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==Overview==
==Overview==
No specific treatment for [[MERS-CoV]] infection is currently available. Clinical management includes supportive management of complications and implementation of recommended infection prevention and  control measures.
Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV. Monitoring for and early management of MERS-CoV-associated complications is also important.


==Medical Therapy==
==Medical Therapy==
[[MERS]] represents a great challenge in terms of treatment because it is caused by a relatively novel [[virus]] to which there is no approved therapy yet. According to
According to the ''International Severe Acute Respiratory & Emerging Infection Consortium'' from the ISARIC and the ''Interim Guidance Document'' from the [[WHO]], supportive medical care is the mainstay of management of [[MERS-CoV]].<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref><ref name=ISARIC>{{cite web | title =  
the ''International Severe Acute Respiratory & Emerging Infection Consortium'' (ISARIC), supportive medical care continues to be the approved treatment for [[MERS]]. The search for broad-spectrum inhibitors aiming to minimize the impact of [[coronavirus]] [[infection]] remains the major goal. Recent studies are showing the potential use of other [[drugs]] and therapies to treat the [[MERS-CoV]], which are based on the experience of treatment of other [[coronaviruses]] like the [[SARS virus]]. This repurposing of [[drugs]] has advantages such as: better availability, lower cost and known safety and tolerability profiles. However, lack of evidence makes these new therapies uncertain.<ref name="pmid24841273">{{cite journal| author=Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J et al.| title=Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection. | journal=Antimicrob Agents Chemother | year= 2014 | volume=  | issue=  | pages=  | pmid=24841273 | doi=10.1128/AAC.03036-14 | pmc= | url=http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }} </ref>
Treatment of MERS-CoV: Decision Support Tool | url = http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }}</ref>


Cell and animal studies have shown conflicting results: the combination of [[ribavirin]] with [[Interferon-α|interferon α]]-2b in a cell study reduced [[viral replication]]<ref name="pmid23594967">{{cite journal| author=Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H| title=Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. | journal=Sci Rep | year= 2013 | volume= 3 | issue=  | pages= 1686 | pmid=23594967 | doi=10.1038/srep01686 | pmc=PMC3629412 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23594967  }} </ref>; another study in rhesus monkeys with combination of [[intramuscular]] [[ribavirin]] and [[Interferon-α|interferon α-2b]], the group that received the treatment did not develop [[breathing]] abnormalities nor [[radiographic]] evidence of [[pneumonia]]<ref name="pmid24013700">{{cite journal| author=Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP et al.| title=Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. | journal=Nat Med | year= 2013 | volume= 19 | issue= 10 | pages= 1313-7 | pmid=24013700 | doi=10.1038/nm.3362 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24013700  }} </ref>; however, when tried in 5 critically ill patients in Saudi Arabia, this combination was inefficient in all cases, leading to a fatal outcome.<ref name="pmid24406736">{{cite journal| author=Al-Tawfiq JA, Momattin H, Dib J, Memish ZA| title=Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. | journal=Int J Infect Dis | year= 2014 | volume= 20 | issue=  | pages= 42-6 | pmid=24406736 | doi=10.1016/j.ijid.2013.12.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24406736  }} </ref>
===Supportive Care===


Despite the absence of a specific therapy, some approaches are considered to be more worth of experimentation than others. These include:<ref name=ISARIC>{{cite web | title = Treatment of MERS-CoV: Decision Support Tool | url = http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416 }}</ref><ref name="pmid23782860">{{cite journal| author=Guery B, van der Werf S| title=Coronavirus: need for a therapeutic approach. | journal=Lancet Infect Dis | year= 2013 | volume= 13 | issue= 9 | pages= 726-7 | pmid=23782860 | doi=10.1016/S1473-3099(13)70153-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23782860  }} </ref><ref name="pmid23549610">{{cite journal| author=Ren Z, Yan L, Zhang N, Guo Y, Yang C, Lou Z et al.| title=The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease. | journal=Protein Cell | year= 2013 | volume= 4 | issue= 4 | pages= 248-50 | pmid=23549610 | doi=10.1007/s13238-013-2841-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23549610  }} </ref><ref name=WHO>{{cite web | title = WHO-ISARIC joint MERS-CoV Outbreak Readiness Workshop: Clinical management and potential use of convalescent plasma | url = http://www.who.int/csr/disease/coronavirus_infections/MERS_outbreak_readiness_workshop.pdf }}</ref><ref name="pmid23993766">{{cite journal| author=Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA| title=Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)--possible lessons from a systematic review of SARS-CoV therapy. | journal=Int J Infect Dis | year= 2013 | volume= 17 | issue= 10 | pages= e792-8 | pmid=23993766 | doi=10.1016/j.ijid.2013.07.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23993766  }} </ref>
The supportive medical care aims to minimize as much as possible the damages caused by [[MERS]]. It is divided into 4 categories, according to the clinical status of the patient. These categories include:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*'''Convalescent [[plasma]]''' - this therapy, along with others that involve [[antibodies]] for the [[MERS-CoV]] has the strongest evidence for intervention. [[Plasma]] from patients who recovered from [[MERS-CoV]] [[infection]] contains neutralizing [[antibodies]], which represents the best therapy to neutralize the [[extracellular]] [[virus]].
*'''[[Interferon]]''' - there is supporting evidence from ''[[in vitro]] ([[SARS virus]] and [[MERS-CoV]])'' and ''[[in vivo]] ([[SARS virus]])'' studies that [[interferon]] inhibits [[viral replication]], especially when administered in the early course of the disease. Additionally it is commonly more available than [[plasma]].
*'''[[Corticosteroids]]''' - there is no evidence of the benefit in the [[mortality rate]] and their use is only recommended in a planned treatment regimen or when the benefits of the [[drug]] outweigh the potential harms. When used, constant monitoring is mandatory and the ideal timing is the early course of the disease, during the period of maximal [[inflammatory response]].
*'''[[Ribavirin]]''' - the most commonly used [[drug]] in the treatment of [[SARS]]. Due to the controversial results of [[clinical trials]] relating to the use of [[ribavirin]] for [[MERS]] and its high level of [[toxicity]] in humans, some experts recommend the withhold of the [[drug]].


==Supportive Care==
====Supportive Management of Primary Infection====
The supportive medical care aims to minimize as much as possible the damages caused by [[MERS]]. It is divided into 4 categories, according to the clinical status of the patient. These categories include:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*Provide [[oxygen]] therapy to patients with severe acute [[respiratory infections]], presenting with [[hypoxemia]] or [[shock]]
*Administer empiric [[antibiotics]] until the diagnosis of MERS-CoV is confirmed
*Administer fluids carefully in patients with severe acute [[respiratory infections]], even in the absence of [[shock]], since volume overload may jeopardize [[oxygenation]]
*Monitor forpossible clinical deterioration of patients with severe acute [[respiratory infections]]
*Avoid high-dose systemic [[corticosteroids]] to prevent side-effects such as opportunistic [[infections]] and [[avascular necrosis]]


===Early recognition===
====Management of Acute Respiratory Distress Syndrome====
This section focuses on the early recognition of [[symptoms]] and management of patients with severe acute [[respiratory infections]]. This includes:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*Recognition of severe manifestations of acute [[respiratory infections]], such as [[pneumonia]] or [[sepsis]]
*Prevention of [[infection]] by implementing measures like [[droplet]] or airborne precautions
*Providing [[oxygen]] therapy to patients with severe acute [[respiratory infections]], presenting with [[hypoxemia]] or [[shock]]
*Specimen collection for laboratory testing, from [[Upper respiratory tract|upper]] and [[lower respiratory tract]]s
*Empiric [[antibiotics]] until diagnosis of is confirmed
*Careful fluid administration in patients with severe acute [[respiratory infections]], even in the absence of [[shock]], since volume overload may jeopardize [[oxygenation]]
*Monitoring of possible clinical deterioration of patients with severe acute [[respiratory infections]]
*Avoidance of high-dose systemic [[corticosteroids]] to prevent side-effects such as opportunistic [[infections]] and [[avascular necrosis]]


====Acute Respiratory Distress Syndrome====
{{Details|Acute respiratory distress syndrome medical therapy|the management of ARDS}}


This section focuses on management of patients who deteriorate and develop [[ARDS]]. It includes:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
This section focuses on management of patients who deteriorate and develop [[ARDS]]. Management includes the following:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
*Recognition of severe cases where [[oxygen]] therapy may not be enough and a higher flow system may be required
*Recognition of severe cases where [[oxygen]] therapy may not be enough and a higher flow system may be required
*[[Mechanical ventilation]] in patients with [[respiratory distress]] or [[hypoxemia]] that does not resolve with high-flow [[oxygen]] therapy
*[[Mechanical ventilation]] in patients with [[respiratory distress]] or [[hypoxemia]] that does not resolve with high-flow [[oxygen]] therapy
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*Fluid management in [[ARDS]] patients, in the absence of [[shock]], in order to decrease duration of [[mechanical ventilation]]
*Fluid management in [[ARDS]] patients, in the absence of [[shock]], in order to decrease duration of [[mechanical ventilation]]


====Septic Shock====
====Management of Septic Shock====
This section targets the adequate management of [[septic shock]]. It includes:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
 
{{Details|Sepsis medical therapy|the management of septic shock}}
 
This section targets the adequate management of [[septic shock]]. Management includes the following:<ref name=WHO>{{cite web | title = Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do | url = http://www.who.int/csr/disease/coronavirus_infections/InterimGuidance_ClinicalManagement_NovelCoronavirus_11Feb13u.pdf }}</ref>
 
*Recognition of [[septic shock]] in the presence of persistent [[hypotension]] after fluid administration or signs of peripheral [[hypoperfusion]], followed by [[resuscitation]]
*Recognition of [[septic shock]] in the presence of persistent [[hypotension]] after fluid administration or signs of peripheral [[hypoperfusion]], followed by [[resuscitation]]
*Administration of [[intravenous]] crystalloids in [[septic shock]]
*Administration of [[intravenous]] crystalloids in [[septic shock]]
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*Reduce [[weakness]] by immobilization
*Reduce [[weakness]] by immobilization


==''In Vitro'' Studies==
==Antimicrobial regimen==
The development of an [[antiviral drug]] is a long-winded process that may not be compatible with the need of a [[drug]] to treat [[coronaviruses]], specifically [[MERS-CoV]]. Therefore, some studies using existing therapies are being developed in order to find a [[drug]] that will likely inhibit the [[infection]] by [[MERS-CoV]].<ref name="de WildeJochmans2014">{{cite journal|last1=de Wilde|first1=A. H.|last2=Jochmans|first2=D.|last3=Posthuma|first3=C. C.|last4=Zevenhoven-Dobbe|first4=J. C.|last5=van Nieuwkoop|first5=S.|last6=Bestebroer|first6=T. M.|last7=van den Hoogen|first7=B. G.|last8=Neyts|first8=J.|last9=Snijder|first9=E. J.|title=Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture|journal=Antimicrobial Agents and Chemotherapy|year=2014|issn=0066-4804|doi=10.1128/AAC.03011-14}}</ref><ref name="pmid23620378">{{cite journal| author=de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW et al.| title=MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. | journal=J Gen Virol | year= 2013 | volume= 94 | issue= Pt 8 | pages= 1749-60 | pmid=23620378 | doi=10.1099/vir.0.052910-0 | pmc=PMC3749523 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23620378  }} </ref>
*'''Middle East Respiratory Syndrome treatment'''<ref>http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf?ua=1</ref>
One of these studies was performed on cell cultures, in the hope of finding a previously approved [[FDA]] compounds that would inhibit the replication of the [[virus]] ''in vitro''. It was able to find four molecule inhibitors of the replication of [[MERS-CoV]]:<ref name="de WildeJochmans2014">{{cite journal|last1=de Wilde|first1=A. H.|last2=Jochmans|first2=D.|last3=Posthuma|first3=C. C.|last4=Zevenhoven-Dobbe|first4=J. C.|last5=van Nieuwkoop|first5=S.|last6=Bestebroer|first6=T. M.|last7=van den Hoogen|first7=B. G.|last8=Neyts|first8=J.|last9=Snijder|first9=E. J.|title=Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture|journal=Antimicrobial Agents and Chemotherapy|year=2014|issn=0066-4804|doi=10.1128/AAC.03011-14}}</ref><ref name="pmid23620378">{{cite journal| author=de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW et al.| title=MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. | journal=J Gen Virol | year= 2013 | volume= 94 | issue= Pt 8 | pages= 1749-60 | pmid=23620378 | doi=10.1099/vir.0.052910-0 | pmc=PMC3749523 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23620378  }} </ref>
*[[Chloroquine]]


*[[Chlorpromazine]]
:* Preferred regimen: supportive care.
:* Note: There is no antiviral recommended for this infection at this moment, even though experimental therapies are at research (IFNs, [[Ribavirin]], [[Lopinavir]], [[Mycophenolic acid]], [[Cyclosporine]], [[Chloroquine]], [[Chlorpromazine]], [[Loperamide]], [[6-mercaptopurine]] and [[6-thioguanine]]). Supportive care include: administer oxygen to patients with severe acute pulmonary infection with signs of respiratory distress, hypoxaemia or shock; use conservative fluids management, avoid administering high-dose systemic glucocorticoids, use non-invasive ventilation, but, if its nor effective, do not delay endotracheal intubation; use lung-protective strategy for intubated patients, recognize sepsis as early as possible and treat it accordingly.


*[[Loperamide]]
==References==
{{reflist|2}}


*[[Lopinavir]]
[[Category:Disease]]
 
Although the selectivity index of some compounds was limited, the researchers were able to determine a [[concentration]] of [[drug]] that inhibited the replication of the [[virus]] by more than 80%, preserving the viability of the [[cell]]. These [[drugs]] were also found to be able to inhibit the replication of other [[coronaviruses]], namely the ''HCoV-229E'' and the ''[[SARS-CoV]]''. The [[off-label]] use of these [[drugs]], particularly when used in combination, might be able to reduce the [[viral load]] of the host, therefore halting the course of [[infection]] and allowing the building of a proper [[immune response]] by the host's [[immune system]].<ref name="de WildeJochmans2014">{{cite journal|last1=de Wilde|first1=A. H.|last2=Jochmans|first2=D.|last3=Posthuma|first3=C. C.|last4=Zevenhoven-Dobbe|first4=J. C.|last5=van Nieuwkoop|first5=S.|last6=Bestebroer|first6=T. M.|last7=van den Hoogen|first7=B. G.|last8=Neyts|first8=J.|last9=Snijder|first9=E. J.|title=Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture|journal=Antimicrobial Agents and Chemotherapy|year=2014|issn=0066-4804|doi=10.1128/AAC.03011-14}}</ref>
 
Further studies will evaluate the potential benefit of the combination of 2+ of these [[drugs]], along with [[interferon]] as well. Of the above mentioned, the two presenting as better options for more [[animal studies]] and/or [[off-label]] use, are the [[chloroquine]] and [[lopinavir]]. This potential use is due to the fact that these [[drugs]] were able to inhibit replication of the [[virus]], in the tested cell cultures, in [[concentrations]] that are possible to be achieved in the human [[plasma]].<ref name="de WildeJochmans2014">{{cite journal|last1=de Wilde|first1=A. H.|last2=Jochmans|first2=D.|last3=Posthuma|first3=C. C.|last4=Zevenhoven-Dobbe|first4=J. C.|last5=van Nieuwkoop|first5=S.|last6=Bestebroer|first6=T. M.|last7=van den Hoogen|first7=B. G.|last8=Neyts|first8=J.|last9=Snijder|first9=E. J.|title=Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture|journal=Antimicrobial Agents and Chemotherapy|year=2014|issn=0066-4804|doi=10.1128/AAC.03011-14}}</ref>
 
==References==
{{Reflist|2}}


{{WH}}
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{{WS}}
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[[Category:Infectious disease]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Antiviral therapy against MERS-CoV is not yet recommended. Supportive care is the mainstay of management of MERS-CoV. Monitoring for and early management of MERS-CoV-associated complications is also important.

Medical Therapy

According to the International Severe Acute Respiratory & Emerging Infection Consortium from the ISARIC and the Interim Guidance Document from the WHO, supportive medical care is the mainstay of management of MERS-CoV.[1][2]

Supportive Care

The supportive medical care aims to minimize as much as possible the damages caused by MERS. It is divided into 4 categories, according to the clinical status of the patient. These categories include:[1]

Supportive Management of Primary Infection

Management of Acute Respiratory Distress Syndrome

Further information: Acute respiratory distress syndrome medical therapy and the management of ARDS

This section focuses on management of patients who deteriorate and develop ARDS. Management includes the following:[1]

Management of Septic Shock

Further information: Sepsis medical therapy and the management of septic shock

This section targets the adequate management of septic shock. Management includes the following:[1]

Prevention of Complications

This section is mainly based on preventing possible complications. It includes:[1]

  • preferring oral intubation
  • performing frequent antiseptic oral care
  • adjusting the patient to a reclined position
  • preferring a closed suctioning system
  • changing the ventilator circuit for every patient
  • monitoring the status of heat moisture exchanger
  • reducing intermittent mandatory ventilation

Antimicrobial regimen

  • Middle East Respiratory Syndrome treatment[8]
  • Preferred regimen: supportive care.
  • Note: There is no antiviral recommended for this infection at this moment, even though experimental therapies are at research (IFNs, Ribavirin, Lopinavir, Mycophenolic acid, Cyclosporine, Chloroquine, Chlorpromazine, Loperamide, 6-mercaptopurine and 6-thioguanine). Supportive care include: administer oxygen to patients with severe acute pulmonary infection with signs of respiratory distress, hypoxaemia or shock; use conservative fluids management, avoid administering high-dose systemic glucocorticoids, use non-invasive ventilation, but, if its nor effective, do not delay endotracheal intubation; use lung-protective strategy for intubated patients, recognize sepsis as early as possible and treat it accordingly.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do" (PDF).
  2. ↑ "Treatment of MERS-CoV: Decision Support Tool".
  3. ↑ "NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary" (PDF).
  4. ↑ Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM; et al. (2013). "Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012". Crit Care Med. 41 (2): 580–637. doi:10.1097/CCM.0b013e31827e83af. PMID 23353941.
  5. ↑ Papazian, Laurent; Forel, Jean-Marie; Gacouin, Arnaud; Penot-Ragon, Christine; Perrin, Gilles; Loundou, Anderson; Jaber, Samir; Arnal, Jean-Michel; Perez, Didier; Seghboyan, Jean-Marie; Constantin, Jean-Michel; Courant, Pierre; Lefrant, Jean-Yves; Guérin, Claude; Prat, Gwenaël; Morange, Sophie; Roch, Antoine (2010). "Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome". New England Journal of Medicine. 363 (12): 1107–1116. doi:10.1056/NEJMoa1005372. ISSN 0028-4793.
  6. ↑ Messerole E, Peine P, Wittkopp S, Marini JJ, Albert RK (2002). "The pragmatics of prone positioning". Am J Respir Crit Care Med. 165 (10): 1359–63. doi:10.1164/rccm.2107005. PMID 12016096.
  7. ↑ Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S; et al. (2006). "An intervention to decrease catheter-related bloodstream infections in the ICU". N Engl J Med. 355 (26): 2725–32. doi:10.1056/NEJMoa061115. PMID 17192537.
  8. ↑ http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf?ua=1
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