septic shock and sepsis syndrome obstetric patients

Infectious Diseases in Obstetrics and Gynecology 2:190-201 (1994)(C) 1994 Wiley-Liss, Inc.

Septic Shock and Sepsis Syndrome in Obstetric Patients

Peter G. Pryde and Bernard GonikDepartment of Obstetrics and Gynecology, Division of Maternal and Fetal Medicine, Wayne State

University School of Medicine, Detroit, MI

ABSTRACT

Septic shock is a life-threatening clinical syndrome that, despite its rare occurrence in obstetrics,remains a leading cause of maternal mortality. Its pathophysiology is explained by a profoundsystemic response to a complex variety of host cellular and humoral mediators elaborated afterexposure to microbial toxins. Early recognition, prompt diagnostic workup, and immediate initiationof therapy improve outcomes. Therefore, recent publications have popularized the concept of the"sepsis syndrome," a preshock list of clinical criteria associated with progressive sepsis. Neededdiagnostic studies should never be withheld because of "pregnancy concerns." With critically illpatients, the risk-to-benefit ratio supports the use of these diagnostic studies in almost all circum-stances. Standard therapy is directed principally at restoring tissue perfusion by intravascularvolume expansion and in some instances vasoactive pharmacological intervention. Simultaneously,identification of the source of infection and commencement of appropriate empiric antibiotic treat-ment are critical. In some cases, surgical abscess drainage or debridement of infected necrotic tissuewill need to be considered. Novel approaches to treatment that attempt to reduce the systemicresponse to microbial toxins are promising and under active investigation. Pregnancy-specific con-siderations include the following: 1) initial signs or symptoms of septic shock may be masked bynormal physiologic alterations of pregnancy; 2) a mixed polymicrobial group of organisms, consis-tent with lower genital tract flora, should be anticipated; and 3) initial therapy should be directedat maternal concerns since adverse fetal effects are most likely the result of maternal decompensa-tion. (C) 1994 Wiley-Liss, Inc.

KEY WORDS

Pregnancy, diagnosis, therapy

he term sepsis refers to the presence of pyogenicor other pathogenic organisms and their toxins

in tissues or in the blood. Shock is the inability,regardless of the underlying cause, of the circula-tory system to maintain adequate cellular perfusion.Inadequate perfusion at the cellular level leads to

membrane dysfunction, metabolic derangement,and finally cell death. The clinical definition ofshock includes foremost hypotension [typically, a

systolic blood pressure (BP) of <90 mmHg or a

>40 mmHg decrement in baseline systolic BP]and can be accompanied by laboratory evidence ofmultiple organ injury. If inadequately treated, the

patient will progress relentlessly, and ultimatelyirreversibly, to multiple-organ-system failure anddeath. When the shock syndrome occurs as a result ofsepsis, it is by definition septic shock.

Recently, in an attempt to identify patients at

increased risk for developing septic shock, the sepsissyndrome was defined for a nonobstetrical popula-tion. The diagnosis of this preshock syndrome isbased on criteria consisting of readily recognizedand easily acquired clinical data which include sev-eral of" the more common manifestations of sepsis(Table 1). The objective of defining such a syn-drome is to encourage earlier recognition of evolv-

Address correspondence/reprint requests to Dr. Bernard Gonik, Department of Obstetrics and Gynecology, Wayne StateUniversity School of Medicine, 4707 St. Antoine Boulevard, Detroit, MI 48201.

Received March 24, 1994Review Article Accepted June 3, 1994

OBSTETRIC-ASSOCIATED SEPSIS PRYDE AND GONIK

TABLE I. Definition of the septic syndrome

Clinical suspicion of infectionFever or hypothermiaTachypneaTachycardiaManifestations of impaired organ-system perfusion

Central nervous system: altered mental status

Pulmonary shunt: hypoxemiaAnaerobic metabolism: elevated plasma lactateRenal: oliguria

Modified from Balk and Bone.

ing sepsis with the goal of timely institution oftherapeutic measures. This goal emphasizes the cru-cial concept that, in managing these potentially crit-ically ill patients, early and aggressive treatment

improves outcomes. Although not formally estab-lished for pregnancy, many of the above criteriawould empirically apply to this patient populationas well and should therefore be utilized.

EPIDEMIOLOGY/RISK FACTORSEvidence of localized infection is not uncommonon an obstetrical service. Rates of puerperal infec-tions in indigent patients have been reported from

to 2% following vaginal delivery to a remarkableincrease to 38.5-85% after cesarean section. 2’3 Inantepartum patients, the most common infection isasymptomatic bacteriuria, with an incidence esti-mated at 4-7%, of which 40% of untreated casesare likely to develop pyelonephritis. 4-6 Other in-fections, which are considerably less common butsignificant in aggregate, include chorioamnionitis,septic abortion, wound infection, and pneumonia.

Despite the clearly elevated risk for developinglocalized infection during pregnancy or the puer-perium, the life-threatening consequences are com-

paratively rare. Bacteremia occurs in only 8-10%of these infected patients. 7-9 More importantly, ofthose involving bacteremia, only 4-12% will de-velop clinical septic shock. 7-9 This is in contrast toa general medicine service on which only about 5%of patients have or develop signs of localized sep-sis. 10 Yet, among these, nearly twice as many as inthe obstetrical population become bacteremic(20%), and a much higher proportion of bactere-mic patients (approximately 50%) manifest shock. 10

An additional important distinction between obstet-rical and general medical patients is that the obstet-rical patient is much less likely to die of complica-

tions of septic shock. Mortality rates with thiscondition have been estimated at approximately 3%compared with approximately 50% in obstetricaland nonobstetrical patients, respectively. 7-9’ 11 Nev-ertheless, given the relative rarity of maternal deathin general, we should consider septic shock amongits leading causes. 12

PATHOGENESIS OF SEPTIC SHOCKShock associated with sepsis can be caused by a

variety of pathologic phenomena. This discussionshall focus principally on the pathophysiologicevents leading to shock which can be attributed to

an overwhelming systemic immune response to in-fection. Still, it needs to be recalled that other mech-anisms can be responsible. 1 For example, hypo-volemic shock can occur under conditions of sepsisdue to massive fluid accumulation at the local site ofinfection, from gastrointestinal losses, or rarely,due to hemorrhage at a vessel with mycotic aneu-

rysm formation and rupture. Other nonimmuno-genic causes of shock during sepsis that requireconsideration are cardiogenic causes. These includevalve dysfunction due to bacteremic seeding of theendocardium and primarily diminished myocardialperformance which can be secondary to myocarditisor metastatic bacterial pericarditis.

The most common and clinically importantmechanism of septic shock is related to the pro-found systemic response to immunologic processestriggered by proliferating infecting organisms or

their byproducts. The sequence begins with a focusof infection such as an abscess, pyelonephritis, peri-tonitis, chorioamnionitis, or cellu!itis. The offend-ing microorganisms then either invade the blood-stream (bacteremia) or locally proliferate and releaseimmunoreactive mediators into the bloodstream.These mediators consist principally of structuralcomponents of microorganisms such as endotoxin(lipopolysaccharide) in gram-negative bacteremia,exotoxin (peptidoglycan/techoic-acid complex) ingram-positive infections, and polysaccharide sub-stances in yeast sepsis. 13-15

The host response to these immunoreactive mi-crobial byproducts is manifested through the acti-vation of a complex and mutually interactive arrayof host mediator cells and humoral homeostatic sys-tems. 16-19 Exposed endothelium releases vasoac-tive eicosanoids and nitric oxide as well as interleu-kins and procoagulant. Activated neutrophils

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY


produce and release platelet-activating factor, a va-

riety of interleukins, vasoactive arachidonic-acidmetabolites, lysosomal enzymes, and toxic molecu-lar-oxygen derivatives. Activated macrophagesprincipally release cachectin, also known as tumor

necrosis factor, and histamine. Many of these host-cell products, in addition to potentiating one anoth-er’s state of "activation," enhance microbial-medi-ated activation of several humoral-defense processesincluding the complement, coagulation, kinin, andadrenocorticotropic hormone (ACTH)/endorphinsystems. The activated humoral systems in turn

potentiate immune-cell activation.While these host responses generally serve use-

ful local antimicrobial functions, it is evident thatwith overwhelming infection they are activated sys-temically to an extent that their byproducts initiateand propagate the cascade of events that progress to

the state of shock. 16,17 For example, local activa-tion of the complement system enhances the bacteri-cidal activity of circulating neutrophils. However,it also triggers intravascular events that, when elab-orated at the systemic level, result in microvascularinstability and histamine-mediated vasodilation. 10

Similarly, activated neutrophils produce numerous

substances, listed above, that contribute to host de-fense by killing phagocytized microbes,g Yet,when systemically activated, these cells are observedto clump and adhere to vascular endothelium wheretheir released byproducts are destructive to "by-stander" host endothelium. The resulting microvas-cular damage contributes to several phenomenacausing diffuse capillary leak. The products of acti-vated leukocytes may also participate with immune-complex precipitants and humoral vasospastic sub-stances in the complex events leading to specificend-organ damage such as acute respiratory diseasesyndrome (ARDS) and acute tubular necrosis. 21,22

The activated ACTH/endorphin system, whichprovides modulation of pain and discomfort to thehost, may at high levels contribute to vasodilata-tion, diffuse capillary leak, and hypotension. 23 Fi-nally, the coagulation system, which has an obvioushomeostatic function when activated at the locationof microbial-mediated tissue destruction, can besystemically activated resulting in thrombocytope-nia from widespread platelet aggregation. 24 Inmany cases, frank disseminated intravascular coag-ulation is observed. Also activated in the coagula-

tion cascade is the kinin system which elaborates thepowerful vasodilator bradykinin. This substancepotentiates the profoundly decreased systemic vas-cular-resistance (SVR) characteristic of septicshock. 11

The cumulative impact ofthis overpowering im-mune response is a markedly decreased SVR andincreased capillary permeability. o, 11,16 Togetherthese cause decreased effective circulating bloodvolume and simultaneously diminished preload andafterload. The intact autonomic nervous system re-

flexly responds to this stimulus with an enormous

output of catecholamines which stimulates a com-

pensatory increase in cardiac output and regionalincreases in vascular resistance. o, 11,16

Additional endogenous substances which appearto play an increasingly important role in later stagesof septic shock are the myocardial depressant fac-tors (MDF). 25 The chemical nature, biologicalsource, and relevance of these substances to humanseptic shock remain to be fully characterized. How-ever, because myocardial depressant activity seemsto parallel serum levels of pancreatic lysosymes,these are considered possible candidates. 26 If so,MDF are presumably released under conditions ofshock-related pancreatic ischemia, O

CLINICAL FEATURES OF SEPTIC SHOCKSeptic shock can be divided conceptually into 3clinical phases which together represent a stepwisedeterioration of clinical status. 27 These phases arelabeled 1)"early" (warm), 2)"late" (cold), and 3)"secondary" (irreversible) shock. In an effort to

encourage earlier therapeutic intervention, whichalmost certainly improves outcomes, Balk andBone have recently defined the previously men-tioned "preshock" phase which they have called"sepsis syndrome."

Earl), Septic Shock

The earliest clinical sign of bacteremia is oftenextremes of body temperature. Typically, there isfever in excess of 40.6C, although occasionallyhypothermia is observed. 10 Tachycardia, warm ex-

tremities, and shaking chills will accompany thesetemperature changes. Symptoms may be nonspe-cifi such as agitation, malaise, nausea, and diar-rhea. However, a virtually uniform early symptomof which clinicians must be aware is dyspnea. 1

192 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY


Paradoxically, despite the predominant nature ofthis complaint, there are often minimal associatedphysical examination findings. This symptom istypically accompanied by tachypnea which needs to

be regarded as a worrisome sign possibly presagingthe onset of early ARDS. In some instances, therewill be a rapid evolution of further clinical signssuggesting end-organ hypoperfusion, includingmental status changes, and oliguria, ll Concomi-tantly, or soon after these signs are recognized, theonset of hypotension is likely to be observed. 10,11

This array of clinical findings represents the"warm" or vasodilated phase of septic shock. He-modynamically, it is characterized by a profoundlyhyperdynamic state with increased cardiac outputand markedly diminished SVR. 10, 1,16 When thereduction of SVR exceeds the physiologic capacityfor compensatory increases in cardiac output, hy-potension occurs. Laboratory findings may initiallyshow a paradoxically decreased white blood cell(WBC) count due to the characteristic aggregationand endothelial adherence of activated neutro-

phils. 17 Platelets may also be decreased as an earlymanifestation of systemic activation of the coagula-tion cascade. 24 Electrolytes, transaminases, and re-

nal function tests will initially be normal in most

instances. In some cases, there may be transientlyelevated serum glucose due to the high levels ofcirculating catecholamines and possibly decreasedtissue utilization. 28 Arterial blood gasses in the earlytachypneic phases will show only respiratory alkalo-sis reflecting a postulated direct effect of endotoxin

29or other mediators on the respiratory center.

Late Septic Shock

As the syndrome progresses to the "late" phase ofshock, worsening hypotension is observed. The ex-

tremities become cool and cyanotic because of reflexperipheral vasoconstriction. Frank oliguria and de-teriorating mental status reflect increasingly severe

hypoperfusion of the renal parenchyma and cere-

bral cortex, respectively. Respiratory failure mayensue.

Hemodynamic evaluation during this phase mayshow transiently improved SVR due to peripheralvasoconstriction. However, the cardiac index be-gins to decrease (probably from a combination ofvasoconstrictor-mediated increases in right and leftventricular afterload in addition to the escalating

influence ofMDF),24’26 and consequently hypoten-sion persists. Laboratory parameters at this pointare more clearly abnormal. The leukopenia oftenmanifested in earlier stages of septic shock is typi-cally reversed, and a marked leukocytosis is ob-served. Thrombocytopenia may become more se-vere with additional derangements in coagulationparameters indicating evolving disseminated intra-vascular coagulation (DIC). 24 Serum electrolytesnow show an anion gap with decreased bicarbonateand elevated blood lactate levels indicating meta-

bolic acidosis from inadequate oxygen delivery andtissue extraction. Serum glucose may fall whiletransaminases rise, indicative of evolving hepaticdysfunction secondary to hypoperfusion ("shockliver").3 Mixed venous oxygen saturation levelsmay be increased despite relatively high cardiacoutput suggesting a significant contribution ofbloodflow maldistribution and possibly a metabolic blockto oxygen and other substrate utilization at the cel-lular level. 31 The arterial blood gas confirms met-abolic acidosis and, in cases of developing ARDS,demonstrates hypoxia of variable severity. 16,21

In some cases the condition continues to deterio-rate with progression to severe ARDS and/or mul-tiple-organ-system failure. 10,16 ARDS is a condi-tion of noncardiogenic (or "capillary-leak")pulmonary edema. The diagnosis is made on thebasis of progressive hypoxemia with characteristicdiffuse pulmonary infiltrates on chest X-ray, de-creased pulmonary compliance, and a normal pul-monary capillary wedge pressure (PCWP). 21 Theterm multiple-organ-systemfailure refers to the clin-ical detection of dysfunction in 2 or more organsystems, e.g., central nervous system, renal, respi-ratory, gastrointestinal, coagulation.2 In patientsdying of multiple organ failure, there is a charac-teristic sequence of pulmonary followed by hepaticand renal failure. Clinical outcomes are directlycorrelated with the number of organs failing. Re-ported mortality ranges from 50% with ARDSalone to 80-100% when 3 or more organs fail.

Secondary Septic Shock

Myocardial depression becomes a prominent fea-ture of prolonged "late" phase shock as the patientslips into "secondary" shock. 11,16,25,26 Widespreadterminal vasodilatation and pooling of the effectivecirculatory volume also occur. The hemodynamic

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 193


TABLE 2. Hemodynamic, ventilatory, and hematologic parameters in pregnancy

Parameter Nonpregnant Pregnant

Central venous pressure I-I 0 mmHg UnchangedPCWP 3-10 mmHg UnchangedCardiac output 4-7 I/min Increased 30-45%SYR 770-1,500 dyne/sec/cm-s Decreased 25%Pulmonary vascular resistance 20-120 dyne/sec/cm- Decreased 35%Arterial pO 90-95 mmHg 104-108 mmHgArterial pCO2 38-40 mmHg 27-32 mmHgArterial pH 7.35-7.40 7.40-7.45A/V oxygen difference 4-5.5 ml/dl Slightly decreased or unchangedOxygen consumption 173-311 ml/min 249-331 ml/min

Creatinine clearance 80-110 ml/min Increased 35-50%Hemoglobin 13.5 g/dl 12 g/dlPlatelets 270-280 ( 109/I) 250-265 ( 109/I)Fibrinogen 170-4 0 mg/I 264-615 mg/I

picture shows remarkable decrements in cardiacoutput in the face of profoundly low SVR and ex-

treme hypotension. Prolonged diffuse tissue hy-poxia is reflected clinically by obtundation andanuria. Spontaneous bleeding may occur. Labora-tory findings show severe metabolic acidosis, coag-ulopathy, and renal failure. In cases of lethalARDS, worsening hypoxia with respiratory acido-sis superimposed on metabolic acidosis is observeddespite maximum ventilatory support.

)1 By thisphase, shock is usually irreversible and death inev-itable. 32,33

ASPECTS OF SEPTIC SHOCK SPECIFICTO PREGNANCY

As mentioned, the reported mortality rates in preg-nant and puerperal women with septic shock are

considerably lower than in their counterparts on

general medical or surgical services. Several expla-nations for this have been suggested. Foremost,obstetrical patients on the whole are younger andhealthier than hospitalized medical patients. Assuch, they rarely have underlying debilitating dis-eases that are known to complicate sepsis and in-crease mortality. Furthermore, in obstetrical infec-tions, the pathogens tend to be "garden-variety"endogenous flora that are less often resistant to stan-dard antibiotic regimens. Finally, these infectionsare usually etiologically straightforward and ame-

nable to medical or, if necessary, surgical interven-tion.

Because of 1) the well-described physiologic ad-aptations of virtually every organ system to normalpregnancy and 2) the less well-defined pregnancy-related immunologic modifications, differences inresponse to septic shock in gravid women comparedwith age-matched healthy nongravid women wouldbe anticipated. However, probably due to the in-frequent occurrence of septic shock in pregnancy,this area has received little attention in the litera-ture. Nevertheless, data are available regarding res-

piratory, hemodynamic, and other physiologic al-terations in normal human pregnancy (Table2). 34’5 It is important that caretakers of criticallyill pregnant women be cognizant of such data andapply them for guidance of therapeutic interven-tions.

Using experimental animals, investigators havestudied septic shock in pregnant animals comparedwith nonpregnant controls. The preponderance ofdata indicates an increased susceptibility to thepathologic effects of endotoxin in several mamma-lian species at term.6-8 Although the pathophysi-ologic basis for such observations remains specula-tive, it has been suggested on the basis of theseresults that gravidas be considered compromisedhosts. Regarding the effect of endotoxin on thefetus, data in experimental animals are less clear.Sheep fetuses were shown in one study to tolerateendotoxin in doses 10-fold higher than those thatwould be lethal to their mothers.8 The investiga-tors hypothesized that the immature status of thefetus modified its vasoactive response, protecting it



from lethal hypotension. In a separate study, thefetus of a pregnant baboon showed signs of rapiddeterioration and asphyxia following maternal ad-ministration of endotoxin. 37 In this study, the fetaleffects were attributed to maternal endotoxin-medi-ated hypotension and uterine hypercontractility,both of which contribute to hypoperfusion of theuteroplacental unit.

MANAGEMENT OF SEPTIC SHOCKThe principles of septic shock management in thepregnant or puerperal woman are similar to thosein any septic patient. 27 The goal is to maximizetissue oxygen delivery. 10,11,16,27 This is accom-

plished by establishing and maintaining optimalfunctional levels of 1) circulating fluid volume, 2)cardiac output, 3) blood oxygen carrying capacity,and 4) pulmonary gas exchange. Also of criticalimportance is to identify the potential sources ofsepsis and perform appropriate diagnostic evalua-tions. Finally, empiric antibiotic therapy is initi-ated targeting the clinically most likely pathogens.If a surgically sigMficant source is apparent, drain-age should be accomplished.

During pregnancy, many difficult managementissues are amplified by concerns about the fetus.Still, optimal therapy for the mother remains thest priority. Fetal compromise under these circum-

stances is directly attributable to maternal cardio-vascular decompensation and the attendant decreasein uteroplacental blood flow. Hence, improvementsin maternal hemodynamic stability will have posi-tive effects on the fetus. In addition, efforts to

intervene on behalf of the fetus by operative deliv-ery of an unstable mother may end in catastrophicresults for both the fetal and the maternal patients.The obvious exception to this axiom is when thesource of sepsis is the fetal compartment in whichcase delivery becomes a critical part of therapy,i.e., surgical "drainage."

The traditional therapeutic interventions em-

ployed in septic shock management are aimed at

reversing the physiologic aberrations encounteredin septic shock. Decrements in effective circulatingvolume and oxygen delivery to tissues are treatedby fluid replacement, pressor and inotropic drugtherapy, and blood transfusions. Coagulopathy ismanaged with selective transfusions. Support forpulmonary dysfunction is initiated by increased

fractional inspiratory oxygen concentration and, ifnecessary, mechanical ventilation. With recent in-sights regarding the pathophysiologic mechanismsof hemodynamic deterioration in septic shock, sev-

eral innovative avenues of therapy have been sug-gested and investigational protocols initiated basedon attempts to arrest or modify the overzealousactivation of host immune cells and humoral sys-tems. Such approaches include novel antiendotoxin,antieicosanoid, and antiendorphin pharmacothera-pies.

Circulatory Volume Expansion andHemodynamic Monitoring

The initial resuscitation for septic shock is by ag-gressive circulatory volume expansion. Such ther-apy is essential in all cases, and the sooner it isinitiated the better. In responding patients, clinicalimprovement is indicated by increments in cardiacoutput and tissue oxygen consumption, with a con-comitant decrease in arterial lactate levels. Remark-able quantities of replacement fluid are often neededdue to the enormous redistribution of circulatoryblood volume by the combined effect of extensivevasodilatation and the "third-space" loss of previ-ously intravascular fluids attributed to increasedcapillary permeability.

Most authors27’39’40 agree that the initial fluidbolus should be crystalloid (0.9% saline or lactatedringers) at a volume of 1-2 1. While the bolus isbeing infused, it is recommended that central he-modynamic monitoring be initiated. For this, a

flow-directed pulmonary-artery catheter is recom-mended which allows the most accurate availableassessment of left ventricular filling pressures (orpreload) to guide fluid management. 41 A variety ofprotocols have been described for monitoring fluidchallenges after pulmonary-artery catheterization.The popular method of Shubin and associates42

includes serial boluses of 200 cc of intravenous (IV)fluid over 10 rain. Measurements of PCWP aredetermined between boluses. For pressure increases<7 mmHg, boluses are repeated. The aim of ther-apy is a PCWP of approximately 10-15 mmHgwhich, in septic shock patients, represents the pointat which left ventricular preload is optimized ac-

cording to the Frank-Starling law. 43 Additionalinformation provided by the pulmonary-artery cath-eter includes estimation of the cardiac output, mea-



surement of mixed venous oxygen saturation, anddata for calculations of vascular resistance and oxy-gen utilization. All of these parameters providevaluable information not only for fluid manage-ment but for the guidance of all hemodynamic in-terventions applied to shock patients.

Vasoactive PharmacotherapyIn patients who fail to respond adequately to opti-mization of preload with pulmonary-artery-cathe-ter-guided fluid management, the next step in sep-tic shock therapy is the use of exogenouscatecholamines or sympathomimetic agents. Mostclinicians employ dopamine as the first-line vasoac-

tive agent. 16’27’39’4’44 A feature unique to thisdrug is its dose-related catecholamine-receptor se-

lectivity. At low infusion rates (0.5-3.0 pg/kg/rain), the observed physiologic actions are primar-ily dopaminergic receptor mediated and arecharacterized by renal, splanchnic, and cerebralvasodilatation. 45 The attendantly increased renalperfusion at such doses leads to improved urinaryoutput. At higher infusion rates (5-10 Ixg/kg/min),[3-adrenergjc-mediated effects predominate. Ino-tropic cardiac effects are observed without signifi-cant peripheral vasoconstriction. However, as rates

of infusion approach and exceed 15 I,g/kg/min,e-receptor-mediated effects become dominant. Un-der these conditions, there is widespread peripheralvasoconstriction and reversal of the selective va-

sodilatory effects of lower-dose dopamine. 46 Thephysiologic results at high doses, all of which are

countertherapeutic in septic shock patients, are di-minished systemic perfusion as well as increasedafterload and cardiac work. 44

Other sympathomimetic drugs that may be usedin the setting of septic shock include dobutamineand norepinephrine. Dobutamine, due to its pre-dominance of [3-1 and [3-2 adrenergic effects com-bined with a relative absence of ot-adrenergic ef-fect, simultaneously provides inotropic support anddecreased SVR.44 This allows improved cardiacoutput without considerable increases in cardiacwork or cardiac oxygen demand. 47 Hence, it maybe an appropriate choice when low cardiac outputbecomes a dominant feature in patients with ad-vanced septic shock. In contrast, norepinephrine isprincipally an c-adrenergic stimulatory catechola-mine.44 Its effects are peripheral vasoconstriction.

In early septic shock, one of the pathophysiologicphenomena with which the physician must contendis profound systemic vasodilation. Some investiga-tors44’48 have suggested that norepinephrine incombination with low-dose dopamine (to preserverenal blood flow) be used to ameliorate this prob-lem. An animal model has documented an improve-ment of cardiovascular parameters while improv-ing renal blood flow on such a regimen, but a

therapeutic benefit in humans remains to be dem-onstrated. 49

Therapy for Respiratory Failure

As mentioned, respiratory failure in the form ofARDS is a common complication of septic shock. 21The diagnosis is usually made on the basis of pro-gressive hypoxemia, diffuse infiltrates on the chestX-ray, and decreased pulmonary compliance de-spite a normal PCWP. It should be kept in mindthat ARDS is not a disease entity but a unifyingpulmonary complication of multiple varied criticaldisease processes. Therefore, therapy is supportivewith the goal of maintaining ventilation and oxy-genation. While the primary disease (the septicsource) is treated and reverses, the secondary pul-monary injury will generally resolve. As with alltypes of respiratory failure unresponsive to nonin-vasive therapy, treatment is initiated with intuba-tion followed by ventilation using high-fractionalinspiratory concentrations ofoxygen. Subsequently,an attempt is made to rapidly decrease inspiredoxygen levels to nontoxic doses (generally thoughtto be <50%). An arterial sampling catheter is usu-ally placed for serial blood gas monitoring to guideventilator changes. Frequently, in cases of ARDS,achieving nontoxic inspired oxygen levels requiresthe employment of positive-end expiratory pressure(PEEP). 16,21 The limiting factors with PEEP are

related to barotrauma (including pneumothorax andalveolar overexpansion) and negative influences oncardiac output, both ofwhich occur at higher PEEP

16,21pressures.

Identification of Septic Source andAntibiotic Initiation

Optimal therapy for the septic shock patient re-

quires rapid and aggressive initiation of treatmentdirected at the underlying septic source. Thus, si-multaneously with efforts to support cardiovascular



and respiratory status of the patient, a careful inves-tigation into the location and cause of the responsi-ble infection needs to be performed. As quickly as

possible, empiric antimicrobial therapy must thenbe started.

The diagnostic workup for a septic source is ofcrucial importance as its findings 1) guide antibi-otic choice and 2) may uncover a locus requiringsurgical intervention for definitive therapy. In ob-stetrics, the source is frequently but not alwaysobvious. In every case, a thorough evaluation isessential beginning with a complete physical exam-

ination and proceeding with directed laboratoryevaluation, culture of appropriate body fluids, andin most instances performance of selected imagingtechniques. In virtually all cases, the minimal eval-uation should include a chest X-ray and microbio-logic evaluation of the blood, urine, sputum, andany wound (including the postpartum endom-etrium) which may be present. When the patient isstill pregnant, an additional etiology that requiresstrong consideration is amnionitis. This is easilyevaluated by amniocentesis which, in the absence ofdefinitive evidence of an alternative source, must

be performed. Some cases may require ultrasound,computed tomography, or magnetic resonance im-aging of the abdomen and pelvis when the specificsource remains elusive or the physical examinationstrongly suggests an abscess in one of these cavities.

After completion of the sepsis workup, empiricantibiotic therapy is initiated without delay. Basedon the likely sources of infection in the obstetricalpatient, antimicrobial therapy must target a broadspectrum of bacteria including aerobic and anaero-

bic (gram-positive and gram-negative) bacteria.Most authors agree that combination parenteraltherapy is most appropriate. 27’39’4 Although a va-

riety of protocols have been suggested, a well-estab-lished regimen includes a penicillin at high dose,an aminoglycoside at the appropriate weight-ad-justed dose, and an antianaerobic agent such as

clindamycin or metronidazole. Because ofthe neph-rotoxic risk of aminoglycoside therapy, it is essen-tial that peak and trough levels be monitored anddosages adjusted accordingly with target levels of6-10 and <2 Ixg/ml, respectively. In patients withpreexisting or rapidly evolving renal insufficiency,an alternative antibiotic regimen substituting aztre-

onam for the aminoglycosides may be considered.

This preserves gram-negative coverage while de-creasing nephrotoxic risk. Empiric combinationtherapy is continued pending culture and sensitiv-ity results. When available, these results allow ad-justment of the regimen in order to be more antibi-otic selective and specific-microbe directed.

Surgical Intervention

A classical surgical principle maintains that "thetreatment of abscess is incision and drainage." Re-cently, this dogma has been challenged under somecircumstances such as an uncomplicated tubo-ova-rian complex in which resolution with antibiotics

50alone has been well documented in many cases.

Still, when faced with septic shock with an identi-fied source, most clinicians agree that drainage ofinfected fluid collections and removal of devital-ized tissues should improve survival. Similarly, inpatients in whom the septic source is not obvious, a

delay in clinical improvement or progression to

multiple-organ-system failure despite maximalmedical therapy should suggest an undrained locusof infection.

In obstetrical patients with septic shock, thereare several scenarios in which the physician must

contemplate surgical intervention. Septic abortion,for example, requires prompt initiation of broad-spectrum antibiotics and hemodynamic stabiliza-tion. Subsequently, the uterus must be evacuated, sl

This should be done expeditiously and can be ef-fected either by dilation and evacuation or by med-ical induction of labor. The former has the advan-tage of predictable and timely removal of the septicsource. However, it requires operator experiencewhich, for advancing gestational ages, is increas-ingly rare among obstetricians.

In patients presenting with chorioamnionitis, theobstetrician is faced with the difficult judgment ofbalancing maternal and fetal risks. After initialresuscitation of the mother, a plan must be madeand initiated as to the route of delivery. When a

vaginal delivery is imminent and both the maternaland fetal patients are stable, antibiotics should beinitiated and a cesarean section often can be avoided.However, in cases remote from potential vaginaldelivery, the risk of cesarean section to a criticallyill parturient may be warranted. Our anecdotalexperiences suggest that in such cases the improvedchances for the fetus by effecting urgent delivery,

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 197


coupled with the uncertain risk to the mother ofdelaying removal of the nidus of infection, justifycesarean section. A decision in some cases will bedifficult and must be individualized. It is impor-tant to emphasize that delivery is usually not indi-cated for septic shock patients in whom the septicsource is extrauterine, i.e., appendicitis, pyelone-phritis, pneumonia.A final scenario deserving mention is the postop-

erative cesarean section patient with clinical deteri-oration despite optimal antibiotic coverage. In somecases, the explanation is extensive myometrial mi-croabscess formation and definitive therapy requireshysterectomy. Other conditions to be consideredunder such circumstances include septic pelvic-veinthrombosis (which in most cases responds whenanticoagulation therapy is added to the antibioticregimen) and episiotomy or other wound infections(which require subcutaneous and in many cases

extensive fascial debridement). 52

Miscellaneous Therapeutic ConcernsAdditional complications not unique to but fre-quently encountered in septic shock patients areacute renal failure and coagulopathy. 24’s3 In allshock patients, an indwelling urinary catheter isplaced for hourly assessment of urine production.This provides a clinical parameter for end-organperfusion. As output begins to diminish serial se-

rum creatinine, an examination of the urine sedi-ment and comparison of urinary to plasma sodiumand osmolality provide useful data for distinguish-ing prerenal from renal parenchymal damage (acutetubular necrosis) due to prolonged hypoperfusion.Patients with prerenal oliguria will have low frac-tional excretion of sodium with high urinary osmo-lality and will respond to intravascular volume ex-

pansion. Patients having acute tubular necrosis willhave high fractional excretion of sodium, low uri-nary osmolality, and often "dirty" tubular casts in a

spun urine. These patients typically remain oligu-tic but may manifest a nonoliguric renal insuffi-ciency with progressive increments in serum creat-

inine. In most cases, the renal parenchymal damageis reversible with the resolution of the compro-mised hemodynamic state of shock, although therecovery may be sufficiently delayed to requireshort-term dialysis. Rarely, renocortical necrosismay occur, in which case the renal failure is most

likely permanent. 53

Coagulation abnormalities reflecting variable-severity DIC are a frequent finding in septic shockpatients, and serial evaluation of platelets, fibrino-gen, and fibrin degradation products is suggested. 24

In the absence of frank clinical bleeding, the man-agement is mainly a reversal of the underlyingcondition after which the coagulopathy spontane-ously resolves. However, when spontaneous bleed-ing does occur, e.g., bleeding mucous membranes,oozing at venipuncture or arterial-puncture sites,postoperative incisional bleeding, or when plateletsfall below 20,000/ml (the level below which spon-taneous internal hemorrhage is thought to occur),selective blood-product transfusion including an ap-propriate combination of platelets, fresh-frozenplasma, and cryoprecipitate may be indicated. 16

Controversial and InvestigationalTreatment Modalities

A longstanding controversy in the treatment of sep-tic shock is the use of pulse-dose corticosteroids.The rationale for such an approach is firmly sup-ported by the present conceptualization of overzeal-ous host inflammatory-mediated pathophysiologicevents culminating in clinical septic shock. Earlyexperimental and clinical studiess4 reported in-creased survival with pharmacologic doses of ste-roids. However, more recent reports, including 2large multicenter studies, ss’s6 failed to demonstrateimproved outcomes in steroid-treated septic shockpatients. In fact, the subgroup of patients havingrenal insufficiency had apparently increased mor-

tality in the steroid-treated group, s6 Similarly, inhigh-risk patients, no decrease in the progression to

septic shock or the development of ARDS could beestablished with prophylactic high-dose steroids, s6

Consequently, few intensivists are recommendingsteroids for the treatment of septic shock except inpatients with suspected adrenal insufficiency or

other specific indications.Endorphins are endogenous opiates that are

known to be elaborated during sepsis. ) They havepotent vasodilatory effects and have been impli-cated as contributors to the hemodynamic instabil-ity characteristic of septic shock. Naloxone is an

opiate antagonist that will reverse endorphin-in-duced hypotension in experimental animals.2

However, both experimental and clinical studieshave yielded inconclusive data regarding the hemo-dynamic benefits of naloxone administered for sep-



tic shock. 23’57 More work needs to be done prior to

clinical implementation of this therapy. An addi-tional concern about naloxone specific to pregnancyis the unexplained observation of gradual increasesin steady-state endorphin levels with advancing ges-tation, s8 The importance of this phenomenon to

normal physiology and its relevance under condi-tions of septic shock in pregnant women are not

known.Immunologic therapy for the treatment and pre-

vention of" septic shock is an area of" active andpromising investigation. Most attention in this areahas been focused on antibodies directed against en-dotoxin, s9 Endotoxin, which is released during bac-terial lysis in gram-negative septicemia, has beenshown in experimental animals to produce many of"the acute physiologic and long-term pathologicevents observed in human septic shock, sg’

Bioengineered antiendotoxin antibodies have beenshown in these models to prevent some of" thesechanges. The most ef’f’icacious antibodies seem to bethose directed specifically toward the innermost por-tion (lipid A) of" the complex endotoxin molecule.In contrast to the earlier constructed antibodies di-rected at the outermost species-specific oligosaccha-ride (O) region of" the endotoxin molecule, theantilipid A antibodies bind to a wide spectrum of"gram-negative organisms.6 In clinical studies, suchantibodies have demonstrated clear enhancement of"survival and earlier reversal of" organ dysfunctioncompared with placebo in series of" medical andsurgical patients with septic shock. 62’3 A reduc-tion in incidence of" septic shock and deaths relatedto sepsis was also demonstrated in high-risk surgi-cal patients randomized to a regimen of" prophylac-tic antiendotoxin. 62 Studies specifically in obstetri-cal patients are limited. One small mixed series64

of" obstetrical and gynecologic patients showed im-proved survival (93% vs. 54%) and shorter hospi-tal stays in those administered an antilipopolysac-charide compared with those given no therapy.Other avenues of" immune therapy under current

investigation involve antibodies directed againstmacrophage-derived tumor necrosis factor 18 andefforts to derive nontoxic derivatives of lipid A toattenuate the systemic response to endotoxin. 6s

A final strategy for septic shock therapy by mod-ification of the host response to septicemia is via theeicosanoid system. As mentioned, several ei-cosanoids (including a variety of prostaglandins,

leukotrienes, and thromboxane) appear to be im-portant mediators of septic shock. o, 11,16,17,20 Sev-eral studies66’67 suggest that prostaglandin syn-thetase, leukotriene, and thromboxane inhibitorsattenuate the hemodynamic response and improvesurvival in experimental endotoxic and bacteremicshock. Rigorous clinical trials of this applicationfor these drugs are forthcoming, but initial data are

promising.

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