SEPSIS ON THE GO.

Will you be careless about a lacerated sports injury or an unknown bite on your leg? Have you ever neglected a skin abrasion by a metal piece or thorn? Do insect bites need attention? Here is the story of a young labourer, a worker from a farm, who succumbed to death following sepsis due to an unattended injury/bite on his leg about which he was totally unaware.
This man was complaining of pain on his left hip and leg for two days.The left thigh appeared swollen with mild bluish discolouration on the anterolateral aspect.. He had no past history of any systemic illness and was in good health while joining the farm. Since 1 day he had low grade fever and there was progre ssive increase in difficulty of breathing. Examination showed tachypnea, dyspnea, Pulse: 122/mt, BP: 88/64 mm Hg, SPO2: 78% on room air, Pallor +, ABG: mild metabolic acidosis, Chest: b/l crepitations,CVS: tachycardia, CNS: alert and conscious, ABD: mild splenomegaly and abdominal wall edema, Swollen, warm and tender left leg with knee effusion and normal dorsalis pedis pulsation.A definite or identifiable mark of injury was not observed on the limb. A provisional diagnosis of cellulitis with septicemia or DVT with pulmonary embolism, was made. Patient was shifted to ICU for close observation of vitals and cardiorespiratory support. IV fluids started and  oxygen by mask applied, dopamine 10-15 mic/kg/mt and dobutamine 5-10 mic/kg/mt were on flow. Blood investigations were ordered.Fluid aspirated from thigh and knee was serosanguinous in nature and awaited culture reports. Empirical broad spectrum antibiotics were started.Doppler ultrasound ruled out DVT or limb ischemia due to thrombus.X ray of left femur was normal.ECG showed sinus tachycardia, and CXR was normal. CT chest, abdomen and limb were considered but deferred as contrast could not be given due to derranged RFT, hypotension and abnormal coagulation profile. The echo cardiogram revealed Dilated left ventricle and impaired systolic function with EF 40%, and global hypokinesia, consistent with myocarditis.Fresh blood transfusion and FFP commenced. The blood investigations now showed

Hb 12.9 gm/dl, Platelet 100 K/UL, Derranged coagulation, RBS 120 mg/dl,CRP ++, ESR 70mm/hr, WBC 16K/uL, Uric acid 417 micmol/Lt.,LDH 820 u/l, CK 9495u/l, Liver function  elevated bilirubin total and direct with high ALP and AST . RFT : creatinine 200 mic mol/ltr, Hypoalbuminemia, FDP 80 mic gram/ml, Urine Hemoglobin +++ and myoglobin + peripheral smear --> WBC more than 17% bands with toxic changes along with 10% atypical lymphocytes, Microcytic Hypochomic Anemia and Megakaryocytes


A diagnosis of septicemia with multi organ failure was confirmed. Central line was not attempted as coagulation was persistently derranged. Oxygenation was adequate on non invasive ventilatory strategies and guided by frequent ABGs.The patient's condition deteriorated in next 8 hours as there was progressive tachypnea, dyspnea, hypotension non refractory to blood and fluid resuscitation, peripheral cyanosis, reduced or nil urinary output and restlessness and agitation . Chest b/l crepitations and CVS sinus tachycardia with absent peripheral pulses and cold extremities. Immediate intubation and ventilatory support initiated. The CXR showed ARDS

Central line placement attempted irrespective of derranged coagulation as benefit outweighs risk(Paul Marino suggests derranged coagulation is not a contraindication to central venous cannulation)Inspite of all active interventions the patient developed asystole and expired in another 2 hours.


Sepsis means systemic inflammatory response to infection particularly by gram negative bacteria like klebsiella, pseudomonas,enterococci or e-coli. Coagulase negative staphylococci are also implicated.The other agents responsible are fungi and viruses. Infetion leads to activation of neutrophils, endothelial injury, tissue parenchymal injury, organ damage and multiorgan failure.The noxious substances released due to infection including proteolytic enzymes and metabolites are responsible for this systemic inflammatory response and can be harmful to the body when the natural defence mechanisms of the body are overwhelmed.Thats why antibiotics are not much useful and corticosteroids are playing hide and seek in sepsis management.

Sepsis Syndromes: According to ACCC (society of critical care consensus conference (critical care medicine 1992;20:864-74) sepsis syndromes can be classified as

Stage 1) Systemic Inflammatory Response Syndrome (SIRS) if 2 or more of the following criteria are met
                 a) Temp >38deg or less than 36degree
                 b) Heart rate greater than 90/m
                 c) Respiratory  rate greater than 20/mt or paCO2 less than 32mmHg
                 d) WBC count greater than 12000/micltr or less than 4000micltr or greater than 10% bands

Stage 2) Sepsis;   SIRS with a culture documented infection

Stage 3) Severe sepsis;   sepsis plus organ dysfunction, hypotension or hypoperfusion(lactic acidosis,oliguria,hypoxemia or acute alteration in mental status)

Stage 4) Septic shock;  hypotension despite fluid resuscitation plus evidence of hypoperfusion
 
The features of severe sepsis include ARDS, Lactic acidosis, ATN,  Liver dysfunction Septic shock, Altered mentation and DIC.The risk factors for acquiring infection are

Diabetes, Anemia, Invasive procedures, Immunocompromised state ( AIDS TB or chemotherapy) Antibiotic abuse, Genetic predisposition, Drug addiction and severe road traffic accidents.

Investigations: should be aimed at identifying the source or site of infection. Unfortunately all lab findings are nonspecific to sepsis diagnosis.Those which are helpful are

• Elevated WBCs with bands
• ABG for respiratory compromise
• Plasma lactate for tissue hypoxia
• Coag profile for DIC
• Blood culture:   40% cases organism can be isolated, Gram study and culture of serosanguinous fluids or bronchial aspirates are carried out.
• RFT for renal failure
• LFT  hepatic derrangement
• CXR:  to find out pneumonia
• CT or MRI to locate the septic focus of infection eg: retroperitoneal or intra abdominal abscess

Differential Diagnosis: Pulm embolism, MI, metabolic diseases, severe burns or trauma

Treatment
Oxygenation
Remember that tissue oxygenation is not impaired in sepsis as the defect is in cellular oxygen utilisation a condition called cytopathic hypoxia. So tissue concentration of oxygen  is high in severe sepsis. (Fink MP, Cytopathic hypoxia, mitochondrial dysfunction as mechanism for organ dysfunction in sepsis, criti care clinics 2001;17: 219-237). Keep SPO2 more than 90-95%. Permissive hypercapnea is allowed.Consider low tidal volume and low inspiratory pressure if on ventilator
General principles:

• Rapid and prompt initial resuscitation
• Good glycemic control
• Stress ulcer prophylaxis
• DVT prophylaxis;  Elastic stockings if  LMWH contra indicated
• Strict infection control
• Adequate nutrition, preferably early enteral route
• Maintenance of normothermia
• Early mobilisation

Initial resuscitation

Central venous pressure: 8–12 mm Hg
Mean arterial pressure 65 mm Hg
Urine output 0.5ml/kg/hr
Central venous (superior vena cava) or mixed
venous oxygen saturation 70%

Fluid challenge:
1)Infuse 50-100ml crystalloid or 300-500ml colloid over 30 minutes
2)Repeat as needed until goal reached or fluid overload imminent
5% albumin preferred in sepsis as hypoalbuminemia is usually associated with sepsis(Marik PE treatment of hypoalbuminemia in the critically ill patients, Heart Lung 1993; 22, 166-170)

Vasopressors: Dopamine 5-20 mic/kg/mt,or norepinephrine 0.2 -1.3 mic/kg/mt(1-10 mic/mt for 70 kg patient)
Still refractory consider vasopressin, a pure vasoconstrictor at the dose of 0.01 to 0.04 units/mt

Steroids: previously not considered for sepsis management but evidence shows that low doses are beneficial especially in adrenal shut down, low dose Hydrocortisone 6th hrly or 200-300mg IV OD for 7 days improved survival in 'pressor unresponsive' sepsis(if administered in less than 8 hrs of presentation)
Norepinephrine: greater than 0.4mic/kg  is anNalternative for pressor resistant septic shock.
Activated protein C  if given before 48 hrs of onset improves outcome
Anti inflammatory antibodies agaist endotoxins, TNF, IL-1etc. under trial, Polyclonal
intravenous immunoglobulin has been reported to reduce mortality rate and is a promising adjuvant in the treatment of sepsis and septic shock.
Surgical drainage of pus
Granulocyte colony stimulating factors improves immunity
Anti oxidant therapy:
Free radicals produced during inflammation are thought to be the cause for tissue injury. Hence Antioxidants act as "free radical scavengers" and prevent and repair damage done by these free radicals. eg: Coenzyme Q10 (CoQ10) ,Glutathione superoxide dismutase (SOD) ,catalase glutathione peroxidase etc Now under experimental trial
Others: Plasmapheresis, GIK regimen, Hemofiltration
Sepsis resuscitation bundles
complete within 6 hours
Measures serum lactate
Obtain blod cultures prior to antibiotic administration
Administer broad spectrum antibiotics within 3 hours of emergency department admission and within 1 hour on emergency department admission
In the event of hypotension or serum lactate more than 4 mmol/L20ml/Kg of crystalloid or equal volume of colloid then use vasopressors to keep mean BP more than 65mmHg  if not responding to fluid.
If still hypotensive achieve CVP more than 8mmHg and SCvo2 more than 70 or SVo2 more than 65
complete within 24 hours
Give low dose steroid for shock
Administer activated protein C
Maintain glucose between 70-150 mg/dl
Mean insp plateau pressure less than 30 cm of water

Ref: R. Phillip Dellinger, MD; Jean M. Carlet, MD; Henry Masur, MD;et al; Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock, Critical Care Med 2004 Vol. 32, No. 3
http://www.survivingsepsis.org/
Paul Marino; The ICU Book, second and third editions.
Current critical care diagnosis and treatment second edition
Mervin Singer, Andrew Web; Oxford Hand Book of Critical Care, 3rd edition

Other sites of interest:
Advances in Sepsis
http://www.advancesinsepsis.com/
European Society of Intensive Care Medicine
http://www.esicm.org/
International Sepsis Forum Website
http://www.sepsisforum.org/
Society of Critical Care Medicine
http://www.sccm.org/