Generation COVID-19
Building the case to protect young people’s future health
원문 링크

교육감 선거시 학생들의 ‘수면권’과 관련하여 논란이 되었던 한국에서도 참고하면 좋을 문헌

From the American Academy of Pediatrics
Policy Statement
School Start Times for Adolescents
ADOLESCENT SLEEP WORKING GROUP, COMMITTEE ON ADOLESCENCE, COUNCIL ON SCHOOL HEALTH

The American Academy of Pediatrics recognizes insufficient sleep in adolescents as an important public health issue that significantly affects the health and safety, as well as the academic success, of our nation’s middle and high school students. Although a number of factors, including biological changes in sleep associated with puberty, lifestyle choices, and academic demands, negatively affect middle and high school students’ ability to obtain sufficient sleep, the evidence strongly implicates earlier school start times (ie, before 8:30 AM) as a key modifiable contributor to insufficient sleep, as well as circadian rhythm disruption, in this population. Furthermore, a substantial body of research has now demonstrated that delaying school start times is an effective countermeasure to chronic sleep loss and has a wide range of potential benefits to students with regard to physical and mental health, safety, and academic achievement. The American Academy of Pediatrics strongly supports the efforts of school districts to optimize sleep in students and urges high schools and middle schools to aim for start times that allow students the opportunity to achieve optimal levels of sleep (8.5–9.5 hours) and to improve physical (eg, reduced obesity risk) and mental (eg, lower rates of depression) health, safety (eg, drowsy driving crashes), academic performance, and quality of life.

韓남성 필리핀 성매매 “피임 안하고 12살 찾아”

Guillermo Domínguez-Cherit, MD; Stephen E. Lapinsky, MB, BCh, MSc; Alejandro E. Macias, MD; Ruxandra Pinto, PhD(Stat); Lourdes Espinosa-Perez, MD; Alethse de la Torre, MD; Manuel Poblano-Morales, MD; Jose A. Baltazar-Torres, MD; Edgar Bautista, MD; Abril Martinez, MD; Marco A. Martinez, MD; Eduardo Rivero, MD; Rafael Valdez, MD; Guillermo Ruiz-Palacios, MD; Martín Hernández, MD; Thomas E. Stewart, MD; Robert A. Fowler, MD, MS(Epi)

JAMA. 2009;302(17):(doi:10.1001/jama.2009.1536).

Objective  To describe baseline characteristics, treatment, and outcomes of consecutive critically ill patients in Mexico hospitals that treated the majority of such patients with confirmed, probable, or suspected 2009 influenza A(H1N1).

Design, Setting, and Patients  Observational study of 58 critically ill patients with 2009 influenza A(H1N1) at 6 hospitals between March 24 and June 1, 2009. Demographic data, symptoms, comorbid conditions, illness progression, treatments, and clinical outcomes were collected using a piloted case report form.

Main Outcome Measures  The primary outcome measure was mortality. Secondary outcomes included rate of 2009 influenza (A)H1N1–related critical illness and mechanical ventilation as well as intensive care unit (ICU) and hospital length of stay.

Results  Critical illness occurred in 58 of 899 patients (6.5%) admitted to the hospital with confirmed, probable, or suspected 2009 influenza (A)H1N1. Patients were young (median, 44.0 [range, 10-83] years); all presented with fever and all but 1 with respiratory symptoms. Few patients had comorbid respiratory disorders, but 21 (36%) were obese. Time from hospital to ICU admission was short (median, 1 day [interquartile range {IQR}, 0-3 days]), and all patients but 2 received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia (median day 1 ratio of PaO₂ to fraction of inspired oxygen, 83 [IQR, 59-145] mm Hg). By 60 days, 24 patients had died (41.4%; 95% confidence interval, 28.9%-55.0%). Patients who died had greater initial severity of illness, worse hypoxemia, higher creatine kinase levels, higher creatinine levels, and ongoing organ dysfunction. After adjusting for a reduced opportunity of patients dying early to receive neuraminidase inhibitors, neuraminidase inhibitor treatment (vs no treatment) was associated with improved survival (odds ratio, 7.4; 95% confidence interval, 1.8-31.0).

Conclusion  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.

INTRODUCTION

On April 21, 2009, the Centers for Disease Control and Prevention reported the detection of 2 cases of human infection with 2009 influenza A(H1N1) in California.¹ The greatest initial burden of critical illness and death occurred in Mexico² between March 18, 2009, and June 1, 2009, with 5029 cases and 97 documented deaths.^2-6 By August 30, 2009, there were more than 116 046 cases with 2234 deaths in the Americas and 277 607 documented cases and at least 3205 deaths worldwide.^{2, 7}

We report on 58 patients in Mexico who developed critical illness from confirmed, probable, or suspected 2009 influenza A(H1N1). This early information may be of considerable value for (1) the early identification of individuals at risk of becoming critically ill and who may benefit from targeted interventions including vaccination and antiviral therapy; (2) pandemic health care resource planning; and (3) providing baseline 2009 influenza A(H1N1)–associated morbidity and mortality data, comparing experiences in different jurisdictions, and identifying changes in disease virulence over time.

METHODS

Study Design

We retrospectively studied all critically ill patients with confirmed, probable, or suspected 2009 influenza A(H1N1) in Mexico admitted between March 24, 2009, and June 1, 2009, to 6 hospitals that were reference centers for the care of patients with influenza (Figure 1). Identification of all such patients was achieved by examining admission logs for all patient care areas, in collaboration with critical care and infectious diseases physicians in each participating hospital and with regional health authorities in Mexico.

We classified patients according to case definitions (confirmed, probable, or suspected) developed by the World Health Organization, Centers for Disease Control and Prevention, and the National Microbiology Laboratory (see eAppendix).^8-10 We defined critically ill patients as those admitted to an adult or pediatric intensive care unit (ICU); requiring mechanical ventilation; having a fraction of inspired oxygen (FIO₂) greater than or equal to 60%; or receiving intravenous infusion of inotropic or vasopressor medication during the hospitalization.

To evaluate the proportion of patients who became critically ill, we compared our study population with the total number of inpatients diagnosed with confirmed, probable, or suspected 2009 influenza A(H1N1) and treated at any of the participating hospitals by June 1, 2009. All patients admitted to these 6 hospitals with respiratory symptoms or fever were routinely screened for 2009 influenza A(H1N1) during the outbreak period.

Case Report Generation, Dissemination, and Ethics Approval

Investigators in Canada collaborated with colleagues in Mexico and developed a data collection form with input from critical care personnel, infectious diseases clinicians, and clinical researchers, including the Canadian Critical Care Trials Group.¹¹ Research ethics board review and approval was granted by Sunnybrook Health Sciences Centre on April 30, 2009, and subsequently by the ethics boards of participating jurisdictions in Mexico. The data collection form was posted on academic institutional and critical care society Web sites on or after May 3, 2009.^12-14 Data collection in Mexico commenced on May 1, 2009, was entered by study site personnel, transmitted to the coordinating center in Toronto, then checked for errors through manual and electronic inspection using prespecified range limits.

Data Collection

Data collection included 2009 influenza A(H1N1) and critical illness eligibility criteria, demographic data, and details of influenza contact, symptoms, comorbid conditions, clinical characteristics, time course of the acute illness, microbiology samples, and treatments (eAppendix). Severity of illness was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score for adults or Pediatric Risk of Mortality III score for children.^15-16 Reporting of ventilatory parameters, arterial blood gas values, and chest radiograph findings, as well as Sequential Organ Failure Assessment (SOFA) scores, was performed on days 1, 3, 7, 14, and 28, using the values closest to 8:00 AM where appropriate.¹⁷ Outcome variables included duration of mechanical ventilation, ICU and hospital length of stay, and ICU and hospital mortality at 14, 28, and 60 days from onset of critical illness.

From the largest referral centers, we were able to collect more detailed information on the total number of patients presenting to the emergency department with influenzalike illness as well as those admitted to the hospital and to the ICU, and to calculate the proportion of patients critically ill with influenza-related pneumonia as a function of total number of ICU beds. In the largest centers, we also collected detailed information on health care worker exposure and illness to assess risk posed to health care professionals through care of patients with 2009 influenza A(H1N1).

Analysis

Descriptive data are presented as frequencies (percentages) for discrete variables and as means (SDs) or medians (interquartile ranges [IQRs]) for continuous variables. Because few patients remained alive and in the ICU at 28 days, nonoutcome variables are presented on days 1, 3, 7, and 14 but not day 28. To determine if there were differences in baseline characteristics between patients who survived vs those who died, we used a 2-sample t test or the Wilcoxon rank sum test for continuous variables and a ² test or Fisher exact test for the discrete variables. Analyses to detect differences in treatment variables between survivors and nonsurvivors are at risk of confounding due to immortal time bias—ie, patients who die quickly have less “opportunity” to be exposed to certain therapies. Therefore, we restricted comparisons of neuraminidase use to patients who did not die within the first 3 days after admission to the hospital and adjusted for differences in severity of illness using the APACHE II score in a multiple logistic regression model.

The Kaplan-Meier method was used to determine the probability of survival over the duration of follow-up and to generate survival curves, censoring at 60 days all individuals discharged from the hospital alive. We compared the discriminative ability of the day-1 SOFA and APACHE II scores on mortality by testing the difference in C statistics (area under the receiver operating characteristic curve).

All statistical tests were 2-tailed, and factors were considered statistically significant at  < .05. SAS version 9.2 (SAS Institute Inc, Cary, North Carolina) was used for all analyses.

RESULTS

Characteristics of Study Patients and Hospitals

During the study period 899 patients with confirmed, probable, or suspected 2009 influenza A(H1N1) were assessed and admitted to study hospitals having a mean of 289 (SD, 167) beds and 16 (SD, 8) critical care beds. Critical illness occurred in 58 patients (6.5%) admitted to the hospital (29 confirmed, 14 probable, 15 suspected). There were no significant differences in demographics, severity of illness, comorbid conditions, or mortality among those with confirmed, probable, or suspected 2009 influenza A(H1N1), and they are described as a single group.

As a result of increased patient volumes, many experienced delay in admission to the ICU, and 4 remained in the emergency department until death. During the period of data collection, there were 5029 cases of 2009 influenza A(H1N1) and 97 deaths in all of Mexico.¹⁸ This cohort from 6 hospitals represents approximately one-quarter of all deaths in Mexico during the study period. We have described the temporal burden of influenza and H1N1 on the largest study center, outlining the number of cases of influenzalike illness presenting to the emergency department and admitted to the hospital and cases of influenza-related illness admitted to the ICU (Figure 1). The usual capacity to care for critically ill patients was exceeded, necessitating care in other patient care areas and the addition of ICU beds and ventilators on 2 occasions.

Study patients were a median age of 44 (range, 10-83) years (Figure 2), 53% were female, and 2 were health care workers (Table 1). Only 2 children (10 and 14 years) were admitted to study centers with critical illness and had mean admission Pediatric Risk of Mortality III scores of 6.5 (SD, 2.1). Among all patients, symptoms included fever in 58 (100%); respiratory complaints (cough, dyspnea, or wheeze) in 57 (98%); generalized weakness in 41 (71%); myalgias in 35 (60%); headache in 33 (57%); and gastrointestinal symptoms of nausea, vomiting, or diarrhea in 18 (30%).

The median number of comorbid conditions was 2 (IQR, 1-4) (Table 1). Only 2 patients had a history of chronic obstructive pulmonary disease. Obesity was the most common comorbid condition (mean body mass index [BMI], 32 [SD, 12], calculated as weight in kilograms divided by height in meters squared). Twenty-one patients (36%) had a BMI greater than 30; 8 (14%) were morbidly obese (BMI >40).

Course of Illness and Treatments Received

Medical Therapies. Patients developed first symptoms a median of 6 (IQR, 4-8) days prior to hospitalization. Time from hospitalization to ICU admission was 1 (IQR, 0-3) day. Among 55 patients confirmed to have received medical therapies (unknown for 3), 52 (95%) were treated with antibiotics, while 45 (78%) received neuraminidase inhibitors (oseltamivir [44], zanamivir [6]), 8 received amantidine (14%), 1 rimantidine (2%), and 40 (69%) corticosteroids. Two patients received recombinant activated protein C. Two had received an influenza vaccination in 2008 or 2009.

Ventilation Support. Fifty-four patients, including 1 of 2 children, required mechanical ventilation (48 invasive, 22 noninvasive, 16 both) during the course of hospitalization (Table 2 and eTable).¹⁹ On the first day of critical illness, the mean FIO₂ was 72% (SD, 26%), set positive end-expiratory pressure (PEEP) was 13 (SD, 5) cm H₂O, and plateau pressure was 27 (SD, 7) cm H₂O. Median ratio of PaO₂ to FIO₂ was 83 (IQR, 59-145) mm Hg, with oxygen saturation of 88% (SD, 13%). Four patients received prone ventilation on their first day in the ICU, owing to severe hypoxia. Tidal volume per ideal body weight was 8.3 (SD, 3) mL/kg. Day 1 chest radiographs demonstrated bilateral disease in 95.6% of patients. Barotrauma occurred in 6 patients (10.3%) over the study. Patients received high FIO₂, high PEEP, and were commonly ventilated in the prone position. Only 1 patient received high-frequency oscillatory ventilation, and none was known to receive nitric oxide or extracorporeal membrane oxygenation.

Nonrespiratory Organ Dysfunction. A large number of patients (34 [58.6%]) initially required inotropic or vasoactive medications at day 1 (Table 2). Creatine kinase level was elevated (285 [IQR, 136-1159] IU/L). Initial other organ dysfunction was mild. Over the course of follow-up, hypotension requiring vasoactive medication support remained common at days 3, 7, and 14. Staphylococcus aureus was the most commonly identified cause of secondary bacterial pneumonia (4 patients).

Outcomes. After 60 days from the onset of critical illness, 24 of 58 patients (41.4%; 95% confidence interval [CI], 28.9%-55.0%) had died (Table 3, Figure 3). In Mexico, most (19) patients died within the first 2 weeks after becoming critically ill. An additional 4 patients died by day 28, with only 1 additional death occurring within 60 days.

Four patients died in the emergency department, 3 within 8 hours and 1 within 24 hours of arrival. All deaths within 28 days were primarily related to respiratory failure, with only 1 late death primarily related to multisystem organ dysfunction. The 2 included children both survived and were discharged from the hospital. Intensive care unit length of stay among survivors was 13.5 (IQR, 6-24) days, while nonsurvivors died 7.0 (IQR, 2-13) days after ICU admission (Table 3). Duration of mechanical ventilation among survivors was 15 (IQR, 8-26) days and among nonsurvivors was 7.5 (IQR, 3-13.5) days. Many patients received ventilation outside of the ICU.

Comparison of Survivors and Nonsurvivors. Patients who died were more likely to have a higher APACHE II and SOFA score, lower mean arterial pressure at admission, evidence of renal and hepatic organ injury, lower ratio of PaO₂ to FIO₂, and higher set PEEP at admission to the ICU (Table 4). There were no significant differences in tidal volume or ventilation strategies between survivors and nonsurvivors. Patients with higher creatine kinase levels had a greater likelihood of dying at 28 days. Both APACHE II and day-1 SOFA score were significantly associated with 28-day mortality (P < .001 for both), and there was no difference in predictive value (C = 0.83 and C = 0.87, respectively; P = .52). After excluding patients dying early (within 72 hours of illness onset), who may have had less opportunity to be exposed to neuraminidase inhibitors, survivors were more likely to have received treatment with neuraminidase inhibitors (odds ratio, 7.4; 95% CI, 1.8-31.0; P = .006).

Risk to Health Care Workers. Among the 3 largest centers caring for 65.6% of the patients in this series, 40 of 6755 health care workers (0.6%) developed 2009 influenza A(H1N1), including 10 of 2421 workers (0.5%) from clinical areas. Only 1 health care worker became critically ill, and this patient was believed to have acquired H1N1 outside of the workplace.

COMMENT

Our analysis of critically ill patients with 2009 influenza A(H1N1) reveals that this disease affected a young patient group. 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. These patients had severe hypoxia and acute respiratory distress syndrome and required high FIO₂, PEEP, and ventilatory pressures. Within 60 days, 41% of critically ill patients had died.

The mortality rate of 41% for 2009 influenza A(H1N1)–associated critical illness is not dissimilar to that for acute respiratory distress syndrome resulting from other influenza but is higher than that for severe acute respiratory syndrome (SARS), and deaths in Mexico appear to have been more directly related to respiratory rather than multiorgan failure.^20-22 The low median age and relatively good prior health of this critically ill group are different from those for seasonal influenza and SARS,²² in which older patients appear more susceptible to severe disease.

Although serologic studies suggest that 2009 influenza A(H1N1) is a novel influenza strain with little protection afforded by seasonal influenza vaccination, adults older than 60 years appear to have some preexisting immunity to this novel virus.²³ While a degree of cross-immunity might be afforded through a long history of annual vaccination, the specific effect of uncommon prior seasonal influenza vaccination, if any, is unclear. The age distribution of the general population in Mexico differs from that in many developed nations, with a much larger proportion of the population in lower age categories, and therefore it may not be surprising that young individuals comprise a greater proportion of those infected.²⁴

Approximately 18% of critically ill patients with SARS were health care workers.²² With SARS, viral shedding appeared to peak at about 7 days, coinciding with the time of ICU admission for many patients. Viral shedding in seasonal influenza is maximal near onset of the disease, then decreases rapidly.²⁵ These patients presented to the hospital and were admitted to the ICU a median of 6 days after disease onset, which may in part explain the apparent lack of nosocomial transmission among critically ill patients. Avian influenza A(H5N1) outbreaks would appear to have a significantly higher mortality than 2009 influenza A(H1N1) in patients requiring advanced organ support (approximately 90%, with median time from hospital admission to death of 6 days).^26-28 These baseline data will allow evaluation of whether the morbidity and mortality of this infection are worsening over time, which has been the case in many other pandemics.²⁹

We found that certain baseline characteristics of critically ill patients with 2009 influenza A(H1N1) may be associated with increased mortality, including cardiovascular, respiratory, and renal organ dysfunction. Novel findings include possible worse outcomes among patients presenting with an elevated creatine kinase level. Elevated creatine kinase levels and rhabdomyolysis have been previously reported to complicate seasonal influenza, although more commonly in children.^30-31 Obesity was the most common comorbid condition in these patients and was more prevalent (36%) in this series than the general population prevalence (30%) in Mexico.³² However, mortality was not significantly higher among obese patients compared with nonobese patients. Among other patient cohorts with undifferentiated acute respiratory distress syndrome, increased BMI has not emerged as a predictor of mortality.³³

A better understanding of these factors, which were common, or those that suggest a higher mortality may provide health care professionals an earlier opportunity to identify and treat high-risk groups. Importantly, we found in this cohort that either SOFA or APACHE II scores may help to identify patients at high risk of death. Some authors have previously suggested the use of SOFA scores for triage during pandemic periods, owing to their relative ease of calculation.³⁴

The strengths of this study include a large and detailed description of patients critically ill as a result of 2009 influenza A(H1N1). We have highlighted what appear to be differences in severity of illness, associations, and outcomes from other recent infectious respiratory outbreaks. The methods of rapid case report modification, research ethics approval, international dissemination, and analysis provide a potential example for future outbreak characterization¹¹ and potential for international comparisons among countries with different health care systems and capacity for care.

This study has several potential limitations. First, it represents a relatively early examination of the epidemiology of a severe infectious disease. Early reports risk overestimating the case-fatality rate through selective recognition and screening of the most severely ill patients. This may partially explain a high mortality in Mexico early in the outbreak; however, our cohort included all patients hospitalized with critical illness, not only those selected for admission to an ICU, thus minimizing the effect of selective triaging of critically ill patients (by age, comorbidity, etc) and minimizing the potential for overrepresentation of patients with certain characteristics or severity of illness. Also, the 6 hospitals participating in this cohort study had specific criteria for 2009 influenza A(H1N1) screening among all hospitalized patients, minimizing the risk of exposure ascertainment bias through overestimation of disease among only the sickest patients. For this early report, we deliberately included suspected, in addition to confirmed and probable, cases of 2009 influenza A(H1N1) because in the earliest stages of the outbreak, confirmatory testing was sometimes unavailable for patients who died rapidly and in settings with resources that did not initially permit testing. We performed all analyses in duplicate and found no significant differences in outcomes when including only confirmed and probable cases.

It is possible that the 2009 influenza A(H1N1) experience described here is somewhat unique to Mexico and may be related to a variety of factors, including climate, air quality, and altitude (2240 m above sea level) in Mexico City; or, noting the long duration between illness onset and presentation to the hospital with severe disease, potential differences in the timing of access or presentation of the population to acute care compared with other settings. These critically ill patients presented to the hospital already very ill. Four patients died before admission to the ICU, 3 of these within 8 hours of presentation to the hospital. Despite these potential differences with other recently characterized outbreaks, the experience in Mexico may well represent a global “median” of illness presentation and outcome for 2009 influenza A(H1N1) more appropriate than reports only from the most well-resourced health care settings.²²

As of August 30, 2009, the World Health Organization reported 254 206 cases of 2009 influenza A(H1N1) and 2837 deaths, for a case-fatality rate of approximately 1%—yet this may well be an overestimate, because testing is no longer being reported in many jurisdictions.² The case-fatality rate in previous influenza pandemics has varied widely, and all such reports may be inaccurate owing to difficulty in assessing the denominator (ie, the total number of cases).³⁵ The Spanish flu of 1918 is reported as causing 50 million deaths in 500 million individuals infected (10% case-fatality rate), while the Hong Kong flu of 1968-1969 caused 33 000 deaths among 50 million infected (<0.1% case-fatality rate).³⁶ The case-fatality rate of avian influenza A(H5N1) was initially reported to be as high as 60% but is more likely in the range of 14% to 33%.²⁸

From the Mexico experience, it is clear that in certain environments, critical illness from 2009 influenza A(H1N1) may be associated with severe acute lung injury, refractory hypoxia, and a high mortality rate in young individuals. Influenza pandemics of the past century have been associated with a remarkably consistent epidemiologic curve, with peaks in the spring, fall, and later winter.⁷ 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.

AUTHOR INFORMATION

Corresponding Author: Robert Fowler, MD, MS(Epi), Sunnybrook Health Sciences Center, 2075 Bayview Ave D478, Toronto, ON M5N 3M5, Canada (rob.fowler@sunnybrook.ca ).

Published Online: October 12, 2009 (doi:10.1001/jama.2009.1536).

Author Contributions: Drs Dominguez-Cherit and Fowler had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Domínguez-Cherit, Lapinsky, Stewart, Fowler.

Acquisition of data: Domínguez-Cherit, Macias, Espinosa-Perez, de la Torre, Poblano-Morales, Baltazar-Torres, Bautista, A. Martinez, M. Martinez, Rivero, Valdez, Ruiz-Palacios, Hernández, Fowler.

Analysis and interpretation of data: Domínguez-Cherit, Lapinsky, Espinosa-Perez, Pinto, Stewart, Fowler.

Drafting of the manuscript: Domínguez-Cherit, Lapinsky, Macias, Pinto, Espinosa-Perez, de la Torre, Poblano-Morales, Baltazar-Torres, Bautista, A. Martinez, M. Martinez, Rivero, Valdez, Ruiz-Palacios, Hernández, Stewart, Fowler.

Critical revision of the manuscript for important intellectual content: Domínguez-Cherit, Macias, Espinosa-Perez, de la Torre, Ruiz-Palacios, Stewart, Fowler.

Statistical analysis: Pinto, Fowler.

Administrative, technical, or material support: Domínguez-Cherit, Lapinsky, Espinosa-Perez, Baltazar-Torres, Stewart, Fowler.

Study supervision: Domínguez-Cherit, Stewart, Fowler.

Financial Disclosures: None reported.

Participating Centers: Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” México City, México; Hospital General “Dr. Manuel Gea Gonzalez,” México City; School of Medicine Instituto Tecnologico de Monterrey, Monterrey City, México; Hospital Juarez de Mexico, México City; Hospital San Jose-Tec de Monterrey, Monterrey City, México; Instituto Nacional de Enfermedades Respiratorias, México City; Instituto Nacional de Diagnóstico y Referencia Epidemiológicos, México City.

Previous Presentations: Presented in part at the International Conference of the American Thoracic Society; May 20, 2009; San Diego, California.

Additional Contributions: We thank the following persons for providing input on the study design and conduct: Mexico: Instituto Nacional de Ciencias Medicas y Nutrición “Salvador Zubiran”: Delia Borunda-Nava, MD, Carlos Rodriguez-Osorio, MD, Silvio Antonio Ñamendys, MD, MSc, Antonio Fonseca, MD, Guadalupe Morales, RN, Martha Huertas, RN; Patricia Leal, MD, Arturo Galindo Fraga, MD, Rafael Franco, MD, Sarbelio Moreno-Espinosa, MD, MSc; Hospital General “Dr Manuel Gea Gonzalez” Influenza Committee: Simon Kawa Karasik, MD, Araceli Contreras Molina, RN, Rafael Figueroa Moreno, MD, Jose Jesús Acevedo Mariles, MD, Carlos Alberto San Juan Martínez, MD, Guillermo Bierzwinsky Sneider, MD, Laura Ramírez Preciado, MD, Alejandro Avalos Bracho, MD, Lucina Gutierrez Sánchez, RN, Antonio Martínez Conde, MD, Antonio Lavalle Villalobos, MD, Lorena Hernández Delgado, MD, Gerardo Lara Figueroa, MD, Hector Prado Calleros, MD, Jeremy Farrar, MD, Alejandro Flores (emergency room technician); Hospital de Especialidades CMN la Raza IMSS: Alejandro Sanchez Hurtado, MD, Claudia Lopez Nava, MD; Hospital Juarez de México: Jose M. Conde-Mercado, MD, Monica Cureño-Diaz, MD, Ariel Estrada-Aguilera, MD, Claudia Vazquez-Zamora, MD, Mayte Martinez-Velazquez, MD, David Hernandez-Lopez, MD; Hospital San Jose Tec de Monterrey: Javier Valero Gomez, MD, Carlos Diaz Olachea, MD, Estrella Gonzalez, MD; School of Medicine Tecnologico de Monterrey: Rocio Cabrera (bioengineer); and all the Intensive Care Unit and Medical Intensive Care Unit nurse staff for all the effort and devotion of their work at the Inistituto Nacional de Enferemedades Respiratorias. Canada and United States: John Marshall, MD, Arthur Slutsky, MD, Phil Hebert, MD, PhD, Blair Henry, MSc, Francois Lamontagne, MD, Gordon Rubenfeld, MD, MSc, Andy Simor, MD, Muhammad Mamdani, PharmD, MA, MPH, Judith Hall, MSc, Bryan Boodhoo, and the Li Ka Shing Knowledge Institute of St. Michael’s Hospital; Neill Adhikari, MDCM, MSc, Damon Scales, MD, PhD, Richard Mraz, PEng, Barry McLellan, MD, Karen Choong, MD, Kusem Menon, MD, MSc, Dominique Piquette, MD, MSc, Michael Christian, MD, Jeff Singh, MD, MSc, Orla Smith, MSc, Ellen McDonald, RN, Claudio Martin, MD, MSc, Francois Lellouche, MD, Nicole Zytaruk, RN, Lauralyn McIntyre, MD, MSc, Tom Stelfox, MD, PHD, John Granton, MD, Anand Kumar, MD, Ryan Zarychanski, MD, MSc, David Wensley, MD, Dermot Doherty, MD, Sandra Dial, MD, Sean Keenan, MD, MSc, Sheldon Magder, MD, David Hornstein, MD, David Leasa, MD, Rick Hall, MD, Mark Crowther, MD, MSc, Donald Griesdale, MD, Jamie Hutchison, MD, Jan Friedrich, MD, DPhil, Nial Ferguson, MD, MSc, Jacques Lacroix, MD, Peter Dodek, MD, MHSc, Philippe Jouvet, MD, PhD, Steve Webb, MD, Simon Finfer, MD, Jamie Cooper, MD, Allison McGeer, MD, Tex Kissoon, MD, Brian Cuthbertson, MB, ChB, Cathy Tansey, PhD, Ari Joffe, MD, Craig Coopersmith, MD, the American Thoracic Society, the Society of Critical Care Medicine, the University of Toronto Interdepartmental Division of Critical Care Medicine, and the Canadian Critical Care Trials Group.

Author Affiliations: Division of Pulmonary and Critical Care (Dr Domínguez-Cherit), Hospital Epidemiology Department (Drs de la Torre and Macias), Infectious Disease Department (Dr Ruiz-Palacios), and Department of Critical Care Medicine (Dr Rivero), Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” México City, México; Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto and Mount Sinai Hospital, Toronto, Ontario, Canada (Dr Lapinsky); School of Medicine, Instituto Tecnologico de Estudios Superiores de Monterrey, Monterrey, México (Dr Espinosa-Perez); Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto and Sunnybrook Health Sciences Centre, Toronto (Dr Pinto); Hospital Juarez de México, México City (Dr Poblano-Morales); Hospital de Especialidades Centro Medico La Raza, IMSS, México City (Dr Baltazar-Torres); Instituto Nacional de Enfermedades Respiratorias, México City (Dr Bautista); Department of Internal Medicine (Drs A. Martinez and M. A. Martinez) and Infectious Disease Hospital (Dr Valdez), Hospital General “Dr. Manuel Gea Gonzalez,” México City; Hospital San Jose-Tec de Monterrey, Monterrey City (Dr Hernández); Interdepartmental Division of Critical Care Medicine and Department of Medicine and Anaesthesia, University of Toronto, Mount Sinai Hospital, University Health Network, Toronto (Dr Stewart); and Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto and Sunnybrook Health Sciences Centre, Toronto (Dr Fowler).

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JAMA-EXPRESS
Critically Ill Patients With 2009 Influenza A(H1N1) Infection in Canada

Anand Kumar, MD; Ryan Zarychanski, MD; Ruxandra Pinto, PhD; Deborah J. Cook, MD, MSc; John Marshall, MD; Jacques Lacroix, MD; Tom Stelfox, MD, PhD; Sean Bagshaw, MD, MSc; Karen Choong, MD; Francois Lamontagne, MD; Alexis F. Turgeon, MD, MSc; Stephen Lapinsky, MD; Stéphane P. Ahern, MD; Orla Smith, MSc; Faisal Siddiqui, MD; Philippe Jouvet, MD, PhD; Kosar Khwaja, MD; Lauralyn McIntyre, MD, MSc; Kusum Menon, MD, MSc; Jamie Hutchison, MD; David Hornstein, MD; Ari Joffe, MD; Francois Lauzier, MD; Jeffrey Singh, MD, MSc; Tim Karachi, MD; Kim Wiebe, MD; Kendiss Olafson, MD; Clare Ramsey, MD; Satendra Sharma, MD; Peter Dodek, MD, MHSc; Maureen Meade, MD, MSc; Richard Hall, MD; Robert Fowler, MD, MSc; for the Canadian Critical Care Trials Group H1N1 Collaborative

출처 : JAMA. 2009;302(17):(doi:10.1001/jama.2009.1496).
http://jama.ama-assn.org/cgi/content/full/2009.1496

Context  Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America.

Objective  To describe characteristics, treatment, and outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection.

Design, Setting, and Patients  A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009.

Main Outcome Measures  The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay.

Results  Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The 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). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean [SD] score of 6.8 [3.6] on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean [SD] ratio of PaO₂ to fraction of inspired oxygen [FIO₂] of 147 [128] mm Hg) at ICU admission. Mechanical ventilation was received by 136 patients (81.0%). The median duration of ventilation was 12 days (IQR, 6-20 days) and ICU stay was 12 days (IQR, 5-20 days). Lung rescue therapies included neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), high-frequency oscillatory ventilation (11.9%), extracorporeal membrane oxygenation (4.2%), and prone positioning ventilation (3.0%). Overall mortality among critically ill patients at 90 days was 17.3% (95% confidence interval, 12.0%-24.0%; n = 29).

Conclusion  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.

INTRODUCTION

The reemergence of pandemic influenza has been anticipated since the Hong Kong (H3N2) influenza pandemic of 1968. In recent years, there has been substantial concern that a pandemic would involve the novel H5N1 avian flu variant, which has demonstrated an ability to cause severe disease when transmitted to humans.^1-2 However, this spring the US Centers for Disease Control and Prevention reported the occurrence of a 2009 influenza A(H1N1) in 2 children in southern California.³ Subsequently, infection with this virus has been reported in virtually every country.^4-7 The World Health Organization declared the first phase 6 global influenza pandemic of the century on June 11, 2009.⁸

The largest numbers of confirmed cases have been documented in the United States, Mexico, Canada, Chile, and Australia.⁹ Mexico and Canada have both experienced large localized outbreaks of infection with severe illness requiring intensive care unit (ICU) admission and ventilator support. This report describes the epidemiological characteristics, clinical features, treatments, and outcomes of a multicenter cohort of critically ill adult and pediatric Canadian patients.

METHODS

Study Design

In response to an outbreak of 2009 influenza A(H1N1) in Mexico, members of the Canadian Critical Care Trials Group (CCCTG) designed a multicenter observational study of critically ill patients infected with 2009 influenza A(H1N1) (eAppendix). After several cycles of feedback and pilot testing, forms were widely disseminated to ICU physicians, and uploaded to the CCCTG and other critical care society Web sites on May 3, 2009.¹⁰ Data were collected retrospectively or prospectively on all patients with 2009 influenza A(H1N1)–related critical illness admitted to the ICU between April 16 and August 12, 2009. Research ethics board approval was granted by Sunnybrook Health Sciences Centre as the central coordinating center on April 30, 2009, and by each participating local research ethics board. The need for a priori informed consent was waived because of the noninterventional study design.

Data Collection

Eligible patients included all adult and pediatric critically ill individuals admitted to participating hospitals in Canada with confirmed, probable, or suspected 2009 influenza A(H1N1) infection, according to case definitions developed by the World Health Organization and the Canadian National Microbiology Laboratory.^10-11 Critically ill patients were defined as (1) those admitted to a pediatric or adult ICU or those requiring mechanical ventilation (invasive or noninvasive), (2) those with a fraction of inspired oxygen (FIO₂) concentration greater than or equal to 60%, or (3) those with the need for intravenous infusion of inotropic or vasopressor medication. Suspected cases of 2009 influenza A(H1N1) in the presence of a strong epidemiologic link were initially included because confirmatory testing was unavailable in some hospitals when diagnostic laboratories were overwhelmed with testing requests once the pandemic was under way.

Eligibility criteria were confirmed and data were recorded by research coordinators or site investigators at each center (eAppendix). Severity of illness was assessed in adults and children using the Acute Physiology and Chronic Health Evaluation (APACHE) II and Pediatric Risk of Mortality (PRISM) III scores.^12-13 Comorbidities, including major comorbidities defined a priori, were recorded as the presence of 1 or more of the following chronic medical conditions: congestive heart failure; cerebrovascular, neoplastic, chronic liver or renal diseases; and use of immunosuppressant medications.¹⁴

The primary outcome measure was mortality at 28 days after the onset of critical illness as defined by the eligibility criteria. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU and hospital stay. Data were submitted to the coordinating center and checked for errors by manual inspection and electronic range limits.

Analysis

Descriptive statistics included frequency analysis (percentages) for categorical variables and means and standard deviations or medians and interquartile ranges (IQRs) for continuous variables. To test for differences in baseline characteristics between those with confirmed or probable and those with suspected disease, and those who survived vs those who died, a 2-sample t test or the Wilcoxon rank sum test was used for continuous variables as appropriate and the ² test or Fisher exact test was used for discrete variables. Daily variables are presented at days 1, 3, 7, and 14.

The Kaplan-Meier method in which patients discharged from the ICU alive were censored at 28 days was used to depict the probability of survival over the duration of follow-up and to generate survival curves. The discriminative ability of the day 1 APACHE II and SOFA scores on mortality were compared by testing the difference in C statistics (area under the receiver operating curve). The 95% confidence intervals (CIs) and P values were reported to reflect a 2-tailed level of .05. The statistical analyses were conducted using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina).

RESULTS

Characteristics of Study Patients and Hospitals

Between April 16 and July 13, 2009, 215 critically ill patients were admitted to 38 study ICUs (median of 16 ICU beds^15-34; median hospital size, 463 beds [IQR, 238-524 beds]) with confirmed (n = 162), probable (n = 6), or suspected (n = 47) 2009 influenza A(H1N1) infection. Patients having confirmed or probable 2009 influenza A(H1N1) infection were significantly younger, had a longer duration of mechanical ventilation and ICU stay, and higher mortality than those with suspected disease. Therefore, all analyses were restricted to the 168 patients with confirmed or probable 2009 influenza A(H1N1) infection (Table 1). The mean (SD) age was 32.3 (21.4) years; 113 patients were female (67.3%), 50 were children (29.8%), and there were 43 aboriginal Canadians (25.6%). There were 52 critically ill patients from the greater Winnipeg region, in the province of Manitoba, and 116 patients were from other provinces (Figure 1). Sixteen cases originated from nosocomial transmission; none of these were health care workers.

Among adults, the mean (SD) APACHE II score was 19.7 (8.7); and among pediatric patients, the mean (SD) PRISM III score was 9.1 (9.8). At presentation, comorbidities were present in 165 patients (98.2%) (Table 2). However, major comorbidities were present in only 51 patients (30.4%). The most common individual comorbidities were chronic lung disease (41.1%), obesity (33.3%), hypertension (24.4%), and ever smoking (22.6%). The mean (SD) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 34.6 (11.0) and 28 patients (23.7%) were morbidly obese (BMI >40). The most common presenting symptoms were fever (90.5%), respiratory symptoms (94.6%), weakness (55.9%), and myalgias (40.1%). Concomitant presenting conditions included possible bacterial pneumonia (54 cases; 32.1%), hypotension requiring vasopressors (23 cases; 13.7%), asthma or chronic obstructive pulmonary disease exacerbation (23 cases; 13.7%), altered level of consciousness (17 cases; 10.1%), acute kidney injury (12 cases; 7.1%), and ischemic chest pain (5 cases; 3.0%).

Course of Illness and Treatments Received

The median time from symptom onset to hospital admission was 4 days (IQR, 2-7 days)^2-7 and from hospitalization to ICU admission was 1 day (IQR, 0-2 days) after presentation to the hospital. Only 10 patients (6%) had received a seasonal influenza vaccination in either of the past 2 years. Most patients (70.8%) had bilateral chest radiograph infiltrates (41.1% with 4-quadrant involvement) and 72.6% had acute lung injury at the onset of critical illness.

Of all patients, 136 (81.0%) were mechanically ventilated on the first day of ICU admission; 128 (76.2%) invasively and 55 (32.7%) noninvasively. Forty-seven patients (85.4%) who received noninvasive ventilation ultimately required invasive ventilation. The mean (SD) day 1 ratio of PaO₂ to FIO₂ was 147 (128) mm Hg (Table 3); the mean (SD) day 1 FIO₂ value was 74% (26%) and the mean (SD) day 1 positive end-expiratory pressure (PEEP) was 9.8 (4.0) cm H₂O (eTable).

The mean daily PEEP was greater than 10 cm H₂O for the first 2 weeks of mechanical ventilation. Over the first 2 weeks of critical illness, tidal volumes ranged from 8 to 9.1 mL/kg of ideal body weight; and carbon dioxide elimination was not substantially impaired. Barotrauma occurred in 14 patients (8.3%). Therapies for oxygenation failure included neuromuscular blockade (47 patients; 28.0%), inhaled nitric oxide (23 patients; 13.7%), high-frequency oscillatory ventilation (20 patients; 11.9%), extracorporeal membrane oxygenation (7 patients; 4.2%), and prone positioning ventilation (5 patients; 3.0%) (eTable).

Inotropes or vasopressors were used in 55 patients (32.7%) on day 1 after the onset of critical illness (Table 3), often with high levels of sedatives to facilitate patient-ventilator synchrony. Drug treatments included neuraminidase inhibitors (152 patients [90.5%] for a median of 5 days^4-8), antibiotics (166 patients; 98.8%), and corticosteroids (85 patients; 50.6%).

Creatine kinase was moderately elevated over the first week of critical illness (median level, 580 U/L [IQR, 203-1728 U/L] by day 3; to convert creatine kinase to µkat/L, multiply by 0.0167) (Table 3). The mean leukocyte count was normal at admission and remained in the normal range for the first week. Clinical evidence of secondary bacterial pneumonia following ICU admission was found in 41 cases (24.4% of all patients) including 18 cases caused by Staphylococcus aureus and 5 cases caused by Streptococcus pneumoniae.

Outcomes

Among 168 critically ill patients with 2009 influenza A(H1N1) infection, 29 died (17.3%; 95% CI, 12.0%-24.0%). Eighteen patients died (10.7%; 95% CI, 6.6%-16.6%) within the first 14 days and 24 died (14.3%; 95% CI, 9.5%-20.7%) within 28 days from the onset of critical illness (Table 4 and Figure 2). Twenty-one of those who died were female (72.4%) and 8 were male (27.6%). Of 50 children, only 4 died (8.0%). Of 9 health care workers, 5 required mechanical ventilation and none died. The median length of ICU stay was 12 days (IQR, 5-20 days)^5-20; 12 days for survivors^5-22 and 10 days for nonsurvivors.^4-19 The median duration of ventilation was 12 days (IQR, 6-20 days) for both survivors^6-20 and nonsurvivors.^4-20 One patient died on a medical ward, while all others died in the ICU.

The primary reported causes of death included severe acute respiratory distress syndrome and hypoxemia, or complications thereof⁵; secondary infection and sepsis⁶; multiorgan dysfunction syndrome,² malignancy,² chronic obstructive pulmonary disease,¹ primary cardiac arrest¹; tension pneumothorax,¹ cerebral edema¹; and undetermined etiologies. Pulmonary embolism was believed to be contributory but not causal in 1 death.

Comparison of Survivors With Nonsurvivors

Patients who died were more likely to have higher severity of illness at presentation and greater organ dysfunction (Table 5). Although this overall population was young, older patients were more likely to die. There were no statistically significant differences in female sex distribution or aboriginal vs nonaboriginal status. The APACHE II and day 1 SOFA scores were significantly associated with overall mortality (P<.001 and P = .002, respectively) and there was no difference between the predictive value of these 2 scores (C statistics: 0.757 and 0.688, respectively; P = .13). Because nearly all patients received early treatment with neuraminidase inhibitors, we were unable to investigate differences in outcome due to treatment or timing of these agents (Figure 3).

Comparison of All Patients

As of August 22, 2009, in the general Canadian population, among 7107 reported cases, 1441 required hospitalization (20.3%), 278 were admitted to the ICU (3.9%) (the 215 admitted by July 13, 2009, are reported in this series).¹⁵ In comparing characteristics of all patients infected with 2009 influenza A(H1N1) infection, patients hospitalized, those admitted to the ICU, and those who died, the median age of patients was progressively greater along this continuum and there was a progressively greater proportion of patients with at least 1 underlying medical condition. The proportion of females was greater among those admitted to the ICU and among those who died compared with those infected and those admitted to hospital. There were a greater proportion of pregnant women requiring admission to the hospital and who died compared with the proportion among all of those infected.¹⁵

COMMENT

The spring outbreak of 2009 influenza A(H1N1) infection in Canada affected primarily young, female, and aboriginal patients without major comorbidities, and conferred a 28-day mortality of 14.3% among critically ill patients. A history of lung disease or smoking, obesity, hypertension, and diabetes were the most common comorbidities. Critical illness occurred rapidly after hospital admission and was associated with severe oxygenation failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.

We identified unusual features of severe disease in the current pandemic compared with most previous well-characterized pandemics, including the (probable) H2N2 1890 Russian influenza pandemic, the H2N2 1957 Asian influenza pandemic, and the H3N2 1968 Hong Kong pandemic.^16-18 In these previous influenza pandemics, an increased predilection for infection among children and young adults has been documented,^{9, 19} although mortality curves were U shaped with increased deaths in the very young and the aged.

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.^20-22 Few patients older than 60 years in this study were admitted to the ICU (Figure 1). A potential biological basis for this observation is that patients in this age group have a cross-reactive antibody to 2009 influenza A(H1N1) at much higher rates than younger patients.²³

The increased fraction of the aboriginal community presenting with severe 2009 influenza A(H1N1) infection is notable but not unique. This finding is reflected in the history of the 1918 H1N1 Spanish influenza pandemic during which mortality in aboriginal communities in North America (3%-9%) was many times higher than nonaboriginal communities (generally <0.75%).^24-29 In 1918, mortality within Alaskan and Labrador Inuit populations was 30% to 90%.^{24, 28-29} Although mortality was not substantially greater among aboriginal Canadians in this report, the number of patients with severe disease and knowledge of prior illness patterns in this community is cause for concern.

The tendency of females to develop severe 2009 influenza A(H1N1) infection in this series is striking. A general female susceptibility has not been observed in other influenza case series of variable severity including the initial reports of 2009 influenza A(H1N1) infections.^30-31 In most infectious diseases and related conditions such as sepsis and septic shock, males represent a larger proportion of cases and have a higher mortality.^32-33 The explanation for increased risk of severe disease and death among females in this report is unclear but the role of pregnancy as a risk factor has been noted in previous influenza pandemics.^34-35

The most common comorbidities among critically ill patients in our study were lung disease, obesity, hypertension, and a history of smoking or diabetes, each occurring in 30% to 40% of patients. All these conditions are known to be increased in frequency in the aboriginal population that comprises a substantial portion of cases within this cohort.³⁶ The extent to which these comorbidities contribute to severity of disease is unclear because a large portion of the aboriginal population (which may be a risk factor itself on the basis of genetic susceptibility) often have such comorbidities.

Among critically ill patients, obesity has been shown to be a risk factor for increased morbidity, but not consistently with mortality.^37-38 The association of obesity with severe 2009 influenza A(H1N1) infection has been reported by others³⁹ and may be a novel finding of this pandemic; however, even though obesity was more common in our series than in the general Canadian population (33% vs approximately 24%), we did not find a significant difference in BMI between survivors and nonsurvivors.⁴⁰

Critically ill patients with diabetes and hyperglycemia also are known to be at increased risk of complications and death; similarly, alcohol abuse, which is known to be a risk factor for acute respiratory distress syndrome, may have been a risk factor some patients in our series.⁴¹ These relationships also have been reported with seasonal influenza.⁴² The relative absence of serious comorbidities emphasizes that young, relatively healthy adults were the primary population affected by severe 2009 influenza A(H1N1) infection during this outbreak.

Patients with 2009 influenza A(H1N1) infection–related critical illness experienced symptoms for an average of 4 days prior to hospital presentation, but rapidly worsened and required care in the ICU within 1 to 2 days. Apart from the usual symptoms seen in seasonal influenza, these cases stand out for the presence of gastrointestinal tract symptoms, dyspnea, purulent sputum production, and occasional frothy lung fluid on cough or endotracheal aspiration. Chest radiographs demonstrating bilateral mixed interstitial or alveolar infiltrates were found in three-quarters of the patients.

Approximately one-third of patients required vasopressor support on day 1 following ICU admission; however, in many cases this appeared temporally associated with the need for substantial sedation to optimize ventilation. Broad-spectrum antibacterial agents were initiated in almost all patients because of the initial suspicion of community-acquired bacterial pneumonia. However, actual bacterial lung infection was typically documented later in the course of critical illness.

In addition, approximately one-third of patients in our cohort required advanced ventilatory support and rescue therapies for profound hypoxemic respiratory failure, including high levels of inspired oxygen and PEEP, pressure control, and airway pressure release ventilation, high-frequency oscillatory ventilation, prone positioning ventilation, neuromuscular blockade, inhaled nitric oxide, and extracorporeal membrane oxygenation. The fact that severe illness arises in a young, previously healthy population with a high probability of survival given the availability of appropriate resources has important societal implications.

In Winnipeg, Manitoba, Canada, site of the largest pandemic cohort of patients, the capacity for the care of critically ill patients was seriously challenged at the outbreak peak in June (Figure 1) with full occupancy of all regional ICU beds, similar to the 2002 Toronto, Ontario, Canada, experience with severe acute respiratory syndrome.⁴³ If, as expected, the prevalence of 2009 influenza A(H1N1) infection increases with the upcoming flu season, there will be an acutely increased demand for ICU care, including the need for rescue therapies that are not currently widely available.^44-46 Clinicians and policy makers will need to examine feasible methods to optimally expand and deploy ICU resources to meet this need.

This study has a number of strengths. It represents the largest series of patients with severe 2009 influenza A(H1N1) infection yet described, and includes both adults and children from geographically and racially diverse settings across Canada, which improves the generalizability of our results to other regions. These observations of the epidemiological risk factors, typical clinical features, response to therapy, and prognosis should aid in the recognition, diagnosis, and clinical management of such infections. Our finding that patients can often be supported through 2009 influenza A(H1N1) infection–related critical illness with prolonged, aggressive life support, and the expectation that the number of cases will likely increase substantially over the next 6 months, highlight important potential limitations in critical care capacity.

This study also has limitations. Our focus on severe disease requiring ICU admission may not reflect important presenting features in less severe cases. The ongoing deaths throughout the course of the study period suggest the possibility of late deaths after the observation period. This may result in a final hospital mortality rate that exceeds the mortality rate we are reporting. Although we describe cases in most regions of Canada, many were from an outbreak in a single province (Manitoba) and involved an aboriginal Canadian population near Winnipeg, which is Manitoba’s largest city. This may lead to overrepresentation or underrepresentation of certain comorbidities and clinical features.

In conclusion, 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. With such therapy, we found that most patients can be supported through their critical illness.

AUTHOR INFORMATION

Corresponding Author: Anand Kumar, MD, Section of Critical Care Medicine, Health Sciences Centre, JJ 399, 700 William Ave, Winnipeg, MB R3E-0Z3 Canada (akumar61@yahoo.com ).

Published Online: October 12, 2009 (doi:10.1001/jama.2009.1496).

Author Contributions: Drs Kumar and Fowler had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kumar, Zarychanski, Cook, Marshall, Stelfox, Lamontagne, Lapinsky, Ahern, Hutchison, Joffe, Dodek, Hall, Fowler.

Acquisition of data: Kumar, Zarychanski, Cook, Marshall, Stelfox, Bagshaw, Choong, Lamontagne, Turgeon, Lapinsky, Ahern, Smith, Siddiqui, Khwaja, McIntyre, Menon, Hutchison, Hornstein, Joffe, Lauzier, Singh, Karachi, Ramsey, Sharma, Meade, Hall, Fowler.

Analysis and interpretation of data: Kumar, Zarychanski, Pinto, Cook, Lacroix, Stelfox, Ahern, Jouvet, Menon, Wiebe, Olafson, Ramsey, Sharma, Fowler.

Drafting of the manuscript: Kumar, Zarychanski, Pinto, Cook, Ahern, Hall, Fowler.

Critical revision of the manuscript for important intellectual content: Kumar, Zarychanski, Pinto, Cook, Marshall, Lacroix, Stelfox, Bagshaw, Choong, Lamontagne, Turgeon, Lapinsky, Smith, Siddiqui, Jouvet, Khwaja, McIntyre, Menon, Hutchison, Hornstein, Joffe, Lauzier, Singh, Karachi, Wiebe, Olafson, Ramsey, Sharma, Dodek, Meade, Fowler.

Statistical analysis: Kumar, Pinto, Fowler.

Obtained funding: Kumar, Ahern, Fowler.

Administrative, technical or material support: Cook, Marshall, Lacroix, Bagshaw, Lamontagne, Turgeon, Ahern, Smith, Siddiqui, Hutchison, Joffe, Lauzier, Sharma, Meade, Fowler.

Study supervision: Kumar, Cook, Lacroix, Siddiqui, Khwaja, Menon, Fowler.

Financial Disclosures: None reported.

Funding/Support: The Public Health Agency of Canada, the Ontario Ministry of Health and Long-term Care, the Heart and Stroke Foundation Canada, and the Canadian Institutes of Health Research provided support for this article.

Role of the Sponsor: The Public Health Agency of Canada, the Ontario Ministry of Health and Long-term Care, the Heart and Stroke Foundation Canada, and the Canadian Institutes of Health Research had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Canadian Critical Care Trials Group H1N1 Collaborative Writing Committee: Anand Kumar, Ryan Zarychanski, Ruxandra Pinto, Philippe Jouvet, Jacques Lacroix, John Marshall, Deborah J. Cook, Rob Fowler. Canadian Critical Care Trials Group H1N1 Collaborative Clinicians: Nova Scotia: Halifax: Richard Hall, Rob Green, Dietrich Heinzler, Lisa Julien, Debra Wright (Queen Elizabeth II Health Sciences Centre). Québec: Québec City: François Lauzier, Alexis Turgeon, Caroline Roy (CHA-Hôpital de l’Enfant-Jésus); François Lellouche, Marie-Claude Ferland (Institut Universitaire de Cardiologie et de Pneumologie de Québec). Longueuil: Germain Poirier (Hôpital Charles-LeMoyne). Sherbrooke: François Lamontagne (Centre Hospitalier Universitaire de Sherbrooke). Montreal: Phillippe Jouvet, Jacques Lacroix (CHU Sainte-Justine); Denny Laporta, David Hornstein (SMBD-Jewish General Hospital); Kosar Khwaja, Laura Banici (McGill University Health Centre); Stéphane P. Ahern, Yoanna Skrobic, Johanne Harvey (Hôpital Maisonneuve Rosemont); Martin Albert, Isabelle Arsenault (Hôpital du Sacré-Coeur de Montréal). Ontario: Ottawa: Lauralyn McIntyre, Claude Gaudet, Ray Saginur, Joe Pagliarello, Irene Watpool, Tracy Mcardle (Ottawa Hospital); Kusum Menon, Dermot Doherty, Sonny Dhanani, Roxanne Ward (Children’s Hospital of Eastern Ontario). Kingston: John Muscedere, Nicole Godfrey, Susan Fleury (Kingston General Hospital). Toronto: Robert Fowler, Ruxandra Pinto, Neill Adhikari (Sunnybrook Hospital); Stephen Lapinsky, Cheryl Ethier, Tom Stewart (Mount Sinai Hospital); Orla Smith, John Marshall, Jan Friedrich, Karen Burns (St Michael’s Hospital); Jeffrey M. Singh, John Granton, Nancy Brockest, Niall Ferguson, Andrea Matte (University Health Network); Jamie Hutchison (Hospital for Sick Children); Rob Cirone (St Joseph’s Health Centre). Hamilton: Deborah Cook, Ellen MacDonald, Kelly Wilton, Andrea Tkaczyk (St Joseph’s Healthcare); Karen Choong, Mark Duffett (McMaster University Children’s Hospital); Maureen Meade (Hamilton Health Sciences Center, general site); Andy Freitag (Hamilton Health Sciences Center, McMaster site); Tim Karachi (Hamilton Health Sciences Center, Henderson site). Guelph: Gerry Hollinger (Guelph General Hospital). London: Claudio Martin (London Health Sciences Centre). Windsor: Eli Malus, Maureen Hrytsyk (Hotel Dieu Grace Hospital). Thunder Bay: Ravi Agarwala (Thunderbay Regional Health Sciences Centre). Manitoba: Winnipeg: Anand Kumar, Ryan Zarychanski, Faisal Siddiqui, Duane Funk, Allan Garland, Wendy Janz, Nicole Marten, Kim Wiebe, Mandy Siddiqui, Clare Ramsey, Satendra Sharma, Kendiss Olafson, Stasa Veroukis, Murray Kesselman (Health Sciences Centre/St Boniface Hospital/Grace Hospital/Victoria Hospital/Concordia Hospital/Seven Oaks Hospital). Brandon: Charles Penner (Brandon Regional Health Authority). Alberta: Calgary: Tom Stelfox (Foothills Medical Centre). Edmonton: Sean M. Bagshaw (University of Alberta Hospital); Mark Heule (Misericordia Hospital); Curtis Johnston (Royal Alexandria Hospital); Marcia Johnson (Public Health Division, Alberta Health Services); Sean Norris (Sturgeon Hospital); Ari Joffe (Stollery Children’s Hospital). British Columbia: Vancouver: Peter Dodek (St Paul’s Hospital); Peter Skippen (BC Children’s Hospital); Donald E. G. Griesdale, Denise Foster (Vancouver General Hospital). New Westminster: Sean Keenan, Steven Reynolds (Royal Columbian Hospital).

Additional Contributions: We thank our patients and the health care professionals who have delivered exemplary care to these patients in the face of uncertain risks. We also thank the following research assistants, who have worked tirelessly in the last several months: Davie Wong, Joel Braun, Aaron Guinn, Allison Stasiuk, Joan Tien, Raji Kaler, Alyson Mahar, Phil Hebert, MD, Blair Henry, MSc, Richard Mraz, PEng, Barry McLellan, MD, Michael Christian, MD, Steve Webb, MD, Simon Finfer, MD, Jamie Cooper, MD, Allison McGeer, MD, Tex Kissoon, MD, Brian Cuthbertson, MD, Mark Crowther, MD, MSc, Cathy Tansey, PhD, Craig Coopersmith, MD, and Arthur Slutsky, MD; Muhammad Mamdani, PharmD, Judith Hall, MSc, Magda Melo, MSc, Bryan Boodhoo, MSc (University of Toronto Interdepartmental Division of Critical Care Medicine); and Rachel Rodin, MD (Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital); and the National Microbiology Laboratory of Canada, Winnipeg, the American Thoracic Society, and the Society of Critical Care Medicine. The persons listed in this section were not financially compensated for their work.

Author Affiliations: Section of Critical Care Medicine, Health Sciences Centre and St Boniface Hospital, Winnipeg, Manitoba, Canada (Drs Kumar, Siddiqui, Wiebe, Olafson, Ramsey, and Sharma); Department of Medical Oncology and Hematology, Cancercare Manitoba, Winnipeg (Dr Zarychanski); Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Drs Pinto and Fowler); Departments of Clinical Epidemiology and Biostatistics (Drs Cook and Meade) and Medicine (Dr Karachi), McMaster Children’s Hospital (Dr Choong), McMaster University, Hamilton, Ontario, Canada; Department of Critical Care Medicine, St Michael’s Hospital, Toronto, Ontario, Canada (Dr Marshall and Ms Smith); Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada (Drs Lacroix and Jouvet); Departments of Critical Care Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada (Dr Stelfox); Division of Critical Care Medicine, University of Alberta, Edmonton (Drs Bagshaw and Joffe); Department of Medicine, Centre Hospitalier, Université de Sherbrooke, Sherbrooke, Quebec, Canada (Dr Lamontagne); Centre de Recherche du CHA, Hôpital de l’Enfant-Jésus, Université Laval, Quebec City, Quebec, Canada (Drs Turgeon and Lauzier); Intensive Care Unit, Mount Sinai Hospital (Dr Lapinsky) and University Health Network (Dr Singh), University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Hôpital Maisonneuve-Rosemont, University of Montréal, Montréal, Quebec, Canada (Dr Ahern); Trauma Services, McGill University Health Centre, Montréal, Quebec, Canada (Dr Khwaja); Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Ontario, Canada (Dr McIntyre); Clinical Research Unit, Children’s Hospital of Eastern Ontario, Ottawa (Dr Menon); Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada (Dr Hutchison); SMBD-Jewish General Hospital, Montréal, Québec, Canada (Dr Hornstein); University of British Columbia, Vancouver (Dr Dodek); and Department of Anesthesia, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada (Dr Hall).

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Caring for the Critically Ill Patient Section Editor: Derek C. Angus, MD, MPH, Contributing Editor, JAMA (angusdc@upmc.edu ).

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Swine flu risk to youths, healthy adults: studies

출처 : AFP Mon Oct 12, 9:43 pm ET