Key Points
- ▪
Patients with severe sepsis are at particular risk for hepatic and renal injuries.
- ▪
The major cardiovascular events in sepsis are vasoplegia, reduced stroke volume, and microcirculatory failure.
- ▪
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.
- ▪
A patient with active tuberculosis represents major infection risk for other patients and health care workers.
- ▪
Intra-abdominal abscesses are walled-off collections of pus or parasites surrounded by fibrotic tissue, induced by inflammation.
- ▪
Anesthesiologists are involved with necrotizing fasciitis patients at initial presentation (fulminant sepsis) or during subsequent OR visits (tissue debridement).
- ▪
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.
- ▪
In emergency care of patients with organophosphate poisoning, the anesthesiologist usually secures the airway, initiates mechanical ventilation, and transfers the patient to the ICU.
- ▪
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 ).
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 ). ,
* Infection, documented or suspected, and defined as a pathologic process induced by a microorganism, and some of the criteria listed.
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
< 90 mm Hg, MAP < 70 mm Hg, or SBP decrease > 40 mm Hg in adults or < 2 SD below normal for age)
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.
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 ).
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 ).
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 ).
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.
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.
o 2 , mixed venous oxygen saturation. 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.
o 2 , mixed venous oxygen saturation; RBC, red blood cell. 
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 ).
o 2 , mixed venous oxygen saturation; RBC, red blood cell. 
o 2 it was 70. CVP, central venous pressure; S 
o 2 , mixed venous oxygen saturation. 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.
| 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
Catheter-Related Bloodstream Infection
There is a strong possibility of infection with staphylococci, coagulase positive or negative.
- ▪
Vancomycin should be added to, for example, piperacillin + tazobactam.
Once the infecting organisms have been isolated, the spectrum of antimicrobials should be narrowed; if methicillin-resistant S. aureus (MRSA) is isolated, the piperacillin + tazobactam should be discontinued.
- ▪
Vancomycin + piperacillin + tazobactam or ciprofloxacin
Community-Acquired Pneumonia
The most likely organisms are pneumococci, Mycoplasma, and Legionella. The patient requires coverage for both gram-positive and atypical organisms (IV, intravenously; PO, orally).
- ▪
Cephalosporin IV + macrolide PO or fluoroquinolone
- ▪
Cefuroxime/ceftriaxone IV + azithromycin PO or levofloxacin
Intra-Abdominal Sepsis
The most likely infecting organisms are Enterobacteriaceae, enterococci, S. pneumoniae, and anaerobes. Broad-spectrum treatment is required, without cover for Pseudomonas.
- ▪
Penicillin + β-lactam inhibitor or ampicillin + aminoglycoside + antianaerobic agent
- ▪
Ampicillin + sulbactam or piperacillin + tazobactam or ampicillin + gentamicin/aztreonam + metronidazole or imipenem
Urosepsis
The most common organisms causing urinary tract infections are Enterobacteriaceae and enterococci, and the treatment is ciprofloxacin or ampicillin and gentamicin. In this case, however, the patient has been admitted from a nursing home, and Pseudomonas is a strong possibility. Twin therapy is often required, not mixing β-lactam antibiotics:
- ▪
Antipseudomonal quinolone or aminoglycoside + antipseudomonal penicillin or cephalosporin
- ▪
Ciprofloxacin/gentamicin/amikacin + piperacillin or ceftazidime
Cellulitis
The most likely organisms are streptococci and staphylococci. If the infection is community acquired, cloxacillin is adequate. Again, this patient was institutionalized, and the infection must be treated as hospital acquired:
- ▪
Vancomycin + gentamicin
Necrotizing Fasciitis
Type 1 (see later) is caused by group A streptococci, and type 2 is polymicrobial and caused by streptococci, staphylococci, Bacteroides, and Clostridium.
- ▪
Penicillin (high dose) or ciprofloxacin (if penicillin allergic) + clindamycin
- ▪
Add ampicillin + sulbactam or piperacillin + tazobactam
Meningococcemia
Bacterial meningitis is meningococcal septicemia until proved otherwise. The most likely alternative organisms are pneumococci, Haemophilus influenzae, and rarely, Enterobacteriaceae and Listeria.
- ▪
Third-generation cephalosporin + vancomycin (if penicillin-resistant S. pneumoniae suspected) + ampicillin (if Listeria suspected)
- ▪
Cefotaxime + vancomycin
Stage 3: source control
Source control is the essential curative measure in the management of sepsis and the associated inflammatory response. Although there is a myriad of potential causes of sepsis, beyond medical causes, such as pneumonia or meningitis, source control can be neatly summarized by applying the “four Ds” rule ( Fig. 12-12 ) : abscesses should be drained, necrotic tissue should be debrided, infected devices removed, and recurrent sources of infection/inflammation (e.g., cholecystitis or diverticulitis) definitively controlled. This represents the major involvement of anesthesiologists within the sepsis paradigm: patients travel to the OR for source control under anesthesia.
Stage 4: prevention of further complications
A significant aspect of the critical care management of septic patients is prevention of complications. This applies also to their perioperative care. Many patients with acute severe sepsis have a concomitant hypoxic lung injury (e.g., ARDS) requiring intensive mechanical ventilatory support. This usually involves the application of high mean airway pressures to prevent derecruitment of involved lung tissue. It is imperative that lung volume be maintained perioperatively. If the patient is requiring more than 10 cm H 2 O of positive end-expiratory pressure (PEEP) or is on inverse-ratio pressure-controlled or airway pressure–release ventilation, the following guidelines should be followed :
- 1.
The OR mechanical ventilator must be of sufficient capacity to maintain high mean airway pressure. Although some modern ventilators have this capacity, the majority of “bag in bottle” bellows are insufficient. When there is doubt, the patient should be transferred to the OR with their ICU ventilator.
- 2.
Extreme care must be taken to avoid disconnection from the ventilator; even short periods of disconnection (i.e., for changing from ventilator to anesthesia machine) may result in significant derecruitment of the lung and life-threatening hypoxemia.
- 3.
The endotracheal tube should be clamped before disconnections to maintain lung recruitment.
- 4.
If accidental disconnection should occur, sustained inflation maneuvers should be performed to re-recruit the lung.
- 5.
Critically ill patients are usually nursed in the semirecumbent position. Patients lie supine in the OR. This often results in an increase in chest wall elastance, requiring higher levels of PEEP to maintain lung volumes.
- 6.
The standard of care in the management of patients with ARDS is to limit end inspiratory lung volumes to a plateau pressure of 30 cm H 2 O or less and tidal volume of 6 mL/kg or less. This is to avoid “volutrauma,” a ventilator-associated lung injury.
Care must be taken to maintain circulating volume and blood flow to tissues. During surgical debridement of, for example, necrotizing pancreatitis or fasciitis, handling of inflamed or infected tissues usually leads to significant systemic release of cytokines, worsening vasoplegia and increasing myocardial depression. The anesthesiologist must be careful to titrate vasopressors and bolus fluids in response to rapidly changing hemodynamics.
Patients with severe sepsis are at significant risk of secondary organ injuries, particularly to the liver and kidneys. Medications that are renally metabolized or excreted (e.g., pancuronium, morphine) should be used with caution. Aminoglycosides and glycopeptides (e.g., vancomycin) must be administered with reference to pharmacokinetics. Nonsteroidal anti-inflammatory drugs should be avoided because NSAIDs may precipitate acute renal failure, worsen coagulopathy, and induce upper GI bleeding in a vulnerable population. Although hepatic metabolism is well preserved in patients with liver dysfunction in sepsis, consideration should be given to the use of agents metabolized independently of the liver (e.g., cisatracurium rather than vecuronium or pancuronium; remifentanil rather than fentanyl or morphine).
The choice of anesthesia agents depends on several factors. Many patients are transported to the OR in an induced coma (e.g., lorazepam or midazolam plus morphine or hydromorphone infusions), and minimal additional anesthesia is required. In the awake patient being induced, care should be taken as described previously. For maintenance of anesthesia, sufficient agents must be administered to maintain hypnosis and amnesia. Frequently, this is not possible with volatile agents because of peripheral vasodilation and hypotension. Ketamine is a good alternative, particularly if accompanied by an infusion of fentanyl or remifentanil, or hydromorphone.
Patients with acute severe sepsis are at high risk for perioperative bleeding as a result of sepsis-induced coagulopathy and thrombocytopenia. Aggressive volume repletion with red blood cells, thawed plasma, and platelets is recommended. APC (drotrecogin alfa activated) significantly increases the risk of bleeding and must be discontinued at least 2 hours before surgical procedures and not restarted until at least 2 hours after surgery ( Box 12-3 ).
Monitoring: Continuation of all monitoring procedures in ICU
Fluid administration: Goal directed, based on predetermined end points
Anesthesia agents: Determined by hemodynamic stability, whether the patient will tolerate volatile agents, pre-existing infusions (e.g., lorazepam, morphine), and pharmacokinetics
Mechanical ventilation: Transport with ICU ventilator if PEEP > 10 cm H 2 O, inverse-ratio pressure-controlled or airway pressure–release ventilation in use
Avoid ventilator disconnection (use clamp)
Accidental disconnection should be followed by recruitment maneuvers
Inhaled nitric oxide or prostacyclin should be continued
Vasopressors: Therapy should be continued; additional bags of medication should be available to avoid catastrophic cessation
Corticosteroids (for adrenal insufficiency) should be continued
Nutrition: Gastric feeding should be discontinued 6 hours before surgery; postpyloric feeding may be continued (at anesthesiologist’s discretion)
Total parenteral nutrition should be continued
Coagulation: All anticoagulants should be stopped before surgery
Activated protein C should be stopped 2 hours before surgery
Renal replacement therapy: Continuous therapy should be stopped 6 hours before surgery to allow autoreversal of heparin
Antimicrobials: Dosage based on predicted microbes, resistance patterns of patient and hospital, renal function, and pharmacokinetics
ICU, Intensive care unit; PEEP, positive end-expiratory pressure.
Transmissible infections
Hepatitis B
Hepatitis B virus (HBV) is a small, double-stranded (ds) DNA hepadnavirus. HBV is spread by sexual intercourse, with a high degree of infectivity, via secretions and blood products. Health care workers are at particularly high risk of exposure through handling of blood/tissue or needlestick injuries. The outer core of the virus contains a surface antigen (HBsAg) that elicits production of a neutralizing antibody (anti-HBs). In addition, the body generates a separate antibody (anti-HBc) against the viral core antigen (HBcAg). A third viral antigen—the hepatitis B e antigen (HBeAg)—is also released from the core. The presence of this antigen in the serum is indicative of active viral replication. The presence of the antibody to this particle (anti-HBe) is indicative of the end of active viral replication.
One to 6 weeks after exposure, HBsAg appears in the serum; its disappearance after 6 months indicates recovery ( Fig. 12-13 ). The presence of HBsAg for greater than 6 months indicates chronic disease/carrier status (5%-10% of infections). Past exposure of immunization can be detected by anti-HBs. In the majority of patients, anti-HBs does not rise to detectable levels until several weeks after the disappearance of the surface antigen and remains detectable for life. There may be a window in which neither antibody nor antigen is detectable. Consequently, another test is required to ensure diagnosis. This is to detect the presence of immunoglobulin M (IgM) antibody directed against the core antigen (IgM anti-HBc), which is the earliest discernible anti–hepatitis B antibody. The presence of HBeAg implies high infectivity; it is usually present from 1½ to 3 months after acute infection. The presence of anti-HBc indicates past exposure (see Fig. 12-13 ).
After exposure, the incubation period is approximately 12 weeks, with resolution of symptoms after 30 to 60 days. Symptoms include a prodrome of pyrexia, anorexia, myalgia, urticaria, and nausea, followed by jaundice, hepatosplenomegaly, and lymphadenopathy. There is an increase in serum bilirubin and hepatic transaminases. From 5% to 10% of patients go on to develop chronic active hepatitis.
Anesthetic considerations
Patients with acute HBV infection who present for surgery represent a unique risk for health care personnel, particularly anesthesiologists. Universal precautions should be taken when dealing with tissues or body fluids ( Box 12-4 ). Following needlestick injury, the risk of developing clinical hepatitis B or serologic conversion, in a worker who is not immune, if the blood is positive for both HBsAg and HBeAg, is approximately 25% and 50%, respectively. If the blood is HBsAg positive and HBeAg negative, however, the respective risks are only 3% and 30%.
- 1.
Use barrier protection at all times to prevent skin and mucous membrane contamination with blood, body fluids containing visible blood, or other body fluids (cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids, semen and vaginal secretions).
- a.
Barrier protection should be used with all tissues.
- b.
The type of barrier protection used should be appropriate for the type of procedures being performed and the type of exposure anticipated. Examples of barrier protection include disposable laboratory coats, gloves, and eye/face protection.
- a.
- 2.
Wear gloves when the potential exists for hand or skin contact with blood, other potentially infectious material, or items and surfaces contaminated with these materials.
- 3.
Wear face protection (face shield) during procedures that are likely to generate droplets of blood or body fluid to prevent exposure to mucous membranes of the mouth, nose, and eyes.
- 4.
Wear protective body clothing (disposable laboratory coats) when there is a potential for splashing of blood or body fluids.
- 5.
Wash hands or other skin surfaces thoroughly and immediately if contaminated with blood, body fluids containing visible blood, or other body fluids to which universal precautions apply.
- 6.
Wash hands immediately after gloves are removed.
- 7.
Avoid accidental injuries caused by needles, scalpel blades, and laboratory instruments when performing procedures, cleaning instruments, handling sharp instruments, and disposing of used equipment (e.g., needles, pipettes).
- 8.
Used needles, disposable syringes, scalpel blades, pipettes, and other “sharps” are placed in puncture-resistant containers marked with a biohazard symbol for disposal.
Health care workers who have antibodies to HBV either from pre-exposure vaccination or prior infection are not at risk. In addition, if a susceptible worker is exposed to HBV, postexposure prophylaxis with hepatitis B immune globulin and initiation of hepatitis B vaccine is more than 90% effective in preventing HBV infection ( Table 12-2 ).
| Treatment | |||
|---|---|---|---|
| Vaccination and Antibody Response Status of Exposed Workers * | Source HBsAg † Positive | Source HBsAg Negative | Source Unknown or Not Available for Testing |
| Unvaccinated | HBIG ‡ × 1 and initiate HB vaccine series § | Initiate HB vaccine series | Initiate HB vaccine series |
| Previously vaccinated known responder || | No treatment | No treatment | No treatment |
| Known nonresponder ¶ | HBIG × 1 and initiate revaccination or HBIG × 2 ** | No treatment | If known high risk source, treat as if source were HBsAg positive |
| Antibody response unknown | Test exposed person for anti-HBs †† | No treatment | Test exposed person for anti-HBs |
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