Sepsis: recognition and management

Case Scenario

Mr Walker, aged 59 and weighing 100 kg, is found at home acting erratically. His clothing is drenched, the shower is running and his medicines are scattered everywhere. His Glasgow Coma Scale (GCS) score is fluctuating between 5 and 14 and he is agitated. The ambulance transports him to hospital.

Initial observations are: temperature 37.8°C, blood pressure (BP) 106/64 mmHg, heart rate 105 bpm, respiratory rate 16 breaths/minute, oxygen saturation 98%. Initial labs show white cell count 25×10⁹/L, creatinine 160 micromol/L (baseline 60). Urgent blood cultures have been sent, and 2 L of 0.9% sodium chloride has been administered intravenously. His BP is now 98/67 mmHg. A central line is inserted and noradrenaline infusion commenced.

Already read the CPD in the journal? Scroll to the bottom to SUBMIT ANSWERS.

Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹ It is a medical emergency which, if left untreated, progresses to septic shock, multi-organ failure and death.¹ It is the final pathway to death from most infectious diseases worldwide. It can be caused by bacterial, viral or fungal pathogens.^2,3

In Australia alone, there are 55,000 cases of sepsis annually resulting in 8,700 deaths.² The economic annual cost is estimated at $1.5 billion.²

Globally, the situation is even worse, as sepsis is the leading cause of death in hospitals and is related to 20% of all deaths.²

Epidemiology, aetiology, pathophysiology and risk factors

Infection, sepsis and septic shock exist on a spectrum. An infection which may initially be localised (e.g. cellulitis or pneumonia) can progress to sepsis, septic shock and subsequent death.⁴

This is when a patient develops significant hypotension, a key feature of sepsis, due to peripheral vasodilation caused by endotoxin and inflammatory cytokine interaction with vascular endothelial cells. The resulting endothelial injury, whereby intravascular components such as albumin leak into the interstitial space, worsens the shock state further, leading to organ dysfunction.⁵ Multi-organ failure is the last stage of uncontrolled sepsis, which can result in death.

Any person who acquires an infection is at risk of developing sepsis. However, certain groups are at higher risk. These include^2,3:

• the very young and old (age extremities)
• those with compromised immune systems
• hospitalised patients
• pregnant or recently pregnant women.

Measures which prevent a person from acquiring an infection can reduce the risk of potential sepsis. These measures include, but are not limited to:

• vaccination
• hand hygiene
• sanitation measures
• infection control within health care
• pandemic response measures.

Recognising sepsis

Sepsis is a medical emergency similar in severity to a myocardial infarction or stroke, where delays in treatment reduce the patient’s chance of survival. For every hour of delay in commencing appropriate antibiotics for a person presenting with sepsis and hypotension, there is a 7.6% decrease in survival over the first 6 hours.⁶ It is essential that all healthcare practitioners, including pharmacists, are familiar with the signs of sepsis to ensure prompt treatment.⁶

Any patient with a potential infection who appears to be very sick will likely benefit from additional diagnostic workup. This should include assessment of the most likely focus of infection and markers of organ dysfunction.⁴

Presentation of sepsis can differ between adults and children. The most common signs are listed in Table 1 below.

Table 1 – Signs and symptoms of sepsis

References: Australian Sepsis Network², World Health Organization³

* Skin may be flushed or have a red rash in the earlier stages before mottling as shock progresses.

Treatment

The Surviving Sepsis Campaign, led by an expert panel of intensive care and infectious diseases clinicians, has developed evidence-based guidelines for the management of sepsis. The Hour-1 Bundle for sepsis details the key treatments that must be initiated within the first hour of the patient presenting with sepsis.⁷

The components of this sepsis bundle are^6,7:

• Measure lactate level. Remeasure if initial lactate is >2 mmol/L; serum lactate is a surrogate measure of tissue perfusion and can assist with identifying a patient progressing into septic shock (not included in paediatric sepsis bundle).
• Obtain blood cultures prior to administration of antibiotics; however, antibiotic administration should not be delayed in order to obtain blood cultures. While not listed in the Hour-1 sepsis bundle, other cultures such as cerebrospinal fluid, sputum and urine may also be obtained to help with pathogen identification. These should not delay initiation of antibiotics.⁸
• Administer broad-spectrum antibiotics.
• Begin rapid administration of a minimum of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L. In paediatrics, up to 40–60 mL/kg as 10–20 mL/kg boluses may be given, over the first hour.
• Apply vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean arterial blood pressure (MAP) ≥65 mmHg. 

Antibiotic choice, dose and administration 

It is imperative when treating sepsis that the initial antibiotics administered are broad-spectrum to cover the potential infecting pathogen.⁷

The following should be considered to determine the most appropriate antibiotic⁸:

• most likely source of infection
• local antibiotic resistance patterns
• recent antibiotic exposure
• patient allergies
• individual patient factors (e.g. recent hospitalisations, immunosuppression, overseas travel)
• any known multi-resistant organisms (MROs) colonisation.

Pharmacists should obtain a medication history with particular focus on allergies and any recent antibiotics received. If a patient has been taking antibiotics prior to presentation, then antibiotics from another class, or higher doses, may need to be considered. The hospital pharmacy service should ensure that access to appropriate broad-spectrum antibiotics is always available in order to prevent delay in treatment.

Antibiotic choice should be reviewed and rationalised in response to changes in patient condition and the results of microbiological cultures as they become available.

Antibiotic pharmacokinetics and dose

Patients who are in septic shock can experience pathophysiological changes that can affect the pharmacokinetics of medicines. These changes need to be taken into consideration when dosing antibiotics.⁹

Absorption

Absorption from the gastrointestinal tract (GIT) is reduced in septic shock, as blood supply is diverted away from the GIT to the essential organs, the brain, lungs and heart. This means that oral administration of antibiotics is less likely to be effective due to delayed or reduced absorption.⁹ The intravenous (IV) route of administration is therefore preferred for septic patients.⁹ If there are difficulties in obtaining IV access, then intraosseous (IO) administration is the second-line option.⁸

Distribution

In sepsis, peripheral vasodilation and changes in the endothelium of blood vessels results in loss of intravascular blood components such as albumin into the interstitial space. This physiological change, combined with the large volumes of fluid administered to counteract the resulting hypotension, result in an increased volume of distribution (Vd) for many medicines. This is important for hydrophilic antibiotics such as beta- lactams, carbapenems and glycopeptides, as a loading dose is required to ensure adequate levels for effective antimicrobial activity.⁹ If the infection is located in a part of the body in which antibiotics don’t easily penetrate, such as the central nervous system (CNS) or in a deep-seated abscess, this is even more important.⁹

The Therapeutic Guidelines: Antibiotic has a chapter on sepsis, including septic shock, with recommendations on antibiotic dosing in sepsis.¹⁰

Metabolism

Reduction in hepatic blood flow as a result of shock can lead to a decrease in drug metabolism.⁹ If liver function is significantly reduced as evidenced by elevated liver function tests, then dosage adjustments to hepatically cleared medications may be required.

Elimination

Hydrophilic antimicrobials are predominantly cleared by the kidneys. Clearance may be increased initially due to the hyperdynamic state of sepsis and fluid loading resulting in increased renal blood flow.⁹ Hypoalbuminemia results in an increased unbound fraction of highly protein-bound medications which is therefore able to be filtered by the kidneys, increasing clearance.⁹

If prolonged hypotension occurs, blood flow to the kidneys will reduce and organ dysfunction will begin. Sepsis is the leading cause of acute kidney injury. Many patients with septic shock-induced renal failure will go on to require renal replacement therapy for a period.⁹

Pharmacists involved in managing patients with sepsis, and particularly septic shock, should be reviewing the pharmacokinetics of these patients daily and ensuring that the antibiotic doses are adjusted appropriately. Therapeutic drug monitoring, where available, should be used.

Fluid administration

Fluids are administered to maintain intravascular volume in patients who are hypotensive or have an elevated lactate level, demonstrating tissue hypoperfusion.⁷

The sepsis bundle specifies use of crystalloid solutions. Crystalloid solutions such as 0.9% sodium chloride (“normal” saline), or balanced solutions such as Hartmann’s or Plasma-Lyte

are all options. Crystalloids are preferred over albumin and are cheaper and more available.⁷

Monitoring

Patients with sepsis should be closely monitored to ensure there is an improvement with treatment. Should their condition deteriorate, antibiotic treatment needs to be reviewed. The Australian Commission on Safety and Quality in Health Care’s Sepsis Clinical Care Standard recommends that antimicrobial therapy be managed in line with the Antimicrobial Stewardship Clinical Care Standard, including a review within 48 hours from the first dose. Pharmacists should review that the initially prescribed antibiotic is still appropriate and the dose sufficient; this may include using therapeutic drug monitoring. If abscesses or other sources of infection have not been managed, surgical intervention may be required.¹¹

Complications

Treatment delays or inadequate treatment may result in the patient progressing into septic shock and subsequent death.¹¹

Septic shock

Patients who remain hypotensive despite fluid administration are said to be in septic shock. These patients will require vasopressor infusions to be administered.¹²

Noradrenaline is the first-line treatment in septic shock. It may be administered peripherally for up to 1 hour via a large vein, prior to central access being obtained.⁸

Metaraminol and phenylephrine are alternatives which may be administered peripherally for a longer duration. Vasopressin is often administered second- line to replete the relative vasopressin deficiency which occurs in septic shock and allows for a reduction in noradrenaline requirements.¹²

Steroids may be administered to patients with septic shock. The 2018 ADRENAL trial did not show a mortality benefit with a 200 mg daily intravenous infusion of hydrocortisone but did show improvements in secondary outcomes of time off ventilation and length of ICU stay.¹³

What is the pharmacist’s role?

Patients who are developing sepsis may present to their local pharmacy for advice and request medicines for symptom management. Community pharmacists should be aware of the symptoms and risk factors for sepsis and refer patients to the acute care setting if there is any suspicion of sepsis.

Pharmacists working in a hospital setting should ensure that medication history on admission includes allergy documentation, recent antibiotic courses, and vaccination history. Broad-spectrum antibiotics should be readily available. This can be done as part of an antimicrobial stewardship program.

Hospital protocols should include recommendations for treating hospital-acquired sepsis in specific patient groups (e.g. neutropenic sepsis or post-partum sepsis), and include appropriate starting doses of antibiotics with loading doses where recommended. Pharmacists should review septic patients daily; this review should include microbiology, antibiotic choice and dose and therapeutic drug monitoring, where appropriate.

Patients with septic shock may require their regular medicines to be withheld. Other medicines may require dose adjustment based on any organ failure. The ward pharmacist is best placed to ensure regular medicines are only recommenced as appropriate.

Pharmacists should ensure that hospitalised patients are prescribed venous thromboembolism (VTE) prophylaxis, as septic patients are at high risk of developing blood clots.⁸

Knowledge to practice

Sepsis is a medical emergency. Time to initiation of antibiotics is a key factor in patient survival. All healthcare workers need to be aware of the signs and symptoms of sepsis to ensure prompt treatment. Pharmacists can ensure that prescribed antibiotics are appropriate for the clinical condition and specific patient factors. Patients should be monitored closely to ensure they are improving, and antibiotic dose and choice reviewed as the patient’s condition changes and more information becomes available.

If you do get an enrolment error, please click here

FURTHER INFORMATION

• The Australian Sepsis Network provides advice for health practitioners and the community.
• The Australian Commission on Safety and Quality in Health Care recently released the Sepsis Clinical Care Standard. 

1. Singer M, Deutschman C, Seymour W et al, The Third International Definitions of Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801-810.
2. Australian Sepsis Network. Some Facts About Sepsis. 2021 At: www.australiansepsisnetwork.net.au/world-sepsis-day
3. World Health Organisation. Sepsis. 2020. At: https://www.who.int/news-room/fact-sheets/detail/sepsis
4. Perner A, Holst L, Haase N etal. Common Sense Approach to Managing Sepsis. Crit Care Clin 2018; 34: 127-138
5. Russell J A, Rush B, Boyd J, Pathophysiology of Septic Shock. Crit Care Clin 2018; 34:43-61.
6. Kumar A, Roberts D, Wood KE, et al, Duration of Hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6) 1589-1586.
7. Levy MM, Evans LE, Rhodes A, The Surviving Sepsis Campaign Bundle: 2018 Update. Intensive Care Medicine 2018; 44: 925-928.
8. Rhodes, A., Evans, LE, Alhazzani, W., et.al, Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377
9. Varghese JM, Roberts JA, Lipman J. Antimicrobial Pharmacokinetics and Pharmacodynamic Issues in the Critically Ill with Severe Sepsis and Septic Shock. Critical Care Clinics 2011; 27(1) 19-34.
10. Antibiotic Expert Group. Antibiotic, version 16. Melbourne, Therapeutic Guidelines 2021.
11. Weiss S, Peters M, Alhazzani W, et al. Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 2020; 46(Suppl 1): S1-S9.
12. Jentzer JC, Coons JM, Link CB et al. Pharmacotherapy Update on the Use of Vasopressors and Inotropes in the Intensive Care Unit. Journal of Cardiovascular Pharmacology and Therapeutics 2015; 20(3) 249-266.
13. Venkatesh B, Finfer S, Cohen J et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. NEJM 2018; 378: 797-808.

BELINDA BADMAN BPharm, GradDipClinPharm, AdvPP(II), MSHP is Senior Critical Care Pharmacist and Critical Care Team Leader at Princess Alexandra Hospital, Brisbane.