Effects of Code Sepsis Implementation on Emergency Department (ED) Sepsis Care
Phase: NA
Conditions: Sepsis
Sponsor: Intermountain Health Care, Inc.

 
Effects of Code Sepsis Implementation on ED Sepsis Care (Code Sepsis) 
 
 
 
Protocol version: 
Version 9.0 
 
Updated: 
 
February 1, 2023 
 
Principal Investigator:  Ithan Peltan, MD, MSc 
 
 
 
 
 
Trial steering committee: 
Ithan Peltan, MD, MSc 
 
 
 
Samuel Brown, MD, MPH 
 
 
 
Joseph Bledsoe, MD 
 
Facilities involved: 
Intermountain Medical Center 
 
Utah Valley Hospital 
 
 
Dixie Regional Medical Center 
 
Sponsor:  
National Institutes of Health (1K23 GM12966-01A1)  
 
 
 

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TABLE OF CONTENTS 
 
1. ABBREVIATIONS AND DEFINITIONS .......................................................................................... 4 
1.1 Abbreviations ............................................................................................................................................... 4 
1.2 Definitions ..................................................................................................................................................... 5 
2. STUDY SUMMARY ................................................................................................................................ 6 
2.1 Title ................................................................................................................................................................ 6 
2.2 Primary Objective ........................................................................................................................................ 6 
2.3 Primary Hypothesis ..................................................................................................................................... 6 
2.4 Study Design ................................................................................................................................................. 6 
2.4.1 Study groups and phases .................................................................................................................................................. 6 
2.4.2 Inclusion criteria ................................................................................................................................................................... 6 
2.4.3 Exclusion criteria .................................................................................................................................................................. 6 
2.4.5 Primary analysis cohort ..................................................................................................................................................... 7 
2.4.6 Primary outcome ................................................................................................................................................................. 7 
2.4.7 Secondary outcomes .......................................................................................................................................................... 7 
2.4.8 Data analysis .......................................................................................................................................................................... 7 
2.4.9 Sample size ............................................................................................................................................................................. 7 
3. TRIAL DESCRIPTION ............................................................................................................................. 8 
3.1 Background ................................................................................................................................................... 8 
3.2 Overall Study Motivation, Aim and Hypothesis ..................................................................................... 8 
3.3 Primary Objective ........................................................................................................................................ 9 
3.4 Primary Hypothesis ..................................................................................................................................... 9 
3.5 Study Overview ............................................................................................................................................ 9 
3.6 Analysis cohorts ......................................................................................................................................... 10 
3.6.1 Primary analysis cohort .................................................................................................................................................. 10 
3.6.2 Secondary and sensitivity analysis cohorts .............................................................................................................. 10 
3.6.3 Subgroups ............................................................................................................................................................................ 10 
3.7 Endpoints .................................................................................................................................................... 10 
3.7.1 Primary outcome .............................................................................................................................................................. 10 
3.7.2 Secondary outcomes ....................................................................................................................................................... 10 
4. STUDY POPULATION AND ENROLLMENT ..................................................................................... 12 
4.1 Setting .......................................................................................................................................................... 12 
4.2 Study Population ........................................................................................................................................ 12 
4.2.1 Exposure groups ................................................................................................................................................................ 12 
4.2.2 Inclusion criteria: ............................................................................................................................................................... 13 
4.2.3 Exclusion criteria: .............................................................................................................................................................. 13 
4.2.4 Inclusion/exclusion criteria rationale ......................................................................................................................... 13 
4.3 Waivers of Informed Consent and HIPAA authorization ..................................................................... 13 
4.4 Minorities and Women ............................................................................................................................. 13 
4.5 Vulnerable Subjects ................................................................................................................................... 13 
5. STUDY PROCEDURES ........................................................................................................................ 15 
5.1 Standard Care ............................................................................................................................................. 16 
5.2 Code Sepsis Protocol ................................................................................................................................. 16 
6. DATA COLLECTION AND VARIABLES .............................................................................................. 18 
6.1 Data Collection ........................................................................................................................................... 18 
6.2 Anonymous Data Collection For Protocol Development and During Live Code Sepsis Activation
 ............................................................................................................................................................................. 18 
6.3 Active Follow-Up for Patients Undergoing Code Sepsis ...................................................................... 18 

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6.4 Protected Health Information ................................................................................................................. 18 
6.5 Variables/data elements .......................................................................................................................... 18 
6.6 Data Management ..................................................................................................................................... 20 
7. DATA ANALYSIS ................................................................................................................................. 21 
7.1 Introduction to Quasi-Experimental Analysis ....................................................................................... 21 
7.2 Multivariable models ................................................................................................................................ 21 
7.3 Sample size/power analysis ..................................................................................................................... 21 
8. RISK ASSESSMENT ............................................................................................................................ 23 
8.1 Potential Risks ............................................................................................................................................ 23 
8.1.1 Risk of confidentiality breach ....................................................................................................................................... 23 
8.1.2 Risks for control group patients ................................................................................................................................... 23 
8.1.3. Risks to patients exposed to the Code Sepsis protocol ...................................................................................... 23 
8.2 Alternatives to Participation .................................................................................................................... 23 
8.3 Minimization of Risks ................................................................................................................................ 23 
8.3.1 Protections against invasion of privacy or breach of confidentiality .............................................................. 24 
8.3.2 Incidental findings ............................................................................................................................................................ 24 
8.3.3 Protection against medicolegal risk ............................................................................................................................ 24 
8.3.4 Optimization of Code Sepsis targeting ...................................................................................................................... 24 
8.3.4 Protections against overtreatment and anchoring bias ...................................................................................... 24 
8.3.5 Protections against overtreatment and adverse drug reactions ...................................................................... 25 
8.4 Potential Benefits of the Proposed Research to Human Subjects and Others ................................ 25 
8.5 Importance of the Knowledge to be Gained ......................................................................................... 25 
9. HUMAN SUBJECTS ............................................................................................................................ 26 
9.1 Selection of Subjects ................................................................................................................................. 26 
9.2 Waiver of Informed Consent and HIPAA Authorization ...................................................................... 26 
9.2.1 Research involves no more than minimal risk ........................................................................................................ 26 
9.2.2 No adverse effects on the rights and welfare of participants ........................................................................... 26 
9.2.3 The research could not practicably be carried out without waiver of informed consent ....................... 26 
9.2.4 Information on the Code Sepsis protocol and study will be available to all ED patients ......................... 27 
9.2.5 The minimal necessary amount of protected information will be obtained ............................................... 27 
9.2.6 All data, including PHI, will be securely guarded from improper disclosure ................................................ 27 
10. MONITORING AND SAFETY REPORTING ..................................................................................... 28 
10.1 Potential Risks and Benefits for Participants ...................................................................................... 28 
10.2 Adverse Event and Serious Adverse Event Collection ....................................................................... 28 
10.2.1 Adverse event .................................................................................................................................................................. 28 
10.2.2 Serious Adverse Event (SAE) ....................................................................................................................................... 29 
10.2.3 Adverse event monitoring ........................................................................................................................................... 29 
10.3 Adverse Event and Serious Adverse Event Reporting ....................................................................... 29 
10.4 Interim Analysis ....................................................................................................................................... 30 
10.5 Data and Safety Monitoring ................................................................................................................... 30 
10.5.1 Safety Monitoring Procedures ................................................................................................................................... 30 
10.5.2 Enrollment, procedure, regulatory, and data quality monitoring ................................................................. 31 
10.5.3 Frequency of data and safety monitoring .............................................................................................................. 31 
10.5.4 Independent safety monitor identify and affiliation .......................................................................................... 31 
10.5.5 Conflict of interest for independent safety monitor .......................................................................................... 31 
10.5.6 Independent safety monitor responsibilities ........................................................................................................ 31 
10.6 Confidentiality During Adverse Event Reporting ............................................................................... 32 
11. BIBLIOGRAPHY ................................................................................................................................ 33 
APPENDIX A — Eligible IV and IV-equivalent antibiotics .................................................... 35 

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APPENDIX B — “Sepsis mimic” ICD codes ................................................................................. 37 
B.1 Heart failure diagnosis codes1 .......................................................................................................... 37 
B.2 Pulmonary embolism diagnosis codes1,2 ....................................................................................... 38 
B.3 Deep vein thrombosis diagnosis codes1,2 ...................................................................................... 39 
APPENDIX C — Diagnosis codes for adverse drug reaction ................................................ 42 
 
 
 

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1. ABBREVIATIONS AND DEFINITIONS 
 
1.1 Abbreviations 
 
AE = Adverse event 
CHF = Congestive heart failure 
ED = Emergency Department 
GCS = Glasgow Coma Scale  
HIPAA = Health Insurance Portability and Accountability Act 
IRB = Institutional Review Board 
ICU = Intensive Care Unit   
ICD-9-CM = International Classification of Disease, version 9, clinical modification 
ICD-10-CM = International Classification of Disease, version 10, clinical modification 
INR = International normalized ratio  
ISM = Independent safety monitor 
ITT = Intent to treat  
MAP = Mean arterial pressure 
NIH = National Institutes of Health 
PE = Pulmonary embolism 
PI = Principle investigator 
PHI = Protected Health Information 
REDCap = Research Electronic Data Capture 
RR = Respiratory rate 
SOFA score = Sequential Organ Failure Assessment score  
SBP = Systolic blood pressure  
SpO2 = Oxygen saturation via pulse oximetry  
SUSAR = Serious and Unexpected Suspected Adverse Reactions  
SAEs= Serious Adverse Events  
WBC = White blood cell count  
  
 

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1.2 Definitions 
 
• 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a study 
procedure, whether or not considered drug related.  
• 
Adverse reaction: An adverse reaction means any adverse event caused by a study intervention. An 
adverse reaction is a subset of all suspected adverse reactions where there is a reason to conclude 
that the study intervention caused the event.  
• 
Door-to-antibiotic time: Primary outcome; the time from the first recorded arrival time in ED 
(usually ED triage or registration) and the time the first eligible antibiotic was administered.  
• 
Hypotension: SBP <90 mmHg or MAP <65 mmHg or, where applicable, receipt of vasopressor 
medication 
• 
Intention to Treat (ITT): All eligible patients who present to the ED will be included in the ITT cohort 
for the purposes of analyzing the primary and secondary study outcomes.  
• 
PHI: identifiable health information that is used, maintained, stored, or transmitted by a HIPAA-
covered entity 
• 
SAEs: Serious Adverse Events Adverse events that are serious and unexpected and have a 
reasonable possibility that the event was due to a study procedure  
• 
Sepsis: Life-threatening organ dysfunction resulting from a dysregulated host response to infection, 
clinically identified in the emergency department (ED) by an acute rise in the Sequential Organ 
Failure Assessment (SOFA) score while in the ED ≥2 points above baseline plus suspected or 
confirmed infection in the ED.1 
• 
Sepsis mimic: Clinical condition which may cause patient to exhibit and/or be treated for sepsis 
even though infection is not actually present. For the present study, pulmonary embolism (PE) and 
congestive heart failure (CHF) have been identified as sepsis mimic conditions. 
• 
Septic shock: Sepsis associated with hypotension requiring administration of vasopressors. 
• 
Study hospital: Defined as the hospital where the patient presented to the ED. 
• 
Suspected adverse reaction: any adverse event for which there is a reasonable possibility that the 
study procedures caused the adverse event. Reasonable possibility means there is evidence to 
suggest a causal relationship between the study procedures and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction (21 CFR 
312.32(a)).  
• 
Suspected or confirmed infection in the emergency department: Identified based on clinical 
behaviors of clinicians as the combination of administration of an IV- or IV-equivalent antibiotic plus 
collection of a body fluid culture or a positive molecular test for infection. 
• 
Suspected Unexpected Serious Adverse Reaction (SUSAR) An adverse reaction that is both 
unexpected (not consistent with the risks outlined in the protocol or investigator brochure), serious, 
and meets the definition of a Suspected Adverse Reaction  
 
 
 
 

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2. STUDY SUMMARY 
 
2.1 Title 
Effects of Code Sepsis Implementation on ED Sepsis Care (Code Sepsis) 
 
2.2 Primary Objective 
Determine the effects of reorganizing ED sepsis care (Code Sepsis protocol) on door-to-antibiotic time 
for ED patients with sepsis. 
 
2.3 Primary Hypothesis 
Early activation of a multidisciplinary, coordinated, team-based assessment and treatment protocol for 
patients with potential sepsis will decrease door-to-antibiotic time for ED patients with sepsis. 
 
2.4 Study Design 
Pragmatic phase 2a pre/post single-center implementation study with contemporaneous controls 
testing reorganization of standard ED sepsis care around a protocol for early, coordinated, 
multidisciplinary protocol for assessment of patients with potential sepsis (Code Sepsis protocol). 
1. We will emphasize pragmatic, real-world implementation of the Code Sepsis protocol in a single 
ED. 
2. We will compare care delivered to ED patients after Code Sepsis protocol implementation in the 
intervention ED to care received in this ED prior to Code Sepsis implementation. 
3. We will conduct a quasi-experimental analysis using contemporaneous control data obtained 
from two non-intervention hospitals to control for temporal trends in studied outcomes not 
resulting from the tested intervention. 
4. We will measure the effects of protocol implementation on all ED patients with sepsis (including 
patients not treated under the Code Sepsis protocol) as well as potential bystander effects. 
 
2.4.1 Study groups and phases 
Phase #1: Pre intervention (November 13, 2018 to November 12, 2019) 
• 
Control EDs: Standard care 
• 
Intervention ED: Standard care 
Phase #2: Intervention roll-in (November 13, 2019 to February 12, 2020) 
• 
Control EDs: Standard care 
• 
Intervention ED: Launch and fine-tuning of Code Sepsis protocol, fine tuning of Code Sepsis 
activation mechanism.  
Phase #3: Full intervention (February 13, 2020 to February 12, 2021) 
• 
Control EDs: Standard care 
• 
Intervention ED: Full implementation of Code Sepsis protocol 
 
2.4.2 Inclusion criteria 
1. Age ≥18 years 
2. Arrival to intervention or a control ED during study period 
 
2.4.3 Exclusion criteria 
1. Age <18 years 

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2. Trauma patient 
 
2.4.5 Primary analysis cohort 
ED patients with clinical sepsis, as identified by the combination of 
1) Acute organ failure: SOFA score while in the ED ≥2 points above baseline 
2) Suspected or confirmed infection while in the ED, as identified by both: 
a) Administration of ≥1 IV or IV-equivalent antibiotics while in the ED 
b) Collection of ≥1 body fluid cultures while in the ED 
 
2.4.6 Primary outcome 
Door-to-antibiotic time 
 
2.4.7 Secondary outcomes 
• 
Mortality (including 30-day, 1-year, hospital) 
• 
Hospital charges 
• 
Hospital length of stay 
• 
Code Sepsis activation rate  
• 
Code Sepsis activation accuracy 
• 
Antibiotic utilization fraction 
• 
Antibiotic spectrum 
• 
Antibiotic overtreatment rate 
• 
Adverse drug & allergic reaction incidence (e.g. anaphylaxis, new onset Clostridium difficile 
infection) 
 
2.4.8 Data analysis 
The primary analysis will use quasi-experimental methods to compare sepsis patients’ adjusted mean 
door-to-antibiotic time (primary outcome) at the intervention hospital pre- versus post-implementation 
of the Code Sepsis protocol using the measured change at non-intervention hospitals to control for pre-
versus post-intervention changes not attributable to protocol implementation. Secondary analyses will 
compare the change in secondary outcomes using similar methods.  
 
2.4.9 Sample size 
Assuming 4.5 sepsis patients per day at the intervention ED, treatment of 30% of these patients by Code 
Sepsis teams during study phase #3, and 6 total sepsis patients daily in control EDs (all conservative 
estimates), I will have 90% power to detect a change ≥16 minutes in the overall average door-to-
antibiotic time among all ED sepsis patients after Code Sepsis implementation at the intervention 
hospital. 
 
 
 

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3. TRIAL DESCRIPTION 
 
3.1 Background  
Sepsis, the combination of infection and acute organ dysfunction, is a common, morbid, and often lethal 
syndrome.1,2 Sepsis hospitalizes 1.3 million patients each year, kills 20%, and costs $23.7 billion.2-4 Early, 
appropriate antibiotic initiation is critical: sepsis survival decreases with every hour’s delay. 5-13 While 
guidelines and government mandates thus emphasize prompt antibiotics, international guidelines’ have 
admitted a lack of data to support the feasibility or implementation of their one-hour door-to-antibiotic 
goal.14,15 
 
Among patients presenting to the emergency department (ED) with sepsis, we previously found that 
non-patient contextual cues could improve rapid antibiotic initiation, whereas ED busyness was 
associated with delayed antibiotics.16,17 I also discovered five-fold variation between physicians in 
median door-to-antibiotic time.5 ED care reorganization could bypass these cognitive, stylistic, and 
resource barriers to timely sepsis treatment. In fact, ED protocols linking prehospital notification to a 
multidisciplinary, team-based response are common and effective for trauma, stroke, and myocardial 
infarction,18-22 conditions that are less common and less mortal than sepsis but require similarly time-
sensitive treatment.23 Given that sepsis has a less definitive presentation, however, analogous protocols 
for sepsis could waste resources or promote anchoring bias and overtreatment of patients without 
sepsis, issues observed with door-to-antibiotic standards for pneumonia.24-26  
 
We hypothesize that reorganizing ED sepsis care around multidisciplinary “Code Sepsis” teams activated 
prior to or upon patients’ ED arrival will reduce door-to-antibiotic times — with tolerable overtreatment 
rates — by mobilizing personnel, systematizing illness severity and infection risk assessment,27 
facilitating test completion, and eliminating any gap between treatment decision and antibiotic infusion. 
This study will therefore evaluate the effectiveness and tradeoffs of a Code Sepsis program for ED sepsis 
patients. 
 
3.2 Overall Study Motivation, Aim and Hypothesis 
Many emergency department (ED) patients with sepsis do not receive antibiotics and other care within 
intervals recommended in international guidelines. Efforts to accelerate treatment, however, may lead 
to overtreatment and other adverse effects. The goal of this project is to determine the potential 
effectiveness and tradeoffs of a Code Sepsis program for ED sepsis patients. 
 
Aim:  
 Establish the feasibility and effects of a team-based Code Sepsis protocol designed to 
accelerate antibiotic initiation for ED patients with suspected sepsis.  
 
 
 Using preexisting infrastructure, implement prehospital- or triage-activated Code Sepsis ED 
teams in a single ED and compare sepsis patients’ door-to-antibiotic times pre- and post-
implementation, controlling for unrelated temporal trends with observational data from two 
non-intervention EDs. 
 
 Hypothesis: Prehospital or triage-based activation of an ED team prepared to rapidly diagnose 
and treat sepsis decreases door-to-antibiotic time without increasing 
overtreatment. 
 

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3.3 Primary Objective 
Determine the effect of reorganizing ED sepsis care (Code Sepsis protocol) on door-to-antibiotic time for 
ED patients with sepsis. 
 
3.4 Primary Hypothesis 
Early activation of a multidisciplinary, coordinated, team-based assessment and treatment protocol for 
patients with potential sepsis will decrease door-to-antibiotic times for ED patients with sepsis. 
 
3.5 Study Overview 
To assess feasibility and test the preliminary efficacy of ED-based Code Sepsis teams activated on or 
before patients’ ED arrival, we will pursue a Phase 2a implementation trial involving Code Sepsis team 
activation in one ED (Intermountain Medical Center [IMC]) while collecting contemporaneous control 
data at two other urban EDs (Utah Valley Hospital and Dixie Regional Medical Center [control sites], 
Table 1). 
• Months 1-12: Collect baseline data (all sites), refine Code Sepsis protocol, and train ED staff at IMC. 
Portions of baseline data may be 
collected in a retrospective fashion. 
At the intervention site during this 
period, we may also undertake 
preparatory work to Code Sepsis 
protocol launch, including 
anonymous patient care 
observations to evaluate care 
processes; pilot testing of the draft 
Code Sepsis protocol or its 
components; and testing of the 
accuracy of Code Sepsis activation mechanisms.  
• Months 13-15: Run-in period: implement Code Sepsis protocol at IMC, optimize protocol & its trigger. 
• Months 25-36: Continue Code Sepsis protocol at site A (intervention ED). Continue standard care 
processes for sepsis without change (control condition) at two non-intervention EDs 
Using contemporaneous controls and rigorous statistical methods, we will assess how implementation 
of the Code Sepsis protocol affects process and patient outcomes in the intervention ED (Figure 1). 
Continuation of the Code Sepsis protocol (with or without revision) by the intervention ED and/or 
adoption elsewhere within the Intermountain Healthcare system is expected to be contingent on the 
results of these analyses. 
 
 
 
 
Figure 1. Code Sepsis implementation and data collection for Aim III. 

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3.6 Analysis cohorts 
3.6.1 Primary analysis cohort 
ED patients with clinical sepsis, as identified by the combination of 
1) Acute organ failure: SOFA score while in the ED ≥2 points above baseline 
2) Suspected or confirmed infection while in the ED, as identified by both: 
c) Administration of ≥1 IV or IV-equivalent antibiotics while in the ED (see Appendix A) 
d) Collection of ≥1 body fluid cultures while in the ED 
 
3.6.2 Secondary and sensitivity analysis cohorts 
1) All eligible ED patients 
2) ED patients with a “sepsis mimic” diagnosis based on a primary ICD-10 discharge diagnosis codes for 
congestive heart failure or venous thromboembolism with no diagnostic code for infection (see 
Appendix B).  
3) “Likely” sepsis patients based on simple triage assessment to include fever and at least 1 out of 3 of 
hypotension (SBP <90 mmHg), altered mental status (GCS ≤14), or respiratory failure (RR ≥22 or 
SpO2 ≤85%). 
 
3.6.3 Subgroups 
A priori subgroups will include: sex; hypotension (SBP <90 mmHg or MAP <65 mmHg) present on ED 
arrival. 
 
3.7 Endpoints 
Analysis will be conducted on an intention to treat basis.  
 
3.7.1 Primary outcome 
Door-to-antibiotic time among all ED sepsis patients. Door-to-antibiotic time is the time from the first 
recorded arrival time in ED (usually ED triage or registration) and the time the first eligible antibiotic was 
administered (Appendix A). 
 
3.7.2 Secondary outcomes 
• 
Clinical/patient-centered secondary outcomes (measured among all ED sepsis patients): 
1) All-cause mortality to day 30  
2) All-cause mortality to 1 year  
3) In-hospital all-cause mortality  
4) Hospital charges: Amount charged to patient for their medical care during index ED visit and 
associated hospitalization. 
5) Hospital length of stay 
 
• 
Process/feasibility secondary outcomes 
1) Code Sepsis activation rate: Measured as the percentage of all ED patients for whom the Code 
Sepsis protocol was activated.  
2) Code Sepsis activation accuracy metrics. Accurate Code Sepsis activation is defined as activation 
for patients who have sepsis while in the ED and no activation for patients who do not have 
sepsis in the ED. 
 
• 
Adverse effects and unintended outcomes of protocol implementation 

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1) Antibiotic utilization percentage: measured as the fraction of  (1) all ED patients; (2) Code Sepsis 
activation patients; or (3) “likely” sepsis patients who received IV or IV-equivalent antibiotics. 
2) Antibiotic spectrum: Total Stenehjem antibiotic spectrum score28 for all antibiotics administered 
in first 24 hours, measured for (1) all ED patients or (2) sepsis patients 
3) Antibiotic overtreatment rate: Percentage of “sepsis mimic” patients who received IV or IV-
equivalent antibiotics in the ED. 
4) New onset C. difficile colitis incidence: Percentage of (1) all ED patients and (2) ED sepsis 
patients with a positive stool test for Clostridium difficile colitis between 72 hours and 90 days 
after ED arrival. 
5) Adverse drug & allergic reaction incidence: Measured as the fraction of 1) all ED patients and (2) 
ED sepsis patients with a discharge diagnosis code consistent with anaphylaxis or with an 
adverse reaction to antibiotics (see Appendix C). 
 
• Potential exploratory outcomes 
1) Measures of organ failure trajectory, to include change in the SOFA score between hospital day 
1 and hospital day 3, and overall and organ-specific measures of organ failure-free days through 
day 28.  
§ 
Organ-failure free days (OFFD) are defined as the number of days from the time of the first 
SOFA score ≤1 above baseline to day 28 after ED arrival, assuming survival for at least two 
consecutive calendar days after the SOFA score ≤1 above baseline and continued SOFA 
score ≤1 point above baseline to day 28. If a patient has SOFA score rise again to ≥2 points 
above baseline and subsequently achieves SOFA score ≤1 point above baseline to day 28, 
VFDs will be counted from the end of the last period of SOFA score ≤1 to day 28. If a patient 
had SOFA score ≥2 points above baseline at day 27 or dies prior to day 28, OFFD will be zero 
§ 
Support-free days (i.e. ventilator-free days) are calculated similar to OFFD 
2) Mortality at other intervals 
3) Testing and treatment utilization. Outcomes measured among (1) among all ED sepsis patients; 
(2) all ED patients; (3) “likely” sepsis patients 
4) Code Sepsis care process timing: measured among patients who received Code Sepsis protocol 
activation as time from protocol activation until completion of key protocol steps, to include 
blood culture collection, chest X-ray collection, team huddle, antibiotic initiation 
5) Timing of testing & care processes among all sepsis patients, to include ED clinician assessment, 
ED room placement, ED departure, blood culture collection, radiology testing, and order entry 
for antibiotics. Measured analogous to door-to-antibiotic time. 
6) Code Sepsis protocol adherence: measured as performance of protocol steps in correct order 
both individually and as a fraction of all possible. 
 
 

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4. STUDY POPULATION AND ENROLLMENT 
 
4.1 Setting 
Intermountain Healthcare (hereafter “Intermountain”) is a nonprofit health system based in Salt Lake 
City, Utah with 23 hospitals in Utah and Idaho. Code Sepsis implementation will occur in a teaching ED 
(IMC, my “home” hospital) providing 89,000 visits annually (2.8% with clinical sepsis) for an  
economically and ethnically diverse population of 1.1 million in Salt Lake County, Utah plus referrals 
from Wyoming, Nevada, and Idaho. To avoid 
spillover effects, concurrent control data will be 
electronically abstracted from two 
Intermountain EDs (Utah Valley Hospital and 
Dixie Regional Medical Center) staffed by other 
physician groups (Table 1). 
 
4.2 Study Population 
We will study adult, non-trauma patients from the IMC ED and two control EDs during three phases 
(Figure 1): baseline (1 year, standard care at all sites); run-in (3 months, IMC ED launches/fine tunes the 
Code Sepsis protocol); and Code Sepsis implementation (1 year, Code Sepsis at IMC, standard care in 
control EDs). For this pre/post implementation trial, in which there will be no direct patient contact and 
in which we are comparing current standard care processes to a new, redesigned standard care 
processes in a non-randomized fashion, 
all ED patients who meet inclusion and 
do not meet exclusion criteria will be 
included in the analysis. 
 
4.2.1 Exposure groups 
The group within which patient is 
analyzed is determined by the 
combination of (1) when the patient 
presents to the ED and (2) which 
hospital/ED to which the patient 
presents (Figures 1 and 2).  
A. Pre-implementation control group 
at non-intervention hospitals: 
Admission to ED at non-
intervention hospitals (Utah Valley 
Hospital and Dixie Regional Medical Center) prior to Code Sepsis implementation (estimated 
N=135,000) 
B. Pre-implementation control group at intervention hospital: Admission to ED at IMC prior to Code 
Sepsis implementation (estimated N=100,000) 
C. Post-implementation control group at non-intervention hospitals: Admission to ED at non-
intervention hospitals (Utah Valley Hospital and Dixie Regional Medical Center) after 
implementation of Code Sepsis protocol at IMC (estimated N=170,000) 
D. Exposure group: Admission to ED at IMC during full Code Sepsis implementation (estimated 
N=125,000) 
 
Table 1. Study hospital characteristics 
Site 
Description 
Hospital 
beds 
ED 
beds 
Annual ED 
visits 
IMC 
Tertiary/teaching 
472 
56 
89,000 
Utah Valley 
Regional referral 
395 
28 
49,000 
DRMC 
Regional referral 
321 
35 
65,000 
 
Figure 2. Subject allocation by study phase and hospital 

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4.2.2 Inclusion criteria: 
o ED patient at Intermountain Medical Center, Utah Valley Hospital, Dixie Regional Medical Center 
o ED arrival beginning 1 year prior to date of Code Sepsis implementation at Intermountain 
Medical Center and continuing through 15 months after Code Sepsis implementation date.  
o Age ≥18 years 
 
4.2.3 Exclusion criteria: 
o Age <18 years 
o Trauma patient 
 
4.2.4 Inclusion/exclusion criteria rationale 
Patients <18 years of age are excluded because the mechanisms, manifestations, and management of 
sepsis in children <18 years of age are often distinct from those applicable to adults, and in fact will vary 
depending on age group across childhood. Additionally, children are managed in most EDs by a distinct 
team of clinicians using distinct protocols.  As such, prehospital or triage-based sepsis prediction models 
applicable to adults are unlikely to work for children <18 years. Due to the above issues, implementation 
of a single sepsis care protocol for individuals age <18 years and age ≥18 years would impair the efficacy, 
feasibility, and generalizability of the proposed Code Sepsis protocol. Trauma patients are excluded 
because clinical identification of these patients is straightforward and triggers preexisting team-based 
care protocols with options for prehospital activation.  
 
4.2.5 Study phase dates 
ED patients arriving to study EDs will be assigned to a study phase based on their ED arrival date. 
• 
Phase #1 (pre-intervention analysis phase): November 13, 2018 to November 12, 2019 
• 
Phase #2 (intervention roll-in): November 13, 2019 to February 12, 2020 
• 
Phase #3 (full intervention analysis phase): February 13, 2020 to February 12, 2021 
 
4.3 Waivers of Informed Consent and HIPAA authorization 
This study comparing standard care to a new form of standard care will be carried out under a waiver of 
informed consent and HIPAA authorization (see section 9). 
 
4.4 Minorities and Women  
Women and minorities will be enrolled in proportion to their representation in the population base from 
which this study was developed, specifically patients presenting to Intermountain hospitals located in 
Utah’s Salt Lake, Washington, and Weber Counties.  In order to provide generalizable data for the ED 
patient diagnosis groups studied in each Aim, there will be no specific selection criteria that differ 
between sex/gender and racial/ethnic groups. Hospitals in this study serve counties with a combined 
population of over 1.5 million individuals, including over 26% who are Hispanic or non-white race. We 
expect the sex, ethnic and racial mix of the enrolled patients to reflect the population served. 
 
4.5 Vulnerable Subjects 
We anticipate that potentially vulnerable subjects are eligible for the study. Potentially vulnerable 
patient subjects include pregnant women, prisoners, and/or individuals with decisional impairment. The 
purpose of this project is to identify a cohort that reflects the diversity of the U.S. sepsis population. 
Therefore, we believe these individuals should not be excluded from the study since the study is of no 
more than minimal risk. 

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1. Data on vulnerable population membership will not be explicitly collected, and in fact 
attempting to identify and exclude members of potentially vulnerable populations could 
increase risk to both vulnerable patients and the overall subject cohort.  
2. Altered mental status is also a common manifestation or complication of sepsis. Excluding 
patients with decisional impairment would therefore severely bias results of the planned 
analyses. 
3. In implementation studies such as this, it is generally not possible to exclude vulnerable 
subjects. Aim III’s intervention involves testing a new option for standard care for ED sepsis 
management, so excluding vulnerable populations could actually subject these patients to harm 
because exclusion would prevent their receiving standard care. Assessment for vulnerability 
status, moreover, would largely preclude the planned intervention by preventing activation of 
prehospital or ED triage alerts. 
 
 

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5. STUDY PROCEDURES 
 
This study will measure the effect of a redesign of standard care for ED sepsis patients, specifically 
implementation of Code Sepsis protocol at Intermountain Medical Center. The study will include three 
phases with two groups during each phase. The primary analysis will only use data from phases #1 and 
#3 (see Figure 1 and 2). 
Phase #0: Protocol development (1 year, overlaps with phase #1) 
• 
Control EDs: N/A 
• 
Intervention ED: A small number of suspected sepsis patients (<10) may undergo 
anonymous observation to understand care processes involved in ED sepsis care. In 
addition, testing and iterative optimization of the accuracy of the Code Sepsis activation 
may employ direct observation of care for a convenience sample of patients during ED 
triage and comparison of activation criteria to clinician judgment, final sepsis diagnosis 
based on chart review, and electronic sepsis queries. Finally, pilot testing of the draft 
protocol may be conducted on a small convenience sample of patients (<20) identified by ED 
clinicians as having possible sepsis. We will collect anonymous data about completion of 
Code Sepsis processes during pilot testing. 
Phase #1: Pre intervention (1 year) 
• 
Control EDs: Standard care 
• 
Intervention ED: Standard care.  
Phase #2: Intervention roll-in 
• 
Control EDs: Standard care 
• 
Intervention ED: Launch and fine-tuning of Code Sepsis protocol, fine tuning of Code Sepsis 
activation mechanism.  
Phase #3: Full intervention 
• 
Control EDs: Standard care 
• 
Intervention ED: Full implementation of Code Sepsis protocol 
Phase #4 (operational): Continuation of the Code Sepsis protocol (with or without revision) by the 
intervention ED and/or adoption elsewhere within the Intermountain Healthcare system is 
expected to be contingent on observed effects of protocol implementation. It is possible that an 
inadequate benefit/risk ratio could lead to a decision not to continue the Code Sepsis protocol. 
 
 
 

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5.1 Standard Care 
Patients arriving to the control EDs (all study phases) and the intervention ED during study Phase #1 will 
receive care as per then-current ED practices and protocols, guided by clinician judgment within a 
system-wide care process model for sepsis. As of early 2019, ED standard care for sepsis applicable at all 
study sites includes a standardized Care Process Model, expected completion of a standardized 
checklist, and standardized order sets. 
 
5.2 Code Sepsis Protocol 
The Code Sepsis protocol (Figure 3) has six steps developed in collaboration with ED-based study team 
members and ED leaders (including physicians, nurses, pharmacists, and others) from the 
implementation ED and the Intermountain system. The current draft protocol was further iteratively 
revised based on input derived from the proposed multidisciplinary team during in situ high-fidelity 
simulation and during informal/ad hoc operationally-oriented pilot testing of steps 1-5 during live 
patient care.  The below protocol will be adapted further prior to and after implementation to ensure 
the protocol is feasible, efficient, and functions as intended based on stakeholder input and, as needed, 
additional protocol element testing during simulation and/or live patient care. Further revision will 
occur, during the protocol run-in phase and as needed based on observed findings and stakeholder 
input.  
 
Figure 3. Current Code Sepsis protocol based on iterative revision using simulation testing, stakeholder input, & live pilot testing. 
 
1) Identify likely sepsis patient from prehospital notification call data (nurse), at ED triage 
(nurse/physician), or on ED room placement (nurse or physician), adapting local and national 
practice for stroke team activation.29,30  
2) Mobilize ED personnel and equipment to meet patients on arrival to the ED room using methods 
and communication networks already developed for ED trauma and stroke teams. 
3) Concurrent patient evaluation and data collection by multiple disciplines (20-25 minutes), to include 
bedside assessment (e.g. history, examination, vital signs, allergy and medication history) by the 
physician, nurse and pharmacist; IV placement; blood and urine sampling; point-of-care laboratory 
testing, including lactate and urinalysis; and portable X-ray imaging. Appropriate therapeutic 
interventions will continue in parallel during the nominal data collection phase. 
4) Team “huddles” to decide if sepsis diagnosis has been confirmed, disproven, or remains 
indeterminate. The physician may complete this step by announcing clinical decision-making to the 
team at any time. The nurse will request a decision huddle at 25 minutes into the Code Sepsis event 
if it has not previously been performed.  

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5) Proceed with next therapeutic and/or diagnostic steps including, for confirmed sepsis patients, 
immediate initiation of an appropriate antibiotic regimen chosen from a range of options contained 
in a Code Sepsis antibiotic pack brought to the bedside by a pharmacist on protocol activation. Code 
Sepsis antibiotic regimens have been selected based on published guidelines and local antibiotic 
resistance patterns with input from ED clinicians, pharmacists, and infectious disease/antibiotic 
stewardship personnel. 
6) If initial huddle pronounced sepsis status as “indeterminate,” return to step #4 after additional 20-
25 minutes to follow up on additional diagnostic results (e.g. urinalysis, complete blood count 
7) For antibiotic-treated patients, follow-up by antibiotic stewardship pharmacist active de-escalation 
or cessation as appropriate. 
 
Additional protocol elements/details: 
• 
Code Sepsis team members:  
o   ED attending physician +/- ED resident physician or medical student 
o   ED triage nurse 
o   ED unit coordinator (i.e. unit secretary) 
o   ED nurses x2 
o   ED patient care technician 
o   ED phlebotomist x1-2 
o   ED pharmacist as available 
o   ED X-ray technician 
• 
Code Sepsis electronic order entry: Code Sepsis order sets for diagnostic evaluation and antibiotic 
treatment will be constructed and activated at the intervention ED's electronic medical record with 
the beginning of study Phase #2. Order sets will help speed up diagnostic testing and treatment 
initiation, aid care standardization, and facilitate Code Sepsis event tracking and data collection.   
• 
Code Sepsis clinical team training: With active support from intervention hospital clinical leadership 
as well as Intermountain's system-wide ED leadership team, the Code Sepsis ED Implementation 
Team will provide clinical staff in the implementation ED with training on the Code Sepsis protocol 
during the months prior to study Phase #2. Primary training will include distribution of instructional 
materials, direct education at clinical staff meetings, targeted in-person education, and in situ 
simulation. Primary training will complete early in study Phase #2, with consolidation training, 
protocol reminders, physician detailing, and targeted clinician reeducation continuing through study 
Phase #3.  
 
 

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6. DATA COLLECTION AND VARIABLES 
 
Core analyses will employ data collected during routine clinical care and hospital operations. There will 
be no direct patient contact for collection of identifiable data or specimens. 
 
6.1 Data Collection 
Intermountain’s Enterprise Data Warehouse (EDW) is a centrally-managed, well-curated, and accessible 
database linking system-wide clinical, billing, laboratory, and other data.31  Eligible patient subjects will 
be identified by project data managers from EDW data, who will generate a dataset specific to the 
proposed study by linking EDW data to additional data abstracted from the electronic health record. 
Manual chart review and direct queries to bedside clinicians will be employed as needed to supplement 
electronically-available data. This encounter level data will be linked to additional data on hospital 
characteristics, physician and nurse staffing. Long-term mortality data will be obtained through a 
preexisting linkage to Utah state death records and/or the federal Social Security Death Index. 
Encounter data will be linked to data on race, ethnicity, and hospital admissions (admit date, type, 
diagnoses, and costs) stored in the Utah Population Databank. We will employ a preexisting linkage to 
Utah State death records and the federal Social Security Death Index for mortality ascertainment.  
 
6.2 Anonymous Data Collection For Protocol Development and During Live Code Sepsis 
Activation 
The study team will receive notification of Code Sepsis activations. As part of the study operational 
process, ED clinical leadership and study personnel will directly observe a convenience sample of these 
events to anonymously record protocol parameters, including team composition and process 
completion times. In addition, a convenience sample of intervention hospital patients (<10) with sepsis 
may be observed during the pre-Code Sepsis implementation phase to understand care processes 
involved in sepsis care. No identifying information about the patient or clinical team will be recorded. 
 
6.3 Active Follow-Up for Patients Undergoing Code Sepsis 
Via the electronic medical record, a member of the study team will actively monitor Code Sepsis 
activation patients every 1-3 days until hospital day #7. There will be no direct patient contact. 
 
6.4 Protected Health Information 
Protected health information including subject encounter codes, medical record numbers, birthdates, 
encounter event date and times, address, and social security number will be collected during the 
electronic query to allow manual chart abstraction and manual review of electronic record for data 
completion and verification. 
 
6.5 Variables/data elements 
• 
Patient medical record number(s) 
• 
Patient encounter ID code 
• 
Hospital/facility 
• 
Date of birth 
• 
Age 
• 
Sex 
• 
Race 

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• 
Ethnicity 
• 
Marital status 
• 
Preferred language 
• 
Insurance status/type 
• 
Address/zip code (for determination of residence at a nursing facility or other long-term care facility 
and estimation of socioeconomic status) 
• 
Social Security Number (to assist matching of encounter data to Social Security Death Index and 
Utah state death records) 
• 
ED disposition 
• 
Hospital disposition 
• 
Date/time of all events related to ED visit and hospitalization (e.g. ED arrival & departure, hospital 
admission & discharge) 
• 
Date/time antibiotics administered 
• 
Antibiotic utilization 
• 
APACHE II score 
• 
APACHE IV score 
• 
Acute physiology score 
• 
Charlson index 
• 
Elixhauser index 
• 
SOFA score 
• 
Baseline SOFA score over preceding 10 years 
• 
Source of admission (e.g. home, SNF, LTAC, outside hospital) 
• 
Source of infection 
• 
Clinician infection determination, patient illness severity, sepsis status, and agreement with Code 
Sepsis activation 
• 
Sepsis presence/absence 
• 
Culture results 
• 
Admission diagnosis 
• 
Mode of arrival to ED 
• 
ED triage data including triage acuity score 
• 
Resident involvement in ED care 
• 
Results of all laboratory testing 
• 
Date/time of all laboratory testing  
• 
ED length of stay 
• 
ED vital signs 
• 
ED medications 
• 
ED interventions/procedures 
• 
Date/time, elapsed time, and type of ED events including provider interaction, room placement, 
disposition 
• 
Date/time of diagnostic testing, vasopressor initiation and other interventions, and management 
• 
Date/time of interventions 
• 
Date/time of blood or body fluid cultures 
• 
Discharge diagnosis and procedure codes  
• 
Billing diagnosis and procedure codes 
• 
Diagnosis-related group 
• 
Hospital length of stay 

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• 
In-hospital mortality 
• 
Long-term mortality (e.g. 30d, 90d and 1y mortality) 
• 
Healthcare charges 
• 
ED patient census 
• 
Number of ED beds 
• 
ED patient flow (including counts of patient arrivals, boarding, and admissions) 
• 
Attending physician ED staffing 
• 
Nurse staffing 
• 
Trauma registration status 
• 
Allergies 
• 
Adverse drug reaction events and date/time 
• 
Code Sepsis team activation (Y/N) 
• 
Code Sepsis activation date/time  
• 
Code Sepsis care process completion date/times 
• 
Code Sepsis team function 
• 
Code Sepsis team composition (by role) 
• 
Code Sepsis process adherence 
 
6.6 Data Management 
Data analysts and research coordinators will collect data and record it in a custom-designed computer 
database. Data abstraction from electronic medical records will employ either standardized paper data 
sheets or a custom-designed interface maintained within Intermountain’s secure Research Electronic 
Data Capture (REDCap) platform.32 Outside REDCap, all study data will be kept in a protected database 
on a protected computer. Each subject will be assigned a study identification number, and we will 
maintain minimal patient identifiers. Data for analysis will use study ID codes for patient subjects. 
Shared or presented data will be in anonymized or aggregate format such that individual patient 
subjects cannot be reidentified. Any hard copy case report forms will only include study identification 
numbers, and will be stored in a locked file cabinet. 
 
 
 

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7. DATA ANALYSIS  
 
7.1 Introduction to Quasi-Experimental Analysis 
This study will measure the effect of implementing a team-
based Code Sepsis protocol for ED sepsis patients by 
comparing risk-adjusted process and patient-centered 
outcomes before versus after protocol implementation at a 
single hospital. Results from simple pre/post analyses, 
however, may be subject to misinterpretation due to secular 
trends (changes in the measured outcomes over time not 
attributable to the study intervention). Analyses of Aim III 
primary and secondary outcomes will therefore employ 
quasi-experimental methods to eliminate confounding due 
to secular trends when estimating the effect of Code Sepsis 
implementation on outcomes. More complex methods of 
quasi-experimental analysis includes interrupted time series 
and regression discontinuity, but are analogous to the relatively simpler approach called difference-in-
difference analysis (Figure 4).33 Difference-in-difference analysis uses multivariable linear regression to 
compare the adjusted mean door-to-antibiotic time (primary outcome) at the intervention hospital pre- 
versus post-implementation of the Code Sepsis protocol using the measured change at non-intervention 
hospitals to control for pre-/post-intervention changes not attributable to protocol implementation.34 
This model tests the difference in 
intervention ED versus non-intervention 
EDs’ differences in outcome before versus 
after the Code Sepsis implementation 
(Figures 4-5). The b3 parameter from the 
regression model depicted in Figure 5 
provides the adjusted difference-in-differences estimate and significance tests for the influence of the 
Code Sepsis intervention on the outcome of interest.  
 
7.2 Multivariable models 
Multivariable models will be adjusted for demographic and clinical parameters with known or plausible 
associations with both door-to-antibiotic time and treatment hospital, presentation before or after Code 
Sepsis implementation, and/or Code Sepsis activation. Evaluation of secondary outcomes will employ an 
analogous approach using multivariable linear, Poisson, or logistic regression as appropriate. Repeating 
the quasi-experimental analysis for the primary and key secondary outcomes after stratification (rather 
than adjustment) by (1) sex and (2) hypotension present versus absent on ED arrival will allow 
evaluation of whether these patient characteristics modify the effects of Code Sepsis implementation. In 
order to measure how the Code Sepsis protocol influences the care of its core target population, we will 
perform analyses comparing selected outcomes among the subset of patients who have ED triage data 
suggesting a strong possibility of sepsis. Outcomes to be evaluated in the sensitivity analyses will include 
door-to-antibiotic time, antibiotic treatment fraction, and antibiotic treatment spectrum. 
 
7.3 Sample size/power analysis 
Using 2013 to 2017 data from our study hospitals, we estimated conservatively that the intervention ED 
provides care for 1,650 sepsis patients annually (approximately 4.5 sepsis patients per day) and the 
 
Figure 4. Difference-in-differences analysis  
𝒀𝒊= 𝛽"ERA# + 𝛽$HOSP + 𝜷𝟑𝐄𝐑𝐀𝒊× 𝐇𝐎𝐒𝐏𝒊+ 𝛽&(Z#) 
Figure 5. Simplified difference-in-differences equation. Yi is the door-to-
antibiotic time for patient i, HOSP and ERA are, respectively, indicator 
variables for care at the intervention hospital or an ED arrival date after 
Code Sepsis implementation, and Z is a vector of covariates. b3 is the 
coefficient of interest. 

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control EDs together care for a total of 2,200 sepsis patients annually (approximately 6 sepsis patients 
per day). Based on the design and our pilot testing of the Code Sepsis protocol, a very conservative 
estimate of door-to-antibiotic time for patients who receive antibiotics after evaluation under the Code 
Sepsis protocol is 50 minutes. By comparison, our preliminary data from 2013 to 2017 indicates current 
mean (SD) door-to-antibiotic time for ED sepsis patients is 170 (±75) minutes and that only 5% of 
patients currently receive antibiotics within 1 hour of ED arrival. Assuming (again conservatively) that 
the Code Sepsis protocol is activated for 30% of sepsis patients treated in the intervention ED during the 
full implementation phase (study phase #3), we will have 90% power to detect a difference-in-
differences change of 16 minutes or more in door-to-antibiotic time associated with Code Sepsis 
implementation, with the measurement population being all ED sepsis patients. Power calculations 
employed Monte Carlo simulations, for which technical details are available upon request. 
 
 

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8. RISK ASSESSMENT 
This study involves a before-and-after analysis of the effects of reorganizing standard ED care for sepsis. 
Patient care will be studied under two designs for standard sepsis care. 
 
8.1 Potential Risks 
8.1.1 Risk of confidentiality breach 
Potential consequences of a breach of confidentiality to the subject could include identify loss of 
privacy, medicolegal liability, theft, embarrassment, or harassment. 
 
8.1.2 Risks for control group patients 
Aside from issues discussed above, there are no foreseeable risks for ED patients receiving care at a non-
intervention hospital or at the intervention hospital during study phase #1 and #2. Sepsis patients 
arriving to control hospitals will receive standard care throughout the study.  
 
8.1.3. Risks to patients exposed to the Code Sepsis protocol  
Patients presenting to the intervention hospital during phases #2 and 3 (run-in implementation and full 
implementation) will be exposed to and may receive care using the “Code Sepsis” version of standard 
care. The Code Sepsis protocol is designed to accelerate evaluation, testing, and treatments that the 
patient would have eventually received under now current standard care. The Code Sepsis intervention 
is therefore expected to pose no more than minimal risks to ED patients exposed to the protocol, 
including specifically sepsis patients for whom the Code Sepsis protocol is activated. The potential risks 
to subjects due to this protocol include:  
1) Adverse drug reactions or antibiotic-associated infections related to unnecessary or 
overtreatment antibiotic treatment with prespecified regimens. 
2) Delay in diagnosis of non-infectious problems due to focus on sepsis or infection related to Code 
Sepsis activation. 
3) Delay in care related to resource allocation away from non-Code Sepsis patients without sepsis 
(bystanders without sepsis).  
4) For sepsis patients for whom the Code Sepsis protocol is not activated (i.e. bystanders with 
sepsis), delay in care related to lower index of suspicion for sepsis leading to delayed diagnosis 
or resource allocation away from these patients.  
 
 
8.2 Alternatives to Participation 
There are no alternatives to participation in this pragmatic before/after implementation research study. 
 
8.3 Minimization of Risks 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to subjects are minimized by using 
procedures which are consistent with sound research design. We will review the electronic medical 
record of all Code Sepsis activations for potential adverse effects related to study procedures. This will 
include review of standardized Code Sepsis documentation incorporated into clinical care as part of the 
care redesign. While there are no foreseeable effects of data collection on the care of patients who 
receive standard care at the control hospitals (all study phases) or during the pre-intervention phase at 
Intermountain Medical Center, monitoring of aggregate data quality will include all hospitals and study 
phases. As necessary, after consultation with the Independent Safety Monitor, study procedures 
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identified. There are several specific elements of study design inherent in the present protocol that 
meet this human subject protection requirement.  
 
8.3.1 Protections against invasion of privacy or breach of confidentiality 
Protection of subject identity and prevention of unintentional release of protected information is of 
paramount importance to the research team.  
• 
Data storage and transfer: Data will be maintained in password-protected, encrypted research 
servers, REDCap (a secure, HIPAA-compliant system), or password-protected, encrypted 
computers. Patient identifiers for prehospital data linkage in Aim I will be provided in secure, 
encrypted electronic format to Department of Health staff for identification of ambulance 
patient care reports. Matched records will be returned in secure, encrypted electronic format. 
All devices will have been approved by Intermountain Healthcare or (during matching of ED data 
to prehospital data) the Utah Department of Health for use with clinical and research data. Both 
Intermountain and the State of Utah deploy comprehensive information technology support 
systems to maintain and regularly update computer systems and maintain physical and 
electronic safeguards for data management. Any paper case report forms will only include study 
identification numbers, and will be stored in a locked file cabinet. Datasets used for statistical 
analyses will be deidentified. 
• 
Data access: Only the PI and the study team will have access to identifying information. All 
individuals with access to identifiable data will have all necessary human subjects training, 
including Good Clinical Practice training as required by NIH policy for applicable study team 
members involved in the clinical trial proposed.  
• 
Training: All study personnel will maintain appropriate training in human subjects research and 
data protection. The PI, primary mentor, and study staff responsible for study coordination, data 
collection, and data management of the associated clinical trial will maintain Good Clinical 
Practice training as per NIH policy (NOT-OD-16-148). 
 
8.3.2 Incidental findings 
Data review and analysis will use only data collected as part of routine clinical care and operations. We 
therefore do not expect identification of incidental findings relevant to patient care. 
 
8.3.3 Protection against medicolegal risk 
Data on subjects studied in the proposed aims will be kept confidential in accordance with applicable 
laws and statues.  
 
8.3.4 Optimization of Code Sepsis targeting  
Optimization of team activation mechanism during phase #2 of Aim III (intervention run-in and 
optimization) will help maximize false positive and minimize false negative team activations.  
 
8.3.4 Protections against overtreatment and anchoring bias 
Physicians and other providers will be educated intensively about the protocol, with particular emphasis 
on the corresponding concepts that (1) a sepsis team activation does not establish a sepsis diagnosis and 
(2) that the sepsis prediction tool was specifically not designed to capture all patients with sepsis and 
that, as a consequence, many patients with sepsis will not trigger a Code Sepsis.  
 

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8.3.5 Protections against overtreatment and adverse drug reactions 
Part of this redesign of standard care is incorporation of both direct pharmacist involvement in the Code 
Sepsis team and antibiotic stewardship monitoring of antibiotic-treated Code Sepsis patients to reduce 
antibiotic overtreatment. Pharmacist involvement will also help minimize the risk of preventable 
adverse drug or allergic reactions.  
 
8.4 Potential Benefits of the Proposed Research to Human Subjects and Others 
This study has the potential to generate important findings for patients with sepsis and their treating 
clinicians, including methods to identify sepsis patients at ED triage or in the prehospital setting.  Sepsis 
patients treated in the intervention ED after implementation of the full Code Sepsis protocol could 
receive faster evaluation, diagnosis, and treatment initiation, leading to improved patient outcomes. 
The risks to patient confidentiality and the risks for adverse drug reactions appear substantially less than 
the potential benefit to sepsis patient subjects and the important knowledge gained about delivery of 
ED sepsis care. 
 
8.5 Importance of the Knowledge to be Gained 
Patients with sepsis —a syndrome defined by infection associated with acute organ dysfunction — have 
high mortality. This syndrome is also common, affecting nearly 3% of ED patients in our data. Early 
antibiotic initiation improves sepsis outcomes, but many ED patients do not receive timely antibiotics. 
The overall hypothesis of this phase 2a study is that reorganizing standard ED sepsis care around 
multidisciplinary “Code Sepsis” teams activated prior to or immediately upon patients’ ED arrival will 
reduce door-to-antibiotic times. Aim III of this proposal will determine whether the Code Sepsis protocol 
is feasible, safe, and effective at decreasing door-to-antibiotic time. Data from human subjects are also 
necessary to validate triage- or prehospital-based sepsis prediction models that can be customized by 
users planning sepsis screening, intensive resource mobilization (as is planned here) for sepsis care, or to 
aid risk/benefit decisions for sepsis treatments with more than minimal risks (Aim I) and to understand 
how practice patterns or systems of care may be optimized to accelerate time-dependent treatment 
while minimizing unintended consequences (Aim II). The no-more-than-minimal risks to subjects from 
observational research (Aims I and IIA), interviews (Aim IIB), or systematically reorganizing sepsis care to 
accelerate evaluations and treatments patients would receive anyway under current standard care (Aim 
III) are acceptable in the context of the important knowledge to be gained to improve care for the 
common and deadly sepsis syndrome. 
 
 

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9. HUMAN SUBJECTS 
We will prospectively assess the effect of a system-level intervention on the organization of ED sepsis 
care using an augmented pre-/post-intervention design. In the post-intervention period, the studied 
intervention — early activation of ED teams for patients likely to have sepsis — will be adopted as 
standard care at Intermountain Medical Center. As such, no patients arriving to any ED during the pre-
intervention or to a non-intervention control ED will be exposed to the intervention. Conversely, all 
patients arriving to the Intermountain Medical Center ED in the post-intervention phase will be exposed 
to the intervention.  
 
9.1 Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. All eligible patients will 
be enrolled. Study exclusion criteria neither unjustly exclude classes of individuals from participation in 
the research nor unjustly include classes of individuals from participation in the research. Hence, the 
recruitment of subjects conforms to the principle of distributive justice.  
 
9.2 Waiver of Informed Consent and HIPAA Authorization 
To allow analysis of patient outcomes in all patients during both the pre- and post-intervention phases 
and to facilitate future research through creation of a research registry, we will request a waiver of 
informed consent and HIPAA authorization based on the following criteria as per 45 CFR 46.116(d) and 
the HIPAA Privacy Rule. 
 
9.2.1 Research and registry involve no more than minimal risk  
Acceptance is widespread for protocols using pre-arrival notification to activate ED teams for the 
treatment of other critical illnesses where time-to-treatment determines outcomes. Since the tested 
exposure will be incorporated into ED care processes as standard care, and will merely accelerate 
evaluation, testing, and treatment sepsis patients would receive during current (pre-intervention) 
standard care, patients will overall experience only the risks associated with standard ED clinical care. 
Research and registry creation involve no direct contact between the study team and patients, only 
review of records routinely collected for administration and medical care. For a small number of 
subjects, there will be anonymized monitoring of ED operations in the form of non-interactive 
observation of Code Sepsis protocol completion involving collection of anonymous data, which would be 
standard during implementation of any approach to improving standard ED care.  
 
9.2.2 No adverse effects on the rights and welfare of participants 
Exposure to standard care in the form of the Code Sepsis protocol and research team abstraction of data 
routinely collected in the course of clinical care should have no influence on the welfare of study 
subjects. Analysis and registry storage of data recorded as part of routine clinical care and operations 
should have no influence on the welfare of study subjects. Because risk is minimal given this design, the 
waiver of consent and authorization will not adversely affect the rights or welfare of subjects. 
 
9.2.3 The research and registry could not practicably be carried out without waiver of informed 
consent 
Given the large number of eligible patient subjects (up to 530,000, including approximately 9,450 
patients with sepsis in the primary analysis cohort), the research and registry could not practicably be 
carried out without the waiver of consent. The sample size for this chart review is large enough that 
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and would compromise the scientific validity of the study, as a large proportion of the data would be 
eliminated if obtaining consent were a requirement. Obtaining consent would also preclude rapid 
initiation of the Code Sepsis protocol and rapid antibiotic initiation. The subjects whose records will be 
reviewed will not be followed beyond their hospitalization (except for routine use of data on long-term 
mortality obtained via existing linkages) and would be mostly lost to follow up. The proportion of 
subjects who have relocated or have passed away will likely be a significant percentage of the subject 
population, and so the research results would not be meaningful and would lose statistical power if 
obtaining consent were a requirement. 
 
9.2.4 Information on the Code Sepsis protocol and study will be available to all ED patients 
We will make available patient information sheets describing the Code Sepsis protocol in the 
intervention emergency department (e.g. lobby, patient information stations, and on request). It is 
otherwise not possible to provide patient subjects with information about the study as there is no 
feasible mechanism by which to notify subjects, attempting to do so would substantially increase the 
risk of a confidentiality breach, and because the information that is found will have no impact on 
subjects’ clinical care. 
 
9.2.5 The minimal necessary amount of protected information will be obtained 
Only data necessary for the completion of the study will be collected. The patient ID, encounter ID, 
social security number, address, and date of birth are necessary to allow data linkage, identification of 
the specific patient encounter for supplemental data abstraction. Event date/times are necessary for 
care process and outcome measurement, including calculation of the elapsed time related to various 
patient management actions include the primary outcome. Identifiers will maintained in the registry to 
facilitate future research. 
 
9.2.6 All data, including PHI, will be securely guarded from improper disclosure  
High-level safeguards will be in place to protect subject identity and confidential data, including in data 
maintained in the research registry. The study and registry data will be kept on encrypted, password-
protected computers. These computers are routinely used for storage of patient data and research data 
including subject identifiers. The data will only be accessible to members of the research team, and all 
members of the research team have completed Human Subjects Protections and understand the 
importance of protecting subject privacy and confidentiality. No PHI will be recorded on the CRFs for the 
study dataset. Protected health information will not be reused or disclosed to any other person or 
entity, except as required by law, for authorized oversight of the research project, for other research as 
approved by an IRB, or for other research for which the use or disclosure of protected health 
information would be permitted by under applicable regulations. Minimal identifiers will be maintained 
linked to the data. Maintaining minimal identifiers linked to the data is necessary to allow (1) manual 
abstraction of additional data from the electronic medical record and (2) potential future linkage – with 
IRB approval -- of the data to additional datasets. No individual subject data will be presented in any 
presentation, publication or report related to this research. Data will be presented only in anonymized 
or aggregate or as results of statistical analyses and will not include any individual-level data that could 
be traced to a particular subject.  
 
 
 

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10. MONITORING AND SAFETY REPORTING 
 
On the basis of established precedents in implementation research, using toolkits supplied by NIH 
institutes and the University of Washington’s CTSA-supported Institute for Translational Health Sciences 
and in consultation with the Intermountain Institutional Review Board (IRB) and National Institutes of 
Health (NIH) staff, we believe the proposed clinical trial represents no more than minimal risk to 
exposed patients. The study will thus be overseen by an Independent Safety Monitor (ISM), a practicing 
ICU physician with extensive experience performing clinical trials but not affiliated with the current trial. 
 
10.1 Potential Risks and Benefits for Participants 
• 
Potential risks: The risk level associated with this study is estimated to be no more than minimal, 
since the studied intervention — prehospital activation of ED-based Code Sepsis teams — will be 
adopted as standard care and is designed to accelerate evaluation, testing, and treatments that 
the patient would have eventually received under current standard care. While the efficient 
coordination of therapies is novel and likely to improve care overall, we will monitor for the 
possibility of effects potentially relevant to faster antibiotic therapy, specifically receipt of 
antibiotics to which the patient is known to be allergic. This possibility is protected against 
through inclusion of a pharmacist in the Code Sepsis team. Other risks are also minimal and 
related to loss of confidentiality of data. 
• 
Potential benefits: The potential benefits to study subjects with sepsis treated in the 
intervention ED after implementation of the full Code Sepsis protocol include faster evaluation, 
diagnosis, and treatment initiation leading to improved patient outcomes. 
 
10.2 Adverse Event and Serious Adverse Event Collection 
10.2.1 Adverse event 
A clinical trial adverse event is any untoward medical event associated with the use of the study 
procedure, whether or not it is considered related to a drug or study procedure. After Code Sepsis 
intervention, adverse events related or possibly related to study procedures must be evaluated by the 
PI. The PI, with assistance from study co-investigators as needed, will assess whether there is a 
reasonable possibility that the study procedure caused the event, based on the criteria below. 
Investigators will also consider whether the event is unanticipated or unexplained given the patient’s 
clinical course, previous medical conditions, and concomitant medications. If the severe adverse event is 
judged to be reportable, as outlined below, then the investigator will report to the ISM and IRB his 
assessment of the potential relatedness of each adverse event to protocol procedure. 
 
The study uses the following AE attribution scale: 
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s 
clinical state or other therapies; and c) Evaluation of the patient’s clinical state indicates 
to the investigator that the experience is definitely related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria 
for “Definitely Associated”. If in the investigator’s opinion at least one or more of the 
criteria are not present, then “probably” or “possibly” associated should be selected.  
• 
Probably Not Related: The event occurred while the patient was on the study but can 
reasonably be explained by the known characteristics of the patient’s clinical state or 
other therapies.  

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• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or 
by other modes of therapy administered to the patient. 
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
 
10.2.2 Serious Adverse Event (SAE) 
An SAE is any AE that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Event requiring prolongation of existing hospitalization. As per 
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if 
admission to the hospital or prolongation of hospitalization was a result of the adverse 
event. Emergency room visits that do not result in admission to the hospital should be 
evaluated for one of the other serious outcomes (e.g., life-threatening; required 
intervention to prevent permanent impairment or damage; other serious medically 
important event). 
• 
Persistent or significant disability/incapacity. As per 
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if the 
adverse event resulted in a substantial disruption of a person's ability to conduct normal 
life functions, i.e., the adverse event resulted in a significant, persistent or permanent 
change, impairment, damage or disruption in the patient's body function/structure, 
physical activities and/or quality of life. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
10.2.3 Adverse event monitoring 
The PI will review potential adverse events monthly for patients for whom the Code Sepsis protocol was 
activated during the patient’s ED visit. The PI will also review within 72 hours of identification any 
potential anaphylaxis cases occurring within 24 hours of ED antibiotic initiation in Code Sepsis patients. 
Adverse events will be monitored via review of the medical record for the first 3 days after Code Sepsis 
activation or until hospital discharge, whichever occurs first, regardless of the investigator's opinion of 
causation. Thereafter, serious adverse events are not required to be collected unless routine clinical 
care monitoring or the PI believes that the event was possibly, probably, or definitely to the Code Sepsis 
protocol.  
 
10.3 Adverse Event and Serious Adverse Event Reporting 
We emphasize in AE reporting for this study that the intervention under study is an expedited bundling 
of established elements of clinical care. Study-specific clinical outcomes of sepsis and ED clinical care are 
exempt from adverse event reporting unless the investigator deems the event to be related to the 
administration of study drug or the conduct of study procedures (or of uncertain relationship). The 
following are examples of events that will be considered routinely recorded clinical outcomes: 
• 
Death not related to study procedures.  
• 
Adverse drug reaction (excluding anaphylaxis associated with antibiotic administration) not 
related to study procedures 
• 
Secondary and healthcare associated infections 
• 
Persistent or progressive organ failure 

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• 
Prolonged hospitalization 
 
The PI will report to the ISM within 72 hours of identification all AEs that are serious and possibly, 
probably, or definitely related to study procedure (or of uncertain relationship) or are unexpected. If the 
ISM concurs with the PI’s assessment, the AE will be reported to the IRB within 7 business days. Other 
AEs will be reviewed by the PI on a monthly basis and reported in aggregate to the ISM on a quarterly 
basis. A summary report on all adverse events will be submitted to the IRB during annual recertification 
as per IRB guidelines. Good Clinical Practice will be followed for conduct of the study.  
 
10.4 Interim Analysis 
There will be no interim analyses. 
 
10.5 Data and Safety Monitoring 
Given that this study is using pre-post method to study implementation of a method to deliver clinical 
standard-of-care therapies in a more efficient, expeditious, and coordinated manner, the safety 
monitoring plan will be implemented with the use of an Independent Safety Monitor (ISM). The ISM will 
monitor participant safety, evaluate the progress of the study, review procedures for maintaining the 
confidentiality of data, and monitor the quality of data collection, management, and analyses. The PI 
and study personnel will provide all necessary and requested reports to the ISM in a timely manner. The 
ISM will have full capacity to end the study at her/his discretion if there is an important safety signal, 
according to a safety monitoring charter that will be finalized in consultation with NIH and the ISM 
before study launch. Notably, given that the “intervention” in this trial is a non-randomized 
implementation of a bundle of timely care for sepsis treatment, the safety monitoring plan will focus on 
monitoring the Code Sepsis activations. The PI will be responsible for ensuring participants’ safety and 
that the study is conducted according to the IRB-approved research plan on a daily basis.  
 
10.5.1 Safety Monitoring Procedures 
1. Since this research examines implementation of a method to deliver clinical standard-of-care 
therapies in a more efficient, expeditious, and coordinated manner, the foundation for safety 
monitoring for this study is the routine quality assurance monitoring of the study hospital’s 
Emergency Department. This quality assurance activity includes review of incident reports for 
clinical adverse events. The ED physician who serves as site medical director and currently has 
lead responsibility for monitoring of care quality and safety in each study ED. The study team 
will be in monthly contact via telephone or email with the ED medical director overseeing 
quality assurance efforts at the intervention hospital to identify potential concerns possibly, 
probably, or definitely related to Code Sepsis implementation. If necessary, comparisons to 
control hospital EDs will be performed on the basis of reports from their medical directors. 
2. Specific to study procedures, all Code Sepsis activations will be individually evaluated. The PI will 
review all Code Sepsis activations on a monthly basis. AEs will be reported to the ISM in 
aggregate on a quarterly basis. The PI will report to the ISM within 72 hours of identification all 
AEs that are serious and possibly, probably, or definitely related to study procedure (or of 
uncertain relationship) or are unexpected. The ISM and PI together will reach consensus on the 
ultimate characterization of these possible serious adverse events (SAEs). If disagreement 
persists after discussion between the ISM and PI, the ISM will make the final decision about the 
status of the possible SAE. SAEs will be reported to the IRB within 7 business days.  
3. If required by NIH or other governing bodies, or based on issues observed during trial conduct, 
we will convene a Data Safety Monitoring Board (DSMB) of clinical experts and members with 

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expertise in implementation trials with assistance from the Utah Center for Clinical and 
Translational Science. 
 
10.5.2 Enrollment, procedure, regulatory, and data quality monitoring 
Our data monitoring plan will include 
1. Review of accrued data at monthly study team meetings 
2. Review of data safety and interim data analysis performed by the independent safety monitor 
3. Semi-annual audits of study materials by the Intermountain PCCM regulatory affairs group 
4. An annual review performed by the Intermountain Healthcare IRB 
 
Careful monitoring of the data collection, regulatory adherence, data quality, and study procedures will 
help to protect the safety of study subjects, the quality of data, and the integrity of the study. The PI or 
study staff will review all data collection on an ongoing basis for data completeness and accuracy as well 
as protocol compliance. Data verification for key demographic, exposure, and outcome parameters will 
be performed on an ongoing basis for a random 5% of all Code Sepsis patients. This will occur on the 
basis of data reabstraction by someone other than the individual who originally collecting the data or by 
blinded duplicate data entry. The results of the ongoing data review will be incorporated into each 
review with the ISM. A statement reflecting the results of the ongoing data review will be incorporated 
into the annual report for the IRB.  
 
10.5.3 Frequency of data and safety monitoring  
The PI and study team will review data quality and adverse event reports monthly and meet with the 
ISM quarterly, either in-person or by teleconference call, to review study progress, data quality, and 
participants’ safety. A summary report on all adverse events and data quality will be submitted to the 
IRB during annual recertification as per IRB guidelines. 
 
10.5.4 Independent safety monitor identify and affiliation 
The following individual has agreed to serve as the independent safety monitor for the study: 
Eliotte Hirshberg, MD, MS 
Division of Pulmonary & Critical Care Medicine, Intermountain Medical Center 
Associate Professor of Medicine, University of Utah School of Medicine 
 
10.5.5 Conflict of interest for independent safety monitor 
The ISM will have no direct involvement with the study investigators or intervention. The independent 
safety monitor will sign a Conflict of Interest Statement which includes current affiliations, if any, with 
pharmaceutical and biotechnology companies (e.g., stockholder, consultant), and any other relationship 
that could be perceived as a conflict of interest related to the study and/or associated with commercial 
interests pertinent to study objectives. 
 
10.5.6 Independent safety monitor responsibilities 
• 
Review and approve the research protocol and plans for data safety and monitoring; 
• 
Evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual, participant risk versus benefit, and other factors that can affect study 
outcome; 

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• 
Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the trial; 
• 
Review study performance, make recommendations and assist in the resolution of problems 
reported by the PI; 
• 
Protect the safety of the study participants; 
• 
Make recommendations to the PI concerning continuation, termination or other modifications of 
the trial based on the observed adverse effects of the treatment under study; 
• 
Ensure the confidentiality of the study data and the results of monitoring; and, 
• 
Assist the IRB by commenting on any concerns related to study conduct, enrollment, sample size, 
and/or data collection. 
 
10.6 Confidentiality During Adverse Event Reporting  
AE reports and annual summaries will not include subject- or group-identifiable material. Each report 
will only include the identification code. Data will be presented in a blinded manner during any open 
sessions involving the ISM. At meetings with the ISM or in IRB reports, data and discussion are 
confidential. Participant identities will not be known to the ISM or to the IRB. 
 
 
 

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11. BIBLIOGRAPHY 
 
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. 
Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe 
sepsis in the United States. Crit Care Med. 2013;41:1167–74.  
3. 
Torio CM, Moore BJ. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 
2013: Statistical Brief #204. Healthcare Cost and Utilization Project. 2016. Available at: 
https://www.hcup-us.ahrq.gov/reports/statbriefs/sb204-Most-Expensive-Hospital-
Conditions.jsp.: Accessed July 6, 2017. 
4. 
Kaukonen K-M, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and 
septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 
2014;311:1308–16.  
5. 
Peltan ID, Mitchell KH, Rudd KE, et al. Physician variation in time to antimicrobial treatment for 
septic patients presenting to the emergency department. Crit Care Med. 2017;45:1011–8.  
6. 
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis 
and septic shock. New Engl J Med. 2001;345:1368–77.  
7. 
ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for 
early septic shock. New Engl J Med. 2014;370:1683–93.  
8. 
ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for 
patients with early septic shock. New Engl J Med. 2014;371:1496–506.  
9. 
Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective 
antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 
2006;34:1589–96.  
10. 
Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients 
with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the 
emergency department. Crit Care Med. 2010;38:1045–53.  
11. 
Liu VX, Fielding-Singh V, Greene JD, et al. The timing of early antibiotics and hospital mortality in 
sepsis. Am J Respir Crit Care Med. 2017;196:856–63.  
12. 
Seymour CW, New York State Office of Quality and Patient Safety, Prescott HC, et al. Time to 
treatment and mortality during mandated emergency care for sepsis. New Engl J Med. 
2017;376:2235–44.  
13. 
Peltan ID, Brown SM, Bledsoe JR, et al. Emergency department door-to-antibiotic time and long-
term mortality in sepsis. Chest. 2019.  
14. 
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.  
15. 
Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive 
Care Med. 2018;44:925–8.  
16. 
Peltan ID, Mitchell KH, Rudd KE, et al. Prehospital care and emergency department door-to-
antibiotic time in sepsis. Ann Am Thorac Soc. 2018;15:1443–50.  
17. 
Peltan ID, Bledsoe JR, Oniki TA, et al. ED crowding is associated with delayed antibiotics for 
sepsis. Ann Emerg Med. 2018.  
18. 
MacKenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma-center 
care on mortality. New Engl J Med. 2006;354:366–78.  
19. 
Kim SK, Lee SY, Bae HJ, et al. Pre-hospital notification reduced the door-to-needle time for IV tPA 
in acute ischaemic stroke. Eur J Neurol. 2009;16:1331–5.  
20. 
Mosley I, Nicol M, Donnan G, Patrick I, Kerr F, Dewey H. The impact of ambulance practice on 

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acute stroke care. Stroke. 2007;38:2765–70.  
21. 
Pedersen SH, Galatius S, Hansen PR, et al. Field triage reduces treatment delay and improves 
long-term clinical outcome in patients with acute ST-segment elevation myocardial infarction 
treated with primary percutaneous coronary intervention. J Am Coll Cardiol. 2009;54:2296–302.  
22. 
Sejersten M, Sillesen M, Hansen PR, et al. Effect on treatment delay of prehospital 
teletransmission of 12-lead electrocardiogram to a cardiologist for immediate triage and direct 
referral of patients with ST-segment elevation acute myocardial infarction to primary 
percutaneous coronary intervention. Am J Cardiol. 2008;101:941–6.  
23. 
Seymour CW, Rea TD, Kahn JM, Walkey AJ, Yealy DM, Angus DC. Severe sepsis in pre-hospital 
emergency care: analysis of incidence, care, and outcome. Am J Respir Crit Care Med. 
2012;186:1264–71.  
24. 
Wachter RM, Flanders SA, Fee C, Pronovost PJ. Public reporting of antibiotic timing in patients 
with pneumonia: lessons from a flawed performance measure. Ann Intern Med. 2008;149:29–32.  
25. 
Singer M. Antibiotics for sepsis: Does each hour really count, or is it incestuous amplification? Am 
J Respir Crit Care Med. 2017;196:800–2.  
26. 
Klompas M, Calandra T, Singer M. Antibiotics for sepsis — Finding the equilibrium. JAMA. 
2018;320:1433–4.  
27. 
Croskerry P. From mindless to mindful practice--cognitive bias and clinical decision making. New 
Engl J Med. 2013;368:2445–8.  
28. 
Stenehjem E, Hersh AL, Sheng X, et al. Antibiotic use in small community hospitals. Clin Infect Dis. 
2016;63:1273–80.  
29. 
Call K, Donohue M, Fontaine G, et al. Care Process Model: Emergency Management of Acute 
Ischemic Stroke. Intermountain Healthcare. 2017. Available at: 
https://intermountainhealthcare.org/ext/Dcmnt?ncid=520500199.: Accessed October 27, 2018. 
30. 
George P, Wisco DR, Gebel J, Uchino K, Newey CR. Nurses are as specific and are earlier in calling 
in-hospital stroke alerts compared to physicians. J Stroke Cerebrovasc Dis. 2017;26:917–21.  
31. 
Clayton PD, Narus SP, Huff SM, et al. Building a comprehensive clinical information system from 
components: the approach at Intermountain Health Care. Methods Inf Med. 2003;42:1–7.  
32. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational 
research informatics support. J Biomed Inform. 2009;42:377–81.  
33. 
Dimick JB, Ryan AM. Methods for evaluating changes in health care policy: the difference-in-
differences approach. JAMA. 2014;312:2401–2.  
34. 
Peltan ID, Brown CE, Burke AK, Chow EJ, Rowhani-Rahbar A, Crull MR. The July Effect on maternal 
peripartum complications before and after resident duty hour reform: a population-based 
retrospective cohort study. Am J Perinatol. Thieme Medical Publishers, 2017;34:818–25.  
 
 
 

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APPENDIX A — Eligible IV and IV-equivalent antibiotics 
 
Antibiotic 
Brand/alternative name 
Eligible 
routes 
Acyclovir 
Zovirax 
IV 
Amikacin 
Amikin 
IV 
Amphotericin 
Amphotec, Ambisome 
IV 
Ampicillin 
Principen 
IV 
Ampicillin/sulbactam 
Unasyn 
IV 
Anidulafungin 
Eraxis 
IV 
Azithromycin 
Zithromax, Zmax, Sumamed 
IV 
Aztreonam 
Azactam 
IV 
Caspofungin 
Cancidas 
IV 
Cefazolin 
Ancef 
IV 
Cefdericol 
Fetroja 
IV 
Cefepime 
Maxipime 
IV 
Cefoperazone 
Cefobid 
IV 
Cefotaxime 
Claforan 
IV 
Cefotetan 
Cefotan 
IV 
Cefoxitin 
Mefoxin 
IV 
Ceftaroline 
Teflaro 
IV 
Ceftazidime 
Fortaz 
IV 
Ceftazidime/avibactam 
Avycaz 
IV 
Ceftizoxime 
Cefizox 
IV 
Ceftolozane/tazobactam 
Zerbaxa, Ceftolozane 
IV 
Ceftriaxone 
Rocephin 
IV 
Cefuroxime 
Ceftin, Zinacef 
IV 
Chloramphenicol 
Chloromycetin 
IV 
Cidofovir 
Vistide 
IV 
Ciprofloxacin 
Cipro, Ciprobay, Ciproxin 
IV 
Clindamycin 
Cleocin 
IV 
Colistin 
Colymycin 
IV 
Dalbavancin 
Dalvance 
IV 
Daptomycin 
Cubicin 
IV 
Delafloxacin 
Baxdela 
IV 
Doripenem 
Doribax 
IV 
Doxycycline 
Doxychel, Vibramycin 
IV 
Eravacycline 
Xerava 
IV 
Ertapenem 
Invanz 
IV 
Erythromycin 
Erythocin, Erythroped 
IV 
Fidaxomycin 
Dificid 
PO 
Fluconazole 
Diflucan 
IV 
Ganciclovir 
Cytovene 
IV 
Gentamicin 
Garamycin 
IV 
Imipenem/cilastin 
Primaxin 
IV 
Isavuconazole 
Cresemba, Isavuconazonium 
IV 
Itraconazole 
Sporanox, Onmel 
IV 
Levofloxacin 
Levaquin 
IV 
Linezolid 
Zyvox 
IV 

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Antibiotic 
Brand/alternative name 
Eligible 
routes 
Meropenem 
Merrem 
IV 
Meropenem/vaborbactam 
Vabomere 
IV 
Metronidazole 
Flagyl 
IV 
Micafungin 
Mycamine 
IV 
Minocycline 
Minocin 
IV 
Moxifloxacin 
Avelox 
IV 
Nafcillin 
Unipen, Nallpen 
IV 
Ofloxacin 
Floxin 
IV 
Omadadcycline 
Nuzyra, Paratek 
IV 
Oritavancin 
Orbactiv 
IV 
Oseltamavir 
Tamiflu 
PO 
Oxacillin 
Bastocillin 
IV 
Penicillin 
Penicillin V, Pencillin G, Pen VK, Bicillin, Veetids, 
Pentids, Permapen, Pfizerpen,  
IV 
Peramavir 
Rapivab 
IV 
Piperacillin/tazobactam 
Zosyn 
IV 
Plazomicin 
Zemdri 
IV 
Posaconazole 
Noxafil 
IV 
Quinuopristin/dalfopristin 
Synercid 
IV 
Remdesivir 
Veklury 
IV 
Rifampin 
Rifadin 
IV 
Telavancin 
Vibativ 
IV 
Tetracycline 
Achromycin, Tetracyn, Sumycin, Tetrachel 
IV 
Ticarcillin/clavulanate 
Timentin 
IV 
Tidezolid 
Sivextro 
IV 
Tigecycline 
Tygacil 
IV 
Tobramycin 
  
IV 
Trimethoprim/sulfamethoxazole Bactrim, Septra, Sulfatrim 
IV 
Vancomycin 
Vancocin 
PO 
Vancomycin 
Vancocin 
IV 
Voriconazole 
Vfend 
IV 
Zanamivir 
Relenza 
IV 
 
 
 

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APPENDIX B — “Sepsis mimic” ICD codes 
B.1 Heart failure diagnosis codes1 
 
ICD-9  
ICD-10  
Description 
 
398.,91  
I09.81 
 
Rheumatic heart failure 
402.01  
I11.0 
 
Hypertensive heart disease with heart failure 
402.11  
I11.0 
 
Hypertensive heart disease with heart failure 
402.91  
I11.0 
 
Hypertensive heart disease with heart failure 
404.01  
I13.0 
 
Hypertensive heart/kidney dz w/heart failure, stage 1-4 CKD or unspec 
404.03  
I13.2 
 
Hypertensive heart/kidney dz w/heart failure, stage 5 CKD or ESRD 
404.11  
I13.0 
 
Hypertensive heart/kidney dz w/heart failure, stage 1-4 CKD or unspec 
404.13  
I13.2 
 
Hypertensive heart/kidney dz w/heart failure, stage 5 CKD or ESRD 
404.91  
I13.0 
 
Hypertensive heart/kidney dz w/heart failure, stage 1-4 CKD or unspec 
404.93  
I13.2 
 
Hypertensive heart/kidney dz w/heart failure, stage 5 CKD or ESRD 
428.0  
I50.9 
 
Heart failure, unspecified 
428.1  
I50.1 
 
Left heart failure 
428.20  
I50.20 
 
Unspecified systolic heart failure 
428.21  
I50.21 
 
Acute systolic heart failure 
428.22  
I50.22 
 
Chronic systolic heart failure 
428.23  
I50.23 
 
Acute on chronic systolic heart failure 
428.30  
I50.30 
 
Unspecified diastolic heart failure 
428.31  
I50.31 
 
Acute diastolic heart failure 
428.32  
I50.32 
 
Chronic diastolic heart failure 
428.33  
I50.33 
 
Acute on chronic diastolic heart failure 
428.40  
I50.40 
 
Unspecified combined systolic and diastolic heart failure 
428.41  
I50.41 
 
Acute combined systolic and diastolic heart failure 
428.42  
I50.42 
 
Chronic combined systolic and diastolic heart failure 
428.43  
I50.43 
 
Acute on chronic combined systolic and diastolic heart failure 
428.9  
I50.810  
Right heart failure, unspecified 
428.9  
I50.811  
Acute right heart failure 
428.9  
I50.812  
Chronic right heart failure 
428.9  
I50.813  
Acute on chronic right heart failure 
428.9  
I50.814  
Right heart failure due to left heart failure 
428.9  
I50.82 
 
Biventricular heart failure 
428.9  
I50.83 
 
High output heart failure 
428.9  
I50.84 
 
End stage heart failure 
428.9  
I50.89 
 
Other heart failure 
428.9  
I50.9 
 
Heart failure, unspecified 
 
Use only if below is primary diagnosis and one of above is second diagnosis 
425.4  
I42.0 
 
Dilated cardiomyopathy 
425.5  
I42.6 
 
Alcoholic cardiomyopathy 
425.9  
I42.7 
 
Cardiomyopathy due to drug and external agent 
425.9  
I42.8 
 
Other cardiomyopathy 
425.9  
I42.9 
 
Cardiomyopathy, unspecified 
425.8  
I43 
 
Cardiomyopathy in diseases classified celsewhere 
429.83  
I51.81 
 
Takotsubo cardiomyopathy 
 
1 Adapted from: Heart Failure CCW Chronic Conditions Algorithm. CMS Chronic Conditions Data 
Warehouse. 2018. Available at: https://www.ccwdata.org/web/guest/condition-categories.: Accessed 

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February 13, 2019. 
 
B.2 Pulmonary embolism diagnosis codes1,2 
 
ICD-9 
ICD-10 
Description (from ICD-10) 
 
415.11  
 
 Iatrogenic pulmonary embolism and infarction 
415.13  
I26.02 
Saddle embolus of pulmonary artery with acute cor pulmonale 
415.19  
I26.09 
Other pulmonary embolism with acute cor pulmonale 
415.13  
I26.92 
Saddle embolus of pulmonary artery without acute cor pulmonale 
415.19  
I26.99 
Other pulmonary embolism without acute cor pulmonale 
673.20  
O88.219 
Thromboembolism in pregnancy, unspecified trimester 
673.21  
O83.22 
Thromboembolism in childbirth 
673.22  
O88.22 
Thromboembolism in childbirth 
673.23  
O83.211 
Thromboembolism in pregnancy, first trimester 
673.23  
O83.212 
Thromboembolism in pregnancy, second trimester 
673.23  
O83.213 
Thromboembolism in pregnancy, third trimester 
673.24  
O83.23 
Thromboembolism in puerperium 
 
Adapted from: 
1. 
Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy P-M, Fine MJ. Derivation and 
validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 
2005;172:1041–1046.  
2. 
Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: 
evidence of overdiagnosis. Arch Intern Med 2011;171:831–837.  
 
 
 

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B.3 Deep vein thrombosis diagnosis codes1,2 
 
ICD-9 
ICD-10 
Description (from ICD-10) 
 
451.11  
I80.10 
Phlebitis/thrombophlebitis of unspecified femoral vein 
451.11  
I80.11  
Phlebitis/thrombophlebitis of right femoral vein 
451.11  
I80.12  
Phlebitis/thrombophlebitis of left femoral vein 
451.11  
I80.13  
Phlebitis/thrombophlebitis of bilateral femoral vein 
451.19  
I80.201 
Phlebitis/thrombophlebitis of unspecified deep vessels of right lower extremity 
451.19  
I80.202 
Phlebitis/thrombophlebitis of unspecified deep vessels of left lower extremity 
451.19  
I80.203 
Phlebitis/thrombophlebitis of unspecified deep vessels of bilateral lower extremity 
451.19  
I80.209 
Phlebitis/thrombophlebitis of unspecified deep vessels of unspecified lower extremity 
451.19  
I80.221 
Phlebitis/thrombophlebitis of right popliteal vein  
451.19  
I80.222 
Phlebitis/thrombophlebitis of right popliteal vein 
451.19  
I80.223 
Phlebitis/thrombophlebitis of bilateral popliteal vein 
451.19  
I80.229 
Phlebitis/thrombophlebitis of unspecified popliteal vein 
451.19  
I80.231 
Phlebitis/thrombophlebitis of right tibial vein  
451.19  
I80.232 
Phlebitis/thrombophlebitis of right tibial vein 
451.19  
I80.233 
Phlebitis/thrombophlebitis of bilateral tibial vein 
451.19  
I80.239 
Phlebitis/thrombophlebitis of unspecified tibial vein 
451.19  
I80.291 
Phlebitis/thrombophlebitis of other deep vessels of right lower extremity 
451.19  
I80.292 
Phlebitis/thrombophlebitis of other deep vessels of left lower extremity 
451.19  
I80.293 
Phlebitis/thrombophlebitis of other deep vessels of bilateral lower extremity 
451.19  
I80.299 
Phlebitis/thrombophlebitis of other deep vessels of unspecified lower extremity 
451.81  
I80.211  
Phlebitis/thrombophlebitis of right iliac vein 
451.81  
I80.212 
Phlebitis/thrombophlebitis of left iliac vein 
451.81  
I80.213  
Phlebitis/thrombophlebitis of bilateral iliac vein 
453.81  
I80.219  
Phlebitis/thrombophlebitis of unspecified iliac vein 
451.11  
I80.10 
Phlebitis/thrombophlebitis of unspecified femoral vein 
451.11  
I80.11  
Phlebitis/thrombophlebitis of right femoral vein 
451.11  
I80.12  
Phlebitis/thrombophlebitis of left femoral vein 
451.11  
I80.13  
Phlebitis/thrombophlebitis of bilateral femoral vein 
451.19  
I80.201 
Phlebitis/thrombophlebitis of unspecified deep vessels of right lower extremity 
451.19  
I80.202 
Phlebitis/thrombophlebitis of unspecified deep vessels of left lower extremity 
451.19  
I80.203 
Phlebitis/thrombophlebitis of unspecified deep vessels of bilateral lower extremity 
451.19  
I80.209 
Phlebitis/thrombophlebitis of unspecified deep vessels of unspecified lower extremity 
451.19  
I80.221 
Phlebitis/thrombophlebitis of right popliteal vein  
451.19  
I80.222 
Phlebitis/thrombophlebitis of right popliteal vein 
451.19  
I80.223 
Phlebitis/thrombophlebitis of bilateral popliteal vein 
451.19  
I80.229 
Phlebitis/thrombophlebitis of unspecified popliteal vein 
451.19  
I80.231 
Phlebitis/thrombophlebitis of right tibial vein  
451.19  
I80.232 
Phlebitis/thrombophlebitis of right tibial vein 
451.19  
I80.233 
Phlebitis/thrombophlebitis of bilateral tibial vein 
451.19  
I80.239 
Phlebitis/thrombophlebitis of unspecified tibial vein 
451.19  
I80.291 
Phlebitis/thrombophlebitis of other deep vessels of right lower extremity 
451.19  
I80.292 
Phlebitis/thrombophlebitis of other deep vessels of left lower extremity 
451.19  
I80.293 
Phlebitis/thrombophlebitis of other deep vessels of bilateral lower extremity 
451.19  
I80.299 
Phlebitis/thrombophlebitis of other deep vessels of unspecified lower extremity 

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ICD-9 
ICD-10 
Description (from ICD-10) — CONTINUED 
 
451.81  
I80.211  
Phlebitis/thrombophlebitis of right iliac vein 
451.81  
I80.212 
Phlebitis/thrombophlebitis of left iliac vein 
451.81  
I80.213  
Phlebitis/thrombophlebitis of bilateral iliac vein 
453.81  
I80.219  
Phlebitis/thrombophlebitis of unspecified iliac vein 
451.83  
 
Phlebitis/thrombophlebitis of deep vein of upper extremity 
453.40  
I82.401 
Acute embolism/thrombosis of unspecified deep veins of right lower extremity 
453.40  
I82.402 
Acute embolism/thrombosis of unspecified deep veins of left lower extremity 
453.40  
I82.403 
Acute embolism/thrombosis of unspecified deep veins of bilateral lower extremity 
453.40  
I82.409 
Acute embolism/thrombosis of unspecified deep veins of unspecified lower extremity 
453.40  
I82.491 
Acute embolism/thrombosis of other deep veins of right lower extremity 
453.40  
I82.492 
Acute embolism/thrombosis of other deep veins of left lower extremity 
453.40  
I82.493 
Acute embolism/thrombosis of other deep veins of bilateral lower extremity 
453.40  
I82.499 
Acute embolism/thrombosis of other deep veins of unspecified lower extremity 
453.41  
I82.411 
Acute embolism/thrombosis of right femoral vein 
453.41  
I82.412 
Acute embolism/thrombosis of left femoral vein 
453.41  
I82.413 
Acute embolism/thrombosis of bilateral femoral vein 
453.41  
I82.419 
Acute embolism/thrombosis of unspecified femoral vein 
453.41  
I82.421 
Acute embolism/thrombosis of right iliac vein 
453.41  
I82.422 
Acute embolism/thrombosis of left iliac vein 
453.41  
I82.423 
Acute embolism/thrombosis of bilateral iliac vein 
453.41  
I82.429 
Acute embolism/thrombosis of unspecified iliac vein 
453.41  
I82.4Y1 
Acute embolism/thrombosis of unspecified veins of right proximal lower extremity 
453.41  
I82.4Y2 
Acute embolism/thrombosis of unspecified veins of left proximal lower extremity 
453.41  
I82.4Y3 
Acute embolism/thrombosis of unspecified veins of bilateral proximal lower extremity 
453.41  
I82.4Y9 
Acute embolism/thrombosis of unspecified veins of unspecified prox lower extremity 
453.42  
I82.431 
Acute embolism/thrombosis of right popliteal vein 
453.42  
I82.432 
Acute embolism/thrombosis of left popliteal vein 
453.42  
I82.433 
Acute embolism/thrombosis of bilateral popliteal vein 
453.42  
I82.439 
Acute embolism/thrombosis of unspecified popliteal vein 
453.42  
I82.441 
Acute embolism/thrombosis of right tibial vein 
453.42  
I82.442 
Acute embolism/thrombosis of left tibial vein 
453.42  
I82.443 
Acute embolism/thrombosis of bilateral tibial vein 
453.42  
I82.449 
Acute embolism/thrombosis of unspecified tibial vein 
453.42  
I82.4Z1 
Acute embolism/thrombosis of unspecified veins of right distal lower extremity 
453.42  
I82.4Z2 
Acute embolism/thrombosis of unspecified veins of left distal lower extremity 
453.42  
I82.4Z3 
Acute embolism/thrombosis of unspecified veins of bilateral distal lower extremity 
453.42  
I82.4Z9 
Acute embolism/thrombosis of unspecified veins of unspecified distal lower extremity 
 
 
I82.621 
Acute embolism/thrombosis of deep veins of right upper extremity 
 
 
I82.622 
Acute embolism/thrombosis of deep veins of left upper extremity 
 
 
I82.623 
Acute embolism/thrombosis of deep veins of bilateral upper extremity 
 
 
I82.629 
Acute embolism/thrombosis of deep veins of unspecified upper extremity 
 
 

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ICD-9 
ICD-10 
Description (from ICD-10) — CONTINUED 
 
671.30  
O22.30 
Deep phlebothrombosis in pregnancy, unspecified trimester 
671.31  
O87.1 
Deep phlebothrombosis in the peurperium 
671.33  
O22.31 
Deep phlebothrombosis in pregnancy, first trimester 
671.33  
O22.32 
Deep phlebothrombosis in pregnancy, second trimester 
671.33  
O22.33 
Deep phlebothrombosis in pregnancy, third trimester 
671.40  
O87.1 
Deep phlebothrombosis, postpartum, unspecified as to episode of care 
671.42  
O87.1 
Deep phlebothrombosis, postpartum, delivered 
671.44  
O87.1 
Deep phlebothrombosis, postpartum, postpartum condition 
 
 
Adapted from: 
1. 
White RH, Garcia M, Sadeghi B, Tancredi DJ, Zrelak P, Cuny J, Sama P, Gammon H, Schmaltz S, 
Romano PS. Evaluation of the predictive value of ICD-9-CM coded administrative data for venous 
thromboembolism in the United States. Thromb Res 2010;126:61–67.  
2. 
Kniffin WD, Baron JA, Barrett J, Birkmeyer JD, Anderson FA. The epidemiology of diagnosed 
pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–
866.  
 
 
 

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APPENDIX C — Diagnosis codes for adverse drug reaction 
 
Adapted from:  Hohl CM, Karpov A, Reddekopp L, Doyle-Waters M, Stausberg J. ICD-10 codes used to 
identify adverse drug events in administrative data: a systematic review. J Am Med 
Inform Assoc. 2014;21:547–57.  
 
ICD-10-CM Anaphylaxis Description 
A0471 
 
Enterocolitis due to Clostridium difficile, recurrent 
A0472 
 
Enterocolitis due to Clostridium difficile, not specified as recurrent 
D590 
 
Drug-induced autoimmune hemolytic anemia 
D592 
 
Drug-induced nonautoimmune hemolytic anemia 
D7212 
 
Drug rash with eosinophilia and systemic symptoms syndrome 
E064 
 
Drug-induced thyroiditis 
E160 
 
Drug-induced hypoglycemia without coma 
G210 
 
Malignant neuroleptic syndrome 
G2402 
 
Drug induced acute dystonia 
G2409 
 
Other drug induced dystonia 
G251 
 
Drug-induced tremor 
G4440 
 
Drug-induced headache, not elsewhere classified, not intractable 
G4441 
 
Drug-induced headache, not elsewhere classified, intractable 
G620 
 
Drug-induced polyneuropathy 
G720 
 
Drug-induced myopathy 
I427 
 
Cardiomyopathy due to drug and external agent 
I952 
 
Hypotension due to drugs 
J702 
 
Acute drug-induced interstitial lung disorders 
J704 
 
Drug-induced interstitial lung disorders, unspecified 
K710 
 
Toxic liver disease with cholestasis 
K7110 
 
Toxic liver disease with hepatic necrosis, without coma 
K7111 
 
Toxic liver disease with hepatic necrosis, with coma 
K712 
 
Toxic liver disease with acute hepatitis 
K716 
 
Toxic liver disease with hepatitis, not elsewhere classified 
K719 
 
Toxic liver disease, unspecified 
K8530 
 
Drug induced acute pancreatitis without necrosis or infection 
K8531 
 
Drug induced acute pancreatitis with uninfected necrosis 
K8532 
 
Drug induced acute pancreatitis with infected necrosis 
L233 
 
Allergic contact dermatitis due to drugs in contact with skin 
L244 
 
Irritant contact dermatitis due to drugs in contact with skin 
L251 
 
Unspecified contact dermatitis due to drugs in contact with skin 
L270 
 
Generalized skin eruption due to drugs and medicaments taken internally 
L271 
 
Localized skin eruption due to drugs and medicaments taken internally 
L278 
 
Dermatitis due to other substances taken internally 
L279 
 
Dermatitis due to unspecified substance taken internally 
L500 
 
Allergic urticaria 
L509 
 
Urticaria, unspecified 
L510 
 
Nonbullous erythema multiforme 
L511 
 
Stevens-Johnson syndrome 
L512 
 
Toxic epidermal necrolysis [Lyell] 

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ICD-10-CM Anaphylaxis Description 
L513 
 
Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome 
L518 
 
Other erythema multiforme 
L519 
 
Erythema multiforme, unspecified 
L52 
 
Erythema nodosum 
L530 
 
Toxic erythema 
L531 
 
Erythema annulare centrifugum 
N141 
 
Nephropathy induced by other drugs, medicaments and biological 
substances 
N142 
 
Nephropathy induced by unspecified drug, medicament or biological 
substance 
N144 
 
Toxic nephropathy, not elsewhere classified 
R502 
 
Drug induced fever 
T360X1A 
 
Poisoning by penicillins, accidental (unintentional), initial encounter 
T360X1D 
 
Poisoning by penicillins, accidental (unintentional), subsequent encounter 
T360X1S 
 
Poisoning by penicillins, accidental (unintentional), sequela 
T360X4A 
 
Poisoning by penicillins, undetermined, initial encounter 
T360X4D 
 
Poisoning by penicillins, undetermined, subsequent encounter 
T360X4S 
 
Poisoning by penicillins, undetermined, sequela 
T360X5A 
 
Adverse effect of penicillins, initial encounter 
T360X5D 
 
Adverse effect of penicillins, subsequent encounter 
T360X5S 
 
Adverse effect of penicillins, sequela 
T360X6A 
 
Underdosing of penicillins, initial encounter 
T360X6D 
 
Underdosing of penicillins, subsequent encounter 
T360X6S 
 
Underdosing of penicillins, sequela 
T361X1A 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, accidental 
(unintentional), initial encounter 
T361X1D 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, accidental 
(unintentional), subsequent encounter 
T361X1S 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, accidental 
(unintentional), sequela 
T361X4A 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, 
undetermined, initial encounter 
T361X4D 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, 
undetermined, subsequent encounter 
T361X4S 
 
Poisoning by cephalosporins and other beta-lactam antibiotics, 
undetermined, sequela 
T361X5A 
 
Adverse effect of cephalosporins and other beta-lactam antibiotics, initial 
encounter 
T361X5D 
 
Adverse effect of cephalosporins and other beta-lactam antibiotics, 
subsequent encounter 
T361X5S 
 
Adverse effect of cephalosporins and other beta-lactam antibiotics, 
sequela 
T361X6A 
 
Underdosing of cephalosporins and other beta-lactam antibiotics, initial 
encounter 
T361X6D 
 
Underdosing of cephalosporins and other beta-lactam antibiotics, 
subsequent encounter 
T361X6S 
 
Underdosing of cephalosporins and other beta-lactam antibiotics, sequela 

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ICD-10-CM Anaphylaxis Description 
T362X1A 
 
Poisoning by chloramphenicol group, accidental (unintentional), initial 
encounter 
T362X1D 
 
Poisoning by chloramphenicol group, accidental (unintentional), 
subsequent encounter 
T362X1S 
 
Poisoning by chloramphenicol group, accidental (unintentional), sequela 
T362X4A 
 
Poisoning by chloramphenicol group, undetermined, initial encounter 
T362X4D 
 
Poisoning by chloramphenicol group, undetermined, subsequent 
encounter 
T362X4S 
 
Poisoning by chloramphenicol group, undetermined, sequela 
T362X5A 
 
Adverse effect of chloramphenicol group, initial encounter 
T362X5D 
 
Adverse effect of chloramphenicol group, subsequent encounter 
T362X5S 
 
Adverse effect of chloramphenicol group, sequela 
T362X6A 
 
Underdosing of chloramphenicol group, initial encounter 
T362X6D 
 
Underdosing of chloramphenicol group, subsequent encounter 
T362X6S 
 
Underdosing of chloramphenicol group, sequela 
T363X1A 
 
Poisoning by macrolides, accidental (unintentional), initial encounter 
T363X1D 
 
Poisoning by macrolides, accidental (unintentional), subsequent 
encounter 
T363X1S 
 
Poisoning by macrolides, accidental (unintentional), sequela 
T363X4A 
 
Poisoning by macrolides, undetermined, initial encounter 
T363X4D 
 
Poisoning by macrolides, undetermined, subsequent encounter 
T363X4S 
 
Poisoning by macrolides, undetermined, sequela 
T363X5A 
 
Adverse effect of macrolides, initial encounter 
T363X5D 
 
Adverse effect of macrolides, subsequent encounter 
T363X5S 
 
Adverse effect of macrolides, sequela 
T363X6A 
 
Underdosing of macrolides, initial encounter 
T363X6D 
 
Underdosing of macrolides, subsequent encounter 
T363X6S 
 
Underdosing of macrolides, sequela 
T364X1A 
 
Poisoning by tetracyclines, accidental (unintentional), initial encounter 
T364X1D 
 
Poisoning by tetracyclines, accidental (unintentional), subsequent 
encounter 
T364X1S 
 
Poisoning by tetracyclines, accidental (unintentional), sequela 
T364X4A 
 
Poisoning by tetracyclines, undetermined, initial encounter 
T364X4D 
 
Poisoning by tetracyclines, undetermined, subsequent encounter 
T364X4S 
 
Poisoning by tetracyclines, undetermined, sequela 
T364X5A 
 
Adverse effect of tetracyclines, initial encounter 
T364X5D 
 
Adverse effect of tetracyclines, subsequent encounter 
T364X5S 
 
Adverse effect of tetracyclines, sequela 
T364X6A 
 
Underdosing of tetracyclines, initial encounter 
T364X6D 
 
Underdosing of tetracyclines, subsequent encounter 
T364X6S 
 
Underdosing of tetracyclines, sequela 
T365X1A 
 
Poisoning by aminoglycosides, accidental (unintentional), initial 
encounter 
T365X1D 
 
Poisoning by aminoglycosides, accidental (unintentional), subsequent 
encounter 
T365X1S 
 
Poisoning by aminoglycosides, accidental (unintentional), sequela 
T365X4A 
 
Poisoning by aminoglycosides, undetermined, initial encounter 

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ICD-10-CM Anaphylaxis Description 
T365X4D 
 
Poisoning by aminoglycosides, undetermined, subsequent encounter 
T365X4S 
 
Poisoning by aminoglycosides, undetermined, sequela 
T365X5A 
 
Adverse effect of aminoglycosides, initial encounter 
T365X5D 
 
Adverse effect of aminoglycosides, subsequent encounter 
T365X5S 
 
Adverse effect of aminoglycosides, sequela 
T365X6A 
 
Underdosing of aminoglycosides, initial encounter 
T365X6D 
 
Underdosing of aminoglycosides, subsequent encounter 
T365X6S 
 
Underdosing of aminoglycosides, sequela 
T366X1A 
 
Poisoning by rifampicins, accidental (unintentional), initial encounter 
T366X1D 
 
Poisoning by rifampicins, accidental (unintentional), subsequent 
encounter 
T366X1S 
 
Poisoning by rifampicins, accidental (unintentional), sequela 
T366X4A 
 
Poisoning by rifampicins, undetermined, initial encounter 
T366X4D 
 
Poisoning by rifampicins, undetermined, subsequent encounter 
T366X4S 
 
Poisoning by rifampicins, undetermined, sequela 
T366X5A 
 
Adverse effect of rifampicins, initial encounter 
T366X5D 
 
Adverse effect of rifampicins, subsequent encounter 
T366X5S 
 
Adverse effect of rifampicins, sequela 
T366X6A 
 
Underdosing of rifampicins, initial encounter 
T366X6D 
 
Underdosing of rifampicins, subsequent encounter 
T366X6S 
 
Underdosing of rifampicins, sequela 
T367X1A 
 
Poisoning by antifungal antibiotics, systemically used, accidental 
(unintentional), initial encounter 
T367X1D 
 
Poisoning by antifungal antibiotics, systemically used, accidental 
(unintentional), subsequent encounter 
T367X1S 
 
Poisoning by antifungal antibiotics, systemically used, accidental 
(unintentional), sequela 
T367X4A 
 
Poisoning by antifungal antibiotics, systemically used, undetermined, 
initial encounter 
T367X4D 
 
Poisoning by antifungal antibiotics, systemically used, undetermined, 
subsequent encounter 
T367X4S 
 
Poisoning by antifungal antibiotics, systemically used, undetermined, 
sequela 
T367X5A 
 
Adverse effect of antifungal antibiotics, systemically used, initial 
encounter 
T367X5D 
 
Adverse effect of antifungal antibiotics, systemically used, subsequent 
encounter 
T367X5S 
 
Adverse effect of antifungal antibiotics, systemically used, sequela 
T367X6A 
 
Underdosing of antifungal antibiotics, systemically used, initial encounter 
T367X6D 
 
Underdosing of antifungal antibiotics, systemically used, subsequent 
encounter 
T367X6S 
 
Underdosing of antifungal antibiotics, systemically used, sequela 
T368X1A 
 
Poisoning by other systemic antibiotics, accidental (unintentional), initial 
encounter 
T368X1D 
 
Poisoning by other systemic antibiotics, accidental (unintentional), 
subsequent encounter 
T368X1S 
 
Poisoning by other systemic antibiotics, accidental (unintentional), 

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ICD-10-CM Anaphylaxis Description 
sequela 
T368X4A 
 
Poisoning by other systemic antibiotics, undetermined, initial encounter 
T368X4D 
 
Poisoning by other systemic antibiotics, undetermined, subsequent 
encounter 
T368X4S 
 
Poisoning by other systemic antibiotics, undetermined, sequela 
T368X5A 
 
Adverse effect of other systemic antibiotics, initial encounter 
T368X5D 
 
Adverse effect of other systemic antibiotics, subsequent encounter 
T368X5S 
 
Adverse effect of other systemic antibiotics, sequela 
T368X6A 
 
Underdosing of other systemic antibiotics, initial encounter 
T368X6D 
 
Underdosing of other systemic antibiotics, subsequent encounter 
T368X6S 
 
Underdosing of other systemic antibiotics, sequela 
T3691XA 
 
Poisoning by unspecified systemic antibiotic, accidental (unintentional), 
initial encounter 
T3691XD 
 
Poisoning by unspecified systemic antibiotic, accidental (unintentional), 
subsequent encounter 
T3691XS 
 
Poisoning by unspecified systemic antibiotic, accidental (unintentional), 
sequela 
T3694XA 
 
Poisoning by unspecified systemic antibiotic, undetermined, initial 
encounter 
T3694XD 
 
Poisoning by unspecified systemic antibiotic, undetermined, subsequent 
encounter 
T3694XS 
 
Poisoning by unspecified systemic antibiotic, undetermined, sequela 
T3695XA 
 
Adverse effect of unspecified systemic antibiotic, initial encounter 
T3695XD 
 
Adverse effect of unspecified systemic antibiotic, subsequent encounter 
T3695XS 
 
Adverse effect of unspecified systemic antibiotic, sequela 
T3696XA 
 
Underdosing of unspecified systemic antibiotic, initial encounter 
T3696XD 
 
Underdosing of unspecified systemic antibiotic, subsequent encounter 
T3696XS 
 
Underdosing of unspecified systemic antibiotic, sequela 
T370X1A 
 
Poisoning by sulfonamides, accidental (unintentional), initial encounter 
T370X1D 
 
Poisoning by sulfonamides, accidental (unintentional), subsequent 
encounter 
T370X1S 
 
Poisoning by sulfonamides, accidental (unintentional), sequela 
T370X4A 
 
Poisoning by sulfonamides, undetermined, initial encounter 
T370X4D 
 
Poisoning by sulfonamides, undetermined, subsequent encounter 
T370X4S 
 
Poisoning by sulfonamides, undetermined, sequela 
T370X5A 
 
Adverse effect of sulfonamides, initial encounter 
T370X5D 
 
Adverse effect of sulfonamides, subsequent encounter 
T370X5S 
 
Adverse effect of sulfonamides, sequela 
T370X6A 
 
Underdosing of sulfonamides, initial encounter 
T370X6D 
 
Underdosing of sulfonamides, subsequent encounter 
T370X6S 
 
Underdosing of sulfonamides, sequela 
T371X1A 
 
Poisoning by antimycobacterial drugs, accidental (unintentional), initial 
encounter 
T371X1D 
 
Poisoning by antimycobacterial drugs, accidental (unintentional), 
subsequent encounter 
T371X1S 
 
Poisoning by antimycobacterial drugs, accidental (unintentional), sequela 
T371X4A 
 
Poisoning by antimycobacterial drugs, undetermined, initial encounter 

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ICD-10-CM Anaphylaxis Description 
T371X4D 
 
Poisoning by antimycobacterial drugs, undetermined, subsequent 
encounter 
T371X4S 
 
Poisoning by antimycobacterial drugs, undetermined, sequela 
T371X5A 
 
Adverse effect of antimycobacterial drugs, initial encounter 
T371X5D 
 
Adverse effect of antimycobacterial drugs, subsequent encounter 
T371X5S 
 
Adverse effect of antimycobacterial drugs, sequela 
T371X6A 
 
Underdosing of antimycobacterial drugs, initial encounter 
T371X6D 
 
Underdosing of antimycobacterial drugs, subsequent encounter 
T371X6S 
 
Underdosing of antimycobacterial drugs, sequela 
T372X1A 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
accidental (unintentional), initial encounter 
T372X1D 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
accidental (unintentional), subsequent encounter 
T372X1S 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
accidental (unintentional), sequela 
T372X4A 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
undetermined, initial encounter 
T372X4D 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
undetermined, subsequent encounter 
T372X4S 
 
Poisoning by antimalarials and drugs acting on other blood protozoa, 
undetermined, sequela 
T372X5A 
 
Adverse effect of antimalarials and drugs acting on other blood protozoa, 
initial encounter 
T372X5D 
 
Adverse effect of antimalarials and drugs acting on other blood protozoa, 
subsequent encounter 
T372X5S 
 
Adverse effect of antimalarials and drugs acting on other blood protozoa, 
sequela 
T372X6A 
 
Underdosing of antimalarials and drugs acting on other blood protozoa, 
initial encounter 
T372X6D 
 
Underdosing of antimalarials and drugs acting on other blood protozoa, 
subsequent encounter 
T372X6S 
 
Underdosing of antimalarials and drugs acting on other blood protozoa, 
sequela 
T373X1A 
 
Poisoning by other antiprotozoal drugs, accidental (unintentional), initial 
encounter 
T373X1D 
 
Poisoning by other antiprotozoal drugs, accidental (unintentional), 
subsequent encounter 
T373X1S 
 
Poisoning by other antiprotozoal drugs, accidental (unintentional), 
sequela 
T373X4A 
 
Poisoning by other antiprotozoal drugs, undetermined, initial encounter 
T373X4D 
 
Poisoning by other antiprotozoal drugs, undetermined, subsequent 
encounter 
T373X4S 
 
Poisoning by other antiprotozoal drugs, undetermined, sequela 
T373X5A 
 
Adverse effect of other antiprotozoal drugs, initial encounter 
T373X5D 
 
Adverse effect of other antiprotozoal drugs, subsequent encounter 
T373X5S 
 
Adverse effect of other antiprotozoal drugs, sequela 
T373X6A 
 
Underdosing of other antiprotozoal drugs, initial encounter 

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ICD-10-CM Anaphylaxis Description 
T373X6D 
 
Underdosing of other antiprotozoal drugs, subsequent encounter 
T373X6S 
 
Underdosing of other antiprotozoal drugs, sequela 
T374X1A 
 
Poisoning by anthelminthics, accidental (unintentional), initial encounter 
T374X1D 
 
Poisoning by anthelminthics, accidental (unintentional), subsequent 
encounter 
T374X1S 
 
Poisoning by anthelminthics, accidental (unintentional), sequela 
T374X4A 
 
Poisoning by anthelminthics, undetermined, initial encounter 
T374X4D 
 
Poisoning by anthelminthics, undetermined, subsequent encounter 
T374X4S 
 
Poisoning by anthelminthics, undetermined, sequela 
T374X5A 
 
Adverse effect of anthelminthics, initial encounter 
T374X5D 
 
Adverse effect of anthelminthics, subsequent encounter 
T374X5S 
 
Adverse effect of anthelminthics, sequela 
T374X6A 
 
Underdosing of anthelminthics, initial encounter 
T374X6D 
 
Underdosing of anthelminthics, subsequent encounter 
T374X6S 
 
Underdosing of anthelminthics, sequela 
T375X1A 
 
Poisoning by antiviral drugs, accidental (unintentional), initial encounter 
T375X1D 
 
Poisoning by antiviral drugs, accidental (unintentional), subsequent 
encounter 
T375X1S 
 
Poisoning by antiviral drugs, accidental (unintentional), sequela 
T375X4A 
 
Poisoning by antiviral drugs, undetermined, initial encounter 
T375X4D 
 
Poisoning by antiviral drugs, undetermined, subsequent encounter 
T375X4S 
 
Poisoning by antiviral drugs, undetermined, sequela 
T375X5A 
 
Adverse effect of antiviral drugs, initial encounter 
T375X5D 
 
Adverse effect of antiviral drugs, subsequent encounter 
T375X5S 
 
Adverse effect of antiviral drugs, sequela 
T375X6A 
 
Underdosing of antiviral drugs, initial encounter 
T375X6D 
 
Underdosing of antiviral drugs, subsequent encounter 
T375X6S 
 
Underdosing of antiviral drugs, sequela 
T378X1A 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
accidental (unintentional), initial encounter 
T378X1D 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
accidental (unintentional), subsequent encounter 
T378X1S 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
accidental (unintentional), sequela 
T378X4A 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
undetermined, initial encounter 
T378X4D 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
undetermined, subsequent encounter 
T378X4S 
 
Poisoning by other specified systemic anti-infectives and antiparasitics, 
undetermined, sequela 
T378X5A 
 
Adverse effect of other specified systemic anti-infectives and 
antiparasitics, initial encounter 
T378X5D 
 
Adverse effect of other specified systemic anti-infectives and 
antiparasitics, subsequent encounter 
T378X5S 
 
Adverse effect of other specified systemic anti-infectives and 
antiparasitics, sequela 
T378X6A 
 
Underdosing of other specified systemic anti-infectives and antiparasitics, 

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ICD-10-CM Anaphylaxis Description 
initial encounter 
T378X6D 
 
Underdosing of other specified systemic anti-infectives and antiparasitics, 
subsequent encounter 
T378X6S 
 
Underdosing of other specified systemic anti-infectives and antiparasitics, 
sequela 
T3791XA 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
accidental (unintentional), initial encounter 
T3791XD 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
accidental (unintentional), subsequent encounter 
T3791XS 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
accidental (unintentional), sequela 
T3794XA 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
undetermined, initial encounter 
T3794XD 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
undetermined, subsequent encounter 
T3794XS 
 
Poisoning by unspecified systemic anti-infective and antiparasitics, 
undetermined, sequela 
T3795XA 
 
Adverse effect of unspecified systemic anti-infective and antiparasitic, 
initial encounter 
T3795XD 
 
Adverse effect of unspecified systemic anti-infective and antiparasitic, 
subsequent encounter 
T3795XS 
 
Adverse effect of unspecified systemic anti-infective and antiparasitic, 
sequela 
T3796XA 
 
Underdosing of unspecified systemic anti-infectives and antiparasitics, 
initial encounter 
T3796XD 
 
Underdosing of unspecified systemic anti-infectives and antiparasitics, 
subsequent encounter 
T3796XS 
 
Underdosing of unspecified systemic anti-infectives and antiparasitics, 
sequela 
T431X5A 
 
Adverse effect of monoamine-oxidase-inhibitor antidepressants, initial 
encounter 
T431X5D 
 
Adverse effect of monoamine-oxidase-inhibitor antidepressants, 
subsequent encounter 
T431X5S 
 
Adverse effect of monoamine-oxidase-inhibitor antidepressants, sequela 
T43215A 
 
Adverse effect of selective serotonin and norepinephrine reuptake 
inhibitors, initial encounter 
T43215D 
 
Adverse effect of selective serotonin and norepinephrine reuptake 
inhibitors, subsequent encounter 
T43215S 
 
Adverse effect of selective serotonin and norepinephrine reuptake 
inhibitors, sequela 
T43225A 
 
Adverse effect of selective serotonin reuptake inhibitors, initial encounter 
T43225D 
 
Adverse effect of selective serotonin reuptake inhibitors, subsequent 
encounter 
T43225S 
 
Adverse effect of selective serotonin reuptake inhibitors, sequela 
T50901A 
 
Poisoning by unspecified drugs, medicaments and biological substances, 
accidental (unintentional), initial encounter 
T50901D 
 
Poisoning by unspecified drugs, medicaments and biological substances, 

Code Sepsis I protocol 
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50 
ICD-10-CM Anaphylaxis Description 
accidental (unintentional), subsequent encounter 
T50901S 
 
Poisoning by unspecified drugs, medicaments and biological substances, 
accidental (unintentional), sequela 
T50904A 
 
Poisoning by unspecified drugs, medicaments and biological substances, 
undetermined, initial encounter 
T50904D 
 
Poisoning by unspecified drugs, medicaments and biological substances, 
undetermined, subsequent encounter 
T50904S 
 
Poisoning by unspecified drugs, medicaments and biological substances, 
undetermined, sequela 
T50905A 
 
Adverse effect of unspecified drugs, medicaments and biological 
substances, initial encounter 
T50905D 
 
Adverse effect of unspecified drugs, medicaments and biological 
substances, subsequent encounter 
T50905S 
 
Adverse effect of unspecified drugs, medicaments and biological 
substances, sequela 
T50906A 
 
Underdosing of unspecified drugs, medicaments and biological 
substances, initial encounter 
T50906D 
 
Underdosing of unspecified drugs, medicaments and biological 
substances, subsequent encounter 
T50906S 
 
Underdosing of unspecified drugs, medicaments and biological 
substances, sequela 
T50991A 
 
Poisoning by other drugs, medicaments and biological substances, 
accidental (unintentional), initial encounter 
T50991D 
 
Poisoning by other drugs, medicaments and biological substances, 
accidental (unintentional), subsequent encounter 
T50991S 
 
Poisoning by other drugs, medicaments and biological substances, 
accidental (unintentional), sequela 
T50994A 
 
Poisoning by other drugs, medicaments and biological substances, 
undetermined, initial encounter 
T50994D 
 
Poisoning by other drugs, medicaments and biological substances, 
undetermined, subsequent encounter 
T50994S 
 
Poisoning by other drugs, medicaments and biological substances, 
undetermined, sequela 
T50995A 
 
Adverse effect of other drugs, medicaments and biological substances, 
initial encounter 
T50995D 
 
Adverse effect of other drugs, medicaments and biological substances, 
subsequent encounter 
T50995S 
 
Adverse effect of other drugs, medicaments and biological substances, 
sequela 
T50996A 
 
Underdosing of other drugs, medicaments and biological substances, 
initial encounter 
T50996D 
 
Underdosing of other drugs, medicaments and biological substances, 
subsequent encounter 
T50996S 
 
Underdosing of other drugs, medicaments and biological substances, 
sequela 
T782XXA 
X 
Anaphylactic shock, unspecified, initial encounter 
T782XXD 
X 
Anaphylactic shock, unspecified, subsequent encounter 

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ICD-10-CM Anaphylaxis Description 
T782XXS 
X 
Anaphylactic shock, unspecified, sequela 
T783XXA 
X 
Angioneurotic edema, initial encounter 
T783XXD 
X 
Angioneurotic edema, subsequent encounter 
T783XXS 
X 
Angioneurotic edema, sequela 
T7840XA 
 
Allergy, unspecified, initial encounter 
T7840XD 
 
Allergy, unspecified, subsequent encounter 
T7840XS 
 
Allergy, unspecified, sequela 
T7841XA 
 
Arthus phenomenon, initial encounter 
T7841XD 
 
Arthus phenomenon, subsequent encounter 
T7841XS 
 
Arthus phenomenon, sequela 
T7849XA 
 
Other allergy, initial encounter 
T7849XD 
 
Other allergy, subsequent encounter 
T7849XS 
 
Other allergy, sequela 
T788XXA 
 
Other adverse effects, not elsewhere classified, initial encounter 
T788XXD 
 
Other adverse effects, not elsewhere classified, subsequent encounter 
T788XXS 
 
Other adverse effects, not elsewhere classified, sequela 
T8051XA 
X 
Anaphylactic reaction due to administration of blood and blood products, 
initial encounter 
T8051XD 
X 
Anaphylactic reaction due to administration of blood and blood products, 
subsequent encounter 
T8051XS 
X 
Anaphylactic reaction due to administration of blood and blood products, 
sequela 
T8052XA 
X 
Anaphylactic reaction due to vaccination, initial encounter 
T8052XD 
X 
Anaphylactic reaction due to vaccination, subsequent encounter 
T8052XS 
X 
Anaphylactic reaction due to vaccination, sequela 
T8059XA 
X 
Anaphylactic reaction due to other serum, initial encounter 
T8059XD 
X 
Anaphylactic reaction due to other serum, subsequent encounter 
T8059XS 
X 
Anaphylactic reaction due to other serum, sequela 
T8089XA 
 
Other complications following infusion, transfusion and therapeutic 
injection, initial encounter 
T8089XD 
 
Other complications following infusion, transfusion and therapeutic 
injection, subsequent encounter 
T8089XS 
 
Other complications following infusion, transfusion and therapeutic 
injection, sequela 
T8090XA 
 
Unspecified complication following infusion and therapeutic injection, 
initial encounter 
T8090XD 
 
Unspecified complication following infusion and therapeutic injection, 
subsequent encounter 
T8090XS 
 
Unspecified complication following infusion and therapeutic injection, 
sequela 
T886XXA 
X 
Anaphylactic reaction due to adverse effect of correct drug or 
medicament properly administered, initial encounter 
T886XXD 
X 
Anaphylactic reaction due to adverse effect of correct drug or 
medicament properly administered, subsequent encounter 
T886XXS 
X 
Anaphylactic reaction due to adverse effect of correct drug or 
medicament properly administered, sequela 

Code Sepsis I protocol 
Version 3.0 
 
52 
ICD-10-CM Anaphylaxis Description 
T887XXA 
 
Unspecified adverse effect of drug or medicament, initial encounter 
T888XXA 
 
Other specified complications of surgical and medical care, not elsewhere 
classified, initial encounter 
T889XXA 
 
Complication of surgical and medical care, unspecified, initial encounter 
Y631 
 
Incorrect dilution of fluid used during infusion 
Y638 
 
Failure in dosage during other surgical and medical care 
Y639 
 
Failure in dosage during unspecified surgical and medical care 
Y640 
 
Contaminated medical or biological substance, transfused or infused 
Y641 
 
Contaminated medical or biological substance, injected or used for 
immunization 
Y651 
 
Wrong fluid used in infusion 
Y66 
 
Nonadministration of surgical and medical care 
Y69 
 
Unspecified misadventure during surgical and medical care