Ebola Facts Symptoms, Diagnosis, Treatments, Protection, Preparedness Updated

Ebola Facts Symptoms, Diagnosis, Treatments, Protection, Preparedness Updated

Ebola Facts Symptoms, Diagnosis, Treatments, Protection, Preparedness Updated 10/21/14 Symptoms of Ebola Initial symptoms are nonspecific - may include fever, chills, myalgias, and malaise. Patients can progress to develop gastrointestinal symptoms: severe watery diarrhea, nausea, vomiting, abdominal pain Other symptoms: chest pain, shortness of breath, headache or confusion, conjunctival injection, hiccups, seizures, and cerebral edema

Bleeding not universally present but can manifest later as petechiae, ecchymosis/ bruising, or oozing. Frank hemorrhage less common. Some develop diffuse erythematous maculopapular rash that can desquamate. Most common symptoms reported during current outbreak: fever (87%) fatigue (76%) vomiting (68%) diarrhea (66%) loss of appetite (65%) Patients with fatal disease develop more severe clinical signs early during infection and die between days 6 - 16 of complications (mean of 7.5 days). In non-fatal cases, patients may have fever for several days and improve, around day 6.

The case fatality proportion in West Africa is about 71% Source: Centers for Disease Control and Prevention. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014 Diagnosis of Ebola Diagnosing Ebola can be difficult at first since early symptoms, such as fever, are nonspecific to Ebola infection. However, if a person has the early symptoms and has had contact with Ebola they should be isolated and public health professionals notified. Samples from the patient can then be collected and tested to confirm infection. Source: Centers for Disease Control and Prevention http://www.cdc.gov/vhf/ebola/diagnosis/index.html Accessed Oct. 14, 2014 Source: http://www.cdc.gov/vhf/ebola/pdf/checklist-patients-eva luated-us-evd.pdf Clinical Progression of Ebola Source: Jonathan B. Perlin, MD, PhD and HCA Clinical Excellence Knowledge Center, 2014

Treatment of Ebola There are no approved treatments available for EVD. Clinical management focus - supportive care of complications: hypovolemia, electrolyte abnormalities, hematologic abnormalities, refractory shock, hypoxia, hemorrhage, septic shock, multi-organ failure, and DIC. Recommended care includes: volume repletion maintenance of blood pressure (with vasopressors if needed) maintenance of oxygenation pain control nutritional support treating secondary bacterial infections and pre-existing comorbidities Among patients from West Africa, large volumes of intravenous fluids have often been required to correct dehydration due to diarrhea and vomiting.

Several investigational therapeutics for Ebola virus disease are in development. There are no approved vaccines available for EVD. Several investigational Ebola vaccines are in development, and Phase I trials are underway for some vaccine candidates. Source: Centers for Disease Control and Prevention. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014 Clinical Evidence CARE COMPONENT Disease Pathophysiology4 CLINICAL MANAGEMENT Research suggests the virus first infects dendritic cells, disabling immune system, and then attacks the vascular system, causing hemorrhage, hypotension and shock. The virus also affects the liver (impacting coagulation proteins), the adrenal gland (affecting steroid synthesis for blood pressure stabilization) and the gastrointestinal tract (diarrhea). Hemodynamic

Support1,2,5-7 Hypotension/Shock: Aggressive IV fluid resuscitation resembling the approach to the septic shock patient is identified by the CDC as one of three interventions that impact mortality through observation and case series. Base fluid selection (Lactated Ringers or Normal Saline) on patient electrolyte status. One animal study examined supplemental fluid resuscitation of infected, hypotensive rhesus macaques, which resulted in improved renal parameters. Hydrocortisone may be considered to support viral disruption in steroid synthesis. Hemorrhage/DIC: Management of hemorrhage is inconsistent in literature. Literature around previous outbreak transfusion strategies includes various blood products, antifibrinolytics, and clotting factors. One recent report suggests the use of melatonin to combat endothelial disruption, disseminated intravascular coagulation (DIC) and multiple organ hemorrhage due to potential benefit, high safety profile, and limited alternative therapies. Hypotension/shock, hemorrhage/DIC Respiratory Support1,2,8-10 Oxygen therapy, ventilation Maintain adequate oxygenation (titrate to SpO2 >90%). To protect the airway and/or treat multisystem

organ failure, standard mechanical ventilation practices should be followed with the addition of HEPA filtration of airflow gases. Methods of non-invasive ventilation are not ideal due to increased potential for aspiration and infection transmission. Additional measures including placement of ventilated patients in a negative pressure room, use of video/optical laryngoscopy for intubation, use of rapid sequence intubation with neuromuscular blockade, and use of a ventilator-patient monitoring system interface to minimize entry into the patient room should be considered.1-2,6-8 Source: Jonathan B. Perlin, MD, PhD and HCA Management Services, L.P. 2014 Clinical Evidence CARE COMPONENT Infection Support1,2,6,11 Fever, secondary infection, malaise, plasma transfusion, antivirals CLINICAL MANAGEMENT Treat fever with acetaminophen (avoid aspirin and NSAIDs due to antiplatelet activity). Identify any additional sources of infection and treat with appropriate empiric antimicrobials. If sepsis develops, administer broad-spectrum IV antibiotics within 1 hour and follow Surviving Sepsis Early Goal Directed Therapy (EGDT). Antiviral and antimalarial agents are not efficacious for Zaire Ebola virus. Consider

passive immunotherapy early in disease course by transfusing whole blood or plasma donated from a convalescent patient. Renal/Hepatic Support1,2,4,6,12,13 Renal: Advanced stage may lead to impaired kidney function, increased creatinine and BUN, and decreased urine output. Renal failure has been reported in fatal cases. Patients may experience persistent oliguria, hematuria and proteinuria despite IV fluid resuscitation. Reports of peritoneal and hemodialysis show no consistent correlation on survivability, and transmission risk to healthcare workers should be considered. Hepatic: Patients demonstrate impaired liver function, hepatomegaly and elevated liver enzymes (ALT/ AST), but severity is lower than that seen in hepatitis A/B or yellow fever. One study showed AST was several times higher than ALT in fatal cases. Pain Management2,14- Treat mild pain with acetaminophen and moderate to severe pain with opioids. Avoid diclofenac, 16 ibuprofen and other NSAIDS due to antiplatelet activity; avoid tramadol due to seizure activity. The management of pain resembling the approach to a critically ill patient with potential multi-organ failure should be followed due to high risk of renal and hepatic failure. Neurologic Support1,6 Monitor the patient for confusion, anxiety and seizures. Treat anxiety and seizures with Anxiety, Confusion, benzodiazepines. Avoid the use of other medications that may reduce seizure threshold. Late in the

Seizures disease progression, monitor neurologic status for increased intracranial pressure and intracranial hemorrhage. Source: Jonathan B. Perlin, MD, PhD and HCA Management Services, L.P. 2014 Clinical Evidence CARE COMPONENT Gastrointestinal Support1,10 Nutrition, Nausea/Vomiting, Diarrhea CLINICAL MANAGEMENT Provide rehydration therapy to prevent volume depletion. Correct abnormal electrolytes. Proton pump inhibitors should be administered for dyspepsia and gastrointestinal bleed prophylaxis. Administer antiemetics for nausea/vomiting. Monitor for dehydration. Survivability2,3 Dependent upon access to basic care and patient immune status. Current West Africa Ebola strain has reported 70% mortality rate (October 14, 2014).

Recovery2,13 Recovery (weeks to months) is highly dependent on supportive care and immunologic response of patient. Men can still transmit Ebola virus through semen for up to 3 months so abstinence is encouraged during this time. Once fully recovered, patients are no longer able to transmit the virus. Development of antibodies last at least 10 years but it is unknown if this confers lifelong immunity or if infection with other strains is possible. Acute complications include: generalized weakness, weight loss, headache, sensory distortion, migratory arthralgias, skin sloughing, alopecia, and persistent anemia. Uveitis and orchitis can occur weeks after illness, and virus can persist in aqueous humor and semen. Experimental Therapies2,4 No experimental vaccines or antiviral medications have been fully tested for safety or efficacy. ZMapp (Mapp Biopharmaceutical, Inc.), is an experimental treatment of three monoclonal antibodies that bind to viral protein. All available doses have been distributed at this time. Several experimental vaccines and treatments in animal models show promise. Source: Jonathan B. Perlin, MD, PhD and HCA Management Services, L.P. 2014 Revised Guidance on PPE for Health Care Workers Updated guidance on PPE to be used and processes for donning and doffing PPE for health

care workers entering a patient room hospitalized with Ebola. Emphasizes the importance of training, practice, competence, and observation of health care workers in correct donning and doffing of PPE selected by the facility. Key principles: Prior to patient contact, all workers must have repeated training and demonstrated competency in Ebola-related infection control, and specifically donning/ doffing proper PPE. While working in PPE no skin should be exposed. Overall safe care must be overseen by onsite manager at all times, and each step of every PPE donning/doffing procedure supervised by a trained observer Ebola is spread through direct contact with blood or body fluids or with contaminated objects. For all workers, full body coverage PPE is recommended to reduce the risk of self-contamination To protect workers, facilities must provide onsite management and oversight on safe use of PPE and implement administrative and environmental controls Source: Centers for Disease Control and Prevention. This guidance is current as of October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Please see website for complete details. Recommended Administrative and Environmental Controls for Healthcare Facilities Protecting workers and preventing spread of Ebola requires proper administrative procedures and safe work practices including : Implement triage protocols to identify potential patients and institute precautions Designate site managers overseeing implementation of safety precautions:

Site managers monitor supply and evaluate care in isolation area At least one site manager always on-site where Ebola patient is being treated Identify ahead of time critical care functions and essential workers: For Ebola patient care For collection of laboratory specimens For environmental management and waste Ensure workers are trained in all recommended protocols and PPE Workers should practice donning/doffing procedures and demonstrate competency during training before caring for patients Use trained observers to monitor correct PPE use and protocol adherence and guide workers using a checklist for every donning /doffing procedure Document observer and worker training in donning/doffing and performing necessary carerelated duties while wearing PPE Designate spaces so that PPE can be donned and doffed in separate areas Source: Centers for Disease Control and Prevention. This guidance is current as of October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Please see website for complete details. Recommended Administrative and

Environmental Controls for Healthcare Facilities Key safe work practices include: Isolate patient in room with closed door and private bathroom as soon as possible. Limit contact with patient and restrict non-essential personnel and visitors. Monitor patient care area and log entry and exit of all workers Ensure trained observer watches each donning and doffing procedure and provides supervisory assurance Ensure workers have sufficient time to don and doff PPE correctly Ensure practical precautions taken during patient care: keeping hands away from the face limiting touch of surfaces and body fluids preventing needlestick and sharps injuries performing frequent disinfection of gloved hands using an alcohol-based hand rub Disinfect visibly contaminated PPE, surfaces, or equipment Perform regular cleaning and disinfection of patient care area surfaces

Performed by nurses or physicians as part of patient care activities to limit workers in room. Implement worker observation in the patient room, if possible Establish exposure management plan that addresses decontamination and follow-up of an affected worker. Training on plan and follow-up should be part of the worker training. Source: Centers for Disease Control and Prevention. This guidance is current as of October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Please see website for complete details. Recommended PPE Key to all PPE is consistent implementation through repeated training and practice. Facility should select and standardize PPE for all essential workers directly interacting with Ebola patients Provide written protocol outlining procedures for donning and doffing of PPE, and review and monitor by trained observer

CDC recommends facilities use a powered air-purifying respirator (PAPR) or an N95 or higher respirator in the event of an unexpected aerosol-generating procedure. For healthcare workers who spend extended periods in PPE, safety and comfort are critical. Standardizing attire under PPE (e.g., surgical scrubs or disposable garments and dedicated washable footwear) facilitates donning and doffing process and eliminates concerns of contamination of personal clothing. If facilities elect to use different PPE from what is outlined by CDC (e.g., coveralls with either an integrated hood or a surgical hood with integrated full face shield), they must train workers and ensure that donning and doffing procedures are adjusted and practiced accordingly. Source: Centers for Disease Control and Prevention. This guidance is current as of October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Please see website for complete details. Recommended PPE PAPR or N95 Respirator PAPR: A PAPR with a full face shield, helmet, or headpiece. Any reusable helmet or headpiece must be covered with a single-use

(disposable) hood that extends to shoulders and fully covers neck and is compatible with selected PAPR. N95 Respirator: Single-use (disposable) N95 respirator in combination with single-use (disposable) surgical hood extending to shoulders and single-use (disposable) full face shield. If N95 respirators are used instead of PAPRs, careful observation is required to ensure workers are not inadvertently touching faces under face shield during care. Single-use (disposable) fluid-resistant or impermeable gown that extends to at least mid-calf or coverall without integrated hood. Coveralls with or without integrated socks are acceptable. Consideration should be given to gowns or coveralls with thumb hooks to secure sleeves over inner glove. Single-use (disposable) nitrile examination gloves with extended cuffs. Two pairs of gloves should be worn. At a minimum, outer gloves should have extended cuffs. Single-use (disposable), fluid-resistant or impermeable boot covers that extend to at least mid-calf or singleuse (disposable) shoe covers. Boot and shoe covers should allow for ease of movement and not present a slip hazard to the worker.

A PAPR with a self-contained filter and blower unit integrated inside the helmet is preferred. A PAPR with external belt-mounted blower unit requires adjustment of the sequence for donning and doffing. Single-use (disposable) fluid-resistant or impermeable shoe covers are acceptable only if they will be used in combination with a coverall with integrated socks. Single-use (disposable), fluid-resistant or impermeable apron that covers torso to level of mid-calf should be used if Ebola patients have vomiting or diarrhea. If a PAPR will be worn, consider selecting an apron that ties behind the neck to facilitate easier removal during the doffing procedure. Source: Centers for Disease Control and Prevention. This guidance is current as of October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html. Please see website for complete details. For more detail on PPE for Health Care Workers, please visit: http://www.cdc.gov/vhf/ ebola/hcp/infection-prev ention-and-control-reco mmendations.html

Source: http://www.cdc.gov/vhf/ebola/pdf/ppe-pos ter.pdf Accessed Oct. 14, 2014 External (Non-CDC) Resources on PPE Emory Healthcare: Ebola Preparedness Protocols University of Nebraska Medical Center: PPE for Ebola Mdecins Sans Frontires (Doctors without Borders): Filovirus Haemorrhagic Fever Guideline, 2008[PDF - 1 34pages] World Health Organization (WHO): Infection preventi on and control guidance for care of patients in health -care settings, with focus on Ebola Source: Centers for Disease Control and Prevention. Accessed October 20, 2014 from http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html Hospital Preparedness Checklist Every hospital should ensure that it can detect a patient with Ebola, protect health care workers, and respond in a coordinated fashion. Many signs and symptoms of Ebola are non-specific and similar to common diseases.

Transmission can be prevented with appropriate infection control measures. Checklist highlights key areas for hospital emergency management officers, infection control practitioners, and clinicians to detect possible Ebola cases, protect employees, and respond appropriately. Hospitals should review infection control procedures and incorporate plans for administrative, environmental, and communication measures, as well as personal protective equipment (PPE) training and education. Hospitals should also define the individual work practices that will be required to detect the introduction of a patient with Ebola, prevent spread, and manage the impact on patients, the hospital, and staff. Source: Centers for Disease Control and Prevention;. Accessed October 15, 2014 http://www.cdc.gov/vhf/ebola/pdf/hospital-checklist-ebola-preparedness.pdf Hospital Preparedness Checklist Detect: Screen patients for symptoms and risk factors for Ebola, including fever of greater than 101.5 degrees and travel to West Africa (in particular, Guinea, Liberia and Sierra Leone). Patients meeting criteria should be immediately isolated and tested. Conduct periodic checks to confirm screening procedures and notification, isolation and personal protective equipment (PPE) procedures. Protect: Use CDC-recommended infection control practices Review, implement and drill with first-contact personnel, clinicians, ancillary staff, and others as

appropriate on: Infectious disease procedures and protocols Triage techniques and Ebola screening questions Disease identification, testing, specimen collection and transport procedures Isolation, quarantine and security procedures Communications and reporting procedures Cleaning and disinfection procedures Respond: All staff should know what to do when encountering a suspected Ebola patient. Ebola is a nationally notifiable disease and must be reported to public health authorities. Ensure hospital is in contact with local/state health department to confirm communication strategies. Review plans and protocols, and exercise/test ability to share relevant health data. Source: American Hospital Association, adapted from Centers for Disease Control and Prevention Detailed Hospital Checklist for Ebola Preparedness. http://www.cdc.gov/vhf/ebola/pdf/hospital-checklist-ebola-preparedness.pdf Accessed October 15, 2014 Surgical Protocol for Possible or Confirmed Ebola Cases Elective surgical procedures should not be performed in cases of suspected or confirmed Ebola. In cases where an emergency operation must be performed this protocol should be implemented to minimize risk to hospital personnel.

The choice of operative approach (open or MIS) should take into consideration minimizing potential hazards to all members of the OR team. Although protocols for Personal Protective Equipment (PPE) are in place, there is no guideline for operating room personnel and surgical providers. The American College of Surgeons has adapted Centers for Disease Control and Prevention recommendations to the OR environment. Source: American College of Surgeons. https://www.facs.org/ebola/surgical-protocol Updated October 6, 2014. Accessed October 16, 2014 Surgical Protocol - Possible or Confirmed Ebola Cases Patient Transport and Transfer to OR Health care providers should wear the following to transport and transfer a patient to OR. Gloves Level 3 AAMI fluid resistant gown eye protection (goggles or face shield) Facemask Surgical Checklist Ebola status discussed in pre- and post-op briefing as integral part of Safe Surgery Checklist All personnel should be aware of potential risks of exposure

OR Staff Personal Protection Equipment Due to significant risk of exposure all OR room personnel should wear: Personal Protective Gear AAMI Level 4* Impervious Surgical Gowns Leg coverings with full plastic film coating over fabric not just over foot area Full face shield Mask Double gloves Surgical hood *Level 4 AAMI rated gowns, drapes, and protective apparel demonstrate the ability to resist liquid and viral penetration in a laboratory test, ASTM F1671. Source: American College of Surgeons. https://www.facs.org/ebola/surgical-protocol, Updated Oct. 6, 2014. Accessed October 16, 2014 Surgical Protocol - Possible or Confirmed Ebola Cases Surgical Drapes AAMI Level 4* drapes should be used Instrumentation and Sharps Keep sharps to a minimum Use instruments, rather than fingers, to grasp needles, retract tissue, and load/unload needles and scalpels Give a verbal announcement when passing sharps

Avoid hand-to-hand passage of sharp instruments by using a basin or neutral zone that has been agreed upon at the case start Use alternative cutting methods such as blunt electrocautery Substitute endoscopic surgery for open surgery when possible Use round-tipped scalpel blades instead of pointed sharp-tipped blades Use elctrocautery preferentially to scalpel for incisions No needles or sharps on the Mayo stand No recapping of needles Use blunt tip suture needles when possible Continue sharps safety techniques during OR table clean up post-procedure Source: American College of Surgeons. https://www.facs.org/ebola/surgical-protocol, Updated Oct. 6, 2014. Accessed October 16, 2014 Surgical Protocol - Possible or Confirmed Ebola Cases 6. OR Staff Exposure Persons with percutaneous or mucocutaneous exposures to blood, body fluids, secretions, or excretions should: Stop working and immediately wash affected skin surfaces with soap and water Mucous membranes (e.g., conjunctiva) should be irrigated with copious amounts of water or eyewash solution Immediately contact hospital Infectious Disease consultant for post-exposure evaluation. --------------------------------------------------------------------------------------------------------------------References

http://www.cdc.gov/hicpac/pdf/isolation/Isolation2007.pdf http://www.cdc.gov/sharpssafety/resources.html http://www.cdc.gov/vhf/ebola/hcp/infection-prevention-and-controlrecommendations.html Source: American College of Surgeons. https://www.facs.org/ebola/surgical-protocol, Updated Oct. 6, 2014. Accessed October 16, 2014 References Baize S. et al. Emergence of Zaire Ebola Virus Disease in Guinea Prepminary Report. N Engl J Med. 2014 Apr 16. epub Feldmann H , Geisbert TW. Ebola Haemorrhagic Fever. Lancet. 2011 Mar 5;377(9768):849-62. Fowler RA, Fletcher T, Fischer WA, et al. Caring for Critically Ill Patients with Ebola Virus Disease: Perspectives from West Africa. Am J Respir Crit Care Med. 2014 Aug 25. Epub Kortepeter MG, Bausch DG, Bray M. Basic Cpnical and Laboratory Features of Filoviral Hemorrhagic Fever. J Infect Dis. 2011 Nov;204 Suppl 3:S810-6 WHO Ebola Response Team. Ebola Virus Disease in West Africa The First 9 Months of the Epidemic and Forward Projections. N Eng J Med. 2014 Sept 23. Epub Source: http://www.cdc.gov/vhf/ebola/index.html Accessed Oct. 14, 2014 REFERENCES AND EVIDENCE CLASSIFICATION

1. Clinical management of patients with viral haemorrhagic fever: a pocket guide for the front-line health worker. World Health Organization. World Health Organization , 2014. April 2014. Level 3 2. Ebola (Ebola Virus Disease). Centers for Disease Control and Prevention website http://www.cdc.gov/vhf/ebola/. Updated October 3, 2014. Accessed October 16, 2014. Level 3 3. WHO finds 70 percent Ebola mortality rate. Aljazeera.com Aljazeera America, 15 Oct 2014. Web. 16 Oct 2014. 4. Ansari AA. Clinical features and pathobiology of Ebolavirus infection J Autoimmun 2014 Sep 23. Doi: 10.1016/j.jaut/2014.09.001. [Epub ahead of print] Level 3 5. Kortepeter MG, Salwer JV, Hensley LE, et al. Real-time monitoring of cardiovascular function in rhesus macaques infected with Zaire ebolavirus. J Infect Dis 2011 Nov;204 Suppl 3:S1000-10. Animal study 6. Clark DV, Jahrling PB, Lawler JV. Clinical management of filovirus-infected patients. Viruses. 2012; 4, 1668-1686. Level 3 7. Tan DX, Korkmaz A, Reiter RG, Manchester LC. Ebola virus disease: potential use of melatonin as treatment. J Pineal Res 2014 Sep 27. doi: 10.1111/jpi.12186. [Epub ahead of print] Level 3 8. Ebola Clinical Care Guidelines: a guide for clinicians in Canada. http://www.ammi.ca/media/69846/Ebola%20Clinical%20Care%20Guidelines%202%20Sep%202014.pdf. Updated August 29, 2014. Accessed October 16, 2014. Level 3 9. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. The Lancet. 2011;377(9768):849-62. Level 3 10. Fowler RA, Fletcher T, Fischer WA, 2nd, Lamontagne F, Jacob S, Brett-Major D, et al. Caring for critically ill patients with ebola virus disease. Perspectives from west Africa. Am J Respir Crit Care Med. 2014;190(7):733-7. Level 3 11. Mupapa K, Massamba M, Kibadi K, Kuvala K, Bwaka, et al. Treatment of ebola hemorrhagic fever with blood transfusion from convalescent patients. J Infect Dis. 1999; 179(Suppl 1):S18-23. Level 2 12. Roddy P, Colebunders R, Jeffs B, et al. Filovirus hemorrhagic fever outbreak case management: a review of current and future treatment options. Infect Disease. 2011; 204: S791-S795. Level 3 13. Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. Infect Disease. 2011; 204: S810-S816. Level 3

14. WHO: IMAI District Clinician Manual: Hospital Care for Adolescents and Adults- Guidelines for the Management of Common Illnesses with Limited Resources, 2011. Available at http://apps.who.int/iris/bitstream/10665/77751/1/9789241548281_Vol1_eng.pdf. Level 3 15. Sprecher A. Filovirus haemorrhagic fever guidelines. Mdecins Sans Frontires Belgium 2013. (in draft) Level 3 16. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263. Level 3 See handout for evidence classification. Source: Jonathan B. Perlin, MD, PhD and HCA Management Services, L.P. 2014

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