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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5537_Библиотеки_им_академика_М_И_Перельмана.pdf
cells. Cellular necrosis and damage associated molecular patterns
(DAMPs) may also be recognized and result in amplification or may
substitute for PAMP response, in part explaining the similar mediator
profile in noninfectious etiologies of SIRS.
TLR-4 signaling results in a rapid transcriptional response through
NF-κB and other transcription factors. NF-κ B activation triggers a cascade
of mediators, including TNF-alpha. Experimentally, TNF-alpha infusion
recapitulates all the lethal features of sepsis. Downstream from TNF-alpha,
endotoxin related signaling involves hundreds of interrelated mediators.
364
T. Kalb
Table 1B. Diagnostic Criteria for Sepsis-Associated Organ Dysfunction Criteria
Excerpted from 2001 International Sepsis Definitions Conference
1
General parameters:
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over 24 hr)
Hyperglycemia (plasma glucose >110 mg/dL) in the absence of diabetes
Inflammatory parameters:
Normal white blood cell count with >10% immature forms
Plasma C-reactive protein >2 SD above the normal value
Hemodynamic parameters:
Arterial hypotension (systolic blood pressure <90 mmHg, mean arterial pressure <70,
or a systolic blood pressure decrease >40 mmHg)
Mixed venous oxygen saturation >70%
Cardiac index >3.5l min
−1m2
Organ dysfunction parameters:
Arterial hypoxemia (PaO
2
/FIO2<300)
Acute oliguria (urine output <0.5 mL kg
-1h-1
)
Creatinine increase >0.5 mg/dl
Coagulation abnormalities (INR > 1.5 or APTT >60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 uL)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL)
Tissue perfusion parameters:
Hyperlactatemia (>3 mmol/L)
Decreased capillary refill or mottling
The signaling through TLRs is rapid, complex, and involves multiple interwoven pathways for inflammation, metabolic pathways, and prothrombotic
pathways. The clinical observation that inflammation triggers thrombogenicity has been understood within the context of an evolutionary connection
between trauma and infection, wherein survival depends upon simultaneous
hemostasis, restoration of immune barriers, and pathogen elimination.
3
Adequate host defense against bacterial and nonbacterial pathogens is
necessary for survival, and yet excess, systemic, dysregulated, or prolonged stimulation may result in the organ dysfunction that is seen in sepsis. Endotoxin induces its own counterregulation. Reflecting the complex
nature of cellular response to pathogen, patients with sepsis manifest
aspects of both proinflammatory and counterregulatory or compensatory
anti-inflammatory responses.
One way to think about cellular response to pathogens in sepsis is to
consider the endothelium a global “organ of injury,” in that vessel injury
and dysfunction contribute to gas exchange disturbance, hypotension,
microcirculatory disturbance, mitochondrial decoupling, and diffuse
organ damage. Thus, endothelial injury results in a disturbance in the
pathway for oxygen uptake, delivery, and consumption.
What Causes Shock in Sepsis
Shock is clinically defined as acute hypoperfusion that results in organ
dysfunction.
Several peptide and nonpeptide mediators of shock in sepsis have
been identified, and early mediators such as TNF-alpha and excess iNOS
may be amplified or substituted in their activity by late mediators such as
adrenomedullin and HMGB1.
Patients with severe sepsis and shock often have multiple disturbances in perfusion that contribute to overall presentation and impact
upon therapeutic decisions. In essence, three physiologic forms of shock
comingle in patients with sepsis with shock.
Preload deficit is often the most prominent feature at initial presentation of shock in patients with severe sepsis or sepsis with shock. Venous
365
Manifestations and Management of the Host/Pathogen/Physician Response
return is a complex function of circulating blood volume, vasomotor tone,
and blood flow distribution.
4
Thus, preload deficiency is not equivalent to
hypovolemia, and all patients with signs of hypoperfusion require volume
resuscitation irrespective of total body volume status.
Cardiac dysfunction in severe sepsis is estimated to occur early in as
many as 25% of patients with severe sepsis and shock manifesting a low
cardiac index despite fluid resuscitation. However, even in the absence of
low output, many patients with sepsis will have myocyte dysfunction
detected by troponin leak and poor contractility often with tachycardia.
5
Vasodilatory shock with dysfunctional vasorelaxation and maldistribution of blood flow is accompanied by endothelial injury and capillary
leak that results in extravascular fluid redistribution, V/Q mismatch, and
ultimately in tissue dysoxia and mitochondrial dysfunction.
6
Table 2 outlines the three forms of shock in sepsis, pointing out the monitoring and
management principles for intervention based on this physiological
underpinning.
What Is the Cause of Microcirculatory Disturbance in Sepsis
Restoration of target levels of perfusion does not necessarily restore
microcirculatory disturbance in severe sepsis. Survival is associated with
restored microcirculatory flow, and the absence of restored capillary flow
is an independent marker of mortality in sepsis.
7
Several pathological
processes contribute to capillary dysfunction in sepsis, including
increased thrombogenicity, disturbances in adhesiveness, rheology, autonomic tone, and mitochondrial dysfunction.
Sepsis Recognition and Intervention: Principles and Action Plan
Key Recognition Principles and Guidelines
Effective therapy is time-sensitive and requires accurate and early
recognition of severe sepsis. The overall concept of early goal-directed
366
T. Kalb
367
Manifestations and Management of the Host/Pathogen/Physician Response
p
Table 2. Three Physiologic Forms of Shock with Sepsis
Defining Physiology Surrogate Primary
Form (gold standard Clinical Markers Clinical Clinical
of Shock measurement) (*best clinical utility) Treatment Comments
Preload shock Low LVEDV <70 cm
3/m2
CVP <8 Isotonic crystalloid • Preload deficit most
(left ventricular end Wedge pressure 20—30 mL/kg bolus prominent form of shock
diastolic volume) <12 Stroke volume (over 20 min optimally) at presentation.
determined by variation • Preload shock does
biplane contrast (SVV) >13% not equal hypovolemia.
echocardiography *IVC inspiratory • Static meausurement of
collapsibility LVEDV >70 does not
index >18% preclude IVF response.
Passive leg raise • Wedge no better than CVP
Augmented stroke and CVP performs poorly to
volume >12.5% predict fluid responsiveness
in sepsis.
Cardiac shock Low contractility index *Low stroke volume Consider additional • High cardiac output
(sBP/LVESVI) <35 mL after volume fluid challenge common after volume
(by Doppler resuscitation Consider inotropic resuscitation though
echocardiograpy) Low cardiac output support (dobutamine) contractility defect, and
<2.5 Consider vasodilator troponin leak in up to 25%.
Low ejection fraction (rarely employed) • Chronotropy may offset
<45 benefit of dobutamine.
(Continued )
368
T. Kalb
p
Table 2. (Continued )
Defining Physiology Surrogate Primary
Form (gold standard Clinical Markers Clinical Clinical
of Shock measurement) (*best clinical utility) Treatment Comments
Vasodilatory Low peripheral (systemic) *MAP <65 mmHg after *Norepinephrine: begin • Dopamine hampered by
shock vascular resistance fluid bolus at 2.5 mcg/min, excess chronotropy.
(by pulmonary artery SBP <90 or 40 increase by Vasopressin particularly
catheter) decreased from 2.5 every 5 min to useful if excess adrenergic
baseline after fluid therapeutic plateau/ chronotropy develops.
bolus maximal 20 mcg/min • Avoid pure alpha adrenergic
Poor capillary refill Dopamine: alternative agents associated with drop
>2 s primary agent in cardiac performance.
Mottled appearance Vasopressin: • Corticosteroid provides
norepinephrine- pressor-sparing effect.
sparing effect Benefit debated.
Corticosteroids:
(hydrocortisone
<300 mg/day) for
pressor-dependent sepsis
with shock
therapy (EGDT), defined as a bundled care plan for the initial management of sepsis, has been widely adopted after a seminal publication by
Rivers et al. from a single center showing impressive mortality benefit,
though not all elements of the original description are universally
adopted.
Over the ensuing decade, it has become generally agreed that the
major advantage of bundled therapy is that a coordinated approach to sepsis improves implementation of therapy and provides a checklist to reduce
omissions.
8
The major caveat to universal acceptance of bundled therapy
is that the demonstrated benefit cannot be easily distinguished among constituent interventions, leaving open the possibility that some aspects are
counterproductive or ineffective.
The core elements of EGDT, accepted by most, is the implementation
of a system for early recognition and initiation of fluid resuscitation,
antibiotics, and source control. Far more contentious are the debates that
remain concerning resuscitation targets, monitoring tools, and adjunctive
therapies such as blood product and inotropic therapy.
In the setting of ongoing debate over the implementation of EGDT,
consensus statements such as the “Surviving Sepsis Campaign” provide
useful guidelines from expert panels that examine and grade evidence,
helping to demonstrate the data that support or limit evidence-based
practice including EGDT in sepsis (Tables 3 and 4). The reader should
be cautiously aware of the substantial debate among critical care
experts. The major caveat for expert panel recommendations is that
investigator bias and sponsorship may influence the interpretation of
weighted evidence.
9
No therapy bundle can be initiated until the patient is accurately recognized, so that a great deal of attention has recently been placed on sepsis prediction models that may enhance the process by which the early
signs are picked up early and improve the “time zero” for EGDT implementation. If validated and automated, such algorithmic approaches raise
the prospect of “pre-emptively” intervening with EGDT and may enhance
the opportunity for targeted therapy that is active against early mediators
of sepsis.
9
369
Manifestations and Management of the Host/Pathogen/Physician Response
370
T. Kalb
Table 3. Initial Resuscitation and Infection Issues
Strength of recommendation and quality of evidence have been assessed using the
GRADE criteria, presented in parentheses after each guideline
• Indicates a strong recommendation, or “we recommend”
Indicates a weak recommendation, or ‘‘we suggest”
Initial resuscitation (first 6 hours)
• Begin resuscitation immediately in patients with hypotension or elevated serum lactate
> 4 mmot/L; do not delay pending ICU admission (1C)
• Resuscitation goals (1C) CVP 8–12 mm Hg
a
Mean arterial pressure ≥ 65 mm Hg
Urine output ≥ 0.5 mL-kg
−1hr−1
Central venous (superior vena cava) oxygen saturation ≥ 70% or mixed venous ≥ 65%
If venous oxygen saturation target is not achieved (2C)
Consider further fluid
Transfuse packed red blood cells if required to hematocrit of ≥ 30% and/or
Start dobutamine infusion, maximum 20 µg kg
−1
min
−1
Diagnosis
• Obtain appropriate cultures before starting antibiotics provided this does not
significantly delay antimicrobial administration (1C)
Obtain two or more BCs
One or more BCs should be percutaneous
One BC from each vascular access device in place >48 hrs
Culture other sites as clinically indicated
• Perform imaging studies promptly to confirm and sample any source of infection, if
safe to do so (1C)
Antibiotic therapy
• Begin intravenous antibiotics as early as possible and always within the first hour of
recognizing severe sepsis (1D) and septic shock (1B)
• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens
and with good penetration into presumed source (1B)
• Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid
toxicity, and minimize costs (1C)
Consider combination therapy in Pseudomonas infections (2D)
Consider combination empiric therapy in neutropenic patients (2D)
Combination therapy ≤3–5 days and de-escalation following susceptibilities (2D)
• Duration of therapy typically limited to 7–10 days; longer if response is slow or there
are undrainable foci of infection or immunologic deficiencies (1D)
• Stop antimicrobial therapy if cause is found to be noninfectious (1D)
(Continued )
371
Manifestations and Management of the Host/Pathogen/Physician Response
Table 3. (Continued )
Source identification and control
• A specific anatomic site of infection should be established as rapidly as possible (1C)
and within first 6 hrs of presentation (1D)
• Formally evaluate patient for a focus of infection amenable to source control measures
(e.g. abscess drainage, tissue debridement) (1C)
• Implement source control measures as soon as possible following successful initial
resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention
is best delayed) (2B)
• Choose source control measure with maximum efficacy and minimal physiologic
upset (1D)
• Remove intravascular access devices if potentially infected (1C)
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ICU, intensive care
unit; CVP, central venous pressure; BC, blood culture.
a
A higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical ventilation or
pre-existing decreased ventricular compliance.
With permission from Dellinger et al. (2008) Crit Care Med 36: 296–327.
Table 4. Hemodynamic Support and Adjunctive Therapy
Strength of recommendation and quality of evidence have been assessed using the
GRADE criteria, presented in parentheses after each guideline
• Indicates a strong recommendation, or “we recommend”
• Indicates a weak recommendation, or “we suggest”
Fluid therapy
• Fluid-resuscitate using crystalloids or colloids (1B)
• Target a CVP of ≥8 mm Hg (≥12 mmHg if mechanically ventilated) (1C)
• Use a fluid challenge technique while associtated with a hemodynamic improvement
(1D)
• Give fluid challenges of 1000 mL of crystalloids or 300–500 mL of colloids over
30 mins. More rapid and larger volumes may be required in sepsis-induced tissue
hypoperfusion (1D)
• Rate of fluid administration should be reduced if cardiac filling pressures increase
without concurrent hemodynamic improvement (1D)
(Continued )
372
T. Kalb
Table 4. (Continued )
Vasopressors
• Maintain MAP ≥ 65 mmHg (1C)
• Norepinephrine and dopamine centrally administered are the initial vasopressors of
choice (1C)
• Epinephrine, phenylephrine, or vasopressin should not be administered as the initial
vasopressor in septic shock (2C), Vasopressin 0.03 units/min may be subsequently added
to norepinephrine with anticipation of an effect equivalent to norepinephrine alone
• Use epinephrine as the first alternative agent in septic shock when blood pressure is
poorly responsive to norepinephrine or dopamine (2B)
• Do not use low-dose dopamine for renal protection (1A)
• In patients requiring, vasopressors, insert an arterial catheter as soon as practical (1D)
Inotropic therapy
• Use dobutamine in patients with myocardial dysfunction as supported by elevated
cardiac filling pressures and low cardiac output (1C)
• Do not increase cardiac index to predetermined supranormal levels (1B)
Steroids
• Consider intravenous hydrocortisone for adult septic shock when hypotension
responds poorly to adequate fluid resuscitation and vasopressors (2C)
• ACTH stimulation test is not recommended to identify the subset of adults with
septic shock who should receive hydrocortisone (2B)
• Hydrocortisone is preferred to dexamethasone (2B)
• Fludrocortisone (50 µg orally once a day) may be included if an alternative to
hydrocortisone is being used that lacks significant mineralocorticoid activity
Fludrocortisone if optional if hydrocortisone is used (2C)
• Steroid therapy may be weaned once vasopressors are no longer required (2D)
• Hydrocortisone dose should be ≤300 mg/day (1A)
• Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s
endocrine or corticosteroid history warrants it (1D)
Recombinant human activated protein C
• Withdrawn from the market as of October 2011, based on negative results of
PROWESS-SHOCK study that showed no benefit in adult patients with
sepsis-induced organ dysfunction with clinial assessment of high risk of death.
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; CVP, central
venous pressure; MAP, mean arterial pressure; ACTH, adrenocorticotropic hormone; rhAPC,
recombinant human activated protein C; APACHE, Acute Physiology and Chronic Health Evaluation.
(With permission from Dellinger et al. (2008) Crit Care Med 36: 296–327.)
373
Manifestations and Management of the Host/Pathogen/Physician Response
Key Intervention Principles
Aggressive fluid resuscitation combined with monitoring of preload
deficit resolution is a key component of EGDT. All patients with severe
sepsis or sepsis with shock should receive at least 25 ml/kg isotonic
crystalloid (e.g. plasmalyte) as a bolus over <1 hr. No convincing outcome advantage to colloid administration has been demonstrated. A
history of CHF, renal insufficiency, or other condition that predisposes
to accumulation of extravascular lung water should not preclude an
adequate fluid challenge in order to address acute hypoperfusion,
through careful monitoring of respiratory status, and support with
assisted ventilation offered for ventilatory compromise. Likewise,
static indirect measures of preload sufficiency such as CVP or LVEDV
do not predict accurately the response to fluid, and no perceived threshold value should preclude fluid challenge in patients who manifest
signs of hypoperfusion.
Early and effective antibiotic administration is a critical timesensitive component of EGDT. Delay in effective antibiotics is associated
with significant mortality.
10
(Fig. 1).
After initial fluid resuscitation, patients who remain hypotensive
should have pressors initiated. Norepinephrine is presently recommended,
though vasopressin and dopamine are acceptable alternatives. Purported
benefits of primary therapy with vasopressin have not been validated,
though the addition of vasopressin infusion may allow a rapid decrease in
the required norepinephrine dose. Consensus guidelines recommend
avoiding unopposed or maximal alpha adrenergic agonists such as
phenylephrine and do not advocate the use of dopamine for renal
“protection.”
11
The use of inotropes to support cardiac contractility defects or to
target indirect signs of tissue dysoxia such as ScvO
2
is a poorly defined
element of EGDT, with limited data and poor clinical fidelity despite
attractive physiological rationale. A conservative recommendation is to
reserve dobutamine for patients with a cardiac index <2.5 L/min/m
2
despite adequate volume and pressor support.