Septic shock: Difference between revisions

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===Corticosteroids===
===Corticosteroids===
====Practice guidelines====
[[Clinical practice guideline]]s by American College of Critical Care Medicine conclude "hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents."<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba |issn=}}</ref> In a [[meta-analysis]] that was included with the guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignficant) trend towards benefit in mortality".<ref name="pmid18496365"/>


{| class="wikitable" align="right"
Regarding whether the use of steroids should be confined to patients with relative adrenal insufficiency, the guidelines state "ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GC".<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba |issn=}}</ref>
|+ Comparison of major trials of corticosteroids
 
!  &nbsp;!! CORTICUS, 2008<ref name="pmid18184957">{{cite journal |author=Sprung CL, Annane D, Keh D, ''et al'' |title=Hydrocortisone therapy for patients with septic shock |journal=N. Engl. J. Med. |volume=358 |issue=2 |pages=111–24 |year=2008 |pmid=18184957 |doi=10.1056/NEJMoa071366 |issn=|url=http://content.nejm.org/cgi/content/full/358/2/111}}</ref>!! French study, 2002<ref name="pmid12186604">{{cite journal |author=Annane D, Sébille V, Charpentier C, ''et al'' |title=Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock |journal=JAMA |volume=288 |issue=7 |pages=862–71 |year=2002 |month=August |pmid=12186604 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12186604 |issn=}}</ref>
====Randomized, controlled trials====
|-
{| class="wikitable"
| colspan="3"| Patients:
|+ Major trials of corticosteroids for septic shock among patients with relative adrenal insufficiency.<ref name="pmid18184957">{{cite journal |author=Sprung CL, Annane D, Keh D, ''et al'' |title=Hydrocortisone therapy for patients with septic shock |journal=N. Engl. J. Med. |volume=358 |issue=2 |pages=111–24 |year=2008 |pmid=18184957 |doi=10.1056/NEJMoa071366 |issn=|url=http://content.nejm.org/cgi/content/full/358/2/111}}</ref><ref name="pmid12186604">{{cite journal |author=Annane D, Sébille V, Charpentier C, ''et al'' |title=Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock |journal=JAMA |volume=288 |issue=7 |pages=862–71 |year=2002 |month=August |pmid=12186604 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12186604 |issn=}}</ref>
|-
! rowspan="2"|Trial!!rowspan="2"|Patients!!rowspan="2"|Interventions!!rowspan="2"|Outcomes!!colspan="2"|Results for patients with relative adrenal insufficiency
| &nbsp;&nbsp;Prevalence of [[adrenal insufficiency]]||align="center"| 47% ||align="center"| 76%
|-
| &nbsp;&nbsp;onset of shock|| align="center"|within the previous 72 hours|| align="center"|within the previous 3 hours
|-
| &nbsp;&nbsp;[[Critical_care#SAPS_II|SAPS II score]]<br>&nbsp;&nbsp;(higher is sicker)|| align="center"|50|| align="center"|59
|-
| Intervention || align="center"|200 mg/day of hydrocortisone|| align="center"|200 mg/day of hydrocortisone<br>50 microgram/day fludrocortisone
|-
|-
| colspan="3"| Results:
! Control!!Intervention
|-
|-
| &nbsp;&nbsp;28-day survival in control group|| align="center"|69%|| align="center"|27%
| CORTICUS<ref name="pmid18184957"/><br/>2008||&bull;&nbsp;Onset of shock &le; 72 hours<br/>&bull;&nbsp;[[Adrenal insufficiency]]: 47%<br/>&bull;&nbsp;[[Critical_care#SAPS_II|SAPS II score]]: 50<br/>&bull;&nbsp;Intratracheal intubation: 100%<br/>&bull;&nbsp;Arterial [[lactic acid|lactate]]: 4.0|| align="center"|200 mg/day of hydrocortisone|| 28-day mortality||align="center"|36%||align="center"|39%
|-
|-
| &nbsp;&nbsp;Mortality at 28 days|| align="center"| no reduction in mortality<br>regardless of [[adrenal insufficiency]]|| align="center"|reduced mortality<br>for patients with [[adrenal insufficiency]]
| French study<ref name="pmid12186604"/><br/>2002||&bull;&nbsp;Onset of shock &le; 3 hours<br/>&bull;&nbsp;[[Adrenal insufficiency]]: 76%<br/>&bull;&nbsp;[[Critical_care#SAPS_II|SAPS II score]]: 59<br/>&bull;&nbsp;Intratracheal intubation: 88%<br/>&bull;&nbsp;Arterial [[lactic acid|lactate]]: 4.5|| align="center"|200 mg/day of hydrocortisone<br>50 microgram/day fludrocortisone||28-day mortality||align="center"|63%||align="center"|53%
|}
|}
;Practice guidelines and meta-analysis
[[Clinical practice guideline]]s by American College of Critical Care Medicine conclude "hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents."<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba |issn=}}</ref>


In a [[meta-analysis]] that was included with the guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignficant) trend towards benefit in mortality".<ref name="pmid18496365"/>
Although the largest and most recent [[randomized controlled trial]] (CORTICUS<ref name="pmid18184957">{{cite journal |author=Sprung CL, Annane D, Keh D, ''et al'' |title=Hydrocortisone therapy for patients with septic shock |journal=N. Engl. J. Med. |volume=358 |issue=2 |pages=111–24 |year=2008 |pmid=18184957 |doi=10.1056/NEJMoa071366 |issn=}}</ref>) was negative, its patients were less sick (as evidenced by less stringent inclusion criteria and less mortality in the control group) and mineralcorticoids were not given as a co-treatment as compared to the French trial be Annane<ref name="pmid12186604">{{cite journal |author=Annane D, Sébille V, Charpentier C, ''et al'' |title=Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock |journal=JAMA |volume=288 |issue=7 |pages=862–71 |year=2002 |month=August |pmid=12186604 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12186604 |issn=}}</ref>. In a post hoc analysis of the CORTICUS study, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.<ref name="pmid18184957"/>


Prior meta-analyses have concluded that steroids are beneficial but these analyses did not include the CORICUS trial published in 2008.<ref name="pmid15238370">{{cite journal |author=Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C |title=Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose |journal=Ann. Intern. Med. |volume=141 |issue=1 |pages=47–56 |year=2004 |month=July |pmid=15238370 |doi= |url= |issn=}}</ref><ref name="pmid15289273">{{cite journal |author=Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y |title=Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis |journal=BMJ |volume=329 |issue=7464 |pages=480 |year=2004 |month=August |pmid=15289273 |pmc=515196 |doi=10.1136/bmj.38181.482222.55 |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=15289273 |issn=}}</ref>
The lack of mineralocorticoid  in the new study may not be important. In the new trial, the total hydrocortisone per day in the new trial is 200 mg. This equates to 200/250 or 0.8 mg (800 microgram) fludrocortisone (see relative potency table for [[corticosteroid]]s). The French study by Annane used 50 microgram daily of fludrocortisone.<ref name="pmid12186604"/>


Regarding whether the use of steroids should be confined to patients with relative adrenal insufficiency, the guidelines state "ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GC".<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba |issn=}}</ref> The recommendation is based on the similar impact of steroids on shock reversal at seven days regardless of adrenal status. However, mortality data in the French study by Annane only found benefit in the patients with relative adrenal insufficiency. Although the CORTICUS study by Sprung found no mortality benefit, these patients were not as ill. In a post hoc analysis of the CORTICUS study, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.<ref name="pmid18184957"/> Thus, confining steroids to the sickest patients who also have relative adrenal insufficiency is supported by mortality data.
[[Meta-analysis|Meta-analyses]] of the French trial and prior trials have concluded that steroids are beneficial but these analyses did not include the CORTICUS trial published in 2008.<ref name="pmid15238370">{{cite journal |author=Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C |title=Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose |journal=Ann. Intern. Med. |volume=141 |issue=1 |pages=47–56 |year=2004 |month=July |pmid=15238370 |doi= |url= |issn=}}</ref><ref name="pmid15289273">{{cite journal |author=Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y |title=Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis |journal=BMJ |volume=329 |issue=7464 |pages=480 |year=2004 |month=August |pmid=15289273 |pmc=515196 |doi=10.1136/bmj.38181.482222.55 |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=15289273 |issn=}}</ref> In a [[meta-analysis]] that was included with the American College of Critical Care Medicine guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignficant) trend towards benefit in mortality".<ref name="pmid18496365">{{cite journal |author=Marik PE, Pastores SM, Annane D, ''et al'' |title=Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine |journal=Crit. Care Med. |volume=36 |issue=6 |pages=1937–49 |year=2008 |month=June |pmid=18496365 |doi=10.1097/CCM.0b013e31817603ba |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/CCM.0b013e31817603ba |issn=}}</ref>
 
;Details of individual trials
[[Corticosteroid]]s, perhaps if combined with a [[mineralocorticoid]], may reduce mortality among selected patients who have relative [[adrenal insufficiency]]<ref name="pmid12186604">{{cite journal |author=Annane D, Sébille V, Charpentier C, ''et al'' |title=Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock |journal=JAMA |volume=288 |issue=7 |pages=862–71 |year=2002 |month=August |pmid=12186604 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12186604 |issn=}}</ref> It is unclear whether the corticosteroids should be combined with mineralocorticoids and whether the medications should be reserved for the sickest patients (those with persistent hypotension).
 
Although the largest and most recent [[randomized controlled trial]] was negative, its patients were less sick (as evidenced by less stringent inclusion criteria and less mortality in the control group) and mineralcorticoids were not given as a co-treatment.<ref name="pmid18184957">{{cite journal |author=Sprung CL, Annane D, Keh D, ''et al'' |title=Hydrocortisone therapy for patients with septic shock |journal=N. Engl. J. Med. |volume=358 |issue=2 |pages=111–24 |year=2008 |pmid=18184957 |doi=10.1056/NEJMoa071366 |issn=}}</ref> In a post hoc analysis of the CORTICUS study, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.<ref name="pmid18184957"/>
 
The lack of mineralocorticoid  in the new study may not be important. In the new trial, the total hydrocortisone per day in the new trial is 200 mg. This equates to 200/250 or 0.8 mg (800 microgram) fludrocortisone (see relative potency table for [[corticosteroid]]s). The French study by Annane used 50 microgram daily of fludrocortisone.<ref name="pmid12186604"/>


===Activated protein C===
===Activated protein C===

Revision as of 09:57, 26 May 2009

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In medicine, septic shock is a form of sepsis with "associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status."[1]

Complications

Myocardial dysfunction

Transient myocardial dysfunction may occur in 59% of patients and may resolve within 12 days.[2]

Treatment

Vasopressors

Among the choices for pressors, a randomized controlled trial concluded that there was no difference between the biogenic amines norepinephrine (plus dobutamine as needed for cardiac output) versus epinephrine.[3] Similarly, another randomized controlled trial found no difference between vasopressin and norepinephrine.[4]

Corticosteroids

Practice guidelines

Clinical practice guidelines by American College of Critical Care Medicine conclude "hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents."[5] In a meta-analysis that was included with the guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignficant) trend towards benefit in mortality".[5]

Regarding whether the use of steroids should be confined to patients with relative adrenal insufficiency, the guidelines state "ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GC".[5]

Randomized, controlled trials

Major trials of corticosteroids for septic shock among patients with relative adrenal insufficiency.[6][7]
Trial Patients Interventions Outcomes Results for patients with relative adrenal insufficiency
Control Intervention
CORTICUS[6]
2008
• Onset of shock ≤ 72 hours
• Adrenal insufficiency: 47%
• SAPS II score: 50
• Intratracheal intubation: 100%
• Arterial lactate: 4.0
200 mg/day of hydrocortisone 28-day mortality 36% 39%
French study[7]
2002
• Onset of shock ≤ 3 hours
• Adrenal insufficiency: 76%
• SAPS II score: 59
• Intratracheal intubation: 88%
• Arterial lactate: 4.5
200 mg/day of hydrocortisone
50 microgram/day fludrocortisone
28-day mortality 63% 53%

Although the largest and most recent randomized controlled trial (CORTICUS[6]) was negative, its patients were less sick (as evidenced by less stringent inclusion criteria and less mortality in the control group) and mineralcorticoids were not given as a co-treatment as compared to the French trial be Annane[7]. In a post hoc analysis of the CORTICUS study, the sickest patients ("systolic blood pressure persisting at less than 90 mm Hg within 30 hours") had better outcomes when given corticosteroids.[6]

The lack of mineralocorticoid in the new study may not be important. In the new trial, the total hydrocortisone per day in the new trial is 200 mg. This equates to 200/250 or 0.8 mg (800 microgram) fludrocortisone (see relative potency table for corticosteroids). The French study by Annane used 50 microgram daily of fludrocortisone.[7]

Meta-analyses of the French trial and prior trials have concluded that steroids are beneficial but these analyses did not include the CORTICUS trial published in 2008.[8][9] In a meta-analysis that was included with the American College of Critical Care Medicine guidelines found greater shock reversal (at day 7) with hydrocortisone and a (insignficant) trend towards benefit in mortality".[5]

Activated protein C

Recombinant human activated protein C, also called drotrecogin alpha, has been shown in a randomized controlled trial to be associated with reduced mortality (number needed to treat (NNT) of 16) in patients with multi-organ failure[10] If this is given, heparin should probably be continued.[11]

Tissue factor pathway inhibitor

Recombinant human tissue factor (thromboplastin) pathway inhibitor, also called tifacogin, was found not to be effective in a randomized controlled trial.[12]

References

  1. Anonymous (2024), Septic shock (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Post F, Weilemann LS, Messow CM, Sinning C, Münzel T (November 2008). "B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients". Crit. Care Med. 36 (11): 3030–7. DOI:10.1097/CCM.0b013e31818b9153. PMID 18824903. Research Blogging.
  3. Annane D, Vignon P, Renault A, et al (2007). "Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial". Lancet 370 (9588): 676-84. DOI:10.1016/S0140-6736(07)61344-0. PMID 17720019. Research Blogging.
  4. Russell, J. A., Walley, K. R., Singer, J., Gordon, A. C., Hebert, P. C., Cooper, D. J., et al. (2008). Vasopressin versus norepinephrine infusion in patients with septic shock, N Engl J Med, 358(9), 877-887. DOI:10.1056/NEJMoa067373.
  5. 5.0 5.1 5.2 5.3 Marik PE, Pastores SM, Annane D, et al (June 2008). "Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine". Crit. Care Med. 36 (6): 1937–49. DOI:10.1097/CCM.0b013e31817603ba. PMID 18496365. Research Blogging.
  6. 6.0 6.1 6.2 6.3 Sprung CL, Annane D, Keh D, et al (2008). "Hydrocortisone therapy for patients with septic shock". N. Engl. J. Med. 358 (2): 111–24. DOI:10.1056/NEJMoa071366. PMID 18184957. Research Blogging. Cite error: Invalid <ref> tag; name "pmid18184957" defined multiple times with different content
  7. 7.0 7.1 7.2 7.3 Annane D, Sébille V, Charpentier C, et al (August 2002). "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock". JAMA 288 (7): 862–71. PMID 12186604[e]
  8. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (July 2004). "Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose". Ann. Intern. Med. 141 (1): 47–56. PMID 15238370[e]
  9. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (August 2004). "Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis". BMJ 329 (7464): 480. DOI:10.1136/bmj.38181.482222.55. PMID 15289273. PMC 515196. Research Blogging.
  10. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. PMID 11236773
  11. Levi M, Levy M, Williams MD, et al (2007). "Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated)". Am. J. Respir. Crit. Care Med. 176 (5): 483–90. DOI:10.1164/rccm.200612-1803OC. PMID 17556722. Research Blogging.
  12. Abraham E, Reinhart K, Opal S, et al (July 2003). "Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial". JAMA 290 (2): 238–47. DOI:10.1001/jama.290.2.238. PMID 12851279. Research Blogging.