Distributive Shock Treatment & Management

The primary goals of treatment are to reverse the underlying cause of shock (eg, treat the infection by draining abscesses and debridement) and hemodynamic stabilization of the patient.

The management of patients with shock is multifactorial and guidelines are evolving.^{[19, 20, 21, 22, 23]} Of note, the Surviving Sepsis Campaign (SSC), composed of international experts, assessed the available evidence and published consensus guidelines.^[24]

Monitoring

All patients with distributive shock should be admitted to an intensive care unit (ICU). Vital signs and fluid intake and output should be measured and charted on an hourly basis. Daily weights should be obtained, and adequate intravascular access should be secured. A central venous access device should be considered if vasoactive drug support is required. Placement of pulmonary artery (PA) and arterial catheters should be considered. Most patients should have an indwelling urinary catheter.

Oxygen should be administered immediately by mask. In patients with altered mental status, respiratory distress, or severe hypotension, elective endotracheal intubation and mechanical ventilation should be considered; these avoid emergent intubation in the event of subsequent respiratory arrest. Mechanical ventilation can also aid in hemodynamic stabilization, by decreasing the demands posed by the respiratory muscles on the circulation (as much as 40% of the cardiac output during respiratory distress).

Prophylaxis

All patients should be treated prophylactically against thromboembolic disease, gastric stress ulceration, and pressure ulcers.

Early, efficient resuscitation is the key. The duration of hypotension before antibiotic treatment has been found to be a critical factor in determining mortality.^[25] Rivers et al found a significant decrease in in-hospital mortality when patients were treated with early, goal-directed therapy.^[26] This protocol-driven resuscitation strategy focused on optimizing hemodynamic parameters and reversing hypoperfusion beginning in the emergency department; these protocols have been successfully implemented not only in research centers, but also in community-based settings.^{[27, 28, 29, 30]}

The SSC’s recommendations support protocol-driven resuscitation beginning as soon as hypoperfusion is detected and continuing over the first 6 hours using protocol-defined goals for central venous pressure, mean arterial pressure, urine output, and/or mixed venous oxygen saturation. If central venous oxygen saturation of more than 70% is not achieved in the first 6 hours, SSC recommendations suggest (based on clinical assessment) transfusing packed red blood cells targeting hematocrit at greater than or equal to 30% or treatment with dobutamine.^{[31, 32, 33]}

The choice of fluid for resuscitation has been a matter of ongoing debate. The SSC recommends the use of either colloids or crystalloids, finding inadequate evidence to recommend one over the other. The Saline Versus Albumin Fluid Evaluation (SAFE) trial found crystalloid and colloid to be equally safe and effective for ICU patients. In contrast to prior studies, it also found no difference or increased mortality among patients receiving albumin.^{[34, 35, 36, 37, 38]}

A meta-analysis revealed that passive leg raising-induced changes in cardiac output (PLR-cCO) can reliably predict fluid responsiveness, regardless of ventilation mode and cardiac rhythm.^[39] PLR-cCO has a significantly higher predictive value than arterial pulse pressure.

A retrospective cohort study of trauma patients who received allogeneic packed red blood cells sought to determine the association between infection or death and blood storage duration. Results showed that patients who received 7 units or more of older blood had a higher risk of complicated sepsis compared with patients who received 1 or fewer units. The effects of allogeneic blood is best reduced by avoiding unnecessary transfusions, but it may also be important to avoid transfusions of multiple units of older blood.^[40]

In the Multicenter Randomized Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study, comparing hydroxyethyl starch (HES) to Ringer's lactate, the HES group had higher rates of renal failure and more days on renal replacement therapy. Additional investigation is required to fully appreciate the risks versus benefits of this intervention.^{[41, 42]}

Vasoactive drugs

In patients with hypotension due to sustained septic shock in whom fluid resuscitation does not reverse hypotension, the use of systemic vasopressors is indicated to restore blood flow to pressure-dependent vascular beds (eg, the heart and brain). Either norepinephrine or dopamine should be used as first-line treatment; no evidence suggests the use of one over the other. Several vasopressor agents are available. (See Table 2, below.)

If dopamine is tried first and fails to increase mean arterial pressure to more than 60mm Hg or if excessive tachycardia or tachyarrhythmias develop, norepinephrine (Levophed) should be used. As a second-line treatment, phenylephrine (Neo-Synephrine) may be added to or substituted for dopamine. Dobutamine may be added to the therapeutic regimen when cardiac output is low, recognizing that this drug acts primarily as a positive inotropic agent and may further decrease systemic vascular resistance (SVR).

Importantly, because severe sepsis is usually associated with some degree of myocardial depression, the use of an unopposed alpha stimulant to increase vasomotor tone without a concomitant increase in inotropy decreases cardiac output. This was the universal finding when nitric oxide synthase inhibitors were used to treat the hypotension of septic shock in a large prospective, clinical trial. The doses and cardiovascular characteristics of commonly used vasoactive drugs for shock are summarized in Table 2, below.

Vasopressin

As a second-line treatment, vasopressin may be helpful to increase mean arterial pressure and SVR and may be considered in patients who are refractory to inotropic agents and have a cardiac output that is already more than 3.5 L/min/m². Endogenous vasopressin is released from the pituitary gland as part of the physiologic response to shock, acting on V1 receptors of vascular smooth muscle to induce vasoconstriction. As shock continues, endogenous vasopressin levels may be depressed, perhaps due to depletion of the stores or impaired hypophyseal function in the setting of infection. This contributes to refractory hypotension.^{[43, 44, 45, 46]}

In this setting of hypotension, treatment with exogenous vasopressin has a role. Vasopressin treatment carries the risk of acidosis by causing splanchnic vasodilation and resultant ischemia. Myocardial ischemia is also possible, given increased afterload and coronary vasoconstriction. Although current treatment guidelines support vasopressin’s use, a randomized trial in which vasopressin was added to ongoing norepinephrine treatment did not find a benefit to the use of vasopressin over norepinephrine, suggesting that additional investigation will be required to define vasopressin’s role.^[46]

Table 2. Vasoactive Drugs in Sepsis and the Usual Hemodynamic Responses (Open Table in a new window)

In all patients with suspected sepsis, blood and urine cultures should be collected prior to empiric antibiotic therapy, provided that this does not cause a significant delay in treatment. At least 2 blood cultures should be collected and should be drawn percutaneously, as well as from any vascular access site. Cultures such as respiratory tract secretions and cerebrospinal fluid should be collected if infection at these sites is suspected clinically.

Patients who receive prompt effective antimicrobial therapy are more likely to survive than are patients whose antibiotic therapy is delayed; measurable increases in mortality occur for each hour’s delay in antibiotic treatment. Because initial therapy must be empiric, antimicrobial coverage should be broad and should have good penetration to all suspected sites of infection.

The choice of agent should be guided by history, suspected site of infection, comorbid diseases, and pathogen susceptibility patterns in the hospital and community. Avoid antibiotics recently received by the patient. Treatment of fungal infection should be considered and selection of an antifungal agent should be guided by the local prevalence of Candida species. Recommended empiric antibiotic regimens based on the suspected site are outlined in Table 3, below.

Antimicrobial regimens should be tailored once the causative pathogen and its susceptibility are identified because narrow-spectrum treatment decreases the risk of superinfection with resistant organisms. The duration of therapy varies based on clinical context, but the SSC guidelines suggest that the typical duration will be 7-10 days, with adjustments made for factors such as underlying immune status and undrainable foci of infection.

Consider the removal of any devices, such as intravenous or urinary catheters and prostheses. Surgical drainage or debridement should be performed promptly, when appropriate (eg, intra-abdominal abscess, necrotizing fasciitis).

Table 3. Empiric Antimicrobial Therapy in Septic Shock Based on Suspected Site of Infection (Open Table in a new window)

This has become a strategy for preventing sepsis-related organ failure. Disseminated intravascular coagulation (DIC) is a critical factor in driving the progression of sepsis. Activated protein C (APC), an endogenous protein that decreases thrombosis and inflammation, has been used for septic shock but was withdrawn by the company for lack of significant efficiency.^{[9, 48, 49, 50, 51, 52, 53, 54]}

The role of corticosteroids as an adjunct treatment for septic shock has been an area of debate. The role of corticosteroids in sepsis is a matter of debate, with positive and negative studies in the literature. Low-dose hydrocortisone and fludrocortisone have been used for patients with severe sepsis and adrenal insufficiency who remain hypotensive after fluid resuscitation and pressors and were traditionally thought to reduce mortality in this subgroup.^{[55, 56, 57, 58]}

In contrast to prior studies, however, a multi-site, double-blind, placebo-controlled trial found that low-dose hydrocortisone did not affect mortality at 28 days, although patients receiving hydrocortisone had an earlier reversal of shock. Also in contrast to prior work, this study did not find that a corticotropin stimulation test predicted response to hydrocortisone. Additional studies are required to address these discrepancies.

The SSC recommendations acknowledge this controversy and support giving hydrocortisone only to hypotensive patients poorly responsive to fluid resuscitation and vasopressors. Given findings that suggest the adrenocorticotropic hormone (ACTH) stimulation test does not predict response to steroids, this test is no longer recommended. Hydrocortisone, rather than dexamethasone or fludrocortisone, is the steroid of choice; it is not yet clear if adding fludrocortisone to hydrocortisone provides added benefit.^[59]

Protocol-driven management of glucose (target < 150-180 mg/dL) is recommended, with monitoring every 1-2 hours until glucose levels are stable and then every 4 hours thereafter. This SSC recommendation is based on studies that found decreased mortality, length of stay, and complications such as renal impairment. Of note, intensive glucose management has been associated with higher rates of severe hypoglycemic events and, in some studies, has not been associated with improved mortality.

Pyridoxalated hemoglobin polyoxyethylene (PHP) is a hemoglobin-based nitric oxide (NO) scavenger that has been shown to increase systemic blood pressure and reduce vasopressor and ventilation needs in patients with NO-induced shock without adversely affecting cardiac output, organ function, or survival. The results of its use in distributive shock in a multicenter, randomized, placebo-controlled, phase II study were promising, but further studies are needed to provide a definitive answer.^[60]

If anaphylaxis is suspected, 0.2-0.5 mL subcutaneous of 1:1000 epinephrine should be administered immediately, with repeated doses every 20 minutes as needed. Epinephrine can be administered by continuous infusion of 30-60 mL/h of 1:10,000 dilution in severe reactions. Diphenhydramine 50-80 mg intramuscular or intravenous may be administered for urticaria or angioedema. Inhaled bronchodilators or intravenous steroids can be administered for bronchospasm.

In addition to prompt fluid resuscitation, hemodynamic support with vasoactive drugs, and prompt establishment of broad-spectrum antibiotic coverage, source control is essential to effective treatment of shock. Early efforts should be made to define sources in need of surgical intervention, such as necrotizing fasciitis, cholangitis, abscess, intestinal ischemia, or an infected device. The least-invasive means of intervention should be used.^[61]

Multiple surgical modalities for source control are indicated, including the following:

• Removal of infected catheters, infected prosthesis, and foreign bodies
• Drainage (operative, endoscopic, percutaneous) of intra-abdominal abscess, postoperative collections, soft-tissue abscess, and gallbladder sludge
• Debridement of devitalized (traumatic or infected) tissue, pancreatic necrosis, and soft-tissue infections
• Operative resection of inflamed, infarcted, ischemic, and perforated hollow viscus
• Amputation of gangrenous extremities

Once the initial phase of resuscitation is complete, promptly institute nutritional support, usually within 24 hours. This is especially important in malnourished patients (with temporal muscle atrophy).

In patients who are intubated or obtunded, tube feedings should be initiated through a soft nasogastric or orogastric feeding tube at a slow rate and increased over 12-24 hours to the target rate.

If patients cannot be fed enterally, parenteral nutrition may be instituted until enteral feeding becomes possible. Enteral feeding is preferred because it is less expensive and is associated with lower rates of nosocomial infection than total parenteral nutrition.

Transfer of a patient admitted with distributive shock from the ICU to a stepdown or ward unit is highly individualized. The patient's condition and prognosis must be assessed and matched to the level of care in the receiving unit.

Generally, patients can be considered for transfer when they are hemodynamically stable without vasoactive drugs, when ventilation and oxygenation is stable on supplemental oxygen delivered by nasal cannula, when life-threatening metabolic derangements are absent, and when the patients no longer require the high nursing and respiratory therapy ratios characteristic of ICU care (ie, for frequent suctioning).

Transferring a patient with distributive shock from one hospital to another exposes the patient to risk and should be undertaken only when the receiving institution can offer the patient care that is not available at the transferring hospital.

In general, institutions that care for critically ill patients need an appropriately staffed ICU that is capable of delivering and monitoring mechanical ventilation and invasive monitoring devices such as pulmonary artery (PA) catheters and arterial lines.

Modern surgical facilities, a radiology department equipped with ultrasonographic and CT scanners, dialysis equipment, and medical specialists to deliver these specialized types of care and procedures are also a minimum requirement. Lack of any one of these resources may necessitate transfer.

Under certain circumstances, patients may also benefit from transfer to units that specialize in care for trauma, burns, or cardiac or neurosurgical problems or to units where organ transplantation is available.

Intensivist

Consultation with or primary management by a board-certified medical or surgical intensivist is indicated for all patients with distributive shock.

Experienced intensivists may be trained in pulmonary/critical care medicine, cardiology, surgery, or anesthesiology. The choice of consultant may depend on patient characteristics and the availability of local subspecialists.

Infectious disease specialist

Consultation with a subspecialist in infectious disease is appropriate whenever sepsis is suspected as a cause of distributive shock.

This is particularly true when the locus of infection is unknown or unique patient characteristics (such as travel history or occupation) raise the possibility of an unusual or rare infectious process.

Surgeon

Consultation with a surgeon should always be obtained when an abdominal source of sepsis is suspected. Other indications for consultation with a surgeon include, but are not limited to, necrotizing fasciitis, soft tissue abscess, empyema (thoracic surgeon), or brain abscess (neurosurgeon).