Turn the course of sepsis

Sepsis is not contagious, but some infections causing sepsis can be transmissible. Most infections – community or hospital acquired – can cause sepsis. Septic patients can be found in the emergency department, but also hospital wards and the intensive care unit (ICU).

Sepsis can be caused by a specific toxin (endotoxin) entering the blood stream. Endotoxin, or lipopolysaccharide (LPS), is a major component of the cell wall of gram-negative bacteria. When endotoxin is released into the bloodstream, a strong reactive response is produced by the immune system which can develop into sepsis. ¹⁰ Sepsis can be a life-threatening symptom of gram-negative bacterial infection.

Several factors can cause dangerously high levels of endotoxin, resulting in endotoxemia and potentially sepsis, septic shock and death.

• Almost any type of infection – community or hospital acquired – can cause sepsis, including (most commonly) bacterial, ¹¹ viral (including COVID-19) and fungal
• Gram-negative bacterial infections in particular can cause sepsis ¹²
• Complement activation from certain types of medical treatment can cause endotoxin levels to increase ^13,14
• The intestines normally contain several kilograms of gram-positive and gram-negative bacteria. In hypotensive patients with splanchnic hypoperfusion, for instance during cardiac surgery or in severe gram-positive infections, ^15,16,17 bacteria can cross the mucosal epithelia and enter the bloodstream. This is called translocation.
• Gram-positive bacteria can cause hypersensitivity to endotoxin ¹⁸
• Antibiotics have the potential to liberate endotoxin from the bacterial cell-wall when killing the bacteria, and this can lead to a rapid clinical deterioration for the patient ^19,20
• Antibiotic treatment in the absence of a bacterial infection can also cause a release of endotoxin, triggering endotoxemia and over-production of pro-inflammatory cytokines – an antibiotic-induced inflammatory storm ²¹
• Bacteria can move from local infection to bloodstream via lymphatics ²²

Some common bacterial infections that can result in bacteraemia, sepsis and ICU admission are:

• Pneumonia
• Urinary infections
• Gastro-intestinal and abdominal infections
• Post-operative infections
• Wound infections
• Meningitis

The most common causes of sepsis in all age groups are diarrheal diseases and lower respiratory infections. The proportion of gram-positive, gram-negative, and fungal sepsis is:

• 16-40% of sepsis cases are estimated to be attributable to gram-positive bacterial infections
• 34-64% of sepsis cases are estimated to be attributable to gram-negative bacterial infections
• 9-19% of sepsis cases are estimated to be attributable to fungal infections. ²³

Sepsis has both short-term and long-term consequences for the individual as well as the healthcare system. It is the most expensive healthcare problem in the US ²⁴ and can result in:

• tissue damage
• amputations – it is estimated that up to 8% of sepsis patients need one or more surgical amputations. ²⁵
• health consequences such as cognitive impairment, mental health disorders, functional disabilities, rehospitalization, increased post-discharge mortality
• Up to 50% of sepsis survivors go through post-sepsis syndrome. This means a higher risk of rehospitalization, infection, stroke, heart attack, and effects such as impaired cognitive and/or physical functions and post-traumatic stress disorder (PTSD). ²⁶ and long-term morbidity ²⁷
• multiple organ failure or dysfunction syndrome (MOF or MODS)
• the need for acute and possibly chronic dialysis treatment• death. The mortality for sepsis ranges from 20% up to 50% in the ICU. ²⁸

Sepsis is one of the most common causes of death in modern intensive care. With nearly 49 million cases worldwide and 11 million deaths globally per year – or 1 in 5 – it is now thought that sepsis kills more people than cancer. ²⁹

The incidence of sepsis is very high; around 189 per 100,000 person-years. The highest sepsis incidence and mortality occurs in lower-middle-income countries. Up to 85% of sepsis cases and related deaths happen in low/low-middle/middle income countries, and sub-Saharan Africa and Southeast Asia in particular. ³⁰

Symptoms seen in sepsis are, for example:

• Change in mental status
• Low blood pressure (hypotension)
• High respiratory rate, difficulty breathing
• Fever and/or chills
• Confusion or disorientation, slurred speech
• Fast heart rate
• Extreme pain
• Changes in coagulation

And in septic shock, additional symptoms are seen:

• blood pressure dropping to dangerously low levels and the need for medication to maintain systolic blood pressure greater than or equal to 65 mm Hg.
• High levels of lactic acid (serum lactate), indication that cells are not using oxygen properly. ³¹

Early diagnosis and treatment of sepsis is crucial as it increases the chance of survival. ^32,33 The condition can however be hard to identify at an early stage. For instance, a third or more of patients initially diagnosed with sepsis turn out to have other, non-infectious conditions. ³⁴ There is no gold-standard, single test to diagnose sepsis but research into potential diagnostic and prognostic biomarkers is ongoing. ³⁵

Sepsis can happen to anyone, but individuals who are more susceptible to contract an infection are also at higher risk of sepsis: infants, the elderly and people who have an impaired immune system. ³⁶ The most common risk factor for sepsis is hospitalization: the longer the admission time, the higher the risk of a nosocomial infection. ³⁷

There are several risk factors for sepsis, meaning sepsis occur more frequently in certain patient groups. For example:

• Older age
• Children under 5 (almost half of all sepsis cases) and neonates
• Maternal sepsis (during pregnancy, childbirth, post abortion or the postpartum period), causing almost 11% of maternal mortality, almost all cases occurring in low/middle income countries
• Compromised immune system
• Diabetes
• Chronic kidney or liver disease
• Admission to intensive care unit or longer hospital stays. 1 in 4 cases of sepsis were acquired in the hospital, 1 in 2 In the ICU. ³⁸
• Invasive devices, such as intravenous catheters or breathing tubes
• Genetic factors are associated with risk of severe sepsis ³⁹

The clinical severity is usually sepsis, followed by septic shock. The clinical syndrome MOF (Multiple Organ Failure) or MODS (Multiple Organ Dysfunction Syndrome) may occur in the progression of sepsis. ⁴⁰

“Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%.” ⁴¹

The sequential organ failure assessment (SOFA) score system is used to predict clinical outcomes of critically ill patients and determine, based on six different scores: for respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems of the patient. Score ranges from 0-24 points, where 24 represent the worst clinical condition. A light version, quick sequential organ failure assessment (qSOFA) score is also being used by clinicians, ranging from 0-3 points. ⁴² An increase in qSOFA score ≥ 2 is suggestive of sepsis. ⁴³

Example of how sepsis should be treated from international guidelines:

• Intravenous antibiotics
• Oxygen
• Fluids
• Vasopressor support to stimulate the heart and maintain adequate blood pressure

Treating sepsis early and preventing the progression to septic shock is important in several aspects:

• To save the patient’s life in the acute situation.
• To prevent post sepsis syndrome. Up to 50% of sepsis survivors go through post-sepsis syndrome. This means a higher risk of rehospitalization, infection, stroke, heart attack, and effects such as impaired cognitive and/or physical functions and post-traumatic stress disorder (PTSD). ⁴⁴ It is estimated that up to 8% of sepsis patients need one or more surgical amputations. ⁴⁵
• To avoid organ failure and multiple organ failure. Saving the kidneys from failing may save the need for acute CRRT treatment. Sepsis is the leading cause of acute kidney injury (AKI) in ICU – 45 to 70% of all AKI is associated with sepsis. ⁴⁶