Sepsis medical therapy: Difference between revisions

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Latest revision as of 01:50, 3 January 2023

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

Adherence to bundles of care is associated with improved outcomes^[11].

Fluid therapy

Guidelines

The 2012 Surviving Sepsis Campaign (SSC) recommendations proposed:^[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) guidelines, 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

Randomized controlled trials of various strategies for fluids^[12]^[13]^[14]^[15]^[16]
	Rivers, 2001^[12]	ProCESS, 2014^[13]	ARISE, 2014^[14]	ProMISe, 2015^[15]	CLASSIC, 2022^[16]
Lactate, mean (treatment; control	6.9; 7.7	4.8; 5.0	6.7; 6.6	7.0; 6.8	3.8; 3.9 (median)
Fluids in first 6 hours (treatment; control)	4900; 3500	3300; 2800	2000; 1700	2000; 1800 (median)	1000; 1700 (24 hours)
Mortality (treatment; control)	44%; 57% (60 days)	21%; 18%	19%; 19%	30%; 29%	42%; 42%

EGDT to guide fluid therapy

Regarding underlying evidence, a systematic review of randomized control trials concluded:^[17]

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:^[18]

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:^[19]

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^[20] of the three most recent trials^[14]^[13]^[15] 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^[18] 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.

Trials of other protocols to guide fluid therapy

Mottling score^[21]
Score	Description
0	No mottling
1	"Small mottling area (coinsize) localized to the center of the knee"
2	"A mottling area that does not exceed the superior edge of the knee cap"
3	"A mottling area that does not exceed the middle thigh"
4	"A mottling area that does not go beyond the fold of the groin"
5	"An extremely severe mottling area that goes beyond the fold of the groin

In the CLASSIC randomized controlled trial, after an initial 30 ml/kg fluid bolus, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg. Further fluids in the experimental group (fluid boluses of 250–500 mL every 30 minutes) were allow if^[22]:

Lactate level of at least 4 mmol/L
"MAP below 50 mmHg in spite of the infusion of norepinephrine"
"Mottling beyond the edge of the kneecap (mottling score^[21] greater than 2)"
"Oliguria, but only in the first 2 h after randomisation, defined as urinary output at most 0.1 mL/kg IBW in the last hour."

The trial found an insignificant trend towards benefit in the experimental group.

In the ANDROMEDA-SHOCK randomized controlled trial, after an initial 20 mL/kg or more over 60 minutes, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg (in patients with chronic hypertension, a higher goal might be used). Further fluids in the experimental group (500 mL of crystalloids every 30 minutes) were allowed if^[23]:

Capillary refill time (CRT) was greater than 3 seconds. The CRT was measured by "applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure was increased until the skin was blank and then maintained for 10 seconds. The time for return of the normal skin color was registered with a chronometer". "The CRT was evaluated every 30 minutes, because of its faster rate of recovery, until normalization and then every hour during the intervention period". The intervention period was 8 hours.
Central venous pressure safety was not elevated
The patient became fluid unresponsive as measured by one of several methods^[24]

The trial found an insignificant trend towards benefit in the experimental group.

In the small, pilot Echo vs EGDT randomized controlled trial at Intermountain Healthcare, after a median of 35 mL/kg of fluids, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg. Further fluids in the experimental group (1 L of crystalloids every hour) were allowed if^[25]

CVP less than 8–12 mm Hg or, if no central line, shock index ≥ 1
IVC collapsibility present. Collapsibility was defined by "the maximum diameter was < 5 mm or if vena cava collapsibility index (VCCI), defined as the difference in diameter during a respiratory cycle divided by the maximum diameter, was > 50%"

No differences were found in the results; however, 70% of patients has reached their lactate clearance goal after initial resuscitation and before the trial protocol started.

In the small RIFTS randomized controlled trial that compared ≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care found no less fluids administered in the intervention without a difference in mortality≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care^[26] .

Timing of fluid therapy

Two cohort studies examined the impact of the timing of fluid therapy for severe sepsis and septic shock. Taken together, the cohorts suggest fluids should be started as fast as possible, but the total amount to be infused and the infusion rate are not clear.

Regarding administration of 30 ml/kg of fluids, reduced time to start of administration is associated with increased survival; however, there is not a clear relationship between mortality and time of completion of fluid bolus as this was not measured in this study^[27].
Completing a 3 hour bundle for sepsis care and rapidly administering antibiotics showed a lower risk-associated in-hospital mortality. However, there was insufficient evidence in this study to conclude that rapid completion of the initial fluid bolus affected mortality^[28].

Speed of fluid therapy

Regarding the speed fluid administration, only two trials revealed an explicit protocol^[13]^[29]. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes.

Composition of fluids

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."^[30]

A more recent trial of patients with diverse diagnoses found no difference.^[31]

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.^[32]

A systematic review in 2017 found that conservative fluids after resuscitation may be beneficial^[33]

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.^[34]

Excessive fluid therapy

Positive fluid balance may be associated with worse outcomes in most^[35]^[36]^[37]^[38]^[39]^[40]^[41], but not all^[42] 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.^[40]

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.^[22] Expert opinion suggests positive fluid balance should be addresses within three days of resuscitation. ^[43]

Lactate level

Lactate elevation seems due to aerobic glycolysis in skeletal muscle secondary to epinephrine stimulation^[44].

The 2016 Surviving Sepsis Guidelines recommend:^[45]

"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)."

The guidelines by the Surviving Sepsis Campaign (SSC) do not specify how to response to slow lactate clearance. Two trails, both reporting reduced mortality from lactate-guided therapy, provide specific suggestions for responding to slow clearance:

When the clearance falls by less than 10% over 1 hours, transfuse pack red blood cells or infuse the inotrope dobutamine is recommended by Jones^[46]. Since publication of this trial, a subsequent trial showed that a hemoglobin of 7 g/dl is adequate^[47]. In addition, subsequent guidelines by the SSC recommend norepinephrine as the first-choice vasopressor^[45].
When the clearance falls by less than 20% over 2 hours, either administer fluids, transfuse pack red blood cells, infuse the inotrope dobutamine, or increase administration of oxygen is recommended by Jansen^[48]. However, since publication of this trial, subsequent guidelines by the SSC recommend norepinephrine as the first-choice vasopressor^[45].

Evidence

Randomized controlled trials of monitoring lactate clearance to guide fluid resuscitation over the first 12 hours of resuscitation in sepsis and septic shock have been summarized in meta-analyses. A meta-analysis of four randomized controlled trials with 547 patients reported mortality benefit (RR=0.67, p=0.002) when lactate clearance strategies were used compared with early goal-directed therapy (EGDT) or usual care^[49]. A meta-analysis of 4 trials with 448 patients showed a comparable mortality benefit (RR=0.64) with the use of lactate clearance strategies versus EGDT^[19].

Hemodynamic monitoring

Regarding the monitoring of fluid administration, few randomized controlled trials used an explicit protocol^[13]^[29]. 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.^[20]

Methods of assessing fluid responsiveness

Various methods are available and have been reviewed.^[50]^[51]^[52]^[53]

Antibiotics

For every hour delay in the administration of appropriate antibiotic therapy there is an associated 4% rise in mortality.^[54]

The Infectious Disease Society of America (IDSA) recommends that only patients with septic shock need antibiotics within one hour^[55].

Timing of antibiotics

A systematic review found benefit from administration of antibiotics within one hour of diagnosis.^[56] Several more recent observational studies have found benefits as well^[57]^[58]. A recent cohort found benefit, "Each hour until initial antimicrobial administration was associated with a 8.0% increase in progression to septic shock".^[59]

Administrating antibiotics before cultures will reduce the positivity rate of cultures. Two cohorts have found a decrease in positivity^[60]^[61]^[61]; one looked at varying intervals and suggests harm starts as soon as 30 minutes after antibitoics^[61].

Dissenting views

In 2019, a systematic review found no statistically significant difference in survival between projects that targeted antibiotics administered within 1 hour (7 studies) and 3 hours (8 studies)^[62]. However, the studies did not reliably achieve rapid antibiotic administration. For example, among the studies targeting antibiotics within one hour, before project implementation, the rate of rapid administration was 55% and afterwards was 63%^[63]. Thus, this study shows the difficulty in achieving effectiveness from administration within one hour rather than the efficacy when all patients receive antibiotics within one hour^[64].

While an older 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:^[65]

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.^[66]
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.^[67]
One article^[68] 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.^[69]

The two largest studies in the meta-analysis both found positive correlations between delays in antibiotics and mortality.^[68]^[70]

Methods to improve speed of antibiotic administration

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. ^[71]

Antibiotic selection

The use of appropriate antibiotics, defined by most researchers as having in vitro activity against an isolated pathogen, in patients with bacteremia and/or severe sepsis or septic shock is associated with decreased mortality^[72]^[73]^[74]. Lee (OR 2.26, 95% CI 1.10-5.13, p=0.04) and Nygard (OR 2.17, 95% CI 1.10-4.27, p=0.027) found that inappropriate antibiotics were associated with increased 28-day mortality^[74]^[75]. Garnacho reported that adequate antibiotics are protective against mortality (OR 0.40, 95% CI 0.24-0.65, p<0.001)^[75]. Observing a population of sixteen patients with urosepsis, Flaherty had similar conclusions, citing 18% overall mortality versus 25% among four patients who did not receive adequate antibiotic therapy^[72].

Existing literature demonstrates that emergency department (ED) physicians prescribe appropriate initial antibiotic therapy 82-90% of the time^[72]^[76], when treating patients with severe sepsis or septic shock. Other studies demonstrated similar rates of 80-81% among non-ED physicians^[77]^[78]. Capp, et al. posited that inappropriate antibiotics were more likely to be prescribed in cases of gram-negative organisms^[76]. Similarly, Flaherty, et al. found that antibiotic coverage was most appropriately chosen in patients presenting with pneumonia (97%); treatment failure was more common among the subgroup of patients with urinary tract infections, likely due to multidrug resistance^[72].

Delivery method

Continuous infusion may be more effective.^[79]

Pressors

Pressors that have been used are:

Dopamine
Epinephrine - Alpha and beta-agonist. Transiently raises the lactate level from baseline of 4.1 to 4.9^[80].
Norepinephrine - Alpha and beta-agonist

Vasopressin

Evidence

In a randomized controlled trial comparing dopamine and norepinephrine, efficacy was similar but less adverse effect with norepinephrine^[81] The change in lactate levels was similar in the two groups^[81].

Pressors titrated to MAP of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg does not change affect mortality among patients who already received a minimum 30 mL/kg within 6 hours prior to the start of catecholamines^[82].

Giving pressors too early may be harmful^[83].

Steroids

Corticosteroids may reduce mortality among patients with septic shock according to a meta-analysis^[84] that includes the APROCCHSS^[85] and ADRENAL^[86] randomized controlled trials.

Corticosteroids may reduce mortality among patients with septic shock according to a systematic review by the Cochrane Collaboration.^[87] However, a second systematic review published the same year found insignificant benefit from steroids^[88].

The subsequent HYPRESS randomized controlled trial of patients with severe sepsis showed no benefit.^[89]

Non-randomized studies reach conflicting conclusions with benefit found in the Intermountain cohort^[5] and harm found in the Surviving Sepsis cohort^[90].

The benefit of steroids may be confined to patients who have the SRS 1 variant (immunosuppressed) of the transcriptomic sepsis response signatures (SRS)^[91].

The somewhat results of the Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock (ADRENAL) and ADRENAL and Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) randomized controlled trials has been extensively debated^[92].

Mineralocorticoid

Fludrocortisone was not effective in the COIITSS randomized controlled trial as a add on treatment to hydrocortisone^[93].

Role of relative adrenal insufficiency

Patients who had a low response to at corticotropin stimulation test were not more likely to respond to a combination of hydrocortisone and fludrocortisone in the APROCCHSS trial^[85].

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.^[47]

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.^[12] 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,^[46]^[12]^[94] the more recent ProCESS^[13] 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:^[94]

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.

2018 Surviving Sepsis Campaign update

A major change with the update is that the 3 hour and 6 hour bundles were combined into one “Hour-1 Bundle.”^[95] Per the Surviving Sepsis Campaign^[96]:

The hour-1 bundle should be viewed as a quality improvement opportunity moving toward an ideal state. For critically ill patients with sepsis or septic shock, time is of the essence. Although the starting time for the Hour-1 bundle is recognition of sepsis, both sepsis and septic shock should be viewed as medical emergencies requiring rapid diagnosis and immediate intervention.
The hour-1 bundle encourages clinicians to act as quickly as possible to obtain blood cultures, administer broad spectrum antibiotics, start appropriate fluid resuscitation, measure lactate, and begin vasopressors if clinically indicated. Ideally these interventions would all begin in the first hour from sepsis recognition but may not necessarily be completed in the first hour. Minimizing the time to treatment acknowledges the urgency that exists for patients with sepsis and septic shock.
*Note that the description of the hour-1 bundle above is the most current description, having passed all approval points effective October 10, 2019.

Hour-1 Bundle Pocket Card and Infographic

SSC Hour-1 Bundle of Care Elements:

Measure lactate level*
Obtain blood cultures before administering antibiotics.
Administer broad-spectrum antibiotics.
Begin rapid administration of 30mL/kg crystalloid for hypotension or lactate level ≥ 4 mmol/L.
Apply vasopressors if hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg.

* Remeasure lactate if initial lactate is elevated (> 2 mmol/L).

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

2016 Bundle.^[32]

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

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. ^[97]

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

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↑ 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.
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↑
Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC; et al. (2017). "Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis". Intensive Care Med. 43 (2): 155–170. doi:10.1007/s00134-016-4573-3. PMID 27734109.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) </. Two previous 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).<ref name="pmid26475246">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.
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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).<ref name="pmid26475246">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.

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@@ Line 1: / Line 1: @@
 __NOTOC__
+{{Siren|Sepsis}}
 {{Sepsis}}
-{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com];
+{{CMG}}; {{AE}} [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]]{{ADG}}
 ==Overview==
-The "Surviving Sepsis Campaign" was an international effort organized by physicians that developed and promoted widespread adoption of practice improvement programs grounded in evidence-based guidelines. The goal was to improve diagnosis and treatment of sepsis. Included among the guidelines were sepsis 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. These and similar guidelines have been tested by a number of hospitals and have shown potential for decreasing hospital mortality due to sepsis.<ref name="urlProducts - Data Briefs - Number 62 - June 2011">{{cite web |url=http://www.cdc.gov/nchs/data/databriefs/db62.htm |title=Products - Data Briefs - Number 62 - June 2011 |format= |work= |accessdate=2012-09-17}}</ref><ref name="pmid2826633">{{cite journal |author=Wiedermann CJ, Adamson IY, Pert CB, Bowden DH |title=Enhanced secretion of immunoreactive bombesin by alveolar macrophages exposed to silica |journal=[[Journal of Leukocyte Biology]] |volume=43 |issue=2 |pages=99–103 |year=1988 |month=February |pmid=2826633 |doi= |url=http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=2826633 |accessdate=2012-09-17}}</ref>
+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.<ref name="pmid23353941">{{cite journal| author=Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.| title=Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. | journal=Crit Care Med | year= 2013 | volume= 41 | issue= 2 | pages= 580-637 | pmid=23353941 | doi=10.1097/CCM.0b013e31827e83af | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23353941  }} </ref><ref name="pmid23361625">{{cite journal| author=Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.| title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. | journal=Intensive Care Med | year= 2013 | volume= 39 | issue= 2 | pages= 165-228 | pmid=23361625 | doi=10.1007/s00134-012-2769-8 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23361625  }} </ref> These and similar guidelines have been tested by a number of hospitals and have shown potential for decreasing hospital mortality due to sepsis.<ref name="pmid26109396">{{cite journal| author=Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D et al.| title=The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 9 | pages= 1620-8 | pmid=26109396 | doi=10.1007/s00134-015-3906-y | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26109396  }} </ref><ref name="pmid25275252">{{cite journal| author=Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R et al.| title=Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. | journal=Crit Care Med | year= 2015 | volume= 43 | issue= 1 | pages= 3-12 | pmid=25275252 | doi=10.1097/CCM.0000000000000723 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25275252  }} </ref><ref name="pmid23631750">{{cite journal| author=Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR et al.| title=Multicenter implementation of a severe sepsis and septic shock treatment bundle. | journal=Am J Respir Crit Care Med | year= 2013 | volume= 188 | issue= 1 | pages= 77-82 | pmid=23631750 | doi=10.1164/rccm.201212-2199OC | pmc=PMC3735248 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23631750  }} </ref> In addition, hospital length of stay may be shortened.<ref name="pmid23631750" /><ref name="pmid27085369">{{cite journal| author=Leisman D, Wie B, Doerfler M, Bianculli A, Frances Ward M, Akerman M et al.| title=Association of Fluid Resuscitation Initiation Within 30 Minutes of Severe Sepsis and Septic Shock Recognition With Reduced Mortality and Length of Stay. | journal=Ann Emerg Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27085369 | doi=10.1016/j.annemergmed.2016.02.044 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27085369  }} </ref>
+Electronic alerts in the electronic health record may<ref name="pmid26573784">{{cite journal| author=Narayanan N, Gross AK, Pintens M, Fee C, MacDougall C| title=Effect of an electronic medical record alert for severe sepsis among ED patients. | journal=Am J Emerg Med | year= 2016 | volume= 34 | issue= 2 | pages= 185-8 | pmid=26573784 | doi=10.1016/j.ajem.2015.10.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26573784  }} </ref> or may not<ref name="pmid25867906">{{cite journal| author=Semler MW, Weavind L, Hooper MH, Rice TW, Gowda SS, Nadas A et al.| title=An Electronic Tool for the Evaluation and Treatment of Sepsis in the ICU: A Randomized Controlled Trial. | journal=Crit Care Med | year= 2015 | volume= 43 | issue= 8 | pages= 1595-602 | pmid=25867906 | doi=10.1097/CCM.0000000000001020 | pmc=PMC4506222 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25867906  }} </ref> improve outcomes for sepsis patients.<ref>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.</ref><ref name="pmid27229639">{{cite journal| author=Harrison AM, Gajic O, Pickering BW, Herasevich V| title=Development and Implementation of Sepsis Alert Systems. | journal=Clin Chest Med | year= 2016 | volume= 37 | issue= 2 | pages= 219-29 | pmid=27229639 | doi=10.1016/j.ccm.2016.01.004 | pmc=4884325 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27229639  }} </ref> Alerts may trigger intervention by a [[hospital rapid response team]].
 ==Medical Therapy==
-The delay in administering therapy after sepsis has been recognized, is the main problem in the adequate management of septic patients. For every hour delay in the administration of appropriate [[antibiotic]] therapy there is an associated 7% rise in mortality. A large international collaboration was established to educate people about sepsis and to improve patient outcomes with sepsis, entitled the "Surviving Sepsis Campaign".
-==2008 Surviving Sepsis Campaign International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>==
-===Initial Resuscitation (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
-{{cquote|
-'''1.''' The guideline committee recommends the protocolized [[resuscitation]] of a patient with [[sepsis]]-induced shock, defined as tissue [[hypoperfusion]] ([[hypotension]] persisting after initial fluid challenge or blood [[lactate]] concentration equal to or greater than 4 mmol/L). This protocol should be initiated as soon as hypoperfusion is recognized and should not be delayed pending [[intensive care unit]] (ICU) admission. During the first 6 hours of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following as one part of a treatment protocol:
-*[[Central venous pressure]] (CVP) 8–12 mm Hg
-*[[Mean arterial pressure]] (MAP) >65 mm Hg
-*Urine output >0.5 mL/kg/hour
-*Central venous ([[superior vena cava]]) or mixed venous oxygen saturation >70% or >65%, respectively. (Grade 1C)
-'''2.''' The guideline committee suggests that during the first 6 hours of resuscitation of [[severe sepsis]] or [[septic shock]], if central venous oxygen saturation (SCVO2) or mixed venous saturation (SvO2) of 70% or 65% respectively is not achieved with fluid resuscitation to the CVP target, then transfusion of [[packed red blood cells]] to achieve a [[hematocrit]] of >30% and/or administration of a [[dobutamine]] infusion (up to a maximum of 20 micrograms/kg/min) be utilized to achieve this goal. (Grade 2C)
+Adherence to bundles of care is associated with improved outcomes<ref name="pmid34364867">{{cite journal| author=Townsend SR, Phillips GS, Duseja R, Tefera L, Cruikshank D, Dickerson R | display-authors=etal| title=Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study. | journal=Chest | year= 2021 | volume=  | issue=  | pages=  | pmid=34364867 | doi=10.1016/j.chest.2021.07.2167 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34364867  }} </ref>.
-}}
-===Antibiotic Therapy (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+===Fluid therapy===
-{{cquote|
+====Guidelines====
-'''1.''' The guideline committee recommends that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (Grade 1B) and severe sepsis without septic shock (Grade 1D). Appropriate cultures should be obtained before initiating [[antibiotic]] therapy, but should not prevent prompt administration of [[antimicrobial]] therapy. (Grade 1D)
+The 2012 Surviving Sepsis Campaign (SSC) recommendations proposed:<ref name="pmid23353941">{{cite journal| author=Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.| title=Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. | journal=Crit Care Med | year= 2013 | volume= 41 | issue= 2 | pages= 580-637 | pmid=23353941 | doi=10.1097/CCM.0b013e31827e83af | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23353941  }} </ref><ref name="pmid23361625">{{cite journal| author=Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al.| title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. | journal=Intensive Care Med | year= 2013 | volume= 39 | issue= 2 | pages= 165-228 | pmid=23361625 | doi=10.1007/s00134-012-2769-8 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23361625  }} </ref>
+* 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]].”
-'''2a.''' The guideline committee recommends that initial empirical anti-infective therapy include one or more drugs that have activity against all likely pathogens ([[bacterial]] and/or [[fungal]]) and that penetrate in adequate concentrations into the presumed source of sepsis. (Grade 1B)
+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
-'''2b.''' The guideline committee recommends that the antimicrobial regimen be reassessed daily to optimize activity, to prevent the development of resistance, to reduce toxicity, and to reduce costs. (Grade 1C)
+In [[National Institute for Health and Care Excellence]] (NICE) guidelines, 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
+* [[IV fluids|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====
-'''2c.''' The guideline committee suggests combination therapy for patients with known or suspected [[Pseudomonas]] infections as a cause of severe sepsis. (Grade 2D)
+{| class="wikitable"
-'''2d.''' The guideline committee suggests combination empiric therapy for [[neutropenic]] patients with severe sepsis. (Grade 2D)
+|+ [[Randomized controlled trial]]s of various strategies for fluids<ref name="pmid11794169">{{cite journal| author=Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B | display-authors=etal| title=Early goal-directed therapy in the treatment of severe sepsis and septic shock. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 19 | pages= 1368-77 | pmid=11794169 | doi=10.1056/NEJMoa010307 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794169  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=11985431 Review in: ACP J Club. 2002 May-Jun;136(3):90] </ref><ref name="pmid24635773">{{cite journal| author=ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA | display-authors=etal| title=A randomized trial of protocol-based care for early septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 18 | pages= 1683-93 | pmid=24635773 | doi=10.1056/NEJMoa1401602 | pmc=4101700 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635773  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=24935515 Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9] </ref><ref name="pmid25272316">{{cite journal| author=ARISE Investigators. ANZICS Clinical Trials Group. Peake SL, Delaney A, Bailey M, Bellomo R | display-authors=etal| title=Goal-directed resuscitation for patients with early septic shock. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 16 | pages= 1496-506 | pmid=25272316 | doi=10.1056/NEJMoa1404380 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25272316  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=25775347 Review in: Ann Intern Med. 2015 Mar 17;162(6):JC4] </ref><ref name="pmid25776532">{{cite journal| author=Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD | display-authors=etal| title=Trial of early, goal-directed resuscitation for septic shock. | journal=N Engl J Med | year= 2015 | volume= 372 | issue= 14 | pages= 1301-11 | pmid=25776532 | doi=10.1056/NEJMoa1500896 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25776532  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=26280432 Review in: Ann Intern Med. 2015 Aug 18;163(4):JC10] </ref><ref name="pmid35709019">{{cite journal| author=Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M | display-authors=etal| title=Restriction of Intravenous Fluid in ICU Patients with Septic Shock. | journal=N Engl J Med | year= 2022 | volume= 386 | issue= 26 | pages= 2459-2470 | pmid=35709019 | doi=10.1056/NEJMoa2202707 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35709019  }} </ref>
-'''2e.''' When used empirically in patients with severe sepsis, the guideline committee suggests that combination therapy should not be administered for more than 3 to 5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. (Grade 2D)
+!
-'''3.''' The guideline committee recommends that the duration of therapy typically be 7 to 10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of [[infection]], or who have immunologic deficiencies including [[neutropenia]]. (Grade 1D)
+! Rivers, 2001<ref name="pmid11794169"/>
-'''4.''' If the presenting clinical syndrome is determined to be due to a noninfectious cause, the guideline committee recommends antimicrobial therapy be stopped promptly to minimize the likelihood that the patient will become infected with an [[antibiotic]] resistant pathogen or will develop a drug related adverse effect. (Grade 1D)
+! ProCESS, 2014<ref name="pmid24635773"/>
-}}
-===Source Control (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+! ARISE, 2014<ref name="pmid25272316"/>
-{{cquote|
-'''1a.''' The guideline committee recommends that a specific anatomic diagnosis of infection requiring consideration for emergent source control - for example [[necrotizing fasciitis]], diffuse [[peritonitis]], [[cholangitis]], intestinal [[infarction]] – be sought and diagnosed or excluded as rapidly as possible (Grade 1C) and within the first 6 hours following presentation. (Grade 1D)
-'''1b.''' The guideline committee further recommends that all patients presenting with severe sepsis be evaluated for the presence of a focus of [[infection]] amenable to source control measures, specifically the drainage of an [[abscess]] or local focus of [[infection]], the debridement of infected necrotic tissue, the removal of a potentially infected device, or the definitive control of a source of ongoing microbial contamination. (Grade 1C)
+! ProMISe, 2015<ref name="pmid25776532"/>
-. The guideline committee suggests that when infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and non-viable tissues has occurred. (Grade 2B)
+! CLASSIC, 2022<ref name="pmid35709019"/>
-. The guideline committee recommends that when source control is required, the effective intervention associated with the least physiologic insult be employed, for example, percutaneous rather than surgical drainage of an [[abscess]]. (Grade 1D)
+|-
-. The guideline committee recommends that when intravascular access devices are a possible source of severe sepsis or [[septic shock]], they be promptly removed after establishing other vascular access. (Grade 1C)
+| Lactate, mean<br />(treatment; control
-}}
-===Fluid Therapy (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+| 6.9; 7.7
-{{cquote|
-'''1.''' The guideline committee recommends fluid [[resuscitation]] with either natural/artificial [[colloids]] or [[crystalloids]]. There is no evidence-based support for one type of fluid over another. (Grade 1B)
-'''2.''' The guideline committee recommends fluid resuscitation initially target a [[CVP]] of at least 8 mm Hg (12 mm Hg in mechanically ventilated patients). Further fluid therapy is often required. (Grade 1C)
+| 4.8; 5.0
-'''3a.''' The guideline committee recommends that a fluid challenge technique be applied, wherein fluid administration is continued as long as the hemodynamic improvement (for example, arterial pressure, [[heart rate]], urine output) continues. (Grade 1D)
+| 6.7; 6.6
-'''3b.''' The guideline committee recommends fluid challenge in patients with suspected hypovolemia be started with at least 1000 mL of [[crystalloid]]s or 300 to 500 mL of [[colloid]]s over 30 minutes. More rapid administration and greater amounts of fluid may be needed in patients with [[sepsis]] induced tissue hypoperfusion (see initial resuscitation recommendations). (Grade 1D)
+| 7.0; 6.8
-'''3c.''' The guideline committee recommends the rate of fluid administration be reduced substantially when cardiac filling pressures ([[CVP]] or pulmonary artery balloon-occluded pressure) increase without concurrent hemodynamic improvement. (Grade 1D)
+| 3.8; 3.9<br />(median)
-}}
-===Vasopressors (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+|-
-{{cquote|
-'''1.''' The guideline committee recommends [[mean arterial pressure]] (MAP) be maintained >65 mm Hg. (Grade 1C)
-'''2.''' The guideline committee recommends either [[norepinephrine]] or [[dopamine]] as the first choice [[vasopressor]] agent to correct [[hypotension]] in [[septic shock]] (administered through a central catheter as soon as one is available). (Grade 1C)
+| Fluids in first 6 hours<br />(treatment; control)
-'''3a.''' The guideline committee suggests that [[epinephrine]], [[phenylephrine]], or [[vasopressin]] should not be administered as the initial [[vasopressor]] in septic shock. (Grade 2C) [[Vasopressin]] .03 units/min may be subsequently added to [[norepinephrine]] with anticipation of an effect equivalent to norepinephrine alone.
+| 4900; 3500
-'''3b.''' The guideline committee suggests that [[epinephrine]] be the first chosen alternative agent in [[septic shock]] that is poorly responsive to [[norepinephrine]] or [[dopamine]]. (Grade 2B)
+| 3300; 2800
-'''5.''' The guideline committee recommends that low dose [[dopamine]] not be used for [[renal]] protection. (Grade 1A)
+| 2000; 1700
-'''6.''' The guideline committee recommends that all patients requiring vasopressors have an arterial line placed as soon as practical if resources are available. (Grade 1D)
+| 2000; 1800<br />(median)
-}}
-===Inotropic Therapy (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+| 1000; 1700<br />(24 hours)
-{{cquote|
-'''1.''' The guideline committee recommends a [[dobutamine]] infusion be administered in the presence of myocardial dysfunction as suggested by elevated cardiac filling pressures and low [[cardiac output]]. (Grade 1C)
-'''2.''' The guideline committee recommends against the use of a strategy to increase cardiac index to predetermined supranormal levels. (Grade 1B)
+|-
-}}
-===Corticosteroids (DO NOT EDIT)<ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+| Mortality<br />(treatment; control)
-{{cquote|
-'''1.''' The guideline committee suggests intravenous [[hydrocortisone]] be given only to adult [[septic shock]] patients after [[blood pressure]] is identified to be poorly responsive to fluid resuscitation and [[vasopressor]] therapy. (Grade 2C)
-'''2.''' The guideline committee suggests the adrenocorticotropic hormone ([[ACTH]]) stimulation test not be used to identify the subset of adults with [[septic shock]] who should receive [[hydrocortisone]]. (Grade 2B)
+| 44%; 57%<br />(60 days)
-'''3.''' The guideline committee suggests that patients with septic shock should not receive [[dexamethasone]] if hydrocortisone is available. (Grade 2B)
+| 21%; 18%
-'''4.''' The guideline committee suggests the daily addition of oral [[fludrocortisone]] (50 micrograms) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used. (Grade 2C)
+| 19%; 19%
-'''5.''' The guideline committee suggests clinicians wean the patient from [[steroid]] therapy when vasopressors are no longer required. (Grade 2D)
+| 30%; 29%
-'''6.''' The guideline committee recommends doses of [[corticosteroid]]s comparable to >300 mg [[hydrocortisone]] daily not be used in severe sepsis or septic shock for the purpose of treating septic shock. (Grade 1A)
+| 42%; 42%
-'''7.''' The guideline committee recommends corticosteroids not be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress-dose steroids if the patient's endocrine or corticosteroid administration history warrants. (Grade 1D)
+|}
-}}
-===Surviving sepsis campaign: international guidelines for Recombinant Human Activated Protein C (rhAPC) in severe sepsis and septic shock: 2008 (DO NOT EDIT) <ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+=====EGDT to guide fluid therapy=====
+Regarding underlying evidence, a [[systematic review]] of randomized control trials concluded:<ref name="pmid25982917">{{cite journal| author=Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E| title=Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis. | journal=Intern Emerg Med | year= 2015 | volume= 10 | issue= 6 | pages= 731-43 | pmid=25982917 | doi=10.1007/s11739-015-1248-y | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25982917  }} </ref>
+* 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:<ref name="pmid27364620">{{cite journal| author=Nguyen HB, Jaehne AK, Jayaprakash N, Semler MW, Hegab S, Yataco AC et al.| title=Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. | journal=Crit Care | year= 2016 | volume= 20 | issue= 1 | pages= 160 | pmid=27364620 | doi=10.1186/s13054-016-1288-3 | pmc=4929762 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27364620  }} </ref>
+* 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.
-{{cquote|
+A third meta-analysis concluded:<ref name="pmid27546746">{{cite journal| author=Simpson SQ, Gaines M, Hussein Y, Badgett RG| title=Early goal-directed therapy for severe sepsis and septic shock: A living systematic review. | journal=J Crit Care | year= 2016 | volume= 36 | issue=  | pages= 43-48 | pmid=27546746 | doi=10.1016/j.jcrc.2016.06.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27546746  }} </ref>
-====Recombinant Human Activated Protein C (rhAPC)====
+* 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.
-'''1.''' The guideline committee suggests that adult patients with sepsis induced organ dysfunction associated with a clinical assessment of high risk of death, most of whom will have Acute Physiology and Chronic Health Evaluation II '''(APACHE II) ≥25 or multiple organ failure''', receive recombinant human activated protein C (rhAPC) if there are no contraindications (Grade 2B except for patients within 30 days of surgery where it is Grade 2C). Relative contraindications should also be considered in decision making.
+Another [[meta-analysis]] by the recent trialists<ref name="pmid25952825">{{cite journal| author=Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ et al.| title=A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 9 | pages= 1549-60 | pmid=25952825 | doi=10.1007/s00134-015-3822-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25952825  }} </ref> of the three most recent trials<ref name="pmid25272316">{{cite journal| author=ARISE Investigators. ANZICS Clinical Trials Group. Peake SL, Delaney A, Bailey M, Bellomo R et al.| title=Goal-directed resuscitation for patients with early septic shock. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 16 | pages= 1496-506 | pmid=25272316 | doi=10.1056/NEJMoa1404380 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25272316  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25775347 Review in: Ann Intern Med. 2015 Mar 17;162(6):JC4] </ref><ref name="pmid24635773">{{cite journal| author=ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al.| title=A randomized trial of protocol-based care for early septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 18 | pages= 1683-93 | pmid=24635773 | doi=10.1056/NEJMoa1401602 | pmc=PMC4101700 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635773  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24935515 Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9] </ref><ref name="pmid25776532">{{cite journal| author=Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD et al.| title=Trial of early, goal-directed resuscitation for septic shock. | journal=N Engl J Med | year= 2015 | volume= 372 | issue= 14 | pages= 1301-11 | pmid=25776532 | doi=10.1056/NEJMoa1500896 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25776532  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26280432 Review in: Ann Intern Med. 2015 Aug 18;163(4):JC10] </ref> 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<ref name="pmid27364620">{{cite journal| author=Nguyen HB, Jaehne AK, Jayaprakash N, Semler MW, Hegab S, Yataco AC et al.| title=Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. | journal=Crit Care | year= 2016 | volume= 20 | issue= 1 | pages= 160 | pmid=27364620 | doi=10.1186/s13054-016-1288-3 | pmc=4929762 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27364620  }} </ref> 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.
-'''On October 25, 2011 the U.S. Food and Drug Administration (FDA) notified healthcare professionals and the public that Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [drotrecogin alfa (activated)]. In a recently completed clinical trial (PROWESS-SHOCK trial), Xigris failed to show a survival benefit for patients with severe sepsis and septic shock.'''
+=====Trials of other protocols to guide fluid therapy=====
+{| class="wikitable floatright"
+|+Mottling score<ref name="pmid21373821" />
+! Score!! Description
+|-
+| 0|| No mottling
+|-
+| 1|| "Small mottling area (coinsize) localized to the center of the knee"
+|-
+| 2|| "A mottling area that does not exceed the superior edge of the knee cap"
+|-
+| 3|| "A mottling area that does not exceed the middle thigh"
+|-
+| 4|| "A mottling area that does not go beyond the fold of the groin"
+|-
+| 5|| "An extremely severe mottling area that goes beyond the fold of the groin
+|}
+In the CLASSIC [[randomized controlled trial]], after an initial 30 ml/kg fluid bolus, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg. Further fluids in the experimental group (fluid boluses of 250–500 mL  every 30 minutes) were allow if<ref name="pmid27686349">{{cite journal| author=Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettilä V et al.| title=Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. | journal=Intensive Care Med | year= 2016 | volume= 42 | issue= 11 | pages= 1695-1705 | pmid=27686349 | doi=10.1007/s00134-016-4500-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27686349  }} </ref>:
+# Lactate level of at least 4 mmol/L
+# "MAP below 50 mmHg in spite of the infusion of norepinephrine"
+# "Mottling beyond the edge of the kneecap (mottling score<ref name="pmid21373821">{{cite journal| author=Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J et al.| title=Mottling score predicts survival in septic shock. | journal=Intensive Care Med | year= 2011 | volume= 37 | issue= 5 | pages= 801-7 | pmid=21373821 | doi=10.1007/s00134-011-2163-y | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21373821  }} </ref> greater than 2)"
+# "Oliguria, but only in the first 2 h after randomisation, defined as urinary output at most 0.1 mL/kg IBW in the last hour."
+The trial found an insignificant trend towards benefit in the experimental group.
-The guideline committee recommends that adult patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC. (Grade 1A)
+In the ANDROMEDA-SHOCK [[randomized controlled trial]], after an initial 20 mL/kg or more over 60 minutes, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg (in patients with chronic hypertension, a higher goal might be used). Further fluids in the experimental group (500 mL of crystalloids every 30 minutes) were allowed if<ref name="pmid30772908">{{cite journal| author=Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J et al.| title=Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. | journal=JAMA | year= 2019 | volume=  | issue=  | pages=  | pmid=30772908 | doi=10.1001/jama.2019.0071 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30772908  }} </ref>:
-}}
+* Capillary refill time (CRT) was greater than 3 seconds. The CRT was measured by "applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure was increased until the skin was blank and then maintained for 10 seconds. The time for return of the normal skin color was registered with a chronometer". "The CRT was evaluated every 30 minutes, because of its faster rate of recovery, until normalization and then every hour during the intervention period". The intervention period was 8 hours.
+* Central venous pressure safety was not elevated
+* The patient became fluid unresponsive as measured by one of several methods<ref name="pmid27858374">{{cite journal| author=Monnet X, Marik PE, Teboul JL| title=Prediction of fluid responsiveness: an update. | journal=Ann Intensive Care | year= 2016 | volume= 6 | issue= 1 | pages= 111 | pmid=27858374 | doi=10.1186/s13613-016-0216-7 | pmc=5114218 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27858374  }} </ref>
-'''For Level of evidence and classes click [[ACC AHA Guidelines Classification Scheme|here]].'''
+The trial found an insignificant trend towards benefit in the experimental group.
-===Surviving sepsis campaign: international guidelines for blood product administration in severe sepsis and septic shock: 2008 (DO NOT EDIT) <ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
+In the small, pilot Echo vs EGDT [[randomized controlled trial]] at Intermountain Healthcare, after a median of 35 mL/kg of fluids, the goal of resuscitation was mean arterial pressure (MAP) of at least 65 mm Hg. Further fluids in the experimental group (1 L of crystalloids every hour) were allowed if<ref name="pmid30123511">{{cite journal| author=Lanspa MJ, Burk RE, Wilson EL, Hirshberg EL, Grissom CK, Brown SM| title=Echocardiogram-guided resuscitation versus early goal-directed therapy in the treatment of septic shock: a randomized, controlled, feasibility trial. | journal=J Intensive Care | year= 2018 | volume= 6 | issue=  | pages= 50 | pmid=30123511 | doi=10.1186/s40560-018-0319-3 | pmc=6090604 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30123511  }} </ref>
+* CVP less than 8–12 mm Hg or, if no central line, shock index ≥ 1
+* IVC collapsibility present. Collapsibility was  defined by "the maximum diameter was < 5 mm or if vena cava collapsibility index (VCCI), defined as the difference in diameter during a respiratory cycle divided by the maximum diameter, was > 50%"
-{{cquote|
+No differences were found in the results; however, 70% of patients has reached their lactate clearance goal after initial resuscitation and before the trial protocol started.
-====Blood Product Administration====
+In the small RIFTS [[randomized controlled trial]] that compared ≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care found no less fluids administered in the intervention without a difference in mortality≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care<ref name="pmid30985449">{{cite journal| author=Corl KA, Prodromou M, Merchant RC, Gareen I, Marks S, Banerjee D et al.| title=The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study. | journal=Crit Care Med | year= 2019 | volume=  | issue=  | pages=  | pmid=30985449 | doi=10.1097/CCM.0000000000003779 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30985449  }} </ref>
+.
-'''1.''' Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis (see recommendations for initial resuscitation), the guideline committee recommends that red blood cell transfusion occur when hemoglobin decreases to <7.0 g/dL (<70 g/L) to target a hemoglobin of 7.0 to 9.0 g/dL (70 to 90 g/L) in adults. (Grade 1B)
+=====Timing of fluid therapy=====
-'''2.''' The guideline committee recommends that [[erythropoietin]] not be used as a specific treatment of [[anemia]] associated with severe sepsis, but may be used when septic patients have other accepted reasons for administration of erythropoietin such as [[renal failure]]-induced compromise of red blood cell production. (Grade 1B)
+Two cohort studies examined the impact of the timing of fluid therapy for severe sepsis and septic shock. Taken together, the cohorts suggest fluids should be started as fast as possible, but the total amount to be infused and the infusion rate are not clear.
+* Regarding administration of 30 ml/kg of fluids, reduced time to start of administration is associated with increased survival; however, there is not a clear relationship between mortality and time of completion of fluid bolus as this was not measured in this study<ref name="pmid29298189">{{cite journal| author=Pruinelli L, Westra BL, Yadav P, Hoff A, Steinbach M, Kumar V et al.| title=Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock. | journal=Crit Care Med | year= 2018 | volume= 46 | issue= 4 | pages= 500-505 | pmid=29298189 | doi=10.1097/CCM.0000000000002949 | pmc=5851815 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29298189  }} </ref>.
+* Completing a 3 hour bundle for sepsis care and rapidly administering antibiotics showed a lower risk-associated in-hospital mortality. However, there was insufficient evidence in this study to conclude that rapid completion of the initial fluid bolus affected mortality<ref name="pmid28528569">{{cite journal| author=Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS et al.| title=Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. | journal=N Engl J Med | year= 2017 | volume= 376 | issue= 23 | pages= 2235-2244 | pmid=28528569 | doi=10.1056/NEJMoa1703058 | pmc=5538258 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28528569  }} </ref>.
-'''3.''' The guideline committee suggests that [[fresh frozen plasma]] not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. (Grade 2D)
+=====Speed of fluid therapy=====
+Regarding the speed fluid administration, only two trials revealed an explicit protocol<ref name="pmid24635773">{{cite journal| author=ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al.| title=A randomized trial of protocol-based care for early septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 18 | pages= 1683-93 | pmid=24635773 | doi=10.1056/NEJMoa1401602 | pmc=PMC4101700 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635773  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24935515 Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9] </ref><ref name="pmid26475246">{{cite journal| author=Kuan WS, Ibrahim I, Leong BS, Jain S, Lu Q, Cheung YB et al.| title=Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial. | journal=Ann Emerg Med | year= 2016 | volume= 67 | issue= 3 | pages= 367-378.e3 | pmid=26475246 | doi=10.1016/j.annemergmed.2015.09.010 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26475246  }} </ref>. These showed the fluids being administered in 500-1,000mL boluses every 30 minutes.
-'''4.''' The guideline committee recommends against antithrombin administration for the treatment of severe sepsis and septic shock. (Grade 1B)
+=====Composition of fluids=====
+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."<ref name="pmid25904181">{{cite journal| author=Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D et al.| title=Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 9 | pages= 1561-71 | pmid=25904181 | doi=10.1007/s00134-015-3794-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25904181  }} </ref>
-'''5.''' In patients with severe sepsis, the guideline committee suggests that '''platelets should be administered when counts are <5000/mm3 (5 × 109/L) regardless of apparent bleeding. Platelet transfusion may be considered when counts are 5,000 to 30,000/mm3 (5 to 30 × 109/L)''' and there is a significant risk of bleeding. Higher platelet counts (>50,000/mm3 (50 × 109/L) are typically required for surgery or invasive procedures. (Grade 2D)
+A more recent trial of patients with diverse diagnoses found no difference.<ref name="pmid26444692">{{cite journal| author=Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C et al.| title=Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. | journal=JAMA | year= 2015 | volume= 314 | issue= 16 | pages= 1701-10 | pmid=26444692 | doi=10.1001/jama.2015.12334 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26444692  }} </ref>
-}}
+=====Fluid administration in cardiac and renal disease=====
-'''For Level of evidence and classes click [[ACC AHA Guidelines Classification Scheme|here]].'''
+The 2016 Surviving Sepsis guidelines do not make specific reference to fluid resuscitation in the setting of cardiorenal dysfunction.<ref name="pmid28101605">{{cite journal| author=Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al.| title=Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. | journal=Intensive Care Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28101605 | doi=10.1007/s00134-017-4683-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28101605  }} </ref>
-===Surviving sepsis campaign: international guidelines for supportive therapy in severe sepsis and septic shock: 2008 (DO NOT EDIT) <ref name="pmid18158437">{{cite journal |author=Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL |title=Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 |journal=[[Critical Care Medicine]] |volume=36 |issue=1 |pages=296–327 |year=2008 |month=January |pmid=18158437 |doi=10.1097/01.CCM.0000298158.12101.41 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=36&issue=1&spage=296 |accessdate=2012-09-16}}</ref>===
-{{cquote|
+A [[systematic review]] in 2017 found that conservative fluids after resuscitation may be beneficial<ref name="pmid27734109">{{cite journal| author=Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC et al.| title=Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. | journal=Intensive Care Med | year= 2017 | volume= 43 | issue= 2 | pages= 155-170 | pmid=27734109 | doi=10.1007/s00134-016-4573-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27734109  }} </. Two previous studies suggest possible benefits of including this subset of patients in sepsis protocol bundles administration without significant harm:
-===Supportive Therapy of Severe Sepsis===
-====Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)====
+*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).<nowiki><ref name="pmid26475246"></nowiki>{{cite journal| author=Kuan WS, Ibrahim I, Leong BS, Jain S, Lu Q, Cheung YB et al.| title=Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial. | journal=Ann Emerg Med | year= 2016 | volume= 67 | issue= 3 | pages= 367-378.e3 | pmid=26475246 | doi=10.1016/j.annemergmed.2015.09.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26475246  }}</ref>
+* 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.<ref name="pmid26695114">{{cite journal| author=Liu VX, Morehouse JW, Marelich GP, Soule J, Russell T, Skeath M et al.| title=Multicenter Implementation of a Treatment Bundle for Patients with Sepsis and Intermediate Lactate Values. | journal=Am J Respir Crit Care Med | year= 2016 | volume= 193 | issue= 11 | pages= 1264-70 | pmid=26695114 | doi=10.1164/rccm.201507-1489OC | pmc=4910898 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26695114  }} </ref>
-'''1.''' The guideline committee recommends that clinicians target a [[tidal volume]] of 6 mL/kg (predicted) body weight in patients with [[acute lung injury]]/[[acute respiratory distress syndrome]] (ALI/ARDS). (Grade 1B)
+====Excessive fluid therapy====
+Positive fluid balance may be associated with worse outcomes in most<ref name="pmid27352125">{{cite journal| author=Neyra JA, Li X, Canepa-Escaro F, Adams-Huet B, Toto RD, Yee J et al.| title=Cumulative Fluid Balance and Mortality in Septic Patients With or Without Acute Kidney Injury and Chronic Kidney Disease. | journal=Crit Care Med | year= 2016 | volume= 44 | issue= 10 | pages= 1891-900 | pmid=27352125 | doi=10.1097/CCM.0000000000001835 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27352125  }} </ref><ref name="pmid27553826">{{cite journal| author=Brotfain E, Koyfman L, Toledano R, Borer A, Fucs L, Galante O et al.| title=Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after discharge from intensive care unit. | journal=Am J Emerg Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27553826 | doi=10.1016/j.ajem.2016.07.058 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27553826  }} </ref><ref name="pmid26394090">{{cite journal| author=Mitchell KH, Carlbom D, Caldwell E, Leary PJ, Himmelfarb J, Hough CL| title=Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock. | journal=Ann Am Thorac Soc | year= 2015 | volume= 12 | issue= 12 | pages= 1837-44 | pmid=26394090 | doi=10.1513/AnnalsATS.201504-187OC | pmc=4722831 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26394090  }} </ref><ref name="pmid26073560">{{cite journal| author=Acheampong A, Vincent JL| title=A positive fluid balance is an independent prognostic factor in patients with sepsis. | journal=Crit Care | year= 2015 | volume= 19 | issue=  | pages= 251 | pmid=26073560 | doi=10.1186/s13054-015-0970-1 | pmc=4479078 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26073560  }} </ref><ref name="pmid25269788">{{cite journal| author=de Oliveira FS, Freitas FG, Ferreira EM, de Castro I, Bafi AT, de Azevedo LC et al.| title=Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock. | journal=J Crit Care | year= 2015 | volume= 30 | issue= 1 | pages= 97-101 | pmid=25269788 | doi=10.1016/j.jcrc.2014.09.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25269788  }} </ref><ref name="pmid20975548">{{cite journal| author=Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA| title=Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. | journal=Crit Care Med | year= 2011 | volume= 39 | issue= 2 | pages= 259-65 | pmid=20975548 | doi=10.1097/CCM.0b013e3181feeb15 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20975548  }} </ref><ref name="pmid26494153">{{cite journal| author=Wang N, Jiang L, Zhu B, Wen Y, Xi XM, Beijing Acute Kidney Injury Trial (BAKIT) Workgroup| title=Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. | journal=Crit Care | year= 2015 | volume= 19 | issue=  | pages= 371 | pmid=26494153 | doi=10.1186/s13054-015-1085-4 | pmc=4619072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26494153  }} </ref>, but not all<ref name="pmid27030514">{{cite journal| author=Cronhjort M, Hjortrup PB, Holst LB, Joelsson-Alm E, Mårtensson J, Svensen C et al.| title=Association between fluid balance and mortality in patients with septic shock: a post hoc analysis of the TRISS trial. | journal=Acta Anaesthesiol Scand | year= 2016 | volume= 60 | issue= 7 | pages= 925-33 | pmid=27030514 | doi=10.1111/aas.12723 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27030514  }} </ref> 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.<ref name="pmid20975548" />
-'''2.''' The guideline committee recommends that plateau pressures be measured in patients with ALI/ARDS and that the initial upper limit goal for plateau pressures in a passively inflated patient be <30 cm H2O. Chest wall compliance should be considered in the assessment of plateau pressure. (Grade 1C)
+====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]].<ref name="pmid27686349">{{cite journal| author=Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettilä V et al.| title=Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. | journal=Intensive Care Med | year= 2016 | volume=  | issue=  | pages=  | pmid=27686349 | doi=10.1007/s00134-016-4500-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27686349  }} </ref> Expert opinion suggests positive fluid balance should be addresses within three days of resuscitation. <ref name="pmid27635489">{{cite journal| author=Benes J| title=Cumulative Fluid Balance: The Dark Side of the Fluid. | journal=Crit Care Med | year= 2016 | volume= 44 | issue= 10 | pages= 1945-6 | pmid=27635489 | doi=10.1097/CCM.0000000000001919 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27635489  }} </ref>
-'''3.''' The guideline committee recommends that hypercapnia (allowing partial pressure of arterial carbon dioxide [PaCO2] to increase above its pre-morbid baseline, so-called permissive hypercapnia) be allowed in patients with ALI/ARDS if needed to minimize plateau pressures and tidal volumes. (Grade 1C)
+===Lactate level===
+[[File:ARISE_Trial_-_lactate_values.png|200px|thumb|left|Lactate levels over time]]
+Lactate elevation seems due to aerobic glycolysis in skeletal muscle secondary to epinephrine stimulation<ref name="pmid10465191">{{cite journal| author=James JH, Luchette FA, McCarter FD, Fischer JE| title= is an unreliable indicator of tissue hypoxia in injury or sepsis. | journal=Lancet | year= 1999 | volume= 354 | issue= 9177 | pages= 505-8 | pmid=10465191 | doi=10.1016/S0140-6736(98)91132-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10465191  }} </ref>.
-'''4.''' The guideline committee recommends that positive end-expiratory pressure (PEEP) be set so as to avoid extensive lung collapse at end-expiration. (Grade 1C)
+The 2016 Surviving Sepsis Guidelines recommend:<ref name="pmid28098591">{{cite journal| author=Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al.| title=Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. | journal=Crit Care Med | year= 2017 | volume= 45 | issue= 3 | pages= 486-552 | pmid=28098591 | doi=10.1097/CCM.0000000000002255 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28098591  }} </ref>
-'''5.''' The guideline committee suggests prone positioning in ARDS patients requiring potentially injurious levels of fraction of inspired oxygen (FIO2) or plateau pressure who are not at high risk for adverse consequences of positional changes in those facilities who have experience with such practices. (Grade 2C)
+* "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)."
-'''6a.''' Unless contraindicated, the guideline committee recommends mechanically ventilated patients be maintained with the head of the bed elevated to limit aspiration risk and to prevent the development of ventilator-associated pneumonia. (Grade 1B)
+The guidelines by the Surviving Sepsis Campaign (SSC) do not specify how to response to slow lactate clearance. Two trails, both reporting reduced mortality from lactate-guided therapy, provide specific suggestions for responding to slow clearance:
+* When the clearance falls by less than 10% over 1 hours, transfuse pack red blood cells or infuse the inotrope [[dobutamine]] is recommended by Jones<ref name="pmid20179283">{{cite journal| author=Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA et al.| title=Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. | journal=JAMA | year= 2010 | volume= 303 | issue= 8 | pages= 739-46 | pmid=20179283 | doi=10.1001/jama.2010.158 | pmc=2918907 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20179283  }} </ref>. Since publication of this trial, a subsequent trial showed that a hemoglobin of 7 g/dl is adequate<ref name="pmid25270275">{{cite journal| author=Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S et al.| title=Lower versus higher hemoglobin threshold for transfusion in septic shock. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 15 | pages= 1381-91 | pmid=25270275 | doi=10.1056/NEJMoa1406617 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25270275  }} </ref>. In addition, subsequent guidelines by the SSC recommend norepinephrine as the first-choice vasopressor<ref name="pmid28098591" />.
+* When the clearance falls by less than 20% over 2 hours, either administer fluids, transfuse pack red blood cells,  infuse the inotrope [[dobutamine]], or increase administration of oxygen is recommended by Jansen<ref name="pmid20463176">{{cite journal| author=Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP et al.| title=Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. | journal=Am J Respir Crit Care Med | year= 2010 | volume= 182 | issue= 6 | pages= 752-61 | pmid=20463176 | doi=10.1164/rccm.200912-1918OC | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20463176  }} </ref>. However, since publication of this trial, subsequent guidelines by the SSC recommend norepinephrine as the first-choice vasopressor<ref name="pmid28098591" />.
-'''6b.''' The guideline committee suggests that the head of bed is elevated approximately 30 to 45 degrees. (Grade 2C)
+====Evidence====
+[[Randomized controlled trial]]s of monitoring lactate clearance to guide fluid resuscitation over the first 12 hours of resuscitation in sepsis and septic shock have been summarized in [[meta-analysis|meta-analyses]]. A meta-analysis of four [[randomized controlled trial]]s with 547 patients reported mortality benefit (RR=0.67, p=0.002) when lactate clearance strategies were used compared with early goal-directed therapy (EGDT) or usual care<ref name="pmid26154408">{{cite journal| author=Gu WJ, Zhang Z, Bakker J| title=Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 10 | pages= 1862-3 | pmid=26154408 | doi=10.1007/s00134-015-3955-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26154408  }} </ref>. A meta-analysis of 4 trials with 448 patients showed a comparable mortality benefit (RR=0.64) with the use of lactate clearance strategies versus EGDT<ref name="pmid27546746">{{cite journal| author=Simpson SQ, Gaines M, Hussein Y, Badgett RG| title=Early goal-directed therapy for severe sepsis and septic shock: A living systematic review. | journal=J Crit Care | year= 2016 | volume= 36 | issue=  | pages= 43-48 | pmid=27546746 | doi=10.1016/j.jcrc.2016.06.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27546746  }} </ref>.
-'''7.''' The guideline committee suggests that noninvasive mask ventilation (NIV) only be considered in that minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure (responsive to relatively low levels of pressure support and PEEP) with stable hemodynamics who can be made comfortable and easily arousable, who are able to protect the airway, spontaneously clear the airway of secretions, and are anticipated to recover rapidly from the precipitating insult. A low threshold for airway intubation should be maintained. (Grade 2B)
+===Hemodynamic monitoring===
+Regarding the monitoring of fluid administration, few [[randomized controlled trial]]s used an explicit protocol<ref name="pmid24635773">{{cite journal| author=ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al.| title=A randomized trial of protocol-based care for early septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 18 | pages= 1683-93 | pmid=24635773 | doi=10.1056/NEJMoa1401602 | pmc=PMC4101700 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635773  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24935515 Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9] </ref><ref name="pmid26475246">{{cite journal| author=Kuan WS, Ibrahim I, Leong BS, Jain S, Lu Q, Cheung YB et al.| title=Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial. | journal=Ann Emerg Med | year= 2016 | volume= 67 | issue= 3 | pages= 367-378.e3 | pmid=26475246 | doi=10.1016/j.annemergmed.2015.09.010 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26475246  }} </ref>. 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.)
-'''8.''' The guideline committee recommends that a weaning protocol be in place, and mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials on a regular basis to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) FIO2 requirements that could be safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation (see Appendix E in the original guideline document). Spontaneous breathing trial options include a low level of pressure support, continuous positive airway pressure (approximately 5 cm H2O) or a T-piece. (Grade 1A)
+A [[meta-analysis]] of [[randomized controlled trial]]s using early goal directed therapy found no significant benefit of the mandated use of [[central venous catheterization]] and central hemodynamic monitoring in all patients.<ref name="pmid25952825">{{cite journal| author=Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ et al.| title=A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 9 | pages= 1549-60 | pmid=25952825 | doi=10.1007/s00134-015-3822-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25952825  }} </ref>
-'''9.''' The guideline committee recommends against the routine use of the pulmonary artery catheter for patients with ALI/ARDS. (Grade 1A)
+====Methods of assessing fluid responsiveness====
+Various methods are available and have been reviewed.<ref name="pmid27155605">{{cite journal| author=Teboul JL, Saugel B, Cecconi M, De Backer D, Hofer CK, Monnet X et al.| title=Less invasive hemodynamic monitoring in critically ill patients. | journal=Intensive Care Med | year= 2016 | volume= 42 | issue= 9 | pages= 1350-9 | pmid=27155605 | doi=10.1007/s00134-016-4375-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27155605  }} </ref><ref name="pmid26318314">{{cite journal| author=Stens J, Oeben J, Van Dusseldorp AA, Boer C| title=Non-invasive measurements of pulse pressure variation and stroke volume variation in anesthetized patients using the Nexfin blood pressure monitor. | journal=J Clin Monit Comput | year= 2016 | volume= 30 | issue= 5 | pages= 587-94 | pmid=26318314 | doi=10.1007/s10877-015-9759-7 | pmc=5023739 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26318314  }} </ref><ref name="pmid27673307">{{cite journal| author=Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT| title=Will This Hemodynamically Unstable Patient Respond to a Bolus of Intravenous Fluids? | journal=JAMA | year= 2016 | volume= 316 | issue= 12 | pages= 1298-309 | pmid=27673307 | doi=10.1001/jama.2016.12310 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27673307  }} </ref><ref name="pmid22531454">{{cite journal| author=Porhomayon J, Zadeii G, Congello S, Nader ND| title=Applications of minimally invasive cardiac output monitors. | journal=Int J Emerg Med | year= 2012 | volume= 5 | issue=  | pages= 18 | pmid=22531454 | doi=10.1186/1865-1380-5-18 | pmc=3353182 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22531454  }} </ref>
-'''10.''' To decrease days of mechanical ventilation and ICU length of stay the guideline committee recommends a conservative fluid strategy for patients with established acute lung injury who do not have evidence of tissue hypoperfusion. (Grade 1C)
+===Antibiotics===
+For every hour delay in the administration of appropriate [[antibiotic]] therapy there is an associated 4% rise in mortality.<ref name="SeymourGesten2017">{{cite journal|last1=Seymour|first1=Christopher W.|last2=Gesten|first2=Foster|last3=Prescott|first3=Hallie C.|last4=Friedrich|first4=Marcus E.|last5=Iwashyna|first5=Theodore J.|last6=Phillips|first6=Gary S.|last7=Lemeshow|first7=Stanley|last8=Osborn|first8=Tiffany|last9=Terry|first9=Kathleen M.|last10=Levy|first10=Mitchell M.|title=Time to Treatment and Mortality during Mandated Emergency Care for Sepsis|journal=New England Journal of Medicine|year=2017|issn=0028-4793|doi=10.1056/NEJMoa1703058}}</ref>
-====Sedation, Analgesia, and Neuromuscular Blockade in Sepsis====
-'''1.''' The guideline committee recommends sedation protocols with a sedation goal when sedation of critically ill mechanically ventilated patients with sepsis is required. (Grade 1B)
-'''2.''' The guideline committee recommends intermittent bolus sedation or continuous infusion sedation to predetermined end points (e.g., sedation scales) with daily interruption/lightening of continuous infusion sedation with awakening and retitration if necessary for sedation administration to septic mechanically ventilated patients. (Grade 1B)
+The [[Infectious Disease Society of America]] (IDSA) recommends that only patients with septic shock need antibiotics within one hour<ref name="pmid32374861">{{cite journal| author=Rhee C, Chiotos K, Cosgrove SE, Heil EL, Kadri SS, Kalil AC | display-authors=etal| title=Infectious Diseases Society of America Position Paper: Recommended Revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Sepsis Quality Measure. | journal=Clin Infect Dis | year= 2020 | volume=  | issue=  | pages=  | pmid=32374861 | doi=10.1093/cid/ciaa059 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32374861  }} </ref>.
-'''3.''' The guideline committee recommends that neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with monitoring the depth of blockade with train-of-four monitoring should be used. (Grade 1B)
+====Timing of antibiotics====
+A [[systematic review]] found benefit from administration of antibiotics within one hour of diagnosis.<ref name="pmid28916120">{{cite journal| author=Sherwin R, Winters ME, Vilke GM, Wardi G| title=Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock? | journal=J Emerg Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28916120 | doi=10.1016/j.jemermed.2016.12.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28916120  }} </ref> Several more recent observational studies have found benefits as well<ref name="pmid28345952">{{cite journal| author=Liu VX, Fielding-Singh V, Greene JD, Baker JM, Iwashyna TJ, Bhattacharya J et al.| title=The Timing of Early Antibiotics and Hospital Mortality in Sepsis. | journal=Am J Respir Crit Care Med | year= 2017 | volume= 196 | issue= 7 | pages= 856-863 | pmid=28345952 | doi=10.1164/rccm.201609-1848OC | pmc=5649973 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28345952  }} </ref><ref>Pruinelli L, Westra BL, Yadav P, et al.Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock*. Critical Care Medicine. 2018;46(4):500–505. doi: 10.1097/CCM.0000000000002949.</ref>. A 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>
-====Glucose Control====
+Administrating antibiotics before cultures will reduce the positivity rate of cultures. Two cohorts have found a decrease in positivity<ref name="pmid29879482">{{cite journal| author=Scheer CS, Fuchs C, Gründling M, Vollmer M, Bast J, Bohnert JA | display-authors=etal| title=Impact of antibiotic administration on blood culture positivity at the beginning of sepsis: a prospective clinical cohort study. | journal=Clin Microbiol Infect | year= 2019 | volume= 25 | issue= 3 | pages= 326-331 | pmid=29879482 | doi=10.1016/j.cmi.2018.05.016 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29879482  }} </ref><ref name="pmid31525774">{{cite journal| author=Cheng MP, Stenstrom R, Paquette K, Stabler SN, Akhter M, Davidson AC | display-authors=etal| title=Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study. | journal=Ann Intern Med | year= 2019 | volume= 171 | issue= 8 | pages= 547-554 | pmid=31525774 | doi=10.7326/M19-1696 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31525774  }} </ref><ref name="pmid31525774">{{cite journal| author=Cheng MP, Stenstrom R, Paquette K, Stabler SN, Akhter M, Davidson AC | display-authors=etal| title=Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis: A Diagnostic Study. | journal=Ann Intern Med | year= 2019 | volume= 171 | issue= 8 | pages= 547-554 | pmid=31525774 | doi=10.7326/M19-1696 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31525774  }} </ref>; one looked at varying intervals and suggests harm starts as soon as 30 minutes after antibitoics<ref name="pmid31525774"/>.
-'''1.''' The guideline committee recommends that, following initial stabilization, patients with severe sepsis and hyperglycemia who are admitted to the ICU receive intravenous (IV) insulin therapy to reduce blood glucose levels. (Grade 1B)
+=====Dissenting views=====
+In 2019, a systematic review found no statistically significant difference in survival between projects that targeted antibiotics administered within 1 hour (7 studies) and 3 hours (8 studies)<ref name="pmid31369426">{{cite journal| author=Pepper DJ, Sun J, Cui X, Welsh J, Natanson C, Eichacker PQ| title=Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1). | journal=Crit Care Med | year= 2019 | volume= 47 | issue= 10 | pages= 1290-1300 | pmid=31369426 | doi=10.1097/CCM.0000000000003892 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31369426  }} </ref>.  However, the studies did not reliably achieve rapid antibiotic administration. For example, among the studies targeting antibiotics within one hour, before project implementation, the rate of rapid administration was 55% and afterwards was 63%<ref name="pmid28825234">{{cite journal| author=Ferreras Amez JM, Arribas Entrala B, Sarrat Torres MA, García Noain A, Caudevilla Martínez A, Colás Oros C et al.| title=[Before-after study of the effect of implementing a sepsis code for emergency departments in the community of Aragon]. | journal=Emergencias | year= 2017 | volume= 29 | issue= 3 | pages= 154-160 | pmid=28825234 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28825234  }} </ref>. Thus, this study shows the difficulty in achieving ''effectiveness'' from administration within one hour rather than the ''efficacy'' when all patients receive antibiotics within one hour<ref name="pmid10480802">{{cite journal| author=Haynes B| title=Can it work? Does it work? Is it worth it? The testing of healthcareinterventions is evolving. | journal=BMJ | year= 1999 | volume= 319 | issue= 7211 | pages= 652-3 | pmid=10480802 | doi=10.1136/bmj.319.7211.652 | pmc=1116525 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10480802  }} </ref>.
-'''2.''' The guideline committee suggests use of a validated protocol for insulin dose adjustments and targeting glucose levels to the <150 mg/dL range. (Grade 2C)
+While an older [[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:<ref name="pmid26121073">{{cite journal| author=Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE| title=The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. | journal=Crit Care Med | year= 2015 | volume= 43 | issue= 9 | pages= 1907-15 | pmid=26121073 | doi=10.1097/CCM.0000000000001142 | pmc=4597314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26121073  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26459374 Review in: Evid Based Med. 2015 Dec;20(6):214-5] </ref>
+* 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.<ref>[http://handbook.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm 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</ref>
+* 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.<ref name="pmid26974458">{{cite journal| author=Kumar A| title=Systematic Bias in Meta-Analyses of Time to Antimicrobial in Sepsis Studies. | journal=Crit Care Med | year= 2016 | volume= 44 | issue= 4 | pages= e234-5 | pmid=26974458 | doi=10.1097/CCM.0000000000001512 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26974458  }} </ref>
+* One article<ref name="pmid24717459">{{cite journal| author=Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP et al.| title=Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. | journal=Crit Care Med | year= 2014 | volume= 42 | issue= 8 | pages= 1749-55 | pmid=24717459 | doi=10.1097/CCM.0000000000000330 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24717459  }} </ref> 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.<ref name="pmid27635498">{{cite journal| author=Shirakura Y, Kuriyama A| title=Timing of Antibiotic Administration in Sepsis and Septic Shock: The Impact That a Meta-Analysis Does Not Depict. | journal=Crit Care Med | year= 2016 | volume= 44 | issue= 10 | pages= e1004 | pmid=27635498 | doi=10.1097/CCM.0000000000001891 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27635498  }} </ref>
-'''3.''' The guideline committee recommends that all patients receiving intravenous insulin receive a glucose calorie source and that blood glucose values be monitored every 1 to 2 hours until glucose values and insulin infusion rates are stable and then every 4 hours thereafter. (Grade 1C)
+The two largest studies in the meta-analysis both found positive correlations between delays in antibiotics and mortality.<ref name="pmid24717459" /><ref name="pmid16625125">{{cite journal| author=Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al.| title=Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. | journal=Crit Care Med | year= 2006 | volume= 34 | issue= 6 | pages= 1589-96 | pmid=16625125 | doi=10.1097/01.CCM.0000217961.75225.E9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16625125  }} </ref>
-'''4.''' The guideline committee recommends that low glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may overestimate arterial blood or plasma glucose values. (Grade 1B)
+=====Methods to improve speed of antibiotic administration=====
+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>
-====Renal Replacement====
+====Antibiotic selection====
-The guideline committee suggests that continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. (Grade 2B)
+The use of appropriate antibiotics, defined by most researchers as having in vitro activity against an isolated pathogen, in patients with bacteremia and/or severe sepsis or septic shock is associated with decreased mortality<ref name="pmid25218723">{{cite journal| author=Flaherty SK, Weber RL, Chase M, Dugas AF, Graver AM, Salciccioli JD et al.| title=Septic shock and adequacy of early empiric antibiotics in the emergency department. | journal=J Emerg Med | year= 2014 | volume= 47 | issue= 5 | pages= 601-7 | pmid=25218723 | doi=10.1016/j.jemermed.2014.06.037 | pmc=4254037 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25218723  }} </ref><ref name="pmid26307060">{{cite journal| author=Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Fernández-Delgado E, López-Sánchez JM| title=Adequate antibiotic therapy prior to ICU admission in patients with severe sepsis and septic shock reduces hospital mortality. | journal=Crit Care | year= 2015 | volume= 19 | issue=  | pages= 302 | pmid=26307060 | doi=10.1186/s13054-015-1000-z | pmc=4549859 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26307060  }} </ref><ref name="pmid22205015">{{cite journal| author=Lee CC, Lee CH, Chuang MC, Hong MY, Hsu HC, Ko WC| title=Impact of inappropriate empirical antibiotic therapy on outcome of bacteremic adults visiting the ED. | journal=Am J Emerg Med | year= 2012 | volume= 30 | issue= 8 | pages= 1447-56 | pmid=22205015 | doi=10.1016/j.ajem.2011.11.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22205015  }} </ref>. Lee (OR 2.26, 95% CI 1.10-5.13, p=0.04) and Nygard (OR 2.17, 95% CI 1.10-4.27, p=0.027) found that inappropriate antibiotics were associated with increased 28-day mortality<ref name="pmid22205015">{{cite journal| author=Lee CC, Lee CH, Chuang MC, Hong MY, Hsu HC, Ko WC| title=Impact of inappropriate empirical antibiotic therapy on outcome of bacteremic adults visiting the ED. | journal=Am J Emerg Med | year= 2012 | volume= 30 | issue= 8 | pages= 1447-56 | pmid=22205015 | doi=10.1016/j.ajem.2011.11.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22205015  }} </ref><ref name="pmid24588984">{{cite journal| author=Nygård ST, Langeland N, Flaatten HK, Fanebust R, Haugen O, Skrede S| title=Aetiology, antimicrobial therapy and outcome of patients with community acquired severe sepsis: a prospective study in a Norwegian university hospital. | journal=BMC Infect Dis | year= 2014 | volume= 14 | issue=  | pages= 121 | pmid=24588984 | doi=10.1186/1471-2334-14-121 | pmc=3975934 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24588984  }} </ref>. Garnacho reported that adequate antibiotics are protective against mortality (OR 0.40, 95% CI 0.24-0.65, p<0.001)<ref name="pmid24588984" />. Observing a population of sixteen patients with urosepsis, Flaherty had similar conclusions, citing 18% overall mortality versus 25% among four patients who did not receive adequate antibiotic therapy<ref name="pmid25218723" />.
-The guideline committee suggests the use of continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients. (Grade 2D)
-====Bicarbonate Therapy====
+Existing literature demonstrates that emergency department (ED) physicians prescribe appropriate initial antibiotic therapy 82-90% of the time<ref name="pmid25218723" /><ref name="pmid21371846">{{cite journal| author=Capp R, Chang Y, Brown DF| title=Effective antibiotic treatment prescribed by emergency physicians in patients admitted to the intensive care unit with severe sepsis or septic shock: where is the gap? | journal=J Emerg Med | year= 2011 | volume= 41 | issue= 6 | pages= 573-80 | pmid=21371846 | doi=10.1016/j.jemermed.2010.10.024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21371846  }} </ref>, when treating patients with severe sepsis or septic shock. Other studies demonstrated similar rates of 80-81% among non-ED physicians<ref name="pmid19696123">{{cite journal| author=Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE et al.| title=Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. | journal=Chest | year= 2009 | volume= 136 | issue= 5 | pages= 1237-1248 | pmid=19696123 | doi=10.1378/chest.09-0087 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19696123  }} </ref><ref name="pmid22108843">{{cite journal| author=van der Velden LB, Tromp M, Bleeker-Rovers CP, Hulscher M, Kullberg BJ, Mouton JW et al.| title=Non-adherence to antimicrobial treatment guidelines results in more broad-spectrum but not more appropriate therapy. | journal=Eur J Clin Microbiol Infect Dis | year= 2012 | volume= 31 | issue= 7 | pages= 1561-8 | pmid=22108843 | doi=10.1007/s10096-011-1478-5 | pmc=3364419 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22108843  }} </ref>. Capp, et al. posited that inappropriate antibiotics were more likely to be prescribed in cases of gram-negative organisms<ref name="pmid21371846" />. Similarly, Flaherty, et al. found that antibiotic coverage was most appropriately chosen in patients presenting with pneumonia (97%); treatment failure was more common among the subgroup of patients with urinary tract infections, likely due to multidrug resistance<ref name="pmid25218723" />.
-The guideline committee recommends against the use of sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH >7.15. (Grade 1B)
-====Deep Vein Thrombosis Prophylaxis====
+====Delivery method====
-'''1.''' The guideline committee recommends that severe sepsis patients receive deep vein thrombosis (DVT) prophylaxis with either (a) low-dose unfractionated heparin (UFH) administered twice daily or three times daily or (b) daily low-molecular weight heparin (LMWH) unless there are contraindications (i.e., thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage). (Grade 1A)
+Continuous infusion may be more effective.<ref name="pmid26974879">{{cite journal| author=Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J et al.| title=Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials. | journal=Am J Respir Crit Care Med | year= 2016 | volume= 194 | issue= 6 | pages= 681-91 | pmid=26974879 | doi=10.1164/rccm.201601-0024OC | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26974879  }} </ref>
-'''2.''' The guideline committee recommends that septic patients who have a contraindication for heparin use receive mechanical prophylactic device such as graduated compression stockings (GCS) or intermittent compression devices (ICD) unless contraindicated. (Grade 1A)
-'''3.''' The guideline committee suggests that in very high-risk patients such as those who have severe sepsis and history of DVT, trauma, or orthopedic surgery, a combination of pharmacologic and mechanical therapy be used unless contraindicated or not practical. (Grade 2C)
-'''4.''' The guideline committee suggests that in patients at very high risk, LMWH be used rather than UFH as LMWH is proven superior in other high-risk patients. (Grade 2C)
-====Stress Ulcer Prophylaxis (SUP)====
+===Pressors===
-'''1.''' The guideline committee recommends that stress ulcer prophylaxis (SUP) using H2 blocker (Grade 1A) or proton pump inhibitor (Grade 1B) be given to patients with severe sepsis to prevent upper gastrointestinal (GI) bleed.
+Pressors that have been used are:
+* Dopamine
+* Epinephrine - Alpha and beta-agonist. Transiently raises the lactate level from baseline of 4.1 to 4.9<ref name="pmid21037469">{{cite journal| author=Levy B, Perez P, Perny J, Thivilier C, Gerard A| title=Comparison of -dobutamine to epinephrine for hemodynamics,  metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. | journal=Crit Care Med | year= 2011 | volume= 39 | issue= 3 | pages= 450-5 | pmid=21037469 | doi=10.1097/CCM.0b013e3181ffe0eb | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21037469  }} </ref>.
+* Norepinephrine - Alpha and beta-agonist
-'''2.''' Benefit of prevention of upper GI bleed must be weighed against potential effect of an increased stomach pH on development of ventilator-associated pneumonia.
+* Vasopressin
-====Selective Digestive Tract Decontamination (SDD)====
+====Evidence====
-'''1.''' The guideline committee was evenly split on the issue of selective digestive tract decontamination (SDD), with equal numbers weakly in favor and against recommending the use of SDD (see Appendix H of the original guideline document). The committee therefore chose not to make a recommendation for the use of SDD specifically in severe sepsis at this time. The final consensus on use of SDD in severe sepsis was achieved at the last nominal committee meeting and subsequently approved by the entire committee.
+In a randomized controlled trial comparing dopamine and norepinephrine, efficacy was similar but less adverse effect with norepinephrine<ref name="pmid20200382">{{cite journal| author=De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C et al.| title=Comparison of dopamine and  in the treatment of shock. | journal=N Engl J Med | year= 2010 | volume= 362 | issue= 9 | pages= 779-89 | pmid=20200382 | doi=10.1056/NEJMoa0907118 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20200382  }} </ref> The change in lactate levels was similar in the two groups<ref name="pmid20200382" />.
-}}
-'''For Level of evidence and classes click [[ACC AHA Guidelines Classification Scheme|here]].'''
-==Early Goal Directed Therapy (EGDT) <ref name="EGDT">{{cite journal |author=Rivers E, Nguyen B, Havstad S, ''et al'' |title=Early goal-directed therapy in the treatment of severe sepsis and septic shock |journal=N. Engl. J. Med. |volume=345 |issue=19 |pages=1368-77 |year=2001 |pmid=11794169 |doi=}}</ref>==
+Pressors titrated to MAP of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg does not change affect mortality among patients who already received a minimum 30 mL/kg within 6 hours prior to the start of catecholamines<ref name="pmid24635770">{{cite journal| author=Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N et al.| title=High versus low blood-pressure target in patients with septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 17 | pages= 1583-93 | pmid=24635770 | doi=10.1056/NEJMoa1312173 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635770  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25023273 Review in: Ann Intern Med. 2014 Jul 15;161(2):JC7] </ref>.
-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]]. 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. More recently, the GENESIS Project has validated this approach.<ref name="pmid22902347">{{cite journal| author=Cannon CM, Holthaus CV, Zubrow MT, Posa P, Gunaga S, Kella V et al.| title=The GENESIS Project (GENeralized Early Sepsis Intervention Strategies): A Multicenter Quality Improvement Collaborative. | journal=J Intensive Care Med | year= 2012 | volume=  | issue=  | pages=  | pmid=22902347 | doi=10.1177/0885066612453025 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22902347  }} </ref>
+Giving pressors too early may be harmful<ref name="pmid17924093">{{cite journal| author=Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O| title=Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study. | journal=Intensive Care Med | year= 2008 | volume= 34 | issue= 1 | pages= 157-62 | pmid=17924093 | doi=10.1007/s00134-007-0862-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17924093  }} </ref>.
+===Steroids===
+[[Corticosteroid]]s may reduce mortality among patients with septic shock according to a [[meta-analysis]]<ref name="pmid29913493">{{cite journal| author=Duran BA, Badgett RG, Simpson SQ| title=Hydrocortisone plus fludrocortisone reduced mortality at 90 days in patients with septic shock. | journal=Ann Intern Med | year= 2018 | volume= 168 | issue= 12 | pages= JC68 | pmid=29913493 | doi=10.7326/ACPJC-2018-168-12-068 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29913493  }} </ref> that includes the APROCCHSS<ref name="pmid29490185">{{cite journal| author=Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S et al.| title=Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. | journal=N Engl J Med | year= 2018 | volume= 378 | issue= 9 | pages= 809-818 | pmid=29490185 | doi=10.1056/NEJMoa1705716 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29490185  }} </ref> and ADRENAL<ref name="pmid29347874">{{cite journal| author=Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R et al.| title=Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. | journal=N Engl J Med | year= 2018 | volume= 378 | issue= 9 | pages= 797-808 | pmid=29347874 | doi=10.1056/NEJMoa1705835 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29347874  }} </ref> [[randomized controlled trial]]s.
+[[Corticosteroid]]s may reduce mortality among patients with septic shock according to a [[systematic review]] by the [[Cochrane Collaboration]].<ref name="pmid26633262">{{cite journal| author=Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y| title=Corticosteroids for treating sepsis. | journal=Cochrane Database Syst Rev | year= 2015 | volume=  | issue= 12 | pages= CD002243 | pmid=26633262 | doi=10.1002/14651858.CD002243.pub3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26633262  }} </ref> However, a second systematic review published the same year found insignificant benefit from steroids<ref name="pmid26100123">{{cite journal| author=Volbeda M, Wetterslev J, Gluud C, Zijlstra JG, van der Horst IC, Keus F| title=Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. | journal=Intensive Care Med | year= 2015 | volume= 41 | issue= 7 | pages= 1220-34 | pmid=26100123 | doi=10.1007/s00134-015-3899-6 | pmc=4483251 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26100123  }} </ref>.
+The subsequent HYPRESS [[randomized controlled trial]] of patients with ''severe sepsis'' showed no benefit.<ref name="pmid27695824">{{cite journal| author=Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S et al.| title=Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. | journal=JAMA | year= 2016 | volume= 316 | issue= 17 | pages= 1775-1785 | pmid=27695824 | doi=10.1001/jama.2016.14799 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27695824  }} </ref>
+Non-randomized studies reach conflicting conclusions with benefit found in the Intermountain cohort<ref name="pmid23631750">{{cite journal| author=Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR et al.| title=Multicenter implementation of a severe sepsis and septic shock treatment bundle. | journal=Am J Respir Crit Care Med | year= 2013 | volume= 188 | issue= 1 | pages= 77-82 | pmid=23631750 | doi=10.1164/rccm.201212-2199OC | pmc=3735248 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23631750  }} </ref> and harm found in the Surviving Sepsis cohort<ref name="pmid23064466">{{cite journal| author=Casserly B, Gerlach H, Phillips GS, Lemeshow S, Marshall JC, Osborn TM et al.| title=Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign. | journal=Intensive Care Med | year= 2012 | volume= 38 | issue= 12 | pages= 1946-54 | pmid=23064466 | doi=10.1007/s00134-012-2720-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23064466  }} </ref>.
+The benefit of steroids may be confined to patients who have the SRS 1 variant (immunosuppressed) of the transcriptomic sepsis response signatures (SRS)<ref name="pmid30365341">{{cite journal| author=Antcliffe DB, Burnham KL, Al-Beidh F, Santhakumaran S, Brett SJ, Hinds CJ et al.| title=Transcriptomic Signatures in Sepsis and a Differential Response to Steroids: From the VANISH Randomized Trial. | journal=Am J Respir Crit Care Med | year= 2018 | volume=  | issue=  | pages=  | pmid=30365341 | doi=10.1164/rccm.201807-1419OC | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30365341  }} </ref>.
+The somewhat results of the Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock (ADRENAL) and  ADRENAL and Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) randomized controlled trials has been extensively debated<ref name="pmid31738260">{{cite journal| author=Venkatesh B, Cohen J| title=The authors reply. | journal=Crit Care Med | year= 2019 | volume= 47 | issue= 12 | pages= e1035-e1036 | pmid=31738260 | doi=10.1097/CCM.0000000000004014 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31738260  }} </ref>.
+====Mineralocorticoid====
+Fludrocortisone was not effective in the COIITSS [[randomized controlled trial]] as a add on treatment to hydrocortisone<ref name="pmid20103758">{{cite journal| author=COIITSS Study Investigators. Annane D, Cariou A, Maxime V, Azoulay E, D'honneur G et al.| title=Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. | journal=JAMA | year= 2010 | volume= 303 | issue= 4 | pages= 341-8 | pmid=20103758 | doi=10.1001/jama.2010.2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20103758  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20479022 Review in: Ann Intern Med. 2010 May 18;152(10):JC5-5] </ref>.
+====Role of relative adrenal insufficiency====
+Patients who had a low response to at corticotropin stimulation test were not more likely to respond to a combination of hydrocortisone and fludrocortisone in the APROCCHSS trial<ref name="pmid29490185">{{cite journal| author=Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S et al.| title=Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. | journal=N Engl J Med | year= 2018 | volume= 378 | issue= 9 | pages= 809-818 | pmid=29490185 | doi=10.1056/NEJMoa1705716 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29490185  }} </ref>.
+===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.<ref name="pmid25270275">{{cite journal| author=Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S et al.| title=Lower versus higher hemoglobin threshold for transfusion in septic shock. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 15 | pages= 1381-91 | pmid=25270275 | doi=10.1056/NEJMoa1406617 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25270275  }} </ref>
+==Protocolized therapy==
+Several protocols have been recommended and studied. Compliance with bundles of care is associated with reduced mortality.<ref name="pmid23631750">{{cite journal| author=Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR et al.| title=Multicenter implementation of a severe sepsis and septic shock treatment bundle. | journal=Am J Respir Crit Care Med | year= 2013 | volume= 188 | issue= 1 | pages= 77-82 | pmid=23631750 | doi=10.1164/rccm.201212-2199OC | pmc=PMC3735248 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23631750  }} </ref>
+===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]].<ref name="pmid11794169">{{cite journal| author=Rivers E, Nguyen B,  Havstad S, Ressler J, Muzzin A, Knoblich B et al.| title=Early  goal-directed therapy in the treatment of severe sepsis and septic  shock. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 19 |  pages= 1368-77 | pmid=11794169 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=11794169  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscsa.edu&retmode=ref&cmd=prlinks&id=11985431 Review in: ACP J Club. 2002 May-Jun;136(3):90] </ref> 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,<ref name="pmid20179283">{{cite journal|  author=Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline  JA et al.| title=Lactate clearance vs central venous oxygen saturation  as goals of early sepsis therapy: a randomized clinical trial. |  journal=JAMA | year= 2010 | volume= 303 | issue= 8 | pages= 739-46 |  pmid=20179283 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscsa.edu&retmode=ref&cmd=prlinks&id=20179283  | doi=10.1001/jama.2010.158 }}  </ref><ref name="pmid11794169">{{cite journal| author=Rivers E, Nguyen B,  Havstad S, Ressler J, Muzzin A, Knoblich B et al.| title=Early  goal-directed therapy in the treatment of severe sepsis and septic  shock. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 19 |  pages= 1368-77 | pmid=11794169 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=11794169  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscsa.edu&retmode=ref&cmd=prlinks&id=11985431 Review in: ACP J Club. 2002 May-Jun;136(3):90] </ref><ref name="pmid22902347">{{cite journal| author=Cannon CM, Holthaus CV, Zubrow MT, Posa P, Gunaga S, Kella V et al.| title=The GENESIS Project (GENeralized Early Sepsis Intervention Strategies): A Multicenter Quality Improvement Collaborative. | journal=J Intensive Care Med | year= 2012 | volume=  | issue=  | pages=  | pmid=22902347 | doi=10.1177/0885066612453025 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22902347  }} </ref> the more recent ProCESS<ref name="pmid24635773">{{cite journal| author=ProCESS Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA et al.| title=A randomized trial of protocol-based care for early septic shock. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 18 | pages= 1683-93 | pmid=24635773 | doi=10.1056/NEJMoa1401602 | pmc=PMC4101700 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24635773  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24935515 Review in: Ann Intern Med. 2014 Jun 17;160(12):JC9] </ref> and ARISE<ref name="pmid25272316" /> 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:
@@ Line 217: / Line 280: @@
 * 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.<ref name="EGDT" /> The Surviving Sepsis Campaign guidelines recommends EGDT for the initial resuscitation of the septic patient with a level B strength of evidence (single [[randomized control trial]]).<ref name="campaign" />
+* 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==
+===GENESIS Project===
-The protocol per the GENESIS Project is:<ref  name="pmid22902347">{{cite journal| author=Cannon CM, Holthaus CV,  Zubrow MT, Posa P, Gunaga S, Kella V et al.| title=The GENESIS Project  (GENeralized Early Sepsis Intervention Strategies): A Multicenter  Quality Improvement Collaborative. | journal=J Intensive Care Med |  year= 2012 | volume=  | issue=  | pages=  | pmid=22902347 |  doi=10.1177/0885066612453025 | pmc= |  url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22902347   }} </ref>
+The protocol per the GENESIS Project is:<ref name="pmid22902347">{{cite journal| author=Cannon CM, Holthaus CV,  Zubrow MT, Posa P, Gunaga S, Kella V et al.| title=The GENESIS Project  (GENeralized Early Sepsis Intervention Strategies): A Multicenter  Quality Improvement Collaborative. | journal=J Intensive Care Med |  year= 2012 | volume=  | issue=  | pages=  | pmid=22902347 |  doi=10.1177/0885066612453025 | pmc= |  url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22902347   }} </ref>
 * 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
+* If hypotensive or serum lactate 4 mmol/L:
-** 20 mL/kg of crystalloid
+** Administer 20 mL/kg of crystalloid
 ** If needed, add [[vasopressor]]s to keep mean arterial pressure >65 mm  Hg
 ** If needed, aim for central venous pressure 8 mm Hg
@@ Line 230: / Line 293: @@
 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]].
+===2018 Surviving Sepsis Campaign update===
+A major change with the update is that the 3 hour and 6 hour bundles were combined into one “Hour-1 Bundle.”<ref name="pmid29675566">{{cite journal| author=Levy MM, Evans LE, Rhodes A| title=The Surviving Sepsis Campaign Bundle: 2018 update. | journal=Intensive Care Med | year= 2018 | volume= 44 | issue= 6 | pages= 925-928 | pmid=29675566 | doi=10.1007/s00134-018-5085-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29675566  }} </ref>  Per the Surviving Sepsis Campaign<ref>Adult Patients. Available at https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/Adult-Patients</ref>:
+<blockquote><q>The hour-1 bundle should be viewed as a quality improvement opportunity moving toward an ideal state. For critically ill patients with sepsis or septic shock, time is of the essence. Although the starting time for the Hour-1 bundle is recognition of sepsis, both sepsis and septic shock should be viewed as medical emergencies requiring rapid diagnosis and immediate intervention.
+The hour-1 bundle encourages clinicians to act as quickly as possible to obtain blood cultures, administer broad spectrum antibiotics, start appropriate fluid resuscitation, measure lactate, and begin vasopressors if clinically indicated. Ideally these interventions would all begin in the first hour from sepsis recognition but may not necessarily be completed in the first hour. Minimizing the time to treatment acknowledges the urgency that exists for patients with sepsis and septic shock.
+<nowiki>*</nowiki>Note that the description of the hour-1 bundle above is the most current description, having passed all approval points effective October 10, 2019.</q></blockquote>
+====Hour-1 Bundle Pocket Card and Infographic====
+SSC Hour-1 Bundle of Care Elements:
+* Measure lactate level*
+* Obtain blood cultures before administering antibiotics.
+* Administer broad-spectrum antibiotics.
+* Begin rapid administration of 30mL/kg crystalloid for hypotension or lactate level ≥ 4 mmol/L.
+* Apply vasopressors if hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mm Hg.
+<nowiki>*</nowiki> Remeasure lactate if initial lactate is elevated (> 2 mmol/L).
+===2016 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)===
+====2016 Bundle.<ref name="pmid28101605">{{cite journal| author=Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al.| title=Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. | journal=Intensive Care Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28101605 | doi=10.1007/s00134-017-4683-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28101605  }} </ref>====
+{| style="margin: 5px 10px;"
+| style="font-size: 85%; background: #545454; color: #F8F8FF; padding: 5px 10px; font-weight: bold;" | TO BE COMPLETED WITHIN 3 HOURS:
+|-
+| style="font-size: 85%; background: #DCDCDC; padding: 5px 10px;" |
+* 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.
+|-
+| 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: #F5F5F5; padding: 5px 10px;" |
+* 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.
+|}
+====<span style="background: #DCDCDC;">Initial Resuscitation</span>====
+=====<span style="background: #FFFFF0;">Initial Resuscitation</span>=====
+. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately (BPS).
+. 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).
+. 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.
+. 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).
+. We suggest that dynamic over static variables be used to predict fluid responsiveness, where available.
+. 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).
+. 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>=====
+. We recommend that hospitals and hospital systems have a performance improvement program for sepsis, including sepsis screening for acutely ill, high risk patients (BPS). &nbsp;
+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. <ref name="pmid26386734">{{cite journal| author=Hayden GE, Tuuri RE, Scott R, Losek JD, Blackshaw AM, Schoenling AJ et al.| title=Triage sepsis alert and sepsis protocol lower times to fluids and antibiotics in the ED. | journal=Am J Emerg Med | year= 2016 | volume= 34 | issue= 1 | pages= 1-9 | pmid=26386734 | doi=10.1016/j.ajem.2015.08.039 | pmc=4905767 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26386734  }} </ref>
+=====<span style="background: #FFFFF0;">Diagnosis</span>=====
+. 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). &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
+=====Antimicrobial Therapy=====
+. 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).
+. 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).
+. We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS).
+. We recommend against sustained systemic antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).
+. 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).
+. 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.
+. 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.
+. 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.
+. 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).
+. 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).
+. 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).
+. 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).
+. We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock (BPS).
+. 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).
+. 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).
+=====<span style="background: #FFFFF0;">Source Control</span>=====
+. 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).
+. 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: #FFFFF0;">Fluid Therapy (of Severe Sepsis)</span>=====
+. We recommend that a fluid challenge technique be applied where fluid administration is continued as long as hemodynamic factors continue to improve (BPS).
+. 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).
+. We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak recommendation, low quality of evidence).
+. 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).
+. We recommend against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (strong recommendation, high quality of evidence).
+. We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock (weak recommendation, low quality of evidence).
+=====<span style="background: #FFFFF0;">Vasoactive Medications</span>=====
+. We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence).
+. 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.
+. 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).
+. We recommend against using low-dose dopamine for renal protection (strong recommendation, high quality of evidence).
+. 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.
+. 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>=====
+. 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).
+====<span style="background: #DCDCDC;">Other Supportive Therapy of Severe Sepsis</span>====
+=====<span style="background: #FFFFF0;">Blood Products</span>=====
+. 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).
+. We recommend against the use of erythropoietin for treatment of anemia associated with sepsis (strong recommendation, moderate quality of evidence).
+. 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).
+. 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>=====
+. 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;">Blood Purification</span>====
+. We make no recommendation regarding the use of blood purification techniques.
+====<span style="background: #FFFFF0;">Anticoagulants</span>====
+. We recommend against the use of antithrombin for the treatment of sepsis and septic shock (strong recommendation, moderate quality of evidence).
+. 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>=====
+. 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).
+. 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).
+. 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).
+. We suggest using recruitment maneuvers in adult patients with sepsis-induced, severe ARDS (weak recommendation, moderate quality of evidence).
+. 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).
+. We recommend against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS (strong recommendation, moderate quality of evidence).
+. We make no recommendation regarding the use of noninvasive ventilation for patients with sepsis-induced ARDS.
+. 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).
+. 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).
+. 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).
+. We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS (strong recommendation, high quality of evidence).
+. 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).
+. 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).
+. We recommend using spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning (strong recommendation, high quality of evidence).
+. 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).
+=====<span style="background: #FFFFF0;">Sedation and Analgesia</span>=====
+. We recommend that continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration end points (BPS).
+=====<span style="background: #FFFFF0;">Glucose Control</span>=====
+. 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 ≤
+mg/dL rather than an upper target blood glucose level ≤ 110 mg/dL (strong recommendation, high quality of evidence).
+. 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).
+. 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).
+. 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>=====
+. 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)
+. We suggest using continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence).
+.  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).
+. 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).
+. 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).
+. We suggest combination pharmacologic VTE prophylaxis and mechanical prophylaxis, whenever possible (weak recommendation, low quality of evidence).
+. We suggest mechanical VTE prophylaxis when pharmacologic VTE is contraindicated (weak recommendation, low quality of evidence).
+=====<span style="background: #FFFFF0;">Bicarbonate Therapy</span>=====
+. 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;">Stress Ulcer Prophylaxis</span>=====
+. 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).
+. We suggest using either proton pump inhibitors or histamine-2 receptor antagonists when stress ulcer prophylaxis is indicated (weak recommendation, low quality of evidence).
+. We recommend against stress ulcer prophylaxis in patients without risk factors for GI bleeding (BPS).
+=====<span style="background: #FFFFF0;">Nutrition</span>=====
+. 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).
+. 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).
+. 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).
+. 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).
+. 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).&nbsp;
+. 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.
+. 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).
+. 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).
+. We recommend against the use of IV selenium to treat sepsis and septic shock (strong recommendation, moderate quality of evidenence).
+. We suggest against the use of arginine to treat sepsis and septic shock (weak recommendation, low quality of evidence).
+. We recommend against the use of glutamine to treat sepsis and septic shock (strong recommendation, moderate quality of evidence).
+. We make no recommendation about the use of carnitine for sepsis and septic shock.
+=====<span style="background: #FFFFF0;">Setting Goals of Care</span>=====
+. &nbsp;We recommend that goals of care and prognosis be discussed with patients and families (BPS).
+. &nbsp;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). &nbsp;
+. &nbsp;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). &nbsp;
 ==References==
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Sepsis medical therapy: Difference between revisions

Latest revision as of 01:50, 3 January 2023

Overview

Medical Therapy

Fluid therapy

Guidelines

Evidence

EGDT to guide fluid therapy

Trials of other protocols to guide fluid therapy

Timing of fluid therapy

Speed of fluid therapy

Composition of fluids

Fluid administration in cardiac and renal disease

Excessive fluid therapy

De-escalation and removal of fluids

Lactate level

Evidence

Hemodynamic monitoring

Methods of assessing fluid responsiveness

Antibiotics

Timing of antibiotics

Dissenting views

Methods to improve speed of antibiotic administration

Antibiotic selection

Delivery method

Pressors

Evidence

Steroids

Mineralocorticoid

Role of relative adrenal insufficiency

Transfusion

Protocolized therapy

Early Goal Directed Therapy (EGDT)

GENESIS Project

2018 Surviving Sepsis Campaign update

Hour-1 Bundle Pocket Card and Infographic

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

2016 Bundle.[32]

Initial Resuscitation

Initial Resuscitation

Screening for Sepsis and Performance Improvement

Diagnosis

Antimicrobial Therapy

Source Control

Hemodynamic Support and Adjunctive Therapy

Fluid Therapy (of Severe Sepsis)

Vasoactive Medications

Corticosteroids

Other Supportive Therapy of Severe Sepsis

Blood Products

Immunoglobulins

Blood Purification

Anticoagulants

Mechanical Ventilation

Sedation and Analgesia

Glucose Control

Renal Replacement Therapy

Bicarbonate Therapy

Stress Ulcer Prophylaxis

Nutrition

Setting Goals of Care

References

Navigation menu

2016 Bundle.^[32]