OBJECTIVETo investigate the current status of studies on drug therapy for apnea of prematurity (AOP) in the past decade in China and abroad, and to describe the research trends in the field.

METHODSCNKI and MEDLINE were searched with the key words "apnea of prematurity" and "treatment" for articles published in the past decade (January 2006 to December 2015). The articles were screened and the key words were extracted to establish the co-occurrence matrix. Ucinet 6.2 was used to plot the knowledge map.

RESULTSA total of 26 Chinese key words and 20 English key words were included. Those in the center of the co-existent knowledge map of Chinses keywords were "preterm infants", "apnea", "primary apnea", "naloxone" and "aminophylline"; while "apnea", "preterm infants" and "caffeine" located in the central place of the co-existent knowledge map of English keywords.

CONCLUSIONSMethylxanthines are still the major drugs for AOP; however, aminophylline is mainly used in China, while caffeine is mainly used in foreign countries. Other drugs such as naltrexone are also used in the clinical treatment of AOP.

Aminophylline ; therapeutic use ; Apnea ; drug therapy ; Caffeine ; therapeutic use ; Humans ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases ; drug therapy

OBJECTIVETo study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days).

METHODSA total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups.

RESULTSThe steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups.

CONCLUSIONSIn VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed.

Aminophylline ; pharmacokinetics ; pharmacology ; Apnea ; drug therapy ; Female ; Humans ; Infant, Newborn ; Infant, Very Low Birth Weight ; Male

BACKGROUNDObstructive sleep apnea hypopnea syndrome, characterized by chronic intermittent hypoxia (CIH), is closely correlated with genioglossus dysfunction. CIH has been identified to mediate mitochondrial damage in genioglossus. It has been reported that endoplasmic reticulum stress (ERS) could be induced by mitochondrial dysfunction. This study aimed to investigate the role of ERS in CIH-induced genioglossus injury, as well as the possible intervention effect of adiponectin (Ad) supplement in rats.

METHODSForty-five male Wistar rats were randomly divided into three groups and submitted to room air (group A, n=15) as a control or CIH (groups B and C, n=15, respectively). Throughout the exposure period, intravenous Ad was given in group C; while intravenous normal saline was simultaneously given in groups A and B. After 35-day exposure, genioglossus samples were obtained from the pentobarbital-anaesthetized rats via surgical dissection, following blood sampling. Western blotting was applied to detect expressions of ERS signals and associated apoptotic pathways in genioglossus. Serum adiponectin levels were assessed via enzyme-linked immunosorbent assay (ELISA).

RESULTSSignificant hypoadiponectinemia was revealed in group B only (P < 0.05). Compared to those in groups A and C, expressions of markers involved in ERS, such as glucose regulated protein 78 (GRP78), p-PERK, phosphorylated eukaryotic initiation factor 2a (p-eIF2a), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1a (p-IRE1a), spliced X-Box binding protein 1 (XBP1s) and activating transcription factor 6 (ATF6), were significantly enhanced in group B (all P < 0.01); while no significant difference was shown between groups A and C (all P > 0.05). ERSassociated apoptotic pathways were remarkably activated in group B. The involved markers detected as the expression of CCAAT/enhancer binding protein homologous protein (CHOP), B-cell lymphoma/leukemia associatied X protein (BAX) and caspase-12 were significantly elevated (all P < 0.01). Transvenous adiponectin supplement improved the above CIHinduced pathological changes in group C.

CONCLUSIONBeyond hypoadiponectinemia, CIH could enhance ERS and induce activation of ERS-associated apoptotic pathways in genioglossus, which could be significantly improved by adiponectin supplement.

Adiponectin ; administration & dosage ; therapeutic use ; Animals ; Endoplasmic Reticulum Stress ; drug effects ; Hypoxia ; drug therapy ; physiopathology ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Sleep Apnea, Obstructive ; drug therapy

Anticoagulants ; therapeutic use ; Female ; Humans ; Male ; Pulmonary Embolism ; drug therapy ; Sleep Apnea, Obstructive ; complications ; Warfarin ; therapeutic use

Anticoagulants ; therapeutic use ; Female ; Humans ; Male ; Pulmonary Embolism ; drug therapy ; Sleep Apnea, Obstructive ; complications ; Warfarin ; therapeutic use

OBJECTIVETo observe the clinical curative effect of anti-reflux treatment for obstructive sleep apnea hypopnea syndrome (OSAHS) in children.

METHODSTwenty children with sleep-disordered breathing were included in this study. There were 15 males and 5 females, aged 3-9 years old, median 6 years old. The electronic laryngoscope, polysomnography (PSG) monitoring, Reflux symptom index (RSI) questionnaire and Reflux finding score (RFS) were used to establish the initial diagnosis of OSAHS with LPRD, preclude adenoid hypertrophy and tonsil hypertrophy and nasal disorders. Oral Domperidone and Omeprazole were given for treatment. For children under 3-year-old, the dosage of Domperidone was 0.6 ml.kg⁻¹.day⁻¹.For children over 3-year-old, Domperidone combined with Omeprazole were given with the dosage of 0.3 mg.kg⁻¹.day⁻¹.

RESULTSAfter 4 weeks of treatment, 19 patients symptoms of OSAHS include disturbed sleep, dyspnoea and apneic attack improved. After 8 weeks of treatment, 20 cases with OSAHS symptoms improved than before treatment. Under the electronic laryngoscope, the decrease in pharyngeal lymphoid follicles, the epiglottis, aryepiglottic fold and scoop intergenic region erythema shallow, edema lessened. After treatment of 4 weeks and 8 weeks, there was statistically significant (P < 0.05). Before and after treatment, the difference of RFS was statistically significant (P < 0.05); PSG monitoring proved significant effect in 3 cases (15.0%), effective in 11 cases (55.0%) and 6 cases were ineffective (30.0%). Twenty patients with obstructive apnea index change was not obvious (P > 0.05), apnea hypopnea index and lowest artery oxygen saturation better, differences were statistically significant (Z of 2.819 and 2.733 respectively, P < 0.05).

CONCLUSIONThe treatment of LPRD can improve the symptoms of OSAHS, these two diseases may coexist in mutual relations.

Child ; Child, Preschool ; Female ; Humans ; Laryngopharyngeal Reflux ; complications ; drug therapy ; Male ; Sleep Apnea Syndromes ; complications ; drug therapy ; Surveys and Questionnaires ; Treatment Outcome

OBJECTIVETo evaluate the effectiveness and safety of different doses of caffeine in treatment of primary apnea in preterm infants.

METHODA total of 164 preterm infants (<32 weeks gestation), presented with primary apnea, were recruited in Tianjin Central Hospital of Gynecology and Obstetrics from October 2013 to December 2014. The patients were prospectively allocated into low-dose (loading 20 mg/kg and maintenance of 5 mg/(kg·d) after 24 h, n=82) and high-dose (loading 20 mg/kg and maintenance of 15 mg/(kg·d) after 24 h, n=82) groups of caffeine citrate treatment by using a random number table. The treatment effects, side effects of caffeine, and the clinical outcome of the preterm infants were compared between groups by χ(2) test or nonparametric test.

RESULTThe patients in low-dose group had birth weight of (1,237 ± 338) g, male gender of 43 (52%) and gestational age of (29.8 ± 3.4) weeks. The patients in high-dose group had birth weight of (1 262 ± 296) g, male gender of 45 (55%) and gestational age of (29.9 ± 2.7) weeks. The baseline characteristics including birth weight, gender and gestational age were comparable between the two groups. Frequency of apnea was significantly lower in high-dose group compared with low-dose group (10 (8, 15) vs.18 (13, 22), Z = -2.610, P = 0.009), and the success rate of removal of the ventilator was significantly higher in high-dose group compared with low-dose group (85% (70/82) vs.70% (57/82), χ(2) = 5.898, P = 0.015). The effective rate of caffeine treatment was significantly higher in high-dose group compared with low-dose group (82% (67/82) vs.61% (50/82), χ(2)=8.619, P = 0.003). No significant differences were observed concerning the incidence of caffeine-associated side effects including tachycardia, irritability, difficulty in feeding, hyperglycemia, hypertension, digestive disorders and electrolyte disturbances between two groups (P all > 0.05). There were no significant differences in the clinical outcomes of the preterm infants including death during hospitalization, chronic lung disease, other complications and duration of hospital stay between two groups (P all > 0.05).

CONCLUSIONA therapeutic regimen consisting of a loading dose of 20 mg/kg and maintenance dose of 15 mg/(kg·d) of caffeine citrate could improve the treatment effects and keep safety for primary apnea in preterm infants, and will not cause more adverse events.

Apnea ; drug therapy ; Birth Weight ; Caffeine ; administration & dosage ; Citrates ; administration & dosage ; Female ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Premature ; Infant, Premature, Diseases ; drug therapy ; Male ; Pregnancy ; Treatment Outcome

BACKGROUNDChronic intermittent hypoxia is the most important pathophysiologic feature of sleep apnea syndrome. The present study aimed to determine whether chronic intermittent hypoxia, which is associated with sleep apnea syndrome, can cause or increase damage to liver cell ultrastructure induced by isoniazid and rifampicin in mice.

METHODSBased on a 2 × 2 full factorial design consisting of two factors of chronic intermittent hypoxia and isoniazid plus rifampicin, 32 male C57B6J mice were randomized into the control group, the chronic intermittent hypoxia group, the isoniazid plus rifampicin group, and the chronic intermittent hypoxia + isoniazid plus rifampicin group. Twelve weeks after treatment, we examined the ultrastructure of liver cells and quantitatively analyzed mitochondrial morphology in C57B6J mice.

RESULTSChronic intermittent hypoxia did not significantly affect the ultrastructure of liver cells. The main effect of chronic intermittent hypoxia did not lead to an increase of mean profile area or mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P > 0.05). Isoniazid plus rifampicin significantly affected liver cell ultrastructure. The main effect of isoniazid plus rifampicin resulted in an increase of mean profile area and mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria (all P < 0.05). Moreover, there was a positive interaction among the chronic intermittent hypoxia and the isoniazid plus rifampicin groups for mean profile area, mean perimeter, and numerical density on area of mitochondria (all P < 0.05).

CONCLUSIONChronic intermittent hypoxia and isoniazid plus rifampicin treatment lead to synergistic liver cell ultrastructural injury.

Animals ; Hypoxia ; drug therapy ; Isoniazid ; therapeutic use ; Liver ; drug effects ; ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron, Transmission ; Rifampin ; therapeutic use ; Sleep Apnea Syndromes ; complications

Diagnostic Techniques, Respiratory System ; Female ; Follow-Up Studies ; Homeodomain Proteins ; analysis ; therapeutic use ; Humans ; Hypoventilation ; physiopathology ; Male ; Sleep Apnea Syndromes ; diagnosis ; drug therapy ; therapy

OBJECTIVETo determine the prevalence of sleep-disordered breathing in patients with stable, optimally treated chronic congestive heart failure and the effect of short-term oral theophylline therapy on periodic breathing in these patients.

METHODSPatients with stable, optimally treated chronic congestive heart failure were monitored by polysomnography during nocturnal sleep. The effects of theophylline therapy on periodic breathing associated with stable heart failure were observed before and after treatment.

RESULTSPatients were divided into two groups. Group I (n = 21) consisted of individuals with 15 episodes of apnea and hypopnea [as determined by the apnea-hypopnea index (AHI)] per hour or less; Group II (n = 15, 41.7%) individuals had an index of more than 15 episodes per hour. In group II, the AHI varied from 16.8 to 78.8 (42.6 +/- 15.5) in which the obstructive AHI was 11.1 +/- 8.4 and the central AHI was 31.5 +/- 9.6. Group II had significantly more arousals (36.8 +/- 21.3 compared with 19.4 +/- 11.2 in group I) that were directly attributable to episodes of apnea and hypopnea, lower arterial oxyhemoglobin saturation (76.7% +/- 4.6% compared with 86.5% +/- 2.8%) and lower left ventricular ejection fraction (24.2% +/- 8.8% compared with 31.5% +/- 10.6%). Thirteen patients with compensated heart failure and periodic breathing received theophylline orally (at an average dose of 4.3 mg/kg) for five to seven days. After treatment, the mean plasma theophylline concentration was (11.3 +/- 2.5) micro g/ml. Theophylline therapy resulted in significant decreases in the number of AHI (20.8 +/- 13.2 vs. 42.6 +/- 15.5; P < 0.001) and the number of episodes of central apnea-hypopnea per hour (10.1 +/- 7.6 vs. 31.5 +/- 9.6; P < 0.001). Furthermore, the percentage of total sleep time during which arterial oxyhemoglobin saturation (SaO(2)) was less than 90 percent (8.8% +/- 8.6% vs. 23.4% +/- 24.1%; P < 0.05) and the arousals per hour (18.7 +/- 21.2 vs. 36.8 +/- 21.3; P < 0.05) were also lower. There were no significant differences in the characteristics of sleep or obstructive AHI before and after theophylline treatment.

CONCLUSIONSThe prevalence of sleep-disordered breathing (mainly periodic respiration or cheyne-stokes respiration with central sleep apnea) is high in patients with stable chronic congestive heart failure. The sleep-disordered breathing episodes are associated with severe nocturnal arterial blood oxyhemoglobin desaturation and excessive arousals. In these patients, oral theophylline therapy may reduce the number of episodes of central apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during nocturnal sleep.

Aged ; Chronic Disease ; Female ; Heart Failure ; complications ; Humans ; Male ; Middle Aged ; Sleep Apnea Syndromes ; drug therapy ; Theophylline ; therapeutic use ; Treatment Outcome