Medication Summary
The most important aspects of medical therapy for patients with sepsis include adequate oxygen delivery, crystalloid fluid administration, and broad-spectrum antibiotics. Although colloid solution is mentioned, a mortality benefit of colloid over crystalloid solution has not been proved. Blood transfusion may also be beneficial for patients with low hemoglobin concentrations.
Vasopressors are important for patients whose conditions are refractory to adequate fluid resuscitation. Steroid administration should be considered in patients whose conditions are refractory to both fluids and vasopressors.
Vasopressors
Class Summary
In cardiovascular disorders, vasopressors are used to elevate blood pressure. They induce vasoconstriction and elevate mean arterial pressure, as well as provide hemodynamic support in acute heart failure and shock.
Vasopressors are used as second-line agents in the treatment of septic shock. There is no evidence that one vasopressor is superior compared to the other.
Norepinephrine (Levophed)
Norepinephrine is used in protracted hypotension after adequate fluid replacement. It stimulates beta1- and alpha-adrenergic receptors, thereby in turn increasing cardiac muscle contractility and heart rate as well as vasoconstriction. As a result, it increases systemic blood pressure and cardiac output. Adjust and maintain the infusion to stabilize the blood pressure (eg, 80-100 mm Hg systolic blood pressure) sufficiently to perfuse vital organs.
Dopamine (Intropin)
Dopamine stimulates both adrenergic and dopaminergic receptors. Its hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Higher doses produce cardiac stimulation and renal vasodilation. After therapy is initiated the dosage may be increased by 1-4 µg/kg/min every 10-30 minutes until a satisfactory response is attained. Maintenance dosages lower than 20 µg/kg/min are usually satisfactory for 50% of the patients treated.
Dobutamine
Dobutamine is a sympathomimetic amine with stronger beta than alpha effects. It produces systemic vasodilation and increases the inotropic state. Vasopressors augment the coronary and cerebral blood flow during the low-flow state associated with shock. Sympathomimetic amines with both alpha- and beta-adrenergic effects are indicated in cardiogenic shock.
Dobutamine is used in early goal-directed therapy if there is evidence that tissue hypoperfusion and myocardial dysfunction is related to sepsis. Dopamine and dobutamine are the drugs of choice for improving cardiac contractility, with dopamine the preferred agent in hypotensive patients. Higher dosages of dobutamine may cause an increase in heart rate, exacerbating myocardial ischemia.
Epinephrine (Adrenalin)
Epinephrine is used for hypotension that is refractory to dopamine or norepinephrine. It stimulates alpha- and beta-adrenergic receptors, resulting in relaxation of bronchial smooth muscle, increased cardiac output, and increased blood pressure.
Vasopressin (ADH, Vasostrict)
Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. It increases water resorption at the distal renal tubular epithelium (ADH effect). Vasopressin promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.
Phenylephrine
Phenylephrine is a strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity. It produces vasoconstriction of arterioles and increased peripheral vascular resistance. This agent causes reflex myocardial depression and decreased heart rate; therefore, it must be used with caution. Phenylephrine is a first-line agent in patients with hypotension and extreme tachycardia. It can be used as an adjunct to norepinephrine or dopamine to augment peripheral vasoconstriction.
Synthetic human angiotensin II (Giapreza)
Angiotensin II, the major bioactive component of the renin-angiotensin-aldosterone system (RAAS), serves as one of the body’s central regulators of blood pressure. It raises blood pressure by vasoconstriction and increased aldosterone release; direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein–coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction. It is indicated for adults with septic or other distributive shock.
Isotonic crystalloids
Class Summary
Isotonic sodium chloride solution (normal saline [NS]) and lactated Ringer (LR) solution are isotonic crystalloid fluids, the standard intravenous (IV) fluids used for initial volume resuscitation. Another crystalloid solution used is Plasmalyte. These solutions expand the intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays in the intravascular space; therefore, large quantities may be required to maintain adequate circulating volume.
NS and LR solution are isotonic and have equivalent volume-restoring properties. Although some differences exist in the metabolic changes observed with the administration of large quantities of the 2 fluids, 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 NS and resuscitation with LR solution.
Normal saline (NS, 0.9% NaCl)
Normal saline restores interstitial and intravascular volume. It is used in initial volume resuscitation.
Lactated Ringer
LR solution restores interstitial and intravascular volume. It is used in initial volume resuscitation.
Plasmalyte
Normal saline restores interstitial and intravascular volume. It is used in initial volume resuscitation.
Volume Expanders
Class Summary
Colloids are used to provide oncotic expansion of plasma volume. They expand plasma volume to a greater degree than isotonic crystalloids and reduce the tendency toward pulmonary and cerebral edema. About 50% of the administered colloid stays intravascular.
Albumin (Buminate, Albuminar)
Albumin is given for certain types of shock or impending shock. It is useful for plasma volume expansion and maintenance of cardiac output. A solution of NS and 5% albumin is available for volume resuscitation. The 5% solutions are indicated for expanding plasma volume, whereas the 25% solutions are indicated for raising oncotic pressure.
Antibiotics
Class Summary
Early empiric antibiotic therapy is the only other proven medical treatment in septic shock. Use of broad-spectrum or multiple antibiotics provides the necessary wide coverage. In children who are immunocompetent, monotherapy with a third-generation cephalosporin (eg, cefotaxime, ceftriaxone, or ceftazidime) is possible. In immunocompetent adults, an antipseudomonal penicillin or carbapenem is used as monotherapy.
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 or metronidazole) or a fluoroquinolone plus clindamycin. All antibiotics should initially be administered IV.
Cefotaxime (Claforan)
Cefotaxime is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Cefotaxime is used to treat against an increasing prevalence of penicillinase-producing microorganisms. This agent inhibits bacterial cell-wall synthesis by binding to 1 or more penicillin-binding proteins. Cell-wall autolytic enzymes lyse bacteria, and cell-wall assembly is arrested.
Ticarcillin-clavulanate (Timentin)
Ticarcillin-clavulanate consists of an antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positive organisms (except for variable coverage against Staphylococcus epidermidis and no coverage against methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative organisms, and anaerobes.
Piperacillin-tazobactam (Zosyn)
Piperacillin-tazobactam inhibits the biosynthesis of cell-wall mucopeptide and is effective during the stage of active multiplication. It has antipseudomonal activity.
Imipenem-cilastatin (Primaxin)
Imipenem-cilastatin is a carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. It is used for treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of their potential for toxicity.
Meropenem (Merrem)
Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci relative to imipenem. Compared with imipenem, it is less likely to cause seizures and better able to penetrate the blood-brain barrier.
Clindamycin (Cleocin)
Clindamycin is primarily used for its activity against anaerobes. It has some activity against Streptococcus species and methicillin-sensitive S aureus (MSSA).
Metronidazole (Flagyl)
Metronidazole is an imidazole ring-based antibiotic that is active against various anaerobic bacteria and protozoa. It is usually combined with other antimicrobial agents, except when used for Clostridium difficile enterocolitis, in which monotherapy is appropriate.
Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell-wall synthesis by binding to 1 or more penicillin-binding proteins. Cell-wall autolytic enzymes lyse bacteria, and cell-wall assembly is arrested.
Ciprofloxacin (Cipro)
Ciprofloxacin is a fluoroquinolone with variable activity against Streptococcus species, activity against methicillin-sensitive S aureus and Staphylococcus epidermidis, activity against most gram-negative organisms, and no activity against anaerobes. It is a synthetic broad-spectrum antibacterial compounds with a novel mechanism of action, targeting bacterial topoisomerase II and IV, thus leading to a sudden cessation of DNA replication. Oral bioavailability is near 100%.
Cefepime (Maxipime)
Cefepime is a fourth-generation cephalosporin. It has gram-negative coverage comparable to that of ceftazidime but has better gram-positive coverage (comparable to that of ceftriaxone). Cefepime is active against Pseudomonas species. It has increased effectiveness against extended-spectrum beta lactamase (ESBL)-producing organisms. Its poor capacity to cross the blood-brain barrier precludes its use for treatment of meningitis.
Levofloxacin (Levaquin)
Levofloxacin is a fluoroquinolone with excellent gram-positive and gram-negative coverage. It is an excellent agent for pneumonia and has excellent abdominal coverage as well. Its high urine concentration necessitates reduced dosing in urinary tract infection.
Vancomycin
Vancomycin provides gram-positive coverage and good hospital-acquired MRSA coverage. It is being used increasingly often because of the high incidence of MRSA. Vancomycin should be given to all septic patients with indwelling catheters or devices. It is advisable for skin and soft-tissue infections.
Corticosteroids
Class Summary
Corticosteroids are powerful anti-inflammatory agents. They may maintain vascular tone in states of shock. These agents are most likely to be beneficial if therapy is initiated within 8 hours of the onset of severe septic shock, but no consistent proof of increased survival outcomes have been seen in clinical trials.
Hydrocortisone (A-Hydrocort, Solu-Cortef)
Endogenous cortisol is a stress hormone that acts in part to maintain vascular tone in states of shock. Some evidence suggests that exogenous hydrocortisone administration may increase mean arterial pressure and improve outcomes in patients with septic shock who have persistent hypotension despite adequate crystalloid resuscitation and vasopressor support.
Dexamethasone
Dexamethasone has many pharmacologic benefits, but it also has significant adverse effects. This agent stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-2, and interferon gamma). The inhibition of chemotactic factors and factors that increase capillary permeability hinders recruitment of inflammatory cells into affected areas.
Dexamethasone suppresses lymphocyte proliferation through direct cytolysis, and it inhibits mitosis. It breaks down granulocyte aggregates and improves pulmonary microcirculation. Adverse effects include hyperglycemia, hypertension, weight loss, gastrointestinal (GI) bleeding or perforation, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose- or duration-dependent.
Dexamethasone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. It lacks the salt-retaining property of hydrocortisone. Patients can be switched from an IV to PO regimen in a 1:1 ratio.
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Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
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Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
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A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the presence of Neisseria meningitidis. The skin manifestation seen in this image is characteristic of severe meningococcal infection and is called purpura fulminans.
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Gram stain of blood showing the presence of Neisseria meningitidis.
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Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This photomicrograph shows early stage (exudative stage) DAD.
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Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of early stage (exudative stage) DAD.
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Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has occurred; hyaline membranes as well as collagen and fibroblasts are present.
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Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, which may develop into fibrotic stage of DAD.
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Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.
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Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.
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A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.
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An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.
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A 28-year-old woman who was a former intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to bilateral pneumococcal pneumonia.
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Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.
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Soft-tissue infection secondary to group A streptococci, leading to toxic shock syndrome.
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Necrotizing cellulitis of toxic shock syndrome.
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Necrosis of the little toe of the right foot and cellulitis of the foot secondary to group A streptococcal infection.
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Group A streptococci cause beta hemolysis on blood agar.
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Gram stain of blood showing group A streptococci that was isolated from a patient who developed toxic shock syndrome. Image courtesy of T. Matthews.
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A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The leg was incised to exclude underlying necrotizing infection. Image courtesy of Rob Green, MD.
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A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). This patient also had streptococcal pharyngitis. Image courtesy of Rob Green, MD.
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A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. Image courtesy of Rob Green, MD.
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A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. He improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over his palms and soles. Image courtesy of Rob Green, MD.
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Progression of soft-tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Image courtesy of S. Manocha.
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Extensive debridement of necrotizing fasciitis of the hand.
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Healing of the hand after aggressive surgical debridement of necrotizing fasciitis (same patient as in previous image).
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A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). Computed tomography (CT) scanning helped to evaluate the extent of the infection and to exclude other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
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Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
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Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
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Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema.
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Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema (same lesion as shown in previous computed tomography image).
Tables
System |
0 Points |
1 Point |
2 Points |
3 Points |
4 Points |
Respiration PaO2a/FiO2b |
≥400 mm Hg |
< 400 mm Hg |
< 300 mm Hg |
< 200 mm Hg (with respiratory support) |
< 100 mm Hg (with respiratory support) |
Coagulation Platelet count |
≥150 x 103/µL |
< 150 x 103/µL |
< 100 x 103/µL |
< 50 x 103/µL |
< 20 x 103/µL |
Liver Bilirubin level |
< 1.2 mg/dL |
1.2-1.9 mg/dL |
2-5.9 mg/dL |
6-11.9 mg/dL |
>12 mg/dL |
Cardiovascular |
MAPc ≥70 mm Hg |
MAP >70 mm Hg |
Dopamine < 5 or dobutamine (any dose)e |
Dopamine 5.1-15 or epinephrine ≤0.1 or norepinephrine ≤0.1e |
Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1e |
Central nervous system GCSd score |
15 |
13-14 |
10-12 |
6-9 |
< 6 |
Renal Creatinine Urine output |
< 1.2 mg/dL |
1.2-1.9 mg/dL |
2-3.4 mg/dL |
3.5-4.9 mg/dL < 500 mL/day |
>5 mg/dL < 200 mL/day |
aPaO2=Partial pressure of oxygen. bFiO2=Fraction of inspired oxygen. cMAP=Mean arterial pressure. dGCS=Glasgow Coma Scale (range, 3-15, with higher indicating better function). eCatecholamine doses administered as µg/kg/min for ≥1 hour. |
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Organ System |
Sepsis Criteria |
Severe Sepsis Criteria |
Pulmonary |
Arterial hypoxemia: PaO2/FIO2< 300 |
Arterial hypoxemia: PaO2/FIO2< 250 in absence of pneumonia and < 200 in presence of pneumonia |
Hepatic |
Hyperbilirubinemia: Plasma total bilirubin >4 mg/dL or 70 µmol/L |
Hyperbilirubinemia: Plasma total bilirubin >2 mg/dL or 34.2 µmol/L |
Renal |
Creatinine increase >0.5 mg/dL or 44.2 µmol/L Acute oliguria: Urine output < 0.5 mL/kg/hr for ≥2 hr despite adequate fluid resuscitation |
Creatinine >2 mg/dL or 176.8 µmol/L Acute oliguria: Urine output < 0.5mL/kg/hr for ≥2 hr despite adequate fluid resuscitation |
Gastrointestinal |
Ileus: Absent bowel sounds |
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Hematologic |
INR >1.5, aPTT >60 s, or platelets < 100,000/µL |
INR >1.5 or platelets < 100,000/µL |
Cardiovascular |
Hyperlactatemia >1 mmol/L; decreased capillary refill or mottling Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg |
Hyperlactatemia: Above upper limits of laboratory normal Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg |
Central nervous system |
Confusion, lethargy, coma |
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aPTT = activated partial thromboplastin time; FIO2 = fraction of inspired oxygen; INR = international normalized ratio; MAP = mean arterial pressure; PaO2 = partial pressure of oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time; SBP = systolic blood pressure. Source: Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. [11] |
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Type |
Mediator |
Activity |
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Cellular mediators |
LPS |
Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators |
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Lipoteichoic acid |
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Peptidoglycan |
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Superantigens |
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Endotoxin |
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Humoral mediators |
Cytokines |
Activate inflammatory pathways |
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Potent proinflammatory effect |
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Acts as pyrogen, stimulates B- and T-cell proliferation |
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Neutrophil chemotactic factor, activation and degranulation of neutrophils |
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Inhibits cytokine production, induces immunosuppression |
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Activates macrophages and T cells |
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Promotes neutrophil and macrophage, platelet activation |
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Complement |
Promotes neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects |
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Nitric oxide |
Involved in hemodynamic alterations of septic shock; cytotoxic, augments vascular permeability, contributes to shock |
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Lipid mediators |
Enhance vascular permeability and contribute to lung injury |
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Arachidonic acid metabolites |
Augment vascular permeability |
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Adhesion molecules |
Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis; increased levels of VAP-1 activity and anchor protein SDC-1 content have been found in critically ill patients with septic shock [12] |
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Late mediator of endotoxin-induced lethality and tissue repair |
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G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPS = lipopolysaccharide; MIF = macrophage inhibitory factor; PAF = platelet-activating factor; SDC-1 = syndecan-1; TNF = tumor necrosis factor; VAP-1 = vascular adhesion protein–1. Source: Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304. [13] |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- General Treatment Guidelines in Septic Shock
- Goals of Hemodynamic Support
- Fluid Resuscitation
- Vasopressor Therapy
- Inotropic Therapy and Augmented Oxygen Delivery
- Empiric Antimicrobial Therapy
- Corticosteroid Therapy
- Glycemic Control
- DVT Prophylaxis and Management of DIC
- Management of Acute Respiratory Distress Syndrome
- Surgical Treatment
- Prevention
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