SIRS and Septic Shock

Attending Version

SIRS and Septic Shock

created by Dr. Dana Davis

Objectives:

1. Define and differentiate bacteremia and the clinical spectrum of SIRS, sepsis, severe sepsis, and septic shock.

2. Identify typical choices for empirical antibiotics for patients with sepsis.

3. Identify patient groups with increased risk for the development of sepsis, increased morbidity or mortality, or uncommon etiologic organisms.

4. Describe the indications, contraindications and side effects of therapeutic agents including fluids, vasopressors, antibiotics, steroids, and activated protein C in the treatment of sepsis.

References:

1. Lorente JA, et al, Time course of hemostatic abnormalities in sepsis and its relation to outcome., Chest, 1993, May, 103(1536-42)

2. McGill, Endothelial cells: role in infection and inflammation. World J Surg - 01-FEB-1998; 22(2): 171-8

3. Levi M, Disseminated intravascular coagulation. N Engl J Med - 19-AUG-1999; 341(8): 586-92

(antibiotics)

4. Bernard GR . Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med - 8-MAR-2001; 344(10): 699-709

5. O’Brien JM. New approaches to the treatment of sepsis. Clinics in Chest Medicine. Volume 24 • Number 4 • December 2003

6. The International Sepsis Forum. Guidelines for the management of severe sepsis and septic shock. Intensive Care Med 2001;27(Suppl. 1):S1–134.

7. Simon D, Trenholme G. Antibiotic selection for patients with septic shock. Crit Care Clin. 2000;16:215–230.

8. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862-71.

9. 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 : 723–732

10. 14th European Congress of Clinical Microbiology and Infectious Diseases, May 1–4, 2004

11. Kumar A, Roberts D, Wood KE, et al. Delays in antimicrobial therapy for sepsis. Crit Care Med. 2004;32:A11.

12. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:85.

CASE

History:

33 y/o F presents with Fever, non-productive cough, sore throat and head ache. URI sxs X 5 days. Came in b/c feeling tired and a little SOB. Not eating or drinking much. . 2 kids at home both of whom have had recent URI/sore throat about 2 weeks ago.

PMH

MVA à spleenectomy at age 9

Immunization status unknown

No medications

G2 P2

NKDA

ROS

Neg. except as reported in HPI

T 35.8 P 98 R 20 (PaCO2 will be 30) BP 100/56, O2 sat 91% RA

A&O X 4. Skin is dry.

HEENT – pharynx injected. Neck supple. No adenopathy

CV – no murmurs

Lungs – L posterior crackles

Abdomen – benign

Skin – no rash

Lymph – no adenopathy

Normal genital/rectal exams

No muscle or joint swelling.

WBC 24.5 (85 PMN - automated(15 Bands, 70 Segs), 5 lymphs, 10 monos), H/H 13.6/40, Plt 166 K

Chem 10 Na 148, K 4.6, Cl 105, Bicarb 24, BUN 22, Cr 1.2 , Ca 9.4, PO4 5, Mg 2.0

CXR – Possible LLL pneumonia

Hospital course:

Patient admitted to the hospital with suspected pneumonia in an asplenic patient. Initial blood cultures were taken, as were sputum and urine cultures. Antibiotics were ordered in the Emergency Room, but were delayed for approximately 2 hours. Initially she was started on cefotaxime and doxycycline.

She was started on IV fluids, bolused with lL of NS and infused with 1/2 NS at 150 cc per hour.

At the time that the antibiotics were being administered it was noted that her pulse was now 110 to 124 and her blood pressure was 98/46. The patient was complaining of worsening headache and photophobia. The remainder of her vitals were unchanged.

Suspecting meningitis a CT was performed which was normal.

An LP was performed.

Gram stain showed Gram positive diplococci. WBC count was 1500 with 200 RBC. Glucose 44 and protein 88. At that time a call from the lab was received that the patient was noted to have Gram + diplococci on her peripheral blood smear.

Vancomycin was added to her antibiotics and she was switched from cefotaxime to ceftriaxone and was given a single dose of dexamethasone.

Two hours later the patient began to complain of bilateral leg numbness and weakness. She was noted to have diminished strength in both lower extremities, as well as decreased pinprick sensation and reduced sphincter tone. The exam was also significant for a pulse of 138, BP of 86/42, she appeared mottled with multiple bruises where she had been stuck for lab draws and IVs, and she was oriented to person only.

Repeat labs were ordered:

Chem 10 – Na 144, K – 4.9, Cl – 98, Bicarb – 20, BUN – 32, Cr – 1.6, PO4 – 2.2, Mg – 1.7

CBC - WBC 12.5 (15 Bands, 55 Segs, 5 metamyelocytes, 12 Monos, 13 Lymphs), H/H – 11/33, Plt - 70

PT – 28 (INR 9.2), PTT – 65

LFTs – AST 108, ALT 114, Alk. Phos 88, Total Bili. 5.2, Direct Bili. 1.1, Albumin 3.6, Total Protein 8.6

MRI of L / S spine showed hematoma present in lumbar spinal cord.

The patient was transferred to the MICU and dopamine was instituted. Shortly after transfer the patient became hypoxic and required mechanical ventilation. A repeat CXR showed diffuse “white out” consistent with severe ARDS.

The following day the patient developed unrelenting seizures. Once the seizures were controlled with lorazepam and fosphenytoin a repeat CT scan was done which showed intracerebral hemorrhage. The patient also had bilateral dilated pupils and lacked brainstem reflexes.

After discussions with her family life support was withdrawn and the patient died shortly thereafter. Autopsy was performed. The blood cultures and spinal fluid grew out pneumococcus which was sensitive to ceftriaxone. The official cause of death was determined to be pneumococcal sepsis resulting in coagulopathy and subsequent intracerebral hemorrhage.

Discuss management of this patient including use of fluids, antibiotics, pressors, steroids as well as significance of results from lab/diagnostic tests.

Outline and discussion

Definitions:

1)Bacteremia – presence of viable bacteria in circulating blood

2)SIRS - is a widespread inflammatory response to a variety of severe clinical insults. This syndrome is clinically recognized by the presence of two or more of the following:

Temperature >38ºC or <36ºC

Heart rate >90 beats/min

Respiratory rate >20 breaths/min or PaCO2 <32 mmHg

WBC >12,000 cells/mm3, <4000 cells/mm3, or with >10 percent immature (band) forms

Tissue injury secondary to activation of the inflammatory system may complicate noninfectious disorders (eg, acute pancreatitis or pulmonary contusion). The term systemic inflammatory response syndrome (SIRS) is used in this setting to refer to the consequences of a dysregulated host inflammatory response which may or may not be associated with infection. Infections cause approximately 26% of cases of SIRS.

Non-infectious causes of SIRS

Trauma / burns (34 %)

CVA (6%)

GI bleeding (5%)

Pancreatitis, vaginal delivery, CHF, TTP, malignancies, acute coronary syndrome, thromboembolism, and DKA.

SIRS + infection = Sepsis à Severe Sepsis à Septic Shock

3) Sepsis - This is a systemic inflammatory response to a documented infection. The manifestations of sepsis are the same as those previously defined for SIRS.

4) Severe Sepsis - This is sepsis and SIRS associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

With severe sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion also must be included:

Alteration in mental state

Hypoxemia (PaO2 <72 mm Hg at FiO2 [fraction of inspired oxygen] 0.21; overt pulmonary disease not the direct cause of hypoxemia)

Elevated plasma lactate level

Oliguria (urine output <30 mL or 0.5 mL/kg for at least 1 h)

5)Septic Shock A subset of people with severe sepsis develop hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may not be hypotensive by the time that they manifest hypoperfusion abnormalities or organ dysfunction.

6) MODS (multiple organ dysfunction syndrome) This is the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention.

Epidemiology:

Patient characteristics which increase risk of sepsis:

Extremes of age (<10 y and >70 y)

Cirrhosis

Alcoholism

Diabetes mellitus

Cardiopulmonary diseases

Solid malignancy

Hematologic malignancy

Immunosuppression

Neutropenia

Immunosuppressive therapy

Corticosteroid therapy

Intravenous drug abuse

Compliment deficiencies

Asplenia

Major surgery, trauma, burns

Invasive procedures

Catheters

Intravascular devices

Prosthetic devices

Hemodialysis and peritoneal dialysis catheters

Endotracheal tubes

Prior antibiotic treatment

Prolonged hospitalization

Other factors - Childbirth, abortion, and malnutrition

Infections which lead to sepsis can originate in any tissue. Most commonly the infection arises from lungs (>25% of cases of sepsis), the urinary tract (25% of cases of sepsis), followed by abdominal (15%) and skin infections (15%). 6 – 15% of the time there are multiple sites of infection.

Microorganisms: Prior to the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causing sepsis. More recently, gram-negative bacteria and fungal infections have become key pathogens causing severe sepsis and septic shock.

Pathophysiology

SIRS results from a dysregulated inflammatory response.

Typically, with localized infection or inflammatory response to a non-infectious stimulant cytokine release is instrumental in maintaining localization of the infection and activating the host response of macrophages, monocytes and neutrophils. However, if this response is systemic it can lead to host cell damage and hypoperfusion.

Tumor necrosis factor (TNF), interleukin (IL)-1 are most often cited as factors contributing to the normal as well as exaggerated response. Other factors which seem to be implicated are IL-6, IL-8, monocyte chemoatractant protein-1, IL-10, interferon-gamma, IL-12, macrophage migration inhibition factor, granulocyte colony-stimulating factor (GCSF) and gransulocyte macrophage colony-stimulating factor(GM-CSF). Activation of the complement system leads to generation of bradykinin and nitric oxide which have been implicated in the induction of hypotension and hyperdynamic shock.

Abnormalities of coagulation and fibrinolysis homeostasis in sepsis

An imbalance of homeostatic mechanisms lead to subclinical coagulopathy and occasionally disseminated intravascular coagulopathy (DIC) and microvascular thrombosis causing organ dysfunction and death. Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating production of thrombin. Furthermore, the levels of protein C and endogenous activated protein C also are decreased in sepsis. Endogenous activated protein C is an important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin via thrombomodulin activates protein C that functions as an antithrombotic in the microvasculature. Endogenous activated protein C also enhances fibrinolysis by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death.

Circulatory pathophysiology of septic shock

The predominant hemodynamic feature of septic shock is arterial vasodilation. Diminished peripheral arterial vascular tone may result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output often is limited by hypovolemia.

Peripheral circulation during septic shock

An elevation of cardiac output occurs; however, the arterial-mixed venous oxygen difference usually is narrow, and the blood lactate level is elevated. This is a result of maldistribution of blood flow and oxygen delivery/extraction.

The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activity of central mechanisms (eg, autonomic nervous system). The regional regulation, release of vasodilating substances (eg, nitric oxide, prostacyclin), and vasoconstricting substances (eg, endothelin) affect the regional blood flow. Development of increased systemic microvascular permeability also occurs, remote from the infectious focus, contributing to edema of various organs, particularly the lung microcirculation and development of acute respiratory distress syndrome (ARDS).

Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathological supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock.

Diagnostic Tests

CBC – Evaluate for anemia which may further impair oxygen delivery.

Abnormal WBC count with immature forms is part of diagnostic criteria.

Platelet count may be decreased suggesting DIC.

Chemistry - Sodium and chloride to evaluate fluid status.

Bicarbonate and anion gap to evaluate for acidosis.

BUN/Cr to assess renal function.

Liver tests to assess for MODS, or suggest biliary origin, pancreatitis, or hepatitis.

Lactate

Coagulation studies – May indicate DIC.

Blood and Urine cultures, preferably prior to initiation of antibiotics.

Chest x-ray

Abdominal films, possibly including CT if unable to localize site of infection, especially if the patient has abdominal complaints.

Lumbar puncture if the patient has meningeal signs or altered mental status.

Treatment

General supportive care: Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion.

The hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if needed, optimizing the perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.

Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation

Hemodynamic support of septic shock

Evidence of inadequate tissue perfusion and oxygenation:

MAP < 60 mmHg, or a decrease in MAP of greater than 40 mm Hg.

Elevated blood lactate.

Mixed venous saturation of less than 65%.

Evidence of end-organ damage – acute coronary syndrome, renal dysfunction (decrease urine output or increase in creatinine), decreased level of consciousness, elevated transaminases, ileus or malabsorption.