SMFM & CMQCC Guidelines: Management of Sepsis in Pregnancy

SUMMARY:

Sepsis remains a significant and potentially preventable cause of maternal morbidity and mortality. SMFM highlights the importance of implementing an ‘early warning system’ to avoid delay and recommends that

…sepsis and septic shock be considered medical emergencies and that treatment and resuscitation begin immediately (GRADE 1B)

We recommend that providers consider the diagnosis of sepsis in pregnant patients with otherwise unexplained end-organ damage in the presence of an infectious process, regardless of the presence of fever

Clinical Actions

• Order
  • Cultures: Blood | Sputum | Urine and other samples as indicated
    • CMQCC recommends cultures be drawn upon diagnosis even if antibiotic therapy has already been initiated
  • Serum lactate levels
• Begin
  • Antibiotics within 1 hour (see ‘Key Points’ below)
  • Broad Spectrum (anaerobic and aerobic gram-positive and gram negative bacteria)
• Determine source as early as possible following initiation of resuscitation and initiation of antibiotics
  • Imaging as necessary
  • Manage depending on findings (e.g. abscess drainage as required)
  • Use the least invasive approach possible (e.g. percutaneous best when appropriate) except in case where more invasive approach is desirable (e.g., debridement if indicated)

Fluids

• SMFM cautions that aggressive fluid resuscitation in pregnant women may result in ‘third spacing’ and recommends initial administration of 1-2 liters of crystalloids (Grade 1C)
• CMQCC states

We recommend that resuscitation from sepsis-induced hypoperfusion include at least 30 mL/kg of intravenous crystalloid fluid within three hours of recognition of sepsis

Surviving Sepsis Campaign does not recommend one crystalloid over another

• Do not use CVP or pulmonary artery occlusion pressure to guide fluid resuscitation
• Determine if patient is fluid responsive
  • Pulse pressure variation using arterial line wave form
    • Reliable with [1] sedation [2] positive pressure controlled mechanical ventilation and [3] in sinus rhythm
    • Pulse pressure should vary ≥13% with the respiratory cycle
  • Passive leg raise to 30-45 degrees (spontaneous breathing or not in sinus)
    • Auto transfusion results in increased cardiac output
    • May not be a good test in third trimester: Use 250 – 500cc cardiac bolus rather than leg raise

Vasopressors and Inotropes

• Use vasopressors in hypotensive patients if
  • Not fluid responsive or
  • Further fluid therapy is contraindicated (e.g. pulmonary edema)
• First line: Norepinephrine
  • Target MAP: >65 mmHg
  • SMFM recommends individualizing in pregnant patients taking in to account clinical context and overall perfusion
  • Norepinephrine appears to be safe in pregnancy although high-quality data is limited
• Other vassopressors
  • Data on other vasopressors more limited
• Consider dobutamine (inotrope) to increase cardiac output if
  • • Patient remains hypotensive following fluids and vasopressors
    • Myocardial dysfunction is present
• Start hydrocortisone 200 mg/day (continuous infusion) if no response to norepinephrine

Note: Initiate DVT prophylaxis

KEY POINTS:

Antibiotic Therapy

• Consider the following when beginning antimicrobial therapy
  • Initially, choice of antibiotic will likely be empiric
  • Choice of antibiotic will be dependent on
    • Source | Local resistance | Hospital protocols
  • Start with broad spectrum coverage, including anaerobic and aerobic gram-positive and gram-negative bacteria
  • Consultation with infectious disease may be appropriate

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CMQCC Antibiotic Recommendations if Source Unknown (at least
one antibiotic for Gram-negative and anaerobic coverage PLUS one for Gram-positive coverage)

7 to 10 day duration usually adequate

• Gram-negative plus anaerobic coverage
  • Piperacillin/tazobactam 3.375 g IV q8h (extended infusion) or 4.5 g IV q6h or
  • Meropenem 1 g IV q8h (if recent hospitalization or concern for multi-drug resistant organisms) or
  • Cefepime 1-2g IV q8h plus metronidazole 500 mg IV q8h or
  • Aztreonam 2 g IV q8h (for women with severe penicillin allergy) plus metronidazole 500 mg IV q8h or
  • Aztreonam 2g IV q8h plus clindamycin 900 mg IV q8h

PLUS

• Gram-positive coverage
  • Vancomycin 15-20 mg/kg q8h-q12h (goal trough 15-20 mcg/mL) or
  • Linezolid 600 mg IV/PO q12h (for women with severe vancomycin allergy)

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SMFM Guidance Provides Antibiotic Recommendations Dependent on Source

• Community-acquired pneumonia
  • Cefotaxime | Ceftriaxone | Ertapenem | Ampicillin plus azithromycin | Clarithromycin | Erythromycin
• Hospital-acquired pneumonia: Low risk
  • Piperacillin-tazobactam | Meropenem | Imipenem | Cefepime
• Hospital-acquired pneumonia: High risk or mortality
  • Double coverage for Pseudomonas
    • Beta lactam plus an aminoglycoside or quinolone
    • MRSA coverage: Vancomycin or linezolid
  • Chorioamnionitis
    • Ampicillin plus gentamicin
    • Cesarean: Add clindamycin or metronidazole for anerobic coverage
  • Endomyometritis
    • Ampicillin, gentamicin, and metronidazole (or clindamycin) or
    • Cefotaxime or
    • Ceftriaxone plus metronidazole
  • UTI
    • Gentamicin plus ampicillin or
    • Carbapenem or
    • Piperacillin-tazobactam
  • Abdominal infections: Uncomplicated
    • Ceftriaxone | Cefotaxime | Ceftazidime | cefepime plus metronidazole
  • Abdominal infections: Complicated
    • Carbapenem | Piperacillin-tazobactam
  • Skin and soft tissues (necrotizing)
    • Vancomycin plus piperacillin-tazobactam
    • If Streptococcus Group A or Clostridium perfringens are present: Penicillin G plus clindamycin

Fetal Assessment and Delivery

• Fetal assessment: Consider the following
  • Electronic fetal monitoring ≥24 weeks
  • Corticosteroids for fetal lung maturity >23 to 24 weeks of pregnancy
• Delivery (Grade 1B recommendations)
  • SMFM recommends against delivery for sepsis if this is the sole indication
  • Delivery should be dictated based on obstetric indications

Learn More – Primary Sources:

SMFM Consult Series: Sepsis during pregnancy and the puerperium

The Surviving Sepsis Campaign Bundle 2018 Update

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016

CMQCC Toolkit: Improving Diagnosis and Treatment of Maternal Sepsis

SMFM & CMQCC Guidelines: Making the Diagnosis of Sepsis in Pregnancy

SUMMARY:

SMFM  and CMQCC have both released guidance on sepsis in pregnancy. Sepsis remains a major cause of maternal morbidity and mortality. Sepsis is considered a preventable cause of maternal mortality. Because vital signs are altered in pregnancy (and may mimic infection such as increased maternal heart rate), both professional organizations emphasize the importance of recognizing that sepsis screening tools may need modification during pregnancy.  There are multiple tools to screen and diagnose sepsis. SMFM provides the SOFA method and CMQCC has developed its own algorithm (see details below)

Risk Factors

• Nulliparity
• Black race
• Insurance: public or none
• Cesarean delivery
• ART
• Multiple gestation

Note: Presence of co-morbidities increases maternal mortality risk

Definitions and Clinical Criteria

The Third Internal Consensus Definitions for Sepsis and Septic Shock (2016)

Definitions

• Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response to infection
• Septic shock: Sepsis with circulatory and cellular/metabolic abnormalities profound enough to substantially increase mortality

Clinical Criteria

• Sepsis
  • Suspected or documented infection and an acute increase of ≥2 SOFA (Sequential Organ Failure Assessment) points (see ‘Key Points’ below)
    • Proxy for organ dysfunction
• Septic Shock
  • Sepsis and vasopressor therapy needed to
    • Elevate MAP ≥ 65 mmHg and lactate > 2 mmol/L (18 mg/dL) after adequate fluid resuscitation

qSOFA System to Rapidly Identify Those at Risk

• Bedside tool used outside the ICU
• Assign 1 point each to the following criteria
  • SBP: ≤100 mmHg
  • Respiratory rate: ≥22 breaths per min
  • Altered mentation: Glasgow coma scale<15
• If score ≥2
  • Assess for organ dysfunction
  • Escalate therapy
  • Increase monitoring and transfer to ICU may be required

CMQCC 2-Step System for Maternal Sepsis Screening and Diagnosis

Step 1 – Sepsis Screen: ≥2 elements considered positive 

• Oral temperature: < 36°C (98.6°F) or ≥ 38°C (100.4°F)
• HR: > 110 beats per minute and sustained for 15
  minutes
• RR: > 24 breaths per minute and sustained for
  15 minutes
• WBC: > 15,000/mm3 or < 4,000/mm3 or >
  10% immature neutrophils (bands)

Note: Verify abnormal values | Obtain a complete set of vital signs (i.e., include 02 sat) and repeat in 15 minutes | Do not wait for fever if there are other suspicious clinical signs that infection is present | Corticosteroids will elevate WBCs but peak expected within 24 hours and should be baseline again after 96 hours

If Step 1 Positive – Obtain the following 

• Laboratory values: CBC
  • Coags: Prothrombin time | INR | PTT
  • Comprehensive metabolic panel
  • Venous lactic acid
• Bedside assessment
  • Urine output (Foley catheter with urometer
  • Pulse oximetry
  • Mental status assessment

Step 2 Confirmation: CMQCC Sepsis Diagnosis Algorithm (only 1 criteria required for sepsis diagnosis) 

• Respiratory function
  • Need for invasive or non-invasive mechanical
    ventilation or
  • PaO2/FiO2 < 300
• Coag studies
  • Platelets < 100 x 109/L or
  • INR: > 1.5 or
  • PTT: > 60 seconds
• Liver function
  • Bilirubin > 2 mg/dL
• Cardiovascular function (persistent hypotension)
  • SBP < 85 mm Hg or
  • MAP < 65 mm Hg or
  • > 40 mm Hg decrease in SBP
• Renal function
  • Creatinine > 1.2 mg/dL or
  • Doubling of creatinine or
  • Urine output < 0.5 mL/kg/hour (for 2 hours)
• Mental status
  • Agitation | Confusion | Unresponsiveness
• Lactic acid
  • 2 mmol/L
  • Can be used for diagnosis in the absence of labor | For women in labor with an elevated lactic acid and positive step 1 screen but negative step 2 confirmation, CMQCC recommends close surveillance with repeated bedside evaluation and repeated lactic acid levels over time

Note: CMQCC has not evaluated its algorithm in a research setting, but based on clinical practice data sets, the anticipated performance is estimated to be 97% for sensitivity and 99% for specificity

Sepsis and Septic Shock are Medical Emergencies

• Resuscitation and treatment should begin immediately
• Consider sepsis in pregnant women “otherwise unexplained end-organ damage in the presence of an infectious process”
• Treat regardless of whether or not fever is present
• Multiple organ systems aside from cardiovascular, pulmonary and CNS may be affected including
  • GI (ileus) | Hepatic injury or failure | Renal injury or failure | Coagulation (low platelets or DIC) | Endocrine system (adrenal / insulin resistance)
• CMQCC emphasizes that a MAP of <65 mm Hg that persists after a 30ml/kg fluid load in the setting of infection “directly defines septic shock”

KEY POINTS:

SOFA Score: Sepsis defined as an acute increase of 2 or more points

• Respiratory system: PaO2/FiO2 (mmHg)
  • ≥ 400 score 0
  • < 400 score +1
  • < 300 score +2
  • < 200 and mechanically ventilated score +3
  • < 100 and mechanically ventilated score +4

• Nervous system: Glasgow coma scale
  • 15 score 0
  • 13–14 score +1
  • 10–12 score +2
  • 6–9 score +3
  • < 6 score +4

• Cardiovascular system: MAP or vasopressors required
  • MAP ≥ 70 mmHg score 0
  • MAP < 70 mmHg score +1
  • dopamine ≤ 5 µg/kg/min or dobutamine (any dose) score +2
  • dopamine > 5 µg/kg/min OR epinephrine ≤ 0.1 µg/kg/min OR norepinephrine ≤ 0.1 µg/kg/min score +3
  • dopamine > 15 µg/kg/min OR epinephrine > 0.1 µg/kg/min OR norepinephrine > 0.1 µg/kg/min score +4

• Liver: Bilirubin (mg/dl) [μmol/L]
  • < 1.2 [< 20] score 0
  • 1.2–1.9 [20-32] score +1
  • 2.0–5.9 [33-101] score +2
  • 6.0–11.9 [102-204] score +3
  • 12.0 [> 204] score +4

• Coagulation: Platelets×10³/µl
  • ≥ 150 score 0
  • < 150 score +1
  • < 100 score +2
  • < 50 score +3
  • < 20 score +4

• Kidneys: Creatinine (mg/dl) [μmol/L] (or urine output)
  • < 1.2 [< 110] score 0
  • 1.2–1.9 [110-170] score +1
  • 2.0–3.4 [171-299] score +2
  • 3.5–4.9 [300-440] (or < 500 ml/d) score +3
  • 5.0 [> 440] (or < 200 ml/d) score +4

Clinical Features and Considerations Specific to Pregnancy if Using SOFA

• SOFA does not take in to account the physiologic changes of pregnancy
  • Creatinine at ≥2 mg/dL: This SOFA threshold above pregnancy norm
  • MAP: Healthy pregnant women may have MAP <70 mmHg
• SOMANZ (Society of Obstetric Medicine Australia and New Zealand) developed an obstetrically modified qSOFA score for pregnant women (1 point each; ≥2 escalate)
  • SBP <90 mmHg
  • Respiratory rate >25/min
  • Altered mental status (any non-alert state)
• SOMANZ also made modifications to the SOFA scoring system
  • Simplified to account for lack of Glasgow score use on L&D
  • Healthy pregnancy will usually have MAP <70 mmHg so premorbid blood pressure should be taken in to consideration
  • Positive score is a change of ≥2 so scores of 3 and 4 removed for sake of simplicity

SOMANZ obstetrically modified SOFA- (omSOFA)

• Respiration: PaO2/FIO2
  • ≥400 score 0
  • 300 – <400 score +1
  • <300 score +2

• Coagulation: Platelets, x106/L
  • ≥150 score 0
  • 100-150 score +1
  • <100 score +2

• Liver: Bilirubin (mg/dl) [μmol/L]
  • ≤1.2 [≤20] score 0
  • 1.2-1.9 [20-32] score +1
  • >1.9 [>32] score +2

• Cardiovascular: MAP (mmHg)
  • ≥70 score 0
  • <70 score +1
  • Vasopressors required score +2

• Central Nervous System
  • Alert score 0
  • Rousable by voice score +1
  • Rousable by pain score +2

• Renal: Creatinine (mg/dl) [μmol/L]
  • ≤1.0 [≤90] score 0
  • 1.0-1.4 [90-120] score +1
  • >1.4 [>120] score +2

Learn More – Primary Sources:

SMFM Consult Series: Sepsis during pregnancy and the puerperium

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

qSOFA calculator

Serial Evaluation of the SOFA Score to Predict Outcome in Critically Ill Patients

JAMA: Consensus Definitions for Sepsis and Septic Shock

SOMANZ Guidelines for the Investigation and Management of Sepsis in Pregnancy

CMQCC: Improving Diagnosis and Treatment of Maternal Sepsis