Infectious Diseases and Biologic Weapons

Key Points

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Patients with severe sepsis are at particular risk for hepatic and renal injuries.
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The major cardiovascular events in sepsis are vasoplegia, reduced stroke volume, and microcirculatory failure.
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Patients with multiorgan dysfunction syndrome (MODS) become confused, delirious, and ultimately stuporous and comatose.
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The four main pillars in the management of the patient with severe sepsis are immediate resuscitation, empiric therapy, source control, and prevention of further complications.
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Infection with HIV is the most feared of all occupationally acquired diseases. Management of HIV-seropositive pregnant women includes minimizing the infant's risk of acquired infection. Patients with HIV are at particular risk for biliary tract disease.
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A patient with active tuberculosis represents major infection risk for other patients and health care workers.
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Intra-abdominal abscesses are walled-off collections of pus or parasites surrounded by fibrotic tissue, induced by inflammation.
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Anesthesiologists are involved with necrotizing fasciitis patients at initial presentation (fulminant sepsis) or during subsequent OR visits (tissue debridement).
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Soft tissue infections of the neck are of particular importance to anesthesiologists because of possibly significant airway obstruction.
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In epiglottitis patients, intubation should be performed by the most skilled anesthesiologist, with a full airway team, including otolaryngologist, and open tracheostomy pack.
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In a terrorist biologic attack, the anesthesiologist is involved with triage and resuscitation of injured patients and should be familiar with potential bioweapons.
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Anesthesiologists may be involved with the critical care management of the patient with inhalational anthrax, for intubation and supportive care. There is no risk of person-to-person transmission.
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With plague patients, the anesthesiologist should wear a gown, mask, and eye protection because of the potential for contagion.
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In emergency care of patients with organophosphate poisoning, the anesthesiologist usually secures the airway, initiates mechanical ventilation, and transfers the patient to the ICU.
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Infection has killed more soldiers in war than gunfire. Although the age of infectious diseases has all but passed in the Western world, infection, and the means by which the body deals with it, remains a major problem in critical care and perioperative medicine.

A clear distinction must be made between infections, sepsis, infectiousness, and carrier states. Infection refers to the host response to the presence of microorganisms or tissue invasion by microorganisms. The microorganisms may be bacteria, viruses, fungi, parasites, or prions. Sepsis is a syndrome—the systemic inflammatory response to the microorganism and associated toxins. Infectiousness or contagiousness refers to the transmissibility of pathogens from one host to another. A carrier state refers to the persistence of a contagious organism within a host who may not demonstrate signs of infection.

Each of these situations is of importance to anesthesiologists. For example, patients with fulminant surgical sepsis (e.g., necrotizing pancreatitis or gas gangrene) may come to the operating room (OR) for debridement and source control. Anesthesia management is significantly influenced by the immunologic and hemodynamic impact of sepsis. Likewise, patients with transmissible diseases (e.g., tuberculosis, HCV, HIV) represent a significant risk to health care personnel, who may contract the disease. The anthrax fatalities after September 2001 refocused attention of previously eradicated infectious organisms as potential weapons of terrorism.

Sepsis and systemic inflammatory response syndrome

Physicians managing intensive care units (ICUs) have long used a variety of terms to describe illnesses associated with infection or with infectious-appearing illnesses. These terms included sepsis, septicemia, bacteremia, infection, septic shock, and toxic shock. Unfortunately, there were no strict definitions for the terms used, which were often used incorrectly, and emerging evidence indicated that systemic inflammation, rather than infection, was responsible for multiple-organ failure. In the 1990s the American College of Chest Physicians (ACCP) and Society for Critical Care Medicine (SCCM) redefined inflammation and sepsis ( Box 12-1 ).

Box 12-1

Sepsis and Organ Failure: Definitions and Therapeutic Guidelines

From Bone RC, et al: Crit Care Med 20:864-874, 1992. Pa co ₂ , Partial pressure (tension) of carbon dioxide in arterial blood; WBC, white blood cell.

Infection

A host response to the presence of microorganisms or tissue invasion by microorganisms.

Bacteremia

The presence of viable bacteria in circulating blood.

Systemic Inflammatory Response Syndrome (SIRS)

The systemic inflammatory response to a wide variety of severe clinical insults, manifested by two or more of the following conditions:

Temperature > 38 ° C or < 36 ° C
Heart rate > 90 beats/min
Respiratory rate > 20 breaths/min or Pa co ₂ < 32 mm Hg
WBC count > 12,000/mm, < 4000/mm, or > 10% immature (band) forms

Sepsis

The systemic inflammatory response to infection. In association with infection, manifestations of sepsis are the same as those previously defined for SIRS. It should be determined whether they are a direct systemic response to the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities. The clinical manifestations would include two or more of the following conditions as a result of a documented infection:

Temperature > 38 ° C or < 36 ° C
Heart rate > 90 beats/min
Respiratory rate > 20 breaths/min or Pa co ₂ < 32 mm Hg
WBC count > 12,000/mm, < 4000/mm, or > 10% immature (band) forms

Severe Sepsis/SIRS

Sepsis (SIRS) associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

Refractory (Septic) Shock/SIRS Shock

A subset of severe sepsis (SIRS) and defined as sepsis (SIRS)–induced hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic (SIRS) shock.

Multiple Organ (Multiorgan) Dysfunction Syndrome (MODS)

Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

The host response to both infectious and noninfectious injuries is similar ; the clinical signs are essentially the same. This inflammatory response is determined, qualitatively and quantitatively, by genetic and environmental factors. Thus, the term “sepsis” had come to be used, incorrectly, to describe the host response to a variety of infectious and noninfectious injuries ( Fig. 12-1 ). The term systemic inflammatory response syndrome (SIRS) was introduced to describe the process of inflammation without infection. This terminology is now accepted, with some reservations. ^,

Infection is a microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms. Sepsis is the presence of a systemic inflammatory response to infection. A second consensus conference in 2001 addressed the ongoing problem with the vagueness of the definition of SIRS. The strengths and weaknesses of the current sepsis definitions were reviewed. The definitions were left unchanged with the exception of an expansion in the list of signs and symptoms of sepsis to reflect the spectrum of manifestations at the bedside. These definitions have significant epidemiologic value: there is a clear increase in mortality as patients pass from SIRS, with progressive organ failure, to sepsis, to septic shock ( Box 12-2 ). ^,

Box 12-2

Diagnostic Criteria for Sepsis *

* Infection, documented or suspected, and defined as a pathologic process induced by a microorganism, and some of the criteria listed.

From Levy MM, et al: Crit Care Med 31:1250-1256, 2003. Note: Diagnostic criteria for sepsis in the pediatric population are signs and symptoms of inflammation plus infection with hyperthermia or hypothermia (rectal temperature > 38.5 ° C or < 35 ° C), tachycardia (may be absent in hypothermic patients), and at least one of the following indications of altered organ function: altered mental status, hypoxemia, increased serum lactate level, or bounding pulses.

General

Fever (core temperature > 38.3°C)
Hypothermia (core temperature < 36°C)
Heart rate > 90 beats/min or > 2 SD above normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (> 20 mL/kg over 24 hours)
Hyperglycemia (plasma glucose > 120 mg/dL or 7.7 mmol/L) in absence of diabetes

Inflammatory

Leukocytosis (WBC count > 12,000/μL)
Leukopenia (WBC count < 4000/μL)
Normal WBC count with > 10% immature forms
Plasma C reactive protein > 2 SD above the normal value
Plasma procalcitonin > 2 SD above the normal value
Hemodynamic variables
Arterial hypotension ^† (SBP

† S o ₂ > 70% is normal in children (normal, 75%-80%), and cardiac index of 3.5 to 5.5 L/min/m is normal in children; therefore, neither should be used as a sign of sepsis in newborns or children.

< 90 mm Hg, MAP < 70 mm Hg, or SBP decrease > 40 mm Hg in adults or < 2 SD below normal for age)
S o ₂ > 70% ^†
Cardiac index > 3.5 L/min/m

Organ Dysfunction

Arterial hypoxemia (Pa o ₂ /Fi o ₂ < 300)
Acute oliguria (urine output < 0.5 mL/kg/hr for at least 2 hr)
Creatinine increase > 0.5 mg/dL
Coagulation abnormalities (INR > 1.5 or aPTT > 60 seconds)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000/μL)
Hyperbilirubinemia (plasma total bilirubin > 4 mg/dL or 70 mmol/L)

Tissue Perfusion

Hyperlactatemia (> 1 mmol/L)
Decreased capillary refill or mottling

SD, Standard deviation; WBC, white blood cell; SBP, systolic blood pressure; MAP, mean arterial pressure; S o ₂ , mixed venous oxygen saturation; Pa o ₂ , arterial oxygen partial pressure; Fi o ₂ , fraction of inspired oxygen concentration; INR , international normalized ratio; aPTT, activated partial thromboplastin time.

Pathophysiology of Sepsis

The presence of pathogens in the bloodstream or tissues elicits an inflammatory response. There are five stages : (1) establishment of infection, (2) preliminary systemic inflammatory response, (3) overwhelming systemic inflammatory response, (4) compensatory anti-inflammatory response, and (5) immunomodulatory failure.

Microbes possess specific virulence factors to overcome host defenses. The cell wall of gram-negative bacteria consists of an inner phospholipid bilayer and an outer layer that contains lipopolysaccharide (LPS). This consists of polysaccharide O, which protrudes from the exterior cell surface, a core polysaccharide, and a lipid component (lipid A) that faces the cell interior. Lipid A, or endotoxin, is responsible for the toxicity of this molecule. It is released with cell lysis. In meningococcemia, plasma levels of endotoxin correlate well with the development of multiorgan dysfunction syndrome (MODS).

Gram-positive organisms, such as Staphylococcus, Streptococcus, and Enterococcus species, actively secrete an exotoxin, which consists of two polypeptide components: the first binds the protein to the host cell, and the second has toxic effects. Staphylococcus aureus produces four cytolytic exotoxins, the most important of which—α toxin—punctures holes in the membranes of cells, leading to osmotic lysis. In addition, S. aureus produces a number of superantigens that have an affinity for T-cell receptor major histocompatibility complex (MHC) class II antigen complexes. They activate a large number of T cells, leading to massive release of cytokines and toxic shock. Clostridium difficile produces two exotoxins: toxin A and toxin B.

In addition to toxins, bacteria possess a variety of virulence factors that contribute to the establishment of infection. For example, group A streptococci produce hyaluronidase and various proteases and collagenases, which facilitate the spread of the bacteria along tissue planes. Staphylococcus epidermidis produces a biofilm that coats intravascular devices and endotracheal tubes, making elimination by antibiotics almost impossible. Coliform bacteria and Pseudomonas species have pili that allow the organism to bind and anchor to the epithelium, potentially a mechanism of bacterial translocation.

Fungal infections are common in the hospitalized population. Commensal organisms, such as Candida spp., become pathogenic as a result of host factors (e.g., immunosuppression, concomitant infection, diabetes) and iatrogenic factors (e.g., multiple antibiotics, critical illness, parenteral nutrition, abdominal surgery). The gastrointestinal (GI) tract appears to be an important source of Candida; the mechanism of candidemia is unclear ( Fig. 12-2 ).

Figure 12-2, The PIRO model of sepsis and SIRS.

The inflammatory cascades

Tissue injury or pathogens (bacteria, viruses, fungi, or parasites) cause monocyte activation, which produces interleukin (IL-1, IL-6), tumor necrosis factor alpha (TNF-α), plasminogen activator inhibitor 1 (PAI-1), and interferon-γ (IFN-γ). ^, These cytokines subsequently modulate the release and activation of a medley of different agents: interleukin-8 (IL-8), complement, histamine, kinins, serotonin, selectins, eicosanoids, and neutrophils. This leads to local vasodilation, release of various cytotoxic chemicals, and destruction of the invading pathogen. The release of cytotoxic material and proinflammatory cytokines results in the systemic inflammatory response: fever or hypothermia, tachypnea, tachycardia, and leukocytosis or neutropenia.

A subgroup of patients has an abnormal (“malignant”) inflammatory response: tissue destruction by neutrophils, endothelial cell destruction, and massive systemic release of mediators. The result is vasoplegia, capillary leak, and activation of clotting cascades.

Damage to the endothelium exposes a procoagulant factor known as tissue factor. Tissue factor exists in the subendothelial space and has a reparative role after tissue damage. In sepsis, there is massive exposure. Tissue factor binds to activated factor VII. The resulting complex activates in turn factors IX and X. Factor X converts prothrombin into thrombin, which cleaves fibrinogen into fibrin—a blood clot. At the same time, the fibrinolytic system is inhibited. Cytokines and thrombin stimulate the release of PAI-1 from platelets and the endothelium. In the human body, when a clot forms, it is ultimately broken down by plasmin, which is activated by tissue plasminogen activator (t-PA) from plasminogen; PAI-1 inhibits t-PA.

Thrombin itself is an activator of inflammation and inhibitor of fibrinolysis. The latter is achieved by the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Thrombomodulin, another modulator of fibrinolysis, is impaired by inflammation and endothelial injury. The function of this compound is to activate protein C. Activated protein C modifies the inflammatory and coagulant response at several different levels; a deficiency results from inhibition of thrombomodulin in sepsis.

Hemodynamic derangement in sepsis

Three major cardiovascular events occur in sepsis, as follows:

1.
Vasoplegia. Pathologic vasodilation results from loss of normal sympathetic tone, caused by the combination of local vasodilator metabolites. There is activation of adenosine triphosphate–sensitive potassium channels, leading to hyperpolarization of smooth muscle cells. ^, There is increased production of inducible nitric oxide synthetase (iNOS), which manufactures massive amounts of nitric oxide. In addition, there is acute depletion of vasopressin. Vasoplegia leads to relative hypovolemia. Vascular tone is characteristically resistant to catecholamine therapy but very sensitive to vasopressin.
2.
Reduced stroke volume. This results from the presence of a circulating myocardial depressant factor, probably TNF-α. There is reversible biventricular failure, a decreased ejection fraction, myocardial edema, and ischemia. Cardiac output is maintained by a dramatic increase in heart rate.
3.
Microcirculatory failure. The small blood vessels vasodilate, and there is widespread capillary leak, maldistribution of flow, arteriovenous shunting, and oxygen (O ₂ ) utilization defects. These abnormalities are incompletely understood. In addition, there is initial activation of the coagulation system and deposition of intravascular clot, causing ischemia.

The relative hypovolemia of early sepsis is virtually indistinguishable from hypovolemic or hemorrhagic shock. In response to intravascular volume depletion (distributive or hypovolemic shock), the precapillary arterioles and postcapillary venules vasoconstrict, increasing blood flow velocity, which draws fluid in from the interstitium (a net influx of fluid into the circulation). This is known as transcapillary refill. Fluid effectively shifts from the extravascular to the intravascular space. An O ₂ debt is incurred, and there may be lactic acidosis. At this stage, patients are highly sensitive to volume resuscitation.

Eventually, persistent release of cytokines leads to depletion of reserve: there is hyperpolarization of vascular smooth muscles, massive release of iNOS, vasopressin depletion, and widespread increase in vascular permeability. The result is vasoplegia and sequestration of intravascular fluid into extracellular space. The patient has interstitial edema, hemoconcentration, and increased blood viscosity. There is parallel activation of clotting cascades, intravascular thrombosis, and bleeding. The capacity of mitochondria to extract O ₂ is impaired, and multiorgan dysfunction results ( Fig. 12-3 ).

Figure 12-3, Mortality in SIRS/sepsis/septic shock.

Multiorgan Dysfunction Syndrome

The brain and kidneys are normally protected from swings in blood pressure (BP) by autoregulation. In early sepsis the autoregulation curve shifts rightward (because of an increase in sympathetic tone). In late sepsis, vasoplegia occurs and autoregulation fails, making these organs susceptible to the swings that occur in systemic BP. In addition, “steal” phenomena may occur (areas of ischemia may have their blood “stolen” by areas with good perfusion). This is known as vasomotor neuropathy. Acute tubular necrosis results from cellular apoptosis, toxic injury (mechanism unclear, possibly cellular lysosomes and debris), hypotension, and hypovolemia.

Patients with multiorgan dysfunction syndrome (MODS) become confused, delirious, and ultimately stuporous and comatose as a result of a variety of insults: hypoperfusion injury, septic encephalopathy, metabolic encephalopathy, and, of course, drugs used for sedation.

Myocardial O ₂ supply is dependent on diastolic BP, which falls following vasoplegia, and on intravascular volume depletion. This may lead to ischemia. There is reversible biventricular dilation, decreased ejection fraction, and decreased response to fluid resuscitation and catecholamine stimulation. A circulating myocardial depressant substance is responsible for this phenomenon. This substance has been shown to represent low concentrations of TNF-α and IL-1β acting in synergy on the myocardium through mechanisms that include nitric oxide and cyclic guanosine monophosphate generation.

In the lungs, ventilation/perfusion mismatches occur, initially from increased dead space (caused by hypotension and fluid shifts) and subsequently from shunt. There is increased extravascular lung water and widespread disruption of the alveolar-capillary basement membrane, leading to acute lung injury. Up to 70% of patients develop nosocomial pneumonia. Cytokines released as a result of ventilator-induced lung injury may have adverse effects at distant organs. This hypothesis was confirmed from data in the Acute Respiratory Distress Syndrome (ARDS) Network trial supported by the National Institutes of Health. Blood samples were obtained from 204 of the first 234 patients for measurement of plasma IL-6 concentration. Levels of this cytokine were significantly higher in the “high stretch” (tidal volume, 10- 12 mL/kg) compared with the “low stretch” (tidal volume, 5-6 mL/kg) group. In addition to lower mortality, this group had a significantly lower incidence of nonpulmonary organ injury (the lung origin theory of sepsis).

There is significant hepatic dysfunction in sepsis. Uncontrolled production of inflammatory cytokines by the Kupffer cells (of the liver), primed by ischemia and stimulated by endotoxin (derived from the gut), leads to cholestasis and hyperbilirubinemia. There is decreased synthesis of albumin, clotting factors, cytochrome P450, and biliary transporters. Impaired ketogenesis, ureagenesis, and gluconeogenesis are caused by decreased expression of genes encoding gluconeogenic, β-oxidative, and ureagenic enzymes. Gut mucosa is usually protected from injury by autoregulation. Hypotension and hypovolemia lead to superficial mucosal injury. This results in atrophy and possible translocation of bacteria into the portal circulation, stimulating liver macrophages, causing cytokine release, and amplifying SIRS (the gut origin theory of sepsis). ^,

Metabolic abnormalities in sepsis include hyperglycemia caused by glycogenolysis, insulin resistance, and massive release of catecholamines and lactic acidosis. A generalized catabolic state leads to muscle breakdown, not unlike marasmus. The patient has relative hypothyroidism, hypopituitarism, and adrenal insufficiency. ^,

Activated protein C

Protein C is an important anticoagulant and anti-inflammatory protein. The main effect of activated protein C (APC) is to reduce the production of thrombin, by inactivating factors Va and VIII. Thrombin is proinflammatory, procoagulant, and antifibrinolytic. In addition, protein C inhibits the influence of tissue factor on the clotting system, reduces the production of IL-1, IL-6, and TNF-α by monocytes, and has profibrinolytic properties through the inactivation of PAI-1. The Prowess trial suggested that exogenous administration of APC to patients, in severe sepsis, may improve outcome. However, the results of the single trial have been controversial, and there is no survival benefit in patients with severe sepsis and Apache II scores less than 25. The major clinical drawback of treatment with APC is bleeding, particularly in perioperative patients.

Treating the Patient with Septic Shock

Patients with acute severe sepsis (e.g., necrotizing fasciitis or gas gangrene) are infrequently brought to the OR for emergent source control. In this circumstance, the anesthesiologist will be required to both administer anesthesia, ensuring amnesia, analgesia, and hypnosis, and resuscitate the patient. A familiarity with modern resuscitation practices is thus important. The four main pillars in the management of the patient with severe sepsis are immediate resuscitation, empiric therapy, source control, and prevention of further complications ( Fig. 12-4 ).

Figure 12-4, Treating sepsis: the four pillars of therapy.

Stage 1: immediate resuscitation

Immediate Stabilization (Airway and Breathing)

The initial treatment priority in patients with severe sepsis is to reverse life-threatening physiologic abnormalities. The airway must be controlled and the patient oxygenated and ventilated. This usually requires endotracheal intubation and initiation of mechanical ventilation. Care must be taken when administering anesthetic agents for gaining airway control. Propofol usually causes dramatic hypotension, from peripheral vasodilation and vagotonia, and should be avoided. Etomidate and ketamine are reasonable choices. Although frequently used in cardiac anesthesia for hemodynamic stability, opioids have significant antiadrenergic effects in sepsis and may cause dramatic hypotension. Therapies directed at slowing heart rate should be avoided, because tachycardia is the main compensatory mechanism in maintenance of cardiac output.

After intubation, extreme care must be taken with institution of positive-pressure ventilation. The increase in intrathoracic pressure will reduce venous return: aggressive “bagging” invariably leads to severe hypotension.

Re-establishing the Circulation

Volume Resuscitation

In early sepsis, hypotension is caused by relative hypovolemia, secondary to peripheral vasodilation. Later, hypotension is caused by myocardial depression, vasoplegia, and absolute hypovolemia secondary to capillary leak ( Fig. 12-5 ). Regardless, the initial resuscitative effort is to attempt to correct the absolute and relative hypovolemia by refilling the vascular tree. Volume resuscitation should be early (in OR or emergency department), aggressive, and goal directed.

Figure 12-5, Two phases of sepsis resuscitation.

The choice of fluids early in resuscitation remains controversial. Initial resuscitation should include isotonic crystalloid, to replete interstitial fluid debt. Subsequent efforts are directed at maintenance of intravascular volume. If crystalloid resuscitation is continued, there is significant extravasation of fluid, and the patient becomes edematous. ^, Many favor high-molecular-weight (“colloid”) compounds as a means of minimizing resuscitation volume and for potential positive oncotic effects. Although the use of colloid is controversial, ^, evidence supports its use in perioperative medicine and critical illness as part of a goal-directed paradigm. The main limiting factors for colloids are availability (gelatins and pentastarches are not available in the United States) and cost. Available colloids include blood products, hydroxyethyl starches, and albumin. Previous concerns regarding albumin safety are unfounded.

The goal-directed approach to resuscitation involves the use of specific monitors to measure input (fluid loading), tissue blood flow, and response ( Fig. 12-6 ). Arterial and central lines are placed, and goals for resuscitation are set: these include a central venous pressure (CVP) of 8 to 12 cm H ₂ O; a mean arterial pressure (MAP) of more than 65 mm Hg; and, if the appropriate device is placed, a mixed venous oxygen saturation (S o ₂ ) of more than 70%; and stroke volume (SV) between 0.7 and 1 mL/kg.

Figure 12-6, Goal-directed resuscitation.

Central Venous and Pulmonary Artery Catheters

The Surviving Sepsis Campaign promotes the use of oximetric CVP catheters to monitor input and flow ( Fig. 12-7 ) based on the work of Rivers et al. Fluid is administered until the CVP reaches and stays in the target range: 8 to 12 cm H ₂ O for the majority of patients ( Fig. 12-8 ). Once fluid loading has been achieved, hypotension is managed with vasopressors (norepinephrine or dopamine; see later) to a target MAP of 65 mm Hg. If S o ₂ is less than 70%, with CVP and MAP in the target range, blood is transfused until the hematocrit exceeds 30% (hemoglobin [Hb] 10 g/L). If this fails to restore the S o ₂ , an inotrope is added, such as dobutamine or a phosphodiesterase inhibitor.

Figure 12-7, Goal-directed resuscitation using oximetric central venous pressure (CVP) catheter based on the Surviving Sepsis Campaign.

Figure 12-8, Goal-directed approach using central venous pressure.

A more elegant approach involves insertion of an oximetric pulmonary artery catheter rather than a CVP line. In this paradigm, SV is used as the main end point of resuscitation, and CVP or pulmonary artery pressure is used to determine the presence of heart failure ( Fig. 12-9 ); a Starling curve is constructed ( Fig. 12-10 ). Fluid is administered to the patient until SV is a sustained 0.7 to 1 mL/kg ( Fig. 12-11 ).

Figure 12-9, Using stroke volume to construct Starling curves.

Figure 12-10, Algorithm for goal-directed resuscitation.

Figure 12-11, Goal-directed approach to determine effectiveness of fluid resuscitation.

Overresuscitation

An SV in excess of 1 mL/kg is indicative of overresuscitation, and fluids are withheld until the SV drifts back into normal range. If the SV exceeds 1.5 mL/kg, serious consideration should be given to the administration of diuretics.

Vasopressor Therapy

Hypotension, unresponsive to fluid therapy, in patients with sepsis is an indication for vasopressor use ( Table 12-1 ). The ideal pressor agent would restore BP while maintaining cardiac output and preferentially perfuse the midline structures of the body (brain, heart, splanchnic organs, kidneys). Currently, norepinephrine is the agent of choice in the fluid-resuscitated patient.

Table 12-1

Pharmacologic Support of the Circulation in Sepsis

Agent	α ₁	β ₁	β ₂	Heart Rate	Organs Perfused
Epinepthrine	++++	++++	++++	↑↑↑↑	Skin, muscle
Norepinephrine	++++	++++	++	↑↑	Central organs
Dopamine	++	++	++++	↑↑↑↑	Skin, muscle
Phenylephrine	++	—	—	—	No real change

Norepinephrine

Norepinephrine has pharmacologic effects on both α ₁ and β ₁ adrenoceptors. In low-dosage ranges, the beta effect is noticeable, with a mild increase in cardiac output. In most dosage ranges, vasoconstriction and increased MAP are evident. Norepinephrine does not increase heart rate. The main beneficial effect of norepinephrine is to increase organ perfusion by increasing vascular tone. Studies comparing norepinephrine to dopamine favored the former in terms of overall improvements in O ² delivery, organ perfusion, and O ₂ consumption. Norepinephrine is more effective at fulfilling targeted end points than dopamine, is less metabolically active than epinephrine, and reduces serum lactate levels. Norepinephrine significantly improves renal perfusion and splanchnic blood flow in sepsis, ^, particularly when combined with dobutamine.

Dopamine

Dopamine has predominantly β-adrenergic effects in low to moderate dose ranges (up to 10 MIC/kg/ min), although there is much interpatient variability. This effect may result from its conversion to norepinephrine in the myocardium and its activation of adrenergic receptors. In higher dose ranges, α-adrenoceptor activation increases and causes vasoconstriction. Dopamine is thus a mixed inotrope and vasoconstrictor. At all dose ranges, it is a potent chronotrope. Much controversy has surrounded other metabolic functions of this agent. Dopamine is a potent diuretic; it neither saves nor damages the kidneys. Dopamine has complex neuroendocrine effects; it may interfere with thyroid and pituitary function and may have an immunosuppressive effect. Overall, there is no benefit to dopamine administration over norepinephrine.

Dobutamine

Dobutamine is a potent β ₁ agonist, with predominant effects in the heart, where it increases myocardial contractility and thus SV and cardiac output. Dobutamine is associated with much less increase in heart rate than dopamine. In sepsis, dobutamine, although a vasodilator, increases O ₂ delivery and consumption. Dobutamine appears particularly effective at splanchnic resuscitation, increasing pHi (gastric mucosal pH) and improving mucosal perfusion in comparison with dopamine.

Epinephrine

Epinephrine has potent β ₁ -, β ₂ -, and α ₁ -adrenergic activity, although the increase in MAP in sepsis is mainly from an increase in cardiac output (SV). Epinephrine has three major drawbacks: (1) it increases myocardial oxygen demand; (2) it increases serum glucose lactate, which may be caused by a worsening of perfusion to certain tissues or by a calorigenic effect (increased release and anaerobic breakdown of glucose); and (3) it appears to have adverse effects on splanchnic blood flow, redirecting blood peripherally as part of the “fight or flight” response. The metabolic and hemodynamic effects make epinephrine an unsuitable first-line agent in sepsis.

Phenylephrine

Phenylephrine is an almost pure α ₁ agonist with moderate potency. Although widely used in anesthesia to treat iatrogenic hypotension, it is an ineffective agent in sepsis. Phenylephrine is a less effective vasoconstrictor than norepinephrine or epinephrine. Compared with norepinephrine, phenylephrine reduces splanchnic blood flow, O ₂ delivery, and lactate uptake.

Vasopressin

Vasopressin has emerged as an additive vasoconstrictor in septic patients who have become resistant to catecholamines. There appears to be a quantitative deficiency of this hormone in sepsis, ^, and administration in addition to norepinephrine surprisingly increases splanchnic blood flow and urine output. The most efficacious dose appears to be 0.04 unit/min, and this is not titrated. This relatively low dose has little or no effect on normotensive patients.

Stage 2: empiric therapy—antibiotics

The selection of specific antibiotics depends on the following:

1.
The presumed site of infection (see Box 12-1 )
2.
Gram's stain results
3.
Suspected or known organisms
4.
Resistance patterns of the common hospital microbial flora
5.
Patient's immune status (especially neutropenia and immunosuppressive drugs), allergies, renal dysfunction, and hepatic dysfunction
6.
Antibiotic availability, hospital resistance patterns, and clinical patient variables to be treated

Suggested Antimicrobial Regimens

Sepsis Source Unknown

Combining either an antipseudomonal cephalosporin (ceftazidime) or an antipseudomonal penicillin (piperacillin + tazobactam) (particularly if anaerobes are suspected) with either an aminoglycoside (gentamicin or amikacin) or a fluoroquinolone (ciprofloxacin) can be done. If an antipseudomonal cephalosporin is used and anaerobes are a possible cause, the addition of metronidazole or clindamycin should be considered.

▪
Piperacillin + tazobactam/imipenem + gentamicin/ciprofloxacin

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