SSG 2016

Question 1

sepsis definition:

Answer 1

life-threatening organ dysfunction caused by a dysregulated host response to infection

Question 2

Septic shock definition:

Answer 2

subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality

Question 3

A. INITIAL RESUSCITATION

1. Sepsis and septic shock are
2. sepsis-induced hypoperfusion, at least ——– of IV crystalloid fluid be given within the first ——- h (strong recommendation, low quality of evidence).
3. following initial fluid resuscitation, additional fluids be guided by
4. 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).

Answer 3

medical emergencies, and treatment and resuscitation begin immediately (BPS).

30 mL/kg of IV crystalloid fluid
3 h

frequent reassessment of hemodynamic status (BPS)

4. 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).

Question 4

5. We suggest that —– over ——- variables be used to predict fluid responsiveness, where available (weak recommendation, low quality of evidence).
6. We recommend an initial target mean arterial pressure (MAP) of
7. We suggest guiding resuscitation to normalize

Answer 4

dynamic over static variables

65 mm Hg in patients with septic shock requiring vasopressors (strong recommendation, moderate quality of evidence).

lactate levels as a marker of tissue hypoperfusion (weak recommendation, low quality of evidence)

Question 5

EGDT was challenged following

Answer 5

challenged following the failure to show a mortality reduction in three subsequent large multicenter RCTs [17–19].

No harm was associated with the interventional strategies; thus, the use of the previous targets is still safe and may be considered.

Question 6

use of CVP alone to guide fluid resuscitation…

Dynamic measures of assessing whether a patient requires additional fluid have been proposed in an effort to improve fluid management and have demonstrated

These techniques encompass

Answer 6

can no longer be justified bc the ability to predict a response to a fluid challenge when the CVP is within a relatively normal range (8–12 mm Hg) is limited

better diagnostic accuracy at predicting those patients who are likely to respond to a fluid challenge by increasing stroke volume

passive leg raises
fluid challenges against stroke volume measurements
MV variations in systolic pressure
pulse pressure
stroke volume to changes in intrathoracic pressure induced by mechanical ventilation

Question 7

review of five studies of the use of pulse pressure variation to predict fluid responsiveness in patients with sepsis or septic shock demonstrated a sensitivity

Answer 7

sensitivity of 0.72 (95% CI 0.61–0.81)
specificity of 0.91 (95% CI 0.83–0.95)

the quality of evidence was low due to imprecision and risk of bias (ESM 3) [24]. A recent multicenter study demonstrated limited use of cardiac function monitors during fluid administration in the ICUs.

Question 8

sum of studies comparing MAP of 85 vs 65 concluded:

Answer 8

desirable consequences of targeting MAP of 65 mm Hg (lower risk of atrial fibrillation, lower doses of vasopressors, and similar mortality) led to a strong recommendation favoring an initial MAP target of 65 mm Hg over higher MAP targets

When a better understanding of any patient’s condition is obtained, this target should be individualized to the pertaining circumstances.

Question 9

Is serum lactate a direct measure of tissue perfusion:

Answer 9

No
Increases in the serum lactate level may represent tissue hypoxia, accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation, or other causes (e.g., liver failure)

Regardless of the source, increased lactate levels are associated with worse outcomes

Question 10

Five randomized controlled trials evaluated lactate-guided resuscitation of patients with septic shock:
sum of results:

Answer 10

significant reduction in mortality was seen in lactate-guided resuscitation

no evidence for difference in ICU length of stay

Two other meta-analyses of the 647 patients who were enrolled in these trials demonstrate moderate evidence for reduction in mortality when an early lactate clearance strategy was used, compared with either usual care (nonspecified) or with a Scvo2 normalization strategy

Question 11

We recommend screening program for sepsis:

We recommend Sepsis performance improvement programs:

Answer 11

sepsis screening has been associated with decreased mortality
implementation of a core set of recommendations (bundle) has been a cornerstone of sepsis performance improvement programs
SSC bundles have been developed separately from the guidelines in conjunction Institute for Healthcare

A study of 1794 patients from 62 countries with severe sepsis (now termed “sepsis” after the Sepsis-3 definition [1] or septic shock demonstrated a 36–40% reduction of the odds of dying in the hospital with compliance with either the 3- or 6-h SSC bundles

Question 12

Dx:
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

Answer 12

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)

Question 13

which sites:

Pan culture?

Answer 13

all sites considered to be potential sources of infection if it results in no substantial delay in the start of antimicrobials
including blood, CSF, urine, wounds, respiratory secretions, and other body fluids

Not bronchoscopy or open surgery

discouraged (unless the source of sepsis is not clinically apparent), because this practice can lead to inappropriate antimicrobial use

specific anatomic site of infection, cultures of other sites (apart from blood) + BLOOD

45 min i.e. be no substantial delay

Question 14

How many samples and what type:

Catheter and blood - if concerned about catheter related infection?

Answer 14

Two or more sets
aerobic and anaerobic of blood cultures

Data are inconsistent regarding the utility of differential time to blood culture positivity (i.e., equivalent volume blood culture from the vascular access device positive more than 2 h before the peripheral blood culture) in suggesting that the vascular access device is the source of the infection

Question 15

ANTIBIOTICS:

We recommend that administration of IV antimicrobials be initiated

Answer 15

as soon as possible after recognition
and within 1 h for both sepsis and septic shock (strong recommendation, moderate quality of evidence; grade applies to both conditions)

Question 16

2. We recommend empiric ______ with ______ 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 antimicrobial therapy be narrowed once

Answer 16

empiric broad-spectrum
one or more antimicrobials

sensitivities are established and/or adequate clinical improvement is noted (BPS)

Question 17

Several factors in determining the appropriate antimicrobial regimen 
(a) 
(b) 
(c) 
(d) 
(e)

Answer 17

(a) The anatomic site of infection with respect to the typical pathogen profile and to the properties of individual antimicrobials to penetrate that site
(b) Prevalent pathogens within the community, hospital, and even hospital ward
(c) The resistance patterns of those prevalent pathogens. (d) The presence of specific immune defects such as neutropenia, splenectomy, poorly controlled HIV infection and acquired or congenital defects of immunoglobulin, complement or leukocyte function or production
(e) Age and patient comorbidities including chronic illness (e.g., diabetes) and chronic organ dysfunction (e.g., liver or renal failure), the presence of invasive devices (e.g., central venous lines or urinary catheter) that compromise the defense to infection.

Question 18

prophylaxis Ab in severe inflammatory states of noninfectious origin (e.g., severe pancreatitis, burn injury) (BPS).

Answer 18

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

Question 19

distinctions with Ab dosing in sepsis:

most importantly with respect to initial empiric antimicrobial dosing

Answer 19

frequency of hepatic and renal dysfunction
high prevalence of unrecognized immune dysfunction predisposition to infection resistant organisms

increased volume of distribution for most antimicrobials, in part due to the rapid expansion of extracellular volume as a consequence of aggressive fluid resuscitation. This results in an unexpectedly high frequency of suboptimal drug levels with a variety of antimicrobials in patients with sepsis and septic shock

Question 20

β-lactams, the key pharmacodynamics correlate to microbiologic and clinical response is the time that the plasma concentration of the drug is above the pathogen MIC relative to the dosing interval (T > MIC)

A minimum T > MIC of 60% is generally sufficient to allow a good clinical response to

T > MIC of 100% for

simplest way to increase T > MIC is to:

Answer 20

mild to moderate illness

severe

use increased frequency of dosing

some meta-analyses suggest that extended/continuous infusion of β-lactams may be more effective than intermittent rapid infusion, particularly for relatively resistant organisms and in critically ill
recent individual patient data meta-analysis of randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis demonstrated an independent protective effect of continuous therapy after adjustment for other correlates of outcome

Question 21

How many Ab. septic shock

Answer 21

empiric combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at the most likely bacterial pathogen(s) (weak recommendation, low quality of evidence).

Question 22

combination therapy for bacteremia and sepsis without shock?

Answer 22

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

Question 23

combination therapy for the routine treatment of neutropenic sepsis/bacteremia?

Answer 23

against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong recommendation, moderate quality of evid

Question 24

If combination therapy is initially used for septic shock, we recommend

Answer 24

de-escalation with discontinuation of combination therapy within the first few days in response to clinical improvement and/C&S

Question 25

“combination therapy” in the context of this guideline means

combination therapy produces higher survival in severely ill septic patients with a high risk of death, particularly in those with septic shock

Answer 25

two different classes of antibiotics (usually a β-lactam with a fluoroquinolone, aminoglycoside, or macrolide) for a single putative pathogen expected to be sensitive to both, particularly for purposes of accelerating pathogen clearance.

not used where the purpose of a multidrug strategy is to strictly broaden the range of antimicrobial activity (e.g., vancomycin added to ceftazidime, metronidazole added to an aminoglycoside or an echinocandin added to a β-lactam

Question 26

neutropenia
multidrug therapy to broaden pathogen coverage

combination therapy using a β-lactam and an aminoglycoside for purposes of accelerating pathogen clearance is

Answer 26

may be useful

not beneficial for less severely ill “low-risk” patients

Question 27

We suggest that an antimicrobial treatment duration of

11. We suggest that longer courses are appropriate in

Answer 27

7–10 days is adequate for most serious infections associated with sepsis and septic shock (weak recommendation, low quality of evidence)

slow clinical response, undrainable foci of infection, bacteremia with S. aureus, some fungal and viral infections, or immunologic deficiencies, including neutropenia (weak recommendation, low quality of evidence).

Question 28

treatment duration continued

some evidence short is as effective

Answer 28

treatment duration of 3–5 days or fewer was as effective as a duration of up to 10 days. Similarly, studies have shown that a treatment duration of <7 days is as effective as longer durations in the management of acute pyelonephritis with or without bacteremia [201], uncomplicated cellulitis [203], and spontaneous bacterial peritonitis

Question 29

We suggest that measurement of procalcitonin levels can be used to

Answer 29

support shortening the duration of antimicrobial therapy in sepsis patients (weak recommendation, low quality of evidence).
AND
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).

Question 30

can procalcitonin be used to assist in differentiating infectious and noninfectious conditions

Answer 30

procalcitonin can also be used to assist in differentiating infectious and noninfectious conditions at presentation

The strongest evidence appears to relate to bacterial pneumonia versus noninfectious pulmonary pathology where meta-analysis suggests that procalcitonin may assist in predicting the presence of bacteremia, particularly in ICU patients

Question 31

SOURCE CONTROL

1. We recommend ….. (BPS)
2. We recommend prompt removal of …..(BPS)

Answer 31

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

Question 32

time frame

Answer 32

6–12 h after diagnosis appears to be sufficient for most cases

Observational studies generally show reduced survival beyond that point.

Question 33

some more severe presentations will not stabilize or improve despite rapid resuscitation and provision of appropriate antimicrobials.

Answer 33

prolonged efforts at medical stabilization prior to source control for severely ill patients, particularly those with septic shock, are generally not warranted

Question 34

FLUID THERAPY
1. We recommend that a fluid challenge technique be applied where fluid administration is continued as long as ….

2. We recommend ____ 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).

Answer 34

FLUID THERAPY
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. crystalloids

Question 35

4. We suggest using albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement in patients with
5. We recommend against using ….. (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).

Answer 35

sepsis and septic shock WHEN patients require substantial amounts of crystalloids (weak recommendation, low quality of evidence)

hydroxyethyl starches (HESs)

Question 36

albumin

SAFE study

A meta-analysis aggregated data from 17 randomized trials (n = 1977) of albumin versus other fluid solutions in patients with sepsis or septic shock

Answer 36

absence of any clear benefit following the administration of colloid compared to crystalloid solutions in the combined subgroups of sepsis, in conjunction with the expense of albumin, supports a strong recommendation for the use of crystalloid solutions in the initial resuscitation of patients with sepsis and septic shock

SAFE study indicated that albumin administration was safe and equally effective as 0.9% saline in ICU patients requiring fluid administration

279 deaths occurred 961 albumin-treated patients (29%)
vs. 343 deaths among 1016 patients (34%) with other fluids, favoring albumin (OR 0.82; 95% CI 0.671.00). When albumin-treated patients were compared with those receiving crystalloids (seven trials, n = 144), the odds ratio of dying was significantly reduced for albumin-treated patients (OR 0.78; 95% CI 0.62–0.99).

Question 37

The ALBIOS trial

a subgroup analysis suggested that the albumin group was associated with lower 90-day mortality in patients with

quality of evidence

Answer 37

no mortality benefit of albumin in combination with crystalloids compared to crystalloids alone in patients with sepsis or septic shock (RR 0.94; 95% CI 0.85–1.05)

septic shock (RR 0.87; 95% CI 0.77–0.99)

Fluid administration continued for 28 days or until discharge and was not targeted for acute resuscitation. In addition, the amount of 20% albumin was guided by serum albumin level with the ultimate goal of achieving levels >30 g/L. These results are limited by significant indirectness and imprecision, resulting in low quality of evidence.

Question 38

NaCl

Answer 38

acute kidney injury and RRT in patients managed with a chloride-liberal strategy compared to a chloride-restrictive strategy [236].

There is indirect low-quality evidence from a network meta-analysis suggesting improved outcome with balanced salt solutions as compared to saline in patients with sepsis [237] (ESM 6).

Question 39

HESs are colloids for which there are safety concerns in patients with sepsis.

A meta-analysis of nine trials (3456 patients) comparing 6% HES 130/0.38–0.45 solutions to crystalloids or albumin in patients with sepsis showed

recommendation strength

Gelatin is another synthetic colloid that can be used for fluid resuscitation; however, high-quality studies comparing gelatins to other fluids in patients with sepsis or septic shock are lacking.

did not increase mortality (RR 1.10; 95% CI 0.85–1.43; low-quality evidence) or acute kidney injury (RR 1.35; 95% CI 0.58–3.14; very low-quality evidence) compared to albumin or crystalloid. These results are limited by indirectness, since the studies did not focus on critically ill patients

Given the low quality of the available data and the cost associated with gelatin use, we issued a weak recommendation favoring the use of crystalloids over gelatins.

Answer 39

no difference in all-cause mortality (RR 1.04; 95% CI 0.89–1.22) [250]. However, when low risk of bias trials were analyzed separately,
HES use resulted in higher risk of death compared to other fluids (RR 1.11; 95% CI 1.01–1.22; high-quality evidence), which translates to 34 more deaths per 1000 patients.
Furthermore, HES use led to a higher risk of RRT (RR 1.36; 95% CI 1.08–1.72; high-quality evidence)

subsequent network meta-analysis focused on acute resuscitation of patients with sepsis or septic shock and found that HES resulted in higher risk of death

strong recommendation against the use of HES in resuscitation of patients with sepsis or septic shock.

Question 40

G. VASOACTIVE MEDICATIONS

1. We recommend _____ as the firstchoice vasopressor (strong recommendation, moderate quality of evidence).
2. We suggest adding either ____ or ____ to norepinephrine with the intent of raising MAP to target,

or adding _____ (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage

3. We suggest using ____ 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 _____ (strong recommendation, high QOE)
5. We suggest using ______ in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents (weak recommendation, low quality of evidence).

Answer 40

1. norepinephrine

2. 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 MAP to target

or adding vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage.

3. dopamine
4. renal protection
5. 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)

Question 41

We suggest that all patients requiring vasopressors have an _____ placed as soon as practical if resources are available (weak recommendation, very low quality of evidence).

Answer 41

arterial catheter

Question 42

H. CORTICOSTEROIDS
1. We suggest _____ 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).

Answer 42

H. CORTICOSTEROIDS

against

Question 43

One French multicenter RCT of patients in vasopressor-unresponsive septic shock (systolic blood pressure <90 mm Hg despite fluid resuscitation and vasopressors for more than 1 h) showed

Answer 43

significant shock reversal and reduction of mortality rate in patients with relative adrenal insufficiency [defined as a maximal postadrenocorticotropic hormone (ACTH) cortisol increase ≤ 9 μg/dL]

Question 44

(CORTICUS) that enrolled patients with systolic blood pressure of <90 mm Hg despite adequate fluid replacement or need for vasopressors had a lower risk of death than the French trial and failed to show a mortality benefit with steroid therapy

Answer 44

There was no difference in mortality in groups stratified by ACTH response.

Question 45

no difference in outcome of septic shock patients if low-dose hydrocortisone is used for 3 or 7 days; hence, we suggest tapering steroids when

Answer 45

vasopressors are no longer needed

Question 46

ADRENAL

no difference in 90d mortality

Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo

Answer 46

In mechanically ventilated patients with septic shock, low dose hydrocortisone administered via an infusion for up to 7 days does not reduce or increase mortality at 90 days
Secondary outcomes demonstrated that patients in the hydrocortisone group had a reduced time to resolution of shock, reduced duration of ICU but not hospital stay, reduced time to cessation of mechanical ventilation and a reduction in the use of blood transfusion. Adverse events were low, but significantly increased in the hydrocortisone group

Question 47

. BLOOD PRODUCTS

1. We recommend that RBC transfusion occur only when hemoglobin concentration decreases

Answer 47

<7.0 g/dL in adults in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, or acute hemorrhage (strong recommendation, high quality of evidence).

Question 48

Septic Shock (TRISS) trial addressed a transfusion threshold of 7 versus 9 g/dL in septic shock patients after admission to the ICU

Answer 48

Results showed similar 90-day mortality, ischemic events, and use of life support in the two treatment groups with fewer transfusions in the lower-threshold group.

Question 49

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).

Answer 49

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).

Question 50

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 × 109/L)] are advised for active bleeding, surgery, or invasive procedures (weak recommendation, very low quality of evidence).

Answer 50

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 × 109/L)] are advised for active bleeding, surgery, or invasive procedures (weak recommendation, very low quality of evidence).

Question 51

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

EUPHRATES trial 2018

Answer 51

Polymyxin B haemoperfusion was not shown to be superior to placebo in the management of septic shock. I will not be incorporating this therapy in the management of septic shock patients on the Intensive Care Unit
The heterogenous nature of patients with sepsis means that there are limitations in researching targeted therapies. Studies such as this one, incorporating a specific subgroup of septic patients, are welcome

Question 52

ANTICOAGULANTS

1. We recommend against the use of antithrombin for the treatment of sepsis and septic shock (strong recommendation, moderate quality of evidence)

____the most abundant anticoagulant circulating in plasma.

Answer 52

Rationale Antithrombin is the most abundant anticoagulant circulating in plasma. The decrease of its plasma activity at onset of sepsis correlates with disseminated intravascular coagulation (DIC) and lethal outcome. However, a phase III clinical trial of high-dose antithrombin for adults with sepsis and septic shock as well as systematic reviews of antithrombin for critically ill patients did not demonstrate any beneficial effect on overall mortality. Antithrombin was associated with an increased risk of bleeding

Question 53

2. We make no recommendation regarding the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.

Answer 53

2. We make no recommendation regarding the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.

Question 54

M. MECHANICAL VENTILATION
1. We recommend using a target tidal volume of _____predicted body weight (PBW) compared with 12 mL/kg in adult patients with sepsisinduced ARDS (strong recommendation, high quality of evidence).

2. We recommend using an upper limit goal for plateau pressures of ____ cmH2O over higher plateau pressures in adult patients with sepsis-induced severe ARDS (strong recommendation, moderate quality of evidence).

Answer 54

6 mL/kg

30 cmH2O

Question 55

used the 2012 Berlin definition and the terms mild, moderate, and severe ARDS

Answer 55

(Pao2/Fio2 ≤300, ≤200, and ≤100 mm Hg, respectively)

Question 56

largest trial of a volume- and pressure-limited strategy showed 9% absolute decrease in mortality in ARDS patients ventilated with tidal volumes of 6 mL/kg compared with 12 mL/kg PBW, and aiming for plateau pressure ≤ 30 cmH2O

Answer 56

Brower RG, Matthay MA, Morris A et al (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342(18):1301–1308

ARDSnet: Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome (ARMA)
The ARDSnet Investigators. N Engl J Med 2000; 342:1301-1308.

Question 57

12–15 cmH2O may be advantageous in patients without spontaneous breathing efforts [359]. Prospective validation of tidal volume titration by driving pressure is needed before this approach can be recommended.

Answer 57

Amato MB, Meade MO, Slutsky AS et al (2015) Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 372(8):747–755

Question 58

what if plateau pressure remains >30 cmH2O after reduction of tidal volume to 6 mL/kg PBW

Answer 58

tidal volume may be further reduced to as low as 4 mL/kg PBW. Respiratory rate should be increased to a maximum of 35 breaths/min during tidal volume reduction to maintain minute ventilation. Volume- and pressurelimited ventilation may lead to hypercapnia even with these maximum tolerated set respiratory rates; this appears to be tolerated and safe in the absence of contraindications (e.g., high intracranial pressure

Question 59

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

moderate or severe ARDS (Pao 2 / Fio 2≤200 mm Hg) had decreased mortality with the use of higher PEEP, whereas those with mild ARDS did not

Answer 59

higher PEEP if driving pressure fell with increased PEEP, presumably indicating increased lung compliance from opening of lung units

Question 60

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

Answer 60

Selected patients with severe hypoxemia may benefit from recruitment

maneuvers in conjunction with higher levels of PEEP, but little evidence supports the routine use in all ARDS patients

Question 61

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).

Answer 61

ARDS and a Pao2/Fio 2 ratio <150, the use of prone compared with supine position within the first 36 h of intubation, when performed for >16 h a day, showed improved survival

Question 62

ards net

Answer 62

INCLUSION CRITERIA: Acute onset of
1. PaO2/FiO2 ≤ 300 (corrected for altitude)
2. Bilateral (patchy, diffuse, or homogeneous) infiltrates consistent with
pulmonary edema
3. No clinical evidence of left atrial hypertension

PART I: VENTILATOR SETUP AND ADJUSTMENT

1. Calculate predicted body weight (PBW)
2. Select any ventilator mode
3. Set ventilator settings to achieve initial VT = 8 ml/kg PBW
4. Reduce VT by 1 ml/kg at intervals ≤ 2 hours until VT = 6ml/kg PBW.
5. Set initial rate to approximate baseline minute ventilation (not > 35bpm).
6. Adjust VT and RR to achieve pH and plateau pressure goals below

PLATEAU PRESSURE GOAL: ≤ 30 cm H2O
Check Pplat (0.5 second inspiratory pause), at least q 4h and after each change in PEEP or VT.
If Pplat > 30 cm H2O: decrease VT by 1ml/kg steps (minimum = 4ml/kg).
If Pplat < 25 cm H2O and VT< 6 ml/kg, increase VT by 1 ml/kg until Pplat > 25 cm H2O or VT = 6 ml/kg.
If Pplat < 30 and breath stacking or dys-synchrony occurs: may increase VT in 1ml/kg increments to 7 or 8 ml/kg if Pplat remains < 30 cmH2O

pH GOAL: 7.30-7.45
Acidosis Management: (pH < 7.30)
If pH 7.15-7.30: Increase RR until pH > 7.30 or PaCO2 < 25
(Maximum set RR = 35).
.
If pH < 7.15: Increase RR to 35.
If pH remains < 7.15, VT may be increased in 1 ml/kg steps until pH > 7.15 (Pplat target of 30 may be exceeded).
May give NaHCO3
Alkalosis Management: (pH > 7.45) Decrease vent rate if possible

Question 63

6. We recommend against using high-frequency oscillatory ventilation (HFOV) in adult patients with sepsis-induced ARDS (strong recommendation, moderate quality of evidence).
   why?

Answer 63

increase in barotrauma
however, this was based on very low-quality evidence. The role of HFOV as a rescue technique for refractory ARDS remains unclear; however, we recommend against its early use in moderate-severe ARDS

Question 64

8. We suggest using neuromuscular blocking agents (NMBAs) for

improve —-
reduce —

peak airway pressures

Answer 64

≤48 h in adult patients with sepsis induced ARDS and a Pao2/Fio2 ratio <150 mm Hg (weak recommendation, moderate quality of evidence).

improve chest wall compliance
prevent respiratory dyssynchrony
and reduce peak airway pressures
Muscle paralysis may also reduce oxygen consumption by decreasing the work of breathing and respiratory muscle blood flow [392].

However, a placebo-controlled RCT in patients with severe sepsis demonstrated that oxygen delivery, oxygen consumption, and gastric intramucosal pH were not improved during deep neuromuscular blockade [393].

An RCT of continuous infusions of cisatracurium in patients with early ARDS and a Pao2/Fio2 <150 mm Hg showed improved adjusted survival rates and more organ failure-free days without an increased risk of ICU-acquired weakness compared with placebo-treated patients

Question 65

ACURASYS trial performed in 2010 showed a statistically significant reduction in mortality in patients with moderate-to-severe ARDS treated with cisatracurium, compared with deeply sedated control patients, albeit after an adjusted analysis of the primary end point
Neuromuscular blockade has been weakly recommended in the management of ARDS, and uptake by clinicians has been variable

Answer 65

The management of critically ill patients has altered over the past decade, and deep sedation is no longer routine current practice
With so many questions remaining, the Prevention and Early Treatment of Acute Lung injury (PETAL) group designed a phase III trial

Question 66

ROSE trial:
Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome
The National Heart, Lung and Blood Institute PETAL Clinical Trials Network. NEJM 2019; 380: 1997-2008. doi: 10.1056/NEJMoa1901686

Answer 66

In this trial, deep sedation combined with an infusion of cisatracurium did not improve 90-day mortality when compared with a light sedation strategy in a cohort of patients recruited early in the course of moderate-to-severe ARDS
This does not change my practice of using neuromuscular blockade in selected patients to improve ventilator synchrony

Question 67

We recommend a conservative fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion

Answer 67

Mechanisms for the development of pulmonary edema in patients with ARDS include increased capillary permeability, increased hydrostatic pressure, and decreased oncotic pressure [403]. Small prospective studies in patients with critical illness and ARDS have suggested that low weight gain is associated with improved oxygenation [404] and fewer days of mechanical ventilation [405, 406]. A fluid-conservative strategy to minimize fluid infusion and weight gain in patients with ARDS, based on either a CVP or a pulmonary artery (PA) catheter (PA wedge pressure) measurement, along with clinical variables to guide treatment, led to fewer days of mechanical ventilation and reduced ICU LOS without altering the incidence of renal failure or mortality rates

Question 68

10. We recommend against the use of β-2 agonists for the treatment of patients with sepsis-induced ARDS without bronchospasm (strong recommendation, moderate quality of evidence)

Answer 68

ARDS often develop increased vascular permeability; preclinical data suggest that β-adrenergic agonists may hasten resorption of alveolar edema

Pooled analysis suggests β-agonists may reduce survival to hospital discharge in ARDS patients (RR 1.22; 95% CI 0.95–1.56) while significantly decreasing the number of ventilator-free days (MD, −2.19; 95% CI −3.68 to −0.71) [412]. β-Agonist use also led to more arrhythmias (RR 1.97; 95% CI 0.70–5.54) and more tachycardia

Question 69

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).

Answer 69

Low tidal volume ventilation (4–6 mL/kg) has been shown to be beneficial in patients with established ARDS [422] by limiting ventilator-induced lung injury

effect of volume- and pressure-limited ventilation is less clear in patients with sepsis who do not have ARDS. Meta-analysis demonstrates the benefits of low tidal volume ventilation in patients without ARDS, including a decrease in the duration of mechanical ventilation (MD, 0.64 days fewer; 95% CI 0.49–0.79) and the decreased development of ARDS (RR 0.30; 95% CI 0.16–0.57) with no impact on mortality

Question 70

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

Answer 70

50% of the patients who were fed enterally in the supine position developed VAP, compared with 9% of those fed in the semi-recumbent position

Question 71

14. We recommend using spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning (strong recommendation, high quality of evidence).

Rationale Spontaneous breathing trial options include a

A recently published clinical practice guideline suggests the use of

Daily spontaneous breathing trials in appropriately selected patients reduce

Answer 71

low level of pressure support, CPAP (≈5 cmH2O)
or use of a T-piece

the use of inspiratory pressure augmentation rather than T-piece or CPAP for an initial spontaneous breathing trial for acutely hospitalized adults on mechanical ventilation for more than 24 h [427].

the duration of mechanical ventilation and weaning duration both in individual trials as well as with pooled analysis of the individual trials [428–430]. These breathing trials should be conducted in conjunction with a spontaneous awakening trial [431]. Successful completion of spontaneous breathing trials leads to a high likelihood of successful early discontinuation of mechanical ventilation with minimal demonstrated harm

Question 72

15. We recommend using a weaning protocol in mechanically ventilated patients with sepsisinduced respiratory failure who can tolerate weaning (strong recommendation, moderate quality of evidence).

protocol weaning vs usual care:

Answer 72

Protocols allow for standardization of clinical pathways to facilitate desired treatment [432]. These protocols may include both spontaneous breathing trials, gradual reduction of support, and computer-generated weaning. Pooled analysis demonstrates that patients treated with protocolized weaning compared with usual care experienced shorter weaning duration (–39 h; 95% CI −67 h to −11 h), and shorter ICU LOS (–9 h; 95% CI −15 to −2). There was no difference between groups in ICU mortality (OR 0.93; 95% CI 0.58–1.48) or need for reintubation (OR 0.74; 95% CI 0.44–1.23)

Question 73

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

Answer 73

reduces the duration of mechanical ventilation and ICU and hospital LOS, and allows earlier mobilization [433, 434]. While these data arise from studies performed in a wide range of critically ill patients, there is little reason to believe that septic patients will not derive the same benefits from sedation minimization.

Question 74

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

2. We recommend that blood glucose values be monitored every 1–2 h until glucose values and insulin infusion rates are stable, then every 4 h 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).
   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).

Answer 74

> 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).

Question 75

2009 NICE-SUGAR

Answer 75

A blood glucose target of less than 10.0 mmol/L (180 mg/dL) resulted in lower mortality than a target of 4.5 to 6.0 mmol/L (81 to 108 mg/dL), and the authors do not recommend use of the lower target in critically ill adults.

Question 76

2009 NICE-SUGAR

hypoglycemia, and wide swings in glucose levels that have been associated with mortality

Answer 76

A blood glucose target of less than 10.0 mmol/L (180 mg/dL) resulted in lower mortality than a target of 4.5 to 6.0 mmol/L (81 to 108 mg/dL), and the authors do not recommend use of the lower target in critically ill adults.

Question 77

RENAL REPLACEMENT THERAPY
2 indications for CRRT:

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).

Answer 77

1. We suggest that either continuous RRT (CRRT) or intermittent RRT be used in patients with sepsis and acute kidney injury (weak recommendation, moderate quality of evidence).
2. We suggest using CRRT to facilitate management of fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence).

Question 78

Q. 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).

Answer 78

may be useful in limiting tidal volume in ARDS in some situations of permissive hypercapnia, no evidence supports the use of sodium bicarbonate therapy in the treatment of hypoperfusion-induced lactic acidemia associated with sepsis. Two blinded, crossover RCTs that compared equimolar saline and sodium bicarbonate in patients with lactic acidosis failed to reveal any difference in hemodynamic variables or vasopressor requirements

Bicarbonate administration has been associated with sodium and fluid overload, an increase in lactate and Paco2, and a decrease in serum ionized calcium, but the directness of these variables to outcome is uncertain. The effect of sodium bicarbonate administration on hemodynamics and vasopressor requirements at lower pH, as well as the effect on clinical outcomes at any pH level, is unknown. No studies have examined the effect of bicarbonate administration on outcomes.

Question 79

R. VENOUS THROMBOEMBOLISMPROPHYLAXIS
1. We recommend pharmacologic prophylaxis ____against venous thromboembolism (VTE) in the absence of contraindications to the use of these agents (strong recommendation, moderate quality of evidence).

2. We recommend ___ rather than ____for VTE prophylaxis in the absence of contraindications to the use of LMWH (strong recommendation, moderate quality of evidence).
3. We suggest combination pharmacologic VTE prophylaxis and mechanical prophylaxis, whenever possible (weak recommendation, low quality of evidence).
4. We suggest mechanical VTE prophylaxis when pharmacologic VTE is contraindicated (weak recommendation, low quality of evidence).

Answer 79

[unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH)]

LMWH rather than UFH

Question 80

incidence of DVT and PE in ICU

independant risk factor

Answer 80

DVT acquired in the ICU may be as high as 10%

the incidence of acquired PE may be 2–4%

Vasopressor use, which is frequent in these patients, has been found to be an independent risk factor for ICU-acquired DVT

Question 81

S. STRESS ULCER PROPHYLAXIS
1. We recommend that stress ulcer prophylaxis be given to patients with sepsis or septic shock who have

moa

2. We suggest using either proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) 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).

Answer 81

risk factors for gastrointestinal (GI) bleeding (strong recommendation, low quality of evidence).

Stress ulcers develop in the GI tract of critically ill patients and can be associated with significant morbidity and mortality [530]. The exact mechanism is not completely understood, but is believed to be related to disruption of protective mechanisms against gastric acid, gastric mucosal hypoperfusion, increased acid production, and oxidative injury to the digestive track [

Question 82

Risk factors:

Answer 82

strongest clinical predictors of GI bleeding risk in critically ill patients are mechanical ventilation for >48 h and coagulopathy [532]. A recent international cohort study showed that preexisting liver disease, need for RRT, and higher organ failure scores were independent predictors of GI bleeding risk [533]. A multicenter prospective cohort study found the incidence of clinically important GI bleeding to be 2.6% (95% CI 1.6–3.6%) in critically ill patients [533]; however, other observational studies showed lower rates of GI bleeding

Question 83

T. NUTRITION 1. We recommend against the administration of early parenteral nutrition alone or parenteral nutrition in combination with enteral feedings (but rather initiate ….

CALORIES

Answer 83

early enteral nutrition) in critically ill patients with sepsis or septic shock who can be fed enterally (strong recommendation, moderate quality of evidence).

No evidence showed that early parenteral nutrition reduced mortality or infection risk, but ICU LOS was increased

In the largest randomized trial that addressed this study question…were fewer episodes of hypoglycemia and vomiting in the early parenteral group, but no differences in death between the study groups

Due to the lack of mortality benefit, the added cost of parenteral nutrition in absence of clinical benefit and the potential physiologic benefits of enteral feeding we recommend early enteral nutrition as the preferred route of administration in patients with sepsis or septic shock who can be fed enterally.

Question 84

2. We recommend against the administration of parenteral nutrition alone or in combination with enteral feeds (but rather to initiate…

Answer 84

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).

In summary, due to the lack of mortality benefit, the increased risk of infection, and the extra cost for parenteral nutrition in the absence of clinical benefit [568], current evidence does not support the initiation of early parenteral nutrition over the first 7 days of care for patients with contraindications or intolerance to enteral nutrition.

Question 85

maintenance of gut integrity and prevention of intestinal permeability, dampening of the inflammatory response, and modulation of metabolic responses that may reduce insulin resistance [561, 562]. To examine evidence for this nutrition strategy, we asked if early full feeding (started within the first 48 h and feeding goals to be met within 72 h of ICU admission or injury) as compared to a delayed strategy (feeds delayed for at least 48 h) improved the outcome of our critically ill patients.

Answer 85

Since the present evidence does not suggest harm with early versus delayed institution of enteral feeding, and there is possible benefit from physiologic evidence suggesting reduced gut permeability, inflammation, and infection risk, the committee issued a weak recommendation to start feeding early in patients with sepsis and septic shock.

Question 86

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).

Answer 86

Due to the uncertainty of benefit, the potential for harm, and the excess cost and varied availability of omega-3 fatty acids, we make a strong recommendation against the use of omega-3 fatty acids for patients with sepsis and septic shock outside the conduct of RCTs.

Question 87

6. We suggest against routinely monitoring gastric residual volumes (GRVs) 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 This recommendation refers to nonsurgical critically ill patients with sepsis or septic shock.

Answer 87

The rationale for measurement of GRVs is to reduce the risk for aspiration pneumonia by either ceasing or modifying the enteral feeding strategy based on the detection of excess gastric residuals. The inherent controversy is that observational and interventional studies have not consistently confirmed a relationship between the measurement of GRVs (with thresholds ranging from 200 mL to no monitoring of GRVs) and outcomes of vomiting, aspiration, and pneumonia

suggest against routine monitoring of GRVs in all patients with sepsis unless the patient has demonstrated feeding intolerance (e.g., vomiting, reflux of feeds into the oral cavity) or for patients who are considered to be at high risk for aspiration (e.g., surgery, hemodynamic instability). We recommend the generation of further evidence through the conduct of future randomized controlled trials targeted to higher-risk patient groups such as the surgical population or those in shock to determine the threshold and frequency with which GRVs should be monitored.

Question 88

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).

Answer 88

Prokinetic agents, including metoclopramide (D2 antagonist), domperidone (D2 recp antagonist), and erythromycin, are frequently used in the ICU. Each of these agents has different pharmacodynamics and pharmacokinetic properties; however, these agents may be associated with prolongation of QT interval and ventricular arrhythmias. A large case–control study in non-ICU patients showed a threefold increase in risk of sudden cardiac death with domperidone use at doses >30 mg/day

Question 89

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

Answer 89

Selenium was administered in the hope that it could correct the known reduction of selenium concentration in sepsis patients and provide a pharmacologic effect through an antioxidant defense. Although some RCTs are available, the evidence for the use of IV selenium is not convincing.

Question 90

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

Answer 90

Arginine availability is reduced in sepsis, which can lead to reduced nitric oxide synthesis, loss of microcirculatory regulation, and enhanced production of superoxide and peroxynitrite. However, arginine supplementation could lead to unwanted vasodilation and hypotension [619, 620]. Human trials of l-arginine supplementation have generally been small and reported variable effects on mortality [621–624]. The only study in septic patients showed improved survival, but had limitations in study design [623]. Other studies suggested no benefit or possible harm in the subgroup of septic patients [621, 624, 625]. Some authors found improvement in secondary outcomes in septic patients, such as reduced infectious complications) and hospital LOS, but the relevance of these findings in the face of potential harm is unclear.

Question 91

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

Answer 91

Glutamine levels are also reduced during critical illness. Exogenous supplementation can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation. Other potential benefits are enhanced immune cell function, decreased proinflammatory cytokine production, and higher levels of glutathione and antioxidative capacity [619, 620]. However, the clinical significance of these findings is not clearly established.

Question 92

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

Answer 92

Glutamine levels are also reduced during critical illness. Exogenous supplementation can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation. Other potential benefits are enhanced immune cell function, decreased proinflammatory cytokine production, and higher levels of glutathione and antioxidative capacity [619, 620]. However, the clinical significance of these findings is not clearly established.

Question 93

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

What is carnitine:
MoA:

Answer 93

Carnitine, endogenously manufactured from lysine and methionine
required for the transport of long-chain fatty acids into the mitochondria and the generation of energy

As such, carnitine utilization is essential for enabling the switch from glucose to long-chain fatty acid metabolism during the sepsis energy crisis. This is the basis for the rationale of employing l-carnitine as a therapeutic in sepsis. One small randomized trial in patients with sepsis reported a 28-day mortality decrease in septic shock patients treated with IV l-carnitine therapy within 24 h of shock onset; however, the trial was underpowered to detect such a difference [637]. Larger, ongoing trials should provide more evidence of the usefulness of carnitine supplementation.

Question 94

U. 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 h of ICU admission (weak recommendation, low quality of evidence).

Answer 94

establishing realistic ICU treatment goals is paramount [638], especially because inaccurate expectations about prognosis are common among surrogates

someone appointed by a doctor or nurse to make medical decisions