Distributive Shock

Pathophysiology

In distributive shock, the inadequate tissue perfusion is caused by loss of the normal responses of vascular smooth muscle to vasoconstrictive agents coupled with a direct vasodilating effect. The net result in a fluid-resuscitated patient is a hyperdynamic, hypotensive state associated with increased mixed venous O₂ saturation; however, evidence of tissue ischemia as manifest by an increased serum lactate, presumably due to intraorgan functional shunts.

Early septic shock (warm or hyperdynamic) causes reduced diastolic blood pressure; widened pulse pressure; flushed, warm extremities; and brisk capillary refill from peripheral vasodilation, with a compensatory increase in cardiac output. In late septic shock (cold or hypodynamic), myocardial contractility combines with peripheral vascular paralysis to induce a pressure-dependent reduction in organ perfusion. The result is hypoperfusion of critical organs such as the heart, brain, and liver.

The hemodynamic derangements observed in septic shock and SIRS are due to a complicated cascade of inflammatory mediators. Inflammatory mediators are released in response to any of a number of factors, such as infection, inflammation, or tissue injury. For example, bacterial products such as endotoxin activate the host inflammatory response, leading to increased pro-inflammatory cytokines (eg, tumor necrosis factor (TNF), interleukin (IL) –1, and IL-6. Toll-like receptors are thought to play a critical role in responding to pathogens as well as in the excessive inflammatory response that characterizes distributive shock; these receptors are considered possible drug targets.

Cytokines and phospholipid-derived mediators act synergistically to produce the complex alterations in vasculature (eg, increased microvascular permeability, impaired microvascular response to endogenous vasoconstrictors such as norepinephrine) and myocardial function (direct inhibition of myocyte function), which leads to maldistribution of blood flow and hypoxia. Hypoxia also induces the upregulation of enzymes that create nitric oxide, a potent vasodilator, thereby further exacerbating hypoperfusion.

The coagulation cascade is also affected in septic shock. Activated monocytes and endothelial cells are sources of tissue factors that activate the coagulation cascade; cytokines, such as IL-6, also play a role. The coagulation response is broadly disrupted, including impairment of antithrombin and fibrinolysis. Thrombin generated as part of the inflammatory response can trigger disseminated intravascular coagulation (DIC). DIC is found in 25-50% of patients with sepsis and is a significant risk factor for mortality.^{[2, 3]}

During distributive shock, patients are at risk for diverse organ system dysfunction that may progress to multiple organ failure (MOF). Mortality from severe sepsis increases markedly with the duration of sepsis and the number of organs failing.

In distributive shock due to anaphylaxis, decreased SVR is due primarily to massive histamine release from mast cells after activation by antigen-bound immunoglobulin E (IgE), as well as increased synthesis and release of prostaglandins.

Neurogenic shock is due to loss of sympathetic vascular tone from severe injury to the nervous system.

References

Etiology

The most common etiology of distributive shock is sepsis. Other causes include the following:

SIRS due to noninfectious conditions such as pancreatitis, burns, or trauma
TSS
Anaphylaxis
Adrenal insufficiency
Reactions to drugs or toxins
Heavy metal poisoning
Hepatic insufficiency
Neurogenic shock

All of these conditions share the common characteristic of hypotension due to decreased SVR and low effective circulating plasma volume.

Septic shock

The most common sites of infection, in decreasing order of frequency, include the chest, abdomen, and genitourinary tract.

Septic shock is commonly caused by bacteria, although viruses, fungi, and parasites are also implicated. Gram-positive bacteria are being isolated more, with their numbers almost similar to those of gram-negative bacteria, which in the past were considered to be the predominant organisms. Multidrug-resistant organisms are increasingly common.^[4]

Systemic inflammatory response syndrome

Causes of SIRS include the following:

Infection
Burns
Surgery
Trauma
Pancreatitis
Fulminant hepatic failure

Toxic shock syndrome

TSS can result from infection with Streptococcus pyogenes (group A Streptococcus) or Staphylococcus aureus.

Adrenal insufficiency

Adrenal insufficiency can result from the following:

Destruction of adrenal glands due to autoimmune disease, infection (tuberculosis, fungal infection, acquired immunodeficiency syndrome [AIDS]), hemorrhage, cancer, or surgical removal
Suppression of hypothalamic-pituitary-adrenal axis by exogenous steroid, usually with doses at 20 mg daily or higher
Hypopituitarism
Metabolic failure in hormone production due to congenital conditions or drug-induced inhibition of synthetic enzymes (eg, metyrapone, ketoconazole)

Anaphylaxis

Anaphylaxis can develop as a result of the following:

Drugs such as penicillins and cephalosporins
Heterologous proteins such as Hymenoptera venom, foods, pollen, and blood serum products

References

Epidemiology

Occurrence in the United States

Sepsis develops in more than 750,000 patients per year in the United States. Angus and colleagues estimated that, by 2010, 1 million people per year would be diagnosed with sepsis.^[5]From 1979-2000, the incidence of sepsis increased by 9% per year.

International occurrence

Sepsis is a common cause of death throughout the world and kills approximately 1,400 people worldwide every day.^{[6, 7]}

Age-related demographics

Increased age correlates with increased risk of death from sepsis.

References

Prognosis

The mortality rate after development of septic shock is 20-80%.^[8]Data suggest that mortality due to septic shock has decreased slightly because of new therapeutic interventions.^[9]Early recognition and appropriate therapy are central to maximizing good outcomes. Identifying patients with septic shock in the emergency department, as opposed to identifying them outside of it, results in significantly improved mortality. In one study, the mortality rate for emergency department-identified patients was 27.7%, compared with 41.1% for patients identified outside of the emergency department.^[10]

Higher mortality rates have also been associated with the following:

Advanced age
The finding of positive blood cultures
Infection with antibiotic-resistant organisms such as Pseudomonas aeruginosa
Elevated serum lactate levels
Impaired immune function
Alcohol use
Poor functional status prior to the onset of sepsis.

Mortality rates associated with other forms of distributive shock are not well documented.

Complications

Duration of delirium is an independent predictor of long-term cognitive impairment. At 3-month and 12-month follow-up, as many as 79% and 71% of patients have cognitive impairment. About one third remain severely impaired.^{[11, 12, 13]}

References

History

Patients with shock frequently present with tachycardia, tachypnea, hypotension, altered mental status changes, and oliguria.

Patients with septic shock or systemic inflammatory response syndrome (SIRS) may have prior symptoms that suggest infection or inflammation of the respiratory tract, urinary tract, or abdominal cavity.

Septic shock occurs frequently in hospitalized patients with risk factors such as indwelling catheters or venous access devices, recent surgery, or immunosuppressive therapy.

Patients with anaphylaxis commonly have recent iatrogenic (drug) or accidental (bee sting) exposure to an allergen and coexisting respiratory symptoms, such as wheezing and dyspnea, pruritus, or urticaria.

Staphylococcal toxic shock syndrome (TSS) is still observed most commonly in women who are menstruating, but it is also associated with recent soft-tissue injury, cutaneous infections, postpartum and cesarean delivery, wound infections, pharyngitis, and focal staphylococcal infections, such as abscess, empyema, pneumonia, and osteomyelitis. Patients often have a history of influenzalike illness (fever, arthralgias, myalgias) and a desquamating rash.

Pancreatitis may be another cause of distributive shock; expect symptoms of abdominal pain that radiate to the back, as well as nausea and vomiting. Burns also have been described as a cause of distributive shock.

Adrenal insufficiency

Adrenal insufficiency as a cause of shock should be considered in any patient with hypotension who lacks signs of infection, cardiovascular disease, or hypovolemia.

Long-term treatment with corticosteroids may result in inadequate response of the adrenal axis to stress, such as infection, surgery, or trauma, and subsequent onset or worsening of shock.

If the clinical picture is consistent with adrenal insufficiency in a person without this diagnosis, consider that this could be the first presentation of this disorder.

There is a high incidence of adrenal insufficiency in critically ill patients infected with the human immunodeficiency virus (HIV), although this incidence varies with the criteria used to diagnose adrenal insufficiency.^[14]

References

Physical Examination

Cardinal features of distributive shock include the following:

Change in mental status
Heart rate - Greater than 90 beats per minute (note that heart rate elevation is not evident if the patient is on a beta blocker)
Hypotension - Systolic blood pressure less than 90 mm Hg or a reduction of 40 mm Hg from baseline
Respiratory rate - Greater than 20 breaths per minute
Extremities - Frequently warm, with bounding pulses and increased pulse pressure (systolic minus diastolic blood pressure) in early shock; late shock may present as critical organ dysfunction
Hyperthermia - Core body temperature greater than 38.3°C (101°F)
Hypothermia - Core body temperate less than 36°C (96.8°F)
Pulse oximetry - Relative hypoxemia
Decreased urine output

Clinical symptoms of the underlying infections found in distributive shock include the following:

Pneumonia - Dullness to percussion, rhonchi, crackles, bronchial breath sounds
Urinary tract infection - Costovertebral angle tenderness, suprapubic tenderness, dysuria and polyuria
Intra-abdominal infection or acute abdomen - Focal or diffuse tenderness to palpation, diminished or absent bowel sounds, rebound tenderness
Gangrene or soft-tissue infection - Pain out of proportion to lesion, skin discoloration and ulceration, desquamating rash, areas of subcutaneous necrosis

Anaphylaxis is characterized by the following clinical symptoms:

Respiratory distress
Wheezing
Urticarial rash
Angioedema

TSS is characterized by the following clinical symptoms:

High fever
Diffuse rash with desquamation on the palms and soles over a subsequent 1-2 weeks
Hypotension (may be orthostatic) and evidence of involvement of 3 other organ systems

Streptococcal TSS more frequently presents with focal soft-tissue inflammation and is less commonly associated with diffuse rash. Occasionally, it can progress explosively within hours.

Adrenal insufficiency is characterized by the following clinical symptoms:

Hyperpigmentation of skin, oral, vaginal, and anal mucosal membranes may be present in chronic adrenal insufficiency.
In acute or acute-on-chronic adrenal insufficiency brought on by physiologic stress, hypotension may be the only physical sign.

References

Approach Considerations

All patients with evidence of distributive shock should undergo the following studies:

Complete blood count (CBC) with differential
Urinalysis
Electrolytes
Blood urea nitrogen (BUN)
Creatinine
Glucose
Urine cultures
Blood cultures
Possibly arterial blood gas or at least venous blood gas
Serum lactate - Especially with metabolic acidosis or if an elevated anion gap is present

If pneumonia is suspected, sputum Gram stain and culture should be performed.

All patients with a suspected intra-abdominal pathologic condition or hepatic insufficiency should undergo the following studies:

Serum bilirubin
Alkaline phosphatase
Aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Prothrombin time (PT)/activated partial thromboplastin time (aPTT)/INR (international normalized ratio)
Amylase, lipase

All patients with suspected disseminated intravascular coagulation (DIC) should undergo the following studies:

Obtain PT, aPTT, fibrin split products, D-dimer assay, fibrinogen level, and platelet count.
Examine peripheral blood smear for signs of erythrocyte microangiopathic changes, such as schistocytes.

Electrocardiography

Electrocardiography should be performed to examine the patient for evidence of underlying pathologic cardiac conditions (left ventricular hypertrophy, cor pulmonale, low voltage, bundle branch block) or acute changes of ischemia or pericarditis.

References

Imaging Studies

Imaging studies may be integral to defining the source of infection and identifying areas in need of drainage. All patients should undergo chest radiography (see the images below). However, radiographic studies may not be sensitive enough to reveal intra-abdominal pathologic conditions. Consequently, computed tomography (CT) scanning has become the diagnostic test of choice for suspected intra-abdominal causes of sepsis. Consider abdominal and pelvic CT scans with oral contrast and intravenous contrast if these sites are found to be clinically suspicious for infection.

In suspected cases of cholecystitis or pancreatitis, abdominal ultrasonography is most useful to assess for cholelithiasis, biliary dilatation, and fluid collections around the gallbladder or the head of the pancreas.

Point-of-care ultrasonography/echocardiography may be performed at the bedside in critically ill patients to evaluate cardiac function, fluid status, and response to hemodynamic intervention and to exclude tamponade.

View Image

An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are a rare cause of septic shock.

View Image

A 28-year-old woman who was a previous intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to....

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Procedures

Lumbar puncture

Lumbar puncture (LP) is indicated in patients with nuchal rigidity, headache, or unexplained neurologic findings or in patients with sepsis and altered level of consciousness without another apparent source of infection. A CT scan of the head should be performed prior to LP whenever feasible.

Arterial catheters

The use of pulmonary artery catheters (PACs) was the standard of care for decades (see Table 1, below). However, data now suggest an increase in mortality with the use of PAC monitoring, calling this practice into question. Additionally, current parameters for PAC-guided resuscitation may not be appropriate. A randomized trial of the use of PACs in elderly, high-risk surgical patients found no benefit to therapy directed by PACs compared with treatment per the standard of care.^{[15, 16]}

Table 1. Pulmonary Artery Catheter Findings in Common Shock States

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Arterial catheter placement should be considered in hemodynamically unstable patients who are receiving continuous infusions of vasoactive drugs or in patients requiring frequent arterial blood gas measurements (eg, patients on mechanical ventilation). The arterial catheter can be placed radially, femorally, axillary, but never brachially. Some patients can be managed with the pulse oximetry wave graphic only.

Transthoracic and transesophageal echocardiography

Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) may be used to estimate right atrial filling and right ventricular volumes in patients with undetermined fluid status. TTE is a noninvasive method for the assessment of left ventricular function. This technique has several limitations, being time consuming, operator dependent, and limited by preexisting pulmonary disease or chest wall injuries.

TEE is a somewhat more invasive test that provides excellent structural information in the critically ill patient. This technique allows the assessment of preload, ventricular wall motion abnormalities, and the pericardium.

Other minimally invasive techniques

Thoracic bioelectrical impedance (TBI)

This technique relies on formulas to estimate stroke volume and cardiac output based on the measured bioimpedance of blood velocity and volume of blood flow through the aorta.

Pulse-induced CO (PiCO), lithium dilution CO (LiCO), and FloTrac

Via an arterial catheter, cardiac output (CO) can be continuously monitored. FloTrac does not require calibration. Stroke volume and continuous systemic vascular resistance (SVR) can be measured and calculated using basic patient information.

Total circulating blood volume (TCBV)

This is measured using indocyanine green infusion and is quantified using spectrophotometry.

Microcirculatory imaging

Microcirculatory imaging techniques, such as orthogonal polarization spectral and side-stream dark-field imaging, have allowed direct observation of the microcirculation at the bedside. They have demonstrated different types of heterogenous flow patterns of microcirculatory abnormalities in different types of distributive shock and may complement early goal-directed therapy in shock.^{[17, 18]}

References

Approach Considerations

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.

References

Resuscitation

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]}

As soon as hypoperfusion is detected, continue fluid 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 a hematocrit at greater than or equal to 30% or treatment with dobutamine.^{[31, 32, 33]}However, two major studies (ARISE [Australasian Resuscitation in Sepsis Evaluation],^[34]ProCESS [Protocolized Care for Early Septic Shock]^[35]) have not shown improved survival with protocol-based therapy, as compared with nonprotocol "usual" therapy. Furthermore, a major study on a perioperative, cardiac output–guided hemodynamic therapy algorithm, with the use of inotropic medication for patients with major gastrointestinal surgery, also did not show increased survival.^[36]The impact of these three studies on protocol-based therapy is currently controversial.

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.^{[37, 38, 39, 40, 41]}

Owing to the findings of various trials such as ARISE,^[34]ProCESS,^[35]and OPTIMISE (Optimisation of Cardiovascular Management to Improve Surgical Outcome),^[36]the 2016 SSC guidelines now recommend frequent clinical reassessment of patients after initial fluid resuscitation.^[42]A plausible way to do so is with point-of-care ultrasound. Monitoring of fluid status via ultrasound assessment of the inferior vena cava^{[43, 44]}and the lungs^{[45, 46, 47]}has been studied to assess fluid responsiveness in sepsis/septic shock.

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.^[48]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.^[49]

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.^{[50, 51]}

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 60 mm 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).

In December 2017, synthetic human angiotensin II (Giapreza) was approved by the US Food and Drug Administration for adults with septic or other distributive shock. Approval was based on the ATHOS-3 clinical trial (n = 321) in patients with vasodilatory shock and critically low blood pressure. Eligible patients had vasodilatory shock despite intravenous volume resuscitation with at least 25 mL/kg over the previous 24 hours and the administration of high-dose vasopressors. Significantly more patients responded to treatment with the angiotensin II injection added to conventional therapy compared with those on conventional therapy plus placebo. At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (P = .01).^[52]

Important to note, 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.^{[53, 54, 55, 56]}

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.^[56]In a 2012 meta-analysis, Serpa et al found that vasopressin treatment in patients with vasodilatory shock was safe and was associated with reduced mortality.^[57]

Table 2. Vasoactive Drugs in Sepsis and the Usual Hemodynamic Responses

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References

Antimicrobial Treatment

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

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References

Preventing Microvascular Thrombosis

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, 59, 60, 61, 62, 63, 64, 65]}

References

Corticosteroids

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.^{[66, 67, 68, 69]}

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.^[70]

References

Glucose

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.

References

NO Scavenger

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.^[71]

References

Treatment of Anaphylaxis

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.

References

Surgical Control of Shock Sources

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.^[72]

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

References

Diet

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.

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Inpatient Care

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).

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Transfer

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.

References

Consultations

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).

References

Guidelines Summary

The Surviving Sepsis Campaign (SSC) published International Guidelines for Management of Sepsis and Septic Shock in 2016. These guidelines serve as an update to the previously printed 2012 guidelines.^[42]A number of significant updates have been made to the guidelines for the management of septic shock between 2012 and 2016. The 2012 SSC guidelines, like their predecessors, reflected the Early Goal-Directed Therapy (EGDT) protocol established by the Rivers trial.^[26]The EGDT protocol was a single urban-center trial published in 2001, which demonstrated that using a protocol that featured aggressive resuscitation (titrated to certain physiologic values such as mean arterial pressure, central venous pressure, and mixed venous oxygen saturation) along with early antibiotic initiation led to absolute risk reduction in mortality of up to 16% of patients with severe sepsis or septic shock. One of the criticisms of EGDT, however, was identifying which intervention conferred a survival benefit.

In 2014, the ProCESS multicenter trial sought to compare the EGDT protocol versus a novel protocol (using noninvasive monitoring) versus usual care as directed by the treating physicians.^[35]The ProCESS trial found that among patients with septic shock, there was no significant difference in all-cause mortality at 60 days, 90 days, or 1 year. Furthermore, there was no significant difference in the need for organ support. The ProCESS trial, while having impactful results, was primarily performed with patients enrolling at academic medical centers. The ARISE trial of 2014 also showed no reduction in all-cause mortality at 90 days while enrolling 1600 randomized patients with severe sepsis or septic shock at 51 academic and nonacademic medical centers in 5 different countries.^[34]A third trial, known as the OPTIMISE trial, was a multicenter randomized, observer-blinded trial held in the United Kingdom.^[36]This trial sought to evaluate the outcome of EGDT 30-day mortality in high-risk gastrointestinal surgical patients as the primary outcome. The OPTIMISE trial found no outcome benefit with EGDT versus usual care. Furthermore, OPTIMISE found no difference between EGDT and usual care on secondary outcome measures, such as morbidity on day 7, infection, critical care–free days, all-cause mortality at 30/180 days, and length of stay.

The aforementioned trials are three prime examples of investigations on whether or not EGDT as the method of initial resuscitation is truly beneficial. Because of the evidence, the SSC 2016 campaign revisited their guidelines to include the findings of such trials. The 2016 guidelines^[42]are paraphrased below.

A. Initial resuscitation

Septic shock is a medical emergency. Intravenous fluid resuscitation for sepsis-induced hypoperfusion should consist of at least 30 mL/kg of intravenous crystalloid fluid being given within the first 3 hours. After initial fluid resuscitation is performed, additional fluids should be given based on frequent assessment of the patient's hemodynamic status. Dynamic over static variables are favored in assessing patient response to fluid resuscitation, with a particular goal of keeping an initial target mean arterial pressure of 65 mm Hg in patients with septic shock requiring vasopressors. Normalizing elevated lactate levels is also recommended, as lactate levels serve as a marker of tissue hypoperfusion.

B. Screening for sepsis and performance improvement

Hospitals and hospital systems should have a performance improvement program in place for sepsis, including screening practices.

C. Diagnosis

It is recommended that appropriate microbiologic cultures be collected prior to antibiotic administration for patients with suspected sepsis/septic shock.

D. Antimicrobial therapy

Empiric broad-spectrum intravenous antibiotics should be initiated within 1 hour for both sepsis and septic shock. The antibiotics should cover all likely pathogens (including bacterial and potentially fungal or viral coverage). Upon discovery of the offending organism and the corresponding antibiotic sensitivities result, the antibiotic spectrum should be narrowed. However, sustained antibiotics should not be given in shock states of known noninfectious origins (eg, distributive shock due to pancreatitis).

If combination antibiotic therapy is used for septic shock, the recommendation is to discontinue the combination therapy within the first few days in response to clinical improvement and/or evidence of infection resolution. This is recommended in both culture-positive and culture-negative infections. Antimicrobial treatment of 7-10 days is adequate for most serious infections associated with septic shock; however, certain infections may require longer clinical courses, such as the case for patients who have a slow clinical response, undrainable foci of infection, bacteremia with methicillin-resistance Staphylococcus aureus (MRSA), some fungal and viral infections, or immunologic deficiencies.

E. Source control

Rapid identification or exclusion of an anatomic nidus of infection is recommended. Any required intervention to eradicate the source of infection should be done as soon as possible. This incudes prompt removal of intravenous devices such as central lines.

F. Fluid therapy

Crystalloids are the intravenous fluids of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock. Hydroxyethyl starches for intravascular volume replacement or gelatins are not recommended choices for fluid resuscitation.

G. Vasoactive medications

Norepinephrine is the first-choice vasopressor for patients in septic shock. Either vasopressin or epinephrine can be added to norepinephrine to raise the mean arterial pressure to target. Dopamine is another alternative vasopressor agent to norepinephrine in patients with low risk of arrhythmias, although this is a weak recommendation with low quality of evidence. Low-dose dopamine is not recommended for renal protection.

Dobutamine is another vasopressor that is recommended in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents. The dose of dobutamine should be titrated to the specific endpoint of tissue perfusion. The dose should also be reduced in the setting of worsening hypotension and arrhythmias. Blood pressure should be monitored via an arterial line when using vasopressors.

H. Corticosteroids

The guidelines suggest against using intravenous hydrocortisone to treat septic shock in patients adequately treated with vasopressors and fluid resuscitation. If this is not possible, 200 mg of intravenous hydrocortisone is recommended per day to help augment blood pressure to goal.

I. Blood products

It is recommended that packed red blood cell transfusion occur when the hemoglobin is below 7.0 g/dL. Red blood cell transfusion should occur only when the hemoglobin concentration decreases to less than 7.0 g/dL in adults in the absence of acute hemorrhage, myocardial ischemia, or severe hypoxemia. Erythropoietin is not recommended for the treatment of sepsis-related anemia.

J. Immunoglobulins

The use of intravenous immunoglobulins is not recommended in patients with sepsis or septic shock.

K. Blood purification

There is no recommendation regarding the use of blood purification techniques.

L. Anticoagulants

Antithrombin is not recommended for the treatment of sepsis and septic shock. There is no recommendation for the use of thrombomodulin or heparin for the treatment of sepsis or septic shock.

M. Mechanical ventilation

A tidal volume of 6 mL/kg for predicted body weight compared with 12 mL/kg in adult patients with sepsis-induced acute respiratory distress syndrome (ARDS) is recommended. The upper limit goal for plateau pressures is 30 cm water for sepsis-induced ARDS. Higher positive end-expiratory pressure (PEEP) and recruitment maneuvers in adult patients is preferred in sepsis-induced moderate-to-severe ARDS. While on the ventilator, patients should be positioned between 30° and 45° to limit the risk of aspiration. Spontaneous breathing trials should be initiated for patients who are ready to be weaned off the mechanical ventilator.

With regard to patient positioning, prone over supine position is recommended in adult patients with sepsis-induced ARDS and ratio of arterial oxygen saturation to fraction of inspired oxygen (PaO₂/FIO₂ ratio) of less than 150. Neuromuscular agents for 48 hours are also recommended with the aforementioned ratio. The campaign recommends against using high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS

If there is no evidence of tissue hypoperfusion, a conservative fluid strategy is preferred for patients with established sepsis-induced ARDS. ß-2 agonists are not recommended for sepsis-induced ARDS without bronchospasm. Finally, routine use of pulmonary artery catheters (Swan-Ganz) for hemodynamic measurements is not recommended in sepsis-induced ARDS.

N. Sedation and analgesia

Conscious or intermittent sedation should be minimized in mechanically ventilated sepsis patients.

O. Glucose control

In septic ICU patients, there should be a protocol for insulin dosing when two consecutive blood glucose levels are greater than 180 mg/dL, with a target of 110-180 mg/dL. Furthermore, glucose levels should be monitored every 1-2 hours until stabilization of insulin infusion and glucose levels.

P. Renal replacement therapy

Continuous or intermittent forms of renal replacement therapy can be used to facilitate management of fluid balance in hemodynamically unstable septic patients, or in septic patients with acute kidney injury who have an increase in creatinine/oliguria.

Q. Bicarbonate therapy

Sodium bicarbonate therapy may improve hemodynamics in patients with lactic acidemia and a pH of less than 7.15.

R. Venous thromboembolism prophylaxis

In the absence of contraindications, pharmacologic prophylaxis against venous thromboembolism (VTE) should be initiated. Low molecular weight heparins are preferred over unfractionated heparin for VTE. Whenever possible, a combination of pharmacologic and mechanical prophylaxis is recommended. However, when pharmacologic prophylaxis is not possible (eg, hemorrhagic shock, intracranial bleeding), mechanical VTE prophylaxis is suggested.

S. Stress ulcer prophylaxis

If a patient has risk factors for gastrointestinal bleeding, stress ulcer prophylaxis should be given with either proton pump inhibitors or histamine-2 receptor antagonists. If a patient does not have risk factors for gastrointestinal bleeding, stress ulcer prophylaxis is not recommended.

T. Nutrition

Early initiation of enteral feeding instead of complete fasting or intravenous glucose is recommended only in critically patients with sepsis or septic shock who can be fed enterally. Feeds should either be early tropic/hypocaloric or early full enteral feeding. Parenteral nutrition is not recommended as a stand-alone feeding modality or in combination with enteral feedings. Parenteral nutrition is also not recommended over the first 7 days in critically ill sepsis/septic shock patients who cannot be fed enterally. Omega-3 fatty acids as immune supplements are not recommended in this patient population.

In addition, monitoring of gastric residual volumes is recommended in those patients on enteral feeds at high risk of aspiration. Postpyloric feeding tubes should be placed in critically ill patients with sepsis or septic shock if they have feeding intolerance or are at high risk for aspiration. Prokinetic agents may also be helpful in this patient population if they have feeding intolerance.

U. Setting goals of care

Goals of care and prognosis should be discussed with patients and their families or healthcare proxies. The goals should be addressed as early as possible while being incorporated into treatment and end-of-life planning, using principles of palliative medicine where appropriate.

References

Medication Summary

Because initial therapy must be empiric, antimicrobial coverage should be broad, with good penetration to all suspected sites of infection. Other important factors in choosing an agent include history, suspected site of infection, comorbid diseases, and pathogen susceptibility patterns in the hospital and community. Avoid antibiotics recently received by the patient.

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 role of corticosteroids as an adjunct treatment for septic shock has been an area of debate. Recommendations from the Surviving Sepsis Campaign (SSC) support giving hydrocortisone only to hypotensive patients who are poorly responsive to fluid resuscitation and vasopressors. Hydrocortisone is the steroid of choice.^[70]

The use of systemic vasopressors is indicated in patients with hypotension due to sustained septic shock in whom fluid resuscitation does not reverse hypotension. Systemic vasopressors are used 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.

References

Nafcillin

Dosing, Interactions, etc.

Clinical Context: Nafcillin is the initial therapy for suspected penicillin G–resistant streptococcal or staphylococcal infections. Use parenteral therapy initially in severe infections, and change to oral therapy as the condition warrants. Because of thrombophlebitis, particularly in elderly patients, administer nafcillin parenterally for only a short period (1-2 d); change to the oral route as clinically indicated.

References

Ceftazidime (Fortaz, Tazicef)

Dosing, Interactions, etc.

Clinical Context: Ceftazidime is a third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

References

Levofloxacin (Levaquin)

Dosing, Interactions, etc.

Clinical Context: Levofloxacin is used for infections caused by multidrug-resistant, gram-negative organisms.

References

Ampicillin

Dosing, Interactions, etc.

Clinical Context: Ampicillin has bactericidal activity against susceptible organisms. It serves as an alternative to amoxicillin when the patient is unable to take medication orally. It is rarely used in septic shock.

References

Clindamycin (Cleocin)

Dosing, Interactions, etc.

Clinical Context: Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). Clindamycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes that cause RNA-dependent protein synthesis to arrest. It also counteracts bacterial toxins.

References

Gentamicin

Dosing, Interactions, etc.

Clinical Context: Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. It is used in combination with an agent against gram-positive organisms and one that covers anaerobes.

Gentamicin is not the drug of choice (DOC). Consider using it if penicillins or other less-toxic drugs are contraindicated, when it is clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens for gentamicin are numerous; adjust the dose based on creatinine clearance (CrCl) and changes in the volume of distribution. It may be administered intravenously or intramuscularly.

References

Tobramycin (TOBI)

Dosing, Interactions, etc.

Clinical Context: Tobramycin is indicated in the treatment of staphylococcal infections when penicillin or potentially less-toxic drugs are contraindicated and when bacterial susceptibility and clinical judgment justifies its use.

References

Amikacin

Dosing, Interactions, etc.

Clinical Context: Amikacin irreversibly binds to the 30S subunit of bacterial ribosomes. It blocks the recognition step in protein synthesis, causing growth inhibition. Use the patient's ideal body weight (IBW) for the dosage calculation.

References

Vancomycin

Dosing, Interactions, etc.

Clinical Context: Vancomycin is a potent antibiotic that is directed against gram-positive organisms and is active against Enterococcus species. It is useful in the treatment of septicemia and skin structure infections. Vancomycin is indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or who have infections with resistant staphylococci. For abdominal penetrating injuries, vancomycin is combined with an agent that is active against enteric flora and anaerobes.

To avoid toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, drawn 0.5 hour prior to the next dosing. Use creatinine clearance to adjust the dose in patients diagnosed with renal impairment.

Vancomycin is used in conjunction with gentamicin for prophylaxis in patients allergic to penicillin who are undergoing gastrointestinal or genitourinary procedures.

References

Erythromycin (Erythrocin, E.E.S., Ery-Tab, EryPed)

Dosing, Interactions, etc.

Clinical Context: Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes that cause RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.

In children, age, weight, and the severity of infection determine proper dosage. When twice-daily dosing is desired, the half-total daily dose may be taken every 12 hours. For more severe infections, double the dose.

References

Azithromycin (Zithromax, Zmax)

Dosing, Interactions, etc.

Clinical Context: Azithromycin is used to treat mild to moderate microbial infections.

References

Linezolid (Zyvox)

Dosing, Interactions, etc.

Clinical Context: Linezolid provides gram-positive coverage, similar to vancomycin coverage.

References

Piperacillin/tazobactam (Zosyn)

Dosing, Interactions, etc.

Clinical Context: This combination provides broad-spectrum coverage for gram-positive, gram-negative, and anaerobic bacteria. It does not cover MRSA.

References

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

References

Hydrocortisone (Solu-Cortef, Cortef)

Dosing, Interactions, etc.

Clinical Context: Hydrocortisone is the corticosteroid of choice in shock because of its mineralocorticoid activity and glucocorticoid effects. It may be given to hypotensive patients who are poorly responsive to fluid resuscitation and vasopressors.

References

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

References

Norepinephrine (Levarterenol, Levophed)

Dosing, Interactions, etc.

Clinical Context: Norepinephrine is used in protracted hypotension following adequate fluid replacement. It stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility and heart rate, as well as vasoconstriction. As a result, it increases systemic blood pressure and cardiac output. Adjust and maintain infusion to stabilize blood pressure (eg, 80-100 mm Hg systolic) sufficiently to perfuse vital organs.

References

Synthetic human angiotensin II (Giapreza)

Dosing, Interactions, etc.

Clinical Context: Angiotensin II, the major bioactive component of the renin-angiotensin-aldosterone system (RAAS), serves as one of the body’s central regulators of blood pressure. It raises blood pressure by vasoconstriction and increased aldosterone release; direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein–coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction. It is indicated for adults with septic or other distributive shock.

References

Vasopressin (ADH, Pitressin)

Dosing, Interactions, etc.

Clinical Context: Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. It increases water resorption at the distal renal tubular epithelium (ADH effect). It promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction is also increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.

References

Dopamine

Dosing, Interactions, etc.

Clinical Context: Dopamine stimulates adrenergic and dopaminergic receptors. Its hemodynamic effect is dose dependent. Lower doses predominantly stimulate dopaminergic receptors that, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses.

After initiating therapy, increase the dose by 1-4mcg/kg/min every 10-30 minutes until the optimal response is obtained. More than 50% of patients are maintained satisfactorily on doses of less than 20mcg/kg/min.

References

Class Summary

These agents augment coronary and cerebral blood flow present during a state of low blood flow.

References

Author

Klaus-Dieter Lessnau, MD, FCCP, Former Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory, Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital