Septic shock is a dangerous medical condition that can lead to multiple organ failure and death. It occurs when sepsis, a systemic inflammatory response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. Septic shock has a high mortality rate, with estimates ranging from 20-50%. Identifying and treating the underlying infection early is crucial to improving outcomes in septic shock. However, even with treatment, septic shock can rapidly progress and lead to death. So what is the most common cause of death in patients with septic shock? Let’s review the pathophysiology and explore the current evidence.
What is septic shock?
Sepsis occurs when the body’s immune response to an infection injures its own tissues and organs. It develops when an infection — most often bacterial, but sometimes viral or fungal — overwhelms the body and causes systemic inflammation. Sepsis ranges in severity from sepsis to severe sepsis to septic shock. Septic shock is the most serious type of sepsis and is defined by:
- Suspected or confirmed infection
- Systemic inflammatory response syndrome (fever or hypothermia, tachycardia, tachypnea, abnormal white blood cell count)
- Persisting hypotension (low blood pressure) despite adequate fluid resuscitation
- Presence of hypoperfusion abnormalities such as lactic acidosis, oliguria, or altered mental status
When sepsis progresses to septic shock, the hypotension and hypoperfusion lead to multi-organ dysfunction. Septic shock has a mortality rate of 40-60% and requires immediate aggressive treatment.
What causes septic shock?
Septic shock begins with an infection. Common sources include:
- Lungs (pneumonia)
- Abdomen (diverticulitis, bowel perforation)
- Urinary tract (pyelonephritis, urosepsis)
- Skin and soft tissue (cellulitis, necrotizing fasciitis)
- Indwelling catheters
- Bones and joints
- Heart (endocarditis)
- Central nervous system (meningitis, brain abscess)
Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae used to be the most frequent causes. However, gram-negative bacteria have become increasingly prevalent and now cause over 60% of septic shock cases. Common gram-negative organisms include Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
In response to invading pathogens, the immune system releases cytokines and other inflammatory mediators. While an appropriate response fights infection, an exaggerated release can cause systemic inflammation and cellular dysfunction. Septic shock occurs when this excessive host response injures tissues and organs.
Key factors in the development of septic shock include:
- Bacterial load – Higher inoculum of bacteria triggers greater inflammatory response
- Virulence factors – Toxins produced by certain bacteria amplify inflammation
- Host factors – Older age, chronic disease, immunosuppression increase risk of severe sepsis
So while infection initiates septic shock, the uncontrolled immune response it provokes precipitates the dangerous sequelae.
Pathophysiology of septic shock
In septic shock, the interplay between invading microbes and the exaggerated immune response creates a cascade of pathologic changes:
- Systemic inflammation – Massive cytokine release damages endothelial cells lining blood vessels, increasing vascular permeability and leaking fluid into tissues.
- Vasodilation – Nitric oxide and other vasodilators cause peripheral vasodilation, increasing blood flow and reducing vascular resistance.
- Myocardial dysfunction – Inflammatory mediators impair cardiac contractility and ventricular response to fluid resuscitation.
- Intravascular volume depletion – Capillary leakage results in loss of intravascular fluid into the extravascular space.
- Impaired oxygen delivery and utilization – Microvascular dysfunction, myocardial depression, and mitochondrial abnormalities impair oxygen delivery and extraction.
- Microthrombi – Widespread small clots obstruct microcirculation, further limiting oxygen delivery.
- Cellular changes – Mitochondrial damage, metabolic changes, and apoptosis lead to cellular dysfunction and organ failure.
These derangements manifest clinically as hypotension, hypoperfusion, and shock. They precipitate ischemic injury and multi-organ failure characteristic of septic shock.
Multi-organ dysfunction in septic shock
In septic shock, vital organs do not receive enough oxygen and nutrients due to poor perfusion. This leads to multi-organ system dysfunction:
- Lungs – Hypoxemia, acute respiratory distress syndrome
- Heart – Myocardial depression, arrhythmias
- Kidneys – Acute kidney injury, oliguria
- Liver – Impaired synthetic function, cholestasis
- Adrenals – Adrenal hemorrhage, impaired cortisol response
- Brain – Altered mental status, seizures
- Intestines – Ischemic bowel, intestinal perforation
- Blood – Disseminated intravascular coagulation
This multi-organ failure underlies the high mortality of septic shock. Treatment must therefore not only eradicate infection but also restore adequate oxygen delivery and cellular function.
Most common causes of death in septic shock
Given the pathophysiology of septic shock, what are the most frequent causes of death?
Refractory hypotension
Refractory hypotension that does not respond to fluid resuscitation and vasopressor medications is the most common proximate cause of death in septic shock. Sepsis-induced arterial and venous dilatation along with myocardial depression lead to low blood pressure. Fluid boluses and vasopressors such as norepinephrine help maintain blood pressure and organ perfusion. However, vasoplegic shock that remains refractory to treatment impairs tissue oxygen delivery and leads to death.
Multiple organ failure
Widespread organ dysfunction is both a result of persistently low blood pressure as well as an independent mechanism of mortality in septic shock. Accumulated oxygen debt and mitochondrial injury lead to cellular apoptosis and loss of organ function. Multiple organ failure involving the lungs, heart, liver, and kidneys is a common terminal event in septic shock. Preventing development of multi-organ failure through prompt hemodynamic stabilization and treatment of infection is key to improving survival.
Overwhelming infection
While less common than refractory shock or organ failure, uncontrolled infection can also directly cause death in septic shock. This may occur from immune paralysis with inability to contain infection, delayed administration of antimicrobials, or multidrug-resistant organisms. Infection induces sepsis, so eradicating the pathogen is crucial. Inability to control infection allows ongoing inflammation and tissue damage, hastening mortality.
| Cause of Death | Frequency |
|---|---|
| Refractory hypotension | Most common |
| Multiple organ failure | Very common |
| Uncontrolled infection | Less common |
Risk factors for mortality in septic shock
Many factors influence an individual patient’s chance of surviving septic shock:
- Older age – Advanced age weakens the immune system and worsens comorbidities.
- Chronic illnesses – Chronic diseases like diabetes, lung disease, malignancy, and liver disease increase mortality risk.
- Delayed presentation and treatment – Waiting to seek care allows greater progression to severe sepsis.
- Critical illness severity – Profound shock, ARDS, coagulopathy and thrombocytopenia predict higher mortality.
- Positive fluid balance – Excessive fluid overload from resuscitation worsens oxygenation and outcomes.
- Immunosuppression – Impaired host response from illness or medications reduces ability to fight infection.
- Nosocomial or multidrug-resistant infection – Hospital-acquired or resistant organisms have higher mortality.
These factors contribute to the pathogenesis and progression of septic shock. Patients with multiple high-risk features face amplified risk of death.
Scoring systems
Objective scoring systems like APACHE II and SOFA provide mortality risk stratification in septic shock based on clinical and lab parameters:
- APACHE II – Assesses degree of acute physiologic dysfunction, with higher scores indicating greater mortality risk.
- SOFA – Sequential Organ Failure Assessment quantifies degree of organ dysfunction, also correlating with higher scores and mortality.
These scores help prognosticate, guide treatment intensity, and standardize research. However they have limitations in predicting individual patient outcomes.
How is septic shock treated?
As septic shock follows a rapid clinical course, prompt diagnosis and management are critical. Core principles of treatment include:
- Early administration of broad-spectrum antibiotics after cultures
- Hemodynamic resuscitation with intravenous fluids and vasopressors
- Source control procedures when indicated such as drainage of infected fluid collections
- Adjunctive therapies to modulate host response and stabilize cellular function
- Supportive care for organ dysfunction such as mechanical ventilation for respiratory failure
Adhering to sepsis treatment bundles and published guidelines improves outcomes. However, even with excellent care, some patients will not survive due to the pathophysiologic severity of illness.
Conclusion
In summary, septic shock is a dangerous syndrome with life-threatening circulatory, cellular and metabolic dysfunction precipitated by uncontrolled infection. Refractory hypotension unresponsive to treatment is the most frequent direct cause of death. However, multiple organ failure driven by tissue hypoperfusion and cellular bioenergetic changes also commonly leads to mortality. While optimal care continues to improve survival, septic shock still carries high risk of death due to its severe physiologic derangements. Ongoing research seeks to better understand its pathogenesis to guide the development of new therapies targeting disordered inflammation, coagulation, and metabolism in sepsis.