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Optimal management of septic shock

Rapid recognition and institution of therapy are crucial

Stephen J. Fitch, MD; James R. Gossage, MD

VOL 111 / NO 3 / MARCH 2002 / POSTGRADUATE MEDICINE


CME learning objectives

  • To understand the importance of organ hypoperfusion in septic shock
  • To become familiar with various vasoactive agents used in septic shock
  • To review the role of fluids in treatment of septic shock

The authors disclose no financial interest in this article.


This is the second of two articles on critical care.

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Preview: Septic shock is the most common cause of death in intensive care units in the United States, and its incidence is rising. This growth is most likely due to the increased use of invasive devices and immunosuppressive therapies, higher numbers of immunocompromised patients, and increasing antibiotic resistance. In this article, Drs Fitch and Gossage discuss the natural history and diagnosis of septic shock and optimal management, including optimization of organ perfusion, fluid therapy, and use of vasoactive agents.
Optimal management of septic shock: rapid recognition and institution of therapy are crucial. Fitch SJ, Gossage JR. Postgrad Med 2002;111(3):53-66


About 400,000 cases of sepsis, 200,000 cases of septic shock, and 100,000 deaths from both occur each year in the United States (1). Sepsis is defined as the systemic response to infection (2). In the absence of infection, it is called systemic inflammatory response syndrome and is characterized by at least two of the follow-ing: temperature greater than 38°C or less than 36°C; heart rate greater than 90 beats per minute; respiratory rate more than 20/minute or PaCO2 less than 32 mm Hg; and an alteration in white blood cell count (>12,000/mm3 or <4,000/mm3).

Septic shock is a subset of severe sepsis defined as sepsis-induced hypotension that persists despite fluid resuscitation and is associated with tissue hypoperfusion. Patients receiving vasoactive agents are also considered to have septic shock if they have tissue hypoperfusion despite correction of the hypotension.

Natural history

The last 30 years have yielded much information about the underlying abnormalities in septic shock, but many unanswered questions remain regarding the pathophysiology of this process. A detailed discussion of the molecular events associated with septic shock is beyond the scope of this article. However, it is important to understand the underlying cytokine cascade (figure 1). Local inflammation and substances elaborated from organisms, especially endotoxin, activate neutrophils, monocytes, and tissue macrophages. This results in a cascade of proinflammatory and anti-inflammatory cytokines and other mediators, such as IL-1, IL-8, IL-10, tumor necrosis factor-alpha, prostaglandin E1, endogenous corticosteroids, and catecholamines. Effects of this complex mediator cascade include cellular chemotaxis, endothelial injury, and activation of the coagulation cascade. An imbalance in favor of anti-inflammatory cytokines may result in relative immunosuppression and, if persistent, in increased risk of death (3).

[Figure 1]

The initial cardiovascular response includes decreased systemic vascular resistance and depressed ventricular function. Low systemic vascular resistance occurs in response to substances elaborated from infectious agents, cytokines, mediators such as nitric oxide, and down-regulation of peripheral catecholamine receptors. The origin of the decreased ventricular function is unknown, but various inflammatory mediators and tissue edema have been implicated (4).

If this initial cardiovascular response is uncompensated, generalized tissue hypoperfusion results. Aggressive fluid resuscitation may improve cardiac output and systemic blood pressure, resulting in the typical hemodynamic pattern of septic shock (ie, high cardiac index and low systemic vascular resistance). The response to volume loading in survivors of sepsis is ventricular dilatation (4,5); nonsurvivors may show little change in cardiac output. However, despite improvement in central hemodynamics, abnormalities in regional and microcirculatory blood flow often persist. These abnormalities may lead to cellular dysfunction, lactic acidosis and, ultimately, multiorgan failure. Death from septic shock usually results from rapid and overwhelming progression of sepsis unresponsive to all therapeutic maneuvers, multi-organ failure, or secondary nosocomial infection or complication.

Diagnosis

A patient who is hypotensive and in shock should be examined and treated as soon as possible. The evaluation should focus on differentiation of septic or hyperdynamic shock from other types, identification of the site of infection, and monitoring for end-organ dysfunction. Pertinent history should be obtained and a physical examination performed.

The early phases of septic shock may produce evidence of volume depletion, such as dry mucous membranes, and cool, clammy skin. After resuscitation with fluids, however, the clinical picture is typically more consistent with hyperdynamic shock, including tachycardia, bounding pulses with a widened pulse pressure, a hyperdynamic precordium on palpation, and warm extremities. Signs of possible infection include fever, localized erythema or tenderness, consolidation on chest examination, abdominal tenderness, and meningismus. Signs of end-organ hypoperfusion include tachypnea, oliguria, cyanosis, mottling of the skin, digital ischemia, abdominal tenderness, and altered mental status. Often, a definitive diagnosis cannot be made on the basis of initial findings on history taking and physical examination, and treatment for several possible conditions commences simultaneously.

Laboratory studies should include measurement of arterial blood gases, lactic acid level, electrolytes, renal function, and liver enzyme levels, as well as a chest radiograph. Cultures of blood, urine, and sputum should be obtained before antibiotics are administered. Cultures of pleural, peritoneal, and cerebrospinal fluid may be appropriate in some patients. If thrombocytopenia or bleeding is present, tests for disseminated intravascular coagulation should be performed (fibrinogen, d-dimer assay, platelet count, peripheral smear for schistocytes, prothrombin time, and partial thromboplastin time). It is important to compare the potential benefit of each diagnostic test or procedure with the time lost at the bedside attending to the fundamental goals of ensuring good gas exchange and tissue perfusion.

Treatment

Meticulous supportive care increases the likelihood of survival. The importance of adopting an aggressive tempo of resuscitation cannot be overemphasized. Almost all the interventions in early management of septic shock are aimed at rapidly establishing the diagnosis and restoring mean arterial pressure to 65 to 75 mm Hg to improve organ perfusion. The response to resuscitation should be monitored closely by frequent reassessment of tissue perfusion.

Clinical clues to tissue perfusion include skin temperature, mental status, and urine output. Lactic acid measurements also have been shown to be useful in assessing tissue perfusion. More invasive techniques, such as mixed venous oxygen saturation, gastric tonometry, and sublingual capnometry, have been investigated but have not proved useful in clinical management. We believe that the clinical assessment, urine output (goal, >20 to 30 mL/hr), and serial lactic acid levels are the best indicators of effectiveness of therapy. Lactic acid levels should decrease within 24 hours if therapy is effective, although normal values may not be reached for several days.

Intravenous access and monitoring
Close monitoring of hemodynamic parameters is central to therapy in patients with septic shock. Intravenous access is most rapidly obtained through peripheral sites, ideally with two 16- to 18-gauge catheters. More stable access can be achieved later with central intravenous access, especially if vasopressors are required. Placement of a large-bore introducer catheter in the right internal jugular or left subclavian vein is especially advantageous because it allows the most rapid rate of infusion (6) and provides easy access for placing a pulmonary artery catheter if needed.

Arterial lines should be placed in all patients with septic shock. They allow for more reliable monitoring of blood pressure and provide stable access for monitoring blood gases and other laboratory values. The most common sites are the radial, brachial, and femoral arteries. In general, we prefer the femoral site because it is easiest to access; also, central blood pressure is more reliable in patients with septic shock.

Pulmonary artery catheters are able to provide important data, such as cardiac output, systemic vascular resistance, pulmonary artery wedge pressure, and mixed venous oxygen saturation. In some cases, these data are useful in determining the origin of the shock state and providing rapid assessment of response to various therapies. Although the use of pulmonary artery catheters remains controversial, we believe that potential indications in septic shock include the persistent need for moderate or high doses of vasoconstrictors (eg, norepinephrine [Levophed], >10 micrograms/min) despite adequate fluid resuscitation, severe respiratory failure, and the presence of known heart disease and progressive renal insufficiency. Rigorous adherence to standards for data collection and a thorough understanding of hemodynamic physiology are central to the optimal use of pulmonary artery catheters.

Fluids
A number of human and animal studies (7-10) have shown that aggressive volume resuscitation is one of the centerpieces in treatment of septic shock. An initial bolus of fluid is appropriate in any shock state. The goal of fluid therapy is rapid volume expansion, which results in increased cardiac output and oxygen delivery. Because of the vasodilatation and capillary leak that occur in septic shock, most patients require 1 to 2 L of colloid or 4 to 8 L of crystalloid to adequately restore circulating volume (8). In general, we prefer to administer this fluid as a bolus, rather than a continuous infusion, because this allows more rapid restoration of circulating volume and minimizes the duration of inadequate organ perfusion. Typically, our goal is to increase mean arterial pressure to 65 to 75 mm Hg and improve organ perfusion within 1 hour of the onset of hypotension. While these maneuvers may improve hemodynamics initially, patients often continue to require large volumes of fluid in the 24 to 72 hours after the initial phase.

Physicians have debated about whether fluid should be administered in the form of crystalloid, colloid, or blood products. Crystalloid has the advantages of being relatively inexpensive and readily available. However, 1 L of crystalloid expands plasma volume by only about 200 to 250 mL and may predispose to pulmonary edema. Theoretically, colloids such as albumin and hydroxyethyl starch (Hespan) have the advantage of remaining longer in the intravascular space. Infusion of 1 L of 5% albumin typically expands plasma volume by 500 to 1,000 mL and equilibrates with the interstitium over 7 to 10 days (11). Infusion of 1 L of hydroxyethyl starch typically expands volume by 700 to 1,000 mL, with perhaps 40% of the peak effect persisting for 24 hours (11). Blood products have the advantage of remaining almost wholly intravascular; however, their availability is limited, and they carry a small risk of disease transmission and transfusion reaction.

The type of fluid used probably has no significant clinical impact on outcome as long as appropriate clinical end points are used. We generally use repeated boluses of crystalloid (isotonic sodium chloride solution or lactated Ringer's injection), 500 to 1,000 mL intravenously over 5 to 10 minutes, until mean arterial pressure and tissue perfusion are adequate (about 4 to 8 L total over 24 hours for the typical patient). Boluses of 250 mL might be appropriate for patients who are elderly or who have heart disease or suspected pulmonary edema. Because colloids are likely to stay in the vascular space longer, they may have a role when pulmonary edema is a concern. Red blood cells should be reserved for patients with a hemoglobin value of less than 10 g/dL (100 g/L) and either evidence of decreased oxygen delivery or significant risk from anemia (eg, coronary artery disease). Maintaining hemoglobin levels at greater than 8 to 10 g/dL (80 to 100 g/L) has not been shown to be beneficial in other patients (12).

The main complication of fluid resuscitation is tissue edema. Pulmonary edema is the most serious and is commonly manifested by tachypnea, hypoxemia, or decreased pulmonary compliance. Soft-tissue edema typically does not cause a problem, with the exception of a possible increased risk of skin breakdown. The occurrence of these problems is chiefly related to reduced microvascular permeability, increased hydrostatic pressure, and decreased colloid oncotic pressure.

Vasoactive agents
Patients who do not respond to fluid therapy should receive vasoactive agents. Physicians have debated about which vasoactive agents are best in septic shock. The primary goal is to rapidly normalize tissue perfusion pressure by increasing mean arterial pressure to 65 to 75 mm Hg. Increases in myocardial contractility, when appropriate, and improved oxygen delivery to tissues also are desirable.

Agents most commonly used are dopamine hydrochloride (Intropin), norepinephrine, dobutamine (Dobutrex), epinephrine, and phenylephrine hydrochloride (Neo-Synephrine). The receptor activities, hemodynamic effects, and typical dosing regimens of these agents are shown in tables 1 and 2. The doses listed are those typically used in clinical practice, but they may vary greatly in individual patients. Dopamine traditionally has been used as the initial therapy in hypotension, primarily because it is thought to increase systemic blood pressure through both improved cardiac performance and increased systemic vascular resistance. However, dopamine is a relatively weak vasoconstrictor in septic shock. Additionally, we do not recommend the use of low-dose dopamine, because a recent randomized placebo-controlled trial (13) failed to demonstrate its efficacy in improving renal function.

Table 1. Receptor activity of vasoactive agents
Agent Activity at receptors
alpha1 beta1 beta2 Dopaminergic

Dopamine HCl (Inotropin)* 2+ 3+ 2+ 3+

Norepinephrine (Levophed) 3+ 2+ ? 0

Dobutamine (Dobutrex) 1/2+ 3+ 2+ 0

Epinephrine* 2/3+ 3+ 3+ 0

Phenylephrine HCl (Neo-Synephrine) 3+ 0 0 0

Ratings indicate degree of activity from none (0) to maximal (3+).

*Activity is dose-dependent.


Table 2. Hemodynamic effects of vasoactive agents
Agent Dose Effect
CO MAP SVR

Dopamine HCl (Inotropin)* 5-20 micrograms/kg/min 2+ 1+ 1+

Norepinephrine (Levophed) 0.05-5 micrograms/kg/min -/0/+ 2+ 2+

Dobutamine (Dobutrex) 5-20 micrograms/kg/min 2+ -/0/+ -

Epinephrine* 0.05-2 micrograms/kg/min 2+ 2+ 2+

Phenylephrine HCl (Neo-Synephrine) 2-10 micrograms/kg/min -/0 2+ 2+

Ratings indicate degree of effect from modest decrease (-) to marked increase (2+). CO, cardiac output; MAP, mean arterial pressure; SVR, systemic vascular resistance.

*Activity is dose-dependent.


Many patients have persistently low blood pressure when receiving dopamine therapy. Evidence suggests that norepinephrine is superior to dopamine in the treatment of hypotension associated with septic shock. Martin and colleagues (14) studied 32 patients with septic shock unresponsive to fluids. They randomly assigned patients to receive a 6-hour infusion of either dopamine or norepinephrine. Fifteen of 16 patients in the norepinephrine group had improved hemodynamics compared with 5 of 16 in the dopamine group. Patients who received norepinephrine had higher urine output and more improvement in lactic acid levels than patients who received dopamine. Several other studies have shown improved splanchnic tissue perfusion with norepinephrine compared with dopamine.

Like norepinephrine, epinephrine and phenylephrine are more potent vasoconstrictors than dopamine. Few clinical studies have compared these agents, but limited data thus far suggest that norepinephrine is the agent of choice for treatment of hypotension related to septic shock. Dobutamine should be reserved for patients with a persistently low cardiac index or underlying left ventricular dysfunction. In general, we do not set an upper limit on such agents as norepinephrine or phenylephrine, but it is our experience that patients who require more than 200 micrograms/min of norepinephrine for longer than 24 hours rarely survive.

Vasopressin (Pitressin) also has been evaluated in a few studies to assess its pressor effect in septic shock. It has little pressor effect in healthy persons, but it has been shown to increase blood pressure in patients with sepsis (15,16). This may occur through improvement of sympathetic function, which has been shown to be abnormal in sepsis. Patients with septic shock have been shown to have low circulating levels of vasopressin. The data to this point are too limited to make firm recommendations, but further study is warranted.

Antibiotics
Antibiotics remain one of the few therapies that have been shown to reduce mortality rates in septic shock. They should be administered within 2 hours of the recognition of sepsis. The agent chosen depends largely on the host status and suspected causative organism. Important factors to consider include the suspected source of infection, nature of the pathogen most likely responsible (community or nosocomial), local resistance patterns, and underlying immune status of the patient. Sicker patients require broader coverage. For any given pathogen or source, numerous regimens are likely to be effective (table 3).

Table 3. Recommended antibiotics in septic shock
Suspected source Recommended antibiotics

Pneumonia Second- or third-generation cephalosporin plus macrolide (antipseudomonal beta lactam plus aminoglycoside if hospital-acquired)

Urinary tract Ampicillin plus gentamicin (Garamycin) or third-generation cephalosporin

Skin or soft tissue Nafcillin sodium (Nafcil, Nallpen, Unipen) (add metronidazole [Flagyl, Metro IV, Protostat] or clindamycin if anaerobic infection suspected)

Meningitis Third-generation cephalosporin

Intra-abdominal Third-generation cephalosporin plus metronidazole or clindamycin

Primary bacteremia Ticarcillin and clavulanate potassium (Timentin) or piperacillin sodium and tazobactam sodium (Zosyn)

The overuse of vancomycin hydrochloride (Vancocin, Vancoled) and its contribution to the development of multidrug-resistant pathogens are of great concern. Use of vancomycin should be restricted to settings in which the causative agent is most likely resistant Enterococcus, methicillin-resistant Staphylococcus aureus, or high-level penicillin-resistant Streptococcus pneumoniae.

Oxygen balance
Lactic acidosis, a hallmark of septic shock, is a result of an imbalance between oxygen delivery and consumption. Potential causes of this imbalance include inadequate oxygen delivery, increased oxygen consumption, and an inability of tissues to optimally use oxygen. Oxygen delivery to the tissues can be optimized by maintaining arterial oxygen saturation at more than 90% and hemoglobin at more than 8 g/dL (80 g/L) and by increasing the cardiac index to between 4.5 and 6 L/min per square meter of body surface area. The latter can be accomplished by the use of fluids to maintain adequate pulmonary artery wedge pressure (10 to 14 mm Hg) and through use of such positive inotropic agents as dobutamine. These interventions are often best achieved with the aid of a pulmonary artery catheter.

Initial investigation suggested that routinely maintaining supranormal oxygen delivery improves outcome, especially in high-risk surgical patients (17). However, these results have not been duplicated in most studies of septic shock, and therefore this approach is not recommended. While lactic acidosis most commonly represents poor tissue perfusion, experimental models also have demonstrated abnormal oxidative metabolism by peripheral tissues despite normal perfusion pressure and oxygen delivery (18,19).

Oxygen balance in septic shock also can be improved by reducing oxygen consumption. Control of fever can reduce oxygen consumption by about 20% (20). If the work of breathing is substantial, intubation and mechanical ventilation, along with sedation and neuromuscular blockade, can have similar effects (21).

Other therapies
Even with aggressive treatment of septic shock, a substantial number of patients remain hypotensive or demonstrate significant tissue hypoperfusion, or both. Several other therapies are used in refractory septic shock.

Use of corticosteroids in the treatment of septic shock has been controversial. Numerous studies in the 1980s and early 1990s generally showed no significant improvement with corticosteroid therapy, and some even showed increased morbidity (22). More recently, investigations have focused on use of more modest doses of corticosteroid in patients with refractory shock despite adequate resuscitation. A recent randomized placebo-controlled study of hydrocortisone (100 mg every 8 hours) in 41 patients with refractory shock (23) showed a significant improvement in hemodynamics and a trend toward improved survival rates regardless of the results of a corticotropin stimulation test. The data in this area are limited, but these and other results suggest that corticosteroids may be beneficial in a subset of patients with refractory shock.

Infusions of sodium bicarbonate long have been advocated to correct persistent metabolic acidosis. The argument is made that infusion of sodium bicarbonate results in increased pH with less cellular dysfunction, improved cardiac contractility, and improved activity of vasopressor agents. It also is argued that there is little detrimental effect and that this therapy should be tried as a last resort to improve the patient's clinical status. In a recent review (24), the data supporting sodium bicarbonate infusion were evaluated. It seems clear from animal data that artificially increasing the pH does not improve such parameters as cardiac function, although this is difficult to measure in humans. Furthermore, it is not clear that raising the serum pH has any effect on pH at a local tissue or intracellular level. Finally, sodium bicarbonate is converted to carbon dioxide and water, resulting in increased carbon dioxide levels and possible further depression of pH. We do not advocate the routine use of sodium bicarbonate in lactic acidosis.

Nitric oxide, which is released from endothelial cells, probably contributes to vasodilatation and perhaps to cardiac depression. Inhibition of nitric oxide synthesis by methylene blue (Methblue 65, Urolene Blue) has been shown to improve mean arterial pressure in patients with septic shock (25,26) but may have deleterious effects; data are limited. Naloxone hydrochloride (Narcan), an opioid antagonist, may block the endorphin effect that occurs in sepsis and improve hemodynamics in patients with septic shock (27,28). A recent meta-analysis (29) of three randomized controlled clinical trials of this agent showed modest hemodynamic improvement but no clear improvement in mortality rates. Further investigation probably is warranted before either of these therapies is universally adopted.

A host of multicenter randomized trials have evaluated inhibition of various cytokines thought to participate in the sepsis cascade. Monoclonal antibody to endotoxin, antibody to IL-1 receptor, antibradykinin, antiplatelet activating factor, anti-tumor necrosis factor, and nonsteroidal anti-inflammatory drugs have been studied. Improvement in mortality rates in sepsis or septic shock has not been demonstrated with any of these agents. This likely reflects the complexity of interactions between exogenous factors and the inflammatory and anti-inflammatory cascades.

An exciting recent finding has been the role of activated protein C in the treatment of septic shock. This compound has antithrombotic, profibrinolytic, and anti-inflammatory properties. A recent multicenter randomized placebo-controlled trial of more than 1,600 patients (30) showed that patients with septic shock who underwent treatment with activated protein C had a relative reduction in risk of death of 20%. The treated group had a small but statistically significant risk of bleeding. This winter, activated protein C (drotrecogin alfa) (Xigris) received approval from the US Food and Drug Administration for treatment in patients with severe sepsis who are at high risk of death. We recommend consideration of drotrecogin alfa mainly in patients with an APACHE II score greater than or equal to 25 or with significant organ dysfunction (especially refractory dysfunction or multiorgan dysfunction). Ultimately, the potential risks and benefits of this agent must be carefully weighed in each patient. Drotrecogin alfa is administered as a 96-hour infusion at a cost of about $6,800 for treatment in a 154-lb patient.

Summary

Septic shock is a common problem in hospitalized patients. Optimal management depends on rapid recognition, aggressive restoration of circulating volume with fluid boluses, initiation of appropriate antibiotic therapy, implementation of adequate monitoring, and meticulous attention to the details of care. Mean arterial pressure should be increased to between 65 and 75 mm Hg as soon as possible to reduce the likelihood of multiorgan dysfunction. Despite these therapeutic maneuvers, however, mortality rates are likely to remain high until the development of therapies that better target the underlying mechanisms of sepsis.

References

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Dr Fitch is a third-year fellow in pulmonary and critical care medicine, and Dr Gossage is associate professor of medicine and director of the multidisciplinary intensive care unit, section of pulmonary and critical care medicine, department of medicine, Medical College of Georgia School of Medicine, Augusta. Correspondence: James R. Gossage, MD, Medical College of Georgia School of Medicine, Section of Pulmonary and Critical Care Medicine, BBR-5513, 1120 15th St, Augusta, GA 30912-3135. E-mail: jgossage@mail.mcg.edu.


Symposium Index

  • EDITOR'S NOTE: Those critical first minutes by Peter A. Setness, MD, with Mary Van Beusekom
  • EARLY INTERVENTION IN MASSIVE PULMONARY EMBOLISM: A guide to diagnosis and triage for the critical first hour by James R. Gossage, MD
  • OPTIMAL MANAGEMENT OF SEPTIC SHOCK: Rapid recognition and institution of therapy are crucial by Stephen J. Fitch, MD, James R. Gossage, MD


Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock - Djillali Annane, etc.  
JAMA. August 21, 2002;288:862-871
Conclusion:   In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.