Sepsis is a clinical condition that evokes an inflammatory response of the host immune system in response to clinically-suspected infections. It usually occurs in an individual with a weak immune system such as a post-surgery patient, organ transplant patient, cancer patients or an AIDS patient. It spreads throughout the body via the bloodstream. There are several degrees of sepsis such as severe sepsis, septic shock and refractory septic shock (Morrell, Micek & Kollef, 2009) that together make up the systemic inflammatory response syndrome (SIRS) (Mayr, Yende & Angus, 2014). Sepsis and septic shock are some of the leading causes of death in the world, with a mortality rate ranging from 30% to 60% in both developing and developed countries (Morrell et al., 2009).
During the 1960s, when the development of various antibiotics was in full swing, it was thought that the world would be free of any form of infection. However, half a century later, clinical infections are still plaguing the world through genetic adaptations and resistance development (Lyle, Pena, Boyd & Hancock, 2014). Another theory suggests that the incidence of sepsis, septic shock and emergence of new infectious pathogens have increased rapidly in the last few decades owing to an increase in immuno-deficient diseases such as AIDS, chemotherapy and organ transplantations and an increase in numbers of aged people with weakened immune system, (Bateman, Schmidt, Berman & Bittner, 2010). Current management strategies include source control, airway stabilization, antibiotic treatment, vasoactive agents, activated protein C, prevention of pneumonia and other nosocomial infections (Morrell et al., 2009).
Prevalence and risk factors of sepsis and septic shock
In the UK, 35,000 people are hospitalized annually for sepsis and consequent septic shock among which, 45% do not survive (Spanos, Jhanji, Vivian-Smith, Harris & Pearse, 2010). In the US, sepsis and septic shock are the tenth leading cause of death with a mortality rate of 30% (Lyle et al., 2014) and are responsible for nearly 10% of the deaths every year (Morrell et al., 2009). Studies show that in the US, 50% of the sepsis and septic shock cases are developed outside the ICUs and 25% of the patients die in spite of aggressive treatment (Mayr et al., 2014). Men are 1.28 fold more predisposed to develop sepsis compared to women (Artero, Zaragoza & Nogueira, 2012). Alcohol dependence, cancer, immune-deficiency, non-Caucasians, presence of underlying disease conditions and genetics are some of the risk factors of sepsis and septic shocks (Morrell et al., 2009).
A study by Harrison, Welch and Eddleson (2006) on the epidemiology of severe sepsis in England, Wales and Northern Ireland indicated that 27% of the cases admitted into hospitals were diagnosed with severe sepsis in the first 24 hours. Hospital mortality decreased from 48.3% to 44.7%, but the number of deaths increased from 9000 to 14,000 in a decade. This data reveals that the number of patients with severe sepsis of septic shock are increasing every year due to various reasons but early detection and aggressive treatment have helped save lives.
Etiology
The most common causative agents of sepsis and septic shock are Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli and Pseudomonas aeruginosa (Saha, Das, Chatterjee & Kaur, 2010). 62.2 % of the infections are caused by Gram-negative organisms while 46.8% of the infections are caused by Gram-positive organisms. The infections could also be fungal or parasitic in origin. The common sites of infection are the lungs, followed by urinary tract (primary site of infection in elderly patients), abdominal tract, blood stream through open wounds and soft tissues (Mayr et al., 2014). The severity of sepsis and septic shock depends on whether an organ failure occurs during the course of infection and not on the causative organism or mode of infection. Lungs and kidneys are the organs that fail quite often followed by heart failure, circulatory failure, metabolic failure and brain death (Artero et al., 2012).
Clinical presentation
The most common presentation of sepsis and associated conditions are fever, hypothermia in very young and elderly patients, hypotension and laboratory-identified infection (Gauer, 2013). Sepsis is characterized by high fever, tachyponea (rapid breathing), tachycardia (increased heart rate) and leukocytosis (increased leukocyte count). When sepsis is accompanied by single organ hypoperfusion (decreased circulation of oxygenated blood to the organ’s tissues with a capillary refill time greater than 3 seconds) or dysfunction is termed as severe sepsis. Severe sepsis is also characterized by lowered renal output, elevated lactate (greater than 2 mmol/L), depleted platelet count (less than 100,000/ml) and behavioral changes (Gauer, 2013). Septic shock is characterized by symptoms of severe sepsis along with very low blood pressure (less than 60 mm Hg and less than 80 mm Hg in case of hypertension patients) that does not normalize through intravenous fluids. The patient would also need low levels of dopamine to regulate the required blood pressure (Gauer, 2013). In refractory septic shock, the patient requires high levels of dopamine (more than 15μg per kg per min) or norepipherine to maintain normal blood pressure (Morrell et al., 2009).
Pathophysiology
The pathophysiology of severe sepsis and septic shock can be divided into two categories, namely, organism-related component and host-related component. The organism –related event commences with the pathogen entering the host through an exposed site on the body and adhering to an epithelial cell inside the host. Once inside the host, the bacteria establish a quorum sensing system to regulate their population to escape detection by the host immune system. Once the population is sufficient, the bacteria signal each other to invade the host immune system and even modulate it, thereby weakening the immune response. This act establishes the infection within the host (Nduka & Parrillo, 2009).
The infection results in an inflammatory response, which leads to shock and organ failure during the later stages. Coagulation abnormality is a well-known feature of sepsis and septic shock, which is characterized by the appearance of clots throughout the body at various sites. This mechanism is thought to be brought on by a weakened anticoagulation system and a damaged fibrin removal system that is essential to maintain blood circulation in the body. Organ dysfunction is thought to be manifested due to decreased supply of oxygenated blood (Angus & van der Poll, 2013).
The host-related events include pathogen recognition that is facilitated by host pattern recognition receptors (PRRs). The pathogens do not share any receptor or structural similarity to the host cells and thus, are recognized early by the immune system. However, in a compromised immune system that is ‘short-staffed’, the infection goes undetected before it is too late (Namas et al., 2011).
Diagnosis
The diagnosis of sepsis and septic shock are done based on the clinical presentation and microbial lab cultures. Percutaneous blood, blood from each vascular device attached to the patient, urine, mucous, stool, soft tissues and sputum are some of the samples used as lab cultures for infection identification. The laboratory tests would include whole and differential blood count, microbial pathogen analysis, coagulation time and factor assessment, lactate level assessment, urinalysis to test presence of protein, blood cells and pathogens that could indicate kidney infection and metabolic panel test. In case the tests reveal coagulation abnormalities, the fibrin degradation product levels and fibrinogen levels must be measured. The diagnosis must not be solely dependent on blood tests because blood cultures of 50 to 65% of the patients come up with negative results. Endocarditis is diagnosed using echocardiography. A computed tomography (CT) scan would be helpful in revealing clots and abdominal infection. An ultrasonography is recommended for detection of renal failure. A chest x-ray is an excellent tool to determine lung infection (Gauer, 2013).
Management
Fluid resuscitation
The first priority in case of sepsis or septic shock would be to stabilize the breathing and airways of the patient followed by assessment of perfusion using a sphygmomanometer (Morrell et al., 2009). First line management techniques include fluid resuscitation using intravenous fluid line containing isotonic crystalloid or colloid fluid, which is critical in preventing hypoxia, hypotension and hypovolemia. The optimal fluid volume to be administered in the first 12 hours would be 5 to 6 liters while the [fluid intake-urine output] must be a positive value, preferably between 3 to 4 liters at the end of the 12 hour period (Gauer, 2013).
Vasopressor and inotrope therapy
In case of failed intravenous fluid resuscitation, vasopressor therapy is administered using dopamine and norepinephrine. Norepinephrine is an ideal choice for vasoactive therapy due to its positive effect on mean arterial pressure maintenance while promoting no change in the heart rate. Due to this pleasing quality, norepinephrine is used as a first line drug in most septic shock cases. Dopamine is more prone to cause arrhythmia and is contraindicated in patients with renal dysfunction (Gauer, 2013). Dopamine’s actions are dosage dependent and thus, require causation during administration. In lower doses, dopamine causes vasodilation, while in higher doses, it increases heart rate and cardiac contraction. Phenylephrine is a α-adrenergic agonist that results in no change in the heart rate, making it an excellent choice when other vasopressors are ineffective. Inotrope such as dobutamine could be used in patients who exhibit decreased cardiac output but have a compensatory mean arterial pressure and ventricular filling pressure (Morrell et al., 2009).
Antibiotic therapy
Infection control is established by using antibiotic therapy using a combination of antibiotics such as carbapenems, quinolones, aminoglycosides, anti-Gram positive antibiotics, macrolides and β-lactams (Lyle, et al., 2014). For initial infection control prior to the identification of the causative pathogen, a combination of two broad spectrum antibiotics is recommended. In case of multi-drug resistant strains such as pan resistance P. aeruginosa and Klebsiella pneumoniae carbapenemase it is advisable to use antibiotics such as colistin. Sometimes, an appropriate antibiotic combination could also be lethal (Morrell et al., 2009); this requires careful monitoring after administration.
Conclusion
Nearly six decades have passed since the discovery of antibiotics. Considering the amount of medical accomplishment achieved by the human race, pathogenic infections should have been a thing of the past. However, due to increased resistance posed by the infecting organisms along with an increase in immunosuppressant therapies, it has become imperative to develop novel therapeutic management methods that could save thousands of lives each year. There is a lack of large-scale study to measure the efficacy of new drugs and a general lack of breakthrough in recent years in the antibiotic field to treat sepsis and septic shock. The heterogeneity among the patient groups has been one of the hindrances in understanding the genetic basis of sepsis.
References
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