INTRODUCTION
Sepsis is the most common cause of death in medical/surgical intensive care units. It occurs at an estimated incidence of more than 500,000 cases per year, with mortality rates ranging from 5%-90%, depending upon severity. The yearly incidence is increasing due to multiple factors, including; the aging of the population, increased use of invasive procedures and immunosuppressive agents, aggressive management of malignant
conditions, and the emergence of resistant organisms.

ACCM/SCCM DEFINITION
The lack of clear clinical and laboratory definitions for sepsis, and the resulting inconsistency in patient diagnosis, patient care, and clinical studies, led the American College of Chest Physicians and the Society of Critical Care Medicine (ACCP/SCCM) to convene a Consensus Conference in 1991. Its purpose was to agree on definitions in order to facilitate early recognition and therapy.^l At the conference, the terms 'sepsis', 'severe sepsis' and 'septic shock' were defined.  Bacteremia, which had been closely associated with sepsis as a predictor of poor prognosis, was determined inessential to establishing a diagnosis. The term 'septicemia' was abandoned, and the term systemic
inflammatory response syndrome (SIRS) was introduced (Table 2).

Systemic inflammatory response syndrome is the term applied to the diffuse inflammatory reaction as a result of any physiologic insult, such as trauma, bums, pancreatitis, toxins or infection. Regardless of etiology, SIRS is manifested  by two or more of the following symptoms: fever or hypothermia, tachycardia, tachypnea, and leukocytosis. SIRS involves all organs and cells, and is triggered by a host of endogenous inflammatory mediators. Once initiated, the inflammatory response may continue even after the inciting insult has been resolved. Although the SIRS definition is broad, it should be used to screen patients who are at risk for developing sepsis.

The SIRS criteria^21,32 have proved sensitive for early identification of patients with sepsis. A study of the history of  50% - 90% SIRS followed 2527 patients admitted to the hospital who met these criteria. Among them, 26% (649) developed sepsis,  18% (467) severe sepsis, and 4% (110) septic shock. The median interval and likelihood of progression to sepsis was related to the number of SIRS criteria met on presentation. The mortality rate increased from 6% if two out of four criteria were met, to 18% if all four criteria were met. The mortality rate progressed from 7% in SIRS to 46% in septic shock (Table 2).

*The goal is to recognize sepsis as early as possible and to initiate therapy immediately.

The progression from sepsis or severe sepsis to septic shocky with its increased mortality, may be prevented by the early initiation of appropriate antibiotic therapy.

Adapted from BoneRC⁶,  Rangel-Frallstd², Knaus²¹, Brun-Buisso⁹
*  Associated with twice the mortality rate of febrile patients
** Lethargy, stupor, coma, or disorientation to person, place, or time

In addition to antimicrobial therapy, measures to eliminate the source of infection should be pursued. Abscess cavities must be drained and intravascular devices or surgical prosthetic materials that are potential sources of infection may need to be removed.

Patients with hypotension and hypoperfusion may require as much as 10 liters of isotonic crystalloid fluids and I liter of colloids in the first 24 hours of resuscitation.

Fluid Resuscitation 

Fluid resuscitation is the first step in the management of hypotension/hypoperfusion due to sepsis. Hypovolemia is a common problem as result of vasodilation, capillary leak, poor intake and increased insensible fluid losses. The goals of therapy are to achieve a systolic blood pressure ³ 90 mm Hg, a heart rate of < 110 beats/min, and improvement in mental status and urine output. Patients with severe sepsis/shock may need large volumes of fluid to correct deficits. In the first 24 hours of resuscitation, as much as 10 liters of isotonic crystalloid fluids (normal saline or Ringer's lactate) and 1 liter of colloids may be required.^31,35 Fluids should be delivered through two large-bore peripheral IVs or a venous access central line as quickly as possible. Continue to monitor vital signs, urine output and mental status to assure that treatment goals are attained. ¹⁸

Vasopressors
When hypotension is not rapidly reversed by adequate fluid resuscitation, vasopressors or
inotropic drugs should be initiated (Table 5). Infusion through a large-bore IV or central
access venous line is preferred. Dopamine is the initial vasopressor of choice and should be
titrated to a maximum of 10 to 20 mcg/kg/min. Norepinephrine should be employed early in the course 
of shock if dopamine is ineffective. Once norepinephrine is started, dopamine should be rapidly reduced to a renal
dose of < 2 mcg/kg/min (Table 5).

If the patient remains hypotensive after aggressive resuscitation with fluids and
pressors, evaluate prescription medications taken within the last 24 hours. Withold any
medications which may impact blood pressure (e.g. calcium channel blockers, beta blockers,
ACE inhibitors) until the patient is hemodynamically stable.

If the patient has hypotension that is refractory to fluids and pressors, a random cortisol level
should be drawn, and the patient started on a stress dose of hydrocortisone (300-400 mg/d)
until the random cortisol level is available. The ACTH (cosyntropin) test is not required in
an emergency situation.

Titrated to achieve MAP³ 60-70 mm Hg
Titrated to achieve MAP³ 60-70 mm Hg and cardiac index > 2.8 liters

Even in the absence of adrenal failure, a significant improvement in hemodynamics
and a trend towards improved 28-day mortality have been documented in recent studies using
hydrocortisone. The patients with pressor-dependent septic shock were administered
modest doses of hydrocortisone for a mean of > 96 hours.^5,8The dosage used in the first 24
hours was a 100 mg hydrocortisone IV bolus, plus a continuous IV infusion of 200-300 mg
over 24h. These studies reflect that, in the setting of pressor-dependent septic shock, this
dosage of hydrocortisone should be strongly considered and administered for 3-5 days.

This practice is in strong contrast to previous use of high-dosage corticosteroid. (two grams
of methylprednisolone). Several studies have shown that the use of high-dose corticosteroids
results in higher mortality, and currently is not advised. ^7,37

Hemodynamic Monitoring
(Pulmonary Artery Catheter)
If the patient shows evidence of persistent hypoperfusion after adequate fluid
resuscitation and pressor agents have not achieved resuscitation goals, then
hemodynamic monitoring should be considered. In the presence of coronary
disease, renal dysfunction or pulmonary edema, hemodynamic monitoring may be
required to guide further titration of fluids and pressors.²⁶ There is ongoing debate about the
value of this procedure, since no clinical studies have shown that the use of pulmonary
artery catheters has improved patient outcomes.¹² Therefore, they should be used in
appropriately selected patients and managed by an experienced team of critical care physicians
and nurses.²⁹ Treatment with inotropes to increase cardiac output and oxygen delivery to
supra-normal levels has not been shown to improve outcomes. ⁵ In the presence of
hemodynamic monitoring, the treatment goals should be MAP  ³60-70 mm Hg and
cardiac index > 2.8 liters.

CLINICAL MANIFESTATIONS
Mental Status
Altered mental status due to sepsis encephalopathy is more common in elderly
patients and is associated with more than twice the mortality. Therefore, sedation or narcotics
should be avoided as much as possible in sepsis patients, in order to aid diagnosis.

Hypothermia
Hypothermia is found in 9%-13% of patients and especially in the elderly. The methyl-
prednisolone sepsis study ¹¹ found a higher failure to recover from shock (66% vs. 26%)
and more than twice the mortality rate (62% vs. 26%) in hypothermic patients (< 96° F)
when compared with febrile patients.

Pulmonary Manifestations
The earliest pulmonary responses are tachypnea and respiratory alkalosis, which are
probably caused by the mediators of sepsis. Subsequent ventilation-perfusion mismatch
frequently results in hypoxemia with a normal chest x-ray. As sepsis progresses, capillary
leak/edema with increasing shunt, airway resistance, and dead space also contribute to
ventilatory failure and hypoxemia. In addition, fever, shivering and increased carbon
dioxide production lead to very high minute ventilation demands in sepsis, SIRS, or acute
respiratory distress syndrome (ARDS) patients.²⁰

The metabolic acidosis and increased minute ventilation of sepsis place a very high demand
on the respiratory pump (i.e. the diaphragm and intercostal muscles). These muscles have
a limited ability to meet the ventilatory demand because of poor perfusion, hypoxemia.
acidosis, and electrolyte imbalance. Studies have shown muscle contractile force to be
reduced by 20%-30% in sepsis.¹⁹ As sepsis progresses, respiratory muscle fatigue occurs
rapidly and results in respiratory acidosis and eventual arrest. Therefore, early intervention
with endotracheal intubation and mechanical ventilation is very important.

It is crucial to review the patient or agent's preferences for aggressive treatment and
to document code status as the clinical situation and prognosis evolve.

Mechanical Ventilation
The recognition of respiratory acidosis and impending respiratory failure in a patient with
metabolic acidosis is important and may be easily overlooked. In simple metabolic
acidosis, the respiratory compensation results in low pCO².  As the respiratory pump fatigues,
the pCO², rises, signaling imminent respiratory arrest. Calculate the predicted ², in simple
acidosis by either of the methods listed in the box below.^*27

If the pCO² on arterial blood gas measurements is higher than the calculated
pCO² the patient is showing evidence of respiratory muscle pump fatigue. Most
likely, the patient needs intubation and mechanical ventilation, particularly if the
fatigue is associated with altered mental status, tachypnea, or hypoxemia. Non-
invasive mechanical ventilation (BiPAP) in patients with respiratory failure due to
sepsis/ARDS is not indicated, and delaying endotracheal intubation may result in a poor
outcome. These patients should be kept on NPO status until respiratory and mental status
are stable or improved.
 

Multiple Organ Dysfunction (MOD)

CONTACT INFORMATION
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Permanente computer network.
The Permanente Medical Group (TPMG) clinical practice guidelines and statements have been developed
to assist clinicians by providing an analytical framework for the evaluation and treatment of selected
common problems encountered by patients. These guidelines and statements are not intended to establish
a protocol for all patients with a particular condition. While they provide one approach to evaluating a
problem, clinical conditions may vary significantly from individual to individual. Therefore, the clinician
must exercise independent judgment and make decisions based upon the situation presented. While
great care has been taken to assure the accuracy of the information presented, the reader is advised that TPMG 
cannot be responsible for continued currency of the information
for any errors or omissions in this statement, or for any consequences arising from their use.

DISCHARGE EVALUATION
Once the patient has responded to treatmen and his/her vital signs have stabilized, plans
for discharge should be initiated. The patient may be discharged to the home, to home
health care, or to a skilled nursing facility.

The following should be evident before patient discharge is considered:
*Temperature normal or normalizing
*White blood cell count returning to normal
*Respiration rate at or near baseline
*Q² , saturation ³ 90% with or without oxygen or at baseline
*Pneumococcal and influenza vaccine given, as appropriate