Severe Sepsis During Pregnancy.pdf

Severe Sepsis DuringPregnancy

LUIS D. PACHECO, MD,*w GEORGE R. SAADE, MD,*and GARY DV. HANKINS, MD*

*Department of Obstetrics and Gynecology, Division of MaternalFetal Medicine; and wDepartment of Anesthesiology, Division ofSurgical Critical Care, The University of Texas Medical Branchat Galveston, Galveston, Texas

Abstract: Severe sepsis is a major cause of mortalityamong critically ill patients. Early recognition accom-panied by early initiation of broad-spectrum antibi-otics with source control and fluid resuscitationimproves outcomes. Hemodynamic resuscitationstarts with fluid therapy followed by vasopressors ifnecessary. Cases refractory to first-line vasopressors(norepinephrine) will require second-line vasopressors(epinephrine or vasopressin) and low-dose steroidtherapy. Resuscitation goals should include optimiza-tion of central venous oxygenation and serum lactate.Key words: sepsis, septic shock, pregnancy

IntroductionSepsis occurs as the result of a systemicmaladaptive inflammatory response to aninfectious insult. It is the leading cause ofmortality in intensive care units (ICUs) indeveloped countries, and the incidence isincreasing worldwide.1 The literature re-gardingmanagement of sepsis in the preg-nant patient is limited, and pregnantwomen have typically been excluded from

landmark trials that have guided theman-agement of sepsis over the last decades.Most cases of severe sepsis/septic shockare managed in ICUs; therefore, obstetri-cians and maternal fetal medicine special-ists are unfamiliar with managementprinciples. The present article describesthe cardinal points of modern manage-ment of sepsis, and key points are organ-ized in an algorithm.

Pathophysiology of SepsisThe pathophysiology of sepsis is not com-pletely understood. After exposure to amicroorganism (bacteria, virus, parasite,fungi), the inflammatory cascade is acti-vated. Massive production of inflamma-tory cytokines, together with endothelialfactors like nitric oxide and other media-tors like prostaglandins, leukotrienes, andcomplement, lead to loss of vasomotortone with profound vasodilation and in-creased vascular permeability (secondaryto cytokine-induced endothelial injury)with subsequent third spacing. Edema de-velops in extravascular compartments (in-terstitium, pleural and pericardial spaces,lung, brain, abdomen, heart walls), leading

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The authors declare that they have nothing to disclose.

Correspondence: Luis D. Pacheco, MD, Divisions ofMaternal Fetal Medicine and Surgical Critical Care,Deprtments of Obsterics, Gynecology, and Anesthesi-ology, The University of Texas Medical Branch atGalveston, 301University Blvd. Galveston, TX. E-mail:[email protected]

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 00 / NUMBER 00 / ’’ 2014

CLINICAL OBSTETRICS AND GYNECOLOGYVolume 00, Number 00, 000–000r 2014, Lippincott Williams & Wilkins

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited

mailto:[email protected]

to a state of increased total body water butdecreased intravascular volume. The pro-found decrease in systemic vascular resis-tances facilitates the so-called ‘‘increasedcardiac output’’ seen in septic patients.However, the myocardium function in sep-sis is also profoundly altered by the actionof substances like nitric oxide, interleukin-1, oxygen-derived free radicals, and tumornecrosis factor-a. Up to 60% of patientswith sepsis have an ejection fraction of<45%. Both systolic and diastolic dys-function may occur. Not infrequently, my-ocyte injury from proinflammatorycytokinesmay lead to leakage of troponins.Typically, patients with systolic dysfunc-tion tend to present with biventricular di-lation. The latter appears to be an adaptiveresponse as dilation will allow for moreintracavitary filling, leading to an increasedstroke volume despite a decrease in ejectionfraction (preload recruitment). These car-diac changes tend to resolve spontaneouslyamong survivors of sepsis.

Almost all patients with severe sepsishave clotting abnormalities ranging fromsilent biochemical changes to full-blowndisseminated intravascular coagulopathy.Activation of the clotting cascade in sepsisresults from tissue factor expression in mo-cocytes, neutrophils, and the endotheliumaspart of the inflammatory response. Oncetissue factor is expressed in the surface ofthese cells, it bindsFactorVII, activating theclotting cascade through the extrinsic path-way. Development of disseminated intra-vascular coagulopathy contributes toorgan hypoperfusion (secondary to micro-vascular occlusion) and multiorgan failure.

Another important pathway is that ofactivated protein C. Once thrombin is gen-erated, it interacts with an endothelial sur-face receptor known as thrombomodulin.This interaction leads to activation of pro-teinC,which inhibits clottingFactorsVandVIII, promotes fibrinolysis, and has anti-inflammatory properties. Cytokines de-crease theactivityof thrombomodulin, lead-ing to a lack of protein C activity in sepsis.

Mitochondrial dysfunction is also com-monly seen in severe sepsis. Even in thepresence of adequate oxygen delivery, ad-equate oxygen consumption cannot beguaranteed if themitochondria are dysfunc-tional and cannot extract oxygen and use itin oxidative respiration. The latter explainswhy patients with sepsis may have normalor above normal saturations of hemoglobinin the central or pulmonary circulationsdespite adequate oxygen delivery.

In summary, sepsis is characterized by amassive inflammatory response leading tohypotension secondary to a decrease insystemic vascular resistances, cardiac dys-function, activation of the clotting cascade,inhibition of natural anticoagulant path-ways, and mitochondrial impairment.

Definition/Diagnosis of SepsisThe definition of sepsis has been modifieddramatically in the last decades.

The American College of Chest Physi-cians and the Society of Critical CareMedicine introduced the concept of sys-temic inflammatory response syndrome(SIRS) in 1992.2

A patient is considered to have SIRS ifZ2 of the following criteria are present:(1) Temperature >381C or <361C.(2) Heart rate >90bpm.(3) Respiratory rate >20 breaths/minute

or a PaCO2<32mm Hg.(4) White blood cell count>12,000/mm3

or <4000/mm3 or bandemia>10%.Sepsis has typically been defined as

SIRS resulting from an infectious etio-logy. For example, a patient with pyelo-nephritis with a heart rate of 110 bpm anda respiratory rate of 26 breaths/minute isconsidered to have sepsis.

Severe sepsis is defined as sepsis withsigns of at least 1 organ dysfunction (eg,confusion, respiratory failure, acute kid-ney injury, thrombocytopenia, prolonga-tion of clotting times, elevation of liverenzymes, hypotension).

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Septic shock is defined as severe sepsiswith hypotension despite adequate fluidresuscitation. This subset of patients willrequire vasopressors to maintain hemo-dynamic stability.

This definition of sepsis has beencriticized for being too sensitive and non-specific, as most critically ill patients willmeet SIRS criteria even in the absence ofinfection. Adding to the problem, physio-logical changes of pregnancymay include aheart rate>90bpm, aPaCO2<32mmHg,and a white blood cell count >12,000/mm3. This definition is even more non-specific in the pregnant population.

In 2001, extended criteria for sepsisdiagnosis were developed to improve thediagnostic accuracy of the clinical re-sponse to infection.3 These signs andsymptoms are depicted in Table 1. The

reader should understand that this list ofsigns is a guide, and not all patients withsepsis will have them, just as nonsepticpatients may have some of them.

A fundamental principle in sepsis man-agement is that the earlier therapy isinstituted, the better the outcomes willbe. The clinician should suspect the pres-ence of sepsis in any pregnant womanwith an infectious process and some ofthe signs and symptoms listed in the Table.

TreatmentOnce the diagnosis of severe sepsis isestablished, early aggressive support isessential to achieve good outcomes.Manyof the interventions described in the fol-lowing paragraphs are commonly per-formed simultaneously.

Cultures should be obtained as clinicallyindicated (blood, urine, sputum, cerebro-spinal fluid, vaginal secretions, wound col-lections, pleural fluid, amniotic fluid,abscess), ideally before starting broad-spectrum antibiotics. Broad-spectrumantibiotics (with coverage against gram-positive bacteria, gram-negative bacteria,and anaerobes) and immediate source con-trol should be accomplished as soon aspossible.4 The least invasive method toachieve source control is recommended(eg, percutaneous rather than surgicaldrainage of an abscess).4 Importantly, ini-tiation of antibiotics should not be delayeddue to inability to obtain cultures.

Respiratory difficulty secondary tononcardiogenic pulmonary edema is com-mon in severe sepsis and should be ad-dressed early. Ventilatory support withoxygen therapy, noninvasive mechanicalventilation, or intubation and mechanicalventilation should be started as needed.Of paramount importance is to utilizesmall tidal volumes (around 6 to 8mL/kg, lean body weight), as this is theonly intervention that has demonstratedimproved outcomes in themanagement of

TABLE 1. Signs and Symptoms of SepsisAccording to the 2001 SepsisDefinitions Conference

Infection, documented or suspected, and some ofthe followingFever or hypothermiaTachycardia or tachypneaAltered mental statusSignificant positive fluid balance (>20mL/kgover 24 h)

Hyperglycemia (not explained by other medicalconditions)

Leukocytosis, leukopenia, or bandemiaElevated procalcitonin levelsArterial hypotension (SBP<90mm Hg,MAP<65mm Hg, or SBP decrease >40mmHg)

Arterial hypoxemia (PaO2/FIO2<300)Acute kidney injury (acute elevation of serumcreatinineZ0.3mg/dL or urine output<0.5mL/kg/h for 6 h)

Coagulation abnormalities (prolonged aPTT orINR, decreased fibrinogen)

Ileus (absent bowel sounds)ThrombocytopeniaHyperbilirubinemiaHyperlactatemiaDecreased capillary refill or mottling

aPTT indicates activated partial thromboplastin time; FiO2,fraction of inspired oxygen; INR, international normalizedratio; MAP, mean arterial blood pressure; PaO2, partialpressure of oxygen; SBP, systolic blood pressure.

Severe Sepsis During Pregnancy 3



noncardiogenic pulmonary edema (acuterespiratory distress syndrome).5

Institution of thromboprophylaxis andearly enteral feeding is recommended andshould be addressed accordingly.

Pregnancies that are considered viable(>24wk) should ideally undergo continu-ous electronic fetal monitoring in a facilitywith the capacity to perform a bedsidecesarean section if required. After 20weeks, patients should be placed in the leftor right lateral positions (alternating toprevent development of decubitus ulcers),avoiding the supine position to minimizehemodynamic disturbances secondary todecreased preload from inferior vena cavacompression by the gravid uterus. If ste-roids to promote fetal lung maturity areindicated, they can be used even in thesetting of sepsis.6

HEMODYNAMIC RESUSCITATION

Classically, hemodynamic resuscitationin severe sepsis has been directed towardachieving a mean arterial blood pressure(MAP) of 65mm Hg. The cornerstone ofresuscitation in sepsis is fluid administra-tion followed by use of pressors if fluidadministration does not achieve the de-sired target. The ultimate goal is to im-prove tissue perfusion and oxygenation.

FLUID RESUSCITATION

Early aggressive fluid resuscitation im-proves tissue perfusion by increasing driv-ing pressure and also modulates earlyinflammation by decreasing concentra-tions of proinflammatory cytokines. Re-cent guidelines in nonpregnant patientsrecommend starting fluid therapy withcrystalloids (eg, normal saline, lactate ring-ers) at a dose of 30mL/kg.4 There is noevidence that the use of albumin is superiorto crystalloids.7 Hydroxyethyl starch(Hespan) should be avoided in the septicpatient, as is associatedwith highermortal-ity and risk of acute kidney injury.8 Fluidtherapy has traditionally been titratedbased on static measurements of preload,

such as central venous pressure (CVP). AsCVP is only a static measure, it will notnecessarily guarantee an increase in cardiacoutput after a fluid challenge. A recent trialshowed that among patients with a CVP of<8mm Hg, the positive predictive valuefor fluid responsiveness, defined as an in-crease in cardiac index ofZ15%, was only47%.9 A systematic review of the literatureshowed that there was no association be-tween CVP values and circulating bloodvolumeand thatCVPdoes not predict fluidresponsiveness.10 Furthermore, the re-ceiver operator characteristic curve areaunder the curve for CVP was only 0.56.Despite the latter limitations, the SurvivingSepsis Campaign’s recent guidelines stillrecommend titration of fluid therapy to aCVP of at least 8mm Hg.4 Most expertsagree that fluid responsiveness is betterpredicted by using dynamic measures ofpreload that will predict if fluid adminis-tration will result in increased cardiac out-put before administering the fluid bolus.Two scenarios are possible. First, in pa-tients who are intubated, who are in sinusrhythm, and who are not triggering theventilator (not having spontaneous venti-lations), one can easily predict fluid respon-siveness by measuring pulse pressurevariation (PPV) on the arterial line tracing(an arterial line is required). If the latterconditions are met, variation in the pulsepressure with the respiratory cycle above13% (most modern hemodynamic moni-tors will calculate PPV automatically) willpredict fluid responsiveness with both sen-sitivity and specificity of >90%.11 Thesecond scenario involves patients who donotmeet the prior criteria (not intubated ornot in sinus rhythm). In these patients, PPVis not valid. A simple method to predictfluid responsiveness in this population is toperformapassive leg raising (PLR)maneu-ver. Using a noninvasive cardiac outputmonitoring device (commonly availablein ICUs), a baseline cardiac output isdocumented. PLR leads to transfer of ap-proximately 300mL of blood from the

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vasculature of the legs into the centralcirculation. If the cardiac output increasesby >10% after performing the PLR, thenthe patient still will respond to further fluidtherapy. Fluid therapy should be adminis-tered until the MAP reaches 65mm Hg oruntil PPV is <13% or cardiac outputaugmentation with PLR is <10% if thepatient remains hypotensive. The validityof PLR during pregnancy is still unknown.Recent data on the accuracy of PLRduringpregnancy to predict fluid responsivenessreported a positive predictive value of100%, specificity of 100%, and sensitivityof 75%.12When performing themaneuver,we recommend that the patient be placedon the left lateral decubitus to avoid uterinecompression of the inferior vena cava,which can potentially lead to false-negativeresults (no cardiac output augmentationwith PLR as uterine-mediated vein com-pression prevents blood in the lower ex-tremities from reaching the heart). Insummary, fluid should be administereduntil aCVPof at least 8mmHg is achieved.If hypotension persists, further fluid ther-apy may be guided by the use of PPV orPLR.

ADDITION OF PRESSORS

If, despite adequate fluid therapy, theMAP remains<65mmHg, then vasopres-sors should be started. Recent guidelinesrecommend norepinephrine as the pressorof choice in the septic patient.4 In thesetting of septic shock, restoring maternalperfusion pressure is of paramount impor-tance, and it should override any theo-retical concerns of vasopressor-induceduterine vasculature constriction. Increasingthe MAP will improve perfusion pressureto organs, including the gravid uterus.

If hypotensionpersists despite fluid ther-apy and norepinephrine, second-line press-ors like epinephrine or vasopressin may beconsidered. No good data exist regardingthe use of vasopressin for septic shock inpregnant women. Theoretically, it mayactivate uterine V1a receptors, leading to

uterine contractions. Caution is recom-mended if this agent is used during preg-nancy. Patients with pressor-resistantseptic shock should be started on low-dosesteroids with a presumptive diagnosis ofsepsis-associated adrenal failure.13 Hydro-cortisone should be administered at a doseof 200mg/d in a continuous 24-hour infu-sion. Steroid therapy should bemaintaineduntil the vasopressors areweaned, and thenthe steroid should be tapered offgradually.4

TISSUE PERFUSION ANDOXYGENATION

Commonly, the main goal of resuscitationefforts in sepsis has been to achieve ‘‘nor-mal’’ vital signs (MAP>65mm Hg, urineoutput >0.5mL/kg/h, normal heart rate).Unfortunately, clinical signs and symp-toms lack sensitivity for predictingadequate tissue oxygenation. Organ hypo-perfusion and anaerobic metabolism maybe present evenwith ‘‘normal’’ vital signs.14

Occult shock may be present even though‘‘hemodynamic stability’’ has beenachieved. Serum lactate levels and determi-nationofmixed central venoushemoglobinoxygen saturation (ScVO2) may aid infurther resuscitative efforts.14 Elevated lac-tate levels and low ScVO2 (<70%) areindicative of decreased oxygen delivery.

ScVO2 is the hemoglobin saturation ofa blood sample obtained from the junc-tion of the superior vena cava and theright atrium. To obtain it, the clinicianonly needs a central venous catheter. Thenormal value is >70%. Hypoperfusedtissues will extract more oxygen in anattempt to maintain aerobic metabolism.Such increased extraction will lead to adecrease in the saturation of hemoglobinreturning to the central circulation, re-flected by the low oxygen saturation(<70%) in the blood sample obtainedfrom the central venous catheter.

To our knowledge, the normal value ofScVO2 during pregnancy has not beendetermined. During pregnancy, there is a




20% increase in basalmetabolic rate com-pared with a 40% to 50% increase incardiac output. The higher the cardiacoutput, the faster the red blood cells travelthrough the distal tissues. The latter willdecrease the time available for perfusedtissues to extract oxygen from hemo-globin, leading to higher hemoglobinsaturation in the venous circulation. Con-sequently, one would expect that duringpregnancy, SvO2 (and probably ScvO2)would be higher than values in

nonpregnant patients. However, Hankinset al15 reported a mean SvO2 of 72% in agroup of normal pregnant volunteers whohad a pulmonary artery catheter placed inthe third trimester. This value is not differ-ent from those reported in healthy non-pregnant individuals.

If decreased oxygen delivery is sus-pected, attempts to improve oxygen deliv-ery should follow. Further volumeexpansion in an attempt to increase car-diac output (if the CVP is <8mm Hg or,

Sepsis suspected • Obtain cultures • Start broad-spectrum antibiotics• Immediate source control• Ventilation support (ETT, NIPPV)

• Electronic fetal monitoring if > 24 weeks

• Early enteral nutrition• DVT prophylaxis

Hemodynamic Management

• Start with fluid therapy (crystalloids 30 mL/kg initially)

• Target CVP > 8 mmHg

Patient on ventilator, not triggering, sinus rhythm, TV of 8–10 mL/kg

Patient spontaneously breathing, or on ventilator, but no sinus rhythm (cannot use pulse pressure variation)

Continue fluids until MAP>65 mmHg or as long as pulse pressure variation is > 13% if hypotension remains

Continue fluids until MAP> 65 mmHg or as long as non invasive cardiac output increase > 10% with passive leg raising maneuver if hypotension remains

MAP remains < 65 mmHg despite fluid therapy

• Start norepinephrine (0.05–3.3 µg/kg/min)• Titrate to MAP > 65 mmHg

Patient on norepinephrine and s/p initial fluid resuscitation

Persistent hypotension

• Start hydrocortisone 200 mg/day• Start second-line pressors like epinephrine• Consider vasopressin at 0.03–0.04 U/min

MAP> 65 mmHg achieved, UO > 0.5 cc/kg/hr, normal pulse

Serum lactic acid and ScVO2

If lactic acid > 2 mmol/L and/or ScVO2 < 70%

Patient with MAP > 65 mmHg with fluid therapy

Increase O2 delivery with PRBC’s (target hematocrit 30%) and/or dobutamine (2.5–20 µg/kg/min)

• Target hematocrit to increase oxygen delivery of 30% mainly used during the rst 6 hours of resuscitation aspart of the early goal-directed therapy concept.

• At every point during the algorithm, the clinician should - reassess need for further uid after the initial resuscitation phase (documented by presence of pulse pressure

variation or cardiac output recruitability with passive leg raising).- evaluate the fetal heart tracing. Worsening shock may require delivery.

_

_ _

_

_

_

FIGURE 1. Algorithm for hemodynamic management. CVP indicates central venous pressure;DVT, deep venous thrombosis; ETT, endotracheal tube; MAP, mean arterial blood pressure;NIPPV, non invasive positive pressure ventilation; PRBC, packed red blood cells; TV, tidalvolume; UO urine output.

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alternatively, if either PPV or response toPLR is present) may be accomplished bydirectly increasing cardiac output with aninotrope (dobutamine) or by increasingarterial oxygen content with packed redblood cell transfusions to raise the hemo-globin level. Current guidelines recom-mend that during early sepsis (first 6 h ofresuscitation), a hemoglobin of 10 g/dLmay be targeted in an attempt to increaseoxygen delivery if the ScVO2 is <70%.16

After the first 6 hours of treatment, trans-fusions should be withheld unless thehemoglobin level decreases <7 g/dL.17

Summary and Future ResearchFigure 1 summarizes the management ofsevere sepsis/septic shock as recom-mended in this article. Table 2 providesa summary of the desired resuscitationtargets and doses of commonly used med-ications in sepsis resuscitation.

In summary, management of severesepsis/septic shock requires early aggres-sive resuscitative efforts if a good out-come if desired. Most of the dataavailable come from trials that have ex-cluded pregnant women.Despite a lack ofspecific data for the pregnant population,the basic principles of management aresimilar to those in the nonpregnant pop-ulation, and maternal fetal medicine spe-cialists should be familiar with theseprinciples. Research in critical care duringpregnancy is desperately needed. Regard-ing sepsis treatment specifically, futureareas of research should include deter-mining the optimal fluid choice, optimalpressor agent, and validation in preg-nancy of well-established resuscitationgoals (like ScVO2) utilized in nonpreg-nant individuals.

References1. Nduka OO, Parrillo JE. The pathophysiology of

septic shock. Crit Care Clin. 2009;25:677–702.2. ACCP-SCCMConsensus Conference: definitions

of sepsis andmultiple organ failure and guidelinesfor the use of innovative therapies in sepsis. CritCare Med. 1992;20:864–874.

3. Levy MM, Fink MP, Marshall JC, et al. 2001SCCM/ESICM/ACCP/ATS/SIS InternationalSepsis Definitions Conference. Crit Care Med.2003;31:1250–1256.

4. Dellinger RP, LevyMM, Rhodes A, et al. Surviv-ing Sepsis Campaign: international guidelines formanagement of severe sepsis and septicshock: 2012. Crit Care Med. 2013;41:580–637.

5. Ventilation with lower tidal volumes as comparedwith traditional tidal volumes for acute lunginjury and the acute respiratory distress syn-drome. Acute Respiratory Distress SyndromeNetwork. N Engl J Med. 2000;342:1301–1308.

6. ACOG Practice Bulletin. Critical care in preg-nancy. Obstet Gynecol. 2009;113:443–449.

7. The saline versus albumin fluid evaluation(SAFE) study investigators. A comparison ofalbumin and saline for fluid resuscitation in theintensive care unit. N Engl J Med. 2004;350:2247–2256.

8. Perner A, Haase N, Guttormsen AB, et al. Hy-droxyethyl starch 130/0.4 versus Ringer’s acetatein severe sepsis.N Engl JMed. 2012;367:124–134.

9. Osman D, Ridel C, Ray P, et al. Cardiac fillingpressures are not appropriate to predict

TABLE 2. Quick-Reference Values forTargets, Concentrations, andDosages in the Management ofSevere Sepsis

Variables Desired Target/Dosage

Mean arterialblood pressure

65mm Hg

Pulse pressurevariation

If >13%, indicates fluidresponsiveness

Passive leg raising If procedure recruits cardiacoutput (>10% increase),indicates fluidresponsiveness

ScVO2 >70%Lactic acid <2mmol/LInitial fluid bolus 30mL/kgHematocrit 30% during first 6 h of

resuscitation (early goal-directed therapy)

Norepinephrine 0.05-3.3 mg/kg/minDobutamine 2.5-20 mg/kg/minVasopressin 0.03-0.04U/minEpinephrine 0.03-1 mg/kg/minHydrocortisone 200mg/d (continuous

infusion)




hemodynamic response to volume challenge. CritCare Med. 2007;35:64–68.

10. Marik PE, Baram M, Vahid B. Does centralvenous pressure predict fluid responsiveness?Chest. 2008;134:172–178.

11. Enomoto TM, Harder L. Dynamic indices ofpreload. Crit Care Clin. 2010;26:307–321.

12. Brun C, Zieleskiewicz L, Textoris J, et al. Predictionof fluid responsiveness in severepreeclampticpatientswith oliguria. Intensive Care Med. 2012;39:593–600.

13. Annane D, Sebille V, Charpentier C, et al. Effectof treatmentwith lowdoses of hydrocortisone andfludrocortisone on mortality in patients withseptic shock. JAMA. 2002;288:862–871.

14. Okorie ON, Dellinger P. Lactate: biomarker andpotential therapeutic target. Crit Care Clin.2011;27:299–326.

15. Hankins GVD, Clark SL, Uckan E, et al. Mater-nal oxygen transport variables during the thirdtrimester of normal pregnancy. Am J ObstetGynecol. 1999;180:406–409.

16. Rivers E,NguyenB,Haystand S, et al. Early goal-directed therapy in the treatment of severe sepsisand septic shock. N Engl J Med. 2001;345:1368–1377.

17. Hebert P, Tinmouth A, Corwin HL. Controver-sies in RBC transfusion in the critically ill. Chest.2007;131:1583–1590.

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Severe Sepsis During Pregnancy.pdf