Sepsis is internationally recognized as a medical emergency.1 As a result, clinicians’ attitudes toward its treatment has evolved over the last 10 years, and treatment regimes in both ambulance services and hospitals have become more aggressive. The key research finding that underpins these changes is that early antimicrobial therapy is essential in reducing mortality.2,3 The therapy also reduces in-hospital complications and shortens patient recovery times.
The most commonly adopted treatment for sepsis comprises administration of IV fluid alongside antimicrobial therapy.2,3 Evidence and support for the more aggressive treatment of sepsis come from both sides of the Atlantic, and include the International Sepsis Forum, the United Kingdom Sepsis Trust, the Society of Critical Care Medicine and the Surviving Sepsis Campaign.
The main sepsis diagnostic tool is use of SIRS criteria. Photo courtesy St. John, N.Z.
Internationally, the incidence of sepsis is significant, with global mortality figures showing a death from sepsis occurring every four seconds.4
In the U.K., approximately 100,000 people were diagnosed with Sepsis in 2013. Of those, 37,000 died, resulting in a mortality rate of 37%.1 In the United States, numbers for 2012 reveal that 751,000 people were diagnosed with sepsis, 383,000 of whom required ventilator support, with a further 215,000 patients losing their life to sepsis.2,5
In New Zealand and Australia, a total of 101,064 patients were diagnosed with sepsis within a 12-year period. Of those, 24,255 died, resulting in a mortality rate of 24%.6
The pathophysiology of sepsis is complex and can depend on both the bacterial mediator and the patient’s immune status. Sepsis is in some ways similar to anaphylaxis, in that it’s an uncontrolled amplification of the body’s immune response.7,8
There’s no one single mediator/system/pathway/pathogen that drives the pathophysiology of sepsis, so not all aspects of its pathophysiology will be covered here.
A stepwise breakdown of the progression from infection to sepsis includes:
- Local infection;
- Bacteria infiltrate circulatory system;
- Bacteria release endotoxins;
- Macrophages attempt to combat this by releasing inflammatory mediators, causing endothelial damage;
- A cytokine storm begins, releasing up to 150 inflammatory markers;
- Massive vasodilation causes the release of tissue and clotting factors from the damaged endothelium, which inhibits fibrinolysis; and
- Hypotension and uncontrolled coagulation leads to poor perfusion and lactate build-up. At this point, end organ damage is inevitable.
The approach needed to make a diagnosis of sepsis is multifaceted. In-hospital tests usually involve blood cultures to help identify a particular bacterial pathogen. Lactate levels are an indicator of sepsis severity, with the majority of guidelines suggesting a lactate level exceeding 4 mmol/L as significant (normal lactate levels range from 0.5—1 mmol/L).2,5
Despite these bedside tests, the main diagnostic tool in both hospital and ambulance is use of the systemic inflammatory response syndrome (SIRS) criteria, along with a full physical exam and thorough health history.
It’s important to note that meeting the SIRS criteria isn’t in itself grounds for a definitive diagnosis of sepsis, since many other conditions may cause SIRS, such as:
- Complications of surgery;
- Adrenal insufficiency;
- Pulmonary embolism;
- Complex aortic aneurysm;
- Cardiac tamponade;
- Drug overdose;
- Burns; and
- Pancreatic ischemia.
However, when SIRS is present and there’s a suspected or confirmed site of infection, a patient is most likely septic. When poor perfusion or poor urine output is also present, the patient has severe sepsis. (See Table 1.)
Treatment with antimicrobial agents, such as ceftriaxone, should begin before this point, since a patient’s chance of survival drops rapidly once they reach this stage, and it becomes a race against the clock. The mortality rate can increase by as much as 8% for every hour a severely septic patient goes without antimicrobial therapy.9
The Sepsis Non-STEMI
A patient with sepsis can present with few to no signs of SIRS. A recent study found a total of 109,663 patients who were diagnosed with infection and organ failure over a 13-year period. Of these, 87.9% met the SIRS criteria for severe sepsis, meaning 12.1% were still SIRS-negative.10
These studies reveal that an average of 1 in 8 patients with severe sepsis won’t meet the SIRS criteria. Therefore, similar to STEMI vs. non-STEMI when looking at myocardial infarction, sepsis can be divided into SIRS vs. non-SIRS sepsis 10,11
There are many factors affecting patient presentation that may result in a non-SIRS septic patient. The clinician must have a high index of suspicion and ask themselves
- Is the patient on beta-blockers?
- Is the patient paced with an implantable cardioverter defibrillator /pacemaker?
- Is the patient an athlete or very fit?
- Have they had an antipyretic within the last few hours?
- Are they on opiates or any sort of respiratory suppressants?
- Are they on chemotherapy?
- Are they a child? (Pediatric patients compensate well, then decompensate rapidly.)
Paramedics in New Zealand are equipped with the tools, knowledge and guidelines to allow them to treat sepsis aggressively and quickly. The two main ambulance companies in New Zealand are St John and Wellington Free Ambulance, which operate under two different, but very similar, set of sepsis guidelines: gaining peripheral IV access, the administration of IV antibiotics, and fluid resuscitation coupled with a positive inotrope should there be no improvement in patient condition. (See Figure 1.)
In some Australian States, such as Victoria, ambulance guidelines for treating sepsis aren’t specific, and a guideline for inadequate perfusion is used instead. (See Figure 2.) Given the prevalence of sepsis and its potential complications, Ambulance Victoria is currently investigating adopting a more specific guideline for its treatment.
The treatment regime in these more general protocols isn’t as aggressive or as open as those used in New Zealand. They stipulate a patient must be in septic shock, and that adrenaline is given first, reserving the use of an antibiotic only if transport is likely to exceed one hour. Even then, the attending clinician must consult prior to administration. In light of the potential 8% rise in mortality for every hour without antimicrobial therapy,9 this seems overly conservative.
Despite the New Zealand guidelines offering slightly more autonomy than some of the Australian states, some septic patients in New Zealand are still deprived of antibiotic therapy due to paramedic opinion and misinformation. There are still a number of myths that exist in the minds of paramedics concerning the use of antibiotics.
Myth 1: You need to be careful administering ceftriaxone to anyone with renal issues as it can lead to kidney failure.
Ceftriaxone, along with a large number of antibiotics, isn’t metabolized systemically. Only the intestinal flora transform the agent into inactive metabolites.12
Myth 2: Anyone with a penicillin allergy has a 10% chance of having a reaction to ceftriaxone.
Crossover between penicillin allergy and third-generation cephalosporin is < 1%.12,13
Myth 3: Prehospital administration of antibiotics contributes to bacterial resistance.
Bacterial resistance is more likely when antibiotics are inappropriately prescribed to patients with viral illness. Bacteria naturally develop immunity and can share DNA, acquiring an immunity from other bacteria. Resistance can be caused when someone starts to feel better and then doesn’t complete a course of antibiotics.
Myth 4: Antibiotic therapy should be delayed so that cultures can be taken and therapy can then be better targeted.
In many cases, it takes a minimum of 24 hours to grow cultures, and up to five days for some bacteria. The ED won’t wait for 24 to 72 hours for culture results; most staff prefer to give a broad spectrum fourth-generation cephalosporin to combat the microbial infection. This is then followed up with a targeted therapy once the culture results come back.
Irrespective of the country, Australasian hospitals have similar criteria and protocols in place for treating severe sepsis. Currently, these protocols focus on goal-driven therapies and “bundles” as specified in the Surviving Sepsis Campaign.3 The current focus is on lactate clearance, antimicrobial therapies, cultures and supportive measures as soon as it’s possible to achieve. However, with new research being published all the time on sepsis treatment, this landscape is always likely to change.
In New Zealand, Wellington ED has a fast-track process for suspected sepsis patients. In Australia, the Clinical Excellence Commission is responsible for leading safety and quality improvement in the New South Wales public health system. They have published a pathway for adult sepsis.
Knowledge and understanding of the pathophysiology of sepsis has been developed greatly through ongoing research. With this evolution has come more specific guidelines around treatment that focuses on sepsis as a distinct provisional diagnosis, rather than lumping it in with the more generic guidelines around inadequate perfusion.
However, ambulance services in New Zealand and Australia still have a way to go to get the message out there among all paramedics that sepsis is an insidious killer that demands prompt recognition and treatment if patients are to have a positive prognosis. Like all myths, education based on robust research can be the key to dispel misinformation, and in so doing improve patient care.
1. McPherson D, Griffiths C, Williams M, et al. Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010. BMJ Open. 2013;3(8).
2. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(21):2063.
3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580—637.
4. World Sepsis Day. (n.d.) Sepsis facts. Retrieved July 15, 2016, from www.world-sepsis-dayorg/?MET=SHOWCONTAINER&vCONTAINERID=11.
5. Bakker J, Perner A, Timsit JF. Evaluation of 7.5 years of Surviving Sepsis Campaign Guidelines. Intensive Care Med. 2015;41(1):151—153.
6. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000—2012. JAMA. 2014;311(13):1308—1316.
7. Hong Z, Xin L, Jiang Z. (2006.) Sepsis treatment-Challenge and chance. CNKI. Retrieved July 15, 2016, from http://en.cnki.com.cn/Article_en/CJFDTotal-DSDX201302000.htm.
8. Jiang M, Zhou M, Han Y, et al. Identification of NF-ÎºB Inhibitors in Xuebijing injection for sepsis treatment based on bioactivity-integrated UPLC-Q/TOF. J Ethnopharmacol. 2013;147(2):426—433.
9. McGregor C. Improving time to antibiotics and implementing the “Sepsis 6.” BMJ Qual Improv Rep. 2014;2(2):145—149.
10. Kaukonen KM, Bailey M, Pilcher D, et al. Systemic Inflamatory Response Syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629—1638.
11. Klein Klouwenberg PM, Ong DS, Bonten MJ, et al. Classification of sepsis, severe sepsis and septic shock: the impact of minor variations in data capture and definition of SIRS criteria. Intensive Care Med. 2012;38(5):811—819.
12. Floridis J, Ward A. Penicillin allergies: Facts, fiction and development of a protocol. Australian Med Student J. 2015:5(1);12—21.
13. Lee QU. Use of cephalosporins in patients with immediate penicillin hypersensitivity: Cross-reactivity revisited. Hong Kong Med J. 2014;20(5):428—436.