Sepsis is a time-critical condition that requires prompt recognition and rapid initiation of treatment and pharmacists need to be able to recognise the deteriorating patient and ensure appropriate treatment
Fraser Hanks MRPharmS
Highly Specialist Pharmacist – Critical Care
Guy’s and St Thomas NHS Foundation Trust,
Snehal Shah MRPharmS
Senior Pharmacist – Critical Care
Royal Brompton & Harefield NHS Trust,
Sepsis should no longer be regarded as a ‘niche’ problem confined to intensive care units (ICU). It can affect all age groups, may present in the community, in long-term facilities and among patients admitted to hospital under the care of any, and every, medical speciality making it unique amongst other acute conditions.
International estimates of the incidence of sepsis vary, but have shown to be as high as 300 cases per 100,000 population per annum1 with an estimated mortality of 50% for septic shock.2 In addition, sepsis is costly and carries a significant economic burden. It has been estimated in European studies that a typical episode of sepsis costs a healthcare organisation approximately €25,000.3 The cost and incidence of severe sepsis are expected to increase as the population ages.
Severe sepsis is a time-critical condition that can lead to organ damage, multi-organ failure, septic shock and eventually death. There is strong evidence that treating patients with sepsis earlier and in a more coordinated manner reduces mortality.4 Healthcare professionals including pharmacists working on inpatient wards should be able to assist in the early identification of septic patients, understand fluid resuscitation and contribute to antibiotic treatment decisions. This is to ensure the patient receives early and appropriate management of their sepsis.
Sepsis is defined as a systemic inflammatory response to an infection. It is identified through the presence of systemic inflammatory response syndrome (SIRS) (Figure 1). Acute organ dysfunction caused by the infection is defined as severe sepsis, which when combined with persistent hypotension unresponsive to fluid resuscitation is defined as septic shock. The mortality rate increases as the disease progresses.5
Physiological changes that characterise sepsis
The source of the underlying infection resulting in sepsis is most frequently bacterial in origin, although fungi and viruses may be responsible. The most common source(s) of proven or suspected non-ICU acquired infections in ICU patients are shown in Figure 2.2 The total percentage does not equal to 100 as patients may have more than one source of infection.
The overwhelming systemic disease that results from infection with a microbial pathogen leads to excessive release of pro-inflammatory mediators, such as cytokines, which cause vasodilatation, capillary leak and endothelial dysfunction (sepsis). This is initially compensated for by an increase in cardiac output to maintain blood pressure and adequate organ perfusion. The physiological changes due to this inflammatory response manifest as fever, tachypnoea, altered white cell count and tachycardia.
As the syndrome progresses the systemic vascular resistance decreases more profoundly, with a concurrent fall in cardiac output. This is accompanied by an increase in microvascular permeability resulting in transcapillary loss of fluid and plasma proteins, including albumin. This leads to a relative intravascular hypovolaemia with accompanying tissue oedema. The end result is a fall in arterial blood pressure, inadequate organ perfusion and oxygenation. This may then progress to single organ failure (severe sepsis) or multiple organ dysfunction syndrome (MODS).
Recognising the deteriorating patient
Early Warning Scores are used to assist in the prompt recognition and early escalation of a deteriorating patient. Any patient identified as at risk of deterioration (for example, triggering the Early Warning Score) should be screened for sepsis. If the patient is found to have two or more SIRS criteria plus suspected or proven infection, then prompt sepsis management should be initiated. Suspicion of an infective cause is all that is required and treatment should not be delayed while awaiting microbiological investigations such as blood culture results.
Pharmacists can contribute to the early recognition of sepsis by:
- Observing physiological signs of inflammation/infection (HR/MAP/RR/temperature).
- Monitoring inflammatory markers including WCC, CRP and platelets.
- Surveillance of potential sources of infection (for example, sputum, chest X-ray changes, flank pain, dysuria etc., see box 2, Figure 1).
The Sepsis Six recommendations (Figure 3) are derived from the International Guidelines for management of severe sepsis and septic shock published by the Surviving Sepsis Campaign (SSC) Committee. The mainstay of treatment is the administration of effective antimicrobial therapy within the first hour, informed by the results of blood or infection site cultures where possible.
This should be supplemented with appropriate fluids to counteract hypoperfusion and hypotension. If the Sepsis Six is initiated but the patient continues to deteriorate, despite adequate fluid resuscitation, they should be transferred to a critical care area, such as an ICU, for ongoing management.
It may take time to elucidate the nature of the initial infection. In addition, microbiological culture results may take 24 hours or more to process. Therefore the initial therapy is often empiric with broad-spectrum intravenous antibiotics guided by local guidelines to cover any likely focus of infection. Appropriate antibiotic therapy must be administered as early as possible and this should occur within the first hour of sepsis recognition. In a retrospective study of patients with septic shock, Kumar et al reported that delay of appropriate antibiotic administration by each hour increased mortality by 7.6%.8
Deciding on the first dose of antibiotic in a septic patient is also very important. Critically ill septic patients often have vasodilatation, capillary leak, altered cardiac, hepatic and/or renal function, and modification of serum protein levels and protein binding. Antibiotic dosing is especially challenging in these patients as these physiological changes can cause increased volume of distribution (Vd) and changes in clearance (Cl) that may increase or decrease plasma antibiotic levels. The loading dose (LD) of any drug is calculated from the volume of distribution (Vd) and the required serum concentration (Css) using the formula LD = Vd x Css. As renal function plays no role in this calculation, the LD should not be adjusted for creatinine clearance. In septic patients, there is a larger than predicted Vd of hydrophilic antibiotics and therefore a larger required LD. Lipophilic antibiotics are less affected by pathophysiological changes in sepsis and are less likely to require dose adjustment.
The Sepsis Six
Completing these six steps within the first hour of sepsis
recognition could double your patient’s chance of survival7
1) Administer high-flow oxygen
2) Take blood cultures and consider infective source
3) Administer intravenous antibiotics
4) Give intravenous fluid resuscitation
5) Check haemoglobin and serial lactates
6) Commence hourly urine output measurement
Reassess/urgent senior review/referral to critical care
A significant number of septic patients may present with multi-organ failure including acute kidney injury (AKI). This will result in decreased antibiotic clearance of hydrophilic antibiotics (such as beta-lactams and aminoglycosides), prolonged half-life and potential toxicity from elevated antibiotic plasma concentrations and accumulations of metabolites.
Dosing recommendations for patients with or without renal impairment are often derived from pharmacokinetic studies in non-critically ill patients. As the consequence of therapeutic failure of antibiotic therapy in sepsis could lead to further organ injury or death, therapeutic drug monitoring should be considered where possible to achieve adequate antibiotic plasma concentrations. Additionally antibiotic dosing regimens need to be tailored to the individual case with expert guidance from critical care pharmacy, medical and microbiology teams. Dosing schedules may need to be optimised during the early phase of sepsis to ensure adequate plasma levels are achieved. Antibiotic regimens should be reviewed frequently to ensure appropriate de-escalation and dose adjustment according to changes in renal function and the patient’s response to therapy.
The role of ward pharmacists in relation to antibiotic treatment:
(1) Ensuring allergy status is established and documented clearly on drug charts and where appropriate in medical notes.
(2) Working with clinicians to ensure that patients receive antimicrobial therapy within the hour following diagnosis. A solution may include storing empiric choices of antimicrobial agents to improve efficiency.
(3) Optimising antibiotic dosing based on knowledge of pharmacokinetics and pharmacodynamics of commonly used antibiotics in combination with therapeutic drug monitoring (TDM). This will help to select appropriate dosage regimens and schedule intervals that will contribute to therapeutic efficacy and improve clinical outcome.
(4) Reviewing antibiotic therapy daily and ensuring that therapy is refined in light of antimicrobial cultures and sensitivities. The duration of antibiotic therapy in practice is often guided by trends in inflammatory markers (WCC, temperature, C-reactive protein) and clinical signs of response.
(5) When AKI is present or the patient needs renal replacement therapy, individualising antibiotic therapy and making dose adjustments to reflect these changes.
Non-invasive clinical indices of tissue/organ perfusion that may be used to guide fluid therapy
- Systolic BP <100mmHg
- Heart rate >90 beats per minute
- Capillary refill >2 seconds or cold peripheries to touch
- Respiratory rate >20 breaths per minute
- Decreased urine output (less than 0.5mg/kg/hr)
- 45o passive leg raising may suggest fluid responsiveness
Invasive monitoring – may require insertion of arterial or central venous catheters and transfer to critical care
- Central venous pressure (CVP).
– Used as a measure of intravascular volume, however there are numerous factors that may affect the accuracy of the CVP as a measure of intravascular volume.5 The change in CVP may be helpful in assessing responsiveness rather than the values obtained.
- Mean arterial pressure (MAP).
– Used as a proxy of organ perfusion pressure.
– MAP = (2/3 (diastolic pressure) + 1/3 (systolic pressure)).
- Blood lactate.
- Mixed venous oxygen saturation SmvO2 (or ScvO2).
- Or invasive or non-invasive cardiac output monitoring performed within critical care.
The goal of fluid resuscitation is to improve blood pressure and organ perfusion pressure. Blood pressure decreases in severe sepsis due to vasodilatation and loss of intravascular volume into the interstitium, as described above. Fluid status needs to be optimised in the initial management of sepsis in order to restore adequate blood pressure, tissue perfusion pressure and therefore attempt to match oxygen delivery with oxygen demand from the tissues. It is thought that impaired tissue perfusion/oxygen delivery may be responsible for the deterioration of organ function that occurs in severe sepsis and MODS.
The aim of fluid resuscitation is to ensure that the ventricles of the heart are appropriately filled to ensure optimum stretch of the myocardial muscle fibres. This allows the most efficient force of contraction (Starling’s Law of the Heart). This is achieved by administering fluid boluses as a “fluid challenge”. Commonly 250–500ml of crystalloid is administered over 15 minutes and the patient is observed for an improvement in their haemodynamics (blood pressure, heart rate, MAP, CVP, cardiac output or urine out; Figure 4). An improvement in these parameters demonstrates that the patient is “fluid responsive”. The fluid challenge may be repeated as required until there is no further improvement, or the patient shows symptoms of pulmonary oedema.
The choice of resuscitation fluid between colloid and crystalloid solutions has been the subject of much debate and controversy. Colloids are suspensions of larger molecular weight molecules (commonly semi-synthetic modified gelatins, hydroxyethyl starch (HES) or albumin) in sodium chloride 0.9% or a balanced fluid. The perceived benefit of colloids is that they exert more oncotic pressure and so produce greater plasma volume expansion compared to crystalloids. Recent studies, however, have cast doubt over the benefits of HES and succinylated gelatin infusions for fluid resuscitation in sepsis.
The SSC guidelines now recommend that hydroxyethyl starch solution should not be used in fluid resuscitation due to lack of evidence of benefit over crystalloids,11 increased cost, increased rates of renal replacement therapy12 and increased mortality.13 The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) have recommended that HES solutions should “no longer to be used in patients with sepsis or burn injuries or in critically ill patients”.14 PRAC did state that HES solutions may be continued to be used to treat hypovolaemia caused by acute blood loss, however the patient’s renal function should be monitored.14 Similarly, there is a lack of evidence for benefit of semi-synthetic gelatin-based infusions over crystalloids and potential for harm.15 Therefore, gelatin-based solutions are also no longer recommended by the SSC for initial fluid resuscitation.
The SSC guidelines recommend initial fluid resuscitation with a crystalloid for hypotension or a lactate >4mmol/l. They recommend a fluid volume of at least 20ml/kg and up to 30ml/kg to achieve these aims.
The SSC does not make any recommendations on which crystalloid solution to use. Glucose solutions are usually avoided as they may induce hyponatraemia. Hartmann’s or a balanced crystalloid such as Plasma-Lyte® are the solutions of choice as their electrolyte contents are similar to plasma. Sodium chloride 0.9% infusions are often avoided due to the risk of hypernatraemia and hyperchoraemic acidosis as they provide a higher sodium and chloride content than plasma.
The pharmacist has a key role to play in ensuring that the septic patient receives the correct management as early as possible in an attempt to ameliorate the detrimental effects of sepsis on the body. The pharmacist should review the patient’s vital signs and physiological observations as part of their daily clinical screen and be vigilant for signs of SIRS, sepsis and severe sepsis. The pharmacist can assist the multidisciplinary team by ensuring that appropriate antibiotics are prescribed, supplied and administered within the first hour of sepsis recognition. The pharmacist should clinically screen the patient’s fluid prescription as they would any other intravenous medication and be confident that the fluid regimen is appropriate.
The pharmacist should consider the patient’s regular medication and make a risk–benefit decision on whether regular medication should be continued or held (for example, antihypertensives) and that these decisions are effectively documented so that the regular medication can be restarted at a more appropriate time.
- Early recognition and effective treatment of sepsis saves lives.
- Patients with severe sepsis, septic shock or mulitple organ dysfunction syndrome are treated within critical care units; however, sepsis can occur in any clinical area.
- It is imperative that clinical pharmacy staff are aware of these features and of the initial management of this life-threatening condition.
- The key early management steps in treating sepsis are to administer high-flow oxygen, take blood cultures, administer intravenous antibiotics and give intravenous fluid resuscitation.
- Ideally this should all occur within the first hour of sepsis recognition.
- Hall MJ et al. Inpatient care for septicemia or sepsis: A challenge for patients and hospitals. NCHS data brief, no 62. Hyattsville, MD: National Center for Health Statistics;2011.
- Vincent JL et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323–9.
- Vincent JL et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344–53.
- Dellinger R et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock 2012. Crit Care Med 2013;41(2):580–637.
- Martin G. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes Expert Rev Anti Infect Ther 2012;10(6):701–6.
- Levy MM et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 2003;29:530–8.
- http://survivesepsis.org/the-sepsis-six/ (accessed 15 January 2015).
- Kumar A 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):1589–96.
- Marik PE et al. Hemodynamic parameters to guide fluid therapy. Ann Intensive Care 2011;1:1.
- National Institute for Health and Care Excellence. Intravenous fluid therapy in adults in Hospital. Clinical guideline 174. www.nice.org.uk/guidance/cg174 (accessed 15 January 2015).
- Guidet B et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care 2012;16(3):R94.
- Myburgh JA et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901–11.
- Perner A et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012;367:124–34. [Erratum, N Engl J Med 2012;367:481.
- European Medicines Agency’s Pharmacovigilance Risk Assessment Committee statement 14/06/2013. www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Solutions_for_infusion_containing_hydroxyethyl_starch/European_Commission_final_decision/WC500162361.pdf (accessed 15 January 2015).
- Bayer O et al. Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison. Crit Care Med 2011;39:1335–42.