Septic Shock: A Clinical Perspective

Infections in the CriticaUy ZU

Septic Shock: A Clinical Perspective Robert L. lverson, M.D.*

Septic shock is a complex series of events leading to perfusion failure and, frequently, death that is precipitated by the entry of micro-organisms or their toxins into the bloodstream. Although gram-negative coliform endotoxemia is most often incriminated, a long list of other organisms may initiate the syndrome, including gram-positive cocci and bacilli, gram-negative cocci, spirochetes, rickettsias, viruses, fungi, and parasites. Reliable epidemiologic statistics are few, but reports over the past 30 years suggest that the number of septic shock cases per 1000 hospital admissions per year is progressively increasing. Epidemiologic reports often fail to distinguish between bacteremia and septic shock, but a Centers for Disease Control panel has estimated that as many as 140,000 cases of gram-negative bacteremia occur annually,21with approximately half of them progressing to hank septic shock. Of patients in septic shock, 40 to 60 per cent die if diagnosis and therapy are prompt, whereas 90 to 95 per cent die if medical intervention comes late. Incidence rates would undoubtedly be higher if all microorganisms causing sepsis were included. Recent literature has emphasized nosocomial septic shock in the intensive care unit (ICU), with discussions of catheter-induced sepsis, malnutrition, poor hand washing technique, inappropriate antibiotic use, contaminated respiratory therapy devices, or improperly followed isolation procedures. Although there is no doubt that these are critically important factors, it is the author's experience that most patients with septic shock admitted to the ICU are debilitated patients transferred from home, chronic care facilities, or the general medical or surgical ward. Many of the deaths in this group could be prevented by early diagnosis and treatment of common infections and the timely recognition of the first signs of septic shock. Many excellent reviews of septic shock have recently appeared, with particular attention to research on vasoactive mediators, products of arachidonate metabolism, cytotoxic free radicals, and beta-endorphins, complement activation and their possible roles in the biochemistry of the sepsis ~ y n d r o m e . ' . ~ ~This .'~.'~ discussion will focus instead on the clinical manifes*Assistant Professor of Medicine, Division of Critical Care/Pulmonary Medicine, Wayne State University School of Medicine; and Director, Medical Intensive Care Unit, Hutzel Hos-

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Critical Care Clinics-Vol.

4, No. 2, April 1988

215

tations of septic shock, the pathophysiologic foundation for rational therapy, and firm up-to-date guidelines for treatment.

HOST FACTORS Certain host factors increase the risk of septic shock in infected patients. The young, previously healthy patient with severe infection usually does not develop septic shock. However, the elderly, diabetic, or debilitated patient and the intravenous drug or alcohol abuser are at much greater risk. The patient of any age, regardless of prior health, who has multiple organ failure is at particular risk. Additionally, in~inunocompromisedpatients not only experience an increased incidence of septic shock but also present special considerations for unusual opportunistic organisms as well as predictable patterns of infection by the usual pathogens. Patients with severe neutropenia (less than 500 per mm3) from cancer chemotherapy have a greater than 50 per cent incidence of sepsis, primarily involving gram-negative bacilli, Staphylococcus aureus, and Candida species. B-lymphocyte defects in patients with multiple myeloilla or chronic lymphocytic leukemia predispose to infection by Streptococcus pneunzoniae and Haernophilus influenzae with possible septic shock. Complement-factor deficiencies associated with cirrhosis, systemic lupus erytheinatosus, and sickle cell disease may lead to septicemia and shock from Strep. pneunzoniae, Neisseria gonorrhoeae, or N . meningitidis. Hyposplenism due to Hodgkin's disease, hemolysis, or splenectomy also predisposes to life-threatening infection by Strep. pneuinoniae and H. influenzae.

A practical understanding of the pathophysiology of septic shock, particularly the hemodyna~nicderangements, is essential for guiding aggressive and effective therapy. Septic shock, as opposed to the taxonomic elegance of a disease state, with (usually) a well-defined etiology and pathology, is more properly accorded a syndrome status: a clinical constellation of signs and symptoins that appear to be temporally related but for which precise causal relations have not been established. Future research may well explicate the precise primary elements that precipitate and sustain the biochemical cascade manifesting itself as the sepsis syndrome. Nevertheless, certain hernodynamic alterations have been well described that are virtually unique to septic shock and which create therapeutic imperatives. Whatever the inciting event, the first manifestations of septic shock appear to be organ cellular dysfunction and vasodilation reflected by a reduction in whole-body oxygen consuinption (VO,) and reduced systemic vascular resistance (SVR). In the absence of preexisting heart disease, the compensatory cardiac response is reflected by tachycardia and high cardiac output (CO). Although the healthy heart inay be capable of doubling or tripling its normal output, in septic shock, the hyperdynainic response is inadequate to correct the perfusion failure.

-. . Hx!deed, &e $~._istotoxli.it~: , g- siiu:h that ceiiui~i-sxygen nt&zation is sufi=,c;eritbr ir:~paired so that V 0 2 may noi b e totally delivery depeiider?t. Corlpounding e h tissue ~ perfusion faihi-e is the loss of integrity of capillary membranes of varieras severities, leading to the ioss of plasma volume Pri111arily because 6.f' vasodilation ax:$ the creation of a prohund venocapscitznce, and secol~dariiybecame of plasma leakage, the venous blood return to the right side of the heart and the left venbisuiar preload are i~~aPked!;i reduced, This preload reduction, reflected by a low pulmonary artery wedge ". p? .-L,,aLre, > 6- C further compronlises tissue per-lasion by Iillrifiilg cardiac outpert. As tissue pedusicjn becomes inadequate, anaerobic metabolism aand lactic acidosis pi.-vide negative i n s t r ~ p - ceffects. E ~ ~ i d e n calso e stlroicgiy siiggests the eiaboration of a biochemical clrcu!atii?g Imyacardiai "dep-essant fictor" impairing cardiac outpu:. The two principal consequences ic septic shock, . L-e&~y.-ed Xis, e ~ islpaired d 9::~7gi?n del;lre.-~i(Gg,), :!lere&iie, irigly, &era;pentic interveniiea is dii-eeted to:wari iracreasing VO, aild DO,. d

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Rrducr;d 113,appears to be the 1-esuEt primaiii;/ of t w ~&..ctors: (1) . impaired ceil&.r ~llifochct3-,dr~a~ oxygeil t:tiiizaiien in tKe pl-esen-e (11 s;:ito. F b3:'1in~activ&:ed 01- rele;rsed in the I;iochem:-ai cascade; al?d (2) ifi tile absoiuti: qcaltiiy gf oxygen deiirrere$ the (DO,). Current is ei/a]catil;g cli~iltof :eb[;;.t-t.> --"'. b/
fir

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An.te:iai ~ x,~ed-A . i ~c~n<:e?: c;> (Tj,s,) in :urn is de';e:.miiied by tji 72tieni's .. - globin conceiitratic:c, che v,W~L> ccmbining capacity, <>xyt?;eil .;aturetic;n

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of the arterial blood (S,O,), and the amount of 0, physically dissolved in the plasma (equation 2): C,O, = [Hgb

x

1.34

x

S,0,]

+ [0.0031 x

P,O,]

This equation is derived from the facts: (1)that 1.0 gm of hemoglobin can bind an estimated 1.34 ml of oxygen when fully saturated, and (2) that oxygen can go into solution with a coefficient of solubility of 0.0031, depending on the partial pressure of 0, (mm Hg) in p l a ~ m aTherefore, .~ it is readily apparent that improved DO, is a function of increased cardiac function, optimal oxygenation, and an adequate number of red blood cells. For practical clinical purposes, the fraction of 0, dissolved in the plasma may be ignored except in situations of severe anemia, when a high P,O, may contribute significantly to C,O, until blood transfusion is performed. Further, even though 0, is loaded and delivered, considerations of 0,-Hgb dissociation factors may be relevant to ultimate 0, release and transport to the cell. Although to the author's knowledge the Bohr effect* on the shift of the 0,-Hgb dissociation curve has not been shown to be clinically relevant to cellular 0, uptake, prudence would suggest avoidance of an alkaline plasma pH. Sufficient red blood cell 2,3-diphosphoglyceric acid is also required for the adaptive rightward shift of the 0,-Hgb dissociation curve and is partly dependent on the availability of sufficient plasma inorganic phosphorus for its synthesis. This may be clinically relevant in critically ill patients with malnutrition or who are h ,v-~ o ~ h o s ~ h a t e m because ic of transcellular shifts. calcium infusions, or frequent hemodialysis. Although the oxygen extraction ratio (VOJDO,) is decreased in patients with.septic shock, not all septic patients demonstrate increased VO, when the DO, is increased after therapeutic intervention. There is some evidence that those septic patients with a cellular oxygen debt manifested by lactic acidosis may indeed have a higher VO, following improvement in their DO, and conversely that those with serum lactate levels below 2.2 mM per L may not similarly benefit from increased Figure 1, adapted from Cain,4 depicts the relation between VO, and DO,. In the septic patient, various pathologic factors may reduce cellular 0, uptake, such as altered vasoregulation, peripheral arteriovenous shunting, interstitial edema, or impaired cell-membrane 0, transport. Therefore, the 0, delivery curve may be shifted up and to the right in the septic state, reflecting the need first, for a higher DO, to maintain the VO, observed in the normal state and, second, that the VO, may be driven higher if supranormal DO, is a ~ h i e v e d . ~ Unfortunately, in the late phase of septic shock, many patients exhibit an apparently fixed or progressively decreasing VO, associated with progressive lactacidemia despite maintenance of supranormal DO,, a situation possibly reflecting cell death in the preterminal state.

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L,

&

*Bohr effect: In the pH range 7.0 to 7.4, the hemoglobin subunit binding of protons increases as the pH falls, thereby decreasing the &nity of hemoglobin for oxygen at the tissue level. This results in an increased P, and the rightward shift of the 0,-Hgb dissociation curve, theoretically enhancing 0, delivery.

Oxygen Delivery ( ~ 0 ~ )

Figure 1. A, Normal delivery dependent and B, independent 0, uptake curves. Altered delivery dependent curve (C) observed in septic shock. The rightward shlfted delivery curve ( C ) reflects clinical observations in some septic patients that 0, uptake may be "driven" by higher O2 delivery.

DIAGNOSIS The first principle for early diagnosis of septic shock is to maintain a high index of suspicion in a clinical setting that predisposes a patient to sepsis. Any patient with an infection is at risk. The risk is heightened by the various host factors previously outlined. In the ICU, the risk of infection is increased in the presence of vascular catheters, tracheal and chest tubes, peritoneal dialysis catheters, bladder and rectal tubes, abdominal drains, and intracranial pressure monitoring lines. These factors are addressed elsewhere in this issue. The clinical signs of early septic shock are often vague and nonspecific and may b e elusive to the inexperienced house officer, but the alert clinician will almost always recognize the clues8 Most commonly, the patient will have a fever; less often, the temperature will be normal or low, particularly in the elderly debilitated patient or one receiving corticosteroid therapy. The onset of mild confusion or agitation without apparent explanation is frequently an early sign. The patient may be oliguric despite provision of maintenance amounts of fluid and may proceed to acute renal failure if tissue perfusion is not improved. Tachycardia is almost always present, and arterial blood pressure changes may not be prominent. In the early shock state, the systolic blood pressure may decrease 10 to 20 mm Hg from baseline yet remain in the normal range until the eventual onset of frank hypotension. The extremities are warm and flushed, certainly not suggestive of the classic onset of shock and hypovolemia. The patient is usually tachypneic, and cardiac auscultation may reveal a new systolic flow murmur consistent with a hmerdvnamic state. In the res shock a r t e r h l o n r l gas s t 1 ~ ; 7 reveal only a simple mild respiratory alkalosis. Later, as tissue perfusion

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worsens, a primary metabolic (lactic) acidosis will be prominent. Mild relative hypoxemia is commonly present in early sepsis, which does not necessarily herald the onset of permeability pulmonary edema but rather reflects VIQ mismatching in early sepsis. The white blood cell count is usually increased and is associated with the presence of toxic granulation and a left shift toward immature forms in the differential count. Not infrequently, however, the white count is normal or low in the elderly or debilitated patient. Laboratory studies are usually neither specific nor sensitive for the early diagnosis of sepsis. Mild liver function abnormalities are commonly observed. Mild hyperglycemia may be observed, as well as trace proteinuria. Marked hypoglycemia is seen occasionally in severe or late septic shock. Lactic acidosis is universally present in late sepsis but is infrequently present in the early phase. Coagulation studies may reveal mild prolongation of the prothrombin time and activated partial thromboplastin time, but this is more common in the later phase of sepsis. The signs and symptoms are admittedly nonspecific and may well raise the suspicion of pulmonary embolism as much as they suggest early septic shock. Nevertheless, their appearance in the patient with a known or suspected infection (especially in a compromised host) constitutes a medical emergency and should be presumed to mean septic shock until proved otherwise. Immediate transfer to the ICU is mandatory for proper volume resuscitation and aggressive supportive care. A leisurely approach toward "working up" the patient on the general hospital ward, the initiation of singleantibiotic therapy for the newly discovered urinary tract infection, the efforts at rehydration by increasing the intravenous fluids to the inadequate rate of 150 to 200 ml per hour, or the desire to obtain a ventilation-perfusion lung scan are all examples of unacceptable homeopathic, temporizing measures that all but assure the demise of the patient.

TREATMENT Time is critical if the patient with septic shock is to be salvaged. In the Detroit Medical Center Hospitals, the medical intensive care guidelines enjoin the house officers to manage early sepsis as a medical emergency. Once the diagnosis is clinically presumed, a number of diagnostic and therapeutic tasks are expected to be performed within 20 minutes: establishment of central venous access; infusion of 500 to 1000 ml of isotonic saline; acquisition of blood, urine, sputum, and other appropriate specimens for microbiologic culture; and emergency transfer of the patient to the ICU. Administration of at least two broad-spectrum antibiotics is also encouraged if all culture specimens have been obtained. Such a rapid response with these activities is unusual or difficult at most hospitals in view of logistics. However, the medical director of one medical ICU in the Detroit Medical Center has assembled a mobile septic shock resuscitation cart that is stored in the ICU. When the septic shock patient is identified, the intensivist or medical ICU fellow quickly wheels the cart to the patient's bedside on the general ward and initiates the septic shock protocol prior to transfer.

Table P.

Nemodyna~nicProfile Typical of Early Septic Shock NORMAL -

Blood pressure = 105150 mm Hg Heart rate = 120Imin Cardiac output = 10.1 Llmin Pullnonary artery wedge pressure = 3 inn1 Hg Pulmonary artery pressure = 21112 mm Hg Right atrial pressure = 10 mm Hg Hemoglobin = 10.2 gmldl S , O , = 9 4 % S , 0 2 = 8 1 % B.S.A. = 2 . 0 m L Cardiac index = 5.1 Llminlm2 Mean arterial pressure = 68 mm Hg Mean pulmonary artery pressure = 15 mm Hg Systemic vascular resistance = 459 dynes/sec/cmr5 Pulmonary vascular resistance = 95 dyneslseclcm-5 Stroke volume index = 42 mllbeatlml Ci,.,i02 = 1.7 vol % DO,I = 1293 ml O,/minlmL V021 = 86 ml Odmin/m2 Left ventricular SWI = 37 gm.m/rn2 0, extraction ratio = 13.2% Arterial lactate = 2.5 mM/L

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2.8-4.2 85-95 10-20 900-1300 60-100 35-45 3.5-5.0 550-600 110-160 40-60 22-28 12.0

The resemblance to the Code Blue procedure cart is not accidental. The survival and discharge rate of patients (excluding coronary care unit patients) experiencing in-hospital cardiopullnonary arrest and cardiopulmonary resuscitation is approximately 15 per cent,3 a higher mortality rate than that of patients resuscitated from early septic shock. Paradoxically, most I~ospitalmedical staffs exert great effort to provide efficient code teams, yet septic shock patients often are not treated urgently despite their better survival rate. These observations may justify detaching the intensivist from the ICU when needed for urgent consultation in the patient with suspected early septic shock.

All patients with septic shock require arterial catheterization for close blood pressure monitoring and puln~onaryartery catheterization, not only for assessment of cardiac function and volume status, but to guide the required aggressive fluid resuscitation. Indeed, the hernodynamic profile in suspected early sepsis inay confirm the diagnosis even before evidence of active infection is available. A typical hernodynamic profile before fluid resuscitation in early sepsis mav be reuresented as in Table 1. Notable features of this nrofile include: high cardiac index, low pulmonary artery wedge pressure, high S,,O,, low VO,,low C,,.,,O,, low extraction ratio, low SVR, and increased arterial lactate levels. Except for patients with severe liver disease with intrahepatic shunting or an anatomic left-to-right shunt (such as in ventricular septa1 defect), this hemodynamic profile would appear to be unique to septic shock and therefore could be considered presunlptively diagnostic in early sepsis.

The therapeutic imperatives dictated by the previously described hemodynamic derangements call first for the rapid increase in left ventricular preload. This is best accomplished with a fluid challenge protoco120delivering 150 to 200 ml of an isotonic volume expander every 10 minutes and raising the pulmonary artery wedge pressure to a level consistent with the maximum possible cardiac output. This may require 5 to 15 or even more liters. The optimun~pulmonary wedge pressure will differ from patient to patient, and it is important to extrapolate an imputed left ventricular function curve for each patient, recognizing further that this curve may change from day to day in the same patient as the clinical course of sepsis changes. In general, the optimum wedge pressure will be in the range of 12 to 18 mm Hg. The fluid used for volume resuscitation may be either crystalloid or colloid; however, the total fluid volume required for optimum preload may be much less with colloid use. The kev concern is the timeliness of resuscitation, and the use of colloid may facilitate more-rapid volume repletion. If blood transfusion is required as well, packed red blood cells would be the preferred agent. In some regions of the world, fresh whole blood is used routinelv and is auicklv available: but the transfusion of fresh blood in the setting of septic shock is not indicated and, indeed, is associated with welldefined risks. The anemic, septic patient requires only component therapy with red blood cells and should not be subiected to the risk of allergic " reactions to unnecessary plasma components, leukocytes, or platelets. Fresh whole blood stored less than 48 hours contains active coagulation factors and may be advantageous in the septic patient with hemorrhage due to disseminated intravascular coagulation IDIC). However, most blood banks are Drepared to provide safer and more economical component therapy for the specific needs of the patient. To this end, it is recommended in septic shock to maintain the hemoglobin at 12.0 to 14.0 gm per dl. In most other clinical circumstances, a hemoglobin level of 10 gm per dl is adequate. Hqwever, in sepsis with low VO, and higher 0, delivery dependency, the DO, will be substantially improved with added packed red cells for greater 0,-carrying capacity. By increasing the hemoglobin from 10 gm per dl to 14 gm per dl, an additional 500 1111 of oxygen per minute can be delivered to the tissues (assuming a cardiac output of 10 L per minute and 95 per cent S,O,). The thermodilution cardiac output and hemodynamic profile studies should be repeated after volume resuscitation, transfusion, and final adjustment of oxygen supply for attaining an S,O, of at least 90 per cent. If the mean arterial blood Dressure continues to fall d e s ~ i t evolume loading, then dopamine should Ge infused at 5 to 15 pg per k g p e r minute and titrated to maintain a mean pressure of at least 60 mm Hg. If, on the other hand, the pressure is adequate after administration of intravenous fluids but there is no improvement in the DO, or VO, or if the blood lactate continues to rise, it is recommended to infuse dobutamine at 1 to 20 pg per kg per minute to improve the hemodynamic characteristics. Often, with fluids and low-dose vasoactive drug infusion, the blood lactate decreases within hours, associated with a rise in the blood pressure and oxygen delivery parameters. If the patient has severe preexisting heart disease or the sepsis remains

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refractory to the aforementioned regimen, other vasoactive drugs may be considered. Some authors have revisited the use of levarterenol at low rates (2 to 8 pg per minute) combined with "renal perfusing doses" of dopamine (3 to 5 pg per kg per minute), suggesting that the dopamine may preserve renal blood flow by blunting the renal vasoconstrictive effects of levarterenol. Other anecdotal reports suggest that the combination of dopamine and dobutamine may b e more effective than either drug alone at any infusion rate. Once this refractory stage is reached, however, the prognosis is poor.

Other contributors to this issue address the specific recommendations for antibiotic therapy in septic shock. However, certain fundamental principles are common to these recommendations, which relate primarily to those factors influencing the final selection of empiric antibiotics. In general, one's goal should be to select drugs with broad-spectrum bactericidal activity against the most likely offending organisms until microbiologic data become available to guide more specific therapy. It is especially critical to attempt to identify the likely focus of infection, employing the patient's history and a meticulous physical examination. Frequently, the source of the infection will be obvious in cases of pneumonia, infected catheter-insertion site, pyelonephritis, intra-abdominal catastrophe, or septic arthritis. However, at times, the focus of infection is totally elusive. Selection of antibiotics may be guided not only by the suspicion of a certain focus of infection, but also by whether the infection was hospital or community acquired. Organisms causing a hospital-acquired infection may be more resistant, thereby suggesting alternative drug therapy, particularly for gram-negative bacilli. Review of culture data obtained on the patient prior to the development of sepsis may suggest a pathogen or antibiotic resistance that would guide one's drug selection. Drug-resistance patterns within the hospital or community may also alter one's approach to antibiotic selection. A high prevalence of methicillin-resistant staphylococci in the population would favor the use of vancomycin instead of nafcillin or a firstgeneration cephalosporin. In our institution, it recently became apparent that approximately 30 to 40 per cent of the isolates of Bacillus fragilis are resistant to clindamycin, thus necessitating the use of metronidazole as the drug of choice for anaerobic coverage in suspected intra-abdominal sepsis. The awareness of the alarming prevalence of penicillin-resistant gonococci in Detroit would militate against the use of penicillin in the empiric therapy of suspected gonococcal septicemia. Local drug-resistance patterns in the ICU must also be considered. The presence of resistant Acinetobacter species, Serratia, or Enterobacter species in several patients in an ICU may dictate alternative empiric antibiotic combinations for the next septic patient encountered in that unit. Host factors have obvious implications for antibiotic therapy. The splenectomized patient is predisposed to sometimes-fulminant infections with H. influenzae, Strep. pneumoniae, and N . menin~itidis.Whereas t b s t commonly used empiric drug regimens may cover the latter two organisms,

care must be taken to provide effective therapy against H. influenzae. The granulocytic patient requires special consideration in that the prevalence of pseudomonal septicemia is higher here than in other populations. Rational therapy would include the synergistic combination of an aminoglycoside and an antipseudomonal penicillin such as ticarcillin, with yet a third drug added for antistaphylococcal coverage in appropriate cases. The combination of imipenem-cilastin and an aminoglycoside may also be effective. Other host factors described previously in this article are associated with certain specific infections that must be considered in drug selection. Empiric therapy for sepsis of unknown etiology must include at least two broad-spectrum antibiotics, one of which should be an aminoglycoside. The regimen should provide activity against the most common gram-positive organisms (streptococcal and staphylococcal species) and gram-negative bacilli. The cornerstone of therapy would include the aminoglycoside such as gentamicin and a penicillinace-resistant penicillin such as nafcillin. The penicillin-allergic patient should be given vancomycin. In the setting of possible pseudomonal infection, tobramycin or amikacin may be preferred to gentamicin, and a third-generation antipseudomonal cephalosporin such as ceftazidime may be added as a third drug in the empiric combination. Enthusiasm for new antibiotics combined with aggressive drug marketing techniques has led to the use of additional empiric antibiotic regimens. In most cases, less-expensive traditional antibiotics of confirmed efficacy and similar toxicities should be preferred to the newer antibiotics, such as the third-generation cephalosporins, other new beta-lactams (e.g., imipenem and aztreonam), and the new carboxyquinolines (norfloxacin and ciprofloxacin). Widespread and indiscriminant prescription of these new drugs may result in significant expense without additional clinical benefit. Moreover, new and promising antibiotics should always be held in reserve for the specific, difficult infection and for certain drug-resistant infections, especially when economical proven regimens are available. Further, the abuse of new antibiotics frequently results in the unfortunate emergence of resistant institutional organisms. The selection of antibiotics is only part of the solution. The patient with septic shock frequently requires rapid intervention by a number of consultants. One person, often the intensivist, must coordinate the patient's care and ensure that all recommended diagnostic and therapeutic procedures are completed rapidly. The removal and culture of tubes and catheters, lumbar puncture, abdominal paracentesis, arthrocentesis, wound cultures (and other specimens), and needle aspiration of possible abscesses should be performed quickly. All too frequently, antibiotic therapy is delayed while waiting for these procedures, and, regrettably, sometimes antibiotics are given before proper cultures are obtained. The need to continue multipledrug empiric therapy beyond 48 hours simply because of incomplete culture data is not to be condoned. The definitive treatment of septic shock sometimes requires urgent surgical drainage and debridement of infected tissues or abscesses. Interdepartmental consultations can be slow, and person-to-person contact is mandatory in anticipation of possible emergency surgery. To compound the difficulties, septic patients in the ICU usually are not ideal surgical candi-

dates. Once the decision for surgery has been made, the intensivist must deal effectively with the dilemma of taking time for preoperative stabilization and preparation and risking further patient deterioration during the delay. In the author's experience, urgent completion of surgery is preferable to preparatory delay. Frequently, direct coordination with the anesthesiologist regarding ongoing therapeutic interventions, coagulation status, ventilator settings, and hemodynamics facilitates a successful operation.

Recent data strongly suggest that high-dose steroids given early in septic shock do not reduce the mortality rate.l3J9The Methylprednisolone Severe Sepsis Study Group (MSSSG) and the Veterans Administration Systemic Sepsis Cooperative Study Group conducted independent multicenter, randomized, double-blind, placebo-controlled trials of methylprednisolone in a total of 605 septic patients enrolled from 1982 to 1986. The conclusions were similar: (1)no improvement was noted in the prevention or reversal of shock or in the mortality rate, and (2) use of steroids appeared to impair resolution of secondary infections in one group, whereas in the other, steroids were associated with a higher mortality rate from secondary infections. The MSSSG trial additionally concluded that the subgroup of patients having a serum creatinine of greater than 2.0 mg per dl who received steroids had higher mortality rate than the placebo-controlled subgroup. Therefore, on the basis of the best available data, steroids appear not to be beneficial in the treatment of septic shock and have been associated with significant morbidity and mortality rates.

The use of endorphin antagonists such as naloxone has been effective in reversing or ameliorating shock in animal models. However, naloxone has brought about no reduction in the mortality rate in humans with septic . ' ~ the other hand, prosshock and therefore cannot be r e ~ o m m e n d e d . ~On taglandin inhibitors appear to be promising in animal studies of septic shock; their efficacy in septic humans awaits clinical trials.

Although most septic patients may not develop a frankly hemorrhagic coagulopathy from DIC, almost all will manifest a low-grade DIC on admission to the ICU. Appropriate initial evaluation of septic patients will include baseline coagulation studies: prothrombin time, partial thromboplastin time, fibrinogen level, and platelet count. Marginally abnormal coagulation function does not usually require therapeutic intervention apart . . fr of the coagulation tests may facilitate early intervention and prevention of

hemorrhagic complications. Early identification of clotting dysfunction may also assist in the selection of the most appropriate volume-resuscitation fluid, since fresh frozen plasma may be indicated along with other colloid or crystalloid solutions. The use of full-dose heparin therapy in DIC remains controversial and is not encouraged in our ICUs. Septic patients are also at risk for the development of permeability pulmonary edema (adult respiratory distress syndrome; ARDS), thus necessitating frequent monitoring of arterial blood gases. Some physicians perceive a therapeutic dilemma in the occurrence of an increased alveolar-arterial oxygen gradient and ARDS. Recognizing the potential benefit of fluid restriction to improve oxygenation in ARDS, and on the other hand appreciating the need for aggressive fluid resuscitation to increase preload, the clinician may be tempted to err on the side of fluid reduction, especially if the patient is not yet tracheally intubated. This is tantamount to preferring oxygenation over circulation in the conduct of cardiopulmonary resuscitation. Treatment of perfusion failure must not be compromised, even in the setting of ARDS. The fluid challenge protocol should be aggressively pursued while concurrently preparing for elective tracheal intubation, mechanical ventilation, and the possible application of positive end-expiratory pressure. In proper clinical practice, there is in reality no dilemma; both adequate oxygenation and fluid therapy can be achieved in most cases. It must be emphasized that early elective tracheal intubation in this setting is preferable to late emergency intubation of a septic patient who is already severely hemodynamically compromised. Anticipation of possible early respiratory failure should be paramount in the initial management of the patient. Too often, septic patients are efficiently transferred to the ICU, prepared and sterilely draped for pulmonary artery catheterization, only to develop respiratory failure during the procedure out of sight beneath the sterile drapes.

IMPACT ON SHOCK MORTALITY RATE OF INTENSIVIST STAFFING Three recent studies report the beneficial impact on septic shock mortality rates of the presence of full-time intensive care physicians in the ICU. One report from a community hospital revealed a reduction in the mortality rate from 92 per cent to 61 per cent comparing the year before and the year after the intensivists were employed. l2 The remaining studies were reported from two academic hospitals in our Detroit Medical Center. In the Detroit Receiving Hospital medical ICU, the septic shock mortality rate was reduced from 80 per cent to 60 per cent after the arrival of formally trained critical care specialists.16 The fraction of patients ultimately discharged home increased from 10 per cent to 32 per cent, With the exception of arterial line insertions, there was no increase in the frequency of invasive monitoring nor decreased use of subspecialty consultations. A similar study at Harper Hospital2 evaluated mortality rates in leukemia and lymphoma patients with septic shock during the &year periods before and after the arrival of critical care specialists. Provision of full-time staffing was associated with a reduction in the mortality rate from 82 per cent to 45 per cent.

A p:-o.~i\-atlv,"renir: dkcied :;?gr:aiji:i/ Spnre:; i!-a

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13 terti::ry-r;&re iie ti:, . r j j t j - . iaarticrliar at:eniiorl I@U mcysia&2g patterns and adr;linistrative i,rgan;z>:tion. '1 ("'.ne~:ospi~al talbt;~ rate maricediy low91- than predzcted, lvbici; Iuas avLributed to irrlicl~?l\i , successfi~l conrdinatioil I~etweenthe 1CU nnrsifig 2nd physician per-soni~el.L,IthougB~,:his s t ~ d Isoked y at o7,~eraiIIGU mortality rate and iiot 1in:lit its afialysis tc; septic shock patleilts, the importance of :>jeY]-orga-nized colBkzhoraiive ICU care of septic patients is clear. 7~

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Irdiiril the current state of the art, inadequate tixugh it inay seei.2, an ogecsive pcsture t w a r d greijention cf bactermia and seetic shock is the best ~Ir~zieai course. As ear!l,i as 1982, a vacci~ierlirected 2gainst E , cot( endot3xiit was admiristered to patients :.vith gram-negative infections, re. contri?ls.'"j'\rr&er adsulting in a redtreed umrtalic~irate c o ~ p a r d with vances in this area &re eagerly awaited. The parsimonious use of I n v a s i ~ ~ e technology, early treatment of simpie infectionsj reducing the abuse of b1-oad-spectrram antib~otics,provision of adequate nutrition in hospitalized patients, development of less-toxic cancer therapy, and the application of good cEinicaI judgment in patiei?t care inaj contril:ure to the prever~tior:of sepszs

Sepiic shock majl occur in ofhenvise normal individuals but is lCrequently a fatal sequel tci infectisn in the elderly, the diabetic, or the debilitated patient. Mortality rates r m g e fiorn 40 to 95 per cent depending bcth ,911 host factoss and .an the speed of initiation of d p p i . ~ p ~ i atl~erapy te The corn-r3;,zltles ti'. . 9f shsck pathophysiology a d bioL1:errzisiry are dusive, but certain hen~odynramicd e r m g e ~ e n t sare clearly descril:ed and create ~ R v i e u sther~tpeutieirnpera.tiries. !Correction of the supply-dependent phase of srygenz covsum~tionis the cornerstone of supporti-~etherapy. Scrviva! is pPn-tarity 3e3errdent or; the rapid delivery &the appropriate aintibrotics, surgiczl drainege ana, elehriaemetl~of e1ly infected tisstres or abscesses, and aggressivi= iroiuiine rer?.rscitafis:i a t tile 7ti?/ery;inle e3.ril:/ sepsjs is Cliitgi~~sed. S ~ : I Cs I ~ ~ c ~ is a medical emergency '

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e i a:. Role ;~i'~lir~-~~l:cic:~r!e, pi.ostagiar~dirir::i-d !~e~.k(,irie~~c.i :,ei,tic sl::;ck. ii!tc'ri.;li~:- Car- 'leci i2:11(:, 1686 .2 B:indcr- !), 21~1iii1Ji,, iver,,or! RL. et a!. The iiiipact o!' ?L~lI-rimezriticei - a y e I ? I ~ L : ~ C:?c ctatfing o? ixoriaiiiy ir pai:r:~is :.;lth hei?aio!og:c :~!ailgni:~:cic!>ir! 2 rlrtdical ICU (&srrJ.e:). ::
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4. Cain S: Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol 42:228, 1977 5. Comroe JH: Physiology of Respiration. Chicago, Year Book bledical Publishers, 1974, p 186 6. DeMaria A, Craven DE, Jeffernan JJ, et al: Naloxone versus placebo treatment of septic shock. Lancet 1:1363, 1985 7. Gilbert EM, Haupt blT, blandanas RY, et al: The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis. Am Rev Respir Dis 134:873, 1986 8. Harris RL, hlusher Dbl, Bloom K, et al: Manifestations of sepsis. Arch Intern bled 147:1895, 1987 9. Haupt MT: Oxygen supply dependency in the adult respiratory distress syndrome and sepsis. Intensive Crit Care Dig, in press 10. Haupt MT, Gilbert EM, Carlson RTV: Fluid loading increases oxygen consumption in septic patients with lactic acidosis. Am Rev Respir Dis 131:912, 1983 11. Knaus \VA, Draper EA, Wagner DP, et al: An evaluation of outcome from intensive care in major medical centers. Ann Intern Med 104:410, 1986 12. Li TCM, Phillips 41, Shaw L, et al: The impact of tertiary physicians on a community hospital intensive care unit. JAMA 25232023, 1984 13. blethylprednisolone Severe Sepsis Study Group: A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317:653, 1987 14. Morrison DC, Ryan JL: Endotoxins and disease mechanisms. Annu Rev bled 38:417, 1987 15. Parillo JP: Septic shock in humans: Recent insights regarding pathogenesis, cardiovascular dysfunction, and therapy. I n Chernow B, Shoemaker WC (eds): Critical Care State of the Art-1986. Los Angeles, Society of Critical Care Medicine, 1986, p 383 16. Reynolds HK, Haupt MT, Thill-Baharozian blC, et al: Critical care physician st&ng in a university hospital medical intensive care unit-impact on patients with sepsis (abstract). Crit Care bled 14:357, 1986 17. Rock P, Silverman H, Plump D, et al: Efficacy and safety of naloxone in septic shock. Crit Care Med 13:28, 1985 18. Root RK, Sande MA (eds): Septic Shock (Contemporary Issues in Infectious Diseases. Vol. 4). New York, Churchill Livingstone, 1983 19. Veterans Administration Systemic Sepsis Cooperative Study Group: Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 317:659, 1987 20. Weil WH, Shubin H: Critical Care Medicine. Hagerstown, Maryland, Harper and Row, 1976, pp 95 21. Wolff SM, Bennett JV: Gram-negative rod bacteremia (editorial). N Engl J Med 291:733 1974 22. Ziegler EJ, blccutchan JA, Fierer J, et al: Treatment of gram-negative bacteremia and shock with human antiserum to a mutant E. coli. N Engl J Med 30731225, 1982 Medical Intensive Care Unit Hutzel Hospital 4707 St. Antoine Blvd. Detroit, Michigan 48201