Multiple Organ Dysfunction Syndrome in Sepsis Treatment & Management

Treatment of patients with septic shock has the following three 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 used 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.

General management is as follows ^[20] :

• Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion

• Goals during the first 6 hours of resuscitation are (1) central venous pressure 8-12 mm Hg, (2) mean arterial pressure (MAP) above 65 mm Hg, (3) urine output above 0.5 mL/kg/h, (4) central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively

• In patients with elevated lactate levels, targeting resuscitation to normalize lactate as rapidly as possible

• Screening for sepsis and performance improvement

Diagnosis is as follows ^[20] :

• Cultures as clinically appropriate before antimicrobial therapy if no significant delay (45 min) in the start of antimicrobial(s)

• At least 2 sets of blood cultures obtained before antimicrobial therapy

• Imaging studies performed promptly to confirm a potential source of infection

Antimicrobial therapy is as follows ^[20] :

• Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy

• Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis

• Antimicrobial regimen should be reassessed daily for potential deescalation

• Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic but have no subsequent evidence of infection

• Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens

• Duration of therapy typically 7-10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with Staphylococcus aureus, some fungal and viral infections, or immunologic deficiencies (including neutropenia)

• Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin

• Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause

Source control is as follows ^[20] :

• A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible

• Intervention be undertaken for source control within the first 12 hours after the diagnosis is made, if feasible

Infection prevention is as follows ^[20] :

• Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; this infection control measure can then be instituted in healthcare settings and regions where this methodology is found to be effective

• Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associate pneumonia in ICU patients with severe sepsis

Choice of resuscitation fluid is as follows ^[20] :

• Surviving Sepsis Campaign: Recommend using crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock and recommend against the use of hydroxyethyl starches (HES). Albumin can be used in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids.

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 norepinephrine, epinephrine, vasopressin, dopamine, 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 65 mm Hg) on the basis of clinical indices for organ perfusion.

Norepinephrine is the first-choice vasopressor. Epinephrine (added to and potentially substituted for norepinephrine) can be used when an additional agent is needed to maintain adequate blood pressure. Vasopressin at 0.03 units/minute can be added to norepinephrine with the intent of either raising MAP or decreasing norepinephrine dosage. Dopamine as an alternative vasopressor agent to norepinephrine is used only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). Phenylephrine is not recommended in the treatment of septic shock, except in circumstances when norepinephrine is associated with serious arrhythmias, cardiac output is known to be high and blood pressure is persistently low, or as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve MAP target. ^[20]

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 0.2-1.35 µg/kg/min; doses as high as 3.3 µg/kg/min have been used because alpha-receptor down-regulation 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. ^{[21, 22]}

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 adequate cardiac output is maintained.

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.

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 only partially 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

In healthy volunteers, infusion of dopamine at low doses (0.5-2 mg/kg/min) increases both renal blood flow and the glomerular filtration rate by selective stimulation of renal dopaminergic receptors. However, “beneficial” effects of such renal-dose dopamine in sepsis are unsubstantiated. 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.

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.

Angiotensin II

Angiotensin II targets the renin-angiotensin-aldosterone system (RAAS), a powerful mediator of arterial blood pressure. Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was conducted to determine whether the addition of angiotensin II to background vasopressors would improve blood pressure in patients with catecholamine-resistant vasodilatory shock. ^[23] In that study, 321 patients with vasodilatory shock were randomized to receive either angiotensin II (163 patients) or placebo (158 patients). Enrolled patients had shock despite receiving more than 0.2 μg/kg/min of norepinephrine or another vasopressor in a similar dose. The primary endpoint was a response with respect to MAP at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. The primary endpoint was reached by more patients in the angiotensin II group than in the placebo group. At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score was greater in the angiotensin II group than in the placebo group. There was no statistically significant difference in mortality between the two groups.

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. However, if there is inadequate cardiac index, MAP, mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and vasopressor therapy, a trial of dobutamine infusion up to 20 µg/kg/min be administered or added to 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%). ^[24] 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. ^[25] 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, hydrocortisone can be given at 200-300 mg/day for up to 7 days or until vasopressor support is no longer required for patients with refractory septic shock.

Trials have demonstrated positive results from administration of stress-dose corticosteroids to patients in severe and refractory shock. ^[26] Large clinical trials have documented a clear benefit of hydrocortisone plus fludrocortisone for adults with septic shock, reducing the time on ventilator and the severity of acute kidney injury, along with overall lower Sequential Organ Failure Assessment (SOFA) scores. ^[27] Thus, it is reasonable to provide stress-dose steroid coverage plus mineralocorticoid supplement to septic shock patients, and especially those 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 useful to identify patients with relative adrenal insufficiency, defined as failure to raise levels above 9 µg/dL.

A protocolized approach to blood glucose management in ICU patients with severe sepsis is recommended, commencing insulin dosing when 2 consecutive blood glucose levels are of more than 180 mg/dL. This approach should target an upper blood glucose level equal or more than 180 mg/dL rather than an upper target blood glucose of equal or less than 110 mg/dL. ^[20]

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 7 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

Long-term outcomes

For patients who survive sepsis and MODS, the road to recovery is often long and challenging. Post hospital discharge, patients may have physical, emotional, and cognitive consequences. In addition, these patients have a higher risk of repeat sepsis episodes. Aggressive rehabilitation programs, including psychological treatments, may be helpful. ^[28]

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 systematic review by Nathens presented no benefit in medical patients but a reduced mortality in surgical trauma patients. ^[29] 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.