Sepsis medical therapy: Difference between revisions

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Standard treatment of infants with suspected sepsis consists of supportive care, maintaining fluid status with intravenous fluids, and the combination of a beta-lactam antibiotic (such as [[ampicillin]]) with an aminoglycoside such as [[gentamicin]].
Standard treatment of infants with suspected sepsis consists of supportive care, maintaining fluid status with intravenous fluids, and the combination of a beta-lactam antibiotic (such as [[ampicillin]]) with an aminoglycoside such as [[gentamicin]].


===2012 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>===
===2016 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)===
 
====2016 Bundle====
 
====2012 Bundle<ref name="ssc2012bundle">{{cite web |url=http://www.survivingsepsis.org/Bundles/ |title=Bundles | date = 2012 | publisher = Surviving Sepsis Campaign | accessdate=2016-02-25}}</ref>====


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* Administer broad spectrum antibiotics
* Administer broad spectrum antibiotics
* Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
* Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
* "Time of presentation" is defined as the time of triage in the emergency department or, if presenting from another care venue, from the earliest chart annotation consistent with all elements of severe sepsis or septic shock ascertained through chart review.
|-
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| style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px; font-weight: bold;" | TO BE COMPLETED WITHIN 6 HOURS:
| style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px; font-weight: bold;" | TO BE COMPLETED WITHIN 6 HOURS:
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* Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg
* Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg
* In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL):
* In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion and document findings according to Table 1.
: - Measure central venous pressure (CVP). Target CVP: ≥8 mm Hg.
* Re-measure lactate if initial lactate elevated {| class="wikitable" |TABLE 1  DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE PERFUSION WITH:  EITHER:  • Repeat focused exam (after initial fluid resuscitation) including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings. OR TWO OF THE FOLLOWING: • Measure CVP  • Measure ScvO2  • Bedside cardiovascular ultrasound  • Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge  Of note, the 6-hour bundle has been updated from 2012; the 3-hour SSC bundle is not affected. |}
: - Measure central venous oxygen saturation (ScvO2). Target ScvO2: ≥70%.
* Remeasure lactate if initial lactate was elevated. Target lactate: normalization.
|}
|}


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=====<span style="background: #FFFFF0;">Initial Resuscitation</span>=====
=====<span style="background: #FFFFF0;">Initial Resuscitation</span>=====
1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L). Goals during the first 6 hrs of resuscitation:
1. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately (BPS).
* Central venous pressure 8–12 mm Hg
* Mean arterial pressure (MAP) ≥ 65 mm Hg
* Urine output ≥ 0.5 mL/kg/hr
* Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively. {{GRADE1|C}}


2. In patients with elevated lactate levels targeting resuscitation to normalize lactate. {{GRADE2|C}}
2. We recommend that, in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours (strong recommendation, low quality of evidence).


=====<span style="background: #FFFFF0;">Screening for Sepsis and Performance Improvement</span>=====
3. We recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status (BPS).
1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy. {{GRADE1|C}}


2. Hospital–based performance improvement efforts in severe sepsis.
Remarks: Reassessment should include a thorough clinical examination and evaluation of available physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output, and others, as available) as well as other noninvasive or invasive monitoring, as available.


=====<span style="background: #FFFFF0;">Diagnosis</span>=====
4. We recommend further hemodynamic assessment (such as assessing cardiac function) to determine the type of shock if the clinical examination does not lead to a clear diagnosis (BPS).
1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s). {{GRADE1|C}} At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted. {{GRADE1|C}}


2. Use of the 1,3 beta-D-glucan assay {{GRADE2|B}}, mannan and anti-mannan antibody assays {{GRADE2|C}}, if available and invasive candidiasis is in differential diagnosis of cause of infection.
5. We suggest that dynamic over static variables be used to predict fluid responsiveness, where available.


3. Imaging studies performed promptly to confirm a potential source of infection.
6. We recommend an initial target mean arterial pressure of 65 mm Hg in patients with septic shock requiring vasopressors (strong recommendation, moderate quality of evidence).
7. We suggest guiding resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion (weak recommendation, low quality of evidence).
=====<span style="background: #FFFFF0;">Screening for Sepsis and Performance Improvement</span>=====
1. We recommend that hospitals and hospital systems have a performance improvement program for sepsis, including sepsis screening for acutely ill, high risk patients (BPS).  


====<span style="background: #DCDCDC;">Infection Issues</span>====
=====<span style="background: #FFFFF0;">Diagnosis</span>=====
* At least 2 sets of blood cultures should be drawn before antibiotic therapy (percutaneous and through vascular access). This should be done only if there was no significant delay in antibiotic administration (<45 mins). {{GRADE1|B}} for septic shock, and {{GRADE1|C}} for severe sepsis.
1. We recommend that appropriate routine microbiologic cultures (including blood) be obtained before starting antimicrobial therapy in patients with suspected sepsis or septic shock if doing so results in no substantial delay in the start of antimicrobials (BPS).
* Broad-spectrum antibiotics should be initiated within the first hour of recognition of severe sepsis or septic shock, with daily reassessment for de-escalation. {{GRADE1|B}}
* Initial broad-spectrum antibiotics should consist of one or more drugs covering all likely sources (bacterial, and/or fungal or viral). With good penetration in sufficient concentrations into tissue of presumed source. {{GRADE1|B}}
* Low [[procalcitonin]] levels could be used to re-assess patient status for purposes of discontinuation of broad-spectrum antibiotics, in patients who appear septic but have no evidence of infection. {{GRADE2|C}}
* Combination broad-spectrum antibiotic therapy is recommended for: Neutropenic patients with severe sepsis, and patients with multidrug resistant bacterial pathogens (such as Acinetobacter and Pseudomonas app.) {{GRADE2|B}}
* Patients with severe infections associated with respiratory failure and septic shock, combination broad-spectrum antibiotics is recommended. A broad-spectrum beta lactam with either an [[aminoglycoside]] or a [[fluoroquinolone]] for P.aeruginosa bacteremia, and broad-spectrum beta lactam with a macrolide for Streptococcus pneumoniae. {{GRADE2|B}}
* Combination broad-spectrum antibiotic therapy should be de-escalated to the most appropriate single therapy as soon as the susceptibility profile is known. Combination therapy should not be administered for more than 3-5 days. {{GRADE2|B}}
* Duration of therapy should typically last 7-10 days; but longer courses could be necessary for patients with slow clinical response, undrainable niche of infection, bacteremia with S.aureus; some fungal or viral infections, or immunological deficiencies. {{GRADE2|C}}
* Antibacterial therapy is not recommended for patients with severe inflammatory states without an infectious source. GRADE: UG
=====Antimicrobial Regimen=====
======Sepsis, adult======


* 1. '''Sepsis, adult'''
Remarks: Appropriate routine microbiologic cultures always include at least two sets of blood cultures (aerobic and anaerobic).           
:* 1.1 '''Empiric antimicrobial therapy'''<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>
=====Antimicrobial Therapy=====
::* 1.1.1 '''History of intravenous drug use with high prevalence of MRSA'''
1. We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within one hour for both sepsis and septic shock (strong recommendation, moderate quality of evidence).
:::* Perferred regimen: [[Vancomycin]] 1 g IV q12h


::* 1.1.2 '''Sepsis associated with petechiae'''
2. We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage) (strong recommendation, moderate quality of evidence).
:::* Perferred regimen: [[Ceftriaxone]] 2 g IV q12h


::* 1.1.3 '''Biliary source'''
3. We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS).
*'''1. Community-acquired acute cholecystitis of mild-to-moderate severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
:* Preferred regimen (1): [[Cefazolin]]  1–2 g IV q8h
:* Preferred regimen (2): [[Cefuroxime]] 1.5 g IV q8h
:* Preferred regimen (3): [[Ceftriaxone]] 1–2 g IV q12–24 h


* '''2. Community-acquired acute cholecystitis of severe physiologic disturbance, advanced age, or immunocompromised state''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
4. We recommend against sustained systemic antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).
:* Preferred regimen (1):Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (2):[[Meropenem]]  1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (3):[[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (4):[[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (5):[[Ciprofloxacin]]  400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (6):[[Levofloxacin]]  750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (7):[[Cefepime]]  2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h


* '''3. Acute cholangitis following bilio-enteric anastamosis of any severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
5. We recommend that dosing strategies of antimicrobials be optimized based on accepted pharmacokinetic/pharmacodynamic principles and specific drug properties in patients with sepsis or septic shock (BPS).
:* Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (2): [[Meropenem]] 1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (3): [[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (4): [[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (5): [[Ciprofloxacin]] 400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (6): [[Levofloxacin]] 750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
:* Preferred regimen (7): [[Cefepime]] 2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h


* '''4. Health care-associated biliary infection of any severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
6. We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence.
:* Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (2): [[Meropenem]] 1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (3): [[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (4): [[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (5): [[Ciprofloxacin]] 400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (6): [[Levofloxacin]] 750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
:* Preferred regimen (7): [[Cefepime]] 2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h


:* '''Note''': Antimicrobial therapy of established infection should be limited to 4–7 days, unless it is difficult to achieve adequate source control. Longer durations of therapy have not been associated with improved outcome.
Remarks: Readers should review Table 6 for definitions of empiric, targeted/definitive, broad-spectrum, combination, and multidrug therapy before reading this section.


::* 1.1.4 '''Community-acquired pneumonia'''
7. We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence).
:::* Preferred regimen: ([[Levofloxacin]] 750 mg IV q24h {{or}} [[Moxifloxacin]] 400 mg IV q24h) {{and}} [[Piperacillin-Tazobactam]] 3.375 g IV q4h {{and}} [[Vancomycin]] 1 g IV q12h


::* 1.1.5 '''Unclear infection source'''
Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
:::* Preferred regimen: ([[Doripenem]] 500 mg IV q8h {{or}} [[Ertapenem]] 1 g IV q24h {{or}} [[Imipenem]] 0.5 g IV q6h {{or}} [[Meropenem]] 1 g IV q8h) {{and}} [[Vancomycin]] 1 g IV q12h


::* 1.1.6 '''Low prevalence of ESBL and/or carbapenemase-producing aerobic GNB'''
8. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence).
:::* Preferred regimen: [[Piperacillin-Tazobactam]] 3.375 g IV q4h {{and}} [[Vancomycin]] 1 g IV q12h


::* 1.1.7 '''High prevalence of ESBL and/or carbapenemase-producing aerobic GNB'''
Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
:::* Preferred regimen: [[Colistin]] 2.5 mg/kg single dose followed by 1.5 mg/kg IV q12h {{and}}  [[Meropenem]] 1 g IV q8h {{and}} [[Vancomycin]] 1 g IV q12h


=====Sepsis, pediatric=====
9. If combination therapy is used for septic shock, we recommend de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This applies to both targeted (for culture-positive infections) and empiric (for culture-negative infections) combination therapy (BPS).
*1. '''Sepsis, pediatric'''
:*1.1 '''Empiric antimicrobial therapy'''<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>
::*1.1.1 '''Children aged > 1 month'''
:::* Preferred regimen: ([[Cefotaxime]] 50 mg/kg IV q8h {{or}} [[Ceftriaxone]] 100 mg/kg IV q24h) {{and}} [[Vancomycin]] 15 mg/kg IV q6h
:::* Alternative regimen: [[Aztreonam]] 7.5 mg/kg IV q6h {{and}} [[Linezolid]] 10 mg/kg IV q8h


::*1.1.2 '''Children aged < 1 month'''
10. We suggest that an antimicrobial treatment duration of 7 to 10 days is adequate for most serious infections associated with sepsis and septic shock (weak recommendation, low quality of evidence).
:::* Preferred regimen: [[Ampicillin]] 25 mg/kg IV q8h {{and}} [[Cefotaxime]] 50 mg/kg q12h {{withorwithout}} [[Vancomycin]] 15 mg/kg IV q12h (if suspecting [[MRSA]])
:::* Alternative regimen: [[Ampicillin]] 25 mg/kg IV q6h {{and}} [[Ceftriaxone]] 75 mg/kg IV q24h {{withorwithout}} [[Vancomycin]] 15 mg/kg IV q12h (if suspecting [[MRSA]])


=====<span style="background: #FFFFF0;">Source Control</span>=====
11. We suggest that longer courses are appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with Staphylococcus aureus, some fungal and viral infections, or immunologic deficiencies, including neutropenia (weak recommendation, low quality of evidence).
1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible. {{GRADE1|C}}


2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred. {{GRADE2|B}}
12. We suggest that shorter courses are appropriate in some patients, particularly those with rapid clinical resolution following effective source control of intra-abdominal or urinary sepsis and those with anatomically uncomplicated pyelonephritis (weak recommendation, low quality of evidence).


3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than surgical drainage of an abscess).
13. We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock (BPS).


4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established.
14. We suggest that measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients (weak recommendation, low quality of evidence).


=====<span style="background: #FFFFF0;">Infection Prevention</span>=====
15. We suggest that procalcitonin levels can be used to support the discontinuation of empiric antibiotics in patients who initially appeared to have sepsis, but subsequently have limited clinical evidence of infection (weak recommendation, low quality of evidence).
1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective. {{GRADE2|B}}


1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis. {{GRADE2|B}}
=====<span style="background: #FFFFF0;">Source Control</span>=====
1. We recommend that a specific anatomic diagnosis of infection requiring emergent source control should be identified or excluded as rapidly as possible in patients with sepsis or septic shock, and that any required source control intervention should be implemented as soon as medically and logistically practical after the diagnosis is made (BPS).


2. We recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established (BPS).
====<span style="background: #DCDCDC;">Hemodynamic Support and Adjunctive Therapy</span>====
====<span style="background: #DCDCDC;">Hemodynamic Support and Adjunctive Therapy</span>====


=====<span style="background: #FFFFF0;">Fluid Therapy of Severe Sepsis</span>=====
=====<span style="background: #FFFFF0;">Fluid Therapy (of Severe Sepsis)</span>=====
1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. {{GRADE1|B}}
1. We recommend that a fluid challenge technique be applied where fluid administration is continued as long as hemodynamic factors continue to improve (BPS).


2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. {{GRADE1|B}}
2. We recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock (strong recommendation, moderate quality of evidence).


3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. {{GRADE2|C}}
3. We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak recommendation, low quality of evidence).


4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. {{GRADE1|C}}
4. We suggest using albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock, when patients require substantial amounts of crystalloids (weak recommendation, low quality of evidence).


5. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.
5. We recommend against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (strong recommendation, high quality of evidence).


=====<span style="background: #FFFFF0;">Vasopressors</span>=====
6. We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock (weak recommendation, low quality of evidence).
1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg. {{GRADE1|C}}
=====<span style="background: #FFFFF0;">Vasoactive Medications</span>=====
1. We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence).


2. Norepinephrine as the first choice vasopressor. {{GRADE1|B}}
2. We suggest adding either vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to norepinephrine with the intent of raising mean arterial pressure to target, or adding vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage.


3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. {{GRADE2|B}}
3. We suggest using dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (e.g., patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (weak recommendation, low quality of evidence).
 
4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage.
 
5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents).
 
6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). {{GRADE2|C}}
 
7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. {{GRADE1|C}}
 
8. Low-dose dopamine should not be used for renal protection. {{GRADE1|A}}
 
9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.
 
=====<span style="background: #FFFFF0;">Inotropic Therapy</span>=====
 
1. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. {{GRADE1|C}}
 
2. Not using a strategy to increase cardiac index to predetermined supranormal levels. {{GRADE1|B}}


4. We recommend against using low-dose dopamine for renal protection (strong recommendation, high quality of evidence).
5. We suggest using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (weak recommendation, low quality of evidence).
Remarks: If initiated, dosing should be titrated to an end point reflecting perfusion, and the agent reduced or discontinued in the face of worsening hypotension or arrhythmias.
6. We suggest that all patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available (weak recommendation, very low quality of evidence).
=====<span style="background: #FFFFF0;">Corticosteroids</span>=====
=====<span style="background: #FFFFF0;">Corticosteroids</span>=====
1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day. {{GRADE2|C}}
1. We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day (weak recommendation, low quality of evidence).
 
2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. {{GRADE2|B}}
 
3. In treated patients hydrocortisone tapered when vasopressors are no longer required. {{GRADE2|D}}
 
4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock. {{GRADE1|D}}
 
5. When hydrocortisone is given, use continuous flow. {{GRADE2|D}}


====<span style="background: #DCDCDC;">Other Supportive Therapy of Severe Sepsis</span>====
====<span style="background: #DCDCDC;">Other Supportive Therapy of Severe Sepsis</span>====


=====<span style="background: #FFFFF0;">Blood Product Administration</span>=====
=====<span style="background: #FFFFF0;">Blood Products</span>=====
1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults. {{GRADE1|B}}
1. We recommend that RBC transfusion occur only when hemoglobin concentration decreases to < 7.0g/dL in adults in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, or acute hemorrhage (strong recommendation, high quality of evidence).
 
2. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis. {{GRADE1|B}}


3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. {{GRADE2|D}}
2. We recommend against the use of erythropoietin for treatment of anemia associated with sepsis (strong recommendation, moderate quality of evidence).


4. Not using antithrombin for the treatment of severe sepsis and septic shock. {{GRADE1|B}}
3. We suggest against the use of fresh frozen plasma to correct clotting abnormalities in the absence of bleeding or planned invasive procedures (weak recommendation, very low quality of evidence).


5. In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures. {{GRADE2|D}}
4. We suggest prophylactic platelet transfusion when counts are < 10,000/mm3 (10×109/L) in the absence of apparent bleeding and when counts are < 20,000/mm3 (20×109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥ 50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures (weak recommendation, very low quality of evidence).


=====<span style="background: #FFFFF0;">Immunoglobulins</span>=====
=====<span style="background: #FFFFF0;">Immunoglobulins</span>=====
1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock. {{GRADE2|B}}
1. We suggest against the use of IV immunoglobulins in patients with sepsis or septic shock (weak recommendation, low quality of evidence).


====<span style="background: #FFFFF0;">Selenium</span>====
====<span style="background: #FFFFF0;">Blood Purification</span>====
1. Not using intravenous selenium for the treatment of severe sepsis. {{GRADE2|C}}
1. We make no recommendation regarding the use of blood purification techniques.


=====<span style="background: #FFFFF0;">History of Recommendations Regarding Use of Recombinant Activated Protein C (rhAPC)</span>=====
====<span style="background: #FFFFF0;">Anticoagulants</span>====
1. A history of the evolution of SSC recommendations as to rhAPC (no longer available) is provided.
1. We recommend against the use of antithrombin for the treatment of sepsis and septic shock (strong recommendation, moderate quality of evidence).
2. We make no recommendation regarding the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.
=====<span style="background: #FFFFF0;">Mechanical Ventilation</span>=====
1. We recommend using a target tidal volume of 6 mL/kg predicted body weight compared with 12 mL/kg in adult patients with sepsis-induced acute respiratory distress syndrome (ARDS) (strong recommendation, high quality of evidence).


=====<span style="background: #FFFFF0;">Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)</span>=====
2. We recommend using an upper limit goal for plateau pressures of 30 cm H2O over higher plateau pressures in adult patients with sepsis-induced severe ARDS (strong recommendation, moderate quality of evidence).
1. Target a tidal volume of 6mL/kg predicted body weight in patients with sepsis-induced ARDS ({{GRADE1|A}} vs. 12 mL/kg).


2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung be ≤30 cm H2O. {{GRADE1|B}}
3. We suggest using higher positive end-expiratory pressure (PEEP) over lower PEEP in adult patients with sepsis-induced moderate to severe ARDS (weak recommendation, moderate quality of evidence).


3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma). {{GRADE1|B}}
4. We suggest using recruitment maneuvers in adult patients with sepsis-induced, severe ARDS (weak recommendation, moderate quality of evidence).


4. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis-induced moderate or severe ARDS. {{GRADE2|C}}
5. We recommend using prone over supine position in adult patients with sepsis-induced ARDS and a PaO2/FIO2 ratio < 150 (strong recommendation, moderate quality of evidence).
6. We recommend against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS (strong recommendation, moderate quality of evidence).
7. We make no recommendation regarding the use of noninvasive ventilation for patients with sepsis-induced ARDS.


5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia. {{GRADE2|C}}
8. We suggest using neuromuscular blocking agents for ≤ 48 hours in adult patients with sepsis-induced ARDS and a PaO2/FIO2 ratio < 150 mm Hg (weak recommendation, moderate quality of evidence).


6. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤ 100mm Hg in facilities that have experience with such practices. {{GRADE2|B}}
9. We recommend a conservative fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion (strong recommendation, moderate quality of evidence).


7. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia. {{GRADE1|B}}
10. We recommend against the use of ß-2 agonists for the treatment of patients with sepsis-induced ARDS without bronchospasm (strong recommendation, moderate quality of evidence).
11. We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS (strong recommendation, high quality of evidence).
12. We suggest using lower tidal volumes over higher tidal volumes in adult patients with sepsis-induced respiratory failure without ARDS (weak recommendation, low quality of evidence).


8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks. {{GRADE2|B}}
13. We recommend that mechanically ventilated sepsis patients be maintained with the head of the bed elevated between 30 and 45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (strong recommendation, low quality of evidence).


9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria:
14. We recommend using spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning (strong recommendation, high quality of evidence).
* Arousable
15. We recommend using a weaning protocol in mechanically ventilated patients with sepsis-induced respiratory failure who can tolerate weaning (strong recommendation, moderate quality of evidence).
* Hemodynamically stable (without vasopressor agents)
=====<span style="background: #FFFFF0;">Sedation and Analgesia</span>=====
* No new potentially serious conditions
1. We recommend that continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration end points (BPS).
* Low ventilatory and end-expiratory pressure requirements
* Low Fio2 requirements which can be met safely delivered with a face mask or nasal cannula
: If the spontaneous breathing trial is successful, consideration should be given for extubation. {{GRADE1|A}}


10. Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS. {{GRADE1|A}}
=====<span style="background: #FFFFF0;">Glucose Control</span>=====
1. We recommend a protocolized approach to blood glucose management in ICU patients with sepsis, commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL. This approach should target an upper blood glucose level ≤


11. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypo perfusion. {{GRADE1|C}}
180 mg/dL rather than an upper target blood glucose level ≤ 110 mg/dL (strong recommendation, high quality of evidence).


12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis-induced ARDS. {{GRADE1|B}}
2. We recommend that blood glucose values be monitored every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours thereafter in patients receiving insulin infusions (BPS).


=====<span style="background: #FFFFF0;">Sedation, Analgesia, and Neuromuscular blockade in Sepsis</span>=====
3. We recommend that glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution because such measurements may not accurately estimate arterial blood or plasma glucose values (BPS).
1. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints. {{GRADE1|B}}
4. We suggest the use of arterial blood rather than capillary blood for point-of-care testing using glucose meters if patients have arterial catheters (weak recommendation, low quality of evidence).
=====<span style="background: #FFFFF0;">Renal Replacement Therapy</span>=====
1. We suggest that either continuous or intermittent renal replacement therapy (RRT) be used in patients with sepsis and acute kidney injury (weak recommendation, moderate quality of evidence)


2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used. {{GRADE1|C}}
2. We suggest using continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence).


3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a Pao2/Fio2 < 150 mm Hg. {{GRADE2|C}}
3. We suggest against the use of RRT in patients with sepsis and acute kidney injury for increase in creatinine or oliguria without other definitive indications for dialysis (weak recommendation, low quality of evidence).


=====<span style="background: #FFFFF0;">Glucose Control</span>=====
4. We recommend pharmacologic prophylaxis (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) against venous thromboembolism (VTE) in the absence of contraindications to the use of these agents (strong recommendation, moderate quality of evidence).
1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL. {{GRADE1|A}}


2. Blood glucose values be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter. {{GRADE1|C}}
5. We recommend LMWH rather than UFH for VTE prophylaxis in the absence of contraindications to the use of LMWH (strong recommendation, moderate quality of evidence).


3. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values.
6. We suggest combination pharmacologic VTE prophylaxis and mechanical prophylaxis, whenever possible (weak recommendation, low quality of evidence).


=====<span style="background: #FFFFF0;">Renal Replacement Therapy</span>=====
7. We suggest mechanical VTE prophylaxis when pharmacologic VTE is contraindicated (weak recommendation, low quality of evidence).
1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. {{GRADE2|B}}
 
2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients. {{GRADE2|D}}


=====<span style="background: #FFFFF0;">Bicarbonate Therapy</span>=====
=====<span style="background: #FFFFF0;">Bicarbonate Therapy</span>=====
1. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥7.15. {{GRADE2|B}}
1. We suggest against the use of sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15 (weak recommendation, moderate quality of evidence).
 
=====<span style="background: #FFFFF0;">Deep Vein Thrombosis Prophylaxis</span>=====
1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE). {{GRADE1|B}} This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) ({{GRADE1|B}} versus twice daily UFH, {{GRADE2|C}} versus three times daily UFH). If creatinine clearance is &#60;30 mL/min, use dalteparin {{GRADE1|A}} or another form of LMWH that has a low degree of renal metabolism {{GRADE2|C}} or UFH {{GRADE1|A}}.
 
2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible. {{GRADE2|C}}
 
3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive pharmacoprophylaxis {{GRADE1|B}}, but receive mechanical prophylactic treatment, such
as graduated compression stockings or intermittent compression devices {{GRADE2|C}}, unless contraindicated. When the risk decreases start pharmacoprophylaxis. {{GRADE2|C}}


=====<span style="background: #FFFFF0;">Stress Ulcer Prophylaxis</span>=====
=====<span style="background: #FFFFF0;">Stress Ulcer Prophylaxis</span>=====
1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors. {{GRADE1|B}}
1. We recommend that stress ulcer prophylaxis be given to patients with sepsis or septic shock who have risk factors for gastrointestinal (GI) bleeding (strong recommendation, low quality of evidence).


2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA. {{GRADE2|D}}
2. We suggest using either proton pump inhibitors or histamine-2 receptor antagonists when stress ulcer prophylaxis is indicated (weak recommendation, low quality of evidence).


3. Patients without risk factors do not receive prophylaxis. {{GRADE2|B}}
3. We recommend against stress ulcer prophylaxis in patients without risk factors for GI bleeding (BPS).


=====<span style="background: #FFFFF0;">Nutrition</span>=====
=====<span style="background: #FFFFF0;">Nutrition</span>=====
1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock. {{GRADE2|C}}
1. We recommend against the administration of early parenteral nutrition alone or parenteral nutrition in combination with enteral feedings (but rather initiate early enteral nutrition) in critically ill patients with sepsis or septic shock who can be fed enterally (strong recommendation, moderate quality of evidence).  


2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated. {{GRADE2|B}}
2. We recommend against the administration of parenteral nutrition alone or in combination with enteral feeds (but rather to initiate IV glucose and advance enteral feeds as tolerated) over the first 7 days in critically ill patients with sepsis or septic shock for whom early enteral feeding is not feasible (strong recommendation, moderate quality of evidence).


3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock. {{GRADE2|B}}
3. We suggest the early initiation of enteral feeding rather than a complete fast or only IV glucose in critically ill patients with sepsis or septic shock who can be fed enterally (weak recommendation, low quality of evidence).


4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis. {{GRADE2|C}}
4. We suggest either early trophic/hypocaloric or early full enteral feeding in critically ill patients with sepsis or septic shock; if trophic/hypocaloric feeding is the initial strategy, then feeds should be advanced according to patient tolerance (weak recommendation, moderate quality of evidence).


=====<span style="background: #FFFFF0;">Setting Goals of Care</span>=====
5. We recommend against the use of omega-3 fatty acids as an immune supplement in critically ill patients with sepsis or septic shock (strong recommendation, low quality of evidence). 
1. Discuss goals of care and prognosis with patients and families. {{GRADE1|B}}


2. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. {{GRADE1|B}}
6. We suggest against routinely monitoring gastric residual volumes in critically ill patients with sepsis or septic shock (weak recommendation, low quality of evidence). However, we suggest measurement of gastric residuals in patients with feeding intolerance or who are considered to be at high risk of aspiration (weak recommendation, very low quality of evidence).


3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission. {{GRADE2|C}}
Remarks: Ths recommendation refers to nonsurgical critically ill patients with sepsis or septic shock.


7. We suggest the use of prokinetic agents in critically ill patients with sepsis or septic shock and feeding intolerance (weak recommendation, low quality of evidence).


====<span style="background: #DCDCDC;">Special Considerations in Pediatrics</span>====
8. We suggest placement of post-pyloric feeding tubes in critically ill patients with sepsis or septic shock with feeding intolerance or who are considered to be at high risk of aspiration (weak recommendation, low quality of evidence).


=====<span style="background: #FFFFF0;">Initial Resuscitation</span>=====
9. We recommend against the use of IV selenium to treat sepsis and septic shock (strong recommendation, moderate quality of evidenence).
1. For respiratory distress and hypoxemia start with face mask oxygen or if needed and available, high flow nasal cannula oxygen or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseus access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation. {{GRADE2|C}}


2. Initial therapeutic end points of resuscitation of septic shock: capillary refill of ≤2 secs, normal blood pressure for age, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL·kg-1·hr-1, and normal mental status. Scvo2 saturation ≥70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter. {{GRADE2|C}}
10. We suggest against the use of arginine to treat sepsis and septic shock (weak recommendation, low quality of evidence).


3. Follow American College of Critical Care Medicine-Pediatric Life Support (ACCM-PALS) guidelines for the management of septic shock. {{GRADE1|C}}
11. We recommend against the use of glutamine to treat sepsis and septic shock (strong recommendation, moderate quality of evidence).


4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock. {{GRADE1|C}}
12. We make no recommendation about the use of carnitine for sepsis and septic shock.


=====<span style="background: #FFFFF0;">Antibiotics and Source Control</span>=====
=====<span style="background: #FFFFF0;">Setting Goals of Care</span>=====
1. Empiric antibiotics be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible but this should not delay administration of antibiotics. The empiric drug choice should be changed as epidemic and endemic ecologies dictate (eg H1N1, MRSA, chloroquine resistant malaria, penicillin-resistant pneumococci, recent ICU stay, neutropenia). {{GRADE1|D}}
1.  We recommend that goals of care and prognosis be discussed with patients and families (BPS).
 
2. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension. {{GRADE2|D}}
 
3. Early and aggressive source control. {{GRADE1|D}}
 
4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease. {{GRADE1|A}}
 
=====<span style="background: #FFFFF0;">Fluid Resuscitation</span>=====
1. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusion of isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent) over 5–10 minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises) blood transfusion is considered superior to crystalloid or albumin bolusing. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Inotropes/Vasopressors/Vasodilators</span>=====
1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid resuscitation. {{GRADE2|C}}
 
2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given vasodilator therapies in addition to inotropes. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Extracorporeal Membrane Oxygenation (ECMO)</span>=====
1. Consider ECMO for refractory pediatric septic shock and respiratory failure. {{GRADE2|C}}
 
====<span style="background: #FFFFF0;">Corticosteroids</span>====
1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insufficiency. {{GRADE1|A}}
 
=====<span style="background: #FFFFF0;">Protein C and Activated Protein Concentrate</span>=====
No recommendation as no longer available.
 
=====<span style="background: #FFFFF0;">Blood Products and Plasma Therapies</span>=====
1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (< 70%), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower target > 7.0 g/dL can be considered reasonable. {{GRADE1|B}}
 
2. Similar platelet transfusion targets in children as in adults. {{GRADE2|C}}
 
3. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Mechanical Ventilation</span>=====
1. Lung-protective strategies during mechanical ventilation. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Sedation/Analgesia/Drug Toxicities</span>=====
1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis. {{GRADE1|D}}
 
2. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events. {{GRADE1|C}}
 
=====<span style="background: #FFFFF0;">Glycemic Control</span>=====
1. Control hyperglycemia using a similar target as in adults ≤ 180 mg/dL. Glucose infusion should accompany insulin therapy in newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Diuretics and Renal Replacement Therapy</span>=====
1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration (CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload. {{GRADE2|C}}
 
=====<span style="background: #FFFFF0;">Deep Vein Thrombosis (DVT) Prophylaxis</span>=====
No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.
 
=====<span style="background: #FFFFF0;">Stress Ulcer (SU) Prophylaxis</span>=====
No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.
 
=====<span style="background: #FFFFF0;">Nutrition</span>=====
Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot. {{GRADE2|C}}
 
===Contraindicated Medications===
{{MedCondContrAbs|MedCond =Sepsis|Etanercept|Sitagliptin And Metformin Hydrochloride}}


2.  We recommend that goals of care be incorporated into treatment and end-of-life care planning, utilizing palliative care principles where appropriate (strong recommendation, moderate quality of evidence).
3.  We suggest that goals of care be addressed as early as feasible, but no later than within 72 hours of ICU admission (weak recommendation, low quality of evidence).  
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 19:48, 14 February 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2]

Overview

The goals for the treatment of sepsis per the Surviving Sepsis Campaign include screening for high-risk patients; taking bacterial cultures soon after the patient arrived at the hospital; starting patients on broad-spectrum intravenous antibiotic therapy before the results of the cultures are obtained; identifying the source of infection and taking steps to control it (e.g., abscess drainage); administering intravenous fluids to correct a loss or decrease in blood volume; and maintaining glycemic (blood sugar) control.[1][2] These and similar guidelines have been tested by a number of hospitals and have shown potential for decreasing hospital mortality due to sepsis.[3][4][5] In addition, hospital length of stay may be shortened.[5][6]

Improving speed of treatment

Electronic alerts in the electronic health record may[7] or may not[8] improve outcomes.[9]

Medical Therapy

  • The delay in administering therapy is associated with outcomes among septic patients.
  • For every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality.

Fluid therapy

Guidelines

The 2012 Surviving Sepsis Campaign (SSC) recommendations proposed (see details below):[1][2]

  • Fluid challenge of at least 30 ml/kg of crystalloid in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia.
  • However, due to variable patient response to treatment, the SSC guidelines also state that “more rapid administration and greater amounts of fluid may be needed in patients with sepsis-induced tissue hypoperfusion.”

The SSC guidelines also targeted a mean arterial pressure (MAP) of at least 65 mmHg and a central venous pressure (CVP) of

  • At least 8 mmHg in the non mechanically-ventilated patient
  • At least 12-15 mmHg in the mechanically-ventilated patient

In National Institute for Health and Care Excellence (NICE) guideline No. 51 (PMID 27441326), as proposed by the National Guideline Centre (UK), a systematic review of randomized controlled trials concluded that patients over 16 years with severe sepsis or septic shock requiring fluid resuscitation should receive

  • “crystalloids containing sodium in the range 130–154 mmol/litre with a bolus of 500 ml over less than 15 minutes.”
  • The patient should then be reassessed and, if fluid status has not improved, receive a second bolus.
  • If the patient’s status does not improve following the second bolus, the guidelines recommend consultation of a specialist.


Evidence

Regarding underlying evidence, a systematic review of randomized control trials concluded:[10]

  • Strict adherence to early goal directed therapy of septic shock is not necessary. However, principles of early identification and fluid resuscitation, prompt administration of antibiotics, and adequate monitoring of patient parameters should be considered in treatment of patients with severe sepsis and septic shock.

A second systematic review of ProCESS, ProMISe, and ARISE randomized controlled trials, concluded:[11]

  • Early goal directed therapy remains the gold standard for treatment of severe sepsis and septic shock given that EGDT has proven internal and external validity.
  • While non-inferior outcomes may be able to be achieved using alternative treatment strategies, there is a lack of sufficient evidence backing other protocols.

A third meta-analysis concluded:[12]

  • In patient populations with higher mortality, EGDT or lactate level and central venous pressure normalization are viable therapies.
  • Newer evidence challenges the need for strict adherence to six hour bundle goals in populations with lower mortality.

Another meta-analysis by the recent trialists[13] of the three most recent trials[14][15][16] found that low mortality was achieved even in the control groups in all three studies which was based on the standard care at each institution. The amount of fluid administered in these three trials was 30 ml/kg prior to enrollment[11] and then ranged from 1.9-2.6 L in the first three hours prior to diagnosis of septic shock. Approximately 1.7-3.3 L of additional fluid was given once the septic shock protocol was initiated in both the control and EGDT groups. Total fluids at 9 hours averaged between 4.0 - 5.5 L.

Regarding the speed fluid administration, only two trials revealed an explicit protocol[15][17]. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes.

Regarding type of fluids, a meta-analysis concluded "among the patients with sepsis, fluid resuscitation with crystalloids compared to starch resulted in reduced use of RRT; the same may be true for albumin versus starch."[18] A more recent trial of patients with diverse diagnoses found no difference.[19]

Fluid administration in cardiac and renal disease

The 2016 Surviving Sepsis guidelines do not make specific reference to fluid resuscitation in the setting of cardiorenal dysfunction.[20]

Two studies suggest possible benefits of including this subset of patients in sepsis protocol bundles administration without significant harm:

  • In one open-labeled randomized controlled trial, results for a subgroup of patients identified with underlying fluid overload status showed that the intervention group received clinically significant more IV fluids than the control group (difference = 975 mls, 95% CI -450ml- 1725 ml) and attained shorter hospital lengths of stay (difference -4.5 days, 95% CI -9.5-2.5 days).[17]
  • A retrospective review addressing the implementation of a sepsis bundle for sepsis patients and intermediate patients (lactate levels between 2 and 4 mmol/L) found that patients with a known history of heart failure or chronic kidney disease had a statistically significant decrease in 30 day mortality from 12.5% to 8.7% after implementation of the bundle and subsequent increase in mean fluid totals from 1.4L to 1.7L.[21]

Excessive fluid therapy

Positive fluid balance may be associated with worse outcomes in most[22][23][24][25][26][27][28], but not all[29] studies. For example, a retrospective review of patient in Vasopressin in Septic Shock Trial (VASST) determined positive fluid balance initially at 12 hr and cumulatively at 4 days resulted in higher mortality.[27]

De-escalation and removal of fluids

Avoidance of fluid overload may be avoid be careful restriction of fluids after the initial 30 ml/kg bolus according to a randomized controlled trial.[30] Expert opinion suggests positive fluid balance should be addresses within three days of resuscitation. [31]

Hemodynamic monitoring

Regarding the monitoring of fluid administration, few randomized controlled trials used an explicit protocol[15][17]. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes interspersed with more frequent patient reassessment than is currently required by both the Surviving Sepsis and CMS protocols. The patients in these studies were reevaluated at the time of each bolus administration (every 30 minutes.)

A meta-analysis of randomized controlled trials using early goal directed therapy found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients.[13]

Methods of assessing fluid responsiveness

Various methods are available and have been reviewed.[32][33][34][35]

Pulse contour analysis

Analysis of the pulse contour, whether assesses invasively by photo-plethysmography or nonivasively, can estimate cardiac output and other parameters. The accuracy of non-invasive photo-plethysmography is unclear.[36] Commercial products include the invasive PICCO or the non-invasive ClearSight or Nexfin by Edwards.

Bioimpedance and bioreactance

Commercial products include the NICOM by Cheetah Medical.

Antibiotics

Timing

While a systematic review found there was no significant mortality benefit from administering antibiotics within 3 hours of emergency department triage ( OR 1.16, 0.92 to 1.46, p = 0.21) or within 1 hour of shock recognition (OR 1.46, 0.89 to 2.40, p = 0.13) in severe sepsis and septic shock, several concerns exist:[37]

  • The meta-analysis reported heterogeneity as insignificant (p = 0.09) with Cochran Q test. However, this is a significant result per the Cochrane collaboration's interpretation of the Cochran Q test.[38]
  • The study grouped patients by time to administration of antimicrobial therapy, but did not consider time to administration of appropriate antimicrobial therapy- likely lessening the effect of early therapy.[39]
  • One article[40] contributed the majority of the sample size for the 1h group- with said sample including patients with higher sepsis severity scores, higher rates of septic shock, and higher rates of mortality- leading to a potential underestimation of the impact of early antibiotic use.[41]

The two largest studies in the meta-analysis both found positive correlations between delays in antibiotics and mortality.[40][42]

Delivery method

Continuous infusion may be more effective.[43]

Steroids

Corticosteroids may reduce mortality among patients with septic shock according to a systematic review by the Cochrane Collaboration.[44]

The subsequent HYPRESS randomized controlled trial of patients with severe sepsis showed now benefit.[45]

Transfusion

In septic shock, leukoreduced erythrocyte transfusion is associated with similar clinical outcomes (90 day mortality and ischemic events) among patients who are administered erythrocyte transfusion at a hemoglobin threshold of 7 g/dL compared to those who receive it at a higher threshold of 9 g/dL.[46]

Protocolized therapy

Several protocols have been recommended and studied. Compliance with bundles of care is associated with reduced mortality.[5]

Early Goal Directed Therapy (EGDT)

Early Goal Directed Therapy (EGDT), developed at Henry Ford Hospital by E. Rivers, MD, is a systematic approach to resuscitation that has been validated in the treatment of severe sepsis and septic shock.[47] It is meant to be started in the Emergency Department. The theory is that one should use a step-wise approach, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues.

Although initial studies reported benefit from EGDT,[48][47][49] the more recent ProCESS[15] and ARISE[14] trials failed to demonstrate any benefit. However, the outcomes in the control groups of these trials were much more favorable than in the earlier trials. The extent of protocol-based care in the 'usual care' of the control groups is not known.

In Early Goal Directed Therapy:

  • Fluids are administered until the central venous pressure (CVP), as measured by a central venous catheter, reaches 8-12 cm of water (or 10-15 cm of water in mechanically ventilated patients).
  • If the mean arterial pressure is less than 65 mmHg or greater than 90 mmHg, vasopressors or vasodilators are given as needed to reach the goal.
  • The central venous saturation (ScvO2), i.e. the oxygen saturation of venous blood as it returns to the heart as measured at the superior vena cava, is optimized. If the ScvO2 is less than 70%, blood is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the ScvO2 is optimized. Elective intubation may be performed to reduce oxygen demand if the ScvO2 remains low despite optimization of hemodynamics.
  • Urine output is also monitored, with a goal of 0.5 mL/kg/h. In the original trial, mortality was cut from 46.5% in the control group to 30.5% in the intervention group. The Surviving Sepsis Campaign guidelines recommends EGDT for the initial resuscitation of the septic patient with a level B strength of evidence.

GENESIS Project

The protocol per the GENESIS Project is:[49]

  • Measure serum lactate
  • Obtain blood cultures and administer broad-spectrum antibiotic within 3 hours of emergency department admission
  • If hypotensive or serum lactate 4 mmol/L:
    • Administer 20 mL/kg of crystalloid
    • If needed, add vasopressors to keep mean arterial pressure >65 mm Hg
    • If needed, aim for central venous pressure 8 mm Hg
    • If needed, aim for central venous oxygen saturation 70%

Standard treatment of infants with suspected sepsis consists of supportive care, maintaining fluid status with intravenous fluids, and the combination of a beta-lactam antibiotic (such as ampicillin) with an aminoglycoside such as gentamicin.

2016 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)

2016 Bundle

TO BE COMPLETED WITHIN 3 HOURS:
  • Measure lactate level
  • Obtain blood cultures prior to administration of antibiotics
  • Administer broad spectrum antibiotics
  • Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
  • "Time of presentation" is defined as the time of triage in the emergency department or, if presenting from another care venue, from the earliest chart annotation consistent with all elements of severe sepsis or septic shock ascertained through chart review.
TO BE COMPLETED WITHIN 6 HOURS:
  • Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65 mm Hg
  • In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion and document findings according to Table 1.
  • Re-measure lactate if initial lactate elevated {| class="wikitable" |TABLE 1 DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE PERFUSION WITH: EITHER: • Repeat focused exam (after initial fluid resuscitation) including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings. OR TWO OF THE FOLLOWING: • Measure CVP • Measure ScvO2 • Bedside cardiovascular ultrasound • Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge Of note, the 6-hour bundle has been updated from 2012; the 3-hour SSC bundle is not affected. |}


Initial Resuscitation

Initial Resuscitation

1. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately (BPS).

2. We recommend that, in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours (strong recommendation, low quality of evidence).

3. We recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status (BPS).

Remarks: Reassessment should include a thorough clinical examination and evaluation of available physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output, and others, as available) as well as other noninvasive or invasive monitoring, as available.

4. We recommend further hemodynamic assessment (such as assessing cardiac function) to determine the type of shock if the clinical examination does not lead to a clear diagnosis (BPS).

5. We suggest that dynamic over static variables be used to predict fluid responsiveness, where available.

6. We recommend an initial target mean arterial pressure of 65 mm Hg in patients with septic shock requiring vasopressors (strong recommendation, moderate quality of evidence). 7. We suggest guiding resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion (weak recommendation, low quality of evidence).

Screening for Sepsis and Performance Improvement

1. We recommend that hospitals and hospital systems have a performance improvement program for sepsis, including sepsis screening for acutely ill, high risk patients (BPS).  

Diagnosis

1. We recommend that appropriate routine microbiologic cultures (including blood) be obtained before starting antimicrobial therapy in patients with suspected sepsis or septic shock if doing so results in no substantial delay in the start of antimicrobials (BPS).

Remarks: Appropriate routine microbiologic cultures always include at least two sets of blood cultures (aerobic and anaerobic).           

Antimicrobial Therapy

1. We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within one hour for both sepsis and septic shock (strong recommendation, moderate quality of evidence).

2. We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage) (strong recommendation, moderate quality of evidence).

3. We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS).

4. We recommend against sustained systemic antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).

5. We recommend that dosing strategies of antimicrobials be optimized based on accepted pharmacokinetic/pharmacodynamic principles and specific drug properties in patients with sepsis or septic shock (BPS).

6. We suggest empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) for the initial management of septic shock (weak recommendation, low quality of evidence.

Remarks: Readers should review Table 6 for definitions of empiric, targeted/definitive, broad-spectrum, combination, and multidrug therapy before reading this section.

7. We suggest that combination therapy not be routinely used for ongoing treatment of most other serious infections, including bacteremia and sepsis without shock (weak recommendation, low quality of evidence).

Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.

8. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence).

Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.

9. If combination therapy is used for septic shock, we recommend de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This applies to both targeted (for culture-positive infections) and empiric (for culture-negative infections) combination therapy (BPS).

10. We suggest that an antimicrobial treatment duration of 7 to 10 days is adequate for most serious infections associated with sepsis and septic shock (weak recommendation, low quality of evidence).

11. We suggest that longer courses are appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with Staphylococcus aureus, some fungal and viral infections, or immunologic deficiencies, including neutropenia (weak recommendation, low quality of evidence).

12. We suggest that shorter courses are appropriate in some patients, particularly those with rapid clinical resolution following effective source control of intra-abdominal or urinary sepsis and those with anatomically uncomplicated pyelonephritis (weak recommendation, low quality of evidence).

13. We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock (BPS).

14. We suggest that measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients (weak recommendation, low quality of evidence).

15. We suggest that procalcitonin levels can be used to support the discontinuation of empiric antibiotics in patients who initially appeared to have sepsis, but subsequently have limited clinical evidence of infection (weak recommendation, low quality of evidence).

Source Control

1. We recommend that a specific anatomic diagnosis of infection requiring emergent source control should be identified or excluded as rapidly as possible in patients with sepsis or septic shock, and that any required source control intervention should be implemented as soon as medically and logistically practical after the diagnosis is made (BPS).

2. We recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established (BPS).

Hemodynamic Support and Adjunctive Therapy

Fluid Therapy (of Severe Sepsis)

1. We recommend that a fluid challenge technique be applied where fluid administration is continued as long as hemodynamic factors continue to improve (BPS).

2. We recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock (strong recommendation, moderate quality of evidence).

3. We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak recommendation, low quality of evidence).

4. We suggest using albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock, when patients require substantial amounts of crystalloids (weak recommendation, low quality of evidence).

5. We recommend against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (strong recommendation, high quality of evidence).

6. We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock (weak recommendation, low quality of evidence).

Vasoactive Medications

1. We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence).

2. We suggest adding either vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to norepinephrine with the intent of raising mean arterial pressure to target, or adding vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage.

3. We suggest using dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (e.g., patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (weak recommendation, low quality of evidence).

4. We recommend against using low-dose dopamine for renal protection (strong recommendation, high quality of evidence). 5. We suggest using dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (weak recommendation, low quality of evidence). Remarks: If initiated, dosing should be titrated to an end point reflecting perfusion, and the agent reduced or discontinued in the face of worsening hypotension or arrhythmias. 6. We suggest that all patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available (weak recommendation, very low quality of evidence).

Corticosteroids

1. We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day (weak recommendation, low quality of evidence).

Other Supportive Therapy of Severe Sepsis

Blood Products

1. We recommend that RBC transfusion occur only when hemoglobin concentration decreases to < 7.0g/dL in adults in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, or acute hemorrhage (strong recommendation, high quality of evidence).

2. We recommend against the use of erythropoietin for treatment of anemia associated with sepsis (strong recommendation, moderate quality of evidence).

3. We suggest against the use of fresh frozen plasma to correct clotting abnormalities in the absence of bleeding or planned invasive procedures (weak recommendation, very low quality of evidence).

4. We suggest prophylactic platelet transfusion when counts are < 10,000/mm3 (10×109/L) in the absence of apparent bleeding and when counts are < 20,000/mm3 (20×109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥ 50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures (weak recommendation, very low quality of evidence).

Immunoglobulins

1. We suggest against the use of IV immunoglobulins in patients with sepsis or septic shock (weak recommendation, low quality of evidence).

Blood Purification

1. We make no recommendation regarding the use of blood purification techniques.

Anticoagulants

1. We recommend against the use of antithrombin for the treatment of sepsis and septic shock (strong recommendation, moderate quality of evidence). 2. We make no recommendation regarding the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.

Mechanical Ventilation

1. We recommend using a target tidal volume of 6 mL/kg predicted body weight compared with 12 mL/kg in adult patients with sepsis-induced acute respiratory distress syndrome (ARDS) (strong recommendation, high quality of evidence).

2. We recommend using an upper limit goal for plateau pressures of 30 cm H2O over higher plateau pressures in adult patients with sepsis-induced severe ARDS (strong recommendation, moderate quality of evidence).

3. We suggest using higher positive end-expiratory pressure (PEEP) over lower PEEP in adult patients with sepsis-induced moderate to severe ARDS (weak recommendation, moderate quality of evidence).

4. We suggest using recruitment maneuvers in adult patients with sepsis-induced, severe ARDS (weak recommendation, moderate quality of evidence).

5. We recommend using prone over supine position in adult patients with sepsis-induced ARDS and a PaO2/FIO2 ratio < 150 (strong recommendation, moderate quality of evidence). 6. We recommend against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS (strong recommendation, moderate quality of evidence). 7. We make no recommendation regarding the use of noninvasive ventilation for patients with sepsis-induced ARDS.

8. We suggest using neuromuscular blocking agents for ≤ 48 hours in adult patients with sepsis-induced ARDS and a PaO2/FIO2 ratio < 150 mm Hg (weak recommendation, moderate quality of evidence).

9. We recommend a conservative fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion (strong recommendation, moderate quality of evidence).

10. We recommend against the use of ß-2 agonists for the treatment of patients with sepsis-induced ARDS without bronchospasm (strong recommendation, moderate quality of evidence). 11. We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS (strong recommendation, high quality of evidence). 12. We suggest using lower tidal volumes over higher tidal volumes in adult patients with sepsis-induced respiratory failure without ARDS (weak recommendation, low quality of evidence).

13. We recommend that mechanically ventilated sepsis patients be maintained with the head of the bed elevated between 30 and 45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (strong recommendation, low quality of evidence).

14. We recommend using spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning (strong recommendation, high quality of evidence). 15. We recommend using a weaning protocol in mechanically ventilated patients with sepsis-induced respiratory failure who can tolerate weaning (strong recommendation, moderate quality of evidence).

Sedation and Analgesia

1. We recommend that continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration end points (BPS).

Glucose Control

1. We recommend a protocolized approach to blood glucose management in ICU patients with sepsis, commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL. This approach should target an upper blood glucose level ≤

180 mg/dL rather than an upper target blood glucose level ≤ 110 mg/dL (strong recommendation, high quality of evidence).

2. We recommend that blood glucose values be monitored every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours thereafter in patients receiving insulin infusions (BPS).

3. We recommend that glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution because such measurements may not accurately estimate arterial blood or plasma glucose values (BPS). 4. We suggest the use of arterial blood rather than capillary blood for point-of-care testing using glucose meters if patients have arterial catheters (weak recommendation, low quality of evidence).

Renal Replacement Therapy

1. We suggest that either continuous or intermittent renal replacement therapy (RRT) be used in patients with sepsis and acute kidney injury (weak recommendation, moderate quality of evidence)

2. We suggest using continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence).

3. We suggest against the use of RRT in patients with sepsis and acute kidney injury for increase in creatinine or oliguria without other definitive indications for dialysis (weak recommendation, low quality of evidence).

4. We recommend pharmacologic prophylaxis (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) against venous thromboembolism (VTE) in the absence of contraindications to the use of these agents (strong recommendation, moderate quality of evidence).

5. We recommend LMWH rather than UFH for VTE prophylaxis in the absence of contraindications to the use of LMWH (strong recommendation, moderate quality of evidence).

6. We suggest combination pharmacologic VTE prophylaxis and mechanical prophylaxis, whenever possible (weak recommendation, low quality of evidence).

7. We suggest mechanical VTE prophylaxis when pharmacologic VTE is contraindicated (weak recommendation, low quality of evidence).

Bicarbonate Therapy

1. We suggest against the use of sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15 (weak recommendation, moderate quality of evidence).

Stress Ulcer Prophylaxis

1. We recommend that stress ulcer prophylaxis be given to patients with sepsis or septic shock who have risk factors for gastrointestinal (GI) bleeding (strong recommendation, low quality of evidence).

2. We suggest using either proton pump inhibitors or histamine-2 receptor antagonists when stress ulcer prophylaxis is indicated (weak recommendation, low quality of evidence).

3. We recommend against stress ulcer prophylaxis in patients without risk factors for GI bleeding (BPS).

Nutrition

1. We recommend against the administration of early parenteral nutrition alone or parenteral nutrition in combination with enteral feedings (but rather initiate early enteral nutrition) in critically ill patients with sepsis or septic shock who can be fed enterally (strong recommendation, moderate quality of evidence).

2. We recommend against the administration of parenteral nutrition alone or in combination with enteral feeds (but rather to initiate IV glucose and advance enteral feeds as tolerated) over the first 7 days in critically ill patients with sepsis or septic shock for whom early enteral feeding is not feasible (strong recommendation, moderate quality of evidence).

3. We suggest the early initiation of enteral feeding rather than a complete fast or only IV glucose in critically ill patients with sepsis or septic shock who can be fed enterally (weak recommendation, low quality of evidence).

4. We suggest either early trophic/hypocaloric or early full enteral feeding in critically ill patients with sepsis or septic shock; if trophic/hypocaloric feeding is the initial strategy, then feeds should be advanced according to patient tolerance (weak recommendation, moderate quality of evidence).

5. We recommend against the use of omega-3 fatty acids as an immune supplement in critically ill patients with sepsis or septic shock (strong recommendation, low quality of evidence). 

6. We suggest against routinely monitoring gastric residual volumes in critically ill patients with sepsis or septic shock (weak recommendation, low quality of evidence). However, we suggest measurement of gastric residuals in patients with feeding intolerance or who are considered to be at high risk of aspiration (weak recommendation, very low quality of evidence).

Remarks: Ths recommendation refers to nonsurgical critically ill patients with sepsis or septic shock.

7. We suggest the use of prokinetic agents in critically ill patients with sepsis or septic shock and feeding intolerance (weak recommendation, low quality of evidence).

8. We suggest placement of post-pyloric feeding tubes in critically ill patients with sepsis or septic shock with feeding intolerance or who are considered to be at high risk of aspiration (weak recommendation, low quality of evidence).

9. We recommend against the use of IV selenium to treat sepsis and septic shock (strong recommendation, moderate quality of evidenence).

10. We suggest against the use of arginine to treat sepsis and septic shock (weak recommendation, low quality of evidence).

11. We recommend against the use of glutamine to treat sepsis and septic shock (strong recommendation, moderate quality of evidence).

12. We make no recommendation about the use of carnitine for sepsis and septic shock.

Setting Goals of Care

1.  We recommend that goals of care and prognosis be discussed with patients and families (BPS).

2.  We recommend that goals of care be incorporated into treatment and end-of-life care planning, utilizing palliative care principles where appropriate (strong recommendation, moderate quality of evidence). 3.  We suggest that goals of care be addressed as early as feasible, but no later than within 72 hours of ICU admission (weak recommendation, low quality of evidence).  

References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 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". Intensive Care Med. 39 (2): 165–228. doi:10.1007/s00134-012-2769-8. PMID 23361625.
  3. ↑ Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D; et al. (2015). "The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study)". Intensive Care Med. 41 (9): 1620–8. doi:10.1007/s00134-015-3906-y. PMID 26109396.
  4. ↑ Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R; et al. (2015). "Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study". Crit Care Med. 43 (1): 3–12. doi:10.1097/CCM.0000000000000723. PMID 25275252.
  5. ↑ 5.0 5.1 5.2 Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR; et al. (2013). "Multicenter implementation of a severe sepsis and septic shock treatment bundle". Am J Respir Crit Care Med. 188 (1): 77–82. doi:10.1164/rccm.201212-2199OC. PMC 3735248. PMID 23631750.
  6. ↑ Leisman D, Wie B, Doerfler M, Bianculli A, Frances Ward M, Akerman M; et al. (2016). "Association of Fluid Resuscitation Initiation Within 30 Minutes of Severe Sepsis and Septic Shock Recognition With Reduced Mortality and Length of Stay". Ann Emerg Med. doi:10.1016/j.annemergmed.2016.02.044. PMID 27085369.
  7. ↑ Narayanan N, Gross AK, Pintens M, Fee C, MacDougall C (2016). "Effect of an electronic medical record alert for severe sepsis among ED patients". Am J Emerg Med. 34 (2): 185–8. doi:10.1016/j.ajem.2015.10.005. PMID 26573784.
  8. ↑ Semler MW, Weavind L, Hooper MH, Rice TW, Gowda SS, Nadas A; et al. (2015). "An Electronic Tool for the Evaluation and Treatment of Sepsis in the ICU: A Randomized Controlled Trial". Crit Care Med. 43 (8): 1595–602. doi:10.1097/CCM.0000000000001020. PMC 4506222. PMID 25867906.
  9. ↑ Harrison AM, Gajic O, Pickering BW, Herasevich V (2016). "Development and Implementation of Sepsis Alert Systems". Clin Chest Med. 37 (2): 219–29. doi:10.1016/j.ccm.2016.01.004. PMC 4884325. PMID 27229639.
  10. ↑ Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E (2015). "Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis". Intern Emerg Med. 10 (6): 731–43. doi:10.1007/s11739-015-1248-y. PMID 25982917.
  11. ↑ 11.0 11.1 Nguyen HB, Jaehne AK, Jayaprakash N, Semler MW, Hegab S, Yataco AC; et al. (2016). "Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE". Crit Care. 20 (1): 160. doi:10.1186/s13054-016-1288-3. PMC 4929762. PMID 27364620.
  12. ↑ Simpson SQ, Gaines M, Hussein Y, Badgett RG (2016). "Early goal-directed therapy for severe sepsis and septic shock: A living systematic review". J Crit Care. 36: 43–48. doi:10.1016/j.jcrc.2016.06.017. PMID 27546746.
  13. ↑ 13.0 13.1 Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ; et al. (2015). "A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators". Intensive Care Med. 41 (9): 1549–60. doi:10.1007/s00134-015-3822-1. PMID 25952825.
  14. ↑ 14.0 14.1 ARISE Investigators. ANZICS Clinical Trials Group. Peake SL, Delaney A, Bailey M, Bellomo R; et al. (2014). "Goal-directed resuscitation for patients with early septic shock". N Engl J Med. 371 (16): 1496–506. doi:10.1056/NEJMoa1404380. PMID 25272316. Review in: Ann Intern Med. 2015 Mar 17;162(6):JC4
  15. ↑ 15.0 15.1 15.2 15.3 ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA; et al. (2014). "A randomized trial of protocol-based care for early septic shock". N Engl J Med. 370 (18): 1683–93. doi:10.1056/NEJMoa1401602. PMC 4101700. PMID 24635773. Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9
  16. ↑ Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD; et al. (2015). "Trial of early, goal-directed resuscitation for septic shock". N Engl J Med. 372 (14): 1301–11. doi:10.1056/NEJMoa1500896. PMID 25776532. Review in: Ann Intern Med. 2015 Aug 18;163(4):JC10
  17. ↑ 17.0 17.1 17.2 Kuan WS, Ibrahim I, Leong BS, Jain S, Lu Q, Cheung YB; et al. (2016). "Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial". Ann Emerg Med. 67 (3): 367–378.e3. doi:10.1016/j.annemergmed.2015.09.010. PMID 26475246.
  18. ↑ Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D; et al. (2015). "Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis". Intensive Care Med. 41 (9): 1561–71. doi:10.1007/s00134-015-3794-1. PMID 25904181.
  19. ↑ Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C; et al. (2015). "Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial". JAMA. 314 (16): 1701–10. doi:10.1001/jama.2015.12334. PMID 26444692.
  20. ↑ Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R; et al. (2017). "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016". Intensive Care Med. doi:10.1007/s00134-017-4683-6. PMID 28101605.
  21. ↑ Liu VX, Morehouse JW, Marelich GP, Soule J, Russell T, Skeath M; et al. (2016). "Multicenter Implementation of a Treatment Bundle for Patients with Sepsis and Intermediate Lactate Values". Am J Respir Crit Care Med. 193 (11): 1264–70. doi:10.1164/rccm.201507-1489OC. PMC 4910898. PMID 26695114.
  22. ↑ Neyra JA, Li X, Canepa-Escaro F, Adams-Huet B, Toto RD, Yee J; et al. (2016). "Cumulative Fluid Balance and Mortality in Septic Patients With or Without Acute Kidney Injury and Chronic Kidney Disease". Crit Care Med. 44 (10): 1891–900. doi:10.1097/CCM.0000000000001835. PMID 27352125.
  23. ↑ Brotfain E, Koyfman L, Toledano R, Borer A, Fucs L, Galante O; et al. (2016). "Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after discharge from intensive care unit". Am J Emerg Med. doi:10.1016/j.ajem.2016.07.058. PMID 27553826.
  24. ↑ Mitchell KH, Carlbom D, Caldwell E, Leary PJ, Himmelfarb J, Hough CL (2015). "Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock". Ann Am Thorac Soc. 12 (12): 1837–44. doi:10.1513/AnnalsATS.201504-187OC. PMC 4722831. PMID 26394090.
  25. ↑ Acheampong A, Vincent JL (2015). "A positive fluid balance is an independent prognostic factor in patients with sepsis". Crit Care. 19: 251. doi:10.1186/s13054-015-0970-1. PMC 4479078. PMID 26073560.
  26. ↑ de Oliveira FS, Freitas FG, Ferreira EM, de Castro I, Bafi AT, de Azevedo LC; et al. (2015). "Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock". J Crit Care. 30 (1): 97–101. doi:10.1016/j.jcrc.2014.09.002. PMID 25269788.
  27. ↑ 27.0 27.1 Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA (2011). "Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality". Crit Care Med. 39 (2): 259–65. doi:10.1097/CCM.0b013e3181feeb15. PMID 20975548.
  28. ↑ Wang N, Jiang L, Zhu B, Wen Y, Xi XM, Beijing Acute Kidney Injury Trial (BAKIT) Workgroup (2015). "Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study". Crit Care. 19: 371. doi:10.1186/s13054-015-1085-4. PMC 4619072. PMID 26494153.
  29. ↑ Cronhjort M, Hjortrup PB, Holst LB, Joelsson-Alm E, Mårtensson J, Svensen C; et al. (2016). "Association between fluid balance and mortality in patients with septic shock: a post hoc analysis of the TRISS trial". Acta Anaesthesiol Scand. 60 (7): 925–33. doi:10.1111/aas.12723. PMID 27030514.
  30. ↑ Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettilä V; et al. (2016). "Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial". Intensive Care Med. doi:10.1007/s00134-016-4500-7. PMID 27686349.
  31. ↑ Benes J (2016). "Cumulative Fluid Balance: The Dark Side of the Fluid". Crit Care Med. 44 (10): 1945–6. doi:10.1097/CCM.0000000000001919. PMID 27635489.
  32. ↑ Teboul JL, Saugel B, Cecconi M, De Backer D, Hofer CK, Monnet X; et al. (2016). "Less invasive hemodynamic monitoring in critically ill patients". Intensive Care Med. 42 (9): 1350–9. doi:10.1007/s00134-016-4375-7. PMID 27155605.
  33. ↑ Stens J, Oeben J, Van Dusseldorp AA, Boer C (2016). "Non-invasive measurements of pulse pressure variation and stroke volume variation in anesthetized patients using the Nexfin blood pressure monitor". J Clin Monit Comput. 30 (5): 587–94. doi:10.1007/s10877-015-9759-7. PMC 5023739. PMID 26318314.
  34. ↑ Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT (2016). "Will This Hemodynamically Unstable Patient Respond to a Bolus of Intravenous Fluids?". JAMA. 316 (12): 1298–309. doi:10.1001/jama.2016.12310. PMID 27673307.
  35. ↑ Porhomayon J, Zadeii G, Congello S, Nader ND (2012). "Applications of minimally invasive cardiac output monitors". Int J Emerg Med. 5: 18. doi:10.1186/1865-1380-5-18. PMC 3353182. PMID 22531454.
  36. ↑ Taton O, Fagnoul D, De Backer D, Vincent JL (2013). "Evaluation of cardiac output in intensive care using a non-invasive arterial pulse contour technique (Nexfin(®)) compared with echocardiography". Anaesthesia. 68 (9): 917–23. doi:10.1111/anae.12341. PMID 23837860.
  37. ↑ Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE (2015). "The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis". Crit Care Med. 43 (9): 1907–15. doi:10.1097/CCM.0000000000001142. PMC 4597314. PMID 26121073. Review in: Evid Based Med. 2015 Dec;20(6):214-5
  38. ↑ Identifying and measuring heterogeneity. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org
  39. ↑ Kumar A (2016). "Systematic Bias in Meta-Analyses of Time to Antimicrobial in Sepsis Studies". Crit Care Med. 44 (4): e234–5. doi:10.1097/CCM.0000000000001512. PMID 26974458.
  40. ↑ 40.0 40.1 Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP; et al. (2014). "Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program". Crit Care Med. 42 (8): 1749–55. doi:10.1097/CCM.0000000000000330. PMID 24717459.
  41. ↑ Shirakura Y, Kuriyama A (2016). "Timing of Antibiotic Administration in Sepsis and Septic Shock: The Impact That a Meta-Analysis Does Not Depict". Crit Care Med. 44 (10): e1004. doi:10.1097/CCM.0000000000001891. PMID 27635498.
  42. ↑ Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S; et al. (2006). "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock". Crit Care Med. 34 (6): 1589–96. doi:10.1097/01.CCM.0000217961.75225.E9. PMID 16625125.
  43. ↑ Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J; et al. (2016). "Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials". Am J Respir Crit Care Med. 194 (6): 681–91. doi:10.1164/rccm.201601-0024OC. PMID 26974879.
  44. ↑ Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y (2015). "Corticosteroids for treating sepsis". Cochrane Database Syst Rev (12): CD002243. doi:10.1002/14651858.CD002243.pub3. PMID 26633262.
  45. ↑ Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S; et al. (2016). "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial". JAMA. 316 (17): 1775–1785. doi:10.1001/jama.2016.14799. PMID 27695824.
  46. ↑ Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S; et al. (2014). "Lower versus higher hemoglobin threshold for transfusion in septic shock". N Engl J Med. 371 (15): 1381–91. doi:10.1056/NEJMoa1406617. PMID 25270275.
  47. ↑ 47.0 47.1 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B; et al. (2001). "Early goal-directed therapy in the treatment of severe sepsis and septic shock". N Engl J Med. 345 (19): 1368–77. PMID 11794169. Review in: ACP J Club. 2002 May-Jun;136(3):90
  48. ↑ Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; et al. (2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial". JAMA. 303 (8): 739–46. doi:10.1001/jama.2010.158. PMID 20179283.
  49. ↑ 49.0 49.1 Cannon CM, Holthaus CV, Zubrow MT, Posa P, Gunaga S, Kella V; et al. (2012). "The GENESIS Project (GENeralized Early Sepsis Intervention Strategies): A Multicenter Quality Improvement Collaborative". J Intensive Care Med. doi:10.1177/0885066612453025. PMID 22902347.
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