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Published on 14 June 2011

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Pharmacotherapeutics of severe sepsis and septic shock

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Dr Rob Shulman
Lead Pharmacist, Critical Care, Pharmacy Department, University College London Hospitals NHS Foundation Trust

The term ‘sepsis’ describes a microbial invasion of normally sterile parts of the body leading to a systemic illness. Sepsis is in the top 10 of all causes of death and has an estimated mortality rate of 30–50 deaths per 100,000 population.

The incidence of sepsis in the US is approximately 750,000 per annum or three per 1,000 population. This incidence is expected to increase with 
an ageing population, resistant infections, more high-risk surgery and immunocompromised patients. The profile of the optimum management of severe sepsis and septic shock has been raised over the last few years by the development of international guidelines and a campaign for greater recognition.1

Although septic patients are treated in the intensive care unit (ICU), their signs and symptoms may arise outside the ICU, so it is crucial for non-critical care staff to be aware of the features and management of this life-threatening condition.

The spectrum of sepsis has been defined, primarily to inform clinical 
trials, but also because the prognosis is so varied depending on the severity. ‘Sepsis’ is defined as a suspected or proven infection-induced syndrome with features of systemic inflammation – for example, fever, tachycardia, tachypnoea and leukocytosis.1 See Figure 1.

It is possible to meet the criteria of sepsis and have only minor signs and symptoms. In the absence of an infection, these features are called the ‘systemic inflammatory response syndrome’ (SIRS).

‘Severe sepsis’ includes the features 
of sepsis but with additional organ dysfunction such as hypoxaemia, hypotension, oliguria, metabolic acidosis, thrombocytopaenia or reduced consciousness. It has a mortality rate of 25–30%, which increases depending 
on the degree and the number of failed organs. ‘Septic shock’ describes severe sepsis with hypotension despite adequate fluid retention; it has a mortality of 40–70%. The term ‘septicaemia’ is sometimes used in lay language but is a less useful term, as it describes all three types of sepsis. Sepsis can occur in all ages, in community, in all hospital specialities and in residents of long-term care facilities. Severely septic patients are usually treated in a critical care unit.

Pathophysiology
The pathophysiology of sepsis is extremely complex and a detailed account is outside the scope of this review. It can be described as an amplified, exaggerated response to infection; homeostasis becomes unbalanced with increases in coagulation and inflammation and a reduction in fibrinolysis.

Simplistically, an infection leads to local mediator release and, sometimes, invasion into the bloodstream. A systemic release of inflammatory mediators follows which can have profound haemodynamic effects. These include myocardial depression, altered vascular tone and increased capillary leak.

These combined effects cause a misdistribution of blood-flow, (usually) reduced systemic vascular resistance and a metabolic acidosis consequent to tissue hypoperfusion. Multi-organ dysfunction can follow, which may be fatal. The virulence and bioburden of the pathogen, the site of infection, the susceptibility of the host and underlying co-morbidities all influence the course of the illness and the ultimate outcome.

Early goal-directed therapy
International consensus guidelines now in their second edition1 have provided a useful focus to raise awareness and improve the management of severe sepsis and septic shock in adults. The guidelines describe a bundle of care for the early hours of sepsis, with prompt antibiotic administration and a further package of care for the rest of the episode.

The initial bundle of care was based on the concept of early goal-directed therapy (EGDT),2 which involves aggressive infusion of intravenous fluids – along with vasopressors and inotropes – for the restoration of blood pressure and tissue perfusion and transfusion of red blood cells. In this study set in an emergency department, of standard therapy versus EGDT, the latter group had a 16% absolute reduction in mortality.

Critics of this approach question some aspects of the bundle of care chosen for EGDT, the general applicability of the results and the high mortality in the control group. However, few dispute the principle of prompt early resuscitation after the recognition of severe sepsis. Several studies have reported on the beneficial impact of instituting the bundles of care3,4 in this patient group 
in before–after studies.

However, it should be acknowledged that it requires considerable organisation within a hospital to recognise the septic patient and institute prompt therapy, often outside of the ICU5,6 and pharmacists can play an important role in this. The rest of this review will focus on the key drug-related elements of the treatment of severe sepsis and septic shock.

Anti-infectives
Confirmation of the initial infection 
can take time to elucidate. Results from microbiological cultures take at least 24 hours and are often complicated by previous antibiotic therapy, sampling error and the growth of non-pathogenic colonising micro-organisms.

Therefore, initial therapy is usually empirical and is chosen by likely sensitivity to typical pathogens for the infection site. Thus the initial therapy 
is generally with broad-spectrum antibiotics, but may be refined in the light of subsequent sensitivities and clinical response. A key element of practice is to start the antibiotics as soon as possible after the sepsis diagnosis is made. Delaying the start of an antibiotic, even by as little as an hour, can potentially have an impact on patient outcome. In a retrospective study of patients with septic shock, Kumar reported that delay of appropriate antibiotic administration by each hour increased mortality by 7.6%.7 Pharmacists could play an important role locally in assessing the time to first-dose anti-infective and look at ways to improve efficiency, aiming for a time from recognition to antibiotic administration within one hour.

Solutions could include storing empirical choices of anti-infectives 
on the ward, instituting ready-to-use antibiotic formulations and arranging multidisciplinary educational sessions 
to emphasise the importance of 
response times.

The optimal duration of an anti-infective therapy is highly contentious. In practice, it is often guided by trends in white cell count, temperature, C-reactive protein and clinical signs of response. In the future, better biomarkers may provide a more precise guide to therapy. For instance, monitoring procalcitonin levels is emerging as a promising technique that may reduce length of antibiotic course without worsening outcome.8

Fluid therapy
Fluid resuscitation represents the fundamental initial treatment of sepsis. 
It can be achieved with either colloids 
or crystalloids.

Colloidal therapy comprises of hydroxyethyl starch, gelatine or 
albumin. Albumin is a blood product 
and is significantly more expensive 
than the alternatives. It is available 
as the iso-oncotic 4.5% and the hyperoncotic 20%.

Hydroxyethyl starches are synthetic polymers derived from maize that 
provide volume expansion. There is some concern that starches have been linked with renal failure and immune modulation in sepsis.9

Gelatines are smaller molecules derived from calfskin collagen that produce volume replacement but may also have renal effects. Newer colloids 
are formulated in a ‘balanced’ solution, similar to Hartmann’s solution.

Larger volumes are generally necessary when crystalloids, such as Hartmann’s solution, sodium chloride 0.9% or glucose 5%, than when colloids are used for resuscitation, as crystalloid fluids redistribute out of the blood compartment quicker than colloids and thus are more prone to cause oedema.

In hypovolaemia, fluids are administered by way of a ‘fluid challenge’ – for example, 200ml colloid against haemodynamic parameters such as stroke volume, central venous pressure or urine output. Fluid resuscitation is in addition to background fluid replacement with crystalloid therapy, which is typically achieved with Hartmann’s solution – which has similar constituents to plasma – at a rate of 1ml/kg/hour.

There is a move away from the use 
of ‘normal’ saline because of the high chloride content that can cause hyperchloraemic acidaemia. The clinical significance of this is, however, uncertain at present.

Vasopressors
These agents are used when the blood pressure is too low to maintain adequate perfusion, such as septic shock. The absolute mean arterial pressure (MAP) target will vary between patients, but the international guidelines1 recommend maintaining the MAP at ≥65mmHg, which is achieved initially with fluids and then with vasopressors.

The recommended vasopressors for initial use are norepinephrine (noradrenaline) or dopamine, which 
both exert their vasopressor effects via stimulation of the alpha1 adrenoreceptor. Norepinephrine has a more potent vasopressor effect, but dopamine may be useful when an additional inotropic effect is required.

Recently, vasopressin and terlipressin have emerged as potential additive vasopressors in septic shock. Here endogenous vasopressin levels are low. The VASST study10 reported that there were benefits in mortality only when vasopressin at a dose of 0.01–0.03u/min was added to norepinephine in less severe septic shock that is 5–15 microg/min of norepinephrine. The vasopressin analogue terlipressin has been used in addition to norephinephine at the more severe end of septic shock as a bolus of 0.25mg, repeated as necessary, or as an infusion.

Inotropes
Inotropes such as epinephrine (adrenaline) or dobutamine are used to treat myocardial failure in sepsis. They increase myocardial contractility by stimulating the ß1 adrenoreceptor, but may increase myocardial ischaemia and cause direct toxicity. The international guidelines1 advocate dobutamine use, but this is simply because dobutamine was used in the Rivers study.2 Generally, the minimum dose possible should be used and weaned as soon as possible.

Human recombinant APC
This is perhaps one of the most controversial areas of sepsis. Drotrecogin alfa is a recombinant human activated protein C (rhAPC) product that is licensed for treating severe sepsis. Many septic patients have low endogenous levels of protein C, because of increased consumption and inflammatory cytokines down-regulating thrombomodulin and the endothelial cell protein C receptor.

APC has several effects including anti-inflammatory, anti-thrombotic and profibrinolytic effects. The PROWESS study11 reported that rhAPC was associated with a 6.1% improvement in absolute survival in severe sepsis patients with multi-organ failure. However, the ADDRESS study12 in less severely septic patients was stopped early due to futility, but reported increased serious bleeding events in the rhAPC group.

Although the international guidelines recommend use of rhAPC in severely septic patients with multi-organ failure and a high risk of death,1 the critical care community is quite divided on the merits of this drug. The ongoing PROWESS-SHOCK study of patients in severe sepsis/septic shock will provide evidence that will decide the future utilisation of this high-cost therapy.

Corticosteroids
The use of corticosteroids has undergone significant change over recent years. Addition of steroid tends to reduce the requirement of a vasopressor and improves time to resolution of shock, though there is a concern of dampening the body’s response to infection.

High doses of corticosteroids may even increase mortality, though hydrocortisone 50mg IV six-hourly was shown to reduce mortality in a cohort of severely ill septic shock patients,13 who were adrenally suppressed – as demonstrated by an impaired cortisol response to a short Synacthen test.

However, in a follow-up study of less sick, septic shock patients,14 this same hydrocortisone regimen did not have any mortality benefits, but led to increased infections. Hence the guidance1 is to add this hydrocortisone regimen only in septic shock patients who are unresponsive to fluids and vasopressors, that is the more severely ill patients.

Adjuvant therapy
The guidelines1 also advocate a range of other therapies that are not specific to sepsis but are applicable to all critically ill patients such as:

  • Thromboprophylaxis
  • Prevention of stress ulceration
  • Analgesia and sedation
  • Blood glucose control.

Indeed, the mnemonic FAST HUG gives a daily checklist to consider: Feeding, Analgesia, Sedation, Thrombosis, Head-up, Ulcer prevention and Glucose control. Selective decontamination of the digestive tract has been shown to reduce hospital-acquired infections and mortality, but the uptake of this practice is low in most countries.

Summary
Severe sepsis is a common syndrome that affects a variety of patient groups. These patients require early diagnosis, resuscitation, antibiotic and supportive therapy. Other treatments such as inotropes, vasopressors, steroids and rhAPC have a role, but clinicians require 
a good knowledge of the trial literature to optimise the use of these agents.

There are many areas of controversy 
in the management of sepsis, but having a bundle of care including the components discussed here and other non-drug aspects have led to improving outcomes. This may be related to an improved overall process of care – for example, early recognition and treatment – rather than any specific constituent.

In general, patients should be treated with the minimum inotropic/vasopressor dose necessary to optimise organ perfusion. Care is required to avoid iatrogenic harm from overtreatment, errors and hospital-acquired infections.

Pharmacists can play a significant role in improving outcomes by guideline production, education, organisation 
of systems to ensure prompt antibiotic therapy and medication chart review to optimise efficacy, avoid medication errors and minimise adverse effects.

References

  1. Dellinger RP et al. Inten Care Med 2008;34:17-60
  2. Rivers E et al. New Engl J Med 2001;345:1368-77
  3. Levy MM et al. Crit Care Med 2010;38:367-74
  4. Jones AE et al. Crit Care Med 2008;36:2734-9
  5. Funk D et al. Curr Opin Crit Care 2009;15:301-307
  6. Ferrer R et al. J Am Med Assoc 2008;299:2294-2303
  7. Kumar A et al. Crit Care Med 2006;34:1589-96
  8. Kopterides P et al. Crit Care Med 2010;38:2229-41
  9. Brunkhorst FM et al. New Engl J Med 2008;358:125-139
  10. Russell JA et al. New Engl J Med 2008;358:877-87
  11. Bernard GR et al. New Engl J Med 2001;344:699-709
  12. Abraham E et al. New Engl J Med 2005;353:1332-41
  13. Annane D et al. J Am Med Assoc 2002;288:862-71
  14. Sprung CL et al. New Engl J Med 2008;358:111-124


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