Author	Affiliation
Rachel E. Bridwell, MD	Brooke Army Medical Center, Department of Emergency Medicine, Fort Sam Houston, Texas
Brandon M. Carius, MPAS, PA-C	Brooke Army Medical Center, Department of Emergency Medicine, Fort Sam Houston, Texas
Brit Long, MD	Brooke Army Medical Center, Department of Emergency Medicine, Fort Sam Houston, Texas
Joshua J. Oliver, MD	Brooke Army Medical Center, Department of Emergency Medicine, Fort Sam Houston, Texas
Gillian Schmitz, MD	Brooke Army Medical Center, Department of Emergency Medicine, Fort Sam Houston, Texas

Introduction
Methods
Discussion
Conclusion

INTRODUCTION

In the United States, sepsis is the fourth leading cause of maternal death.^1-3 Mortality in pregnant patients rose consistently at an average of 9% per year from 2001 to 2010 despite sepsis guidelines updates.^1,4,5 As sepsis occurs in only 0.001% of pregnancies and in 0.002–0.01% of postpartum patients, data and consensus are limited regarding diagnostic and therapeutic interventions.⁴ Additionally, pregnancy is an exclusion criterion in all major sepsis trials to date, relinquishing clinical decisions to provider preference and expert opinion.^6-8

METHODS

In the following narrative review, we sought to comprehensively review the recent literature regarding sepsis in pregnancy. While pregnancy has been an exclusion criterion in every major sepsis trial as well as disease-specific trials, we identified all major observational trials, retrospective cohort studies for clinical rule derivation, and their subsequent validation studies.^6-8 We also searched PubMed and Google Scholar from 1966 to October 2018 for English-language articles using a combination of keywords and medical subject headings “pregnancy” and “sepsis” for production of this narrative review, including case reports and series, retrospective and prospective studies, systematic reviews and meta-analyses, narrative reviews, and clinical guidelines. Three authors decided which studies to include for the review by consensus, with 122 resources selected for inclusion, focusing on ED evaluation and management. This review also highlights areas where more research is needed and underscores the protean nature of this complex physiology. As this is a narrative review and not a systematic review and/or meta-analysis, we did not grade the included resources or pool data.

DISCUSSION

The Pregnant Body: Shifting Homeostasis

The altered physiology of pregnancy can affect the immunologic response and clinical presentation of sepsis. Clinicians must be vigilant of the potentially competing priorities of mother and fetus, as physiologic changes brought on by sepsis in pregnancy in the mother can generate untoward effects on the fetus. It is essential to understand physiologic changes of normal pregnancy to appropriately approach sepsis in pregnancy. These changes occur secondary to altered hormonal levels that continue from conception to post-delivery, as well as anatomic transformations with fetal growth and uterine enlargement.⁹

Normal changes in pregnancy include a relative anemia due to expanding plasma volume that outpaces red blood cell growth.¹⁰ A baseline respiratory alkalosis develops from a rise in respiratory tidal volume with increased minute ventilation.¹¹ Specific gastrointestinal differences likewise affect both normal baseline and disease resuscitation. The gravid uterus increases intragastric pressures, and high levels of progesterone and relaxin decrease lower esophageal sphincter tone.^12,13 A normal delay in gastric emptying and elevation of the diaphragm up to four centimeters (cm) increase aspiration risk, elevating the risk of aspiration pneumonia and complicating intubating conditions.¹⁴

Throughout pregnancy the cardiovascular system undergoes a multitude of changes contributing to the physiology of mother and fetus. Systemic vasodilation begins early in the first trimester, decreasing systemic vascular resistance (SVR) by up to 35–40%, maintaining cardiac output due to a compensatory increase in heart rate.¹⁵ Late in the third trimester, heart rate peaks at rates up to 24% higher than the prepartum baseline.^15,16 This translates to heart rate increases up to 30 beats per minute.^17-19 Multiple gestations can further increase maternal heart rates.²⁰ These compensatory cardiovascular changes generally return to baseline within two weeks of delivery, although a small proportion of patients maintain their pregnant cardiovascular measures at 12 weeks postpartum.^9,21 Blood pressure may fall by 10–15 millimeters of mercury (mm Hg) in a normal pregnancy and nadir around 24 weeks gestation.^18,21,22 Expanding plasma volume and red blood cell mass further work to offset lowered SVR and to maintain normotension from as early as six weeks into pregnancy until 34 weeks gestation.¹⁹

Pregnancy alone can increase white blood cell (WBC) counts to double pregestational levels.²³ WBC counts may reach levels as high as 25,000 cubic millimeters (mm³) in a normal pregnancy.^24-27 The physiologic stress of the peripartum period can push this leukocytosis further as high as 25,000/mm³ immediately postpartum.²⁴ WBC counts may rise even higher in pre-eclampsia, complicating laboratory data interpretation.^28,29 A clinical suspicion for pre-eclampsia taken with immunologic changes may cloud an infectious differential.³⁰ Further normal physiologic changes in pregnancy are highlighted in Table 1.

Other pre-existing comorbidities may complicate physiologic alterations of pregnancy. Long-term medication use in pregnancy has increased commensurately with rates of obesity, non-insulin dependent diabetes mellitus, and hypertension.^31,32 Prescription medication use during pregnancy has increased as much as 60% over the last 30–40 years.³³ In the setting of infection, medications targeting blood pressure and glucose control can obscure physiologic responses. Non- or poorly-compliant pregnant patients further complicate this already-cloudy picture.

The Evolution of Sepsis: Issues with Diagnosis and Guidance

The definition of sepsis continues to evolve. Previously, suspected infection source in conjunction with systemic inflammatory response syndrome (SIRS) criteria was key to identification³⁴ Although these studies excluded pregnant patients, SIRS criteria nevertheless remained the primary standardized assessment tool for sepsis recognition.³⁴ Before the second update to the sepsis guidelines in 2012, guidelines did not accurately identify maternal sepsis, identifying less than two-thirds of obstetric patients in retrospective reviews, highlighting the need to delineate pregnancy-specific guidelines.^3,35

Working in parallel to the Surviving Sepsis Campaign, other parties presented criteria aimed at identifying maternal sepsis. The World Health Organization (WHO) modified the definition of maternal sepsis to “puerperal sepsis.”³⁶ This narrow definition limited pregnant or postpartum sepsis to genitourinary tract infections between the time of rupture of membranes and six-weeks postpartum.^37,38 The WHO provided a definition for septic abortion, which likewise remained isolated to genitourinary tract infections.^36,38 As a result, many early maternal sepsis studies focused solely on the diagnosis and treatment of only these infections.^39-45

Diagnoses were most recently supplemented in the Third International Consensus Definitions for sepsis and septic shock in 2016 by the Sepsis-related Organ Failure Assessment (SOFA) and the quick Sepsis-related Organ Failure Assessment (qSOFA) using SIRS criteria as fundamental principles.^46,47 Similar to preceding trials, pregnancy was an exclusion criterion in these studies that established and validated the SOFA and qSOFA scores, thereby minimizing their utility in the pregnant population.^46,47 As of this review, no studies have externally validating SOFA or qSOFA scores in pregnant patients, despite the fact that the components of these scores have been validated in various combinations in pregnant populations.³⁷

The creation of two scores, the modified early warning scoring systems (MOEWS) and the sepsis in obstetrics (SOS) score, attempted to stratify pregnant patients with concern for sepsis; however, attempts to validate these scores have generated varying utility.^35,48 MOEWS has a number of international variants (Table 2), limiting its application across regions and settings. MOEWS is generally hindered by its outcome “to help detect the early signs of illness and trigger timely medical review with appropriate intervention,” rather than specifically to target sepsis identification.⁴⁹ The lone major MOEWS validation study analyzed 913 cases of chorioamnionitis, but only five cases met the definition of severe sepsis.⁴⁸ Intended to predict severe sepsis by 2.0 guidelines, MOEWS restricts its utility not only by using a recently redefined term, but also by generating a myopic view of sepsis in pregnancy by focusing on chorioamnionitis and not the broader scope of sepsis sources.⁴⁹

In 2014 the SOS sought to establish an obstetric-focused scoring system, incorporating the previously highlighted physiological changes in the cardiovascular, respiratory, and immune systems in pregnancy (Table 3).⁵⁰ Based on the surviving sepsis campaign, the SIRS criteria overestimated morbidity and mortality in an obstetric cohort without accounting for normal physiologic changes.^51-55 With this tailored scoring system, the authors sought to identify pregnant patients at high risk for sepsis with a primary outcome of intensive care unit (ICU) admission within 48 hours of admission. However, ICU admission criteria were not standardized.

Most recently, a single, prospective, internal validation trial of the SOS attempted to evaluate its performance with the same primary outcome.⁵⁶ An SOS score of less than six points had a 64% sensitivity and 98.6% negative predictive value for excluding sepsis, although a score of six points or greater had a sensitivity of only 64% to diagnosis sepsis.⁵⁶ Furthermore, of the 1250 pregnant patients presenting to the ED over a three-year study period, only 1.1% were admitted to the ICU, although ICU admission criteria remain unknown.⁵⁶ While this lone, prospective validation study demonstrates a significant negative predictive value, additional validation studies and a larger sample population are needed to determine its utility in populations with different prevalence of septic pregnant patients.

Despite the need for obstetric-focused scoring systems in sepsis, emergency providers lack substantially validated criteria or schema to bolster decision-making and hospital admission when confronted with a sick pregnant or postpartum patient.

Treatment Considerations Specific to Pregnancy

Pneumonia

Pneumonia is responsible for 30% of infections in pregnant patients with severe sepsis, carrying significant morbidity for both mother and fetus.⁵ In one study, up to one-fifth of pregnant patients experienced a delay in pneumonia diagnosis, while half experienced significant morbidities such as empyema and respiratory failure.⁵⁷ Initial diagnosis is often made by chest radiograph. Appropriate shielding of the abdomen exposes the fetus to less than 0.01 milliGray (mGy), well below the threshold of adverse effects.⁵⁸ The lung may be upwardly displaced by the growing uterus, and the increased density of parenchyma can make definitive diagnosis difficult.⁵⁹ Ultrasound (US) has a 94–97% sensitivity and 94–96% specificity for pneumonia diagnosis in a recent meta-analysis.^59,60 Although chest computed tomography (CT) is rarely required, it can be safely performed if needed for diagnosis.⁴⁶

The most common microbial causes of pneumonia in pregnancy include S. pneumoniae and H. influenzae.⁶¹ Antibiotic coverage should treat these pathogens. However, other sources to consider include Legionella spp., Varicella zoster, and Pneumocystis jirovecii in patients with human immunodeficiency virus (HIV).¹³ While fluoroquinolones should be avoided, penicillins, cephalosporins, and macrolides are all considered safe to use in pregnancy.⁶² For pregnant patients admitted to the ICU, both S. pneumoniae and Legionella spp. should be covered.⁶² A pneumococcal beta lactam, such as cefotaxime or, if not peripartum, ceftriaxone, and a macrolide should be administered.^13,62 Vancomycin and linezolid do not currently have established safety in pregnancy, but should be considered in cases where methicillin-resistant Staphylococcus aureus is suspected.

In a small case series, 59% of pregnant patients with pneumocystis pneumonia required mechanical ventilation due to respiratory failure.⁶³ The authors found a 50% mortality rate for the mothers and 41% mortality for combined fetus and neonates.⁶³ These patients should be treated similarly to their non-pregnant counterparts with trimethoprim-sulfamethoxazole and corticosteroids if the A-a gradient is greater than 35 or the partial pressure of oxygen (PaO₂) is less than 70 mm Hg.⁶⁴ The mother should also be monitored for immune reconstitution inflammatory syndrome.⁶⁴ If treatment is active at the time of delivery, the neonate should be monitored for hyperbilirubinemia.⁶⁴

The course of pneumonia in pregnant patients can be further complicated by decreased secretion clearance and worsening airway obstruction.^13,61 Secondary to pregnancy physiology and treatments routinely administered in the course of delivery, aspiration during labor represents another significant source of infection.¹⁴ Epidural blocks may blunt or inhibit the cough reflex, further increasing the risk of aspiration pneumonitis and pneumonia.⁶⁵

Pregnancy was an exclusion criteria in the PROTECT (prophylaxis for thromboembolism in critical care) trial, which examined risk factors for mortality secondary to pneumonia in patients admitted to the ICU.⁶⁶ ICU admission threshold should be lower for pregnant individuals, as they have decreased tolerance for hypoxemia and may quickly deteriorate with pneumonia.¹³ Blood gas interpretation in pregnant patients should take into account the expected physiologic alkalemia, which may blunt initial laboratory findings of hypercapneic respiratory failure.¹⁴ Anatomical compression of the inferior vena cava in late pregnancy can reduce cardiac preload causing hypotension, exacerbated by the addition of positive pressure from mechanical ventilation.^11,24 This may necessitate placing the patient in the left lateral decubitus position.⁶⁷ Prevention of maternal hypoxemia is critical, as this quickly leads to fetal decompensation. Thus, maintaining a PaO₂ greater than 70 mm Hg can prevent deleterious effects on the fetus.^68,69 Although extrapolated from asthma data and therefore controversial, partial pressure of carbon dioxide should be maintained between 28–32 mm Hg to prevent fetal acidemia and maternal hypercapnia.⁶⁹

Pyelonephritis

Pyelonephritis in pregnancy is a complicated infection requiring intravenous (IV) antibiotics and admission for continued monitoring of mother and fetus.^70,71 Pyelonephritis occurs in approximately 2% of pregnancies in the U.S. but accounts for the largest proportion of maternal inpatient admissions.⁷¹ Up to 20% of cases occur in the second and third trimester.^70-72 Numerous factors predispose pregnant women to pyelonephritis: dilation of the renal calyces secondary to progesterone; stagnation of ureteral peristalsis; mechanical compression of the bladder; and increased glomerular filtration rate, resulting in glucosuria and alkaluria facilitating bacterial growth.⁷³

Acute pyelonephritis in pregnancy can significantly increase the risk of maternal anemia, acute renal failure, respiratory distress, and preterm birth.⁴ Additionally, patients with maternal pyelonephritis demonstrate a 33% increased risk of chorioamnionitis, further predisposing them to sepsis.⁷⁴ More than 80% of acute pyelonephritis cases in pregnancy are from E coli, but other uropathogens include Klebsiella, Streptococcal spp., Proteus mirabilis, and Enterococcus.^74,75 Although pregnant patients are specifically excluded from Infectious Diseases Society of America (IDSA) guidelines, ceftriaxone, cefepime, or ampicillin plus gentamicin are feasible treatment options.^74,75 In patients less than 24 weeks gestation, intramuscular ceftriaxone has demonstrated equal efficacy in length of hospitalization and days until resolution of infection compared to IV ampicillin and gentamicin or cefazolin.⁷⁶ Ceftriaxone should be avoided in the periparturition period, however, due to the risk of neonatal kernicterus.⁶⁷ Urine culture and local resistance patterns should guide empiric therapy.⁷³

Carbapenems or piperacillin-tazobactam could be considered for broader coverage in immunocompromised patients or those with severe pyelonephritis impairing urinary drainage; however, imipenem should be avoided due to adverse fetal effects demonstrated in vivo.^70,73 E. coli and other gram-negative rods cause the vast majority of pyelonephritis in pregnancy, carrying the potential for large-scale endothelial cell damage in capillary beds from endotoxin release.^73-75 This endothelial damage commonly affects renal and pulmonary tissue, resulting in acute respiratory distress syndrome in 1–8% of cases, further complicating the maternal patient.⁷³ Unlike the non-pregnant population, a test of cure is required in maternal patients following clinical resolution.⁶⁷

Appendicitis

Appendicitis occurs less frequently in pregnancy (approximately 1 in 1500) and peaks in the second trimester compared to the non-pregnant population.^77-79 However, 1 in 1000 pregnancies undergo surgical evaluation for possible appendicitis, with increased rates of surgical intervention due to increased perforation risk as well as mortality.^77,78 Maternal mortality secondary to appendicitis is 4%, and complications of perforated appendicitis result in an estimated 43% fetal mortality rate.^80,81

Physiologic changes of pregnancy and atypical presentation make maternal diagnosis particularly challenging. The fundus rises and displaces the appendix from the right lower quadrant (RLQ).⁸¹ Fundal displacement of the omentum prevents it from sealing off an inflamed appendix.⁸² RLQ pain and tenderness are the presenting symptoms in 75% of maternal appendicitis, while another 20% of cases present with right upper quadrant pain.⁸³ However, up to 45% of these cases present with rectal tenderness, which is not commonly associated with or examined with suspected appendicitis.⁸³ Nausea and vomiting, common in pregnancy, can further complicate the clinical picture. Therefore clinicians should note any significant changes to the patient’s “normal” course of “morning sickness” during the history. Maternal leukocytosis is not reliable for diagnosing appendicitis or perforation due to normal physiologic changes. However, the presence of bilirubinemia greater than 1.0 milligrams per deciliter (mg/dL) has demonstrated sensitivity of 70% and specificity of 86% in evaluating for perforation in appendicitis, which may aid clinical judgment.⁸⁴

While ultrasound (US) is safe in pregnancy, wide variation in appendiceal location makes evaluation difficult. Sensitivity and specificity of US for the diagnosis of maternal appendicitis ranges from 67–100% and 83–95%, respectively.⁸⁵ The lower range is significantly less compared to non-pregnant populations in ED-performed bedside US, where sensitivity and specificity approximate 49.5–86.2% and 91.4–99.7%, respectively.⁸⁶ In cases where US is equivocal, magnetic resonance imaging (MRI) is recommended, sparing ionizing radiation to both mother and fetus.⁸⁷ A meta-analysis of MRI in the diagnosis of maternal appendicitis demonstrated a sensitivity of 96.8% and a specificity of 99.2%.⁸⁸

MRIs are routinely run without gadolinium, which poses no hypothetical risk to the fetus.⁸⁷ Early antibiotic coverage should be initiated with a second-generation cephalosporin and clindamycin or metronidazole.⁸⁹ Prompt surgical consultation should be obtained, as the risk of perforation rises with delaying surgical involvement for more than 24 hours.^89,90 Additionally, the risk of fetal loss increases with perforation of the appendix, with a 36% rate of fetal loss, compared to 1.5% without appendiceal rupture, underscoring the importance of early surgical consult in conjunction with antibiotics.⁹¹

Pelvic Inflammatory Disease

Although rare, maternal sepsis from pelvic inflammatory disease (PID) is associated with high-mortality for mother and fetus, as well as increased risk of preterm delivery.⁹² PID in pregnancy presents typically in the first trimester with fever and abdominal pain, adnexal tenderness, and cervical motion tenderness. Bacteria can ascend prior to the mucus plug sealing off the decidua around 12 weeks.⁹³ PID may rapidly progress to tubo-ovarian abscess (TOA), with a mortality up to 9%.⁹⁴ TOA presents similarly to an infected ectopic pregnancy with fever and adnexal tenderness. The presentation of fever, leukocytosis, and diarrhea should prompt consideration of TOA, independently predicted by elevated C-reactive protein.⁹⁵ Pregnancy with PID requires hospitalization for treatment.⁹² Doxycycline, the mainstay treatment for PID per IDSA guidelines, has been repeatedly proven to have severe teratogenicity and therefore should not be used.⁹² Azithromycin should be substituted, in conjunction with an IV second-generation cephalosporin such as cefotetan or cefoxitin.⁹² Penicillin cross-reactivity with second-generation cephalosporins is negligible, providing effective treatment in pencillin-allergic patients.^96,97 This regimen also covers Mycoplasma genitalium, which accounts for up to 8.7% of non-chlamydial and non-gonococcal PID cases.⁹⁸

Endometritis

Endometritis presents with postpartum fever, tachycardia, and foul lochia or malodorous vaginal discharge and occurs with ascension of bacteria during labor that colonizes amniotic fluid and decidua.⁶⁷ Cases are generally polymicrobial, with two-thirds containing both anaerobic (Bacteroides, Clostridium, and Peptostreptococcus spp.) and aerobic bacteria (Group B Streptococcus, E. coli, and enterococcus).⁹⁹ The presence of a hematoma is concerning for S. pyogenes and S. aureus and toxic shock syndrome.⁷⁷ IV gentamicin and clindamycin are efficacious, although this regimen does not cover enterococcus.¹⁰⁰ Doxycycline plus cefoxitin or ampicillin/sulbactam is an additional regimen. In those who do not respond within the first 48–72 hours, ampicillin is added to cover for these pathogens.¹⁰¹ In patients delivering via cesarean section (C-section) who develop endometritis, parametrial cellulitis with phlegmon formation in the broad ligament or, less-commonly, parametrial phlegmon can cause persistent fevers and require interventional radiology consult for drainage.¹⁰¹ Venous drainage post-C-section can also spread infection, generating septic pelvic thrombophlebitis.¹⁰²

Pelvic thrombophlebitis is usually refractory to broad-spectrum antibiotics alone and requires anticoagulation with broad polymicrobial coverage.^102-104 Liberal use of postpartum CT has significantly impacted management. In a retrospective cohort study of 238 postpartum patients, the use of CT resulted in alteration of antibiotic therapy in 10%, addition of low-molecular weight heparin (LMWH) in 12%, and surgical intervention in 17%.¹⁰⁵ This study demonstrated that the addition of CT significantly impacted the clinical course of approximately 40% of patients.¹⁰⁵ Table 4 summarizes these infections.

Approach to Resuscitation in Pregnancy

Optimal stabilization of the fetus depends on adequate resuscitation of the mother.⁷⁷ Initial resuscitation should include IV fluid administration and optimized positioning. The left lateral decubitus position maximizes patient hemodynamics in the third trimester, improving preload by decreasing inferior vena cava compression.⁷⁷ Fluid resuscitation should begin within the first three hours of presentation with an initial recommended volume of 30 milliters per kilogram of crystalloid if either hypotension or lactic acid >4 millimoles per liter (mmol/L) is present.¹⁰⁷ Due to increased blood volume in pregnancy, a lactic acid threshold of 4 mmol/L may lack sensitivity in this population. In a retrospective cohort of 159 septic pregnant patients, the mean lactic acid level of those admitted for ICU level care was 2.6 mmol/L, and those with positive blood cultures had a level of 2.2 mmol/L.¹⁰⁸ This study found increased morbidity with elevated lactic acid, with an adjusted odds ratio of 2.34 per 1 mmol/L increase in lactic acid.¹⁰⁸

No specific guidelines exist for vasopressors preference in pregnant patients. Although there is no explicit recommendation for mean arterial pressure optimization for sepsis in pregnancy, 65 mm Hg is a reasonable resuscitation goal.¹⁰⁷ Fetal monitoring can provide further titration feedback.¹⁰⁹ The 2016 Society of Critical Care Medicine guidelines do not offer recommendations tailored for the pregnant patient, although their current data support the use of norepinephrine as the first-line vasopressor in pregnant septic patients.^77,107,110 Due to the paucity of data, there is scant evidence to suggest that administration of norepinephrine causes negative fetal outcomes, or to suggest how norepinephrine administration impacts fetal outcome.¹¹¹

The choice for second-line vasopressor has been extrapolated from controlled studies with spinal anesthetics and is therefore controversial for application in sepsis.^112-116 Phenylephrine and ephedrine are often used as second-line agents, although with known tachyphylaxis.^1107,114,116 Unlike ephedrine, phenylephrine does not alter the fetal acid-base status, although its alpha stimulation generates reflex maternal bradycardia and diminished cardiac output.^114,115 In comparison, ephedrine does not generate bradycardia, although its indirect action to release pre-existing maternal catecholamines may prove less efficacious in a septic patient who has already exhausted her endogenous stores and expended her cardiac reserve.^113-115

The data on vasopressor use in pregnancy are typically derived from C-section deliveries, many of which are elective.^65,113,114 In the Task Force on Obstetric Anesthesia, the American Society of Anesthesiologists recommended phenylephrine over ephedrine because of the preferred fetal acid-base status, as ephedrine causes fetal acidemia.¹¹² While this choice was supported by an international consensus of counterpart agencies, these data are extrapolated from a different physiologic context.¹¹⁷

In the rare setting of septic myocarditis, dobutamine is the preferred inotrope.¹¹³ Despite its very limited use in the non-pregnant septic population, dobutamine presents a viable option to improve inotropy in pregnant patients already on vasopressors and fluids.^112,118 Based on previous ovine models, dobutamine provides inotropy in pregnant sheep, although it decreases uterine blood flow; it requires further study in humans.¹¹⁹

Other treatment considerations in maternal sepsis include glucose control, steroids, and venous thromboembolism (VTE) prophylaxis. Maternal hyperglycemia can directly cause fetal hyperglycemia and ultimately acidosis, decreasing uterine blood flow and lowering fetal oxygenation.¹⁰⁹ Maternal blood glucose should be maintained less than 180 grams per deciliter.¹⁰⁹ Steroids are recommended by the American College of Obstetrics and Gynecology in women between 24 weeks and 33 weeks and six days who are at risk of a preterm delivery within seven days, which is inclusive of those with rupture of membranes.¹²⁰ Hydrocortisone should be considered in those patients who do not improve with IV fluids and vasopressors.^107,110 Pregnancy alone confers a five-fold increased risk of deep vein thrombosis as compared to the non-pregnant population.¹²² In individuals in septic shock on VTE prophylaxis, there was a 37% incidence in VTEs despite these prophylactic interventions. As septic pregnant patients are at high risk of VTE, patients without contraindications should receive both intermittent compression devices and either daily LMWH or 2–3 times daily administration of unfractionated heparin.^109,122 Direct oral anticoagulants are not currently recommended.¹⁰⁹

CONCLUSION

The anatomic and physiologic changes of pregnancy pose a challenge in early recognition and management of sepsis. Current sepsis guidelines were extrapolated from randomized control trials that specifically excluded pregnant patients. Although new guidelines have been created to risk stratify pregnant patients, they are without significant validation. Further research and validation are needed to help properly recognize and treat this small but critically ill population to improve outcomes for both mother and fetus.

Footnotes

Section Editor: Gabriel Wardi, MD

Full text available through open access at http://escholarship.org/uc/uciem_westjem

Address for Correspondence: Brit Long, MD, Brooke Army Medical Center, Department of Emergency Medicine, 3551 Roger Brooke Dr, Fort Sam Houston, TX 78234. Email: brit.long@yahoo.com. 9 / 2019; 20:822 – 832

Submission history: Revision received April 9, 2019; Submitted May 23, 2019; Accepted June 16, 2019

Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare. The views expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, the Department of Defense, or the U.S. government.

REFERENCES

1. Albright CM, Mehta ND, Rouse DJ, Hughes BL. Sepsis in pregnancy. J Perinat Neonatal Nurs. 2016;30(2):95-105.

2. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance–United States, 1991–1999. MMWR Surveill Summ. 2003;52(2):1-8.

3. van Dillen J, Zwart J, Schutte J, van Roosmalen J. Maternal sepsis: epidemiology, etiology and outcome. Curr Opin Infect Dis. 2010;23(3):249-54.

4. Cordioli RL, Cordioli E, Negrini R, Silva E. Sepsis and pregnancy: Do we know how to treat this situation?. Rev Bras Ter Intensiva. 2013;25(4):334-44.

5. Bauer ME, Bateman BT, Bauer ST, Shanks AM, Mhyre JM. Maternal sepsis mortality and morbidity during hospitalization for delivery. Anesth Analg. 2013;117(4):944-50.

6. Mouncey PR, Osborn TM, Power GS, et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015;19(97):1-150.

7. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-506.

8. Investigators TP. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-93.

9. Duvekot JJ, Peeters LL. Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv. 1994;49(12 Suppl):S1-14.

10. Bernstein IM, Ziegler W, Badger GJ. Plasma volume expansion in early pregnancy. Obstet Gynecol. 2001;97(5 Pt 1):669-72.

11. LoMauro A, Aliverti A. Respiratory physiology of pregnancy: physiology masterclass. Breathe (Sheffield, England). 2015;11(4):297-301.

12. Baggish MSHS. Aspiration as a cause of maternal death. Obstet Gynecol. 1974;43:327-36.

13. Brito V, Niederman MS. Pneumonia complicating pregnancy. Clin Chest Med. 2011;32(1):121-32.

14. Mehta N. Respiratory disease in pregnancy. Reprod Immunol Open Acc. 2016;1:14.

15. Meah VL, Cockcroft JR, Backx K, Shave R, Stöhr EJ. Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses. Heart. 2016;102(7):518-26.

16. Schewitz LJ. Obstetrics: Normal and Problem Pregnancies. JAMA. 1998;279(11):886-7.

17. Robson SC, Hunter S, Boys RJ, Dunlop W. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol Circ Physiol. 1989;256(4):H1060-H1065.

18. Clapp JF, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol. 1997;80(11):1469-73.

19. Mahendru AA, Everett TR, Wilkinson IB, Lees CC, McEniery CM. A longitudinal study of maternal cardiovascular function from preconception to the postpartum period. J Hypertens. 2014;32(4):849-56.

20. Kametas NA, McAuliffe F, Krampl E, Chambers J, Nicolaides KH. Maternal cardiac function in twin pregnancy. Obstet Gynecol. 2003;102(4):806-15.

21. Capeless EL, Clapp JF. When do cardiovascular parameters return to their preconception values?. Am J Obstet Gynecol. 1991;165(4 Pt 1):883-6.

22. James PR, Nelson-Piercy C. Management of hypertension before, during, and after pregnancy. Heart. 2004;90(12):1499-504.

23. Pitkin RM, Witte DL. Platelet and leukocyte counts in pregnancy. JAMA. 1979;242(24):2696-8.

24. Chandra S, Tripathi AK, Mishra S, Amzarul M, Vaish AK. Physiological changes in hematological parameters during pregnancy. Indian J Hematol Blood Transfus. 2012;28(3):144-6.

25. Gatti L, Tenconi PM, Guarneri D, et al. Hemostatic parameters and platelet activation by flow-cytometry in normal pregnancy: a longitudinal study. Int J Clin Lab Res. 1994;24(4):217-9.

26. Rukavina D, GT . Immunobiology and immunopathology of early pregnancy. Early Pregnancy. 1997;3:141-5.

27. Cintesun E, Incesu Cintesun F, Ezveci H, Akyurek F, Celik C. Systemic inflammatory response markers in preeclampsia. J Lab Physicians. 2018;10(3):316.

28. Canzoneri B, Lewis D, Groome L, Wang Y. Increased neutrophil numbers account for leukocytosis in women with preeclampsia. Am J Perinatol. 2009;26(10):729-32.

29. Yücel B, Ustun B. Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume, red cell distribution width and plateletcrit in preeclampsia. Pregnancy Hypertens An Int J Women’s Cardiovasc Heal. 2017;7:29-32.

30. Albright CM, Mehta ND, Rouse DJ, et al. Immunobiology and immunopathology of early pregnancy. Early Pregnancy. 1997;30(3):141-5.

31. Montan S. Increased risk in the elderly parturient. Curr Opin Obstet Gynecol. 2007;19(2):110-2.

32. Lynch CP, Baker N, Korte JE, Mauldin JG, Mayorga ME, Hunt KJ. Increasing prevalence of diabetes during pregnancy in South Carolina. J Womens Health (Larchmt). 2015;24(4):316-23.

33. Mitchell AA, Gilboa SM, Werler MM, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol. 2011;205(1):51.e1-e8.

34. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-74. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1597042. Accessed December 19, 2018.

35. Lappen JR, Keene M, Lore M, Grobman WA, Gossett DR. Existing models fail to predict sepsis in an obstetric population with intrauterine infection. Am J Obstet Gynecol. 2010;203(6):573.e1-573.e5.

36. Organization WH. Managing puerperal infections. Geneva. 2008. Available at: http://www.who.int/maternal_child_adolescent/documents/4_9241546662/en/. Accessed August 9, 2018.

37. Bonet M, Nogueira Pileggi V, Rijken MJ, et al. Towards a consensus definition of maternal sepsis: results of a systematic review and expert consultation. Reprod Health. 2017;14(1):67.

38. Organization WH. Managing complications in pregnancy and childbirth: a guide for midwives and doctors. 2007. Available at: http://www.who.int/maternal_child_adolescent/documents/9241545879/en/. Accessed August 20, 2008.

39. Timezguid N, Das V, Hamdi A, et al. Maternal sepsis during pregnancy or the postpartum period requiring intensive care admission. Int J Obstet Anesth. 2012;21:51-5.

40. Shamil E, Shennan A, Lucas S. The contribution of genital tract sepsis to maternal deaths in London. Arch Dis Child – Fetal Neonatal Ed. 2010;95(Supplement 1):Fa37-Fa38.

41. McClure JH, Cooper GM, Clutton-Brock TH. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–8: a review. Br J Anaesth. 2011;107(2):127-32.

42. Warren S, Tristram S, Bradbury RS. Maternal and neonatal sepsis caused by Haemophilus influenzae type d. J Med Microbiol. 2010;59(3):370-2.

43. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics. 2009;123(5):1314-9.

44. Pineda C, Kaushik A, Kest H, Wickes B, Zauk A. Maternal sepsis, chorioamnionitis, and congenital Candida kefyr infection in premature twins. Pediatr Infect Dis J. 2012;31(3):320-2.

45. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol. 2009;200(4):372.e1-e6.

46. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707-10.

47. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis. JAMA. 2016;315(8):762.

48. Edwards SE, Grobman WA, Lappen JR, et al. Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis. Am J Obstet Gynecol. 2015;212(4):536.e1-8.

49. Maguire PJ, Turner MJ. Modified obstetric early warning systems. Am J Obstet Gynecol. 2015;213(5):748.

50. Albright CM, Ali TN, Lopes V, Rouse DJ, Anderson BL. The Sepsis in Obstetrics Score: a model to identify risk of morbidity from sepsis in pregnancy. Am J Obstet Gynecol. 2014;211(1):39.e1-e8.

51. Stevens TA, Carroll MA, Promecene PA, Seibel M, Monga M. Utility of Acute Physiology, Age, and Chronic Health Evaluation (APACHE III) score in maternal admissions to the intensive care unit. Am J Obstet Gynecol. 2006;194:13-5.

52. Lapinsky SE, Hallett Msc D, Collop N, et al. Evaluation of standard and modified severity of illness scores in the obstetric patient. J Crit Care. 2011;26:535.e1-535.e7.

53. Vasquez DN, Estenssoro E, Canales HS, et al. Clinical characteristics and outcomes of obstetric patients requiring ICU admission. Chest. 2007;131(3):718-24.

54. Afessa B, Green B, Delke I, Koch K. Systemic Inflammatory Response Syndrome, Organ Failure, and Outcome in Critically Ill Obstetric Patients Treated in an ICU*. 2001;120.

55. Hazelgrove JF, Price C, Pappachan VJ, Smith GB. Multicenter study of obstetric admissions to 14 intensive care units in southern England. Crit Care Med. 2001;29(4):770-5.

56. Albright CM, Has P, Rouse DJ, Hughes BL. Internal validation of the sepsis in obstetrics score to identify risk of morbidity from sepsis in pregnancy. Obstet Gynecol. 2017;130(4):747-55.

57. Madinger NE, Greenspoon JSEA. Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome?. Am J Obstet Gynecol. 1989;161:657-62.

58. Groen RS, Bae JY, Lim KJ. Fear of the unknown: ionizing radiation exposure during pregnancy. Am J Obstet Gynecol. 2012;206(6):456-62.

59. Chavez MA, Shams N, Ellington LE, et al. Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis. Respir Res. 2014;15(1):50.

60. Hu Q-J, Shen Y-C, Jia L-Q, et al. Diagnostic performance of lung ultrasound in the diagnosis of pneumonia: a bivariate meta-analysis. Int J Clin Exp Med. 2014;7(1):115-21.

61. Khan S, Niederman MS. Pneumonia in the Pregnant Patient. Pulmonary Problems in Pregnancy. 2009:177-96.

62. Mandell LA, Wunderink RG, Anzueto A, et al. IDSA/ATS Guidelines for CAP in Adults · CID 2007: 44(Suppl 2) · S27 Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. :9.

63. Ahmad H, Mehta NJ, Manikal VM, et al. Pneumocystis carinii pneumonia in pregnancy. Chest. 2001;120(2):666-71.

64. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed December 4, 2018.

65. Gayat E, Lecarpentier ERS. Cough reflex sensitivity after elective caesarean section under spinal anaesthesia and after vaginal delivery. Br J Anaesth. 2007;99:694-8.

66. Li G, Cook DJ, Thabane L, et al. Risk factors for mortality in patients admitted to intensive care units with pneumonia. Respir Res. 2016;17(1):80.

67. Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline D. Tintinalli’s Emergency Medicine :A Comprehensive Study Guide.

68. Powrie R, Greene M, Camann W. De Swiet’s Medical Disorders in Obstetric Practice. :2010. Available at: https://www.wiley.com/en-us/+Swiet%27s+Medical+Disorders+in+Obstetric+Practice%2C+5th+Edition-p-9781444390339. Accessed December 15, 2018.

69. Chan AL, Juarez MM, Gidwani N, Albertson TE. Management of critical asthma syndrome during pregnancy. Clin Rev Allergy Immunol. 2015;48(1):45-53.

70. Bergeron MG. Treatment of pyelonephritis in adults. Med Clin North Am. 1995;79(3):619-49.

71. Gilstrap LC, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am. 2001;28(3):581-91.

72. Duff P. Pyelonephritis in Pregnancy. Clin Obstet Gynecol. 1984;27(1):17-31.

73. Jolley JA, Wing DA. Pyelonephritis in pregnancy. Drugs. 2010;70(13):1643-55.

74. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol. 2014;210(3):219.e1-219.e6.

75. SHARMA P, THAPA L. Acute pyelonephritis in pregnancy: a retrospective study. Aust New Zeal J Obstet Gynaecol. 2007;47(4):313-5.

76. Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Obstet Gynecol. 1998;92(2):249-53.

77. Morgan J, Roberts S. Maternal sepsis. Obstet Gynecol Clin North Am. 2013;40(1):69-87.

78. GILO NB, AMINI D, LANDY HJ. Appendicitis and cholecystitis in pregnancy. Clin Obstet Gynecol. 2009;52(4):586-96.

79. Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol. 1990;132(5):910-25.

80. Mazze RI, Källén B. Appendectomy during pregnancy: a Swedish registry study of 778 cases. Obstet Gynecol. 1991;77(6):835-40.

81. Hodjati H, Kazerooni T. Location of the appendix in the gravid patient: a re-evaluation of the established concept. Int J Gynaecol Obstet. 2003;81(3):245-7.

82. Sivanesaratnam V. The acute abdomen and the obstetrician. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14(1):89-102.

83. Mahmoodian S. Appendicitis complicating pregnancy. South Med J. 1992;85(1):19-24.

84. Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis. Am J Surg. 2009;198(2):193-8.

85. Williams R, Shaw J. Ultrasound scanning in the diagnosis of acute appendicitis in pregnancy. Emerg Med J. 2007;24(5):359-60.

86. Mallin M, Craven P, Ockerse P, et al. Diagnosis of appendicitis by bedside ultrasound in the ED. Am J Emerg Med. 2015;33(3):430-2.

87. Kanal E, Barkovich AJ, Bell C, et al. ACR Guidance Document for Safe MR Practices: 2007. Am J Roentgenol. 2007;188(6):1447-74.

88. Duke E, Kalb B, Arif-Tiwari H, et al. A systematic review and meta-analysis of diagnostic performance of MRI for evaluation of acute appendicitis. Am J Roentgenol. 2016;206(3):508-17.

89. Yilmaz HG, Akgun Y, Bac B, Celik Y. Acute appendicitis in pregnancy–risk factors associated with principal outcomes: a case control study. Int J Surg. 2007;5(3):192-7.

90. Bickell NA, Aufses AH, Rojas M, Bodian C. How time affects the risk of rupture in appendicitis. J Am Coll Surg. 2006;202(3):401-6.

91. Babaknia A, Parsa H, Woodruff JD. Appendicitis during pregnancy. Obstet Gynecol. 1977;50(1):40-4.

92. Pelvic inflammatory disease (PID) – 2015 STD Treatment Guidelines. Available at: https://www.cdc.gov/std/tg2015/pid.htm. Accessed December 15, 2018.

93. Zeger W, Holt K. Gynecologic infections. Emerg Med Clin North Am. 2003;21(3):631-48.

94. Piegzová A, Unzeitig V. Ces Gynekol. 2017;82(4):322-6.

95. Abdou R, Miller T. Postpartum tubo-ovarian abscess, likely arising from pelvic inflammatory disease during pregnancy. BMJ Case Rep. 2017;2017.

96. Park MA, Koch CA, Klemawesch P, Joshi A, Li JT. Increased adverse drug reactions to cephalosporins in penicillin allergy patients with positive penicillin skin test. Int Arch Allergy Immunol. 2010;153(3):268-73.

97. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. 2001;31(3):438-43.

98. Bjartling C, Osser S, Persson K. The association between Mycoplasma genitalium and pelvic inflammatory disease after termination of pregnancy. BJOG An Int J Obstet Gynaecol. 2010;117(3):361-4.

99. Gilstrap LC, Cunningham FG. The bacterial pathogenesis of infection following cesarean section. Obstet Gynecol. 1979;53(5):545-9.

100. French L, Smaill FM. Antibiotic regimens for endometritis after delivery. Cochrane Database of Systematic Reviews. 2004:CD001067.

101. Brown CE, Stettler RW, Twickler D, Cunningham FG. Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy. Am J Obstet Gynecol. 1999;181(1):143-8.

102. Nezhat C, Farhady P, Lemyre M. Septic pelvic thrombophlebitis following laparoscopic hysterectomy. JSLS J Soc Laparoendosc Surg. 2009;13(1):84-6.

103. da Silva Cunha M, Godinho AB, Botelho R, de Almeida JP. Postpartum septic pelvic thrombophlebitis after caesarean delivery: a case report. Case Rep Womens Health. 2018;17:5-7.

104. Fishel Bartal M, Sibai BM, Ben-Mayor Bashi T, et al. Abdominal computed tomography (CT) scan in the evaluation of refractory puerperal fever: impact on management. J Matern Neonatal Med. 2018:1-6.

105. Barton JR, Sibai BM. Severe sepsis and septic shock in pregnancy. Obstet Gynecol. 2012;120(3):689-706.

106. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol. 2014;210(3):219.e1-219.e6.

107. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign. Crit Care Med. 2017;45(3):486-552.

108. Albright C, Ali T, Lopes V, Rouse D, Anderson B. Lactic acid measurement to identify risk of morbidity from sepsis in pregnancy. Am J Perinatol. 2014;32(05):481-6.

109. Plante LA. Management of sepsis and septic shock for the obstetrician–gynecologist. Obstet Gynecol Clin North Am. 2016;43(4):659-78.

110. Neligan PJ, Laffey JG. Clinical review: Special populations – critical illness and pregnancy. Crit Care. 2011;15(4):227.

111. van Nimwegen D, Dyer DC. The action of vasopressors on isolated uterine arteries. Am J Obstet Gynecol. 1974;118(8):1099-103.

112. Practice Guidelines for Obstetric Anesthesia. Anesthesiology. 2016;124(2):270-300.

113. Ngan Kee WD, Khaw KS, Tan PE, Ng FF, Karmakar MK. Placental transfer and fetal metabolic effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology. 2009;111(3):506-12.

114. Nag DS, Samaddar DP, Chatterjee A, Kumar H, Dembla A. Vasopressors in obstetric anesthesia: a current perspective. World J Clin Cases. 2015;3(1):58-64.

115. Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg. 2010;111(5):1230-7.

116. Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2002;94(4):920-6.

117. Kinsella SM, Carvalho B, Dyer RA, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia. 2018;73(1):71-92.

118. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4):243-50.

119. Fishburne JI, Meis PJ, Urban RB, et al. Vascular and uterine responses to dobutamine and dopamine in the gravid ewe. Am J Obstet Gynecol. 1980;137(8):944-52.

120. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews. 2006.

121. Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6(4):632-7.

122. Kaplan D, Casper TC, Elliott CG, et al. VTE Incidence and risk factors in patients with severe sepsis and septic shock. Chest. 2015;148(5):1224-30.