In the late 1960s, several reports appeared describing remote organ failure (eg, pulmonary failure, liver failure) as a complication of severe sepsis. In 1975, a classic editorial by Baue was entitled "Multiple, progressive or sequential systems failure, a syndrome of the 1970s." This concept was formulated as the basis of a new clinical syndrome. Several terms were cloned thereafter, such as multiple organ failure, multiple system organ failure, and multiple organ system failure, to describe this evolving clinical syndrome of otherwise unexplained progressive physiological failure of several interdependent organ systems. More recently, the term multiple organ dysfunction syndrome (MODS) has been proposed as a more appropriate description.
Multiorgan failure from sepsis
Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury. In this syndrome, tissue is removed from the original insult that displayed the signs of inflammation, such as vasodilatation, increased microvascular permeability, and leukocyte accumulation. Multiple organ dysfunction is a continuum, with incremental degrees of physiological derangements in individual organs; it is a process rather than an event. Alteration in organ function can vary widely from a mild degree of organ dysfunction to frank organ failure. The degree of organ dysfunction has a major clinical impact. The term MODS is defined as a clinical syndrome in which the development of progressive and potentially reversible physiological dysfunction in 2 or more organs or organ systems induced by a variety of acute insults, including sepsis, is characteristic.
In 1991, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Panel developed definitions of the various stages of sepsis, which are as follows:
- Infection is a microbial phenomenon in which an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms is characteristic.
- Bacteremia is the presence of viable bacteria in the blood.
- Systemic inflammatory response syndrome (SIRS) may follow a variety of clinical insults, including infection, pancreatitis, ischemia, multiple trauma, tissue injury, hemorrhagic shock, or immune-mediated organ injury.
- Sepsis is a systemic response to infection. This is identical to SIRS, except that it must result from infection.
- Septic shock is sepsis with hypotension (systolic BP <90>
- MODS is the presence of altered organ function in a patient who is acutely ill such that homeostasis cannot be maintained without intervention. Primary MODS is the direct result of a well-defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself. Secondary MODS develops as a consequence of a host response and is identified within the context of SIRS. The inflammatory response of the body to toxins and other components of microorganisms causes the clinical manifestations of sepsis.
The sepsis syndrome is recognized clinically by the presence of 2 or more of the following:
- Temperature greater than 38°C or less than 36°C
- Heart rate greater than 90 beats per minute
- Respiratory rate greater than 20 breaths per minute or a PaCO2 in arterial gas less than 32 mm Hg
- WBC count greater than 12,000 cells/mL, less than 4000 cells/mL, or greater than 10% band forms
Pathophysiology:
Pathogenesis
Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a potent, complex, immunologic cascade ensures a prompt protective response to microorganism invasion in humans. A deficient immunologic defense may allow infection to become established; however, an excessive or poorly regulated response may harm the host through maladaptive release of indigenously generated inflammatory compounds.
Lipid A and other bacterial products release cytokines and other immune modulators that mediate the clinical manifestations of sepsis. Interleukins, tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and other colony-stimulating factors are produced rapidly within minutes or hours after interactions of monocytes and macrophages with lipid A. TNF release becomes a self-stimulating process (an autocrine), and release of other inflammatory mediators, including interleukin-1 (IL-1), platelet activating factor, IL-2, IL-6, IL-8, IL-10, INF, and eicosanoids, further increases cytokine levels. This leads to continued activation of polymorphonuclear leukocytes (PMNs), macrophages, and lymphocytes; proinflammatory mediators recruit more of these cells (a paracrine process). All of these processes create a state of destructive immunologic dissonance.
Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic response to infection to involve otherwise normal tissues and results in MODS.
Specific organ involvement
Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune from the consequences of the inflammatory excesses of sepsis.
Circulation
Significant derangement in autoregulation of circulation is typical of sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection. Nitric oxide plays a central role in the vasodilatation of septic shock. Also, impaired secretion of vasopressin may occur, which may permit persistence of vasodilatation.
Central circulation: Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use of the Frank Starling mechanism, cardiac output often is increased to maintain the BP in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately.
Regional circulation: Sepsis interferes with the normal distribution of systemic blood flow to organ systems; therefore, core organs may not receive appropriate oxygen delivery.
Microcirculation is the key target organ for injury in sepsis syndrome. A decrease in the number of functional capillaries causes an inability to extract oxygen maximally, which is caused by intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells. Increased endothelial permeability leads to widespread tissue edema of protein-rich fluid.
In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause regional tissue distress, therefore, regional hypoxia persists. This condition is termed microcirculatory and mitochondrial distress syndrome (MMDS). Sepsis-induced inflammatory autoregulatory dysfunction persists and oxygen need is not matched by supply, leading to multiorgan system dysfunction.
Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances causes hypotension.
Pulmonary dysfunction
Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membranes. Acute respiratory distress syndrome (ARDS) is a frequent manifestation of these effects.
Gastrointestinal dysfunction and nutrition
The GI tract may help propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may be aspirated into the lungs, producing nosocomial pneumonia. The normal barrier function of the gut may be affected, allowing translocation of bacteria and endotoxins into the systemic circulation and extending the septic response. Septic shock usually causes ileus, and the use of narcotics and sedatives delays institution of enteral feeding. The optimal level of nutritional intake is interfered with in the face of high protein and calorie requirements.
Liver
By virtue of the role of the liver in host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into systemic circulation.
Renal dysfunction
Acute renal failure often accompanies sepsis due to acute tubular necrosis. The mechanism is by systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activation of neutrophils by endotoxins and other peptides, which contribute to renal injury.
Central nervous system dysfunction
Involvement of the CNS in sepsis produces encephalopathy and peripheral neuropathy. The pathogeneses is poorly defined.
Mechanisms of organ dysfunction and injury
The precise mechanisms of cell injury and resulting organ dysfunction in sepsis are not understood fully. Multiorgan dysfunction syndrome is associated with widespread endothelial and parenchymal cell injury because of the following proposed mechanisms:
- Hypoxic hypoxia: The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities contribute to the septic microcirculatory defect in sepsis. The reactive oxygen sepsis, lytic enzymes, and vasoactive substances (nitric oxide, endothelial growth factors) lead to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate the septic microcirculation.
- Direct cytotoxicity: The endotoxin, TNF-alpha, and nitric oxide may cause damage to mitochondrial electron transport, leading to disordered energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to utilize oxygen even when it is present.
- Apoptosis: Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are eliminated normally. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but other tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement of apoptosis plays a critical role in tissue injury of sepsis.
- Immunosuppression: The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance. An inflammatory reaction or immunodeficiency may predominate, or both may be present.
Coagulopathy
Subclinical coagulopathy signified by a mild elevation of the thrombin or activated partial thromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common, but overt disseminated intravascular coagulation (DIC) is rare. Deficiencies of coagulation system proteins, including protein C, antithrombin 3, and tissue factor inhibitors, cause coagulopathy.
Characteristics of sepsis that influence outcomes
Clinical characteristics that relate to the severity of sepsis include an abnormal host response to infection, the site and type of infection, the timing and type of antimicrobial therapy, the offending organism, and the development of shock, underlying disease, and the patients' chronic health condition. The location of patient at the time of septic shock also relates to the severity of sepsis.
Frequency:
- In the US: Current estimates suggest that the incidence of sepsis is greater than 500,000 cases per year. Approximately 40% of patients who are septic may develop shock. Patients who are at risk include those with positive blood cultures. Prevalence rates for SIRS of sepsis vary from 20-60%.
- Internationally: A French study in 1996 found that severe sepsis was present in 6.3% of all ICU admissions.
Treatment
Medical Care: The treatment of patients with septic shock consists of the following 3 major goals: (1) Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. (2) Identify the source of infection and treat with antimicrobial therapy, surgery, or both. (3) Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiorgan system dysfunction.
The principles in the management of septic shock based on current literature include the following components:
- Early recognition
- Early and adequate antibiotic therapy
- Source control
- Early hemodynamic resuscitation and continued support
- Corticosteroids (refractory vasopressor-dependent shock)
- Drotrecogin Alpha (severely ill if APACHE II score > 25)
- Tight glycemic control
- Proper ventilator management with low tidal volume in patients with ARDS
- General supportive care
- Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes a combination of several parenteral antibiotics, removal or drainage of infected foci, treatment of complications, and pharmacologic interventions to prevent further harmful host responses.
- Administer supplemental oxygen to any patient who is septic with hypoxia or respiratory distress. If the patient's airway is not secure or respirations are inadequate, perform endotracheal intubation and mechanical ventilation.
- Intravascular volume resuscitation
- All patients with sepsis require supplemental fluids. Assessment of the patient's volume and cardiovascular status guides the amount and rate of infusion. For adult patients who are hypotensive, administer an isotonic crystalloid solution (sodium chloride 0.9% or Ringer lactate) in boluses of 500 mL (10 mL/kg in children), with repeat clinical assessments after each bolus. Administer repeat boluses until signs of adequate perfusion are restored. A total of 4-6 L may be required. Monitor patients for signs of volume overload, such as dyspnea, pulmonary crackles, and pulmonary edema, on chest radiograph. Improvement, stabilization, and normalization of the patient's mental status, heart rate, BP, capillary refill, and urine output indicate adequate volume resuscitation.
- In some patients, clinically assessing the response to volume infusion may be difficult. By monitoring the response of central venous pressure or pulmonary artery occlusion pressure (PAOP) to fluid boluses, the physician can assess these patients. A control venous pressure of 10-15 mm Hg, a PAOP greater than 18 mm Hg, or a rise in the PAOP by 5 mm Hg or more following fluid bolus indicates adequate volume resuscitation. Such patients are susceptible to volume overload; therefore, administer further fluid carefully. Colloid resuscitation (with albumin or pentastarch) has no proven benefit over isotonic crystalloid resuscitation (normal saline or Ringer lactate).
- Empirical antimicrobial therapy
- Administer initial antibiotics. Selection of particular agents is empirical and is based on an assessment of the patient's underlying host defenses, the potential sources of infection, and the most likely responsible organisms. Antibiotics must be broad spectrum and cover gram-positive, gram-negative, and anaerobic bacteria because all classes of these organisms produce identical clinical pictures. Administer antibiotics parenterally in doses adequate to achieve bactericidal serum levels. Many studies have found that clinical improvement correlates with the achievement of serum bactericidal levels rather than the number of antibiotics administered.
- Include coverage directed against anaerobes in the therapy of patients with intraabdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns. Patients who are immunocompetent usually can be treated with a single drug with broad-spectrum coverage, such as a third-generation cephalosporin. Patients who are immunocompromised usually require dual antibiotic coverage with broad-spectrum antibiotics with overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to others.
- Vasopressor supportive therapy
- When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. These agents are dopamine, norepinephrine, epinephrine, and phenylephrine. These vasoconstricting drugs maintain adequate BP during life-threatening hypotension and preserve perfusion pressure for optimizing flow in various organs. Maintain the mean BP required for adequate splanchnic and renal perfusion (mean arterial pressure [MAP] of 60 or 65 mm Hg) based on clinical indices for organ perfusion.
- If the patient remains hypotensive despite volume infusion and moderate dose dopamine, start a direct vasoconstrictor (eg, norepinephrine) at a dose of 0.5 mcg/kg/min in and titrated to support a systolic BP of 90 mm Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally have been avoided because of their adverse events on cardiac output and renal perfusion, human data has shown that norepinephrine can reverse septic shock in patients unresponsive to volume and dopamine. These patients require invasive hemodynamic monitoring with arterial lines and pulmonary artery catheters. A brief discussion of the hemodynamic drugs used to support patients who are critically ill and septic follows:
- Vasopressor therapy
- Dopamine: A precursor of norepinephrine and epinephrine, dopamine has varying effects based on the doses. A dose of less than 5 mcg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dose of 5-10 mcg/kg/min, beta-1-adrenergic effects induce an increase in cardiac contractility and heart rate. At doses about 10 mcg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and an increase in BP. Dopamine is effective in increasing MAP in patients who are hypotensive with septic shock after volume resuscitation. The BP increases primarily as a result of an inotropic effect and, thus, is useful in patients who have concomitant reduced cardiac function. The undesirable effects are tachycardia, increased pulmonary shunting, potential to decrease splanchnic perfusion, and increased pulmonary arterial wedge pressure.
- Epinephrine: Epinephrine can increase MAP by increasing the cardiac index, stroke volume, systemic vascular resistance, and heart rate. Epinephrine may increase oxygen delivery and consumption and decreases splanchnic blood flow. Epinephrine administration is associated with an elevation of systemic and regional lactate concentrations. The use of epinephrine is recommended in patients who are unresponsive to traditional agents. The undesirable effects are an increase in lactate concentration, a potential to produce myocardial ischemia and arrhythmias, and a reduction in splanchnic flow.
- Norepinephrine: Norepinephrine is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. Norepinephrine can successfully increase BP in patients who are septic and remain hypotensive following fluid resuscitation and dopamine. The dose of norepinephrine may vary from 0.2-1.35 mcg/kg/min; doses as large as 3.3 mcg/kg/min have been used because alpha-receptor down regulation may occur in sepsis. In patients who are septic, indices of regional perfusion, such as urine flow and lactate concentration, have improved following norepinephrine infusion. Two recent trials have shown that a significantly greater proportion of patients treated with norepinephrine were successfully resuscitated as opposed to patients treated with dopamine. Therefore, use norepinephrine early, and do not withhold it as a last resort. The studies have shown no effects on splanchnic oxygen consumption and hepatic glucose production, provided adequate cardiac output is maintained.
- Phenylephrine: Phenylephrine is a selective alpha-1 adrenergic receptor agonist primarily used in anesthesia to increase BP. Although studies are limited, phenylephrine increased the MAP in patients who are septic and hypotensive with an increase in oxygen consumption and potential to reduce cardiac output. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other vasopressors.
- Inotropic therapy: Although myocardial performance is altered during sepsis and septic shock, cardiac output usually is maintained in the patients who are septic and have been volume resuscitated. Data from the 1980s and 1990s suggested a linear relationship between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that oxygen delivery was likely insufficient to meet the metabolic needs of the patient. However, recent investigations have challenged the concept of pathologic supply dependency and the practice of elevating cardiac index and oxygen delivery (hyperresuscitation) because these interventions have not been shown to improve patient outcome. Therefore, the role of inotropic therapy is uncertain unless the patient has an inadequate cardiac index, MAP, mixed venous oxygen saturation, and urine output despite optimal volume resuscitation and vasopressor therapy.
- Renal-dose dopamine: The use of renal-dose dopamine in sepsis is a controversial issue. In the past, low-dose dopamine was routinely used in many units because of the presumed renal protective effects. Dopamine at a dose of 2-3 mcg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated a beneficial effect with prophylactic or therapeutic low-dose dopamine administration in patients who are critically ill. Low-dose dopamine does not protect the patient from developing acute renal failure, and there is no data stating that it preserves mesenteric profusion; the routine use of this practice is not recommended. Aggressively resuscitating patients with septic shock, maintaining adequate perfusion pressure, and avoiding excessive vasoconstriction are effective measures to protect the kidneys.
- Recombinant human-activated protein C
- The inflammatory mediators are known to cause activation of coagulation inhibitors of fibrinolysis, thereby causing diffuse endovascular injury, multiorgan dysfunction, and death. Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation but also may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated protein C. Administration of recombinant activated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation.
- A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated that the administration of recombinant human activated protein C (drotrecogin-alpha, activated) resulted in lower mortality rates (24.7% vs 30.8%) in the treated group compared with placebo. Treatment with drotrecogin-alpha, activated was associated with reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by 6.1%, (P=.005).
- Corticosteroids
- While theoretical and experimental animal evidence exists for the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve the 14-day mortality rate. Therefore, no support exists in the medical literature for the routine use of high doses of corticosteroids in patients with sepsis or septic shock. A meta-analysis of 10 prospective, randomized, controlled trials of glucocorticoid use did not report any benefit from corticosteroids. Therefore, high-dose corticosteroids should not be used in patients with severe sepsis or septic shock.
- Although further studies await further confirmation, current recommendations are as follows:
- Drotrecogin alpha (activated protein C) is the only widely accepted drug specific to the therapy of sepsis. Drotrecogin Alpha should be considered for patients with APACHE II scores greater than 25.
- The main side effect of Drotrecogin alpha is bleeding.
- Recent trials of stress-dose glucocorticoids (Briegel, 1999; Cartlet, 1999) demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock. Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.
- he following key points summarize use of corticosteroids in septic shock:
- Older, traditional trials of corticosteroids in sepsis were likely unsuccessful due to high doses and poor patient selection.
- Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependent and possibly relative adrenal insufficiency) patients have resulted in improved outcome.
- orticosteroids should be initiated for patients with vasopressor-dependent septic shock.
- A cosyntropin stimulation test may be performed to identify patients with relative adrenal insufficiency defined recently as failure to increase levels to more than 9 mcg/dL.
- Tight glycemic control has recently become a prominent emphasis in the care of critically ill patients, and recent data has been extrapolated to potentially apply to septic populations. A 2001 Belgian study of surgical intensive care unit (ICU) patients that remained in the ICU for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucose levels for these patients were maintained between 80 and 110 mg per deciliter through use of intensive insulin therapy. The benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin.
- Based on the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL (Dellinger, 2004).
- Tight glycemic control has been shown to improve mortality in post-operative surgical patients including and particularly those with sepsis
- The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be kept at less than 150 mg/dl
Surgical Care: Take patients with infected foci to surgery after initial resuscitation and administration of antibiotics for definitive surgical treatment. Little is gained by spending hours stabilizing the patient when an infected focus persists.
Consultations:
- Patients who do not respond to therapy or are in septic shock require admission to an ICU for continuous monitoring and observation. Consultation with a critical care physician or internist with expertise is appropriate.
- Seek consultation with an appropriate surgeon for patients with suspected or known infected foci, especially for patients with a suspected abdominal source.
The proven medical treatments for septic shock are restoration of intravascular volume and broad-spectrum empirical antibiotic coverage. All other medical therapies, while theoretically attractive, have not reduced morbidity or mortality.
Drug Category: Isotonic crystalloids -- Standard fluid used for initial volume resuscitation. These fluids expand the intravascular and interstitial fluid spaces. Typically, approximately 30% of administered isotonic fluid remains intravascular; therefore, large quantities may be required to maintain an adequate circulating volume.
| Drug Name | Normal saline (NS) and Ringer lactate (RL) -- Both fluids essentially are isotonic and have equivalent volume restorative properties. While some differences exist between metabolic changes observed with administration of large quantities of either fluid, 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 either NS or RL. The amount of intravascular fluid requirements are related to the degree of vascular endothelial injury and impaired vasomotor tone; thus, not only may very large quantities of fluids be required initially, but continual fluid resuscitation often is required during the initial days of management of these patients. |
|---|---|
| Adult Dose | 1-2 L IV initially, with reassessment of hemodynamic response; amounts required during the first few hours typically are 4-5 L |
| Pediatric Dose | Not established |
| Contraindications | Pulmonary edema in which added fluid promotes more edema and may lead to development of ARDS |
| Interactions | None reported |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Closely monitor cardiovascular and pulmonary function; stop fluids when the desired hemodynamic response is observed or pulmonary edema develops; interstitial edema is a major complication; edema in an extremity is unsightly but not a significant complication; edema in brain or lungs is potentially fatal |
| Drug Name | Albumin 5% (Albuminar, Albunex) -- Used for treatment of certain types of shock or impending shock. Useful for plasma volume expansion and maintenance of cardiac output. Solution of normal saline and 5% albumin is available for volume resuscitation. |
|---|---|
| Adult Dose | 250-500 mL IV over 20-30 min, with reassessment of hemodynamic response |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; pulmonary edema; protein load of 5% albumin |
| Interactions | None reported |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | No proven benefit of colloid resuscitation over isotonic crystalloids is known; protein load tends to exacerbate renal insufficiency, a potential complication of septic shock; studies document an increased incidence of renal failure in patients with colloid resuscitation |
| Drug Name | Cefotaxime (Claforan) -- Used for treatment of septicemia. Also used for treatment of gynecologic infections caused by susceptible organisms. Third-generation cephalosporin with enhanced gram-negative coverage, especially to Escherichia coli, Proteus species, and Klebsiella species. Has variable activity against Pseudomonas species. |
|---|---|
| Adult Dose | 1-2 g IV q4h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Probenecid may decrease cefotaxime clearance, causing an increase in cefotaxime levels; furosemide and aminoglycosides may increase nephrotoxicity when used concurrently |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Adjust dose in severe renal impairment; associated with severe colitis |
| Drug Name | Ceftriaxone (Rocephin) -- Used because of an increasing prevalence of penicillinase-producing microorganisms. Inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested. |
|---|---|
| Adult Dose | 1 g IV q6-12h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Probenecid may decrease ceftriaxone clearance, causing an increase in ceftriaxone levels; ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity when used concurrently |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Adjust dose in renal impairment; use with caution in breastfeeding women and in patients allergic to penicillin |
| Drug Name | Cefuroxime (Zinacef) -- Second-generation cephalosporin that maintains gram-positive activity of the first-generation cephalosporins and adds activity against E coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis. Condition of the patient, severity of the infection, and susceptibility of the microorganism determine proper dose and route of administration. |
|---|---|
| Adult Dose | 1.5 g IV q8h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Alcoholic beverages consumed concurrently within <72> |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Administer one half the dose to patients with creatinine clearance of 10-30 mL/min; administer one fourth the dose to patients with a creatinine clearance of <10> |
| Drug Name | Ticarcillin/clavulanate (Timentin) -- Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positives (variable coverage against Staphylococcus epidermidis and none against methicillin-resistant Staphylococcus aureus [MRSA]), most gram-negative organisms, and most anaerobes. |
|---|---|
| Adult Dose | 3.1 g (ticarcillin 3 g and claculanate 0.1 g) IV q4-6h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; severe pneumonia; do not treat bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during acute stage |
| Interactions | Tetracyclines may decrease effects; high concentrations may physically inactivate aminoglycosides if administered in the same IV line; probenecid may increase penicillin levels; effects when administered concurrently with aminoglycosides are synergistic |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; perform urinalysis, BUN, and creatinine determinations during therapy, and adjust dose if these values become elevated; if renal impairment is known or suspected, adjust dose and monitor blood levels; these measures avoid possible neurotoxic reactions |
| Drug Name | Piperacillin/tazobactam (Zosyn) -- Inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. Has antipseudomonal activity. |
|---|---|
| Adult Dose | 3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; do not treat severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during the acute stage |
| Interactions | Tetracyclines may decrease the effects; high concentrations may physically inactivate aminoglycosides; probenecid may increase penicillin levels; effects when administered concurrently with aminoglycosides are synergistic |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; perform urinalysis, BUN, and creatinine determinations during therapy, and adjust dose if these values become elevated; if renal impairment is known or suspected, adjust dose and monitor blood levels; these measures avoid possible neurotoxic reactions |
| Drug Name | Imipenem and cilastatin (Primaxin) -- Carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. Used for treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to their potential for toxicity. |
|---|---|
| Adult Dose | 500 mg IV q6h |
| Pediatric Dose | <12> >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with cyclosporine may increase CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Adjust dose in renal insufficiency; avoid use in children <12> |
| Drug Name | Meropenem (Merrem) -- Carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem. |
|---|---|
| Adult Dose | 1 g IV q8h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication |
| Drug Name | Clindamycin (Cleocin) -- Primarily used for its activity against anaerobes. Has some activity against streptococcus and methicillin-sensitive S aureus (MSSA). |
|---|---|
| Adult Dose | 600-900 mg IV q8h |
| Pediatric Dose | 5-10 mg/kg IV q8h |
| Contraindications | Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis |
| Interactions | Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Dose adjustment may be necessary in severe hepatic dysfunction; no adjustment is necessary in renal insufficiency; associated with severe and possibly fatal colitis |
| Drug Name | Metronidazole (Flagyl) or Ciprofloxacin (Cipro) -- Metronidazole: Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually employed in combination with other antimicrobial agents, except when it is used for Clostridium difficile enterocolitis in which monotherapy is appropriate. Ciprofloxacin: Fluoroquinolone with variable activity against streptococci, MSSA, S epidermidis, and most gram-negative organisms. No activity against anaerobes. |
|---|---|
| Adult Dose | Metronidazole: Loading dose: Infuse 15 mg/kg IV over 1 h or 1 g for a 70-kg adult Maintenance dose: Infuse 7.5 mg/kg IV over 1 h q6-8h or 500 mg for a 70-kg adult; administer 6 h following the loading dose; not to exceed 4 g in 24 h Ciprofloxacin: 1400 mg IV q12h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Metronidazole: Potentiates anticoagulant effect of warfarin; agents that alter hepatic P450 system affect its clearance; phenytoin and phenobarbital may decrease half-life; may reduce metronidazole clearance and increase toxicity; may increase effect of anticoagulants; may decrease lithium and phenytoin clearance, increasing their toxicity; disulfiramlike reactions may occur when used concurrently with orally ingested ethanol (although the risk for most patients may be slight, exercise caution) Ciprofloxacin: Antacids, iron salts, and zinc salts may interfere with GI absorption of fluoroquinolones, resulting in decreased serum levels; administer antacids 2-4 h before or after fluoroquinolones; cimetidine may interfere with metabolism fluoroquinolones and reduce therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations significantly; ciprofloxacin may increase theophylline and caffeine concentrations and prolong duration of action; may increase nephrotoxic effect of cyclosporine; digoxin serum levels may be increased when used concurrently with ciprofloxacin; monitor digoxin levels; may increase effects of anticoagulants; monitor PT |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Metronidazole: Pregnancy category B; adjust dose in patients with severe hepatic disease because they may metabolize metronidazole slowly; monitor patients for seizures and the development of peripheral neuropathy Ciprofloxacin: Pregnancy category C; in prolonged therapy, perform periodic evaluations of organ system functions, including renal, hepatic, and hematopoietic; patients diagnosed with renal function impairment may require a dose adjustment; prolonged or repeated antibiotic therapy may result in bacterial or fungal overgrowth of nonsusceptible organisms, resulting in secondary infections; take appropriate measures to prevent further complications |
| Drug Name | Drotrecogin alfa (Xigris) -- Indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1 (PAI-1) and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium. |
|---|---|
| Adult Dose | 24 mcg/kg/h IV continuous infusion for 96 h; ideally, initiate within 48 h of sepsis onset |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, presence of epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma) |
| Interactions | None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Bleeding is most common serious adverse effect; caution with conditions that increase risk of bleeding including INR >3, concurrent therapeutic heparin (>15 U/kg/h), within 6 wk of GI bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors administration, within 3 mo of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs |
| Drug Name | Dopamine (Inotropin) -- Used to treat hypotension in fluid-resuscitated patients. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation in health volunteers, but probably have no measurable effect in patients who are critically ill. Higher doses produce cardiac stimulation, tachycardia, and vasoconstriction. |
|---|---|
| Adult Dose | In hypotensive hyperdynamic shock: starting dose of 2-5 mcg/kg/min IV; titrate as needed to maintain a MAP >60 mm Hg; may be increased by 1-4 mcg/kg/min q10-30min IV until satisfactory response; not to exceed 20 mcg/kg/min Maintenance dose: <20> |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; tachycardia; pheochromocytoma; ventricular tachyarrhythmias |
| Interactions | Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAO inhibitors increase and prolong the effects |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Monitor urine flow, cardiac output, pulmonary wedge pressure, and BP closely during the infusion; prior to infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia |
| Drug Name | Norepinephrine (Levophed) -- As with dopamine, it is used to treat hypotension following adequate fluid-volume replacement. Norepinephrine stimulates beta 1-adrenergic and alpha-adrenergic receptors, which increase arterial tone and cardiac contractility. As a result, systemic BP and coronary blood flow increases with norepinephrine, though myocardial oxygen demand also may increase. After obtaining a response, adjust infusion rate to maintain a MAP greater than 60 mm Hg. BP levels below this threshold are insufficient to perfuse vital organs while increasing pressures much greater than 70 mm Hg, using vasopressors does not further increase tissue blood flow. |
|---|---|
| Adult Dose | 0.05-2 mcg/kg/min IV; titrate to effect |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; known hypovolemia; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended |
| Interactions | Atropine sulfate may enhance pressor response of norepinephrine by blocking reflex bradycardia caused by norepinephrine |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Correct blood-volume depletion, if possible, before administering norepinephrine therapy; extravasation may cause severe tissue necrosis, administer into a large vein; use with caution in patients with occlusive vascular disease |
| Drug Name | Vasopressin (Pitressin) -- Has vasopressor and antidiuretic hormone (ADH) activity. Although vasopressin does not increase BP in healthy subjects, it markedly increases vasomotor tone in patients with septic shock. It also increases water resorption at the distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction also is increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels. Vasopressin is not yet routinely used to treat hypotension in septic shock. The dosage of vasopressin used for hypotension is one-tenth that used to treat upper GI bleeding from varices. |
|---|---|
| Adult Dose | Suggested dose: 0.01-0.05 U/min IV; titrate dose as needed |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; coronary artery disease |
| Interactions | Lithium, epinephrine, demeclocycline, heparin, and alcohol may decrease the effects of vasopressin; conversely, chlorpropamide, urea, fludrocortisone, and carbamazepine potentiate its effects |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia |
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