Continuing Education Webinar

Evidence-Based Diagnosis and Management

of Sepsis in Pregnancy

This webinar will be recorded and available on the NPIC/QAS website www.npic.org.

Nurse Planner: Carolyn L. Wood, PhD, RN, Clinical Nurse Consultant Purpose/Goal(s) of this Education Activity: The purpose/goal(s) of this activity is to enable the learner to expand knowledge on the diagnosis and management of sepsis in pregnancy. 1.0 Contact Hour: This continuing nursing education activity was approved by the Northeast Multistate Division (NE-MSD), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. 1.0 AMA PRA Category 1 Credit™: Accreditation: Women & Infants Hospital is accredited by the Rhode Island Medical Society to sponsor intrastate continuing education for physicians. Women & Infants Hospital designates this online educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been approved for 1.0 Risk Management Credit.

Disclosures and Successful Completion of this Activity

No commercial support has been provided for this activity.

No one involved in planning or presenting this program has a conflict of interest.

There will be no discussion of off-label usage of any products.

In order to successfully complete this activity and receive 1.0 Contact Hour(s) or 1.0 AMA PRA Category 1 Credit™, you must attend/watch the webinar and return the completed post-test/evaluation to NPIC/QAS.

Evidence-Based Diagnosis and Management of Sepsis in

Pregnancy

Brenna L. Hughes, MD Director, Women’s Infectious Disease Consultation

Division of Maternal Fetal Medicine

Department of Obstetrics & Gynecology

Warren Alpert Medical School of Brown University

Women & Infants Hospital of Rhode Island

*Slide credits: Catherine Albright, MD

Disclosures

• I have no financial relationship with a commercial entity producing health-care related products and/or services

Objectives

• Identify the most common causes of sepsis in pregnancy

• Describe methods of identification of sepsis

• Discuss the therapeutic strategies for sepsis management based on recent critical care guidelines

• Identify and emergently manage Group A Streptococcal sepsis

Maternal Mortality

• U.S. women have greater lifetime risk of dying of pregnancy-related complications than in 40 other countries

– 5x greater than Greece

– 4x greater than Germany

– 3x greater than Spain

Deadly Delivery, Amnesty International, 2010

U.S. Maternal Mortality

CDC NVSR 2007

Causes of Maternal Death in the U.S.

20%

17%

16% 13%

8%

26% Embolism

Hemorrhage

Pre-eclampsia

Infection

Cardiomyopathy

Other

Deadly Delivery, Amnesty International, 2010

Maternal Sepsis

• Maternal sepsis, especially puerperal sepsis, is a common pregnancy-related condition

– 4th leading cause of maternal mortality in U.S.

• Up to 28% of maternal deaths

• Up to 15% of maternal admissions to the ICU

Oud 2015a, Oud 2015b, Bauer 2013

Causes of Maternal Sepsis

• Obstetric – Chorioamnionitis

– Endometritis

– Septic abortion

– Wound infection (cesarean, laceration/episiotomy)

• Non-obstetric – Appendicitis

– Cholecystitis

– Pyelonephritis

– Pneumonia

Microbiology

• Pathogens

– Principle: aerobic gram-negative rods

• Escherichia coli (~60%)

– Secondary: gram-positive, mixed, fungal

• Enterococci, Beta-hemolytic streptococci

– Increase in severe β-hemolytic streptococci group A (GAS) infections

• Non-pregnant: gram-positive bacteria (~52%)

Blanco 1981, Acosta 2014, Rimawi 2012, Mayr 2006, Martin 2003

Risk Factors

• Cesarean delivery • Low socioeconomic status • Lack of access to prenatal care • Poor nutrition • Primiparity • Obesity • Anemia • Prolonged rupture of membranes • Prolonged labor • Multiple pregnancy

Mohamed-Ahmed 2015, Acosta 2013

Maternal Outcome

• Mortality of pregnant or postpartum women admitted to the ICU with sepsis has been reported as 14% to 39%

• Maternal prognosis favorable when compared to non-obstetric patients – Younger

– Fewer co-morbidities

– Sensitive organisms

– Site of infection amenable to surgical intervention

Guinn 2007

Fetal Outcome

• Increased risk of preterm delivery, low birth weight and perinatal mortality – Fetal mortality approaches 33% with maternal

sepsis requiring ICU admission

• Fetal optimization best accomplished by meeting maternal hemodynamic, oxygenation, and infection treatment goals

• Improving maternal acidemia/ hypoxia improves fetal status

Jin 2003, Knowles 2015, Snyder 2013, Timezguid 2012, Chau 2014

Delivery

• High risk of delivery during hospitalization – 1/3 of women with severe sepsis and all with septic

shock required delivery during the same hospitalization, most requiring emergent delivery

– Most common indication for delivery: worsening maternal respiratory status

• Reserve for obstetric indications • Not likely to improve maternal outcome • May result in prematurely delivering fetus who

may have recovered with adequate resuscitation in utero

Snyder 2013

MAKING THE DIAGNOSIS

Definition of Sepsis

• Based on vital signs, laboratory values • For use in non-pregnant adults to guide

admission and treatment • Predict morbidity and mortality

Dellinger 2013

SIRS Sepsis Severe Sepsis

Septic Shock

New Guidelines

JAMA, Feb 2016

SOFA

Surviving Sepsis Campaign

• Goal to reduce mortality 1. Build awareness 2. Improve diagnosis 3. Increase the use of appropriate treatment 4. Educate healthcare professionals 5. Improve post-ICU care 6. Develop guidelines of care 7. Implement performance improvement programs

Dellinger 2004

Pregnancy?

• Definitions and campaign efforts were developed specifically for non-pregnant adults

Significance

• Rivers 2001

– Early Goal-Directed Therapy (EGDT) versus Routine Care for sepsis

• EGDT = aggressive fluid resuscitation + early initiation of antibiotics with specific hemodynamic goals

– 30% reduction in mortality with EGDT

• Studies following EGDT implementation have shown a close to 20% decrease in overall mortality for septic patients

Rivers 2001, Rivers 2012, Gu 2014, Levy 2015

Disease-Severity Scoring Systems

• Early detection of cases at risk for deterioration necessary

• Development of scoring systems able to identify patients at risk for clinical deterioration

– Specifically excluded pregnant women in their study populations

Disease-Severity Scoring Systems

• Uniformly overestimate morbidity and mortality in pregnant women

• APACHE II scores for 161 obstetric ICU patients (1998-2005) – Predicted mortality = 24%

– Actual = 11%

• SIRS and MEWS for 913 pregnant women with chorioamnionitis – 2/3 met SIRS criteria 1% PPV for disease progression

– 10% had MEWS score ≥5 0.05% PPV

Vasquez 2007, Lappen 2010

Why So Bad?

• Test Performance Characteristics

• Pregnant women (generally) young and without chronic medical conditions

• SIRS and sepsis related morbidity and mortality is lower

• Lower prevalence of disease (in this case disease progression) lower PPV of the test

• Normal physiological changes of pregnancy increase scores for existing, validated scoring systems

• Bias scores to be worse

Physiologic Changes in Pregnancy

Parameter Change

Temperature Unchanged

Systolic Blood Pressure ↓ by 5-10 mmHg in 2nd trimester Return to normal by 3rd trimester

Heart Rate ↑ 15-20%

Respiratory Rate Unchanged [↑TV ↑ minute ventilation ↓ PaCO2 ↓Bicarb]

O2 Saturation/PaO2 Unchanged

Hemoglobin ↓ 5-10% [Dilutional]

Leukocyte count ↑ [Up to 16.9/μL by 3rd trimester]

% Immature Neutrophils Unchanged

Lactic Acid Unknown

Guinn 2007, Abbassi-Ghanavati 2009, Bauer 2014

Lactic Acid in Pregnancy

• Increasing lactic acid associated with adverse maternal outcomes from sepsis

– 2.34x the odds of ICU transfer per 1 mmol/L increase in lactic acid (95% CI, 1.33-4.12)

• VERY IMPORTANT MEASUREMENT

Albright 2014

Can We Do Better?

Sepsis in Obstetrics Score (S.O.S.)

High Abnormal Normal Low Abnormal

Score +4 +3 +2 +1 0 +1 +2 +3 +4

Variable

- Temperature - Systolic Blood Pressure - Heart Rate - Respiratory Rate

- SpO2

- White Blood Cell Count - % Immature Neutrophils - Lactic Acid

Variables

Albright 2014

S.O.S.

High Abnormal Normal Low Abnormal

Score +4 +3 +2 +1 0 +1 +2 +3 +4

Heart Rate

≥180 150-179

130-149

120-129

<120

Albright 2014

Heart Rate

High Abnormal Normal Low Abnormal

Score +4 +3 +2 +1 0 +1 +2 +3 +4

SOS ≥180 150-179

130-149

120-129

<120

SIRS ≤90

Albright 2014

S.O.S.

• S.O.S. ≥ 6 – Sensitivity = 88.9%

– Specificity = 95.2%

– Positive Predictive Value = 16.7%

– Negative Predictive Value = 99.9%

– Adjusted odds ratio = 109

• S.O.S. could identify patients at high risk of requiring ICU transfer

• Prospective validation ongoing

Albright 2014

MANAGEMENT

Back to EGDT

• Correct physiologic abnormalities that accompany sepsis

– Hypotension and hypoxemia

– To improve tissue oxygen delivery

• Recommendations for resuscitation integrated into SSC Bundles

Dellinger 2013

Bundles

• Bundle: selected set of elements that, when implemented as a group, have an effect on outcomes beyond implementing the individual elements alone

– Core of sepsis improvement efforts

– Simplify and streamline care of patients with sepsis

Surviving Sepsis Campaign Bundles

Dellinger 2013

Basic Management I

• Rapid provider evaluation (within 15 minutes) – Draw lactate at presentation (and again in 6 hours if

initially elevated)

• Initiate aggressive fluid resuscitation – Begin an initial crystalloid fluid bolus of 30 ml/kg

– +/- Central Line

– Goals of fluid resuscitation: • MAP > 65 mm Hg within the first six hours of diagnosis

• Urine output ≥ 0.5 mL/kg/hr

• Normalize blood lactate levels

Dellinger 2013

Basic Management II

• Blood cultures

– Draw two sets of blood cultures prior to antibiotic administration

• Antibiotics

– Antibiotic therapy within one hour of the recognition of sepsis (± cultures)

– Choose one or more antibiotics directed to likely pathogens in concentrations adequate for tissue penetration

• Admit/transfer to an ICU if vasopressor use or mechanical ventilation is imminent

Dellinger 2013

Antipyretics?

• No mortality or morbidity benefit with acetaminophen for fever in critically ill non-pregnant patients

• Crucial to use in pregnancy

– Prevent fetal tachycardia and subsequent fetal compromise

Young 2015, Barton 2012

Antimicrobial Therapy

• Time to initiation = strongest predictor of mortality

– Initiation within one hour following onset of hypotension 80% survival to discharge

– For every hour delay in the first six hours survival declined by 7.6%

• Initial administration of inappropriate antibiotic therapy up to 5x increase in mortality

Rivers 2001, Kumar 2006, Proulx 2005, Vazquez-Guillamet 2005, Ferrer 2009, Barie 2005, Ibrahum 2000, Kumar 2009

Source Control

• Intervention should occur within the first 12 hours after the diagnosis is made

• Intervention associated with the least physiologic insult should be used

– Percutaneous rather than surgical drainage of an abscess

• Intravascular access devices, if possible source of severe sepsis/septic shock, should be removed promptly after other access established

Dellinger 2013

Advanced Resuscitation

• Required in patients who are not responsive to the basic management strategies (initial fluid bolus)

• Central line!

• Central venous pressure (CVP) and mixed venous oxygen saturation (SvO2) are acceptable physiologic targets – CVP should be 8-12 mm Hg

– SvO2 should be ≥ 70%

Dellinger 2013

Anything Different for Pregnancy?

• Overall goals of EGDT will aid in restoration of normal maternal and fetal physiologic functioning

• Management algorithm for pregnant women cannot be specifically advocated until adequate studies are performed

• Requires standard EGDT and fetal assessment

Pregnant Women with Sepsis

• General medical principles hold

– Circulation, airway, and breathing

– Initiation of SSC bundles

– Once maternal stability is assured

• Beyond viability: fetal monitor applied

• Below limit of viability: fetal heart rate

– Maternal stabilization plus reassuring fetal testing intermittent fetal monitoring

Phone call from the lab….

• 4/4 bottles

• Gram positive cocci in chains

Group A Streptococcus Streptococcus pyogenes

• β-hemolytic strep

• Causes pharyngitis, puerperal infections, post-operative infections, necrotizing fasciitis

• Colonizes vagina: 1/1000-3500 (personal comm. and Mead and Wynn, 2000)

Clinical Manifestations Phase 1

• Access to deep tissues and blood

• Produces toxins, cytokines, bradykinin causes hypotension

• Prodrome symptoms 24-48hrs then hypotension

• Localized pain precedes clinical evidence of infection by 12-24 hours

Typical

Fever/rigors

Uterine pain

Malodorous vaginal discharge

Atypical

Swelling or pain in extremities or joints

Nausea and vomiting

Copious non-foul smelling vaginal discharge

Bloody secretions from wound

General malaise

Headache

Myalgias

Dyspnea

Rash

Pharyngitis

Confusion/combativeness

Clinical Manifestations Phase 2

• Tachycardia, tachypnea, fever

• Increasingly severe pain

• Patients often seen in ER and given erroneous diagnosis, DVT, viral syndrome, folliculitis, etc

Clinical Manifestations Phase 3

• Shock and organ failure

• Necrotizing fasciitis often a late sign

• Death can occur within 24-48 hours

Treatment

Treatment

• +/- endometrial biopsy or amniocentesis

• Extensive debridement – usually hysterectomy

• Fluid resuscitation

• PCN (superficial) and clindamycin (deep, suppresses toxin production)

• ICU

Rimawi et al, Clin Obstet Gynecol, 2012

Conclusions

• Maternal morbidity and mortality on the rise in the U.S.

• Ability to apply general expertise to septic pregnant patients hindered by lack of data

• Pregnancy = unique challenge – Baseline physiologic changes

– Need to care for the mother and fetus

• Prompt identification and treatment of maternal sepsis best possible maternal and neonatal outcomes

• Early recognition of GAS, potentially lifesaving

References

• Deadly Delivery: The Maternal Health Care Crisis in the USA, Amnesty International: 2010. • The Global Burden of Maternal Sepsis, WHO: 2000. • Mayr VD, Dünser MW, Greil V, Jochberger S, Luckner G, Ulmer H, et al. Causes of death and determinants of outcome in

critically ill patients. Crit Care 2006;10:R154. doi:10.1186/cc5086. • Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence 2014;5:4–11. doi:10.4161/viru.27372. • Wang HE, Devereaux RS, Yealy DM, Safford MM, Howard G. National variation in United States sepsis mortality: a descriptive

study. Int J Health Geogr 2010;9:9. doi:10.1186/1476-072X-9-9. • 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. doi:10.1097/CCM.0b013e31827c09f8. • Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in

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• Kochanek KD, Murphy SL, Xu J. Deaths: Final Data for 2011. Natl Vital Stat Rep 2015;63:1–120. • Oud L. Contemporary Trends of Reported Sepsis Among Maternal Decedents in Texas: A Population-Based Study. Infect Dis

Ther 2015;4:321–35. doi:10.1007/s40121-015-0086-6. • Oud L, Watkins P. Evolving trends in the epidemiology, resource utilization, and outcomes of pregnancy-associated severe

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• Acosta CD, Kurinczuk JJ, Lucas DN, Tuffnell DJ, Sellers S, Knight M, et al. Severe maternal sepsis in the UK, 2011-2012: a national case-control study. PLoS Med 2014;11:e1001672. doi:10.1371/journal.pmed.1001672.

• Rimawi BH, Soper DE, Eschenbach DA. Group A streptococcal infections in obstetrics and gynecology. Clin Obstet Gynecol 2012;55:864–74. doi:10.1097/GRF.0b013e31827362fc.

• Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546–54. doi:10.1056/NEJMoa022139.

References

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• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. doi:10.1097/CCM.0b013e31827e83af.

• Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–73.

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References

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• ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496–506. doi:10.1056/NEJMoa1404380.

• Levy MM. Early goal-directed therapy: what do we do now? Crit Care 2014;18:705. doi:10.1186/s13054-014-0705-8.

• Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E. Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis. Intern Emerg Med 2015;10:731–43. doi:10.1007/s11739-015-1248-y.

• Afessa B, Green B, Delke I, Koch K. Systemic inflammatory response syndrome, organ failure, and outcome in critically ill obstetric patients treated in an ICU. Chest 2001;120:1271–7.

• Vasquez DN, Estenssoro E, Canales HS, Reina R, Saenz MG, Das Neves AV, et al. Clinical characteristics and outcomes of obstetric patients requiring ICU admission. Chest 2007;131:718–24. doi:10.1378/chest.06-2388.

• Lappen JR, Keene M, Lore M, Grobman WA, Gossett DR. Existing models fail to predict sepsis in an obstetric population with intrauterine infection. Am J Obstet Gynecol 2010;203:573.e1–5. doi:10.1016/j.ajog.2010.07.040.

• Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009;114:1326–31. doi:10.1097/AOG.0b013e3181c2bde8.

• Bauer ME, Bauer ST, Rajala B, MacEachern MP, Polley LS, Childers D, et al. Maternal physiologic parameters in relationship to systemic inflammatory response syndrome criteria: a systematic review and meta-analysis. Obstet Gynecol 2014;124:535–41. doi:10.1097/AOG.0000000000000423.

• Albright CM, Ali TN, Lopes V, Rouse DJ, Anderson BL. Lactic Acid Measurement to Identify Risk of Morbidity from Sepsis in Pregnancy. Am J Perinatol 2014. doi:10.1055/s-0034-1395477.

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• Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med 2015. doi:10.1056/NEJMoa1508375.

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Suggested Antimicrobials

Suggested Antimicrobials

High abnormal range Low abnormal range

+4 +3 +2 +1 0 +1 +2 +3 +4

Temp ≥41 39 - 40.9

38.5 - 38.9 36 - 38.4 34 - 35.9 32 - 33.9 30 - 31.9 <30

SBP >90 70 - 90 <70

HR ≥ 180

150 - 179

130 - 149

120 - 129 <120

RR ≥ 50 35 - 49 25 - 34 12 - 24 10 - 11 6 - 9 <6

SpO2 ≤92 % 90 - 91% 85 - 89% <85%

WBC ≥ 40 25 - 39.9 17 - 24.9

5.7 - 16.9 3 - 5.6 1 - 2.9 <1

Bands ≥10 % <10%

LA ≥ 4 <4

Respiratory

Parameter Change ↓↑

Functional residual capacity ↓ 10-25%

Minute ventilation ↑ 20-40%

Respiratory rate Unchanged

PaO2 Unchanged

PaCO2 ↓ to 28-32 mmHg

Serum bicarbonate ↓ to 18-21 mEq/L

Cardiac

Parameter Change ↓↑

Cardiac output ↑ 30-50%

Heart rate ↑ 15-20%

Systemic vascular resistance ↓ 20-30%

Systolic blood pressure ↓ by 5-10 mmHg in 2nd trimester Return to normal by 3rd trimester

Pulmonary vascular resistance ↓ 20-30%

Renal & Gastrointestinal

Parameter Change ↓↑

Glomerular filtration rate ↑ 50%

Creatinine ↓ to 0.3-0.8 mg/dL

Transaminases ↓

Bilirubin ↓

Alkaline phosphatase ↑

LDH Unchanged

Coagulation

Parameter Change ↓↑

Factors VII, VIII, IX, X, and XII, vWF ↑

Fibrinogen ↑

Protein S ↓

Protein C and ATIII Unchanged

Plasminogen activator inhibitor ↓

Hematologic

Parameter Change ↓↑

Hemoglobin ↓ 5-10%

White blood cell count ↑ 10% [16.9/μL by 3rd trimester, 30/μL in labor]

Immature neutrophils Unchanged

Red blood cell mass ↑

Platelet count ↓

Plasma volume ↑

Albumin ↓

Colloid osmotic pressure ↓

Early Goal-Directed Therapy

No Mortality Benefit?!

• Mortality rates in both groups were impressively low in all three studies (18.8 – 29.2%) – Indicates effective treatment

• ‘Usual care' now includes aggressive, early fluid resuscitation and rapid administration of appropriate antibiotics – Reflects impact original trial by Rivers et al

• SSC recommends continued use of EGDT

Mouncey 2015, ProCESS 2014, ARISE 2014, Levy 2014, Levy 2015, Rusconi 2015

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