Multiple Organ Dysfunction Syndrome in Sepsis Treatment & Management

Treatment of patients with septic shock has the following 3 major goals:

• To resuscitate the patient from septic shock, using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation
• To identify the source of infection and treat it with antimicrobial therapy, surgery, or both
• To maintain adequate organ system function, guided by cardiovascular monitoring, and to interrupt the pathogenesis of multiple organ dysfunction syndrome (MODS)

Current management principles employed in addressing these goals include the following:

• Early recognition
• Early hemodynamic resuscitation
• Early and adequate antibiotic therapy
• Source control
• Continued hemodynamic support
• Corticosteroids (refractory vasopressor-dependent shock)
• Tight glycemic control
• Proper ventilator management with low tidal volume in patients with acute respiratory distress syndrome (ARDS)

Recognition of septic shock requires identification of features of the systemic inflammatory response syndrome (SIRS)—mental changes, hyperventilation, distributive hemodynamics, hyperthermia or hypothermia, and a reduced, elevated, or left-shifted white blood cell (WBC) count—along with the existence of a potential source of infection.

Patients in septic shock require immediate cardiorespiratory stabilization with large volumes of intravenous (IV) fluids, infusion of vasoactive drugs, and, often, endotracheal intubation and mechanical ventilation.

Empiric IV antimicrobial therapy should be immediately directed toward all potential infectious sources.

The drugs used for hemodynamic support of patients with sepsis have adverse effects on splanchnic circulation. Accordingly, the ideal hemodynamic therapy in these patients has not been determined. After adequate fluid resuscitation, therapy with dopamine may be initiated, followed by norepinephrine when dopamine fails. Alternatively, therapy may be initiated with norepinephrine, with dobutamine used if inotropic support is needed. The use of epinephrine as a single agent in septic shock is not recommended.

Manipulation of oxygen delivery by increasing the cardiac index has either yielded no improvement or has worsened morbidity and mortality. Routine use of hemodynamic drugs to raise cardiac output to supranormal levels is not recommended.

Drotrecogin alfa (activated protein C) was the only widely accepted drug specific to the therapy of sepsis. However, in a clinical trial (PROWESS-SHOCK trial), this agent failed to show a survival benefit for patients with severe sepsis and septic shock. The results of the trial led to the withdrawal of drotrecogin alfa from the worldwide market on October 25, 2011. The adverse side effect of drotrecogin alfa is bleeding.

Lactic acidosis of septic shock usually causes anion gap metabolic acidosis. Administration of bicarbonate has the potential to worsen intracellular acidosis. Correction of acidemia with sodium bicarbonate has not been proved to improve hemodynamics in critically ill patients with increased blood lactate levels. Nevertheless, bicarbonate therapy has been used in cases where the pH is less than 7.20 or the bicarbonate level is lower than 9 mmol/L, though no data to support this practice exist.

The pathogenesis of septic shock and MODS derives from mediators produced because of the immune response of the host. Despite encouraging data from animal studies, immunosuppressive agents, such as high-dose corticosteroids, have not shown any benefit in humans.

The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be kept at less than 150 mg/dL.

Research has focused on modifying the host response to sepsis via a number of approaches, including the following:

• Antibodies against gram-negative endotoxin
• Gamma globulins
• Monoclonal antibodies against tumor necrosis factor
• Blockade of eicosanoid production
• Blockade of interleukin (IL)–1 activity
• Inhibition of nitric oxide (NO) synthase

These approaches have met with modest success in animal experiments, but at present, they cannot be recommended for general use in humans.

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, MODS, and mortality at 28 days when compared to placebo.^[14]

Initial treatment includes support of respiratory and circulatory function, administration of supplemental oxygen, mechanical ventilation, and volume infusion. Beyond these supportive measures, treatment 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 (see below).

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.

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 lactated Ringer solution) 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 radiographs. Improvement, stabilization, and normalization of the patient’s mental status, heart rate, blood pressure, capillary refill, and urine output indicate adequate volume resuscitation.

In some patients, clinical assessment of the response to volume infusion may be difficult. By monitoring the response of the central venous pressure (CVP) or the pulmonary artery occlusion pressure (PAOP) to fluid boluses, the physician can assess these patients.

A CVP of 10-15 mm Hg, a PAOP greater than 18 mm Hg, or a rise in the PAOP by 5 mm Hg or more after a fluid bolus indicates adequate volume resuscitation. Because such patients are susceptible to volume overload, any further fluid must be administered carefully. Colloid resuscitation (with albumin or pentastarch) has no proven benefit over isotonic crystalloid resuscitation (with normal saline or lactated Ringer solution).

If patients are treated initially in the wards or in the emergency department (ED), after initial attempts at stabilization, they should be transferred to the intensive care unit (ICU) for invasive monitoring and support.

Initial selection of particular antimicrobial agents is empiric and is based on an assessment of the patient’s underlying host defenses, the potential sources of infection, and the most likely pathogens.

Antibiotics must be broad-spectrum and must cover gram-positive, gram-negative, and anaerobic bacteria because all of these classes of organisms produce identical clinical pictures. Administer antibiotics parenterally in doses high enough to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than with the number of antibiotics administered.

Coverage directed against anaerobes is particularly important in the treatment of patients with intra-abdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns.

Patients who are immunocompetent generally can be treated with a single drug that provides broad-spectrum coverage, such as a third-generation cephalosporin. However, patients who are immunocompromised usually must be treated with 2 broad-spectrum antibiotics that provide overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to any other.

When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. The agents used are dopamine, norepinephrine, epinephrine, and phenylephrine. These drugs maintain adequate blood pressure 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) on the basis of 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 µg/kg/min), titrating the dose to support a systolic BP of 90 mm Hg.

Although potent vasoconstrictors such as norepinephrine traditionally have been avoided because of their adverse events on cardiac output and renal perfusion, data from human studies have 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.

Dopamine

A precursor of norepinephrine and epinephrine, dopamine has varying effects, depending on the dose administered. A dose lower than 5 µg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dose of 5-10 µg/kg/min, beta₁ -adrenergic effects induce an increase in cardiac contractility and heart rate. At doses of about 10 µg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and an increase in blood pressure.

Dopamine is effective in increasing MAP in patients who are hypotensive with septic shock after volume resuscitation. The blood pressure increases primarily as a result of an inotropic effect, which is useful in patients who have concomitant reduced cardiac function. The undesirable effects are tachycardia, increased pulmonary shunting, potentially decreased splanchnic perfusion, and increased PAOP.

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 kidney-protecting effects. Dopamine at a dose of 2-3 µg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. However, multiple studies have not demonstrated a beneficial effect with prophylactic or therapeutic low-dose dopamine administration in patients who are critically ill.

Administering low-dose dopamine does not protect the patient from developing acute renal failure, and there is no evidence that it preserves mesenteric profusion. Consequently, 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 for protecting the kidneys.

Epinephrine

Epinephrine can increase MAP by increasing the cardiac index, stroke volume, systemic vascular resistance, and heart rate. It may increase oxygen delivery and consumption and decreases splanchnic blood flow. Administration of epinephrine 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 of this agent include increased lactate concentration, potential production of myocardial ischemia and arrhythmias, and reduced splanchnic flow.

Norepinephrine

Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. It can successfully increase blood pressure in patients who are in a septic state and remain hypotensive after fluid resuscitation and dopamine. Doses range from 0.2 to 1.35 µg/kg/min; doses as large as 3.3 µg/kg/min have been used because alpha-receptor downregulation may occur in sepsis.

In patients with sepsis, indices of regional perfusion (eg, urine flow and lactate concentration) have improved after norepinephrine infusion. In recent controlled trials, no significant difference was noted in the rate of death between patients with shock who were treated with dopamine and those who were treated with norepinephrine; the use of dopamine was associated with a greater number of adverse events, which were mostly cardiac arrhythmias.^{[15, 16]}

Accordingly, use norepinephrine early, and do not withhold it as a last resort. Norepinephrine therapy appears to have no effects on splanchnic oxygen consumption and hepatic glucose production, provided that adequate cardiac output is maintained.

Phenylephrine

Phenylephrine is a selective alpha₁ -adrenergic receptor agonist that is primarily used in anesthesia to increase blood pressure. Although the data are limited, phenylephrine has been found to increase MAP in patients with sepsis who are 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.

Role of inotropic therapy

Although myocardial performance is altered during sepsis and septic shock, cardiac output is usually maintained in patients with sepsis who have undergone volume resuscitation. Data from the 1980s and 1990s suggested a linear relation 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, subsequent investigations challenged the concept of pathologic supply dependency and the practice of elevating cardiac index and oxygen delivery (hyperresuscitation) on the grounds that 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.

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.

An early publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated that administration of recombinant human activated protein C (drotrecogin alfa) resulted in lower mortality (24.7%) in the treatment group than in the placebo group (30.8%).^[17] Treatment with drotrecogin alfa was associated with a 19.4% relative reduction in the risk of death and a 6.1% absolute reduction in the risk of death.

After that early publication, the efficacy and safety of drotrecogin alfa were widely debated. Drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011, after analysis of the PROWESS-SHOCK clinical trial, in which the drug failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock.^[18] Trial results observed a 28-day all-cause mortality of 26.4% in patients treated with drotrecogin alfa, compared with 24.2% in the placebo group.

Despite the theoretical and experimental animal evidence supporting the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies of this practice (except a single study from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve 14-day mortality. Therefore, routine use of high-dose corticosteroids in patients with severe sepsis or septic shock is not indicated.

Although further research is required to address this issue definitively, there are some recommendations that can be made at present. Trials have demonstrated positive results from administration of stress-dose corticosteroids to patients in severe and refractory shock.^[19] These results await further confirmation, but it is reasonable to provide stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.

The following key points summarize current use of corticosteroids in septic shock:

• Older, traditional trials of corticosteroids in sepsis probably failed to show good results because they used high doses and did not select patients appropriately
• Subsequent trials with low-dose (physiologic) dosages in select patient populations (vasopressor-dependent patients and those with potential relative adrenal insufficiency) reported improved outcomes
• 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 as failure to raise levels above 9 µg/dL.

Tight glycemic control has become a prominent emphasis in the care of critically ill patients, and data have been extrapolated for potential application to patients with sepsis. A 2001 Belgian study of surgical ICU patients who remained in the ICU for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control.^[20] The glucose levels for these patients were maintained between 80 and 110 mg/dL through the use of intensive insulin therapy.

Tight glycemic control has been shown to improve mortality in postoperative surgical patients including and particularly those patients with sepsis. The benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia than from the potential therapeutic effect of insulin. On the basis of the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL.^[21]

Seek consultation with an appropriate surgeon for patients with suspected or known infected foci, especially for patients with a suspected abdominal source.

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.

The major focus of resuscitation from septic shock is supporting cardiac and respiratory functions. To prevent MODS, these patients require a very close monitoring and institution of appropriate therapy for major organ function. Problems encountered in these patients include the following:

• Temperature control – Fever generally requires no treatment, except in patients with limited cardiovascular reserve, because of increased metabolic requirements; antipyretic drugs and physical cooling methods, such as sponging or cooling blankets, may be used to lower the temperature
• Metabolic support – Patients with septic shock develop hyperglycemia and electrolyte abnormalities; serum glucose should be kept in normal range with insulin infusion; regular measurement and correction of electrolyte deficiency (including hypokalemia, hypomagnesemia, hypocalcemia and hypophosphatemia) is recommended
• Anemia and coagulopathy – Hemoglobin as low as 8 g/dL is well tolerated and does not warrant transfusion unless the patient has poor cardiac reserve or demonstrates evidence of myocardial ischemia; thrombocytopenia and coagulopathy are common in sepsis and do not necessitate replacement with platelets or fresh frozen plasma, unless the patient develops active clinical bleeding
• Renal dysfunction – Closely monitor urine output and renal function in all patients with sepsis; any abnormalities of renal function should prompt attention to adequacy of circulating blood volume, cardiac output, and blood pressure; correct these if they are inadequate
• Nutritional support – Early nutritional support is of critical importance in patients with septic shock; the enteral route is preferred unless the patient has an ileus or other abnormality; gastroparesis is observed commonly and can be treated with motility agents or placement of a small bowel feeding tube

Patients with impaired host defense mechanisms are at greatly increased risk for sepsis and MODS. The main causes are chemotherapeutic drugs, malignancy, severe trauma, burns, diabetes mellitus, renal or hepatic failure, old age, ventilatory support, and invasive catheters.

One way of helping to prevent severe sepsis is to avoid invasive catheters or remove them as soon as possible. Prophylactic antibiotics in the perioperative phase, particularly after gastrointestinal surgery, may be beneficial. Use of topical antibiotics around invasive catheters and as part of a dressing for patients with burns is helpful. Maintenance of adequate nutrition, administration of pneumococcal vaccine to patients who have undergone splenectomy, and early enteral feeding are other preventive measures.

Topical or systemic antibiotics have been given to prevent sepsis and MODS in high-risk patients. The use of nonabsorbable antibiotics in the stomach to prevent translocation of bacteria and occurrence of bacteremia has been a controversial issue. Numerous trials have been performed over the years using either topical antibiotics alone or a combination of topical and systemic antibiotics.

A systemic review by Nathens presented no benefit in medical patients but a reduced mortality in surgical trauma patients.^[22] The beneficial effect was from a combination of systemic and topical antibiotics, predominantly involving reduction of lower respiratory tract infections in patients who were treated.