Background

The physiologic adjustments that result from pregnancy and the puerperium (ie, the 6 weeks immediately following delivery) introduce numerous challenges to the prompt recognition and appropriate management of sepsis in this population. Specific infectious conditions to which obstetric patients are uniquely susceptible, as well as others to which all patients may be exposed, are mentioned; but a detailed discussion of each of these could fill a volume, and the goal of this section is to highlight patient factors that alter sepsis care compared with the baseline population.

The most recent large, population-based study of pregnancy-associated sepsis cited a rate of 26 hospitalizations per 100,000 pregnancies due to this condition, up from 11 per 100,000 8 years prior. Other differences over that same period included a higher rate of intensive care unit (ICU) admission (78% vs 90%), a higher rate of organ failure (9% vs 35% with ≥3 organ failures), and higher hospital charges (∼$25,000 more). Despite what seems to be a sicker population, the mortality rate did not change significantly ( Table 1 ). Whether this is due to more effective management, variations in recognition, or other factors is not clear. From 2006 to 2008, sepsis was cited as the leading cause of direct maternal death in the United Kingdom; however, as of 2009 to 2012, it had been supplanted by thromboembolic disease.

Diagnosis

Although reports are mixed, most published data suggest that approximately half of pregnancy-related sepsis diagnoses are made in the puerperium. The most common site of infection among septic pregnant patients reported in the literature is uterine (eg, chorioamnionitis, endometritis), though urinary tract infections (UTIs) exceed these in some reports ( Box 2 ). Escherichia coli is the most frequently isolated microbe in both antepartum and puerperal sepsis, though group B streptococcus ( strep ) has been implicated most often among patients with intrapartum sepsis. Pregnant patients diagnosed with sepsis due to group A strep often have rapid progression of illness with high morbidity and mortality according to several reports. Unfortunately, culture data are often not available or not universally reported in relevant studies of maternal sepsis.

Several factors contribute to the potential for delayed recognition of sepsis in obstetric patients. Increased progesterone levels during pregnancy result in a decrease in systemic vascular resistance of approximately 20% and an increase in mean heart rate from 71 beats per minute to 83 to 88 beats per minute. As vasodilation and tachycardia are among the classic findings of nonpregnant patients with sepsis, this effectively removes several of the diagnostic features on which clinicians rely. Pregnant patients also typically have an increased minute ventilation due to a larger tidal volume rather than a higher respiratory rate. Consequently, tachypnea should never be ignored in this population.

Leukocytosis in the third trimester is not unusual when patients may have white blood cell (WBC) counts approaching 17,000/μL. Normal values are expected by 4 weeks post partum.

Elevated lactic acid levels in septic pregnant patients have been associated with an increased risk of positive blood cultures and transfer to a higher level of care. Although the relevant study was small, retrospective, and did not focus on patient-oriented outcomes, the use of lactic acid measurements for prognostication and assessment of response to interventions in the obstetric population is likely similar to that in the nonpregnant population.

The systemic inflammatory response syndrome (SIRS) criteria have been a cornerstone in defining and screening for sepsis. One of the SIRS criteria is heart rate greater than 90 beats per minute, whereas another is WBC greater than 12,000/μL. Pregnant patients without infection may approach or exceed these thresholds even without true sepsis. Indeed, the standard SIRS criteria were found to have such poor specificity in an obstetric population with chorioamnionitis (<20%) that their use has been discouraged. Obstetric SIRS criteria and a Sepsis in Obstetrics Score have been proposed to account for the physiologic changes of pregnancy; they have been used to define cases of maternal sepsis, though they have not been satisfactorily validated to recommend their widespread use.

Creatinine is depressed (ie, lower than normal) during normal pregnancy, meaning that the emergency provider (EP) may be not be alarmed by a creatinine approaching 1.2 mg/dL. Proposed reference values in previously healthy pregnant women include an upper limit of normal of 0.63 to 0.70 mg/dL. Values between this threshold and 1.2 mg/dL are of uncertain significance in the setting of presumed sepsis.

Management

Pregnant patients have been excluded from each of the major sepsis trials; as a result, guidelines for the care of septic obstetric patients are largely based on inferred data or are simply not included in published recommendations.

As with any patient, attention to airway, breathing, and circulation are paramount. Once the first two are secured, attention to hemodynamics follows. Antenatal patients in shock, particularly those in the latter half of pregnancy, should be placed in the left lateral decubitus position to minimize compression of the inferior vena cava by the gravid uterus. Patients exhibiting clinical signs of shock, including but not limited to those who are hypotensive, should be given intravenous crystalloid as the initial resuscitative fluid. There are no evidence-based guidelines to suggest a particular volume, but the recommendation of 30 mL/kg for nonpregnant patients is likely appropriate in most otherwise healthy obstetric patients. Special attention should be paid to the fact that the colloid osmotic pressure is lower in obstetric patients, so there is a higher risk for pulmonary edema with aggressive fluid loading. There is no evidence that colloid solutions (eg, albumin, hydroxyethyl starch) should be used any differently in this population compared with nonpregnant septic patients. Recent literature suggesting lower mortality with the use of balanced crystalloid solutions (eg, lactated Ringer) compared with unbalanced solutions (eg, normal saline) do not specifically address this population.

Although there has been previous debate about the most appropriate vasopressor to be used in patients with sepsis-induced hypotension refractory to fluid therapy, the most recent guidelines for nonpregnant patients unequivocally recommend norepinephrine as the first-line agent. Several reviews centered on maternal sepsis indicate that, although there is a risk of decreased uteroplacental blood flow with this drug, there is not evidence to suggest that the fetal risk is sufficiently high to recommend an alternative vasopressor.

Table 2 lists commonly used antibacterial agents and a brief summary of their role in pregnancy. In summary, most antibiotic agents used in the care of septic patients who are not pregnant are acceptable for use in those who are. As in nonpregnant patients, source control is of utmost importance. Among pregnant patients with nonobstetric infections as the cause for their sepsis (eg, pneumonia), delivery has not been shown to uniformly improve outcomes for the mother or fetus.

Generally speaking, optimal care for maternal sepsis focuses primarily on early recognition and consideration of infectious conditions unique to pregnancy and the puerperium. Once sepsis is identified, the medical management is actually quite similar to that in the nonobstetric population. Certain conditions that are traditionally managed surgically and coincidentally present during pregnancy (eg, acute appendicitis) are complicated by balancing maternal (and, thus, fetal) well-being in the setting of medically managed disease (eg, intravenous antibiotics) versus fetal viability in the setting of operative intervention.

Background

Cirrhosis refers to the diffuse fibrotic changes of the liver that may result from any number of causes (eg, chronic alcohol abuse, nonalcoholic steatohepatitis, viral hepatitis). A recent population-based study in the United States estimates a disease prevalence of 0.27%.

More than half of patients with cirrhosis admitted to the ICU die in the hospital, and the mean hospital length of stay is nearly 2 weeks. Cirrhosis confers an enormous burden of disease, and these patients exhibit a 4- to 5-fold increase in the rate of infection at the time of, or during, hospitalization compared with the general population. Cirrhosis leads to increased risk of infection due to the following: fibrotic changes in the liver’s structure result in a diminished ability to filter bacteria; increased intestinal permeability leads to chronic exposure to translocated bacteria and consequent persistent immune system activation; reduced hepatic synthetic function causes diminished levels of complement and acute phase proteins; circulating immune cells exhibit impaired phagocytic ability; the response to vaccination is blunted.

Spontaneous bacterial peritonitis (SBP) and UTIs are the most common sources of sepsis in this population. Traditionally, Enterobacteriaceae and nonenterococcal strep species have been implicated as the offending agents; however, multidrug-resistant organisms are increasingly being identified. Extended-spectrum beta-lactamase–producing Enterobacteriaceae , Pseudomonas aeruginosa , and methicillin-resistant Staphylococcus aureus (MRSA) were the most frequently isolated in one recent study. Risk factors included hospital-acquired infection, prophylactic or recent antibiotic therapy (especially fluoroquinolones or beta-lactams), and recent history of multidrug-resistant infection.

Diagnosis

Several of the features that suggest sepsis in noncirrhotic patients are already present among nonseptic patients with cirrhosis. Indeed, as many as 30% of noninfected patients with decompensated cirrhosis will exhibit SIRS. Additionally, patients with end-stage liver disease will exhibit tachycardia and hypotension due to arterial vasodilation, rendering the presence of these findings difficult to interpret in the setting of infection. Clinical and laboratory findings are less reliable in this patient population, and trends of serial measurements are emphasized over single results. Although the latter is true of many conditions, its importance is particularly highlighted in this population.

Because of decreased clearance of lactate among nonseptic patients with cirrhosis, a single elevated lactate result is of limited value in the evaluation of a patient in whom there exists concern for sepsis. A normal or down-trending lactate, however, is reassuring. There is no specific lactate threshold that is recommended in this population.

Assessments of volume status and fluid responsiveness are fraught with problems among patients with cirrhosis. Those with large-volume ascites may develop intra-abdominal hypertension, rendering bedside tests, such as passive leg raise, unreliable. Debate remains about the utility of inferior vena cava measurements for assessment of intravascular volume, but there are certainly no studies to date that validate its use in this group of patients.

Patients who have developed esophageal varices due to portal hypertension from cirrhosis may be prescribed a nonselective beta-blocker, such as propranolol. These agents may blunt the tachycardia that often cues providers to a significant inflammatory response to infection. Additionally, they may reduce a patient’s ability to compensate for the vasodilation characteristic of septic shock.

Acute kidney injury (AKI) is the most common organ failure identified among cirrhotic patients with sepsis, and the degree of injury is associated with prognosis. The 30-day mortality of infected cirrhotic patients with AKI that progressed to a persistent need for renal replacement therapy was 10-fold greater than for those patients without AKI.

Management

Multiple factors complicate the management of patients with concomitant cirrhosis and sepsis. Among these are the impaired ability to trend response to therapy and low plasma oncotic pressure that leads to extravascular fluid shifts and the potential for secondary respiratory and cardiovascular compromise. Furthermore, baseline adrenal insufficiency and coagulopathy make operative source control and other procedural interventions more treacherous.

As a result of increased hydrostatic pressure in the mesenteric vessels (due to portal hypertension) and the decreased plasma oncotic pressure that results from hypoalbuminemia, cirrhotic patients may develop ascites. Aggressive fluid resuscitation with crystalloid exacerbates both of these factors and may lead to intra-abdominal hypertension or abdominal compartment syndrome at the extreme end of the spectrum. The principal consequences of this situation in the setting of sepsis are impaired venous return and decreased diaphragmatic excursion. Should this occur in the setting of tense ascites, therapeutic paracentesis is recommended. Decisions to pursue this intervention should be based on clinical assessment; routine measurement of intra-abdominal pressures is not encouraged.

Intravascularly depleted patients should initially receive crystalloid at a lower-than-standard volume of 10 to 20 mL/kg. There may be a benefit to balanced crystalloid solutions, particularly among those cirrhotic patients with relative hyperchloremia (hyponatremia with normal chloride) or in those already exhibiting a hyperchloremic acidosis.

Albumin has proven value in 2 particular situations in the management of cirrhotic patients with sepsis: (1) patients undergoing large-volume (ie, ≥5 L) paracentesis in the setting of tense ascites and (2) patients with sepsis due to SBP. Although no mortality benefit was evident, 2 studies of cirrhotic patients with non-SBP infections showed reduced rates of AKI when they were given albumin. As in noncirrhotic patients, those receiving large volumes of crystalloid with a persistent need for volume expansion may benefit from albumin infusion.

Synthetic colloids, such as hydroxyethyl starch, have been shown to increase rates of acute renal failure and the need for renal replacement therapy; one study showed an independent contribution to 90-day mortality with these agents compared with crystalloid. Consequently, synthetic colloids are discouraged in cirrhotic patients.

Norepinephrine is the first-line vasopressor agent in this population, as in noncirrhotic patients with septic shock. Central venous catheter (CVC) insertion for administration of these drugs may be complicated by coagulopathy resulting from reduced hepatic synthesis of coagulation factors. A compressible site is recommended in this setting in case of arterial puncture or hematoma formation.

Adrenal insufficiency is common in cirrhotic patients with severe sepsis. In fact, it is common in patients with decompensated cirrhosis and may predispose these patients to severe sepsis. The use of corticosteroids is recommended in noncirrhotic patients with septic shock that is refractory to intravenous fluids and vasopressors. Findings have been mixed in patients with cirrhosis, but similar practice is reasonable in this population.

As in all patients with sepsis, early antibiotic therapy is encouraged. Because of the aforementioned increases in multidrug-resistant bacteria causing infection in this population, initial broad-spectrum coverage is encouraged until cultures allow more tailored therapy. In addition to standard cultures (eg, blood, urine), it is especially important to obtain peritoneal fluid (if ascites is present) in cirrhotic patients with sepsis, as this is a common source.