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 2: / Line 2: @@
 {{Siren|Sepsis}}
 {{Sepsis}}
-{{CMG}};  '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh@perfuse.org]
+{{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 is associated with outcomes among septic patients.
-*For every hour delay in the administration of appropriate [[antibiotic]] therapy there is an associated 7% rise in mortality.
+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>.
-*"Surviving Sepsis Campaign" is a large international collaboration that was established to educate individuals about sepsis and to improve patient outcomes following sepsis.
+===Fluid therapy===
+====Guidelines====
+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]].”
+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
+* [[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====
+{| class="wikitable"
+|+ [[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>
+!
+! Rivers, 2001<ref name="pmid11794169"/>
+! ProCESS, 2014<ref name="pmid24635773"/>
+! ARISE, 2014<ref name="pmid25272316"/>
+! ProMISe, 2015<ref name="pmid25776532"/>
+! CLASSIC, 2022<ref name="pmid35709019"/>
+|-
+| Lactate, mean<br />(treatment; control
+| 6.9; 7.7
+| 4.8; 5.0
+| 6.7; 6.6
+| 7.0; 6.8
+| 3.8; 3.9<br />(median)
+|-
+| Fluids in first 6 hours<br />(treatment; control)
+| 4900; 3500
+| 3300; 2800
+| 2000; 1700
+| 2000; 1800<br />(median)
+| 1000; 1700<br />(24 hours)
+|-
+| Mortality<br />(treatment; control)
+| 44%; 57%<br />(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:<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.
+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>
+* 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<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.
+=====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.
+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>
+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<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%"
+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<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>
+.
+=====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<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>.
+=====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.
+=====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>
+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=====
+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>
+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:
+*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>
+====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" />
+====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>
+===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>.
+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>
+* "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<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" />.
+====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>.
+===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.)
+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>
+====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>
+===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>
+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>.
+====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>
+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"/>.
+=====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>.
+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>
+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>
+=====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>
+====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<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" />.
+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" />.
+====Delivery method====
+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>
+===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<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
+* Vasopressin
+====Evidence====
+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" />.
+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>.
+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 nave been recommended and studied:
+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.
+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">{{cite journal| author=The ARISE Investigators and the ANZICS Clinical Trials Group| title=Goal-Directed Resuscitation for Patients with Early Septic Shock. | journal=N Engl J Med | year= 2014 | volume=  | issue=  | pages=  | 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  }} </ref> 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.
+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 27: / Line 283: @@
 ===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
@@ Line 38: / Line 294: @@
 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]].
-===Surviving Sepsis Campaign Care Bundles===
+===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;"
@@ Line 48: / Line 323: @@
 * 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:
@@ Line 53: / Line 329: @@
 | 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 arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL):
+* In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion and document findings according to '''Table 1'''.
-: - Measure central venous pressure (CVP). Target CVP: ≥8 mm Hg.
+* Re-measure lactate if initial lactate elevated
-: - Measure central venous oxygen saturation (ScvO2). Target ScvO2: ≥70%.
-* Remeasure lactate if initial lactate was elevated. Target lactate: normalization.
 |}
+{| class="wikitable"
+|'''TABLE 1'''
-==2012 Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock (DO NOT EDIT)<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>==
+DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE PERFUSION WITH:
-===<span style="background: #DCDCDC;">Initial Resuscitation and Infection Issues</span>===
+EITHER:
-====<span style="background: #FFFFF0;">Initial Resuscitation</span>====
+• Repeat focused exam (after initial fluid resuscitation) including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings.
-. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L). Goals during the first 6 hrs of resuscitation:
-* Central venous pressure 8–12 mm Hg
-* Mean arterial pressure (MAP) ≥ 65 mm Hg
-* Urine output ≥ 0.5 mL/kg/hr
-* Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively. {{GRADE1|C}}
-. In patients with elevated lactate levels targeting resuscitation to normalize lactate. {{GRADE2|C}}
+OR TWO OF THE FOLLOWING:
-====<span style="background: #FFFFF0;">Screening for Sepsis and Performance Improvement</span>====
+• Measure CVP
-. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy. {{GRADE1|C}}
-. Hospital–based performance improvement efforts in severe sepsis.
+• Measure ScvO2
-====<span style="background: #FFFFF0;">Diagnosis</span>====
+• Bedside cardiovascular ultrasound
-. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s). {{GRADE1|C}} At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted. {{GRADE1|C}}
-. Use of the 1,3 beta-D-glucan assay {{GRADE2|B}}, mannan and anti-mannan antibody assays {{GRADE2|C}}, if available and invasive candidiasis is in differential diagnosis of cause of infection.
+• Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge
-. Imaging studies performed promptly to confirm a potential source of infection.
+Of note, the 6-hour bundle has been updated from 2012; the 3-hour SSC bundle is not affected.
+|}
-====Antimicrobial Regimen====
-=====Sepsis, adult=====
-* 1. '''Sepsis, adult'''
-:* 1.1 '''Empiric antimicrobial therapy'''<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>
-::* 1.1.1 '''History of intravenous drug use with high prevalence of MRSA'''
-:::* Perferred regimen: [[Vancomycin]] 1 g IV q12h
-::* 1.1.2 '''Sepsis associated with petechiae'''
-:::* Perferred regimen: [[Ceftriaxone]] 2 g IV q12h
-::* 1.1.3 '''Biliary source'''
-*'''1. Community-acquired acute cholecystitis of mild-to-moderate severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
-:* Preferred regimen (1): [[Cefazolin]]  1–2 g IV q8h
-:* Preferred regimen (2): [[Cefuroxime]] 1.5 g IV q8h
-:* Preferred regimen (3): [[Ceftriaxone]] 1–2 g IV q12–24 h
-* '''2. Community-acquired acute cholecystitis of severe physiologic disturbance, advanced age, or immunocompromised state''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
-:* Preferred regimen (1):Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (2):[[Meropenem]]  1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (3):[[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (4):[[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (5):[[Ciprofloxacin]]  400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (6):[[Levofloxacin]]  750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (7):[[Cefepime]]  2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-* '''3. Acute cholangitis following bilio-enteric anastamosis of any severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
-:* Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (2): [[Meropenem]] 1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (3): [[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (4): [[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (5): [[Ciprofloxacin]] 400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (6): [[Levofloxacin]] 750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-:* Preferred regimen (7): [[Cefepime]] 2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h
-* '''4. Health care-associated biliary infection of any severity''' <ref name="pmid20034345">{{cite journal| author=Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ et al.| title=Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. | journal=Clin Infect Dis | year= 2010 | volume= 50 | issue= 2 | pages= 133-64 | pmid=20034345 | doi=10.1086/649554 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20034345  }} </ref>
-:* Preferred regimen (1): Imipenem-cilastatin 500 mg IV q6h {{or}} 1 g q8h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (2): [[Meropenem]] 1 g IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (3): [[Doripenem]] 500 mg IV q8h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (4): [[Piperacillin-tazobactam]] 3.375 g IV q6h, {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (5): [[Ciprofloxacin]] 400 mg IV q12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (6): [[Levofloxacin]] 750 mg IV q24h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* Preferred regimen (7): [[Cefepime]] 2 g IV q8–12h {{and}} [[Metronidazole]]  500 mg IV q8–12 h {{or}} 1500 mg q24h {{and}} [[Vancomycin]] 15–20 mg/kg IV q8–12 h
-:* '''Note''': Antimicrobial therapy of established infection should be limited to 4–7 days, unless it is difficult to achieve adequate source control. Longer durations of therapy have not been associated with improved outcome.
-::* 1.1.4 '''Community-acquired pneumonia'''
-:::* Preferred regimen: ([[Levofloxacin]] 750 mg IV q24h {{or}} [[Moxifloxacin]] 400 mg IV q24h) {{and}} [[Piperacillin-Tazobactam]] 3.375 g IV q4h {{and}} [[Vancomycin]] 1 g IV q12h
-::* 1.1.5 '''Unclear infection source'''
-:::* Preferred regimen: ([[Doripenem]] 500 mg IV q8h {{or}} [[Ertapenem]] 1 g IV q24h {{or}} [[Imipenem]] 0.5 g IV q6h {{or}} [[Meropenem]] 1 g IV q8h) {{and}} [[Vancomycin]] 1 g IV q12h
-::* 1.1.6 '''Low prevalence of ESBL and/or carbapenemase-producing aerobic GNB'''
-:::* Preferred regimen: [[Piperacillin-Tazobactam]] 3.375 g IV q4h {{and}} [[Vancomycin]] 1 g IV q12h
-::* 1.1.7 '''High prevalence of ESBL and/or carbapenemase-producing aerobic GNB'''
-:::* Preferred regimen: [[Colistin]] 2.5 mg/kg single dose followed by 1.5 mg/kg IV q12h {{and}}  [[Meropenem]] 1 g IV q8h {{and}} [[Vancomycin]] 1 g IV q12h
-====Sepsis, pediatric====
-*1. '''Sepsis, pediatric'''
-:*1.1 '''Empiric antimicrobial therapy'''<ref>{{Cite journal| doi = 10.1097/CCM.0b013e31827e83af| issn = 1530-0293| volume = 41| issue = 2| pages = 580–637| last1 = Dellinger| first1 = R. Phillip| last2 = Levy| first2 = Mitchell M.| last3 = Rhodes| first3 = Andrew| last4 = Annane| first4 = Djillali| last5 = Gerlach| first5 = Herwig| last6 = Opal| first6 = Steven M.| last7 = Sevransky| first7 = Jonathan E.| last8 = Sprung| first8 = Charles L.| last9 = Douglas| first9 = Ivor S.| last10 = Jaeschke| first10 = Roman| last11 = Osborn| first11 = Tiffany M.| last12 = Nunnally| first12 = Mark E.| last13 = Townsend| first13 = Sean R.| last14 = Reinhart| first14 = Konrad| last15 = Kleinpell| first15 = Ruth M.| last16 = Angus| first16 = Derek C.| last17 = Deutschman| first17 = Clifford S.| last18 = Machado| first18 = Flavia R.| last19 = Rubenfeld| first19 = Gordon D.| last20 = Webb| first20 = Steven A.| last21 = Beale| first21 = Richard J.| last22 = Vincent| first22 = Jean-Louis| last23 = Moreno| first23 = Rui| last24 = Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup| title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012| journal = Critical Care Medicine| date = 2013-02| pmid = 23353941}}</ref>
-::*1.1.1 '''Children aged > 1 month'''
-:::* Preferred regimen: ([[Cefotaxime]] 50 mg/kg IV q8h {{or}} [[Ceftriaxone]] 100 mg/kg IV q24h) {{and}} [[Vancomycin]] 15 mg/kg IV q6h
-:::* Alternative regimen: [[Aztreonam]] 7.5 mg/kg IV q6h {{and}} [[Linezolid]] 10 mg/kg IV q8h
-::*1.1.2 '''Children aged < 1 month'''
-:::* Preferred regimen: [[Ampicillin]] 25 mg/kg IV q8h {{and}} [[Cefotaxime]] 50 mg/kg q12h {{withorwithout}} [[Vancomycin]] 15 mg/kg IV q12h (if suspecting [[MRSA]])
-:::* Alternative regimen: [[Ampicillin]] 25 mg/kg IV q6h {{and}} [[Ceftriaxone]] 75 mg/kg IV q24h {{withorwithout}} [[Vancomycin]] 15 mg/kg IV q12h (if suspecting [[MRSA]])
-====<span style="background: #FFFFF0;">Source Control</span>====
-. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible. {{GRADE1|C}}
-. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred. {{GRADE2|B}}
-. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than surgical drainage of an abscess).
-. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established.
-====<span style="background: #FFFFF0;">Infection Prevention</span>====
+====<span style="background: #DCDCDC;">Initial Resuscitation</span>====
-a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective. {{GRADE2|B}}
-b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis. {{GRADE2|B}}
+=====<span style="background: #FFFFF0;">Initial Resuscitation</span>=====
+. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately (BPS).
-===<span style="background: #DCDCDC;">Hemodynamic Support and Adjunctive Therapy</span>===
+. We recommend that, in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours (strong recommendation, low quality of evidence).
-====<span style="background: #FFFFF0;">Fluid Therapy of Severe Sepsis</span>====
+. We recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status (BPS).
-. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. {{GRADE1|B}}
-. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. {{GRADE1|B}}
+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.
-. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids. {{GRADE2|C}}
+. 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).
-. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients. {{GRADE1|C}}
+. We suggest that dynamic over static variables be used to predict fluid responsiveness, where available.
-. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.
+. 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).
-====<span style="background: #FFFFF0;">Vasopressors</span>====
+. 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).
-. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg. {{GRADE1|C}}
+=====<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;
-. Norepinephrine as the first choice vasopressor. {{GRADE1|B}}
+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>
-. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. {{GRADE2|B}}
+=====<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).
-. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage.
+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).
-. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents).
+. 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).
-. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). {{GRADE2|C}}
+. We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS).
-. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. {{GRADE1|C}}
+. We recommend against sustained systemic antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).
-. Low-dose dopamine should not be used for renal protection. {{GRADE1|A}}
+. 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).
-. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available.
+. 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.
-====<span style="background: #FFFFF0;">Inotropic Therapy</span>====
+Remarks: Readers should review Table 6 for definitions of empiric, targeted/definitive, broad-spectrum, combination, and multidrug therapy before reading this section.
-. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. {{GRADE1|C}}
+. 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).
-. Not using a strategy to increase cardiac index to predetermined supranormal levels. {{GRADE1|B}}
+Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
-====<span style="background: #FFFFF0;">Corticosteroids</span>====
+. We recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evidence).
-. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day. {{GRADE2|C}}
-. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. {{GRADE2|B}}
+Remarks: This does not preclude the use of multidrug therapy to broaden antimicrobial activity.
-. In treated patients hydrocortisone tapered when vasopressors are no longer required. {{GRADE2|D}}
+. 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).
-. Corticosteroids not be administered for the treatment of sepsis in the absence of shock. {{GRADE1|D}}
+. 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).
-. When hydrocortisone is given, use continuous flow. {{GRADE2|D}}
+. 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).
-===<span style="background: #DCDCDC;">Other Supportive Therapy of Severe Sepsis</span>===
+. 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).
-====<span style="background: #FFFFF0;">Blood Product Administration</span>====
+. We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock (BPS).
-. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults. {{GRADE1|B}}
-. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis. {{GRADE1|B}}
+. 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).
-. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures. {{GRADE2|D}}
+. 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).
-. Not using antithrombin for the treatment of severe sepsis and septic shock. {{GRADE1|B}}
+=====<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).
-. In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures. {{GRADE2|D}}
+. 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;">Immunoglobulins</span>====
+=====<span style="background: #FFFFF0;">Fluid Therapy (of Severe Sepsis)</span>=====
-. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock. {{GRADE2|B}}
+. We recommend that a fluid challenge technique be applied where fluid administration is continued as long as hemodynamic factors continue to improve (BPS).
-====<span style="background: #FFFFF0;">Selenium</span>====
+. 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).
-. Not using intravenous selenium for the treatment of severe sepsis. {{GRADE2|C}}
-====<span style="background: #FFFFF0;">History of Recommendations Regarding Use of Recombinant Activated Protein C (rhAPC)</span>====
+. We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak recommendation, low quality of evidence).
-. A history of the evolution of SSC recommendations as to rhAPC (no longer available) is provided.
-====<span style="background: #FFFFF0;">Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)</span>====
+. 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).
-. Target a tidal volume of 6mL/kg predicted body weight in patients with sepsis-induced ARDS ({{GRADE1|A}} vs. 12 mL/kg).
-. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung be ≤30 cm H2O. {{GRADE1|B}}
+. We recommend against using hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock (strong recommendation, high quality of evidence).
-. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma). {{GRADE1|B}}
+. 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).
-. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis-induced moderate or severe ARDS. {{GRADE2|C}}
+. 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.
-. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia. {{GRADE2|C}}
+. 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).
-. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤ 100mm Hg in facilities that have experience with such practices. {{GRADE2|B}}
+. We recommend against using low-dose dopamine for renal protection (strong recommendation, high quality of evidence).
-. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia. {{GRADE1|B}}
+. 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).
-. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks. {{GRADE2|B}}
+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.
-. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria:
+. 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).
-* Arousable
+=====<span style="background: #FFFFF0;">Corticosteroids</span>=====
-* Hemodynamically stable (without vasopressor agents)
+. 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).
-* No new potentially serious conditions
-* Low ventilatory and end-expiratory pressure requirements
-* Low Fio2 requirements which can be met safely delivered with a face mask or nasal cannula
-: If the spontaneous breathing trial is successful, consideration should be given for extubation. {{GRADE1|A}}
-. Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS. {{GRADE1|A}}
+====<span style="background: #DCDCDC;">Other Supportive Therapy of Severe Sepsis</span>====
-. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypo perfusion. {{GRADE1|C}}
+=====<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).
-. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis-induced ARDS. {{GRADE1|B}}
+. We recommend against the use of erythropoietin for treatment of anemia associated with sepsis (strong recommendation, moderate quality of evidence).
-====<span style="background: #FFFFF0;">Sedation, Analgesia, and Neuromuscular blockade in Sepsis</span>====
+. 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).
-. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints. {{GRADE1|B}}
-. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used. {{GRADE1|C}}
+. 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).
-. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a Pao2/Fio2 < 150 mm Hg. {{GRADE2|C}}
+=====<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;">Glucose Control</span>====
+====<span style="background: #FFFFF0;">Blood Purification</span>====
-. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL. {{GRADE1|A}}
+. We make no recommendation regarding the use of blood purification techniques.
-. Blood glucose values be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter. {{GRADE1|C}}
+====<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).
-. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values.
+. 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).
-====<span style="background: #FFFFF0;">Renal Replacement Therapy</span>====
+. 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).
-. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure. {{GRADE2|B}}
-. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients. {{GRADE2|D}}
+. We suggest using recruitment maneuvers in adult patients with sepsis-induced, severe ARDS (weak recommendation, moderate quality of evidence).
-====<span style="background: #FFFFF0;">Bicarbonate Therapy</span>====
+. 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).
-. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥7.15. {{GRADE2|B}}
-====<span style="background: #FFFFF0;">Deep Vein Thrombosis Prophylaxis</span>====
+. We recommend against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS (strong recommendation, moderate quality of evidence).
-. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE). {{GRADE1|B}} This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) ({{GRADE1|B}} versus twice daily UFH, {{GRADE2|C}} versus three times daily UFH). If creatinine clearance is &#60;30 mL/min, use dalteparin {{GRADE1|A}} or another form of LMWH that has a low degree of renal metabolism {{GRADE2|C}} or UFH {{GRADE1|A}}.
-. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible. {{GRADE2|C}}
+. We make no recommendation regarding the use of noninvasive ventilation for patients with sepsis-induced ARDS.
-. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive pharmacoprophylaxis {{GRADE1|B}}, but receive mechanical prophylactic treatment, such
+. 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).
-as graduated compression stockings or intermittent compression devices {{GRADE2|C}}, unless contraindicated. When the risk decreases start pharmacoprophylaxis. {{GRADE2|C}}
-====<span style="background: #FFFFF0;">Stress Ulcer Prophylaxis</span>====
+. 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).
-. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors. {{GRADE1|B}}
-. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA. {{GRADE2|D}}
+. 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).
-. Patients without risk factors do not receive prophylaxis. {{GRADE2|B}}
+. We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS (strong recommendation, high quality of evidence).
-====<span style="background: #FFFFF0;">Nutrition</span>====
+. 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).
-. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock. {{GRADE2|C}}
-. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated. {{GRADE2|B}}
+. 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).
-. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock. {{GRADE2|B}}
+. We recommend using spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning (strong recommendation, high quality of evidence).
-. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis. {{GRADE2|C}}
+. 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;">Setting Goals of Care</span>====
+=====<span style="background: #FFFFF0;">Glucose Control</span>=====
-. Discuss goals of care and prognosis with patients and families. {{GRADE1|B}}
+. 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 ≤
-. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. {{GRADE1|B}}
+mg/dL rather than an upper target blood glucose level ≤ 110 mg/dL (strong recommendation, high quality of evidence).
-. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission. {{GRADE2|C}}
+. We recommend that blood glucose values be monitored every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours thereafter in patients receiving insulin infusions (BPS).
-===<span style="background: #DCDCDC;">Special Considerations in Pediatrics</span>===
+. 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).
-====<span style="background: #FFFFF0;">Initial Resuscitation</span>====
+. 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).
-. For respiratory distress and hypoxemia start with face mask oxygen or if needed and available, high flow nasal cannula oxygen or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseus access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation. {{GRADE2|C}}
+=====<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)
-. Initial therapeutic end points of resuscitation of septic shock: capillary refill of ≤2 secs, normal blood pressure for age, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL·kg-1·hr-1, and normal mental status. Scvo2 saturation ≥70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter. {{GRADE2|C}}
+. We suggest using continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence).
-. Follow American College of Critical Care Medicine-Pediatric Life Support (ACCM-PALS) guidelines for the management of septic shock. {{GRADE1|C}}
+.  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).
-. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock. {{GRADE1|C}}
+. 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).
-====<span style="background: #FFFFF0;">Antibiotics and Source Control</span>====
+. 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).
-. Empiric antibiotics be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible but this should not delay administration of antibiotics. The empiric drug choice should be changed as epidemic and endemic ecologies dictate (eg H1N1, MRSA, chloroquine resistant malaria, penicillin-resistant pneumococci, recent ICU stay, neutropenia). {{GRADE1|D}}
-. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension. {{GRADE2|D}}
+. We suggest combination pharmacologic VTE prophylaxis and mechanical prophylaxis, whenever possible (weak recommendation, low quality of evidence).
-. Early and aggressive source control. {{GRADE1|D}}
+. We suggest mechanical VTE prophylaxis when pharmacologic VTE is contraindicated (weak recommendation, low quality of evidence).
-. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease. {{GRADE1|A}}
+=====<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;">Fluid Resuscitation</span>====
+=====<span style="background: #FFFFF0;">Stress Ulcer Prophylaxis</span>=====
-. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusion of isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent) over 5–10 minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises) blood transfusion is considered superior to crystalloid or albumin bolusing. {{GRADE2|C}}
+. 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).
-====<span style="background: #FFFFF0;">Inotropes/Vasopressors/Vasodilators</span>====
+. We suggest using either proton pump inhibitors or histamine-2 receptor antagonists when stress ulcer prophylaxis is indicated (weak recommendation, low quality of evidence).
-. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid resuscitation. {{GRADE2|C}}
-. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given vasodilator therapies in addition to inotropes. {{GRADE2|C}}
+. We recommend against stress ulcer prophylaxis in patients without risk factors for GI bleeding (BPS).
-====<span style="background: #FFFFF0;">Extracorporeal Membrane Oxygenation (ECMO)</span>====
+=====<span style="background: #FFFFF0;">Nutrition</span>=====
-. Consider ECMO for refractory pediatric septic shock and respiratory failure. {{GRADE2|C}}
+. 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).
-====<span style="background: #FFFFF0;">Corticosteroids</span>====
+. 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).
-. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insufficiency. {{GRADE1|A}}
-====<span style="background: #FFFFF0;">Protein C and Activated Protein Concentrate</span>====
+. 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).
-No recommendation as no longer available.
-====<span style="background: #FFFFF0;">Blood Products and Plasma Therapies</span>====
+. 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).
-. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (< 70%), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower target > 7.0 g/dL can be considered reasonable. {{GRADE1|B}}
-. Similar platelet transfusion targets in children as in adults. {{GRADE2|C}}
+. 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;
-. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura. {{GRADE2|C}}
+. 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).
-====<span style="background: #FFFFF0;">Mechanical Ventilation</span>====
+Remarks: Ths recommendation refers to nonsurgical critically ill patients with sepsis or septic shock.
-. Lung-protective strategies during mechanical ventilation. {{GRADE2|C}}
-====<span style="background: #FFFFF0;">Sedation/Analgesia/Drug Toxicities</span>====
+. 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 recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis. {{GRADE1|D}}
-. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events. {{GRADE1|C}}
+. We suggest placement of post-pyloric feeding tubes in critically ill patients with sepsis or septic shock with feeding intolerance or who are considered to be at high risk of aspiration (weak recommendation, low quality of evidence).
-====<span style="background: #FFFFF0;">Glycemic Control</span>====
+. We recommend against the use of IV selenium to treat sepsis and septic shock (strong recommendation, moderate quality of evidenence).
-. Control hyperglycemia using a similar target as in adults ≤ 180 mg/dL. Glucose infusion should accompany insulin therapy in newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant. {{GRADE2|C}}
-====<span style="background: #FFFFF0;">Diuretics and Renal Replacement Therapy</span>====
+. We suggest against the use of arginine to treat sepsis and septic shock (weak recommendation, low quality of evidence).
-. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration (CVVH) or intermittent dialysis to prevent > 10% total body weight fluid overload. {{GRADE2|C}}
-====<span style="background: #FFFFF0;">Deep Vein Thrombosis (DVT) Prophylaxis</span>====
+. We recommend against the use of glutamine to treat sepsis and septic shock (strong recommendation, moderate quality of evidence).
-No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis.
-====<span style="background: #FFFFF0;">Stress Ulcer (SU) Prophylaxis</span>====
+. We make no recommendation about the use of carnitine for sepsis and septic shock.
-No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis.
-====<span style="background: #FFFFF0;">Nutrition</span>====
+=====<span style="background: #FFFFF0;">Setting Goals of Care</span>=====
-Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot. {{GRADE2|C}}
+. &nbsp;We recommend that goals of care and prognosis be discussed with patients and families (BPS).
-====<span style="background: #FFFFF0;">Transfusion</span>====
+. &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;
-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>
-==Contraindicated Medications==
+. &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;
-{{MedCondContrAbs|MedCond =Sepsis|Etanercept|Sitagliptin And Metformin Hydrochloride}}
 ==References==
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 [[Category:Disease]]
 [[Category:Emergency medicine]]
+[[Category:Intensive care medicine]]
+[[Category:Infectious Disease Project]]
+[[Category:Emergency mdicine]]
+[[Category:Up-To-Date]]
 [[Category:Infectious disease]]
-[[Category:Intensive care medicine]]
-[[Category: Infectious Disease Project]]

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]