Chapter 9: Maternal Sepsis

Sepsis, severe sepsis, and septic shock are a continuum in the systemic response to infection. Sepsis is the leading cause of mortality in intensive care units and accounts for 10% of direct maternal deaths in North America. Most deaths in sepsis are due to multiple organ dysfunction syndrome (MODS), the final stage in the sepsis spectrum. The obstetric patient is particularly vulnerable to sepsis because of the association between pregnancy and infectious complications such as pyelonephritis, chorioamnionitis, endometritis, wound infection, necrotizing fascitis, and cholecystitis. Septic shock occurs in up to 4% of bacteremic patients, and 40% to 60% of patients in septic shock have bacteremia. The relationship between bacteremia and sepsis also depends on other contributing factors, such as immune suppression, and associated medical conditions. Overall, gram-negative aerobic bacilli used to be the predominant organisms associated with sepsis. However, the incidence of infection with gram-positive organisms in patients with sepsis has increased and may now equal that of gram-negative infections.

Sepsis is the development of systemic inflammatory response syndrome (SIRS, Table 9-1) in response to infection. Sepsis is called severe when there is evidence of end-organ damage. Septic shock is defined as sepsis-induced hypotension (systolic blood pressure <90 mm Hg, a mean arterial pressure <70 mm Hg, or a reduction in systolic blood pressure of >40 mm Hg from baseline) despite volume replacement (or requirement for vasopressors). Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate (≥4 mmol/L), or oliguria (urine output <0.5 mL/kg/h for at least 2 hours despite adequate fluid resuscitation).

Sepsis has been viewed as an uncontrolled inflammatory response to infection. This hypothesis was based on animal studies as well as measures of immune response in humans, including cytokine levels. This view has been recently challenged by the failure to decrease mortality in clinical trials of anti-inflammatory agents, and by evidence of a severely compromised immune system that is unable to eradicate the infection. The immunological response in patients with sepsis may even be biphasic, with an anti-inflammatory phase following an initial overwhelming response. The cardiovascular manifestations of sepsis are the results of alterations in peripheral vascular tone and cardiac function. The decrease in vascular tone affects both the arterial and venous systems, and is believed to be due to an increase in smooth muscle relaxants such as nitric oxide. Microvascular changes such as endothelial cell swelling, fibrin deposition, and aggregation of circulating cells also contribute to the abnormal blood flow seen in patients with sepsis. Cardiac output depends on the intravascular volume status of the patient. In the early stages of septic shock, cardiac output may be decreased because of hypovolemia and low cardiac filling. Cardiac output increases after fluid replacement. Myocardial dysfunction is seen in most patients with septic shock and affects both the right and left ventricles. Many of the cytokines, as well as nitric oxide, are myocardial depressants.

The diagnosis of sepsis in pregnancy may not be as apparent as in nonpregnant individuals as signs and symptoms of sepsis may be less pronounced. Some of the findings may overlap with those in normal pregnancy, such as tachycardia, tachypnea, leukocytosis, and thrombocytopenia; others may be counterintuitive, such as hypothermia and leukopenia. Oliguria (urine output <0.5 mL/kg/h for at least 2 hours despite adequate fluid resuscitation) and an increase is serum creatinine (increase >0.5 mg/dL) are other findings that can sometimes lead to erroneous diagnoses of preeclampsia or hypovolemia. Other signs and symptoms to keep in mind include vomiting, diarrhea, maculopapular rash, and mental changes. Early identification and treatment requires a high index of suspicion. Sepsis should be considered in any patient suspected to have an infection who develops any of the findings mentioned herein.

The general management guidelines for a patient with sepsis are outlined in Table 9-2. The following discussion will concentrate on the overall principles for the management of sepsis, mostly septic shock. The details of each management option (central hemodynamic monitoring, drug pharmacology, fetal effects, etc) are covered in the different chapters pertaining specifically to these issues. A number of studies have shown that implementation of sepsis protocols for early identification and management improves outcomes.

During the initial evaluation, a search for the source of the infection should take into account the most common sources in a pregnant or postpartum woman (Table 9-3). Testing may include chest x-ray to exclude pneumonia, abdomino-pelvic CT scan, or MRI to search for abscesses, myometrial necrosis, and pyometra, as well as amniocentesis to exclude intra-amniotic infection. Diagnosis of infection relies on clinical suspicion and a search for an infectious agent. Collections identified by radiology should be aspirated and drained under guidance, and samples sent for Gram and fungal staining and culture. Purulent wounds or those with spreading cellulitis should prompt swabbing for culture. When infection is suspected in contaminated or dirty abdominal wounds, anaerobic infections should be assumed irrespective of the culture results. Blood cultures should be taken as soon as possible after the onset of fever or chills, and before starting antibiotics. Blood for culture should be obtained by fresh venipuncture. The skin should be swabbed twice with either 70% isopropyl alcohol or iodine-containing solution. About 10 to 30 mL of blood should be inoculated in each culture bottle, and priority is given to the aerobic bottle if the volume of blood obtained is insufficient. The needle used for venipuncture should be changed prior to inoculation of the blood into the culture bottles. About 2 to 3 sets of blood cultures should be obtained for each suspected episode of bacteremia. In critically ill patients, the source of sepsis is frequently iatrogenic such as caused by a central venous catheter (CVC), urinary indwelling catheter, or ventilator. Specific techniques and procedures should be followed to obtain and interpret cultures from these sources. These include culture of blood aspirated from the CVC, quantitative cultures of the CVC tip, and culture from the CVC insertion site. A sample of secretions aspirated via the endotracheal tube should be sent for Gram staining and for bacterial and fungal culture. Pleural effusions greater than 10 mm should be aspirated, cultured, and sent for Gram and fungal stainings. Unless contraindicated, bronchoscopy should be performed whenever ventilator associated pneumonia is suspected. A policy of routine screening of hospitalized patients for Candida colonization is not recommended. Among septic patients, however, invasive fungal infection is more likely in those patients who are heavily colonized. Blood cultures should be obtained from septic patients colonized by Candida at 2 or more sites.

The first few hours are critical in treatment of septic patients, particularly in those with tissue hypoperfusion. Obstetricians should be on the alert to the development of sepsis in any woman with infection. Treatment and resuscitation should be instituted as soon as sepsis is suspected, and never delayed until the patient is transferred to a higher level of care. For these reasons, obstetricians should be familiar with the early recognition and management of sepsis. Early administration of antibiotics reduces mortality and morbidity in septic patients. The patient should be started empirically on broad-spectrum antibiotics. For pregnancy-related infections, a combination of penicillin, aminoglycoside, and either clindamycin or metronidazole for anaerobes should cover most possible organisms. Alternatively, a carbapenem or a third- or fourth-generation cephalosporin may be used in nonneutropenic patients. Aztreonam and fluoroquinolones do not have adequate activity against gram-positive bacteria and therefore are not recommended for initial empirical treatment. Vancomycin should be used for suspected methicillin-resistant Staphylococcus infection (catheter-related infection, or centers where methicillin-resistant staphylococci predominate). Antifungal agents should not be used as routine empirical therapy. In situations where immune suppression, or other conditions conducive to fungal infection, may have contributed to the initial inciting event, coverage with amphotericin or equivalent antimicrobials should be considered. Fluconazole is as effective as amphotericin B, and less toxic in nonneutropenic patients. However, amphotericin B should be used as first-line therapy in neutropenic septic patients until identification and susceptibility are determined. The initial and subsequent choice of antimicrobials should always be predicated by allergy history, renal and liver function, culture results, and hospital- or community-specific microbial sensitivity testing. It is also important to remember that cultures may be falsely negative or yield incomplete information as some organisms may not be detected. This is especially true in obstetrically related infections which tend to be polymicrobial.

Hemodynamic support in sepsis is one of the central components of the management. The goal is to restore tissue perfusion and normalize cellular metabolism. Volume replacement, most often with fluid alone, is sometimes sufficient to reverse hypotension, restore hemodynamic stability, and improve oxygen delivery. Volume replacement should be titrated according to blood pressure (maintain a systolic blood pressure of at least 90 mm Hg or a mean arterial pressure of 60-65 mm Hg), heart rate, and urine output (≥0.5 mL/kg/h). Initial fluid challenge should be at a minimum of 30 mL/kg. Boluses of 250 to 1000 mL of crystalloids over 5 to 15 minutes are recommended. Hydroxyethyl starches should not be used for fluid resuscitation of severe sepsis and septic shock. Albumin can be used in the fluid resuscitation of severe sepsis and septic shock when substantial amounts of crystalloids are required. Oncotic pressure decreases in pregnancy, with further decrease in malnourished or preeclamptic women. Combined with the propensity for capillary leak in sepsis, the gestational decrease in oncotic pressure predisposes pregnant or postpartum women for pulmonary edema. The initial fluid boluses can be guided by the overall subjective assessment of the patient’s intravascular volume status (prior fluid replacements and losses), intravascular oncotic pressure (nutritional status, conditions decreasing oncotic pressure, etc), and clinical measures of pulmonary function (oxygen saturation, auscultation, etc). If hypotension persists despite the initial attempts, further volume expansion should be guided by central venous pressure (CVP) (maintained at 8-12 mm Hg) or pulmonary capillary wedge pressure (maintained at 12-16 mm Hg), the latter being more appropriate than the former in cases where central venous pressure may not reflect left ventricular end-diastolic pressures (eg, preeclampsia) or when the central venous pressure is elevated. If central monitoring is indicated, the use of a catheter with the capability to measure oxyhemoglobin saturation can be very useful in guiding further management as it can be used to measure superior vena cava or mixed venous oxygen saturations. Systemic oxygen delivery depends on cardiac output and the oxygen-carrying capacity of the blood. Increases in cardiac output can be proportional to the degree of intravascular volume expansion, while increases in the oxygen-carrying capacity can be achieved by increasing the hemoglobin. The recommended hemoglobin concentration in patients with septic shock is 9 to 10 mg/dL.

Vasopressors are required when the fluid and red blood cell replacement fail to restore adequate organ perfusion (Table 9-4). The choice between the different vasopressors depends on the balance between cardiac and peripheral vascular effects. Dopamine and epinephrine are more likely to increase heart rate than norepinephrine and phenylephrine. Dopamine and norepinephrine raise both blood pressure and cardiac index. Overall, recent data suggest that norepinephrine is the best choice for a vasopressor because of less tachycardia, no interference with the hypothalamic-pituitary axis, and a likely survival advantage over other vasopressors. In septic shock, norepinephrine is a more potent vasopressor than dopamine and increases cardiac output, renal blood flow, and urine output. Epinephrine can be added to and potentially substituted for norepinephrine when an additional agent is needed to maintain adequate blood pressure. All patients receiving vasopressors should have an arterial line placed. Despite the negative effect of sepsis on cardiac function, most patients have increased cardiac output especially following intravascular volume expansion, with or without norepinephrine. If cardiac output remains low-normal or decreased, inotropic support is required, with dobutamine being the most appropriate choice (start at 2.5 μg/kg/min and increase by 2.5 μg/kg/min every 30 minutes to achieve a cardiac index of 3 or more). In the presence of hypotension, dobutamine should be used in combination with a vasopressor, preferably norepinephrine. Finally, vasopressin can be added if organ perfusion remains abnormal despite high doses of vasopressors and inotropes. Doses should be limited to 0.01 to 0.04 U/min in order to prevent splanchnic and coronary artery ischemia, as well as decreased cardiac output. Routine intravenous bicarbonate therapy for anion gap acidosis and supranormal oxygen delivery (increasing oxygen delivery to higher than normal values) is no longer recommended. Early recognition of septic shock in patients with infection is critical in order to initiate aggressive and timely cardiovascular management, since the response in the initial few hours has a tremendous bearing on outcome. Within the first 6 hours, the goals of initial resuscitation should be to reach a CVP of 8 to 12 mm Hg, a MAP of greater than or equal to 65 mm Hg, a urine output of greater than or equal to 0.5 mL/kg/h, and a superior vena cava oxygen saturation of 70% or a mixed venous oxygen saturation of 65%. In women with elevated lactate levels, normalization of these levels is another measure of improved tissue perfusion.

The source of infection should be eliminated as soon as the patient’s condition permits. Debridement of infected and devitalized tissue is indicated in cases of wound infection or fasciitis. Ultrasound evaluation of the endometrial cavity can be used to determine the presence of retained products and need for curettage. If well-defined and accessible, intra-abdominal or pelvic abscesses detected on CT scan or MRI can be initially managed by percutaneous drainage, either for definitive treatment or as a temporizing measure while optimizing the patient’s condition in preparation for laparotomy. Laparotomy should be reserved for not well-defined collections, presence of dead tissue that requires debridement, or failure of initial percutaneous drainage. In postpartum patients, the radiologist should be alerted to the possibility of myometrial necrosis, which can be detected on CT scan or MRI, and requires hysterectomy. Amniocentesis may be required to exclude chorioamnionitis in septic patients who are still pregnant, and who have no other obvious source as delivery would be required if intra-amniotic infection is confirmed by low amniotic fluid glucose concentration and Gram staining. Since pregnant and postpartum women are prone to cholelithiasis, cholecystitis should be excluded and cholecystectomy be entertained if present. Similarly, pyelonephritis associated with urinary obstruction should be treated with stenting and drainage.

Early endotracheal intubation and mechanical ventilation should be used in severe sepsis or septic shock. Noninvasive positive-pressure ventilation should be avoided. Indications for mechanical ventilation include severe tachypnea (respiratory rate >40 bpm), muscular respiratory failure (use of accessory muscles), altered mental status, and severe hypoxemia despite supplemental oxygen. Permissive hypercapnia through reduced tidal volume ventilation (6 mL/kg ideal body weight to maintain end-inspiratory plateau pressures at <30 cm H₂O), and prone positioning are a few strategies that can be used in complicated cases. The respiratory management of patients with acute lung injury/acute respiratory distress syndrome (complicates 18%-40% of cases) is discussed in detail in Chap 12.

There are a number of therapies that fall into the supportive category in critically ill patients in general, and septic obstetrical patients in particular. Examples of such therapies include prophylaxis for thromboembolism, nutritional support, stress ulcer prophylaxis, and hemofiltration for renal insufficiency. Sepsis and pregnancy are predisposing factors for thromboembolism and deep vein thrombosis prophylaxis is recommended. Either low-dose unfractionated heparin (5000 units 3 times per day) or low-molecular-weight heparin can be used. Intermittent pneumatic compression devices may be added whenever possible. If the patient has a contraindication to heparin (coagulopathy, active bleeding, allergy), mechanical devices should be substituted. Nutritional support is recommended in septic patients. This topic is dealt with in more detail elsewhere. In summary, oral or enteral nutrition are the preferred methods, with parenteral nutrition as a second choice. The American College of Chest Physicians and the American Society of Parenteral and Enteral Nutrition have issued specific recommendations for septic patients (Table 9-5; not specific to obstetric patients). More recently, however, there has been a move toward lower caloric feeding in the first week (eg, 500 kcal/d). The efficacy of antacids, sucralfate or histamine-2 receptor antagonists in prevention of stress ulcer bleeding has been confirmed in numerous trials of critically ill patients. In patients with severe sepsis, platelets may be administered prophylactically when counts are less than or equal to 10,000/mm³ in the absence of apparent bleeding, or if less than or equal to 20,000/mm³ if the patient has a significant risk of bleeding.

The popularity of certain additional therapies has waxed and waned over time, while others are still in the experimental phase. Corticosteroids are, currently, the favored immunological therapy. Corticosteroids should be reserved for refractory septic shock, and should not be used in sepsis without shock or with mild shock. If fluid resuscitation and vasopressors are not able to restore hemodynamic stability, the hydrocortisone 200 mg per day can be added. Intensive insulin therapy to maintain blood glucose between 80 and 100 mg/dL has fallen out of favor. The current recommendations are to use an upper target blood glucose less than or equal to 180 mg/dL without a lower target other than hypoglycemia. Glucose should be monitored every 1 to 2 hours, and insulin instituted when 2 consecutive blood values are greater than 180 mg/dL. Treatment should avoid hyperglycemia (>180 mg/dL), hypoglycemia, and wide swings in glucose levels. Values obtained using point of care testing of capillary blood should be interpreted with caution in patients with sepsis as they may not reflect circulating glucose level. Granulocyte colony-stimulating factor should not be used in nonneutropenic patients, and hemofiltration should not be used without renal indications. Other therapies that have been tried, but which should not be used for the treatment of sepsis unless additional studies show a clear benefit, include ibuprofen, prostaglandins, pentoxifylline, N-acetylcysteine, selenium, antithrombin III, immunoglobulins, and growth hormone. A Cochrane review found that there is insufficient evidence to support the use of recombinant activated protein C (rhAPC; drotrecogin alpha) in sepsis, and it has been withdrawn from the market.

The effect of pregnancy on the critically ill patient and vice versa is discussed elsewhere. Pregnant septic patients are at risk for utero-placental insufficiency and preterm labor. The decision for continuous fetal heart rate monitoring and/or tocolysis should take into account the gestational age and the patient’s condition. A non-reassuring fetal heart rate pattern or contractions frequently resolve with correction of maternal hypoxemia and acidosis of short-term duration. Longer periods of maternal hypoxemia and acidosis, however, may result in permanent fetal damage or progression into active labor and may require delivery. In the absence of chorioamnionitis, labor, or nonreassuring fetal status, the decision for delivery should also be based on gestational age and the patient’s condition. If respiratory and cardiovascular functions continue to deteriorate despite aggressive management, then decompression of a gravid uterus after 28 weeks’ gestation may improve venous return and lung volumes.