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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 41-49

Sepsis – An overview


Department of Pulmonary Medicine, GMC, Kozhikode, Kerala, India

Date of Submission12-Dec-2020
Date of Decision16-Jan-2021
Date of Acceptance04-Feb-2021
Date of Web Publication21-Jun-2021

Correspondence Address:
Dr. Arjun Chandran
30/183A Chaithanyam (H), Medical College P.O., Kozhikode - 673 008, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jalh.jalh_11_20

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  Abstract 


Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Even with advancement in understanding the pathophysiology and various monitoring tools and treatment measures, sepsis still remains a major cause of mortality and morbidity in critically ill patients. Over the last three decades, significant changes were seen regarding understanding the pathophysiology of sepsis. The management of sepsis has evolved over the last two decades by the advent of the Surviving Sepsis Campaign Guidelines which recommends early recognition and prompt treatment without delay.

Keywords: Sepsis, sepsis bundle, septic shock, sepsis-related organ failure assessment score


How to cite this article:
Suraj K P, Chandran A. Sepsis – An overview. J Adv Lung Health 2021;1:41-9

How to cite this URL:
Suraj K P, Chandran A. Sepsis – An overview. J Adv Lung Health [serial online] 2021 [cited 2021 Jul 28];1:41-9. Available from: http://www.jalh.com/text.asp?2021/1/2/41/318907




  Introduction Top


Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Septic shock is a subset of sepsis with circulatory, cellular, and metabolic dysfunction with higher risk of mortality. Even with advancement in understanding the pathophysiology and various monitoring tools and treatment measures, sepsis still remains a major cause of mortality and morbidity in critically ill patients. The Global Burden of Disease Study reported an estimated 48.9 million cases of sepsis in 2017.[1] In the United States sepsis affects around 1.7 million adults each year and potentially contributes to more than 250 000 deaths.[2] INDICAP study, which was a point prevalence study conducted in 120 intensive care units (ICUs) across India, reported a prevalence of severe sepsis of 28.3%.[3] ANZICS study conducted in Australia and New Zealand ICUs reported a rate of sepsis incidence of 10%.[4] An estimated mortality rate from sepsis was 41% in Europe and 28.3% in the United States.[5] The reported mortality rate from severe sepsis in INDICAP study was 34%.


  Definition Top


The word sepsis was derived from Greek word meaning rotten. With the advent of Germ theory, sepsis was considered as a systemic infection due to host invasion by pathogenic organism that spread in blood stream. However, germ theory could not explain sepsis fully as many patients died despite eradication of inciting pathogen with use of antibiotics. Hence, it was concluded that it was host response that play a key role in the pathogenesis of sepsis.

Over the last three decades, understanding of pathophysiology of sepsis has changed significantly. In 1991, The ACCP-SCCM Conference put forward the first consensus on sepsis and organ failure.[6] In 2001, the second consensus panel by SCCM/ESICM/ACCP/ATS/SIS endorsed most of the old concepts except few changes.[7] The first survival sepsis guideline was published in 2004 for the management of severe sepsis and septic shock, which was updated in 2008 and 2012. In 2016, updated survival sepsis guideline was released [Table 1].
Table 1: Diagnostic criteria for sepsis and septic shock (Courtesy - 2016 surviving sepsis guidelines[10])

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Sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and septic shock was defined as a subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality.[8]

The systemic inflammatory response syndrome is no longer included in the definition since it is not always caused by infection. The sepsis-related organ failure assessment (SOFA score) was originally proposed to determine the extent of organ function or failure rate [Table 2].[9] The 2016 SCCM/ESICM task force modified SOFA score into quick SOFA (qSOFA) score by including three components which was easily identifiable at bed side [Table 3].[10] A qSOFA score ≥2 is associated with poor outcomes due to sepsis. qSOFA should not be used as a diagnostic tool, but rather as a predictive tool that calculates the risk of death from sepsis. It is recommended to use qSOFA to promptly identify infected patients who are likely to develop sepsis and associated mortality.
Table 2: Various parameters used in sepsis-related organ failure assessment score (courtesy Vincent et al.[9])

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Table 3: Quick sepsis-related organ failure assessment scoring

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  Risk Factors for Sepsis Top


  1. Advanced age (≥65 years) - Incidence of sepsis is higher in old age and it is also an independent predictor of mortality[11]
  2. Diabetes and obesity- Both diabetes and obesity alter the immune system and are associated with an increased risk of recurrent, nosocomial, and secondary infections that lead to sepsis[12]
  3. Immunosuppression - Conditions that blunts the host defense (malignancy, HIV, neutropenia, renal failure, liver failure, asplenia) and patients on immunosuppressive medications are more prone for sepsis or septic shock
  4. Previous hospitalization - Recent treatment with antibiotics will alter the human microbiome, and are associated with increased risk of developing sepsis in the subsequent 90 days[13]
  5. Genetic factors - Defects of antibody production, T cells, NK cells, complement and defects in the impaired recognition of pathogen by immune system increases the risk of sepsis.[14]



  Management of Sepsis Top


The management of sepsis has evolved over the last two decades by the advent of Surviving Sepsis Campaign guidelines. The Surviving Sepsis Campaign Guidelines in 2008, incorporated sepsis resuscitation bundle to be achieved in 6 h and sepsis management bundle to be achieved in 24 h. It was updated in 2012, were 6 h bundle was modified into two bundles; severe sepsis 3-h resuscitation bundle and 6-h septic shock bundle.[15] According to the latest update in 2018, the 3-h and 6-h bundles have been combined into a single 1-h bundle.[16]

“1 h bundle”

  • Measure lactate level. Remeasure if initial lactate is >2 mmol/L
  • Obtain blood cultures prior to the administration of antibiotics
  • Administer broad spectrum antibiotics
  • Begin rapid administration of 30 mL/Kg crystalloids for hypotension or lactate ≥4 mmol/L
  • Apply vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean arterial pressure (MAP) ≥65 mm Hg.


The elements in this bundle should be initiated within 1 h, although more than 1 h may be required for resuscitation to be completed.


  Initial Resuscitation Top


Early initiation of fluid resuscitation is of paramount importance in preventing tissue hypoperfusion in sepsis or septic shock. Hypotension, acute organ dysfunction, and elevated serum lactate are indicators of sepsis induced hypoperfusion. Tissue perfusion can be achieved by the administration of at least 30 mL/Kg of crystalloid, which should be started within 1 h and completed within first 3 h. Need for further fluid resuscitation should be guided by frequent assessment of hemodynamic status. Crystalloids are IV fluid of choice for initial resuscitation and subsequent intravascular fluid replacement in patient with sepsis and septic shock. Surviving Sepsis guidelines recommends balanced crystalloids or saline for fluid resuscitation. With large volume resuscitation, normal saline can lead to hyperchloremic metabolic acidosis and acute kidney injury. SMART and SALT-ED trial has showed a significant lower incidence of major kidney adverse event within 30 days in patients resuscitated with balanced crystalloids.[17],[18] The SAFE study and ALBIOS trials did not show a clear benefit with the use of albumin over crystalloids, and is only recommended for resuscitation if large amounts of crystalloids are required.[19],[20] Hydroxyethyl starch and gelatin are currently not recommended. Additional fluid resuscitation may be given by frequent assessment of hemodynamic status by clinical parameters such as heart rate, blood pressure (BP), SpO2, respiratory rate, and urine output. If clinical findings are not clear, further hemodynamic monitoring like assessment of cardiac function using a bedside echocardiography should be done. The use of central venous pressure alone to assess fluid response is not recommended.[21] Static and dynamic methods can be used to assess fluid responsiveness. Dynamic measures are more accurate and are currently preferred over static methods when feasible [Table 4].
Table 4: Methods used to assess fluid responsiveness

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An elevated serum lactate can be seen not only due to tissue hypoxia, but can also be seen in condition like accelerated anaerobic glycolysis by excessive sympathetic discharge, liver failure, and large volume resuscitation with Ringer lactate, drugs, etc.[22] However, laboratory measurement of serum lactate can be used as an objective marker for tissue hypoxia in a patient in shock and hence lactate level may be used as a marker to guide resuscitation in such patients. It is also recommended to target an initial MAP ≥65 mmHg in patients requiring vasopressors.


  Vasoactive Medications Top


Norepinephrine is the vasopressor of choice in septic shock as it increases MAP due to its vasoconstrictive effects with minimal change in heart rate and stroke volume. Norepinephrine is more effective than dopamine in reversing hypotension in septic shock. Dopamine is more arrhythmogenic and can influence endocrine response through hypothalamo-pituitary axis and also have immunosuppressive effects.[23] Hence, dopamine is currently recommended as an alternative to norepinephrine in only selected patients (low risk of tachyarrhythmia and absolute or relative bradycardia). Epinephrine can increase lactate production by stimulating skeletal muscle β2 receptors and can interfere with lactate-guided resuscitation. Vasopressin is an additional agent which can be added with norepinephrine in case of refractory shock (up to 0.03 U/min) or to decrease norepinephrine dosage.[24] Higher doses of vasopressin (>0.03 U/min) should be avoided as it can cause cardiac, digital and splanchnic ischemia. Dobutamine is the first choice inotrope in patients with suspected or measured low cardiac output in patients with adequate left ventricular filling pressure and adequate MAP.[25] Levosimendan is another inotropic agent which acts by increasing cardiac myocyte responsiveness to calcium. Levosimendan opens ATP-dependent Ca2+ channels and hence has both inotropic and vasodilator properties. However, higher cost, lack of availability, and increased risk of supraventricular tachycardia limits its use.[26]

The automated noninvasive BP measuring system in shock states are often inaccurate. Hence, invasive BP monitoring is recommended if feasible in all patients requiring vasopressors.


  Diagnosis and Source Control Top


Appropriate specimen for microbiological cultures should be obtained before starting antimicrobial therapy as sterile cultures can occur within a short time frame following antimicrobial administration.[27] At least, two sets of blood cultures (both aerobic and anaerobic) should be sent. There should not be substantial delay in starting antibiotics as the risk/benefit ratio favors rapid administration of antimicrobials if it is not logistically possible to obtain cultures promptly.

It is prudent that a suspected source or a specific anatomical site of infection must be identified or excluded by clinical history, examination, preliminary investigations, or imaging studies as early as possible. If identified, source control interventions should be implemented promptly (empyema drainage, abscess drainage, and removal of infected devices) ideally between 6 h and 12 h.


  Antimicrobial Therapy Top


Intravenous antimicrobials should be started as soon as possible, ideally within 1 h after obtaining necessary specimens for culture. It is recommended to start with empirical broad spectrum therapy with one or more antimicrobials to cover all likely pathogens in patients with sepsis without shock. Choice of empirical therapy depends on various factors such as:

  • Anatomical site of infection with respect to typical pathogen profile and properties of antimicrobials to penetrate that site
  • The prevalence and resistance pattern of pathogens within the community and hospital
  • Age, comorbidities, chronic organ dysfunction, presence of invasive devices, etc.,
  • The presence of specific immune defects such as neutropenia, HIV, splenectomy, acquired or congenital defects of immunoglobulin, complements or leukocyte production/function.


Coverage should be directed against both Gram-positive and Gram-negative bacteria and if indicated, against fungi and rarely viruses. The most common organisms attributed to cause sepsis include Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae.[28] It is recommended to start with broad spectrum carbapenem or extended spectrum penicillin/β-lactamase inhibitor combination or third or higher generation cephalosporin. The addition of a supplemental Gram-negative agent to the empiric regimen is recommended due to increased incidence of resistance to β-lactams and carbapenems in Gram-negative bacilli.[29] In case of risk for methicillin-resistant Staphylococcus aureus infection, vancomycin (adjusted for renal function) or teicoplanin or other alternative agents (daptomycin/linezolid) should be added. Routine administration of empirical antifungal therapy is not advocated in nonneutropenic critically ill patients. However, if there are definite risk factors for invasive fungal infection or if neutropenia is present appropriate antifungals (echinocandin-candida and voriconazole-Aspergillus) should be added.[30] Serological assessment of β-D Glucan and galactomannan may also provide a supportive role in identifying invasive fungal infection. The establishment of an antibiogram and well-tailored antibiotic policy will help in selecting appropriate empirical coverage.[31] Empirical therapy can be narrowed down once pathogen identification is established and/or adequate clinical improvement is noted.

Dosing strategies of antimicrobials should be optimized based on their pharmacological properties and drug interactions. There is a chance that initial dose of antimicrobials to be suboptimal due to increased volume of distribution owing to rapid expansion of extracellular fluid as a consequence of aggressive fluid resuscitation. Apart from that, other factors such as unstable hemodynamics, increased cardiac output, variable hepatic, and renal perfusion seen in early sepsis can affect drug pharmacokinetics. Hence, antimicrobials should be initiated with a full high end loading dose.

The optimal dosing strategy for aminoglycosides and fluoroquinolones is to attain high peak plasma concentrations (in relation to pathogen minimum inhibitory concentration [MIC]) and failure to attain it is associated with clinical failure. Hence, once daily dosing is sufficient to produce adequate clinical response and reduce renal toxicity with aminoglycosides.[32] For β-lactams, success rate depends on a longer duration of plasma concentration above MIC.[33] Inadequate trough plasma concentration above MIC is associated with clinical failure with vancomycin. Intravenous (IV) loading dose of 25–30 mg/kg is able to attain a trough target of 15–20 mg/L for optimal action.[34] In patients with septic shock, it is recommended to start with empirical combination therapy (at least two antimicrobials of two different classes) for the most likely bacterial pathogen. Combination therapy is not advised in other serious infection including bacteremia and sepsis without shock. Combination therapy should be deescalated in response to clinical improvement or evidence of infection resolution [Table 5]. De-escalation and duration of use of antibiotics should be assessed daily.[35] The duration of antibiotic use should be individualized. Usually, a 7–10 day antimicrobial treatment is often adequate for most of infections causing sepsis and septic shock as recommended by surviving sepsis guidelines. Longer course of antimicrobials is appropriate for patients with slow clinical response, undrainable focus of infection, bacteremia with staph aureus, some fungal and viral infections, immunological deficiency such as neutropenia, endocarditis, osteomyelitis, large abscesses, highly resistant Gram-negative pathogens with marginal or limited sensitivities. There is no role for sustained antimicrobial prophylaxis in patients with severe inflammatory states of noninfectious origin like severe pancreatitis and burns.
Table 5: Management outline (Courtsey - 2016 surviving sepsis guidelines[10])

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Serial measurement of procalcitonin level can be used to reduce the duration of antibiotics and also to discontinue empirical antibiotics in patients who initially appeared to have sepsis, but with subsequent limited evidence of infection.[36]


  Role of Steroids Top


The main rationale to use corticosteroids in patients with sepsis and septic shock is based on the findings that critical illness induces a state of absolute or relative adrenal insufficiency which may contribute to shock.

Corticosteroids are not routinely recommended for the treatment of septic shock provided adequate fluid resuscitation and vasopressor therapy are able to maintain hemodynamic stability. However, steroids are indicated in refractory shock were IV hydrocortisone 200 mg/day is advised.[37] Steroids are also indicated in patients with a history of systemic steroid therapy and adrenal dysfunction. Steroids are usually administered for 5–7 days with a tapered approach to withdrawal to prevent rebound hemodynamic abnormalities.[38] Metabolic abnormalities such as hyperglycemia and hypernatremia should be assessed during steroid therapy.


  Use of Blood Products Top


It is currently recommended to give red blood cell transfusion only when hemoglobin falls below 7.0 g/dL in the absence of conditions such as myocardial ischemia, severe hypoxia, and acute hemorrhage.[39] Platelet transfusion is advised in patients with platelet count <10,000 in the absence of bleeding and when count <20,000 if patients has significant risk of bleeding.[40] Routine use of fresh frozen plasma is not advised to correct clotting abnormalities unless there is documented deficiency of clotting factors or active bleeding or planning for invasive procedure/surgery.[41]


  Mechanical Ventilation Top


It is recommended to use target tidal volume of 6 mL/Kg (predicted body weight) in sepsis induced acute respiratory distress syndrome (ARDS), keeping plateau pressure within 30 cm of H2O.[42] In patients with refractory hypoxemia, recruitment maneuvers, prone ventilation, and extracorporeal membrane oxygenation can be considered. It is also advised to maintain a conservative fluid strategy in sepsis ARDS, who do not have evidence of tissue hypoperfusion.[43] Neuromuscular blocking agents can be used for ≤48 h in patients on mechanical ventilation. Judicious use of sedation is important and should be minimized. Intermittent sedation, daily sedation interruption, primary use of opioids alone, and use of short acting drugs like propofol or dexmedetomidine over benzodiazepines are strategies to be considered for early weaning. Proper adherence and practice of weaning protocol are also important.[44]


  Supportive Treatment Top


Glycemic control

A standardized approach for glycemic control is recommended, with a target blood glucose level ≤180 mg/dL. It is advised to start insulin when two consecutive blood glucose is >180 mg/dL. Arterial blood is more reliable compared to capillary blood for point of care testing due to inaccuracy especially in patients in shock.[45]

Venous thromboembolism prophylaxis

As incidence of deep vein thrombosis in ICU patients is about 10% and subsequent risk of embolism is high, unfractionated heparin, or low-molecular-weight-heparin should be used as pharmacological agents for prophylaxis unless contraindicated. Mechanical VTE prophylaxis can either be combined with pharmacological agents or applied alone when pharmacological agents are contraindicated.

Stress ulcer prophylaxis

Stress ulcer prophylaxis using H2 receptor agonist or proton pump inhibitors are indicated only in patients with risk for GI bleeding.

Nutrition

Enteral feeding should be initiated as early as possible in patients who can tolerate as it not only provides the necessary calories but also has potential physiologic advantages related to the maintenance of gut integrity and prevention of intestinal permeability, dampening of the inflammatory response, and modulation of metabolic responses that may reduce insulin resistance.[46] In those patients in whom enteral feeding is not feasible, it is recommended to initiate IV glucose and proceed to enteral feeds when tolerated. Parenteral nutrition is not recommended as various studies shows lack of mortality benefit, high cost, and increased risk of infections.[47] Prokinetic agents can be used in patients with feeding intolerance provided electrocardiography evaluation of QT interval is done. The placement of post pyloric tubes can also be used in patients with feeding intolerance and risk of aspiration.

Newer therapies under investigations

Most of these new modalities are either proven ineffective or require further trials to prove benefit [Table 6]. Various preliminary studies reported that combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) was associated with reduction in organ failure and mortality in patients with sepsis and septic shock. However, recent studies like The ACTS randomized control trials and The VITAMINS trials have shown that there was no statistically improved outcome and do not support routine use of this combination therapy for patients with septic shock.[61],[62]
Table 6: Newer Treatments

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The surviving sepsis guidelines also advocates against use of IV selenium, arginine, glutamine and also techniques such as blood purification and use of antithrombin and thrombomodulin.


  Prognosis Top


In hospital morbidity and mortality

Mortality rates increase linearly according to the disease severity of sepsis. Mortality associated with sepsis is ≥10% while that associated with septic shock is ≥40%.[63]

Long term prognosis

After hospital discharge, mortality risk is about 20% with most of the deaths occurring within first 6 months, but risk remains up to 2 years.[64] Poorly controlled infection, immunosuppression, complications of intensive care or worsening of underlying comorbidities, all contributes to late death.


  Conclusion Top


Sepsis is a complex disease with a substantial mortality rate even with advances in modern medicine. Early recognition and timely management are of paramount importance in improving the clinical outcome [Figure 1]. Clinicians should also be aware that the latest surviving sepsis guidelines are still not universally accepted. There are lots of researches taking place regarding use of newer therapies which may help in curtailing the mortality rates and reduce post sepsis morbidity in future.
Figure 1: Management in nutshell

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Definition
Risk Factors for...
Management of Sepsis
Initial Resuscit...
Vasoactive Medic...
Diagnosis and So...
Antimicrobial Th...
Role of Steroids
Use of Blood Pro...
Mechanical Venti...
Supportive Treatment
Prognosis
Conclusion
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