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The Role of Macrophage Inflammatory Protein-2 in the Development of Ventilator-Induced Lung Injury in a Rat Model
No full textRationale: Mechanical ventilation may be responsible not only for worsening the underlying lung injury, but may also lead to
the development of new lung injury, i.e., ventilator-induced lung injury (VILI) as well as systemic inflammatory response
syndrome and multiple organ failure. Objectives: To study the role of macrophage inflammatory protein-2 (MIP-2), a
functional equivalent of interleukin-8 of the chemokine group, in the pathogenesis of VILI, and to investigate the
renin-angiotensin system in the involvement of VILI and possible of regulation of MIP-2 expression in VILI. Methods:
Sprague-Dawley rats were mechanically ventilated for four hours with either low (7 ml/kg) or high (40 ml/kg) tidal volumes.
Histologic studies, measurements of the myeloperoxidase activity and nuclear factor-κ B activity, quantification of the mRNA
as well as protein levels of MIP-2 in the lungs, and assessment of the expression after treatment with captopril, and
angiotensin-converting enzyme inhibitor, were performed. Main Results: In the high-volume group, lung tissue neutrophil
infiltration, activity of nuclear factor -κ B, tumor-necrosis factor-α , and macrophage inflammatory protein-2 were significantly
increased, and survival was significantly reduced. Treatment with captopril attenuated the lung neutrophil infiltration,
tumor-necrosis factor-α , macrophage inflammatory protein-2, and nuclear factor-κ B activity in the high-volume group, with
significant survival benefit. Conclusions: Injurious mechanical ventilation is associated with significantly increased expression
of macrophage inflammatory protein-2 in rat lungs, with prominently increased neutrophil infiltration. Treatment with
angiotensin-converting enzyme inhibitor can attenuate MIP-2 expression and ventilator-induced lung injury in the animal
model
Role of the renin-angiotensin system in the development and treatment of acute respiratory distress syndrome and ventilator-induced lung injury
No full text急性呼吸衰竭(acute respiratory failure)為臨床上甚為常見的嚴重呼吸系統病症，其中包括急性呼吸窘迫症候群(ARDS)。一般而言ARDS的整體死亡率在40%至60%左右，死亡原因大都以敗血性休克或多重器官衰竭為主。由於ARDS的嚴重性相當高，找出其危險因素並藉以避免其發生，應為重要的課題。然而由於ARDS實際發生在這些具有風險因子的病人機率並不是非常高，故推論應該有部份歸因於基因遺傳的影響；因此研究基因的變異性，或許能夠提供重要的機轉訊息，使吾人更為瞭解其發生機制。呼吸器雖然是ARDS治療的重要工具，它可能也會導致肺臟的不良反應，稱之為呼吸器引發肺損傷(ventilator-induced lung injury, VILI)。傷害性的呼吸器設定不但會引發肺損傷，也會造成肺外傷害及全身性的病變，導致多重器官衰竭。因此持續性地研究ARDS的發生機轉，應該會對臨床治療ARDS和其他嚴重的呼吸衰竭有所幫助。
近年，血管張力素(angiotensin)在肺臟發炎以及肺損傷方面的影響也成為學者研究的目標。第二型血管張力素，而後者正是具有許多重要生理功能的分子。第二型血管張力素被認為是生物體內引起發炎反應的一個重要的媒介物，它能活化發炎的步驟，其機轉係經由其第一型(AT1)和第二型(AT2)受體的作用而在細胞內調節並增加促進發炎的細胞激素和化學激素的表現量，啟動並活化NF-kappaB路徑。因此基於以上的文獻證據，吾人可以認為腎素-血管張力素系統在ARDS以及呼吸器引發肺損傷方面可能扮演具有意義的角色，在肺臟發炎以及肺臟功能異常化的過程中可能參與部分任務。
基於以上的認識，吾人進行了以下的研究。第一部份為分析ARDS的臨床表現之回溯性觀察性研究，目的在呈現醫學中心ARDS之臨床特徵。研究結果在30個月間共145名ARDS病人，其平均年齡為58歲(實際年齡區間為1-96歲)，其中男性病人佔較多數(63%)。病人的原有疾病以惡性腫瘤最為常見(36%)，其次為糖尿病(17%)以及中樞神經疾病(10%)。由於ARDS病人氧合能力明顯減低，其PaO2/FIO2的平均數值為86.8±3.8 mmHg，而肺損傷計分(lung injury score)則為2.89 ± 0.4，皆顯示為嚴重的呼吸衰竭；另外病人亦有明顯的發炎現象(平均白血球數量為15556/mmL)。所有病人中，90%接受呼吸器治療，而118人在加護病房使用呼吸器。全部病人中87%出院時死亡，而其中即使大多數病人雖接受積極性的加護病房治療，仍有74%之出院死亡率。另外，共有77名病人(53%)在診斷ARDS的同時即符合敗血症或敗血性休克之診斷，或在ARDS發生後48小時內出現這些診斷。ARDS診斷14天內有109位病人(75%)死亡，而接受呼吸器治療的130位病人中，46人(35%)死於多重器官衰竭，而36人(28%)則死於嚴重呼吸衰竭。在住進加護病房原因是ARDS的72位病人之中，其出院死亡率為82%。在接受積極性的加護病房治療的70病人中，19人(27%)在住進加護病房7天內死亡，而其出院總死亡率為74% (共52位病人)。這52位接受積極治療但終究不治的病人，其最主要的死因是多重器官衰竭(54%)，其次為呼吸衰竭佔23%和敗血性休克(佔17%)。
第二部分為ARDS基因相關性之前瞻性與觀察性之臨床研究。加護病房ARDS病人、具有風險病人，及未具有風險病人進行臨床資料分析以及ACE基因多型性分析(利用聚合酶鍊鎖反應[PCR]方法)。共納入ARDS101位、具有風險病人138位，以及不具有風險210位。ARDS病人平均年齡為60 ± 21歲，具有風險者為71 ± 16歲，而不具有風險者則為57 ± 13歲。ARDS的男女各為68和33人，「具有風險」者各為86和52人，而「不具有風險」者則各為146和64人。在基因型分析與對偶基因型頻率分析結果方面，顯示每一組的ACE基因型(II, ID, DD)分佈皆未明顯地偏離Hardy-Weinberg平衡，而三組群體的D型對偶基因所佔有的比例皆在0.3以下。比較三組群體的基因型(II, ID, DD)以及對偶基因型分佈(I及D)，顯示ARDS病人、「具有風險」病人，以及「不具有風險」病人這三組群體之間，沒有出現顯著的差異。在ARDS的一組中，若將病人依照基因型再分為II、ID、DD三組，則其性別(II、ID、DD之男性分別佔68%，68%與67%；p=0.87)、年齡(II、ID、DD分別為59 ± 22歲，60 ± 22歲和63 ± 17歲；p=0.995)以及原有慢性疾病等的分佈皆無顯著差異；三組基因型病人的急性呼吸窘迫症候群發生主要危險因子中，社區性肺炎所佔比例 (II、ID、DD分別佔59%，45%與56%；p=0.427)、APACHE II計分(II、ID、DD分別為21 ± 7，23 ± 8與19 ± 6；p=0.16)與肺損傷計分(II、ID、DD分別為3.1 ± 0.6，3.1 ± 0.4與3.2 ± 0.4；p=0.96)亦均未出現顯著差異。在結果方面本研究101位ARDS病人28天內的死亡率為54%，然而不同基因型之間的死亡率卻出現顯著的差異：II基因型為42%，ID為65%，而DD則為75% (p=0.036)。Kaplan-Meier估計曲線顯示三組的存活機率有著明顯的差異，其中II基因型的28天存活機率最高。吾人將DD與ID兩組病人的臨床資料合併統計(稱為「非II基因型」)，顯示II組相對於非II組有著明顯較高的機率存活到第28天。再將可能影響死亡的因素進行單一變項及多重變項存活率分析，顯示ACE的基因型是影響ARDS病人第28天存活機率的獨立因素(多重變項分析之hazard ratio為0.46；95%信賴區間為0.26-0.81；p=0.007)。另外一個獨立影響存活的因素為院內發生之肺炎所引起之ARDS (多重變項分析之HR為2.34；95%信賴區間為1.25-4.40；p=0.008)。另外，APACHE II計分則可能為影響存活機率的因素(p=0.082)。病人出院時之死亡率為71%；不同基因型之間的差別發現有著明顯的差異，依序為：II為 60%，ID為82%，而DD則為88% (p=0.038)。單一變項以及多重變項存活率分析顯示ACE的基因型是影響ARDS病人出院存活機率的獨立因素(多重變項分析之hazard ratio為0.53；95%信賴區間為0.32-0.87；p=0.012)。另外一個獨立影響存活的因素為院內發生之肺炎所引起之ARDS (多重變項分析之hazard ratio為2.13；95%信賴區間為1.24-3.68；p=0.006)。
第三部分為呼吸器引發肺損傷( VILI)之動物實驗模式研究。將200到250公克之大鼠(S-D rat)以小動物呼吸器進行機械通氣，潮氣容積7 ml/kg訂為「低潮氣容積」 (low tidal volume, LV)，40 ml/kg為「高潮氣容積」 (high tidal volume, HV)；呼吸器使用4小時。其他組別接受captopril之預防性投予，或使用同步之losartan或PD123319的投予。肺損傷分析包括組織學、病理性肺損傷計分評估肺損傷之嚴重度，及支氣管肺泡灌洗以及灌洗液中蛋白質含量之測量；肺臟發炎分析方則以Myeloperoxidase (MPO)活性作為評估。肺臟組織內的核醣核酸(RNA)分離與純化後進行肺臟促發炎及抗發炎細胞激素之核醣核酸表現量之定量與分析係利用反轉錄-聚合酶鍊鎖反應(RT-PCR)的方法進行檢定分析。肺臟中的第二型血管張力素濃度則利用酵素免疫分析法(EIA)進行。訊息傳遞機轉之分析探討則以NF-kappaB活性分析為主，分析細胞質液以及細胞核內的NF-kappaB、I-kappaB以及phospho-I-kappaB的濃度。RAS成員基因表現則以即時RT-PCR方法為主。
實驗結果顯示在組織學方面，陽性控制組出現明顯的發炎細胞浸潤及肺泡上皮細胞增生；LV組肺臟組織學型態幾乎與正常肺臟一樣，極少出現發炎細胞浸潤的情形；反觀HV組可見到肺泡有發炎性變化，其病理性肺損傷計分與LV組和控制組皆有顯著差異，但與LPS相比則較輕微。組織學並未顯示結構性的斷裂，細胞的死亡不明顯，透明膜的出現非瀰漫性，發炎細胞的浸潤幾乎都會在組織學檢驗中顯現，但其程度比LPS輕微。HV組亦出現MPO活性增加的現象，LV組活性增加不明顯。HV組進行RT-PCR檢定顯示細胞激素及化學激素mRNA表現量增加。依照時間進行多次取樣所展現的肺臟細胞激素TNF-alpha以及化學激素MIP-2的mRNA表現量逐漸增加，至4小時便會非常明顯；若不進行安樂死繼續予以飼養並觀察後續肺臟的變化，發現TNF-alpha或MIP-2表現量皆逐漸減少，在機械通氣停止約三天後測不到。利用西方墨點法偵測大鼠肺臟中的NF-kappaB相關蛋白質的分析結果，發現LPS能夠明顯地增加細胞核內NF-kappaB的p65含量，並且減少細胞質中的p65含量，而HV也具有相類似的結果，會將細胞質中的p65含量減少，而且增加細胞核內的NF-kappaB的p65含量。與NF-kappaB受到活化的趨勢相對應的就是細胞質內的I-kappaB的磷酸化，導致部分的I-kappaB轉變為phospho-I-kappaB。引此可以見到細胞質液中的I-kappaB含量減少而phospho-I-kappaB增加。吾人亦對肺臟組織以及周邊血液中的血管張力素加以定量。利用酵素免疫檢定法(EIA)所測得的含量，在不同組別所差異。HV可以逐漸增加肺臟中的血管張力素含量，4小時的含量與第0小時相比有顯著差異；LV則不明顯。利用即時RT-PCR的檢定方法來定量基因的mRNA在肺臟組織中的表現量，發現HV會增加angiotensinogen、AT2以及AT2受體的mRNA，但ACE的mRNA則沒有明顯改變；LV則對所有的RAS基因mRNA表現量均沒有明顯的作用。西方墨點法偵測肺臟蛋白質的含量發現ACE、AT1、和AT2的蛋白質含量在各個組皆相近；ACE2的mRNA以及蛋白質表現量定量，顯示HV明顯地減少大鼠肺臟組織中ACE2的mRNA表現量，LV則沒有明顯的作用；與大鼠腎臟與心臟相比，其肺臟組織的ACE2蛋白質含量明顯地較少，定量較為困難，因此本研究的ACE2定量並未顯示ACE2的蛋白質含量會隨著不同的呼吸器設定而有所影響。
為探討RAS在呼吸器引發肺損傷所扮演的角色，利用captopril來測試肺損傷及肺發炎是否因captopril使用而減弱。若先以captopril投予三天，再使用HV，與未接受captopril的相比，組織學檢查顯示肺臟組織嗜中性白血球數量明顯減少，說明了肺臟發炎的情形可以得到減輕。利用MPO檢測也顯示肺臟組織MPO活性明顯地降低。預防性給藥對肺損傷也見到類似的改變：病理學肺損傷計分顯示以三天的預防性使用captopril，能使病理學肺損傷計分明顯地減低。以losartan或PD123319在呼吸器使用時同步注射，也可以得到類似結果。
在研究結果中發現RAS的活性在動物活體的呼吸器模式能被高潮氣容積所增加，導致第二型血管張力素濃度明顯增加。吾人亦發現此系統若被抑制，將使得後續的肺臟組織發炎以及肺損傷得以被降低或是避免其發生。以血管張力素轉化酶抑制劑或血管張力素受體拮抗劑使用在動物時，能降低呼吸器引發肺損傷的程度或是部分預防它的發生，壓制肺臟中促進發炎細胞激素和介質的表現，並且減少肺臟中NF-kappaB的活性。基於以上兩類發現和推論，吾人因此認為RAS應該在呼吸器引發肺損傷致病過程扮演相當重要的角色。
台灣在過去並沒有關於ALI和ARDS發生率的流行病學研究。關於ALI以及ARDS的流行病學研究，或許先以急性缺氧性呼吸衰竭作為研究統計的出發點，也是一個可行的方式。ARDS涵蓋了所有可以符合這個操作型定義的所有臨床異常疾病都將納入這樣的領域中，因此它代表一大類相似的病態生理學異常，而這個異常會以瀰漫性非心因性肺水腫引發的急性呼吸衰竭來作為臨床表現，因此或許以病態生理學的異常作為臨床上遺傳學的研究目標，可能是一個較為實際與確實的作法。ALI和ARDS的臨床狀況個體差異性很大，也可以是為其表現型有很多種變化，而這對於遺傳學研究或是基因體醫學或生物學研究，反而可能是非常有價值的。表現型分類在臨床研究上，越來越受到重視，相對地也越來越複雜。研究方式主要是將病人的多項臨床資料建立為參數，納入統計分析。例如ALI或ARDS病人其危險因子出現和發病成為ARDS的時間間隔、影像醫學檢查的異常嚴重性、氧合功能破壞的程度、全身性發炎指數的高低、其他器官衰竭的程度等等，都可以加以量化。這樣針對每一種指標都可以產生不同的程度上的差異，而目前也有一些軟體可以用來分析不同的標記中是否有一些相關性，這些相關性的研究，若能與基礎方面的發現，如基因體分析或是遺傳學分析，合併進行，可能對研究的方向要更有幫助。
重症醫學的研究，無論在臨床或基礎領域，近年皆有長足的進步，尤其是發炎反應相關的嚴重疾病，例如敗血症，休克，以及急性肺損傷等，學界對於其致病機轉的瞭解越來越多，相互之間的關連性也發現遠比原來想像的複雜。呼吸系統和循環系統一樣，是人體不能停止的重要生理功能，能夠維持適當的呼吸功能，在重症醫學或是呼吸醫學上，一直是非常重要的臨床治療發展方向，亦為基礎研究重要的研究領域。急性肺損傷在這方面的研究尤其扮演非常重要的角色，畢竟肺臟功能嚴重受損，除了危及生命，亦會造成長期呼吸衰竭而需依賴呼吸器支持，在臨床上對於病人以及醫療資源上都是非常大的負擔。肺損傷不但引起肺臟功能受損，也會進而造成全身性發炎反應，造成多重器官衰竭。因此能夠對於引起肺損傷和急性呼吸窘迫症候群的機轉，包括引發的原因，訊息傳遞的途徑，發炎反應的調控，以及傷害修補的過程和藥物治療的可能性等，皆具有很高的臨床應用潛力。吾人在日後的研究中，將持續地，並進一步地針對急性肺損傷、急性呼吸窘迫症候群以及呼吸器引發肺損傷的臨床及基礎醫學進行」深入的探討和研究，期望能更加釐清其機轉，以造福病人。Respiratory failure remains an important clinical problem despite substantial medical progress during the past decades and the emergence of various new modalities of mechanical ventilation as well as intensive care. Among a variety of conditions that may result in severe respiratory failure, the acute lung injury and acute respiratory failure remain the most challenging for intensivists and pulmonologists. The acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by an acute onset of bilateral pulmonary haziness resulting in severely impaired gas exchange functions and poor compliance of the lungs, leading to virtually all patients requiring mechanical ventilation to overcome life-threatening respiratory failure. Despite substantial progress in critical care, the mortality rate of ARDS remains high, and studies have shown that the majority of deaths result from multiple organ failure rather than refractory hypoxemia. Most of the available treatments todate have shown no benefit to patient survival.
Based on current problems and clinical requirement, we interested and engaged in the studies of acute lung injury and ARDS, trying to provide further data and experience in the understanding of these devastating syndromes. First we performed a retrospective analysis of mecical records of ARDS patients treated in a tertiary referred medical center. The clinical picture of patients with ARDS in Taiwan has seldom been reported, although new definitions of ARDS have been introduced over the past years. Therefore we wished to investigate the clinical characteristics, modalities of management, and outcomes in patients with ARDS. Case records were selected trough a computerized search of diagnosis codified at discharge. Patients who met the criteria of the American-European Consensus Conference definition of ARDS were included and their medical records were reviewed. We identified a total of 145 patients (91 men; aged 58 years). Malignancy (n=53) and diabetes mellitus (n=23) were the most common co-morbid conditions. Pneumonia (n=90) was the most common risk factor. The lung injury score at the time of ARDS diagnosis was 2.89 ± 0.40, while the worst value of PaO2/FIO2 was 86.8 ± 3.8 mmHg. Among the 145 patients, 130 received mechanical ventilation and 118 were treated in the intensive care unit. The in-hospital mortality was 87%, while in 70 patients receiving intensive treatment for ARDS, the mortality rate was 74%, with the most common causes of death being multiple organ failure (54%) and respiratory failure (23%). We found that the mortality in patients with ARDS was high in the tertiary referral institution. Our findings suggested that aggressive ventilatory, pharma- cologic, and supportive therapy may be important to achieve a higher survival rate.
Subsequently we conducted a human study to investigate the genetic association and predisposition in the development and evolution of ARDS. During the past decades, the mortality of ARDS has improved to some extent, mainly due to progress of the intensive care, but still remained relatively high; therefore the possibility of prevention had been the mainstay of investigation. However, based on epidemiologic data and current practice, the attempt to prevent the development of ARDS remains difficult because there is a relatively low rate of ARDS in the general population. Several risk factors for ARDS, most notable of which are sepsis and pneumonia, have been identified, but only a small portion of patients with such risk factors subsequently develop ARDS. Therefore the identification of this small portion of patients at risk is currently not possible. It is speculated that genetic factors may play a certain role in development and progression of ARDS; therefore studies examining the polymorphisms of the genes involved in ARDS are a reasonable approach.
Among the pathophysiolic mechanisms and pathways of acute lung injury and ARDS, the putative involvement of angiotensin II has gained increasing interests, and the renin-angiotensin system (RAS) has become one of the study interests in ARDS. Angiotensin-converting enzyme (ACE) is a key enzyme that converts angiotensin to angiotensin II. While the intron 16 of the ACE gene contains a restriction fragment length polymorphism consisting of the presence (insertion, I) or absence (deletion, D) of a 287-bp alu repeat sequence, the I/D polymorphism has been reported to account for 47% of the variance in plasma ACE level, whereas the serum ACE levels correspond to ACE insertion/deletion (I/D) genotypes in the order: II < DI < DD. It has been shown that the DD frequency was increased in ARDS patients compared with the non-ARDS ICU patients, coronary bypass grafting patients, and general population control groups and was significantly associated with mortality. There was no report of ACE genotypes in the Chinese patients with ARDS. For further understanding of the genetic predisposition for ARDS, we wished to study the role of the renin-angiotensin system, and therefore hypothesized that polymorphism of the ACE gene affects the risk and outcome of ARDS in the Chinese population.
We performed a prospective observational study of ARDS patients were >18 yrs of age, who fulfilled the American-European Consensus Committee criteria for ARDS: a) acute onset, b) bilateral pulmonary infiltrates, c) severely impaired oxygenation (i.e., Pao2/Fio2 of <200 mm Hg), and d) pulmonary artery occlusion pressure of <18 mm Hg or no evidence of left atrial hypertension. In addition, two control groups, consisting of “at-risk” patients and “non–at-risk” patients, respectively, were recruited for comparison. The patients in the at-risk group were admitted to the ICU due to acute respiratory failure but did not progress to ARDS throughout the hospital course. The non–at-risk group had no history of respiratory failure or admission to the ICU for any reason.
Clinical data were collected at admission to the ICU, including co-morbidities, Acute Physiology and Chronic Health Evaluation (APACHE II) scores, sex, age, and reason for admission, lung injury scores, and major organ functions. The primary outcome of this study was the survival at the 28th day of ARDS onset. The secondary outcome was the survival at hospital discharge. Peripheral blood samples were obtained, genomic DNA was extracted, and the ACE I/D genotypes were determined by polymerase chain reaction (PCR) amplification of the respective fragments for the D and I alleles from intron 16 of the ACE gene, using primers: 5'CTGGAGACCACTCCCATCCTTTCT3' and 5'GATGTGGCCA- TCACATTCGTCAGAT3'. Because of the concerns about mistyping ID as DD, all samples found to have the DD genotype were subjected to a second, independent PCR amplification with a primer pair recognizing insertion-specific sequence (5'TGGGACCACAGCGCCCGCCACTAC'3 and 5'TCGCCAGCCCTCCCATGCCCATAA'3). Statistical analyses were performed with SPSS software package. Continuous data were expressed as mean ± SD. Comparisons of the continuous data were performed by analysis of variance or two-sample Student's t-tests. The chi-square tables were used to compare the observed number of each genotype with those expected for a population in Hardy-Weinberg equilibrium and to compare the genotype frequencies between the ARDS population and the control groups. Survival curves were estimated by the Kaplan-Meier method, and the statistical significances were tested using the log-rank test. Multivariate analyses for outcomes were performed by the Cox proportional hazard methods. A p value less than 0.05 was considered statistical significant.
For the results of this part of study, we included 101 ARDS patients (age, 60 ± 21 yrs; 68 men), 138 at-risk control group patients (age, 71 ± 16 yrs; 86 men), and 210 non–at-risk control group subjects (age, 57 ± 13 yrs; 146 men). The incidence of ARDS was approximately 1.75% among medical ICU patients. Lung Injury Scores of the ARDS group and the at-risk group were different (p < 0.001), although APACHE II scores were similar (p=0.10). None of them deviated from the Hardy-Weinberg equilibrium. In all groups, the D allele accounted for <0.3 of the allele frequency.
There was no significant difference in the genotype and allele frequ- encies between the ARDS patients and the at-risk group and the non–at-risk group. Sex (p=0.87), age (p=0.995), and underlying diseases were similar in the three genotype groups of ARDS patients. The APACHE II scores (p=0.16) and Lung Injury Scores (p=0.96) were also similar between the three genotypes. The 28-day mortality rate of the ARDS patients was 54%, but of them the mortality rates were significantly diff- erent between the three ACE genotypes (p=0.036), with the II genotype having a higher possibility of 28-day survival. Regrouping as II and non-II also showed a survival benefit of the II group than the non-II group.
Survival analysis showed that the II genotype (p=0.007) and hospital-acquired pneumonia (p=0.008) were independent prognostic factors for 28-day survival. Patients with an APACHE II score >25 tended to have a higher risk for 28-day mortality (p=0.082). The in-hospital mortality rate for ARDS was 71%, which was different between ACE genotypes (p=0.038). The II genotype (p=0.012) and hospital-acquired pneumonia (p=0.006) were independent prognostic factors for the outcome at hospital discharge. Patients with an APACHE II score >25 tended to have a higher risk for in-hospital mortality (p=0.10).
This part of study suggested that the polymorphism of the ACE gene affects the outcome rather than risk for ARDS in the Chinese population. In the western countries the D allele frequency is usually higher than that of I allele, accounting for 0.51 to 0.56 in the general population, whereas in the Asian countries, the frequency of the D allele is lower, with the D allele frequency among ethnic Chinese people being 0.3~0.45. This may result in a smaller proportion of people carrying the DD genotype, ranging from 0.09 to 0.16 in the ethnic Chinese populations.
The findings here may confirm the effect of ACE polymorphism on the outcome of ARDS, but due to a relatively small proportion of people carrying the DD genotype in the general population among Asian people, more cases may be required to assess the risk of ARDS. Although the case numbers in this series are not large, the proportions of the ACE genotypes are similar to those previously reported in Chinese ethnic groups. Because the genotype distribution did not deviate from the Hardy-Weinberg Equilibrium, the possibility of genotyping error is low. There are still no data concerning the estimated incidence of ARDS in Taiwan. Therefore, despite the possibility of an association of the D allele with the risk of ARDS, there is still a lack of data concerning the comparison of incidences of ARDS among Asian and white people.
As the majority of ARDS patients died of multiple organ failure, this study has not explained why the ACE gene polymorphism can affect the outcome. We do not know whether there is another pathway triggered due to ACE polymorphism. This study also has some limitations. The levels of angiotensin II were not determined in the ARDS patients, therefore we lack direct functional evidence of the contribution of gene polymorphism to the clinical presentation. However, correlation between the ACE geno- types and the serum ACE levels has been shown, and in the ethnic Chin- ese population, a report has shown that the plasma ACE activity is highest in the DD genotype, followed by the ID, and lowest in the II genotype. The ACE activity in the ID genotype has been shown to be intermediate.
In our study, the inclusion criteria were similar to other reports, and all patients received a positive end-expiratory pressure level of no less than 10 cm H2O, but the possibility of inclusion of the “transient ARDS,” as described by Ferguson et al., cannot be excluded. It is also difficult to find adequate control groups as the study was not a cohort-based one, and all subjects in the control groups still have the chance of developing ARDS in face of some risks, although the non–at-risk control groups were apparently older. A population-based cohort study should be more powerful in confirming the hypothesis that ACE genotype determines the risk and outcome for ARDS. It is postulated that patients at risk for developing ARDS appear as candidates for preventive treatment with these agents. The relevance of treatment with these agents and the clinical course of the patients require further clinical trials.
In summary, we found that the ACE I/D polymorphism is a significant prognostic factor for the outcome of ARDS in the Chinese population. Patients with the II genotype have a significantly better chance of 28-day survival and at-discharge survival than those with the non-II genotypes.
In the third part, we performed animal studies on the effect of injurious mechanical ventilation on the rat lungs in an in vivo model. Although an indispensable in the management of critically ill patients with respiratory failure, mechanical ventilation (MV) can also subject the lungs to substantial abnormal stretching stress, resulting in structural changes, impaired gas exchange and activation of the inflammatory process and leading to ventilator-induced lung injury (VILI) and significant risk to the patients. Inflammatory cells and pro-inflammatory mediators are considered to play an important role in VILI pathogenesis. However, the exact mechanism by which MV triggers the inflammatory process remains unclear.
Based on our previous clinical study, we were interested in the involvement of the renin-angiotensin system (RAS) in the development of ventilator-induced lung injury. The involvement of the RAS in inflammatory responses has received attention. The RAS is considered to be a key mediator of inflammation. Moreover, angiotensin II, the key factor of the RAS, has been shown in several in vitro studies to activate an inflammatory process by up-regulation of the synthesis of pro-inflammatory cytokines and chemokines via the type 1 (AT1) and type 2 (AT2) angiotensin II receptors and subsequent activation of the NF-kappaB pathway. Thus it is probable that the RAS is actively involved in the development of lung injury. In conditions that can lead to lung inflammation, such as high-volume ventilation, the RAS may play an important role in the development of lung inflammation. We therefore investigated the involvement of the RAS in VILI.
We conducted a series of animal experiments regarding mechanical ventilation and lug injury. Male Sprague-Dawley rats weighing 200-250 g were anesthetized and tracheostomized, and subsequently subjected to mechanical ventilation with a small animal ventilator according to design protocol. Animals were divided into different groups: 1) non-ventilated controls; 2) treated with MV with a high tidal volume (40 ml/kg tidal volume, 3 cmH2O of positive end-expiratory pressure [PEEP], 20 breaths/min, room air); 3) treated with MV with a low tidal volume (7 ml/kg tidal volume, 3 cmH2O of PEEP, 100 breaths/min, room air).
MV was applied for 4 hours and the peak airway pressure was monitored throughout. Additional groups of rats received captopril pre-treatment before MV or were treated with losartan or PD123319 during MV. For the captopril-treated group, 50 mg/kg of captopril was added to the drinking water (500 mg/l) for the three days preceding mechanical ventilation. For the losartan- or PD123319-treated, losartan (10 mg/kg) or PD123319 (10 mg/kg) was injected intravenously via a pump during the 4 hours of MV.
The lungs were removed and fixed, and sections were prepared and stained with hematoxylin and eosin, and scored for lung injury. Myeloperoxidase (MPO) activity, a marker enzyme for neutrophil infil-
Low Serum Level of High-Density Lipoprotein Cholesterol Is a Poor Prognostic Factor for Severe Sepsis
No full textObjective: To assess the initial serum levels of lipids and lipoproteins and their correlations with the clinical outcome for patients with severe sepsis. The ability of high -density lipoprotein (HDL) to attenuate lipopolysaccharide ( LPS)-induced cytokine production was also examined in vitro . Design: Prospective, observational cohort study. Setting: Medical intensive care unit (ICU) of a tertiary-level university hospital. Patients: Sixty-three consecutive patients with severe sepsis. Interventions: Blood samples were drawn within the first day of severe sepsis and the subsequent 14 days. Clinical outcome, including length of ICU stay, infection subsequent to hospital stay, and death, were monitored prospectively. Measurements and Results: Compared with the survivors, patients who died within 30 days had significantly lower levels of HDL cholesterol and apolipoprotein A-I during the first 4 days of severe sepsis. On day 1, HDL cholesterol levels correlated inversely with interleukin-6 (r = -0.72; p 7 days) and the hospital-acquired infection rate were increased among patients with day 1 levels of HDL cholesterol of <20 mg/dL and apolipoprotein A-I of <100 mg/dL. Multivariate analysis identified an HDL cholesterol level of <20 mg/dL on day 1 ( odds ratio, 12.92; 95% confidence interval, 2.73-61.29) and Acute Physiology and Chronic Health Evaluation II score ( odds ratio, 1.15; 95% confidence interval, 1.04-1.26 ) as independent predictors of the overall 30-day mortality rate. In human macrophages, LPS-induced TNF-[alpha] release was attenuated by incremental doses of HDL cholesterol added simultaneously (p < .01). However, HDL failed to suppress LPS-induced TNF-[alpha] production when administered after macrophages were exposed to LPS. Conclusions: A low HDL cholesterol level on day 1 of severe sepsis is significantly associated with an increase in mortality and adverse clinical outcomes. In cultured macrophages, HDL can attenuate LPS-induced TNF-[alpha] production only if added concomitantly with, but not after, LPS exposure
Carotid Atherosclerosis, Circulating Levels of Cell Adhesion Molecules and Total Homocysteine in Healthy Postmenopausal Women: A Comparison between Vegetarians and Omnivores
No full textOutcome of Coal Worker’s Pneumoconiosis with Acute Respiratory Failure
No full textStudy objective: To investigate the clinical features and prognosis of patients with coal worker’s pneumoconiosis ( CWP) requiring invasive mechanical ventilation (MV) in the ICU for their first episode of acute respiratory failure ( ARF), with special attention to the prognostic implication of radiographic progressive massive fibrosis (PMF). Design: Retrospective study. Setting: A 16-bed medical ICU at a community hospital. Patients and methods: We reviewed 53 patients with CWP and ARF requiring invasive MV in the ICU for the first time between August 1998 and March 2002. Results: Of the 53 patients with CWP, 28 patients (53%) with PMF had their first ARF at a younger age than those without PMF (69.1 ± 7.9 years vs 74.8 ± 7.2 years, p = 0.008 [ mean ± SD]). Pneumonia ( 49%) was the most common cause of ARF. The mean APACHE (acute physiology and chronic health evaluation) II score was 26.0 ± 9.9, and the mean ICU stay was 14.7 ± 16.1 days. Twenty-one patients (40%) were weaned successfully in the ICU, with mean ventilator time of 17.0± 25.1 days. The ICU and in-hospital mortality rates were 40% and 43%, respectively. The median survivals for all patients and the ICU survivors were 2.6 months and 14.3 months, respectively. Multivariate analysis showed the following risk (or protective) factors for the ICU mortality : PaCO2 > 45 mm Hg at the time of intubation (adjusted odds ratio [OR], 0.04; 95% confidence interval [CI], 0.003 to 0. 44), PaO2/fraction of inspired oxygen ratio < 200 mm Hg at the time of intubation (OR, 8.78; 95% CI, 1.36 to 56.48), and APACHE II score 25 (OR, 11.99; 95% CI, 1.49 to 96.78). PMF was not associated with the ICU mortality (OR, 1.18; 95% CI, 0.20 to 7 .10)
A Case of Septic Shock Due to Mycobacterium Tuberculosis: An Uncommon and Forgotten Disease Entity?
No full text結核敗血性休克在有效的抗結核藥物問世後就不再被注意,而1990年代開始,有人類 免疫不全病毒感染的病患併結核敗血性休克的病例被報導,然而,1990 年代末期, 開始也有無人類免疫不全病毒感染的病患併結核敗血性休克的病例被注意,我們相信 結核敗血性休克因之前有效結核藥物的發明,及診斷的進步,而在結核盛行的地區被 忽視。我們報告一位43歲女性患者,發生結核敗血性休克,其人類免疫不全病毒血清 學檢查為陰性,在加護病房中,運用脈搏波形分析心排出量監測(PiCCO),並和文獻的資料作印證。 Septic shock caused by Mycobacterium tuberculosis has rarely been reported following the advent of effective anti-tuberculous drugs. Since the emergence of human immunodeficiency virus (HIV) infection , there have been several reports regarding septic shock due to M. tuberculosis in these immunocompromised patients. Recently, this presentation has also been found in non-HIV patients. We described a non- HIV patient presenting with a rapidly fatal course; M. tuberculosis was the only causative micro-organism identified. Pulse contour cardiac output (PiCCO) was used for the first time to document the hemodynamic change in septic shock due to M. tuberculosis
A web-based Utstein style registry system of in-hospital cardiopulmonary resuscitation in Taiwan.
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Carotid and Brachial Arterial Function in Healthy Postmenopausal Women: A Comparison between Vegetarians and Omnivores
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