2025-12-17
台灣兒童感染症學會-兒童發燒處置建議
發燒的機制
- 體溫的定位點 （set-point）：體溫調節中樞 （thermoregulatory center） 位於下視丘（hypothalamus）的前部，在此處有一個理論上體溫的定位點，人體的各種生理反應會隨著體溫定位點的高低而維持恆定的體溫。
- 發燒 （fever）：發炎反應藉由巨噬細胞（macrophage）等免疫系統細胞分泌多種細胞激素（cytokine），作用在下視丘引起體溫定位點的上升。
- 體溫過高 （hyperthermia）：體溫定位點並未上升，但中心體溫超過38°C，例如在炎熱的環境下穿太多衣服、把嬰兒包得太緊、散熱不佳、運動、中暑 （heat stroke）等。
感染之後給予退燒藥物. 在動物實驗曾經發現會增加死亡率. 但目前沒有可靠的人體研究(實驗條件不容易設計?)
Antipyretics 退燒藥物
pyrexia 發熱/發燒狀態
pyrogenic 致熱的, 導致發燒的 (地質學上則翻譯為火成的, 例如火成岩)
endogenous pyrogens 內生性發熱原
exogenous pyrogens 外源性發熱原
pyrogens= fever-producing agents 發熱原/發熱因子
熱原的分類與來源
外源性熱原 (Exogenous Pyrogens): 來自外界，侵入身體後刺激發燒。
1. 內毒素 (Endotoxins)：革蘭氏陰性菌的脂多醣 (LPS)，是常見的外源性熱原。
2. 非內毒素熱原 (NEP)：來自其他微生物（如革蘭氏陽性菌、真菌、病毒）的成分。
3. 非微生物來源：橡膠、塑膠微粒或金屬化合物。
3. 非微生物來源：橡膠、塑膠微粒或金屬化合物。
內源性熱原 (Endogenous Pyrogens): 由人體自身的免疫細胞（如單核細胞）在受到感染刺激後釋放的細胞因子。例如 TNF, IL-1, IL-6
1. 人體的溫度受到下視丘的體溫調節中心(hypothalamic setpoint )控制. 每個人的體溫會有差異. 下視丘的設定體溫受到血中各種發熱因子影響.
2. 假設你的下視丘將體溫設定為36度. 當身體溫度超過36度. 會感覺到熱. 這時候身體需要減少產熱及增加散熱. 於是開始流汗. 當你的體溫因病毒感染的影響. 下視丘將體溫設定在 39 度. 若你當前體溫只有36度. 此時會感覺到冷. 於是身體開始寒顫發抖(chills). 發抖是肌肉不受控制的收縮引起. 肌肉收縮會產熱. 當你的體溫到達39度. 身體就不再感覺冷. 這時候寒顫也消失了.
發燒前的寒顫通常約 30-60 分鐘. 取決於你身體能多快產生足夠熱量. 也取決於下視丘設定的溫度多高.
3. 有些物質會影響下視丘的體溫設定. 造成發燒. 這些物質稱為發熱因子,
下面是關於發燒的生理病理學
Antipyretic Use in Noncritically Ill Patients With Fever: A Review
發熱的病理生理基礎
發燒是一種適應性反應，由於下視丘生理體溫設定點的改變而導致體溫升高[ 16 ]。這種改變是由多種發炎介質在終板血管器中促進前列腺素合成所致。這些介質包括細胞因子，例如腫瘤壞死因子（TNF）、白細胞介素（IL）-6 和 IL-1，它們本身可響應外源性致熱原而產生。此外，有證據表明，局部細胞激素產生和其他神經激素機制可能是下丘腦體溫設定點改變的原因[ 17 ]。體溫設定點的改變隨後會引發身體反應，使核心體溫升高。這些反應，如同許多其他協調的生物過程一樣，由下視丘協調控制[ 18 ]。發熱反應的基本步驟如下圖所示（圖1）。
發燒已被證實對微生物增生具有抑製作用，並能增強內源性免疫反應。這種增強作用貫穿先天性和適應性免疫反應的各個階段。嗜中性球的募集、釋放和活性增加，自然殺手 (NK) 細胞的細胞毒活性增強，巨噬細胞和樹突狀細胞的吞噬活性受到刺激，以及淋巴細胞遷移增加，都是發燒調節免疫反應的途徑[ 2 , 19 ]。這些發熱引起的改變有助於控制和清除致病病原體。儘管從演化角度來看，發熱似乎是個有利因素，但它對人體卻有許多有害影響。代謝需求增加、分鐘通氣量增加、心血管和神經系統壓力都是發燒的有害影響[ 20 , 21 ]。儘管發燒普遍存在，但其治療方法仍有爭議。發燒往往會為患者和臨床醫師帶來不適。
發燒患者退燒藥物的選擇
數百年來，緩解發燒一直是常見的治療目標[ 22 ]。其治療原理在於減輕患者不適，並緩解發燒引起的代謝需求增加和缺氧性神經損傷風險[ 3,4 ] 。目前有多種藥物和非藥物治療方案可用於退燒[23]。常用的藥物包括對乙醯氨基酚和非類固醇抗發炎藥（ NSAIDs），例如布洛芬、水楊酸鹽以及新型COX-2抑制劑，如塞來昔布和羅非昔布。各種退燒藥物最可能的機轉是抑制下視丘中前列腺素E2的合成[ 24 ]。
由於不同研究中報告的製劑、給藥途徑和療效指標各不相同，因此無法對各種退燒藥的相對效力進行全面分析[ 21 ]。儘管如此，一些兒童研究發現，口服布洛芬的退燒效力強於口服對乙醯氨基酚，但差異較小[ 25-27]。另一項研究也表明，其他非類固醇抗發炎藥，如尼美舒利和酮洛芬，對兒科患者也有效[28 ]。因此，對於兒童，口服布洛芬可作為控制發燒的首選藥物。
非類固醇抗發炎藥（NSAIDs）也可有效用於成人發燒管理。 Michie 等人的研究表明，預先服用布洛芬可減輕內毒素刺激志願者體內細胞因子（如腫瘤壞死因子α）升高引起的症狀[ 29 ]。 Bernard 等人進行的另一項隨機、雙盲、安慰劑對照試驗也強調了布洛芬在減輕發燒全身效應方面的有效性。研究於 1989 年 10 月至 1995 年 3 月期間進行，納入 455 例敗血症患者，比較了靜脈注射布洛芬（每次 10 mg/kg，最大劑量 800 mg，每 8 小時一次，共 6 次）與安慰劑的療效。研究發現，布洛芬治療組患者的尿液中前列環素和血栓素 A2 水平顯著降低，同時體溫、心率、耗氧量和乳酸水平也均有所下降。然而，並未報告休克、急性呼吸窘迫症候群或死亡率有顯著降低[ 30 ]。
Vargas 等人對內毒素激發的志願者進行了一項研究，比較了口服對乙醯氨基酚和肌注酮咯酸的療效。這項雙盲、雙模擬、平行研究表明，酮洛酸劑量增加與更高的退燒效果相關，30 mg 肌注酮洛酸與 650 mg 口服對乙醯氨基酚的療效相當[ 31 ]。 Reiner 等人進行的一項雙盲試驗進一步強調了各種退燒藥物的療效差異，該試驗比較了尼美舒利、雙氯芬酸和安慰劑的療效。結果表明，尼美舒利栓劑在退燒和改善發燒體徵（脈搏和血壓）方面與雙氯芬酸栓劑療效相當，且均優於安慰劑[ 32 ]。
數據表明，多種退燒藥物均能有效降低體溫，因此應根據患者的具體情況選擇合適的藥物。不同退燒藥的毒性特徵各異，這在藥物選擇中起著至關重要的作用。
水楊酸鹽類藥物，例如阿斯匹靈，與兒童雷氏症候群的發生有關[ 33 ]。這種罕見但災難性的兒童疾病是由於肝臟粒線體氧化磷酸化受到抑制，進而導致肝衰竭和腦病變[ 34 ]。非類固醇抗發炎藥（NSAIDs）具有多種不良反應，幾乎可以影響所有器官系統（表1）。
非類固醇抗發炎藥（NSAIDs）引起的腎臟和胃腸道毒性是由於其抑制氧合酶（COX）同工酶所致[ 35 ]。研究發現，非選擇性抑制COX酶的藥物比選擇性抑制COX-2酶同工酶的藥物更容易引起胃腸道毒性[ 36 ]。其他重要因素，例如年齡超過60歲、既往有胃腸道疾病史、長期使用NSAIDs以及同時服用其他具有胃腸道毒性的藥物（如皮質類固醇），也會增加胃腸道毒性的風險[ 37 ]。羅非昔布等藥物選擇性抑制COX-2同功酶，可能透過促進血栓形成環境，增加心血管不良反應（如心肌梗塞和中風）的風險[ 38 ]。非類固醇抗發炎藥物是最常見的與腎毒性相關的藥物之一，其作用範圍從間質性腎炎到急性或慢性腎衰竭[ 39 ]。先前患有腎臟疾病的個體以及使用腎毒性藥物的個體發生腎功能障礙的風險增加[ 40 ]。
與非類固醇抗發炎藥（NSAIDs）不同，對乙醯氨基酚對環氧合酶（COX）的活性很低，因此其胃腸道和腎臟毒性也極小[ 36 ]。然而，它會代謝成一種潛在的肝毒性中間體，即N-乙醯對苯醌亞胺（NAPQI）[ 41 ]。穀胱甘肽儲備不足的個體，例如長期飲酒和飢餓者，其毒性風險會增加[ 42 ]。因此，退燒藥的選擇取決於患者的人口統計學特徵、既往病史以及正在服用的其他藥物。為了最大限度地降低全身毒性，必須盡可能縮短所選退燒藥的療程，並使用最低有效劑量。
發燒的利弊
控制身體對發炎的生理反應是否能帶來任何可量化的益處尚存爭議。與任何治療方式一樣，發燒及其控制的風險和益處應進行合理的權衡（圖2）。
退燒的建議優勢
發燒會為患者帶來明顯的不適，緩解患者不適是處方退燒藥的重要原因。改善患者的健康狀況是發燒患者治療的重要原則。煩躁發燒的兒童在服用退燒藥後症狀會迅速改善[ 44 ]。 Ipp等人進行的一項隨機臨床試驗證實了此效果。該試驗研究了383名2至6個月大的嬰兒和70名18個月大的兒童在接種白喉-百日咳-破傷風-脊髓灰質炎聯合疫苗後不良反應的發生頻率和嚴重程度。研究表明，與安慰劑組相比，2至6個月大的嬰兒服用對乙醯氨基酚後局部和全身不良反應的發生率較低，發燒發生率也較低，行為改變也較少。然而，在18個月大的嬰兒中未觀察到這種效果。結論是，在接種白喉-百日咳-破傷風類毒素-小兒麻痺疫苗時，使用對乙醯氨基酚可降低常見不良反應的發生頻率[ 45 ]（表2）。
Chiappini 等人進行的另一項單中心前瞻性觀察研究納入了 172 名因發燒入院的兒科急診患兒，結果顯示對乙醯氨基酚在緩解發燒和不適方面具有有益作用。研究分析了對乙醯氨基酚對發燒和不適（以半定量李克特量表定義）的影響，發現與基線相比，口服對乙醯氨基酚治療的兒童在 60 分鐘時體溫和不適程度均顯著降低 [ 46 ]（表2）。
Oborilová 等人在一項非隨機開放標籤的初步研究中也報告了這種緩解不適的有益效果。該研究比較了三種退燒藥物對多種主要為血液腫瘤患者的療效。共納入 254 例發燒（腋溫至少 38°C），分別以雙氯芬酸（75 mg，短暫靜脈輸注）、甲胺基比林（2500 mg 或 1000 mg，短暫靜脈輸注）或丙帕他莫（2000 mg 或 1000 mg，緩慢靜脈注射或短暫注射治療。記錄腋溫變化、不適改善情況和不良反應。結果顯示，所有退燒藥物均能降低體溫並改善患者不適（87% 的患者表示舒適度有所提高）。然而，各組之間的療效、耐受性和不良事件發生率存在差異。結論認為，退燒藥是緩解不適的有效治療選擇[ 47 ]（表2）。
發燒會藉由增加心肺頻率和耗氧量，導致身體代謝負擔加重。降低體溫被認為是對抗身體代表負擔的重要治療標靶。 Manthous 等人的一項研究強調了這一作用，該研究分析了降溫對發燒危重患者耗氧量的影響。研究表明，當體溫從 39.4 ± 0.8°C 降至 37.0 ± 0.5°C 時，12 例發燒機械通氣患者的耗氧量、二氧化碳生成量和能量消耗均顯著降低 [ 3 ]（表2）。
高燒與認知功能障礙和腦損傷有關。 Reichenberg 等人進行的一項雙盲交叉研究證實了這種對神經功能的不良影響。研究納入 20 名健康男性志願者，分別靜脈注射馬流產沙門氏菌內毒素（0.8 ng/kg）和生理食鹽水。結果顯示，內毒素暴露與核心體溫升高（0.5°C）以及語言和非語言記憶功能下降有關。內毒素暴露也與焦慮程度和憂鬱情緒的短暫但顯著升高有關[ 48 ]（表2）。可惜的是，研究並未檢視退燒藥預防這些神經心理失調的能力。 Beisel 等人進行的另一項研究表明，在實驗誘發白蛉熱的志願者中，退燒藥可以減輕疾病相關的工作表現下降。即使發燒和其他症狀尚未完全緩解，也能觀察到這種有益效果[ 49 ]（表2）。發燒對神經系統疾病（例如中風）患者的影響已被較為深入的研究。 Hajat 等人進行的一項薈萃分析表明，發燒與急性中風患者的發病率和死亡率增加有關[ 50 ]。考慮到上述許多益處，有人推測退燒可能在一定程度上提高存活率。 Bernard 等人於 1989 年 10 月至 1995 年 3 月期間，在 455 例膿毒症患者中開展了一項隨機、雙盲、安慰劑對照試驗，比較了布洛芬與安慰劑的療效，以此驗證了這一假設。研究結果表明，布洛芬給藥可降低前列腺素和血栓素的合成，進而降低發燒、耗氧量和乳酸生成。然而，布洛芬並未預防休克或呼吸窘迫的發生，也未降低死亡率[ 30 ]（表2）。
退燒的潛在缺點
與其他任何治療方法一樣，退燒藥並非完全沒有副作用。除了上述諸多副作用外，退燒還可能導致一些不利影響。例如，非類固醇抗發炎藥（NSAIDs）會抑制體內前列腺素的合成。這種內源性介質生成的阻斷會對多個器官系統造成損害。 Friedman 等人的研究表明，對冠狀動脈疾病患者使用吲哚美辛會導致冠狀動脈血管阻力增加和冠狀動脈血流量減少。這種影響可能與血管舒張性前列腺素合成減少有關[ 51 ]（表3）。因此，在對患有冠狀動脈疾病的患者使用此類藥物時，需要謹慎。退燒的一個主要缺點是理論上有抑制身體自體免疫反應的風險。這種保護性免疫反應的減弱被認為會延長病程。 Doran 等人進行的一項隨機、雙盲、安慰劑對照試驗提供了支持這一觀點的證據。該試驗研究了對乙醯氨基酚對兒童水痘的影響。研究納入了 1 至 12 歲患有水痘的兒童，並將他們隨機分為兩組，分別接受對乙醯氨基酚（n = 37）或安慰劑（n = 31）治療。研究人員測量了搔癢、食慾、活動和整體狀況等症狀，以及最後一個水皰出現的時間、所有皮損結痂的時間和完全癒合的時間。一名兒童退出研究，三名兒童未完成研究。結果顯示，與活性治療組相比，安慰劑組的完全結痂時間和搔癢症狀均有所改善。因此，研究得出結論：對乙醯氨基酚在緩解兒童水痘症狀方面沒有顯著作用，反而可能延長病程[ 52 ]（表3）。
這種透過控制發燒來延長自限性疾病病程的趨勢在其他研究中也有發現。 Graham 等人進行了一項雙盲、安慰劑對照試驗，研究常用非處方鎮痛/退燒藥對60名健康志願者鼻內感染2型鼻病毒後病毒脫落、免疫反應和臨床狀況的影響。受試者被隨機分配接受阿斯匹靈、對乙醯氨基酚、布洛芬或安慰劑治療。其中56名受試者感染並出現病毒脫落。隨後，研究人員密切監測了病毒脫落、免疫球蛋白水平、症狀和體徵以及白血球計數。令人驚訝的是，研究發現阿斯匹靈和對乙醯氨基酚與血清中和免疫球蛋白的顯著抑制以及鼻部症狀的加重有關。各組之間的病毒脫落沒有統計學上的顯著差異，但服用對乙醯氨基酚和阿斯匹靈有延長病毒脫落時間的趨勢[ 53 ]（表3）。
Plaisance 等人進行的回顧性觀察研究也觀察到了類似的與使用退燒藥相關的疾病延長現象。研究評估了退燒藥對實驗性甲型流感、宋內氏志賀菌和立克次體感染的影響。研究對象包括實驗性甲型流感（n = 54）、宋內氏志賀菌（n = 45）和立克次體（n = 21）感染者。研究人員給予對乙醯氨基酚或阿斯匹靈以緩解症狀。多因子分析顯示，甲型流感和宋內氏志賀菌感染者使用退燒藥會延長疾病持續時間，而立克次體感染者則不會[ 54 ]（表3）。
一些研究甚至表明，退燒藥可能對特定患者群體有害，並可能與死亡率升高有關。 Lee 等人進行的一項多中心前瞻性觀察研究，探討了發燒和退燒藥對 1425 例成年危重患者（無神經系統損傷）死亡率的影響，這些患者包括膿毒症患者和非膿毒症患者。研究納入了至少需要 48 小時重症監護的患者。研究發現，非類固醇抗發炎藥 (NSAID) 或對乙醯氨基酚的使用與敗血症患者 28 天死亡率升高獨立相關，但在非敗血症患者中未觀察到這種關聯 [ 55 ]（表3）。
Ye 等人也觀察到，在接受退燒藥治療的膿毒症患者中，死亡率出現了類似的增加，該研究對象為患有膿毒症且需要機械通氣的危重患者（n = 8711）[ 56 ]（表3）。
結論
目前有多種藥物和非藥物方法可用於退燒。各種藥物的療效和耐受性通常相近，藥物的選擇通常取決於患者的特定情況。當口服耐受性差或需要快速緩解發燒時，應考慮使用注射劑型的退燒藥。處方退燒藥時，必須考慮患者的年齡、共病、營養狀況、其他正在服用的藥物。各種藥物的選擇性毒性特徵也可作為處方指導。
使用退燒藥是否能帶來任何實質益處仍存疑。迅速緩解患者不適感可能是臨床醫師和患者的重要治療目標。然而，追求這一治療目標是否會以相對免疫抑制和延長病程為代價，目前尚不清楚。退燒藥的使用並未顯示出能顯著降低發病率或死亡率，且在敗血症患者中可能弊大於利。在中風領域，體溫控制已被證明能帶來良好的預後。這種神經保護作用是否適用於非重症患者，還需要進一步釐清。最後，沒有任何一種藥物可以完全避免不良反應。所有退燒藥都可能引起嚴重的毒性反應，但不同類別的退燒藥所涉及的器官範圍有所不同。
我們的研究表明，退燒藥的益處可能被過度誇大，其使用也可能過度。不必要的用藥可能弊大於利，限制用藥或許可以降低醫療成本並減少併發症風險。與所有醫療幹預措施一樣，退燒藥的使用也應仔細權衡利弊，並考慮其風險和益處。還需要進一步的研究來確定，對於非危重發燒患者，不進行任何干預是否也是可接受的選擇。
Introduction and background
Fever or pyrexia is caused by an increased hypothalamic thermoregulatory setpoint due to several infectious and non-infectious causes. The various inciting agents cause a release of endogenous or exogenous pyrogens (fever-producing agents) that act on the neurological system to instigate a prostaglandin-mediated alteration in the temperature setpoint [1]. An increase in body temperature offers numerous physiological advantages in times of stress or infection possibly due to changes in the host immune system [2]. The same adaptive response can also prove detrimental by increasing the body’s metabolic demand, oxygen consumption, minute ventilation, and contributing to adverse neurological outcomes [3-5]. Several pharmacological and non-pharmacological treatment modalities are available for mitigating fever.
Drugs, such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase 2 (COX-2) inhibitors, and physical therapies, such as cooling blankets and immersion, are commonly used in febrile individuals to achieve temperature reduction [6-8]. Despite fever being a ubiquitous symptom, the evidence surrounding the selection of an appropriate antipyretic regimen, dosing, route of administration, and drug choice is limited [9]. Some studies even suggest that antipyretic use in infectious etiologies has detrimental outcomes. This may be due to the loss of microbial suppressive effects of fever [10,11]. This premise is supported by the theoretical risk of relative immunosuppression caused by normothermia [12]. Furthermore, antipyretics can also have prominent hemodynamic side effects and can contribute to renal and hepatic dysfunction [13-15]. Selective toxicities of the available antipyretics may limit their use in specific patients. The data on the usage of antipyretics for controlling temperature are limited when considering noncritical patients. There are no clear-cut guidelines or recommendations specifying the choice of a particular agent, the route of administration, or data on comparative safety and efficacy.
This literature review aimed to analyze the various available modalities of temperature control and their relative safety and efficacy. The review also investigated factors that may help direct the selection of a particular agent. Finally, the advantages and disadvantages of fever control and toxicities of the antipyretics were evaluated.
Review
Pathophysiological basis of fever
Fever is an adaptive response that results in increased body temperature secondary to an alteration in the physiological temperature setpoint in the hypothalamus [16]. This alteration is caused by increased prostaglandin synthesis in the organum vasculosum of lamina terminalis by numerous inflammatory mediators. Some of these mediators include cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1, which can be themselves produced in response to exogenous pyrogens. Furthermore, there is evidence that local cytokine production and other neurohormonal mechanisms may be responsible for alteration in the hypothalamic setpoint [17]. Alteration of the setpoint then leads to bodily responses that raise the core body temperature. These responses, like many other coordinated biological processes, are coordinated in the hypothalamus [18]. The basic steps involved in the generation of febrile response are illustrated below (Figure 1).
Pyrexia has been shown to have an inhibitory effect on microorganism proliferation and amplifies the endogenous immunological response. This amplification is seen throughout the innate and adaptive immune response. Increased neutrophilic recruitment, release, and activity, enhanced natural killer (NK) cell cytolytic activity, stimulation of phagocytic activity of macrophages and dendritic cells, and increased lymphocytic trafficking are some of the ways fever modulates the immune response [2,19]. These pyrexia-induced alterations aid in controlling and eliminating the offending infectious agent. Although seemingly advantageous from an evolutionary point of view, fever has numerous deleterious consequences on the human body. Increased metabolic demand, increased minute ventilation, and cardiovascular and neurological stresses are some of the harmful effects of fever [20,21]. Despite its ubiquitous nature, the management of pyrexia remains controversial. Fever tends to be a source of discomfort both for the patient and the clinician.
Choice of Antipyretic Agent in Febrile Patients
Alleviation of fever has been a common therapeutic target for hundreds of years [22]. The therapeutic rationale behind this is to reduce patient discomfort and mitigate the effects of increased metabolic demand and risk of hypoxic neurological injury that can be caused by fever [3,4]. Numerous pharmacological and non-pharmacological treatment options are available for antipyresis [23]. Common pharmacological agents include acetaminophen and NSAIDs, such as ibuprofen, salicylates, and novel COX-2 inhibitors, such as celecoxib and rofecoxib. The most likely mechanism behind the various antipyretics is the inhibition of prostaglandin E2 synthesis in the hypothalamus [24].
A comprehensive analysis of data on the relative potencies of various antipyretic drugs is not possible due to differing formulations, routes of administration, and measures of efficacy reported in various studies [21]. Nevertheless, several studies in children have found that oral ibuprofen is a more potent antipyretic than oral acetaminophen though the difference is small [25-27]. Another study also showed that other NSAIDs, such as nimesulide and ketoprofen, were also useful antiinflammatory agents in pediatric patients [28]. In children, therefore, oral ibuprofen can be considered initially for fever control.
NSAIDs can also be used effectively for fever management in adults. A study conducted by Michie et al. demonstrated that pretreatment with ibuprofen blunted the symptoms resulting from an increase in cytokines, such as tumor necrosis alpha in endotoxin-challenged volunteers [29]. Another randomized, double-blind, placebo-controlled trial conducted by Bernard et al. highlighted the effectiveness of ibuprofen in reducing the systemic effects of fever. This study conducted between October 1989 and March 1995 on 455 patients who presented with sepsis compared the effect of intravenous ibuprofen (10 mg/kg per dose, maximum dose 800 mg, given every eight hours for six doses) with that of placebo. The study found a significant reduction in urinary levels of prostacyclin and thromboxane A2, along with reductions in temperature, heart rate, oxygen consumption, and lactate levels in patients treated with ibuprofen. However, no significant reduction in the development of shock, acute respiratory distress syndrome, or mortality was reported [30].
Another study conducted by Vargas et al. in endotoxin-challenged volunteers compared the efficacy of oral acetaminophen and intramuscular ketorolac. This double-blind, double-dummy, parallel study showed that increasing doses of ketorolac are associated with a higher antipyretic effect and comparative efficacy was seen between 30 mg intramuscular ketorolac and 650 mg oral acetaminophen [31]. This comparative efficacy of the various antipyretics was further highlighted in the double-blind trial conducted by Reiner et al., which compared the efficacy of nimesulide with that of diclofenac and placebo. It was seen that nimesulide suppositories were as effective as diclofenac suppositories in the reduction of fever and mitigation of objective signs of fever (pulse and blood pressure), and both were superior to placebo [32].
The data suggest that various antipyretic agents are effective in temperature reduction, and thus the choice of agent used should be determined by the individual patient profile. The several antipyretic groups have varying toxicity profile that plays a crucial role in the selection of a particular agent.
Salicylates, such as aspirin, have been linked with the development of Reye’s syndrome in children [33]. This rare but catastrophic childhood disorder results from the inhibition of hepatic mitochondrial oxidative phosphorylation and subsequent development of hepatic failure and encephalopathy [34]. NSAIDs have a myriad of adverse effects involving almost any organ system (Table 1).
Renal and gastrointestinal toxicity from NSAIDs results from the inhibition of COX isoforms [35]. Agents with nonselective inhibition of COX enzymes have been found to cause greater gastrointestinal toxicities than agents that selectively inhibit COX-2 enzyme isoforms [36]. Other important factors, such as age of more than 60 years, presence of previous gastrointestinal disorder, prolonged duration of NSAID use, and concomitant intake of other agents with gastrointestinal toxicity, such as corticosteroids, also increase the risk of gastrointestinal toxicity [37]. Drugs, such as rofecoxib, selectively inhibit COX-2 isoforms, which are associated with a higher likelihood of cardiovascular adverse effects, such as myocardial infarction and stroke possibly by promoting a more thrombogenic environment [38]. NSAIDs are one of the most common agents associated with renal toxicity with effects, ranging from interstitial nephritis to acute or chronic renal failure [39]. Individuals with preexisting renal disease and those using nephrotoxic agents are at an increased risk of developing renal dysfunction [40].
Unlike NSAIDs, acetaminophen has little activity against COX enzymes and thus has minimal gastrointestinal and renal toxicity [36]. It is however metabolized to a potentially hepatotoxic intermediate known as N-acetyl-p-benzoquinoneimine (NAPQI) [41]. The risk of toxicity increases in individuals with depleted glutathione reserves, e.g., chronic ethanol ingestion and starvation. [42]. Thus, the choice of antipyretic agent depends on the patient's demographic, preexisting medical conditions, and concurrent medication usage. It is of utmost importance to administer the selected antipyretic for the shortest duration and at the lowest effective dose to limit systemic toxicity.
Pros and Cons of Fever
Whether control of the body’s physiological response of the body to inflammation offers any quantifiable benefit is debatable. Like any treatment modality, the risks and benefits of fever and its control should be sensibly considered (Figure 2).
Suggested Advantages of Fever Control
Pyrexia can cause significant discomfort in a febrile patient and relieving patient discomfort is an important reason for prescribing antipyretics. Improving patient well-being is an important therapeutic rationale in febrile individuals. Children who are irritable and pyretic show prompt improvement after the administration of an antipyretic agent [44]. This effect was demonstrated in a randomized clinical trial conducted by Ipp et al., in which 383 infants aged two to six months and 70 children aged 18 months were studied for frequency and severity of adverse reactions following administration of diphtheria-pertussis-tetanus toxoids-polio vaccine. The study showed that acetaminophen-treated infants between the ages of two to six months had a lower incidence of local and systemic effects, a lower incidence of fever, and a reduction in behavioral changes compared to placebo. However, this effect was not seen in infants aged 18 months. It was concluded that acetaminophen use reduced the frequency of common adverse effects at the time of administration of primary vaccination with diphtheria-pertussis-tetanus toxoids-polio [45] (Table 2).
Another single-center prospective observational study conducted by Chiappini et al. in 172 febrile children who were admitted to a pediatric emergency department showed the beneficial effects of acetaminophen in alleviating fever and discomfort. This study analyzed the effect of acetaminophen on fever and discomfort (defined using a semiquantitative Likert scale) and found significant reductions in both body temperature and levels of discomfort at 60 minutes when compared to baseline in children treated with oral paracetamol [46] (Table 2).
This beneficial effect on discomfort relief was also reported by Oborilová et al. in their non-randomized open-label pilot study comparing the effects of three antipyretics agents in various mainly hemato-oncological patients. A total of 254 episodes of fever (axillary temperature of at least 38°C) were treated with either diclofenac (75 mg, brief intravenous (IV) infusion) or metamizol (2500 mg or 1000 mg, brief IV infusion) or propacetamol (2000 mg or 1000 mg, slow IV injection or brief IV infusion). Changes in axillary temperature, improvement in discomfort, and adverse effects were recorded. It was observed that all antipyretics were associated with a reduction in temperature and improvement in patient discomfort (87% of patients declared improvement in comfort). However, efficacy, tolerability, and occurrences of adverse events differed between the groups. It was concluded that antipyretics provide a useful therapeutic option for the alleviation of discomfort [47] (Table 2).
Pyrexia is associated with increased metabolic strain on the body via increased cardio-respiratory rate and oxygen consumption. Lowering temperature has been suggested as an important therapeutic target to counteract the metabolic strain on the body. This effect was highlighted in a study conducted by Manthous et al., which analyzed the effect of cooling on oxygen consumption in febrile critically ill patients. This study showed that cooling resulted in a statistically significant reduction in oxygen consumption, carbon dioxide production, and energy expenditure in 12 febrile, mechanically ventilated patients when the temperature was reduced from 39.4 +/- 0.8°C to 37.0 +/- 0.5°C [3] (Table 2).
High fever has been linked to cognitive dysfunction and brain damage. This adverse effect on neurological function was demonstrated in a double-blind, crossover study conducted by Reichenberg et al. in 20 healthy male volunteers exposed to intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) while compared to saline. The study showed that endotoxin exposure was associated with a rise in core body temperature (0.5°C) and depressed verbal and non-verbal memory functions. Endotoxin exposure was also associated with a transient but significant increase in anxiety levels and depressed mood [48] (Table 2). Unfortunately, this study did not examine the ability of antipyretics to prevent these neuropsychological disturbances. Another study conducted by Beisel et al. did show a reduction in illness-related decrements in work performance in volunteers with experimentally induced sandfly fever. The beneficial effect was even observed when fever and other symptoms were not completely relieved [49] (Table 2). The effect of fever in patients with neurological conditions, such as stroke, is more well-studied. A meta-analysis conducted by Hajat et al. suggested that pyrexia is associated with increased morbidity and mortality in patients with acute stroke [50]. When considering the numerous above-mentioned benefits, it has been postulated that fever reduction may provide some degree of survival benefit. This hypothesis was tested by Bernard et al. in a randomized, double-blind, placebo-controlled trial conducted in 455 septic patients between October 1989 to March 1995 comparing the effects of ibuprofen to that of placebo. The research concluded that ibuprofen administration was associated with a reduction of prostaglandin and thromboxane synthesis and subsequently with reduced fever, oxygen consumption, and lactate production. However, it did not prevent the development of shock or respiratory distress or offer any mortality benefit [30] (Table 2).
Suggested Disadvantages of Fever Reduction
Antipyretics like any other treatment are not completely free from adverse effects. Apart from the myriad of adverse effects mentioned above fever reduction can result in the production of certain less than favorable effects. An example is the interruption of constitutively produced prostaglandins by NSAIDs. This blockade in the production of endogenous mediators can have detrimental effects on various organ systems. In a study done by Friedman et al., indomethacin administration to patients with coronary artery disease was associated with an increase in coronary vascular resistance and a decrease in coronary blood flow. This effect was likely related to the decreased synthesis of vasodilatory prostaglandins [51] (Table 3). Hence, a cautious approach is needed when prescribing these agents in patients with underlying coronary artery disease. One major drawback of fever reduction is the theoretical risk of blunting an organism's natural immune response. Mitigation of this protective, natural response thus has been postulated to prolong illness. Evidence supporting this was seen in the randomized, double-blind, placebo-controlled trial conducted by Doran et al., which studied the effects of acetaminophen on childhood varicella. The study enrolled children between the ages of one and 12 years who had chickenpox and randomized them to receive either acetaminophen (n = 37) or placebo (n = 31), and symptoms, such as pruritis, appetite, activity, and overall condition were measured along with time to eruption of last vesicle, time to scabbing of all lesions, and time to total healing. One child was withdrawn and three did not complete the study. It was seen that the time to total scabbing and pruritis were better in placebo when compared with the active treatment. Thus, it was concluded that acetaminophen plays no significant role in the alleviation of symptoms in children with varicella and may prolong illness duration [52] (Table 3).
This tendency of fever control in prolonging the duration of self-limited illness is also seen in other studies. In a double-blind, placebo-controlled trial conducted by Graham et al., the effect of commonly used over-the-counter analgesic/antipyretics on virus shedding, immunological response, and clinical status of 60 healthy volunteers challenged intranasally with rhinovirus type 2. The participants were randomized to receive aspirin, acetaminophen, ibuprofen, or placebo. Fifty-six were infected and showed evidence of viral shedding. Subsequently, viral shedding, immunoglobulin levels, symptoms and signs, and white blood cell counts were carefully monitored. It was surprisingly seen that aspirin and acetaminophen were associated with statistically significant suppression of serum-neutralizing immunoglobulins and increased nasal signs and symptoms. No statistically significant difference was seen in viral shedding among the groups, but there was a trend toward longer viral shedding with acetaminophen and aspirin use [53] (Table 3).
A similar prolongation of illness associated with the use of antipyretics was also seen in a retrospective observational study conducted by Plaisance et al., which evaluated the effects of antipyretics on experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. The participants comprised of individuals with experimentally induced influenza A (n = 54), S. sonnei (n = 45), and R. rickettsii (n=21) infections. Acetaminophen or aspirin was offered for symptomatic relief. Multivariate analysis revealed prolongation of illness associated with the use of antipyretics in individuals with influenza A and S. sonnei infections but not with R. rickettsii infections [54] (Table 3).
Some studies even suggest that antipyretics may be harmful in select groups of patients and may be related to increased mortality. A multi-center, prospective observational study conducted by Lee et al. studied the effect of fever and antipyretics on mortality in 1,425 adult critically ill patients (without neurological injury) with and without sepsis. Individuals who required intensive care of at least 48 hours were included in the study. It was found that NSAID or acetaminophen use was independently associated with increased 28-day mortality in septic patients but not in non-septic patients [55] (Table 3).
A similar increase in mortality in septic patients treated with antipyretics was also seen by Ye et al. in critically ill patients with sepsis and requiring mechanical ventilation (n = 8711) [56] (Table 3).
Limitations
Our review was limited to the studies indexed in the PubMed database. Another limitation was the lack of recent randomized controlled trials evaluating the efficacy of antipyretics in noncritically ill patients. These shortcomings are in addition to the inherent limitations of narrative review, such as lack of completeness of literature review, potential bias in interpretation, and objectivity.
Conclusions
Several pharmacological and nonpharmacological agents are available to combat fever. The numerous pharmacological agents usually have comparative efficacy and tolerability, and the choice of agent usually depends on the patient profile. When oral tolerability is poor or rapid relief is required, parenteral formulation of antipyretic agents should be considered. The patient’s age, comorbid conditions, nutritional status, and concurrent medication use must be considered when prescribing antipyretics. The selective toxicity profile of various pharmacological agents can also guide prescription.
Whether any meaningful benefit is gained from the administration of antipyretics is still questionable. Prompt alleviation of patient discomfort may be an important therapeutic target for both clinicians and patients. Whether pursuing this therapeutic target comes at the cost of relative immunosuppression and prolongation of illness is not known. Antipyretic administration has not been shown to provide any major morbidity or mortality benefit and may cause more harm than good in septic patients. Stroke is an area where temperature control is has shown to produce favorable outcomes. Whether this neuroprotection translates to noncritical patients is an area that needs further clarification. Finally, no agent is universally free from adverse events. All antipyretics can cause serious toxicities though the spectrum of organ involvement varies according to the class of antipyretics used.
Our review shows that the perceived beneficial effects of antipyretics may be overstated and their use excessive. Unnecessary drug administration may be causing more harm than good and restrictive use may reduce healthcare costs and decrease the risk of complications. Antipyretic administration like all medical interventions should be carefully weighted. Their risks and benefits are considered. Further studies are needed to determine if no intervention is an acceptable option for noncritically ill febrile patients.
1. 人體的溫度受到下視丘的體溫調節中心(hypothalamic setpoint )控制. 每個人的體溫會有差異. 下視丘的設定體溫受到血中各種發熱因子影響.
2. 假設你的下視丘將體溫設定為36度. 當身體溫度超過36度. 會感覺到熱. 這時候身體需要減少產熱及增加散熱. 於是開始流汗. 當你的體溫因病毒感染的影響. 下視丘將體溫設定在 39 度. 若你當前體溫只有36度. 此時會感覺到冷. 於是身體開始寒顫發抖(chills). 發抖是肌肉不受控制的收縮引起. 肌肉收縮會產熱. 當你的體溫到達39度. 身體就不再感覺冷. 這時候寒顫也消失了.
發燒前的寒顫通常約 30-60 分鐘. 取決於你身體能多快產生足夠熱量. 也取決於下視丘設定的溫度多高.
3. 有些物質會影響下視丘的體溫設定. 造成發燒. 這些物質稱為發熱因子,
下面是關於發燒的生理病理學
Antipyretic Use in Noncritically Ill Patients With Fever: A Review
發熱的病理生理基礎
發燒是一種適應性反應，由於下視丘生理體溫設定點的改變而導致體溫升高[ 16 ]。這種改變是由多種發炎介質在終板血管器中促進前列腺素合成所致。這些介質包括細胞因子，例如腫瘤壞死因子（TNF）、白細胞介素（IL）-6 和 IL-1，它們本身可響應外源性致熱原而產生。此外，有證據表明，局部細胞激素產生和其他神經激素機制可能是下丘腦體溫設定點改變的原因[ 17 ]。體溫設定點的改變隨後會引發身體反應，使核心體溫升高。這些反應，如同許多其他協調的生物過程一樣，由下視丘協調控制[ 18 ]。發熱反應的基本步驟如下圖所示（圖1）。
發燒已被證實對微生物增生具有抑製作用，並能增強內源性免疫反應。這種增強作用貫穿先天性和適應性免疫反應的各個階段。嗜中性球的募集、釋放和活性增加，自然殺手 (NK) 細胞的細胞毒活性增強，巨噬細胞和樹突狀細胞的吞噬活性受到刺激，以及淋巴細胞遷移增加，都是發燒調節免疫反應的途徑[ 2 , 19 ]。這些發熱引起的改變有助於控制和清除致病病原體。儘管從演化角度來看，發熱似乎是個有利因素，但它對人體卻有許多有害影響。代謝需求增加、分鐘通氣量增加、心血管和神經系統壓力都是發燒的有害影響[ 20 , 21 ]。儘管發燒普遍存在，但其治療方法仍有爭議。發燒往往會為患者和臨床醫師帶來不適。
發燒患者退燒藥物的選擇
數百年來，緩解發燒一直是常見的治療目標[ 22 ]。其治療原理在於減輕患者不適，並緩解發燒引起的代謝需求增加和缺氧性神經損傷風險[ 3,4 ] 。目前有多種藥物和非藥物治療方案可用於退燒[23]。常用的藥物包括對乙醯氨基酚和非類固醇抗發炎藥（ NSAIDs），例如布洛芬、水楊酸鹽以及新型COX-2抑制劑，如塞來昔布和羅非昔布。各種退燒藥物最可能的機轉是抑制下視丘中前列腺素E2的合成[ 24 ]。
由於不同研究中報告的製劑、給藥途徑和療效指標各不相同，因此無法對各種退燒藥的相對效力進行全面分析[ 21 ]。儘管如此，一些兒童研究發現，口服布洛芬的退燒效力強於口服對乙醯氨基酚，但差異較小[ 25-27]。另一項研究也表明，其他非類固醇抗發炎藥，如尼美舒利和酮洛芬，對兒科患者也有效[28 ]。因此，對於兒童，口服布洛芬可作為控制發燒的首選藥物。
非類固醇抗發炎藥（NSAIDs）也可有效用於成人發燒管理。 Michie 等人的研究表明，預先服用布洛芬可減輕內毒素刺激志願者體內細胞因子（如腫瘤壞死因子α）升高引起的症狀[ 29 ]。 Bernard 等人進行的另一項隨機、雙盲、安慰劑對照試驗也強調了布洛芬在減輕發燒全身效應方面的有效性。研究於 1989 年 10 月至 1995 年 3 月期間進行，納入 455 例敗血症患者，比較了靜脈注射布洛芬（每次 10 mg/kg，最大劑量 800 mg，每 8 小時一次，共 6 次）與安慰劑的療效。研究發現，布洛芬治療組患者的尿液中前列環素和血栓素 A2 水平顯著降低，同時體溫、心率、耗氧量和乳酸水平也均有所下降。然而，並未報告休克、急性呼吸窘迫症候群或死亡率有顯著降低[ 30 ]。
Vargas 等人對內毒素激發的志願者進行了一項研究，比較了口服對乙醯氨基酚和肌注酮咯酸的療效。這項雙盲、雙模擬、平行研究表明，酮洛酸劑量增加與更高的退燒效果相關，30 mg 肌注酮洛酸與 650 mg 口服對乙醯氨基酚的療效相當[ 31 ]。 Reiner 等人進行的一項雙盲試驗進一步強調了各種退燒藥物的療效差異，該試驗比較了尼美舒利、雙氯芬酸和安慰劑的療效。結果表明，尼美舒利栓劑在退燒和改善發燒體徵（脈搏和血壓）方面與雙氯芬酸栓劑療效相當，且均優於安慰劑[ 32 ]。
數據表明，多種退燒藥物均能有效降低體溫，因此應根據患者的具體情況選擇合適的藥物。不同退燒藥的毒性特徵各異，這在藥物選擇中起著至關重要的作用。
水楊酸鹽類藥物，例如阿斯匹靈，與兒童雷氏症候群的發生有關[ 33 ]。這種罕見但災難性的兒童疾病是由於肝臟粒線體氧化磷酸化受到抑制，進而導致肝衰竭和腦病變[ 34 ]。非類固醇抗發炎藥（NSAIDs）具有多種不良反應，幾乎可以影響所有器官系統（表1）。
非類固醇抗發炎藥（NSAIDs）引起的腎臟和胃腸道毒性是由於其抑制氧合酶（COX）同工酶所致[ 35 ]。研究發現，非選擇性抑制COX酶的藥物比選擇性抑制COX-2酶同工酶的藥物更容易引起胃腸道毒性[ 36 ]。其他重要因素，例如年齡超過60歲、既往有胃腸道疾病史、長期使用NSAIDs以及同時服用其他具有胃腸道毒性的藥物（如皮質類固醇），也會增加胃腸道毒性的風險[ 37 ]。羅非昔布等藥物選擇性抑制COX-2同功酶，可能透過促進血栓形成環境，增加心血管不良反應（如心肌梗塞和中風）的風險[ 38 ]。非類固醇抗發炎藥物是最常見的與腎毒性相關的藥物之一，其作用範圍從間質性腎炎到急性或慢性腎衰竭[ 39 ]。先前患有腎臟疾病的個體以及使用腎毒性藥物的個體發生腎功能障礙的風險增加[ 40 ]。
與非類固醇抗發炎藥（NSAIDs）不同，對乙醯氨基酚對環氧合酶（COX）的活性很低，因此其胃腸道和腎臟毒性也極小[ 36 ]。然而，它會代謝成一種潛在的肝毒性中間體，即N-乙醯對苯醌亞胺（NAPQI）[ 41 ]。穀胱甘肽儲備不足的個體，例如長期飲酒和飢餓者，其毒性風險會增加[ 42 ]。因此，退燒藥的選擇取決於患者的人口統計學特徵、既往病史以及正在服用的其他藥物。為了最大限度地降低全身毒性，必須盡可能縮短所選退燒藥的療程，並使用最低有效劑量。
發燒的利弊
控制身體對發炎的生理反應是否能帶來任何可量化的益處尚存爭議。與任何治療方式一樣，發燒及其控制的風險和益處應進行合理的權衡（圖2）。
退燒的建議優勢
發燒會為患者帶來明顯的不適，緩解患者不適是處方退燒藥的重要原因。改善患者的健康狀況是發燒患者治療的重要原則。煩躁發燒的兒童在服用退燒藥後症狀會迅速改善[ 44 ]。 Ipp等人進行的一項隨機臨床試驗證實了此效果。該試驗研究了383名2至6個月大的嬰兒和70名18個月大的兒童在接種白喉-百日咳-破傷風-脊髓灰質炎聯合疫苗後不良反應的發生頻率和嚴重程度。研究表明，與安慰劑組相比，2至6個月大的嬰兒服用對乙醯氨基酚後局部和全身不良反應的發生率較低，發燒發生率也較低，行為改變也較少。然而，在18個月大的嬰兒中未觀察到這種效果。結論是，在接種白喉-百日咳-破傷風類毒素-小兒麻痺疫苗時，使用對乙醯氨基酚可降低常見不良反應的發生頻率[ 45 ]（表2）。
Chiappini 等人進行的另一項單中心前瞻性觀察研究納入了 172 名因發燒入院的兒科急診患兒，結果顯示對乙醯氨基酚在緩解發燒和不適方面具有有益作用。研究分析了對乙醯氨基酚對發燒和不適（以半定量李克特量表定義）的影響，發現與基線相比，口服對乙醯氨基酚治療的兒童在 60 分鐘時體溫和不適程度均顯著降低 [ 46 ]（表2）。
Oborilová 等人在一項非隨機開放標籤的初步研究中也報告了這種緩解不適的有益效果。該研究比較了三種退燒藥物對多種主要為血液腫瘤患者的療效。共納入 254 例發燒（腋溫至少 38°C），分別以雙氯芬酸（75 mg，短暫靜脈輸注）、甲胺基比林（2500 mg 或 1000 mg，短暫靜脈輸注）或丙帕他莫（2000 mg 或 1000 mg，緩慢靜脈注射或短暫注射治療。記錄腋溫變化、不適改善情況和不良反應。結果顯示，所有退燒藥物均能降低體溫並改善患者不適（87% 的患者表示舒適度有所提高）。然而，各組之間的療效、耐受性和不良事件發生率存在差異。結論認為，退燒藥是緩解不適的有效治療選擇[ 47 ]（表2）。
發燒會藉由增加心肺頻率和耗氧量，導致身體代謝負擔加重。降低體溫被認為是對抗身體代表負擔的重要治療標靶。 Manthous 等人的一項研究強調了這一作用，該研究分析了降溫對發燒危重患者耗氧量的影響。研究表明，當體溫從 39.4 ± 0.8°C 降至 37.0 ± 0.5°C 時，12 例發燒機械通氣患者的耗氧量、二氧化碳生成量和能量消耗均顯著降低 [ 3 ]（表2）。
高燒與認知功能障礙和腦損傷有關。 Reichenberg 等人進行的一項雙盲交叉研究證實了這種對神經功能的不良影響。研究納入 20 名健康男性志願者，分別靜脈注射馬流產沙門氏菌內毒素（0.8 ng/kg）和生理食鹽水。結果顯示，內毒素暴露與核心體溫升高（0.5°C）以及語言和非語言記憶功能下降有關。內毒素暴露也與焦慮程度和憂鬱情緒的短暫但顯著升高有關[ 48 ]（表2）。可惜的是，研究並未檢視退燒藥預防這些神經心理失調的能力。 Beisel 等人進行的另一項研究表明，在實驗誘發白蛉熱的志願者中，退燒藥可以減輕疾病相關的工作表現下降。即使發燒和其他症狀尚未完全緩解，也能觀察到這種有益效果[ 49 ]（表2）。發燒對神經系統疾病（例如中風）患者的影響已被較為深入的研究。 Hajat 等人進行的一項薈萃分析表明，發燒與急性中風患者的發病率和死亡率增加有關[ 50 ]。考慮到上述許多益處，有人推測退燒可能在一定程度上提高存活率。 Bernard 等人於 1989 年 10 月至 1995 年 3 月期間，在 455 例膿毒症患者中開展了一項隨機、雙盲、安慰劑對照試驗，比較了布洛芬與安慰劑的療效，以此驗證了這一假設。研究結果表明，布洛芬給藥可降低前列腺素和血栓素的合成，進而降低發燒、耗氧量和乳酸生成。然而，布洛芬並未預防休克或呼吸窘迫的發生，也未降低死亡率[ 30 ]（表2）。
退燒的潛在缺點
與其他任何治療方法一樣，退燒藥並非完全沒有副作用。除了上述諸多副作用外，退燒還可能導致一些不利影響。例如，非類固醇抗發炎藥（NSAIDs）會抑制體內前列腺素的合成。這種內源性介質生成的阻斷會對多個器官系統造成損害。 Friedman 等人的研究表明，對冠狀動脈疾病患者使用吲哚美辛會導致冠狀動脈血管阻力增加和冠狀動脈血流量減少。這種影響可能與血管舒張性前列腺素合成減少有關[ 51 ]（表3）。因此，在對患有冠狀動脈疾病的患者使用此類藥物時，需要謹慎。退燒的一個主要缺點是理論上有抑制身體自體免疫反應的風險。這種保護性免疫反應的減弱被認為會延長病程。 Doran 等人進行的一項隨機、雙盲、安慰劑對照試驗提供了支持這一觀點的證據。該試驗研究了對乙醯氨基酚對兒童水痘的影響。研究納入了 1 至 12 歲患有水痘的兒童，並將他們隨機分為兩組，分別接受對乙醯氨基酚（n = 37）或安慰劑（n = 31）治療。研究人員測量了搔癢、食慾、活動和整體狀況等症狀，以及最後一個水皰出現的時間、所有皮損結痂的時間和完全癒合的時間。一名兒童退出研究，三名兒童未完成研究。結果顯示，與活性治療組相比，安慰劑組的完全結痂時間和搔癢症狀均有所改善。因此，研究得出結論：對乙醯氨基酚在緩解兒童水痘症狀方面沒有顯著作用，反而可能延長病程[ 52 ]（表3）。
這種透過控制發燒來延長自限性疾病病程的趨勢在其他研究中也有發現。 Graham 等人進行了一項雙盲、安慰劑對照試驗，研究常用非處方鎮痛/退燒藥對60名健康志願者鼻內感染2型鼻病毒後病毒脫落、免疫反應和臨床狀況的影響。受試者被隨機分配接受阿斯匹靈、對乙醯氨基酚、布洛芬或安慰劑治療。其中56名受試者感染並出現病毒脫落。隨後，研究人員密切監測了病毒脫落、免疫球蛋白水平、症狀和體徵以及白血球計數。令人驚訝的是，研究發現阿斯匹靈和對乙醯氨基酚與血清中和免疫球蛋白的顯著抑制以及鼻部症狀的加重有關。各組之間的病毒脫落沒有統計學上的顯著差異，但服用對乙醯氨基酚和阿斯匹靈有延長病毒脫落時間的趨勢[ 53 ]（表3）。
Plaisance 等人進行的回顧性觀察研究也觀察到了類似的與使用退燒藥相關的疾病延長現象。研究評估了退燒藥對實驗性甲型流感、宋內氏志賀菌和立克次體感染的影響。研究對象包括實驗性甲型流感（n = 54）、宋內氏志賀菌（n = 45）和立克次體（n = 21）感染者。研究人員給予對乙醯氨基酚或阿斯匹靈以緩解症狀。多因子分析顯示，甲型流感和宋內氏志賀菌感染者使用退燒藥會延長疾病持續時間，而立克次體感染者則不會[ 54 ]（表3）。
一些研究甚至表明，退燒藥可能對特定患者群體有害，並可能與死亡率升高有關。 Lee 等人進行的一項多中心前瞻性觀察研究，探討了發燒和退燒藥對 1425 例成年危重患者（無神經系統損傷）死亡率的影響，這些患者包括膿毒症患者和非膿毒症患者。研究納入了至少需要 48 小時重症監護的患者。研究發現，非類固醇抗發炎藥 (NSAID) 或對乙醯氨基酚的使用與敗血症患者 28 天死亡率升高獨立相關，但在非敗血症患者中未觀察到這種關聯 [ 55 ]（表3）。
Ye 等人也觀察到，在接受退燒藥治療的膿毒症患者中，死亡率出現了類似的增加，該研究對象為患有膿毒症且需要機械通氣的危重患者（n = 8711）[ 56 ]（表3）。
結論
目前有多種藥物和非藥物方法可用於退燒。各種藥物的療效和耐受性通常相近，藥物的選擇通常取決於患者的特定情況。當口服耐受性差或需要快速緩解發燒時，應考慮使用注射劑型的退燒藥。處方退燒藥時，必須考慮患者的年齡、共病、營養狀況、其他正在服用的藥物。各種藥物的選擇性毒性特徵也可作為處方指導。
使用退燒藥是否能帶來任何實質益處仍存疑。迅速緩解患者不適感可能是臨床醫師和患者的重要治療目標。然而，追求這一治療目標是否會以相對免疫抑制和延長病程為代價，目前尚不清楚。退燒藥的使用並未顯示出能顯著降低發病率或死亡率，且在敗血症患者中可能弊大於利。在中風領域，體溫控制已被證明能帶來良好的預後。這種神經保護作用是否適用於非重症患者，還需要進一步釐清。最後，沒有任何一種藥物可以完全避免不良反應。所有退燒藥都可能引起嚴重的毒性反應，但不同類別的退燒藥所涉及的器官範圍有所不同。
我們的研究表明，退燒藥的益處可能被過度誇大，其使用也可能過度。不必要的用藥可能弊大於利，限制用藥或許可以降低醫療成本並減少併發症風險。與所有醫療幹預措施一樣，退燒藥的使用也應仔細權衡利弊，並考慮其風險和益處。還需要進一步的研究來確定，對於非危重發燒患者，不進行任何干預是否也是可接受的選擇。
Introduction and background
Fever or pyrexia is caused by an increased hypothalamic thermoregulatory setpoint due to several infectious and non-infectious causes. The various inciting agents cause a release of endogenous or exogenous pyrogens (fever-producing agents) that act on the neurological system to instigate a prostaglandin-mediated alteration in the temperature setpoint [1]. An increase in body temperature offers numerous physiological advantages in times of stress or infection possibly due to changes in the host immune system [2]. The same adaptive response can also prove detrimental by increasing the body’s metabolic demand, oxygen consumption, minute ventilation, and contributing to adverse neurological outcomes [3-5]. Several pharmacological and non-pharmacological treatment modalities are available for mitigating fever.
Drugs, such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase 2 (COX-2) inhibitors, and physical therapies, such as cooling blankets and immersion, are commonly used in febrile individuals to achieve temperature reduction [6-8]. Despite fever being a ubiquitous symptom, the evidence surrounding the selection of an appropriate antipyretic regimen, dosing, route of administration, and drug choice is limited [9]. Some studies even suggest that antipyretic use in infectious etiologies has detrimental outcomes. This may be due to the loss of microbial suppressive effects of fever [10,11]. This premise is supported by the theoretical risk of relative immunosuppression caused by normothermia [12]. Furthermore, antipyretics can also have prominent hemodynamic side effects and can contribute to renal and hepatic dysfunction [13-15]. Selective toxicities of the available antipyretics may limit their use in specific patients. The data on the usage of antipyretics for controlling temperature are limited when considering noncritical patients. There are no clear-cut guidelines or recommendations specifying the choice of a particular agent, the route of administration, or data on comparative safety and efficacy.
This literature review aimed to analyze the various available modalities of temperature control and their relative safety and efficacy. The review also investigated factors that may help direct the selection of a particular agent. Finally, the advantages and disadvantages of fever control and toxicities of the antipyretics were evaluated.
Review
Pathophysiological basis of fever
Fever is an adaptive response that results in increased body temperature secondary to an alteration in the physiological temperature setpoint in the hypothalamus [16]. This alteration is caused by increased prostaglandin synthesis in the organum vasculosum of lamina terminalis by numerous inflammatory mediators. Some of these mediators include cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1, which can be themselves produced in response to exogenous pyrogens. Furthermore, there is evidence that local cytokine production and other neurohormonal mechanisms may be responsible for alteration in the hypothalamic setpoint [17]. Alteration of the setpoint then leads to bodily responses that raise the core body temperature. These responses, like many other coordinated biological processes, are coordinated in the hypothalamus [18]. The basic steps involved in the generation of febrile response are illustrated below (Figure 1).
Pyrexia has been shown to have an inhibitory effect on microorganism proliferation and amplifies the endogenous immunological response. This amplification is seen throughout the innate and adaptive immune response. Increased neutrophilic recruitment, release, and activity, enhanced natural killer (NK) cell cytolytic activity, stimulation of phagocytic activity of macrophages and dendritic cells, and increased lymphocytic trafficking are some of the ways fever modulates the immune response [2,19]. These pyrexia-induced alterations aid in controlling and eliminating the offending infectious agent. Although seemingly advantageous from an evolutionary point of view, fever has numerous deleterious consequences on the human body. Increased metabolic demand, increased minute ventilation, and cardiovascular and neurological stresses are some of the harmful effects of fever [20,21]. Despite its ubiquitous nature, the management of pyrexia remains controversial. Fever tends to be a source of discomfort both for the patient and the clinician.
Choice of Antipyretic Agent in Febrile Patients
Alleviation of fever has been a common therapeutic target for hundreds of years [22]. The therapeutic rationale behind this is to reduce patient discomfort and mitigate the effects of increased metabolic demand and risk of hypoxic neurological injury that can be caused by fever [3,4]. Numerous pharmacological and non-pharmacological treatment options are available for antipyresis [23]. Common pharmacological agents include acetaminophen and NSAIDs, such as ibuprofen, salicylates, and novel COX-2 inhibitors, such as celecoxib and rofecoxib. The most likely mechanism behind the various antipyretics is the inhibition of prostaglandin E2 synthesis in the hypothalamus [24].
A comprehensive analysis of data on the relative potencies of various antipyretic drugs is not possible due to differing formulations, routes of administration, and measures of efficacy reported in various studies [21]. Nevertheless, several studies in children have found that oral ibuprofen is a more potent antipyretic than oral acetaminophen though the difference is small [25-27]. Another study also showed that other NSAIDs, such as nimesulide and ketoprofen, were also useful antiinflammatory agents in pediatric patients [28]. In children, therefore, oral ibuprofen can be considered initially for fever control.
NSAIDs can also be used effectively for fever management in adults. A study conducted by Michie et al. demonstrated that pretreatment with ibuprofen blunted the symptoms resulting from an increase in cytokines, such as tumor necrosis alpha in endotoxin-challenged volunteers [29]. Another randomized, double-blind, placebo-controlled trial conducted by Bernard et al. highlighted the effectiveness of ibuprofen in reducing the systemic effects of fever. This study conducted between October 1989 and March 1995 on 455 patients who presented with sepsis compared the effect of intravenous ibuprofen (10 mg/kg per dose, maximum dose 800 mg, given every eight hours for six doses) with that of placebo. The study found a significant reduction in urinary levels of prostacyclin and thromboxane A2, along with reductions in temperature, heart rate, oxygen consumption, and lactate levels in patients treated with ibuprofen. However, no significant reduction in the development of shock, acute respiratory distress syndrome, or mortality was reported [30].
Another study conducted by Vargas et al. in endotoxin-challenged volunteers compared the efficacy of oral acetaminophen and intramuscular ketorolac. This double-blind, double-dummy, parallel study showed that increasing doses of ketorolac are associated with a higher antipyretic effect and comparative efficacy was seen between 30 mg intramuscular ketorolac and 650 mg oral acetaminophen [31]. This comparative efficacy of the various antipyretics was further highlighted in the double-blind trial conducted by Reiner et al., which compared the efficacy of nimesulide with that of diclofenac and placebo. It was seen that nimesulide suppositories were as effective as diclofenac suppositories in the reduction of fever and mitigation of objective signs of fever (pulse and blood pressure), and both were superior to placebo [32].
The data suggest that various antipyretic agents are effective in temperature reduction, and thus the choice of agent used should be determined by the individual patient profile. The several antipyretic groups have varying toxicity profile that plays a crucial role in the selection of a particular agent.
Salicylates, such as aspirin, have been linked with the development of Reye’s syndrome in children [33]. This rare but catastrophic childhood disorder results from the inhibition of hepatic mitochondrial oxidative phosphorylation and subsequent development of hepatic failure and encephalopathy [34]. NSAIDs have a myriad of adverse effects involving almost any organ system (Table 1).
Renal and gastrointestinal toxicity from NSAIDs results from the inhibition of COX isoforms [35]. Agents with nonselective inhibition of COX enzymes have been found to cause greater gastrointestinal toxicities than agents that selectively inhibit COX-2 enzyme isoforms [36]. Other important factors, such as age of more than 60 years, presence of previous gastrointestinal disorder, prolonged duration of NSAID use, and concomitant intake of other agents with gastrointestinal toxicity, such as corticosteroids, also increase the risk of gastrointestinal toxicity [37]. Drugs, such as rofecoxib, selectively inhibit COX-2 isoforms, which are associated with a higher likelihood of cardiovascular adverse effects, such as myocardial infarction and stroke possibly by promoting a more thrombogenic environment [38]. NSAIDs are one of the most common agents associated with renal toxicity with effects, ranging from interstitial nephritis to acute or chronic renal failure [39]. Individuals with preexisting renal disease and those using nephrotoxic agents are at an increased risk of developing renal dysfunction [40].
Unlike NSAIDs, acetaminophen has little activity against COX enzymes and thus has minimal gastrointestinal and renal toxicity [36]. It is however metabolized to a potentially hepatotoxic intermediate known as N-acetyl-p-benzoquinoneimine (NAPQI) [41]. The risk of toxicity increases in individuals with depleted glutathione reserves, e.g., chronic ethanol ingestion and starvation. [42]. Thus, the choice of antipyretic agent depends on the patient's demographic, preexisting medical conditions, and concurrent medication usage. It is of utmost importance to administer the selected antipyretic for the shortest duration and at the lowest effective dose to limit systemic toxicity.
Pros and Cons of Fever
Whether control of the body’s physiological response of the body to inflammation offers any quantifiable benefit is debatable. Like any treatment modality, the risks and benefits of fever and its control should be sensibly considered (Figure 2).
Suggested Advantages of Fever Control
Pyrexia can cause significant discomfort in a febrile patient and relieving patient discomfort is an important reason for prescribing antipyretics. Improving patient well-being is an important therapeutic rationale in febrile individuals. Children who are irritable and pyretic show prompt improvement after the administration of an antipyretic agent [44]. This effect was demonstrated in a randomized clinical trial conducted by Ipp et al., in which 383 infants aged two to six months and 70 children aged 18 months were studied for frequency and severity of adverse reactions following administration of diphtheria-pertussis-tetanus toxoids-polio vaccine. The study showed that acetaminophen-treated infants between the ages of two to six months had a lower incidence of local and systemic effects, a lower incidence of fever, and a reduction in behavioral changes compared to placebo. However, this effect was not seen in infants aged 18 months. It was concluded that acetaminophen use reduced the frequency of common adverse effects at the time of administration of primary vaccination with diphtheria-pertussis-tetanus toxoids-polio [45] (Table 2).
Another single-center prospective observational study conducted by Chiappini et al. in 172 febrile children who were admitted to a pediatric emergency department showed the beneficial effects of acetaminophen in alleviating fever and discomfort. This study analyzed the effect of acetaminophen on fever and discomfort (defined using a semiquantitative Likert scale) and found significant reductions in both body temperature and levels of discomfort at 60 minutes when compared to baseline in children treated with oral paracetamol [46] (Table 2).
This beneficial effect on discomfort relief was also reported by Oborilová et al. in their non-randomized open-label pilot study comparing the effects of three antipyretics agents in various mainly hemato-oncological patients. A total of 254 episodes of fever (axillary temperature of at least 38°C) were treated with either diclofenac (75 mg, brief intravenous (IV) infusion) or metamizol (2500 mg or 1000 mg, brief IV infusion) or propacetamol (2000 mg or 1000 mg, slow IV injection or brief IV infusion). Changes in axillary temperature, improvement in discomfort, and adverse effects were recorded. It was observed that all antipyretics were associated with a reduction in temperature and improvement in patient discomfort (87% of patients declared improvement in comfort). However, efficacy, tolerability, and occurrences of adverse events differed between the groups. It was concluded that antipyretics provide a useful therapeutic option for the alleviation of discomfort [47] (Table 2).
Pyrexia is associated with increased metabolic strain on the body via increased cardio-respiratory rate and oxygen consumption. Lowering temperature has been suggested as an important therapeutic target to counteract the metabolic strain on the body. This effect was highlighted in a study conducted by Manthous et al., which analyzed the effect of cooling on oxygen consumption in febrile critically ill patients. This study showed that cooling resulted in a statistically significant reduction in oxygen consumption, carbon dioxide production, and energy expenditure in 12 febrile, mechanically ventilated patients when the temperature was reduced from 39.4 +/- 0.8°C to 37.0 +/- 0.5°C [3] (Table 2).
High fever has been linked to cognitive dysfunction and brain damage. This adverse effect on neurological function was demonstrated in a double-blind, crossover study conducted by Reichenberg et al. in 20 healthy male volunteers exposed to intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) while compared to saline. The study showed that endotoxin exposure was associated with a rise in core body temperature (0.5°C) and depressed verbal and non-verbal memory functions. Endotoxin exposure was also associated with a transient but significant increase in anxiety levels and depressed mood [48] (Table 2). Unfortunately, this study did not examine the ability of antipyretics to prevent these neuropsychological disturbances. Another study conducted by Beisel et al. did show a reduction in illness-related decrements in work performance in volunteers with experimentally induced sandfly fever. The beneficial effect was even observed when fever and other symptoms were not completely relieved [49] (Table 2). The effect of fever in patients with neurological conditions, such as stroke, is more well-studied. A meta-analysis conducted by Hajat et al. suggested that pyrexia is associated with increased morbidity and mortality in patients with acute stroke [50]. When considering the numerous above-mentioned benefits, it has been postulated that fever reduction may provide some degree of survival benefit. This hypothesis was tested by Bernard et al. in a randomized, double-blind, placebo-controlled trial conducted in 455 septic patients between October 1989 to March 1995 comparing the effects of ibuprofen to that of placebo. The research concluded that ibuprofen administration was associated with a reduction of prostaglandin and thromboxane synthesis and subsequently with reduced fever, oxygen consumption, and lactate production. However, it did not prevent the development of shock or respiratory distress or offer any mortality benefit [30] (Table 2).
Suggested Disadvantages of Fever Reduction
Antipyretics like any other treatment are not completely free from adverse effects. Apart from the myriad of adverse effects mentioned above fever reduction can result in the production of certain less than favorable effects. An example is the interruption of constitutively produced prostaglandins by NSAIDs. This blockade in the production of endogenous mediators can have detrimental effects on various organ systems. In a study done by Friedman et al., indomethacin administration to patients with coronary artery disease was associated with an increase in coronary vascular resistance and a decrease in coronary blood flow. This effect was likely related to the decreased synthesis of vasodilatory prostaglandins [51] (Table 3). Hence, a cautious approach is needed when prescribing these agents in patients with underlying coronary artery disease. One major drawback of fever reduction is the theoretical risk of blunting an organism's natural immune response. Mitigation of this protective, natural response thus has been postulated to prolong illness. Evidence supporting this was seen in the randomized, double-blind, placebo-controlled trial conducted by Doran et al., which studied the effects of acetaminophen on childhood varicella. The study enrolled children between the ages of one and 12 years who had chickenpox and randomized them to receive either acetaminophen (n = 37) or placebo (n = 31), and symptoms, such as pruritis, appetite, activity, and overall condition were measured along with time to eruption of last vesicle, time to scabbing of all lesions, and time to total healing. One child was withdrawn and three did not complete the study. It was seen that the time to total scabbing and pruritis were better in placebo when compared with the active treatment. Thus, it was concluded that acetaminophen plays no significant role in the alleviation of symptoms in children with varicella and may prolong illness duration [52] (Table 3).
This tendency of fever control in prolonging the duration of self-limited illness is also seen in other studies. In a double-blind, placebo-controlled trial conducted by Graham et al., the effect of commonly used over-the-counter analgesic/antipyretics on virus shedding, immunological response, and clinical status of 60 healthy volunteers challenged intranasally with rhinovirus type 2. The participants were randomized to receive aspirin, acetaminophen, ibuprofen, or placebo. Fifty-six were infected and showed evidence of viral shedding. Subsequently, viral shedding, immunoglobulin levels, symptoms and signs, and white blood cell counts were carefully monitored. It was surprisingly seen that aspirin and acetaminophen were associated with statistically significant suppression of serum-neutralizing immunoglobulins and increased nasal signs and symptoms. No statistically significant difference was seen in viral shedding among the groups, but there was a trend toward longer viral shedding with acetaminophen and aspirin use [53] (Table 3).
A similar prolongation of illness associated with the use of antipyretics was also seen in a retrospective observational study conducted by Plaisance et al., which evaluated the effects of antipyretics on experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. The participants comprised of individuals with experimentally induced influenza A (n = 54), S. sonnei (n = 45), and R. rickettsii (n=21) infections. Acetaminophen or aspirin was offered for symptomatic relief. Multivariate analysis revealed prolongation of illness associated with the use of antipyretics in individuals with influenza A and S. sonnei infections but not with R. rickettsii infections [54] (Table 3).
Some studies even suggest that antipyretics may be harmful in select groups of patients and may be related to increased mortality. A multi-center, prospective observational study conducted by Lee et al. studied the effect of fever and antipyretics on mortality in 1,425 adult critically ill patients (without neurological injury) with and without sepsis. Individuals who required intensive care of at least 48 hours were included in the study. It was found that NSAID or acetaminophen use was independently associated with increased 28-day mortality in septic patients but not in non-septic patients [55] (Table 3).
A similar increase in mortality in septic patients treated with antipyretics was also seen by Ye et al. in critically ill patients with sepsis and requiring mechanical ventilation (n = 8711) [56] (Table 3).
Limitations
Our review was limited to the studies indexed in the PubMed database. Another limitation was the lack of recent randomized controlled trials evaluating the efficacy of antipyretics in noncritically ill patients. These shortcomings are in addition to the inherent limitations of narrative review, such as lack of completeness of literature review, potential bias in interpretation, and objectivity.
Conclusions
Several pharmacological and nonpharmacological agents are available to combat fever. The numerous pharmacological agents usually have comparative efficacy and tolerability, and the choice of agent usually depends on the patient profile. When oral tolerability is poor or rapid relief is required, parenteral formulation of antipyretic agents should be considered. The patient’s age, comorbid conditions, nutritional status, and concurrent medication use must be considered when prescribing antipyretics. The selective toxicity profile of various pharmacological agents can also guide prescription.
Whether any meaningful benefit is gained from the administration of antipyretics is still questionable. Prompt alleviation of patient discomfort may be an important therapeutic target for both clinicians and patients. Whether pursuing this therapeutic target comes at the cost of relative immunosuppression and prolongation of illness is not known. Antipyretic administration has not been shown to provide any major morbidity or mortality benefit and may cause more harm than good in septic patients. Stroke is an area where temperature control is has shown to produce favorable outcomes. Whether this neuroprotection translates to noncritical patients is an area that needs further clarification. Finally, no agent is universally free from adverse events. All antipyretics can cause serious toxicities though the spectrum of organ involvement varies according to the class of antipyretics used.
Our review shows that the perceived beneficial effects of antipyretics may be overstated and their use excessive. Unnecessary drug administration may be causing more harm than good and restrictive use may reduce healthcare costs and decrease the risk of complications. Antipyretic administration like all medical interventions should be carefully weighted. Their risks and benefits are considered. Further studies are needed to determine if no intervention is an acceptable option for noncritically ill febrile patients.
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