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Detecting Sepsis Early

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Estimates suggest that more than 30 million people worldwide are affected by sepsis each year, with up to six million of these dying from the condition. While vulnerable populations such as the very young, elderly, pregnant women and immunocompromised people are most at risk, sepsis can strike anyone suffering from an infection. Rapid and accurate detection of sepsis is critical to help limit the extent of tissue and organ dysfunction and damage that sepsis can cause.

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We recently spoke to Elena Sukhacheva, Director Medical and Scientific Affairs at Beckman Coulter, to learn about some of the challenges of diagnosing sepsis early, and how measuring Monocyte Distribution Width can be used as a sepsis biomarker to aid the process.

Anna MacDonald (AM): Why is early detection of sepsis so critical?

Elena Sukhacheva (ES):
 Sepsis is one of the most deadly and costly medical conditions physicians and hospitals must face. In fact, statistics show that sepsis is the third leading cause of death in the U.S.1. Mortality rates for sepsis is extremely high – approximately 25-30%—with more individuals dying of sepsis than prostate cancer, breast cancer, and HIV combined 2,3. Hospitalizations due to sepsis cost the healthcare system more than any other condition in the U.S.,4 with a total annual cost greater than 24 billion dollars5.

According to data from the Healthcare Cost and Utilisation Project (HCUP), there was an increase both in the number of cases of sepsis, and the costs associated with sepsis between 2000 and 20097. With sepsis as their primary diagnosis, the mean length of a patient’s hospital stay was close to nine days in 2009, with an average cost per entire stay at $18,500 7.

Early detection of sepsis is critical, as a delay in antibiotic treatment has been documented to result in increased mortality, with a 7.6% increase in death for patients with severe sepsis and septic shock every hour antibiotic administration is delayed8. Therefore, the earlier sepsis is recognised and the earlier the treatment starts, the better the outcome for the patient and the lower the cost that can be expected to be borne by the healthcare system.

AM: What are some of the challenges of rapidly diagnosing sepsis?

ES: 
The main challenge of timely diagnosis is that sepsis may manifest in dramatically different ways. Sepsis may affect anyone. For example, a young patient acquiring an infection from an appendectomy, for whom a dysregulated immune response leads to organ failure and death, or a patient undergoing aggressive cancer treatments, whose immune system is unable to fight infection due to immunosuppression. In both cases, the diagnosis would be “sepsis”, but symptoms in these two patients might look very different.

It is also important to mention that most (two-thirds) of patients diagnosed with sepsis enter the healthcare system through A&E9. Therefore, it is very important to ensure that efficient sepsis detection practices are used at this entry point. Symptoms are not always clear, so in practice, clinicians only order a test for sepsis when symptoms become clearer in the patient and they are more obviously septic. This delay in the diagnosis and treatment for patients with ambiguous presentation often results in a worse outcome10.

AM: How is sepsis currently diagnosed? What are the limitations of these methods and markers? 


ES: 
Before we talk about diagnosing sepsis, let’s define what sepsis is. As you may know, for many years we had the so-called sepsis-2 definition, which was introduced in 199214. That definition of sepsis was based on the presence of at least 2 SIRS criteria (systemic inflammatory response syndrome) and either a clinically suspected or proven infection. In 2016, a new definition was established for sepsis, and today, sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection15. Deaths from sepsis result, not from the infection itself, but from dysregulated immunity and organ dysfunction, which makes it impossible to efficiently fight against the infection.

Practically speaking, clinicians may use SIRS criteria (if they are still using sepsis-2) or the SOFA score (sequential organ failure assessment, if they use the sepsis-3 definition) to diagnose sepsis. Additionally, laboratory tests are used to test for infection and help confirm a suspicion of sepsis; for example by measuring the patient’s WBC (white blood cell) count, Procalcitonin, C-Reactive Protein, Interleukin-6 or presepsin levels, or culturing body fluids such as blood or urine for infectious organisms. While positive cultures may be diagnostic of infection, none of these tests can definitively confirm a diagnosis of sepsis, so clinicians must rely on all the clinical and laboratory information available together to diagnose sepsis.

Additionally, it is important to note that not all tests are routinely performed for all patients, but only ordered when a clinician suspects infection or sepsis. Therefore, diagnosing sepsis early is very challenging, because symptoms may not be obvious and clear at the time at which the patient presents at the hospital.

AM: Can you tell us more about the Early Sepsis Indicator?

ES: 
The Early Sepsis Indicator is the only FDA-cleared hematologic biomarker that is available to be automatically reported as part of a complete blood count (CBC) with differential test for adults entering through the A&E or emergency department. The new sepsis biomarker is available exclusively on the Beckman Coulter hematology analyser, DxH 900. The parameter, Monocyte Distribution Width (MDW), is based on morphological changes in monocytes in response to infection. Since the Early Sepsis Indicator is included as part of a CBC-Diff analysis, it does not require additional blood to be drawn or a special order, and it is automatically reported for all adult patients.

Two scientific papers have already demonstrated the analytical performance of the Early Sepsis Indicator. The first results about early sepsis detection in ED with Monocyte Distribution Width were published in the journal, Chest in 201719. This study, which was conducted by Ohio State University, demonstrated that an elevated MDW value was able to discriminate sepsis from non-sepsis (according to sepsis-2 criteria) with a Receiver-Operator Curve Area Under the Curve (AUC) of 0.79, 77% sensitivity and 73% specificity. The study also analysed the performance of the WBC count and the combination of WBC and MDW. When MDW and WBC values were combined, they produced an AUC of 0.89, which was significantly higher than the AUC for each individual parameter [WBC AUC was 0.74].

Another study published in Critical Care Medicine included more than 2,100 consecutive adult emergency-department patients, and was conducted in three U.S. University Hospitals. This clinical trial confirmed the discriminatory capacity of MDW alone, and MDW with WBC20.

AM: What role do monocytes play in the development of sepsis? What are the benefits of using Monocyte Distribution Width as a sepsis biomarker?

ES: 
Monocytes are cells of the innate immune system. They are closely involved in two key events in sepsis pathogenesis, the cytokine storm and sepsis-induced immunosuppression.

Three main cytokines that contribute to a cytokine storm are Tumor Necrosis Factor-alpha, Interleukin 1-beta and Interleukin-6. They are produced mainly by monocytes and macrophages. Interestingly, one monocyte subtype, the so-called “classic” monocytes, are able to further differentiate into macrophages in response to infection and contribute to cytokine production. IL-1 beta is the main initiator of the cascade of cytokines, TNF-a and IL-6 induce production of acute phase proteins and activate other immune cells. Production of these inflammatory cytokines and mediators by monocytes/macrophages contribute to the efficient growth control and dissemination of invading pathogens. However, excessive and uncontrolled production of these inflammatory cytokines and mediators may lead to serious systemic complications including microcirculatory dysfunction, liver and kidney damage, and septic shock with high mortality rates.

The second main factor contributing to the high mortality rate of patients diagnosed with sepsis is sepsis-induced immunosuppression. Immunosuppression of innate immunity in sepsis will manifest as chronic inflammation, decreased pro-inflammatory cytokine production, increased anti-inflammatory cytokine production, reduced phagocytosis, and contracted antigen presentation.

If we look at monocytes, these cells in septic patients can be very heterogeneous. Recent research has demonstrated that monocytes in the course of sepsis can be polarised from a pro-inflammatory state to an immunosuppressive state21. We hypothesize that this increased functional heterogeneity of monocytes in sepsis probably results in increased morphological variability, which is measured as MDW. An MDW value above the FDA-cleared cut off indicates an increased probability that the patient has sepsis or will develop sepsis within 12 hours of the ED encounter.

The benefits of using the Early Sepsis Indicator include that it is reported automatically with a CBC-Diff analysis, results of which are very quickly returned to the physician; The test takes less than a minute, it requires no extra blood to be drawn, and there is no need to order the test, making it a powerful and convenient tool that clinicians can use to alert them that a patient may have sepsis or develop sepsis within 12 hours of presentation at A&E. Taken together with the WBC count, which is also part of a CBC-Diff analysis, along with other laboratory findings and clinical information, the Early Sepsis Indicator provides a qualitative assessment of sepsis risk from a single whole-blood venous sample22.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been clinically tested to significantly improve microcirculation.

D’OXYVA works to prevent sepsis, and resulting septic shock, using life-restoring molecule carbon dioxide (CO₂) and gentle vapor dissolved across the skin in a fast, painless, handheld  5-minute application — performed either in a clinical setting or in the comfort and privacy of your own home.

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Cause of sepsis-induced lung injury

A KAIST research team succeeded in visualizing pulmonary microcirculation and circulating cells in vivo with a custom-built 3D intravital lung microscopic imaging system. They found a type of leukocyte called neutrophils aggregate inside the capillaries during sepsis-induced acute lung injury (ALI), leading to disturbances and dead space in blood microcirculation. According to the researchers, this phenomenon is responsible for tissue hypoxia causing lung damage in the sepsis model, and mitigating neutrophils improves microcirculation as well as hypoxia.

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According to the researchers, this phenomenon is responsible for tissue hypoxia causing lung damage in the sepsis model, and mitigating neutrophils improves microcirculation as well as hypoxia.

The lungs are responsible for exchanging oxygen with carbon dioxide gases during the breathing process, providing an essential function for sustaining life. This gas exchange occurs in the alveoli, each surrounded by many capillaries containing the circulating red blood cells.

Researchers have been making efforts to observe microcirculation in alveoli, but it has been technically challenging to capture high-resolution images of capillaries and red blood cells inside the lungs that are in constant breathing motion.

Professor Pilhan Kim from the Graduate School of Medical Science and Engineering and his team developed an ultra-fast laser scanning confocal microscope and an imaging chamber that could minimize the movement of a lung while preserving its respiratory state. They used this technology to successfully capture red blood cell circulation inside the capillaries of animal models with sepsis.

During the process, they found that hypoxia was induced by the increase of dead space inside the lungs of a sepsis model, a space where red blood cells do not circulate. This phenomenon is due to the neutrophils aggregating and trapping inside the capillaries and the arterioles. It was also shown that trapped neutrophils damage the lung tissue in the sepsis model by inhibiting microcirculation as well as releasing reactive oxygen species.

Further studies showed that the aggregated neutrophils inside pulmonary vessels exhibit a higher expression of the Mac-1 receptor (CD11b/CD18), which is a receptor involved in intercellular adhesion, compared to the neutrophils that normally circulate. Additionally, they confirmed that Mac-1 inhibitors can improve inhibited microcirculation, ameliorate hypoxia, while reducing pulmonary edema in the sepsis model.

Their high-resolution 3D intravital microscope technology allows the real-time imaging of living cells inside the lungs. This work is expected to be used in research on various lung diseases, including sepsis.

The research team’s pulmonary circulation imaging and precise analytical techniques will be used as the base technology for developing new diagnostic technologies, evaluating new therapeutic agents for various diseases related to microcirculation.

Professor Kim said, “In the ALI model, the inhibition of pulmonary microcirculation occurs due to neutrophils. By controlling this effect and improving microcirculation, it is possible to eliminate hypoxia and pulmonary edema — a new, effective strategy for treating patients with sepsis.”

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been clinically tested to significantly improve microcirculation.

D’OXYVA works to prevent sepsis, and resulting septic shock, using life-restoring molecule carbon dioxide (CO₂) and gentle vapor dissolved across the skin in a fast, painless, handheld  5-minute application — performed either in a clinical setting or in the comfort and privacy of your own home.

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The Microcirculation in Sepsis

Deterioration of the Microcirculation in Diabetes

Sepsis is a leading cause of mortality in critically ill patients. The pathophysiology of sepsis involves a highly complex and integrated response, including the activation of various cell types, inflammatory mediators, and the haemostatic system.

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Recent evidence suggests an emerging role of the microcirculation in sepsis, necessitating a shift in our locus away Irom the macrohaemodynamics to ill icrohaemodynanmics in a septic patient. This review article provides a brief overview of the microcirculation, its assessment techniques, and specific therapies to resuscitate the microhaemodynamics.

Introduction

Sepsis and its progression to severe sepsis, septic shock and multiple organ dysfunction syndrome is a major cause of ICU admissions and mortality. Severe sepsis and septic shock may be characterized by a derangement in global cardiac indices typically leading to low peripheral resistance, which the body tries to compensate for by increasing the cardiac output. However, despite this increase in cardiac output, the tissues are unable to utilize oxygen as evidenced by the high lactate levels, deranged acid-base balance, and increased gastric carbondioxide level. The presence of tissue hypoxia despite adequate systemic oxygen transport has been blamed on altered microhaemodynamics as well as in itochondrial dysfunction during sepsis. However, the relative contributions of disturbed microcirculation and impaired mitochondrial function for sepsis related tissue dysoxia are still debatable. The present review aims to highlight the former cause of tissue hypoxia in sepsis i.e., involvement of the microcirculation. It moves from recapitulating relevant anatomy of microcirculation, to its current role in pathophysiology of sepsis, optimization during sepsis and lastly the modalities for its assessment.

Microcirculatory perfusion as an endpoint

Much of the research pertaining to resuscitation during sepsis has focused on restoring the macrodynamics of circulation such as blood pressure, oxygen delivery and oxygen extraction ratio. The pathologic shunting occurring in the microcirculation is not depicted by systemic haemodynamic derived and oxygen derived variables. The difference between macrocirculation and microcirculation was recognized very early on when it was pointed that changes in total peripheral resistance could not provide information regarding local vascular resistance changes since “dilation in one vascular bed may be accompanied by constriction elsewhere”. Also, the cause of alterations in the macrohaemodynamics lies in the microcirculation e.g., the decrease in systemic vascular resistance and hypotension result from arteriolar vasodilatation and hypovolemia from capillary leak. Thus, it needs to be answered whether resuscitating the microcirculation rather than the macrocirculation will finally answer the quest for improving survival in sepsis.

There is previous evidence that resuscitating the macrohaemodynamics is not always associated with improved microhaemodynamics, organ function, or survival. A study by LeDoux and colleagues observed the effect of norepinephrine on global haemodynamic parameters and measures of tissue oxygenation during septic shock. While the mean blood pressure increased from 65 to 85 mmHg along with expected increase in heart rate and cardiac index (p<0.05), there was no improvement in organ function or tissue oxygenation as evidenced by decrease in urine output, no change in capillary red blood cell velocity, fall in capillary blood flow and increase in gastric pCO2. The authors thus concluded that resuscitation of mean blood pressure or cardiac output alone in septic shock is inadequate. Microcirculatory independence from arterial blood pressure in septic shock has also been proven using direct imaging of microcirculation,. DeBacker et al reported a significant decrease in vessel density and proportion of small perfused vessels in septic patients, the alterations being more severe in non-survivors and were not related to the mean arterial pressure. Sakr and colleagues further explored these findings by studying the microcirculation in 49 septic patients. The small vessel perfusion was seen to improve rapidly in survivors as compared to non-survivors, with no difference in the global haemodynamic variables. Together with the evidence showing that organ function improves and mortality decreases when resuscitation boosts microcirculatory flow, the microcirculation does appear to be a new target for resuscitation during sepsis.

Assessment of microcirculation

Till date, there is no single objective gold standard to assess the microcirculation. In clinical practice, microcirculatory perfusion has been traditionally judged by the color, capillary refill and temperature of the distal parts of the body (i.e., finger, toes, earlobes and nose). Amongst the investigational modalities available to assess microcirculation, both indirect indicators as well as direct techniques exist, even though any single objective reliable method is still not recognized. Indirect techniques involve measurement of ‘downstream’ global derivatives of microcirculatory dysfunction such as lactate, carbondioxide, and oxygen saturation. The direct imaging of microcirculatory perfusion seems a superior approach to assessment of microcirculation. Invention of microscope is perhaps the single most important advancement in technology linked to discovering the microcirculation, since experimental investigation of the microcirculation began soon after its advent. Studies of human microcirculation began at the end of 19th century, with Hueter using a microscope with reflected light to investigate vessels on inner border of lower lip.

Future aspects

With several clinical and laboratory indicators of identifying hypoperf ision due to the microcirculation dysfunction being available, it is perhaps time to recognize shock in sepsis keeping tissue hypoperfusion as distinct from hypotension. A perfusion based scoring system has been proposed by Spronk et al. It emphasizes the need of extending recognition of shock severity to include microcirculatory parameters, besides global haemodynamic and oxygen-derived parameters.

Therapy in shock should be aimed at optimizing cardiac function, arterial hemoglobin saturation, and tissue perfusion. This not only includes correction of hypovolemia, but the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport as well. The role of vasodilators in recruiting the microcirculation will need to be looked into further.

Direct monitoring of sublingual microcirculation monitoring appears to be a promising endpoint for resuscitating the microcirculation. An integrative approach incorporating both macrocirculatory and microcirculatory haemodynamic data may indeed hold the answer to resuscitation in sepsis.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been validated to significantly improve microcirculation.

D’OXYVA works to prevent sepsis, and resulting septic shock, using life-restoring molecule carbon dioxide (CO₂) and gentle vapor dissolved across the skin in a fast, painless, handheld  5-minute application — performed either in a clinical setting or in the comfort and privacy of your own home.

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The microcirculation and its measurement in sepsis

The microcirculation describes the smallest elements of the cardiovascular conducting system and is pivotal in the maintenance of homeostasis. Microcirculatory dysfunction is present early in the pathophysiology of sepsis, with the extent of microcirculatory derangement relating to disease severity and prognosis in ICU patients.

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At present microcirculatory function is not routinely monitored at the bedside. This article describes the pathophysiology of microcirculatory derangements in sepsis, methods of its measurement and evidence to support their clinical use.

Sepsis and the microcirculation

Sepsis affects all elements of the microcirculation. It is associated with a decrease in capillary density and increased heterogeneity of perfusion caused by inappropriate vasodilatation and vasoconstriction, leading to decreased oxygen delivery, tissue hypoxia and organ dysfunction. Mechanisms of microcirculatory dysfunction in sepsis include arteriolar hyporesponsiveness and capillary dysfunction, leading to extravasation of fluid protein and neutrophils.

The importance of microcirculatory assessment in sepsis

Several studies have demonstrated that: (a) improvements in the microcirculatory function in sepsis after early resuscitation are associated with a decreased incidence of organ dysfunction and (b) persistent microcirculatory dysfunction after resuscitation is associated with worse outcomes., However, the microcirculation is difficult to monitor in practice and so current resuscitation goals rely on the monitoring and restoration of macro-haemodynamic values (such as systemic arterial pressure, cardiac output, heart rate), along with restoration of organ perfusion (inferred from normalisation of serum lactate and ScVO2). Moreover, restoration of macro-haemodynamic variables such as arterial pressure, especially with vasoactive agents such as noradrenaline, does not guarantee improvements in microcirculatory flow; in fact, noradrenaline can inhibit microcirculatory function irrespective of the presence of hypotension.

Summary

Microcirculatory derangement is common in patients with sepsis and cannot necessarily be predicted from macro-haemodynamic values. Improvement in macro-haemodynamic values in the critically ill does not imply improvement in microcirculatory flow and patients whose microcirculation fails to improve following resuscitation are at increased risk of mortality. Detection of microcirculatory dysfunction may aid diagnosis and risk stratification in patients with sepsis; restoration of the function of the microcirculation may be a useful therapeutic target for resuscitation but further data are needed.

HOW D’OXYVA CAN HELP?

D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been clinically tested to significantly improve microcirculation.

D’OXYVA works to prevent sepsis, and resulting septic shock, using life-restoring molecule carbon dioxide (CO₂) and gentle vapor dissolved across the skin in a fast, painless, handheld  5-minute application — performed either in a clinical setting or in the comfort and privacy of your own home.