Multiple organ dysfunction syndrome Presence of progressive organ dysfunction in an
acutely ill patient, such that homeostasis cannot be
maintained without intervention.
MAP, mean arterial pressure; SOFA, Sequential Organ Failure Assessment.
Sequential Organ Failure Assessment Score
Bilirubin, mg/dL <1.2 1.2–1.9 2–5.9 6–11.9 >12
DA, dopamine; DOB, dobutamine; Epi, epinephrine; FiO2
, fraction of inspired oxygen; GCS, Glasgow Coma Scale;
MAP, mean arterial pressure; NE, norepinephrine; PaO2
, arterial partial pressure of oxygen.
aCatecholamine doses are expressed as mcg/kg/minute for at least 1 hour.
bGCS scores range from 3 to 15; higher score indicating better neurologic function.
Septic shock is characterized initially by a normal or high CO and a low SVR
(Table 17-3). Hypotension is caused by the low SVR and alterations in
macrovascular and microvascular tone, which result in maldistribution of blood flow
and volume. Changes in the microvasculature can lead to loss of normal
microvascular autoregulatory mechanisms, resulting in constriction of capillaries,
changes in cellular rheology, fibrin deposition, and neutrophil adherence. This causes
vascular “sludging” and, in some cases, arteriovenous shunts that bypass capillary
beds. Loss of intravascular fluid caused by increased vascular permeability and third
spacing of fluid further adds to hypovolemia.
In an effort to compensate for the
changes in volume and SVR, the body goes into a hyperdynamic state and increases
CO. Most patients exhibit myocardial dysfunction as manifested by decreased
myocardial compliance, reduced contractility, and ventricular dilation, but they
maintain a normal CO because of tachycardia and cardiac dilatation which increases
75 Although the cause of, and mechanism for, this abnormality is
not fully understood, it is not believed to be attributable to myocardial ischemia.
Rather, it is thought to be caused by one or more circulating inflammatory mediators,
late septic shock, the body is no longer able to compensate because of the cardiac
effects of the inflammatory mediators and resultant myocardial edema, thus resulting
in a decreased CO. The end product of this complicated pathway is cellular
ischemia, dysfunction, and eventually cellular death unless the chain of events is
The complex pathogenesis of sepsis is more fully understood now, but some of the
exact mechanisms are still not completely clear. The changes that take place during
sepsis are caused by the immunologic host response to infection, which involves
inflammatory (SIRS) and immunodepressive (compensatory anti-inflammatory
response) mediators that are present from the onset of the immune response.
The inflammatory stage of sepsis is initiated by an infection with a microorganism,
most commonly bacterial. Organisms can either enter the bloodstream directly
(producing positive blood cultures) or may indirectly elicit a systemic inflammatory
response by locally releasing their toxins or structural components at the site of
infection. The lipopolysaccharide endotoxin of gram-negative bacteria is the most
potent soluble product of bacteria that can initiate a response and is the most studied,
but other bacterial products can initiate the response, including exotoxins,
enterotoxins, peptidoglycans, and lipoteichoic acid from gram-positive organisms.
The binding of these toxins to cell receptors promotes proinflammatory cytokine
production, primarily TNF-α and interleukin-1 (IL-1). These toxins stimulate the
production and release of numerous endogenous mediators that are responsible for
the inflammatory consequences of sepsis. The cytokines act synergistically to directly
affect organ function and stimulate the release of other proinflammatory cytokines,
such as IL-6, IL-8, platelet-activating factor, complement, thromboxanes,
leukotrienes, prostaglandins, NO, and others.
The presence of these cytokines promotes inflammation and vascular endothelial
injury, but it also causes an overwhelming activation in coagulation. Thrombin has
potent proinflammatory and procoagulant activities, and its production is increased in
sepsis. The human body normally counteracts these effects by increasing fibrinolysis,
but the homeostatic mechanisms in the septic patient are dysfunctional. There are
decreases in the levels of protein C, plasminogen, and antithrombin III as well as
increased activity of plasminogen activator inhibitor-1 and thrombin-activatable
fibrinolysis inhibitor, endogenous agents that inhibit fibrinolysis.
coagulopathic state, which promotes formation of microvascular thrombi, leading to
hypoperfusion, ischemia, and, ultimately, organ failure. Multiple organ failure is
responsible for about half the deaths caused by septic shock.
The clinical features of sepsis are highly variable and depend on multiple factors:
site of infection, causative organism, degree of organ dysfunction, baseline patient
health status, and delay to initial treatment.
78 The working definition of sepsis
accounts for the presence of systemic manifestations of infection and organ
dysfunction, which may be subtle (Table 17-8). Serum biomarkers are the subject of
intense research as they could aid the early diagnosis of sepsis, guide treatment, and
of these biomarkers have high negative predictive values, but lack high specificity
and positive predictive value.
Characteristic laboratory findings include leukocytosis or leukopenia,
thrombocytopenia with or without coagulation abnormalities, and, often,
hyperbilirubinemia. These features are usually readily detectable and occur within
24 hours after bacteremia develops, particularly if gram-negative organisms cause
the bacteremia. In extremes of age (very young or very old) or in debilitated patients,
hypothermia can be present and positive findings may be limited to unexplained
hypotension, mental confusion, and hyperventilation.
Persons dying of septic shock often have a normal or elevated CO. Death within
the first week after the onset of sepsis occurs as a result of intractable hypotension
that is secondary to significantly depressed SVR. This causes extensive
maldistribution of blood flow in the microvasculature, with subsequent tissue
hypoxia and development of lactic acidosis. Death occurring beyond the first week
usually is caused by multiple organ failure that began during acute circulatory failure.
Severe, unresponsive hypotension as a result of a decreased CO occurs in a
subpopulation of patients with septic shock; cardiogenic shock becomes
superimposed on the distributive shock of sepsis, but this is a less common cause of
Clinical and Hemodynamic Features
exceedingly poor oral intake for several days prior to admission.
and right lower extremity below-the-knee amputation.
Physical findings include a temperature of 38.7°C, BP 95/60 mm Hg, pulse 120 beats/minute, and RR 28
Pertinent laboratory values are as follows:
ABG measurements on 2 L/minute nasal cannula (FiO2
following hemodynamic profile:
What hemodynamic and clinical features of E.B. are consistent with septic shock?
E.B. would not be classified in septic shock at this time because she has not been
adequately fluid resuscitated. Though, she would be classified as having sepsis
because of the manifestations of infection and organ dysfunction.
Hemodynamic signs consistent with sepsis include hypotension, tachycardia,
elevated CO, low SVR, and low PCWP. Although the absolute value for CO is high
or at the upper limits of the normal range, in septic shock it is inadequate to maintain
a BP that will perfuse the essential organs in the face of a decreased SVR, evidenced
. E.B. has a metabolic acidosis (pH 7.31, PaCO2 32 mm Hg,
− 16 mEq/L), indicating anaerobic metabolism and lactic acidosis most likely
caused by decreased perfusion, and a CO that is inadequate to meet the oxygen
Other features consistent with sepsis in E.B. include declining urine output
indicating decreased renal perfusion, hypoglycemia, a rising WBC count, and a
The management of septic shock is directed toward three primary areas: (a)
eradication of the source of infection, (b) hemodynamic support and control of tissue
hypoxia, and (c) inhibition or attenuation of the initiators and mediators of sepsis.
ERADICATING THE SOURCE OF INFECTION
shock? What are the potentialsources of infection in E.B.?
Systemic infection caused by either aerobic or anaerobic bacteria is the leading
cause of septic shock. Fungal, mycobacterial, rickettsial, protozoal, or viral
infections can also be encountered. Among sepsis syndromes caused by aerobic
bacteria, gram-negative organisms (e.g., Pseudomonas, Enterobacteriaceae, and
Acinetobacter, in decreasing order of frequency) are implicated slightly more often
than gram-positive bacteria (e.g., Staphylococcus aureus, Enterococcus,
Staphylococcus epidermidis, and Streptococcus, from highest to lowest frequency).
Even these trends vary, however, depending on the infection site. For example, when
an organism can actually be cultured in the blood, slightly more gram-positive
infections (35% to 40%) than gram-negative infections (30% to 35%) are found. In
non-bloodstream infections (e.g., respiratory tract, genitourinary system, and the
abdomen, in descending order of frequency) 40% to 45% can be attributed to gramnegative
organisms, and 20% to 25% are caused by gram-positive organisms.
Polymicrobial infections make up the next largest group, followed by fungi,
anaerobes, and others. In up to 33% of sepsis syndrome cases, no organisms can be
isolated. Careful consideration of the patient’s history and clinical presentation often
reveals the most likely cause.
Eradicating the source of infection involves the early administration of
antimicrobial therapy, and, if indicated, surgical drainage. The use of an appropriate
antibiotic regimen within 1 hour of the diagnosis of sepsis or septic shock is
associated with a significant increase in survival. Appropriate cultures should be
obtained before starting antibiotic therapy, unless this would result in a significant
(greater than 45 minutes) delay in therapy.
4 The selection of antibiotics should take
into account the presumed site of infection; whether the infection is community- or
health care-associated; recent invasive procedures, manipulations, or surgery; any
predisposing conditions; drug intolerances; and the likelihood of drug resistance.
Ideally, the primary source of infection can be determined and therapy specifically
tailored to the most likely organisms. If the source of infection is unclear, however,
early institution of broad-spectrum antibiotics against all likely pathogens is
generally recommended while awaiting culture results. Empiric broad-spectrum
therapy usually requires combinations of antimicrobials because of the increasing
frequency of polymicrobial infections and antimicrobial resistance. Even so, there
are no data demonstrating better outcomes with combination therapy over adequate
monotherapy, except in severely ill, septic patients with a high risk of death.
Empiric regimens must be determined by patient factors and broad enough to cover
all likely pathogens. Mortality for septic shock may be as much as fivefold higher
when an empiric regimen fails to cover the offending pathogen.
range of variables must be considered in the selection of empiric regimens (e.g.,
anatomic site of infection, pathogen prevalence, resistance patterns), a specific
regimen cannot be recommended for all episodes of sepsis or septic shock (see
Chapter 62, Principles of Infectious Diseases). Generally, empiric regimens target
gram-positive cocci, aerobic gram-negative bacilli, as well as anaerobes and include
(1) an anti-pseudomonal penicillin, third- or fourth-generation cephalosporin, or
carbapenem plus (2) vancomycin to cover methicillin-resistant Staphylococcus
aureus. Combination gram-negative coverage (e.g., aminoglycoside, fluoroquinolone)
is recommended for critically ill patients at risk of infection with difficult-to-treat,
multidrug-resistant pathogens, such as Pseudomonas and Acinetobacter spp.
Additional coverage should be considered based on the presence of other risk factors
(e.g., Candida species, atypical pathogens).
Individuals with diabetes are presumed to be at an increased risk of infection
because of multiple host factors, including hyperglycemia-induced
immunosuppression, vascular insufficiency, peripheral neuropathies, and
colonization with S. aureus and Candida species. The most likely potential sources of
sepsis in E.B. are a combination of skin and soft tissue infections. E.B. has a severe
diabetic foot infection involving her left heel with inflammation, purulence, and
systemic manifestations of infection. She also has a large stage III sacral decubitus
ulcer. A urinary tract infection and vulvovaginal candidiasis should be considered as
well because of her history of diabetes. Other sources of infection are less likely
based on her presentation. All IV catheters from the skilled nursing facility should be
Infected pressure ulcers and diabetic foot infections are usually polymicrobial
wounds. These infections should be treated with parenteral broad-spectrum
antibiotics to cover methicillin-sensitive and methicillin-resistant S. aureus,
Streptococcus spp., Enterobacteriaceae, Pseudomonas aeruginosa, and obligate
anaerobes (e.g., Peptostreptococcus, Peptococcus, Bacteroides fragilis, and
Clostridium perfringens). As such, empiric therapy should include vancomycin in
combination with one of the following: piperacillin–tazobactam, ceftazidime,
ceftaroline, cefepime, aztreonam, or a carbapenem. If aztreonam or a cephalosporin
is chosen then metronidazole or clindamycin should be considered to cover
anaerobic organisms, particularly for ischemic or necrotic wounds.
debridement, and wound dressing should accompany antibiotic therapy.
Antimicrobial therapy should be adjusted once cultures are finalized.
CASE 17-4, QUESTION 3: What are the immediate goals of therapy in E.B.? How can they be achieved
The goals in treating septic shock, in addition to eradicating the precipitating
infection, are to optimize ḊO2
to the tissues and to control abnormal use of oxygen
and anaerobic metabolism by reducing the tissue oxygen demand. Tissue injury is
widespread during sepsis, most likely because of vascular endothelial injury with
fluid extravasation and microthromboses, which decrease oxygen and substrate
utilization by the affected tissues. The mainstay of therapy is volume expansion to
increase intravascular volume, enhance CO, and ultimately delay associated
development of refractory tissue hypoxia.
Increasing CO with fluids will improve capillary circulation and tissue
oxygenation by maintaining sufficient intravascular volume. At least 30 mL/kg of IV
crystalloid fluid should be given within the first 3 hours of resuscitation.
not correct the hypoxia or if filling pressures are increased, the sequential addition of
vasopressors and inotropic agents is indicated. Blood transfusions should be used if
the Hgb is less than 7 g/dL unless there is an active source of bleeding, severe
hypoxemia, or a history of cardiac disease, in which case the Hgb value would be
4 Crystalloids (with electrolytes to correct imbalances)
should be initiated to maintain the CI goal as well as a MAP of 65 mm Hg. Although
MAP is not an absolute measure of blood flow to all vital organs, it is considered the
therapeutic end point that will sustain myocardial and cerebral perfusion. A higher
MAP could be considered in septic patients with a history of hypertension or those
who clinically improve with a higher BP.
1 After optimization with fluid therapy,
vasopressor and inotropic agents are indicated if the patient remains hypotensive
with a low CI or if signs of inadequate tissue perfusion persist.
The therapeutic goals used for hemodynamic resuscitation are controversial. The
issue is whether therapy should be directed to physiologic end points of tissue
perfusion or clinical end points, such as BP and urine output. The physiologic end
points include clearance of blood lactate concentrations, base deficit, SvO2
increased CO. Serum lactate concentrations may be elevated through various
mechanisms (e.g., tissue hypoxia, excessive beta-adrenergic stimulation, liver
association with a significantly reduced mortality rate compared with usual care.
Many institutions have developed “sepsis bundles” that incorporate these same
variables and therapeutic end points as early as possible in the treatment of sepsis.
Sepsis bundles often include many additional issues addressed in the Surviving
4 such as ventilatory support, initial choice of
antibiotics, glucose control, and stress ulcer prophylaxis.
One study by Rivers et al. combined physiologic and clinical end points of
resuscitation during the early stages of sepsis.
83 CVP, MAP, Hct, and ScvO 2 were
optimized during at least 6 hours of continuous care in the ED. This was compared to
conventional therapy that targeted only CVP, MAP, and urine output. In-hospital
mortality was significantly lower in the early goal-directed therapy
(EGDT) group (30.5% vs. 46.5%, p = 0.009). EGDT was adopted as the standard
of care in the treatment of sepsis and septic shock. However, there are several
limitations to the EGDT approach. As noted above, CVP is an unpredictable marker
38 and fluid overload is common after EGDT resuscitation.
Furthermore, the Hct target of 30% is unnecessarily high because transfusions of
PRBCs to achieve a Hgb above 7 g/dL do not increase ScvO2
could also be harmful if used to increase ScvO2
Several large, multicenter studies have shown no improvement in patient outcomes
using EGDT for severe sepsis and septic shock. Protocol-based resuscitation did not
improve in-hospital mortality among 1,341 patients in the ProCESS study.
ARISE and ProMISe studies, EGDT did not reduce all-cause mortality compared to
86,87 The mortality rates among the usual care groups from these trials
) were similar to the EGDT group in the Rivers et al.
study. These findings could be because of an improvement in our standard of care
over that time period, chiefly the early identification and treatment. Nonetheless, the
most recent Surviving Sepsis Campaign Guidelines
4 have departed from the EGDTguided resuscitation strategy from the Rivers study.
E.B. should receive fluid boluses to maintain perfusion with a MAP of at least 65
mm Hg. Reassessment of E.B.’s hemodynamic status should include a thorough
clinical examination as well as assessment of available physiologic variables (e.g.,
, RR, temperature, urine output) and measurements from her PA
catheter. A minimum of 30 mL/kg crystalloid fluid challenge is recommended within
the first 3 hours of resuscitation. Albumin may be substituted if large volumes of
crystalloids are required, but hydroxyethyl starches should be avoided because of an
increased risk of acute renal dysfunction and potential increased mortality.
Continued, excessive fluid challenges to increase preload in E.B. must be
approached cautiously because she has an enlarged heart on chest radiograph,
coronary artery disease, and multiple risk factors for heart failure. In addition,
patients in septic shock are susceptible to experiencing non-cardiogenic pulmonary
edema or ARDS, which can cause severe deterioration in pulmonary function. Fluid
boluses should be given with ongoing monitoring to determine the CVP and PCWP at
which CO is maximal. This approach will avoid excessive CVP and PCWP beyond
which CO is no longer increased, reducing potential pulmonary edema.
In summary, the immediate goal of therapy is to maximize ḊO2
resuscitation is the mainstay of therapy and improves ḊO2 by increasing CO;
however, inotropic and vasopressor agents are often required for additional
cardiovascular support. A favorable response to immediate resuscitative efforts will
be reflected by a reversal or halt in the progression of the metabolic acidosis,
improved sensorium, and increased urine output. In E.B., surgical evaluation and
debridement and selection of appropriate antibiotics while maintaining hemodynamic
support are the clinical goals of therapy.
Fluid Therapy Versus Inotropic Support
following hemodynamic profile (previous values in parentheses):
BP (S/D/M), 95/48/64 mm Hg (90/48/62 mm Hg)
HR, 124 beats/minute (122 beats/minute)
Urine output, 0.25 mL/kg/hour (0.4 mL/kg/hour)
, 534 mL/minute (508 mL/minute)
, 198 mL/minute (324 mL/minute)
boluses, an increase in the norepinephrine infusion rate, or initiation of a different vasopressor?
E.B. continues to be hypotensive despite a PCWP of 16 mm Hg and a
norepinephrine infusion rate of 0.3 mcg/kg/minute. The goals of therapy remain the
same (i.e., maximize arterial oxygen content and ḊO2
E.B.’s PaO2 of 85 mm Hg correlates with an oxygen–hemoglobin saturation of
approximately 96%, which should provide an adequate arterial oxygen content.
However, ḊO2 still may be inadequate despite the CI being above 3.5 L/minute/m2
because ḊO2 and O2 have not reached normal levels. E.B.’s Hgb and Hct should be
checked to ensure adequate oxygen-carrying capacity in the blood. In addition,
decreased tissue oxygen utilization can contribute to the continued acidosis. Further
attempts to enhance the CI and, hence, ḊO2 are appropriate. E.B. has a dilated heart
and a history of cardiovascular disease and chronic kidney disease that will
influence the choice of therapeutic options.
Although fluid administration is the mainstay of therapy in septic shock, the
elevation of E.B.’s PCWP to 16 mm Hg without a significant increase in CO suggests
that an optimal PCWP has been reached. Therefore, additional fluid therapy to
maintain BP may cause pulmonary edema and compromise pulmonary gas exchange.
A plot of CO versus PCWP (ventricular function curve) would provide a more
accurate assessment of the PCWP at which CO is maximal. Additional fluid boluses
at this time should be used only to maintain the current level of intravascular volume
VASOPRESSORS AND INOTROPIC AGENTS
When fluid therapy fails to maintain a satisfactory MAP despite an elevated CO, the
use of a vasopressor should be considered. Maintaining a goal MAP does not
correlate with decreased mortality, but it helps sustain myocardial and cerebral
perfusion. If it is necessary to increase CO, then inotropic agents should be used.
Although the use of inotropic agents is well established, controlled comparative
studies have not clearly determined which agent, or combination of agents, is most
useful in the management of septic shock. Because differences among the inotropic
agents are significant, however, selection of the most appropriate drug should be
guided by careful consideration of the patient’s hemodynamic status.
Norepinephrine is predominantly an α-adrenergic agonist (Table 17-7) and is the
recommended first-line vasopressor for sepsis.
4 Norepinephrine has been titrated to
0.3 mcg/kg/min, but E.B.’s HR will likely limit the utility of further increases in the
Dopamine has frequently been another initial pharmacologic agent chosen for the
treatment of septic shock. A trial that
randomized 1,679 patients with shock to dopamine or norepinephrine for BP
support found no significant difference in the primary outcome of 28-day mortality
but an increased risk of arrhythmic events with dopamine.
randomized trials of septic patients found dopamine was associated with an
increased risk of death and arrhythmias compared to norepinephrine.
another meta-analysis that included six randomized trials found norepinephrine was
associated with a lower in-hospital and 28-day mortality compared to dopamine as
well as a lower incidence of arrhythmias.
In light of these findings, the Surviving Sepsis Campaign relegated dopamine from
a first-line to alternative vasopressor. Dopamine is now reserved for patients with
absolute or relative bradycardia and a low risk of tachyarrhythmias, which is
4 Accordingly, dopamine is not an appropriate therapeutic option
Low-dose dopamine should not be used for renal protective purposes.
improvement in renal blood flow and a possible increase in urine output, dopamine
does not decrease the time to recovery of renal function or the need for renal
Epinephrine stimulates α- , β1
-adrenergic receptors (Table 17-7). CO is
augmented via increased contractility and HR, with the contribution of each being
highly variable. Blood vessels in the kidney, skin, and mucosa constrict in response
t o α-adrenergic stimulation, whereas vessels in the skeletal muscle vasodilate
because of β2 effects. A biphasic response in SVR is observed as β2
activated at the lower range and α1
-receptors are stimulated at higher infusion rates.
The improvement in CO, therefore, may be negated by an increase in afterload at
Historically, epinephrine was reserved as a last-line therapy because of the
studies that showed harmful splanchnic and renal vasculature effects and elevated
lactate levels. Despite these effects, there are no clinical studies showing that
epinephrine causes worse outcomes in sepsis. In fact, two prospective, double-blind,
randomized controlled trials comparing epinephrine and norepinephrine in patients
with septic shock found similar mortality rates, time to hemodynamic recovery, and
time to vasopressor withdrawal.
90,91 Both studies showed lower arterial pH values
associated with impaired serum lactate clearance in the epinephrine-treated groups.
Therefore, lactate clearance would not be recommended to guide resuscitation when
Infliximab UC: moderate-tosevere induction
CD: moderate-tosevere induction
CD: fistulizing disease Low Strong
Adalimumab UC: moderate-tosevere
CD: moderate-tosevere induction
CD: fistulizing disease Low Strong
CD: moderate-tosevere induction
Natalizumab CD: moderate-tosevere induction
Vedolizumab UC: moderate-tosevere
ADR, adverse drug reaction; CD, Crohn’s disease; CNS, central nervous system; HA, headache; IM,
colitis ACG, American College of Gastroenterology.
Comparison of Aminosalicylate Compounds
Generic (Trade) Delivery System
Balsalazide (Colazal) Bacterial cleavage of azo
Mesalamine (Apriso) Polymer matrix/enteric
Ileum (distal), colon 1.5 g PO every morning
Mesalamine (Asacol HD) pH-dependent coating
Ileum (distal), colon 1.6 g PO TID
Mesalamine (Delzicol) pH-dependent coating
Ileum (distal), colon 800 mg PO TID 1 hour
Mesalamine (Lialda) Multi-matrix (pH-sensitive
Ileum (distal), colon 2.4–4.8 g PO every day
Mesalamine (Pentasa) Controlled-release
Direct topical therapy Rectum 1 g PR at bedtime after
Direct topical therapy Descending colon/rectum 4 g/60 mL enema PR at
Olsalazine (Dipentum) Bacterial cleavage of azo
Sulfasalazine (Azulfidine) Bacterial cleavage of azo
Colon Initially 500 mg PO BID;
BID, 2 times daily; PO, orally; PR, per rectum; QID, 4 times daily; TID, 3 times daily.
Adapted with permission from Fernandez-Becker NQ, Moss AC. Improving delivery of aminosalicylates in
2015. http://www.wolterskluwercdi.com/facts-comparisons-online/. Accessed August 26, 2015.
Corticosteroids are the most commonly used agents in the treatment of acute flares in
patients with moderate-to-severe IBD.
24 The anti-inflammatory actions of
corticosteroids are well known, but how these translate into their full mechanism of
25 Data are insufficient to demonstrate any difference between single
versus divided oral doses or continuous versus intermittent bolus intravenous (IV)
administration. IV doses should be equivalent to hydrocortisone 300 to 400 mg/day
or methylprednisolone 48 to 60 mg/day.
Topical steroids can serve as an adjunct in patients with proximal rectal disease
who have failed topical 5-ASA therapy.
22 Oral enteric-coated budesonide is
approved for the treatment of CD. Budesonide possesses a high degree of topical
anti-inflammatory activity with low systemic bioavailability.
formulation of budesonide delivers drug primarily to the ileum and ascending colon.
Short-term corticosteroid-associated adverse effects may be less than with
traditional agents, and its use up to 1 year seems to be well tolerated.
with traditional corticosteroids, budesonide has a number of potential drug
interactions owing to its metabolism via the cytochrome P450 3A4 system.
suggest that budesonide is as effective as traditional corticosteroids for the treatment
of mild-to-moderate CD localized to the right colon or ileum, and recent guidelines
identify budesonide as the preferred agent in this situation.
Azathioprine (AZA) and 6-mercaptopurine (6-MP) may be used for the management
of corticosteroid-dependent and quiescent IBD. AZA is converted to 6-MP, which is
then metabolized to thioinosinic acid by thiopurine methyltransferase (TPMT), the
active agent that inhibits purine ribonucleotide synthesis and cell proliferation. It also
alters the immune response by inhibiting natural killer cell activity and suppressing
cytotoxic T-cell function. AZA (1.5–2.5 mg/kg/day) and 6-MP (1–1.5 mg/kg/day) are
used in the treatment of UC and CD in patients whose conditions have not responded
to systemic steroids, or as “steroid-sparing” agents.
16,17,32 Because of the long onset
of action of 6-MP and AZA, these agents should be reserved for maintaining
remission. Adverse effects of 6-MP and AZA include rash, nausea, pancreatitis,
alopecia, and diarrhea. Myelosuppression, especially neutropenia, may have a
delayed onset, and clinicians should monitor the complete blood count monthly for
the first 3 months of treatment, then every 3 months thereafter. Pharmacogenomic
testing for TPMT before initiation is recommended.
Comments
Post a Comment
اكتب تعليق حول الموضوع