Prehospital Sepsis Research Update 2024 Rom Duckworth

Duckworth, R. L. (2016a, January 25). The ABCs of Pediatric Sepsis | EMSWorld.com. EMS World Magazine.
Duckworth, R. L. (2016b, April 18). Sepsis 3.0: Implications for paramedics and prehospital care | EMS1.com. EMS1.com.
Duckworth, Rommie. (2018). Development of a program to mitigate the loss of critical information during patient handover
[Executive Fire Officer Applied Research Project, National Fire Academy]. https://usfa.bibliovation.com/app/work/247291

What’s right for
your system?

What’s right for
your patient?

Topics
Pathophysiology
• Heterogeneity
Sepsis Identification
• Biomarkers
• SepsisAlerts
PrehospitalTreatment
• FluidAdministration
• Vasopressors
• Antibiotics

Pathophysiology
Macrocirculation
Body systems and organs
BP, MAP, pulse, shock index, etc.
Microcirculation
Endothelial, smooth muscle, red blood, leukocytes, more
Arterioles, capillary beds, venules, microlymphatics
Gavelli, F., Castello, L. M., & Avanzi, G. C. (2021). Management of sepsis and septic shock in the emergency department. Internal and Emergency
Medicine, 16(6), 1649–1661. https://doi.org/10.1007/s11739-021-02735-7

Pathophysiology
Microcirculation dysfunction:What
Endothelial cells
Loss of overall response
and regulation
Increased permeability
ROS production cycle
Glycocalyx lining disruption
Miranda, M., Balarini, M., Caixeta, D., & Bouskela, E. (2016). Microcirculatory dysfunction in sepsis: Pathophysiology, clinical monitoring, and potential
therapies. American Journal of Physiology-Heart and Circulatory Physiology, 311(1), H24–H35. https://doi.org/10.1152/ajpheart.00034.2016

Pathophysiology
Smooth muscle cells
Loss of regulation
Loss of sensitivity
Nitric oxide affected
Loss of tone
Heterogenous shunting

Pathophysiology
Red blood cells
Decreased deformability
Increased aggregation
Decreased ability to release
vasodilators during hypoxia

Pathophysiology
Leukocytes
Increased adhesion
Cytokine release

Pathophysiology
Microcirculation dysfunction:Where
Arteriole
Vasodilation
Vasopressor hyporeactivity
Not Septic Septic
Not Septic Septic
Not Septic
Septic

Pathophysiology
Capillary bed
Endothelial dysfunction
Microthrombosis
Not Septic Septic
Not Septic Septic
Not Septic
Septic

Pathophysiology
Venule
Neutrophil adhesion
Neutrophil aggregation
Not Septic Septic
Not Septic Septic
Not Septic
Septic

Pathophysiology
Microcirculation dysfunction
• Hypoxia doesn’t produce expected vasodilation->decrease flow->decrease gas exchange
• Capillaries don’t regulate, they leak
• Red blood cells don’t deform, reducing flow
• Smooth muscle vasodilation where you don’t need it, no vasodilation where you need it
• Neutrophils adhere and aggregate
• Coagulation increases
• All resulting in decreased microcirculation that doesn’t make itself immediately apparent
Trzeciak, S., Cinel, I., Dellinger, R. P., Shapiro, N. I., Arnold, R. C., Parrillo, J. E., & Hollenberg, S. M. (2008). Resuscitating the Microcirculation in Sepsis: The Central
Role of Nitric Oxide, Emerging Concepts for Novel Therapies, and Challenges for Clinical Trials. Academic Emergency Medicine : Official Journal of the Society for
Academic Emergency Medicine, 15(5), 399–413. https://doi.org/10.1111/j.1553-2712.2008.00109.x

Patients arriving via EMS
tend to be
more sick
but receive care
more quickly
Loza-Gomez, A., Hofmann, E., NokLam, C., & Menchine, M. (2021). Severe sepsis and septic shock in patients transported by prehospital services versus
walk in patients to the emergency department. The American Journal of Emergency Medicine, 45, 173–178. https://doi.org/10.1016/j.ajem.2020.08.021
Depinet, H. E., Eckerle, M., Semenova, O., Meinzen-Derr, J., & Babcock, L. (2018). Characterization of Children with Septic Shock Cared for by Emergency
Medical Services. Prehospital Emergency Care
Femling, J., Weiss, S., Hauswald, E., & Tarby, D. (2014). EMS Patients and Walk-In Patients Presenting With Severe Sepsis: Differences in Management
and Outcome. Southern Medical Journal, 107(12), 751–756. https://doi.org/10.14423/SMJ.0000000000000206

Every hour of
delay can
increase
mortality 4%
Bisarya, R., Song, X., Salle, J., Liu, M., Patel, A., & Simpson, S. Q. (2022). Antibiotic Timing and Progression to Septic Shock Among Patients in the ED With Suspected Infection. CHEST, 161(1), 112–120.
https://doi.org/10.1016/j.chest.2021.06.029

EMS-specific
education
improves
care
Alam, N., Oskam, E., Stassen, P. M., Exter, P. van, van de Ven, P. M., Haak, H. R., Holleman, F., Zanten, A. van, Leeuwen-Nguyen, H. van, Bon, V., Duineveld, B. A. M., Nannan Panday, R. S.,
Kramer, M. H. H., Nanayakkara, P. W. B., & PHANTASi Trial Investigators and the ORCA (Onderzoeks Consortium Acute Geneeskunde) Research Consortium the Netherlands. (2018). Prehospital
antibiotics in the ambulance for sepsis: A multicentre, open label, randomised trial. The Lancet. Respiratory Medicine, 6(1), 40–50. https://doi.org/10.1016/S2213-2600(17)30469-1

70% of sepsis
symptoms
present in the
field
Walchok, J. G., Pirrallo, R. G., Furmanek, D., Lutz, M., Shope, C., Giles, B., Gue, G., & Dix, A. (2017). Paramedic-Initiated CMS Sepsis Core Measure Bundle Prior to Hospital Arrival: A Stepwise Approach.
Prehospital Emergency Care, 21(3), 291–300. https://doi.org/10.1080/10903127.2016.1254694

6%-36% of
cases of sepsis
are identified
by prehospital
clinicians*
Desai, M. D., Tootooni, M. S., & Bobay, K. L. (2022). Can Prehospital Data Improve Early Identification of Sepsis in Emergency Department? An Integrative Review of Machine Learning Approaches. Applied Clinical
Informatics, 13(1), 189–202. https://doi.org/10.1055/s-0042-1742369
Walchok, J. G., Pirrallo, R. G., Furmanek, D., Lutz, M., Shope, C., Giles, B., Gue, G., & Dix, A. (2017). Paramedic-Initiated CMS Sepsis Core Measure Bundle Prior to Hospital Arrival: A Stepwise Approach. Prehospital
Emergency Care, 21(3), 291–300. https://doi.org/10.1080/10903127.2016.1254694

In one large US EMS system
Approximately
50% of
prehospital
sepsis patients
do not get any
fluid therapy
Miller, N. S., Patel, M. D., Williams, J. G., Bachman, M. W., Cyr, J. M., Cabañas, J. G., & Brice, J. H. (2023). Prehospital Fluid Administration for Suspected Sepsis in a Large EMS System: Opportunities to Improve Goal
Fluid Delivery. Prehospital Emergency Care, 1–6. https://doi.org/10.1080/10903127.2023.2203526

In one large US EMS system
Approximately
50% getting
fluids did not
meet their fluid
resus goal
Miller, N. S., Patel, M. D., Williams, J. G., Bachman, M. W., Cyr, J. M., Cabañas, J. G., & Brice, J. H. (2023). Prehospital Fluid Administration for Suspected Sepsis in a Large EMS System: Opportunities to Improve Goal
Fluid Delivery. Prehospital Emergency Care, 1–6. https://doi.org/10.1080/10903127.2023.2203526

Prehospital Sepsis Alert
decreased time to treatment
30-60minutes
13.6% vs 26.7%
Halimi, K., Freeman-Garrick, J., Agcaoili, C., Choy, K., Claridge, F., Jacobs, M., & Taigman, M. (2011). Prehospital identification of sepsis patients and alerting of receiving hospitals: impact on early goal-directed therapy.
Crit Care, 15, P26. https://doi.org/10.1186/cc10395

EMS identifies between 6%-36%.
Higher scores were related to more in-
depth evaluations.
Sjösten, O., Nilsson, J., Herlitz, J., Axelsson, C., Jiménez-Herrera, M., & Andersson Hagiwara, M. (2019). The prehospital assessment of patients with a final hospital
diagnosis of sepsis: Results of an observational study. Australasian Emergency Care, 22(3), 187–192. https://doi.org/10.1016/j.auec.2019.02.002

“Early detection and treatment of sepsis
improves chances of survival; however,
sepsis is often difficult to diagnose initially.
This is especially true in the prehospital
setting, where resources are scarce, yet time
is of great significance.”
Oanesa, R. D., Su, T. W.-H., & Weissman, A. (2023). Evidence for Use of Validated Sepsis Screening Tools in the Prehospital
Population: A Scoping Review. Prehospital Emergency Care, 0(0), 1–9. https://doi.org/10.1080/10903127.2023.2224862

SIRS
qSOFA
BAS 90-30-90
Robson
MEWS
NEWS
HEWS
CIP
MBIS
PITSTOP
SIGARC
PRESS
MSI,SI
RETTS
PRESEP
Miami
SEPSIS
SIP
PSPoT
ESI
DTS
De Silva, M., Chadwick, W., & Naidoo, N. (2023). Screening tools for sepsis identification in paramedicine and other emergency
contexts: A rapid systematic review. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 31(1), 74.
https://doi.org/10.1186/s13049-023-01111-y

“…there is currently a paucity of evidence in the
emergency setting and further research is
required.”
“The authors propose that the implementation
of a sepsis screening tool is prudent in the
emergency setting…”
De Silva, M., Chadwick, W., & Naidoo, N. (2023). Screening tools for sepsis identification in paramedicine and other emergency
contexts: A rapid systematic review. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 31(1), 74.
https://doi.org/10.1186/s13049-023-01111-y

“…we recommend future efforts focus on combining standardized
prehospital care with clinical judgment to provide timely
interventions for unstable patients where infection is considered a
likely etiology, in addition to improving sepsis education for
prehospital clinicians.
At most, EWS can be used as an adjunct to these efforts, but they
should not be relied on alone for prehospital sepsis identification.”

“The variety of available EWS and study
design heterogeneity suggest it is unlikely
that new research can identify a single gold
standard score.”

“No strategy is ideal but using NEWS2 alongside
paramedic diagnostic impression of infection or
sepsis could identify one-third to half of sepsis
cases without prioritising unmanageable
numbers. No other score provided clearly
superior accuracy to NEWS2.”
Goodacre, S., Sutton, L., Thomas, B., Hawksworth, O., Iftikhar, K., Croft, S., Fuller, G., Waterhouse, S., Hind, D., Bradburn, M., Smyth, M. A., Perkins,
G. D., Millins, M., Rosser, A., Dickson, J. M., & Wilson, M. J. (2023). Prehospital early warning scores for adults with suspected sepsis: Retrospective
diagnostic cohort study. Emergency Medicine Journal, 40(11), 768–776. https://doi.org/10.1136/emermed-2023-213315

The qSOFA
Shu, E., Ives Tallman, C., Frye, W., Boyajian, J. G., Farshidpour, L., Young, M., & Campagne, D. (2019). Pre-hospital qSOFA as a predictor
of sepsis and mortality. The American Journal of Emergency Medicine, 37(7), 1273–1278. https://doi.org/10.1016/j.ajem.2018.09.025

Machine Learning &
Artificial Intelligence

AI / Machine Learning Models
Artificial Intelligence has potential to improve identification of septic patients.
Generalizability of artificial intelligence (AI) algorithms is still poor.
AI models are often at high risk of bias due to predictor variables in the outcome.
Insufficient availability of data will decreaseAI accuracy in clinical practice.
There is a large gap between creation and clinical implementation of algorithms.
Desai, M. D., Tootooni, M. S., & Bobay, K. L. (2022). Can Prehospital Data Improve Early Identification of Sepsis in Emergency Department?
An Integrative Review of Machine Learning Approaches. Applied Clinical Informatics, 13(1), 189–202. https://doi.org/10.1055/s-0042-
1742369
Schinkel, M., Paranjape, K., Nannan Panday, R. S., Skyttberg, N., & Nanayakkara, P. W. B. (2019). Clinical applications of artificial intelligence
in sepsis: A narrative review. Computers in Biology and Medicine, 115, 103488. https://doi.org/10.1016/j.compbiomed.2019.103488
Koyama, S., Yamaguchi, Y., Gibo, K., Nakayama, I., & Ueda, S. (2019). Use of prehospital qSOFA in predicting in-hospital mortality in patients
with suspected infection: A retrospective cohort study. PLOS ONE, 14(5), e0216560. https://doi.org/10.1371/journal.pone.0216560

Heterogeneity
Sepsis classification stratified by illness severity or age without
differentiation by pathophysiology
Patients with sepsis are highly heterogeneous
Recommendations often show overall benefit, but do not
necessarily benefit the patient in front of you
Recommendations serve as a starting point
DeMerle, K. M., Angus, D. C., Baillie, J. K., Brant, E., Calfee, C. S., Carcillo, J., Chang, C.-C. H., Dickson, R., Evans, I., Gordon, A. C., Kennedy, J., Knight,
J. C., Lindsell, C. J., Liu, V., Marshall, J. C., Randolph, A. G., Scicluna, B. P., Shankar-Hari, M., Shapiro, N. I., … Seymour, C. W. (2021). Sepsis Subclasses:
A Framework for Development and Interpretation. Critical Care Medicine, 49(5), 748–759. https://doi.org/10.1097/CCM.0000000000004842

Heterogeneity
Potential groupings
• Preexisting comorbid disease
• Presence of multiple organ dysfunction
• High risk of mortality
• Likelihood of responding to a specific therapy based on
an underlying biological mechanism, irrespective of
prognosis
Schuler, A., Wulf, D. A., Lu, Y., Iwashyna, T. J., Escobar, G. J., Shah, N. H., & Liu, V. X. (2018). The impact of acute organ dysfunction on long-term survival
among sepsis survivors. Critical Care Medicine, 46(6), 843–849. https://doi.org/10.1097/CCM.0000000000003023
Seymour, C. W., Gomez, H., Chang, C.-C. H., Clermont, G., Kellum, J. A., Kennedy, J., Yende, S., & Angus, D. C. (2017). Precision medicine for all?
Challenges and opportunities for a precision medicine approach to critical illness. Critical Care, 21, 257. https://doi.org/10.1186/s13054-017-1836-5

Biomarkers
Lactate and ETCO2
“While ETCO2 predicted the initial ED
lactate levels it did not predict diagnosed
infection, admission to the hospital or
ICU admission in our patient population
but did predict mortality.”
Hunter, C. L., Silvestri, S., Ralls, G., Stone, A., Walker, A., & Papa, L. (2016). A prehospital screening tool utilizing end-tidal carbon dioxide predicts sepsis
and severe sepsis. The American Journal of Emergency Medicine, 34(5), 813–819. https://doi.org/10.1016/j.ajem.2016.01.017
Weiss, S. J., Guerrero, A., Root-Bowman, C., Ernst, A., Krumperman, K., Femling, J., & Froman, P. (2019). Sepsis alerts in EMS and the results of pre-hospital
ETCO2. The American Journal of Emergency Medicine, 37(8), 1505–1509. https://doi.org/10.1016/j.ajem.2018.11.009

Biomarkers
An elevated shock index mirrors an elevated
lactate and as such appears to provide a reliable
“invisible lactate” surrogate for use in the field.
Banerjee, A., Stead, T., Barbera, A., Weech, M., Melton, J., Campion, B., Ganti, L., & Banerjee, P. (2021). 6 Evaluation of the Shock Index for
Out-of-Hospital Sepsis Recognition. Annals of Emergency Medicine, 78(4), S3–S4. https://doi.org/10.1016/j.annemergmed.2021.09.014

Shock Index
SI < 0.6 NORMAL
SI > 0.6 - <1.0 MILD
SI > 1.0 - <1.4 MOD.
SI > 1.4 SEVERE
HR/SBP=SI
80/120=0.6
100/100=1
120/100=1.2
Banerjee, A., Stead, T., Barbera, A., Weech, M., Melton, J., Campion, B., Ganti, L., & Banerjee, P. (2021). 6 Evaluation of the Shock Index for Out-of-
Hospital Sepsis Recognition. Annals of Emergency Medicine, 78(4), S3–S4. https://doi.org/10.1016/j.annemergmed.2021.09.014
Berger, T., Green, J., Horeczko, T., Hagar, Y., Garg, N., Suarez, A., Panacek, E., & Shapiro, N. (2013). Shock Index and Early Recognition of Sepsis in the
Emergency Department: Pilot Study. Western Journal of Emergency Medicine, 14(2), 168–174. https://doi.org/10.5811/westjem.2012.8.11546

Mod. Shock Index
MSI < 1.0 NORMAL
MSI > 1.0- <1.3 MILD
MSI > 1.4 - <2.0 MOD.
MSI > 2.0 SEVERE
HR/MAP=MSI
80/80=1.0
100/70=1.4
120/65=1.8
Althunayyan, S. M., Alsofayan, Y. M., & Khan, A. A. (2019). Shock index and modified shock index as triage screening tools for sepsis. Journal of Infection
and Public Health, 12(6), 822–826. https://doi.org/10.1016/j.jiph.2019.05.002

Biomarkers
Procalcitonin (PCT)
A peptide precursor of calcitonin widely used for differentiating bacterial vs. non-
bacterial infections or other inflammatory conditions.
PCT associated with clinical evaluation was less effective than clinical evaluation
alone with respect to deciding when to start antimicrobials
Correlates with lactate and mortality.
Is not a “sepsis test”
Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C., Schorr, C., Simpson,
S., Joost Wiersinga, W., Alshamsi, F., Angus, D. C., Arabi, Y., Azevedo, L., Beale, R., Beilman, G., … Levy, M. (2021). Executive Summary: Surviving Sepsis Campaign:
International Guidelines for the Management of Sepsis and Septic Shock 2021. Critical Care Medicine, 49(11), 1974.

Biomarkers
C-reactive protein (CRP)
An acute phase reactant and a sensitive marker found in sepsis
When there is an acute infection or inflammation, the concentration ofCRP in the
blood can be measured, which can be elevated as early as two hours after the
triggering event, reaching peak values in 48 hours
Is not a “sepsis test”
Tan, M., Lu, Y., Jiang, H., & Zhang, L. (2019). The diagnostic accuracy of procalcitonin and C-reactive protein for sepsis: A systematic review and meta-analysis.
Journal of Cellular Biochemistry, 120(4), 5852–5859. https://doi.org/10.1002/jcb.27870

Biomarkers
Presepsin (PSP)
A soluble N-terminal fragment of the cluster of differentiation
marker protein 14 (CD14)
Proposed as alternative biomarker to PCT because of its higher
accuracy in the identification and prognostic prediction of
sepsis/septic shock
Higher costs and lower laboratory availability
Shozushima, T., Takahashi, G., Matsumoto, N., Kojika, M., Okamura, Y., & Endo, S. (2011). Usefulness of presepsin (sCD14-ST) measurements as a
marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. Journal of Infection
and Chemotherapy: Official Journal of the Japan Society of Chemotherapy, 17(6), 764–769. https://doi.org/10.1007/s10156-011-0254-x
Velissaris, D., Zareifopoulos, N., Karamouzos, V., Karanikolas, E., Pierrakos, C., Koniari, I., & Karanikolas, M. (2021). Presepsin as a Diagnostic and
Prognostic Biomarker in Sepsis. Cureus, 13(5), e15019. https://doi.org/10.7759/cureus.15019

Biomarkers
High MobilityGroup Box Protein 1 (HMGB1)
Released into circulation as part of an early inflammatory response
Activates innate immune cells.
Finding to cell surface receptors, HMGB1 activates endothelial cells, further
increasing the production of pro-inflammatory cytokines and chemokines
Higher concentrations of HMGB1 are associated with mortality in sepsis, and
modulation of HMGB1-mediated responses has been shown to reduce mortality
in animal models.
Shozushima, T., Takahashi, G., Matsumoto, N., Kojika, M., Okamura, Y., & Endo, S. (2011). Usefulness of presepsin (sCD14-ST) measurements as a
marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. Journal of Infection
and Chemotherapy: Official Journal of the Japan Society of Chemotherapy, 17(6), 764–769. https://doi.org/10.1007/s10156-011-0254-x

Biomarkers
Nanotechnology
Nanoparticles (NPs) such as magnetic NPs, gold NPs, fluorescent (silica and quantum
dots), and lipid-based NPs have all been discussed to contribute to the detection of
sepsis-related microbial infections.
Detect and quantify sepsis
Antibiotic effects
Reducing inflammation and reactive oxygen and nitrogen species (RONS) in sepsis
Toxicity of nanotherapies in clinical translation is a major issue
Choudhary, R. (2022). Sepsis Management, Controversies, and Advancement in Nanotechnology: A Systematic Review.
Cureus, 14(2), e22112. https://doi.org/10.7759/cureus.22112
Vasconcelos, I., & Santos, T. (2023). Nanotechnology Applications in Sepsis: Essential Knowledge for Clinicians.
Pharmaceutics, 15(6), Article 6. https://doi.org/10.3390/pharmaceutics15061682

Biomarkers
Nanotechnology
Soap bubble site-specific deliver of antibiotics
Horsley, H., Owen, J., Browning, R., Carugo, D., Malone-Lee, J., Stride, E., & Rohn, J. L. (2019). Ultrasound-activated
microbubbles as a novel intracellular drug delivery system for urinary tract infection. Journal of Controlled Release,
301, 166–175. https://doi.org/10.1016/j.jconrel.2019.03.017

Vasconcelos, I., & Santos, T. (2023). Nanotechnology Applications in Sepsis: Essential Knowledge for Clinicians. Pharmaceutics,
15(6), Article 6. https://doi.org/10.3390/pharmaceutics15061682

SEPSIS ALERT
Code Sepsis
Sepsis Alert

SIRS
qSOFA
BAS 90-30-90
Robson
MEWS
NEWS
HEWS
CIS
MBIS
PITSTOP
SIGARC
PRESS
MSI,SI
RETTS
PRESEP
Miami
SEPSIS
SIP
PSPoT
ESI
DTS

Sepsis Alerts/Code Sepsis
Prehospital sepsis alerts decrease time
to antibiotics, fluid administration, and
sepsis bundle delivery, but do not appear
to improve morbidity and mortality
Within a system that already had robust sepsis care
care
Troncoso, R., Garfinkel, E. M., Hinson, J. S., Smith, A., Margolis, A. M., & Levy, M. J. (2023). Do prehospital sepsis alerts decrease time to
complete CMS sepsis measures? The American Journal of Emergency Medicine, 71, 81–85. https://doi.org/10.1016/j.ajem.2023.06.024

Fluid
Administration
CLOVERSTrial:
Early Restrictive or Liberal Management for
Sepsis-Induced Hypotension
Restrictive strategy had no lower or higher
mortality by 90 days
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro, N. I., Douglas,
I. S., Brower, R. G., Brown, S. M., Exline, M. C., Ginde, A. A., Gong, M. N., Grissom, C. K., Hayden, D., Hough, C. L., Huang, W., Iwashyna, T. J.,
Jones, A. E., Khan, A., Lai, P., Liu, K. D., Miller, C. D., Oldmixon, K., … Self, W. H. (2023). Early Restrictive or Liberal Fluid Management for
Sepsis-Induced Hypotension. The New England Journal of Medicine, 388(6), 499–510. https://doi.org/10.1056/NEJMoa2212663

Fluid
Administration
CLOVERSTrial:
Early Restrictive or Liberal Management for
Sepsis-Induced Hypotension
Hypotensive unresponsive 1-3L in 4 hrs (not
early for EMS)
5L before pressor or pressor +500mL
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro, N. I., Douglas,
I. S., Brower, R. G., Brown, S. M., Exline, M. C., Ginde, A. A., Gong, M. N., Grissom, C. K., Hayden, D., Hough, C. L., Huang, W., Iwashyna, T. J.,
Jones, A. E., Khan, A., Lai, P., Liu, K. D., Miller, C. D., Oldmixon, K., … Self, W. H. (2023). Early Restrictive or Liberal Fluid Management for
Sepsis-Induced Hypotension. The New England Journal of Medicine, 388(6), 499–510. https://doi.org/10.1056/NEJMoa2212663

Fluid
Administration
CLASSICTrial:
Restriction of Intravenous Fluid in ICU
Patients withSepticShock
Restrictive strategy had no lower or
higher mortality by 90 days
Meyhoff, T. S., Hjortrup, P. B., Wetterslev, J., Sivapalan, P., Laake, J. H., Cronhjort, M., Jakob, S. M., Cecconi, M., Nalos, M., Ostermann, M., Malbrain, M., Pettilä,
V., Møller, M. H., Kjær, M.-B. N., Lange, T., Overgaard-Steensen, C., Brand, B. A., Winther-Olesen, M., White, J. O., … CLASSIC Trial Group. (2022). Restriction of
Intravenous Fluid in ICU Patients with Septic Shock. The New England Journal of Medicine, 386(26), 2459–2470. https://doi.org/10.1056/NEJMoa2202707

Fluid
Administration
CLASSICTrial:
Restriction of Intravenous Fluid in ICU
Patients withSepticShock
Lactate over 2 mmol/dL
On pressors + 1L already
Meyhoff, T. S., Hjortrup, P. B., Wetterslev, J., Sivapalan, P., Laake, J. H., Cronhjort, M., Jakob, S. M., Cecconi, M., Nalos, M., Ostermann, M., Malbrain, M., Pettilä,
V., Møller, M. H., Kjær, M.-B. N., Lange, T., Overgaard-Steensen, C., Brand, B. A., Winther-Olesen, M., White, J. O., … CLASSIC Trial Group. (2022). Restriction of
Intravenous Fluid in ICU Patients with Septic Shock. The New England Journal of Medicine, 386(26), 2459–2470. https://doi.org/10.1056/NEJMoa2202707

Fluid Administration
“The administration of
prehospital fluid and
placement of intravenous
access were associated with
decreased odds of hospital
mortality compared with no
prehospital catheter or fluid.”
Seymour, C. W., Cooke, C. R., Heckbert, S. R., Spertus, J. A., Callaway, C. W., Martin-Gill, C., Yealy, D. M., Rea, T. D., & Angus, D. C.
(2014). Prehospital intravenous access and fluid resuscitation in severe sepsis: An observational cohort study. Critical Care
(London, England), 18(5), 533. https://doi.org/10.1186/s13054-014-0533-x

5Cohort studies (2 EMS/3 ED)
Improved mortality with earlier fluid resuscitation
Ward, M. A., Kuttab, H. I., Tuck, N., Taleb, A., Okut, H., & Badgett, R. G. (2022). The Effect of Fluid Initiation Timing on Sepsis Mortality:
A Meta-Analysis. Journal of Intensive Care Medicine, 37(11), 1504–1511. https://doi.org/10.1177/08850666221118513

“Intravenous fluids provided by
paramedics were associated with
reduced in-hospital mortality for
patients with sepsis and hypotension
but not for those with a higher initial
systolic blood pressure.”
Lane, D. J., Wunsch, H., Saskin, R., Cheskes, S., Lin, S., Morrison, L. J., & Scales, D. C. (2018). Association Between
Early Intravenous Fluids Provided by Paramedics and Subsequent In-Hospital Mortality Among Patients With Sepsis.
JAMA Network Open, 1(8), e185845. https://doi.org/10.1001/jamanetworkopen.2018.5845

“Pre-hospital fluid resuscitation in septic
shock is mainly performed using crystalloids
with quantitative fluid expansion lower than
recommended. Low pre-hospital fluid
expansion was associated with increased
mortality. Further prospective studies are
needed to evaluate the impact of optimized
early fluid expansion on mortality in the
prehospital management of septic shock.”
Jouffroy, R., Saade, A., Muret, A., Philippe, P., Michaloux, M., Carli, P., & Vivien, B. (2018). Fluid resuscitation in pre-hospital
management of septic shock. The American Journal of Emergency Medicine, 36(10), 1754–1758.
https://doi.org/10.1016/j.ajem.2018.01.078

Fluid resuscitation in patients with sepsis
reduces in-hospital mortality
Bigger differences with more fluid and more
severe septic shock
Too much is bad, but EMS tends to not give
enough
Kabil, G., Liang, S., Delaney, A., Macdonald, S., Thompson, K., Saavedra, A., Suster, C., Moscova, M., McNally, S., Frost, S., Hatcher, D., & Shetty, A. (2022).
Association between intravenous fluid resuscitation and outcome among patients with suspected infection and sepsis: A retrospective cohort study.
Emergency Medicine Australasia, 34(3), 361–369. https://doi.org/10.1111/1742-6723.13893
Miller, N. S., Patel, M. D., Williams, J. G., Bachman, M. W., Cyr, J. M., Cabañas, J. G., & Brice, J. H. (2023). Prehospital Fluid Administration for Suspected Sepsis
in a Large EMS System: Opportunities to Improve Goal Fluid Delivery. Prehospital Emergency Care, 1–6. https://doi.org/10.1080/10903127.2023.2203526

Individualized treatment targeted toward
“glycocalyx resuscitation” according to fluid
tolerance (FT) and fluid responsiveness (FR)
FR may be evaluated by passive leg raise or
POCUS monitoring of the collapse of the
inferior vena cava
Bakker, J., Kattan, E., Annane, D., Castro, R., Cecconi, M., De Backer, D., Dubin, A., Evans, L., Gong, M. N., Hamzaoui, O., Ince, C., Levy, B., Monnet, X., Ospina Tascón, G. A.,
Ostermann, M., Pinsky, M. R., Russell, J. A., Saugel, B., Scheeren, T. W. L., … Hernandez, G. (2022). Current practice and evolving concepts in septic shock resuscitation.
Intensive Care Medicine, 48(2), 148–163. https://doi.org/10.1007/s00134-021-06595-9
Guarino, M., Perna, B., Cesaro, A. E., Maritati, M., Spampinato, M. D., Contini, C., & De Giorgio, R. (2023). 2023 Update on Sepsis and Septic Shock in Adult Patients:
Management in the Emergency Department. Journal of Clinical Medicine, 12(9), Article 9. https://doi.org/10.3390/jcm12093188

Interventions
Time
Standard care: slow initial
shock reversal, long-term f
overload
Early reversal of
shock &
hypotension Stabilization, titration
of vasopressors
De-resuscitation:
further fluid intake
minimized, diuresis
c/o Dr. Mark Phiel

Vasoactive Agents
Target MAP of >65 mm/Hg
Consider 60-65 mm/Hg
Lower is bad
Greater showed no significant benefit
Lamontagne, F., Meade, M. O., Hébert, P. C., Asfar, P., Lauzier, F., Seely, A. J. E., Day, A. G., Mehta, S., Muscedere, J., Bagshaw, S. M.,
Ferguson, N. D., Cook, D. J., Kanji, S., Turgeon, A. F., Herridge, M. S., Subramanian, S., Lacroix, J., Adhikari, N. K. J., Scales, D. C., …
Canadian Critical Care Trials Group. (2016). Higher versus lower blood pressure targets for vasopressor therapy in shock: A
multicentre pilot randomized controlled trial. Intensive Care Medicine, 42(4), 542–550. https://doi.org/10.1007/s00134-016-4237-3
Lamontagne, F., Richards-Belle, A., Thomas, K., Harrison, D. A., Sadique, M. Z., Grieve, R. D., Camsooksai, J., Darnell, R., Gordon, A.
C., Henry, D., Hudson, N., Mason, A. J., Saull, M., Whitman, C., Young, J. D., Rowan, K. M., Mouncey, P. R., & 65 trial investigators.
(2020). Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory
Hypotension: A Randomized Clinical Trial. JAMA, 323(10), 938–949. https://doi.org/10.1001/jama.2020.0930

Vasoactive Agents
Norepinephrine (NE)
An α-1/β-1 adrenergic agonist that enhances
vascular filling pressure and redistributes blood flow
via a venoconstrictive effect
NE is a primary pressor in managing sepsis
Hernández, G., Teboul, J.-L., & Bakker, J. (2019). Norepinephrine in septic shock. Intensive Care Medicine, 45(5), 687–689. https://doi.org/10.1007/s00134-018-5499-8
Shi, R., Hamzaoui, O., De Vita, N., Monnet, X., & Teboul, J.-L. (2020). Vasopressors in septic shock: Which, when, and how much? Annals of Translational Medicine,
8(12), 794. https://doi.org/10.21037/atm.2020.04.24

Vasoactive Agents
Norepinephrine (NE)
Various studies have demonstrated that early
administration (at a dose of 0.1–1.2 μg/kg/min) may improve
outcomes
Shown to be effective in shortening length of
stay (LOS) and reducing mortality
Alshahrani, M. S., & Alatigue, R. (2021). Association Between Early Administration of Norepinephrine in Septic Shock and Survival. Open Access
Emergency Medicine : OAEM, 13, 143–150. https://doi.org/10.2147/OAEM.S298315
Xu, F., Zhong, R., Shi, S., Zeng, Y., & Tang, Z. (2022). Early initiation of norepinephrine in patients with septic shock: A propensity score-based analysis.
The American Journal of Emergency Medicine, 54, 287–296. https://doi.org/10.1016/j.ajem.2022.01.063

Vasoactive Agents
Norepinephrine (NE)
Since the β-adrenergic component of cardiomyocytes
has not yet been altered in the early stages of shock,
prompt NE infusion improves coronary perfusion by
increasing atrial diastolic pressure
Early inotropic administration seems to successfully
resuscitate microcirculation, with a consequent
improvement in tissue perfusion and oxygenation
Hamzaoui, O., Jozwiak, M., Geffriaud, T., Sztrymf, B., Prat, D., Jacobs, F., Monnet, X., Trouiller, P., Richard, C., & Teboul, J. L. (2018). Norepinephrine exerts an
inotropic effect during the early phase of human septic shock. British Journal of Anaesthesia, 120(3), 517–524. https://doi.org/10.1016/j.bja.2017.11.065

Vasoactive Agents
Vasopressin (VP)
May be considered a second-line choice for septic shock
treatment alone or in addition to NE to obtain the target
MAP by decreasing the dosage of the latter and
reducing the side effects due to adrenergic overload
Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., Machado, F. R., Mcintyre, L., Ostermann, M., Prescott, H. C.,
Schorr, C., Simpson, S., Joost Wiersinga, W., Alshamsi, F., Angus, D. C., Arabi, Y., Azevedo, L., Beale, R., Beilman, G., … Levy, M. (2021). Executive
Summary: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock 2021. Critical Care Medicine,
49(11), 1974. https://doi.org/10.1097/CCM.0000000000005357

Vasoactive Agents
Epinephrine
Epinephrine should be considered as a third-line
treatment for septic shock, and its use should be
limited to those cases with inadequate MAP levels
despite NE andVP administration*
Townsend, S. R., Phillips, G. S., Duseja, R., Tefera, L., Cruikshank, D., Dickerson, R., Nguyen, H. B., Schorr, C. A., Levy, M. M., Dellinger, R. P.,
Conway, W. A., Browner, W. S., & Rivers, E. P. (2022). Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality
Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study. Chest, 161(2), 392–406.
https://doi.org/10.1016/j.chest.2021.07.2167

Vasoactive Agents
Push-dose (bolus) pressors
Epi andVasopressin remain controversial
Push dose (bolus) pressors can rapidly reverse
decompensating shock
Kubena, A., Weston, S., & Alvey, H. (2022). Push-dose vasopressors in the Emergency Department: A narrative review.
Journal of Emergency and Critical Care Medicine, 6, 22–22. https://doi.org/10.21037/jeccm-21-98

Vasoactive Agents
Multiple vasopressors
Early administration of multimodal vasopressors may
have several benefits.
First, different vasopressors have complementary
mechanisms of action
Changes in the host genotype varying organ-specific
receptor expressions, and downregulation of distinct
tissues may result in a heterogeneous response to
different types of vasopressors
Tong, X., Xue, X., Duan, C., & Liu, A. (2023). Early administration of multiple vasopressors is associated with better survival in patients with sepsis:
A propensity score-weighted study. European Journal of Medical Research, 28(1), 249. https://doi.org/10.1186/s40001-023-01229-w

Prehospital Antibiotics
Alam, N., Oskam, E., Stassen, P. M., Exter, P. van, van de Ven, P. M., Haak, H. R., Holleman, F., Zanten, A. van, Leeuwen-Nguyen, H. van, Bon, V.,
Duineveld, B. A. M., Nannan Panday, R. S., Kramer, M. H. H., Nanayakkara, P. W. B., & PHANTASi Trial Investigators and the ORCA (Onderzoeks
Consortium Acute Geneeskunde) Research Consortium the Netherlands. (2018). Prehospital antibiotics in the ambulance for sepsis: A
multicentre, open label, randomised trial. The Lancet. Respiratory Medicine, 6(1), 40–50. https://doi.org/10.1016/S2213-2600(17)30469-1
PHANTASiTrail:
“EMS personnel training improved early
recognition and care in the whole acute
care chain. However, giving antibiotics in
the ambulance did not lead to improved
survival, regardless of illness severity.”

Martel, T., Melmer, M., Leaman, S., Kassen, N., Kozlowski, S., Pangia, J., Gutovitz, S., & Jehle, D. (2020). Prehospital Antibiotics Improve Morbidity and
Mortality of Emergency Medical Service Patients with Sepsis. HCA Healthcare Journal of Medicine, 1(3). https://doi.org/10.36518/2689-0216.1063
Nannan Panday, R. S., Lammers, E. M. J., Alam, N., & Nanayakkara, P. W. B. (2019). An overview of positive cultures and clinical outcomes in septic
patients: A sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial. Critical Care, 23, 182. https://doi.org/10.1186/s13054-019-2431-8
Schinkel, M., Paranjape, K., Kundert, J., Nannan Panday, R. S., Alam, N., & Nanayakkara, P. W. B. (2021). Towards Understanding the Effective Use of
Antibiotics for Sepsis. Chest, 160(4), 1211–1221. https://doi.org/10.1016/j.chest.2021.04.038
Schinkel, M., Paranjape, K., Nannan Panday, R. S., Skyttberg, N., & Nanayakkara, P. W. B. (2019). Clinical applications of artificial intelligence in sepsis: A
narrative review. Computers in Biology and Medicine, 115, 103488. https://doi.org/10.1016/j.compbiomed.2019.103488
PHANTASiTrail:
Subgroup analysis showed benefits of prehospital antibiotics
among younger patients, patients who meet a modified qSOFA
score and others
Application ofAI to combat the problem of heterogeneity

Martel, T., Melmer, M., Leaman, S., Kassen, N., Kozlowski, S., Pangia, J., Gutovitz, S., & Jehle, D. (2020). Prehospital Antibiotics Improve Morbidity
and Mortality of Emergency Medical Service Patients with Sepsis. HCA Healthcare Journal of Medicine, 1(3). https://doi.org/10.36518/2689-
0216.1063
Systematic Review and Meta-analysis
“prehospital antibiotics can significantly
lower mortality in sepsis patients
compared to patients who do not receive
prehospital antibiotics.”

Poynter, M. J., Farrugia, A., Kelly, E., & Simpson, P. M. (2023). Prehospital administration of antibiotics in addition to usual care versus usual care
alone for patients with suspected sepsis – a systematic review. Paramedicine, 27536386231207055.
https://doi.org/10.1177/27536386231207055
“found insufficient evidence that
prehospital administration of antibiotics in
addition to usual care to patients with
sepsis, compared to usual care alone
(oxygen and IV fluids), makes a significant
difference in mortality, length of stay in
hospital, or length of stay in ICU.”

Poynter, M. J., Farrugia, A., Kelly, E., & Simpson, P. M. (2023). Prehospital administration of antibiotics in addition to usual care versus usual care
alone for patients with suspected sepsis – a systematic review. Paramedicine, 27536386231207055.
https://doi.org/10.1177/27536386231207055
“A recommendation for implementation of a
protocol for routine empirical administration
cannot be made, and future research should be sure
to explore the threshold, in relation to prehospital
time interval and severity of sepsis, at which
prehospital antibiotics should be administered to
patients with sepsis. Investigation of harms and/or
safety, and health economics were beyond the scope
of this review but require exploration alongside
future research examining effectiveness..”

PRO
• Benefit of earlier tx
• Many FP or culture neg
• Alive for longerABX tx
• New bottles decrease antibiotic
activity by 90% within 1-2 hours
ABX prior to BloodCultures
CON
• IncreasedC. Difficile
• Bacterial resistance
• Hospital bed availability
• Questions remain on
significance of benefit of
waiting forABX in the ED

Eye contact
Environment
Ensure ABCs
Structured report
Supply documentation
Duckworth, R. L. (2016). Five Ways to Perfect the Patient Handoff It’s a perilous transition for the patient; here’s how to help it go smoother.
EMS World, 45(11), 38–44, 64.
Duckworth, R. L. (2018). Development of a program to mitigate loss of critical information during patient handover. National Fire Academy,.

Quality Improvement
“Significant challenges to implementation of a
sepsis protocol and delivery of prehospital
sepsis care are perceived by jurisdictional
medical directors
Additional investment and dedication to sepsis
care will advance prehospital sepsis treatment”
Kotnarin, R., Sirinawee, P., & Supasaovapak, J. (2023). Impact of Prehospital Antibiotics on in-Hospital Mortality in Emergency
Medical Service Patients with Sepsis. Open Access Emergency Medicine : OAEM, 15, 199–206.
https://doi.org/10.2147/OAEM.S413791

Prehospital Sepsis Research Update 2024 Rom Duckworth

Prehospital Sepsis Research Update 2024 Rom Duckworth

Recommended

Recommended

More Related Content

Similar to Prehospital Sepsis Research Update 2024 Rom Duckworth

Similar to Prehospital Sepsis Research Update 2024 Rom Duckworth (20)

More from Rommie Duckworth

More from Rommie Duckworth (20)

Recently uploaded

Recently uploaded (20)

Prehospital Sepsis Research Update 2024 Rom Duckworth