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A more recent cohort found benefit, "Each hour until initial antimicrobial administration was associated with a 8.0% increase in progression to septic shock".<ref name="pmid28169944">{{cite journal| author=Whiles BB, Deis AS, Simpson SQ| title=Increased Time to Initial Antimicrobial Administration Is Associated With Progression to Septic Shock in Severe Sepsis Patients. | journal=Crit Care Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28169944 | doi=10.1097/CCM.0000000000002262 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28169944  }} </ref>
A more recent cohort found benefit, "Each hour until initial antimicrobial administration was associated with a 8.0% increase in progression to septic shock".<ref name="pmid28169944">{{cite journal| author=Whiles BB, Deis AS, Simpson SQ| title=Increased Time to Initial Antimicrobial Administration Is Associated With Progression to Septic Shock in Severe Sepsis Patients. | journal=Crit Care Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28169944 | doi=10.1097/CCM.0000000000002262 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28169944  }} </ref>
Regarding the improvement of speed to antibiotic administration, a controlled case series demonstrated a shorter time interval between ordering an antibiotic and its administration by using a [[hospital rapid response team]] (RRT) (median time in group without RRT activation was 157 minutes vs group with RRT activation of 54 minutes; p < .01). The RRT in this case series included a pharmacist. <ref name="pmid18419048">{{cite journal| author=Sarani B, Brenner SR, Gabel B, Myers JS, Gibson G, Phillips J et al.| title=Improving sepsis care through systems change: the impact of a medical emergency team. | journal=Jt Comm J Qual Patient Saf | year= 2008 | volume= 34 | issue= 3 | pages= 179-82, 125 | pmid=18419048 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18419048  }} </ref>


====Delivery method====
====Delivery method====

Revision as of 16:32, 18 April 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] Electronic alerts in the electronic health record may[7] or may not[8] improve outcomes for sepsis patients.[9][10] Alerts may trigger intervention by a hospital rapid response team.

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:[11]

  • 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:[12]

  • 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:[13]

  • 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[14] of the three most recent trials[15][16][17] 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[12] 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[16][18]. 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."[19] A more recent trial of patients with diverse diagnoses found no difference.[20]

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.[21]

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 (11% of total) with a diagnosis of underlying fluid overload state (defined as a history of heart failure, ejection fraction less than 50%, or end-stage renal disease) showed that the intervention group received clinically significant more IV fluids than the control group (difference = 975 mls, 95% CI: -450 ml to +1725 ml) and attained shorter hospital lengths of stay (difference -4.5 days, 95% CI -9.5-2.5 days).[18]
  • 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 for a subgroup of patients (46% of total) with a known history of heart failure or chronic kidney disease (both defined by any previous diagnosis) 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.[22]

Excessive fluid therapy

Positive fluid balance may be associated with worse outcomes in most[23][24][25][26][27][28][29], but not all[30] 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.[28]

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.[31] Expert opinion suggests positive fluid balance should be addresses within three days of resuscitation. [32]

Hemodynamic monitoring

Regarding the monitoring of fluid administration, few randomized controlled trials used an explicit protocol[16][18]. 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.[14]

Methods of assessing fluid responsiveness

Various methods are available and have been reviewed.[33][34][35][36]

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.[37] 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:[38]

  • 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.[39]
  • 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.[40]
  • One article[41] 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.[42]

The two largest studies in the meta-analysis both found positive correlations between delays in antibiotics and mortality.[41][43]

A more recent cohort found benefit, "Each hour until initial antimicrobial administration was associated with a 8.0% increase in progression to septic shock".[44]

Regarding the improvement of speed to antibiotic administration, a controlled case series demonstrated a shorter time interval between ordering an antibiotic and its administration by using a hospital rapid response team (RRT) (median time in group without RRT activation was 157 minutes vs group with RRT activation of 54 minutes; p < .01). The RRT in this case series included a pharmacist. [45]

Delivery method

Continuous infusion may be more effective.[46]

Steroids

Corticosteroids may reduce mortality among patients with septic shock according to a systematic review by the Cochrane Collaboration.[47]

The subsequent HYPRESS randomized controlled trial of patients with severe sepsis showed now benefit.[48]

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.[49]

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.[50] 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,[51][50][52] the more recent ProCESS[16] and ARISE[15] 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:[52]

  • 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.[21]

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
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).  

In a retrospective, quasi experimental study conducted in the Emergency Department, an EHR-based triage sepsis alert system and standardized protocol was implemented in an effort to identify adult patients with suspected sepsis, severe sepsis, or septic shock and improve patient outcomes. Using SIRS criteria in conjunction with physician approval, this triage system led to a significant reduction in the time to fluids and time to antibiotics, although no difference in mortality was found. [53]

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. ↑ GitHub Contributors. Sepsis alerts to improve diagnosis: a living systematic review. GitHub. Available at https://github.com/openMetaAnalysis/Sepsis-alerts-to-improve-diagnosis/blob/master/README.md. Accessed March 15, 2017.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 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.
  14. ↑ 14.0 14.1 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.
  15. ↑ 15.0 15.1 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
  16. ↑ 16.0 16.1 16.2 16.3 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
  17. ↑ 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
  18. ↑ 18.0 18.1 18.2 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 21.0 21.1 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 28.0 28.1 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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
  39. ↑ 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
  40. ↑ 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.
  41. ↑ 41.0 41.1 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ Whiles BB, Deis AS, Simpson SQ (2017). "Increased Time to Initial Antimicrobial Administration Is Associated With Progression to Septic Shock in Severe Sepsis Patients". Crit Care Med. doi:10.1097/CCM.0000000000002262. PMID 28169944.
  45. ↑ Sarani B, Brenner SR, Gabel B, Myers JS, Gibson G, Phillips J; et al. (2008). "Improving sepsis care through systems change: the impact of a medical emergency team". Jt Comm J Qual Patient Saf. 34 (3): 179–82, 125. PMID 18419048.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 50.0 50.1 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
  51. ↑ 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.
  52. ↑ 52.0 52.1 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.
  53. ↑ Hayden GE, Tuuri RE, Scott R, Losek JD, Blackshaw AM, Schoenling AJ; et al. (2016). "Triage sepsis alert and sepsis protocol lower times to fluids and antibiotics in the ED". Am J Emerg Med. 34 (1): 1–9. doi:10.1016/j.ajem.2015.08.039. PMC 4905767. PMID 26386734.
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