Treatment of sepsis and septic shock: A review

CONTINUING EDUCATION

Treatment of sepsis and septic shock: A review

William H. Wiessner, MS, RN, Larry C. Casey, MD, PhD, and J o s e p h P. Zbilut, PhD, DNSc, CS, Chicago, Ill. Septic shock is one of the leading causes of death in intensive care units, and its incidence is increasing, Mortality rates as high as 95% are reported, with rates of 60% or more even when diagnosed and treated promptly, This review examines the definition of septic shock, its pathogenesis, and supportive therapy, with particular attention to intervention during the septic shock cascade, (HEART LUNG| 1995;24:380-92)

INSTRUCTIONS TO CE ENROLLEES The closed-book, multiple-choice examination that follows this article is designed to test your understanding of the educational objectives listed below. To enroll in Single Topics, see the instructions at the end of this article. EDUCATIONAL OBJECTIVES Based on the content of the article, the enrollee should be able to: 1. Describe the pathophysiology of septic shock. 2. Identify clinical findings of septic shock.

Septic shock is one of the leading causes of death in intensive care units, and its incidence is increasing. 13 It is estimated that despite antibiotic therapy, gram-negative sepsis has increased tenfold in the past 10 years. 4 Mortality rates as high as 95% are reported for septic shock, with rates of 60% or more even when diagnosed and treated promptly.], 5-7 In the United States alone, 150,000 people per year may die of septic shock, s Reported sepsis increased 140% between the years 1979 and 1987. There has been no improvement in the mortality rate, but promising new therapies are being studied. 9 Considering the high mortality rate and increasing incidence, critical care practitioners must stay abreast of current understanding of the disease process and its treatment. From Rush University, Chicago. Reprint requests: William H. Wiessner, MS, 2509 Cochran St., Blue Island, IL 60406 Copyright 9 1995 by Mosby-Yem"Book, Inc, 0147-9563/95/$5.00 + 0 2/2/66651

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DEFINITIONS Although the progression through the syndrome associated with sepsis is unique for each patient, it is agreed generally that septic shock is an element in a continuum that progresses through sepsis and a septic syndrome to septic shock and death. 1~ Death usually occurs as a result of hypotension from decreased systemic vascular resistance and myocardial depression, or multiple system organ failure. The hypotension or multiple system organ failure results from a continuum of events, initiated by the infecting organism, that may be'perpetuated by mediators of the inflammatory response and shock state, even if the infecting organism has been successfully eliminatedfi, 12-14Because there are no universally agreed on definitions to clearly distinguish points along this continuum, considerable confusion has resulted.15, 16 Many terms are used interchangeably by various authors and clinicians in reference to the entire spectrum of the syndrome, to vague points along its continuum, or to components of the sepHEART & LUNG |

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tic process, a7 The definitions presented are based on those used in a preponderance of the current literature. The American College of Chest Physicians and the Society for Critical Care Medicine Consensus Conference on Standardized Definitions of Sepsis, held August 16 and 17, 1991, has resulted in accepted new definitions (Table). It is anticipated that these definitions will b o t h promote early treatment, by making early bedside detection possible, and provide a basis for standardization of research protocols and better communication offindingsJ s Time and studies to confirm their usefulness will tell if these, or some other set of definitions, will be universally a d o p t e d ) 9, 20 The following series of definitions probably best reflect a system to which conflicting definitions in the literature can be most readily translated./6' 17 The numerous other definitions f o u n d throughout the literature will not be discussed. Sepsis is defined as the combined physiologic responses to infection in the blood or tissues. The infection may be either proved or reasonably suspected as long as clinical evidence of systemic response is present. Evidence such as hyperthermia or hypothermia, tachypnea, or tachycardia may be considered. Sepsis syndrome can be defined as sepsis with evidence of hypopeffusion of at least one end-organ. Typical manifestations of end-organ hypopeffusion are change in level of consciousness, lacticacidemia, oliguria, or unexplained hypoxemia or coagulopathies. Bacteremia and hypotension are seen frequently but not required for a diagnosis of septic syndrome. This or any similar definition of sepsis syndrome allows for the institution of therapy before the acquisition of positive blood cultures and before the onset of septic shock. Many incidents of septic shock occur that are never accompanied by positive blood cultures. 16, 17 Shock is a problem of decreased tissue peffusion, not of hypotension. A patient may have normal or high blood pressure, yet be in shock, or have low blood pressure, yet not be in shock. 6' 21 It nonspecifically characterizes the spectrum of pathophysiologic processes that result in global cellular dysfunction, or inadequate delivery of substrate relative to the metabolic demands of tissues such that organ system dysfunction ensues. 22 Septic shock, though it contains elements of cardiogenic shock, is the most common form of distributive shock type and differs from shocks of differing pathogenesis in important ways.2~ Vincent and VanDerLinden 24 describe it as a special kind of circulatory failure. Septic shock, as defined by the Consensus Conference, is sepsis-induced HEART & LUNG| VOL. 24, NO. 5

Definitions of sepsis and organ failure from Consensus Conference, 1992 Table.

SIRS (systemic inflammatory response syndrome), the inflammatory process, independent of its cause

Sepsis, SIRS when it is the result of a confirmed infectious process

Infection, "a microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms" Bacteremia, "the presence of viable bacteria in the blood"; other pathogens in the blood are similarly described (i.e., viremia, fungemia, parasitemia). Severe sepsis, "sepsis associated with organ dysfunction, hypoperfusion abnormality, or sepsis-induced hypotension" Sepsis-induced hypotension, "systolic blood pressure of less than 90 mm Hg or its reduction by 40 mm Hg or more from baseline in the absence of other causes for hypotension" Septic shock, "a subset of severe sepsis.., sepsisinduced hypotension, persisting despite adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities or organ dysfunction" (From Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:164455. Copyright 1992 by Chest. Adapted by permission of the publisher.)

hypotension, persisting despite adequate fluid resuscitation, along with the presence of hypopeffusion abnormalities or organ dysfunction.25 Septic shock, as defined by Bone 16 in earlier literature, is sepsis syndrome with hypotension that is responsive to fluid loading or pharmacotherapy. Bone also defined refractoryshock as sepsis syndrome with hypotension that is not responsive to fluid loading or pharmacotherapy for a period of greater than 1 h o u r ) 6' 17 The Consensus Conference definitions do not include the term refractory shock. PATHOGENESIS OF SEPTIC SHOCK A nidus of infection must be present, though it may prove difficult or impossible to find. Although a local infection and inflammation can create a hypovolemic shock state through fluid shifts, hemorrhage, or diarrhea, septic shock is more classically a result of a systemic response to some organism in the blood--usually a bacteremia, viremia, or fungemia. Some substance in the cell wall, usually endotoxin in the wall of gram-negative bacteria, activates the complement, kinin, endorphin, and monokine systems.14, 26, 27A host of mediators are released, and a cascade that leads to septic shock and death is begun. 27' 28 The complement system is a cascade of enzymes that initiate, enhance, or " c o m p l e m e n t " inflammation. When the complement system is activated by a trigger such as endotoxin or antigen-antibody 381

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GRAM POS

GRAM NEG t

ANTIBIOTICS

l TNF

ANTI-LPS

ANTI-TNF

q

IL-1 q

IL-1 Ra ANTI-IL6

EICOSANOIDS

NSAID

4

FEVER~NEUROEND~OCRINE~CARDIOVASCULAR

DEATH Fig. 1. Graphic representation of some possible treatments that attempt to disrupt septic cascade.

complexes, vasodilation, increased capillary permeability, activation, and enhanced activity of phagocytic cells and direct attack by complement enzymes on pathogens result. The activated kinin system further vasodilates and increases capillary permeability and phagocytic activity. Activated phagocytes, predominantly neutrophils, release free radicals during the phagocytic process. Free radicals can further damage tissues and vascular endothelium, thus further stimulating the inflammatory process and increasing capillary permeability. Macrophages, though phagotizing antigens, release several mediators of sepsis, including the monokine tumor necrosis factor (TNF), interleukin-1 (IL-1), and complement--all of which further stimulate the inflammatory response. TNF can mimic sepsis in otherwise healthy animals. TNF and IL-1 synergistically affect numerous cells, tissues, and mediator pathways. The n u m b e r of known mediators is increasing rapidly, whereas discovery of their individual roles appears increasingly complicated. More than 100, often interacting, mediators have been identified. 29 CLINICAL FEATURES

A high cardiac output is observed initially, with low systemic vascular resistance and normal or increased blood pressure. This high cardiac output is sustained despite a sometimes severely decreased ejection fraction (as low as 20% to 25%) caused by a circulating myocardial depression factor. 3 Later, which may be days or a few hours, as the various mediators continue their effects, cardiac function 382

is further depressed, shunting and severe capillary leak develops (probably from the effects of various mediators on the vascular endothelium), and blood pressure declines. 27 This drop in blood pressure may be refractory to aggressive fluid tilerapy, inotropic agents, and vasopressors. Death may ensue as a direct result of the hypotension or as a result of organ failures secondary to prolonged hypoperfusion. A complex hypermetabolism is present along with lactic acidosis. Normal metabolism of glucose, fat. and protein may be impaired, Hyperthermia, sometimes followed by hypothermia, usually is present. Tachypnea and hyperventilation often are present, concurrent with or preceding hypoxemia. Hypoxemia, because of a ventilation/perfusion mismatch that results from increased capillary permeability and edema, is common. Confusion, lethargy, or agitation are c o m m o n because of a combination of factors such as low cerebral blood flow, hypoxemia, and metabolic alterations. Organ failures, such as adult respiratory distress syndrome or acute renal failure, also may occur as a result of other processes initiated by mediators of the inflammatory response, or iatrogenically by treatments such as antibiotic therapy. Multisystem organ failure is frequently a terminal point on the septic continuum. TREATMENT

Treatment is based on support of organ perfusion with fluids and vasoactive agents while attempts are made to interrupt the septic cascade at some point. For example, antibiotics for bacteria, HEART & LUNG |

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antibodies against bacterial endotoxins, and blockers of, or antibodies against, mediators of the sepsis cascade can be used (Fig. 1).s~ Adequate cellular oxygenation is the goal of all supportive treatment. 31 Septic shock is a collaborative health care probl e m - a l l aspects must be addressed if the high mortality rate of septic shock is to be successfully challenged. Basic care issues including immobility, activity intolerance, sleep, communication, and pain need to be addressed while both classic medical therapy and newer, often experimental, approaches are initiated. Though the general nursing and medical support historically provided has not improved the mortality rate, enhanced support may provide the additional time necessary for curative treatments to show efficacy. Additionally, should the patient recover, rehabilitation time may be reduced greatly if complications have been minimized. N i d u s . The nidus of infection must be determined and its site quickly and aggressivelysought. 32 Sputum, urine, and other obvious sites should be cultured. Multiple aerobic and anaerobic blood cultures, blood counts, serum electrolytes, chest radiographs, and other reasonable diagnostic tests such as gallium scans and more extensive radiographs should be obtained. Removal or drainage of the nidus of infection must be accomplished immediately, if possible, because removal before the septic cascade has b e g u n is optimal. 32 If the cascade has begun, or if it has reached some yet unidentified critical point, it may prove harder, if not impossible, to reverse. Anyinvasive site, trauma site, potential gastric ulceration, or obvious site of infection should be suspect. Any retained necrotic tissue may trigger the septic cascade and should be debrided promptly. Antibiotic therapy. Sepsis should be considered a medical emergency and either prevented or rapidly treated. Once a patient progresses into septic shock, antibiotic therapy may have little or no effect. 3s Broad-spectrum antibiotic coverage is instituted at the first indication of sepsis, before a source is identified, and refined when and if septicemia is confirmed by culture. Broad-spectrum empiric coverage, such as monotherapy with a carbapenem, or combination therapy with a [3-1actam and an aminoglycoside should be administered immediately on suspected diagnosis. 5 The sooner this therapy is begun, the greater likelihood that the septic cascade may be interrupted, by preventing an increase in the n u m b e r of microorganisms present and thus minimizing the amount of endo~ T

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toxin eventually released. ~ When bacteria are killed by bactericidal antibiotics, they release the endotoxin from their cell walls, often creating a rise in endotoxin level. 4 Therefore caution should be taken that in the presence of low vital signs, adequate cardiovascular support is instituted before antibiotics are administered. If not, an antibioticinduced increase in endotoxin may precipitate a severe deterioration in the patient's condition despite successful antibiotic therapy. 34 It has been shown that initiation of improper antibiotics increases the n u m b e r of deaths. Careful consideration must be given to deciding what pathogen most likely is present. The major prominent pathogens in a given geographic area or institution may differ widely because of factors such as patterns of antibiotic usage and patient population. 35 Trends such as the increasing incidence of gram-positive infection should be monitored carefully for additional clues in pathogen identification and proper antibiotic choice. 35, 36 However, newer, more potent antibiotics have not been shown to decrease the number of deaths. 35 Some interest exists in selective decontamination of the gut with nonabsorbable antibiotics to eliminate aerobic bacteria while leaving the norm a l anaerobic flora intact. 37This may be beneficial because in sepsis the bowel seems to become more permeable. As the basement membrane of surface epithelia detaches, subepithelial blebs form, then rupture, separating the epithelium from villus tips and allowing bacteria to cross over to the circulation. 37 Additionally, bacteria involved in many secondaryinfections seem to colonize the gut first and then are aspirated into the lungs. 37, 3s Selective decontamination has been shown to reduce secondary infection in patients with sepsis, though only in limited surgical populations and with no significant effect on number of deaths or progression to multisystem organ failure. 3043 Other studies, however, indicate that the same results might be obtained by maintenance of gastric pH at safe, but not alkaline, levels through acidification of normally alkaline enteral feedings, or simply by care taken not to overdose with antacids. 38 Because sucralfate, which does not raise gastric pH, has been found to be as effective as H 2 blockers or antacids in preventing stress ulcers, it may be the drug of choice to prevent gastric bleeding in patients with sepsis, s~ Oxygen: In sepsis it is generally thought that a maldistribution and drop in regional capillary blood flow creates an inadequate gradient for oxygen perfusion that results in cellular hypoxemia.6, 37 The ratio of oxygen delivery to utilization 383

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becomes delivery d e p e n d e n t over a wider than normal range, even at high Pao2 .6, 37 Ventilation/perfusion mismatch develops as a result of interstitial and alveolar edema secondary to increased permeability of damaged capillary endothelium. An extreme of this is seen in adult respiratory distress syndrome, which occurs in 5% to 40% of patients with sepsis. Eventually, hyperCapnia may develop as a result of fatigue in respiratory muscles that are working to overcome the ventiladon/perfusion mismatch. This may progress to respiratory failure requiring mechanical ventilation. As soon as impending septic shock is questioned, oxygen delivery should be increased to eliminate delivery-dependent oxygen consumption and lacdc acidosis. Oxygen delivery at least high enough to correct lactic acidosis and match oxygen demand and uptake should be maintained.12, 24 This will sometimes prove impossible because of blood flow inadequacy at the capillary or complications such as adult respiratory distress syndrome. Initially a nasal cannulashould be adequate, but therapy should be increased aggressively as necessary. Hyperventilation, apparently unrelated to hypoxemia or metabolic acidosis, causes respiratory alkalosis early i n sepsis and further exacerbates an already increased metabolic demand. Additionally, relief from the work of breathing may allow blood to move from respiratory muscles to other organs, thus increasing their perfusion and preventing multisystem organ failure. 44 Early intubation is therefore urged by many, both t o augment oxygen delivery and to reduce oxygen demand.24, 44 It should, however, be noted that much of the current knowledge about sepsis is unproven theory. Disagreement exists as to the reasons for the apparent cellular hypoxia indicated by lactic acidosis and more delivery-dependent oxygen consumption. It may be that these symptoms are due to other mechanisms. 45, 46 However, early initiation of high oxygen delivery is considered imperative. Hemodynamic support. Currently most supportive medical treatment is designed to maintain tissue and organ perfusion despite the inability to stop the septic cascade. Initially an aggressive fluid resuscitation is begun. Though type of fluid replacement is controversial, most believe that normal saline solution or lactated Ringer's solution should be infused until maximal ventricular performance is reached. This m a y require a pulmonary capillary wedge pressure as high as 15 to 18

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mm Hg; however, endpoint requires individual assessment. Fluids other than crystalloids, such as albumin and hetastarch, have been used, but they occasionally carry unwanted side effects not seen in the much cheaper crystalloids. 47 Infusions of packed red blood cells sufficient to attain normal hematocrit levels generally are recommended, but their efficacy is debated. 48-5~After adequate fluid and pressor resuscitation, infusion of red blood cells beyond a normal hematocrit shows no benefit. 51-5aCare should be taken to maintain adequate intravascular volume because capillary leakage occurs during the septic course. When optimal fluid balance is no longer sufficient to maintain blood pressure adequate for tissue perfusion, vasopressor and inotropic support are indicated. I t should be stressed that vasoactive agents should never be used in the absence of adequate volume replacement, and that the minimum dose of vasoactive agent necessary to maintain adequate perfusion should be used. There has been much discussion of the choice of a first-line drug, and there are some indications that one may be as good a~s another. 54, 55 Dopamine, however, a drug with combined ~-, and [3-adrenergic and dopaminergic activity, is often the first drug of choice because of the combination of its vasopressor and inotropic effects, with its potentia 1 for maintenance of kidney perfusion through its renal dilation effect. When dopamine (5 to 20 p g / k g / m i n ) is no longer adequate, norepinephrine (0.05 to >0.30 p g / k g / m i n ) for increased vasopressor support, or dobutamine (2 to 20 p g / kg/min) for increased inotropic support is the usual progression. 14, 29 Dobutamine, a [3-adrenergic inotropic agent, is the drug of choice for improvement of cardiac output and oxygen delivery in septic shock. 56 Indeed dobutamine is now often begun before hypotension ensues to improve the decreased stroke volume found present despite normal or increased cardiac output. Early in sepsis, despite decreased stroke volume, cardiac output is maintained by increased heart rate or ventricular dilation thought caused by a circulating myocardial depressant substance, a, 57 A combination dopamine-dobutamine therapy is therefore frequently initiated. Norepinephrine, a potent (x-adrenergic agent with some [3-adrenergic effects, is usually the drug of choice for increased vasopressor support when dobutamine and dopamine are no longer adequate. Practitioners may choose norepinephrine over dopamine as the first-line vasopressor, but they often supplement it with 1 to 3 p g / k g / m i n of dopamine to maintain renal perfusion. 58, 59 HW~T & LUNG| SEe'rEMBER/OCTOBER 1995

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Although ~x-adrenergic agents are routinely used, there a r e few data to support that they improve outcome. They have the potential to cause adverse effects by increasing systemic metabolism requirements, and by compromising effective blood flow by increasing the peripheral vascular resistance. Phenylephrine, however, is a selective oq-agonist that may improve oxygen consumption while providing hemodynamic support. Phenylephrine is a phenethylamine rather than a catecholamine that may be especially beneficial in patients with marked propensity toward tachyarrhythmic response to catecholamine therapy.60, 61 There is little published information on the clinical use of phenylephrine in the hemodynamic support of septic shock. Regardless of the order, when dopamine, dobutamine, and norepinephrine become inadequate, epinephrine is initiated. 62 The need for epinephrine is generally a poor prognostic sign because it indicates a general failure of adrenergic response. Indeed the need for any pharmacologic support is a poor prognostic sign because it signals greater than 80% chance of death. 63 The art in hemodynamic support is to balance between pressure and flow, and to maximize oxygen delivery and consumption.37, 64-66 Nutrition. Sepsis creates a hypermetabolic state that should be supported with adequate but not excessive nutrition, though this is hard to assess.12, 44, 67 Caloric requirements should be established based on body size and degree of hypermetabolism. This may vary widely, but 20 to 25 kcal/ kg/day is average. 12, 32, 68, 69 Malnourishment has been shown to decrease maximum voluntary ventilation, vital capacity, and ventilatory response to hypoxia. 6v Excessive calories, especially if provided as carbohydrates, may increase carbon dioxide production, necessitating an increase in minute ventilatio n that the patient may be unable to attain or maintain. This may result in unnecessary intubation or, more likely, make it more difficult to wean from mechanical ventilation. 67 Insulin-resistant hyperglycemia (>200 mg/dl) is common, and lowering with insulin is difficult. Hyperglycemia due to relative insulin resistance and abnormal skeletal muscle metabolism of glucose develops in 40% of patients. This hyperglycemia is an indicator of poor prognosis. 7~ Later, as cardiac output falls, gluconeogenesis fails and hypoglycemia results as a preterminal event. Intravenous long-chain fatty acid triglycerides are used for partial caloric replacement in total parenteral nutrition to avoid complications of excess CO2 production, h o r m o n e activation, and innXART &: LUNG| VOL 24, NO. 5

creased energy expenditure induced by excessive glucose administration. The protein sparing effect of long-chain fatty acid triglycerides is at least equivalent to that of glucose. 71 The increased protein requirements of patients with sepsis is met by administration of nutritional support with modification of amino acid to maintain nitrogen balance in the hypermetabolic state. Protein administration must be monitored carefully because its elimination is affected by decreased renal function. 12 Enteral feedings may alter progression to organ failure by protecting hepatic function through a hypothesized reduction in cholestasis or biliary sludging, preventing stress ulcers and preventing bacterial translocation from the gut. 7>73 They should be used when possible. 12 Additionally, if enough nutrition can be absorbed enterally, the increased danger o f further infection from total parenteral nutrition lines can be eliminated. TM This usually is possible, and it has replaced parenteral hyperalimentation as a mainstay of treatment.6s, 69 The underlying cause of the metabolic alterations seen in sepsis may be attributable to some of the mediators of other aspects of sepsis) z' 20 Nitrogen balance, for example, often is not attainable because skeletal muscle, in response to mediators, continues to release amino acids despite apparently adequate parenteral nutrition. 2~ In turn, nutrition may at some point be part of mediator control. Vitamins C and E, for example, are both free oxygen radical scavengers that eventually may prove beneficial in high doses. As yet, however, the efficacy of high vitamin dosage is only speculative and cannot be recommended. 75 Temperature regulation. Thermal regulation is highly complex. It is affected by central and peripheral neuronal influences and hormonal balance--all of which can be, and probably are, affected by endogenous pyro~ens, sepsis mediators, a n d pharmacotherapy. 76,~7 Treatment of fever is controversial. The bactericidal effects of a normal immune response appear enhanced at moderately elevated temperatures. Endotoxin activity, however, appears likewise enhanced. 78 Metabolic demands are significantly increased by hyperthermia, exacerbating an already taxed system. 79 Hypothermia has been shown to be a poor prognostic indicator in sepsis. In one study hypothermia signaled a doubling of incidence of death. 76 No evidence exists that raising the temperature of these patients would alter mortality rate, but doing so would beneficially affect both 385

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the coagulation cascade and probably additional, yet undefined systems as well.8~ Mild hypothermia also has been shown to detrimentally affect left ventricular cardiac function, but this was not studied in the presence of sepsis. 7s Though current therapy varies, general opinion holds that until more evidence points otherwise, temperature should be regulated to near normal with antipyretics, environmental control, and cooling blankets if necessary. 78 Monoelonal antibodies. Endotoxins or any of the mediators of sepsis may be viewed also as antigens. Antigens are substances introduced into or produced by the body that stimulate a specific imm u n e response. Antibodies are proteins produced in response to an antigen, sl Antibodies can bind to antigens and inhibit their function. Monoclonal antibodies, immunoglobulin molecules synthesized from hybrid clones of B lymphocytes, are specific for one antigen, s2 They can bind to a specific antigen and signal the body to dispose of it. s2 Much of the current activity in sepsis research surrounds the development of monoclonal antibodies against individual mediators of sepsis, s2 Inactivation of any one mediator might break or control the septic cascade, or at least part of it. Prevention of any of the adverse sequelae, such as adult respiratory distress syndrome, disseminated intravascular coagulation, or multiorgan failure, may improve the possibility of survival. Direct neutralization of endotoxin may prevent the septic cascade from even beginning. Attention has been focused mainly at two points. Endotoxin clearly has been shown to activate the extremely complicated myriad of events occurring in the immune response. If endotoxin can be inactivated before these normal responses get out of control, the sepsis cascade might be contained. Further down the sepsis cascade, the second major effort is focused on blocking TNF with monoclonal antibodies. TNF, a cytokine released by macrophages on their activation by endotoxin, is among the most potent mediators of sepsis. 33 When injected into healthy animals it induces a host of responses usually seen in septic shock such as fever, capillary leak, acidosis, hypotension, and death. 83 Though endotoxin is the most potent tumor necrosis releasing factor known, TNF seems to be one common pathway to septic shock whether or not the causative factor is a gram-negative organism. 33, 84 Monoclonal antibodies against any specific lipopolysaccharide, such as endotoxin, may block its interaction with neutrophils and macrophages 386

thus blocking the release of TNF. s5 Monoclonal antibodies to endotoxin bind to the lipid A portion of the molecule, signaling the body to dispose of it.s2, 85 The same p h e n o m e n o n is observed in patients with chronic infections---often urinary tract infections--who also exhibit lipid A antibody titers and thus seem to be protected from septic shock, s Antiendotoxin antibodies HA-1A and E5 have been tested. Although results of some subsets of subjects indicated a possible efficacy, neither antibody improved overall survival i n the full set of subjects, s6-ss IL-1 is a proinflammatory cytokine that induces fever, inflammation, and hemodynamic shock (Fig. 1). It also induces other proinfiammatory cytokines and acts synergisticallywith TNF. s3 IL-1 receptor antagonist is a naturally occurring protein that competes with the binding of IL-1 to its cell surface receptors. It has been tested extensively in animals.S3, s9, 90 One study on gram-negative sepsis in rats reported a 71% survival rate for treated animals versus 20% for those untreated. 9~ Phase III clinical trials of recombinant IL-1 receptor antagonist reported no statistically significant increase in total survival time. Secondary and retrospective analysis suggested dose-related improvement in a subset of patients with organ dysfunction a n d / o r with 24% or greater predicted mortality risk. 91 Antibodies to TNF have not been tested so extensively. Studies in mice and baboons have shown beneficial results. 33 Because TNF is produced quickly in response to endotoxin and then activates a myriad of events involved in the sepsis cascade before being quickly cleared, timing of monoclonal antibody therapy may be crucial. 84 Indeed many sepsis mediators appear for very short periods and so, though probably amenable to treatment with monoclonal antibody therapy, may offer very small windows of opportunity that will need to be identified before therapy can be successful. Two proteins, both found in normal human urine and in h u m a n serum during sepsis, have been identified as the extracellular domains of TNF receptors. 83, 02, 93 These proteins are hypothesized to shed from cells during the inflammatory process. They bind TNF equally as well as intact receptors and so block its effects.92 This natural block seems to have a regulatory effect at lower levels of infection. Animal studies indicate the possible efficacy of injected, recombinant, soluble receptors of TNF in the treatment of more serious infection.92 Interleukin-6 is another cytokine that may play an important role in sepsis (Fig. 1). 94,95 It is HEART & LUNG| SEPTEMBF~/OCTOBER 1995

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elevated along with TNF and IL-1, and its plasma level correlates with death. However, because infusion of interleukin-6 alone results in no significant hemodynamic changes, it may be a marker of inflammation rather than a mediator of sepsis. 96, 97 Selection of appropriate candidates for monoclonal antibodies will prove difficult initially.86, 9s As with other agents, monoclonal antibodies may be most effective if given prophylactically to patients at high risk for sepsis. ~ They are, however, likely to be very expensive until their use becomes common and technology is developed for more inexpensive production. 9s H u m a n monoclonal antibody HA-1A was priced in the Netherlands at $3750 per dose. At this cost it could add $2.3 to $6.2 billion to annual health costs in the United States. 99 At least one assessment of the cost-effectiveness of treatment with HA-1A has been completed already. It measured cost-effectiveness of treatment of all patients with sepsis versus treatment of only those with gram-negative bacteremia. Treating all patients costs $24.100 per year of life saved versus $14,900 per year of life saved when treatment was based on gram-negative bacteremia. 99 Such early studies on potential therapies will help direct the development of, and treatment strategy for, this burgeoning new technology. Criteria will need to be developed to identify patients most likely to benefit from specific antibodies at specific points in time. 98 It is likely that combinations of therapies will continue to be the mode of treatment, rather than the exclusive use of these or any other single therapies, s~ Cyelooxygenase inhibitors. On stimulation by substances such as endotoxin and catecholamines or by trauma, arachidonic acid is liberated from the phospholipids present in most cell walls. It is then metabolized into various eicosanoids through, depending on the cell types, either the lipoxygenase pathway to leukotrienes or the cyclooxygenase pathway to prostaglandins and thromboxanes (Fig. 2). These metabolites have various, sometimes antagonistic, effects on physiologic functions such as vasomotor tone. vascular permeability, platelet aggregation, temperature regulation, and mediator release. 29 95 Though attempts have been made with some success to block each arachidonic acid metabolite, the most promising agents are the cyclooxygenase inhibitors. 47, 95 Cyclooxygenase inhibitors, such as ibuprofen, reduce the production of arachidonic acid metabolites that are significant in the inflammatory response. 1~176 During inflammation arachidonic acid is released from phospholipids and converted to endoperoxides by cyclooxygenase. HEART & LUNG| VOL. 24, NO. 5

1

Cell membrane phospholipid

,l

[Phooho,,oase activation

Arachidonicacid released q

Lipoxygenase

pathway

t

]

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,,,it CyclooxygenaseI pathway

Prostaglandins Thromboxanes

Fig. 2. Arachidonic acid metabolism. (Reprinted from Huddleston VB. Mtfltisystem organ failure, pathophysiology and clinical implications. St Louis: Mosby-Year Book, 1992.)

Prostaglandins, thromboxane, and prostacyclin are end products of the arachidonic acid cascade t h a t contribute significantly to capillary leak. t~176 They modulate responses to stimuli such as cytokines and tissue fluid components generated by the inflammatory process. Ibuprofen is the most studied cyclooxygenase inhibitor. It functions as a nonsteroidal antiinflammatory agent. It works not only to block arachidonic acid metabolism but also to stabilize cell membranes. Stabilization of the lysosomal membrane ofneutrophils thereby decreases the release of sepsis mediators, t~176 As with any nonsteroidal antiinflammatory drug, its 'adverse side effects must be weighed against its benefits. Cyclooxygenase inhibitors have been under investigation for some time and show promise. Ibuprofen has shown efficacy in animal models, but results of h u m a n studies are conflicting.1~ t02 At least one randomized, placebo-controlled trial has shown a doubling of shock reversal in patients treated with ibuprofenl and a larger investigation is in progress. 1~ An interesting point to consider is the extremely low cost of ibuprofen therapy, especially when compared with therapies such as monoclonal antibodies that will likely sell at thousands of dollars per dose. Endogenous opiate antagonist. Naloxone is a narcotic antagonist that binds opiate receptor sites. It has been studied in the treatment of sepsis predominantly for its ability to block the effects of endorphins, endogenous opiates that have potent vasodilatory effects that contribute to cardiovascular instability,t, 104 Interest was aroused in this inquiry partly because of the similarities between shock and opiate overdose. 1~ 387

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To be effective against endorphins, naloxone must be given as a continuous infusion, because the endorphins are being continuously released. Some human studies have reported an overall increase in systolic blood pressure and mean arterial pressure when continuous naloxone infusion is begun early in the course of shock. 1~176 Later in the course of shock, when hypothermia and acidemia become major factors, its efficacy appears less promising. 1~176 Studies of human septic shock have, however, thus far generally shown naloxone to have little impact on survival. 1~ 106 More promising animal studies may be due to species differences or to the timing of dosage very early in sepsis. 1~ One human study, however, showed 100% survival in the subgroup of subjects who clinically responded to naloxone. 1, 105 Naloxone has met with mixed reviews but may have efficacy if high doses (on the order of 0.03 m g / k g intravenous push followed immediately by 0.2 m g / k g / h r continuous intravenous infusion) are used at an early but yet to be determined stage. At very high doses it blocks not only the opioid receptors but also the receptors that mediate vasodilation, for which naloxone has a 30 times lesser affinity. 106 Because of its ease of initiation, relative lack of significant side effects, and ability to improve mean arterial blood pressure early in septic shock, naloxone may prove useful as a temporizing agent while other therapies are initiated or optimized. 1~ 106 Platelet-activating factor antagonists. Plateletactivating factor is a phospholipid mediator, activated by a variety of stimuli including endotoxin, that increases microvascular permeability, aggregates platelets and leukocytes, promotes arachidonic acid release, and exhibits negative inotropic effect on the heart. 9, 107 It is a powerful example of the nonprotein class of mediators and is strongly implicated as a key mediator in sepsis, l~ Several agents under study, such as L-652,731, L-659,989 (Merck, Sharp, and Dohme), SCH 37370 (Schering-Plough), WEB 2086, and WEB 2170 (Boehringer Ingelheim), have been encouraging in animal models, but no results of human studies in sepsi s have been reported. 9' 107,108 Results in animal models indicate positive effects on hypotension and vascular leak and on survival time. 1~ Corticosteroids. High-dose corticosteroids were thought useful in the early treatment of septic shock through decreased eicosanoid synthesis, inhibition of TNF, and protection of organs through cellular stabilization in low-flow states. 47, 109 Early human studies indicated improved survival and created much excitement. More recent multi388

center studies, however, have shown no improvement in outcome and, in some cases, a detrimental effect on survival. 1, 27, 110 Additionally, patients receiving high-dose corticosteroids had an increased incidence of secondary infections and related deaths. 5, 27 The study of corticosteroid therapy for treatment of sepsis seems at least temporarily to be closed. Corticosteroids are no longer indicated for treatment of sepsis or septic shock, except in patients with suspected adrenal insufficiency or for specific indications. 5' 27, 29, 111 Dialysis, pheresis, and hemof'fltration. Dialysis, pheresis, and hemofiltration have been used in attempts to remove sepsis mediators from circulating blood in hopes of reducing septic complications. These procedures all face the difficulty of removing both detrimental and helpful products indiscriminately within given parameters such as molecular weights. The explosion in the number of mediators being identified and their complex interaction further highlights this difficulty. Though some small studies have shown encouraging mild improvement in hemodynamics and pulmonary gas exchange in cardiogenic shock, these treatments await technology that makes discriminate filtration more feasible. 112 FUTURE

Multiple therapy appears to be the current therapeutic "approach. Therapies directed at the invading organism, at tile endotoxin or other excitatory substance it can"ies, and at any or all mediators o f the septic cascade will likely be the norm. 113 New mediators are being identified rapidly, and each offers a possibility for interruption of the septic process. Though exciting and encouraging, this rapid identification of new, interacting, often very short-lived (perhaps only seconds or less) mediators is creating a picture of extreme complexity and forcing long-held beliefs about the pathogenesis and treatment of sepsis to be reevaluated. Nitric oxide has been identified as a neurotransmitter, potent vasodilator, and possible mediator in the sepsis cascade.114 One study discovered high levels of nitric oxide in patients with gram-negative septic shock b u t not in trauma-induced septic shock, indicating that endotoxin might stimulate high levels of nitric oxide. 114,115 Some evidence exists to indicate that the vasodilation caused by these high nitric oxide levels might be successfully treatedwith nitric oxide synthase inhibitors such as N;-monomethyl-L-arginine. 116-118 Administration of magnesium-adenosine triphosphate during septic shock seems to improve H~ART & LUNG | SEPTEMBER/OCTOBER 1995

WIESSNER, CASE'Y, AND ZBILUT

both cellular and organ function after reversal of the shock state, n9 Pentoxifylline may block endotoxin-induced synthesis of TNF. 12~ Ulinastatin may stabilize cell membranes and thus inhibit release of cytokines.124 Aprotinin may inhibit proteases. 125The list grows steadily and rapidly longer. Ultimately, manipulation of genes may allow control over production and secretion of any known mediator. 84 PREVENTION AND EARLY DETECTION Until therapy is developed that can reliably block or reverse septic shock, prevention may be the one most important single measure for control. Nosocomial infection rates of 15% to 25% are reported for the critically ill. 21 Simple, commonly known preventive techniques must be practiced diligently. Failure to do so must be considered serious malpractice. Aseptic technique is introduced early in health care education, yet some of the more common precipitants of nosocomial infection seem to be basic violations: uncovered stopcock ports, nonremoval of gloves at the end of procedures, uncapping of needles and tubing with teeth, unsterile suctioning, contaminated scissor blades, gross reflux from drainage vessels, stripping tape onto tables or bed rails before applying, and most basic and perhaps most important, simple failure to wash h a n d s ) s, 21, 32, 62 Additionally, special attention must be given to many only slightly less basic practices, some of which have been previously discussed and only a few of which are listed here. Necrotic tissue must be debrided whenever possible. Invasive lines must be monitored for any signs of inflammation and records kept of both sites of insertion and indwelling times. If inserted on an emergency basis with unsterile technique, lines must be discontinued as soon as the patient's condition is stabilized, and new lines can be inserted properly at new sites. Care should be taken to protect the acid barrier in the intestinal tract from overdosage of antacid and H2 blockers.32, 62 These are only a few of the many simple elements of care that may make a difference in a patient's outcome. Some may be new, but most are simply elements of well-established, generally accepted, sometimes neglected standards of sound practice. Early detection of sepsis, before clinical signs and symptoms appear, has so far been evasive. Many chemical markers are under investigation, but none has yet emerged as both reliable and practical. Until they arrive, simply remembering HEART & LUNG |

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that time is of the essence in treating suspected sepsis may reduce deaths. 3a Identification and special attention to frequent assessment of patients at high risk for sepsis should be expected. 126 Action must be taken immediately to treat suspected sepsis--minutes and maybe seconds, count. Hoyt7 states that infection often stems from invasive devices and procedures vital to maintaining the patient's life. Although this is correct, there is much we can do to minimize the risk, Treatment of sepsis and septic shock is a collaborative effort that encompasses everyone on the health care team: nurses, doctors, pharmacists, aides, housekeepersmattention to simple detail saves lives. REFERENCES 1. 2. 3. 4.

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Putterman C. Modern approaches to the therapy of septic shock. Am J Emerg Med 1990',8:152-61. ThmTn JR. Septic shock: evaluation of a life-threatening condition. Postgrad Med 1990;87:53-8. ParrilloJE. The cardiovascular pathophysiology of sepsis. Annu Rev Med 1989;40:469-85. Zimmermann JJ. Therapy for overwhelming sepsis---clues for treating disease and not just symptoms. Crit Care Med 1990; 18:118-9. Roach AC. Antibiotic therapy in septic shock. Crit Care Nurs Clin North Am 1990;2:179-86. Pryor RW, Kline MW, Matson JR. Septic shock: principles of management in the emergency department. Pediatr Emerg Care 1990;5:193-7. Hoyt NJ. Preventing septic shock. Crit Care Nurs Clin North Am 1990;2:287-97. Marget W. The last round against bacterial infections? Infection 1990;18:197-9. Bone RC. Phospholipids and their inhibitors. Crit Care Med 1992;20:884-90. Rice V. Shock, a clinical syndrome: an update---part 2, the stages of shock. Crit Care Nurse 1991;11:74-85. Knaus WA, Sun X, Nystrom P, Wagner DP. Evaluation of definidons for sepsis. Chest 1990;101:1656-62. Macho JR, Luce JM. Rational approach to the management of multiple systems organ failure. Crit Care Clin 1989;5:379-93. SheagrenJN. Mechanism-oriented therapy for multiple systems organ failure. Crit Care Clin 1989;5:393-409. BoydJL III, Stanford GG, Chernow B. The pharmacotherapy of septic shock. Crit Care Clin 1989;5:133-50. Bone RC. Sepsis and coagulation: an important link. Chest 1992;101:594-6. Bone RC. Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann Intern Med 1991;114:332-3. Bone RC. Let's agree on terminology: definitions of sepsis. Crit Care Med 1991;19:973-6. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644-55. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure: Chest 1992;i01:1481-3. Griffin GE. Parenteral nutrition in sepdc shock. J Antimicrob Chemother 1989;23:176-7. Rice V. Shock, a clinical syndrome: an update--part 4, nursing care of the shock patien t. Crit Care Nurse 1991;11:2843. Pinsky MR, Matuschak GM. Multiple systems organ failure: failure of a host defense homeostasis. Crit Care Clin 1989;5:199-220.

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Bone RC. Abnormal cellular metabolism in sepsis. JAMA 1992;267:1518-9. Fry DE, ed. Multiple system organ failure. St Louis: Mosby-Year Book, 1992. Reinhart K, H a n n e m a n n L, Kuss B. Optimal oxygen delivery in critically ill patients. Intensive Care Med 1990;16(suppl 2) :S14055. Cane RD. Hemoglobin: how much is enough? Crit Care Med 1990;18:1046-7. Ognibene F, Cunnion RE, Parrillo JE. Fluid loading in septic shock [Letter response]. Ann Intern Med 1990;113:991-2. Conrad SA, Dietrich KA, Herbert CA, Romero MD: Effect of red cell transfusion on oxygen consumption following fluid resuscitation in septic shock. Circ Shock 1990;31:419-29. Greenburg AG. To transfuse or not to transfuse--that is the question. Crit Care Med 1990;18:1045. Dietrich KA, Conrad SA, Herbert CA, Levy GL, Romero MD. Cardiovascular and metabolic response to red blood cell transfusion in critically ill volume-resuscitated non surgical patients. Crit Care Med 1990;18:940-4. Schreuder WO, Schneider AJ, Groeneveld ABJ, Thijs LG. Effect o f dopamine vs norepinephrine on hemodynamics in septic shock: emphasis on right ventricular performance. Chest 1990; 95:1283-8. Martin C, Saux P, Eon B, Aknin P, Gouin F. Septic shock: a goaldirected therapy using volume loading, dobutamine a n d / o r norepinephrine. Acta Anaesthesiol Scand 1990;34:413-7. Vincent J, Roman A, Kahn RJ. Dobutamine administration in septic shock: addition to a standard protocol. Crit Care Med 1990;18:689-93. Schremmer B, DhainautJ. Heart failure in septic shock: effects of inotropic support. Crit Care Med 1990;18(suppl):S49-55. Mackenzie SJ, Kapadia F, Nimmo GR, Armstrong IR, Grant IS. Adrenaline in treatment of septic shock: effects on haemodynamics and oxygen transport. Intensive Care Med 1991;17:36-9. DastaJF. Norepinephrine in septic shock: renewed interest in an old drug. Ann Pharmacother 1990;24:153-6. Bonfiglio MF, DastaJF, GregoryJS et al. High-dose phenylephfine infusion in the hemodynamic support of septic shock. Ann Pharmacol 1990;24:936-9. GregoryJS, Bonflglio MF, DastaJF et al. Experience with phenylephrine as a component of the pharmacologic support of septic shock. Crit Care Med 1991;19:1395-1400. Bollaert PE, Bauer P, Audibert G, Lasmbert H, Larcan A. Effects of epinephrine on hemodynamics and oxygen metabolism in dopamine-resistant septic shock. Chest 1990;98:949-53. EdwardsJD. Practical application of oxygen transport principles. Crit Care Med 1990;18(suppl):S45-8. EdwardsJD. Oxygen transport in cardiogenic and septic shock. Crit Care Med 1991;19:658-63. I@use JA. Use of vasoactive drugs to support oxygen transport in sepsis. Crit Care Med 1991;19:144-6. Tuchschmidt J, Oblitas D, Fried JC. Oxygen consumption in sepsis and septic shock. Crit Care Med 1991;19:664-71. Liggett SB, Renfro AD. Energy expenditures of mechanically ventilated non surgical patients. Chest 1990;98:682-6. Ackerman MH, Evans NJ, Ecklund MM. Systemic inflammatory response syndrome, sepsis, and nutritional support. Crit Care Nurs Clin North Am 1994;6:321-40. McClave SA, Lowen CC, Snider HL. Immunonutfifion and enteral hyperalimentation of critically ill patients. Dig Dis Sci 1992;37:1152-61. Balk RA, ParrilloJE. Septic shock: clinical syndrome, management, outcome, and sequelae. In: Fishman AP, ed. Update: pulmonary diseases and disorders. New York: McGraw-Hill, 1992: 185-95.

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Cerra FB. Metabolic manifestations of multiple systems organ failure. Crit Care Clin 1989;5:119-31. Cerra FB, Shronts EP, Konstantinides N,.et al. Enteral feedings in sepsis: a prospective randomized, double blind trial. Surgery 1985;98:632-9. Cerra FB. Hypermetabolism, organ failure, and metabolic support. Surgery 1987;101:1-14. Wendon J, Coltart J. Intensive care medicine--a review. Postgrad M e d J 1989;65:875-80. Bone RC. Inhibitors of complement and neutrophils: a critical evaluation of their role in the treatment of sepsis. Crit Care Med 1992;20:891-98. Clemmer TP, Fisher CJ, Bone RC, et al. Hypothennia in the sepsis syndrome and clinical outcome. Crit Care Med 1992; 20:1395-401. Balk RA, Parrillo JE. Prognostic factors in sepsis: the cold tacts. Crit Care Med 1992;20:1373-4. Greene PS, Cameron DE, Mohlala ML, et al. Systolic and diastolic left ventricular dysfunction due to mild hypothermia. Circulation 1989;80:(suppl III):III44-8. Mostow SR. Management of gram-negative septic shock. Hosp Pract (Off Ed) 1990;15:121-30. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med 1992;20:1402-5. Seeley RR, Trent DS, Tate P. Anatomy and physiology. 2nd ed. St Louis: Mosby-Year Book, 1992. Erickson D. Of mice and men. How form affects function in monoclonal antibody drugs. Sci Am 1990;262:76-7. Diuarello CA. The prointlammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J Infect Dis 1991;163:1177-84. Simpson SQ, Casey LC. Role of tumor necrosis factor in sepsis and acute lung injury. Crit Care Clin 1989;5:27-47. Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A h u m a n monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324:429-35. Clmnion RE. Clinical trials of immunotherapy for sepsis. Crit Care Med 1992;20:721-3. McCloskey RV, Straube PC, Sanders C, et al. Treatment of septic shock with monoclonal antibody HA-1A: a randomized, double-blind, placebo-controlled trial--CHESS Trial Study Group. Ann Intern Med 1994;121:1-5. Greenman RE, Schein RM, Martin MA, et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis: the XOMA Sepsis Study Group. JAMA 1991;266:1097-102. Alexander HR, Doherty GM, Venzon DJ, Merino MJ, Fraker DL, NortonJA. Recombinant interleukin-1 receptor antagonist (ILlra): effective therapy against gram-negative sepsis in rats. Surgery 1992;112:188-94. Fischer E, Van Zee KA, Marano MA, et al. Interleukin-1 receptor antagonist circulates in experimental inflammation and in h u m a n disease. Blood 1992;79:2196-200. Fisher CJJr, DhainautJF, Opal SM, et al. Recombinant h u m a n interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial Phase III rhIL-lra Sepsis Syndrome Study Group. JAMA 1994;271:1836-43. Van Zee K, Kohno T, Fisher E, Rock CS, Moldawer L, Lowry S. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Nail Acad Sci U S A 1992;89:4845-9. Engelman H, HolUnann H, Brakebusch C, et al. Antibodies to

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a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 1990;265:14497-504. Damas P, Ledoux D, Nys M, et al. Cytokine serum level during severe sepsis in h u m a n IL-6 as a marker of severity. Ann Surg 1992;215:356-62. Calandra T, GerainJ, H e u m a n n D, et aL High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytoldnes. Am J Med 1991;91:23-8. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993;119:171-8. PreiserJC, Schmartz D, Van Der Linden P, et al. Intefleukin-6 administration has no acute hemodynamic or hematologic effect in the dog. Cytokine 1991;3:1-4. Fant WK. Selecting patients for monoclonal antibody therapy: A m J Hosp Pharm 1990;47(suppl 3):S16-9. Schulman KA, Glick HA, Rubin H, EisenbergJM. Cost-effectiveness of ha-la monoclonal antibody for gram-negative sepsis. JAMA 1991;266:3466-71. Rockwell WB. Ibuprofen in acute-care therapy. Ann Surg 1990;211:78-83. Balk RA, Jacobs RF, Tryka A.F, Townsend JW, Walls RC, Bone RC. Effects of ibnprofen on neutrophil function and acute lung injury in canine endotoxin shock. Crit Care Med 1988;16: 1121-7. Balk RA, Jacobs RF, Tryka AF, Walls RC, Bone RC. Low dose ibuprofen reverses tile hemodynamic alterations of canine endotoxin shock. Crit Care Med 1988;16:1128-31. Bernard GR, Reines HD, Metz CA, et al. Effects of short course ibuprofen in patients with severe sepsis [Abstract] Am Rev Respir Dis 1988;137(Pt 2):137. Schumann LL, Remington MA. The use ofnaloxone in treating endotoxic shock. Crit Care Nurse 1990;10:63-73. Safani M, Blair J, Ross D, Waki R, Li C, Libby G. Prospective, controlled, randomized trial of naloxone infusion in early hyperdynamic septic shock. Crit Care Med 1989;17:1004-9. Hackshaw KV, Parker CA, RobertsJW. Naloxone in septic shock. Crit Care Med 1990;18:47-51. Anderson BO, Bensard DD, Harken AH. The role of platelet activating factor mad its antagonists in shock, sepsis and multiple organ failure. Surg Gynecol Obstet 1991;172:415-24. Rabinovici R, Yue T, Farhat M, et al. Platelet activating factor (pat) and tumor necrosis factor-alpha (mr-alpha) interactions in endotoxemic shock: studies with bn50739, a novel paf antagonist. J Pharmacol Exp Ther 1990;255:256-63. Cohen J, Glinzer MP. Septic shock: treatment. Lancet 1991; 338:736-9. Nicholson DP. Review of corticosteroid treatment in sepsis and septic shock: pro or con. Crit Care Clin 1989;5:151-5. WegJG. Critical care medicine. JAMA 1989;261:2836-7. Groeneveld ABJ. Septic shock and multiple organ failure: treatment with haemofiltration. Intensive Care Med 1990;16:489-90. Goldsmith MF. Excitement over immunomodulation inundates clinical research meetings. JAMA 1991;265:2768-73. Snyder SH. Nitric oxide: first in a new class ofneurotransmitters? Science 1992;257:494-6. OchoaJB, Udekwu AO, Billiar TR, et al. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991; 214:621-6. Petros A, Bennett D, Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 1991;338:1557-8. Amir S, English AM. An inhibitor of nitric oxide production, Ag-nitro-L-arginine-methylester, improves survival in anaphylactic shock. EurJ Phannacol 1991;203:125-7.

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118. Vallance P; Moncada S. Role of endogenous nitric oxide in septic shock. New Horizons 1993;1:77-86. 119. HarkemaJM, Chaudry IH. Magnesium-adenosine triphosphate in the treatment of shock, ischemia, and sepsis. Crit Care Med 1992;20:263-72. 120. Sarma PSA. Pentoxifylline in septic shock. Postgrad Med J 1990;66:980-1. 121. Ridings PC, Windsor AC, Sugermau HJ, et al. Beneficial cardiopulmonary effects of pentoxifylline in experimental sepsis are lost once septic shock is established. Arch Surg 1994; 129:1144-52. 122. Lechner AJ, Rouben LR, Potthoff LH, Tredway TL: Effects of pentoxifylline on tumor necrosis factor production and survival

during lethal E. coli sepsis vs disseminated candidiasis wifla fungal septic shock. Circ Shock 1993;39:306-15. 123. Refsum SE, McCaigue M, Campbell GR, et al. Pentoxifylline modulates cytokine responses in a sepsis model Prog Clin Biol Res 1994;388:323-33. 124. Endo S, Inada K, Taki K, Hoshi S, Yoshida M. Inhibitory effects of ulinastatin on the production of cytokines: implications for the prevention of septicemic shock. Clin Ther 1990;12: 323-6. 125. Putterman C. Aprotinin therapy in septic shock [Letter]. Acta Chir Scand 1989;155:367. 126. Barry SA. Septic shock: special needs of patients with cancer. Oncol Nuts Forum 1989;16:31-5.

CE TEST INSTRUCTIONS Test identification No. H0951 Contact hours/CERPS: 1.0 Passing score: 7 correct answers (70%)

Approved for AACN Category A Florida Content Code: 2502

This continuing education activity is administered and sponsored by Buchanan & Associates, which is accredited as a provider of Continuing Education in Nursing by the American Nurses Credentialing Center's Commission on Accreditation; California Board of Nursing Provider No. CEP9473; Florida Board of Nursing Provider No. 271 1004; and the Iowa Board of Nursing Provider No. 244. This test was written by Jean Marshall, MS, RN. Single Topics. To receive CE credit for this test, mark Your answers on the answer form that follows the test, complete the enrollment information, and submit it with the $9.00 processing fee (in U.S. dollars) to Buchanan & Associates. Answer forms must be postmarked by September 19, 1997. Within 3 weeks of receiving your test form, Buchanan & Associates will send a CE certificate. 1. What is the mortality rate of septic shock? a. 5% to 10% b. 20% to 25% c. 45% to 55% d. 60% to 95% 2. What clinical signs are present in sepsis? a. Hypothermia, bradycardia, hypercarbia. b. Hyperthermia, hypothermia, tachypnea, tachycardia. c. Lacticacidemia, hypoxemia, altered level of consciousness, d. Hyperthermia, hypoventilation, bradycardia. 3. What are the clinical signs of septic syndrome? a. Hypothermia, bradycardia, hypercapnia. b. Lacticacidemia, hypoxemia, altered level of consciousness. c. Hypotension, hypoventilation, bradycardia. d. Bacteremia, hypothermia, tachypnea, 4. What is refractory shock? a. Sepsis-induced hypotension with fluid resuscitation. b. Sepsis syndrome with hypotension responsive to fluid resucitation. c. Sepsis syndrome with hypotension not responsive to fluids or medication lasting more than 1 hour.

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d.

Sepsis syndrome with hypotension not responsive to fluids or medications lasting less than 1 hour. 5. What is the result of an activated complement system? a. Vasoconstriction, increased capillary permeability. b. Vasodilation, decreased capillary permeability. c. Vasoconstriction, decreased capillary permeability. d. Vasodilation, increased capillary permeability. 6. What nursing consideration is taken before the administration of antibiotics in septic shock? a. Ensure that the antibiotic is broad spectrum. b. Assess for adequate cardiovascular support to normalize the vital signs. c. Ensure that antibiotic treatment is begun within the first 24 hours. d. Ensure that decontamination of the gut has been instituted. 7. What is the occurrence of adult respiratory distress syndrome in patients with sepsis? a. 2% to 5% b. 5% to 40% c. 50% to 75% d. 60% to 95%

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