were independently associated with the severity of RDS as assessed by ventilatory index (r = 0.75, P < 0.0001; number of samples = 256). Infants with a relapse response to surfactant (n = 9) had levels of SP-A/ALB and SP-BC/ALB similar to those measured in the sustained group (n = 23), but had significantly lower SM count and SM count/SP-A plus SP-BC between 24 and 96 h of age. Conclusion Surfactant therapy normalizes the sur factant and respiratory status of infants with RDS. Surfactant dysfunction rather than depletion may explain the relapse response seen in some surfactant recipients.

EXOGENOUS SURFACTANT THERAPY IN INFANTS WITH RDS: COMPARISON OF EARLY VS LATE TREATMENT

We report successful treatment of RDS with exogenous surfactant (TA). We studied the clinical course of three groups of infants with RDS. Control Grp. (C,n10) did not receive TA, early Grp. (E,n 10) received TA at a [xmacr ] age of 3½ hrs. Late Grp. (L,n10) received surfactant at [xmacr ]=8½ hrs. of age. TA surfactant dispersed in saline was given via endotracheal tube. Results of sequential MAP and a/APO2 are shown below. There were no differences in B.Wt. and GA between the Grps. Before treatment MAP and a/APO2 were the same in all Grps. Following therapy, MAP dropped significantly both in E & L Grps. (p<.01) by 1 hr. It decreased steadily in Grp. E. The differences between Grps. E and L were also significant (p<.01). Similarly, a/APO2 improved significantly (p<.01) in both Grps. E and L 1 hr. following treatment. Chest x-rays cleared rapidly in E & L Grps., but not in Grp. C. However, treated Grp. had high incidence of silent PDA. There were no deaths in any group. We conclude that: a) TA treatment rapidly improves the course of RDS; b) E treatment rapidly decreases MAP than Grp. L; and c) both E & L treatment are equally beneficial.

SURFACTANT TA (FUJIWARA) AND DRY SURFACTANT (MORLEY): EFFECTSON LUNG MECHANICS AND ALVEOLAR SIZE DISTRIBUTION IN PREMATURE RABBITS

We compared the efficacy of surfactant TA (Fujiwara) and the dry DPL+PG surfactant (DS, Morley) on pulmonary compliance (Cl), P-V curves and alveolar size distribution by texture analyzing systems (Leitz) in 4 groups of rabbits; 21 received 800 μg of TA suspended in saline (Gr.TA), 15 received DS surfactant (Gr.DS), 16 were premature controls (Gr.PC). All three groups were preterm delivered at 27 days gestation. Fourth group was mature controls (Gr.MC n=26). (Table: Mean ± S.E., *p <0.001).Premature controls had low volumes at P5 and P30 as compared to matures. Lung volumes reached mature levels in Gr.TA; in Gr.DS, improvement was less than in Gr.TA. Alveolar size distribution in Gr.TA was identical to mature controls, but marked non-homogeneous distribution of alveolar size was noted in Gr.DS. P-V curves and compliance differences were: Gr.TA showing mature pattern superior to Gr.DS. These results suggest that saline suspended S-TA improves pulmonary mechanics and alveolar histology to mature patterns to a greater extent than the dry surfactant of Morley et.al. (Abbr. in Table: P5 and P30=Pressure at 5 and 30 cm. H2O).

DOSE DEPENDANT EFFECTS OF SURFACTANT ON LUNG MECHANICS

Although exogenous surfactant replacement was proven to improve lung mechanics in clinical HMD (Fujiwara et.al. TA), optimal concentration and dose were not known. We studied the effect of different concentrations and quantity of TA in premature rabbits before first breath. Group A was treated with fixed lipid quantity, but variable TA concentration. Group B was treated with fixed concentration, but variable lipid quantity. We measured P-V curve (P-V) and lung-thorax compliance (CL) at 5 mg/ml to 40 mg/ml of concentration and 25 μg to 400 μg of quantity. Group A P-V curve data is given below. (Mean ± S.E.). In Group A, when lipid quantity was kept constant the variable concentration 10 mg/ml to 40 mg/ml of TA did not change the P-V curve and the CL. However when concentration of TA dropped to 5 mg/ml, the P-V curve and the CL changed adversely (p<0.02). Group B P-V curve and CL improved to maximum at 800 μg irrespective of concentrations. Further, the lipid quantity of 800 μg to 4000 μg had no further beneficial or adverse effect. We conclude 10 to 40 mg/ml of TA concentration,and lipid quanity of 800 μg to 4000 μg will have optimal effect on P-V curve and CL when instilled before the first breath.(*P5=5 cmH20 distending pr.).