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Kaiser Diagnostic and Treatment Documents 

NOVEMBER 1999 KAISER PERMANENTE CLINICAL PRACTICE STATEMENT for ADULT SEPSIS

ENDORSED BY: CHIEFS OF CRITICAL CARE CHIEFS OF EMERGENCY MEDICINE CHIEFS OF MEDICINE CHIEFS OF SURGERY HBS PEER GROUP REGIONAL CHAIRS OF PULMONARY MEDICINE SUB-CHIEFS OF INFECTIOUS DISEASE

GUIDING PRINCIPLES Prevention of sepsis is facilitated by: recommending vaccinations, such as pneumovax and influenza; the appropriate early treatment of pneumonia, urinary tract, and other infections; use of sterile precautions; routine hygiene; and judicious use of Foley catheters and other invasive devices. See Table I for conditions leading to high risk for sepsis. The early recognition of sepsis is vital to prevent disease progression and increased risk of mortality. It is important to continually monitor vital signs, urine output and mental status and to pay close attention to deteriorating trends. See Table 2 for definitions of different stages of sepsis. Septic patients require rapid treatment tuith antibiotics and fluids. Do not delay antibiotic treatment if cultures can not be readily obtained. See Tables 3 and 4 for antimicrobial recommendations and treatment algorithm. 

 

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Determine advance directives, patient preferences for care, and establish code status with a physician order.  These should be documented and respected at all times, and treatment plans modified accordingly.

Many recent studies evaluating innovative therapies have failed to show any improvement inpatient outcomes.  Therefore, this clinical practice statement emphasizes standard therapies.

TREATMENT GOALS Attain the following treatment goals as rapidly as possible. See Table 4 for treatment algorithm.

* Systolic blood pressure ³90 mm Hg or MAP ³6 0-70 mm Hg *SaO₂  ³90% * Urine output > 0.5cc/kg/hr * Resolving acidosis * Improved mental status

The goal of the clinical practice statement - to promote early recognition of sepsis in adults to facilitate early intervention in order to reduce morbidity and mortality.

Audience - all phy­si­cians treating patients in the hospital and emergency depart­ment, hospital and emergency nurses, as well as phy­si­cians and nurse practitioners seeing patients in the outpatient and urgent care setting.

Development - by a multidisciplinary team of intensivists, hospital based specialists, emergency and primary care phy­si­cians, and emergency and intensive care nurses. Widely reviewed throughout the Northern California region. To be reviewed at least every two years and revised as needed.

Foundation - due to insufficient evidence from large, randomized, controlled clinical trials, the Statement is based upon standard practice, expert opinion, and, when available, well- designed, randomized, controlled clinical trials.

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.

Certain segments of the population are particularly prone to developing sepsis.Preventive measures, such as the pneumovax and influenza vaccines and limited use of invasive devices, are vital for these groups. It is especially important to consider sepsis in any high-risk patient who meets the criteria for systemic inflammatory response syndrome (SIRS). Table I. Conditions Leading to High Rick for Sepsis

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*Age > 65 * Chronic liver disease *Chronic lung disease *Chronic renal disease *Diabetes mellitus *Heart disease *Hematologic disorder *Immunodeficiency *Indwelling catheters *Infection in previous year *Malignant neoplasm *Non-cardiac vascular disease *Organic cognitive disorder *Spinal cord injury *Substance abuse *Adapted from Quartin,³⁰ Kreger²⁴

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.

*A patient can progress rapidly from sepsis to septic shock even when treated appropriately. Term Definition Predicted Mortality Rate Systemic Inflammatory Response Syndrome (SIRS) At least 2 of the following: *Hypothermia < 96.1°F*  *Body temperature > IO1° F   (Note: tympanic temperature may be unreliable) *Tachypnea (respiration > 20 breaths/min   or minute ventilation > 10 L/min) *Tachycardia ( > 90 beats/min) *WBC >12K cells/³ or < 4Kcells/mm³ or > lO% band 5% - 10% Sepsis SIRS plus clinical evidence of any infection that could lead to rapid & significant physiological deterioration (as in severe sepsis or septic shock) 5% - 16% Severe Sepsis Sepsis plus altered organ per fusion with at least one of the following: *Acute mental status change** *Hypoxia (PO² < 60 mm Hg on room air) *Increased lactic acid or metabolic acidosis   Oliguria < 0.5 cc/kg/hr 20% - 25% Septic Shock Severe Sepsis with hypotension: *Systolic BP < 90 mm Hg or drop in MAP > 40 mm from baseline *Responsive to IV fluids and pressors 25% - 50% Refractory Septic Shock Septic shock which: *Does not respond to initial fluids *Requires high doses of pressors 40% - 60% Multiple-Organ Dysfunction (MOD) Altered organ function * See Table 6 50% - 90%

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

Table 3. Empirical Choice of Antimicrobial Regimes for Sepsis Unknown Source Gram (-) bacilli ® Gentamicin or Tobramycin* (slow IV) 5 mg/kg/dsingle dose plus 3rd generation cephalosporin Pulmonary Strep pneumoniae, Gram () bacilli Less Common: Hemophilus, Anaerobes, Legionella If atypical pneumonia is likely ® ® Cefotaxime 2gmq 8h or Cefuroxime 750-1500 mgq 8h or Ceftriaxone 1-2 gm q 24h or Levofloxadn (NF) 500mgq 24h Add Azithromycin (NF)500mgq 24h to beta-lactams Urinary Gram (-) bacilli Enterococcus ® ® Gentamicin or Tobramycin* (slow IV) 5 mg/kg/d single dose or Ceftizoxime 1-2 gm q 8h Ampidilin 2gm q 6h Intra-Abdominal Gram(-)bacilli. Anaerobes

Enterococcus

® ® Gentamicin or Tobramycin* (slow IV) 5mg/kg/dsingle dose plus Clindamydn 600-900 mgq8h or Ceftizoxime 1-2 gm q 8h or Cefotetan l'2 gm q 12h plus Metronidazole 500 mgq8h Consider adding Ampicillin to all of the above regimens Cardiovascular (Endocarditis, IV-cathetev related) Staph aureus Strep species, Gram (-) bacilli

Candida

® ® ® Nafdilin 2 gm q 4-6h or Cefazolin l-2 gm q 8h Gentamicin or Tobramycin* (slow IV) l-2mg/kg/d BID dosing plus Ampicillin 12 gm/d as q 4-6h or continous infusion or plus Penicillin 12-18 Mu/das q 4-6h or continuous infusion or plus Ceftriaxone 2 gm q 24h Fluconazole 400 mg q 24h or Amphoteridn B 0.5-1.0 mg/kg q 24h Central Nervous System Meningitis: Pneumococci Meningococci (less common) Listeria (less common) Abcess: Staph, Strop, Gram (-) bacillli, Anaerobes ® ® ® ® Vancomycin 1 gm q 12h plus Ceftriaxone 2 gm q 12h until resistance known Ceftriaxone 2 gm q 12h Ampicillin 2-3 gm q 4h or 18gm/d as continuous infusion Ceftriaxone 2 gm q 12h plus Metronidazole 500 mg q 8h Soft Tissue & Skin Cellulitis: Staph aureus Necrotizing fasditis: Strep ® ® Cefazolin l-2 gm q 8h or Clindamycin 900 gm q 8h Clindamycin 900 gm q 8h plus Ciprofloxacin 400 mg q 12h Neutropenic Patients⁴ Gram (+) & Gram (-) bacilli Fungi ® ® Ceftazidime l-2 gm q 8h with or without Gentamicin or Tobramycin* (slow IV) 5mg/kg/d single loading dose Fluconazole 400 mg q 24h or Amphotericin B 0.5- 1.0mg/kg q 24h *  Adjust Gentamicin or Tobramycin dosage for renal function per pharmacy protocol.  Quantities over 200mg should be given over at least two hours.

NF - Not in formulary

I  Not all scenarios can be covered in this table.  Call the Infectious Disease consultant prn, especially if resistant organisms are suspected.  Revise medication immediately upon receipt of identification and sensitivity results. 2  Choices are not listed in order of preference.  Discuss with local Infectious Disease consultant prn. 3  May need adjustment in cases of renal and/or hepatic dysfunction. 4  For man­age­ment of oncology patients with chemotherapy-induced neutropenia, refer to your local protocol or the on-line clinical library.

TABLE 4. TREATMENT ALGORITHM FOR SEPSIS (Systemic Inflammatory Response Syndrome with Clinical Evidence of Potentially Serious Infection) ASSESSMENT & MONITORING DIAGNOSTIC MEASURES TREATMENT TREATMENT GOALS Evaluate: *Temperature

*Blood pressure

*Heart rate

*Respiratory rate

*Pulse oximetry

*Mental status

Determine source of sepsis and rule out non-infectious causes (e.g. pancreatitis, drugs, toxins): *Cultures: 2 sets of blood cultures;urine, sputum, CSF and other sites as indicated *UA *CBC *Glucose *Na, K, Cl, HCO₃,  Creatinine *12-lead ECG *Chest X-ray *Review previous history of infection Consider: *Bilirubin and SGPT *Amylase *PT/PTT (consider fibrinogen, D-dimer if  indicated) *ABG (if hypoxemia or metabolic acidosis is present) *Random cortisol level *Urine gram stain Continue search for source of occult infection: *Ultrasound *Spinal tap *CT scan Sepsis: *Antibiotics to treat expected source,or broad-spectrum (see Table 3)must be administered immediately *Maintain hydration *NPO status until respiratory & mental status are stable/improved

Severe sepsis, add: *Rapid fluid resuscitation - 1 to 4 liters of isotonic crystalloids with frequent monitoring of changes in BP, urine output, SaO₂ Frequent clinical assessment for complications, such as pulmonary edema

*Supplemental high dose oxygen to maintain SaO₂ ³90%. Consider intubation if patient has signs of respiratory fatigue or pulmonary edema

*Septic shock, add: *If adequate  organ  perfusion  cannot be rapidly achieved with fluid resuscitation, pressor agents should be administered, preferably through a large bore, peripheral IV or central venous access line

*Systolic blood pressure ³ 90 mm Hg or MAP ³ 60-70 mm Hg SaO₂ ³ 90% *Urine output > 0.5 cc/kg/hr * Improved mental status Advance directives, patient preferences for care and code status should be determined and documented. The patient or agent's preferences should be respected at all times, and treatment modified accordingly

The Next 12 Hours ASSESSMENT * MONITORING DIAGNOSTIC MEASURES TREATMENT TREATMENT GOALS Frequent monitoring: *Temperature *Urine output *Blood pressure *Mental status *Heart rate *Respiratory rate *Metabolic acidosis *Pulse oximetry

Consider: *Arterial line if patient remains hypotensive on pressors *Hemodynamic monitoring with pulmonary artery catheter for selected patients (renal failure, pulmonary edema, fluid status unknown)

Repeat lab tests to assess therapy, as clinically appropriate: *Need for pRBCs *ABG *Check gram stains, if  available *CBC *Electrolytes *BUN *Creatinine *Glucose *K *Lactic acid/anion gap *DIC panel Sepsis: *Continue antibiotics *Maintain hydration Severe sepsis/Septic shock, add: *Up to 10 liters of crystalloids (and up to 1  liter of colloids if necessary) in first 24 hours (for shock/hypoperfusion) to achieve treatment goals *Continue infusion of pressors to achieve treatment goals General measures: *Stress ulcer prophylaxis *DVT prophylaxis For persistent hypotension: *Consider adrenal insufficiency *Is the patient being treated with calcium channel blockers or other hypotensive medi­ca­tions? *Consider early intubation for respiratory distress or impending failure. *Systolic blood pressure ³90 mm Hg or MAP³ 60-70 mm Hg Sa02₂ ³ 90% *Urine output > 0.5cc/kg/hr *Improved mental status *Acidosis resolving Subsequent Care ASSESSMENT & MONITORING DIAGNOSTIC MEASURES TREATMENT Reassess all clinical parameters as before, and determine if patient is at appropriate level of care.

Evaluate complications of therapy, e.g.: *ATN *Pulmonary edema *Altered mental status *Hypotension

Continue to monitor for clinical stability & organ function: *CBC *Electrolytes/anion gap *BUN *Creatinine *Glucose *SGPT, bilirubin *Mg and K *DIC panel, as appropriate *ABG, as appropriate Consider: *Hemodynamic monitoring with pulmonary artery catheter for selected patients (renal failure, pulmonary edema, fluid status unknown) Ongoing support of organ function:

*Maintain fluids to support resuscitation goals, e.g. blood products *Dialysis *Ventilator support Re-evaluation of antibiotic therapy based on culture results Resume patient's regular medi­ca­tions, as appropriate

General measures: *Nutrition *DVT prophylaxis *Stress ulcer prophylaxis *Psychosocial support *Physical therapy *Discharge planning

 

TREATMENT GOALS

*Systolic blood pressure ³  90 mm Hg or MAP³  60-70 mm Hg SaO₂ ³  90%

*Urine output > 0.5 cc/kg/hr *Improved mental status *Acidosis resolving

Advance directives' patient preferences for care and code status should be determined and documented, The patient or agent's preferences should be respected at all times, and treatment modified accordingly. Hebert ¹⁶ Knaus²¹, Herbert¹⁷,  Bakker³, Hayes¹⁵

DIAGNOSIS & TREATMENT

Sepsis has myriad clinical manifestations. The goal is to recognize sepsis as early as possible and to initiate therapy immediately. See Table I for groups at high risk for sepsis.

The progression from sepsis or severe sepsis to septic shock, with its increased mortality, may be prevented by the early initiation of appropriate antibiotic therapy. Frequently, sepsis does not have a source that can be quickly identified. In that case, broad spectrum antibiotic coverage for both Gram nega­tive and Gram positive organisms is recommended in the initial hospital course. Antibiotic therapy may need to be adjusted according to additional information obtained in the course of hospitalization.

Cultures of blood, and other appropriate sources, such as urine and sputum, or of spinal, peritoneal, pleural, or joint fluids, should be obtained rapidly, preferably before the institution of antibiotic therapy. However, therapy must not be delayed if cultures cannot be rapidly obtained. It is also important to obtain baseline tests of organ function for future comparison in the event of organ dysfunction (Table 6). If initial evaluation does not reveal the source of sepsis, continue to search for an occult source, such as sub-acute endocarditis or intra-abdominal process.

Septic patients may not be febrile, and may be hypothermic. The absence of a fever does not rule out sepsis and may, infact, portend a poorer prognosis. Patients may be afebrile because of unappreciated antipyretic use prior to presentation. In the patient with severe sepsis, initiate fluids and antibiotics as rapidly as possible. A patient can progress quickly from sepsis to septic shock even when treated appropriately.

Antibiotics Early institution of empiric antibiotic therapy is of great importance in the man­age­ment of sepsis (Table 3). When choosing initial antibiotics, consider factors such as the presumed site of infection and the likelihood of nosocomial infection with resistant species.

Pulmonary infections are the most common source, followed by genitourinary and gastro-intestinal, depending upon the population. Empiric antibiotic therapy for septic shock usual­ly includes mul­ti­ple drugs. Advantages include a greater likelihood of antibiotic coverage against the infecting agent, prevention of the emergence of resistant strains, and possible synergistic antibacterial activity of some combinations. The disadvantages include increased risk of toxicity, super-infection with opportunistic organisms (e.g. fungi), and possible antagonism of antibacterial activity.

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

CRYSTALLOIDS & COLLOIDS

Multiple studies have shown that patients in septic shock may be resuscitated with crystalloids, with or without colloid solutions. These studies show no significant difference in mortality rates using colloids compared with crystalloids as long as appropriate resuscitation goals are reached. ^10,34 Crystalloid fluids are preferred for resuscitation.

If resuscitation goals are not achieved after 4-6 liters of crystalloids, some clinicians add colloids. Studies have shown that adding colloids will increase blood pressure and cardiac index more rapidly and with less volume than crystalloids alone. This is crucial, since leaving the patient with persistent hypotension and hypoperfusion will result in mul­ti­ple organ dysfunction and higher mortality. Larger, well-designed, randomized trials will be required to detect potentially small differences in treatment effects, mortality, and pulmonary function, if they truly exist. Hetastarch (Hespanâ) and albumin are the most commonly used colloids. Colloid resuscitation can be initiated with a bolus of 250 cc of hetastarch, and repeated as needed.31 This is as effective as albumin and may have fewer adverse effects.^l4 Fresh frozen plasma is useful if the patient has coagulopathy (e.g. INR > 2).

While aggressive fluid resuscitation may lead to pulmonary edema, this concern should not dissuade phy­si­cians from using large amounts of IV fluids when organ hypoperfusion is present.

Patients with rales, decreasing oxygen or increased respiratory rate should have a chest x-ray.

Fluid resuscitation should not be discontinued unless the x-ray reveals pulmonary edema in the presence of worsening respiratory failure.

RED BLOOD CELL COUNT

The minimum maintenance range for hemoglobin in critical care patients is thought to be 7-9 gm/dL after considering blood flow, oxygen delivery and coronary ischemia. For patients with signs of hypoperfusion, coronary disease or bleeding, hemoglobin may need to be maintained at a higher level. ¹⁷

Code Status & Advance Directives Sepsis treatment may require the use of mechanical ventilation and pressor agents. These aggressive measures are used in refractory septic shock, which has a predicted mortality of 40%-60%, and in mul­ti­ple organ dysfunction, with a predicted mortality of 50%-90%. The patient's wishes regarding code status, mechanical ventilation, the use of pressors and other treatments should be discussed in the context of the diagnosis of sepsis and existing comorbidities.  They should be reviewed with the patient or agent (in cases of altered mental status), written in the orders and respected throughout treatment.

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.

Adrenal InsufficiencyAdrenal insufficiency should be considered in patients with septic shock who do not respond to fluids and pressors.³⁶ It is thought to occur in 30%-40% of critically ill patients, but can be easily overlooked. Adrenal failure/insufficiency or hemorrhage is found on autopsy in 30%-50% of patients in refractory septic shock.  It is vital that phy­si­cians be aware  that this is a treatable component of shock. The classic laboratory features of hyponatremia, hyperkalemia and acidosis are often absent, and should not be relied upon. Since the use of short-duration stress-dose steroids is safe, it is advisable to over-suspect and treat, rather than miss this diagnosis.²⁸

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.

Studies have documented that patients with normal adrenal function under stress, such as surgery, sepsis or hypotension, will have random cortisol levels > 20 mcg/dL. If the random level is < 20, steroids should be continued, as adrenal failure is likely.

AGENT USUAL DOSE COMMENTS Dopamine 2.0 mcg/kg/min; titrated to maximum dose of 20 mcg/kg/min Initial agent recommended  by most dinicians for man­age­ment of septic shock.ls Avoid during coronary ischemia if possible. May cause angina or tachycardia, or increase likelihood of infarction Norepinephrine 0.05 mcg/kg/min; increase to 0.5 mcg/kg/min Usually effective in raising BP in patients with septic shock who have not responded to fluids and dopamine.¹³  Consider if patient isnot responding to 10-20 mcg/kg/min of dopamine^15,25 or suffers from excessive tachycardia.  Use of low-dose dopamine concurrently with norepinephrine may helppreserve renal perfusion and urine output.33 Epinephrine 0.1  mcg/kg/min;  increase to 0.5 mcg/kg/min In high doses produces increase in cardiac output and BP, even in patients who do not respond to norepinephrine. Increases heart rate and myocardial oxygen consumption; may precipitate myocardial ischemia. Must be used with care, particularly in older patients. Dobutamine² (for use in the ICU only, with hemodynamic monitoring) 2 mcg/kg/min; increase to 20 mcg/kg/min May improve myocardial performance and oxygen delivery in septic shock. May cause beta-adrenergically mediated vasodilation; may worsen hypotension caused by decrease in systemic vascular resistance. Likely to be most beneficial in patients whose cardiac output is not elevated (cardiac index < 2.8 liters) and who have low oxygen delivery 800 ml/min) and lactic acidosis.15 Should be used only if SBP is > 90 mm Hg.

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.  

Calculation of Predicted CO²

Expected pCO²: a.  [(Measured HCO³ x 1.5)+8] ± 2 OR  b. ³ the last 2 digits of the pH Example of ABG showing respiratory muscle fatigue pH = 7.20, measured pCO²= 28, measured serum HCO³ = 8 [8 x  1.5]+8 ± 2 = 20 ± 2 Thus, the expected pCO ²should be from 18-22. Since the measured pCO² = 28, this patient has both respiratory acidosis and metabolic acidosis. *These formulae do not apply to patients with chronic CO, retention.

Multiple Organ Dysfunction (MOD)

CONTACT INFORMATION Kaiser Permanente Northern California TPMG Department of Quality and Utilization 1800 Harrison Street, 4th floor Oakland, CA 94612 510-987-2950 or tie-line 8-427-2950 To obtain more information about KPNC Clinical Practice Guidelines and Statements, printed copies. or permission to reproduce any portion, please contact the TPMG Dept. of Quality & Utilization, or send an e-mail message to clil.EiC.l~l.gzlidelilzes@kp. org KPNC Clinical Practice Guidelines and Statements can be viewed on-line on the Kaiser Permanente Northern California intranet website at htt{)://clinical 'library, ca. kp. org CME Credit: ContinumH Education Credit for phy­si­cians and nurses is available for review ol Statement. The CME Pro- and Post-Tests are available on-line at the above website address. This website is accessible only from the Kaiser

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.

Copyripht 1999 The Permanente Medical Group, Inc. Rapid and appropriate resuscitation in shock is important to prevent mul­ti­ple organ dysfunction (see Table 6 for criteria). The etiology of MOD is very complex and not yetclearly understood. A patient's prognosis is related to age and the number of organ systems involved. The average risk of death increases by 20 percent with the failure of each additional organ system.^22,16 Several studies have shown^4,9,21,32 that mortality was 30-40% with single organ dysfunction, greater than 60% with two dysfunctional systems and more than 90% in patients with three or more dysfunctional systems.

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

Table 6. Criteria for Organ System Dysfunction Respirator Dysfunction or  Acute Lung Injury All of the following: * Chest X-ray bilateral infiltrates

CONTACT INFORMATION Kaiser Permanente Northern California TPMG Department of Quality and Utilization 1800 Harrison Street, 4th floor Oakland, CA 94612 510-987-2950 or tie-line 8-427-2950 To obtain more information about KPNC Clinical Practice Guidelines and Statements, printed copies. or permission to reproduce any portion, please contact the TPMG Dept. of Quality & Utilization, or send an e-mail message to clil.EiC.l~l.gzlidelilzes@kp. org KPNC Clinical Practice Guidelines and Statements can be viewed on-line on the Kaiser Permanente Northern California intranet website at htt{)://clinical 'library, ca. kp. org CME Credit: ContinumH Education Credit for phy­si­cians and nurses is available for review ol Statement. The CME Pro- and Post-Tests are available on-line at the above website address. This website is accessible only from the Kaiser

Permanente computer net­work.

CONTACT INFORMATION Kaiser Permanente Northern California TPMG Department of Quality and Utilization 1800 Harrison Street, 4th floor Oakland, CA 94612 510-987-2950 or tie-line 8-427-2950 To obtain more information about KPNC Clinical Practice Guidelines and Statements, printed copies. or permission to reproduce any portion, please contact the TPMG Dept. of Quality & Utilization, or send an e-mail message to clil.EiC.l~l.gzlidelilzes@kp. org KPNC Clinical Practice Guidelines and Statements can be viewed on-line on the Kaiser Permanente Northern California intranet website at htt{)://clinical 'library, ca. kp. org CME Credit: ContinumH Education Credit for phy­si­cians and nurses is available for review ol Statement. The CME Pro- and Post-Tests are available on-line at the above website address. This website is accessible only from the Kaiser

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.

Copyripht 1999 The Permanente Medical Group, Inc.

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.

Copyripht 1999 The Permanente Medical Group, Inc. * PAO²/FiO² ratio < 175 * PA wedge pressure < 18 (measured by PA catheter) Neurologic Dysfunction Any of the following: * Glasgow Coma Scale < 11 * Seizure * New stroke Renal Dysfunction *Serum creatinine concentration > 2 mg/dL or doubling from baseline or *Acute dialysis Hepatic Dysfunction Any of the following: * Serum bilirubin value > 6 mg/dL * Serum amylase value > 1000 IU/L * Transaminase > 2 x normal * Ischemic bowel * Albumin < 2.0 gm/dL * PT > 4 seconds above normal  INR > 2 Hematologic Dysfunction Any of the following:  WBC count < 1000 cells/mm³  Platelet count < 20,000 cells/mm³  Hematocrit < 20% * Disseminated intravascular coagulation (DIC) by laboratory data Cardiovascular Dysfunction Any of the following: *Recent  myocardial  infarction  ( 3  days  previously) *Symptomatic ventricular or atrial arrhythmias *Systolic BP < 90 mm Hg, not secondary to sepsis or low filling pressure *MAP < 50 mm Hg

Modified from Rangel-Frausto³², Hebert, ¹⁶ andKollef²³  

REFERENCES 1.  American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992:20: 864-74.

2.  Annane D, Jars-Guincestre MC, Paraire F. Incidence of bilateral hemorrhagic necrotic adrenals in patients with septic shock: a necropsic study. Abstracts of the 6th European Congress on Intensive Care Medicine. Barcelona, Spain. Int Care Med 1992:18: Suppi. 2, S179.

3.  BakkerJ, Coffemils M, Leon M, et al. Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock. Chest 1991:99:956-62.

4.  Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s: systemic inflammatory response and organ dysfunction. JAMA 1994; 271:226-33.

5.  Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supra- physiologic doses of hydrocortisone. Crit Care Med 1998:26:645-50.

6.  Bone RC. .Let's agree on terminology: definitions of sepsis. Crit Care Med 1991;19:973-6.

7.  Bone RC, Fisher CJJr, Clemmer TP, et al. A controlled clinical trial of high-dose methyl- prednisolone in the treatment of severe sepsis and septic shock. NEnglJMed 1987:317: 653-8.

8.  Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double- blind, single-center study. Crit Care Med 1999;27:723-32.

9.  Brun-Buisson C, Doyon F, CarletJ, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995:274:968-74.

10.  Choi PT-L, Yip G, Quinonez LG, et al. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med 1999;27: 200-10.

Clemmer TP, Fisher CJJr, Bone RC, et al. Hypothermia in the sepsis syndrome andclinical outcome. TheMethylprednisolone Severe Sepsis Study Group. Crit Care Med 1992;20:1395-401.

Connors AFJr, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients.

SUPPORT Investigators. AMA 1996:279: 889-97.

Desjars P, Pinaud M, Potel G, et al. A reappraisal of norepinephrine therapy in human septic shock. Crit Care Med 1987;15:134-7.

Ernest D, Belzberg AS, Dodek PM. Distribution of normal saline and 5% albumin infusions in septic patients. Crit Care Med 1999:27:46-50. Hayes MA, Timmins AC, Yau EH, et al. Oxygen transport patterns in patients with sepsis syndrome or septic shock: influence of treatment and relationship to outcome. Crit Care Med 1997:25:926-36. Hebert PC, Drummond AJ, Singer J, et al. A simple mul­ti­ple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. Chest 1993; 104:230-5.

Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. NEnglJMed 1999;340:409-17. HopkinsJA, Shoemaker WC, Chang PC, et al. Clinical trial of an emergency resuscitation algorithm. Crit Care Med 1983:11:621-9. Hussain SN, Sirnkus G, Roussos C. Respiratory muscle fatigue: a cause of ventilatory failure in septic shock. JApplPhysiol 1985; 58:2033-40.

Kiiski R, TakalaJ. Hypermetabolism and efficiency of CO₂, removal in acute respiratory failure. Chest 1994;105:1198-203. Knaus WA, Sun X, Nystrom 0, et al. Evaluation of definitions for sepsis. Chest 1992:101: 1656-62.

Knaus WA, Wagner DP. Multiple systems organ failure: epidemiology and prognosis. Crit Care lin 1989:5:221-32.Kollef MH, Eisenberg PR. The relationship of the ACCP/SCCM Consensus Conference classification of sepsis to mortality and multi-organ dysfunction among medical ICU patients.J Intensive CareMed 1996:11: 326-32.

Kreger BE, Craven DE, McCabe WR. Gram-nega­tive bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. AmJMed 980;68:344-55. Meadows D, Edwards JD, Wilkins RG, et al. Reversal of intractable septic shock with norepinephrine therapy. Crit CareMed 1988:16:663-6.

Mimoz 0, Rauss A, Rekik N, et al. Pulmonary artery catheterization in critically ill patients: a prospective analysis of outcome changes associated with catheter-prompted changes in therapy. Crit CareMed 1994:22:573-9. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine (Baltimore) 1980;59:l6l-87. Oelkers W. Adrenal insufficiency. NEnglJMed 1996:335:1206-12.

The Pulmonary Artery Catheter Consensus Conference; consensus statement. Crit Care Med 997;25:910-25. Quartin AA, Schein RM, Kelt DH, et al. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA 1997:277:1058-63.

Rackow EC, FalkJL, Fein IA, et al. Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crsit are Md 193:11:839-50.

Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective sMy.JAMA 1995:273:117-23. SchaerGL,FinkMP,ParrilloJE. Norepinephrine alone versus norepinephrine plus low-dose dopamine: enhanced renalblood flow with combination pressor therapy.

Grit are Md 195:13:492-6. Schierhout G, Roberts 1. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. MJ 1998:316:961-4.

35.  Shoemaker WC, Appel PL, Kram HB, et al. Hemodynamic and oxygen transport monitoring to titrate therapy in septic shock. NewHoriz 1993:1:145-59.

36.  Soni A, Pepper GM,WyrwinskiPM, etal. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. ArnJMed 1995:98:266-71.

37.  The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. NEnglJMed 1987:317:659-65.

ACKNOWLEDGMENTS

Clinical Leader Nazir Habib, MD; Intensivist, Vallejo Work Group

Doug Chartier, MD; Chief of Utilization Management, Oakland

Jay Colas, RN; Assistant Manager, Emergency Department, Walnut Creek

Janice Manjuck, MD; Intensivist, San Francisco

Bill Plautz, MD; Emergency Medicine, South San Francisco

Terry Segeike, RN; Intensive Care Unit, Vallejo

Kurt Swartout, MD; Hospital Based Specialist, Sacramento

Project Management

Laura Finkler, MPH; TPMG Department of Quality & Utilization

Kathleen Martin; TPMG Department of Quality & Utilization Reviewers

Reviewers who made significant contributions to the text:

Tricia Bell, MD; Intensive Care/Internal Medicine, San Rafael

Eric Koscove, MD; Chief of Emergency Medicine, Santa Clara

Chinh Le, MD; Chair, Chiefs of Infectious Disease, Santa Rosa

Lou Lehman, MD, Co-Chair, Regional Hospital Based Specialists and Chair, Regional Chiefs of Critical Care, San Francisco

Lisa Hammer Reig, PharmD, Divisional Drug Information/Professional Services, Southern California

David J. Witt, MD; Chief of Infectious Disease, South San Francisco

Thanks to the following reviewers for their careful reading and comments:

Drew Baker, MD; Chief of Emergency Medicine, Hayward

Roger Baxter, MD; Chief of Infectious Disease, Oakland

George Bulloch, MD; Chief of Emergency Medicine, Redwood City

James Cadden, MD; Chief of Emergency Medicine, Santa Rosa

David Campen, MD; Chair, TPMG Formulary Subcommittee, Santa Clara

Uli Chettipally, MD; Chief of Emergency Medicine, South San Francisco

Michael Coppolino, MD; Critical Care, San Francisco

Paul Feigenbaum, MD; Chief of Medicine, San Francisco

John Fitzgibbon, MD; Chief of Utilization Management, Sacramento

Maurice Franco, MD; Critical Care, Hayward

Lauren Freeman, MD; Hospital Based Specialist, South Sacramento

Dale Grahn, MD; Chief of Utilization Management, Diablo Service Area

Chris Gronbeck, MD; Critical Care, San Rafael

Jianfei Hu, MD; Hospital Based Specialist, Walnut Creek

Daniel Klein, MD; Chief of Infectious Disease, Hayward

Aye Koko, MD; Hospital Based Specialist, Fresno

David Langkammer, MD; Associate Chief of Medicine, Diablo Service Area

Todd Lasman, MD; Pulmonology, Redwood City

Eleanor Levin, MD; Chair, Chiefs of Cardiology, Santa Clara

Hsiu-Wei Lin, MD; Intensive Care, Walnut Creek

Timothy Lockyer, MD; Hospital Based Specialist, Santa Teresa

Jeff Lou, MD; Hospital Based Specialist, Santa Teresa

Gilbert Mandell, MD; Chief, Pharmacy and Therapeutics and Chief, Hematology/Oncology, South Sacramento

Susan Marantz, MD; Chief of Utilization Management and Chief of Critical Care, Santa Rosa

Suzanne Mierendorf, MD; Hospital Based Specialist, Santa Clara

Robert Mooney, MD; Chief of Emergency Medicine, Walnut Creek

Richard K. Morgan, MD; Internal Medicine,

Kaiser Stanislaus

Bien Nguyen, MD; Chief of Patient Education and Hospital Based Specialist, Santa Teresa

Tom Padgett, MD; Chief of Emergency Medicine, San Francisco

Alien Parsley, MD; Chief of Outpatient Pharmacy and Therapeutics, Walnut Creek

Robert Riesenfeld, MD; Hospital Based Specialist, Walnut Creek Anne Rogers, MD; Critical Care, Walnut Creek

Valeric Scheider MD Critical Care Walnut Creek

Christina Shih, MD; Assistant Physician-in-Chief, San Francisco and Chair, Regional Chiefs of Emergency Medicine

Darshan Sonik, MD; Critical Care, Sacramento Stanley}.

Tillinghast, MD; Hospital Based Specialist, South Sacramento

Abdul Wali, MD; Chief of Hospital Based Services, Diablo Service Area

Joseph Wong, MD; Internal Medicine, Stockton

Patricia Z. Wong, RN; Manager, Emergency Department, Fresno

J. Susan Yee, RN; Manager, Berkeley Regional Laboratory

Editing

Kaiser Foundation Research Institute Medical

Editing Department Linda Bine; TPMG Communications Department

Design & Production GailHolan, CurveyGraphic DesignCONTACT INFORMATION Kaiser Permanente Northern California TPMG Department of Quality and Utilization 1800 Harrison Street, 4th floor Oakland, CA 94612 510-987-2950 or tie-line 8-427-2950

To obtain more information about KPNC Clinical Practice Guidelines and Statements, printed copies or permission to reproduce any portion, please contact the TPMG Dept. of Quality & Utilization, or send an e-mail message to clil.EiC.l~l.gzlidelilzes@kp. org KPNC Clinical Practice Guidelines and Statements can be viewed on-line on the Kaiser Permanente Northern California intranet website at htt{)://clinical 'library, ca. kp. org CME Credit: ContinumH Education Credit for phy­si­cians and nurses is available for review ol Statement. The CME Pro- and Post-Tests are available on-line at the above website address.

This website is accessible only from the Kaiser 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.

Copyripht 1999 The Permanente Medical Group, Inc.