Treatment of Severe Sepsis: Where Next? Current and Future Treatment Approaches After the Introduction of Drotrecogin Alfa

Figures & data

Table 1 Some unsuccessful antiinflammatory treatments for septic shock in humans. All the listed antiinflammatory treatments, with the exception of replacement dose corticosteroids, have failed to demonstrate improvement in clinical outcomes in patients with septic shock

Treatments directed against:

Endotoxin (Lipopolysaccharide, [LPS])

LPS antisera

Murine antibodies against lipid A component of LPS

Human antibodies against lipid A component of LPS (HA–1A)

Bactericidal/permeability-increasing protein

Arachadonic acid metabolites

Ibuprofen (cyclooxygenase inhibitor)

Prostaglandin E1

Ketoconazole

Early cytokines

Antitumor necrosis factor (TNF) fab dimers

AntiTNF fab monomers

Soluble TNF receptor fusion protein

Murine monoclonal antiTNF antibodies

Interleukin-1 receptor antagonist

Nonspecific antiinflammatory treatments:

High dose corticosteroids

Replacement dose corticosteroidsa

Intravenous immunoglobulin

Immunonutrition

Platelet activating factor-acetylhydrolase

Tifacogin (recombinant human tissue factor pathway inhibitor)

a Replacement dose corticosteroids, in combination with fludrocortisone, improved survival in patients with septic shock and relative adrenal insufficiency, as defined by an inadequate response to corticotropin stimulation testing (Annane et al 2002).

Table 2 Elements of the coagulation homeostasis targeted as treatment for humans with septic shock. The only agent targeting coagulation homeostasis that has demonstrated a reduction in mortality to date is drotrecogin alfa (activated), which reduced 28-day all-cause mortality in patients with at least one organ dysfunction attributable to sepsis (Bernard et al 2001)

Platelets:

Platelet activating factor receptor antagonist

Platelet activating factor-acetylhydrolase

Protein C:

Drotrecogin alfa (activated) (Recombinant human activated protein C)

Tissue factor

Tifacogin (recombinant human tissue factor pathway inhibitor)

Antithrombin III

High dose antithrombin III

Table 3 Studies of vasopressin in humans with septic shock. A conglomeration of studies investigating the effects of vasopressin (antidiuretic hormone; [ADH]) in humans with septic shock

Reference	Design	Patient Population/disease	Number of patients	Comparison	Vasopressin Dose Units/minutes	Outcomes
Landry et al 1997b	Prospective, open-label, unrandomized	Septic shock on catecholamines	10	Pre- vs Post-ADH	0.04 U/min	↑ BP
Landry et al 1997b	Prospective, open-label, unrandomized	Septic shock on catecholamines	6	Pre- vs Post-ADH	0.01 U/min	↑ BP
Landry et al 1997b	Prospective, open-label, unrandomized, removal of ADH	Septic shock on catecholamines	6	On ADH vs Post-stopping ADH	0.01 U/min	↓ BP on removal of ADH
Landry et al 1997a	Prospective, open-label, unrandomized case reports	Septic shock on catecholamines	5	Pre- vs Post-ADH	0.03–0.04 U/min	↑ BP, ↓ Cat, ↑ UO
Malay et al 1999	Prospective, randomized, placebo-controlled, double-blinded	Trauma patients with septic shock on catecholamines	10	ADH (n = 5) vs Placebo (n = 5)	0.04 U/min	↑ BP, ↓ NE
Dunser et al 2001	Retrospective	Septic (n = 35) or post-cardiotomy shock (n = 25) on catecholamines	60	Pre- vs Post-ADH	0.07–0.1 U/min	↑ BP, ↓ NE, ↓ HR, ↓ CI, ↓ mean PAP, ↑ liver enzymes, ↓ plt
Holmes, Walley, et al 2001	Retrospective	Septic shock on catecholamines	50	Pre- vs Post-ADH	0.01–0.6 U/min (avg. 0.5 U/min)	↑ BP, ↓ Cat, ↑UO, ↓ CI
Tsuneyoshi et al 2001	Prospective, open-label	Septic shock on catecholamines	16	Pre- vs Post-ADH	0.04 U/min	↑ BP, ↑ UO
Patel et al 2002	Prospective, randomized, blinded	Septic shock	24	ADH (n = 13) vs NE (n = 11)	0.01 U/min titrated up to 0.08 U/min	↑ BP, ↓ NE, ↑ UO, ↑ CCl
Dunser et al 2003	Prospective, randomized, blinded	Cardiopulmonary bypass ± septic shock	48	NE + ADH (n = 24) vs NE alone (n = 24)	0.067 U/min	↑ BP ↓ tachyarrhythmias

Abbreviations: ADH, antidiuretic hormone; BP, blood pressure; Cat, catecholamines; CCl, creatinine clearance; CI, cardiac index; HR, heart rate; NE, norepinephrine; PAP, pulmonary artery pressure; plt, platelets; PVR, peripheral vascular resistance; SVR, systemic vascular resistance; U/min, units/minute; UO, urinary output.

AnnaneDSebilleVCharpentierCEffect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shockJAMA20022888627112186604

 PubMed Web of Science ®Google Scholar

BernardGRVincentJLLaterrePFEfficacy and safety of recombinant human activated protein C for severe sepsisN Engl J Med200134469970911236773

 PubMed Web of Science ®Google Scholar

LandryDWLevinHRGallantEMVasopressin deficiency contributes to the vasodilation of septic shockCirculation1997b95112259054839

 PubMed Web of Science ®Google Scholar

LandryDWLevinHRGallantEMVasopressin pressor hypersensitivity in vasodilatory septic shockCrit Care Med1997a251279829267938

 PubMed Web of Science ®Google Scholar

MalayMBAshtonRCJrLandryDWLow-dose vasopressin in the treatment of vasodilatory septic shockJ Trauma19994769970310528604

 PubMed Web of Science ®Google Scholar

DunserMWMayrAJUlmerHThe effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysisAnesth Analg20019371311429329

 PubMed Web of Science ®Google Scholar

HolmesCLWalleyKRChittockDRThe effects of vasopressin on hemodynamics and renal function in severe septic shock: a case seriesInt Care Med2001b27141621

 PubMed Web of Science ®Google Scholar

TsuneyoshiIYamadaHKakihanaYHemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shockCrit Care Med2001294879311373409

 PubMed Web of Science ®Google Scholar

PatelBMChittockDRRussellJABeneficial effects of shortterm vasopressin infusion during severe septic shockAnesth20029657682

 PubMed Web of Science ®Google Scholar

DunserMWMayrAJUlmerHArginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled studyCirculation200310723131912732600

 PubMed Web of Science ®Google Scholar