The Surviving Sepsis Campaign Ssc

Published Date: 02 Nov 2017

Two major definitions were used to define sepsis. First sepsis was defined as an infection that triggers a Systemic Inflammatory Response Syndrome (SIRS). 1 This is characterized by body temperature outside 36oC - 38oC, HR >90 beats/min, respiratory rate >20/min, WBC count >12,000/mm3 or < 4,000/mm3.2 Three stages were recognized in the inflammatory response. Stage one is patients with infections plus two or more elements of the SIRS, meet the criteria for sepsis. Patients who have end organ failure or dysfunction of one organ or organ system are considered as having severe sepsis. People who have refractory hypotension along with the above said criteria are consider to be in septic shock.1,2

This definition was further expanded after reviewing literature at the International Sepsis Definition Conference in 2001. Sepsis was staged in to 4 separate characteristics represented by an acronym PIRO.1

P- Predisposition (pre-existing co-morbid conditions that would reduce survival)

I- Infection (shows that some pathogenic organisms are more lethal than others)

R- Response (reaction to infectious challenge and developments of SIRS)

O- Organ dysfunction (organ failure or failure of system (eg:-coagulation)

Pathophysiology

Sepsis occurs due to an infection at any site of the body or a primary blood stream infection. The most commonly associated pathogens in sepsis are bacteria but it could be also caused by fungi, viruses and parasites.3 In sepsis when a pathogen invades the host, an innate immune response is triggered via toll-like receptors (TLRs) on immune cells.4 Outer cell membrane components of gram-negative bacteria (eg: lipopolysaccharides (LPS), endotoxin, lipid A) and gram positive bacteria (eg: lipoteichoic acid, peptidoglycan) is recognised and act as mediators. Signalling by these mediators occurs via TLRs that trigger production of pro-inflammatory cytokine release like tumour necrosis factor(TNF) and interleukin 1 and 6(IL1,IL6). 3,4 TNF and IL1 then go on to stimulate endothelial cells via trans membrane proteins activating toxic downstream mediators like prostaglandins, leukotriene, platelet activating factor and phospholipase A2. These toxic mediators damage the endothelial lining causing capillary leakage.3

Mediators like IL1,TNF, LPS initiate coagulation pathways inducing expression of tissue factor on mononuclear and endothelial cells.4 This leads to the conversion of prothrombin to thrombin which in turn generates fibrin from fibrinogen. High plasma levels of plasminogen-activator inhibitor type-1 (PAI-1) prevent the conversion of plasminogen to plasmin therefore inhibiting the breakdown of fibrin by plasmin. This leads to deposition of fibrin clots due to the reduced removal of fibrin. These clots deposits in small blood vessels causing inadequate tissue perfusion and organ failure seen in sepsis.12

IL1 and TNF also causes down regulation of protein C and antithrombin that are modulators of coagulation and inflammation seen in sepsis.3 Activated protein C (APC) and its cofactor protein S turn off thrombin production by inactivating factors Va and VIIIa.7 The reduced levels of APC therefore causes pro-coagulant effects. This leads to impaired tissue oxygenation which is the hypo perfusion and hypotension seen in sepsis.7 On the other hand antithrombin that is downregulated by cytokines, inhibits thrombin production at multiple steps in the coagulation cascade. Antithrombin, when bound to endothelial cell surface glycosaminoglycans (GAGs), leads to the production of the anti-inflammatory molecule prostacyclin prostaglandin I2 [PGI2]).7

Furthermore this activation of the innate immune system results in release of reactive oxygen species, nitric oxide (NO), proteases pore forming molecules bringing about bacterial killing. These molecules that are released damage the host like NO is a potent vasodilator that causes sepsis-induced mitochondrial dysfunction and reduced systemic vascular resistance leading to septic shock.3,4

Patients with sepsis have been shown to have a decrease in number of perfused capillaries and capillary oedema.4,8 This means Oxygen and other nutrients would therefore take further to diffuse from capillaries to cell causing the organs to become hypoxic. In addition to shunting impairing oxygen supply to some capillary beds, NO has direct effects on the mitochondrial oxygen transport chain.  NO further combine with O2 radicals to produce peroxynitrite (ONOO−). These potent free radicals combine either reversibly or irreversibly with proteins of the electron trans-port chain. This causes the ATP levels to fall resulting in reduced cellular energy levels. These falling intra-cellular ATP concentrations could be attributed to the severe symptoms such as complete anuria and hypotension seen in sepsis.3

Overall in sepsis as the adaptive immunity kicks in and the inflammatory cascade of sepsis unfolds, the balance is shifted towards cell death and a state of relative immunosuppression.3 At this late stage, there is an increase in lymphocyte apoptosis and production of pro-inflammatory mediators may reduce further leading to end organ dysfunction. These mediators like NO, IL-1 cause vasodilatation and increase capillary permeability at the site of infection. In sepsis core organs may not receive appropriate oxygen delivery, and the resulting in regional hypoperfusion.8 Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of mediators like IL-1 causes hypotension. 8 Research has shown that micro-vascular dysfunction caused by disruption of blood flow and disruption of mitochondrial energy pathways leads to the development of organ failure.3,4,8 See image 1 9

Organ failure

One of the organs affected in sepsis is the heart. Patients are typically tachycardic, and markers of myocardial injury such as troponins I and T can appear in the blood, even in the absence of coronary artery disease. This is usually attributed to the cardial hypoperfusion in sepsis.4However with patients in septic shock heart failure is caused due to cardiac depression9 which is linked to reduction in myocyte contractility leading to hypotension. Myocardial depression is seen in septic shock after 24-48 hours after onset of sepsis. 10The marked drop in systemic vascular resistance due to NO, TNF and IL 1 results in a reduction in left ventricular afterload and an increase in cardiac output to maintain blood pressure is seen in the early phases of sepsis.4,8 To compensate the body sustain these changes by increasing the heart rate also increasing left arterial filling pressure and end diastolic and end systolic volumes are increased.4 However decompensation occurs when this mechanism is exhausted leading to hypo-perfusion and shock11.

The lung in sepsis

Another organ that is affected in sepsis is the lungs. During the early stages of the inflammatory process of sepsis respiratory dysfunction occurs due to endothelial leakage of fluids and proteins, infiltration of neutrophils, and loss of surfactant. 4, 9 Acute respiratory distress syndrome could occur in late stages due to the inflammatory pulmonary oedema.4

The kidney in sepsis

Acute renal failure(ARF) also occurs in sepsis due to the effects of NO release seen is sepsis. 4, 9 NO affects the distribution of blood between renal cortex and medulla. Further since NO as mentioned earlier has direct and indirect effects on mitochondrial energy production therefore it has an effect on tubular function which is highly energy dependent. 4

The activation of the renin-angiotensin-aldosterone system results in hypotension. This increases sympathetic tone and the release of vasopressin from the pituitary. The resulting vasoconstriction causes sodium and water retention and a predisposition to ARF. Further glomerular blood flow and filtration is reduced by secretion of endothelin, another vasopressor hormone which is elevated in sepsis. 4

Outcomes

Although the incidence of severe sepsis is increasing, mortality rates continue to decrease.3

20-35% mortality rate of people with severe sepsis

30-70% mortality rate of septic shock

Lactate is a method used to determine prognosis

Lactate > 4 mmol/l has a mortality of 40%

Lactate < 2 mmol/l mortality rate of 15% 11

Prognostic stratification system MEDS and APACHE II are used in the Emergency department to estimate the risk of patient dying from severe sepsis. Various physiological variables such as person’s age, underlying condition etc are used to determine this. Usually the severity of the underlying disease most strongly influences the risk of death. Short- term and long term mortality is also determined by septic shock. 12

Incidence

It is estimated that there are100,000 sepsis cases a year in the UK leading to 37,000 deaths in UK and 8 million worldwide. These incidence keep rising yearly due to people living longer the ageing population are more vulnerable to sepsis. 13 In septic patients, older age, positive fluid balance, co morbid diseases on admission; cancer and cirrhosis are the most important variables of mortality. 14

The Role of Critical Care

Treatment

Initially before treating sepsis at the A&E the patient would be treated to reverse any life threatening physiological abnormalities she may have. For example her severe hypoxia is treated using an endotracheal intubation and intermittent positive pressure ventilation (IPPV). 15 This reduces her physical exhaustion 4 by reducing the acidosis caused due accelerated oxygen demand by respiratory muscles. 15

Then adequate oxygenation of (PaO2 about 10 Kpa) with a 60% inspired concentration is given. 4 In the emergency department they follow all elements of the Severe Sepsis Resuscitation Bundle (RB). Sepsis six was developed by SSC to summarise the basic tasks in the resuscitation bundle that needs to be carried out within the first hour. (See image 2)16

After obtaining a full history the first steps that will be done once admitted is to: 4,15

Measure serum lactate.

Obtain blood cultures prior to antibiotic administration therefore when a specific bacterium has been identified a more focused antibiotic can be given.

Administer broad-spectrum antibiotics within 1 hour of diagnosis with acute sepsis until results of the blood culture 17

Tight control of the blood glucose level during sepsis (8.3 mmol/l) to decrease the rate of infectious complications

This patient is hypoxic shown by the PaO2 value, caused by poorly perfused tissue beds. Further the elevated serum lactate levels of >6 mmol shows she has a built up of lactic acid. This is caused by cells respiring anaerobically due to lack of oxygen caused by hypo-perfusion and hypotension. This lactic acidosis leads to metabolic acidosis.17 Therefore she requires intravenous fluids or colloid to expand the circulating volume and effectively restore perfusion pressure. 3 Further the oligo-anuria suggests that she may have acute renal failure, therefore, one she is stabilised a decision needs to be made if she needs treatment like haemofiltration. 18 Further urine output needs to be continuously measured to assess renal perfusion during treatment.

Further management is done using Early Goal-directed therapy (EGDT) to adjust the cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand.19 Initially in EGDT she would be given a rapid fluid challenge- minimum of 20 ml/kg of crystalloid (or colloid equivalent) to achieve central venous pressure >8 mmHg. 4 If hypotension still remains which is a mean arterial pressure <65mmHg, a vasopressor is given like norepinephrine infusion or dopamaine via central line to correct the hypotension. 20 Dopamine works by increasing the cardiac index due to the increase in stroke volume which means it prevents development of cardiac shock and also increase systemic vascular resistance. On the other hand norepinephrine is a potent vasoconstrictor therefore helping to reverse the hypotension with little change in heart rate or cardiac output, leading to increased systemic vascular resistance. 20 Further oxygen delivery is optimized by EGDT through central venous catheters that monitors and maintain a central venous O2 saturation (ScvO2)of 70%. Even after all this if there is evidence of hypoperfusion (O2 saturaion<70%)23 then adequate haemoglobin will be given by transfusion of red blood cells to reach a haematocrit of 30%. If she continues to have a low cardiac output (oliguria, poor peripheral perfusion) inotropes like dobutamine can be given. This would also treat her tachycardia keeping her heart rate <100 bpm to minimise myocardial oxygen demand.

SSC Management Bundle

Further IV steroids can be given to those with septic shock who don’t respond to adequate fluid and vasopressor resuscitation.21 Low dose steroids work by reducing pro-inflammatory cytokines therefore reducing the inflammatory process in sepsis. 22

 

Standardising treatment

The Surviving Sepsis Campaign (SSC) 23 that was originally launched in 2002 with the stated goal to reduce mortality by 25%. The primary method to achieve this goal was the development of evidence-based sepsis care guidelines that were published in 2004.23 and recently revised in 2008. The introduction of ‘care bundles’ by the SSC allowed to reach this goal and improve outcome by standardizing patient care using multiple evidence-based components bundled together in care plans for sepsis. These SSC care bundles were accepted as standardised treatment to sepsis when a patient was admitted. It allows assessing the compliance of treatment with the care bundles recommended by the SSC. Two bundles are now being promoted in critical care Resuscitation Bundle, tobecompletedwithin6 hours of recognition of treatment, and the Management Bundle, to be completed within 24 hours.24

Discuss the potential sources for the infection in this woman.

Several potential sources could have caused the infection that led to sepsis in this woman. The source of infection could be from the lungs (pneumonia), bladder and kidneys (urinary tract infections), skin (cellulitis), abdomen (appendicitis), and other areas (such as meningitis) can spread and lead to sepsis.25,26 To identify this accurately a full history is required. It is more likely that sepsis was related to the miscarriage. Firstly since she has had a miscarriage the source of infection could have been due to an incomplete miscarriage. If some of the foetal or placental materials remain in the uterus after a miscarriage she has an increased risk of developing an infection.27 These retained products provides a medium for bacterial growth causing an infection that could have further led to a generalized infection causing sepsis.

On the other hand she could have developed puerperal sepsis which is a serious form of septicemia contracted by women after a miscarriage.28 Usually if a baby miscarries after 14 weeks a woman goes in to labour.29 After labour the genital tract has a large bare surface, which can become infected. An infectious pathogen could have entered the birth canal of the woman during the miscarriage. Inflammation of the vagina and of the uterus or the cervix occurs first, and then the infection spread and may become generalized causing puerperal sepsis. 29

In urosepsis which is severe infection of the urinary tract has features consistent with systemic inflammatory response syndrome.30 Urospeis is caused due to Structural and functional abnormalities of the genitourinary tract that could have been acquired during pregnancy. This leads to an infection due to the impeding of urine flow.

Further if any medical devices were inserted into the body to remove any tissue from the miscarriage this itself may introduce bacteria to the body hence an infection causing the miscarriage that then leads to sepsis. 25