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作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　October 12, 2009 — 根據10月12日美國醫學會期刊(JAMA)的加拿大和墨西哥研究結果與編輯評論，H1N1重症大多是影響年輕人且經常致命。
　　
　　加拿大聖博尼法斯醫院健康科學中心的Anand Kumar醫師與加拿大重症照護試驗小組H1N1聯合小組的夥伴寫道，在2009年3月至7月之間，北美有最多的2009新型A型流感(H1N1)確認案例。
　　
　　這個前瞻性觀察研究的目標是評估加拿大罹患2009新型A型流感(H1N1)之重症病患的臨床特徵、治療與結果。在2009年4月16日至8月12日之間，加拿大的38個成人與小兒加護病房(ICU)共有168名2009新型A型流感(H1N1)重症病患，追蹤他們之後28天與90天的死亡率。次級研究終點包括ICU住院期間以及使用機械式輔助呼吸器的頻率和期間。
　　
　　在215名重症病患中，162人經確認、6人為很可能、47人為疑似社區感染之2009新型A型流感(H1N1)。168名確認或很可能是2009新型A型流感(H1N1)之重症病患的平均年紀為32.3 ± 21.4歲；113名病患(67.3%)為婦女或女孩、50名病患(29.8%)為小孩、43名病患(25.6%)為加拿大原住民。
　　
　　這些重症病患中，整體的28天死亡率為14.3% (95%信心區間[CI]為9.5% – 20.7%)，常有休克和非肺部急性器官衰竭(隨後第1天的器官衰竭評估平均分數為6.8 ± 3.6)。90天時，整體死亡率為17.3% (95% CI，12.0% – 24.0%；n = 29人)。
　　
　　ICU住院期間，所有病患都有嚴重低血氧(動脈氧分壓[PaO2]與吸入氧氣分率[FIO2]之平均比率為147 ± 128 mm Hg)。從發生症狀到住院的天數中位數為4天(四分位差[IQR]為2 – 7天)，從住院到轉入ICU的天數中位數為1天(IQR為0 – 2 天)。
　　
　　多數重症病患接受神經胺酶抑制劑(n = 152人[90.5%])以及機械式輔助呼吸(n = 136人[81.0%])。使用呼吸器天數的中位數為12天(IQR為6 – 20天)，ICU住院天數的中位數為12天(IQR為5 – 20天)。有些病患還需要肺部復甦治療，包括有28%病患使用神經肌肉阻斷劑、13.7%病患吸入一氧化氮、11.9%病患使用高頻振盪式呼吸、4.2%病患使用葉克膜－體外循環維生系統、3.0%病患使用俯臥通氣。
　　
　　研究作者寫道，在加拿大，住院後因2009新型A型流感(H1N1)迅速變成重症的，多數為年輕成人，與嚴重低血氧、多重器官衰竭、需要持續使用機械式輔助呼吸、經常需要使用復甦治療等有關。我們的資料認為，目前發生的重症與死亡集中在10至60歲這些相對健康的青少年與成人，這種W型模式只有在1918年的西班牙H1N1大流行時發生過。
　　
　　研究限制包括，聚焦在需住進ICU的重症病患，可能在觀察期間之後才死亡，某些共病症和臨床特徵可能有過度表現或低度表現。
　　
　　研究作者結論表示，我們認為，2009新型A型流感(H1N1)感染相關之重症主要影響年輕成人，較少嚴重共病症，且與嚴重低血氧呼吸衰竭有關，通常需要持續使用機械式輔助呼吸與復甦治療。藉由這類研究我們發現多數病患可在支持下度過重症。
　　
　　【墨西哥研究】
　　第二篇觀察研究的目標是描述墨西哥6家醫院確認、可能是或疑似2009新型A型流感(H1N1)的重症病患，一些基本的特徵、治療與結果。在2009年3月24日至6月1日之間，研究者蒐集58名2009新型A型流感(H1N1)重症病患的人口統計學資料、症狀、共病症狀況、疾病進程、治療與臨床結果。主要研究終點為死亡率，次級終點為2009新型A型流感(H1N1)相關重症比率、使用機械式輔助呼吸比率以及住院天數和住ICU天數。
　　
　　確認、可能是或疑似2009新型A型流感(H1N1)住院的899名病患中，58人(6.5%)為重症。全部都有發燒，其中57人有呼吸道症狀；年齡中位數為44.0歲(範圍為10 – 83歲)。少數病患同時有呼吸道異常，21人(36%)為肥胖。住院到轉ICU之天數的中位數為1天(IQR為0 – 3天)。有56名病患需要機械式輔助呼吸治療嚴重急性呼吸窘迫症候群與頑固型低血氧。第1天的PaO2與FIO2比率之中位數為83 mm Hg (IQR為59 – 145)。
　　
　　60天之死亡率為41.4% (24人死亡；95% CI為28.9% – 55.0%)，其中19人在前兩週內死亡。與死亡率有關的因素包括疾病嚴重度較高、低血氧惡化、肌酸激酶值較高、肌酸酐值較高、持續器官功能不佳。在那些較早死亡的病患中，校正接受神經胺酶抑制劑的機會較少之因素後，使用神經胺酶抑制劑治療(相較於無治療)有較佳的存活 (勝算比為7.4；95% CI, 1.8 – 31.0)。
　　
　　來自墨西哥市國立醫藥與營養研究中心、Salvador Zubiran的Guillermo Dominguez-Cherit醫師等人寫道，墨西哥2009新型A型流感(H1N1)重症發生在年輕成人，與嚴重急性呼吸窘迫症候群及休克有關，估計死亡率高。幾乎在所有案例中，發燒和呼吸道症狀都是疾病先兆。發生症狀到住院之間的期間相對較長，之後急性和嚴重呼吸道惡化期很短。
　　
　　研究限制包括，嚴重感染症的流行病學檢查相對較早，可能高估了估計死亡率。
　　
　　研究作者結論表示，爆發時，藉由一致的呼吸道疾病和發燒症狀及早確認疾病，促進使用神經胺酶抑制劑和積極使用氧氣支持、避免後續的器官失能，或許可以提供有別於墨西哥的緩和疾病惡化與死亡率的機會。
　　
　　編輯評論中，Douglas B. White醫師JAMA 特約編輯、賓州匹茲堡大學醫學院的Derek C. Angus醫師指出，許多美國醫院沒有適當的員工來提供2009新型A型流感(H1N1)重症病患之及時治療。
　　
　　White醫師與Angus醫師寫道，醫院必須發展可公正確認哪些人需要、哪些人不需要接受生命支持療法的明確政策，這不容忽視。任何因2009新型A型流感(H1N1)而死亡的案例都是令人遺憾的，但如果是因為計畫不充分以及準備不週所導致的話，更是可悲。
　　
　　加拿大公共衛生局、安大略健康與長照部、加拿大心臟與中風基金會、加拿大健康研究中心等支持加拿大的這項研究。兩篇研究之作者皆宣告沒有相關財務關係。
　　
　　JAMA. 線上發表於2009年10月12日。

H1N1 Critical Illness Mostly Affects Young Patients and Is Often Fatal

By Laurie Barclay, MD
Medscape Medical News

October 12, 2009 — H1N1 critical illness mostly affects young patients and is often fatal, according to the results of a Canadian and Mexican study and an editorial published online October 12 in the Journal of the American Medical Association (JAMA).

"Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America," write Anand Kumar, MD, from the Health Sciences Centre and St. Boniface Hospital in Winnipeg, Manitoba, Canada, and colleagues with the Canadian Critical Care Trials Group H1N1 Collaborative.

The goal of this prospective observational study was to evaluate clinical characteristics, treatment, and outcomes of critically ill patients who had 2009 influenza A (H1N1) infection in Canada. Between April 16 and August 12, 2009, 168 critically ill patients with 2009 influenza A (H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada were followed up for 28-day and 90-day mortality. Secondary study endpoints included frequency and duration of mechanical ventilation and duration of ICU stay.

Of 215 patients with critical illness, 162 had confirmed, 6 had probable, and 47 had suspected community-acquired 2009 influenza A (H1N1) infection. Mean age was 32.3 ± 21.4 years in the 168 patients with confirmed or probable 2009 influenza A (H1N1); 113 patients (67.3%) were women and girls, 50 patients (29.8%) were children, and 43 patients (25.6%) were aboriginal Canadians.

Among critically ill patients, overall 28-day mortality was 14.3% (95% confidence interval [CI], 9.5% – 20.7%), and shock and nonpulmonary acute organ dysfunction were common (sequential organ failure assessment mean score 6.8 ± 3.6 on day 1). At 90 days, overall mortality was 17.3% (95% CI, 12.0% – 24.0%; n = 29).

At ICU admission, all patients were severely hypoxemic (mean ratio of partial pressure of oxygen in arterial blood [PaO2] to fraction of inspired oxygen [FIO2] of 147 ± 128 mm Hg). Median time from symptom onset to hospital admission was 4 days (interquartile range [IQR], 2 – 7 days) and from hospitalization to ICU admission was 1 day (IQR, 0 – 2 days).

Most critically ill patients received neuraminidase inhibitors (n = 152 [90.5%]) and mechanical ventilation (n = 136 [81.0%]). Median duration of ventilation was 12 days (IQR, 6 – 20 days) and of ICU stay was 12 days (IQR, 5 – 20 days). Some patients also required lung rescue therapies, including neuromuscular blockade in 28% of patients, inhaled nitric oxide in 13.7%, high-frequency oscillatory ventilation in 11.9%, extracorporeal membrane oxygenation in 4.2%, and prone positioning ventilation in 3.0%.

"Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies," the study authors write. "Our data suggest that severe disease and mortality in the current outbreak is concentrated in relatively healthy adolescents and adults between the ages of 10 and 60 years, a pattern reminiscent of the W-shaped curve previously seen only during the 1918 H1N1 Spanish pandemic."

Limitations of this study include focus on severe disease requiring ICU admission, possible late deaths occurring after the observation period, and possible overrepresentation or underrepresentation of certain comorbidities and clinical features.

"We have demonstrated that 2009 influenza A(H1N1) infection–related critical illness predominantly affects young patients with few major comorbidities and is associated with severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies," the study authors conclude. "With such therapy, we found that most patients can be supported through their critical illness."

Mexican Study

The goal of the second observational study was to describe baseline characteristics, treatment, and outcomes of critically ill patients with confirmed, probable, or suspected 2009 influenza A (H1N1) in 6 Mexico hospitals. Between March 24 and June 1, 2009, the investigators collected demographic data, symptoms, comorbid conditions, illness progression, treatments, and clinical outcomes from 58 critically ill patients with 2009 influenza A (H1N1). The main study endpoint was mortality, and secondary endpoints were rate of 2009 influenza A (H1N1)–related critical illness and mechanical ventilation and length of stay in the hospital and ICU.

Of 899 patients hospitalized with confirmed, probable, or suspected 2009 influenza (A) H1N1, 58 (6.5%) were critically ill. All presented with fever, and 57 of 58 presented with respiratory symptoms; median age was 44.0 years (range, 10 – 83 years). Although comorbid respiratory disorders occurred in few patients, 21 patients (36%) were obese. Median time from hospital to ICU admission was 1 day (IQR, 0 – 3 days). Mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia was needed in 56 of 58 patients. Median day 1 ratio of PaO2 to FIO2 was 83 mm Hg (IQR, 59 – 145).

Mortality by 60 days was 41.4% (24 deaths; 95% CI, 28.9% – 55.0%), with 19 deaths occurring within the first 2 weeks. Factors associated with mortality were greater initial severity of illness, worse hypoxemia, higher creatine kinase levels, higher creatinine levels, and ongoing organ dysfunction. Neuraminidase inhibitor treatment (vs no treatment) was associated with better survival, after adjustment for a reduced opportunity to receive neuraminidase inhibitors among patients dying early (odds ratio, 7.4; 95% CI, 1.8 – 31.0).

"Critical illness from 2009 influenza A(H1N1) in Mexico occurred in young individuals, was associated with severe acute respiratory distress syndrome and shock, and had a high case-fatality rate," write Guillermo Dominguez-Cherit, MD, from Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubiran," Mexico City, and colleagues. "Fever and respiratory symptoms were harbingers of disease in almost all cases. There was a relatively long period of illness prior to presentation to the hospital, followed by a short period of acute and severe respiratory deterioration."

Study limitations include relatively early examination of the epidemiology of a severe infectious disease with possible overestimation of case-fatality rate.

"Early recognition of disease by the consistent symptoms of fever and a respiratory illness during times of outbreak, with prompt medical attention including neuraminidase inhibitors and aggressive support of oxygenation failure and subsequent organ dysfunction, may provide opportunities to mitigate the progression of illness and mortality observed in Mexico," the study authors conclude.

In an accompanying editorial, Douglas B. White, MD, MAS, and JAMA Contributing Editor Derek C. Angus, MD, MPH, from the University of Pittsburgh School of Medicine in Pennsylvania, note that many US hospitals may be inadequately staffed to provide treatment of the most seriously ill patients with 2009 influenza A (H1N1) in a timely fashion.

"Hospitals must develop explicit policies to equitably determine who will and will not receive life support should absolute scarcity occur," Dr. White and Dr. Angus write. "Any deaths from 2009 influenza A(H1N1) will be regrettable, but those that result from insufficient planning and inadequate preparation will be especially tragic."

The Canadian Public Health Agency of Canada, the Ontario Ministry of Health and Longterm Care, the Heart and Stroke Foundation Canada, and the Canadian Institutes of Health Research supported the Canadian study. The authors of both studies have disclosed no relevant financial relationships.

JAMA. Published online October 12, 2009.