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Multisystem Organ Failure of Sepsis: Treatment & Medication

Coauthor(s): Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital; Gregg Eschun, MD, Assistant Professor, Department of Internal Medicine, Sections of Respirology and Critical Care, St Boniface Hospital, University of Manitoba, Canada
Contributor Information and Disclosures

Updated: Apr 28, 2009

Treatment

Medical Care

The treatment of patients with septic shock consists of the following 3 major goals: (1) Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. (2) Identify the source of infection and treat with antimicrobial therapy, surgery, or both. (3) Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiorgan system dysfunction.

The principles in the management of septic shock based on current literature include the following components:

1. Early recognition
2. Early and adequate antibiotic therapy
3. Source control
4. Early hemodynamic resuscitation and continued support
5. Corticosteroids (refractory vasopressor-dependent shock)
6. Drotrecogin alfa (severely ill if APACHE II score >25)
7. Tight glycemic control
8. Proper ventilator management with low tidal volume in patients with ARDS

• General supportive care
  • Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes a combination of several parenteral antibiotics, removal or drainage of infected foci, treatment of complications, and pharmacologic interventions to prevent further harmful host responses.
  • Administer supplemental oxygen to any patient who is septic with hypoxia or respiratory distress. If the patient's airway is not secure or respirations are inadequate, perform endotracheal intubation and mechanical ventilation.
• Intravascular volume resuscitation
  • All patients with sepsis require supplemental fluids. Assessment of the patient's volume and cardiovascular status guides the amount and rate of infusion. For adult patients who are hypotensive, administer an isotonic crystalloid solution (sodium chloride 0.9% or Ringer lactate) in boluses of 500 mL (10 mL/kg in children), with repeat clinical assessments after each bolus. Administer repeat boluses until signs of adequate perfusion are restored. A total of 4-6 L may be required. Monitor patients for signs of volume overload, such as dyspnea, pulmonary crackles, and pulmonary edema, on chest radiograph. Improvement, stabilization, and normalization of the patient's mental status, heart rate, BP, capillary refill, and urine output indicate adequate volume resuscitation.
  • In some patients, clinically assessing the response to volume infusion may be difficult. By monitoring the response of central venous pressure or pulmonary artery occlusion pressure (PAOP) to fluid boluses, the physician can assess these patients. A control venous pressure of 10-15 mm Hg, a PAOP greater than 18 mm Hg, or a rise in the PAOP by 5 mm Hg or more following fluid bolus indicates adequate volume resuscitation. Such patients are susceptible to volume overload; therefore, administer further fluid carefully. Colloid resuscitation (with albumin or pentastarch) has no proven benefit over isotonic crystalloid resuscitation (normal saline or Ringer lactate).
• Empirical antimicrobial therapy
  • Administer initial antibiotics. Selection of particular agents is empirical and is based on an assessment of the patient's underlying host defenses, the potential sources of infection, and the most likely responsible organisms. Antibiotics must be broad spectrum and cover gram-positive, gram-negative, and anaerobic bacteria because all classes of these organisms produce identical clinical pictures. Administer antibiotics parenterally in doses adequate to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than the number of antibiotics administered.
  • Include coverage directed against anaerobes in the therapy of patients with intraabdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns. Patients who are immunocompetent usually can be treated with a single drug with broad-spectrum coverage, such as a third-generation cephalosporin. Patients who are immunocompromised usually require dual antibiotic coverage with broad-spectrum antibiotics with overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to others.
• Vasopressor supportive therapy
  • When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. These agents are dopamine, norepinephrine, epinephrine, and phenylephrine. These vasoconstricting drugs maintain adequate BP during life-threatening hypotension and preserve perfusion pressure for optimizing flow in various organs. Maintain the mean BP required for adequate splanchnic and renal perfusion (mean arterial pressure [MAP] of 60 or 65 mm Hg) based on clinical indices for organ perfusion.
  • If the patient remains hypotensive despite volume infusion and moderate dose dopamine, start a direct vasoconstrictor (eg, norepinephrine) at a dose of 0.5 mcg/kg/min in and titrated to support a systolic BP of 90 mm Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally have been avoided because of their adverse events on cardiac output and renal perfusion, human data has shown that norepinephrine can reverse septic shock in patients unresponsive to volume and dopamine. These patients require invasive hemodynamic monitoring with arterial lines and pulmonary artery catheters. A brief discussion of the hemodynamic drugs used to support patients who are critically ill and septic follows:
  • Vasopressor therapy
    • Dopamine: A precursor of norepinephrine and epinephrine, dopamine has varying effects based on the doses. A dose of less than 5 mcg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dose of 5-10 mcg/kg/min, beta-1-adrenergic effects induce an increase in cardiac contractility and heart rate. At doses about 10 mcg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and an increase in BP. Dopamine is effective in increasing MAP in patients who are hypotensive with septic shock after volume resuscitation. The BP increases primarily as a result of an inotropic effect and, thus, is useful in patients who have concomitant reduced cardiac function. The undesirable effects are tachycardia, increased pulmonary shunting, potential to decrease splanchnic perfusion, and increased pulmonary arterial wedge pressure.
    • Epinephrine: Epinephrine can increase MAP by increasing the cardiac index, stroke volume, systemic vascular resistance, and heart rate. Epinephrine may increase oxygen delivery and consumption and decreases splanchnic blood flow. Epinephrine administration is associated with an elevation of systemic and regional lactate concentrations. The use of epinephrine is recommended in patients who are unresponsive to traditional agents. The undesirable effects are an increase in lactate concentration, a potential to produce myocardial ischemia and arrhythmias, and a reduction in splanchnic flow.
    • Norepinephrine: Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. Norepinephrine can successfully increase BP in patients who are septic and remain hypotensive following fluid resuscitation and dopamine. The dose of norepinephrine may vary from 0.2-1.35 mcg/kg/min; doses as large as 3.3 mcg/kg/min have been used because alpha-receptor down regulation may occur in sepsis. In patients who are septic, indices of regional perfusion, such as urine flow and lactate concentration, have improved following norepinephrine infusion. Two recent trials have shown that a significantly greater proportion of patients treated with norepinephrine were successfully resuscitated as opposed to patients treated with dopamine. Therefore, use norepinephrine early, and do not withhold it as a last resort. The studies have shown no effects on splanchnic oxygen consumption and hepatic glucose production, provided adequate cardiac output is maintained.
    • Phenylephrine: Phenylephrine is a selective alpha-1 adrenergic receptor agonist primarily used in anesthesia to increase BP. Although studies are limited, phenylephrine increased the MAP in patients who are septic and hypotensive with an increase in oxygen consumption and potential to reduce cardiac output. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other vasopressors.
    • Inotropic therapy: Although myocardial performance is altered during sepsis and septic shock, cardiac output usually is maintained in the patients who are septic and have been volume resuscitated. Data from the 1980s and 1990s suggested a linear relationship between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that oxygen delivery was likely insufficient to meet the metabolic needs of the patient. However, recent investigations have challenged the concept of pathologic supply dependency and the practice of elevating cardiac index and oxygen delivery (hyperresuscitation) because these interventions have not been shown to improve patient outcome. Therefore, the role of inotropic therapy is uncertain unless the patient has an inadequate cardiac index, MAP, mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and vasopressor therapy.
    • Renal-dose dopamine: The use of renal-dose dopamine in sepsis is a controversial issue. In the past, low-dose dopamine was routinely used in many units because of the presumed renal protective effects. Dopamine at a dose of 2-3 mcg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated a beneficial effect with prophylactic or therapeutic low-dose dopamine administration in patients who are critically ill. Low-dose dopamine does not protect the patient from developing acute renal failure, and there is no data stating that it preserves mesenteric profusion; the routine use of this practice is not recommended. Aggressively resuscitating patients with septic shock, maintaining adequate perfusion pressure, and avoiding excessive vasoconstriction are effective measures to protect the kidneys.
• Recombinant human-activated protein C
  • The inflammatory mediators are known to cause activation of coagulation inhibitors of fibrinolysis, thereby causing diffuse endovascular injury, multiorgan dysfunction, and death. Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation but also may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated protein C. Administration of recombinant activated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation.
  • A study by Jaimes et al was not able to demonstrate beneficial effects of unfractionated heparin in patients with sepsis on length of hospital stay, multiple organ dysfunction, and mortality at 28 days when compared to placebo.⁶
  • A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated that the administration of recombinant human activated protein C (drotrecogin-alpha, activated) resulted in lower mortality rates (24.7% vs 30.8%) in the treated group compared with placebo. Treatment with drotrecogin-alpha, activated was associated with reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by 6.1%, (P =.005).
• Corticosteroids
  • While theoretical and experimental animal evidence exists for the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve the 14-day mortality rate. Therefore, no support exists in the medical literature for the routine use of high doses of corticosteroids in patients with sepsis or septic shock. A meta-analysis of 10 prospective, randomized, controlled trials of glucocorticoid use did not report any benefit from corticosteroids. Therefore, high-dose corticosteroids should not be used in patients with severe sepsis or septic shock.
  • Although further studies await further confirmation, current recommendations are as follows:
    • Drotrecogin alpha (activated protein C) is the only widely accepted drug specific to the therapy of sepsis. Drotrecogin Alpha should be considered for patients with APACHE II scores greater than 25.
    • The main side effect of Drotrecogin alpha is bleeding.
    • Recent trials of stress-dose glucocorticoids (Briegel, 1999; Cartlet, 1999) demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock. Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.
  • The following key points summarize use of corticosteroids in septic shock:
    • Older, traditional trials of corticosteroids in sepsis were likely unsuccessful due to high doses and poor patient selection.
    • Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependent and possibly relative adrenal insufficiency) patients have resulted in improved outcome.
    • Corticosteroids should be initiated for patients with vasopressor-dependent septic shock.
• A cosyntropin stimulation test may be performed to identify patients with relative adrenal insufficiency defined recently as failure to increase levels to more than 9 mcg/dL.
• Tight glycemic control has recently become a prominent emphasis in the care of critically ill patients, and recent data has been extrapolated to potentially apply to septic populations. A 2001 Belgian study of surgical intensive care unit (ICU) patients that remained in the ICU for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucose levels for these patients were maintained between 80 and 110 mg per deciliter through use of intensive insulin therapy. The benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin.
• Based on the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL (Dellinger, 2004).
• Tight glycemic control has been shown to improve mortality in postoperative surgical patients including and particularly those patients with sepsis.
• The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be kept at less than 150 mg/dL.

Surgical Care

Take patients with infected foci to surgery after initial resuscitation and administration of antibiotics for definitive surgical treatment. Little is gained by spending hours stabilizing the patient when an infected focus persists.

Consultations

• Patients who do not respond to therapy or are in septic shock require admission to an ICU for continuous monitoring and observation. Consultation with a critical care physician or internist with expertise is appropriate.
• Seek consultation with an appropriate surgeon for patients with suspected or known infected foci, especially for patients with a suspected abdominal source.

Medication

The proven medical treatments for septic shock are restoration of intravascular volume and broad-spectrum empirical antibiotic coverage. All other medical therapies, while theoretically attractive, have not reduced morbidity or mortality.

Isotonic crystalloids

Standard fluid used for initial volume resuscitation. These fluids expand the intravascular and interstitial fluid spaces. Typically, approximately 30% of administered isotonic fluid remains intravascular; therefore, large quantities may be required to maintain an adequate circulating volume.

Normal saline (NS) and Ringer lactate (RL)

Both fluids essentially are isotonic and have equivalent volume restorative properties. While some differences exist between metabolic changes observed with administration of large quantities of either fluid, for practical purposes and in most situations, the differences are clinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation with either NS or RL. The amount of intravascular fluid requirements are related to the degree of vascular endothelial injury and impaired vasomotor tone; thus, not only may very large quantities of fluids be required initially, but continual fluid resuscitation often is required during the initial days of management of these patients.

Colloids

Resuscitation fluids used because they provide an oncotically active substance that expands plasma volume to a greater degree than isotonic crystalloids and reduces the tendency to pulmonary and cerebral edema. Approximately 50% of the administered colloid remains intravascular.

Albumin 5% (Albuminar, Albunex)

Used for treatment of certain types of shock or impending shock. Useful for plasma volume expansion and maintenance of cardiac output.
Solution of normal saline and 5% albumin is available for volume resuscitation.

Antibiotics

Empirical antibiotics that cover the infecting organism and are started early are the only other proven medical treatment for septic shock. In order to provide the necessary coverage, broad-spectrum and/or multiple antibiotics are started. Monotherapy is possible in adults who are not immunocompromised with either antipseudomonal penicillin or a carbapenem. Combination therapy in adults involves 1 of the following: a third-generation cephalosporin plus anaerobic coverage (clindamycin or metronidazole) or a fluoroquinolone plus clindamycin. Administer all initial antibiotics intravenously in patients with septic shock.

Cefotaxime (Claforan)

Used for treatment of septicemia. Also used for treatment of gynecologic infections caused by susceptible organisms. Third-generation cephalosporin with enhanced gram-negative coverage, especially to Escherichia coli, Proteus species, and Klebsiella species. Has variable activity against Pseudomonas species.

Ceftriaxone (Rocephin)

Used because of an increasing prevalence of penicillinase-producing microorganisms. Inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

Cefuroxime (Zinacef)

Second-generation cephalosporin that maintains gram-positive activity of the first-generation cephalosporins and adds activity against E coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis. Condition of the patient, severity of the infection, and susceptibility of the microorganism determine proper dose and route of administration.

Ticarcillin/clavulanate (Timentin)

Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positives (variable coverage against Staphylococcus epidermidis and none against methicillin-resistant Staphylococcus aureus [MRSA]), most gram-negative organisms, and most anaerobes.

Piperacillin/tazobactam (Zosyn)

Inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. Has antipseudomonal activity.

Imipenem and cilastatin (Primaxin)

Carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. Used for treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to their potential for toxicity.

Meropenem (Merrem)

Carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.

Clindamycin (Cleocin)

Primarily used for its activity against anaerobes. Has some activity against streptococcus and methicillin-sensitive S aureus (MSSA).

Metronidazole (Flagyl) or Ciprofloxacin (Cipro)

Metronidazole: Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually employed in combination with other antimicrobial agents, except when it is used for Clostridium difficile enterocolitis in which monotherapy is appropriate.

Ciprofloxacin: Fluoroquinolone with variable activity against streptococci, MSSA, S epidermidis, and most gram-negative organisms. No activity against anaerobes.

Activated protein C analogs

Exert antithrombic effects, have indirect profibrinolytic activity, and may have anti-inflammatory effect.

Drotrecogin alfa (Xigris)

Indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1 (PAI-1) and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.

Vasopressor supportive therapy

If patient does not respond to several liters of isotonic crystalloid (usually 4 or more) or evidence of volume overload is present, the depressed cardiovascular system can be stimulated by inotropic and vasoconstrictive agents.

Dopamine (Inotropin)

Used to treat hypotension in fluid-resuscitated patients. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation in health volunteers, but probably have no measurable effect in patients who are critically ill. Higher doses produce cardiac stimulation, tachycardia, and vasoconstriction.

Norepinephrine (Levophed)

As with dopamine, it is used to treat hypotension following adequate fluid-volume replacement. Norepinephrine stimulates beta 1-adrenergic and alpha-adrenergic receptors, which increase arterial tone and cardiac contractility. As a result, systemic BP and coronary blood flow increases with norepinephrine, though myocardial oxygen demand also may increase. After obtaining a response, adjust infusion rate to maintain a MAP greater than 60 mm Hg. BP levels below this threshold are insufficient to perfuse vital organs while increasing pressures much greater than 70 mm Hg, using vasopressors does not further increase tissue blood flow.

Vasopressin (Pitressin)

Has vasopressor and antidiuretic hormone (ADH) activity. Although vasopressin does not increase BP in healthy subjects, it markedly increases vasomotor tone in patients with septic shock. It also increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction also is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Vasopressin is not yet routinely used to treat hypotension in septic shock. The dosage of vasopressin used for hypotension is one-tenth that used to treat upper GI bleeding from varices.

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