Postgraduate Medicine

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ipgm20

Review: sepsis guidelines and core measure

bundles

Lia Desposito & Christina Bascara

To cite this article: Lia Desposito & Christina Bascara (2024) Review: sepsis
guidelines and core measure bundles, Postgraduate Medicine, 136:7, 702-711, DOI:
10.1080/00325481.2024.2388021

To link to this article: https://doi.org/10.1080/00325481.2024.2388021

Published online: 07 Aug 2024.

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POSTGRADUATE MEDICINE
2024, VOL. 136, NO. 7, 702–711
https://doi.org/10.1080/00325481.2024.2388021

REVIEW

Review: sepsis guidelines and core measure bundles

Lia Desposito and Christina Bascara
Internal Medicine, Division of Hospital Medicine, Lankenau Medical Center, Wynnewood, PA, USA

ABSTRACT ARTICLE HISTORY

Sepsis is a major cause of mortality worldwide and is the third-leading cause of death in the United Received 7 April 2024
States. Sepsis is resource-intensive and requires prompt recognition and treatment to reduce mortality. Accepted 29 July 2024
The impact of sepsis is not only on in-hospital survival but extends into post-discharge quality of life KEYWORDS
and risk of re-admission. As the understanding of sepsis physiology evolved, so have the recommended Sepsis; core measure bundle;
screening tools and treatment protocol which challenge prior standards of care. There have been infection; screening;
noteworthy efforts by the Surviving Sepsis Campaign, the Third International Consensus Definitions for antimicrobial; fluid
Sepsis and the Centers for Medicare and Medicaid Services to establish core measure bundles. This resuscitation
review highlights both the 2021 SSC International Guidelines and the 2015 CMS Severe Sepsis/Septic
Shock Core Measure Bundle, or SEP-1. Notably, the SEP-1 bundle was implemented as a value-based
purchasing program, linking care of sepsis patients to financial incentives. The objective is to explore
the most current evidence-based data to inform clinical practice while utilizing the available guidelines
as a roadmap.

1. Introduction accounted for up to 1 in six sepsis cases with a mortality rate

The Centers for Disease Control and Prevention (CDC) notes as high as 33% in the first 3 months of the pandemic [3].
that each year at least 1.7 million adults develop sepsis in the CMS adheres to the Severe Sepsis/Septic Shock Core
United States alone. Of those, 350,000 adults die during hospi­ Measure Bundle (SEP-1), which was established in 2015 as
talization or are transitioned to hospice-focused care [1]. It is the a pay-for-reporting initiative. Table 2 highlights notable distinc­
third leading cause of death in United States’ hospitals with tions between the CMS bundle and the SSC guidelines. Since
one-third of hospital deaths having a diagnosis of sepsis. It is 2017, CMS mandates hospitals to report compliance with the
recognized as one of the costliest medical conditions, with SEP-1 bundle. Additionally, CMS has decided to include sepsis
annual expenditures reaching up to 62 billion dollars annually and septic shock in their Value-Based Purchasing program,
across hospital and skilled nursing care settings [1]. Recent connecting hospital performance on this Core Measure Bundle
studies have highlighted the profound long-term effects of with reimbursements in the upcoming year.
sepsis survivors. Individuals with previous functional indepen­
dence often experience a marked reduction in quality of life up
2. A history of sepsis definitions
to 6 months post-discharge. Sepsis survivors reported
decreased mobility, difficulty completing activities of daily living Published in 1992, the first guidelines defined sepsis as
and challenges with self-care [2]. Given this noteworthy impact, a systemic inflammatory response syndrome (SIRS) marked by
there has been extensive effort worldwide to contribute to the presence of two or more SIRS criteria in the context of
guidelines, research and quality improvement projects. suspected infection (Table 1). Sepsis was then classified as severe
Multiple groups including the Surviving Sepsis Campaign in the setting of organ dysfunction, hypoperfusion, or hypoten­
(SSC), the Third International Consensus Definitions for Sepsis sion. Hypoperfusion was evidenced by elevated lactic acid, acute
and the Centers for Medicare and Medicaid Services (CMS) have change in mental status, or oliguria. Septic shock is defined as
gathered to create core measure bundles. The most recent persistent hypotension refractory to adequate fluid resuscitation.
guidelines and focus of this article were published in 2021 by The 2001 revision further characterized the clinical and labora­
the International SSC, a joint initiative by the Society of Critical tory markers for sepsis and identification of end-organ damage.
Care Medicine and the European Society of Intensive Care There was concern that the existing definitions lacked speci­
Medicine. As guidelines for detection and protocolized treat­ ficity, as systemic inflammation response can occur in noninfec­
ment were implemented, sepsis-related death rates declined tious conditions. This likely contributed to discrepancies in sepsis
over two decades from 2000 to 2019. However, in 2021, mor­ incidence and mortality over the years, as the presence of SIRS,
tality rates increased in adults over the age of 65. This is likely even in uncomplicated infections, was characterized as sepsis.
related to the burden of COVID-19 associated sepsis which Therefore, with an improved understanding of sepsis

CONTACT Lia Desposito despositol@mlhs.org Internal Medicine, Division of Hospital Medicine, Lankenau Medical Center, 100 East Lancaster Avenue,
Wynnewood, PA 19096, USA
© 2024 Informa UK Limited, trading as Taylor & Francis Group
 POSTGRADUATE MEDICINE 703

Table 1. Screening Tools for Sepsis. non-ICU patients [7]. Research indicates that only 24% of the
SIRS ● Body temperature > 38°C or < 36 °C infected patients exhibit a qSOFA score of 2 or 3, yet these
● Heart rate > 90 beats per minute
individuals contribute to 70% of the adverse outcomes [7].
● Respiratory rate > 20 breaths per minute
● Leukocyte count > 12000 or < 4000 with at least 10% bands While qSOFA facilitates rapid bedside evaluation, its screening
SOFA ● Arterial oxygen partial pressure (PaO2) to fractional inspired oxygen capability is limited as it is more specific but less sensitive than
(FiO2) SIRS [8,9].
● Platelet count Furthermore, NEWS and MEWS (Table 1) have both shown
● Total bilirubin
● Creatinine higher discrimination for mortality than qSOFA and SIRS.
● Glasgow Coma Scale A retrospective cohort study of 1.5 million hospitalizations
● MAP or vasoactive pressor requirement from 28 hospitals across California and Illinois showed that
qSOFA ● Glasgow Coma Scale < 15 NEWS and MEWS outperformed qSOFA and SIRS in identifying
● Respiratory rate > 22 breaths per minute risk for adverse outcomes including ICU transfer and mortality
● Systolic blood pressure ≤100 mmHg
[10]. This was exhibited in patients both with and without
MEWS ● Systolic blood pressure
suspected infection. Given inferior sensitivity, the SSC guide­
● Respiratory rate
● Heart rate lines recommend against using qSOFA as a single screening
● Temperature tool compared with SIRS, NEWS, and MEWS.
● Mental status
NEWS ● MEWS criteria +
● Oxygen saturation 4. Biomarkers for sepsis diagnosis
There have been several proposed biomarkers for the identi­
fication of sepsis have gained support over the years. These
pathophysiology, the 2016 guidelines eliminated the term SIRS. include lactate and procalcitonin.
Instead, sepsis was redefined as a life-threatening organ dysfunc­
tion caused by the host’s dysregulated response to infection [4].
4.1. Lactate
The 2016 clinical criteria for sepsis required a suspected or
documented infection combined with an acute increase of at An elevated serum lactate level is a well-defined prognostic
least two Sequential Organ Failure Assessment (SOFA) points marker in sepsis with early normalization in resuscitation asso­
(Table 1). The guidelines also introduced a new rapid bedside ciated with decreased mortality [11,12]. It can indicate cellular
clinical tool called quick SOFA (qSOFA) to enhance sepsis screen­ stress in the setting of refractory hypotension and is included
ing (Table 1). Sepsis-3 guidelines notably removed the term in the most recent definitions of septic shock [13]. Elevated
‘severe sepsis’ to avoid underestimating the mortality risk of sepsis lactate can serve as a valuable adjunct in diagnosing sepsis,
alone. Septic shock was defined as hypotension requiring vaso­ especially in patients with undifferentiated symptoms. Lactate
pressors to maintain a mean arterial pressure (MAP) over 65 elevation strengthens the suspicion of sepsis. However, due to
mmHg, along with serum lactate levels greater than 2 mmol/L its variable sensitivity and specificity, lactate levels should not
despite adequate management of hypovolemia [5]. It is important be relied upon in isolation for diagnosis.
to note that CMS and the Sepsis Core Measure Bundle still classify Interestingly, an elevated initial lactate is independently asso­
sepsis into three subsets: sepsis, severe sepsis, and septic shock. ciated with increased mortality even without clinically apparent
The latest 2021 SSC guidelines have introduced updated organ dysfunction or shock [14,15]. Thus, it serves as a valuable
recommendations for sepsis screening, source diagnosis, and biomarker for initiating sepsis evaluation in an otherwise well-
treatment protocols, detailed further in this synopsis. These guide­ appearing patient that is at high-risk for deterioration [16]. While
lines integrate current principles to enhance diagnostic accuracy elevated lactate is typically associated with tissue hypoperfusion,
and improve timely treatment, all while considering antimicrobial lactate clearance may not consistently correlate with the micro­
stewardship and potential adverse effects of standard therapies. circulatory flow index [17]. This implies that persistently elevated
Furthermore, the 2021 revision highlights the comprehensive care lactate levels can stem from non-ischemic factors, apart from
of sepsis patients post-ICU and peri-discharge, addressing socio­ reduced microvascular perfusion.
economic, cognitive, and emotional considerations [6].
4.2. Procalcitonin
3. Sepsis screening
Procalcitonin (PCT) is a precursor to calcitonin involved in cal­
There is still no ‘gold standard’ sepsis screening tool given cium homeostasis. It is typically undetectable in healthy indivi­
variability in predictive value. Nonetheless, screening tools are duals. In sepsis, there is a notable increase and prolonged
recommended for early sepsis recognition and time-sensitive elevation of PCT following endotoxin administration [18].
treatment. The current validated screening tools include SOFA, However, its release may not solely correlate with circulating
qSOFA, National Early Warning Score (NEWS), and Modified endotoxin, but also with broader inflammatory cytokine release.
Early Warning Result (MEWS) (Table 1). This is evidenced by its elevation in non-infection states of
The SOFA score is utilized to predict in-hospital mortality, trauma, cancer, and surgery. A University of Groningen study
specifically within ICU settings. The qSOFA score, a condensed discovered that tumor necrosis factor-α (TNF-α) and interleukin-6
version of the SOFA, effectively predicts in-hospital mortality, (IL-6) stimulate PCT release in a similar fashion to acute-phase
showing a significant 3- to 14-fold increase in mortality among reactants [18]. PCT levels have been proposed to guide the
704 L. DESPOSITO AND C. BASCARA

initiation and termination of antibiotic therapy, especially in administration within 1 hour of sepsis recognition. The SSC
cases where a sepsis diagnosis is ambiguous. When comparing guideline is to balance the mortality benefit of early antimi­
procalcitonin-guided antibiotic initiation with standard care, crobial administration with the risks these medications carry
there is no significant impact on short-term mortality, ICU stay, when applied widely without infection. These risks include
or overall hospitalization length [19–21]. kidney injury, hypersensitivity reactions, cytopenia and
The SSC guidelines suggest against the use of PCT to Clostridioides difficile infection.
determine initiation of antibiotic therapy and rather use clin­
ical evaluation alone. On the other hand, PCT may have utility
in deciding when to discontinue antibiotic therapy. 5.2. CMS core measure bundle
A prospective, multicenter, randomized, control trial across The CMS Core Measure Bundle continues to use a 3- and
15 hospitals in the Netherlands revealed that procalcitonin- 6-hour bundle timeline as opposed to a 1-hour bundle time­
guided discontinuation of antimicrobials in the ICU leads to line (Table 2). Sepsis time zero is noted when there is docu­
a reduction in duration of treatment and daily defined doses mentation of suspected or confirmed infection with two or
[22]. This is subsequently correlated with decreased mortality. more SIRS criteria and at least one organ dysfunction criteria.
Thus, the new SSC guidelines suggest using PCT plus clinical End organ damage is defined by lactate > 2, INR > 1.5 or PTT >
evaluation to decide when to discontinue antimicrobials 60, creatinine increase > 0.5 or creatinine > 2, respiratory fail­
rather than clinical evaluation alone. ure (noninvasive ventilation, invasive ventilation, or high-flow
oxygen), systolic blood pressure > 90 or a drop of 40 mmHg
from baseline or MAP < 65, urine output <0.5 mL/kg/hr for 2
5. Sepsis bundles
hours, platelets < 100,000 and bilirubin > 2.
Sepsis bundles are recommended protocols outlining the Overall, as detailed in Table 2, in the first 3 hours from
time-sensitive standards for diagnosis and treatment of sepsis sepsis time zero it is necessary to obtain lactate level and
and septic shock. The timelines implemented have varied as blood cultures followed by antibiotic administration. If
data evolved, which is illustrated between the CMS Core a patient has septic shock evidenced by hypotension with
Measure Bundle and the Surviving Sepsis Campaign bundle MAP <65 mmHg or elevated lactate ≥4 mmol/L, then the 30
(Table 2). cc/kg fluid bolus must be administered within the first 3 hours
[25]. The CMS bundle allows physicians to administer less than
the sepsis fluid bolus if there is a clinical reason documented
5.1. Surviving sepsis campaign bundle
for this decision with frequent patient volume status reassess­
SSC recommends a 1-hour and a 3-hour bundle based upon ment. From 3 to 6 hours, the patient must be reassessed with
the level of suspicion for sepsis or the presence of septic a sepsis-focused exam and a repeat lactate (if the initial was
shock. They suggest a 1-hour bundle when there is a high >2 mmol/L) after the sepsis fluid bolus is administered. If
likelihood of sepsis or if there is septic shock [23]. Otherwise, if a patient has septic shock, reassessment of ongoing hypoten­
there is possible sepsis and a patient is not exhibiting shock, sion after completion of the fluid bolus and consideration for
a 3-hour bundle should be used with a rapid investigation for initiating vasopressors if MAP < 65 mmHg is indicated.
infectious and noninfectious causes. If clinical suspicion for There is variability among the quality and strength of evi­
sepsis remains after this investigation, then antimicrobials dence supporting the sepsis focused exam. A focused exam
should be administered within 3 hours [24]. On the contrary, must include vital signs, cardiopulmonary exam, capillary refill
if there is no shock present and the likelihood of infection is evaluation, peripheral pulse evaluation and a skin exam.
low, then it is suggested to defer antimicrobials and closely Alternately, the volume status and tissue perfusion exam can
monitor. This timeline is adjusted from the 2016 SSC guide­ be met by obtaining two of the following – central venous
lines, which more narrowly recommends antimicrobial pressure (CVP) measurement, central venous oxygen

Table 2. Core Measure Bundle Comparison.

CMS Core Measure (SEP-1) Surviving Sepsis Campaign
3 Hour Bundle 1 Hour Bundle (septic shock or high likelihood of sepsis)
(1) Lactate (1) Lactate
(2) Blood culture before antibiotics (2) Repeat lactate if initial lactate elevated (>2 mmol/L)
(3) Broad-spectrum antibiotics (3) Blood cultures before antibiotics
(4) 30 mL/kg crystalloid bolus if hypotension, initial lactate ≥4 mmol/L or septic shock (4) Broad-spectrum antibiotics
(5) 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
6 Hour Bundle (balanced crystalloid preferred over normal saline)
Severe Sepsis (6) Vasopressors if hypotensive during or after fluid resuscitation
(1) Repeat lactate if initial lactate elevated to maintain a MAP ≥65 mm Hg
(2) Perform a volume status or perfusion exam*
(3) Vasopressors to target MAP ≥ 65 if persistent hypotension after ≥ 30 cc/kg crystalloid 3 Hour Bundle (possible sepsis without shock):
bolus
* Repeat focused exam: vital signs, cardiopulmonary, capillary refill, pulse and skin findings, (1) Time-limited investigation of infectious and noninfectious
OR two of the following: measure central venous pressure, central venous oxygen saturation, causes
(2) If concern for sepsis persists, administer antibiotics within 3
bedside cardiovascular ultrasound, passive leg raise or fluid challenge
hours
 POSTGRADUATE MEDICINE 705

measurement, bedside cardiovascular ultrasound, and passive which outlines the most common pathogens and susceptibil­
leg raise or fluid challenge [25]. Studies have not shown ities within a region [33].
a mortality benefit when measuring mixed venous oxygen
saturations or CVP measurements, thus, these have largely
6.3. Methicillin-resistant staphylococcus aureus (MRSA)
fallen out of favor in the most recent guidelines.
To begin with, patients considered high-risk for methicillin-
resistant Staphylococcus aureus (MRSA) infection should
6. Antimicrobial administration receive empiric antimicrobials with MRSA coverage. The risk
factors for MRSA infection are shown in Table 3.
6.1. Timing of administration It is key to think about the risks of withholding MRSA
In reviewing the evolution of sepsis treatment bundles, there coverage in these patients versus the risks these medications
is a correlation between prompt antimicrobial administration can have in undifferentiated infections. There is an increased
and a reduction in mortality. This relationship appears stron­ risk of mortality if MRSA treatment is delayed more than 24–
ger in patients with septic shock, while there is more varia­ 48 hours and a high mortality rate of 10–30% associated with
bility in sepsis without shock. It is important to note that the MRSA infection that reaches the bloodstream [34,35]. On the
definitions of sepsis and septic shock can vary across studies alternative side, there is potential harm in broad-spectrum
which can alter results. Several observational analyses on sep­ MRSA coverage if no MRSA infection is present, including
tic shock reveal that with each additional hour of delay in increased mortality [36]. To screen for MRSA infection, there
antimicrobial therapy there is up to a 1.14 increased odds ratio are modalities such as the nasal swab to help narrow antibio­
of in-hospital mortality [26]. Each hour delay of appropriate tics. It has a low positive predictive value (PPV), however, has
antibiotic administration can decrease survival by 7.6% [26]. shown a very high negative predictive value (NPV) up to 99.2%
Meanwhile, other observational studies have failed to iden­ for MRSA pneumonia [37]. A negative MRSA nasal PCR in
tify this mortality benefit with each hour delay once septic pneumonia is a minimally invasive tool to allow more rapid
shock is identified [27]. There was still increased mortality seen narrowing of antibiotics, especially while awaiting culture data
when antimicrobials were first administered after septic shock [38]. Additionally, there is increasing evidence of its high NPV
recognition as compared to before [27]. An RCT study in 2017 in skin and skin structure infections [39].
in Germany involving 4183 patients revealed no affect on 28-
day mortality between treatment times of 1.5 hours versus 2 6.4. Multidrug resistant organisms
hours [28]. A second RCT in 2018 in the Netherlands involving
2698 patients compared the pre-hospital initiation of antibio­ If the patient has risk factors for multi-drug resistant (MDR)
tics in the ambulance versus standard of care in the emer­ organisms, it is suggested to use two antibiotics with gram-
gency department. It revealed no improvement in all-cause negative coverage rather than one. Risk factors include
mortality at 28 days regardless of illness severity, despite up to a broad-spectrum antimicrobial coverage within 90 days, his­
a 90-minute difference in time-to-antibiotic administration tory of antibiotic-resistant infections within one year, local
between groups [29]. Once that delay extends beyond 3–5 antibiograms with prevalence of MDR organisms, healthcare-
hours, observational studies have demonstrated increased in- associated infection and travel to or hospitalization in an
hospital and long-term mortality [25,30]. Because of this spec­ endemic country within 90 days [40]. Otherwise, without
trum of evidence, the most recent SSC guidelines recommend these risk factors, there is no documented benefit of this two-
both a 1-hour and 3-hour bundle. agent gram negative coverage.

6.5. Pseudomonas
6.2. Empiric antimicrobial therapy
Coverage for Pseudomonas aeruginosa is indicated in those
The choice of antimicrobial therapy is dependent upon with hospitalization within 3 months, those residing in health­
patient-related risk factors including patient exposures, under­ care facilities, antibiotic exposure within 30 days and prior
lying medical conditions, prior infections, and colonization. It
is necessary to obtain a thorough history and physical exam to
Table 3. Risk Factors for MRSA Infection.
identify these risk factors to tailor appropriate antimicrobial
Risk Factors for MRSA Infection
therapy early. Given rising resistance patterns over the last
Healthcare exposure within 12 months (i.e. hospitalization, long-term care
several years, there is increasing awareness of antimicrobial facility)
stewardship. The Infectious Diseases Society of America Recent surgery
recommends implementing an antimicrobial stewardship pro­ Hemodialysis
Residence in an area with high colonization rates
gram within hospital systems [31]. Rapid molecular tests Antibiotic use within 6 months
reduce the time to identify causative organisms. Studies History of recurrent skin infections or chronic wounds
have shown reduced mortality when used with an antimicro­ Presence of invasive devices
Severe infections (i.e. severe community acquired pneumonia)
bial stewardship program [32]. Physicians should consider History human immunodeficiency virus (HIV) or other immunosuppression
narrowing the initial broad spectrum antibiotic regimens as Injection substance use
soon as they are clinically feasible. It is important to consider Incarceration
Homelessness
regional antibiograms when deciding on empiric therapy
706 L. DESPOSITO AND C. BASCARA

pseudomonal infection. Pseudomonas is more prevalent in perfusion. There has been significant variability and limited
advanced immunocompromised states such as acquired data; however, on the ideal volume of fluid resuscitation and
immunodeficiency syndrome (AIDS), neutropenia, organ trans­ its effect on patient outcomes. The 2016 SSC guidelines
plant, and steroid exposure longer than 6 weeks. It is also seen strongly recommended at least 30 mL/kg of intravenous crys­
in those with structural lung disease such as cystic fibrosis and talloid fluid for initial resuscitation within the first 3 hours of
bronchiectasis. sepsis recognition. This was based upon observational studies
alone. The 2021 guidelines downgrade this from a strong to
a weak recommendation given the lack of prospective studies
6.6. Extended spectrum beta-lactamase (ESBL) comparing different resuscitative volumes. It is essential to
A class of drug-resistant pathogens with rising prevalence are weigh the risks of excess fluid administration in conditions
those with extended spectrum beta-lactamase (ESBL) activity such as heart and renal failure that could increase risk of AKI
which confer resistance to most beta-lactam antibiotics. The and mortality. Fluid accumulation sequelae include prolonged
SENTRY Antimicrobial Surveillance Program reviewed blood intubation times, pleural effusions, and ultimately cardiac and
and urine cultures from several U.S. hospitals from 1997 to pulmonary failure. An analysis of 23,513 patients admitted to
2000 and 2011–2013 revealing that the prevalence of ESBL- the ICU with sepsis or septic shock revealed significantly
producing Klebsiella rose from 7% to 15% [41]. ESBL infections increased mortality for patients who received more than 5 L
are associated with poorer outcomes, including longer hospi­ of fluid on their first ICU day [44].
tal stay and higher mortality, likely related to delay in appro­
priate antimicrobial initiation. Risk factors for ESBL infections 7.1. Choice of fluids
include prolonged hospitalization greater than 10 days,
chronic indwelling Foley catheter, antibiotics within 30 days, The new guidelines suggest balanced crystalloid fluids rather
presence of a gastrostomy tube, and prior ESBL infection than 0.9% saline, whereas prior bundles recommended either
within 1 year. balanced crystalloid or saline. Albumin is recommended in
When deciding ESBL antimicrobial coverage, patient- patients that received a large volume of resuscitation (weak
specific characteristics and local resistance patterns should recommendation). This is based on a meta-analysis of 14 studies
be considered. For example, carbapenems are often effec­ (18916 patients) which concluded that balanced crystalloids and
tive, but there is rising carbapenem resistance including albumin offer reduced mortality over other fluids including
carbapenem-resistant enterococcus. There are also oral normal saline [45]. The Isotonic Solutions and Major Adverse
agent options for particular ESBL Enterobacterales urinary Renal Events Trial (SMART) trial showed that balanced crystal­
tract infections (ie, trimethoprim-sulfamethoxazole, fluroqui­ loids had reduced 30-day mortality and lower likelihood for new
nolones); however, they have important side effect profiles renal-replacement therapy or persistent renal dysfunction [46].
including neurologic, nephrotoxic, and musculoskeletal The SALT-ED trial showed no difference in hospital-free days
adverse drug effects [42]. between the balanced-crystalloids and saline groups [47]. Yet, it
did show that balanced crystalloids had a lower incidence of
major adverse kidney events within 30 days than saline [47].
6.7. Fungal Risks of saline fluids include hyperchloremic metabolic acidosis,
increased cytokine release, renal vasoconstriction, and acute
In addition to the bacterial considerations, there are special kidney injury related to the high chloride content [48,49].
circumstances to initiate fungal coverage. Although studies
have not yet shown a clear causal benefit between antifungal
therapy and reduction in mortality, antifungal therapy should 7.2. Assessing volume response
be considered in those at high risk. These include patients A patient’s ability to improve their stroke volume in response
with neutropenia or other immunosuppression, particularly if to fluid is based on their position on the Frank–Starling
febrile despite 4–7 days of empiric antibiotic therapy. Like curve which is more complicated in patients with sepsis
certain higher-risk bacterial infections, fungal infections are and septic shock. The current guidelines suggest using
linked to recent antibiotic therapy and prolonged hospitaliza­ dynamic measures rather than physical examination or static
tion. They also have a higher incidence in the setting of techniques. Common static markers of cardiac preload
invasive devices such as central venous catheters, Candida include CVP, systolic blood pressure, arterial oxygenation,
colonization at multiple sites, administration of total parent­ and heart rate.
eral nutrition (TPN), gastrointestinal tract perforations and Dynamic measures include passive leg raising (PLR) with
surgeries, high-dose corticosteroid use and solid organ trans­ a measure of cardiac output (CO), fluid challenges to improve
plants [43]. stroke volume (SV), systolic blood pressure or pulse pressure, and
changes in intrathoracic pressure to improve SV, ie, in mechani­
cally ventilated patients. In a 2017 systematic review and meta-
7. Intravenous fluid resuscitation
analysis of 13 trials (1,652 patients), using dynamic measures to
Fluid resuscitation has been a cornerstone of sepsis treatment guide fluid therapy was associated with reduced mortality, ICU
for over 100 years. There are well-established benefits of length of stay and duration of mechanical ventilation.
restoring intravascular volume to correct hypovolemia, To assist in dynamic evaluation, point of care ultrasound
improve cardiac output, and ultimately increase tissue (POCUS) has become a preferable technique as it is quick,
 POSTGRADUATE MEDICINE 707

affordable, noninvasive and can be performed at the bedside. vasopressors have been shown to carry higher rates of dose-
POCUS can visualize collapsibility of various blood vessels related side effects. The β1 adrenergic activity of dopamine,
including the inferior vena cava (IVC), internal jugular vein, for example, leads to dose-limiting arrhythmia. A systematic
common carotid artery, subclavian vein and femoral vein while review and meta-analysis of 11 RCTs demonstrated a lower
performing dynamic movements. A meta-analysis examined the risk of mortality and arrhythmias with norepinephrine com­
predictive value of variations in IVC diameter (>16%) for fluid pared to dopamine [55]. Another vasopressor epinephrine at
responsiveness revealing a sensitivity and specificity of 71% and lower doses can decrease systemic vascular resistance (SVR)
100%, respectively [50]. Several prospective cohort studies have while increasing CO, which complicates the MAP goal.
demonstrated that an increase in stroke volume over 10% with Epinephrine also carries the risk of arrhythmia, reduced
PLR was predictive of fluid responsiveness with a sensitivity of splanchnic circulation (mostly in severe septic shock), and
77% to 100%, and a specificity of 88% to 99% [51]. increased lactate production via stimulation of β2 adrenergic
If volume assessment indicates further fluids are needed receptor stimulation in skeletal muscle [56].
beyond initial resuscitation, repeated small fluid boluses The stepwise escalation of vasopressor therapy considers
should be given with frequent dynamic monitoring of SV the above potential hemodynamic effects. First-line therapy is
and/or CO. These methods of dynamic monitoring; however, norepinephrine, which can be initiated peripherally for a short
may be less practical in resource-limited areas. time if central access is not available, preferably via an IV
Other less invasive markers of tissue perfusion include capil­ proximal to the antecubital fossa given lower risk for extra­
lary refill time (CRT), temperature of extremities and skin mot­ vasation. Peripheral administration strives to rapidly restore
tling. The ANDROMEDA-SHOCK study in 2019 compared utilizing MAP until central access can be obtained given the increased
normalization of CRT versus normalization or decreasing lactate risk of mortality with this delay. Although large, randomized
levels as the target for resuscitation in septic shock. After 3 days, trials on vasopressor vesicant risk are lacking, it appears overall
the CRT group had significantly less organ dysfunction based on safe for short periods of time of less than 6 hours. A systematic
SOFA score compared to the lactate group. Twenty-eight-day review of 85 articles, mostly case reports, exhibited a low risk
mortality was also lower in the CRT versus the lactate group of extravasation (3.4%) with peripheral vasopressor use and no
(34.9% versus 43.4%), however, not statistically significant [52]. events of tissue necrosis or limb ischemia [57].

8. Vasopressor therapy 8.2. Second line agent: vasopressin

Vasopressor support is indicated in septic shock, which is If MAP remains < 65 despite low-to-moderate dose norepinephr­
defined as sepsis with arterial hypotension refractory to ine (0.25 − 0.5 μg/kg/min), it is suggested to add vasopressin
fluid resuscitation plus evidence of poor perfusion, specifi­ rather than further increase the dose of norepinephrine.
cally, elevated lactate > 2. Vasopressors are required in Vasopressin is an endogenous peptide produced by the
septic shock to maintain a MAP goal of greater than 65 hypothalamus and released by the posterior pituitary. It causes
mmHg once hypovolemia has been treated. MAP correlates vasoconstriction by acting on V1 receptors in the vascular
with systemic filling pressure which promotes venous smooth muscle and is noted to be relatively deficient in septic
return and CO. It is shown that MAP less than 60 mmHg shock after 24–48 hours. A systematic review of 10 RCTs showed
correlates with decreased organ perfusion. The newest that norepinephrine plus vasopressin offered reduced mortality
guidelines recommend a MAP goal of 65 rather than compared to norepinephrine alone [58]. However, it did not
higher MAP goals given multiple RCTs which failed to show lower rates of renal replacement therapy.
show any improved mortality with the higher compared Two other studies, VANISH and VASST determined that vaso­
to the lower target. pressin has a catecholamine-sparing effect which may help
A multicenter, open-label trial across 29 centers in decrease the adrenergic burden associated with vasopressor
France showed no significant difference in mortality therapy [59,60]. The overall data may support vasopressin as
between a target MAP of 65–70 and MAP 80–85 [53]. An having better clinical outcomes than norepinephrine. However,
RCT from 2020 included 2,463 patients aged 65 and older vasopressin is more expensive and less available. It is undecided
with septic shock, and compared ‘permissive hypotension’ at which dose of norepinephrine to add vasopressin; however, it
with MAP goal of 60–65 mm Hg versus a standard of care appears 0.25 − 0.5 μg/kg/min [46]. Vasopressin is infused at
group. The permissive hypotension group required signifi­ a dose of 0.03 units/min given that higher doses were associated
cantly fewer vasopressors than the usual care group and with cardiac, digital, and splanchnic ischemia [57].
there was no difference in 90-day mortality between
groups [54].
8.3. Third line agents: dobutamine and epinephrine
There is a paucity of evidence for the management of shock
8.1. First line agent: norepinephrine
requiring high doses of vasopressors. If there is still evi­
The recommended first-line agent for septic shock is norepi­ dence of cardiac dysfunction and hypoperfusion despite
nephrine, an α1 and β1 adrenergic receptor agonist. It induces initial vasopressor therapy, it is suggested to either add
vasoconstriction to increase MAP while having a preferable dobutamine or switch to epinephrine. If high-dose norepi­
hemodynamic profile with limited effect on heart rate. Other nephrine has already been given, then epinephrine may be
708 L. DESPOSITO AND C. BASCARA

of limited utility due to already saturated and downregu­ If a patient requires intubation of sepsis-induced ARDS,
lated α1 receptors. guidelines recommend a low tidal volume ventilation (LTVV)
strategy of 6 mL/kg of predicted body weight rather than
a high tidal volume of over 10 mL/kg. Lung protective strate­
9. Steroid use gies strive to limit pressure- and volume-related injuries such
as hyperinflation, alveolar rupture, pneumothorax, and release
For patients with septic shock who clinically have not stabi­ of inflammatory mediators. Several meta-analyses support
lized after fluid resuscitation and ongoing vasopressor use, LTVV, with one large trial revealing a 9% reduction in mortality
trials have indicated a benefit from the addition of hydrocor­ by using tidal volumes of 6 mL/kg versus 12 mL/kg [66].
tisone and fludrocortisone to their treatment regimen. The LTVV is also recommended for non-ARDS respiratory failure
SSC defines ongoing pressor use as at least ≥ 0.25 mcg/kg/ in sepsis. In conjunction with a low tidal volume goal,
minute of norepinephrine or epinephrine at least 4 hours a plateau pressure ≤30 cm H2O should be obtained to miti­
after initiation. The recommended dose of IV hydrocortisone gate barotrauma and volutrauma. There is a strong relation­
is 200 mg/day given as 50 mg every 6 hours or as ship between high plateau pressures and mortality [67]. The
a continuous infusion. A systematic review showed that cor­ tidal volume can be decreased further as low as 4 mL/kg to
ticosteroid use had no effect on short- or long-term mortality obtain these plateau pressures. Although be mindful that low
but did show a decrease in ICU stay, time to resolution of tidal volume can lead to ventilator desynchrony, patient dis­
shock and duration of mechanical ventilation. Corticosteroids comfort, and hypercapnia.
were not associated with an increased risk of secondary If there is refractory hypoxemia or hypercapnic respiratory
infection [61]. acidosis despite ventilator optimization, it is recommended to
A multicenter, double-blind, randomized trial of 1,241 initiate veno-venous (VV) extracorporeal membrane oxygena­
patients in the ICU compared a hydrocortisone-plus- tion (ECMO). This is certainly limited to specialized institutions
fludrocortisone group versus a placebo group. The hydrocor­ that can offer this level of care, therefore it is not generalizable
tisone-plus-fludrocortisone group showed improved survival to lower resource settings. ECMO can reduce aggressive ven­
at 90 days of 49.1% compared to 43% in the placebo group tilation methods and has been shown to lower mortality in
[62]. The combined corticosteroid group had increased vaso­ severe ARDS [68].
pressor-free days at day 28 and decreased mortality at time of
ICU and hospital discharge. The rate of serious adverse events
did not differ between the two groups aside from an increased
risk of hyperglycemia in the steroid group [62]. 12. Sepsis survivors
The new sepsis guidelines designate several recommendations
focusing on the long-term outcomes of sepsis patients. They
10. Sodium bicarbonate encompass educating patients and families and ensuring the
Sodium bicarbonate is suggested to not be used (weak recom­ appropriate support is in place upon hospital discharge. Those
mendation) in patients with septic shock and lactic acidemia who survive hospitalization for sepsis often have remaining
to improve hemodynamic values and vasopressor require­ functional limitations, cognitive impairment, stress-related
ments. This is based upon no mortality benefit compared to symptoms, and chronic health conditions. These patients are
normal saline, as seen in two small, blinded crossover RCTs at an increased risk for re-hospitalization than the general
[63,64]. population, with up to 40% being re-admitted within 3
Sodium bicarbonate has the potential adverse effects of months [69]. Providing both verbal and written sepsis infor­
hypernatremia, hypocalcemia, and metabolic alkalosis. There mation can assist patients and their families in better under­
was a multicenter RCT in 2018 involving 400 patients with standing these potential long-term complications. It is
severe metabolic acidemia (pH ≤ 7.20) who received either IV imperative to carry out discussions early regarding the goals
sodium bicarbonate or control. It did not show a difference in of care and prognosis while focusing on palliative-based prin­
the primary outcome of 28-day mortality between the groups. ciples. To ensure a smooth transition on discharge, healthcare
However, it did show mortality benefit in a subgroup of teams should screen for social and financial support and
patients with stage 2 or 3 AKI. Because of this, sepsis guide­ supply resources where needed. Outpatient providers should
lines suggest IV bicarbonate therapy for patients with septic then screen for any physical, cognitive, and emotional con­
shock and severe metabolic acidemia defined as pH ≤ 7.20 cerns in these patients.
plus concomitant AKI (AKI Network score 2 or 3) [65].

13. Conclusion
11. Oxygenation and ventilation
In summary, sepsis stands as a predominant cause of morbid­
Hypoxemia can be prevalent in sepsis in cases of pneumonia ity, mortality, and financial burden worldwide. This review has
or other infections which trigger acute respiratory distress assessed current definitions, guidelines, and treatment bun­
syndrome (ARDS). There is limited evidence regarding types dles for sepsis. As the research progresses, these guidelines
of oxygen therapy and oxygenation goals in patients with and bundles are expected to evolve further, enhancing the
sepsis. timely identification and treatment of sepsis patients [70]*.
 POSTGRADUATE MEDICINE 709

Funding 11. Puskarich M, Trzeciak S, Shapiro N, et al. Whole blood lactate

kinetics in patients undergoing quantitative resuscitation for severe
This paper was not funded. sepsis and septic shock. Chest. 2013;143(6):1548–1553. doi: 10.
1378/chest.12-0878
12. Filbin MR, Hou PC, Massey MJ, et al. The microcirculation is pre­
Declaration of financial/other relationships served in emergency department low-acuity sepsis patients with­
out hypotension. Acad Emerg Med. 2014;21(2):154–162. doi: 10.
The authors have no relevant affiliations or financial involvement with any
1111/acem.12314
organization or entity with a financial interest in or financial conflict with the
13. Morris E, McCartney D, Lasserson D, et al. Point-of-care lactate
subject matter or materials discussed in the manuscript. This includes employ­
testing for sepsis at presentation to health care: a systematic
ment, consultancies, honoraria, stock ownership or options, expert testimony,
review of patient outcomes. Br J Gen Pract. 2017;67(665):e859–
grants or patents received or pending, or royalties. Peer reviewers on this
e870. doi: 10.3399/bjgp17X693665
manuscript have no relevant financial or other relationships to disclose.
14. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is
associated with mortality in severe sepsis independent of organ
failure and shock. Crit Care Med. 2009;37(5):1670–1677. doi: 10.
Author contributions 1097/CCM.0b013e31819fcf68
Lia Desposito and Christina Bascara both collectively researched, orga­ 15. Chebl RB, Tamim H, Dagher GA, et al. Serum lactate as an
nized, drafted, and edited the manuscript. Independent predictor of In-hospital mortality in intensive care
patients. J Intensive Care Med. 2020;35(11):1257–1264. doi: 10.
1177/0885066619854355
ORCID 16. Renuka MK, Sailaja B. Blood lactate in early sepsis: a predictor to
“keep up” rather than “catch up”. Indian J Crit Care Med. 2023
Lia Desposito http://orcid.org/0009-0005-1307-6439 Feb;27(2):83–84. doi: 10.5005/jp-journals-10071-24406. PMID:
Christina Bascara http://orcid.org/0009-0007-7852-3046 36865518; PMCID: PMC9973062.
17. Puskarich MA, Shapiro NI, Massey MJ, et al. Lactate clearance in
septic shock is not a surrogate for improved microcirculatory flow.
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