Sepsis during pregnancy

Evans R. Fernndez-Prez, MD; Salam Salman, MD; Shanthan Pendem, MBBS; J. Christopher Farmer, MD

Objectives: To provide a current review of the literature regarding the assessment and management of sepsis during pregnancy. Design: A comprehensive review of current English-language literature search was performed with Ovid MEDLINE using the Medical Subject Headings pregnancy and sepsis, with Medical Subject Headings or keywords seeking randomized controlled trials and clinical reports, and by reviewing the bibliographies of clinical practice guidelines. Results: Sepsis-related maternal morbidity and mortality is a signicant and persistent problem in the modern critical care obstetric unit. The management of sepsis during pregnancy is challenging. The obstetric intensivist must simultaneously discern the effect of maternal physiologic changes on fetal vulner-

ability and the effect of the fetus on maternal status throughout the various phases of pregnancy. Little direct evidence exists to validate the extrapolation of some sepsis treatment modalities from other nonpregnant patient populations. Nevertheless, early detection, accurate diagnosis, and aggressive appropriate treatment strategies may signicantly improve outcome. Approaches like the Surviving Sepsis Campaign guidelines are unproven but seem reasonable and practical. Conclusions: Sepsis during pregnancy is uncommon yet potentially fatal. Diagnostic and therapeutic guidelines should predominantly pattern those currently utilized for nonpregnant patients. (Crit Care Med 2005; 33[Suppl.]:S286 S293) KEY WORDS: sepsis; systemic inammatory response syndrome; pregnancy; resuscitation

Epidemiology
Incidence and Prevalence. Sepsis is a common cause of mortality and morbidity worldwide. In the United Sates, sepsis is the leading cause of death in the intensive care unit (ICU) and costs approximately $17 billion annually (1, 2). More than 750,000 cases of sepsis are estimated to occur every year, and in the year 2010, it is estimated that there will be 934,000 new sepsis cases (2, 3). The number sepsis cases is expected to rise as a consequence of the aging population, a growing number of immunocompromised patients, increased rate of exposure to invasive procedures and prosthetic materials, the growing problem of antibioticresistant organisms, and increased awareness leading to earlier diagnosis of the condition (4 6). In contrast, maternal sepsis remains an infrequent complication. Martin et al. (7) reported a decline in the number of cases of sepsis during pregnancy from 0.6% to 0.3% between 1979 and 2000, tallying data from a nationally represenFrom the Multidisciplinary Critical Care Medicine Fellowship Program (ERFP, SS) and the Departments of Medicine and Critical Care Medicine (JCF), Mayo Foundation, Rochester, MN. Copyright 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000182479.63108.CD

tative sample of all nonfederal acute care hospitals in the United States. In the United Sates, the estimated prevalence of bacteremia in obstetric patients is 7.5 per 1,000 admissions, and the rate of sepsis in this population is approximately 8 10% (8 12). Blanco et al. (8) reported a rate of bacteremia of 9.7% in 1,950 patients on the obstetric services. Similarly, Ledger et al. (9) reported a rate of bacteremia of 9.9% among 139 obstetric patients. However, most bacteremic obstetric patients do not develop sepsis (8 12). Mabie et al. (13) reported the rate of septic shock to be 1 in 7,654 to 1 in 8,338 deliveries. Similarly, Kankuri et al. (14) observed that 1 of 43,483 mothers developed septic shock during the peripartum period. In fact, the highest reported rate in the literature of septic shock during pregnancy is 12% (in patients with bacteremia) (15). Blanco et al. (8) did not identify any cases of septic shock in obstetric patients with bacteremia, and Ledger et al. (9) only reported a 4% rate of septic shock in pregnant patients. Bryan et al. (12) observed that 68% of documented cases of bacteremia on the obstetrics and gynecologic services were in pregnant patients, and 8.7% were ultimately diagnosed as septic shock. Recently, Afessa et al. (16) retrospectively evaluated the rate of systemic inammatory response syndrome (SIRS), organ

failure, and outcome of critically ill obstetric patients in the ICU. They found that 44 of 74 ICU obstetric patients (59%) developed SIRS, 18 patients had severe sepsis (24%), and only two had septic shock (3%). Mortality. Major racial, ethnic, and socioeconomic disparities exist in sepsisrelated maternal morbidity and mortality around the world. A systematic literature review of 14 severe maternal morbidity studies from different countries showed that despite differences between developing and developed countries, denitions, methods, and classications used, the reported case/fatality ratio of sepsis in the obstetric population is as high as 72% (17). Indeed, sepsis is one of the ve leading causes of pregnancy-related death around the world. The maternal mortality ratio is 1,000 per 100,000 live births (as estimated by World Health Organization, the United Nations Childrens Fund, and the United Nations Population Fund), mainly concentrated in African countries, and is 20 per 100,000 live births in European countries (18). Death from septic shock seems to be uncommon in pregnant patients in the United States. Considering all causes of pregnancy-related death from 1991 to 1999, infection accounted for 12% per 2,519 live births and up to 34% among those who had had a spontaneous or inCrit Care Med 2005 Vol. 33, No. 10 (Suppl.)

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Table 1. Diagnostic criteria for sepsis Infection,a documented or suspected, and some of the followingb General variables Fever (core temperature of 38.3C) Hypothermia (core temperature of 36C) Heart rate of 90 beats/min or 2 SD above the normal value for age Tachypnea Altered mental status Signicant edema or positive uid balance ( 20 mL/kg over 24 hrs) Hyperglycemia (plasma glucose of 120 mg/dL or 7.7 mmol/L) in the absence of diabetes Inammatory variables Leukocytosis (WBC count of 12,000 L 1) Leukopenia (WBC count 4000 L 1) Normal WBC count with 10% immature forms Plasma C-reactive protein of 2 SD above the normal value Plasma procalcitonin of 2 SD above the normal value Hemodynamic variables Arterial hypotensionb (SBP of 90 mm Hg, MAP of 70, or an SBP decrease of 40 mm Hg in adults or 2 SD below normal for age) SvO2 of 70%b Cardiac index of 3.5 L min 1 M 23 Organ dysfunction variables Arterial hypoxemia (PaO2/FIO2 of 300) Acute oliguria (urine output of 0.5 mL kg 1 hr 1 or 45 mmol/L for at least 2 hrs) Creatinine increase of 0.5 mg/dL Coagulation abnormalities (INR of 1.5 or aPTT of 60 secs) Ileus (absent bowel sounds) Thrombocytopenia (platelet count of 100,000 L 1) Hyperbilirubinemia (plasma total bilirubin of 4 mg/dL or 70 mmol/L) Tissue perfusion variables Hyperlactatemia ( 1 mmol/L) Decreased capillary rell or mottling WBC, white blood cell; SBP, systolic blood pressure; MAP, mean arterial blood pressure; SvO2, mixed venous oxygen saturation; INR, international normalized ratio; aPTT, activated partial thromboplastin time. a Infection dened as a pathologic process induced by a microorganism.

duced abortion. However, the foremost shortcoming of these data is that sepsis is neither dened nor identied within the infections category as a cause of mortality (19). Nevertheless, available data suggest that the reported maternal mortality rate in the literature from septic shock ranges from 0% to 3% (9, 20, 21) and as high as 20% to 50% in two reports (22, 23). Most recently, Graves et al. (24) observed that for 24 patients with septic shock admitted to the ICU between 1992 and 2002, the mortality rate was 12.5%. Prognosis of recovery from septic shock in the gravid patient seems favorable, and the risk of death is much lower when compared with that of a nonobstetric population (approximately 30 60%) (2, 7, 25, 26). This has been attributed to a lack of associated underlying co-morbid conditions, younger age group, and a focused site of potential infection such as the pelvis (that may be more amenable to medical and surgical intervention) (25 27). However, mortality from sepsis during pregnancy may be underestimated. Therefore, available information should
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be interpreted cautiously due to the lack of national data on this issue and methodologic differences between studies. In particular, the categorization of sepsis predating the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee denition proposal in 1991 (28) and afterward may have altered recognition and reporting of sepsis. In pregnancy, available studies are limited and are predominantly retrospective so that accurately dening prevalence and mortality is difcult. Denitions. In 1992, the ACCP/SCCM published a consensus report to establish standardized denitions for SIRS, sepsis, severe sepsis, and septic shock in an attempt to provide a practical framework for identifying these disorders (28): 1. Infection is a microbial phenomenon characterized by an inammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms; 2. Bacteremia is the presence of viable bacteria in the blood, may be transient and of no clinical signicance, and presence alone is not suf-

cient to diagnose sepsis; 3. SIRS is a widespread inammatory response to a variety of severe clinical insults. This syndrome is clinically recognized by the presence of two or more of the following: temperature of 38C or 36C, heart rate of 90 beats/min, respiratory rate of 20 breaths/min or PaCO2 of 32 mm Hg, and white blood cell count of 12,000 cells/mm3, 4000 cells/mm3, or with 10% immature (band) forms; 4. Sepsis is the systemic response to infection; 5. Severe sepsis is sepsis with an associated organ failure; 6. Septic shock is sepsis with hypotension refractory to uid resuscitation. The clinical manifestations of sepsis are variable, and the syndrome may only be strongly suspected without microbiological conrmation (29, 30). In an effort to codify the physical and laboratory ndings that prompt an experienced clinician to conclude that an infected patient looks septic, in 2004 a consensus panel published a list of signs and symptoms and ndings indicative of early organ dysfunction in sepsis to aid in the diagnosis of sepsis (Table 1) (29). Finally, multiple organ system dysfunction syndrome refers to the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. Thus, multiple organ system dysfunction syndrome represents the more severe end of the spectrum of severity of illness along the sepsis continuum (29 35). Different prognostic scoring systems have been developed to assess the degree of physiologic derangement and severity of multiple organ system dysfunction syndrome (36 39). However, data from severity scoring systems should be cautiously interpreted in pregnant patients admitted to the ICU. These systems were not statistically validated in this patient population. We nd that the use of models such as the Acute Physiology and Chronic Health Evaluation (APACHE) system in this population reveals conicting results (16). In some published series of critically ill obstetric patients admitted to the ICU, the APACHE II system overestimated actual mortality, whereas other studies found either no difference or lower predicted mortality (16, 40 43). These systems were developed more than a decade ago, based on data from mixed ICU populations (44 46). It is unlikely that they included sufcient obstetric patients for accurate prediction (16). In addition, variable ICU admission criteria and cateS287

Table 2. Infections associated with septic shock and physiological predisposition during pregnancy Infections Pyelonephritis Physiological Adaptations Reduction in renal concentrating ability Smooth muscle relaxation and subsequent ureteral dilatation Bladder accidity increased intravesical and decreased intraureteral pressure leading to vesicoureteral reux Decrease pH and increased glycogen in the vaginal epithelium Elevation of the diaphragm by the gravid uterus Delayed gastric emptying

Chorioamnionitis and septic abortion Pneumonia

gorization of disease severity within the spectrum of SIRS and septic shock across the different studies may have also been confounding. Finally, known physiologic changes that occur during pregnancy, like higher respiratory rate, heart rate, lower hematocrit, and slightly elevated leukocyte count, may all have contributed to falsely elevated mortality predictions (43).

Microbiology and Maternal Risk Factors

Although Gram-negative bacteria are commonly identied in patients with sepsis, Gram-positive sepsis has become the predominant offender among patients over the last decade in the United States (7). In contrast, several reports describing septic obstetric patients conclude that the principal etiologic agents are endotoxin-producing aerobic Gram-negative rods, followed by Gram-positive bacteria, and mixed or fungal infections (26, 47, 48). In the study by Ledger et al. (9), Gram-negative bacteremia was observed in 3.1 of 1,000 obstetric admissions. The most frequently recovered organisms were Escherichia coli, Enterococci, and beta hemolytic streptococci, and the most commonly isolated anaerobes were Peptostreptococci, Peptococci, and Bacteroides (9). This is consistent with other studies showing Gram-negatives as the most frequent isolated microorganism in an obstetric population with sepsis (12, 13, 25, 47). Common antepartum conditions and physiologic adaptations increasing the risk of infection and the development of sepsis are listed in Table 2.

ditions (especially during pregnancy), nutritional status, age, and polymorphism in immune effector molecules and their receptors (2, 5, 49 53). The inammatory process is tightly regulated and functions to locally conne the spread of the infection. If the ability to regulate this response is lost, systemic activation of immune effector cells and a large number of mediators such as proinammatory cytokines results in a widespread systemic hyperinammatory response (54 57). Invading microorganisms and their toxins lead to the induction of transcriptional factors (58 63). Cell wall components of Gram-positive bacteria (e.g., peptidoglycan, lipoteichoic acid, lipopolysaccharide) or components of the outer cell membrane of Gram-negative bacteria bind to carrier proteins and interact with CD14 receptors on the surface of monocytes (64 67). A multiple-step amplication of the inammatory response ensues and, in septic patients, leads to activation of several transcriptional complexes that ultimately invoke the transcription of proinammatory genes.

Abnormalities of Coagulation Homeostasis and Organ Dysfunction

Proinammatory cytokines have multiple direct toxic effects on tissues, including the promotion of endothelial cell leukocyte adhesion, the release of proteases, and disruption of the clotting cascade and the brinolytic system (34, 68, 69). In fact, tumor necrosis factor- has direct effects on the endothelial surface, inducing release of tissue factor, the rst step in the extrinsic pathway of coagulation, and its expression on the surfaces of the endothelium and monocytes (68, 70). Tumor necrosis factor- also downregulates thrombomodulin endothelial

Pathophysiology
The severity of sepsis is determined by the strength of the host inammatory response in all organ systems, virulence of the organism, coexisting clinical conS288

expression, resulting in decreased protein C activity (68). Tissue factor leads to the production of thrombin, which is a proinammatory substance itself. Thrombin, together with thrombomodulin, subsequently activates protein C. Activated protein C and its cofactor protein S inhibit factor Va and VIIIa, thereby providing a negative feedback mechanism for the coagulation cascade. However, along with interleukin-1, tumor necrosis factor- increases the production of plasminogen activator inhibitor-1, a potent inhibitor of brinolysis (71, 72). Ultimately, the net effect of these processes is of a procoagulant state that results in systemic activation of the clotting system and widespread formation of brin clots in the microvasculature. All of this leads to widespread cytopathic injury associated with impairment of tissue oxygen diffusion and extraction and sepsis-induced mitochondrial dysfunction (73, 74). These cellular and subcellular effects can culminate in end-organ dysfunction and potential maternal death or pregnancy failure. The latter is explained by alterations in the gravida immune response. The maternal immune system must tolerate fetal alloantigens at the maternalfetal interface to prevent the mother from rejecting the fetus. Disruption of this interface through systemic inammatory mediators during severe sepsis and multiple organ system dysfunction syndrome can lead to local inammation and therefore induce pregnancy loss (26, 75). However, some animal studies demonstrate that the fetus is more resistant to the direct effects of endotoxin than the mother, possibly due to the undeveloped fetal immune system and inability to mount a vigorous inammatory response (76, 77). Finally, the failure of anti-inammatory agents in several trials to improve outcome (survival) has challenged the concept of sepsis as simply a proinammatory event. Altered homeostasis between hyperinammatory and hypoinammatory activity can also trigger a systemic anti-inammatory response that attempts to compensate for the degree of systemic inammation in the patient (5, 78). This phenomenon is described as the compensatory anti-inammatory response syndrome and can result in signicant suppression of immune function, including a reduction in proinammatory cytokine secretion (79). The immune suppression associated with compensaCrit Care Med 2005 Vol. 33, No. 10 (Suppl.)

tory anti-inammatory response syndrome further complicates sepsis by prohibiting recovery from the initial insult, allowing infection to become established, and leaving patients susceptible to lifethreatening infections (5, 54).

Sepsis and Physiologic Derangements During Pregnancy

Cardiovascular Complications. Sepsis can resemble the normal cardiovascular physiologic changes that occur during pregnancy as manifested by the initial onset of peripheral vasodilatation, increase in heart rate, and augmented cardiac output (80 83). However, concomitant low systemic vascular resistance or decreased myocardial function during sepsis can have severe hemodynamic repercussions along the continuum of the sepsis and septic shock spectrum. The normally observed decrease in blood pressure during pregnancy results from reduced systemic vascular resistance. This is thought to be caused by dilation of peripheral blood vessels and is a consequence of mediators like prostacyclin, nitric oxide, and gestational hormones (84, 85). Unfortunately, this mediator-induced, low-resistance uteroplacental circulation can be exaggerated in the setting of regional dysregulation of blood ow and intravascular volume pooling (i.e., splanchnic). This is due to loss of vasomotor tone. Because of the activation of enzymes such as nitric oxide synthase (leading to excess production of nitric oxide) and mediators such as the complement and bradykinin (proinammatory cytokine release during sepsis), we observe this loss of vasomotor tone (34, 86). Furthermore, maternal cardiovascular function during sepsis may become vulnerable because arterial pressure during pregnancy is already predominantly maintained by increased cardiac output. Finally, sepsisinduced myocardial contractile dysfunction can rapidly lead to hemodynamic collapse in pregnancy. This complex process is characterized by ventricular dilation, decreased biventricular ejection fractions, increased end-diastolic and end-systolic volumes of both ventricles, sepsis-induced decrease in cardiac preload, and the leakage of plasma into the extravascular space (34). This may be exacerbated in pregnant patients who have preexisting cardiac disease, such as peripartum cardiomyopathy (87).
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Early in the course of the disease, the patient can present therefore with hypotension, mental confusion, tachycardia, and ushed skin. However, as the septic shock progresses, the patient develops cool and clammy skin, bradycardia, and cyanosis. As septic shock progresses, signs of hypoperfusion such as cold and clammy skin and limbs, oliguria, and peripheral cyanosis develop (88). Reduced oxygen delivery and tissue extraction results in anaerobic metabolism, lactate accumulation, decreased uterine perfusion and fetal oxygenation, fetal acidosis, and end-organ failure (26, 77). Sepsis-Induced Acute Lung Injury. Enhanced pulmonary microvascular pressure and permeability and the release of inammatory mediators may promote accumulation of extravascular lung water during sepsis (89 91). This can be aggravated because pregnancy decreases plasma colloid-osmotic pressure and may facilitate the development of pulmonary edema and decreased lung compliance (92). Ultimately, increased venous admixture and hypoxemia (further complicated by sepsis-induced hypoxic pulmonary vasoconstriction) leads to respiratory failure and acute respiratory distress syndrome. Once acute respiratory distress syndrome develops in the pregnant patient, mortality ranges between 30% and 60% (9395). In addition to sepsis, common infectious causes associated with acute respiratory distress syndrome during pregnancy are chorioamnionitis, pneumonia, and aspiration (96, 97). Sepsis-Induced Renal Failure. Acute renal failure is seen in 20% patients with severe sepsis when blood cultures are positive and carries a high mortality. In pregnant patients with sepsis, acute tubular necrosis occurs/develops because of hypoperfusion-induced ischemia reperfusion injury, vasoconstriction caused by increased renal sympathetic and angiotensin activity, and cytokinemediated renal cell injury (98). Clotting Dysfunction. Thrombocytopenia and consumption coagulopathy are often associated with severe sepsis. However, there are multiple alterations in the coagulation system during pregnancy leading to a hypercoagulable state. Levels of clotting factors are elevated, including factors I, II, VII, VIII, IX, and XII. Whereas plasminogen activator inhibitor I and II increase 5-fold, antithrombin III and protein C levels are not signicantly affected by pregnancy (99 102). These changes during pregnancy may favor the ensuing

formation of intravascular brin during severe sepsis and possibly contribute to the pathogenesis of disseminated intravascular coagulation and multiple organ system dysfunction syndrome. Hepatic and Gastrointestinal Complications. Pregnancy-induced changes in bile composition predispose these patients to cholelithiasis. Similarly, during sepsis, uncontrolled production of inammatory cytokines by the Kupffer cells (primed by ischemia and stimulated by endotoxin) leads to cholestasis, hyperbilirubinemia, and jaundice. The gastrointestinal mucosa is usually protected from injury by autoregulation. However, during sepsis: 1) gastrointestinal mucosal permeability increases, 2) hypoperfusion leads to mucosal injury, 3) mucosal atrophy and bacteria translocation develop, and 4) bacterial endotoxins cause cytokine release and amplication of sepsis (103105).

Management
Because fetal compromise results mainly from maternal decompensation during sepsis, priorities of treatment should be directed rst toward maternal well-being, especially early in the course of resuscitation. In the following paragraphs, we will focus on the clinical practice guidelines, based largely on the Surviving Sepsis Campaign guidelines that outline important management strategies for patients with severe sepsis and septic shock (29). For the level of evidence see Table 3. Initial Resuscitation. Early recognition of sepsis is paramount because initial aggressive resuscitation (to restore and maintain tissue perfusion) within the rst 6 hrs signicantly improves survival, as demonstrated in a randomized, controlled, single-center study (grade B) (106). According to this study, early goaldirected therapy consists of uid resuscitation (crystalloid or colloid) to achieve a central venous pressure of 8 12 mm Hg. Vasoactive agents were added (to achieve a mean arterial pressure of 6570 mm Hg) when uid resuscitation alone did not adequately restore perfusion pressure. During the rst 6 hrs of resuscitation, if a central venous oxygen saturation of 70% was not achieved (despite maximization of the lling pressures), then transfusion of packed red blood cells was undertaken to achieve a hematocrit of 30% or inotropic agents were administered to achieve this goal (grade E). It is
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Table 3. 2004 Surviving Sepsis Campaign guidelines rating scheme for the strength of the evidence Grading of Evidence A. Large, randomized trials with clear-cut results; low risk of false-positive (alpha) error or falsenegative (beta) error B. Small, randomized trials with uncertain results; moderate-to-high risk of false-positive (alpha) and/or false-negative (beta) error C. Nonrandomized, contemporaneous controls D. Nonrandomized, historical controls and expert opinion E. Case series, uncontrolled studies, and expert opinion

undened whether or not this approach is applicable to pregnant patients with shock and sepsis. However, frequent clinical assessment of organ perfusion, correction of metabolic and physiologic abnormalities (crystalloid, blood product, and vasoactive drug administration), and early fetal monitoring (which can reect derangements of the mothers condition) are essential (35, 54). Source Control and Antibiotics. Despite the lack of randomized, controlled trials in this area, identication of the source and control of infection (including the drainage of an abscess, debridement of necrotic tissue, or removal of infected devices) and early antibiotic administration are crucial in the treatment of sepsis. The general consensus is to initiate empirical broad-spectrum antibiotic therapy within 1 hr of identication of sepsis (grade E). In one study, approximately 40% of septic pregnant patients required delivery of an infected fetus or placenta (22). However, delivery is usually not indicated if pregnancy is not the source of the infection. The antimicrobial regimen should consider the prevalence and susceptibility patterns within the hospital and must be reassessed and adjusted according to culture results and antibiotic sensitivity patterns (grade D). During pregnancy, empirical antibiotic selection should address the safety of it to the infant, especially during the rst trimester, when major organogenesis takes place. The safety of beta-lactams and aminoglycosides in pregnancy is well accepted, whereas category D antibiotics (unsafe to the fetus) such as tetracycline and chloramphenicol should be avoided in pregnant women. Corticosteroids. Relative adrenal insufciency during sepsis has been a popular topic during the last 3 yrs. One multiple-center, randomized, controlled trial of cortisol replacement improved 28-day survival by 10%, when compared with the placebo group (107). This was accomplished with hydrocortisone, 50 mg, adS290

ministered intravenously every 6 hrs and udrocortisone, 0.1 mg, administered enterally daily in patients with refractory shock. In these trials, relative adrenal insufciency was diagnosed when the plasma cortisol increased 9 g/dl 30 and 60 mins after adrenocorticotropic hormone administration (stimulation test). However, the use of corticosteroids in pregnancy may lead to undesired effects in the mother. These potentially include increased risk of infection, a higher prevalence of endometritis and chorioamnionitis in patients with premature rupture of membranes, poor glucose control, and delayed wound healing. Therefore, avoidance of high-dose corticosteroids (hydrocortisone of 300 mg/day) is recommended (grade A). Anticoagulants. Recent clinical trials have evaluated the use of three anticoagulants for treating sepsis. Two of these, antithrombin III and tissue factor pathway inhibitor, were not found effective (108, 109). In contrast, a large, doubleblind, placebo-controlled, multiplecenter trial evaluated the used of recombinant activated protein C (drotrecogin alpha [activated]) (110). Treatment resulted in an absolute mortality reduction of 6.1% as compared with placebo. The effectiveness of recombinant activated protein C also correlated with the number of failed organ systems, as treatment was most effective for patients with the greatest degree of organ failure. The use of recombinant activated protein C during pregnancy has not been studied, except for a few anecdotal reports of its efcacy and safety. Treatment should be considered in patients with severe sepsis and APACHE II scores of 24 or in patients with two or more sepsis-related organ failures (grade B) if there are no contraindications that mostly relate to the anticoagulant properties of the medication. Mechanical Ventilation. Acute respiratory distress syndrome is a common complication in patients with severe sep-

sis. Mechanical ventilation with a lungprotective strategy (moderate-to-high levels of positive end-expiratory pressure and low tidal volume of approximately 6 mL/kg ideal body weight) ensured adequate gas exchange, decreased the local and systemic release of inammatory mediators, and was shown to reduce mortality in a randomized, controlled trial that enrolled 861 patients with acute lung injury and acute respiratory distress syndrome (grade B) (111). Mechanically ventilated patients should be maintained in a semirecumbent position by elevating the head of the bead to 45 degrees to prevent ventilator-associated pneumonia, unless contraindicated (112). In addition, use of spontaneous weaning trials (grade A), sedation protocols that employ intermittent bolus dosing as opposed to a continuous infusion, and daily interruption to produce awakening (grade B) reduce the duration of mechanical ventilation, as demonstrated in one randomized study (113). Other Treatment Modalities. Deep venous thrombosis prophylaxis with lowmolecular weight heparin or low-dose unfractionated heparin and the use of a mechanical intermittent compression device or compression stockings (grade A), when heparin is contraindicated, is recommended. Stress-ulcer prophylaxis with an H-2 blocker or a proton pump inhibitor (grade A) is also recommended. In addition, tight glycemic control, especially to ranges of 80 110 mg/dL, resulted in reduced mortality in a large, randomized, controlled trial (level D) (114). Again, none of these trials have been conrmed in critically ill pregnant patients, but their ndings should be applicable unless specic fetal circumstances dictate otherwise.

Conclusion
Sepsis is an infrequent yet important cause of death in the gravida. Early recognition of sepsis may prevent maternal and fetal complications. Implementation of evidence-based treatment strategies can reduce the overall risk of death in pregnant patients with severe sepsis.

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