臺灣博碩士論文加值系統

中文摘要
呼吸暫停為早產兒常見的問題之一。主要是早產兒中樞及呼吸系統發育不良所造成。這疾病的治療包括藥物及非藥物治療，在我們院內首選的治療藥物為aminophylline（內含85 % theophylline茶鹼）。Theophylline為治療指數狹窄的藥品，用於治療早產兒呼吸暫停的建議血中濃度範圍為6 ~ 13 mg/ml。Theophylline在早產兒已有個體及族群的藥物動態學研究。
本研究主要的目的為套用Moore 等人研究之theophylline族群藥動模式，評估早產兒的藥動參數，之後依據估算的藥動參數，給予適當的建議劑量，並預測其血中濃度，以減少抽血次數並瞭解本院新生兒加護病房使用theophylline治療呼吸暫停的效果、副作用以及血中藥物濃度的關係。
本研究主要分為兩個部分：首先，評估theophylline族群藥動模式，共收集92位新生兒曾使用過theophylline且至少有監測過一次血中濃度，共有429個血中濃度數值。平均懷孕週數及平均出生體重分別為28.6 ± 2.7 週，1,244 ± 0.48 公克。套用模式後所得的平均清除率為0.0309 ± 0.012 L/hr，範圍為0.0095~0.0929 L/hr。出生時有窒息情況的新生兒平均清除率較出生時無窒息情況的新生兒減少了8 %。研究中發現清除率與出生後的正確週數關係較出生後天數好。而給藥劑量與血中濃度呈非線性關係且血中濃度大於15 mg/ml者皆發生在出生後3週內。預估的濃度曲線下面積（AUC）與濃度之間的相關性 (AUC = Dose / CL)，利用出生後正確體重較出生體重相關性較佳。Pearson Correlation Coefficients: 0.54 vs. 0.45, p <0.0001, Linear Regression: r2 = 0.29 vs. 0.21, p < 0.0001。最後新的方程式為：Dose/CL (mg/kg/day)/(L/hr) = 6.6708 Conc. (mg/ml) + 14.971(Conc. = Concentration)。
接著，前瞻性收集了22位新生兒共有133個theophylline血中濃度數值，平均懷孕週數及平均出生體重分別為27.8 ± 1.9 週，1,096 ± 0.31公克。清除率為0.03 ± 0.13 L/hr。所有22位新生兒的殘差值介於-4 ~ -3 mg/ml佔最多部分，而觀察值與預估值的平均錯誤百分比（錯誤百分比 ＝ % [觀察值－預估值] ÷觀察值）為-14.9 %，範圍為1.2 ~ 228 %。在2位早產兒共有3個血中濃度的數值其觀察值及預估值的殘差值在10單位以上者是因在一週內體重變化為24 %的緣故。出生體重小於1,000公克、給藥間隔為q8h及抽血前1天調整劑量者皆會影響預估的血中濃度數值。
在本院新生兒加護病房，自90年12月至91年5月共觀察了24位新生兒theophylline血中濃度與療效及副作用之間的關係。呼吸暫停的發生次數以護理人員記錄為主，在血中濃度為6 ~ 13 mg/ml 時有79 % 的新生兒達治療成功的標準。心跳過快為最常見的副作用，其中有3位因持續性心跳過快而停藥。
總之，因給藥劑量與血中濃度的非線性關係及清除率的變異性大，並無法依據Moore等人研究所得的公式預估本院新生兒正確的藥物血中濃度。正確的給藥劑量及抽血時間點是主要的關鍵。然而theophylline明顯可降低早產兒呼吸暫停的發生次數，適當的療效濃度為6 ~ 13 mg/ml，心跳過快為最常見的副作用。

英文摘要
Apnea of prematurity is a common problem in premature infants. It is related to immaturity of the infant’s neurologic and respiratory systems. Management of apnea of prematurity involves both pharmacological and nonpharmacological treatment, and aminophyllin (contain 85 % theophylline) is the first-line choice in our hospital. The range of effective theophylline serum concentrations is relatively narrow and generally ranged between 6 and 13 mg/ml. The pharmacokinetics of theophylline in premature infants have been studied using either individual analysis methods or population methods.
The aim of the study was to estimate the pharmacokinetic parameters, clearance rate (CL) using the population pharmacokinetic models proposed by Moore et al. Based on the validated population models, serum theophylline level was predicted to reduce the frequency of blood sampling. The relationship between theophylline concentrations and it’s efficacy or adverse effects was also evaluated.
This study consisted of two parts. We first evaluated the population pharmacokinetics models of theophylline using 429 theophylline serum concentration measurements from 92 neonates receiving theophylline and measured theophylline serum concentration at least once. Mean ± SD gestational age and birth weight were 28.6 ± 2.7 wks and 1,244 ± 0.48 g, respectively. The clearance (CL) in the study population was 0.0309 ± 0.012 L/hr (mean ± SD), ranged 0.0095~0.0929 L/hr. Newborns who had experienced birth asphyxia had a mean theophylline clearance 8% lower than nonasphyxiated newborns. Our findings indicate that postconceptional age rather than postnatal age is a better reference during theophylline therapy in premature infants. Theophylline plasma concentrations increased in a nonlinear proportion to the dosage, and most plasma concentrations over 15 mg/ml occurred in the first three weeks of life. Relationship between estimate area under concentration curve (AUC = Dose / CL) and concentration using current weight is better than birth weight (Pearson Correlation Coefficients: 0.54 vs. 0.45, p <0.0001, Linear Regression: r2 = 0.29 vs. 0.21, p < 0.0001). The final new models were: Dose/CL (mg/kg/day)/(L/hr) = 6.6708 Conc. (mg/ml) + 14.971(Conc. = Concentration).
Predictive performance of the new population models was prospectivly evaluated on another group of 22 infants, with Mean ± SD gestational age and birth weight as 27.8 ± 1.9 wks and 1,096 ± 0.31 g, respectively. Clearance was 0.03 ± 0.13 L/hr (mean ± SD). The residue of -3 to -4 mg/ml was obtained and in the majority of in the study. Error percentage (% Error = % measured – expected /measured) was -14.9 % (mean), ranged 1.2 ~ 228 %. Discrepancy greater than 10 mg/ml was observed in three premature infants because of more than 24 % loss of body weight within 1 week of life. Birth weight less than 1,000 g, dosing interval of every eight hour, and change of dose one day before sampling, were three major factors affecting the predicted serum concentrations.
Then, we conducted a prospective, routine monitoring to evaluate the correlation between efficacy or adverse effect and theophylline serum concentrations in 24 premature infants. Data were collected from premature infants treated with aminophylline from December 2001 through May 2002. Apnea was detected from nursing records, and the success rate of aminophylline treatment was 79 %, with serum concentrations of 6 to 13 mg/ml. The most common side effect was tachycardia, and theophylline was discontinued due to persistent tachycardia in three patients.
In brief, there was a nonlinear correlation between dose and plasma concentrations, and plasma theophylline clearance was unpredictable according to the population pharmacokinetic models proposed by Moore et al. Theophylline effectivnely decreases apnea of prematurity at plasma concentration of 6 – 13 mg/ml, and monitoring of serum theophylline levels is mandatory.

目錄 頁碼
中文摘要 I
英文摘要 III
縮寫表 VI
目錄 VII
表目錄 XI
圖目錄 XII
第壹章 研究背景 1
第貳章 文獻回顧 3
第一節 早產兒呼吸暫停的定義、發生率及病態生理學 3
1.1 定義（Definition） 3
1.2 呼吸暫停之分類 （Classification） 3
1.3 發生率（Incidence） 4
1.4 病因（Etiology） 5
1.5 病態生理學（Pathophysiology） 6
第二節 早產兒呼吸暫停之非藥物治療 10
第三節 早產兒呼吸暫停之藥物治療 14
3.1 甲基黃嘌呤類（Methylxanthines） 14
3.1.1 Theophylline 14
3.1.1-1 Theophylline用於早產兒呼吸暫停之建議劑量 16
3.1.2 Caffeine 19
3.1.2-1 Caffeine用於早產兒呼吸暫停之建議劑量 20
3.1.3 Theophylline及Caffeine之副作用 22
頁碼
3.1.4 Theophylline與Caffeine的比較 23
3.1.5 Theophylline與CPAP的比較 25
3.2 Doxapram 25
3.3 其他（others） 26
第四節 早產兒呼吸暫停之預後 27
第五節 Theophylline在新生兒之藥理及生理作用 29
5.1 Theophylline在新生兒之藥理作用 30
5.1.1 Theophylline之一般藥理作用 30
5.1.2 Theophylline之作用機轉 31
5.1.3 Theophylline在新生兒的藥理及生理作用 32
第六節 Theophylline在早產兒之代謝 34
第七節 Theophylline在早產兒之藥物動態學研究 38
第八節 Theophylline的血中濃度監測 42
第九節 影響theophylline血中濃度的因子 43
9.1 Theophylline之吸收 43
9.2 Theophylline之蛋白結合及分佈體積 43
9.3 Theophylline生物轉化（biotransformation） 44
9.3.1 內在因子 44
9.3.2 外在因子 45
第十節 總結 48
第參章 研究目的 49
第肆章 研究方法 50
頁碼
第一節 研究設計 50
4.1. 研究對象 50
4.2 藥品 51
4.3 臨床評估 51
4.4國外族群藥動模式之公式 52
第二節 研究流程 53
第三節 統計分析 56
第伍章 研究結果 57
第一節 研究對象 57
第二節 Theophylline監測情況 62
第三節 計算公式 66
第四節 預測血中濃度 69
第五節 臨床療效及副作用評估 73
第陸章 討論 75
第一節 研究對象與血中濃度監測情況 75
第二節 計算公式與預測血中濃度 78
第三節 臨床療效及副作用評估 83
第柒章 結論 85
參考文獻 87
附錄一 病患記錄表格 101
附錄二 臨床藥事服務 102
第一節 藥物不良反應（Adverse effect）之評估 103
頁碼
第二節 藥物諮詢 107
2.1 藥物血管外滲之處理 107
2.2 早產兒慢性肺疾病之類固醇選擇 109
2.3 早產兒上消化道出血之藥物治療 111
2.4 早產兒使用cisapride用於治療餵食困難（feeding intolerance）
的療效及安全性 113
2.5 Hypoventilation syndrome的藥物治療 115
2.6 新生兒Gentamicin的使用劑量 117
第三節 藥物使用評估 120
3.1 新生兒加護病房全身性黴菌感染之藥物治療 120
3.2 早產兒使用erythromycin 125

表目錄 頁碼
表一 美國食品及藥物管理局公布theophylline之劑量準則 2
表二 呼吸暫停之評估 10
表三 原發性早產兒呼吸暫停之非藥物治療 13
表四 Theophylline在不同年齡層的藥動參數 17
表五 Theophylline用於呼吸暫停及拔除呼吸器的建議劑量 19
表六 Caffeine用於早產兒呼吸暫停的藥動參數 21
表七 Caffeine在新生兒半衰期的變化 21
表八 Theophylline副作用與血中濃度的關係 22
表九 Theophylline與Caffeine在新生兒常見的副作用 23
表十 Theophylline與Caffeine 的藥理作用比較 24
表十一 Theophylline與Caffeine 用於治療早產兒呼吸暫停之比較 24
表十二 建議出院後監測心肺功能的適應症 27
表十三 Theophylline在新生兒的藥物動態學研究 38
表十四 在早產兒維持血中濃度10 mg/ml之theophylline的劑量 40
表十五 Theophylline抽血時間點 42
表十六 影響Theophylline蛋白結合的藥品 44
表十七 疾病對theophylline藥動參數的影響 46
表十八 影響Theophylline血中濃度的藥物 47
表十九 92位及22位新生兒的基本資料 58
表二十 24 位新生兒theophylline臨床療效及血中濃度 74
表二十一 92位新生兒基本資料與其他文獻的比較 80
表二十二 92位新生兒清除率與文獻的比較 82
附錄表格 124

圖目錄 頁碼
圖2.1 呼吸暫停之型態在早產兒出生後的改變 4
圖2.2 影響正常呼吸功能之因素 9
圖2.3 治療呼吸暫停之建議流程 28
圖2.4 Xanthine與Theophylline結構式 29
圖2.5 Theophylline的生理作用 30
圖2.6 Theophylline及Caffeine的代謝路徑 35
圖2.7 Theophylline在新生兒與成人的代謝 36
圖2.8 Caffeine在新生兒與成人的代謝 37
圖4.1 研究流程圖之一 54
圖4.2 研究流程圖之二 55
圖 5.1 92位早產兒懷孕週數分佈情形 60
圖 5.2 92位早產兒出生體重分佈情形 61
圖 5.3 92位新生兒開始使用theophylline的時間 63
圖 5.4 92位新生兒使用theophylline後緩解的時間 63
圖 5.5 92位新生兒之懷孕週數與治療天數 64
圖 5.6 92位早產兒測得之thephylline血中濃度 64
圖 5.7 92位早產兒theophylline血中濃度之分佈情形 65
圖 5.8 92位新生兒theophylline血中濃度與劑量的關係 65
圖 5.9 92位新生兒theophylline血中濃度與Dose/CL 的關係 67
圖5.10 69位新生兒theophylline血中濃度與Dose/CL 的關係 68
圖 5.11 22位新生兒theophylline血中濃度的預估值與觀察值 70
圖5.12 22 位新生兒血中濃度觀察值與預測值的殘差值 71
頁碼
圖 5.13 22位新生兒觀察值與預估值殘差值的分佈 72
圖5.14 22位新生兒血中濃度觀察值與預測值之錯誤百分比 72
圖 6.1 92位新生兒懷孕週數與清除的關係 80
圖 6.2 92位新生兒出生後正確週數與清除率的關係 81
圖 6.3 92位新生兒出生後天數與清除率之關係 81

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