Sepsis resident survival guide

Sepsis Resident Survival Guide
Overview
Diagnostic Criteria
Causes
Focused Initial Rapid Evaluation
Do's
Don'ts

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]; Vidit Bhargava, M.B.B.S [3]

Overview

Diagnostic Criteria

Systemic Inflammatory Response Syndrome

Systemic inflammatory response syndrome (SIRS) represents the complex findings resulting from systemic activation of the innate immune response triggered by localized or generalized infection, trauma, thermal injury, or sterile inflammatory processes. However, criteria for SIRS are considered to be too nonspecific to be of utility in diagnosing a cause for the syndrome or in identifying a distinct pattern of host response.

SIRS is considered to be present when patients have two or more of the following clinical findings:

Body temperature >38 °C (100.4 °F) or <36 °C (96.8 °F) Heart rate >90 beats per minute Hyperventilation evidenced by a respiratory rate of >20 breaths per minute or a PaCO2 <32 mm Hg White blood cell count of >12000 cells/mm³ or <4000 cells/mm³ (>12 x 109 cells/L or <4 x 109 cells/L) or bandemia (>10% band forms)

Sepsis

Sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection. Diagnostic criteria for sepsis are as follows:

Sepsis = infection (documented or suspected) and some of the following:

General variables Fever (>38.3°C) Hypothermia (core temperature <36°C) Heart rate >90/min–1 or more than two SD above the normal value for age Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg over 24 hr) Hyperglycemia (plasma glucose >140mg/dL or 7.7 mmol/L) in the absence of diabetes

Inflammatory variables Leukocytosis (WBC count >12,000 μL–1) Leukopenia (WBC count <4000 μL–1) Normal WBC count with greater than 10% immature forms Plasma C-reactive protein more than two SD above the normal value Plasma procalcitonin more than two SD above the normal value

Hemodynamic variables Arterial hypotension (SBP <90mm Hg, MAP <70mm Hg, or an SBP decrease >40mm Hg in adults or less than two SD below normal for age)

Organ dysfunction variables Arterial hypoxemia (Pao2/Fio2 <300) Acute oliguria (urine output <0.5 mL/kg/hr for at least 2 hrs despite adequate fluid resuscitation) Creatinine increase >0.5mg/dL or 44.2 μmol/L Coagulation abnormalities (INR >1.5 or aPTT >60 s) Ileus (absent bowel sounds) Thrombocytopenia (platelet count <100,000 μL–1) Hyperbilirubinemia (plasma total bilirubin >4mg/dL or 70 μmol/L)

Tissue perfusion variables Hyperlactatemia (>1 mmol/L) Decreased capillary refill or mottling

Severe Sepsis

Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion.

Severe sepsis = sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following thought to be due to the infection)

Sepsis-induced hypotension (SBP of <90 mm Hg or MAP <70 mm Hg or a SBP decrease >40 mm Hg or <2 SD below normal for age in the absence of other causes of hypotension) Lactate above upper limits laboratory normal Urine output <0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation Acute lung injury with PaO2/FIO2 <250 in the absence of pneumonia as infection source Acute lung injury with PaO2/FIO2 <200 in the presence of pneumonia as infection source Creatinine >2.0 mg/dL (176.8 μmol/L) Bilirubin >2 mg/dL (34.2 μmol/L) Platelet count <100,000 μL Coagulopathy (international normalized ratio >1.5)

Septic Shock

Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation, in the absence of other causes for hypotension.

• Septic shock in adult patients refers to a state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes.
• Septic shock in pediatric patients is defined as a tachycardia (may be absent in the hypothermic patient) with signs of decreased perfusion including decreased peripheral pulses compared with central pulses, altered alertness, flash capillary refill or capillary refill 􏰀2 seconds, mottled or cool extremities, or decreased urine output.

Causes

Sepsis is a life-threatening condition and must be treated immediately irrespective of the underlying cause.

• If associated with community-acquired pneumonia

• Streptococcus pneumoniae
• Staphylococcus aureus and MRSA
• Legionella
• Gram-negative bacilli

• If associated with urinary tract infection

• Aerobic gram-negative bacilli
• Enterococcus

• If associated with intra-abdominal infection

• Aerobic gram-negative bacilli
• Anaerobic gram-negative bacilli

• If associated with intravenous drug use

• Staphylococcus
• Nocardia

• If associated with petechiae

• Neisseria meningitidis
• Rocky Mountain spotted fever

FIRE: Focused Initial Rapid Evaluation

Characterize the symptoms: ❑ Fever ❑Hypothermia ❑ Altered mental status ❑ Mottling ❑ Ileus ❑ Oliguria

Examine the patient: ❑ Tachycardia ❑ Tachypnea ❑ Edema ❑ Hyperglycemia ❑ Hypotension after an initial 30 ml/Kg bolus ❑ Decreased capillary refill

Order labs: ❑ Random blood sugar (RBS) ❑ Complete blood count (CBC) ❑ Plasma C reactive protein (CRP) ❑ Plasma procalcitonin ❑ Pulse oximetry ❑ Urinalysis/Renal function tests ❑ PT/INR ❑ Liver function tests ❑ Serum lactate ❑ Central venous pressure (CVP)

Consider alternative diagnosis: ❑ Infections ❑ Acute pancreatitis ❑ Diabetic ketoacidosis Lower gastrointestinal bleeding Myocardial infarction

Initial resuscitation: Goals to achieve in first 6 hours ❑ Central venous pressure (CVP) 8-12 mm Hg ❑ Mean arterial pressure (MAP) ≥ 65 mm Hg ❑ Urine output ≥ 0/5 mL/Kg/hr ❑ Central venous O2 sat. 70% ❑ If lactate levels elevated, target is normalization

Diagnosis: ❑ Perform 2 sets of blood cultures (aerobic and anaerobic) atleast, before starting antibiotics Drawn percutaneously Drawn through each vascular access device present for > 48 hours ❑ Perform 1,3 beta-D-glucan assay, mannan, anti-mannan antibody assay if available ❑ Perform imaging studies as appropriate to locate a source

Antimicrobial therapy: ❑ Initiate within 1st hour of diagnosis Reassess regimen daily ❑ Use low procalitonin levels for prognosis ❑ Usual duration of therapy 10 days ❑ Longer in neutropenics, slow responders, undrainable foci, immunologically compromised

Choice of antibiotics

Unknown organism ❑ Empiric therapy with broad spectrum antbiotic with good tissue penetrance

Neutropenic pt with severe sepsis (goal is to cover Acinetobacter & Pseudomonas spp) ❑ Use combination empirical therapy

Severe infections + resp failure + septic shock ❑ Extended spectrum beta lactam andaminoglycoside/fluoroquinolone

Streptococcus pneumoniae ❑ beta lactam + macrolide

Culture specific organism ❑ Shift to appropriate anti-bacterial, antiviral or antifungal

Remove source/foci of infection: ❑ Use minimally invasive process ❑ Source removal best done in first 12 hours ❑ Remove intravascular access devices if they are a possible source ❑ Oral chlorhexidine gluconate to reduce oral contamination as a risk factor for ventilator associated pneumonia

Hemodynamic support Fluid therapy: ❑ Administer crystalloids, use albumin when demand for fluids is too high ❑ Use dynamic variables (change in pulse pressure, stroke volume) and static variables (arterial pressure,heart rate) to assess status Vasopressors (to achieve target MAP ≥ 65 mm Hg): ❑ Place arterial line as soon as feasible ❑ Administer norepinephrine as 1st choice drug ❑ Use epinephrine - when additional agent needed ❑ Use vasopressin 0.03 units/minute to raise MAP or decrease norepinephrine usage ❑ Selective dopamine (absolute or relative bradycardia) and phenylephrine usage Inotropic therapy: ❑ Trial of dobutamine infusion 20 μg/Kg if cardiac output low with elevated cardiac filling pressure

Corticosteroids: ❑ Use continuous flow IVhydrocortisone 200 mg/day if shock doesn’t improve with fluids & vasopressor ❑ Taper when vasopressors no longer required

Blood products: ❑ Transfuse blood when hemoglobin < 7.0 g/dL ❑ Transfuse platelets if < 10,000/mm3 or < 20,000/mm3 in those with high risk

Mechanical ventilation for sepsis induced ARDS': ❑ Target tidal volume of 6 mL/Kg ❑ Target plateau pressure ≤ 30 mm Hg ❑ Use PEEP (positive end expiratory pressure) to avoid alveolar collapse ❑ Raise patients bed to 30-45° ❑ Attempt weaning when all foll. criteria are met: ❑ Pt arousable ❑ Hemodynamics stable ❑ No new complications ❑ Low ventilatory/fiO2 requirements ❑ Extubate when weaning successful

Other supportive therapy Sedation & neuromuscular blockade: ❑ Use minimal sedation/neuromuscular blockade in mechanically ventilated patients Glucose control: ❑ Blood glucose target value should be ≤ 180 mg/dL ❑ Use insulin infusion and 1-2 hourly monitoring to achieve target Renal replaement therapy: ❑ May be used for management of fluid balance in hemodynamically unstable patients ❑ Use for septic patients withacute renal failure DVT prophylaxis: ❑ Do pharmacoprophylaxis with low molecular weight heparin (LMWH), if no contraindications present ❑ Use pneumatic compression devices whenever possible Stress ulcer prophylaxis ❑ Consider prophylaxis if risk factors are present Feeding: ❑ Enteral & oral feeding preferred over total parenteral feeding (TPN) ❑ Adjust calorie requirement in subsequent days, as tolerated Goals of care: ❑ Discuss goals or care, patient aspirations and future directives with family with 72 hours of admission

Empiric Antibiotic Therapy

History of intravenous drug use with high prevalence of MRSA

Vancomycin 1 gm IV q12h

Sepsis associated with petechiae

Ceftriaxone 2 gm IV q12h

Biliary source

Ampicillin-Sulbactam 3 gm IV q6h OR Piperacillin-Tazobactam 3.375 gm IV q4h OR Ticarcillin-Clavulanate 3.1 gm IV q4h

Community-acquired pneumonia

Levofloxacin 750 mg IV q24h OR Moxifloxacin 400 mg IV q24h AND Piperacillin-Tazobactam 3.375 gm IV q4h AND Vancomycin 1 gm IV q12h

Unclear infection source

Doripenem 500 mg IV q8h OR Ertapenem 1 gm IV q24h OR Imipenem 0.5 gm IV q6h OR Meropenem 1 gm IV q8h AND Vancomycin 1 gm IV q12h

Low prevalence of ESBL and/or carbapenemase producing aerobic gram-negative bacilli

Piperacillin-Tazobactam 3.375 gm IV q4h AND Vancomycin 1 gm IV q12h

High prevalence of ESBL and/or carbapenemase producing aerobic gram-negative bacilli

Colistin 2.5 mg/kg then 1.5 mg/kg IV q12h AND Meropenem 1 gm IV q8h AND Vancomycin 1 gm IV q12h

Optimization of Hemodynamics [Return to FIRE]

Preload Optimization

• Preload optimization involves scrupulous fluid loading, manipulation of PCWP and/or CVP levels, and correction of pulmonary congestion.
  • Protocolized fluid administration titrated to hemodynamic and clinical endpoints secures the efficacy of tissue perfusion and oxygenation.
  • Four elements of the fluid challenge protocol: type of fluid (T), rate of fluid administration (R), objective (O), and limits (L).

  • 1. Type of fluid (T)

  • The choice of crystalloid or colloid solution should be made on the basis of the underlying disease, the nature of fluid deficit, the severity of circulatory failure, the serum albumin concentration, and the risk of bleeding.
  • There were no significant differences in mortality between saline and albumin infusion for critically ill patients.
  • Blood transfusion may be considered in the presence of profound anemia or massive hemorrhage.
  • Hyperchloremic acidosis may be associated with the use of isotonic saline solution.

  • 2. Rate of fluid administration (R)

  • Based on the level of pulmonary capillary wedge pressure or central venous pressure, a volume of 50, 100, or 200 ml of fluid is administered over a 10-minute interval through a peripheral venous catheter.

  Baseline PCWP (mm Hg) Baseline CVP (cm H2O) Rate of fluid administration ≥16 ≥14 50 mL over 10 minutes <16 but ≥12 <14 but ≥8 100 mL over 10 minutes <12 <8 200 mL over 10 minutes

  • 3. Objective (O)

  • Fluid administration should be titrated to reach predetermined clinical endpoints such as resolution of tachycardia or oliguria, improved skin perfusion or level of consciousness, normalization of lactate concentrations, and restoration of adequate blood pressure or ventricular filling pressure.

  • 4. Limits (L)

  • Fluid administration should be stopped if the safety limits are violated to minimize the risk of developing pulmonary edema.
  • Inotropes, vasodilators, or mechanical circulatory device may be required if signs of hypoperfusion persist despite optimal fluid loading.
  • Hemodynamic safety limits based on PCWP (the 7–3 rule) or CVP (the 5–2 rule):

  ↑ PCWP (mm Hg) ↑ CVP (cm H2O) Action ≥7 ≥5 Stop fluid administration <7 but >3 <5 but >2 Wait and recheck pressure after 10 minutes ≤3 ≤2 Continue fluid administration

• Findings suggestive of cardiogenic pulmonary edema:

  • History and clinical manifestations

  • Cough
  • Dyspnea
  • Expectoration of frothy sputum
  • Orthopnea
  • Paroxysmal nocturnal dyspnea
  • Signs and symptoms of heart failure
  • Signs and symptoms of hypoxemia
  • Signs and symptoms of myocardial ischemia
  • Signs and symptoms of valvular dysfunction
  • Tachypnea

  • Physical examination

  • Cool extremities
  • Heart murmurs
  • Hepatomegaly
  • Inspiratory crackles or rhonchi
  • Jugular venous distention
  • S3 gallop
  • Peripheral edema

  • Laboratory and hemodynamic findings

  • BNP > 500 pg/mL
  • PCWP >18 mm Hg

  • Radiologic findings

  • Central infiltrates with peripheral sparing
  • Cephalization of pulmonary vessels
  • Enlarged cardiac silhouette
  • Enlargement of peribronchovascular spaces
  • Increased opacity of acinar areas that coalesce into frank consolidations
  • Kerley B lines
  • Peribronchial cuffing
  • Pleural effusions
  • Vascular pedicle width >70 mm

  • Radiologic manifestations of pulmonary congestion reflect the extent of elevation in wedge pressure:

  PCWP (mm Hg) Phase of Pulmonary Congestion Findings on Chest Radiograph 18–20 Onset of pulmonary congestion Redistribution of pulmonary flow to the upper lobes ("cephalization") and Kerley lines 20–25 Moderate congestion Diminished clarity of the borders of medium-sized pulmonary vessels ("perihilar haze") 25–30 Severe congestion Radiolucent grapelike clusters surrounded by radiodense fluid ("periacinar rosette") >30 Onset of pulmonary edema Coalescence of periacinar rosettes resulting in "Bat's wing" opacities

Afterload Optimization

Nitroglycerin

• Dosage and Administration

• Suggested Initial Dilution:

• Nitroglycerin must be diluted in dextrose (5%) injection or sodium chloride (0.9%) injection prior to its infusion. Transfer 50 mg of nitroglycerin into a 500 mL glass bottle of either dextrose (5%) injection or sodium chloride injection (0.9%). This yields a final concentration of 100 μg/mL. Diluting 5 mg nitroglycerin into 100 mL will yield a final concentration of 50 μg/mL.

• Suggested Maintenance Dilution:

• Consider the fluid requirements of the patient as well as the expected duration of infusion in selecting the appropriate dilution of Nitroglycerin Injection.
• The concentration of nitroglycerin should not exceed 400 μg/mL.

• Suggested Regimen:

• Severe hypotension and shock may occur with even small doses of nitroglycerin. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.
• The initial dosage should be 5 μg/min delivered through an infusion pump. Subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen.
• Initial titration should be in 5 μg/min increments, with increases every 3–5 minutes until some response is noted.
• If no response is seen at 20 μg/min, increments of 10 and later 20 μg/min can be used.
• Once a partial blood pressure response is observed, the dose increase should be reduced and the interval between increases should be lengthened.

• Contraindications

• Pericardial tamponade
• Restrictive cardiomyopathy
• Constrictive pericarditis
• Hypersensitivity to nitroglycerin

Nitroprusside

• Dosage and Administration

• Suggested Dilution:

• Depending on the desired concentration, the solution containing 50 mg of nitroprusside must be further diluted in 250–1000 mL of sterile 5% dextrose injection.

• Suggested Regimen:

• While the average effective rate in adult and pediatric patients is about 3 μg/kg/min, some patients will become dangerously hypotensive at this rate.
• Nitroprusside can induce essentially unlimited blood pressure reduction, the blood pressure must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug.
• Infusion of sodium nitroprusside should be started at a very low rate (0.3 μg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 μg/kg/min) has been reached.

• Contraindications

• Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis.
• Sodium nitroprusside should not be used in the treatment of compensatory hypertension, where the primary hemodynamic lesion is aortic coarctation or arteriovenous shunting.
• Sodium nitroprusside should not be used to produce hypotension during surgery in patients with known inadequate cerebral circulation, or in moribund patients coming to emergency surgery.
• Patients with congenital (Leber’s) optic atrophy or with toxic amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients.

Norepinephrine

• Dosage and Administration

• Suggested Dilution:

• Mix 4 mg of norepinephrine in 250 mL of D5W or D5NS. Avoid dilution in normal saline alone.

• Suggested Regimen:

• Start at a dose of 0.5–1.0 μg/min IV infusion; titrate to maintain SBP at above 90 mm Hg (up to 30–40 μg/min).

• Contraindications

• Norepinephrine should not be given to patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.
• Norepinephrine should also not be given to patients with mesenteric or peripheral vascular thrombosis unless it is necessary as a life-saving procedure.

Dopamine

• Dosage and Administration

• Suggested Dilution: transfer contents of one or more ampuls or vials by aseptic technique to either 250 mL or 500 mL of one of the following sterile intravenous solutions

• Sodium Chloride Injection
• Dextrose (5%) Injection
• Dextrose (5%) and Sodium Chloride (0.9%) Injection
• 5% Dextrose in 0.45% Sodium Chloride Solution
• Dextrose (5%) in Lactated Ringer’s Solution
• Sodium Lactate (1/6 Molar) Injection
• Lactated Ringer’s Injection

• Suggested Regimen:

• Begin administration of diluted solution at doses of 2–5 μg/kg/minute in patients who are likely to respond to modest increments of heart force and renal perfusion.
• In more seriously ill patients, begin administration of diluted solution at doses of 5 μg/kg/minute and increase gradually, using 5–10 μg/kg/minute increments, up to 20–50 μg/kg/minute as needed.
• If doses of 50 μg/kg/minute are required, it is suggested that urine output be checked frequently. Should the urine flow begin to decrease in the absence of hypotension, reduction of dosage should be considered.
• Treatment of all patients requires constant evaluation of therapy in terms of the blood volume, augmentation of myocardial contractility, and distribution of peripheral perfusion. Dosage should be adjusted according to the patient’s response, with particular attention to diminution of established urine flow rate, increasing tachycardia or development of new dysrhythmias as indices for decreasing or temporarily suspending the dosage.

• Contraindications

• Pheochromocytoma
• Uncorrected tachyarrhythmias or ventricular fibrillation

Phenylephrine

• Dosage and Administration

• Suggested Dilution:

• Add 10 mg of the drug (1 mL of 1 percent solution) to 500 mL of Dextrose Injection or Sodium Chloride Injection (providing a 1:50,000 solution).

• Suggested Regimen:

• To raise the blood pressure rapidly, start the infusion at about 100 μg to 180 μg per minute (based on 20 drops per mL this would be 100 to 180 drops per minute).
• When the blood pressure is stabilized (at a low normal level for the individual), a maintenance rate of 40 μg to 60 μg per minute usually suffices (based on 20 drops per mL this would be 40 to 60 drops per minute).
• If a prompt initial pressor response is not obtained, additional increments of phenylephrine (10 mg or more) are added to the infusion bottle. The rate of flow is then adjusted until the desired blood pressure level is obtained.

• Contraindications

• Severe hypertension
• Ventricular tachycardia
• Hypersensitivity to phenylephrine

Vasopressin

• Dosage and Administration

• Suggested Regimen:

• Adjunctive use of a low dose of vasopressin (0.01–0.04 U/min) to catecholamine may reduce its dosage requirement in patients with refractory shock.

• Contraindications

• Anaphylaxis or hypersensitivity to the drug or its components

Cardiac Output Optimization

Dobutamine

• Dosage and Administration

• Suggested Dilution: dobutamine injection must be further diluted in an IV container. Dilute 20 mL of dobutamine in at least 50 mL of diluent and dilute 40 mL of dobutamine in at least 100 mL of diluent. Use one of the following intravenous solutions as a diluent:

• Dextrose Injection 5%
• Dextrose 5% and Sodium Chloride 0.45% Injection
• Dextrose 5% and Sodium Chloride 0.9% Injection
• Dextrose Injection 10%, Isolyte® M with 5% Dextrose Injection
• Lactated Ringer’s Injection
• 5% Dextrose in Lactated Ringer’s Injection
• Normosol®-M in D5-W
• 20% Osmitrol® in Water for Injection
• Sodium Chloride Injection 0.9%
• Sodium Lactate Injection

• Suggested Regimen:

• The rate of infusion needed to increase cardiac output usually ranged from 2.5–15 mcg/kg/min.
• On rare occasions, infusion rates up to 40 mcg/kg/min have been required to obtain the desired effect.

• Contraindications

• Idiopathic hypertrophic subaortic stenosis
• Hypersensitivity to dobutamine

Milrinone

• Dosage and Administration

• Suggested Regimen:

• Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose).
• Loading dose: 50 μg/kg (slowly over 10 minutes)
• Maintenance dose: 0.50 μg/kg/min (0.375–0.75 μg/kg/min)

• Contraindications

• Hypersensitivity to milrinone

Do's

• Patients who are suspected of being severely infected, should be routinely screened for sepsis.

• Administer antimicrobial therapy within 1 hour of diagnosis of sepsis.

• Delay intervention, if source/foci of infection is peri-pancreatic necrosis.

Dont's

• Do not use empiric combination therapy for more than 3-5 days.

• Do not use antimicrobial agents in severely inflamed patients, from a non-infectious cause.

• Do not use hydroxyethyl starch for fluid therapy resuscitation of severe sepsis and septic shock.

• Do not use low dose vasopressin/dopamine/phenylephrine as monotherapy.

• Do not use low dose dopamine for renal protection.

• Do not use corticosteroids in the absence of shock.

• Do not use erythropoietin as a specific treatment of anemia associated with sepsis.

• Do not use antithrombin.

• Do not use fresh frozen plasma to correct clotting abnormalities in the absence of bleeding or planned invasive procedure.

• Do not use following supportive therapies as their role is not clear:

IV immunoglobulins

IV selenium

• Do not routinely use pulmonary artery catheters.

• Do not use bicarbonate therapy as prophylaxis of hypoperfusion induced lactic acidosis if pH > 7.15.

References