The occurrence of severe sepsis and septic shock constitute about 2.9% of hospital admissions in the US, of which 10% are admitted into the intensive care unit and mortality rates exceed 30% (Angus et al., 2001). In a 21-year analysis of sepsis cases in hospitals in the US, it was reported that between 1979 and 2000, the annual rate of increase of sepsis cases was 8.7%. Figures since 1979 also show 164,000 cases (82.7 per 100,000 population) to nearly 660,000 cases (240.4 per 100,000 population) in 2000 (Martin et al., 2003).
However, despite increasing cases annually, the mortality rate was reported to decrease from 27.8% during the 1979 to 1984 period to 17.9% from 1995 to 2000 (Martin et al., 2003). Fairly new technologies and treatment account for this increase. In fact, a recent method using bacteriophage therapy was observed to result in a 66.7% survival rate of mice models infected with gut-derived sepsis infected with Pseudomonas aeruginosa (Watanabe et al., 2007).
Sepsis is described as a syndrome which is characterized by a general, systemic inflammation as a reaction of the body to infection or systemic inflammatory response syndrome, that is, cases where sepsis was also be observed to develop even in the absence of bacterial, viral, fungal or parasitic infection. It is a serious and deadly condition which usually results from a compounded infection problem which may result from another disease, trauma, hemorrhagic shock, old age or a compromised immune system (Bone et al., 1992). Hunter (2006) explains that the reason why sepsis is rarely given attention and popularized for public information and attention is because it is not a disease in itself but a reaction of the body to a lowered immunological response. Nevertheless, it is a major cause of fatalities around the globe, with a predicted value of around 18 million individuals infected annually. In addition, reported cases provide an underestimation of the statistics in some countries where some cases are not diagnosed.
A typical per patient treatment cost of US$22,000 in the US (Slade et al., 2003). In burn patients, contraction of sepsis is responsible for 54% of reported deaths (Church et al., 2006). It is also reported as one of the major causes of mortality and morbidity in intensive care unit cases (Villar et al., 2001). In Europe, where three out of one thousand people are affected, the number of infected individual is rising at a rate of 1.5% every year. In addition, surviving patients experience a reduced quality of life (Hunter, 2006). Data from EU countries state that about half of the reported sepsis cases end up in casualties, this is despite very expensive treatment expenditures totaling €7.6 billion (Hunter, 2006), finances which could have otherwise funded medical and scientific researches, built infrastructure, secured food supply or conducted feeding and literacy programs all over the world. With few surviving victims of this syndrome, European medical associations and the International Sepsis Forum has started a program that aims to educate people about the risks, causes and treatment for sepsis and invoke global support from government and private institutions in order to lower the reported cases of sepsis and septic shock and campaign for its early detection.
During an infection, the body’s defense system is activated to fight the attacking pathogens. These invading pathogens, especially bacteria, possess receptive lipopolysaccharide (LPS) coverings or release exo and endotoxins that activate the T-cells and macrophages and trigger the Toll-like receptors (TLR’s) to respond by releasing antibodies, eicosanoids and cytokines such as tumor necrosis factor (TNF) and interleukins. The antigens may also result in the production of lysozymes and proteases, cationic proteins and lactoferrin that can recognize and kill invading pathogens. Different microbes also induce various profiles of TNF and interleukin to be released. These molecules results in a heightened inflammatory response of the body and vascular dilation. The TLR’s also affect a different cascade that involves coagulation pathways, which results in preventing the bleeding to occur at the area of infection. With too much molecular responses and signals, the recognition of the molecules sometimes fails and attacks even the body’s endothelial cells. These compounded immune and inflammatory actions result in the development of the symptoms of sepsis (Hunter, 2006; Van Amersfoort et al., 2003). Brunn and Platt (2006) believes that events leading to breakdown of the tissue such as injuries or infection, that naturally results in the activation of the immune system, is a major event that causes sepsis. During host infection, the release of tumor necrosis factor and interlekin-1 signals the dilation of the arteries and inflammation. These released cytokines also activate the coagulation pathway to prevent fibrinolysis but an increase in the concentration of these molecules may result in abnormalities in the host’s defense system (Gropper, 2004). The common belief that sepsis is caused by endotoxins released by pathogens has fully been established but genomic advancements is shedding light on current insights that sepsis can also occur without endotoxin triggers, that is even without microbial infections (Hunter, 2006).
Clinical Presentation and Usual Course
Clinical symptoms of sepsis include abnormal body temperature, usually higher than 38o or below 36o, fast heart rate (higher than 90 beats per minute), heavy breathing (higher than 20 breaths per minute), hyperventilation (PaCO2 >32 mmHg), abnormal white blood cell count, usually higher than 20,000/ mm3 or lower than 4,000/ mm3 (Bone et al., 1992), oxygen debt due to high oxygen tissue use but abnormal oxygen extraction capacity, lactic acidosis, urinary retention, abnormal microvascular blood flow (Samsel et al, 1988) and vascular dilation as a result of decreased blood pressure (Hunter, 2006). The latter reference also describes other manifestations such as palpitations, cool blue extremities, and in severe cases, hypotension and blackening of extremities. In chronic cases, conditions include poor respiratory system, muscular atrophy and cognitive dysfunction. Chills, immature neutrophils, skin mottling and hypoglycemia are additional indications according to Gropper, 2004.
Conditions which pose threat to acquiring sepsis include burns, severe wounds e.g. from surgery or accidents, diabetes, AIDS and other diseases characterized by a failing immune system, organ transplant and operations where administered drugs cause an intentional failure of the patient’s immune response and cancer. The elderly population, as well as neonatal conditions, is also prone to sepsis (Hunter, 2006)
Prognosis can be based on the observation that the mortality rate is very high at 30%, but recovery from early diagnosis and treatment programs is frequently achieved with success. Thus, early discovery and accurate identification is crucial to successful treatment. The difficulty lies in problems in identifying early symptoms for diagnosis and identifying causative agents, greater susceptibility of the elderly group and resistance to antibiotics (Slade et al., 2003).
Guideline Based Standards of Care
Based on the surviving sepsis campaign guidelines on the care of sepsis and septic shock patients are also continuously being modified. The FDA imposes regulation guidelines for most medicines used in treating this condition such as warning revisions in erythropoiesis stimulating agents, incorporation of new warnings in Heparin sodium injections or avoidance of the use of Xigris (activated drotrecogin alfa) in infants. Guideline developers also suggest improvements in the previous steps employed for improved outcomes in sepsis patients based on the agreement on the Consensus Development Conference and the Expert Consensus (Delphi). The major recommendations include immediate antibiotic therapy upon recognition of the case using fluid cultures and specifying the antibiotic after a 48-72-hour assessment to avoid toxicity and resistance and utilizing combination therapies for neutropenic patients and those with Pseudomonas infections. Sources of pathogenic infections should also be identified and controlled immediately. Tricky pathogen sources include vascular areas and should be controlled after ensuring vascular access. High scoring recommendations include employing fluid therapy for hypovolimic patients at 500–1,000 mL of crystalloids or 300–500 mL of colloids over 30 minutes, use of vassopressors such as norepinephrine or dopamine administered through an arterial catheter or use of vasopressin in patients exhibiting refractory shock, ionotropic therapy and well-regulated use of ACTH and corticosteroids, as well as glucose level control therapies. Blood product administration, rhAPC, bicarbonate therapy for hypoperfusion-induced lactic acidemia or use of neuromuscular blockers is not highly advised due to major risks. In acute cases hemofiltration, hemodialysis, DVT prophylaxis using low-molecular weight heparin and stress ulcer prophylaxis using H2 are recommended. Early communication with the patient and their families as well as special considerations for infants is also indicated (Dellinger et al., 2004).
Patients with sepsis should be urgently examined to determine the site and source of infection using diagnostic tests. Bacterial culture for urine, blood, sputum and cerebrospinal fluid must initially be tested. As this case is usually accompanied by difficulties in breathing and other respiratory problems, good ventilation and comfort is important, mechanical ventilation also assists in pulmonary failure (Wolf, 2007). Nursing care can provide support by sustaining blood circulation and respiratory systems (Church et al., 2006). Cardiac and arterial pressure, oxygen consumption, blood gases, vascular resistance, oxygen saturation, oxygen extraction and lactate levels should also be determined to aid in treatment and therapy programs (Bateman et al, 2003). The use of antibiotics to ward of pathogens during sepsis has been used as primary care for sepsis caused by pathogen attack. Usually broad-spectrum antibiotic therapy is used (Church et al, 2006). Early adequate nutrition which could be administered via parenteral means and other intravenous fluids should also be directed. The infected fluid is also removed surgically and replaced through fluid resuscitation, hemodialysis and blood transfusion (Wolf, 2007) while some patients are administered with low-dose corticosteroids (Gropper, 2004) which aid in preventing dehydration, hypoglycemia and low blood pressure to occur.
It is predicted that because of the availability of DNA and protein sequences and structure, future drugs designs for sepsis are based on the target TLR4 receptor which mediate the response during pathogen attack. In addition, better understanding of the mechanisms of the immune response can help enlighten scientists on an effective drug design for treatment of sepsis that can hopefully be applied to other auto immune diseases. (Hunter, 2006)
Drug designs based on anticoagulant, antiendotoxins, other cytokine inhibitors (Church et al., 2006) and gene therapy (Villar et al., 2001) are also used. Among the effective treatments used for acute or chronic stages of sepsis is rhAPC, which inhibits TLR4 and acts as an anticoagulant however it does not affect milder forms of sepsis (Hunter, 2006). Also, since a multitude of problems occur as a result of increase in cytokine production during infection, another strategy that holds promise is identifying means to down regulate the action of cytokines and prevent the occurrence of sepsis and other related symptoms. Because of the onset of these promising therapies for sepsis, it is also possible that the molecular strategies to combat other immunosuppressive disorders are underway. As sepsis is induced due to a series of events that occur in the immune system and results to the development of other complications of an infection, the cascade of drug discovery and gene therapy can result in finding the cure for these diseases as well. As Villar et al (2001) puts it, modern technology has indeed produced a stimulating time for medical discoveries.