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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5537_Библиотеки_им_академика_М_И_Перельмана.pdf
The right-heart catheterization is the gold standard for the diagnosis of
pulmonary hypertension. Catheterization is necessary to accurately measure the right atrial, right ventricular, and pulmonary arterial pressures, PVR
and cardiac output. Diastolic dysfunction can be excluded through a normal wedge pressure or a left ventricular end diastolic pressure.
Once the diagnosis of pulmonary hypertension has been established,
it is important to identify secondary causes of pulmonary hypertension
that may be treatable. Ventilation-perfusion scanning is useful in excluding chronic thromboembolic disease. Pulmonary function testing with
diffusion capacity can exclude restrictive or obstructive lung disease.
Decreased diffusion capacity is an early marker of PAH and declines with
worsening disease. Polysomnography is frequently performed as an outpatient to exclude obstructive sleep apnea. Laboratory testing includes
work-up for scleroderma (anti-Scl-70, anti-centromere), systemic lupus
erythematosus (ANA), rheumatoid arthritis (RF, anti-CCP), HIV infection
and hepatitis. If indicated, further evaluation for hypercoaguable states or
interstitial lung disease should be performed. Brain natriueretic peptide
can be elevated with RV dysfunction and may be used to monitor disease
progression.
Medical Treatment
General therapy to be considered for the pulmonary hypertension includes
diuretics, cardiac glycosides, supplemental oxygen and anticoagulation.
Oral anticoagulation has been shown in a retrospective study by
Fuster and colleagues to improve mortality in patients with idiopathic pulmonary arterial hypertension.
4
The target INR in these patients is 1.5 to
2.5 although patients with hypercoaguable states and chronic thromboembolic disease should be maintained at higher INRs (2.5 to 3.5).
Digitalis is commonly administered to patients who have evidence of
RV dysfunction. Diuretics should be used in patients who exhibit clinical
signs of right-heart failure. Excessive diuresis should be avoided as it can
diminish cardiac output due to reduced preload. Patients who are grossly
volume overloaded and have renal dysfunction should be considered for
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A. Nair
short-term ionotropic therapy (dobutamine, dopamine or milrinone).
Supplemental oxygen is appropriate for patients with resting or exertional
hypoxemia.
Calcium channel blockers (CCBs) are indicated for patients who
demonstrate acute vasoreactivity. Less than 10% of patients with IPAH
will be acute responders, however. Nifedipine, amlodipine and diltiazem
are the preferred calcium channel blockers and should be titrated to the
maximum tolerated doses. Calcium channel blockers should not be used
empirically and only 50% of patients who are vasoreactive will be longterm responders to CCBs.
Targeted therapy for pulmonary hypertension includes prostacylcins,
endothelin receptor antagonists and phosphodiesterase inhibitors.
5
These
agents should be used after consultation with a pulmonary hypertension
specialist. Prostacyclins used for PH include epoprostenol, treprostinil, and
iloprost. Patients who have NYHA Class III to IV symptoms and significant right ventricular dysfunction with compromised cardiac outputs
should be considered for epoprostenol. Epoprostenol (Flolan) is administered as a continuous infusion and acts as a pulmonary vasodilator.
Additionally, it inhibits platelet aggregation, is an antiproliferative and acts
as a cardiac iontrope.
6
It has a short half-life (6 minutes) and abrupt discontinuation may lead to rebound pulmonary hypertension and acute right
ventricular failure. Treprostinil, which is a prostacyclin analogue with a
longer half-life (240 minutes), may be administered as a continuous intravenous or subcutaneous infusion or as an inhaled therapy. Iloprost is an
aerosolized prostacyclin that is administered six to nine times a day.
Endothelin promotes vasoconstriction and abnormal proliferation in
pulmonary hypertension. The endothelin antagonists include bosentan,
ambrisentan and sitaxsentan. The first two medications are approved for
use in the US and differ in their specificity for endothelin receptors ETa
and ETb. Bosentan, a non-selective agent, is administered twice daily and
has been shown to reduced mortality and morbidity.
7
It has up to a 10%
risk of hepatic dysfunction and monthly liver function tests are required.
Ambrisentan, which has increased specificity for ETa, produces less hepatotoxicity although it can cause peripheral edema.
8
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Pulmonary Hypertension
Phosphodiesterase-5 (PDE-5) inhibitors enhance nitric oxide activity.
Nitric oxide produces pulmonary vasodilatation, and PDE-5 inhibitors can
produce selective pulmonary vasodilatation without significant systemic
effects. Sildenafil (three times daily) and tadalafil (once daily) are approved
for use in pulmonary hypertension.
9,10
Combination therapies have been studied and should be considered
for patients with severe pulmonary hypertension and right ventricular dysfunction who do not respond to monotherapy.
Surgical Treatment
For patients who are refractory to medical therapy, atrial septostomy and
heart-lung or lung transplant should be considered. Atrial septostomy
allows for decompression of the right ventricle and should be considered as
a palliative measure or as a bridge to transplant. Ultimately, patients failing
medical therapy should be referred for single- or double-lung transplant.
Prognosis
Left untreated, the median survival for pulmonary arterial hypertension is
2.8 years. Therapy for pulmonary hypertension can significantly alter the
overall mortality and morbidity. Lung transplantation offers a five-year
survival of 45–55%, and the rates of transplantation for PH have declined
since the advent of PH-specific therapy.
11
References
1. McLaughlin VV, Archer SL, Badesch DB, et al. (2009) ACCF/AHA
2009 expert consensus document on pulmonary hypertension a report
of the American College of Cardiology Foundation Task Force on
Expert Consensus Documents and the American Heart Association
developed in collaboration with the American College of Chest
Physicians; American Thoracic Society, Inc.; and the Pulmonary
Hypertension Association. J Am Coll Cardiol 53(17): 1573–619.
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A. Nair
2. Simonneau G, Robbins IM, Beghetti M, et al. (2009) Updated
clinical classification of pulmonary hypertension. J Am Coll
Cardiol 54(1 Suppl): S43–54.
3. Rich S, Brundage BH and Levy PS. (1985) The effect of vasodilator
therapy on the clinical outcome of patients with primary pulmonary
hypertension. Circulation 71(6): 1191–6.
4. Fuster V, Steele PM, Edwards WD, et al. (1984) Primary pulmonary
hypertension: Natural history and the importance of thrombosis.
Circulation 70(4): 580–7.
5. Barst RJ, Gibbs JS, Ghofrani HA, et al. (2009) Updated evidencebased treatment algorithm in pulmonary arterial hypertension. JAm
Coll Cardiol 54(1 Suppl): S78–84.
6. Barst RJ, Rubin LJ, Long WA, et al. (1996) A comparison of
continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary
Pulmonary Hypertension Study Group. New Engl J Med 334(5):
296–302.
7. Rubin LJ, Badesch DB, Barst RJ, et al. (2002) Bosentan therapy for
pulmonary arterial hypertension. New Engl J Med 346(12): 896–903.
8. Galie N, Olschewski H, Oudiz RJ, et al. (2008) Ambrisentan for the
treatment of pulmonary arterial hypertension: Results of the
ambrisentan in pulmonary arterial hypertension, randomized, doubleblind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and
2. Circulation 117(23): 3010–9.
9. Galie N, Ghofrani HA, Torbicki A, et al. (2005) Sildenafil citrate ther-
apy for pulmonary arterial hypertension. New Engl J Med 353(20):
2148–57.
10. Galie N, Brundage BH, Ghofrani HA, et al. (2009) Tadalafil therapy
for pulmonary arterial hypertension. Circulation 119(22): 2894–903.
11. Benza RL, Miller DP, Gomberg-Maitland M, et al. (xxxx) Predicting
survival in pulmonary arterial hypertension: Insights from the
Registry to Evaluate Early and Long-Term Pulmonary Arterial
Hypertension Disease Management (REVEAL). Circulation 122(2):
164–72.
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Critical Care
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Sepsis: Manifestations and
Management of the Host/
Pathogen Response
Thomas H. Kalb*
Key Pearls
• Effective intervention in sepsis requires an integrated effort that
includes early recognition, immediate fluids, appropriate antibiotics,
source control, adequate monitoring of resuscitation end points, and
supportive measures for multiple organ dysfunction.
• The adoption of a bundled management plan is associated with significantly improved survival.
• Every hour of delay in administration of appropriate antibiotics is
associated with increased mortality in severe sepsis. Never withhold
antibiotics in sepsis if signs of hypoperfusion are present.
• Source control is a time-sensitive, important component of early
intervention.
• Shock in sepsis is multifactorial, and requires addressing preload
deficits, evaluation of cardiac function with support of forward flow,
and addressing defects in vasomotor tone.
361
31
Chapter
* Feinstein Institute, Hofstra School of Medicine, NY, USA.
Introduction
Sepsis is the systemic response to infection. Severe sepsis and sepsis with
shock reflect progressively life-threatening conditions that result from
pathogen–host interaction. The incidence of sepsis is rising, with over
200,000 attributable deaths each year in North America. Early recognition
and early initiation of therapeutic measures are key to successful management. This chapter outlines the basics of understanding what sepsis is
and provides a brief evidence-based outline for initiating treatment and
management skills including outcome analysis. Clinical controversies and
opportunities for novel therapy are addressed.
Definitions, Pathophysiology, and Epidemiology
What Is SIRS/Sepsis/Severe Sepsis/ Sepsis with Shock
Sepsis is clinically defined as SIRS with a suspected or documented
infection. SIRS (systemic inflammatory response syndrome) is a set of
clinical features associated with systemic inflammation and innate
immune activation.
1
Many patients who manifest SIRS criteria do not
have an infectious etiology. For example, SIRS criteria are often met by
patients with trauma or noninfectious inflammation such as pancreatitis.
The accepted consensus definitions for SIRS, sepsis, severe sepsis,
and sepsis with shock (Table 1A) stem from consensus conference criteria.
1
More than 30% of patients meeting all four SIRS criteria at presentation
progress to sepsis with shock. Signs of hypoperfusion and tissue dysoxia
are the critical defining features of severe sepsis and sepsis with shock.
Such clinical diagnostic schemes are required because there are no clinically validated biomarkers that substitute for or perform better than clinical markers of sepsis.
Mortality rises precipitously to the 30%–50% range in patients with sus-
pected infection who manifest signs of severe sepsis and sepsis with shock.
Sepsis detection incidence is roughly equally divided between ED and
hospitalized patients. Pneumonia is the most prevalent site of infection
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T. Kalb
identified, followed by UTI, abdominal source, catheter related and others.
Hundreds of mediators are known to be involved with the sepsis cascade.
Outcome is linked not only to the severity of sepsis, but also to the
burden of comorbidities, and the timely introduction of effective therapy.
Ultimately, outcome in sepsis is closely correlated with multiorgan failure. Multiple organ dysfunction syndrome (MODS) accounts for the diffuse organ involvement in sepsis. Cardiovascular dysfunction is most
prominent at presentation, followed by pulmonary, renal, hematologic and
hepatic, as well as metabolic and hypothalamic/pituitary derangements
(see Table 1B for organ dysfunction consensus criteria).
What Causes Sepsis
Sepsis has been shown to result from pathogen associated molecular
patterns (PAMPs) which bind and signal through pathogen response
receptors.
2
For example, gram-negative bacterial lipopolysaccharide is
recognized by TLR-4, which is expressed widely on innate immune
effectors as well as many nonimmune cell types, such as endothelial
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Manifestations and Management of the Host/Pathogen/Physician Response
Table 1A. SIRS and Sepsis Consensus Criteria
1
SIRS:
Temperature (core temperature) >38.3°C or <36°C
Heart rate >90 beats/min
Respiratory rate >30 breaths/min
White cell count >12,000 cells/mm
3
or <4000 cells/mm
3
Sepsis = SIRS with suspected or documented infection
Severe sepsis = sepsis-associated organ dysfunction
*
u/o < 20 mL/hr;
Lactate > 2.5,
SOFA score > 4,
or hypotension
Septic shock = hypotension despite adequate fluid resuscitation (at least 20 mL/kg)
MAP<60
SBP <90 mmHg
SBP drop > 40 mmHg from baseline