Sepsis in pregnancy and the puerperium · Sepsis remains a leading cause of maternal morbidity and...

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REVIEW ARTICLE Sepsis in pregnancy and the puerperium C.E.G. Burlinson, a D. Sirounis, b,c K.R. Walley, b,d A. Chau a,c a Department of Anesthesia, British Columbia Women’s Hospital, Vancouver, BC, Canada b Division of Critical Care Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, BC, Canada c Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada d Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada ABSTRACT Sepsis remains a leading cause of maternal morbidity and mortality. Recognition and treatment of maternal sepsis are often delayed due to the physiological adaptations of pregnancy and vague or absent signs and symptoms during its initial presentation. Over the past decade, our understanding of sepsis has evolved and maternal early warning systems have been developed in an effort to help providers promptly identify and stratify parturients who are at risk. In addition, new consensus definitions and care bundles have recently been published by the World Health Organization and the Surviving Sepsis Campaign to facilitate earlier recognition and timely management of sepsis. In this narrative review, we summarize the available evidence about sepsis and pro- vide an overview of the research efforts focused on maternal sepsis to date. Controversies and challenges surrounding the anes- thetic management of parturients with sepsis or at risk of developing sepsis during pregnancy or the puerperium will be highlighted. Ó 2018 Elsevier Ltd. All rights reserved. Keywords: Pregnancy; Sepsis; Puerperium; Obstetric anesthesia; Maternal sepsis Introduction Sepsis during pregnancy and the puerperium remains a leading cause of maternal morbidity and mortality world- wide. 1 The frequent publications from the World Health Organization (WHO), the Surviving Sepsis Campaign (SSC) and the Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries collaboration (MBRRACE-UK) are highlighting the importance and persistence of this problem. The failure to recognize sepsis and institute prompt treatment underlies most cases of maternal sepsis with poor outcomes. 2 The physiological adaptations in pregnancy, combined with the high rates of trauma and surgical intervention that occur during the peripartum periods, put pregnant women at risk of developing infections that may go unrecognized until there is substantial clinical deterioriation. 3 The initial alteration of hemodynamics may be falsely attributed to labor pain or blood loss subsequent to delivery. 4,5 More- over, normal laboratory values in obstetric patients differ from non-obstetric patients, and much of what is estab- lished and used to define sepsis in the general population has not been fully validated in pregnancy. Efforts to implement early warning systems, revise the definition of sepsis, and develop maternal sepsis care bundles, stem from the knowledge that early recognition, diagnosis and management of maternal sepsis lead to better maternal and fetal outcomes. In this narrative review, we summa- rize the recent changes in sepsis definitions, provide an overview of maternal sepsis and review the current evi- dence on early warning systems. Furthermore, we discuss strategies, controversies and challenges surrounding the anesthetic management of parturients with sepsis, or at risk of developing sepsis, during pregnancy and the puerperium. Scope of the problem Globally, sepsis is the direct cause of over 260 000 mater- nal deaths a year; approximately 5% of maternal deaths in developed countries and 11% of maternal deaths in developing nations. 1 Approximately 1 in 1000 women giving birth will develop severe infection with a systemic inflammatory response; half of these will progress to sepsis with organ dysfunction and 3–4% to septic shock. 6 While the absolute risk of death from maternal sepsis is low in developed countries such as the United Accepted April 2018 Correspondence to: Anthony Chau, Department of Anesthesia, British Columbia Women’s Hospital, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada. E-mail address: [email protected] International Journal of Obstetric Anesthesia (2018) 36, 96–107 0959-289X/$ - see front matter Ó 2018 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.ijoa.2018.04.010 www.obstetanesthesia.com

Transcript of Sepsis in pregnancy and the puerperium · Sepsis remains a leading cause of maternal morbidity and...

Page 1: Sepsis in pregnancy and the puerperium · Sepsis remains a leading cause of maternal morbidity and mortality. Recognition and treatment of maternal sepsis are often delayed due to

International Journal of Obstetric Anesthesia (2018) 36, 96–1070959-289X/$ - see front matter � 2018 Elsevier Ltd. All rights reserved.

https://doi.org/10.1016/j.ijoa.2018.04.010

REVIEW ARTICLE

www.obstetanesthesia.com

Sepsis in pregnancy and the puerperium

C.E.G. Burlinson,a D. Sirounis,b,c K.R. Walley,b,d A. Chaua,caDepartment of Anesthesia, British Columbia Women’s Hospital, Vancouver, BC, CanadabDivision of Critical Care Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, BC, CanadacDepartment of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, CanadadCentre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada

ABSTRACT

Sepsis remains a leading cause of maternal morbidity and mortality. Recognition and treatment of maternal sepsis are oftendelayed due to the physiological adaptations of pregnancy and vague or absent signs and symptoms during its initial presentation.Over the past decade, our understanding of sepsis has evolved and maternal early warning systems have been developed in aneffort to help providers promptly identify and stratify parturients who are at risk. In addition, new consensus definitions and carebundles have recently been published by the World Health Organization and the Surviving Sepsis Campaign to facilitate earlierrecognition and timely management of sepsis. In this narrative review, we summarize the available evidence about sepsis and pro-vide an overview of the research efforts focused on maternal sepsis to date. Controversies and challenges surrounding the anes-thetic management of parturients with sepsis or at risk of developing sepsis during pregnancy or the puerperium will behighlighted.� 2018 Elsevier Ltd. All rights reserved.

Keywords: Pregnancy; Sepsis; Puerperium; Obstetric anesthesia; Maternal sepsis

Introduction

Sepsis during pregnancy and the puerperium remains aleading cause ofmaternal morbidity andmortality world-wide.1 The frequent publications from the World HealthOrganization (WHO), the Surviving Sepsis Campaign(SSC) and the Mothers and Babies: Reducing Riskthrough Audits and Confidential Enquiries collaboration(MBRRACE-UK) are highlighting the importance andpersistence of this problem. The failure to recognize sepsisand institute prompt treatment underlies most cases ofmaternal sepsis with poor outcomes.2 The physiologicaladaptations in pregnancy, combined with the high ratesof trauma and surgical intervention that occur duringthe peripartum periods, put pregnant women at risk ofdeveloping infections that may go unrecognized untilthere is substantial clinical deterioriation.3 The initialalteration of hemodynamics may be falsely attributed tolabor pain or blood loss subsequent to delivery.4,5 More-over, normal laboratory values in obstetric patients differfrom non-obstetric patients, and much of what is estab-

Accepted April 2018

Correspondence to: Anthony Chau, Department of Anesthesia, BritishColumbia Women’s Hospital, 4500 Oak Street, Vancouver, BC V6H3N1, Canada.E-mail address: [email protected]

lished and used to define sepsis in the general populationhas not been fully validated in pregnancy. Efforts toimplement early warning systems, revise the definitionof sepsis, and develop maternal sepsis care bundles, stemfrom the knowledge that early recognition, diagnosis andmanagement of maternal sepsis lead to better maternaland fetal outcomes. In this narrative review, we summa-rize the recent changes in sepsis definitions, provide anoverview of maternal sepsis and review the current evi-dence on early warning systems. Furthermore, we discussstrategies, controversies and challenges surrounding theanesthetic management of parturients with sepsis, or atrisk of developing sepsis, during pregnancy and thepuerperium.

Scope of the problem

Globally, sepsis is the direct cause of over 260000 mater-nal deaths a year; approximately 5% of maternal deathsin developed countries and 11% of maternal deaths indeveloping nations.1 Approximately 1 in 1000 womengiving birth will develop severe infection with a systemicinflammatory response; half of these will progress tosepsis with organ dysfunction and 3–4% to septicshock.6 While the absolute risk of death from maternalsepsis is low in developed countries such as the United

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C.E.G. Burlinson et al. 97

States (US) (0.1 per 100000)7 and United Kingdom(UK) (0.6 per 100000, based on the most recent reportby MBRRACE-UK covering 2013–2015; and havingfallen from 2.0 per 100000 in 2009–2012),8 the risk ofmorbidity from maternal sepsis remains high. For everyparturient who dies from sepsis, 50 women are estimatedto suffer severe maternal morbidity (SMM) from sepsis,which includes any unexpected outcomes of labor anddelivery that result in significant short- or long-termconsequences to a women’s health, as defined by theCenters for Disease Control and Prevention.9 Severe

Table 1 Previous and revised definitions of sepsis

PREVIOUS DEFINITIONS

Sepsis-1: 1991 American College of Chest Physicians/Society of C� Systemic inflammatory response syndrome (SIRS): a systemic inflammat(1) temperature >38 �C or <36 �C; (2) heart rate >90/min; (3) respiratory>12 000 or <4000/mm3, or >10% immature neutrophils

� Sepsis: SIRS associated with infection� Severe sepsis: Sepsis complicated by organ dysfunction, hypoperfusion,� Septic shock: Severe sepsis with persistent hypotension despite adequat

REVISED DEFINITION

Sepsis-3: 2016 Third International Consensus Definitions for Seps� Sepsis: a life-threatening organ dysfunction caused by a dysregulated husing the Sequential (Sepsis-related) Organ Failure Assessment (SOFA)total SOFA score �2 points, consequent to the infection. Baseline SOFApre-existing organ dysfunction

� Septic shock: Sepsis with persistent hypotension requiring vasopressorslactate level >2 mmol/L (18 mg/dL)

WORLD HEALTH ORGANIZATION MATERNAL SEPSIS C

� Maternal sepsis is a life-threatening condition defined as organ dysfunctition, or the postpartum period

Fig. 1 Evolution of sepsis definitions. SIRS: systemic inflammOrgan Failure Assessment. qSOFA: quick SOFA.

maternal morbidity may lead to fetal morbidity, includ-ing fetal infection, preterm delivery and fetal demise.10

Long-term complications such as chronic pelvic pain,pelvic adhesions and secondary infertility can alsoresult.11

Definitions

Evolution of sepsis definitionsThe original definitions of sepsis and its relateddisorders are now over 20 years-old and have undergone

ritical Care Medicine Consensus Conference Definitions119

ory response manifested by two or more of the following conditions:rate >20/min or PaCO2 <32 mmHg; and (4) white blood cell count

or hypotensione volume resuscitation or need for inotropic or vasopressor agents

is and Septic Shock13

ost response to infection. Severity of organ dysfunction is assessedscore.20 Organ dysfunction can be identified as an acute change inscore should be assumed to be zero unless patient is known to have

to maintain mean arterial pressure (MAP) �65 mmHg and a serum

ONSENSUS DEFINITION15

on resulting from infection during pregnancy, childbirth, post-abor-

atory response syndrome. SOFA: Sequential (Sepsis-related)

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several revisions by multinational societies (Table 1,Fig. 1). In 2001, the original definitions were retained,despite an admission that they lack specificity, andhopes were raised for future biomarkers to aid futurediagnosis.12 Recently, definitions and clinical criteriawere updated in the 2016 Third International ConsensusDefinitions for Sepsis and Septic Shock (Sepsis-3).13 Thenew definitions acknowledge that sepsis is not simply aninfection with two or more systemic inflammatoryresponse syndrome (SIRS) criteria, and that there arethree essential components to sepsis: infection, hostresponse to infection and organ dysfunction.14 Sincethe inclusion of organ dysfunction in the definition ofsepsis in Sepsis-3, the concept of ‘severe sepsis’ no longerexists. Thus, the Sepsis-3 ‘sepsis’ definition is equivalentto ‘severe sepsis’ used in previous publications, irrespec-tive of SIRS status. Epidemiological figures and studyoutcomes quoted are from publications prior to theadoption of this new terminology, although in thisreview we use Sepsis-3 terminology for consistency.The new WHO maternal sepsis consensus definition isdeveloped from Sepsis-3 and is based on a systematicreview of literature and expert consultations.15

Assessment of organ dysfunctionOrgan dysfunction or failure may manifest in differentways. In 4158 cases of maternal sepsis in the US, respi-ratory dysfunction was seen to be most common at 34%,followed by coagulopathy (19%), kidney injury (16%),cardiovascular dysfunction (12%), hepatic dysfunction(10%) and altered consciousness (8%).7 Sepsis in obstet-ric patients can become rapidly fatal, with a large studyfrom the Netherlands demonstrating that time from firstsymptom of infection to ‘full blown sepsis’ was less than

Table 2 Sequential (Sepsis-related) Organ Failure Assessm

SOFA 1 2

Respiration: PaO2/FiO2,mmHg (kPa)

<400 (53.3) <300

Coagulation:Platelets � 103/mL

<150 <10

Liver: bilirubin,mg/dL (mmol/L)

1.2–1.9 (20–32) 2.0–5.9 (3

Cardiovascular:Hypotension

MAP <70 mmHg dopam�5 mg/kor dobut(any d

Central nervous system:Glasgow Coma Scale Score

13–14 10–1

Renal: serum creatinine,mg/dL (mmol/L)or urine output

1.2–1.9 (110–170) 2.0–3.4 (1

PaO2: partial pressure of oxygen; FiO2: fraction of inspired oxygen; MAPaAdapted from Vincent et al.20

24 hours in 39% of patients, and time from infection todeath was less than 24 hours in 50% of patients.16 In theUK, a national study of maternal sepsis showed that in75% of women with a Group A Streptococcal infection,there was less than nine hours between the first signs ofsystemic infection to the diagnosis of sepsis with organdysfunction; and in 50% of women, this was less thantwo hours.17

The presence of organ dysfunction can effectively beidentified by a predictive scoring system called theSequential (or Sepsis-related) Organ Failure Assessment(SOFA) score (Table 2).

Organ failure-based scores appear to be superior toobstetric-specific scoring systems and APACHE IIscores.18,19 The SOFA score was originally developedto sequentially assess the severity of organ dysfunctionfrom sepsis.20 When measured serially, it can facilitatethe identification of septic patients in the Intensive CareUnit (ICU) who are at a higher risk of death, with sta-tistically greater predictive validity than SIRS criteria.21

For patients outside the ICU, a bedside assessmenttool called the quickSOFA (qSOFA) score predicts in-hospital mortality with statistically greater predictivevalidity than SOFA and SIRS.22,23 The qSOFA scoringsystem is quicker and simpler to use, without the need towait for laboratory results. This is an advantage giventhe increasing emphasis on the early recognition of sep-sis (Table 3). The qSOFA score ranges from 0 to 3points; the presence of 2 of 3 qSOFA points in adultpatients with suspected infection indicates a greater riskof death or prolonged ICU stay.22

The SOFA and qSOFA criteria may be used withoutmodification in the obstetric population. Among obstet-ric patients admitted to the ICU, the mean total SOFA

ent (SOFA) scorea

3 4

(40) <200 (26.7) withrespiratory support

<100 (13.3) withrespiratory support

0 <50 <20

3–101) 6.0–11.9 (102–204) >12.0 (204)

ineg/min,amineose)

dopamine >5 mg/kg/min,or epinephrine�0.1 mg/kg/minor norepinephrine�0.1 mg/kg/min

dopamine>15 mg/kg/min,or epinephrine>0.1 mg/kg/min,or norepinephrine>0.1 mg/kg/min

2 6–9 <6

71–299) 3.5–4.9 (300–440),or urine output<500 mL/day

>5.0 (440) or urineoutput <200 mL/day

: mean arterial pressure.

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Table 3 Quick sepsis-related organ failure assessment

score (qSOFA)a

Assessment qSOFA score

Tachypnea: (�22 breaths/min) 1Hypotension: (SBP �100 mmHg) 1Altered mentation: (GCS <15) 1

SBP: systolic blood pressure; GCS: Glasgow Coma Scale.aAdapted from Singer et al.22

C.E.G. Burlinson et al. 99

score has been shown to perform well as a predictor ofmortality, with a sensitivity of 87%, specificity of 90%and an area-under-the-curve of 0.95 when using a cut-off value of 9 for the total SOFA score at admission.24

An abnormal qSOFA score should prompt investigationof organ dysfunction and initiation or escalation of ther-apy as necessary. However, in a patient at high risk ofdeveloping sepsis, clinical suspicion alone shouldprompt escalation of care, as therapy for sepsis shouldnot be withheld even if qSOFA criteria are not met.Some of the SOFA and qSOFA criteria, such as a respi-ratory rate greater than 22, may overlap with normalphysiologic parameters in the context of different stagesof pregnancy, labor and delivery. Therefore, it is impor-tant to remember that these scoring systems may assist,but do not replace, clinical judgement.

Risk factors for maternal sepsis

Several risk factors for maternal sepsis have been identi-fied,2,6,25 leading to the widespread implementation ofguidelines for the prevention of sepsis in this vulnerablepatient population. It is now routine to screen and treatasymptomatic bacteriuria (present in 2–7% of pregnantwomen)26 and sexually transmitted diseases27 in earlypregnancy and to administer antibiotic prophylaxis forcesarean delivery.28 Importantly, women who are trea-ted with antibiotics in the perinatal period have beenfound to remain at risk of sepsis and septic shock, sug-gesting that a proportion of infections progress follow-ing antibiotic treatment.17 Sepsis is more common inparturients who are more than 35 years-old; and thosethat have co-morbid conditions such as diabetes mellitusand obesity, as well as those who have had invasive orsurgical procedures. With the increase in maternal age,success of assisted reproductive technologies andincreased rates of cesarean delivery, a large proportionof parturients will have at least one risk factor for mater-nal sepsis.

Diagnosis and recognition of maternal sepsis

Challenges in early recognition of maternal sepsisThe physiological changes of pregnancy overlap withhemodynamic changes associated with the initial presen-tation of sepsis. For example, tachycardia represents anormal physiological adaptation to pregnancy and

may also result from pain and increased maternal effortrequired during second stage labor. The expandedplasma volume in pregnancy and progesterone-inducedvasodilatation allow women to compensate for longerbefore rapid deterioration.29 Furthermore, elevation inwhite blood cell count is a normal finding during preg-nancy, making this parameter less distinctive in the fore-warning of an activated host immune response.Moreover, signs of systemic inflammation may be pre-sent in various stages of labor and delivery, as a resultof prostaglandin treatment for induction of labor ortreatment of postpartum hemorrhage. A high index ofsuspicion, with a detailed history and examination, aretherefore paramount for the early recognition of mater-nal sepsis. The 2014 report by MBRRACE-UK states‘think sepsis’ when presented with any unwell pregnant,or recently pregnant, patient.30

Maternal signs and symptoms will vary depending onthe source of sepsis, but particularly ominous signs aretachypnea, neutropenia, hypothermia and altered men-tal status.2 Presentation may be associated with earlypregnancy loss, intrauterine death, fetal tachycardia orfetal bradycardia. While fever is often the first vital signchange that raises the index of suspicion of maternalsepsis for clinicians, temperature alone is not a reliableindicator of sepsis. In the Michigan series of maternaldeaths, 73% of women who died of sepsis were afebrileat presentation and 25% did not develop a fever at allduring their hospitalization.31

Maternal early warning scoring systemsIn the last decade, multiple early warning scoring sys-tems have been developed to facilitate timely identifica-tion of septic patients at risk for poor outcomes.Unfortunately, many of these systems, such as the Mod-ified Early Warning System (MEWS), have not provento be as useful as hoped in the maternal population,because they do not take into account the physiologicalchanges of pregnancy, which overlap with clinical crite-ria for diagnosing sepsis in the general population.32

Attempts have been made to adapt existing scores forthe obstetric population – for example, the ‘Sepsisin Obstetrics Score’ has a higher positive predictivevalue for admission to the ICU (16.7%) than itsnon-obstetric comparators – the Rapid EmergencyMedicine Score (11.1%) and the MEWS (4.6%).33 Inthe US, the National Council for Patient Safety pro-posed the use of the maternal early warning criteria(MERC)34 and in the UK, the 2007 ConfidentialEnquiry into Maternal and Deaths report recommendedroutine use of the Modified Early Obstetric WarningSystem (MEOWS).2 While uptake of maternal earlywarning systems following the recommendation hasbeen high over the past 10 years,35 clear evidence of out-come benefit is lacking36 and validation studies haveshown high sensitivity but low specificity.37–39 Neither

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the MERC nor the MEOWS have been formally evalu-ated to determine if their use might lead to a reductionin maternal morbidity.

A recent large, prospective, multicenter impact studyby Shields et al.40 investigated whether maternal mor-bidity could be reduced with the implementation ofthe ‘Maternal Early Warning Trigger (MEWT)’ tool.Unlike the MERC and MEOWS, the MEWT tool wasdesigned to identify four of the major causes of maternalmorbidity resulting in ICU admission (i.e. sepsis, car-diopulmonary dysfunction, preeclampsia-hypertensionand hemorrhage), and includes prompts to help expeditepatient assessment, investigation, management and adifferential diagnosis (for example it reminds providersto consider the overlap in signs and symptoms betweensepsis and cardiopulmonary dysfunction). Using theCDC-defined SMM and composite maternal morbidity(at least one of CDC-defined SMM, namely hemorrhage>500 mL for vaginal delivery or 1000 mL for cesareandelivery without transfusion; need for dilation andcurettage; or ICU admission) as outcome measures,the authors found that using the MEWT tool led to asignificant reduction in CDC-defined SMM (�18.4%,P=0.01) and in composite maternal morbidity(�13.6%, P=0.01) when compared to pre-implementation of the MEWT tool. Despite thesepromising results, the positive predictive value for pre-dicting sepsis was only 7% and the authors acknowl-edged that the MEWT tool may not be generalizableto centers with a low rate of sepsis. This finding is con-sistent with others that have noted the poor ability ofscreening tools to predict maternal sepsis.32,36

Maternal early warning scores need further refine-ment to improve their ability to predict those with signsof early sepsis and at risk of deterioration. The develop-ment of obstetric scoring systems is, in part, hindered bythe lack of consensus regarding which vital signs shouldbe used and what values reflect normality in the obstet-ric population.41 It has even been suggested that thesevalues should change depending on the stage of

Table 4 Updated initial sepsis bundles from the Surviving S

To be completed within 3 hours of time of presentation:

1. Measure lactate level

2. Obtain blood cultures prior to administration of antibiotics

3. Administer broad spectrum antibiotics

4. Administer 30 mL/kg crystalloid over the first three hours for hypotenor lactate �4 mmol/L

To be completed within 6 hours of time of presentation:

5. Apply vasopressors (for hypotension that does not respond to initial flresuscitation) to maintain a mean arterial pressure �65 mmHg

6. In the event of persistent hypotension after initial administration (M<65 mmHg) or if initial lactate was �4 mmol/L, reassess volume stand tissue perfusion and document findings

7. Re-measure lactate if initial lactate elevated

aAdapted from survivingsepsis.org120 MAP: mean arterial pressure.

pregnancy in which they are being measured.42 ThePregnancy Physiology Pattern Prediction Study (4PStudy) aims to develop a database of physiology duringpregnancy and the postpartum period (NCT01509378).It will provide data to define pregnancy-specificthresholds at which an alert should be triggered andfrom which more robust evidence-based scores can bedeveloped.43

Management of maternal sepsis

Sepsis care bundlesShortly after the 2001 consensus conference, the SSCwas launched by the Society for Critical Care Medicine(SCCM), the European Society for Intensive Care Med-icine (ESICM), and the International Sepsis Forum(ISF), with a goal of reducing sepsis mortality by 25%in five years. They published management guidelines,together with condensed versions of these guidelines or‘care bundles’. Care bundles are groups of interventionsdesigned to guide the timing and implementation ofindividual elements of care to improve outcome. Thefirst care bundles for sepsis were published in 2003,44

drawing many recommendations from those describedby Rivers et al. in the landmark randomized controlledtrial (RCT) of Early-Goal Directed Therapy (EGDT) in2001.45 They have since been updated in 2008,46 2012,47

and most recently in 201648 (Table 4), to take intoaccount the publication of three large RCTs on EGDT,all of which demonstrated no mortality benefit after ini-tial volume resuscitation was complete and early antibi-otic treatment had been initiated.49–51 Survival in allthree of these trials was much better than the originalRivers study,45 suggesting that the management of septicshock has improved with early implementation ofprotocol-driven care, even if not strictly adherent tothe original EGDT protocol. The Royal College ofObstetricians and Gynaecologists (RCOG) recommendsthat sepsis should be managed in accordance with thecare bundles,52 because there is evidence to suggest that

epsis Campaigna

Strength of recommendation, grade of evidence

Weak, low qualityBest practice statementStrong, moderate quality

sion Strong, low quality

uid Strong, moderate quality

APatus

Best practice statement

Weak, low quality

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survival in sepsis is improved by following this guid-ance.53 The elements of the bundles are based on thecurrently available evidence and are designed to be com-pleted in a specific time period. For each element, thestrength of recommendation and grade of evidence areprovided, or it is described as a ‘best practice statement’.No modifications are suggested for the care of obstetricpatients. The UK Sepsis Trust has recently developed aspecific ‘sepsis toolkit’ for use in pregnancy and up to sixweeks postpartum.54 This decision support tool is basedon the 2016 National Institute for Health and CareExcellence (NICE) recommendations on maternal sep-sis, published after the preceding MBRRACE-UKreport.55

It must be remembered that almost all the evidenceused to develop management guidelines for sepsis arebased on RCTs in which pregnancy was an exclusioncriterion. To date, there are no large-scale studies ofsepsis management in the obstetric population, dueto ethical challenges in conducting randomizedresearch in septic parturients. The management of sep-sis in the obstetric population is therefore largelyextrapolated from that of the general population (seeAppendix A).

Antimicrobial therapyObservational studies have repeatedly demonstratedthat delay in initiation of antimicrobial therapy is asso-ciated with poor outcome in sepsis. In an international,multicenter study of over 17990 patients with sepsis orseptic shock, there was a linear increase in mortalityper hour of delay in administration of antibiotics uponrecognition of sepsis.56 Similar results were demon-strated in two recent retrospective studies involving35000 septic patients from 21 emergency departments57

and over 40000 septic patients reported to the NewYork State Department of Health.58 These data suggestthat antibiotics should be commenced as soon as possi-ble after collection of blood cultures and within the firsthour of diagnosis.

The genitourinary tract is colonized with a largevariety of organisms. Not all of these cause infectionand sepsis but pregnant women who develop sepsisare likely to be infected by more than one organism.59

Therefore, the initial choice of antibiotic should bebroad and based on local guidelines and patterns ofresistance, especially if the source is unknown.Because Group A Streptococcus (GAS) and Escheri-chia coli are the most common contributors to sepsisin pregnancy and responsible for a significant propor-tion of deaths, empiric coverage should include theseorganisms. Compared to vaginal delivery, cesareandelivery confers a five to 20-fold increase in risk ofinfection and morbidity:28,60 this risk can be substan-tially reduced by the use of prophylactic antibioticspreoperatively.61 Although GAS is sensitive to

b-lactam antibiotics in vitro, sensitivity does notalways predict efficacy. Protein synthesis inhibitors(e.g. clindamycin) have been demonstrated to be moreeffective than b-lactams in animal models of GASinfection62 and therefore, the Infectious Diseases Soci-ety of America (IDSA) recommends that patients withinvasive GAS infection promptly receive penicillin (2–4 million units every 4–6 hours intravenously) plusclindamycin (600–900 mg every 8 hours intravenously)for 10–14 days.63

Early involvement of an infectious disease specialistcan help with optimization of antimicrobial therapy,especially when there is failure to respond to first-linetreatment.64 Once the culture and sensitivity informa-tion is available, the spectrum of coverage should benarrowed. Individualized antibiotic dosing may helpimprove mortality in the sickest septic patients.65 Inaccordance with the new SSC guidelines, dosing strate-gies should be based on pharmacokinetic and pharma-codynamic principles where possible. Thisrecommendation is based on the observation that ini-tial doses of antibiotics are often insufficient due toan increase in volume of distribution and augmentedrenal clearance,66 two physiological changes invokedby pregnancy. Moreover, maternal obesity is increasingworldwide67 and is an independent risk factor formaternal sepsis.68 Standard dosing of antibiotics inthe obese parturient may be inadequate due to alteredpharmacokinetics and tissue penetration. Swank et al.69

found that using 3 g instead of 2 g of prophylactic cefa-zolin at the time of cesarean delivery, significantlymore women with body mass index >30 kg/m2 wereable to achieve the recommended minimum inhibitoryconcentration for cefazolin. Other proposals to reduceinfections in the obese population include topical andsubcutaneous antibiotic regimens,70,71 prophylacticsubcutaneous drains72 and complex wound dress-ings.73–75

Fluid therapyFluid management is challenging in a septic parturient.A persistent positive fluid balance has been shown tobe an independent risk factor for mortality in sepis.76

Despite its low incidence, fluid overload and pulmonaryedema have contributed to maternal morbidity andmortality.2 Concomitant use of oxytocin, pre-existingcardiac disease or preeclampsia may further complicatefluid management. The improvement in survival frompreeclampsia is largely attributable to more cautiousrestrictive fluid regimens.77 The SSC guidelines recom-mend crystalloid at an initial 30 mL/kg bolus; however,this may be too aggressive in the obstetric population.The choice of crystalloid has long been debated butthere is evidence that balanced crystalloid solutions areassociated with a lower mortality in sepsis as comparedto normal saline.78

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Measuring adequacy of resuscitationThe goal in sepsis resuscitation is to restore normal tis-sue perfusion. Central venous oxygen saturation (ScvO2)and central venous pressure (CVP) have been used asmarkers for adequate tissue perfusion and volumereplacement.45 However, these measurements requirethe insertion of a central venous catheter and currentevidence does not support its widespread adoption.The optimal CVP is unknown in pregnancy and is apoor marker of intravascular volume.79,80 Furthermore,ScvO2 has not been consistently shown to be a goodprognostic indicator or predictor of fluid responsive-ness;81 however, very high ScvO2 levels are associatedwith increased mortality in sepsis and may reflectimpairment of the microcirculation and mitochondrialdysfunction.82,83 Using serum lactate clearance to guideresuscitation in septic shock was shown to result in sim-ilar mortality as using ScvO2.

84 However, neither lactateclearance nor central venous-to-arterial carbon dioxidepressure difference (DP(v-a)CO2) have been shown toconsistently indicate an end-point to treatment or toguide further treatment to improve outcome.85 Recentconsensus recommendations in cardiac output monitor-ing suggest that echocardiography should be the pre-ferred method for diagnosis and sequential monitoringof response to resuscitation in shock, and that invasivecardiac output monitoring is only required in those thatdo not respond to initial treatment.86 Overall, there is atrend away from more invasive to less invasive methodsof cardiac output monitoring. The new SSC guidelinesaccordingly state volume status and tissue perfusionmay be assessed with either focused clinical examinationor two of the following: CVP, ScvO2, bedside cardiacultrasound, or dynamic assessment of fluid responsive-ness via passive leg raise (PLR) or fluid challenge.87

For many obstetric units, the equipment and knowl-edge to perform bedside echocardiography may notalways be obtainable. It has been suggested that PLRis a quick, non-invasive and reversible way to assessfor fluid responsiveness,88 with some evidence to suggestthe hemodynamic response is similar between non-pregnant controls and pregnant women at 22–24 weeks’gestation.89 A standard PLR challenge does requiredirect measurements of cardiac output and stroke vol-ume using a non-invasive cardiac monitor, or other reli-able surrogates such as changes in carotid or femoralDoppler response before and after the maneuver.90 Toperform this on a pregnant patient, after obtaining base-line measurements in a 45� semi-recumbent positionwith left lateral displacement of �30� to minimize aorto-caval compression, the head of the bed is flattened andthe legs are elevated to 45� for 30 seconds while main-taining uterine displacement. One small study in sponta-neously breathing healthy volunteers found that PLRwas 72% sensitive (95% CI 55% to 85%) and 100% speci-fic (95% CI 40% to 100%) for predicting the presence of

fluid responsiveness.91 In ventilated patients, an increasein the cardiac output or a surrogate measure, such asmean arterial pressure (MAP) of �10%, after PLR indi-cates fluid-responsiveness.92 While this remains to bevalidated in the maternal sepsis population, PLR mayrepresent a useful alternative in units without access toechocardiography.

Vasopressors and inotropesSepsis-mediated hypotension is the result of venous andarterial vasoplegia, relative hypovolemia and myocar-dial depression. If vasopressors are required to maintainMAP after fluid resuscitation, SCC recommends nore-pinephrine as the first-line agent,93 although a targetMAP may need to be individualized, as a MAP of65 mmHg may well be too high in a previously healthy,young patient. The MAP should therefore be interpretedwith reference to organ perfusion, urine output, lactateclearance and fetal heart rate tracing if applicable, whichwill give information about placental perfusion.47,94

Again, the SSC guidelines are based on evidence fromnon-pregnant patients and there are little data on theeffect on placental blood flow of vasopressors, althoughin a dual-perfused single-cotyledon human placentalmodel, norepinephrine did not affect perfusion on the‘fetal side’.95

Regional anesthesiaNeuraxial techniques are generally deemed to be rela-tively contraindicated in the septic patient. First, thepresence and degree of systemic vasodilation and cardio-vascular compromise in sepsis makes further sympa-thetic blockade resulting from neuraxial techniquesdangerous. Second, there may be concomitant thrombo-cytopenia or coagulopathy, increasing the risk of bleed-ing complications. Third, there may be an increased riskof meningitis and epidural or spinal abscess.

A recently updated joint report from the AmericanSociety of Anesthesiologists (ASA) and the AmericanSociety of Regional Anesthesia (ASRA) recommendsindividualized plans in patients with suspected sepsiswhere neuraxial techniques are considered.96 Specifi-cally, the guidelines recommend that providers shouldconsider pre-procedure history, physical examination,and review laboratory results, when consideringalternatives in patients that are ‘high risk’– althoughthe term ‘high risk’ is not defined. In addition, the useof prophylactic antibiotics for suspected bacteremicpatients is advocated and selection of the neuraxial tech-nique should be made on a case-by-case basis.96 Theserecommendations are based on case reports, case seriesand surveys of practice and are not specific to the obstet-ric population.

The obstetric anesthesiologist is frequently faced witha dilemma when a febrile parturient with suspectedchorioamnionitis is requesting epidural labor analgesia.

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There is concern that a neuraxial technique may result inseeding of the epidural or subarachnoid space in a bac-teremic patient. It is difficult to base a decision onwhether to perform neuraxial anesthesia on laboratoryresults, due to the normal increase in white cell countin labor, and the poor correlation between white cellcount and presence of bacteremia in pregnancy.97 Fewguidelines exist to guide the use of neuraxial techniquesin the septic or bacteremic parturient.

Fortunately, infections related to labor epidural anal-gesia are extremely rare in obstetric patients. This islikely due to relatively short catheter durations (recentevidence in the non-obstetric population indicates thatinfection risk with epidural catheterization increasesover time, especially after four days),98 the use of pro-phylactic antibiotics in chorioamnionitis and operativedelivery, and the fact that this population is generallyhealthy. The Third National Audit Project (NAP 3) ofThe Royal College of Anaesthetists found an incidenceof 1 in 47000 cases of epidural abscess in the whole pop-ulation of the project, with only one case in an obstetricpatient.99 Another retrospective review found only onecase in 505000 women who received epidural anesthesiafor vaginal or cesarean delivery over a four-yearperiod.100 Although epidural abscesses are rare in theobstetric population and often attributed to a break insterile technique, the presence of underlying medicalconditions such as diabetes may increase the baselinerisk. To complicate matters, epidural abscesses have alsooccurred in low-risk postpartum women who did notreceive neuraxial analgesia.101

The risk of central infection from neuraxial tech-niques is deemed to be very small in patients treatedwith antibiotics.99,102 The current recommendation sug-gests that patients with evidence of systemic infectionmay safely receive single-shot spinal anesthesia, pro-vided antibiotics have been commenced and a responseto treatment has been demonstrated.102 However, theplacement of an indwelling epidural catheter is morecontroversial, although similar criteria are often usedin a clinical setting.

At present, there is no consensus on neuraxial tech-niques in obstetric patients with intrapartum fever, bac-teremia or sepsis. In a UK national survey sent to allmembers of the Obstetric Anaesthetists Association(OAA) via their approved survey system, there was sig-nificant variation in provider responses in relation toinsertion of labor epidural catheters in the presence ofintrapartum fever. In this survey of 571 anesthesiolo-gists, which was limited by only a 31% response rate,31% stated they would site an epidural after antibiotics,30% would site an epidural without antibiotics, 22%would decide on a case-by-case basis, and 17% wouldrefuse to site an epidural and offer alternative analge-sia.103 The findings of this survey highlight a need forclearer guidance on this matter; however, the lack of

robust, high-quality evidence currently defies a definitivestatement on the risk of central nervous system infectionin patients with chorioamnionitis or bacteremia under-going regional anesthesia.

General anesthesiaGeneral anesthesia is often required in a septic parturi-ent due to the inability to safely provide regional anes-thesia or the need to control ventilation andhemodynamics. The same precautions should be takenfor all pregnant and postpartum patients undergoinggeneral anesthesia, taking into account their increasedrisk of aspiration, aortocaval compression from thegravid uterus in the supine position, laryngeal edemaexacerbated by fluid resuscitation leading to increasedrisk of difficult intubation, and the degree of cardiovas-cular compromise due to sepsis.104 In the severely com-promised patient, ketamine may be considered insteadof propofol as the induction agent for general anesthe-sia.105 Once general anesthesia is achieved, invasivemonitoring should be placed to assist detection of earlyhemodynamic changes and to guide vasopressor andinotropic support. Early consultation of an intensivistand transfer of the patient to ICU should be considered.Effective communication with critical care physicians isvital. Often serious incident and root-cause analysis willbe required to learn from what is a relatively rare eventin the majority of hospitals.106,107

Delivery considerationsThe decision of whether as to deliver the fetus or con-tinue the pregnancy is influenced by a number of factorsincluding the patient’s condition, the gestational age ofthe fetus, the fetal condition, the presence of chorioam-nionitis and the stage of labor. Attempting early deliveryin patients with severe cardiovascular compromise dueto sepsis may increase maternal and fetal mortality,108

unless chorioamnionitis is suspected as the source ofsepsis or a septic abortion has occurred.59,109 If the risksof continuing the pregnancy outweigh those of earlydelivery, administration of antenatal steroids and mag-nesium should be considered to improve the outcomeof a premature fetus.110 Decisions relating to deliveryof the baby are ultimately the responsibility of the obste-trician, although the anesthesiologist may advise on tim-ing in relation to resuscitation of the mother.Collaboration and discussion with the neonatal, inten-sive care and microbiology teams; and the patient, arealso vital. If surgical intervention for source control,including cesarean section, is required, the decisionabout whether to proceed under regional or generalanesthesia should be made on a case-by-case basis, hav-ing considered the risks and benefits of each approach.To date, no large, RCTs has addressed the question ofwhether neuraxial or general anesthesia would result inbetter or worse outcomes in maternal sepsis.

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104 Sepsis in pregnancy and the puerperium

One of the goals of sepsis management in the perina-tal period is to maintain oxygenation and perfusion ofvital organs and the placenta, whilst identifying thesource of infection and treating it. In the antenatal per-iod, maternal resuscitation is the key to ensuring fetalwellbeing.111,112 Antepartum sepsis arising from theuterus will require delivery for source control, despitethe fact that neonatal survival is correlated with gesta-tional age. Attempts to delay delivery in this settingare often too dangerous for the mother. Sepsis arisingantenatally from a non-uterine source is a more difficultscenario. When sepsis is diagnosed in the antepartumperiod, one prospective case-control study of a nationaldatabase in the UK from 2011 to 2012 found the median(IQR) gestational age to be 35 weeks (27–40 weeks) andthe diagnosis-to-delivery interval to be zero days (1–7days).9

Future developments

The overlapping physiological changes of pregnancyand clinical features of sepsis in this high-risk patientpopulation would make a reliable biomarker particu-larly useful. There is currently no ideal biomarker thatcan indicate prognosis, predict progression of the dis-ease and guide treatment in sepsis. Early identificationof those at risk of developing life-threatening septicshock would enable early triage and treatment.Biomarkers could also aid the differentiation of sepsisfrom non-infective systemic inflammation in the inten-sive care community, and in the parturient, and mayhelp distinguish likely benign ‘epidural fever’ from infec-tious fever. This could reduce the unnecessary use ofantibiotics in both mothers and neonates, in an age ofincreasing antimicrobial resistance.

Procalcitonin (PCT), a pro-inflammatory biomarker,has been studied to help differentiate bacterial sepsisfrom non-infective SIRS and guide antimicrobial stew-ardship decisions.113 However, a PCT-guided antimicro-bial escalation strategy did not improve survival, and infact prolonged ICU admission.114 A recent large,prospective US study showed that PCT levels that donot decrease by more than 80% independently predictmortality in sepsis;115 however, it remains unclear whatmeasures should be used in patients with non-decreasingPCT levels to improve outcomes.

Other potential areas of interest in developing novelbiomarkers are endothelial proteins, such as angiopoi-etins; cell surface receptors, such as leucocyte surfacereceptors; cytokine/chemokine signaling molecules;immunomodulatory biomarkers; and potential genomicregulators.116 The ExPRES-Sepsis Study that is cur-rently in progress aims to explore the predictive valueof leucocyte surface markers in sepsis.117 Ultimately,with a better understanding of the pathophysiologyand cellular processes driving sepsis, we can better define

sepsis as a set of distinct biochemical disorders thatcan be targeted when creating diagnostic tests andtherapies.

Many challenges remain in the diagnosis and man-agement of maternal sepsis. Further research is neededto establish robust diagnostic criteria for sepsis and sep-tic shock in the obstetric population and then developspecific protocols accordingly. The new maternal defini-tion and identification criteria will be tested and vali-dated in a large global one-week cross-sectional study–The Global Maternal Sepsis Study.118 Information onprevention and management will be collected to informthe development of strategies for reducing maternalinfections and sepsis in all-income countries. The GlobalMaternal and Neonatal Sepsis Initiative will further thedevelopment of identification criteria, prevention strate-gies and management bundles, with the aim of accelerat-ing the reduction of preventable sepsis deaths duringpregnancy and the puerperium by 2030.118

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Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at https://doi.org/10.1016/j.ijoa.2018.04.010.