cc2019b1 Sample

Sepsis Management
By Young Ran Lee, Pharm.D., BCPS, BCCCP; and Taryn B. Bainum, Pharm.D., BCPS
Reviewed by Jeffrey P. Gonzales, Pharm.D., FCCM, BCPS, BCCCP; and Kyle A. Gustafson, Pharm.D., BCCCP
LEARNING OBJECTIVES
1. Assess the updates in guideline definitions and recommendations for managing sepsis and/or septic shock.
2. Evaluate recent literature regarding the management of sepsis and septic shock.
3. Design an evidence-based treatment regimen for a patient with sepsis and/or septic shock.
4. Justify pharmacist involvement in preventing, recognizing, and managing sepsis and/or septic shock.
INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
AKI Acute kidney injury Epidemiology
CVP Central venous pressure Sepsis is a multifaceted clinical syndrome involving the response of
EGDT Early goal-directed therapy a host’s immune system to an invading pathogen. The word “sepsis”
EN Enteral nutrition was used in Greek literature and is derived from the Greek work “sepo,”
MAP Mean arterial pressure which translates to “I rot” (Funk 2009). Throughout history, under-
PLR Passive leg raise standing of the pathophysiology of sepsis has evolved and grown.
qSOFA Quick Sequential Organ Failure However, much remains to be discovered about this disease process.
Assessment A complex interaction between immunity (both innate and adaptive),
RRT Renal replacement therapy inflammation, coagulation, and circulation often results in tissue dam-
Scvo2 Central venous oxygen saturation age and organ failure. Sepsis management aims to target each aspect
SIRS Systemic inflammatory response of this pathophysiology to improve patient survival and outcomes.
syndrome Sepsis continues to be a leading cause of morbidity and mortality
SOFA Sequential Organ Failure in the United States. Trends identified over the past 10 years show that
Assessment the incidence of sepsis and septic shock is increasing (Kadri 2017).
SSC Surviving Sepsis Campaign Using clinical data to identify septic shock, defined as a presumed
SUP Stress ulcer prophylaxis infection with vasopressor use, the incidence of sepsis increased
VTE Venous thromboembolism from 12.8 per 1000 hospitalizations in 2005 to 18.6 per 1000 hospital-
izations in 2014, a 4.9% increase per year. Reports indicate a sepsis
Table of other common abbreviations.
incidence of around 6% in hospitalized patients (Rhee 2017). Despite
the rising occurrence of sepsis, mortality has decreased. The in-hos-
pital mortality rate for septic shock, as identified by clinical criteria,
decreased from 54.9% in 2005 to 50.7% in 2014 (Kadri 2017). Other
reports indicate an in-hospital mortality rate of almost 16% for sepsis
and greater than 40% for septic shock (Singer 2016).
In addition to the increase in morbidity and mortality, sepsis was
the most expensive condition to treat in the U.S. health care system in
2013, accounting for almost $24 billion in annual costs (Torio 2016).
Potential reasons for the increased incidence of sepsis include
increased age of the population, increased use of invasive proce-
dures, and increased use of immunosuppressive therapies. The
evolving sepsis definitions over time may have contributed to a
greater sensitivity in identifying sepsis.
CCSAP 2019 Book 1 • Infection Critical Care 7 Sepsis Management

PATIENT ASSESSMENT AND host response to infection” and septic shock as “subset of
MONITORING sepsis with circulatory and cellular/metabolic dysfunction
Definitions and Classifications associated with higher risk of mortality.” The classification of
severe sepsis as outlined in the 2012 iteration of the Surviving
Identifying and classifying patients with sepsis or sep-
Sepsis Campaign (SSC) guidelines is no longer used in the
tic shock has changed significantly over the past 2 years.
2016 update (Rhodes 2017).
Previously, the systemic inflammatory response syndrome
To meet the Sepsis-3 sepsis definition, patients should
(SIRS) criteria were important in identifying patients with
have a suspected or documented infection and an acute
sepsis/septic shock. However, with the publication of the
increase of at least 2 SOFA points from baseline. If patients
Third International Consensus Definitions for Sepsis and
meet the sepsis criteria and require vasopressor therapy to
Septic Shock guidelines (Sepsis-3) in 2016, the Sequential
meet the mean arterial pressure (MAP) of at least 65 mm
Organ Failure Assessment (SOFA) and quick SOFA (qSOFA)
Hg and their lactate concentration is greater than 2 mmol/L
were recommended in place of the SIRS criteria (Singer 2016)
(18 mg/dL) despite adequate fluid resuscitation, their condi-
(Figure 1). Controversy still exists regarding which criteria
tion is classified as septic shock (Rhodes 2017; Singer 2016).
should be used to identify patients with sepsis. Therefore, the
In Sepsis-3, qSOFA is suggested to identify patients with
pharmacist should be familiar with the different standards
suspected infection who are likely to develop sepsis or sep-
and definitions.
tic shock. This tool can be used outside the ICU, and even
The Society of Critical Care Medicine and the European
outside the hospital, because it is easy to perform by clinical
Society of Intensive Care Medicine defined sepsis as
examination (Singer 2016).
“life-threatening organ dysfunction caused by dysregulated
Monitoring
To identify patients likely to develop sepsis or septic shock,
BASELINE KNOWLEDGE STATEMENTS the qSOFA criteria (includes mental status, systolic blood
pressure, and respiratory rate) should be monitored in patients
Readers of this chapter are presumed to be familiar with a suspected or documented infection. Once patients
with the following: meet at least two qSOFA criteria, organ dysfunction should
• General knowledge of the pathophysiology that be assessed using the SOFA score (see Table 1 for a list of
leads to sepsis and septic shock.
the criteria). An increase in SOFA score of at least 2 points
• Hemodynamic assessment in septic shock. with suspected infection indicates sepsis. A SOFA score of 2
• Pharmacology, pharmacokinetics, pharmacody- or more correlates with a mortality rate of 10% (Singer, 2016).
namics, and spectrum of activity of antimicrobial
The 2018 SSC guideline update does not specifically
agents. (Review article provided in additional
address hemodynamic parameters as resuscitation goals.
readings)
However, the update advocates measuring lactate to guide
Table of common laboratory reference values. resuscitation therapy (Levy 2018).
ADDITIONAL READINGS Challenges Facing Critical Care Practitioners

Because of the complexity of sepsis, it is exceedingly dif-
The following free resources are available for readers ficult to develop a concrete set of criteria for identifying it.
wishing additional background information on this
Although recent guidelines have tried to solidify definitions,
topic.
controversy remains surrounding the suggested classifi-
• Rhodes A, Evans LE, Alhazzani W, et al. Surviving cations, and previous sepsis definitions are still being used
Sepsis Campaign: international guidelines for
management of sepsis and septic shock: 2016. clinically. This ambiguity could hinder evaluating the inci-
Crit Care Med 2017;45:486-552. dence rates of this syndrome over time, as well as identifying
• Levy MM, Evans LE, Rhodes A. The Surviving the condition. Clinicians need to be familiar with proposed old
Sepsis Campaign bundle: 2018 update. Crit Care and new definitions, clinical markers, and pathophysiology of
Med 2018;46:997-1000. sepsis in order to identify patients with this condition.
• Myburgh JA, Mythen MG. Resuscitation fluids. In the 2018 SSC guideline update, the 3- and 6-hour care
N Engl J Med 2013;369:1243-51. bundles are combined into a 1-hour care bundle. Providers
• Varghese JM, Roberts JA, Lipman J. Antimicrobial may find it difficult not only to meet care bundles, but also
pharmacokinetic and pharmacodynamics issues in to distinguish between guideline recommendations and core
the critically ill with severe sepsis and septic measure criteria. Significant discrepancies exist between the
shock. Crit Care Clin 2011;27:19-34.
Centers for Medicare & Medicaid (CMS) early management
bundle, the Severe Sepsis/Septic Shock (SEP-1) core measure,

• Sepsis: Life-threatening organ dysfunction caused by dysregulated host response to infection (associated with > 10%
of hospital mortality)
• Septic shock: Subset of sepsis with circulatory and cellular/metabolic dysfunction associated with higher risk
of mortality (associated with > 40% of hospital mortality)
• qSOFA
○○ Altered mental status = GCS score < 15

○○ Systolic blood pressure (SBP) ≤ 100 mm Hg
○○ Respiratory rate ≥ 22 breaths/min
SOFA Score
Score
System 0 1 2 3 4
Respiration
Pao2 /Fio2, mm Hg ≥ 400 < 400 < 300 < 200 (with respiratory < 100 with respiratory
support support
Coagulation
Plt, × 10 3/mm3 ≥ 150 < 150 < 100 < 50 < 20
Liver
Bilirubin, mg/dL < 1.2 1.2–1.9 2.0–5.9 6.0–11.9 ≥ 12.0
Cardiovascular
MAP ≥ 70 mm Hg MAP < 70 Dopamine (any dose) Dopamine 5.1–15 mcg/ Dopamine > 15 mcg/
mm Hg < 5 mcg/ kg/min or epinephrine kg/min or epinephrine
kg/min or ≤ 0.1 mcg/min or > 0.1 mcg/min or
dobutamine norepinephrine norepinephrine
≤ 0.1 mcg/kg/min > 0.1 mcg/kg/min
Central nervous system
GCS score 15 13–14 10–12 6–9 <6
Renal
SCr, mg/dL < 1.2 1.2–1.9 2.0–3.4 3.5–4.9 > 5.0
Urinary output, < 500 < 200

mL/day
Figure 1. Sepsis definitions according to the 2016 SSC guidelines.

GCS = Glasgow Coma Scale (score); Pao2 /Fio2 = arterial oxygen partial pressure to fractional inspired oxygen.
Information from: Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management
of sepsis and septic shock: 2016 (SSC 2016). Crit Care Med 2017;45:486-552; Singer M, Deutschman CS, Seymour CW, et al.
The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10; and Ferreira FL,
Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001;286:1754-8.

Table 1. EGDT Literature
Study Design and Population Intervention Results Conclusion
Tuchschmidt 1992 RCT Normal treatment (resuscitation Mortality 72% in normal treatment Titration of therapy to increased
Patients with suspected septic goal of cardiac index ≥ 3 L/min/m2 group vs. 50% in optimal treatment concentrations of cardiac index
shock (n=51) and SBP ≥ 90 mm Hg) group (p=0.014) and Do2 may be associated with
Optimal treatment (resuscitation improved survival
goal of cardiac index ≥ 6 L/min/m2
and SBP ≥ 90 mm Hg
Yu 1993 RCT Control group = no specific No significant difference in Supranormal Do2I values may be
Patients with sepsis/septic shock, therapeutic goal mortality between groups associated with increased survival
ARDS, or hypovolemic shock Treatment group = Do2I goal > Subgroup analysis of supranormal in this disease state
CCSAP 2019 Book 1 • Infection Critical Care

with pulmonary arterial catheters 600 mL/min/m2 Do2I vs. normal Do2I mortality (14%
(n=67) vs. 56%, p=0.01)
Haynes 1994 RCT Treatment group = resuscitation No significant difference in Overall outcomes in patients not
Patients with septic shock (n=109) goal of cardiac index > 4.5 L/min/ ventilated days, ICU LOS, hospital improved using dobutamine to
m2, Do2 > 600 mL/min/m2, and O2 LOS, or mortality meet these hemodynamic goals
consumption > 170 mL/min/m2
10
Gattinoni 1995 RCT Normal cardiac index (cardiac index No significant differences Therapeutic goal of supranormal
Critically ill adults (n=762) 2.5–3.5 L/min/m2) in mortality or rate of organ cardiac index or normal Svo2 does
Supranormal cardiac index (cardiac dysfunction not reduce morbidity or mortality
index > 4.5 L/min/m2) in critically ill patients
Normal Svo2 (> 70% or difference
of < 20% between arterial oxygen
saturation and Svo2)
Yu 1998 RCT Control group = resuscitation goal In patients age 50–75, mortality In patients age 50–75, a higher Do2
Critically ill adults ≥ 50 with SIRS, of Do2 450–550 mL/min/m2 was 21% in the treatment group vs. goal improved survival. However,
sepsis, severe sepsis, septic Treatment group = resuscitation 52% in the control group (p=0.01) no benefit occurred in patients
shock, or ARDS unable to achieve goal of Do2 ≥ 600 mL/min/m2 In those > 75, mortality was 57% in > 75
Do2 ≥ 600 mL/min/m2 with fluid the treatment group vs. 61% in the
alone (n=105) control group (p=NS)
Alia 1999 RCT Control group = normal targeted Mortality was 66% in the control Maximizing Do2 as a treatment goal
Patients with severe sepsis or value of Do2 group vs. 74% in the treatment did not reduce mortality
septic shock (n=63) Treatment group = targeted group (p=0.46)
Do2I > 600 mL/min/m2
Sepsis Management
Table 1. EGDT Literature (continued)
Rivers 2001 RCT Standard therapy = hemodynamic In-hospital mortality higher in EGDT has significant short- and
Sepsis, severe sepsis, or septic protocol at physician discretion standard therapy group (p=0.009) long-term benefits
shock (n=236) EGDT group 28-day mortality higher in standard
group (p=0.03)
Lin 2006 RCT Standard therapy = clinician Time to shock reversal lower in GDT GDT resulted in faster shock
Septic shock (n=224) judgment (47 hr vs. 65.4 hr, p<0.001) reversal and mortality benefit than
GDT = algorithm-based treatment In-hospital mortality lower in GDT standard therapy
(53.7% vs. 71.6%, p=0.006)
ICU mortality lower in GDT (50% vs.
67.2%, p=0.009)

Wang 2006 RCT Conventional therapy 7- and 14-day in-hospital mortality Efficacy of GDT better than
[abstract] Patients with septic shock (n=16) GDT with CVP, MAP, and Svo2 goals lower in GDT (p<0.05) conventional therapy
Chen 2007 RCT Control group Incidence of MODS lower in EGDT EGDT may decrease the incidence
[abstract] Early stages of septic shock EGDT (p=0.002) and severity of MODS and can
(n=273) MODS mortality rate lower in EGDT decrease mortality of MODS in the
11
(p=0.007) presence of severe sepsis
He 2007 RCT Control group Mortality in patients with mild In early periods of septic shock,
[abstract] Patients with septic shock (n=203) EGDT organ dysfunction lower in EGDT EGDT can decrease mortality, but
(27.78% vs. 37.5%, p<0.05) this benefit does not extend into
No difference between groups advanced stages of septic shock
among patients with moderate or
severe organ dysfunction
Yan 2010 RCT Conventional therapy 28-day survival higher in EGDT EGDT improves 28-day survival in
Patients with severe sepsis or EGDT (75.2% vs. 57.5%, p=0.001) patients with severe sepsis and
septic shock (n=303) ICU mortality higher in conventional septic shock
therapy (35% vs. 50.7%, p=0.035)
Jones 2010 RCT Scvo2 group = resuscitated to In-hospital mortality insignificantly Adding lactate clearance to
Patients with severe sepsis and normalize CVP, MAP, and Scvo2 lower with lactate clearance group resuscitation goals did not
septic shock (n=300) Lactate clearance group = (23% vs. 17%) decrease mortality
resuscitated to normalize CVP,
MAP, and lactate clearance of at
least 10%
(continued)
Sepsis Management
Table 1. EGDT Literature (continued)
Yealy 2014 RCT Protocol-based EGDT No significant difference in 60- or Protocol-based resuscitation did
(PROCESS) Patients with septic shock (n=1341) Protocol-based standard therapy 90-day mortality or 1-yr mortality not improve outcomes
Usual care
Andrews 2014 RCT Protocol-based care No difference between groups for Results are likely because
Patients with sepsis within 24 hr of Usual care in-hospital mortality (RR 1.05; of factors other than tissue
admission (n=109) 95% CI, 0.79–1.41) hypoperfusion causing end organ
failure, and future studies should
amend inclusion criteria to control
for this

Peake 2014 RCT Usual care No difference in 90-day mortality EGDT did not reduce mortality at
(ARISE) Patients with early septic shock EGDT (18.6% vs. 18.8%, p=0.90) 90 days
(n=796)
Mouncey 2015 RCT Usual care No difference in 90-day mortality EGDT did not improve outcomes
(PROMISE) Patients with early septic shock EGDT (RR 1.01; 95% CI, 0.85–1.20
(n=1260)
12
ARDS = acute respiratory distress syndrome; CVP = central venous pressure; Do2 = oxygen delivery; Do2I = oxygen delivery indexed; EGDT = early goal-directed therapy;
GDT = goal-directed therapy; LOS = length of stay; MODS = multiple organ dysfunction syndromes; RCT = randomized controlled trial; Scvo2 = central venous oxygen saturation;
SIRS = systemic inflammatory response syndrome.
Information from: Tuchschmidt J, Fried J, Astiz M, et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992;102:216-20; Yu M,
Mitchell L, Smith P, et al. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study. Crit
Care Med 1993;21:830-8; Hayes M, Timmins AC, Yau E, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-22;
Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995;333:1025-32; Yu M, Burchell S, Hasaniya N, et
al. Relationship of mortality to increasing oxygen delivery in patients >or=to 50 years of age: a prospective, randomized trial. Crit Care Med 1998;26:1011-9; Alia I, Esteban A,
Federico G, et al. A randomized and controlled trial of effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock. Chest
1999;115:453-61; Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;344:1368-77; Lin
SM, Huang CD, Lin HC, et al. A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial.
Shock 2006;26:551-7; Wang XZ, Lu CJ, Gao FQ, et al. Efficacy of goal-directed therapy in the treatment of septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;18:661-
4; Chen ZQ, Jin YH, Chen H, et al. Early goal-directed therapy lowers the incidence, severity and mortality of multiple organ dysfunction syndrome. Nan Fang Yi Ke Da Xue
Xue Bao 2007;27:1892-5; He ZY, Gao Y, Wang XR, et al. Clinical evaluation for execution of early goal directed therapy in septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi
Xue 2007;19:14-6; Early Goal-Directed Therapy Collaborative Group of Zhejiang Province. The effect of early goal-directed therapy on treatment of critical patients with
severe sepsis/septic shock: a multi-center, prospective, randomized, controlled study. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010;22:331-4; Jones AE, Shapiro NI, Trzeciak
S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739-46; ProCESS Investigators,
Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93; Andrews B, Mechemwa L, Kelly P,
et al. Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia. Crit Care Med 2014;42:2315-24; ARISE Investigators,
ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506; and
Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-11.
Sepsis Management
and the newest SSC 1-hour bundle. Because the SEP-1 require- before SEP-1 implementation and 75.5% afterward (Ramsdell
ments have not been updated to reflect the newest guideline 2017). Even after SEP-1 became a core measure, these results
recommendations, practitioners may need to decide which still indicate room for improvement with compliance rates.
of these to follow. The definitions and requirements outlined New knowledge regarding sepsis is continually coming
in the CMS SEP-1 core measure are shown in Box 1. To be to light, indicating there is still much to learn. The evolving
considered compliant with SEP-1, all measures must be met. body of evidence for sepsis treatment presents the challenge
Many barriers to accomplishing these tasks in the recom- of staying up to date. With the rapid dissemination of infor-
mended time interval often exist. A study assessed adherence mation, practitioners should familiarize themselves with the
to the SSC guideline recommendations of 3- and 6-hour care newest information available, assess the quality of any new
bundles at one institution before and after implementing the evidence, and ultimately incorporate this into their patients’
SEP-1 core measure. The study found a 3-hour bundle com- care plans to improve patient outcomes. This chapter focuses
pliance rate of 31.3% before SEP-1 implementation and 66.4% on updates in the literature regarding sepsis and septic shock
after implementation. The 6-hour compliance rate was 41.7% management.
Box 1. SEP-1 Definitions and Requirements of CMS SEP-1 Core Measure vs. Sepsis-3
Definitions and SSC 1-Hr Bundle
CMS SEP-1 Definitions CMS SEP-1 Requirements
Sepsis = 2 SIRS criteria + suspected infection Severe sepsis
SIRS criteria Within 3 hr of presentation
• Temp > 101°F • Measure serum lactate
• Temp < 96.8°F • Obtain blood cultures before antibiotic administration
• HR > 90 beats/min • Administer antibiotics
• RR > 20 breaths/min Within 6 hr of presentation
• WBC > 12 x 10 cells/mm
3 3
• WBC < 4 x 10 cells/mm

3 3 • Repeat serum lactate if initial lactate is > 2 mmol/L
• > 10% bandemia Septic shock
Within 3 hr of presentation
Severe sepsis = sepsis + ≥ 1 variables of organ dysfunction
Organ dysfunction variables • Measure serum lactate
• Obtain blood cultures before antibiotic administration
• SBP < 90 mm Hg • Administer antibiotics
• MAP < 70 mm Hg • Resuscitation with 30 mL/kg of crystalloid fluids
• SBP decrease > 40 mm Hg from known baseline Within 6 hr of presentation
• SCr > 2.0 mg/dL
• Urinary output < 0.5 mL/kg/hr for > 2 hr • Repeat volume status and tissue perfusion assessment
○○ Physical examination findings – vital signs, cardiopul-
• Bilirubin > 2.0 mg/dL monary examination, capillary refill evaluation, peripheral
• Plt < 100,000/mm 3
pulse evaluation, skin examination
• INR > 1.5 or PTT > 60 s ○○ Document two of the following:
• Altered mental status ▪▪ CVP
• Lactate > 2 mmol/L ▪▪ Scvo2
Septic shock = severe sepsis + hypoperfusion despite ▪▪ Bedside cardiovascular ultrasonography
adequate fluid resuscitation or lactate > 4 mmol/L ▪▪ PLR or fluid challenge
• Vasopressor administration (if hypotension persists after fluid)
Sepsis-3 Definitions SSC 1-Hr Bundle Requirements
Sepsis = suspected/documented infection + increase in Measure lactate concentration. Re-measure if initial lactate is
SOFA score of at least 2 from baseline > 2 mmol/L
Septic shock = sepsis + need for vasopressors and lactate Obtain blood cultures before administering antibiotics
> 2 mmol/L despite adequate fluid resuscitation
Administer broad-spectrum antibiotics
Rapidly administer 30 mL/kg of crystalloid for hypotension or
lactate ≥ 4 mmol/L
Apply vasopressors if patient is hypotensive during or after
fluid resuscitation to maintain MAP ≥ 65 mm Hg
CVP = central venous pressure; HR = heart rate; PLR = passive leg raise; Scvo2 = central venous oxygen saturation; SIRS = systemic inflam-
matory response syndrome.

HEMODYNAMIC STABILIZATION of cardiac output to volume expansion (Monnet 2016). The
Early Goal-Directed Therapy pooled sensitivity of PLR-induced changes in cardiac output
(or surrogate) was 0.85 (0.81–0.88), and the pooled specificity
Early goal-directed therapy (EGDT) was introduced in 2001
was 0.91 (0.88–0.93). For PLR-induced changes in pulse pres-
(Rivers 2001). This study showed that a 6-hour protocol sig-
sure, the pooled sensitivity was 0.56 (0.49–0.53) and pooled
nificantly improved outcomes in patients with severe sepsis
specificity, 0.83 (0.77–0.88). The best threshold was a PLR-
and septic shock compared with usual care. In this study,
induced increase in cardiac output of 10% plus or minus 2%
usual care consisted of a protocol for hemodynamic sup-
or greater. The study concluded that PLR-induced changes
port that did not include parameters such as central venous
in cardiac output reliably indicated cardiac output response
oxygen saturation (Scvo2), and achieving treatment goals
to volume expansion in adults with circulatory failure. When
was left to physician discretion. Since that time, 3 large
using pulse pressure to assess PLR-induced changes,
randomized, multicentered studies (ARISE, PROCESS and
pooled specificity remains intact, but pooled sensitivity is
PROMISE) have reported no mortality benefit with EGDT
poor. Another systematic review and meta-analysis pooled
compared to usual care, making its value somewhat contro-
23 trials to assess how well PLR performed in various set-
versial (see Table 1).
tings (Cherpanath 2016). Pooled sensitivity was 86% (95% CI,
A recent meta-analysis examined trials in which the
79–92), with pooled specificity 92% (95% CI, 88–96). Passive
study population included adults with severe sepsis or sep-
leg raise–induced changes in flow variables such as cardiac
tic shock, the intervention group received EGDT, and the
output yielded a sensitivity of 85% and specificity of 92%,
comparator group consisted of usual care or lactate-guided
whereas changes in pulse pressure on PLR yielded a sensi-
therapy (Lu 2016). On examination of 13 trials, the data anal-
tivity of 58% and specificity of 83% (p<0.001). The authors
yses suggested that EGDT was significantly associated with
of this analysis concluded that PLR performed well diagnos-
decreased mortality compared with usual care (RR 0.87; 95%
tically in various settings and that PLR-induced changes in
CI, 0.77–0.98) but was also significantly associated with
flow variables had a higher predictive value than change in
increased mortality compared with lactate-guided therapy
pulse pressure on PLR.
(RR 1.60; 95% CI, 1.24–2.06).
Although PLR seems like a promising dynamic measure of
A second meta-analysis evaluating 17 trials compar-
volume status and predictor of fluid responsiveness, it has
ing EGDT with usual care found that overall mortality to be
limitations. In patients with conditions such as limb amputa-
reduced with EGDT only if the mortality rate of the usual care
tion, head trauma, spinal trauma, and pelvic fractures, use of
group exceeded 30% (Park 2017).
this technique is precluded for practical reasons. Conditions
On further examination, it appears the mortality bene-
such as increased intra-abdominal pressure may affect the
fit occurred in the subgroup of trials published between the
accuracy of PLR in predicting fluid responsiveness. Most
2004 and the 2012 SSC guidelines. The underlying impli-
studies using PLR are done on patients on positive pressure
cation from these data is that over time, usual care has
ventilation, which can affect certain the interpretation of cer-
improved, resulting in a less pronounced difference in mortal-
tain indicies (Pickett 2017).
ity rates between EGDT and usual care. It is still reasonable
Cardiac ultrasonography can also help determine volume
to follow the care bundles set forth by SSC guidelines and
status and cardiac output in patients with sepsis. A recent
to use dynamic hemodynamic parameters to inform clinical
prospective, randomized controlled trial compared use of
decisions during fluid resuscitation in sepsis.
a fairly new monitor, the ultrasonic cardiac output monitor
Assessment of Hemodynamic Stability (USCOM), with conventional echocardiography in determin-
The current SSC guidelines recommend normalizing lactate as ing cardiac output (Elgendy 2017). The study found that
a resuscitation goal and no longer recommend that parameters stroke volume as measured by USCOM correlated with car-
such as central venous pressure (CVP) and Scvo2 guide therapy diac output measured by conventional echocardiography,
(Rhodes 2017). This change was partly because of literature showing the usefulness of USCOM in examining the hemody-
suggesting poor correlation between parameters such as CVP namic status of critically ill patients.
and volume status obtained by more reliable methods such as These data, together with previous data citing issues with
pulse pressure variation or stroke volume variation. Measuring CVP-based hemodynamic monitoring, suggest that dynamic
these parameters also failed to show mortality benefit in sev- measures such as PLR are more likely than static measures
eral trials. Because no harm has been associated with CVP- and to yield accurate predictions of volume responsiveness in
Scvo2-guided therapy, it may be reasonable to consider these adult patients with shock (Box 2).
parameters when evaluating the efficacy of resuscitation
efforts. However, dynamic measures such as passive leg raise Fluid Resuscitation
(PLR) and fluid challenges should be used as well. On recognition of sepsis-induced hypotension and/or elevated
A systematic review and meta-analysis of 21 studies lactate concentrations, fluid resuscitation is recommended
assessed the accuracy of PLR in predicting the response to be initiated immediately and completed within the first

by observational data as well as the fact that it matches the
Box 2. Dynamic vs. Static Measures
average fluid administered in the PROCESS and ARISE tri-
of Volume Status
als (Rhodes 2017). Although the optimal amount of fluid to
Dynamic Measures be given in sepsis is not known, this is an excellent area for
• PLR future trials to examine. Literature suggests that a sustained
○○ Increase in SV of 10%–15%
positive fluid balance and volume overload are associated
• Fluid challenge against SV measurements
○○ Increase in PPV of 15% with a 500-mL bolus with increased mortality, new organ system dysfunction at
• Variations in systolic pressure, pulse pressure, or SV to discharge, impaired mobility, and discharge to a health care
changes in intrathoracic pressure induced by mechanical facility. Literature also indicates that sustained positive fluid
ventilation
balance is not protective against AKI. Therefore, fluid admin-
○○ PPV ~13%
○○ Systolic pressure variation > 10 mm Hg istration after initial resuscitation should be done cautiously
○○ SV change of > 5%–15% and only if the patient is likely to benefit (Johnson 2018;
Levy 2018; Brotfain 2016; Mitchell 2015). Some patient pop-
Static Measures
ulations may be especially sensitive to volume overload,
• CVP
• Left ventricular end diastolic volume such as those with heart failure. In these populations, clini-
• Pulmonary arterial occlusion pressure cal judgment is often used to determine whether the amount
• Inferior vena cava diameter of fluid administered should be reduced. It is reasonable to
administer smaller boluses in these patient populations and
PPV = pulse pressure variation; SV = stroke volume.
to reevaluate volume status before administering further
Information from: Michard F, Boussat S, Chemla D, et al.
Relation between respiratory changes in arterial pulse pres- boluses. However, the rigidity of the CMS guidelines hinders
sure and fluid responsiveness in septic patients with acute clinicians’ ability to exercise this judgment while following
circulatory failure. Am J Respir Crit Care Med 2000;162:134-8;
this core measure.
Michard F. Changes in arterial pressure during mechanical ven-
tilation. Anesthesiology 2005;103:419-28; Monnet X, Marik PE, Guideline recommendations do not currently advocate
Teboul JL. Prediction of fluid responsiveness: an update. Ann either balanced crystalloids or saline as the resuscitation
Intensive Care 2016;6:111; Pickett JD, Bridges E, Kritek PA, et al.
Passive leg-raising and prediction of fluid responsiveness: fluid of choice in sepsis, but state that either is an appropri-
systematic review. Crit Care Nurse 2017;37:32-47. ate first-line therapy (Rhodes 2017). Although normal saline
may be the most common choice of fluid resuscitation,
there are concerns about its association with hyperchlor-
3 hours (Levy 2018). Guidelines recommend at least a emic metabolic acidosis, AKI, and even increased mortality
30-mL/kg bolus of crystalloid fluid as the initial resuscitation (Semler 2018).
(Rhodes 2017). After the initial fluid resuscitation, additional An unblinded, cluster-randomized, multiple-crossover trial
fluids should be guided by frequent reassessment of intra- of 15,802 patients, the SMART trial, compared the use of bal-
vascular volume and hemodynamic status. Crystalloid is the anced crystalloids with isotonic saline in critically ill adults
fluid of choice for initial resuscitation and subsequent intra- in medical and non-medical ICUs (Semler 2018). A total of
vascular volume replacement in patients with sepsis and 1139 patients (14.3%) in the balanced crystalloid group and
septic shock. Albumin in addition to crystalloids is suggested 1211 patients (15.4%) in the saline group developed a major
when patients require a substantial amount of crystalloids. adverse kidney event within 30 days (p=0.04). There were
However, neither literature nor guidelines provide a clear no significant differences in the components of the primary
definition of what constitutes a substantial amount of crys- outcome or secondary end points such as in-hospital death,
talloid fluid. Rather, clinical judgment should be used to ICU-free days, or ventilator-free days. The subgroup analy-
determine whether albumin might benefit resuscitation after sis of patients with sepsis had a significantly lower rate of
large volumes of crystalloids. Although the guidelines make the composite primary outcome in the balanced crystalloid
no recommendation regarding which concentration of albu- group. Although this study suggests that balanced crystal-
min should be used, 5% albumin is most commonly used in loids are favorable in critically ill patients with sepsis, several
patients with hypovolemia to administer as much volume as limitations such as potential treatment bias limit the gen-
possible. Hydroxyethyl starches are not recommended for eralizability of results. These results were echoed by the
fluid resuscitation in patients with sepsis or septic shock SALT-ED trial, which compared normal saline with balanced
because of the increased risk of death and acute kidney crystalloids in noncritically ill patients and found a lower inci-
injury (AKI)/renal replacement therapy (RRT) in several stud- dence of major adverse kidney events within 30 days in the
ies (Rochwerg 2014; Haase 2013). group receiving balanced crystalloids (Self 2018). As in the
The current guideline recommendation of using at SMART trial, other outcomes such as in-hospital death did
least 30 mL/kg of intravenous crystalloid fluid as an initial not significantly differ between groups. According to these
resuscitation measure is not supported by data from ran- studies, balanced crystalloids are reasonable to reduce the
domized controlled trials. However, this practice is supported risk of adverse kidney events in patients without relative

contraindications such as traumatic brain injury or hyperka- debate whether the early addition of vasopressin should be
lemia. Balanced crystalloids may be preferred in patients with common practice. Past studies have shown varying degrees
hypernatremia or hyperchloremia. of benefits with this practice. However, no clear answer has
Future studies to more definitively determine whether bal- been attained. Other potential agents such as angiotensin II
anced crystalloids offer more benefit than normal saline as will be discussed later in the chapter.
initial fluid resuscitation may help settle this debate. One such The VANISH trial (Gordon 2016) was a factorial, multi-
study is PLUS, which will compare 90-day mortality between center, double-blind, randomized study examining whether
Plasma-Lyte A and normal saline in critically ill patients. This early administration of vasopressin in patients with septic
study is currently recruiting participants and estimated to be shock would better improve kidney outcomes than norepi-
completed in 2021. nephrine. Among the four study groups (vasopressin plus
hydrocortisone, vasopressin plus placebo, norepinephrine
Vasopressor Therapy plus hydrocortisone, and norepinephrine plus placebo), there
In patients with septic shock requiring vasopressors, a targeted was no difference in the primary outcome of kidney fail-
MAP of 65 mm Hg within the first hour is recommended (Levy ure-free days or 28-day mortality. However, the rate of RRT
2018). Norepinephrine is the recommended first-line vasopres- was significantly lower in the vasopressin groups (25.4% vs.
sor in septic shock. If MAP is not maintained at 65 mm Hg or 35.3%; OR 0.4 [95% CI, 0.2–0.73]). The authors concluded that
greater with norepinephrine alone or if the norepinephrine dose the study findings did not support the use of vasopressin over
needs to be decreased, either vasopressin (up to 0.03 unit/min- norepinephrine but that results may point toward a clinically
ute) or epinephrine can be added to norepinephrine (Rhodes useful benefit of vasopressin.
2017). High-dose (greater than 0.03 unit/minute) vasopressin A recent retrospective trial investigated patient char-
is not recommended in patients with septic shock because it acteristics that might predict responsiveness to adding
may cause significant ischemia, especially in myocardium and vasopressin in septic shock (Allen 2018). Considering the
bowel through significant vasoconstriction (Holmes 2008). adjusted logistic regression model results, vasopressin
Dopamine is recommended as an alternative vasopressor to used as an adjunct vasopressor, rather than as the first-line
norepinephrine only in patients with a low risk of tachyarrhyth- agent, was the only variable significantly associated with
mias and absolute or relative bradycardia. Low-dose dopamine responsiveness (OR 1.71 [95% CI, 1.10–2.65]). In the post hoc
drip is not recommended for renal protection. After adequate analysis, female patients had an increased odds of respond-
fluid resuscitation and vasopressor agents, dobutamine can be ing to vasopressin compared with male patients. Despite
considered in patients with persistent hypoperfusion (Rhodes evidence from previous studies that vasopressin may play a
2017). Angiotensin II is a novel agent that was not addressed in role as initial vasoactive therapy, this study shows that vaso-
the guidelines. However, the literature surrounding this agent pressin may be best as an adjunctive agent.
is discussed in the text that follows. Another retrospective study examined vasopressor
Although only briefly discussed in the current SSC guide- agents added to norepinephrine in patients with septic shock
lines, phenylephrine is another potential vasopressor option. (Nguyen 2017). This study reported that mortality was signifi-
The guidelines show that data analyses surrounding phenyl- cantly decreased with dobutamine as a second vasoactive
ephrine use are extremely limited. A systematic review and medication compared with vasopressin after adjusting for
meta-analysis examining differences in outcomes between confounding variables (OR 0.34 [95% CI, 0.14–0.84]). The
vasopressors in septic shock showed no mortality benefit of relative risk of dying was 55.8% lower in patients receiving
norepinephrine over other vasopressors such as phenyleph- dobutamine than in those receiving vasopressin (p<0.001).
rine (Avni 2015). Phenylephrine, though not considered first Although the study’s findings contradict the common clinical
line, can be a useful vasopressor in patients with tachyar- practice of using vasopressin as the second-line vasoactive
rhythmias because it does not increase heart rate. agent when norepinephrine is insufficient to control shock, a
If a clear diagnosis is unavailable by clinical assessment, randomized, prospective trial should corroborate these find-
further hemodynamic assessments of cardiac function (e.g., ings before implementing this into practice.
echocardiography) are recommended to optimize the patient’s A single-center, retrospective cohort study looked at
hemodynamics. Lactate concentrations are used as a surro- patients receiving fixed-dose vasopressin for septic shock
gate marker of tissue perfusion. Lactate concentrations should with other catecholamines (Sacha 2018a). Patients were clas-
therefore be measured and, if elevated by more than 2 sified as responders or nonresponders to vasopressin on the
mmol/L, remeasured in 2–4 hours to guide resuscitation until basis of decreased catecholamine dose requirements and
this value normalizes (Levy 2018). achievement of MAP goal 6 hours after vasopressin initiation.
Responders had lower rates of in-hospital mortality (57%
Choice of Vasoactive Medications vs. 72%, p<0.001) and ICU mortality (50% vs. 68%, p<0.001)
Although norepinephrine is widely regarded as the first- and increased ICU-free days at day 14 (2.3 vs. 1.6, p<0.001).
line vasoactive medication in sepsis, literature continues to Following multivariable analysis, nonmedical ICU location

was associated with increased response (OR 1.7; p=0.0049), preclude or limit the use of angiotensin II in the near future
and elevated lactate concentrations at vasopressin initiation until data on improved clinical outcomes are available or a
was associated with decreased response (OR 0.93; p<0.001). generic version is introduced.
Angiotensin II Weight-Based Dosing and Extremes

As knowledge about vasodilatory shock increases, the search in Body Weight
for optimal medication therapies continues. Angiotensin II Literature has provided no clear answer regarding whether
has sparked interest as a vasoactive medication for distribu- vasopressors should be dosed by weight. The controversy
tive or septic shock. The ATHOS-3 trial evaluated the effects surrounding this clinical question is compounded by patients
of angiotensin II on MAP in patients with vasodilatory shock with extremes in body weight. Because the BMI of a signif-
receiving high doses of catecholamines compared with pla- icant portion of patients falls outside what is considered
cebo. Although lacking in clinically meaningful end points normal, investigating the optimal strategy to dose vasoac-
such as mortality, this trial showed that angiotensin II tive medications in this population could significantly affect
increases mean arterial blood pressure in this population. The patient care.
primary end point of MAP response at hour 3, defined as a MAP A retrospective cohort study that took place in all ICUs
of 75 mm Hg or higher or an increase in MAP from baseline of at the Mayo Clinic in Rochester investigated the effect of
at least 10 mm Hg, was significantly higher in the angiotensin weight-based norepinephrine dosing on patients with sep-
II group than in placebo (69.9% vs. 23.4%, p<0.001). However, tic shock with extremes in body weight (Kotecha 2018). A
only around 30% of patients in the trial had a MAP less than challenge in interpreting this study were the significant dif-
65 mm Hg at baseline. Therefore, these results may be limited ferences in baseline characteristics across the underweight,
in their clinical usefulness. Adverse effects were largely sim- normal weight, and morbidly obese groups. However, the
ilar between the two groups, according to the study results. Charlson Comorbidity Index and SOFA score were similar
There is a warning for an increased risk of thrombotic events across groups. The baseline differences were largely to be
with this medication, with the FDA reporting an incidence expected (e.g., a higher prevalence of diabetes mellitus in
rate of 12.9% compared with 5.1% in placebo group. Because the morbidly obese population). Not surprisingly, the group
of this finding, the FDA recommends prophylactic treatment with obesity had significantly greater total drug exposure.
for blood clots if angiotensin II is used. The expanded sup- In-hospital mortality was inversely related to BMI, giving the
plementary adverse event report from the ATHOS-3 trial also underweight population the highest mortality rate, but this
showed a higher incidence of infections and infestations did not hold true for 1-year mortality. Adjusted univariate and
(30.1% vs. 19%) (Khanna 2017). multivariable predictors showed that norepinephrine expo-
In a post hoc analysis of the ATHOS-3 trial examining sure was an independent predictor of in-hospital and 1-year
patients with AKI treated with RRT at the time of angiotensin mortality. This finding remained after a propensity-matched
II initiation, survival rates through day 28 were higher in the analysis. Overall, increased exposure to norepinephrine was
angiotensin II group than in placebo (53% vs. 30%, p=0.012). associated with increased mortality, length of stay, incidence
Discontinuation rate of RRT by day 7 was higher in the angio- of AKI, and cardiac arrhythmias. The authors concluded that
tensin II group (38% vs. 15%, p=0.007), and MAP response weight-based dosing resulted in higher cumulative norepi-
was achieved in 53% of the angiotensin II group compared nephrine exposure in patients with morbid obesity. Because
with 22% in the placebo group (p=0.001). The authors con- higher norepinephrine doses predicted mortality, prospec-
cluded that these data suggest that patients who develop AKI tive trials comparing weight-based with non–weight-based
requiring RRT in the setting of vasodilatory shock will benefit dosing strategies, particularly in the population with obesity,
from angiotensin II. are needed to further elucidate this subject.
More data are needed to explore exactly where angio- Another retrospective study compared a weight-based
tensin II fits into the treatment algorithm for septic shock. norepinephrine dosing strategy with a historical control
However, currently, data analyses show that angiotensin II of non–weight-based dosing in patients with morbid obe-
can be considered for patients with refractory shock who are sity and septic shock (Vadiei 2017). The primary end point
not responding to other vasoactive medications. The dos- of time to achieving the goal MAP did not significantly differ
ing recommended is 20 ng/kg/minute initially, titrated by between the two groups. Logistic regression analysis iden-
15 ng/kg/minute every 5 minutes to a maximum dose of tified only severity of illness as a predictor for reaching the
80 ng/kg/minute during the first 3 hours of treatment and a goal MAP within 6 hours. Median cumulative norepinephrine
maximum maintenance dose of 40 ng/kg/minute (Lexi-Comp doses were higher in the weight-based dosing group (12.6
OnlineTM). Optimal angiotensin II dosing, effects on microcir- mg vs. 10.5 mg, p=0.04), and time to norepinephrine discon-
culation, clinical outcomes, and efficacy compared with other tinuation was longer in this group (33 hours vs. 27 hours,
vasoactive medications are among the topics that should p=0.03). Although the difference in dose and time to norepi-
be explored in the near future (Antonucci 2017). Pricing may nephrine discontinuation reached statistical significance, the

clinical relevance of these differences is less certain. Adverse discontinuation first remained an independent predictor of
effects, hospital length of stay, and mortality were similar hypotension. Secondary outcomes of time to hypoten-
between groups. Given these findings, the authors suggest sion, hospital length of stay, and ICU mortality did not differ
not pursuing the transition from non–weight-based dosing to between groups. However, the group in whom norepinephrine
weight-based dosing because outcomes did not significantly was discontinued first had a longer ICU length of stay. The
differ and weight-based dosing could increase the cumulative authors concluded that their study contributed to the grow-
exposure and duration of norepinephrine. ing literature stating that discontinuing vasopressin first may
A recent retrospective trial examined the change in MAP 1 result in a higher hypotension rate.
hour after initiating vasopressin in relation to patient weight Another retrospective trial examined 61 patients admit-
(Hodge 2016). For the primary outcome, no correlation was ted to the medical ICU with septic shock who received both
found for change in MAP at 1 hour after vasopressin initiation norepinephrine and vasopressin for hemodynamic support
compared with vasopressin dose in relation to patient weight. (Bissell 2017). The primary outcome, hemodynamic instability,
In the subgroup of patients with a BMI greater than 30 kg/ was defined as hypotension after vasopressor discontinua-
m2, a significantly negative correlation was found between tion (two consecutive MAPs less than 60 mm Hg), fluid bolus
BMI and change in MAP at 6 hours (correlation coefficient administration, greater than a 0.05-mcg/kg/minute increase
r = –0.951, p=0.0009). Linear regression analysis was used to in norepinephrine requirements, or addition of an alternative
account for change in norepinephrine dosing. This analysis vasopressor. Vasopressin was discontinued first in 19 patients,
showed that the vasopressin dose in relation to body weight and norepinephrine was discontinued first in 42 patients.
significantly increased MAP at 1, 6, and 12 hours. The authors Vasopressin discontinuation first resulted in a significantly
concluded that vasopressin dose in relation to body weight higher incidence of hypotension (74% vs. 16.7%, p<0.01). This
did not significantly affect change in MAP at 1 hour before study also suggests that discontinuing vasopressin first is
regression analysis. However, the study raises the question associated with a higher incidence of hemodynamic instability.
of whether fixed-dose vasopressin is adequate for the patient A retrospective cohort study of patients with septic shock
subset with a BMI greater than 30 kg/m2. in medical, surgical, and neuroscience ICUs examined the
These studies raise the concern of risks associated with incidence of hypotension after discontinuing either vaso-
increased cumulative vasopressor exposure. According to pressin or norepinephrine first (Sacha 2018b). The patients
the most recent literature, it seems reasonable to use non– in this study received vasopressin for at least 6 hours in addi-
weight-based dosing strategies for norepinephrine and to be tion to norepinephrine. Vasopressin was discontinued first
cognizant of cumulative exposure if weight-based dosing is in 155 patients, and norepinephrine was discontinued first in
used. More information is needed regarding weight-based 430 patients. Hypotension in the 24 hours after discontinuing
dosing of other catecholamines and the effect of BMI in rela- the first vasopressor occurred at a similar rate between these
tion to fixed-dose vasopressor. groups (55% vs. 50%, p=0.28). After multivariable Cox pro-
portional hazards regression was used to adjust for baseline
Discontinuation Strategies factors, discontinuing vasopressin first was independently
The decision of which vasopressor should be discontinued associated with an increased risk of hypotension, which
first in the recovery phase of septic shock is fairly clini- decreased over time. No differences in outcomes such as
cian-specific. Guidelines offer no insight into this clinical mortality or days alive outside the ICU or hospital were found
question, and data are limited. between the groups. The results of this study are less clear
A retrospective study compared discontinuation strat- than in previously discussed studies and raise the question
egies in critically ill medical patients in the recovery phase of whether incidence of hypotension translates to differences
of septic shock requiring both vasopressin and norepineph- in clinical outcomes.
rine (Hammond 2017). In both the unadjusted and adjusted A prospective, randomized controlled trial evaluated hypo-
analyses, clinically significant hypotension was more likely if tension within 1 hour of discontinuing either vasopressin or
vasopressin was discontinued first. Hospital length of stay norepinephrine in patients with septic shock receiving both
and 28-day mortality did not differ between the groups. of these vasopressors (Jeon 2018). Thirty-eight patients were
A single-center, retrospective chart review examined assigned to have norepinephrine tapered off first, and 40
patients with septic shock receiving both norepinephrine and patients were assigned to have vasopressin tapered off first.
vasopressin for at least 4 hours (Musallam 2018). Comparisons This study was terminated early because of a significantly
were made regarding which vasopressor was discontinued higher incidence of hypotension in the group in whom nor-
first. For the group in which vasopressin was discontinued epinephrine was tapered off first (68.4% vs. 22.5%, p<0.001).
first, significantly higher norepinephrine doses were received. Although the authors concluded that tapering norepinephrine
The primary outcome of hypotension rate was significantly off first may be associated with an increased risk of hypo-
higher in the group for whom vasopressin was discontin- tension, they acknowledged that studies with larger sample
ued first. In univariate and multivariate analysis, vasopressin sizes should confirm these findings.

These studies raise an interesting question that could Steroids
significantly affect patients recovering from septic shock. If hemodynamic stability is achieved with fluid resuscitation
According to this most recent literature, it may be reasonable (with or without vasopressors), intravenous corticosteroids
to discontinue norepinephrine before vasopressin during the are not recommended as a treatment for septic shock.
recovery phase of septic shock. Randomized controlled tri- Intravenous hydrocortisone (200 mg/day) can be considered
als should more definitively answer this question in the future in patients who have not achieved hemodynamic stability
and evaluate the effect of discontinuing vasopressors on with fluid resuscitation plus vasopressors.
clinical outcomes of hypotension. This type of evaluation will A weak recommendation exists to use hydrocortisone for
provide more guidance on optimal vasopressor discontinua- septic shock that is unresponsive to adequate fluid resusci-
tion strategies. tation and vasoactive medications. Evidence of the benefit
associated with steroid use in the population with septic shock
Peripheral Administration is conflicting, and several adverse effects of concern are
Historically, vasoactive medications have been administered associated with steroids, such as hyperglycemia and hyper-
largely through central venous catheters. The reasoning behind natremia (Rhodes 2017).
this is to minimize adverse effects such as extravasation and A recent meta-analysis aimed to categorize steroid use
subsequent tissue injury. A recent single-center retrospective and outcomes in both adults and children with septic shock
chart review documented peripheral administration of vaso- (Gibbison 2017). Although outcomes among the various
active medications and the associated extravasation events types of steroids differed slightly, the authors concluded that
(Lewis 2017). The most common vasopressor to be administered no one glucocorticoid is more likely to reduce mortality or GI
peripherally was norepinephrine, followed by phenylephrine. bleeding than another. Findings suggest that hydrocortisone
Vasopressin, epinephrine, and dopamine were included as well, increases the likelihood of shock reversal compared with pla-
though they were only a very small percentage of the vasopres- cebo or methylprednisolone, which supports the guideline
sor agents administered. The most common administration sites recommendation to use hydrocortisone. Among the limita-
were the forearm and antecubital fossa. Extravasation occurred tions of this analysis is the exclusion of certain outcome
in 4% of patients, equally distributed between norepinephrine and measures because of variability in study definitions. One
phenylephrine. None of these events required administration of such outcome is hyperglycemia, a common and worrisome
antidote or surgical intervention. The median dose of vasopres- adverse effect associated with glucocorticoid use.
sor in norepinephrine equivalents at the time of extravasation An international, double-blind, randomized, placebo-
was 0.11 mcg/kg/minute. The findings of this study suggest that controlled trial investigated the effects of intravenous
extravasation rates are relatively low, even with peripheral admin- hydrocortisone (200 mg/day) compared with placebo in
istration of vasoactive agents. However, if this route is to be used, mechanically ventilated patients with septic shock who had
protocols should be instituted to ensure safe, standardized use. received vasopressor therapy for at least 4 hours (Venkatesh
A case report showed the potential for peripheral adminis- 2018). The primary end point of all-cause mortality at 90 days
tration of low-dose vasopressin to cause skin necrosis (Kahn did not differ between the two groups, nor did 28-day mor-
2002). In this patient, vasopressin was administered by a tality. Secondary end points of time to resolution of shock,
peripheral venous catheter in the patient’s left wrist at a dose time to ICU discharge, incidence of blood transfusions, and
of 0.04 unit/minute for septic shock. After 23 hours of this duration of initial mechanical ventilation were significantly
infusion, the patient developed an area of erythematous skin lower in the hydrocortisone group. However, total days free of
with central necrosis just proximal to the intravenous site. mechanical ventilation, recurrence of shock, time to hospital
Vasopressin was discontinued, the catheter was removed, discharge, rate of recurrent mechanical ventilation, duration
and the necrosis was treated with elevation and warm com- and rate of RRT, and development of new-onset bacteremia or
presses. Twelve hours later, the areas of necrosis expanded, fungemia did not differ between hydrocortisone and placebo.
and bulla formation was noted. The wound was eventually Adverse effects occurred at a higher rate in the hydrocor-
left to heal without requiring skin grafting. However, this tisone group, including hyperglycemia, hypernatremia,
case highlights the potential risks associated with peripheral hypertension, encephalopathy, and myopathy, though the
administration of vasopressin. occurrence rate was relatively low with all of these. This study
Although some data analyses suggest that vasoactive does not show decreased mortality from hydrocortisone use
medications can safely be administered through peripheral as a single agent in this setting. However, hydrocortisone had
intravenous access, there is still a significant risk with this a favorable profile in several of the study’s secondary end
practice and lack of data for certain agents such as angio- points. According to this trial, hydrocortisone may result in
tensin II. Peripheral administration should be reserved for some benefit when used in the subset of patients with septic
when central venous access is not possible, and the lowest shock who require mechanical ventilation.
effective dose should be used until central line access can The APROCCHSS study, a prospective, multicenter, double-
be obtained. blind, placebo-controlled, trial, examined the effects of

hydrocortisone (50 mg intravenously every 6 hours) plus Vitamin C, Hydrocortisone, and Thiamine
fludrocortisone (50 mcg orally daily) on mortality rates, Vitamin C modulates inflammation caused by sepsis in animal
among other end points, in adults with septic shock who models. Because of this, interest has developed in using this
had received vasopressor therapy for at least 6 hours therapy in human patients with sepsis. A randomized, dou-
(Annane 2018). Significantly improved outcomes in the ble-blind, placebo-controlled phase I trial examined the effect
steroid group included the primary end point of all-cause of intravenous ascorbic acid on SOFA scores and CRP, pro-
mortality at 90 days (43% vs. 49%, p=0.03) and the second- calcitonin, and thrombomodulin concentrations in patients
ary end points of death at ICU discharge, death at hospital with sepsis (Fowler 2014). The study deemed the treatment
discharge, death at 180 days, vasopressor-free days, and safe, as evidenced by a lack of adverse events in patients
organ failure–free days. Outcomes that did not differ who received ascorbic acid. Reductions occurred in SOFA
between groups included death at 28 days, decision to scores, CRP, and procalcitonin, as did lack of a rise in throm-
withhold or withdraw active treatment by day 90, and ven- bomodulin compared with the placebo group. The authors
tilator-free days. The total number of adverse events did concluded that vitamin C therapy may attenuate inflamma-
not significantly differ, nor did the incidence of GI bleed- tion in patients with sepsis. This study was small, including
ing or superinfection. However, the hyperglycemia risk was only 24 patients, and did not examine clinical outcomes.
significantly higher in the steroid group (RR 1.07; 95% CI, However, the study generated more interest in ascorbic acid
1.03–1.12; p=0.002). The findings of this study suggest that as an adjuvant treatment option in sepsis.
the combination of hydrocortisone and fludrocortisone Another randomized, double-blind trial compared the effect
in adults with septic shock who do not respond to initial of intravenous ascorbic acid with placebo on vasopressor dose
resuscitation measures improves mortality and patient in patients with septic shock (Zabet 2016). The mean dose of
outcomes. Adding fludrocortisone to the commonly used norepinephrine was 7.44 mcg/kg/minute in the ascorbic acid
hydrocortisone regimen may account for the positive group compared with 13.79 mcg/kg/minute in the placebo
results, but more data analyses are needed to confirm this. group (p=0.004), and the norepinephrine infusion duration was
The patient population examined in this trial matches the lower in the ascorbic acid group (49.64 hours vs. 71.57 hours,
population the guidelines describe as potentially benefit- p=0.007). The study also showed a significantly lower inci-
ing from the addition of glucocorticoid therapy, reinforcing dence in 28-day mortality in the ascorbic acid group compared
the current recommendation. with placebo (14.28% vs. 64.28%, p=0.009). This study was
Interest has been expressed in using glucocorticoids also small, including only 28 patients, and had a short interven-
to prevent septic shock. The HYPRESS trial was a multi- tion period. Although the results seem promising, they must be
center, placebo-controlled, double-blind, randomized study interpreted with caution, given the study’s limitations.
in Germany that examined patients with evidence of sepsis One sepsis trial that gained the most attention in recent
and organ dysfunction (Keh 2016). Patients were random- years was the retrospective before-and-after study exam-
ized to either receive placebo or a hydrocortisone bolus and ining the use of vitamin C, hydrocortisone, and thiamine in
an 11-day tapered continuous infusion regimen. The primary sepsis and septic shock (Marik 2017). The regimen used con-
end point, development of septic shock within 14 days, did sisted of hydrocortisone 50 mg intravenously every 6 hours
not significantly differ between the two groups. Secondary for 7 days or until ICU discharge, followed by a 3-day taper,
end points of 28-day, 90-day, 180-day, ICU, or hospital vitamin C 1.6 g intravenously every 6 hours for 4 days or until
all-cause mortality, ICU or hospital length of stay, and venti- ICU discharge, and thiamine 200 mg intravenously every
lation- or renal replacement-free days did not differ between 12 hours for 4 days or until ICU discharge. Although this was
the two treatment arms. However, the incidence of hyper- a small (n=94) retrospective study, the results were seem-
glycemia was significantly increased in the hydrocortisone ingly impressive, with a significant difference in hospital
group. Total insulin administration, secondary infections, mortality (8.5% in intervention arm vs. 40.4% in control group,
and hypernatremia did not differ between the groups. The p<0.001). Duration of vasopressor therapy, need for RRT for
findings of this study do not support using hydrocortisone to AKI, change in SOFA score, and procalcitonin clearance were
prevent septic shock. all statistically improved in the intervention group, whereas
Although the topic of steroid use in sepsis and septic ICU length of stay did not differ. The authors concluded that
shock is still controversial, no clear mortality benefit has con- the cocktail of vitamin C, thiamine, and hydrocortisone is safe
sistently been shown in the literature, and data analyses for and may prevent organ dysfunction and reduce mortality in
improving other outcomes are mixed. Therefore, it is reason- patients with sepsis and septic shock.
able to continue following guideline recommendations to use A major limitation of this study is the before-and-after
hydrocortisone in the face of septic shock that is unrespon- design, which prohibits the study from proving causality. The
sive to adequate fluid resuscitation and vasopressor therapy, single-center nature of the study as well as the smaller pop-
but its use should not be prioritized. ulation size also limit the ability to generalize these results.

Several confounding factors existed, such as the control and INFECTION MANAGEMENT
treatment periods being in different seasons, which may have Timing of Therapy
influenced the results. Similarly, several potential confound-
Empiric, broad-spectrum intravenous antimicrobials should
ers were not discussed. Despite the authors’ conclusion that
be initiated as soon as possible after recognition, ideally after
the combination of vitamin C, thiamine, and hydrocortisone
collection of blood cultures and other cultures, and within 1
is safe in this setting, more data are needed to determine
hour for both sepsis and septic shock according to the current
whether this treatment is truly without risk. Although this
guidelines with moderate evidence (Levy 2018). Initially, one
study certainly generates hypotheses and questions about
study showed an average 7.6% decrease in survival rate per
using vitamin C, thiamine, and hydrocortisone in sepsis,
every 1-hour delay in antibiotic administration (Kumar 2006).
well-designed, randomized, controlled trials should confirm
Another study later confirmed a similar mortality benefit
these findings before the practice is routinely used. Several
from early administration of antibiotics in a larger population
studies examining the role of vitamin C, thiamine, and hydro-
(Ferrer 2014). Even though a meta-analysis showed no mor-
cortisone in sepsis may shed light on this relatively new area
tality benefit, because of the methodological limitation of the
of interest.
analysis (including low quality studies), a 1-hour antibiotic
administration time is considered as a reasonable target.
ß-Blocker Use in Sepsis
The SSC guidelines advocate broad-spectrum intravenous
A novel potential treatment option in sepsis, β-blockers, has
antibiotics within the first hour of identifying sepsis and sep-
sparked a lot of interest in recent years. The foundation for
tic shock. Although the literature has shown the benefits of
using β-blockers in sepsis and septic shock is the thought that
administering appropriate antimicrobial therapy as quickly as
there may be inappropriate activation of the sympathetic ner-
possible in sepsis, this still represents a logistical obstacle in
vous system in sepsis, causing harmful effects. An association
most institutions (Rhodes 2017).
between high sympathetic stress and sepsis-induced myo-
A recent retrospective analysis with a historic control
cardial depression has been a growing area of interest in the
investigated compliance with SSC recommendations for the
literature, suggesting that heart rate control and modulation of
timing of antimicrobial therapy after implementing a combi-
these effects by β-blockers are beneficial. The concern is that
nation antibiotic bag (Lorenzo 2018). The primary end point
an excess of β-blockers may cause low cardiac output because
of proportion of patients receiving at least two antibiotics
of negative inotropic and chronotropic properties. Recent liter-
and 30 mL/kg of crystalloid fluid challenge within 3 hours
ature has investigated this therapy not only in sepsis, but also
after ED admission was 2.32 (95% CI, 1.67–3.23) times more
in other high-stress disease states such as trauma, burns, and
likely in the intervention group than in the historical control
traumatic brain injury. Although this chapter focuses on outlin-
group. These results remained significant when the end point
ing the most recent literature, Table 2 provides an overview of
was broken into individual components. The combination
studies examining β-blockade therapy in sepsis.
bag in this study contained both cefepime and vancomycin.
A prospective trial in China investigated the effects of esm-
According to these findings, it may be reasonable to consider
olol, a bolus dose and then an intravenous infusion titrated to
using the combination bag to decrease the time to antibiotic
a goal heart rate of 10%–15% less than baseline, on various
administration in patients with sepsis. However, prospective
hemodynamic parameters in patients with septic shock (Du
trials are needed to confirm the benefit.
2016). Significant findings after esmolol initiation included
The importance of prompt antibiotic administration was
decreased lactate concentrations, increased stroke volume,
highlighted in a retrospective analysis of data collected pro-
decreased heart rate, decreased cardiac output, increased
spectively for the SSC (Ferrer 2014). The study examined
left ventricular end diastolic volume, and increased CVP.
17,990 patients who received antibiotics after sepsis identi-
Although this study did not examine clinical outcomes, the
fication. A statistically significant increase in probability of
evidence suggests that adding a β-blocker in patients with
death occurred for each hour that antibiotic administration
sepsis can increase stroke volume and, despite decreasing
was delayed. These results reinforce that delaying antibiotics
cardiac output, avoid decreasing tissue perfusion.
in patients with sepsis is associated with an increased risk of
The guidelines have not yet made any recommendations
mortality.
regarding β-blocker use in septic shock. Although prelimi-
nary studies show a potential benefit of β-blocker therapy
on hemodynamic parameters, large, well-designed random- Antimicrobial Therapy
ized controlled trials are needed to fully show the role of In patients with a severe inflammatory state of noninfec-
β-blockers in septic shock. Practitioners may consider using tious origin, prophylactic systemic antimicrobials are not
β-blockers in patients with septic shock with tachycardia and recommended. Historically, prophylactic antibiotic therapy
high cardiac output. However, data are insufficient to rou- was administered in some situations (e.g., severe necrotizing
tinely recommend β-blocker therapy. pancreatitis, severe burns). However, meta-analyses show

Table 2. Studies of β-Blocker Use in Sepsis
Design and
Study Population Intervention Results Conclusion
Wang 2015 Prospective, Control (C) HR lower in ME group at 12 hr ME may improve cardiac function and
randomized study of Milronone (M) Higher survival rate at 28 days in ME group 28-day survival in severe sepsis
patients with severe Milrinone + esmolol (ME vs. M, p=0.02, ME vs. C, p=0.001)
sepsis (n=90) (ME)
Yang 2014 Prospective, Control Decreased HR (93 vs. 118 beats/min; p<0.05 and β-Blockade may improve cardiac function
[abstract] randomized study of Esmolol (to ↓ HR < cardiac index (3.3 vs. 4.5 L/in/m2; p<0.05) in without decreasing circulation and tissue
patients with septic 100 beats/min within treatment group perfusion
shock (n=41) 2 hr) Increased SVR index (159.2 vs. 130.5; p<0.05)

and global end diastolic volume index (668 vs.
588 mL/m2; p<0.01) in treatment group
Morelli 2013 Open-label, Control Lower HR in esmolol group (p<0.001) Esmolol decreased HR without adverse
randomized, phase II Esmolol infusion Lower NE requirements in esmolol group (p<0.01) effects in patients with septic shock
study of patients with (titrated to HR Increased SV (p=0.03), SVR (p<0.001), and LV stroke Observed decreases in mortality warrant
22
septic shock (n=154) 80–94 beats/min) work (p=0.03) in esmolol group further investigation
Decreased fluid requirements in esmolol group
(p<0.001)
Decreased arterial lactate concentrations in esmolol
group (p=0.006)
Decrease 28-day, ICU, and hospital mortality in
esmolol group (p<0.001)
Balik 2012 Prospective, open-label Esmolol bolus; then Decrease in HR (142 vs. 112 beats/min, p<0.001) and Lowering HR with esmolol did not result in
[abstract] study of patients with continuous infusion cardiac index (4.94 vs. 4.35 L/min/m2, p=NS) adverse events
septic shock with Increase in SV (67.1 vs. 72.9, p=NS) Use of a β-blocker may be safe and
tachycardia (n=10) No change in lactate or NE requirements cardioprotective in patients with septic
shock with high cardiac output
HR = heart rate; LV = left ventricular; NE = norepinephrine; SV = stroke volume; SVR = systemic vascular resistance.
Information from: Wang Z, Wu Q, Nie X, et al. Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial.
Clin Drug Investig 2015;35:707-16; Yang S, Liu Z, Yang W, et al. Effects of the β -blockers on cardiac protection and hemodynamics in patients with septic shock: a prospective
study. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014;26:714-7; Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical
outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013;310:1683-91; and Balik M, Rulisek J, Leden P, et al. Concomitant use of beta-1 adrenoreceptor
blocker and norepinephrine in patients with septic shock. Wien Klin Wochenschr 2012;124:552-6.
Sepsis Management
no benefit from prophylactic antibiotics (Barajas-Nava 2013; compared with other methods such as clinical judgment and
Working Group IAP/APA 2013; Wittau 2011; Avni 2010). other infection markers (Andriolo 2017). No differences in
For optimal antimicrobial dosing strategies, mortality, mechanical ventilation, reinfection, or antimicro-
pharmacokinetic and pharmacodynamic principles and bial therapy duration occurred between the procalcitonin and
specific drug properties should be considered (Rhodes non-procalcitonin groups.
2017). β-Lactams will have a benefit with more frequent The SISPCT trial, a multicenter, randomized, placebo-
dosing or prolonged infusion because they target an f T> MIC controlled trial examining the effect of sodium selenite on
of at least 50 for penicillins, 50–70 for cephalosporins, and outcomes in patients with sepsis as well as the effect of
30–40 for carbapenems (Connors 2013). Aminoglycosides procalcitonin-guided therapy compared with therapy with-
are representative concentration-dependent antibiotics and out procalcitonin guidance, found no difference in 28-day
target an fCpeak/MIC of at least 10–12. Fluoroquinolones are mortality or frequency or diagnostic or therapeutic proce-
also concentration-dependent antibiotics, but they target an dures. However, the study found a statistically significant
fAUC/MIC of greater than 125 for gram-negatives and greater 4.5% reduction in antimicrobial exposure in the procalci-
than 30–50 for gram-positives (Connors 2013). Vancomycin tonin-guided group (Bloos 2016).
therapy requires monitoring of trough concentrations A multicenter, prospective, randomized, controlled, open-
that target 15–20 mg/L. With increasing methicillin- label trial in the Netherlands, the SAPS trial, compared anti-
resistant Staphylococcus aureus MICs to vancomycin, fAUC/ biotic discontinuation on the basis of standard of care with
MIC greater than 400 is the target pharmacodynamic goal that of procalcitonin guidance (de Jong 2016). The procal-
for better clinical outcomes (Connors 2013). citonin group (n=761) had significantly fewer antibiotics, as
Empiric broad-spectrum therapy with one or more antimi- defined by daily doses, as well as significantly lower dura-
crobials is recommended to cover all likely pathogens (Box 3). tions of antibiotic therapy than the standard-of-care group
Especially in patients with septic shock, empiric combination (n=785). This reduction in antibiotic use occurred without an
antibiotic therapy is recommended to target the most likely increase in 28-day mortality (19.6% in the procalcitonin group
pathogen(s). However, combination therapy should not be vs. 25% in the standard-of-care group) or mortality at 1 year
routinely used if multidrug-resistant pathogens are not sus- after randomization (34.8% in the procalcitonin group vs.
pected. Empiric antimicrobial therapy should be narrowed 40.9% in the standard-of-care group). The authors concluded
once pathogen identification and sensitivities are available that adding procalcitonin-guided therapy to clinical judgment
and/or adequate clinical improvement is noted. An antimicro- may decrease antibiotic consumption without increasing
bial treatment of 7–10 days is adequate for most infections mortality.
associated with sepsis and septic shock (Box 3). Another multicenter, randomized controlled trial, the
Daily assessment for de-escalation of antimicrobial ther- ProACT study, examined the effect of using procalcitonin
apy is recommended in patients with sepsis and septic shock. to guide antibiotic therapy compared with usual care
(Huang 2018). This study included 1656 patients with lower
Procalcitonin respiratory tract infections across 14 U.S. hospitals. No
The benefits of using procalcitonin to guide antimicrobial difference was shown in antibiotic-days (4.2 days in pro-
therapy in sepsis are still uncertain. A Cochrane review exam- calcitonin group vs. 4.3 days in usual care, p=0.87). The
ined outcomes when procalcitonin was used to guide therapy authors concluded that using procalcitonin to guide anti-
biotic therapy did not decrease antibiotic exposure in this
population.
Although some data analyses suggest that procalci-
Box 3. Patient Characteristics to
tonin-guided antibiotic therapy can decrease antibiotic
Differentiate Antimicrobial Therapy
exposure, large, randomized controlled trials are needed to
Duration
better understand its usefulness in sepsis and septic shock.
Longer therapy duration (> 10 days)
There are also limitations to using procalcitonin as a marker
• Slow clinical response for sepsis. One such limitation is that procalcitonin may be
• Immunologic deficiencies
elevated in conditions outside bacterial infections, such as
• S. aureus bacteremia
• Fungal and viral infections (e.g., Candida, Aspergillus, severe trauma or surgery (Lee 2013).
influenza virus) Procalcitonin concentrations can be measured to support
• Undrainable foci of infection shortening the antimicrobial therapy duration in patients with
Shorter therapy duration (≤ 10 days) sepsis (Rhodes 2017). However, this is a weak guideline rec-
• Rapid clinical resolution after effective source control ommendation, and procalcitonin concentrations should be
(i.e., intra-abdominal infection or UTI) used in conjunction with the patient’s clinical assessment.
• Uncomplicated pyelonephritis

Patient Care Scenario
A 68-year-old woman has a medical history of heart fail-
ure with reduced ejection fraction and type 2 diabetes. Vital Signs Laboratory Values
She was admitted to the medical floor 2 days ago after • Temperature 100.9°F • WBC 14.2 x 103 cells/mm3
a hip replacement surgery. She refuses to participate in • BP 94/52 mm Hg • Plt 160,000/mm3
the recommended physical therapy while in the hospital (MAP 66 mm Hg) • SCr 1.3 mg/dL
and has declined incentive spirometry several times. The • HR 108 beats/min • Total bilirubin 0.8 mg/dL
patient was seen in a clinic for a routine checkup 1 week • Respiratory rate • Weight 50 kg
before hospital admission. At that time, she had normal 18 breaths/min
mental status, and her baseline vital signs and laboratory • Sao2 96% on room air
values were as follows:
How would you classify this patient at this time? What
Vital Signs Laboratory Values factors did you consider to arrive at this classification? What
is the best treatment course for the patient at this time?
• Temperature 98.6°F • WBC 8.2 x 103 cells/mm3 Broad-spectrum empiric antibiotic therapy is adminis-
• Blood pressure (BP) • Plt 172,000/mm3 tered for suspected pneumonia, and the patient is given a
106/64 mm Hg • SCr 1.0 mg/dL 1500-mL bolus of normal saline. However, 8 hours later,
(MAP 78 mm Hg) • Total bilirubin 0.6 mg/dL the patient’s respiratory and hemodynamic status wors-
• HR 86 beats/min • Weight 50 kg ens, and repeat laboratory values are obtained. The patient
• Respiratory rate 14 is intubated because of hypoxic respiratory failure.
breaths/min
• Sao2 98% on room air Vital Signs Laboratory Values
On hospital day 3, the patient has shortness of breath, • Temperature 101.1°F • WBC 15.4 x 103 cells/mm3
and chest radiography reveals diffuse patchy infiltrates • BP 86/48 mm Hg • Plt 142,000/mm3
in the left lower lobe. The nurse states the patient has (MAP 61 mm Hg) • SCr 1.6 mg/dL
seemed confused at times. During rounds, the team eval- • HR 112 beats/min • Total bilirubin 1.2 mg/dL
uates the patient through a clinical examination and • Respiratory rate 20 • Lactate 4.2 mmol/L
objective laboratory data. The resident finds that the breaths/min
patient’s GCS score is 14. • Fio22 70%
What is best to recommend for the patient, given the

changes in her status?
ANSWER
At first, the patient would be classified as having sepsis. goal. Because of the patient’s history of heart failure, a
Patients with suspected infection should be monitored decreased amount of fluid could be administered for the
with the qSOFA score for the possibility of developing initial bolus to avoid volume overload.
sepsis. In this case, the patient has two criteria from the After the patient’s status worsened, she would be
qSOFA score (altered mental status and hypotension on classified as having septic shock because of her lac-
the basis of systolic blood pressure) and should therefore tate concentration and persistently low MAP. At this
be evaluated using the SOFA score. Her baseline SOFA time, using a dynamic measure of volume status (e.g.,
score at the clinic visit was zero. The patient’s SOFA score PLR) would best determine whether she is fluid respon-
on hospital day 3 is 3 (MAP less than 70 mm Hg = 1 point, sive and could help avoid volume overload. Vasopressor
GCS score of 14 = 1 point, SCr of 1.3 mg/dL = 1 point), therapy should be initiated on the basis of the decreased
which indicates sepsis. The 1-hour bundle would cur- MAP. Norepinephrine would be first line for this patient.
rently be appropriate for the patient. This would include If the patient’s MAP did not improve after adding nor-
administering fluid with a crystalloid, obtaining cul- epinephrine, second-line options such as vasopressin
tures, measuring lactate concentrations, administering could be considered as well as hydrocortisone with
broad-spectrum antibiotics, and providing vasopressor fludrocortisone.
therapy if fluid administration does not maintain the MAP
1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3).
JAMA 2016;315:801-10.
2. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic
shock: 2016. Crit Care Med 2017;45:486-552.

OTHER THERAPIES Sedation
According to the 2018 PADIS guidelines, non-benzodiazepine
Transfusions
agents are first line for sedation in mechanically ventilated
Red blood cell transfusion is recommended only in patients
adults. However, patient-specific characteristics, including
with an Hgb of less than 7 g/dL in the absence of severe
disease states such as septic shock, should also be con-
hypoxemia, myocardial ischemia, or acute hemorrhage.
sidered (Devlin 2018). The SSC guidelines make no detailed
Erythropoietin is not recommended for the treatment of ane-
recommendations regarding which sedative agents to use
mia caused by sepsis. In the absence of bleeding or a planned
but state that non-benzodiazepine agents may result in bet-
invasive procedure, fresh frozen plasma is not recommended
ter outcomes than benzodiazepines (Rhodes 2017). Recent
to correct clotting abnormalities in patients with sepsis or
literature has tried to elucidate which sedative agents may
septic shock.
offer the most benefit in patients with sepsis, focusing mainly
on dexmedetomidine.
Bicarbonate
The DESIRE study was a multicenter, open-label, random-
In patients with hypoperfusion-induced lactic acidemia with
ized clinical trial conducted in Japan assessing the effects
a pH of 7.15 or greater, sodium bicarbonate therapy is not rec-
of dexmedetomidine sedation on patients with sepsis requir-
ommended for improving hemodynamic status or reducing
ing mechanical ventilation for more than 24 hours (Kawazoe
vasopressor needs.
2017). The intervention arm consisted of patients receiving
sedation with dexmedetomidine (n=100) and other seda-
Acetylcysteine
tives, as necessary, and the control arm consisted of patients
Acetylcysteine has anti-inflammatory and antioxidant prop-
receiving treatment with sedatives other than dexmedetomi-
erties that could theoretically benefit patients with sepsis.
dine (n=101). For the co-primary end points of 28-day mortality
Acetylcysteine also has data analyses supporting that it has
and ventilator-free days, the intervention and control arms
vasodilatory properties that may improve microcirculation.
did not differ. Median length of ICU stay, delirium-free days,
A recent review of pooled data on acetylcysteine in sepsis
and frequency and doses of fentanyl did not significantly dif-
showed that although acetylcysteine has been investigated
fer between groups. Rate of well-controlled sedation during
as an adjunctive therapy for sepsis, the results suggesting
ICU stay, as defined by a Richmond Agitation-Sedation
benefit are inconsistent (Chertoff 2018). Benefits through-
Scale (RASS) score of -3 to +1, was significantly higher in
out the review included improvements in regional blood flow,
the dexmedetomidine group, and the frequency and doses of
reductions in lactic acidosis, and reductions in mortality.
propofol and midazolam were significantly lower in the dex-
However, larger randomized controlled trials need to investi-
medetomidine group. Within the subgroup that had APACHE
gate and prove benefit before acetylcysteine therapy can gain
II (Acute Physiology and Chronic Health Evaluation II) scores
popularity.
of 23 or higher, mortality was significantly lower in the dex-
medetomidine group. Bradycardia was more common in the
SUPPORTIVE MANAGEMENT dexmedetomidine group. No data were provided on the type
or amount of other sedatives used in the dexmedetomidine
Pain Management and Sedation
group. The authors concluded that dexmedetomidine in this
Pain Management patient population did not significantly reduce mortality or
The 2018 guidelines for preventing and managing pain, agi- ventilator-free days, but may have better controlled sedation.
tation/sedation, delirium, immobility, and sleep disruption in The authors also noted that the study may have been under-
adult patients in the ICU, or PADIS guidelines, do not specifi- powered to detect differences in mortality; therefore, further
cally address patients with sepsis. However, they recommend research should evaluate these clinical outcomes.
regular pain assessment in critically ill adults and use of A prospective, open-label, crossover study evaluated 38
clinical judgment to balance the risk of negative outcomes patients with septic shock requiring norepinephrine to main-
associated with pain and potential negative effects of opioid tain adequate MAP and requiring deep sedation (RASS score
exposure (Devlin 2018). between -3 and -4) with propofol and remifentanil (Morelli
A retrospective cohort study at two academic medical cen- 2019). Hemodynamic measurements, norepinephrine doses,
ters examined whether acetaminophen use in sepsis might and depth of sedation were all measured while patients were
attenuate the risk of developing AKI (Patanwala 2018). Interest receiving propofol. These parameters were measured again 4
in this topic developed because of data analyses showing hours after changing to dexmedetomidine instead of propofol
that acetaminophen inhibits lipid peroxidation (Boutaud and then a third time 8 hours after changing back to propofol.
2010). Acute kidney injury developed in 16.4% of patients in The norepinephrine dose decreased from 0.69 plus or minus
the acetaminophen group and 19.8% of the patients in the 0.72 mcg/kg/minute to 0.30 plus or minus 0.25 mcg/kg/min-
non-acetaminophen group, a nonstatistically significant dif- ute when propofol was changed to dexmedetomidine and then
ference (Patanwala 2018). increased to 0.42 plus or minus 0.36 mcg/kg/minute when

sedation was changed back to propofol (p<0.005). The propo- including whether nutritional intake should be more closely
fol and remifentanil doses remained unchanged before and matched to expenditure.
after dexmedetomidine infusion. The authors concluded that Many questions remain regarding best nutritional prac-
changing from propofol to dexmedetomidine reduced norepi- tices in patients with sepsis and septic shock, but the current
nephrine requirements. A limitation of this trial is that a light literature suggests that initiating early EN in this population,
level of sedation (RASS score of -2 to 0) is typically desired assuming adequate fluid resuscitation and relative hemody-
in most patients. Therefore, the propofol dose, and thus the namic stability, is safe and may be beneficial.
catecholamine requirements, may have been increased in this
study. VTE Prophylaxis
Although non-benzodiazepine agents are reasonable for Critically ill patients with sepsis are at an increased risk of
sedation whenever possible, further studies investigating venous thromboembolism (VTE). Chemoprophylaxis should
sedative agents specifically in sepsis may provide better be considered for patients without a contraindication to ther-
information regarding optimal treatment regimens. Trials apy. However, patient subsets with sepsis may still be at risk
comparing propofol alone with dexmedetomidine alone or of VTE, despite appropriate chemoprophylaxis. The guide-
with midazolam alone would add to the literature. lines recommend both chemoprophylaxis and mechanical
VTE prophylaxis, when possible. However, this is a weak rec-
Nutrition ommendation with low-quality evidence (Rhodes 2017).
Enteral nutrition (EN) is recommended as soon as feasible in A retrospective study to identify the rate of VTE chemo-
critically ill patients with sepsis or septic shock. Early par- prophylaxis failure in critically ill patients with sepsis (Hanify
enteral nutrition alone or parenteral nutrition in combination 2017) showed that the rate of VTE development despite hep-
with enteral feedings is not recommended in patients who arin or enoxaparin therapy for prophylaxis was 12.5%. Acute
can be fed enterally. In patients who cannot be fed enterally, respiratory distress syndrome and higher positive end-expi-
parenteral nutrition alone or in combination with enteral feed- ratory pressure (10 vs. 8 cm H2O) were both associated with
ings is not recommended over the first 7 days. Monitoring an increased risk of VTE prophylaxis failure. This study also
of gastric residual volumes is not routinely recommended showed that VTE development was associated with increased
in critically ill patients with sepsis or septic shock. Only in ICU and hospital length of stay. This study highlights the need
patients with feeding intolerance or at high risk of aspiration to identify patients who may be at an increased risk of VTE
should gastric residuals be measured and prokinetic agents prophylaxis failure and consider additional measures such as
considered (Rhodes 2017; McClave 2016). sequential compression devices.
The ASPEN guidelines currently recommend that EN be
initiated within 24–48 hours after the diagnosis of severe Stress Ulcer Prophylaxis
sepsis or septic shock, provided resuscitation has been com- The current guidelines recommend that critically ill patients
pleted and the patient is hemodynamically stable. Data are with sepsis with bleed risks should receive stress ulcer pro-
lacking to compare early EN with delayed EN in patients with phylaxis (SUP). However, literature is limited evaluating the
sepsis. However, benefit is expected with this practice, given risk-benefit of this practice. Given the recent concerns with
the GI dysfunction rates and hypermetabolism in sepsis SUP therapy such as increased risk of hospital-acquired pneu-
(McClave 2016). monia and Clostridium difficile infection, this issue should be
A single-center retrospective review of adult patients with explored in the setting of sepsis.
septic shock investigated the tolerance of EN in the set- A prospective, double-blind, placebo-controlled, random-
ting of vasopressor use (Merchan 2017). In this study, 62% ized trial compared intravenous pantoprazole with early EN as
of patients tolerated EN, and the most common reason for SUP in mechanically ventilated patients (El-Kersh 2018). This
intolerance was gastric residual volumes greater than 250 study included 102 patients in the final analysis. One patient
mL. Those who received EN within 48 hours and had norepi- from each group had overt GI bleeding, yielding an overall
nephrine-equivalent doses of 0.14 mcg/kg/minute or less incidence of 1.96% and no statistically significant difference
were more likely to tolerate EN, by multivariate analysis. The in this end point between groups (p=0.99). The authors con-
authors concluded that EN may be safe and well tolerated in cluded that pantoprazole offers no benefit for preventing GI
patients with septic shock after adequate fluid resuscitation bleeding when added to early EN in mechanically ventilated
and for those with lower vasopressor requirements. patients.
A small observational study used indirect calorimetry to Another randomized clinical trial compared intrave-
measure the energy expenditure of patients during and after nous pantoprazole with placebo in mechanically ventilated
mechanical ventilation (Lee 2017). The principal finding of patients (Alhazzani 2017). Upper GI bleeding developed
this study was that energy expenditure was higher during in 6.1% of patients in the pantoprazole group and 4.8% of
mechanical ventilation than afterward. This study poses patients in the placebo group (p=1.0). The incidence of ven-
several interesting questions that necessitate further study, tilator-associated pneumonia was insignificantly lower in the

placebo group (20.4% vs. 14.3%, p=0.58), as was the incidence One study showed the impact of a clinical pharmacist in
of C. difficile infection (4.1% vs. 2.4%, p=1.0). The authors con- the ED on shortening the time to administration and on more
cluded that larger studies should examine the feasibility of appropriate intravenous antibiotics in sepsis (Moussavi 2016).
withholding SUP in this population. Time to antibiotic administration was significantly shorter
A retrospective study in Japan compared patients with when a pharmacist was present than when a pharmacist was
severe sepsis who received SUP within 2 days of admis- not present (0.61 vs. 0.88 hours, p=0.001). However, ED clini-
sion with patients who did not receive SUP using propensity cal pharmacists did not significantly change ICU length of stay,
matching (Sasabuchi 2016). Gastrointestinal bleeding requir- hospital length of stay, ventilator-days, or in-hospital mortality.
ing endoscopic hemostasis, 30-day mortality, and incidence A small retrospective study observed the successful
of C. difficile infection did not significantly differ between the selection of antimicrobial therapy before and after phar-
two groups. However, the proportion of patients with hos- macist intervention, time to administration of antimicrobial
pital-acquired pneumonia was significantly higher in the therapy, and time to appropriate antimicrobial administra-
group that received SUP. The authors concluded that SUP tion in a cohort of patients with septic shock (Laine 2018).
may be unnecessary in this patient population, given these Results showed that the percentage of patients with success-
findings. ful selection of antimicrobial therapy significantly increased
A multicenter, parallel-group, blinded trial examined the with pharmacist intervention from 66% to 80% (p=0.04). The
effect of daily intravenous pantoprazole at a dose of 40 mg study also showed significantly decreased time to appro-
on various outcomes compared with placebo (Krag 2018). priate antimicrobial therapy with pharmacist intervention in
The primary outcome was 90-day mortality. Secondary end patients without initial successful selection of antimicrobial
points included clinically important ICU events, defined as therapy. The authors concluded that pharmacist involvement
clinically important GI bleeding, new-onset pneumonia, C. dif- can improve successful selection of antimicrobial therapy,
ficile infection, or acute myocardial ischemia. Around 20% of facilitate rapid administration, and improve surrogate out-
patients in each group had a coagulopathy, and around 80% comes for mortality in septic shock.
of patients in each group required mechanical ventilation. A review of pharmacist impact on various aspects of sepsis
The primary end points of 90-day mortality occurred in 31.1% management when pharmacists were part of a multidisci-
of the pantoprazole group and 30.4% of the placebo group plinary team ultimately showed decreased time to antibiotic
(p=0.76). These results did not significantly differ after adjust- administration, decreased mortality (by 4.8%), significantly
ment for baseline characteristics. In the treatment group, decreased overall health care costs (around $225,000,000
21.9% of patients had one or more clinically important event billing costs, $3,345,000 in drug charges, and $23,295,000 in
compared with 22.6% in the placebo group (RR 0.96; 95% CI, laboratory charges), and increased appropriate medication
0.83–1.11). Episodes of clinically important GI bleeding did selection (Cavanaugh 2017). Identified pharmacists’ roles
not significantly differ between groups, nor did the incidence included ordering new antibiotics, verifying orders, expediting
of serious adverse events. The authors concluded that panto- preparation or delivery processes, ordering antibiotics on the
prazole did not significantly change patient outcomes. basis of the order set, assessing antibiotic appropriateness,
Although data for SUP in this population are limited, facilitating vasopressor preparation, recommending doses or
risk-benefit should be weighed before routinely using medica- appropriate antibiotics, providing daily ICU patient care rounds,
tions for this purpose. The findings of the studies mentioned and being a medical response team and bedside response.
earlier suggest that routine use of SUP is unnecessary in Although not specific to pharmacy, a time-series analysis
patients with sepsis. Careful consideration should be used found bundle compliance before and after various interventions
when deciding whether to use SUP in patients with sepsis (Grek 2017). One such intervention was the implementation of
rather than simply using it in every patient. a multidisciplinary sepsis and shock response team, which
included a pharmacist. This team was called once patients were
determined to have severe sepsis or septic shock and aimed to
ROLE OF THE PHARMACIST evaluate them within 15 minutes to ensure bundle compliance.
Pharmacists can positively influence patient care in patients Among the ED admissions, in particular, mortality caused by
with sepsis because of their extensive knowledge of the med- sepsis or septic was reduced by implementing this team.
ications used in this disease state. This been supported by The literature advocates developing and implementing mul-
several studies and reviews that show the benefit of pharma- tidisciplinary teams to manage complex disease states such
cist involvement in patient care. as sepsis and septic shock. Each discipline can offer unique
In 2013, authors identified the role of an ED clinical phar- perspectives and benefits to patient care and outcomes.
macist in sepsis management (Weant 2013). Of the 585 Pharmacists are a great resource in sepsis management with
consultations performed for 130 patients, the most common development of guidelines/protocols, appropriate identifica-
consultations provided were dosing recommendations (53%) tion/dosing, improved time to antibiotics/vasopressors, and
and optimizing the empiric antibiotic management (22%). antibiotic de-escalation.

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Practice Points
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Self-Assessment Questions
Questions 1–3 pertain to the following case. C. Septic shock on the basis of signs of organ
M.R., a 43-year-old woman (weight 65 kg), is admitted to the dysfunction
ICU with respiratory failure. Her chief concerns are shortness D. Sepsis on the basis of the qSOFA score of 2
of breath and fever. In the ED, chest radiography reveals left
lower lobe infiltration, and piperacillin/tazobactam and vanco- Questions 5 and 6 pertain to the following case.
mycin are initiated. On ICU admission, M.R.’s blood pressure Z.T., a 72-year-old woman, is admitted to the ICU with pneu-
drops to 80/40 mm Hg (MAP 53 mm Hg). monia. At presentation, she has temperature 101.2°F, blood
pressure 82/44 mm Hg, heart rate 102 beats/minute, respira-
1. Which one of the following is best to recommend for
tory rate 20 breaths/minute, and GCS score 12. The patient’s
M.R.’s initial fluid resuscitation?
CBC shows WBC 16.2 x 103 cells/mm3, Hgb 6.2 mg/dL, and Plt
A. 1000 mL of hydroxyethyl starches
100,000/mm3. Her SCr is 2.1 mg/dL, Na is 145 mEq/L, K is 3.5
B. 1500 mL of 5% dextrose in ½ normal saline
mEq/L, Cl is 115 mEq/L, INR is 1.9, and lactate is 1.5 mmol/L;
C. 1500 mL of 5% albumin
arterial blood gas shows pH 7.2.
D. 2000 mL of normal saline
5. According to the Sepsis-3 guidelines, which one of the
2. After M.R.’s fluid resuscitation, norepinephrine continu-
following best classifies Z.T.’s disease?
ous infusion is administered to maintain a MAP of at least
65 mm Hg. She is receiving norepinephrine at 25 mcg/ A. Sepsis
minute, which was initiated 2 hours ago. Her heart rate is B. Severe sepsis
130 beats/minute and MAP is 60 mm Hg. Her physician C. Septic shock
examination reveals 2+ pitting edema, and a passive leg D. At risk of sepsis
raise (PLR) maneuver results in a stroke volume increase 6. The attending physician asks for a recommendation on
of 8%. Which one of the following is the best next step to balanced versus unbalanced crystalloids for Z.T. Accord-
recommend for M.R.? ing to the SMART and SALT-ED trials, which one of the
A. Increase the norepinephrine rate. following is best to recommend for Z.T.’s initial fluid man-
B. Add vasopressin (at 0.03 unit/minute). agement in sepsis or septic shock?
C. Add methylprednisolone. A. Lactated Ringer solution is preferred to normal
D. Administer a 1-L bolus of normal saline. saline because of decreased ventilator-free days.
3. M.R. continues to receive the norepinephrine continu- B. No preference between balanced and unbalanced
ous infusion, and her lactate concentration has been fluid because of no difference in clinical outcomes.
measured. Initial lactate was 5.7 mmol/L in the ED and, C. Normal saline is preferred to lactated Ringer solution
3 hours later, is 3.2 mmol/L. Which one of the following because of decreased hospital mortality.
best interprets M.R.’s lactate concentrations? D. Balanced crystalloids are preferred to reduce the risk
A. Another vasopressor should be added because of adverse kidney events.
lactate is still greater than 2 mmol/L.
B. Hypoperfusion has not been resolved and the Questions 7 and 8 pertain to the following case.
patient’s hospital mortality is greater than 40%. M.P. is a 49-year-old woman (height 64 in, weight 110 kg)
C. Norepinephrine continuous infusion can be tapered admitted to the ICU 30 minutes ago for septic shock second-
because lactate is trending downward ary to an intra-abdominal infection. The patient has received
D. The most recent lactate is less than 4 mmol/L; adequate volume resuscitation but now requires norepineph-
intravenous fluid should be changed to 5% albumin. rine to maintain her MAP. M.P.’s vital signs are temperature
100.8°F, blood pressure 96/44 mm Hg, heart rate 110 beats/
4. A patient was admitted to the medical floor for a deep
minute, and respiratory rate 20 breaths/minute, and her lab-
venous thrombosis 2 days ago. No complications or abnor-
oratory values are WBC 18.4 x 103 cells/mm3, SCr 1.4 mg/dL,
mal laboratory values were associated with this condition
lactate 2.4 mmol/L, and glucose 212 mg/dL.
when she was admitted. However, imaging now reveals
new lung infiltrates. Her abnormal laboratory values and 7. Which one of the following is best to recommend for
vital signs are SCr 2.0 mg/dL, MAP 60 mm Hg, and GCS M.P.’s vasopressor therapy?
score 13. Which one of the following best classifies this
A. Weight-based dosing should be used to achieve
patient’s disease, according to the Sepsis-3 definitions?
faster goal MAP.
A. Severe sepsis on the basis of the SOFA score B. Non–weight-based dosing should be used to avoid
B. Sepsis on the basis of an increase of 4 in the SOFA score increased cumulative norepinephrine exposure.

C. Norepinephrine should be initiated with the recent literature, which one of the following is best to
vasopressin. recommend for N.Q.?
D. Norepinephrine should be administered peripherally
A. Discontinue norepinephrine.
to avoid central line placement.
B. Initiate hydrocortisone.
8. Which one of the following, if initiated, would best help C. Discontinue vasopressin.
decrease M.P.’s risk of mortality? D. Administer a fluid bolus.
A. Piperacillin/tazobactam and vancomycin 13. A 51-year-old man is admitted to the ICU with sepsis sec-
B. Vitamin C, thiamine, and hydrocortisone ondary to a UTI. His vital signs are temperature 100.2°F,
C. Esmolol continuous infusion blood pressure 104/48 mm Hg (MAP 67) while receiv-
D. Hydrocortisone ing high-dose norepinephrine, heart rate 117 beats/
minute, and respiratory rate 18 breaths/minute. Labo-
Questions 9–12 pertain to the following case. ratory values are as follows: WBC 14.8 x 103 cells/mm3,
N.Q., a 63-year-old woman (weight 74 kg), is admitted to the K 4.1 mEq/L, SCr 1.1 mg/dL, and BUN 18 mg/dL. Appropri-
ICU with shortness of breath and altered mental status. Her ate antimicrobial therapy is administered. The patient’s
medical history includes diabetes mellitus and hypertension. self-reported pain scale is currently 0, and he is in no
N.Q.’s vital signs are temperature 100.6°F, blood pressure apparent distress. His PLR does not show that he would
84/46 mm Hg (MAP 59), heart rate 104 beats/minute, and benefit from additional fluid. Which one of the following
respiratory rate 22 breaths/minute. Chest radiography reveals is best to recommend for this patient to improve heart
bilateral lower lobe infiltrates. N.Q.’s laboratory data are as fol- rate and stroke volume without compromising tissue
lows: Na 150 mEq/L, K 3.2 mEq/L, Cl 115 mEq/L, SCr 1.6 mg/ perfusion?
dL, BUN 37 mg/dL, WBC 16.2 x 103 cells/mm3, and lactate 2.2 A. Add dopamine.
mmol/L. B. Add dobutamine.
9. Which one of the following is best to recommend for C. Add esmolol.
N.Q.’s initial fluid resuscitation? D. Increase norepinephrine dose.
A. 2000 mL of normal saline Questions 14 and 15 pertain to the following case.

B. 100 mL of 5% albumin
J.T. is a 69-year-old man presenting to the ED with altered
C. 2000 mL of lactated Ringer solution
mental status, according to his wife. She states that J.T. has
D. 1500 mL of 5% dextrose in ½ normal saline
had headaches and a sore throat recently. His vital signs on
10. After the initial fluid resuscitation, N.Q.’s MAP remains admission are temperature 101.2°F, blood pressure 92/40
below goal. Which one of the following is best to recom- mm Hg, heart rate 112 beats/minute, and respiratory rate
mend for N.Q.? 18 breaths/minute. Laboratory values are as follows: WBC
A. Repeat the 30-mL/kg fluid bolus. 23.2 x 103 cells/mm3, BUN 22 mg/dL, SCr 1.8 mg/dL, and
B. Monitor change in cardiac output after PLR. glucose 106 mg/dL. Despite adequate fluid resuscitation,
C. Initiate hydrocortisone and fludrocortisone. high-dose norepinephrine and fixed-dose vasopressin are not
D. Obtain central venous pressure (CVP) to determine maintaining J.T.’s MAP above 65 mm Hg.
the need for further fluid. 14. According to the recent literature, which one of the fol-
11. One hour later, N.Q.’s care team determines that vaso- lowing is most likely to reduce J.T.’s risk of mortality?
pressor therapy is needed to maintain her MAP. Which A. Hydrocortisone plus fludrocortisone
one of the following vasopressors is best to recommend B. Methylprednisolone
initiating first for N.Q.? C. Hydrocortisone
A. Angiotensin II D. Dexamethasone
B. Vasopressin 15. J.T.’s nurse wonders whether she can titrate his vaso-
C. Dopamine pressin dose to maintain a MAP of 65 mm Hg or greater.
D. Norepinephrine Which one of the following is best to relate to J.T.’s nurse
12. N.Q. is now in the recovery phase of septic shock, and her regarding high-dose vasopressin?
vasopressor requirements are decreasing. Her MAP has A. May cause myocardial and bowel ischemia.
been 70 mm Hg for the past hour. However, the physician B. May increase the heart rate in patients with septic
is concerned about inducing hypotension. Currently, her shock.
vasoactive medications include norepinephrine 5 mcg/ C. May cause hypernatremia.
minute and vasopressin 0.03 unit/minute. According to D. May not increase blood pressure.

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ADDITIONAL READINGS Challenges Facing Critical Care Practitioners

CCSAP 2019 Book 1 • Infection Critical Care 8 Sepsis Management

○○ Altered mental status = GCS score < 15

Plt, × 10 3/mm3 ≥ 150 < 150 < 100 < 50 < 20

Bilirubin, mg/dL < 1.2 1.2–1.9 2.0–5.9 6.0–11.9 ≥ 12.0

Central nervous system

GCS score 15 13–14 10–12 6–9 <6

SCr, mg/dL < 1.2 1.2–1.9 2.0–3.4 3.5–4.9 > 5.0

Urinary output, < 500 < 200

Figure 1. Sepsis definitions according to the 2016 SSC guidelines.

CCSAP 2019 Book 1 • Infection Critical Care 9 Sepsis Management

Study Design and Population Intervention Results Conclusion

CCSAP 2019 Book 1 • Infection Critical Care

Study Design and Population Intervention Results Conclusion

CCSAP 2019 Book 1 • Infection Critical Care

Study Design and Population Intervention Results Conclusion

CCSAP 2019 Book 1 • Infection Critical Care

• WBC < 4 x 10 cells/mm

CCSAP 2019 Book 1 • Infection Critical Care 13 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 14 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 15 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 16 Sepsis Management

Angiotensin II Weight-Based Dosing and Extremes

CCSAP 2019 Book 1 • Infection Critical Care 17 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 18 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 19 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 20 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 21 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care

CCSAP 2019 Book 1 • Infection Critical Care 23 Sepsis Management

What is best to recommend for the patient, given the

CCSAP 2019 Book 1 • Infection Critical Care 24 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 25 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 26 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 27 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 28 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 29 Sepsis Management

Sacha GL, Lam SW, Duggal A, et al. Hypotension risk based

CCSAP 2019 Book 1 • Infection Critical Care 30 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 31 Sepsis Management

CCSAP 2019 Book 1 • Infection Critical Care 32 Sepsis Management

A. 2000 mL of normal saline Questions 14 and 15 pertain to the following case.

CCSAP 2019 Book 1 • Infection Critical Care 33 Sepsis Management

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