Clinical Issues and Research in Respiratory Failure
from Severe Acute Respiratory Syndrome

Report of a National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention/National Institute of Allergy and Infectious Diseases Workshop

Published in Am J Respir Crit Care Med Vol 171. pp 518-526, 2005 Internet address www.atsjournals.org

Mitchell M. Levy, Melisse S. Baylor, Gordon R. Bernard, Rob Fowler, Teri J. Franks, Frederick G. Hayden, Rita Helfand, Stephen E. Lapinsky, Thomas R. Martin, Michael S. Niederman, Gordon D. Rubenfeld, Arthur S. Slutsky, Thomas E. Stewart, Barbara A. Styrt, B. Taylor Thompson, and Andrea L. Harabin

From the Department of Medicine, Brown University/Rhode Island Hospital, Providence, Rhode Island; Division of Antiviral Drug Products, Food and Drug Administration, Rockville, Maryland; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC; Department of Internal Medicine, University of Virginia, Charlottesville, Virginia; Respiratory and Enteric Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia; Division of Pulmonary and Critical Care Medicine, VA Puget Sound Medical Center, Seattle, Washington; Department of Medicine, Winthrop University Hospital, Mineola, New York; Department of Pulmonary and Critical Care Medicine, University of Washington at Harborview Medical Center, Seattle, Washington; Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Lung Diseases, NHLBI/NIH, Bethesda, Maryland; Interdepartmental Division of Critical Care Medicine, Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario, Canada; Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Critical Care Medicine, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada; Departments of Medicine and Critical Care, St. Michael’s Hospital, Toronto, Ontario, Canada.

This workshop, sponsored by the Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, was held in Bethesda, Md., October 15, 2003.

The National Heart, Lung, and Blood Institute, along with the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases, convened a panel to develop recommendations for treatment, prevention, and research for respiratory failure from severe acute respiratory syndrome (SARS) and other newly emerging infections. The clinical and pathological features of acute lung injury (ALI) from SARS appear indistinguishable from ALI from other causes. The mainstay of treatments for ALI remains supportive. Patients with ALI from SARS who require mechanical ventilation should receive a lung protective, low tidal volume strategy. Adjuvant treatments recommended include prevention of venous thromboembolism, stress ulcer prophylaxis, and semirecumbent positioning during ventilation. Based on previous experience in Canada, infection control resources and protocols were recommended. Leadership structure, communication, training, and morale are an essential aspect of SARS management. A multicenter, placebo-controlled trial of corticosteroids for late SARS is justified because of widespread clinical use and uncertainties about relative risks and benefits. Studies of combined pathophysiologic endpoints were recommended, with mortality as a secondary endpoint. The group recommended preparation for studies, including protocols, ethical considerations, Web-based registries, and data entry systems.

Keywords: acute lung injury; acute respiratory distress syndrome; infectious disease

This report summarizes the findings of a panel convened by the Division of Lung Diseases of the National Heart, Lung, and Blood Institute in cooperation with the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases to discuss clinical issues related to the treatment and study of respiratory failure in critically ill patients from a potential outbreak of Severe Acute Respiratory Syndrome (SARS). It is recognized that there could be a reemergence of illness from the novel virus named the SARSAssociated Coronavirus or other potential agents that could also cause acute lung injury (ALI) and respiratory failure. The goals of the conference were stated at the outset:

  • To develop recommendations for the treatment of patients that progress to critical illness, especially ALI and acute respiratory distress syndrome (ARDS) from SARS and other emerging viral diseases.
  • To determine if most patients with hypoxemic respiratory failure due to SARS admitted to the intensive care unit meet criteria for ALI/ARDS, and to establish a global protocol for its management.
  • To develop a potential clinical research agenda for the investigation of SARS.
  • To incorporate lessons from the Canadian experience with SARS into the overall recommendations of the panel.

The group included pulmonary and critical care clinician scientists knowledgeable in the treatment and pathogenesis of ALI and ARDS, as well as infectious and pulmonary disease experts experienced in the treatment of patients with respiratory failure from SARS, antiviral experts, and representatives of government agencies. Each participating organization or panel member contributed a section to this manuscript according to its particular expertise. The information and recommendations included in the manuscript are based on previous evidence-based reviews and current studies, published elsewhere and referenced in this manuscript (1).

SARS—BACKGROUND AND CLINICAL EXPERIENCE

SARS is a newly recognized infectious illness that rapidly spread throughout many parts of Asia, North America, and Europe. Between November 1, 2002 and August 7, 2003, 8,098 people in 29 countries developed probable SARS, with the heaviest burden of illness felt in China, Hong Kong, Taiwan, Singapore, Viet Nam, and Canada (2, 3). The morbidity, mortality, and apparent speed and ease of transmission associated with SARS have led to international concern. The recent documentation of additional cases related to laboratory acquisition and infection presumably transmitted from an animal reservoir highlight the continuing threat posed by SARS and related viruses (4).

Approximately 23 to 32% of patients with SARS become critically ill (5–7). ALI is the most common severe organ dysfunction and occurs in approximately 16% of all patients with SARS and in 80% of critically ill patients with SARS (6, 7). Nearly all patients with ALI require mechanical ventilation. The worldwide case fatality rate among all SARS outbreaks is about 9.6% (3). Among those with SARS-related critical illness, 50% of patients will die (6, 7). Mortality is increased among older patients and may be increased among those with certain comorbidities such as diabetes mellitus (5). Worldwide, children have been relatively protected from severe illness. There have been very few cases of documented transmission from children to adults, and virtually no evidence of transmission among school children (3). Among pregnant women with SARS, there has been no documented vertical transmission (8).

The most common presenting symptom of SARS is fever (5, 9). Other common presenting symptoms include malaise, myalgias, or headache and nonproductive cough or dyspnea. Lower respiratory symptoms such as cough and shortness of breath typically begin 2 to 7 days after symptom onset, although they are among the initial symptoms in up to 30% of patients. Gastrointestinal symptoms, including nausea, diarrhea, and vomiting, occur with variable frequency. Upper respiratory symptoms such as rhinorrhea are less common, occurring in only 5 to 25% of patients. The median time from exposure to symptom onset is approximately one week, with an interquartile range of 4 to 10 days for most common symptoms (3, 5). Tachycardia and tachypnea have been among the most common signs at presentation (5). Chest radiograph infiltrates also occur in up to two thirds of patients upon presentation to hospital and in virtually all patients by one week into illness. Laboratory abnormalities include moderate lymphopenia and elevations in lactate dehydrogenase (5, 10, 11). Antemortem confirmatory laboratory testing has thus far involved viral serology and/or detection of viral RNA by nucleic acid amplification from samples of serum, nasopharyngeal or respiratory secretions, urine, or stool. Of note, although the number and quality of these tests continue to improve, none of the tests are sufficiently sensitive early in the illness. Negative test results cannot reliably exclude the SARS virus until more than 28 days after symptom onset. Because of the concern of false positive results, especially when the disease incidence is low, positive tests should be confirmed in reference laboratories using validated assays. This requirement may become more challenging as commercial tests become available which have not been validated. Given these caveats of laboratory diagnosis early in the course of the disease, epidemiologic evidence is essential for diagnosing SARS (9).

Nosocomial transmission from patients to healthcare workers has been a prominent and worrisome feature of SARS outbreaks. In Singapore and Toronto, healthcare workers have accounted for half of all SARS cases and about 20% of critically ill SARS cases (5, 7). Concerns that specific ventilation strategies may place healthcare workers at greater risk of contracting SARS, have influenced recommendations for the management of patients with SARS.

LUNG PATHOLOGY IN SARS

The predominant pathology in the lung of patients infected with SARS virus is diffuse alveolar damage with varying degrees of organization (12, 13). In the acute phase, hyaline membranes, interstitial and intraalveolar edema, mild interstitial infiltrates of inflammatory cells, and vascular congestion were present. In the organizing phase, interstitial and airspace fibroblast proliferation and type II cell hyperplasia occurred. In the organizing phase, the bulk of fibroblast proliferation is within alveolar septa. It is important to note that the airspace fibroblast proliferation can easily be misinterpreted as organizing pneumonia. It is essential to separate organizing alveolar damage from organizing pneumonia because the clinical and radiographic features, therapy, and prognosis are quite different. Microscopic examination also revealed injury to both bronchiolar and alveolar epithelial cells in SARS (12, 13).

SPECIFIC TREATMENTS FOR SARS

Antiviral Agents for SARS

An urgent need exists for effective antiviral drugs to prevent and treat SARS. During the first global outbreak, various interventions were used in management, including antivirals like ribavirin, IFN, and protease inhibitors, as well as host immunomodulatory agents, particularly systemic corticosteroids. However, the uncontrolled nature of these observations and the uncertain natural history of untreated SARS mean that no drug interventions of proven therapeutic or prophylactic value have been established to date. Although the search for new antivirals continues, it is noteworthy that there is now documentation regarding in vitro antiviral activity of some potential therapeutic agents against the SARS virus (14–26). Furthermore, there is a lack of standardized in vitro susceptibility testing methods and of data on correlations between in vitro and in vivo antiviral activities. Discussion of the different cell types (e.g., Vero, fetal rhesus monkey kidney), inhibitory endpoints (e.g., reductions in viral cytopathic effect, protein expression, infectious virus yield, or viral RNA levels), and assay conditions used in published reports are beyond the scope of this article, and the reader is referred to publications that detail the specific methodologies used. The main point is that predictive correlations between in vitro activity and antiviral effects in relevant animal models or SARS-infected humans have not been validated as yet (14–26). There have been several reports of in vitro activity of IFN preparations, and there are enough safety data for these products to support a controlled study of IFN therapy if SARS reappears (19–23).

Anumber of compounds inhibit replication of SARS or other coronaviruses in vitro have, but few of these agents have been administered to patients with SARS. The nucleoside analog ribavirin has a broad spectrum of antiviral activity in vitro, encompassing many RNA viruses including human metapneumovirus and some coronaviruses (27), although the clinical relevance is not well established. Oral and intravenous ribavirin in various regimens was used widely for treating patients with SARS. Some evidence indicates that early nasopharyngeal viral RNA positivity is associated with a worse prognosis (28). However, cell culture–based assays have found no evidence for a selective antiviral activity of ribavirin against the SARS virus in vitro (14, 29). Patients treated with combinations of ribavirin and corticosteroids showed a marked increase in viral load in their upper respiratory tract during therapy (30), consistent with ribavirin’s lack of in vitro antiviral effects and the confounding effect of systemic glucocorticoids on viral replication. Furthermore, in patients treated with ribavirin who died, high viral RNA levels were observed in postmortem lung tissues (31). In Toronto, highdose intravenous ribavirin treatment tended to be associated with poor outcomes (5) and high rates of side effects (32).

Several reports suggest activity of other compounds including small interfering RNAs, glycyrrhizin, lopinavir/ritonavir, niclosamide, fusion inhibitors, neutralizing monoclonal antibodies, and cystein protease inhibitors (14–18). Of the non-IFN molecules described to date, neutralizing polyclonal and human monoclonal antibodies have been shown to have activity in vitro and in animals (33, 34). These would also be appropriate candidates for studies of prophylaxis and early treatment of SARS.

Type I IFN inhibit a wide range of RNA and DNA viruses, including human respiratory CoVs and SARS-CoV in vitro (19–23). IFN-alpha modifies coronavirus disease in animals (35), and in humans, intranasal IFN-alpha-2 partially protected against experimental human respiratory coronaviral infections (36, 37). Limited clinical experience with systemic IFN-alfacon-1 in combination with corticosteroids in patients hospitalized with SARS suggested that it is acceptably tolerated and may have improved clinical outcomes compared with historical outcomes in patients treated with systemic corticosteroids alone (38). However, in late-stage disease, four of six critically ill patients in this cohort died despite combination therapy (38), raising the possibility that early treatment is important. In Guangzhou a treatment regimen involving 3 million units of IFN-alpha daily without corticosteroids for the first 14 days was associated with need for mechanical ventilation in 2 of 30 patients, whereas in another cohort none of 60 patients given high-dose corticosteroids, 75% of whom also received IFN, required mechanical ventilation or died (39).

The experience with drug treatments during the first SARS outbreak has lead the National Institute of Allergy and Infectious Diseases’ sponsored Collaborative Antiviral Study Group to develop a placebo-controlled clinical treatment protocol of IFN-alfacon-1 in patients with early SARS.

RECOMMENDATION

  • Treatment with antivirals is not of proven value and should be studied within the context of controlled clinical trials.
  • Active antivirals identified in the laboratory should be subjected to careful testing of their activity and pharmacology in one or more of the animal models that support SARS viral replication.
  • Animal studies are warranted of putative SARS antiviral agents for which there is conflicting evidence.

Community Acquired Pneumonia and SARS

Initially, all patients suspected of SARS who have a new lung infiltrate should receive antibiotic therapy, consistent with published guidelines (40) for community-acquired pneumonia.

In the intensive care unit, all individuals should be treated for drug-resistant and atypical pathogens, but only those with appropriate risk factors (recent hospitalization, recent antibiotics, high dose steroids, malnutrition, structural lung disease) should have coverage for Pseudomonas aeruginosa (40, 41).

For inpatients with community acquired pneumonia, timely and accurate therapy is essential to reduce mortality. The current Medicare and Joint Commission on Accreditation of Healthcare Organizations standard requires the first dose of therapy within 4 hours of arrival to the hospital (42).

Recommendation

  • Initially, all patients suspected of SARS who have a new lung infiltrate should receive antibiotic therapy, consistent with published guidelines for community acquired pneumonia.
  • The first antibiotic dose should be administered within 4 hours of arrival to the hospital.

CLINICAL MANAGEMENT OF SEVERE SARS

The 16% (6, 7) of patients with SARS who develop hypoxemic respiratory failure meet the current definition of ALI and ARDS (43). These include refractory hypoxemia, diffuse, bilateral infiltrates on chest X-ray, and a PaO2/FiO2 ratio less than 300.

Because the clinical and pathologic manifestations of lung injury in patients with severe SARS are indistinguishable from ALI/ARDS, until further studies are available, the recommended clinical management of severe SARS is the same as for patients with ALI/ARDS.

Mechanical Ventilation For Severe SARS

Ventilation with a low tidal volume strategy (6 ml/kg predicted body weight) has been shown to improve survival in patients with ALI/ARDS (44). There remains controversy within the international community regarding the optimal mode of ventilation for patients with respiratory failure from SARS. Some physicians strongly believe that the risks of intubation for nosocomial transmission are substantial and recommend noninvasive ventilation, whereas others favor early intubation. Canadian experience suggests that elective intubation under controlled conditions is preferable and that noninvasive ventilation may be associated with SARS transmission to healthcare workers (45). Furthermore, although noninvasive ventilation might be considered for patients with the expectation of near term improvement, observational
studies of critically ill patients with SARS report that this form of lung injury is generally not rapidly reversible. The efficacy of noninvasive ventilation versus endotracheal intubation and low tidal volume ventilation for ALI from SARS has not been compared in randomized controlled studies.

Recommendation

  • Patients with SARS that progress to ARDS should be treated with a lung protective ventilatory strategy until further direct information on patients with SARS becomes available.
  • The ARDS Network lower tidal volume strategy is recommended. Details of the protocol are widely available (44, 46).

Corticosteroids in Severe SARS

Pulse dose or high dose steroids do not appear to improve survival in patients with early ALI/ARDS or sepsis (47-50) and are not recommended (51). One small study had suggested that steroids for late or unresolving ALI or ARDS might be beneficial (52), but a much larger study by the ARDS Clinical Trials Network
does not suggest such a benefit (46). There is increasing evidence of long-term morbidity, including disabling muscle weakness and neuropathy associated with steroid use (48, 50, 53, 54).

Several small studies have been reported in which patients with SARS were treated with corticosteroids (5, 30, 39, 55-58). Indications varied, but glucocorticoids were generally reserved for patients with suspected SARS and persistent fever, worsening hypoxemia, worsening dyspnea, or signs of radiographic progression. Pulse doses similar to those used to prevent transplant rejection (500-1,000 mg of methylprednisolone intravenously each day for 2-3 days), low doses similar to those studied for late ARDS (2 mg/kg of methylprednisolone per day in divided doses), as well as intermediate doses (8 mg/kg of methylprednisolone per day in divided doses) were used. Initial intravenous therapy was followed by tapering doses of oral prednisone in most reports, with pulse dosing used for salvage therapy in patients
whose condition worsened on lower doses or during tapering. In almost all of these series, ribavirin was used early in the outbreak and some included co-administration of IFN-alpha.

One case series took advantage of differences in practice patterns among clinicians at two Hong Kong hospitals to compare initial pulse dose methylprednisolone to a divided dose regimen that reserved pulse doses for rescue (58). Blinded review of chest radiographs showed more rapid clearing with pulse dosing. A group of investigators in the Guangdong province of China randomized patients into four treatment strategies that varied from steroid use as rescue treatment to initial pulse dosing. More rapid resolution of fever, respiratory symptoms, and radiographic opacities occurred with pulse dosing but no differences in survival or length of hospital stay were noted (30).

None of the above reports included randomized placebocontrolled trials. Because of the rapid spread of SARS in a relatively short time period, this is not surprising. Nearly all the authors reporting clinical experiences with SARS and the use of steroids comment that a clinical trial of steroids for severe SARS is needed.

Recommendation

  • A placebo-controlled clinical trial of corticosteroids is needed for patients with SARS with progression to respiratory failure because of the wide clinical use of steroids.
  • Corticosteroids are not indicated for the routine care of patients with uncomplicated SARS.
  • Because of the uncertainty surrounding the effectiveness of steroids for severe SARS, pulse-dose steroid therapy could be used for patients with clinical deterioration manifest by persistent fever, worsening radiographic opacities, and hypoxemic respiratory failure (59, 60).
  • The decision to use corticosteroids should be based on a careful evaluation of the possible benefits compared with the risks.

Adjuvant Strategies for Severe SARS

Several adjuvant strategies have been proven to decrease morbidity and mortality in critically ill patients. Although none of these recommendations have been tested specifically on groups of patients with ARDS or SARS, all were conducted in the intensive care populations that included large numbers of these patients (1). Until studies are completed in patients with ARDS or SARS, the group recommended the following.

Recommendations

  • Deep vein thombosis prophylaxis should generally be used. This can be pharmacologic or physical depending on risk factors present (61–64).
  • Stress ulcer prophylaxis is recommended (65, 66).H2 receptor inhibitors are more efficacious than sucralfate and are preferred.
  • Sedation protocols should be used for critically ill mechanically ventilated patients. The recommended methods include (1) intermittent bolus sedation or (2) continuous infusion sedation to predetermined endpoints (e.g., sedation scales) or daily interruption/lightening of sedation with awakening and retitration, if necessary (67–69). Low tidal volume ventilation does not appear to require additional sedative or neuromuscular blocker use (75).
  • Neuromuscular blockers should be avoided, if possible because of risks of prolonged muscle weakness and paralysis (70, 71), especially with concomitant steroids (72). If neuromuscular blockade is used, monitoring of depth of block is recommended (73, 74).
  • Semirecumbant position (head of bed elevated 45 degrees) should be routinely used in patients receiving mechanical ventilation (76–79).

PREPARATION OF THE HEALTHCARE WORKER AND THE HEALTHCARE SYSTEM

Several documents describe in detail the experience and conclusions of the outbreak of SARS in Canada (5, 6, 80–82, 84–86). Key issues and some specific recommendations follow from the Canadian experience and CDC guidance (83).

Organizational Planning

Several important issues that require advance organizational planning were identified during the SARS outbreak in Canada. Many of these issues are similar to planning for an influenza pandemic or responding to a bioterrorism event.

There will be a need for a leadership structure to deal with the problems that arise in providing intensive care. This is true for the hospital at large, and the CDC has provided guidance (83) to help healthcare facilities plan for SARS. Ideally a command set-up should be established with identified leadership and delegation of responsibility for a number of key areas that include sustaining the work force, access controls, communication, education, infection control procedures, psychosocial support, data collection, and clinical management.

Local planning groups will need to consider whether patients with SARS will be cared for in one or several institutions. Although usual medical care needs to continue, it is not always easy to distinguish SARS from other illnesses. Thus, every facility needs to have the expertise needed to recognize and handle patients under investigation for SARS. The same issue applies to SARS patients who require intensive care. However, because intensive care has been associated with an increased risk for SARS transmission, use of dedicated intensive care units may be appropriate. In Singapore, for example, patients were restricted to a single unit where less spread was noted (7). Consideration should be given to moving priority patients (i.e., trauma, cardiac surgery) to places where staff is not at increased risk for
SARS exposure. In addition, advance planning for safe transport of potentially contagious SARS patients is required.

During a SARS crisis, staffing shortages may develop. Critical care team members may be lost due to fear, quarantine, and illness. It is important, therefore, to consider methods for finding people to work with patients with SARS. For example, can staff from other units in the facility be reassigned to the intensive care unit or can critical care teams from other institutions be recruited to work in another facility? If so, what are the legal and training implications and how can these be addressed in advance? In addition to staffing, consumable and durable materials and equipment needs should be identified and plans developed for dealing with shortages.

Preplanning for clinical and infection training is critical. A description of a training program used in Canada is available (81) and the CDC provides guidance as well as educational videos (83).

The stress, confusion, and urgency that can accompany hospitalization of a patient with SARS require planning for internal and external communication. Critical care leadership will need to have a system for communicating with the hospital administration, infectious disease specialists, infection control teams, SARS ward physicians, emergency room specialists, SARS clinic physicians, the clinical laboratory, public health officials, and transportation teams. Existing communication infrastructures should be used, but others may need to be developed (83). Teleconferences may play an important role in facilitating communication.

Identifying psychosocial support is another element of SARS planning. Despair, depression, and a sense of isolation are common reactions in healthcare workers during a SARS outbreak (84, 85). Some providers have had the experience of being viewed as high-risk to the health of others because of their work with patients with SARS. Maintaining staff morale is essential to ongoing patient care during an outbreak. Attention must be given to encourage and commend staff about the work being
accomplished. In addition, healthcare workers caring for patients with SARS may have family concerns that need to be addressed (e.g., childcare, economic support, temporary housing).

Infection Control Precautions in the Intensive Care Unit

An essential component of an infection control strategy is the development of clear protocols and staff training. In the intensive care unit, the risk of transmission is high as viral shedding peaks during the second week of illness (30), when admission is usually required. Droplet spread may be increased by aerosol-generating interventions, including the use of nebulizers and procedures such as intubation and bronchoscopy; airborne transmission through small aerosol spread cannot be ruled out.

Infection control measures for healthcare workers in contact with patients with SARS in the intensive care unit involve five key strategies: (1) dilution and removal of airborne contaminants through use of negative pressure isolation rooms; (2) use of personal protective equipment, e.g., gowns, gloves, eye, face, and respiratory
protection; (3) hand hygiene; (4) environmental cleaning and disinfection; and (5) source control measures aimed at containing the patient’s secretions. In addition, administrative measures to limit contact with patients are necessary. Table 1 summarizes the detailed recommendations.

Aerosol-generating procedures should be limited to those essential for patient care. Other high-risk procedures, including endotracheal intubation and bronchoscopy, also require special precautions. Bronchodilators can be delivered using a metereddose inhaler and aerochamber but must be used with caution (83). Intubation should be considered sooner than is customary to give sufficient time for appropriate infection control precautions (86). This should be performed by the most experienced
airway practitioner available, using sedation and possibly neuromuscular blockade, as appropriate for individual patients. Intubation in awake patients may be associated with patient agitation and coughing, which can severely compromise infection control precautions (86). Mechanical ventilation should be performed with the use of a submicron filter on the expiratory port. Procedures that break the integrity of the circuit, such as suctioning and tube changes, should be limited. As discussed above, there is some disagreement about the advisability of noninvasive ventilation as it may increase aerosolization of droplets that could promote airborne spread of SARS.

Respiratory protection should be worn while performing these high-risk procedures. Eye protection is also an important feature of personal protection. The CDC provides guidance on infection control during high-risk procedures (83) and these are included in Table 1.

TABLE 1. SUMMARY OF INFECTION CONTROL PRECAUTIONS FOR SARS IN THE INTENSIVE CARE UNIT (80–86).

Airborne infection isolation room
Monitored negative pressure isolation rooms preferably with antechamber equipped with:

  • sinks with antibacterial soap and/or alcohol-based hand rub
  • sufficient stock of personal protective equipment (PPE)
  • containers for disposable PPE, soiled laundry, and equipment that must be reprocessed

Avoid disruption of negative pressure barrier:

  • Stock individual rooms with supplies including modified cardiac arrest carts
  • Time blood work and therapies to minimize entrance of staff into rooms

PPE
Basic: Gown, gloves, eye protection (i.e., goggles or face shield), and respiratory protection (i.e., N95 mask)
During aerosol generating procedures:

Canadian Group recommends Powered Air Purification Respirator (PAPR) hoods for all members of the team CDC guidance states disposable particulate respirators (e.g., N-95, N-99, or N-100) are the minimum level of respiratory protection and requires that healthcare workers are fit-tested and trained in the use of the respirator

Provide instruction sheet to staff on how to don and remove PPE
Pagers and watches left outside or carefully covered
Avoid touching face and environmental surfaces
Consider monitoring PPE use

Hand hygiene

  • Ensure easy availability of hand hygiene products (i.e., sinks with antibacterial soap and disposable towels and alcohol-based hand rub) in and outside the room Environmental cleaning and disinfection
  • Assign trained personnel to clean SARS patient rooms
  • Clean horizontal and frequently touched surfaces at least daily and more frequently if needed
  • Use an EPA-registered hospital-grade detergent/disinfectant

Equipment and procedures

Oxygen therapy

  • Avoid nebulized humidity: Venturi mask without humidification is recommended
  • Use mask that permits filtration of exhaled gas (e.g., Hi-Ox80; Viasys Healthcare, Conshohocken, PA)

Avoid bag-valve mask ventilation. If required:

  • Use two-person technique to ensure a tight seal at the face
  • Use submicron filter on the exhalation port
  • Use adequate sedation

Intubation

  • Performed by the most skilled clinician available
  • Use adequate sedation. If awake intubation is performed, be prepared for patient agitation and coughing

Mechanical ventilators

  • Submicron filters on exhalation outlet of mechanical ventilators may prevent release of contaminated aerosols The effectiveness of this measure is unknown, but use is prudent, particularly during high-frequency ventilation
  • Disposable circuits and humidifiers
  • Closed (in-line) suction system
  • Turn ventilator to standby and turn PEEP off when disconnecting the circuit

Noninvasive ventilation (e.g., BiPAP) not recommended
High frequency ventilation may be acceptable
Bronchoscopy—avoid if possible

  • Use good sedation or paralysis to minimize coughing
  • Plan for the careful containment of specimens for transport

Patient transportation

Transportation should be avoided unless essential
Consult Infection control before moving

Visitors and personnel

Limit to those essential for patient care and support

Staff education

Provide training on infection control procedures, including practical instruction on donning and removal of PPE, particularly with PAPR hoods
Emphasize importance of vigilance to all infection control precautions
Emphasize importance of alerting supervisors and infection control immediately when breaches occur

SARS RESEARCH: PROPOSALS FOR THE FUTURE

Designing Clinical Studies in SARS

Clinical studies could be designed for critically ill patients with SARS that evaluate the ability of an intervention (drug or treatment) to reduce (1) the mortality in patients that develop ALI/ARDS, (2) the progression to critical illness, or (3) the severity of established ALI/ARDS.

With ALI/ARDS mortality estimated at 30 to 40%, detecting mortality differences of 10% or so requires studies of at least 1,000 patients. Studies to evaluate progression to critical illness would also be difficult, as existing reports suggest that approximately 16% of patients progress to ALI/ARDS. Large samples
sizes would also be required and might not be feasible given the size of the first SARS outbreak.

Clinical studies would be more feasible in terms of sample size that would address whether the severity of ALI/ARDS was affected by treatment. Patients with SARS who develop ALI/ARDS experience substantial morbidity and there are several physiologic abnormalities that could be proposed as alternative endpoints suggestive of ultimate benefit. Combinations of end points could be considered. Surrogate variables could include static lung compliance, indices of oxygenation (e.g., PaO2/FiO2),
time of critical illness such as ventilator-free days, days without shock, days to discharge alive from the intensive care unit, or biochemical markers of inflammation or injury. The disadvantage of such a study is that the relationship of these markers to mortality is not clear. Nevertheless, smaller studies using combined or composite clinical endpoints could provide a rationale for larger studies that test clinical efficacy and mortality. Initial studies should include mortality as a major secondary endpoint.

Recommendation

  • Prospective randomized controlled studies rather than retrospective studies are desirable.
  • Studies of treatments for SARS would be possible in a large epidemic but will require a multicenter approach.
  • Although studies of mortality are the most desirable, the most feasible trial would be a smaller study using combined physiologic or biochemical endpoints in the lungs or systemic circulation that could aid in future refinements of study designs.
  • Potential interactions between the effects of steroids and antivirals may need to be considered in study design and interpretation.

Challenges of Conducting Clinical Research in SARS

The practical challenges facing clinical investigation of ARDS in the intensive care unit are considerable, even without the added concerns brought on by an emergent, highly infectious cause. Proxy consent, short time window for study enrollment, lack of valid surrogate endpoints, inadequate understanding of complex disease mechanisms, and patient heterogeneity due to unreliable case definitions are all well recognized barriers to clinical investigation of ARDS in intensive care. An outbreak
of SARS or another other emerging infection would present additional challenges to clinical investigation in this environment. Experience with SARS suggests that simply providing clinical care to patients, some of whom may be coworkers, with a staff depleted by infection or fear of infection will leave little time for clinical research. Furthermore, there is no way to predict where, or if, the next outbreak will occur, and no way to guarantee that it will occur near a center with expertise in clinical research.

A collaboration of investigators called the Canadian SARS Research Network (87) has formed to improve the understanding of the previous outbreak and develop plans for any future outbreak. There are five research themes including diagnostics, clinical science, epidemiology, modeling, and immunology. Plans are being developed for archiving of biological specimens and for prospective study of patients in another outbreak. Also being developed are new rapid diagnostics, animal studies of pathogenesis, mathematical modeling of transmission and capacity of cities to respond to another outbreak, and retrospective studies of drug treatments in patients and transmission of infection to healthcare workers. There are also sources of information for activities outside of North America, mainly Asia and the UK (88).

Recommendation

  • Develop emergeny clinical research infrastructure including Web-based protocols and forms and IRB applications.
  • Develop a registry for every patient with SARS. These should permit real-time entry of anonymized data.
  • Prepare for collection and storage of biological samples from patients. The value of these samples depends on standardizing the methods and time of collection during the course of illness. Ideally, samples should be collected from patients as well as exposed but unaffected patients and from comparison populations (e.g., those with non-SARS, viral community acquired pneumonia).
  • Collaborate with ongoing SARS investigations throughout the world.

CONCLUSIONS

International experts in infectious disease and epidemiology consider it likely that there will be a recurrent outbreak of SARS or other newly emerging and serious transmissible respiratory pathogen. Clinicians, hospital administrators, and government officials across the globe were unprepared for the last outbreak, leading to confusion, heightened public concern, and increased transmission rates. The purpose of this panel was to develop general recommendations for the management of severe SARS in the intensive care unit and to establish a SARS research agenda. A series of recommendations concerning the care and treatment of patients with SARS was developed based on previous experience with SARS, and experience with studies in ARDS and more general intensive care unit populations that are likely
to be applicable to SARS. Organizational issues concerning the healthcare system and the healthcare worker are of paramount importance. Further research is needed to better understand the etiology of SARS and establish more specific treatment options. Clinical studies in severe SARS will require prior planning, multi-center collaboration, and a rapid response.

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Conflict of Interest Statement:

M.M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.J.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; F.G.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.E.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S.N. has been a consultant, served on an Advisory Board, and been paid lecture fees in the past three years related to community-acquired pneumonia for Pfizer, Bayer, Bristol-Myers Squibb, Aventis, and GlaxoSmithKline; G.D.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.E.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.T.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.L.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment:

The authors are grateful to Linda Chiarello, MS, RN, Epidemiologist, Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, and Ms. Barbara M. Shott for help in preparation of this manuscript. No official support or endorsement of this article by the Food and Drug Administration is intended or should be inferred.

Correspondence and requests for reprints should be addressed to:

Andrea L. Harabin, Ph.D.
Division of Lung Diseases, NHLBI/NIH
6701 Rockledge Drive, Room 10018
Bethesda, MD 20892-7952
E-mail: harabin@nih.gov

 

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