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INTRODUCTION |
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Background:
History of infectious diseases
During thousands of years of human existence, epidemic infectious diseases
probably were rare, with most infections occurring as a result of trauma or from
physical contact with animals. In 2735 BC, Chinese emperor Sheng Nung recorded
the use of an herbal remedy to treat fever. Over the next 2 millennia, epidemics
of cholera, plague (black death), smallpox, measles, tuberculosis, and gonorrhea
spread worldwide, wiping out huge segments of the population. In 1546,
Hieronymus Fracastorius suggested germ theory for infections.
John Pringle, a British army surgeon, proposed the concept of antisepsis for
the first time. In the 19th century, antiseptic practices lead to a reduction in
mortality from puerperal fever from 13.6% to 1.5% in a Vienna hospital. In 1879,
Louis Pasteur identified Streptococcus bacteria as the cause of
puerperal sepsis. In 1892, Richard Pfeiffer identified the toxin that causes
shock in patients. In 1928, Alexander Fleming recognized that his bacterial
cultures were killed by a blue mold, Penicillium notatum. Thus, with
the discovery of penicillin, a new era began, with antibiotics used to treat
bacterial infections. In 1944 in the United States, Waksman discovered that
streptomycin was effective in the treatment of tuberculosis.
Further advances in medical sciences in the late 20th century enhanced our
understanding of sepsis and septic shock—recognition of inflammatory mediators
stimulating nitric oxide production; producing endothelial injury; activating
coagulation cascade; and eventually leading to organ ischemia, damage, and,
ultimately, death. This knowledge will lead to novel approaches to treat severe
sepsis in the future.
Sepsis and septic shock
In 1914, Schottmueller wrote, “Septicemia is a state of microbial invasion
from a portal of entry into the blood stream which causes sign of illness.?The
definition did not change much over the years because the terms sepsis and
septicemia referred to several ill-defined clinical conditions present in a
patient with bacteremia. In practice, the terms often were used interchangeably;
however, less than one half of the patients with signs and symptoms of sepsis
have positive results on blood culture. Furthermore, not all patients with
bacteriemia have signs of sepsis; therefore, sepsis and septicemia are not
identical. In the last few decades, discovery of endogenous mediators of the
host response have led to the recognition that the clinical syndrome of sepsis
is the result of excessive activation of host defense mechanisms rather than the
direct effect of microorganisms. Sepsis and its sequelae represent a continuum
of clinical and pathophysiologic severity.
Serious bacterial infections at any body site, with or without bacteremia,
usually are associated with important changes in the function of every organ
system in the body. These changes are mediated mostly by elements of the host
immune system against infection. Shock is deemed present when volume replacement
fails to increase blood pressure to acceptable levels and associated clinical
evidence indicates inadequate perfusion of major organ systems, with progressive
failure of organ system functions.
Multiple organ dysfunctions, the extreme end of the continuum, are
incremental degrees of physiological derangements in individual organs (a
process rather than an event). Alteration in organ function can vary widely from
a mild degree of organ dysfunction to frank organ failure.
The American College of Chest Physicians (ACCP)/Society of Critical Care
Medicine (SCCM) consensus conference definitions of sepsis, severe sepsis, and
septic shock (Bone, 1992) are outlined below.
Systemic inflammatory response syndrome (SIRS): The systemic inflammatory
response to a wide variety of severe clinical insults manifests by 2 or more of
the following conditions:
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- Temperature greater than 38°C or less than 36°C
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- Heart rate greater than 90 beats per minute (bpm)
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- Respiratory rate greater than 20 breaths per minute or PaCO2
less than 32 mm Hg
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- White blood cell count greater than 12,000/mm3/L, less than
4000/L, or 10% immature (band) forms
Sepsis: This is a systemic inflammatory response to a documented infection.
The manifestations of sepsis are the same as those previously defined for SIRS.
The clinical features include 2 or more of the following conditions as a result
of a documented infection:
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- Rectal temperature greater than 38°C or less than 36°C
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- Tachycardia (>90 bpm)
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- Tachypnea (>20 breaths per min)
With sepsis, at least 1 of the following manifestations of inadequate organ
function/perfusion also must be included:
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- Alteration in mental state
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- Hypoxemia (PaO2 <72 mm Hg at FiO2 [fraction of
inspired oxygen] 0.21; overt pulmonary disease not the direct cause of
hypoxemia)
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- Elevated plasma lactate level
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- Oliguria (urine output <30 mL or 0.5 mL/kg for at least 1 h)
Severe sepsis: This is sepsis and 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. The systemic response to infection is manifested by
2 or more of the following conditions:
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- Temperature greater than 38°C or less than 36°C
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- Heart rate greater than 90 bpm
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- Respiratory rate greater than 20 breaths per minute or PaCO2
less than 32 mm Hg
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- White blood cell count greater than 12,000/mm3/L, less than
4000/L, or 10% immature (band) forms
Sepsis-induced hypotension (ie, systolic blood pressure <90 mm Hg or a
reduction of >40 mm Hg from baseline): This may develop despite adequate fluid
resuscitation, along with the presence of perfusion abnormalities that may
include lactic acidosis, oliguria, or an acute alteration in mental state.
Septic shock: A subset of people with severe sepsis develop hypotension
despite adequate fluid resuscitation, along with the presence of perfusion
abnormalities that may include lactic acidosis, oliguria, or an acute alteration
in mental status. Patients receiving inotropic or vasopressor agents may not be
hypotensive by the time that they manifest hypoperfusion abnormalities or organ
dysfunction.
Multiple organ dysfunction syndrome (MODS): This is the presence of altered
organ function in a patient who is acutely ill and in whom homeostasis cannot be
maintained without intervention.
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Pathophysiology:
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Mediator-induced cellular injury
The evidence that sepsis results from an exaggerated systemic inflammatory
response induced by infecting organisms is compelling; inflammatory mediators
are the key players in the pathogenesis.
The gram-positive and gram-negative bacteria induce a variety of
proinflammatory mediators, including cytokines. Such cytokines play a pivotal
role in initiating sepsis and shock. The bacterial cell wall components are
known to release the cytokines; these include lipopolysaccharide (gram-negative
bacteria), peptidoglycan (gram-positive and gram-negative bacteria), and
lipoteichoic acid (gram-positive bacteria).
Several of the harmful effects of bacteria are mediated by proinflammatory
cytokines induced in host cells (macrophages/monocytes and neutrophils) by the
bacterial cell wall component. The most toxic component of the gram-negative
bacteria is the lipid A moiety of lipopolysaccharide. The gram-positive bacteria
cell wall leads to cytokine induction via lipoteichoic acid. Additionally,
gram-positive bacteria may secrete the super antigen cytotoxins that bind
directly to the major histocompatibility complex (MHC) molecules and T-cell
receptors, leading to massive cytokine production.
A major role for tumor necrosis factor (TNF) and interleukin (IL)-1 has been
demonstrated. Both of these factors also help to keep infections localized, but,
once the infection becomes systemic, the effects are detrimental. Circulating
levels of IL-6 correlate well with the outcome. High levels of IL-6 are
associated with mortality, but its role in pathogeneses is not clear. IL-8 is an
important regulator of neutrophil function, synthesized and released in
significant amounts during sepsis. IL-8 contributes to the lung injury and
dysfunction of other organs. The chemokines (monocyte chemoattractant protein?)
orchestrate the migration of leukocytes during endotoxemia and sepsis. The other
cytokines that have a supposed role in sepsis are IL-10, interferon-gamma,
IL-12, macrophage migration inhibition factor, granulocyte colony-stimulating
factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF).
The complement system is activated and contributes to the clearance of the
infecting microorganisms but probably also enhances the tissue damage. The
contact systems become activated; consequently, bradykinin is generated.
Hypotension, the cardinal manifestation of sepsis, occurs via induction of
nitric oxide. Nitric oxide plays a major role in hemodynamic alteration of
septic shock, which is hyperdynamic shock. A dual role exists for neutrophils;
they are necessary for defense against microorganisms but also may become toxic
inflammatory mediators contributing to tissue damage and organ dysfunction.
The lipid mediators (eicosanoids), platelet activating factor, and
phospholipase A2 are generated during sepsis, but their contributions to the
sepsis syndrome remain to be established.
Table 1. Mediators of Sepsis
Type |
Mediator |
Activity |
Cellular mediators |
Lipopolysaccharide |
Activation of macrophages, neutrophils, platelets, and
endothelium releases various cytokines and other mediators |
Lipoteichoic acid |
Peptidoglycan |
Superantigens |
Endotoxin |
Humoral mediators |
Cytokines |
Potent proinflammatory effect
Neutrophil chemotactic factor
Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibits
cytokine production, induces immunosuppression
Activation and degranulation of neutrophils
Cytotoxic, augments vascular permeability, contributes to shock
Involved in hemodynamic alterations of septic shock
Promote neutrophil and macrophage, platelet activation and chemotaxis, other
proinflammatory effects
Enhance vascular permeability and contributes to lung injury
Enhance neutrophil-endothelial cell interaction, regulate leukocyte
migration and adhesion, and play a role in pathogenesis of sepsis |
TNF-alpha and IL-1b
IL-8
IL-6
IL-10 |
MIF*
G-CSF |
Complement |
Nitric oxide |
Lipid mediators
Phospholipase A2
PAF?/sup>
Eicosanoids |
Arachidonic acid metabolites |
Adhesion molecules
Selectins
Leukocyte integrins |
*Macrophage inhibitory factor
†Platelet activating factor
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Abnormalities of coagulation and fibrinolysis homeostasis in sepsis
An imbalance of homeostatic mechanisms lead to disseminated intravascular
coagulopathy (DIC) and microvascular thrombosis causing organ dysfunction and
death (Lorente, 1993; McGillvary, 1998; Levi, 1999). Inflammatory mediators
instigate direct injury to the vascular endothelium; the endothelial cells
release tissue factor (TF), triggering the extrinsic coagulation cascade and
accelerating production of thrombin (Carvalho, 1994). The coagulation factors
are activated as a result of endothelial damage, the process is initiated via
binding of factor XII to the subendothelial surface. This activates factor XII,
and then factor XI and, eventually, factor 10 are activated by a complex of
factor IX, factor VIII, calcium, and phospholipid. The final product of the
coagulation pathway is the production of thrombin, which converts soluble
fibrinogen to fibrin. The insoluble fibrin, along with aggregated platelets,
forms intravascular clots.
Inflammatory cytokines, such as IL-1a, IL-1b,
and TNF-alpha initiate coagulation by activation of TF, which is the principle
activator of coagulation. TF interacts with factor VIIa, forming factor VIIa-TF
complex, which activates factor X and IX. Activation of coagulation in sepsis
has been confirmed by marked increases in thrombin-antithrombin complex (Levi,
1993) and the presence of D-dimer in plasma, indicating activation of clotting
system and fibrinolysis (Mammen, 1998). Tissue plasminogen activator (t-PA)
facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.
Endotoxins increase the activity of inhibitors of fibrinolysis, which are
plasminogen activator inhibitor (PAI-1) and thrombin activatable fibrinolysis
inhibitor (TAFI). Furthermore, the levels of protein C and endogenous activated
protein C also are decreased in sepsis. Endogenous activated protein C is an
important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin
via thrombomodulin activates protein C that functions as an antithrombotic in
the microvasculature. Endogenous activated protein C also enhances fibrinolysis
by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.
The imbalance among inflammation, coagulation, and fibrinolysis results in
widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis,
ultimately leading to multiple organ dysfunction and death.
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Circulatory and metabolic pathophysiology of septic shock
The predominant hemodynamic feature of septic shock is arterial vasodilation.
Diminished peripheral arterial vascular tone may result in dependency of blood
pressure on cardiac output, causing vasodilation to result in hypotension and
shock if insufficiently compensated by a rise in cardiac output. Early in septic
shock, the rise in cardiac output often is limited by hypovolemia and a fall in
preload because of low cardiac filling pressures. When intravascular volume is
augmented, the cardiac output usually is elevated (the hyperdynamic phase of
sepsis and shock). Even though the cardiac output is elevated, the performance
of the heart, reflected by stroke work as calculated from stroke volume and
blood pressure, usually is depressed. Factors responsible for myocardial
depression of sepsis are myocardial depressant substances, coronary blood flow
abnormalities, pulmonary hypertension, various cytokines, nitric oxide, and
beta-receptor down-regulation.
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Peripheral circulation during septic shock
An elevation of cardiac output occurs; however, the arterial-mixed venous
oxygen difference usually is narrow, and the blood lactate level is elevated.
This implies that low global tissue oxygen extraction is the mechanism that may
limit total body oxygen uptake in septic shock. The basic pathophysiologic
problem seems to be a disparity between the uptake and oxygen demand in the
tissues, which may be more pronounced in some areas than in others. This is
termed maldistribution of blood flow, either between or within organs, with a
resultant defect in capacity to extract oxygen locally. During a fall in oxygen
supply, cardiac output becomes distributed so that most vital organs, such as
the heart and brain, remain relatively better perfused than nonvital organs.
However, sepsis leads to regional changes in oxygen demand and regional
alteration in blood flow of various organs.
The peripheral blood flow abnormalities result from the balance between local
regulation of arterial tone and the activity of central mechanisms (eg,
autonomic nervous system). The regional regulation, release of vasodilating
substances (eg, nitric oxide, prostacyclin), and vasoconstricting substances (eg,
endothelin) affect the regional blood flow. Development of increased systemic
microvascular permeability also occurs, remote from the infectious focus,
contributing to edema of various organs, particularly the lung microcirculation
and development of acute respiratory distress syndrome (ARDS).
In patients experiencing septic shock, the delivery of oxygen is relatively
high, but the global oxygen extraction ratio is relatively low. The oxygen
uptake increases with a rise in body temperature despite a fall in oxygen
extraction.
In patients with sepsis who have low oxygen extraction and elevated arterial
blood lactate levels, oxygen uptake depends on oxygen supply over a much wider
range than normal. Therefore, oxygen extraction may be too low for tissue needs
at a given oxygen supply, and oxygen uptake may increase with a boost in oxygen
supply, a phenomenon termed oxygen uptake supply dependence or pathological
supply dependence. However, this concept is controversial because other
investigators argue that supply dependence is artifactual rather than a real
phenomenon.
Maldistribution of blood flow, disturbances in the microcirculation, and,
consequently, peripheral shunting of oxygen are responsible for diminished
oxygen extraction and uptake, pathological supply dependency of oxygen, and
lactate acidemia in patients experiencing septic shock.
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Multiorgan dysfunction syndrome
Sepsis is described as an autodestructive process that permits the extension
of normal pathophysiologic response to infection (involving otherwise normal
tissues), resulting in multiple organ dysfunction syndrome. Organ dysfunction or
organ failure may be the first clinical sign of sepsis, and no organ system is
immune to the consequences of the inflammatory excesses of sepsis.
Circulation
Significant derangement in the autoregulation of circulation is typical in
patients with sepsis. Vasoactive mediators cause vasodilatation and increase the
microvascular permeability at the site of infection. Nitric oxide plays a
central role in the vasodilatation of septic shock. Impaired secretion of
vasopressin also may occur, which may permit the persistence of vasodilatation.
Central circulation
Changes in both systolic and diastolic ventricular performance occur in
patients with sepsis. Through the use of the Frank Starling mechanism, the
cardiac output often is increased to maintain the blood pressure in the presence
of systemic vasodilatation. Patients with preexisting cardiac disease are unable
to increase their cardiac output appropriately.
Regional circulation
Sepsis interferes with the normal distribution of systemic blood flow to
organ systems; therefore, core organs may not receive appropriate oxygen
delivery.
The microcirculation is the key target organ for injury in patients with
sepsis syndrome. A decrease in the number of functional capillaries causes an
inability to extract oxygen maximally; intrinsic and extrinsic compression of
capillaries and plugging of the capillary lumen by blood cells cause the
inability. Increased endothelial permeability leads to widespread tissue edema
of protein-rich fluid.
Hypotension is caused by the redistribution of intravascular fluid volume
resulting from reduced arterial vascular tone, diminished venous return from
venous dilation, and release of myocardial depressant substances.
Pulmonary dysfunction
Endothelial injury in the pulmonary vasculature leads to disturbed capillary
blood flow and enhanced microvascular permeability, resulting in interstitial
and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation
initiates and amplifies the injury to alveolar capillary membrane. ARDS is a
frequent manifestation of these effects. As many as 40% of patients with severe
sepsis develop acute lung injury.
Acute lung injury is a spectrum of pulmonary dysfunction secondary to
parenchymal cellular damage characterized by endothelial cell injury and
destruction, deposition of platelet and leukocyte aggregates, destruction of
type I alveolar pneumocytes, an acute inflammatory response through all the
phases of injury, and repair and hyperplasia of type II pneumocytes. The
migration of macrophages and neutrophils into the interstitium and alveoli
produces many different mediators, which contribute to the alveolar and
epithelial cell damage.
The acute lung injury may be reversible at an early stage, but, in many
cases, the host response is uncontrolled, and the acute lung injury progresses
to ARDS. Continued infiltration occurs with neutrophils and mononuclear cells,
lymphocytes, and fibroblasts. An alveolar inflammatory exudate persists, and
type II pneumocyte proliferation is evident. If this process can be halted,
complete resolution may occur. In other patients, a progressive respiratory
failure and pulmonary fibrosis develop. The late stage of ARDS is characterized
by an aggressive repair process, infiltration with an excess number of
fibroblasts, and synthesis of the extracellular matrix (ECM) protein, including
collagen. Subsequent deposition of metrics in the alveolar wall impedes gas
exchange and results in a restrictive defect leading to irreversible respiratory
failure.
Gastrointestinal dysfunction and nutrition
The gastrointestinal tract may help to propagate the injury of sepsis.
Overgrowth of bacteria in the upper gastrointestinal tract may aspirate into the
lungs and produce nosocomial pneumonia. The gut's normal barrier function may be
affected, thereby allowing translocation of bacteria and endotoxin into the
systemic circulation and extending the septic response. Septic shock usually
causes ileus, and the use of narcotics and sedatives delays the institution of
enteral feeding. The optimal level of nutritional intake is interfered with in
the face of high protein and energy requirements.
Liver dysfunction
By virtue of the liver's role in the host defense, the abnormal synthetic
functions caused by liver dysfunction can contribute to both the initiation and
progression of sepsis. The reticuloendothelial system of the liver acts as a
first line of defense in clearing bacteria and their products; liver dysfunction
leads to a spillover of these products into the systemic circulation.
Renal dysfunction
Sepsis often is accompanied by acute renal failure caused by acute tubular
necrosis. The mechanism is by systemic hypotension, direct renal
vasoconstriction, release of cytokines (eg, TNF), and activations of neutrophils
by endotoxins and other peptides, which contribute to renal injury.
Central nervous system dysfunction
Involvement of the central nervous system (CNS) in sepsis produces
encephalopathy and peripheral neuropathy. The pathogeneses is poorly defined.
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Mechanisms of organ dysfunction and injury
The precise mechanisms of cell injury and resulting organ dysfunction in
patients with sepsis are not understood fully. Multiorgan dysfunction syndrome
is associated with widespread endothelial and parenchymal cell injury because of
the falling proposed mechanisms.
Hypoxic hypoxia
The septic circulatory lesion disrupts tissue oxygenation, alters the
metabolic regulation of tissue oxygen delivery, and contributes to organ
dysfunction. Microvascular and endothelial abnormalities contribute to the
septic microcirculatory defect in sepsis. The reactive oxygen sepsis, lytic
enzymes, vasoactive substances (nitric oxide), and endothelial growth factors
lead to microcirculatory injury, which is compounded by the inability of the
erythrocytes to navigate the septic microcirculation.
Direct cytotoxicity
The endotoxin, TNF-alpha, and nitric oxide may cause damage to mitochondrial
electron transport, leading to disordered energy metabolism. This is called
cytopathic or histotoxic anoxia, an inability to use oxygen even when present.
Apoptosis
Apoptosis (programmed cell death) is the principal mechanism by which
dysfunctional cells normally are eliminated. The proinflammatory cytokines may
delay apoptosis in activated macrophages and neutrophils, but other tissues,
such as the gut epithelium, may undergo accelerated apoptosis. Therefore,
derangement of apoptosis plays a critical role in tissue injury of patients with
sepsis.
Immunosuppression
The interaction between proinflammatory and anti-inflammatory mediators may
lead to an imbalance and inflammatory reaction, immunodeficiency may
predominate, or both may be present.
Coagulopathy
Subclinical coagulopathy signified by mild elevation of the thrombin or
activated partial thromboplastin time (aPTT) or a moderate reduction in platelet
count is extremely common, but overt DIC is rare. Coagulopathy is caused by
deficiencies of coagulation system proteins, including protein C, antithrombin
3, and tissue factor inhibitors.
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Characteristics of sepsis that influence outcomes
Clinical characteristics that relate to the severity of sepsis include the
following:
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- An abnormal host response to infection
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- Site and type of infection
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- Timing and type of antimicrobial therapy
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- Offending organism
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- Development of shock
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- Any underlying disease
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- Patient's long-term health condition
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- Location of the patient at the time of septic shock
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Frequency:
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- In the US: Since the 1930s, studies have shown an
increasing incidence of sepsis. In 1 study, the incidence of bacteremic sepsis
(both gram-positive and gram-negative sepsis) increased from 3.8 cases per
1000 admissions in 1970 to 8.7 cases per 1000 admissions in 1987. The
incidences of nosocomial blood stream infection in 1 institution from
1980-1992 increased from 6.7 to 18.4 cases per 1000 discharges. The increase
in the number of patients who are immunocompromised and an increasing use of
invasive diagnostic and therapeutic devices predisposing to infection are
major reasons for the increase in incidences of sepsis.
The incidence of sepsis syndrome and septic shock in patients admitted to a
university hospital was reportedly 13.6 and 4.6 cases per 1000 persons,
respectively. In the United States, 200,000 cases of septic shock and 100,000
deaths per year occur from this disease.
A recently published article reported the incidence, cost, and outcome of
severe sepsis in the United States. Analysis of a large sample from the major
centres reported the incidence of severe sepsis as 3 cases per 1000
population, and 2.26 cases per 100 hospital discharges. Out of these cases,
51.1% received intensive care admission, an additional 17.3% were cared for in
intermediate care or coronary care unit. Incidence ranged from 0.2 cases per
1000 admissions in children to 26.2 cases per 1000 admissions in individuals
older than 85 years. The mortality rate was 28.6% and ranged from 10% in
children to 38.4% in elderly people. Severe sepsis resulted in an average cost
of $ 2200 per case, with an annual total cost of $16.7 billion nationally
(Angus, 2001).
- Internationally: A Dutch surveillance study reported that
1.36 cases per 100 hospital admissions were secondary to severe sepsis.
Mortality/Morbidity: The mortality rate in patients with
sepsis varies in the reported series from 21.6-50.8%. Over the last decade,
mortality rates seem to have decreased. In some studies, the mortality rate
specifically caused by the septic episode itself is specified and is 14.3-20%.
Sex: Most studies of septic shock report a male
preponderance. The percentage of male patients varies from 52-66%.
Age: Sepsis and septic shock occur at all ages but most
often in elderly patients. At present, most sepsis episodes are observed in
patients older than 60 years. Advanced age is a risk factor for acquiring
nosocomial blood stream infection in the development of severe forms of sepsis.
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CLINICAL |
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History: The constitutional
symptoms of sepsis usually are nonspecific and include fever, chills, fatigue,
malaise, anxiety, or confusion. These symptoms are not pathognomonic for
infection and may be observed in a wide variety of noninfectious inflammatory
conditions; they may be absent in serious infections, especially in elderly
individuals.
- Sepsis or septic shock is systemic inflammatory response secondary to a
documented infection. Consequently, sepsis is a continuum of detrimental host
responses to infection that ranges from sepsis to septic shock and MODS. The
specific clinical features depend on where the patient falls on that
continuum. The SIRS is defined by the presence of 2 or more of the following:
- Temperature greater than 38°C or less than 36°C
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- Heart rate greater than 90
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- Respiratory rate greater than 20 per minute
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- WBC count more than 12,000/mm3, less than 4000/mm3,
or more than 10% bands
- Fever is a common feature of patients with sepsis. The hypothalamus resets
so that heat production and heat loss are balanced in favor of a higher
temperature. Fever may be absent in elderly patients or patients who are
immunosuppressed.
- Chills are a secondary symptom associated with fever, which is a
consequence of increased muscular activity that produces heat and raises the
body temperature.
- Sweating occurs when the hypothalamus returns to its normal set point and
senses the higher body temperature, stimulating perspiration to evaporate
excess body heat.
- Alteration in mental function often occurs. Mild disorientation or
confusion is especially common in elderly individuals. Apprehension, anxiety,
agitation, and, eventually, coma are manifestations of severe sepsis. The
exact cause of metabolic encephalopathy is not known; alteration in amino acid
metabolism may play a role.
- Hyperventilation with respiratory alkalosis is a common feature of
patients with sepsis secondary to stimulation of the medullary respiratory
center by endotoxins and other inflammatory mediators.
- The localizing symptoms referable to organ systems may provide useful
clues to the etiology of sepsis and are as follows:
- Head and neck infections - Earache, sore throat, sinus pain, or swollen
lymph glands
- Chest and pulmonary infections - Cough (especially if productive),
pleuritic chest pain, and dyspnea
- Abdominal and GI infections - Abdominal pain, nausea, vomiting, and
diarrhea
- Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or
urethral discharge, and urinary frequency and urgency
- Bone and soft tissue infections - Localized limb pain or tenderness,
focal erythema, edema, and swollen joint
Physical: The physical examination should assess the general
condition of the patient. An acutely ill, flushed, and toxic appearance is
observed universally in patients with serious infections.
- Examine vital signs, and observe for signs of hypoperfusion.
- Carefully examine the patient for evidence of localized infection.
- Ensure that the patient's body temperature is measured accurately and that
rectal temperatures are obtained. Oral and tympanic temperatures are not
always reliable.
- Fever may be absent, but patients generally have tachypnea and
tachycardia.
- Observe patients for systemic signs of inadequate tissue perfusion. In the
early stages of sepsis, cardiac output is well maintained or even increased.
The vasodilation may result in warm skin, warm extremities, and normal
capillary refill (warm shock). As sepsis progresses, stroke volume and cardiac
output fall. The patients begin to manifest the following signs of poor
perfusion: cool skin, cool extremities, and delayed capillary refill (cold
shock).
- The following physical signs help to localize the source of an infection:
- CNS infection - Profound depression in mental status and signs of
meningismus (neck stiffness)
- Head and neck infections - Inflamed or swollen tympanic membranes, sinus
tenderness, pharyngeal erythema and exudates, inspiratory stridor, and
cervical lymphadenopathy
- Chest and pulmonary infections - Dullness on percussion, bronchial
breath sounds, and localized crackles
- Cardiac infections - New regurgitant valvular murmur
- Abdominal and GI infections - Abdominal distention, localized
tenderness, guarding or rebound tenderness, and rectal tenderness or
swelling
- Pelvic and genitourinary infections - Costovertebral angle tenderness,
pelvic tenderness, pain on cervical motion, and adnexal tenderness
- Bone and soft tissue infections - Focal erythema, edema, tenderness,
crepitus in necrotizing infections, and joint effusion
- Skin infections - Petechiae, purpura, erythema, ulceration, and bullous
formation
Causes: Most patients who develop sepsis and septic shock
have underlying circumstances that interfere with the local or systemic host
defense mechanisms. The most common disease states predisposing to sepsis are
malignancies, diabetes mellitus, chronic liver disease, chronic renal failure,
and the use of immunosuppressive agents. In addition, sepsis also is a common
complication after major surgery, trauma, and extensive burns.
- In most patients with sepsis, a source of infection can be identified,
with the exception of patients who are immunocompromised with neutropenia,
where an obvious source of infection often is not found.
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- Respiratory tract infection and urinary tract infection are the most
frequent causes of sepsis, followed by abdominal and soft tissue infections.
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- The use of intravascular devices is a notorious cause of nosocomially-acquired
sepsis.
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- Multiple sites of infection may occur in 6-15% of patients.
- Microorganisms: Prior to the introduction of antibiotics in clinical
practice, gram-positive bacteria were the principal organisms causing sepsis.
More recently, gram-negative bacteria have become the key pathogens causing
severe sepsis and septic shock. The following is a list of pathogens that can
infect individual organ systems and lead to severe sepsis and septic shock:
- Lower respiratory tract infections are the cause of septic shock in 25%
of patients. The following are common pathogens:
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- Streptococcus pneumoniae
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- Klebsiella pneumoniae
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- Staphylococcus aureus
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- Escherichia coli
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- Legionella species
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- Haemophilus species
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- Anaerobes
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- Gram-negative bacteria
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- Fungi
- Urinary tract infections are the cause of septic shock in 25% of
patients, and the following are the common pathogens:
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- E coli
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- Proteus species
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- Klebsiella species
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- Pseudomonas species
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- Enterobacter species
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- Serratia species
- Soft tissue infections are the cause of septic shock in 15% of patients,
and the following are the common pathogens:
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- S aureus
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- Staphylococcus epidermidis
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- Streptococci
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- Clostridia
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- Gram-negative bacteria
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- Anaerobes
- GI tract infections are the cause of septic shock in 15% all patients,
and the following are the common pathogens:
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- E coli
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- Streptococcus faecalis
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- Bacteroides fragilis
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- Acinetobacter species
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- Pseudomonas species
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- Enterobacter species
¡@
- Salmonella species
- Infections of the male and female reproductive systems are the cause of
septic shock in 10% of patients, and the following are the common pathogens:
¡@
- Neisseria gonorrhoeae
¡@
- Gram-negative bacteria
¡@
- Gram-negative bacteria
¡@
- Streptococci
¡@
- Anaerobes
- Foreign bodies leading to infections are the cause of septic shock in 5%
of patients, and S aureus, S epidermidis, and fungi/yeasts (Candida
species) are the common pathogens.
¡@
- Miscellaneous infections are the cause of septic shock in 5% of
patients, and Neisseria meningitidis is the common pathogen.
- Anaerobic pathogens are becoming less important as a cause of sepsis. In
one institution, the incidence of anaerobic bacteremia declined by 45% over a
15-year period.
¡@
- Fungal infections are the cause of sepsis in 0.8-10.2% of patients with
sepsis, and their incidence appears to be increasing.
- Polymicrobial sepsis has become a more prevalent cause of sepsis; the
incidence is 5.6-18.4%. The patients with neutropenia particularly are at high
risk for polymicrobial infections.
- Risk factors for severe sepsis and septic shock
- Extremes of age (<10 y and >70 y)
- Primary diseases
¡@
- Liver cirrhosis
¡@
- Alcoholism
¡@
- Diabetes mellitus
¡@
- Cardiopulmonary diseases
¡@
- Solid malignancy
¡@
- Hematologic malignancy
- Immunosuppression
¡@
- Neutropenia
¡@
- Immunosuppressive therapy
¡@
- Corticosteroid therapy
¡@
- Intravenous drug abuse
¡@
- Compliment deficiencies
¡@
- Asplenia
- Major surgery, trauma, burns
- Invasive procedures
¡@
- Catheters
¡@
- Intravascular devices
¡@
- Prosthetic devices
¡@
- Hemodialysis and peritoneal dialysis catheters
¡@
- Endotracheal tubes
- Prior antibiotic treatment
- Prolonged hospitalization
- Other factors - Childbirth, abortion, and malnutrition
|
DIFFERENTIALS |
¡@ |
Acute Renal Failure
Adrenal Crisis
Anaphylaxis
Cardiogenic Shock
Diabetic Ketoacidosis
Disseminated Intravascular
Coagulation
Heat Stroke
Hyperthyroidism
Myocardial Infarction
Myocardial Rupture
Neuroleptic Malignant
Syndrome
Pulmonary Embolism
Sepsis, Bacterial
Shock and Pregnancy
Shock, Distributive
Shock, Hemorrhagic
Systemic Inflammatory
Response Syndrome
Toxicity, Salicylate
¡@
Other Problems to be Considered:
Approach to the initial clinical evaluation of a patient in shock
Any patient presenting with shock must have an early working diagnosis, an
approach to urgent resuscitation, and, then, confirmation of the working
diagnosis.
Shock is identified in most patients by hypotension and inadequate organ
perfusion, which may be caused by either low cardiac output or low systemic
vascular resistance. Circulatory shock can be subdivided into 4 distinct classes
on the basis of an underlying mechanism and characteristic hemodynamics. These
classes of shock should be considered and systemically differentiated before
establishing a definitive diagnosis of septic shock.
Hypovolemic shock: Hypovolemic shock results from the loss of blood volume
caused by such conditions as GI bleeding, extravasation of plasma, major
surgery, trauma, and severe burns. The patient demonstrates tachycardia, cool
clammy extremities, hypotension, dry skin and mucus membranes, and poor turgor.
Obstructive shock: Obstructive shock results from impedance of circulation by an
intrinsic or extrinsic obstruction. Pulmonary embolism and pericardial tamponade
both result in obstructive shock.
Distributive shock: Distributive shock is caused by such conditions as direct
arteriovenous shunting and is characterized by decreased resistance or increased
venous capacity from the vasomotor dysfunction. These patients have high cardiac
output, hypotension, large pulse pressure, a low diastolic pressure, and warm
extremities with a good capillary refill. These findings on physical examination
strongly suggest a working diagnosis of septic shock.
Cardiogenic shock: Cardiogenic shock is characterized by primary myocardial
dysfunction resulting in the inability of the heart to maintain adequate cardiac
output. These patients demonstrate clinical signs of low cardiac output, while
evidence exists of adequate intravascular volume. The patients have cool clammy
extremities, poor capillary refill, tachycardia, narrow pulse pressure, and a
low urine output.
|
WORKUP |
¡@ |
Lab Studies:
¡@
- An adequate hemoglobin concentration is necessary to ensure adequate
oxygen delivery in patients with shock. Ensure that the hemoglobin is
maintained at a level of 8 g/dL.
- Platelets, an acute phase reactant, usually increase at the onset of any
serious stress. However, the platelet count will fall with persistent
sepsis, and DIC may develop.
- The WBC count and the white cell differential count may predict the
existence of a bacterial infection. In adults who are febrile, a WBC count
of greater than 15,000/m3 or a neutrophil band count of greater
than 1500/mm3 is associated with a high likelihood of bacterial
infection.
- White counts of greater than 50,000/mL or less than 300/mL are
associated with significantly decreased rates of survival.
- At regular intervals, obtain metabolic assessment with serum
electrolytes, including magnesium, calcium, phosphate, and glucose.
- Assess renal and hepatic function with the following:
¡@
- Serum creatinine
¡@
- BUN
¡@
- Bilirubin
¡@
- Alkaline phosphate
¡@
- Alanine aminotransferase (ALT)
¡@
- Aspartate aminotransferase (AST)
¡@
- Albumin
- ABG: Measure serum lactate to provide an assessment of tissue
hypoperfusion. Elevated serum lactate indicates that significant tissue
hypoperfusion exists with the shift from aerobic to anaerobic metabolism.
The higher the serum lactate, the worse the degree of shock and the higher
the mortality rate.
- Assess the coagulation status with prothrombin time (PT) and aPTT.
Patients with clinical evidence of a coagulopathy require additional tests
to detect the presence of DIC.
- Blood cultures: The blood culture is the primary means for the diagnosis
for intravascular infections (eg, endocarditis) and infections of indwelling
intravascular devices. The individuals at high risk for endocarditis are
intravenous (IV) drug abusers and patients with prosthetic heart valves.
- The patients at risk for bacteremia include adults who are febrile with
an elevated WBC count or neutrophil band count, elderly patients who are
febrile, and patients who are febrile with neutropenia. These populations
have a 20-30% incidence of bacteremia.
- The incidence of bacteremia increases to at least 50% in patients with
sepsis and evidence of end-organ dysfunction.
- Perform a urinalysis and urine culture for every patient who is septic.
Urinary infection is a common source for sepsis, especially in elderly
individuals. Adults who are febrile without localizing symptoms or signs
have a 10-15% incidence of occult urinary tract infection.
- Obtain secretions or tissue for Gram stain and culture from the sites of
potential infection. The Gram stain is the only immediately available test
that can document the presence of bacterial infection and guide the choice
of initial antibiotic therapy.
Imaging Studies:
¡@
- Several imaging modalities are used to detect a clinically suspected focal
infection, the presence of a clinically occult focal infection, and a
complication of sepsis and septic shock.
- Obtain a chest radiograph in patients with sepsis because the clinical
examination is unreliable for the detection of pneumonia; especially in
elderly patients. Occult infiltrates can be detected by the routine use of
chest radiography in adults who are febrile without localizing symptoms or
signs and in patients who are febrile with neutropenia and without pulmonary
symptoms.
- The chest radiograph results may be normal in early ARDS. The typical
findings of noncardiogenic pulmonary edema are bilateral, hazy, symmetric
homogenous opacities, which may demonstrate air bronchograms. The margins of
pulmonary vessels become indistinct and obscured with disease progression. The
usual findings of metastatic pulmonary edema, such as Kerley A or B lines, are
not usually observed; a perihilar distribution of opacities is also absent.
Furthermore, other findings of cardiogenic pulmonary edema, such as
cardiomegaly, vascular redistribution and pleural effusions, also are not
present.
- With disease progression, the ground glass opacities change into
heterogeneous, linear or reticular infiltrates. Days to weeks later, either
persistent chronic fibrosis may develop or the chest radiograph appearance
becomes more normal. Periodic chest radiographs during the management of ARDS
are particularly important to diagnose barotrauma, adequate postioning of an
endotracheal tube and intravascular catheters, and occurrence of nosocomial
pneumonia.
- Acquire supine and upright or lateral decubitus abdominal films because
they may be useful when an intra-abdominal source of sepsis is suspected.
- Ultrasound is the imaging modality of choice when a biliary tract source
is thought to be the source of sepsis.
- Obesity or the presence of excessive intestinal gas markedly interferes
with abdominal imaging by ultrasonography; therefore, the CT scans are
preferred.
- The CT scan is the imaging modality of choice for excluding an
intra-abdominal abscess or the retroperitoneal source of infection.
- When clinical evidence exists of a deep soft tissue infection, such as
crepitus, bullae, hemorrhage, or foul smelling exudate, obtain a plain
radiograph. The presence of soft tissue gas often dictates surgical
exploration.
- Obtain a head CT scan in patients with evidence of increased intracranial
pressure (papilledema) and in patients thought to have focal mass lesions (eg,
focal defects, previous sinusitis or otitis, recent intracranial surgery).
- If bacterial meningitis is strongly suspected, then a lumbar puncture (LP)
should be performed without the delay of obtaining a CT scan. If the opening
pressure is elevated, then only enough cerebrospinal fluid (CSF) for culture
should be obtained.
Procedures:
¡@
- If a patient is thought to have meningitis or encephalitis, perform an LP
urgently. In patients with an acute fulminant presentation, a rapid onset of
septic shock, and a severe impairment of mental status, use this procedure to
rule out bacterial meningitis.
- Cardiac monitoring, noninvasive blood pressure monitoring, and pulse
oximetry are necessary because these patients often require intensive care
admission for invasive monitoring and support.
- Supplemental oxygen is provided during initial stabilization and
resuscitation.
- Ensure that all patients in septic shock receive adequate venous access
for volume resuscitation. A central venous line also can be used to monitor
central venous pressure to assess intravascular volume status.
- Use an indwelling urinary catheter to monitor urinary output, which is a
marker for adequate renal perfusion and cardiac output.
- Patients who develop septic shock require a right heart catheterization
with a pulmonary artery (Swan Ganz) catheter. This catheter provides an
accurate assessment of the volume status of a septic patient. The cardiac
output measurement can be obtained; furthermore, determination of mixed venous
oxygenation is helpful in determining the status of tissue oxygenation. The
right-sided cardiac catheterization will detect those patients (25%) with
sepsis and hypotension who have underlying congestive heart failure (usually
due to myocardial suppressant factor).
- Most patients with sepsis develop respiratory distress as a manifestation
of severe sepsis or septic shock. The lung injury is characterized
pathologically as diffuse alveolar damage and ranges from acute lung injury to
ARDS. These patients need intubation and mechanical ventilation for optimum
respiratory support.
Staging: Two well-defined forms of MODS of sepsis exist. In
either, the development of acute lung injury or ARDS is of key importance to the
natural history, although ARDS is the earliest manifestation in all cases.
- In the more common form of MODS, the lungs are the predominant, and often
the only, organ system affected until very late in the disease. These patients
most often present with primary pulmonary disorder (eg, pneumonia, aspiration,
lung contusion, near drowning, chronic obstructive pulmonary disease [COPD]
exacerbation, hemorrhage, pulmonary embolism). Progression of lung disease
occurs to meet the ARDS criteria. Pulmonary dysfunction may be accompanied by
encephalopathy or mild coagulopathy and persists for 2-3 weeks. At this time,
the patient either begins to recover or progresses to develop fulminant
dysfunction in other organ systems. Once another major organ dysfunction
occurs, these patients often do not survive.
|
TREATMENT |
¡@ |
Medical Care: The treatment of
patients with septic shock consists of the following 3 major goals: (1)
Resuscitate the patient from septic shock using supportive measures to correct
hypoxia, hypotension, and impaired tissue oxygenation. (2) Identify the source
of infection and treat with antimicrobial therapy, surgery, or both. (3)
Maintain adequate organ system function guided by cardiovascular monitoring and
interrupt the pathogenesis of multiorgan system dysfunction.
- General supportive care: Initial treatment includes support of respiratory
and circulatory function, supplemental oxygen, mechanical ventilation, and
volume infusion. Treatment beyond these supportive measures includes
antimicrobial therapy targeting the most likely pathogen, removal or drainage
of the infected foci, treatment of complications, and interventions to prevent
and treat effects of harmful host responses.
- Administer supplemental oxygen to any patients with sepsis who also have
hypoxemia or are in respiratory distress.
¡@
- If the patient's airway is not secure, the gas exchange or acid-base
balance is severely deranged, and if evidence of respiratory muscle fatigue
exists or if the patient appears markedly distressed, perform an
endotracheal intubation.
¡@
- Patients in septic shock generally require intubation and assisted
ventilation because respiratory failure either is present at the onset or
may develop during the course of the illness.
¡@
- Correction of shock state and abnormal tissue perfusion is the next step
in the treatment of patients with septic shock.
- Hemodynamic support of septic shock
¡@
- Shock refers to a state of inability to maintain adequate tissue
perfusion and oxygenation, ultimately causing cellular, and then organ
system, dysfunction. Therefore, the goals of hemodynamic therapy are
restoration and maintenance of adequate tissue perfusion to prevent multiple
organ dysfunction.
¡@
- Careful clinical and invasive monitoring is required for assessment of
global and regional perfusion. A mean arterial pressure (MAP) of less than
60 mm Hg or a decrease in MAP of 40 mm Hg from baseline defines shock at the
bedside.
¡@
- Elevation of the blood lactate level on serial measurements of lactate
can indicate inadequate tissue perfusion.
¡@
- Mixed venous oxyhemoglobin saturation serves as an indicator of the
balance between oxygen delivery and consumption. A decrease in maximal
venous oxygen (MVO2) can be secondary to decreased cardiac
output; however, maldistribution of blood flow in patients experiencing
septic shock may artificially elevate the MVO2 levels. An MVO2
of less than 65% generally indicates decreased tissue perfusion.
¡@
- Regional perfusion in patients with septic shock is evaluated by
adequacy of organ function. The evaluation includes evidence of myocardial
ischemia, renal dysfunction manifested by decreased urine output or
increased creatinine, CNS dysfunction indicated by a decreased level of
consciousness, hepatic injury shown by increased levels of transaminases,
splanchnic hypoperfusion manifested by stress ulceration, ileus, or
malabsorption.
¡@
- The hemodynamic support in septic shock is provided by restoring the
adequate circulating blood volume, and, if needed, optimizing the perfusion
pressure and cardiac function with vasoactive and inotropic support to
improve tissue oxygenation.
¡@
- Intravascular volume resuscitation
¡@
- Hypovolemia is an important factor contributing to shock and tissue
hypoxia; therefore, all patients with sepsis require supplemental fluids.
The amount and rate of infusion are guided by an assessment of the patient's
volume and cardiovascular status. Monitor patients for signs of volume
overload, such as dyspnea, elevated jugular venous pressure, crackles on
auscultation, and pulmonary edema on the chest radiograph. Improvement in
the patient's mental status, heart rate, MAP, capillary refill, and urine
output indicate adequate volume resuscitation.
¡@
- Large volumes of fluid infusions are required as initial therapy in
patients with septic shock. Administer fluid therapy with predetermined
boluses (500 mL or 10 mL/kg) titrated to the clinical end points of heart
rate, urine output, and blood pressure. Continue fluid resuscitation until
the clinical end points are reached or the pulmonary capillary wedge
pressure exceeds 18 mm Hg. The volume resuscitation can be achieved by
either crystalloid or colloid solutions. The crystalloid solutions are 0.9%
sodium chloride and lactated Ringer solution. The colloids are albumin,
dextrans, and pentastarch. Clinical trials have failed to show superiority
of either crystalloids or colloids as the resuscitation fluid of choice in
septic shock. However, 2-4 times more volume of crystalloids than colloids
are required, and crystalloids take a longer time to achieve the same end
points, whereas the colloid solutions are much more expensive.
¡@
- Data from several studies suggest that formation of pulmonary edema is
no different with crystalloids compared to colloids when the filling
pressures are maintained at a lower level. However, if the higher filling
pressures are required for maintenance of optimal hemodynamics, crystalloids
may increase extravascular fluid fluxes because of a decrease in plasma
oncotic pressure.
¡@
- In some patients, clinically assessing the response to volume infusion
may be difficult. By monitoring the response of the central venous pressure
or pulmonary artery occlusion pressure to fluid boluses, the physician can
assess such patients. A sustained rise in filling pressure of more than 5 mm
Hg after a volume is infused indicates that the compliance of the vascular
system is decreasing as further fluid is being infused. Such patients are
susceptible to volume overload, and further fluid should be administered
with care.
- Vasopressor supportive therapy
¡@
- If the patient does not respond to several liters of volume infusion
with isotonic crystalloid solution (usually 4 L or more) or evidence of
volume overload is present, the depressed cardiovascular system can be
stimulated by inotropic and vasoconstrictive agents. When proper fluid
resuscitation fails to restore hemodynamic stability and tissue perfusion,
initiate therapy with vasopressor agents. These agents are dopamine,
norepinephrine, epinephrine, and phenylephrine. These agents are
vasoconstricting drugs that maintain adequate blood pressure during
life-threatening hypotension and preserve perfusion pressure for optimizing
flow in various organs.
¡@
- The mean blood pressure required for adequate splanchnic and renal
perfusion (MAP of 60 or 65 mm Hg) is based on clinical indices of organ
function. Dopamine is the most commonly used agent for this purpose.
Treatment usually begins at a rate of 5-10 mcg/kg/min IV, and the infusion
is adjusted according to the blood pressure and other hemodynamic
parameters. Often, patients may require high doses of dopamine (as much as
20 mcg/kg/min). Presently, norepinephrine is the preferred drug because
dopamine is known to cause unfavorable flow distribution.
¡@
- If the patient remains hypotensive despite volume infusion and moderate
doses of dopamine, a direct vasoconstrictor (eg, norepinephrine) should be
started at a dose of 0.5 mcg/kg/min and titrated to maintain a MAP of 60 mm
Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally have
been avoided because of their adverse effects on cardiac output and renal
perfusion, data from animal and human studies reveal that norepinephrine can
reverse septic shock in patients unresponsive to volume and dopamine. These
patients require invasive hemodynamic monitoring with arterial lines and
pulmonary artery catheters. Vasopressors may cause more harm than good if
administered to patients whose inadequate intravascular volume is not
restored (ie, a patient "whose tank is not filled").
¡@
- The following is a brief review of the mechanism of action and utility of
drugs used for hemodynamic support of septic shock:
¡@
- Dopamine: A precursor of norepinephrine and epinephrine, dopamine has
varying effects according to the doses infused. A dose of less than 5
mcg/kg/min results in vasodilation of renal, mesenteric, and coronary beds.
At a dose of 5-10 mcg/kg/min, beta1-adrenergic effects induce an increase in
cardiac contractility and heart rate. At doses of about 10 mcg/kg/min,
alpha-adrenergic effects lead to arterial vasoconstriction and elevation in
blood pressure. Dopamine is effective in optimizing MAP in patients with
septic shock who remain hypotensive after volume resuscitation. The blood
pressure increases primarily as a result of inotropic effect and, thus, will
be useful in patients who have concomitant reduced cardiac function. The
undesirable effects are tachycardia, increased pulmonary shunting, potential
to decrease splanchnic perfusion, and increase in pulmonary arterial wedge
pressure.
¡@
- Norepinephrine
¡@
- This agent is a potent alpha-adrenergic agonist with minimal
beta-adrenergic agonist effects. Norepinephrine can increase blood
pressure successfully in patients with sepsis who remain hypotensive
following fluid resuscitation and dopamine. The dose of norepinephrine may
vary from 0.2-1.5 mcg/kg/min, and large doses as high as 3.3 mcg/kg/min
have been used because of the alpha-receptor down-regulation in sepsis.
¡@
- In patients with sepsis, indices of regional perfusion (eg, urine
flow) and lactate concentration have improved following norepinephrine
infusion. Two recent trials have shown that a significantly greater
proportion of patients treated with norepinephrine were resuscitated
successfully, as opposed to the patients treated with dopamine. Therefore,
norepinephrine should be used early and should not be withheld as a last
resort in patients with severe sepsis who are in shock.
¡@
- The concerns about compromising splanchnic tissue oxygenation have not
been proven; the studies have confirmed no deleterious effects on
splanchnic oxygen consumption and hepatic glucose production, provided
adequate cardiac output is maintained.
¡@
- Epinephrine: This agent can increase MAP by increasing cardiac index and
stroke volume, along with an increase in systemic vascular resistance and
heart rate. Epinephrine may increase oxygen delivery and oxygen consumption
and decreases the splanchnic blood flow. Administration of this agent is
associated with an increase in systemic and regional lactate concentrations.
The use of epinephrine is recommended only in patients who are unresponsive
to traditional agents. The undesirable effects are an increase in lactate
concentration, a potential to produce myocardial ischemia, development of
arrhythmias, and a reduction in splanchnic flow.
¡@
- Phenylephrine: This agent is a selective alpha1-adrenergic receptor
agonist that is used primarily in anesthesia to increase blood pressure.
Although studies are limited, phenylephrine increased MAP in patients who
were septic hypotensive with increased oxygen consumption. However, the
concern remains about its potential to reduce cardiac output and lower heart
rate in patients with sepsis. Phenylephrine may be a good choice when
tachyarrhythmias limit therapy with other vasopressors.
¡@
- Inotropic therapy: Although myocardial performance is altered during
sepsis and septic shock, cardiac output generally is maintained in patients
with volume-resuscitated sepsis. Data from the 1980s and 1990s suggest a
linear relationship between oxygen delivery and oxygen consumption
(pathologic supply dependency), indicating that the oxygen delivery likely
was insufficient to meet the metabolic needs of the patient. However, recent
investigators have challenged the concept of pathologic supply dependency,
suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation)
was not associated with improved patient outcome. Therefore, the role of
inotropic therapy is uncertain, unless the patient has inadequate cardiac
index, mean arterial pressure, mixed venous oxygen saturation, and urine
output despite adequate volume resuscitation and vasopressor therapy.
¡@
- Renal-dose dopamine: The use of renal-dose dopamine in patients
experiencing septic shock is a controversial issue. In the past, low-dose
dopamine has been used routinely in many institutions for its presumed renal
protective effects. Dopamine at a dose of 2-3 mcg/kg/min is known to
initiate diuresis by increasing renal blood flow in healthy animals and
volunteers. Multiple studies have not demonstrated a beneficial effect of
prophylactic or therapeutic low-dose dopamine administration in patients
with sepsis who are critically ill. Low-dose dopamine has not been shown to
protect the patient from developing acute renal failure, and scant data
exist that low-dose dopamine favorably alters the mesenteric perfusion;
therefore, this routine practice is not recommended. Aggressive
resuscitation of patients, maintenance of adequate perfusion pressure, and
avoiding excessive vasoconstriction are effective measures to preserve renal
function.
- Empirical antimicrobial therapy
¡@
- Initiate this therapy early in patients experiencing septic shock.
However, antibiotics have little effect on the clinical outcome for at least
24 hours. The selection of appropriate agents is based on the patient's
underlying host defenses, the potential sources of infection, and the most
likely culprit organisms. If the patient is "antibiotic experienced,"
strongly consider the use of an aminoglycoside rather than a quinolone or
cephalosporin for gram-negative coverage. Knowing the antibiotic resistance
patterns of both the hospital itself and its referral base (ie, nursing
homes) is important. Antibiotics must be broad-spectrum agents and must
cover gram-positive, gram-negative, and anaerobic bacteria because the
different classes of these organisms produce an identical clinical picture
of distributive shock.
¡@
- Administer the antibiotics parenterally, in doses adequate to achieve
bactericidal serum levels. Many studies find that the clinical improvement
correlates with the achievement of serum bactericidal levels rather than the
number of antibiotics administered.
¡@
- Include coverage directed against anaerobes in patients with
intra-abdominal or perineal infections. Antipseudomonal coverage is
indicated in patients with neutropenia or burns or in patients who acquired
sepsis while hospitalized. Patients who are immunocompetent usually can be
treated with a single drug with broad-spectrum coverage, such as a
third-generation cephalosporin. Patients who are immunocompromised typically
require dual broad-spectrum antibiotics with overlapping coverage. Within
these general guidelines, no single combination of antibiotics is clearly
superior to others.
- Experimental and other therapies include nonadrenergic vasopressors and
inotropes. The clinical utility of several of these agents remains unproven
despite several studies indicating their beneficial effect on hemodynamic
instability.
¡@
- Dopexamine: This agent has beta2-adrenergic and dopaminergic effects
without any alpha-adrenergic activity and is known to increase splanchnic
perfusion. A few small studies have shown that dopexamine increases cardiac
index and heart rate and decreases systemic vascular resistance in a
dose-dependent manner. The hepatic blood flow and gastric intramucosal pH
improve, but results are not reproducible consistently. This drug appears to
be promising for patients with sepsis and septic shock, but superiority over
the other drugs has not been demonstrated. Dopexamine continues to be an
experimental medication in the United States.
¡@
- Vasopressin: This agent may be useful in patients with refractory septic
shock; however, minimal studies have been conducted. In patients with septic
shock, infusion of 0.04 U/kg/min of vasopressin resulted in improved MAP
secondary to peripheral vasoconstriction.
¡@
- Phosphodiesterases inhibitors: Inamrinone (formerly amrinone) and
milrinone are inotropic agents with vasodilating properties, and each has a
long half-life. The mechanism of action occurs via phosphodiesterase
inhibition. These medications are beneficial in cardiac pump failure, but
their benefit in patients experiencing septic shock is not well established.
Furthermore, these agents have a propensity to worsen hypotension in
patients with septic shock.
¡@
- Nitric oxide inhibitor: This agent is a potent endogenous vasodilator.
Excessive nitric oxide production, because of the cytokines and other
mediators, induces vasodilation and hypotension in patients with sepsis.
Nitric oxide is synthesized from endogenous L-arginine by the enzyme nitric
oxide synthase. Inhibitors of nitric oxide synthase (N-monomethyl-l-arginine,
L-NMMA) in sepsis augment mean arterial pressure, decreased cardiac output,
and increased systemic vascular resistance. Inordinate mortality was the
cause of early termination of a randomized trial of nitric oxide synthase
inhibition with L-NMMA. The clinical benefit of this therapeutic approach in
patients with sepsis remains unproven.
¡@
- Recombinant human activated protein C
¡@
- The inflammatory mediators are known to cause activation of
coagulation inhibitors of fibrinolysis, thereby causing diffuse
endovascular injury, multiorgan dysfunction, and death. Activated protein
C is an endogenous protein that not only promotes fibrinolysis and
inhibits thrombosis and inflammation but also may modulate the coagulation
and inflammation of severe sepsis. Sepsis reduces the level of protein C
and inhibits conversion of protein C to activated protein C.
Administration of recombinant activated protein C inhibits thrombosis and
inflammation, promotes fibrinolysis, and modulates coagulation and
inflammation.
¡@
- A recent publication by the Recombinant Human Activated Protein C
Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated
that the administration of recombinant human activated protein C (drotrecogin-alfa,
activated) resulted in lower mortality rates (24.7% versus 30.8%) in the
treated group compared to placebo. Treatment with drotecogin-alfa,
activated was associated with reduction in the relative risk of death by
19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by
6.1%, (P=.005).
¡@
- Anti-inflammatory therapy: The rationale for anti-inflammatory therapy
is that blocking the production of inflammatory mediators may ameliorate the
deleterious host inflammatory response and, hence, may limit the tissue
injury.
¡@
- High-dose glucocorticoids: While theoretical and experimental animal
evidence exists for the use of large doses of corticosteroids in those with
severe sepsis and septic shock, all randomized human studies (except 1 from
1976) found that corticosteroids did not prevent the development of shock,
reverse the shock state, or improve the 14-day mortality rate. Therefore, no
support exists in the medical literature for the routine use of high doses
of corticosteroids in patients with sepsis or septic shock. A meta-analysis
of 10 prospective, randomized, controlled trials of glucocorticoid use did
not report any benefit from corticosteroids. Therefore, high-dose
corticosteroids should not be used in patients with severe sepsis or septic
shock.
¡@
- Stress-dose glucocorticoids: Recent trials (Briegel, 1999; Cartlet,
1999) demonstrated positive results of stress-dose administration of
corticosteroids in patients with severe and refractory shock. While further
confirmatory studies are awaited, stress-dose steroid coverage should be
provided to patients who have the possibility of adrenal suppression.
¡@
- Ibuprofen: Despite promising results in animal studies, the use of
ibuprofen has not been proven of any benefit in patients with septic shock.
¡@
- Antiendotoxin treatment: The insight that endotoxin, a
lipid-polysaccharide compound found in the cell wall of gram-negative
bacteria, plays a key role in initiating the humoral cascade observed in
septic shock led to the hypothesis that neutralizing the circulating
endotoxin with IV administration of an antiendotoxin antibody might be
beneficial. Several products have been developed and investigated by
carefully conducted human trials. To date, no proven benefit to these agents
has been observed. Other methods of extracorporeal elimination of endotoxin,
polyclonal antiendotoxin antibodies, or monoclonal antiendotoxin antibodies
showed neither improvement in short-term survival nor amelioration of sepsis
in humans with septic shock. Trials with some of these compounds are
ongoing, and, despite a tendency towards benefit, efficacy data are lacking.
¡@
- Anticytokine treatment: Serum levels of TNF and IL-1 are elevated in
patients with septic shock. Both produce hemodynamic effects that duplicate
those found in sepsis. Many studies indicate that both the mediators play
key roles in sepsis and septic shock, and some think that TNF may be the
central mediator in sepsis. As is the case with antiendotoxin antibodies,
antibodies to TNF or IL-1 were hypothesized to be useful in patients with
septic shock. However, anti-TNF or anti–IL-1 antibodies have yet to be shown
to improve the outcome in sepsis or septic shock. Cytokines are the major
mediators of inflammatory cascade. Antibodies or blocking medications
against TNF, interleukins, and their receptor blockers have been developed
and have undergone clinical trials. In 1997, Zeni conducted a meta-analysis
and selected 21 trials representing a total of 6429 patients. A small but
insignificant beneficial effect was demonstrated.
¡@
- Miscellaneous treatment: Several other experimental interventions and
therapies have undergone clinical trials for sepsis. Although several of
these may have shown benefit, no convincing evidence suggests that these
therapies are efficacious. A long list of these interventions or therapies
exists; the important ones include intravenous immunoglobulins, interferon
gamma, antithrombin-3 infusion, naloxone, pentoxifylline, growth hormone, G-CSF,
and hemofiltration or extracorporeal removal of endotoxins. None of these
agents was efficacious in properly designed controlled clinical trials.
Surgical Care: Patients with infected foci should be taken
to surgery after initial resuscitation and administration of antibiotics for
definitive surgical treatment. Little is gained by spending hours stabilizing
the patient while an infected focus persists.
Consultations:
- Patients who do not respond or who are in septic shock require an
intensive care unit facility for continuous monitoring and observation.
Consultation with a critical care physician or internist with expertise is
appropriate.
- Consultation with an appropriate surgeon should be sought for patients
with suspected or known infected foci, especially patients with a suspected
abdominal source. Some of these common foci of infection include
intra-abdominal sepsis (perforation, abscesses), empyema, mediastinitis,
cholangitis, pancreatic abscesses, pyelonephritis or renal abscess from
ureteric obstruction, infective endocarditis, septic arthritis, soft tissue
infection, and infected prosthetic devices.
|
MEDICATION |
¡@ |
Proven medical treatments for patients with septic
shock are restoration of intravascular volume, hemodynamic support, and
broad-spectrum empiric antibiotic coverage. Other medical therapies, while
theoretically attractive, do not reduce morbidity or mortality rates.
Drug Category: Vasopressors -- In
cardiovascular disorders, they are used for their alpha1 and beta1 properties.
They provide hemodynamic support in acute heart failure and shock.
Drug Name
¡@ |
Dopamine (Intropin) -- Stimulates both adrenergic and
dopaminergic receptors. Hemodynamic effect depends on the dose. Lower doses
stimulate mainly dopaminergic receptors that produce renal and mesenteric
vasodilation. Cardiac stimulation and renal vasodilation is produced by
higher doses. After initiating therapy, dose may be increased by 1-4
mcg/kg/min q10-30min until a satisfactory response is attained. Maintenance
doses <20 mcg/kg/min usually are satisfactory for 50% of the patients
treated. |
Adult Dose |
1-5 mcg/kg/min IV titrated according to hemodynamic
response; not to exceed 20 mcg/kg/min |
Pediatric Dose |
Administer as in adults |
Contraindications |
Documented hypersensitivity; pheochromocytoma;
ventricular fibrillation |
Interactions |
Phenytoin, alpha- and beta-adrenergic blockers, general
anesthesia, and MAOIs increase and prolong the effects of dopamine |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Monitor urine flow, cardiac output, pulmonary wedge
pressure, and blood pressure during the infusion; prior to infusion, correct
hypovolemia, monitor central venous pressure or left ventricular filling
pressure |
Drug Name
¡@ |
Epinephrine (Adrenalin) -- Used for hypotension
refractory to dopamine. Stimulates alpha- and beta-adrenergic receptors,
resulting in relaxation of bronchial smooth muscle, increased cardiac
output, and blood pressure. |
Adult Dose |
1 mcg/min IV titrated according to hemodynamic response;
typical dosage range is 1-10 mcg/min |
Pediatric Dose |
0.1-1 mcg/kg/min IV titrated according to hemodynamic
response |
Contraindications |
Documented hypersensitivity; cardiac arrhythmias;
angle-closure glaucoma; local anesthesia in areas such as fingers or toes
because vasoconstriction may produce sloughing of tissue; during labor (may
delay second stage of labor) |
Interactions |
Increases toxicity of beta- and alpha-blocking agents
and halogenated inhalational anesthetics |
Pregnancy |
C - Safety for use during pregnancy has not been
established. |
Precautions |
Caution in elderly patients, prostatic hypertrophy,
hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism,
and cerebrovascular insufficiency; rapid IV infusions may cause death from
cerebrovascular hemorrhage or cardiac arrhythmias |
Drug Name
¡@ |
Norepinephrine (Levophed) -- Used in protracted
hypotension following adequate fluid replacement. Stimulates beta1- and
alpha-adrenergic receptors, which in turn increases cardiac muscle
contractility and heart rate, as well as vasoconstriction. As a result,
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. |
Adult Dose |
0.05-2 mcg/kg/min IV titrated according to hemodynamic
response |
Pediatric Dose |
0.05-0.1 mcg/kg/min IV titrated according to hemodynamic
response; not to exceed 1-2 mcg/kg/min |
Contraindications |
Documented hypersensitivity; peripheral or mesenteric
vascular thrombosis because ischemia may be increased and the area of the
infarct extended |
Interactions |
Atropine sulfate may enhance the pressor response of
norepinephrine by blocking the reflex bradycardia caused by norepinephrine;
effects increase when administered concurrently with tricyclic
antidepressants, MAOIs, antihistamines, guanethidine, methyldopa, and ergot
alkaloids |
Pregnancy |
D - Unsafe in pregnancy |
Precautions |
Correct hypovolemia before administering norepinephrine;
extravasation may cause severe tissue necrosis; therefore, administer into
large vein; use with caution in occlusive vascular disease |
Drug Name
¡@ |
Vasopressin (Pitressin) -- Vasopressor and antidiuretic
hormone (ADH) activity. Increases water resorption at the distal renal
tubular epithelium (ADH effect). Promotes smooth muscle contraction
throughout the vascular bed of the renal tubular epithelium (vasopressor
effects). Vasoconstriction increased in splanchnic, portal, coronary,
cerebral, peripheral, pulmonary, and intrahepatic vessels. |
Adult Dose |
0.01-0.1 U/min IV titrated according to response |
Pediatric Dose |
Not established |
Contraindications |
Documented hypersensitivity; coronary artery disease |
Interactions |
Lithium, epinephrine, demeclocycline, heparin, and
alcohol may decrease vasopressin effects; conversely, chlorpropamide, urea,
fludrocortisone, and carbamazepine are known to potentiate vasopressin
effects |
Pregnancy |
B - Usually safe but benefits must outweigh the risks.
|
Precautions |
Use with caution in patients diagnosed with
cardiovascular disease, seizure disorders, nitrogen retention, asthma, or
migraine; excessive doses may result in hyponatremia |
¡@
Drug Category: Isotonic crystalloids --
Isotonic sodium chloride (normal saline [NS]) and lactated Ringer (LR) are
isotonic crystalloids, the standard IV fluid used for initial volume
resuscitation. They expand the intravascular and interstitial fluid spaces.
Typically, about 30% of administered isotonic fluid stays intravascular;
therefore, large quantities may be required to maintain adequate circulating
volume. Both fluids are isotonic and have equivalent volume restorative
properties. While some differences exist between metabolic changes observed with
the administration of large quantities of either fluid, for practical purposes
and in most situations, the differences are clinically irrelevant. No
demonstrable difference in hemodynamic effect, morbidity, or mortality exists
between resuscitation with either NS or RL.
Drug Name
¡@ |
Normal saline (NS, 0.9% NaCl) --
Restoration of interstitial and intravascular volume. |
Adult Dose |
Initial: 1-2 L IV, with reassessment of
hemodynamic response; amount required during the first few hours typically
is 4-5 L |
Pediatric Dose |
Initial: 20 mL/kg IV administered
rapidly over 20-30 min; amounts approaching 40 mL/kg may be required during
the first few hours; titrate to hemodynamic response |
Contraindications |
Potentially fatal additive edema in
brain or lungs; pulmonary edema may contribute to ARDS; hypernatremia |
Interactions |
May decrease levels of lithium when
administered concurrently |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Monitor cardiovascular and pulmonary
function; stop fluids when desired hemodynamic response is observed or
pulmonary edema develops; interstitial edema may occur; caution in
congestive heart failure, hypertension, edema, liver cirrhosis, and renal
insufficiency |
Drug Name
¡@ |
Lactated Ringer -- Restoration of
interstitial and intravascular volume. |
Adult Dose |
Initial: 1-2 L IV, with reassessment of
hemodynamic response; amount required during the first few hours typically
is 4-5 L |
Pediatric Dose |
Initial: 20 mL/kg IV administered
rapidly over 20-30 min; amounts approaching 40 mL/kg may be required during
the first few hours; titrate to hemodynamic response |
Contraindications |
Potentially fatal additive edema in
brain or lungs; pulmonary edema may lead to ARDS; hypernatremia |
Interactions |
May decrease levels of lithium when
administered concurrently |
Pregnancy |
C - Safety for use during pregnancy has
not been established. |
Precautions |
Monitor cardiovascular and pulmonary
function; stop fluids when the desired hemodynamic response is observed or
pulmonary edema develops; interstitial edema may occur; caution in
congestive heart failure, hypertension, edema, liver cirrhosis, and renal
insufficiency |
Drug Category: Colloids -- Used to provide
oncotic expansion of plasma volume. They expand plasma volume to a greater
degree than isotonic crystalloids and reduce the tendency of pulmonary and
cerebral edema. About 50% of the administered colloid stays intravascular.
Drug Name
¡@ |
Albumin (Buminate) -- Used for certain
types of shock or impending shock. Useful for plasma volume expansion and
maintenance of cardiac output. A solution of NS and 5% albumin is available
for volume resuscitation. Five percent solutions are indicated to expand
plasma volume; whereas, 25% solutions are indicated to raise oncotic
pressure. |
Adult Dose |
250-500 mL (12.5-25 g) IV of 5%
solution over 20-30 min, with reassessment of hemodynamic response; not to
exceed 250 g/48h |
Pediatric Dose |
4-5 mL/kg (200-250 mg/kg) IV of 5%
solution over 30 min, with reassessment of hemodynamic response; not to
exceed 6 g/kg/d |
Contraindications |
Documented hypersensitivity; severe
congestive heart failure; severe anemia; pulmonary edema; the protein load
of 5% albumin tends to exacerbate renal insufficiency, a potential
complication of septic shock; do not dilute albumin 25% with sterile water
for injection (produces hypotonic solution) because, if administered, may
result in life-threatening hemolysis and acute renal failure |
Interactions |
None reported |
Pregnancy |
C - Safety for use during pregnancy has
not been established. |
Precautions |
Caution in renal or hepatic failure;
may cause protein overload; rapid infusion may cause vascular overload or
hypotension; monitor for volume overload; caution in sodium restricted
patients; common adverse effects include CHF, hypotension, tachycardia,
fever, chills, and pulmonary edema |
Drug Category: Antibiotics -- Early treatment
with empiric antibiotics is the only other proven medical treatment in septic
shock. Use of broad-spectrum and/or multiple antibiotics provides the necessary
coverage. In children who are immunocompetent, monotherapy is possible with a
third-generation cephalosporin (eg, cefotaxime, ceftriaxone, ceftazidime). An
antipseudomonal penicillin or carbapenem is used as monotherapy for adults who
are immunocompetent. Penicillinase-resistant synthetic penicillins and a
third-generation cephalosporin are used for combination therapy in children.
Combination therapy in adults involves a third-generation cephalosporin plus
anaerobic coverage (ie, clindamycin, metronidazole) or a fluoroquinolone plus
clindamycin. All antibiotics should be administered IV initially.
Drug Name
¡@ |
Cefotaxime (Claforan) -- Used for
treatment of septicemia. Also used for treatment of gynecologic infections
caused by susceptible organisms. Third-generation cephalosporin with
enhanced gram-negative coverage, especially to E coli, Proteus,
and Klebsiella species. Has variable activity against
Pseudomonas species. |
Adult Dose |
1-2 g IV q4h; not to exceed 12 g/d |
Pediatric Dose |
50 mg/kg IV q8h |
Contraindications |
Documented hypersensitivity |
Interactions |
Probenecid may decrease cefotaxime
clearance, causing an increase in cefotaxime levels; furosemide and
aminoglycosides may increase nephrotoxicity when used concurrently with
cefotaxime |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Adjust dose in patients diagnosed with
severe renal impairment; associated with severe colitis |
Drug Name
¡@ |
Ceftriaxone (Rocephin) --
Third-generation cephalosporin with broad-spectrum, gram-negative activity.
Lower efficacy against gram-positive organisms. Higher efficacy against
resistant organisms. Used for increasing prevalence of penicillinase-producing
microorganisms. Inhibits bacterial cell wall synthesis by binding to 1 or
more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria,
while cell wall assembly is arrested. |
Adult Dose |
1 g IV q8-12h; not to exceed 4 g/d |
Pediatric Dose |
<45 kilograms: 50 mg/kg/d IV divided
q12h; not to exceed 2 g/d
>45 kilograms: Administer as in adults
|
Contraindications |
Documented hypersensitivity; do not use
in neonates with hyperbilirubinemia |
Interactions |
Probenecid may decrease clearance,
causing an increase in ceftriaxone levels; coadministration of ethacrynic
acid, furosemide, and aminoglycosides may increase nephrotoxicity |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Adjust dose in renal impairment;
caution in women who are breastfeeding; potential cross-allergy to
penicillin |
Drug Name
¡@ |
Ticarcillin and clavulanate (Timentin)
-- Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides
coverage against most gram-positive organisms (except variable coverage
against Staphylococcus epidermidis and no coverage against
methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative
organisms, and anaerobes. |
Adult Dose |
<60 kilograms: 75 mg/kg IV q6h
>60 kilograms: 3.1 g IV q4-6h
|
Pediatric Dose |
<60 kilograms: 75 mg/kg IV q6h |
Contraindications |
Documented hypersensitivity; severe
pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or
septic arthritis should not be treated with an oral penicillin during the
acute stage |
Interactions |
Tetracyclines may decrease the effects
of ticarcillin; high concentrations of ticarcillin in vivo or in vitro may
physically inactivate aminoglycosides; probenecid may increase penicillin
levels; synergistic effect when administered concurrently with
aminoglycosides |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Perform CBCs prior to initiation of
therapy and at least weekly during therapy; monitor for liver function
abnormalities by measuring AST and ALT during therapy; caution in patients
diagnosed with hepatic insufficiencies; perform urinalysis, BUN, and
creatinine determinations during therapy and adjust dose |
Drug Name
¡@ |
Piperacillin and tazobactam (Zosyn) --
Inhibits the biosynthesis of cell wall mucopeptide and is effective during
the stage of active multiplication. Has antipseudomonal activity. |
Adult Dose |
3.375 g IV q6h |
Pediatric Dose |
>6 months: 75 mg/kg IV q6h |
Contraindications |
Documented hypersensitivity; severe
pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or
septic arthritis should not be treated with an oral penicillin during the
acute stage |
Interactions |
Tetracyclines may decrease effects of
penicillins; high concentrations of piperacillin in vivo or in vitro may
physically inactivate aminoglycosides; synergistic effect when administered
concurrently with aminoglycosides; probenecid may increase serum penicillin
levels |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Perform CBCs prior to initiation of
therapy and at least weekly during therapy; monitor for liver function
abnormalities by measuring AST and ALT during therapy; urinalysis, BUN, and
creatinine determinations should be performed during therapy and adjust dose
if these values become elevated |
Drug Name
¡@ |
Imipenem and cilastatin (Primaxin) --
Carbapenem with activity against most gram-positive organisms (except MRSA),
gram-negative organisms, and anaerobes. Used for treatment of multiple
organism infections in which other agents do not have wide-spectrum coverage
or are contraindicated due to their potential for toxicity. |
Adult Dose |
500 mg IV q6h; not to exceed 4 g/d |
Pediatric Dose |
>3 months: 10-15 mg/kg IV q6h; not to
exceed 4 g/d for moderately susceptible organisms |
Contraindications |
Documented hypersensitivity |
Interactions |
When administered concurrently with
cyclosporine, the CNS adverse effects of both agents may be increased,
possibly because of additive or synergistic toxicity; when used concurrently
with ganciclovir, generalized seizures may occur, and it should not be used
concomitantly; probenecid may increase toxic potential |
Pregnancy |
C - Safety for use during pregnancy has
not been established. |
Precautions |
Adjust dose with impaired renal
function and in patients <70 kg; avoid in children <12 y due to CNS toxicity |
Drug Name
¡@ |
Meropenem (Merrem) -- Carbapenem with
slightly increased activity against gram-negative organisms and slightly
decreased activity against staphylococci and streptococci compared to
imipenem. Less likely to cause seizures and superior penetration of
blood-brain barrier compared to imipenem. |
Adult Dose |
1 g IV q8h |
Pediatric Dose |
>3 months: 40 mg/kg IV q8h; not to
exceed 6 g/d |
Contraindications |
Documented hypersensitivity |
Interactions |
Probenecid may inhibit the renal
excretion of meropenem, increasing meropenem levels |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Pseudomembranous colitis and
thrombocytopenia may occur, requiring discontinuation of meropenem;
cross-reactivity observed (50%) in patients with penicillin anaphylaxis
history; caution in seizures; adjust dose with renal dysfunction |
Drug Name
¡@ |
Clindamycin (Cleocin) -- Primarily used
for its activity against anaerobes. Has some activity against
Streptococcus species and MSSA. |
Adult Dose |
600-900 mg IV q8h; not to exceed 4.8
g/d |
Pediatric Dose |
5-10 mg/kg IV q8h; not to exceed 4.8
g/d |
Contraindications |
Documented hypersensitivity; regional
enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated
colitis |
Interactions |
Increases duration of neuromuscular
blockade induced by tubocurarine and pancuronium |
Pregnancy |
D - Unsafe in pregnancy |
Precautions |
Adjust dose in severe hepatic
dysfunction; no adjustment necessary in renal insufficiency; associated with
severe and possibly fatal colitis |
Drug Name
¡@ |
Metronidazole (Flagyl) -- Imidazole
ring-based antibiotic active against various anaerobic bacteria and
protozoa. Usually combined with other antimicrobial agents, except when used
for Clostridium difficile enterocolitis, in which monotherapy is
appropriate. |
Adult Dose |
Loading dose: 15 mg/kg IV over 1 h (1 g
IV for 70-kg adult)
Maintenance dose: 7.5 mg/kg IV over 1 h q6-8h (500 mg for a 70-kg adult),
initiated 6 h following loading dose; not to exceed 4 g/d
|
Pediatric Dose |
Administer as in adults; use dose based
on body weight |
Contraindications |
Documented hypersensitivity; first
trimester of pregnancy |
Interactions |
Potentiates the anticoagulant effect of
warfarin; agents that alter the hepatic CYP450 system also affect its
clearance; as a result, phenytoin and phenobarbital may decrease the
half-life of metronidazole; cimetidine may reduce metronidazole clearance
and increase its toxicity; metronidazole may decrease lithium and phenytoin
clearance, increasing their toxicity; disulfiramlike reaction may occur when
used concurrently with orally ingested ethanol (although the risk for most
patients is slight, exercise caution) |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Adjust dose in severe hepatic disease;
monitor patients for seizures and peripheral neuropathy; common adverse
effects include dizziness, headache, nausea, vomiting, and anorexia |
Drug Name
¡@ |
Ciprofloxacin (Cipro) --
Fluoroquinolone with variable activity against Streptococcus
species, activity against methicillin-sensitive S aureus and S
epidermidis, activity against most gram-negative organisms, and no
activity against anaerobes. Synthetic broad-spectrum antibacterial
compounds. Novel mechanism of action, targeting bacterial topoisomerase II
and IV, thus leading to a sudden cessation of DNA replication. Oral
bioavailability is near 100%. |
Adult Dose |
400 mg IV q12h |
Pediatric Dose |
10-15 mg/kg IV q12h |
Contraindications |
Documented hypersensitivity |
Interactions |
Antacids, iron salts, and zinc salts
may reduce serum levels; administer antacids 2-4 h before or after taking
fluoroquinolones; cimetidine and probenecid may increase levels of
fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin;
probenecid may increase ciprofloxacin serum concentrations; fluoroquinolones
may increase serum levels of theophylline, caffeine, cyclosporine, and
digoxin (monitor digoxin levels); may increase effects of anticoagulants
(monitor PT) |
Pregnancy |
C - Safety for use during pregnancy has
not been established. |
Precautions |
In prolonged therapy, perform periodic
evaluations of organ system functions (eg, renal, hepatic, hematopoietic);
adjust dose in renal function impairment; superinfections may occur with
prolonged or repeated antibiotic therapy; do not use in pediatric patients
as first-line agent due to cartilage damage in young animals; may cause CNS
toxicity |
|
FOLLOW-UP |
¡@ |
Further Inpatient Care:
¡@
- Maintaining adequate tissue oxygenation
- Patients with severe sepsis or septic shock have hypermetabolism,
maldistribution of blood flow, and, possibly, suboptimal oxygen delivery;
therefore, attempts at detecting and correcting tissue hypoxia must be made.
Lactic acidosis is an indication of either global ischemia (inadequate
oxygen delivery) or regional (organ-specific) ischemia. Calculation of pH in
the gastric mucosa by gastric tonometry may detect tissue hypoxia in the
splanchnic circulation, this technique has not been validated extensively
and is not available widely.
¡@
- Manipulation of oxygen delivery to deliver supraphysiologic oxygen to
the tissues with blood transfusion, fluid boluses, or use of inotropes has
not improved the outcome in patients who are critically ill. Hayes et al
(1994) reported a higher mortality rate in patients with sepsis who were
maintained on high levels of oxygen delivery. In patients with septic shock,
the inability to increase oxygen consumption and to decrease lactate levels
most likely is a consequence of impaired oxygen extraction or inability to
reverse anaerobic metabolism. Boosting oxygen delivery to supranormal levels
does not reverse these pathophysiologic mechanisms.
¡@
- A trial of increasing oxygen delivery is recommended in patients who
have evidence of tissue hypoxia. If augmentation of oxygen delivery is
associated with reduction in serum lactate levels and improved target organ
perfusion, these interventions may be continued. On the other hand, adequate
clinical parameters, such as a mean arterial pressure, normal cardiac index,
and adequate urine output, should be maintained irrespective of the concerns
about supply dependence.
- The major focus of resuscitation from septic shock is supporting cardiac
and respiratory functions. The other organ systems also may require attention
and support during this critical period.
- Temperature control: Fever generally requires no treatment, except in
patients with limited cardiovascular reserve, because of the increased
metabolic requirements. Antipyretic drugs and physical cooling methods, such
as sponging or cooling blankets, may be used to lower the patient's
temperature.
¡@
- Metabolic support: Patients with septic shock develop hyperglycemia and
electrolytes abnormalities. Serum glucose should be maintained in the
reference range with insulin infusion. Hypokalemia, hypomagnesemia, and
hypophosphatemia should be measured and corrected if deficient.
¡@
- Anemia and coagulopathy: Hemoglobin as low as 8.0 g/dL is well tolerated
and does not require transfusion unless the patient has poor cardiac reserve
or demonstrates evidence of myocardial ischemia. Thrombocytopenia and
coagulopathy are common in patients with sepsis and do not require
replacement with platelets or fresh frozen plasma, unless the patient
develops active clinical bleeding.
- Renal dysfunction: Urine output and renal function must be monitored
closely in all patients with sepsis. Any abnormalities should prompt
attention to adequacy of circulating blood volume, cardiac output, and blood
pressure; these should be corrected if inadequate.
- Nutritional support: Patients with septic shock generally have high
protein and energy requirements. Although a brief period (several days)
without nutrition is not going to cause deleterious effects, prolonged
starvation must be avoided. Enteral nutrition is preferred and should be
carried out unless the patient has recently had abdominal surgery.
Diminished bowel sounds should not prevent a trial of enteral nutrition,
although motility agents or the use of a small bowel feeding tube may be
necessary. The benefits of enteral nutrition are protection of gut mucosa,
avoiding translocation of organisms from the GI tract, lowering the
complication rate, and lowering cost. Early nutritional support is of
critical importance in patients with septic shock. The enteral route is
preferred, unless the patient has an ileus or other intestinal abnormality.
Gastroparesis commonly is observed, which can be treated with motility
agents or placement of a small bowel feeding tube.
¡@
- Glutamine, an essential amino acid influences the mucosal integrity of
the gastrointestinal tract. Insufficient levels of glutamine may occur from
starvation or lack of enteral feeding, a condition commonly observed with
total parenteral nutrition. Glutamine deficiency contributes to mucosal
atrophy, predisposing translocation of bacteria or endotoxin from the gut
lumen. Enteral nutrition with glutamine-containing formulas can prevent this
relapse of SIRS in patients on adequate therapy.
- Acute respiratory distress syndrome
- Acute lung injury or ARDS is a frequent complication of severe sepsis or
septic shock, occurring in as many as 40% of patients with severe sepsis
secondary to gram-negative infection. Acute lung injury is a spectrum of
pulmonary dysfunction secondary parenchymal cellular damage from multiple
etiologies. Acute lung injury and ARDS can be associated with clinical
disorders causing direct lung injury, such as gastric acid aspiration,
thoracic trauma, pneumonia, and near drowning, or indirect lung injury,
including severe sepsis, acute pancreatitis, drug overdose, reperfusion
injury, and severe nonthoracic trauma. Sepsis-associated ARDS carries the
abysmal prognosis and has the highest mortality rates.
- Definition: The American-European Consensus Conference on ARDS (Bernard,
1994) agreed upon the following definitions of acute lung injury and ARDS.
The criteria for acute lung injury include the following: (1) an oxygenation
abnormality with an arterial PaO2/FiO2 ratio less than
300, (2) bilateral opacities on chest radiograph compatible with pulmonary
edema, and (3) a pulmonary artery occlusion pressure less than 18 mm Hg or
no clinical evidence of left atrial hypertension if PaO2 is not
available. ARDS is a more severe form of acute lung injury and is defined
similarly except that PaO2/FiO2 ratio is 200 or less.
- ARDS has a reported incidence ranging from 1.5-8.4 cases per 100,000
population per year (Baughman, 1996). More recent studies report a higher
incidence 12.6 cases per 100,000 population per year for ARDS and 18.9 cases
per 100,000 population per year for acute lung injury. The mortality rate
from ARDS has been documented at approximately 50% in most studies.
¡@
- Clinical manifestations
¡@
- Acute lung injury and ARDS secondary to severe sepsis demonstrate the
manifestations of underlying sepsis and the associated multiple organ
dysfunction. Pulmonary manifestations include acute respiratory distress
and acute respiratory failure resulting from severe hypoxemia caused by
intrapulmonary shunting. Fever and leukocytosis may be present secondary
to the lung inflammation.
¡@
- The severity of ARDS may vary from mild lung injury to severe
respiratory failure. The onset of ARDS usually is within 12-48 hours of
the inciting event. The patients demonstrate severe dyspnea at rest,
tachypnea, and hypoxemia; anxiety and agitation also are present. A scheme
to grade the severity of lung injury, lung injury score has been proposed
(Murray, 1988). The lung injury score is calculated after evaluating the
severity of 4 components—the chest roentgenogram score, hypoxemia score,
PEEP score, and respiratory system compliance score. A lung injury score
of greater than 2.5 is associated with severe lung injury or ARDS.
¡@
- The frequency of ARDS in sepsis has been reported from 18-38%, the
highest with gram-negative sepsis, ranging from 18-25%. Sepsis and
multiorgan failure are the most common cause of death in ARDS patients.
Approximately 16% of patients with ARDS died from irreversible respiratory
failure. Most patients who improved, achieved maximal recovery by 6
months, the lung function improves to 80-90% of predicted values.
¡@
- Pathology of ARDS
¡@
- The central pathological finding in ARDS is severe injury to the
alveolocapillary unit. Following initial extravasation of intravascular
fluid, inflammation and fibrosis of pulmonary parenchyma develops into a
morphologic picture, termed diffuse alveolar damage (DAD). The clinical
and pathological evolution can be categorized into the following 3
overlapping phases (Katzenstein, 1986): (1) the exudative phase of edema
and hemorrhage, (2) the proliferative phase of organization and repair,
and (3) the fibrotic phase of end stage fibrosis.
¡@
- The exudative phase occurs in the first week and is dominated by
alveolar edema and hemorrhage. The other histological features include
dense eosinophilic hyaline membranes and disruption of the capillary
membranes. Necrosis of endothelial cells and type I pneumocytes occur,
along with leukoagglutination and deposition of platelet fibrin thrombi.
¡@
- The proliferative phase is prominent in the second and third week
following onset of ARDS but may begin as early as the third day.
Organization of the intra-alveolar and interstitial exudate, infiltration
with chronic inflammatory cells, parenchymal necrosis, and interstitial
myofibroblast reaction occur. Proliferation of type II cells and
fibroblasts, which convert the exudate to cellular granulation tissue,
occurs; excessive collagen deposition, transforming into fibrous tissue,
occurs.
¡@
- The fibrotic phase occurs by the third or fourth week of the onset,
though the process may begin in the first week. The collagenous fibrosis
completely remodels the lung, the air spaces are irregularly enlarged, and
alveolar duct fibrosis is apparent. Lung collagen deposition increases,
microcystic honeycomb formation, and traction bronchiectasis follows.
¡@
- Pathogenesis: The pathogenesis of sepsis-induced ARDS is a pulmonary
manifestation of SIRS. A complex interaction between humoral and cellular
mediators, inflammatory cytokines and chemokines, is involved in the
pathogenesis of ARDS. A direct or indirect injury to the endothelial and
epithelial cells of the lung increases alveolar capillary permeability,
causing ensuing alveolar edema. The edema fluid is protein rich, the ratio
of alveolar fluid edema to plasma is 0.75-1.0 compared with patients with
hydrostatic cardiogenic pulmonary edema, where the ratio is less than 0.65.
Injury to type II pneumocytes decreases surfactant production; furthermore,
the plasma proteins in alveolar fluid inactivate the surfactant previously
manufactured. These enhance the surface tension at the air-fluid interfaces,
producing diffuse microatelectasis.
¡@
- Management of sepsis-related ARDS
¡@
- The management of ARDS primarily is supportive; the pharmacological
and other innovative therapies have not proven to be very beneficial. The
general supportive management includes adequate treatment of underlying
sepsis with appropriate antibiotics and surgical management if indicated.
Appropriate fluid management to lower the intravascular volume without
affecting the cardiac output and organ perfusion may be beneficial. The
fluid manipulation often requires invasive hemodynamic monitoring. The
goals of mechanical ventilation include improvement in gas exchange,
reduction in work of breathing, avoiding oxygen toxicity, minimizing high
airway pressures, avoiding further lung damage, and allowing the injured
lung to heal.
¡@
- A lung protective and pressure-limited ventilatory strategy has been
shown to improve survival rates and lower rates of barotrauma. Current
recommendations are to use a tidal volume of 5-8 mL/kg, a longer
inspiratory time, and not to exceed a transpulmonary pressure of 30 cm H20.
Permissive hypercapnia may ensue but is tolerated, which may occur with
the use of lesser tidal volumes. The use of PEEP may reduce or prevent
ventilator-induced lung injury. Sufficient PEEP to recruit atelectatic
alveolar units and to increase lung volumes so that respiration happens on
the most compliant part of the pressure volume curve is recommended. In
clinical practice, this can be achieved by measuring plateau pressures and
calculation of lung compliance at different levels of PEEP. The use of
prone positioning and nitric oxide may prove to be beneficial in the short
term; these interventions have not been shown to improve survival rates.
¡@
- High-dose corticosteroids, although not useful in early management of
ARDS, have been reported to improve survival in patients who have
unresolving ARDS. In a study by Meduri et al (1998), prolonged
administration of methylprednisolone in patients with unresolving ARDS was
associated with improvement and reduced mortality. For the treatment group
versus the placebo group, the mortality rate for the treatment group was 0
(0%) of 16 versus 5 (62%) of 8 for the placebo group in the ICU. The rate
of infections, including pneumonia, was similar in both groups.
Transfer:
¡@
- Patients with sepsis initially are observed on the wards or in the
emergency department. After initial attempts at stabilization, transfer the
patient to the ICU for invasive monitoring and support.
Deterrence/Prevention:
¡@
- Patients with impaired host defense mechanisms are at a greatly increased
risk for developing sepsis.
¡@
- The main etiologies of impaired host defenses are as follows:
- Chemotherapeutic drugs
¡@
- Malignancy
¡@
- Severe trauma
¡@
- Burns
- Renal or hepatitic failure
- Ventilatory support and invasive catheters further worsen the risk of
infection. Avoiding the use of catheters or removing them as soon as possible
may prevent severe sepsis.
- Prophylactic antibiotics in the perioperative phase, particularly
following gastrointestinal surgery, may be beneficial.
- The use of topical antibiotics around invasive catheters and as part of
dressing for patients with burns is helpful.
- Maintenance of adequate nutrition, administration of pneumococcal vaccine
in patients who have had a splenectomy, and early enteral feeding are other
preventive measures.
- Prevention of sepsis with topical or systemic antibiotics is suggested for
high-risk patients. Use of nonabsorbable antibiotics in the stomach to prevent
translocation of bacteria and occurrence of bacteremia is a controversial
issue. Numerous trials have been performed over the years using either the
topical antibiotics alone or a combination of topical and systemic
antibiotics. A systemic review by Nathens (1997), presented no benefit in
medical patients but showed a reduced mortality rate in surgical trauma
patients. The beneficial effect was from a combination of systemic and topical
antibiotics, predominantly by reducing lower respiratory tract infections in
treated patients.
Complications:
¡@
- Acute lung injury leading to ARDS is a major complication of patients with
severe sepsis and septic shock. Incidence of ARDS is approximately 18% in
patients with septic shock.
- Acute renal failure occurs in 40-50% of patients with septic shock. Acute
renal failure complicates therapy and worsens the overall outcome.
- DIC occurs in 40% of patients with septic shock.
- Death occurs in 40-50% of patients with septic shock.
Prognosis:
¡@
- Several clinical trials have documented a mortality rate of 40-75% in
patients with septic shock. The poor prognostic factors are advanced age,
infection with a resistant organism, impaired host immune status, poor prior
functional status, and continued need for vasopressors past 24 hours.
Development of sequential organ failure, despite adequate supportive measures
and antimicrobial therapy, is a harbinger of poor outcome. The mortality rates
were 7% with SIRS, 16% with sepsis, 20% with severe sepsis, and 46% with
septic shock (Brun-Buisson, 2000).
- In 1995, a multicenter prospective study published by Brun-Buisson (1995)
reported a mortality rate of 56% during ICU stays and 59% during hospital
stays. Twenty-seven percent of all deaths occurred within 2 days of the onset
of severe sepsis, and 77% of all deaths occurred within the first 14 days. The
risk factors for early mortality in this study were higher severity of illness
score, the presence of 2 or more acute organ failures at the time of sepsis,
shock, and a low blood pH (<7.3).
|
MISCELLANEOUS |
¡@ |
Medical/Legal Pitfalls:
¡@
- Sepsis is the most common cause of shock in most ICUs and is a leading
cause of death.
- Recognition of septic shock requires features of systemic inflammatory
response (eg, mental changes; hyperventilation; distributive hemodynamics;
hyperthermia or hypothermia; reduced, elevated, or left shift of WBCs) in
addition to a potential source of infection.
- Patients in septic shock require immediate cardiorespiratory stabilization
with a large volume of fluids intravenously, infusion of vasoactive drugs,
and, often, endotracheal intubation and mechanical ventilation.
- Intravenous empirical antibiotic therapy directed at all potential
infectious sources should begin immediately.
- Infectious processes requiring drainage or debridement should be treated
surgically expeditiously, even though the patient does not appear stable,
because the patient may not improve without the emergent surgical treatment.
- The effects of drugs used to support hemodynamics of patients with sepsis
have adverse effects on splanchnic circulation; therefore, the ideal
hemodynamic therapy in these patients is not known. Following adequate fluid
resuscitation, therapy with dopamine may be initiated, followed by
norepinephrine when dopamine fails. The alternate approach is initiating
therapy with norepinephrine and using dobutamine if inotropic support is
needed.
- Manipulation of oxygen delivery by increasing cardiac index either has
shown no improvement or has worsened morbidity and mortality. Routine use of
hemodynamic drugs to improve cardiac output to supranormal is not recommended.
- Epinephrine use as a single agent is not recommended for patients with
septic shock. Epinephrine impairs splanchnic circulation and tissue perfusion.
- Lactic acidosis of septic shock usually causes anion gap metabolic
acidosis. Administration of bicarbonate therapy has the potential to worsen
intracellular acidosis. Correction of acidemia using sodium bicarbonate has
not improved hemodynamics in patients who are critically ill with increased
blood lactate. The above not withstanding, bicarbonate therapy has been used
for pH of less than 7.2 or bicarbonate of less than 9 mmol/L, although no data
to support this practice exist.
Special Concerns:
¡@
- A continuum of severity exists from sepsis to septic shock and multiorgan
failure. The clinical spectrum usually begins with infection that potentially
leads to sepsis and organ dysfunction. In one study, 2527 patients were
evaluated, 26% developed sepsis, 18% developed severe sepsis, and 4% developed
septic shock. The incidence of positive results on blood culture was 17% in
patients with sepsis and 69% in patients with septic shock.
- The pathogenesis of septic shock and multiorgan failure occurs from
mediators produced because of the host's immune response. Despite encouraging
data from animal studies, immunosuppressive agents, such as high-dose
corticosteroids, have not shown any benefit in humans.
- Recent research has focused on modifying the host response to sepsis by
infusion of antibody against gram-negative endotoxin, infusion of gamma
globulin, monoclonal antibodies against TNF-alpha, blockage of eicosanoid
production, blockade of IL-1 activity, and inhibition of nitric oxide synthase.
These approaches have demonstrated modest success in animal experimentation
but cannot be recommended for general use at this time.
- A septic patient admitted to the ICU should be monitored carefully to
prevent and treat the infectious complications. These events may perpetuate
the SIRS or trigger relapse of sepsis after the initial improvement. These
infectious complications include sinusitis, urinary tract infection,
intravascular catheter¡Vrelated infections, acalculous cholecystis, and
translocation of bacteria or endotoxin from gut lumen. As several of these
ailments fail to manifest clinically, a high index of suspicion is crucial for
early diagnosis and treatment.
|
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¡@ |
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