Clinical information
Of 172 premature infants, 107 (62.2%) were males and 65 (37.8%) were females. The average GA was 29.8 weeks, the average BW was 1329g (500-2000g), of which 133 cases (77.3%) were very low birth weight (VLBW), 15 cases (8.7%) were extremely low birth weight (ELBW). 154 infants were suitable for gestational age (89.5%) and 16 infants were small gestational age (SGA) (9.3%). Of 120 premature infants with apnea, 67 infants were treated with caffeine, 20 infants received with aminophylline, and another 33 infants didn’t receive any methylxanthine drugs (Table 1). 52 premature infants didn’t present apnea, and 27 infants were given caffeine for preventive treatment, another 25 infants didn't receive any methylxanthine agents. BW, gender, GA, Apgar scores at 1 and 5 minute, mode of delivery, times of pulmonary surfactant (PS) use were recorded. There had no statistically significant difference of clinical features in AOP infants between caffeine, aminophylline using with conservative groups (p>0.05). The mean age of initial caffeine therapy was 3.8 days of life (DOL, 1 to 19 days), and 70% (84/120) premature infants were exposed to caffeine within 5 days after birth. The median caffeine using time were 23.5 days (2-56 days).
Outcomes of premature infants
Clinical outcomes of premature infants were analyzed based on the effect of caffeine and aminophylline use compared with conservative group (Table 2). Caffeine group showed different effects on premature infants in length of stay (LOS) days (37.3±13.2) which is less than conservative and aminophylline group (p<0.01). There was no statistical significance between the aminophylline and conservative group (p=0.483). Caffeine reduced the duration the duration of MV(34.0±30.7 hours) compared to aminophylline (p<0.05), while reduced the duration of nCPAP (24.4±16.2 days) compared to conservation group, however, there was no significant difference compared with aminophylline group. The positive rates of sputum culture were 30.0% in aminophylline, 27.3% in conservative, and 10.4% in caffeine group (p=0.033). The incidence of BPD was 72.7% in conservative treatment group, 65% in minophylline group, and 34.3% in caffeine group (p<0.001). Blood culture was positive in only one case caffeine groups, and there was no statistical significance. Both caffeine and aminophylline increased the proportion of abdominal distension and the incidence of necrotizing enterocolitis (NEC), but the difference have no statistical significance (p>0.05). There were no significant differences in incidences of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and patent ductus arteriosus (PDA) among three groups. Compared to aminophylline and controls, premature infants could benefit from caffeine treatment in reducing the length of stay, duration of MV and decreasing the incidence of BPD.
Prophylactic and early caffeine using
Prophylactic caffeine using had been recommended in premature infants earlier before apnea occurrence in recent years(14). Prophylactic treatment is different from early caffeine using, which is admitted in 2 days after birth whether apnea occurs or not. For caffeine preventive intervention, infants were given drugs without the occurrence of apnea, especially in the situation of extubation. The median of caffeine initial times was 3 days DOL (2-7days). As shown in table 3, of 52 infants without apnea occurrence, 27 infants were given caffeine for apnea prevention, another 25 premature were assigned as controls. There were no significant statistically differences between the two groups in LOS, duration of MV, the incidence of PVL and IVH, as well as the positive rate of sputum or blood culture. However, prophylactic use of caffeine could decrease the risk of development of BPD (P=0.024).
67 premature infants with apnea were divided into two groups to evaluate the effect of caffeine on clinical outcomes according to their caffeine using occasion. Infants who were given caffeine within 48 hours after birth were defined as early caffeine using, and the others were defined as later using. The mean hospitalization days in the early group (36.82±13.01 days) were longer than those in the later group (34.25±10.92, days), but there was no significant difference (p=0.172), while the MV duration in the early group was shorter than that in the later medication group (24.30±16.77 hours, 40.58±36.08 hours) (p=0.02). In addition, there was no significant difference in other complications between the two groups (Table 4).
Effect of caffeine on infants of different GAs
The maturation of premature respiratory center development could affect their reaction to caffeine stimulation. Hence, we analyzed the therapeutic effect of caffeine on premature infants with different GA who were divided into less than 29 weeks, 300-6 wks and 31 0-6 wks. It showed that caffeine significantly reduced the LOS, the duration of MV, NCPAP or nasal cannula oxygen regardless of GA, and the incidence of BPD decreased with the increase of GA (Table 5). In the GA less than 29 weeks, caffeine reduced LOS (p<0.001), and the positive rate of sputum culture (p<0.05), while in premature infants of 300-6 wks , caffeine reduced the duration of CPAP and cannula using and the incidence of BPD, in premature infants of GA with 31 0-6 wks , caffeine significantly shortened the duration of MV using. There was no difference in the incidence of NEC, abdominal distension, PDA and PVL/IVL among three GA groups (p>0.05).
Linear regression analysis was performed to evaluate the relative of caffeine treatment to clinical outcomes with GAs. As figure 2 shows, LOS is negative related to GA growth in caffeine, prevention and conservation group (Figure 2a), however, only caffeine showed statistic significance (p<0.001). The same results were observed in MV and CPAP, in which caffeine treatment reduced the duration of respiratory support along with the GA growth (Figure 2b, 2c). These results infer that premature infants could be benefit more by caffeine intervention in the clinical outcome along with GA growth (p<0.001).
Follow-up of premature infants
77 infants were regularly followed-up by Children Development Monitor System successfully in 6 months to three years after their leaving hospital. Among them, 56 received caffeine treatment, and 21 cases didn’t receive any methylxanthine (Table 6). One infant died of severe pneumonia at sixth month, another premature infant without caffeine using was diagnosed with cerebral palsy. All infants that were followed-up were evaluated by DDST-II regularly each month in the first year, every two months in the second year and six months in the third year. The test results were interpreted as normal, suspicious and abnormal (if untestable over three times). If infants had abnormal development in movement and language aspects, the test results were re-judgment after a period of rehabilitation intervention until the test results were normal. Finally, 46 (82.1%) infants were normal, 7 (12.5%) infants abnormal and 3 (5.4%) suspicious in caffeine group, there was no significant difference compared with the conservative controls (p=0.345).