Emergency Medicine/Sepsis

The incidence of sepsis and septic shock appears to be ever increasing globally. The epidemiological data suggests that there are more than 750,000 cases of sepsis recorded per year in the United States, resulting in more than 200,000 deaths due to this illness. Despite the medical advances in critical care medicine and use of efficacious antimicrobials, the mortality related to sepsis and septic shock ranges between 40 and 60 percent. (Udwadia, 2005)

Definition
The American College of Chest Physician – The Society of Critical Care Medicine (ACCP-SCCM) consensus conference in 1991 proposed clear definitions for the spectrum of this illness.

The Systemic Inflammatory Response Syndrome (SIRS) is characterized by 2 or more of the following features:
 * Temperature > 38 degree Celsius (100.4 F) or < 36 degree Celsius (96.8 F)
 * Tachycardia > 90/minute
 * Tachypnea > 20/min or a PaCO2 < 32 mm Hg
 * White Cell Count < 4000/cubic mm or > 12000/cubic mm or > 10% band forms.

SIRS could be due to an infective or a non infective etiology, and could potentially lead to hypotension, shock, and multi-organ failure. When SIRS is due to a suspected or proven infective etiology, it is known as sepsis. When sepsis is associated with signs of organ dysfunction, hypotension, and hypoperfusion, it is known as severe sepsis. Severe sepsis with hypotension that does not respond to adequate fluid resuscitation, it is known as septic shock (Udwadia, 2005). Although, this classification is found to be very useful and is adopted by clinicians worldwide, it does not allow precise characterization and staging of patients with this disease spectrum. Further, it does not help in predicting patient outcomes. The ACCP-SCCM, the European Society of Intensive Care Medicine (ESICM), the American Thoracic Society (ATS), and the Surgical Infection Societies (SIS) have proposed a staging system called PIRO Classification (Predisposing factors, Infection/Insult, Response, and Organ dysfunction) which is analogous to the TNM cancer staging, that may be useful in risk stratification, management of sepsis and septic shock, and predicting patient outcomes. (Rello, Diaz, & Rodriguez, 2009)

Etiology & Predisposing Factors
Immune compromised states such as underlying malignancies, post chemotherapy status, organ transplant recipients, asplenic, HIV, malnourished, and co-morbid chronic conditions like hepatic or renal failure, diabetes mellitus and patients on prolonged steroid therapy are more prone to produce inadequate immune response to infections. Very young infants and elderly are similarly more susceptible to develop sepsis following infections. Unhygienic iatrogenic procedures and invasive monitoring tools are major source of sepsis within an inpatient setting. Septic shock usually follows a gram negative infection, although in recent times, there have been increasing incidence of gram positive, fungal and viral super infections producing symptoms of sepsis. (Udwadia, 2005)

Pathophysiology
Endotoxic components of gram negative bacteria, and cell wall components of gram positive and fungal organisms triggers off release of numerous inflammatory mediators or cytokines, like the IL-1, GMCSF, TNF, and pro-coagulant activity factors. The host defense system also activates the complement system, coagulation cascade and the kallikrein systems, resulting in endothelial damage, vasodilatation, and vascular leakage. Although, the cardiac output is increased and more blood is pushed through the dilated peripheral arterioles, tissues are unable to exchange oxygen resulting in organ dysfunction. (Goljan, 2009)

Clinical Presentation
Sepsis includes symptoms of SIRS with an infective etiology. There may be hypotension (systolic BP < 90 mm Hg, or a mean arterial BP < 60 mm Hg, or a drop in BP > 40 mm Hg below baseline) in cases of severe sepsis. Mental confusion may be present due to cerebral hypoperfusion and metabolic changes. Acrocyanosis due micro-emboli, pupural rash or petechiae may suggest DIC. Hyperdynamic circulatory state would give rise to warm peripheries, and tachycardia with a bounding pulse. Anaerobic glycolysis within the cell would accumulate lactate, giving rise to lactic metabolic acidosis. A sharp fall in urine output would suggest impending acute renal tubular necrosis due to hypoperfusion and cellular hypoxia. Increased alveolar permeability would give rise to non cardiogenic pulmonary edema. (Fauci, Braunwald, Kasper, Hauser, Longo, Jameson, & Loscalzo, 2009; Udwadia, 2005)

Differential Diagnosis
Pseudosepsis and non infective sepsis like syndrome may present with clinical features or hemodynamics similar to sepsis and must be ruled out. Conditions that mimic sepsis like clinical presentations are:
 * GI hemorrhage
 * Pulmonary embolism & DVT
 * Coronary artery diseases
 * DKA
 * SLE flare ups and systemic vasculitis,
 * Pancreatitis,
 * Anaphylaxis,
 * Diuretic abuse, and
 * Adrenal insufficiency. (Cunha, 2009)

Management
The Management of sepsis and septic shock should begin at the point of diagnosis (Office, ER, or ward), or else it may lead to fatal outcomes. The principles of management would include:

1.	Early diagnosis & laboratory investigations: CBC: 	Leucocytosis/leucopenia, Features of DIC (Raised PT/PTT, decreased fibrinogen, increased FDPs, & Thrombocytopenia) BMP:	 Hyperglycemia is very common; although hypoglycemia is evident in pre-terminal cases of sepsis & septic shock due to hepatic dysfunction. Raised BUN & Creatinine suggests negative nitrogen balance and renal dysfunction. LFTs: 	Increased bilirubin, raised aminotransferases, & alkaline phosphatase are seen in liver dysfunction. ABG:	Presence of metabolic acidosis due to accumulating lactate couple with hypoxia and hypocapnia. Cytokines (IL-6, IL-8), CRP, & Procalcitonin are significantly raised and correlate well with the magnitude of injury. (Udwadia, 2005; Fauci et al., 2009)

Definitive diagnosis would always require identification of nidus of infection and isolating the organism/s. Additional tests such as blood culture, urine culture, wound culture, and culture of body secretions would help in identifying the organism/s and conducting an antibiotic sensitivity. A search of infection source might require imaging studies like an X-ray, CT, or MRI.

2.	Early use of empiric antibiotic therapy after obtaining cultures, and early identification of the source of infection may help in eradicating the infection and improve outcomes. Use of a third generation cephalosporin/ piperacillin/ imipenam-cilatin with an aminoglycoside with/without metronidazole would cover a wide range of organisms, and is often recommended. Any suspected external invasive catheter or device should be removed and changed. Central venous catheter tips should be sent for culture. Suspected intra-abdominal emergencies would require immediate surgical attention and appropriate surgical interventions. (Udwadia, 2005; Fauci et al., 2009)

3.	Maintaining strict blood sugar control < 140 mg/dl through insulin therapy.

4.	Reversal of shock and maintaining hemodynamics: Early and adequate volume infusions to keep PCWP about 12–16 mm Hg, and CVP at 8 – 12 mm Hg. Vasopressors such as norepinephrine or vasopressin may be used to adequately maintain the oxygen transport and perfusion. It is essential to maintain a MAP > 65 mm Hg, urine output > 1 ml/kg/hour, and SpO2 of > 70%. (Udwadia, 2005; Fauci et al., 2009)

5.	Ventilatory support to maintain oxygenation & prompt support to other organ systems such as renal replacement therapy for acute renal failure should be provided.

6.	Use of Activated Protein C (APC) has been indicated in cases of severe sepsis and septic shock as proved by the PROWESS trial. Although, the therapy is useful, it is hugely expensive, carries a major bleeding risk, and numbers needed to treat value of 16 (Bernard, Vincent, Lattere, LaRosa, Dhainaut, Rodriguez, Steingrub, Garber, Helterbrand, Ely, & Fisher, 2001; Rice, & Wheeler, 2003). Another study by Marty-Carvajal, Salanti, & Cardona (2008) found no evidence to advocate the use of APC for treating patients with severe sepsis and septic shock. Furthermore, it concluded that use of APC carried a higher risk of bleeding and should not be used by clinicians unless substantial evidences are obtained by through additional RCTs.

7.	Corticosteroids: Use of hydrocortisone in low doses (50 mg tid/qid) generally is advocated to counter the reduced adrenal reserves. If improvements are seen within first 48 hours, it may be continued for 5 – 7 days.

8.	General Support:
 * Nutritional Supplementation
 * DVT prophylaxis through LMWH or mechanical protective devices
 * Stress ulcer prophylaxis (Udwadia, 2005; Fauci et al., 2009; Rice, & Wheeler, 2003)

Early interventions have shown to improve outcomes. Always screening at triage, obtain serum Lactate levels at the earliest, send for blood cultures before empiric antibiotics use, and initiate intravenous fluid resuscitation.

Disposition
All patients with sepsis and septic shock are admitted and managed in the intensive care unit with periodic monitoring and evaluations of organ functions.