Sepsis and septic shock in pregnancy

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Introduction

Recognition and management of sepsis and septic shock in pregnant women remain a challenge, despite several advances made in the non-pregnant patient population. Recent estimates suggest that infection accounts for 12.7% of maternal mortality in the United States and among this group, 6% are characterized as having sepsis. Recent US data indicate that infection is currently the third most common cause of maternal death, and in contrast to maternal deaths from hypertensive disorders and hemorrhage, the number of deaths related to infection are increasing.¹ This article will review how to recognize sepsis and key principles for management of the condition in pregnant patients.

Surviving Sepsis Campaign guidelines

The Surviving Sepsis Campaign is an ongoing collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine focused on converting current science into practical clinical tools to improve the outcome of sepsis. The guidelines published in 2016 simplified the definition into sepsis and septic shock.² It should be noted that obstetric considerations were not specifically identified when establishing these guidelines and most scientific data utilized excluded pregnant women. Therefore, it is essential to consider physiologic and hemodynamic changes in pregnancy when adapting these guidelines.

The sepsis continuum begins with infection and progresses to shock and multi-organ dysfunction if not interrupted. The systemic inflammatory response syndrome (SIRS) consists of physiologic changes that are associated with underlying infection and include temperature > 38° or < 36°C, heart rate > 90 bpm, RR > 20, or white blood cell count > 12,000 mm³. These criteria are no longer necessary for sepsis diagnosis as they are nonspecific to sepsis and are commonly observed in other clinical scenarios, including pregnancy.³ Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction is present when the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score is ≥ 2. Table 4 outlines the SOFA score, which assesses function of respiratory, hematologic, hepatic, cardiovascular, central nervous, and renal systems.⁴ The World Health Organization defines maternal sepsis as life-threatening organ dysfunction resulting from infection during pregnancy, childbirth, post-abortion, or postpartum period.⁵ Septic shock exists when vasopressors are required to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level is greater than 2 mmol/L following volume resuscitation.² Multiple online SOFA score calculators are available.

Sepsis scoring tools

Early recognition of sepsis allows for implementation of the three primary goals of sepsis management: 1) source control; 2) maintenance of perfusion; and 3) antibiotic therapy.⁶ Scoring systems to identify infected patients at risk for morbidity and mortality from sepsis and to predict likelihood of intensive care (ICU) admission have been widely used in emergency departments, medical and surgical units, and ICUs. Some scoring systems such as the Modified Early Warning Score (MEWS) and quick Sequential (sepsis-related) Organ Failure Assessment score (qSOFA) are intended for patients with suspected sepsis for prediction of ICU admission.^7,8 Others, such as the SOFA score, Acute Physiologic and Chronic Health Evaluation (APACHE), and Simplified Acute Physiologic Score (SAPS) are intended for prediction of mortality in ICU-admitted patients. Only the SOFA and qSOFA score are targeted specifically to the septic patient. However, none of the scoring systems include pregnant women in their prediction models. It is important to note that the SOFA score is validated for use in patients admitted to the ICU and is performed on admission and every 2 hours thereafter. The qSOFA score is intended for assessment of patients outside of the ICU who are suspected of having sepsis and at risk of ICU admission. The qSOFA score is presented in Table 1.

All sepsis scoring tools utilize varying combinations of vital signs, clinical evaluation, and laboratory parameters to predict morbidity and mortality and identify patients who require interventions. As a result, maternal morbidity may be overestimated given the physiologic changes in pregnancy, which artificially increase scores.^9-13 Therefore, applicability of these scoring systems and early recognition of sepsis in pregnant women has been complicated by normal physiologic adaptations to pregnancy. For example, decreases in blood pressure and increases in heart rate and white blood cell count are just a few of the changes that can be difficult to distinguish from pathologic changes in a patient at risk for sepsis.^3,14 The SOFA score has been applied to an obstetric ICU populations in India. Sepsis patients comprised 9% of the ICU admissions. In this population, total SOFA score at admission, mean total SOFA score, and maximum total SOFA score were all found to discriminate between survivors and non-survivors with high sensitivity and specificity.¹⁵ Similarly, in a Brazilian obstetric ICU population, a maximum SOFA score ≥ 6 predicted maternal mortality with 89% sensitivity and 91% specificity.¹⁶

The Sepsis in Obstetrics Score (SOS), outlined in Table 2, was initially proposed in 2014 to identify patients at risk for ICU admission and included modifications accounting for pregnant physiology.¹⁷ Subsequently, SOS was prospectively evaluated and found to have a negative predictive value of 98.6% if the score was less than 6.¹⁸ As a result, a score less than 6 may be reliable for predicting which patients will not require ICU care. However, the study was limited by small numbers and otherwise appeared to perform no differently than other scoring systems in predicting ICU admission.

In 2014, the National Partnership for Maternal Safety proposed Maternal Early Warning Criteria to indicate need for urgent bedside evaluation and potential escalation of care.¹⁹ This was a consensus-driven recommendation that included, but was not specific to, sepsis in pregnancy. Subsequently, a large US hospital system reported improvement in maternal morbidity following implementation of a Maternal Early Warning Triggers Tool (MEWT). The tool was designed to address the 4 most common causes of maternal morbidity: sepsis, cardiopulmonary dysfunction, preeclampsia-hypertension, and hemorrhage. In a patient with abnormal temperature, with 2 or more triggers, a series of interventions was then initiated which ultimately resulted in ICU admission and implementation of the Surviving Sepsis Campaign Bundles, as appropriate. These bundles are addressed later in this manuscript.

Etiologies in obstetrics

Underlying conditions most likely to be associated with development of sepsis in pregnant women are outlined in Table 3. Unsurprisingly, the most common sources are the lungs and genitourinary tract.²⁰ Organisms frequently associated with obstetric sepsis include: beta hemolytic streptococci, Gram-negative rods such as Escherichia coli, Streptococcus pneumoniae and influenza A and B.^21,22 E. coli is the most common sepsis pathogen in pregnancy. Recent data also indicate rising rates of infection due to Group A Streptococcus, a highly virulent pathogen. Group A strep often causes rapid progression along the sepsis continuum, resulting in shock, morbidity, and mortality.²³ Polymicrobial infections in pregnancy are also common and require broad-spectrum antimicrobial coverage; however, in up to 60% of patients, the cause is undetermined.²⁰ Prevention of sepsis hinges on administering prophylactic antibiotic therapy when indicated (i.e. preoperatively), recognizing infection when it develops and initiating appropriate therapy. Appropriate therapy includes culture-driven anti-infective agents when possible and source control. Source control involves eliminating the originating source of infection and may require surgical excision or delivery of the fetus.

Management

When sepsis is suspected, timely intervention with recommended bundle components and early goal-directed therapy is essential. Despite challenges in applying diagnostic and scoring criteria to pregnant women, the sepsis management principles of aggressive fluid resuscitation to maintain perfusion and timely administration of antibiotics apply. Surviving Sepsis Campaign guidelines put forth 2 timeline bundles of care to accomplish in septic patients (Table 5). In the first 3 hours after presentation, management includes:

• Measuring lactate level
• Obtaining blood cultures prior to administration of antibiotics
• Administering broad-spectrum antibiotics
• Administering 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L

Sepsis bundle components should be initiated regardless of the environment of care, with anticipation of ICU admission. Provision of additional volume resuscitation may be necessary as determined by the woman’s noninvasive hemodynamic assessment. If there is a delay in obtaining cultures, antibiotics should be initiated within 1 hour of diagnosis to improve outcomes.

Once these goals are achieved, the interventions become increasingly aggressive, if indicated, depending on patient response (Table 5). The goals of treatment within the first 6 hours of presentation include:

• Reassessment of volume status and tissue perfusion and document findings.
• In the event of persistent hypotension after initial fluid administration (MAP < 65 mmHg) or if initial lactate was ≥4 mmol/L,
• Application of vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥ 65 mmHg 
• Re-measurement of lactate if initial lactate is elevated.

Reassessment of volume status and tissue perfusion can be accomplished in several ways. The first is a clinical evaluation including vital signs, cardiopulmonary evaluation, capillary refill, pulse, and skin assessment findings. Alternatively, 2 of the following procedures can be done to gather information: measurement of central venous pressure (CVP), measurement of central venous oxygen saturation (ScvO₂), performance of bedside
cardiovascular ultrasound, or dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge (SSC). Central venous pressure (CVP) reflects right ventricular end diastolic volume, with lower trending values reflecting volume depletion. A range of 8 to 12 mmHg CVP should be achieved. ScvO₂ measures central venous oxygen saturation in blood collected from the superior vena cava via a central venous catheter. This assessment reflects the overall balance between oxygen delivery and consumption at the tissues. Values less than 70% reflect either decreased delivery (i.e. hypoxemia) or increased metabolic demand, extraction, and utilization (i.e. shivering). Higher numbers in a septic patient may reflect poor perfusion and therefore decreased extraction of oxygen at a tissue level. Newer continuous ScvO₂ catheters allow technology similar to pulse oximetry to evaluate oxygen saturation levels returning to the right side of the heart. Decreasing ScvO₂ values are usually noted prior to evidence of hemodynamic compromise, allowing early detection and intervention. Treatment considerations for low ScvO2 values include: 1) decreasing metabolic demand; 2) increasing oxygen delivery; 3) increasing circulating hemoglobin; and 4) increasing cardiac output. Bedside cardiovascular ultrasound is another option to evaluate size and contractility of the right and left ventricles as well as inferior vena cava size. All of these assessments can determine whether the patient has adequate preload and tissue perfusion. 

Sepsis and septic shock lead to diffuse endothelial damage and vascular permeability. As a result, risk of non-cardiogenic pulmonary edema and resulting hypoxemia should be anticipated. Maintaining SpO₂ values greater than 95% in a pregnant woman is essential. If mechanical ventilation is required, sedation and/or neuromuscular blocking agents can be expected to affect fetal heart rate (FHR) assessment. 

Sepsis may lead to blood glucose derangements. Data regarding optimal blood glucose ranges in the non-pregnant patient are inconclusive.²⁴ However, measures should be taken to avoid hyperglycemic or hypoglycemic episodes in a pregnant woman. Thromboembolism prophylaxis should be implemented early in care. When a woman is managed in a non-obstetric ICU, co-management strategies between the maternal-fetal medicine specialist and the intensivist should be implemented. Consultation with infectious disease specialists should also be considered.

Fetal assessment and delivery

In a woman with sepsis and a viable fetus, frequent (if not continuous) fetal monitoring is recommended. As with any diagnosis, fetal monitoring is only indicated if fetal interventions, including cesarean section, would be considered. In a pregnant patient with sepsis, shunting of circulation away from the uterus is likely if the septic process cannot be interrupted, adequate intravascular volume and cardiac output optimization is not achieved, and hypotension occurs. In addition, use of intravenous vasoconstrictive agents to improve MAP may further reduce uteroplacental perfusion. This results in FHR changes and likely contractions. In a preterm patient, corticosteroids should be considered to promote fetal lung maturity.

Measures to eliminate the source of infection and stop continued infection propagation are described as source control. The source of infection in a pregnant patient may be the uterus, therefore necessitating delivery, regardless of gestational age. In other circumstances, the decision to deliver or not will be based on multiple factors including likelihood of maternal improvement, ability to adequately treat sepsis while undelivered and impact of delivery process on maternal condition. Evidence regarding benefit of delivery in critically ill pregnant women is very limited, conflicting and not compelling.^25,26 Table 6 outlines factors to consider when considering delivery in a septic patient.

Conclusion

Sepsis in obstetric patients is increasing in the United States and a leading cause of maternal mortality. Early recognition of sepsis is essential to preventing disease progression to septic shock and reducing maternal mortality. If the condition is recognized, then timely implementation of sepsis management bundles can be accomplished.
Maternal vital signs and clinical triggers have been proposed in an effort to identify patients with sepsis and facilitate early interventions, however, further study is needed.