Adjunctive procalcitonin measurement in adult bacteremia and pneumonia outcomes

¶ … Treatment to Patients

The main objective of providing treatment to patients is to relieve symptoms along with decreasing the progression of the disease as well as the mortality or morbidity. However, in some cases, this objective is not fully achieved, especially in the case of the patients who are admitted to the ICU with some serious and almost always a terminal stage of the disease. For example, when old patients are admitted in the ICU, their immunity is extremely low and this is the perfect time for the opportunistic infections to make matters worse for these patients. There are many infections that are specifically associated with patients admitted in the hospitals. Pseudomonas Aurigeonosa is a micro-organism that is well documented to cause bacterial pneumonia and bacteremia in the patients who are terminally ill and are receiving treatment in the hospital setting. Since most of the patients in the ICU are not conscious or are in a comatose state, it becomes very difficult for the doctors and the nursing staff to make an early diagnosis of the aforementioned infections. By the time the doctors and the paramedics find out about the deteriorating conditions of the patients because of the opportunistic pathogens, it is usually too late to save the lives of the patients.

Definition of Important Terms

Before we start the discussion based on the PICO question, we will briefly define some of the key terms that will often be used in this paper. First of all, the term "adult patients" has been used in the question. It can be used in two different contexts. Firstly, it can be used in the sense that the adult patients are most prone to infections since they have a depressed immune system. Secondly, it can be implied in the sense that adult patients are the ones who are mostly admitted to the ICU ward of any hospital with usually a terminal disease or a very serious one.

The term "critically ill" would be used many times in this paper. It is used to refer to patients who have been admitted to the ICU with a potentially fatal disease or are in the terminal stages of any disease.

The second key term that has been used in the question is "bacteremia." Bacteremia refers to the presence of bacteria, of any strain or nature, in the circulating bloodstream that has the potential to cause systemic infections whose outcome is normally sepsis or what is commonly known as septic shock.

"Bacterial pneumonia" is basically the infection of the lungs or the lower respiratory tract. The causative agent has to be a bacterium, be it gram positive or gram negative.

The term "adjunctive measurement" has been used with respect to the measurement of pro-calcitonin in systemic infections. This implies that there are some diagnostic tools that have to be used to start treating patients who have developed bacteremia or bacterial pneumonia. However, there are some other diagnostic tools that are also sometimes referred to as the "surrogate markers" that can help the doctors and other nursing staff in the early diagnosis of a condition that can be potentially fatal for the patients who are critically ill.

PICO Question

The question on whose response this paper will be based on revolves around the adult patients that have been admitted in the ICU and are therefore terminally ill. These patients almost always develop bacteremia or bacterial pneumonia because of which their condition becomes worse and their survival rate also decreases. The purpose of this question is to figure out that whether or not the adjunctive measurement of pro-calcitonin levels can be helpful in the early diagnosis of bacteremia and bacterial pneumonia so that these patients could be promptly and appropriately treated so that their mortality/morbidity could be reduced. After reviewing the available literature, the question can be answered.

PICO Outline

Researchers are working day in and day out to devise the tests or the assessment techniques that would make it possible for the clinical professionals to make an early diagnosis of such infections in these patients so that their lives could be saved and a reduction in morbidity could be made. One of such diagnostic criteria that the researchers have come up with is the adjunctive measurement of pro-calcitonin levels. In this paper, we shall discuss how this method and its alternatives can help save the lives of the patient. Apart from this, we shall also look at some of the statistics pertaining to the deaths of critically ill patients due to bacteremia. After analyzing the available data, we will make a conclusion that whether or not the measurement of pro-calcitonin levels is of benefit or whether the data is just inconclusive. At the end of the paper, we shall also answer the PICO question.

Relevance to clinical practice

As mentioned in first part of the paper, the doctors and the paramedic staff are quite concerned about the patients who are admitted in the ICU going into septic shock because of the opportunistic infections. Once the patients develop septicemia or bacteremia, it becomes very difficult to save their lives. In this part of the paper, we see why it is so important for the researchers and the doctors to find out a way through which an early diagnosis of the invasion by pathogens can be made so that the mortality and morbidity can be decreased and the lives of the patients can be saved.

Most of the patients that are admitted to the ICU are normally very old. This means that their immunity is extremely low. Moreover, since they are in the ICU, they are suffering from some serious disease for which they are receiving strong medications that further suppresses their immunity. Under such circumstances, the opportunistic bacteria invade the body and can potentially cause life threatening septicemia or bacterial pneumonia. It is indeed very difficult for the doctors to treat these patients if the diagnosis is not made in the very early stages. Even though fever and dropping blood pressure could be signs of developing bacteremia, these signs are not specific enough for the doctors to make a specific diagnosis. Therefore, the need of time is the development of specific methods for the early diagnosis of worsening health such as the measurement of the pro-calcitonin levels. The next step would be to appropriately treat the patients with bacterial pneumonia and bacteremia.

According to the theory, the automated continuous-monitoring systems allow the doctors and the nursing staff to detect the bacterial invasion just a few hours after the withdrawal of the blood sample. Nonetheless, in actual clinical practice, it takes at least 12 to 24 hours to obtain the result for Gram stain after the blood is drawn from the patient. This is one of the main reasons why the chances are high that the outcome could be worse and the patients have to stay longer in the hospital ICU. On the other hand, the new methods including the polymerase chain reaction allow the doctors to identify the bacteria reliably and quickly but unfortunately, the facility for conducting such tests is not available in most of the clinical centers. There is no doubt in the fact that the clinical manifestations are the best approach to make a diagnosis, but the recently discovered surrogate markers can offer great assistance in identifying the main human bacterial strains within the first few hours of management of patients who have developed bacteremia.

According to a study that was based on 147 patients admitted in five different ICUs, it was found out that the most common source of infection was that of the lower respiratory tract. This implied that 32.0% of the patients who were infected with opportunistic pathogens developed lower respiratory tract symptoms. Some of the drugs that were tested for the treatment of these infections included ceftazidime, imipenem and cirpfloxacin. The aforementioned were the drugs that were found to be the most effective against the bacteria that were isolated from the blood cultures of the patients admitted in the ICUs. The independent risk factors pertaining to mortality were considered to be the development of septic shock and fatal underlying conditions. According to the results, treatment with the appropriate antibiotic did not prove to be of significant help in increasing the survival of these patients. The findings of this study suggested that the prevention of bacterial pneumonia and lower respiratory tract colonization are very critical for decreasing the incident of hospital acquired gram negative septicemia in the ICU patients. The most significant risk factors for death are the underlying disease and septic shock (Jang et. al, 1999).

Effectiveness of Evidence

Serum pro-calcitonin, also known as PCT is a peptide based on 116 amino acids. There has been a strong association between elevation of PCT and systemic bacterial infections. The measurement of serum PCT depends upon a fast and routine laboratory test that has the documented ability to distinguish between non-infectious acute inflammatory conditions and systemic bacterial infection (Digiovine et. al, 1999). On the other hand, serum C-reactive protein and white blood cell count do not have the ability to do so. Furthermore, results have shown that the level of PCT increase has a close association with outcome in patients who are critically ill (Beekmann, 2003).

Some studies have also suggested that the elevation in the levels of PCT vary according to the underlying pathogen causing the infection. This implies that it is expected to achieve a different magnitude of elevation in serum PCT in cases of infective endocarditis, bacterial pneumonia and bacteremia (Luzzani et. al, 2003). Nonetheless, up till now, only a handful of conflicting results pertaining to a PCT magnitude, which has the capability to differentiate between Gram positive or Gram negative bacterial strains, have been issues when taking into consideration the patients who are critically ill and have simultaneously developed sepsis (Opal et. al, 1999). However, the fact that there are differences in the signaling pathways of the inflammatory response that is induced by the two species of the bacteria has been established. Since PCT elevation is considered to have an intricate relationship with the cytokine response of the host to the challenge offered by the microbes, it is assumed that the difference between the values of PCT according to the strain of bacteria is there since the onset of bacterial manifestation (Harbath et. al, 2001).

Analysis

It is indeed very important to improve survival in the critically ill patients with bacterial pneumonia and bacteremia, and is achieved by many interventions, the most important being the administration of broad spectrum antibiotics. Therefore, recent studies have been suggested that the "door-to-needle" time is a crucial factor pertaining to the survival of patients who have developed sepsis. Data collected as a result of clinical studies as well as the latest guidelines are helpful for the doctors when they have to choose a certain antibiotic for empiric treatment (Ibrahim et. al, 2000). Nonetheless, some researchers believe that in 25% of the cases, the antibiotic treatment was changed once the Gram stain results were received by the doctor. Therefore, surrogate markers make it possible for the doctors to choose the appropriate treatment rapidly (Munson et. al, 2003).

Findings of some studies have suggested that the value of PCT elevation has the potential to be significantly higher in patients who have developed Gram Negative bacteremia as compared to the patients with Gram Positive bacteremia. Furthermore, no variable was found to be confounding in the studies that have been conducted. It should be noted that some studies pertaining to the critically ill patients with sepsis have either not addressed the aforementioned issue or have not confirmed it as of now (Muller et. al, 2000). Nonetheless, some studies have suggested that in the patients with S. pneumonia manifestation, PCT was found to be more elevated than it was in GN bacteremia, such as in the case of Legionella, which is an atypical microbe (Prat et. al, 2006)). On the other hand, in the patients with infective endocarditis, it was established that PCT elevation was greater in cases of GN bacteremia as compared to GP bacteremia. The reason for these contradictory results could be the fact that in some studies, the patients were infected by more than one strain and type of bacteria. On the other hand, some authors have suggested and proved in their studies that in patients with established sepsis, PCT was significantly elevated as compared to patients who did not develop sepsis. Therefore, the differences could be more obvious in cases of such patients (Boussekey et. al, 2005).

Since it is thought that PCT is elevated in the blood in direct association with the host's immune response and the inflammatory mediators that are released as a defense mechanism against the offending pathogens, a different set of cytokine response could be responsible for the differences in the pattern of PCT elevation that have been mentioned in the previous paragraphs. The fact, that GN and GP bacteria are known to induce inflammatory responses that depend on different patterns of innate immunity, can support this hypothesis. Therefore, it was suggested that the function of Toll-like receptors in the whole blood response to different bacteria was significantly variable and relied upon the composition of the outer membrane of the offending pathogens. It should be noted that one of the main determinants of the results of Gram stain is the composition of the outer membrane. Therefore, it was seen that the magnitude of the cytokine response depended upon the nature of the invading bacteria. To be more precise, studies have shown that the Tumor necrosis factor-? (TNF-?) has a crucial role to play in the cytokine response to the invading pathogen. Nonetheless, the plasma levels of TNF are not necessarily increased irrespective of the causative pathogen. Since this cytokine plays a critical role in the release of PCT from different cell lines when there is systemic bacterial infection, it could be suggested that the magnitude of PCT elevation could somehow be related to the characteristics owned by the invading bacteria. Some studies have shown in vitro that the peak value of PCT was significantly increased in the supernatants of human cells that were cultured and stimulated with lipopolysaccharide as compared to the ones that were stimulated with muramyl dipeptide, which is a part of the outer membrane of the Gram positive bacteria (Tavares et. al, 2005). It was interesting to note that no significant difference was observed regarding the CRP kinetics. Moreover, studies have previously shown that Candida species circulating in the bloodstream were less likely to induce an elevation in the levels of serum PCT in patients who were critically ill patients as compared to bacteria circulating in the bloodstream. This could also be one of the reasons for the difference in immune response pattern (Charles et. al, 2006).

However, the results of all the studies that have been conducted in this regard should consider with caution. Firstly, the results of the aforementioned studies cannot be generalized to all patients who have developed sepsis since mostly those patients were included in these studies that had developed bacteremia and not necessarily sepsis. Secondly, the probable ratio of a positive test (being PCT less than 16.0ng/mL) is quite low and cannot be applied in a clinical setting with reliability. Thirdly, it was observed that the mortality rate was higher in patients with GN bacteremia as compared with the patients who were infected with GP bacterial strains. Since the magnitude of PCT elevation had a direct link with the severity of the disease and its prognosis, the doctors and nursing staff should never ignore the fact that the patients with GP manifestation are probably less critically ill as compared to the patients with GN pathogen invasion. Even though the SOFA score as well as the admission SAPS II were found to be comparable in patients with GP bacteremia and GN bacteremia, some differences in health status were noted (Garrouste-Orgeas, 2006). Moreover, the possibility that the patients with GP bacteremia were more likely to have received immunosuppressive drugs cannot be excluded. However, none of the patients in any of the studies that have been mentioned above were treated with any immunosuppressive drugs apart from the steroids once they developed septic shock. It should be noted here that the same number of patients from both the GP and GN group developed septic shock at the onset of bacteremia and therefore they were treated with hydrocortisone. Moreover, it has not been established whether or not patients with a depressed immune system tend to show lower levels of serum PCT when bacterial sepsis sets in. Lastly, it is noteworthy that the amount of soft tissue infections was greatly increased in patients with GP manifestation. Therefore, PCT measurement and clinical diagnosis can be made earlier in these patients, and lower levels of PCT could be obtained without considering the Gram stain results. Nonetheless, somewhat similar results can be obtained when the patients having soft tissue infections are not included in the analysis. Apart from this, a low PCT value has been shown to be consistently independent in association with GP bacteremia in a setting that includes soft tissues that are considered a source of infection.

Alternative Solutions to the Problem

The fact that terminally ill patients who are admitted to the ICU almost always develop bacteremia due to which they can develop bacterial pneumonia or these patients can also go into septic shock, has been established. Now the problem at hand is to develop a schema that would make it possible for the doctors to make an early diagnosis of bacterial pneumonia or bacteremia so that these patients can be appropriately and promptly be treated. On the other hand, it is also important for the doctors or the nursing staff to be well aware of the route of infection that leads to bacteremia or bacterial pneumonia. First of all, most of the GN bacteria and also some of the GP bacteria enter the system circulation when the patients are catheterized with a Foley's catheter. It should be remembered that since most of the critically ill patients are not conscious a catheter is inserted in the urethra of these patients so that every time their sphincters relax, the urine flows into the urine bag through the catheter. The urine bag is a good breeding ground for the bacteria and these bacteria then colonize up the catheter and enter the urethra and then the systemic circulation.

Another way through which the bacteria enter the systemic circulation is by way of the ventilator. There are some certain species of GP and GN that breed inside the respirator. The patients who are on respiratory support tend to develop bacteremia or bacterial pneumonia. Moreover, critically ill patients that have developed bed sores on their dependent parts through which bacteria can also enter the systemic circulation.

Keeping in view these routes of infection, the bacteria can be prevented from entering the systemic circulation. Even though the catheters are sterilized before they are inserted in the urethra of the patient, it should be made sure that these catheters are changed frequently so that the bacteria is not given the chance to colonize up to the urethra. Apart from this, the patients can also be given a broad spectrum antibiotic so that the bacteria can be killed that has entered the blood circulation. The patients on the ventilators should also be given broad spectrum antibiotics via the IV line so that any pathogen that is living in the ventilator and has entered the systemic circulation could be killed. The ulcerations that result from the bed sores should also be locally treated frequently so that the bacteria breeding in these wounds are killed.

There is no doubt in the fact that prevention is better than cure, but sometimes despite of the adequate prevention measures, the patients still develop bacteremia and bacterial pneumonia for reasons that have been discussed in the paper. In such cases, it becomes necessary for the doctors to make an intervention. Apart from the PCT elevation, there are also some other markers that have long been used to detect bacteremia. These include white blood cell count (WBC) and measurement of C-reactive protein (Meisner et. al, 1999). Although these markers have long been used for the diagnosis of bacterial infections and otherwise, they do not have the capability of differentiating between Gram Positive and Gram Negative bacteria, which can result in ineffective treatment. Therefore, the reason why elevation in PCT levels and other surrogate markers has gained popularity among the researchers is that it is somewhat more specific. However, there is a need for improved and even more specific diagnostic tools for the detection of bacteremia in elderly patients.

Outcomes of Bacteremia and Bacterial Pneumonia

The reason why it is so important for the doctors to detect bacteria in the circulatory bloodstream of the patients is that the consequences of bacterial invasion can be fatal. When the bacteria enters the bloodstream of the patients who are critically ill, it has the potential to damage almost any organ of the body, both directly and indirectly. When the bacteria enters the lower respiratory tract, it causes pneumonia that is characterized by high grade fever, productive cough that is often blood stained and malaise. Healthy people are able to tolerate these clinical manifestations but things become very crucial and life threatening for patients who are in the ICU. Apart from this, if the bloodstream is invaded by GN strains of bacteria, there is a possibility of development of sepsis that is a life threatening condition and almost always results in death. Moreover, when bacteremia develops, the patients also simultaneously develop hypotension that results in decreased urinary output. When the GFR decreases because of hypotension, the dangerous chemicals are not excreted from the body. When these harmful chemicals are retained in the body, they can also cause damage to the different organ systems. The first organ to get damaged is the brain or the kidneys. After the failure of these vital organs, death is the definite consequence.