THE USE OF PRE-HOSPITAL LACTATE MONITORING IN SEPTIC PATIENTS

THE USE OF PRE-HOSPITAL LACTATE MONITORING IN SEPTIC PATIENTS

Introduction

Sepsis and septic shock are deadly health complications that continue to contribute to the high morbidity and subsequent mortality of septic patients worldwide. The approximated global sepsis burden is to be more than 30 million affected with 6 million fatalities yearly. ( Alaap Mehta, Ali Khalid & Manta Swaroop, 2019). Sepsis causes organ malfunction, which increases mortality risks in as many as more than one in four septic patients. It is a multifaceted complication that is brought up by an unregulated response of the host’s immune system towards an infection. Therefore early detection and management are crucial to improve the effects and reduce patient morbidity and mortality. Better-quality clinical techniques in diagnosis and treatment of sepsis have developed as the World Health Organization (WHO) declared it a global health priority that required diagnosis, management, and prevention resolutions. However, despite significant advances in the comprehension of the pathophysiology of sepsis, the development of advanced hemodynamic monitoring tools, and resuscitation methods, incidences of sepsis remain high, and this is indicative of lack of early detection, misdiagnosis or late treatment of septic patients. Sepsis has also shown to have after long term distressing physiological, cognitive and physical effects on septic survivors (Lars W et al., 2014),

Definitions of Sepsis and Septic Shock

The original meaning of sepsis, published in 1992, was founded on the existence of a suspected or diagnosed infection with at least two or more measures of Systemic Inflammatory Response Syndrome (SIRS) on a patient. This definition focused on the observation of two or more positive SIRS indicators with a proven or suspected infection as the primary cause. If signs and symptoms of organ malfunction and failure occurred, then the diagnosis graduates to severe sepsis. The definition of septic shock concentrated on the observation of arterial hypotension alongside acute circulatory dysfunction and sepsis. (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019).

Until lately, the definitions of septic shock and sepsis have remained based on the SIRS approach, as previously defined until new definition guidelines were published by the Surviving Sepsis Campaign (SCC) in 2016. The SCC is a multifaceted campaign created by the United States’ Society of Critical Care and the European Society of Intensive Care Medicine that developed precise, valuable, and valid definitions and clinical characterizations. This new form of description corrected the past inaccuracies and the utilization of SIRS measures by using the Sequential Organ Failure Assessment (SOFA) and a quick SOFA (qSOFA) score. This new definition was based on organ dysfunction and not inflammation to determine patients that were likely to go into sepsis and septic shock (Nguyen HB et al., 2004)

According to Lars (2014), The Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3) in 2016 defined sepsis as ” a life-threatening organ dysfunction resulting from dysregulated host responses to infection” and septic shock as ” a subset of sepsis in which underlying circulatory, cellular and metabolic abnormalities are profound enough to increase the risk of mortality substantially.” another definition of Septic shock is as “persisting hypotension that requires vasopressors to achieve a mean arterial pressure >65 mmHg despite adequate fluid resuscitation and lactic acid level >2mmol/L.”

SIRS and SOFA

There still lacks a gold standard criterion in the test for sepsis. The utilization of SOFA is, however, recommended over SIRS due to its inaccuracies in characterization. The definition of SIRS focused on an inflammatory reaction by the immune system to an infectious agent. This basis was not inclusive of patients who lacked bacterial or viral infections, biasing them to over-resuscitation and antibiotic therapy. (Alaap Mehta, Ali Khalid & Manta Swaroop 2019).

The identification of sepsis based on the SIRS criterion may have led to the misdiagnosis of sepsis or septic shop. A sepsis study in European intensive care units presented a decisive SIRS tally in eight seven percent intensive care admissions; however, 14.3 percent of them, displaying two or more SIRS indicators, did not bear infections. Additionally, Nguyen et al. (2004) showed that 12.5 percent of patients showed sepsis without SIR indicators, representing approximately one in eight sepsis diagnosed patients.

These inaccuracies shown by the SIRS criterion led to the recommendation of the utilization of SOFA scores in the diagnosis of septic in critical care environments. The SOFA criteria is a biochemical technique that utilizes an aggregate scoring system running from 0-4, evaluating several organ systems in a patient’s body. The parameters assessed include blood coagulation, respiratory system, liver filtration system, the cardiovascular system, and the renal system. An increment in the total tally of two or more systems is indicative of higher mortality risk in suspected septic patients. (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019)

The Surviving Sepsis Campaign also developed the quick SOFA clinical screening tool that based its diagnosis of sepsis based on the patient’s rate of respiration, altered mental state, and systolic blood pressure. A positive outcome of two out of three clinical variables is indicative of a predictive value that represents a definite diagnosis of sepsis in patients.

Pathophysiology of Sepsis

Over the decades, the comprehension of complex immunology and pathobiology of sepsis has improved. Formerly, septic hemodynamic manifestations reflected adverse host immune response to an infectious agent. Nevertheless, molecular studies have uncovered intricate interplays between the host and the infectious agent that display various sepsis manifestations.

Innate Immunity and Activation of Inflammatory Mediators

The activation of innate immune cells such as monocytes, natural killer cells, neutrophils, and macrophages initiate upon contact of the host cells and the infectious pathogen. The activation of immune cells induced through the binding of pathogen-associated molecular patterns (PAMPs) like fungal beta-glucans and bacterial endotoxins to specific pattern recognition receptors present on these cells.

Damage-associated molecular patterns (DAMPs) derived from the release of intracellular molecules from damaged or dead cells are also sources of host and pathogen interaction. The DAMPs bind to receptors on innate immune cells such as C-type leptin, toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, and the retinoic acid-inducible gene 1(RIG-1) like receptors. It leads to the activation of signal transduction pathways intracellularly, which results in pro-inflammatory cytokine transcription and release.

Additionally, other pattern recognition receptors such as the TLRs, NOD, and RIG-1 receptors can aggregate into bigger and complex protein structures known as inflammasomes, which also take part in the making of essential cytokines such as IL-1β, TNFα, and IL-18 which are involved in programmed cell death. During sepsis, pro-inflammatory cytokines result in leukocyte activation and proliferation, hepatic acute phase reactants induction, complement system activation, production of tissue factors, upregulation of chemokine, and endothelial adhesion particles expression. This adverse immune response leads to collateral damage and subsequent cell death.

Immunosuppression

During sepsis, the pro-inflammatory phase supersedes by an extended period of immunosuppression that involves a rapid declination of cytotoxic and helper T cells as a result of programmed cell death and a reduced reaction to pro-inflammatory cytokines. Postmortem studies on septic fatalities showed a global reduction of CD8+ and CD4+ T helper cells located in the lymphoid system. Further studies in septic patients have also demonstrated reduced amounts of key cytokines when reacting to endotoxins. Neutrophils also expressed a smaller number of chemokine receptors leading to reduced chemotaxis response and lymphopenia. These studies suggest that the immunity of septic patients fails to launch an effective defensive response towards secondary microbial infections. Early lymphopenia is an indicative biomarker for immunosuppression during sepsis.

Homeostatic Dysregulation

During sepsis, the inflammatory response intersects with pathways of homeostasis where the inflammatory and coagulation cascades are activated. The breadth of this interaction variates from slight thrombocytopenia to a full-blown disseminated intravascular coagulation (DIC).

In sepsis, the etiology of dysregulation of coagulation focuses on many factors. Hypercoagulability correlates with tissue factors released from polymorphonuclear cells, monocytes, and endothelial cells that completely inhibit inflammation caused by the production of thrombin. Tissue factors, therefore, play a significant part in the activation of systemic coagulation that leads to the formation of a meshwork of fibrin platelet clots, platelet activation, and thrombin production. The microthrombi then causes deficiencies in local perfusion that result in global hypoxia and multiple organ failure.

Additionally, to the procoagulant outcome in sepsis, there is also a declination of the effects of anti-coagulants produced by anti-thrombin and protein C that would generally temper the cascade of coagulation. Thrombomodulin activates protein C, which initiates an anti-coagulant impact by depletion of factors Va and VIIIa. Protein C has also demonstrated its effects through anti-inflammatory effects through the inhibition of crucial chemokines and adhesion to endothelium by monocytes and neutrophils. Sepsis presents severe systemic inflammation with low levels of protein C and thrombomodulin that allow dysregulation coagulation propagation and cascades.

Sepsis also presents low production of fibrinolysis as levels of crucial cytokines such as IL-1β and TNFα increase. The release of tissue plasminogen from vascular endothelial cells activates plasmin factors that are inhibited by a blunted addition in plasminogen activator inhibitor type 1 (PAI-1), resulting in reduced production of fibrin and fibrinolysis. It is the primary cause of microvascular thrombosis in septic patients.

Cell, Tissue and Multiple Organ Failure

Hypoperfusion is the primary underlying mechanism that leads to cellular, tissue, and organ failure in septic patients. The decreased amount of oxygen delivered to the cells is a result of a dysfunction in the cardiac system caused by sepsis. Septic cardiomyopathy incidence varies between 18 and 60 percent. It is linked to crucial circulating cytokines such as IL-1β and TNFα that can interfere with the mitochondrial functions of cardiac myocytes leading to their depression.

Septic cardiomyopathy is acute during its onset with both diastolic and systolic dysfunctions where the left ventricular ejection fraction paired with low left or normal ventricular filling pressures. There are also low stroke volumes with high end-diastolic and systolic volumes with increased compliance by the left ventricle. Inflammatory mediators induce variations in venous and arterial dilations that cause hypotension and septic shock.

During sepsis, heightened dilation of capillaries, arteries, and veins by the loss of the functional capacity of the endothelial barrier caused by tight junctions and endothelial cadherin. The failure of the endothelial barrier permits the seepage of intravascular fluids altering the body’s hemodynamics. This alteration, in addition to thrombosis of micro blood vessels, is a significant contributor that leads to tissue and organ hypoperfusion (Nguyen et al., 2004).

Consequently, sepsis also causes an elevation in anaerobic respiration within the cells leading to higher production and buildup of lactic acid. The inflammatory response mechanism also produces reactive oxygen species (ROS) that interfere with mitochondrial functions and subsequent ATP production. These changes cause severe damage to cells and tissues, leading to impaired or complete dysfunction of organs.

Cumulatively, substantial alterations of the endothelium’s barrier, high rate of leukocyte adhesion, vasodilation of microvascular vessels, and the induction of the procoagulant phase during sepsis results to edema, where intravascular fluid fills up the subcutaneous layer, the interstitial gaps including the lungs and body cavities. This accumulation will result in hypoxia, mismatch in ventilation-perfusion, and low lung compliance leading to acute respiratory distress syndrome (ARDS).  Changes in the endothelial barrier also interfere with the blood-brain barrier, which allows the entry of pathogens, toxins, inflammatory mediators, and cytokines. In the renal system, microvascular defects, low renal perfusions, and acute tubular necrosis produce adverse effects on the kidneys. The high level of permeability of the stomach’s mucosal lining damages the gastrointestinal system. The increased permeability exposes the gut to autodigestion by luminal enzymes and bacterial translocations across the septic patient’s bowel well. The formation of cholestasis damages the liver due to the inhibition of clearing bilirubin from the body system while the central nervous system dysfunctions by displaying episodes of altered mentation. The rapid respiration rate breaks down all available proteins for gluconeogenesis, including muscles leading to a state of catabolism. All these collectively play a significant role in the morbidity and mortality of septic patients. (Nguyen HB et al., 2004)

Etiology of Sepsis

The cause of sepsis is multifactorial and therefore, caused by any type of pathogenic microorganism and can originate in all kinds of environments, including hospitals and communities. Pneumonia is the primary cause of sepsis, accounting for more than half of septic cases, trailed by intra-abdominal and urinary tract pathogenic microorganisms. The most common infection-causing bacteria include Escherichia coli, Pseudomonas aeruginosa, and Klebsiella sp., which represent gram-negative bacteria. Staphylococcus aureus and Streptococcus pneumoniae are the common gram-positive bacteria that cause sepsis. Bloodstream infections (bacteremia) are also a significant cause of sepsis (Lars W et al. 2014),

Risk Factors for Sepsis

Many of the risk factors that lead to sepsis are dependent on the patient’s predisposition to microbiome infection. Sepsis is limited to age groups, patients with autoimmune diseases, patients on immune suppressive medication, catheterized patients, cancer patients, alcoholics, and patients with compromised or altered skin such as burn victims.

Neonatal sepsis affects newborn babies and is categorized based on the period of infection, either during birth (early onset) or after delivery (late start). Babies born underweight and premature are highly predisposed to late-onset neonatal sepsis due to their underdeveloped immune system. Neonatal sepsis remains a significant cause of infant mortality, but with early recognition and treatment, complete recovery is possible with no long term complications. Sex, ethnic race, and age all play a part in the development of sepsis. Sepsis mainly affects infants and elderly individuals, mostly in males with African descent than females of other ethnic groups. (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019)

Clinical Presentation of Sepsis

A septic patient displays signs of pathogenic infection with critical organ dysfunction. These signs can result in acidosis, multiple organ failure, and death. There is a variation of clinical manifestation in septic patients. Septic clinical manifestations are dependent on the location of the infection, the type of infectious pathogen, the systematics of acute organ failure, the status of health of the individual and the pre-hospital care offered before initiation to treatment in a hospital (Su Mi Lee & Won Suk An, 2016),

Septic cardiomyopathy and acute respiratory distress syndrome (ARDS) are clear manifestations of severe organ dysfunction. Respiratory compromise categorized as hypoxemia that is of not of cardiac origin but with bilateral infiltrates. Cardiovascular dysfunction is displayed generally as hypotension or an increased level of serum lactate. Septic patients typically present malaise, tachypnea, tachycardia, and high fever. Doctors determine if patients are predisposed to shock by determining serum lactate levels, high levels of plasma C-reactive protein, and white blood cell counts. (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019)

Diagnosis of Sepsis

The determination of septic is usually through physical findings, patient history, and laboratory test data such as body fluid examination, white blood cell count, and microbial culture. Earlier detection and diagnosis of sepsis in the field and admitted patients is fundamental as nosocomial sepsis linked to more extended periods of stay are also common. The patient should also have a proven or suspected source of infection and, in the least, either two signs of low blood pressure, altered mental state, and faster respiration. Other underlying septic causing illnesses can also be detected using radiology imaging techniques such as ultrasounds, X-rays, and MRIs (Su Mi Lee & Won Suk An, 2016).

In a pre-hospital setting, septic diagnosis is by measuring lactate levels. Higher levels of lactate in the blood indicate the risk of organ dysfunction and septic shock. Point-of-care hand-held lactate measuring devices can determine lactate levels from capillary blood quickly.

Rapid diagnostic kits can significantly contribute to a faster and effective diagnosis of sepsis, especially in pre-hospital settings. The Accelerate PhenoTest BC Kit is a blood test kit manufactured by Accelerate Diagnostic that identifies several of the common sepsis causing bacteria and their antibiotic susceptibility. The test is also very fast, estimated to be 42 hours faster than available sepsis diagnosis procedures. The use of such diagnostic sticks can aid in triage decision making and interventions, therefore, leading to significant patient outcomes and reduced mortality (Paul et al., 2019).

Normal Lactate Production and Clearance

Lactate is a glucose metabolite that is produced by cells and tissues when under insufficient oxygen. Lactic acid or lactate means the same and used interchangeably. The skin generally excretes lactate, erythrocytes, muscles, gastrointestinal tract, and the brain tissue in excess quantities, approximately 20 mmol/kg/day. Additionally, the lungs can also contribute to lactate production without global tissue hypoxia during critical lung injury or respiratory distress. Lactate produced within the red blood cells cannot be broken down further and flows into the bloodstream (Nguyen et al., 2004)

In healthy individuals, the concentration of serum lactate ranges between 0.5-1.5 mmol/L. Therefore an equilibrium exists where the release of lactate into the bloodstream from the red blood cells and the rate of clearance of lactate removal from the body system. Physical exercise is a physiological process that temporarily topples the lactate equilibrium due to the increased production of lactate, in excess of20mmol/L, in temporary oxygen debt. (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019)

Lactate is a by-product of pyruvate formed in the cytosol during glycolysis. The concentration of lactate and pyruvate are generally in equilibrium, at a ratio of 10:1; and sustained by lactate dehydrogenase (LDH). Lactate levels, therefore, elevate when the rate of production of pyruvate it’s breaking down in the mitochondria. Pyruvate Lactate produced as a result of glycolysis. Hence an elevation in the rate of glycolysis, regardless of its cause, can cause the accumulation of lactate.

Lactate can be broken down by the kidneys and liver, accounting for 30 and 60 percent, respectively. occurs either through lactate oxidation or as a glucose source from gluconeogenesis. The produced lactate can be converted into oxaloacetate via the pyruvate metabolic system or can be directly oxidized to produce glycogen that is used by periportal hepatocytes. Kidneys are also a great contributor to the metabolism of lactate, where the medulla produces lactate as the cortex plays the role of a metabolizer by gluconeogenesis. Therefore, the body has an intracellular regulator that balances lactate production and levels through glycolysis, lactate metabolism, and clearance (Su Mi Lee & Won Suk An, 2016),

Significance and Role of Lactate

Lactate is a major player in the metabolism of glucose, cancer metabolism, neurologic functioning, and several functions mediated by the immune system, including the healing of ischemic injuries and wounds. Aerobic glycolysis in the brain is crucial for gene expression and has to the development of neuron projections, neuron synapses, and learning. Specifically, lactate produced in the brain enters the neurons and plays signaling functionalities in the activation of gene expression, which can result in the formation of long term memory (Nguyen et al., 2004).

The rapid growth of cancerous cells utilizes anaerobic glycolysis called the Warburg effect. Lactic acid accumulation around the cancerous cells can rise to levels of 40mmol/L and has rapid tumor growth, metastasis, and minimal survival rates. Lactate accumulation also plays a role in the reduction of the body’s immunity to cancer cell infiltration by inflammatory cells.

Lactate is also involved in the modulation of inflammation and the initiation of immune tolerance. Lactate elevates the secretion of anti-inflammatory cytokines like interleukin-10. It also lowers the activities of pro-inflammatory cytokines including tumor necrosis factors, macrophages, natural killer T cells and macrophages (Su Mi Lee & Won Suk An, 2016),

Wound healing utilizes aerobic glycolysis, where lactate accumulates between 5-25mmol/L around the healing wounds. In acute tissue ischemia, there is an induction of lactic acid production as a cellular response. Lactate production  induced by the plasma membrane sodium proton exchange elevates intracellular sodium levels resulting in an overload of calcium through the calcium-sodium exchange causing cell apoptosis (Alaap Mehta, Ali Khalid & Manta Swaroop, 2019)

Etiologies of High Lactate Levels during Sepsis

The exact origins of high lactate levels (hyperlactatemia) during sepsis and septic shock are still yet to fully comprehended with a high probability that it is caused broadly by multifactorial aspects. Hyperlactatemia arises as a result of a high level of production of lactate by various tissues through respiration and a low rate in the clearance of lactate from the body system. According to Nguyen (2004) and colleagues, there is an increase in lactate levels during endotoxemia as a result of elevated aerobic respirations in tissues and cells but not the muscles.

Cellular function and integrity are dependent on a sufficient supply of oxygen. Acute and critical illness is a reflection of insufficient tissue perfusion and low amounts of oxygen in the blood leading to hypoxia. Multiple organ failure and death soon follow if the tissue hypoxia does not retreat. The lack of sufficient oxygen is among the contributing causes of lactate produced during sepsis and septic shock leading to subsequent global tissue hypoxia and anaerobic glycolysis. Additionally, catecholamine enhances glycolytic processes leading to further lactate accumulation (Sebastien Gibot, 2012).

In some septic cases, there are high levels of accumulating lactate h despite sufficient delivery of oxygen that can fully satisfy the body’s oxygen requirement. This lactate accumulation demonstrates the dysfunction of the tissue-oxygen extraction mechanism, where less than 50 percent critical oxygen extraction ratio was available. Anaerobic environments allow an increment in the formation and accumulation of lactate at oxygen deliveries that would usually be abundant to meet aerobic respiration demands. Dysfunctions at the microvascular level and the mitochondria in sepsis weakens the distribution and utilization of oxygen, even when in sufficient amounts. Microvascular dysfunctions activate anaerobic respiration leading to the conversion of pyruvate into lactate. Severe sepsis and sepsis shock inhibit gluconeogenesis, which results in the saturation of the monocarboxylate transporter mechanism and intracellular acidosis (Paul et al. 2009).

In sepsis and septic patients, exogenous and endogenous catecholamines have correlated to the high production of lactic acid. High concentrations of epinephrine are associated with the stimulation of aerobic glycolysis. Epinephrine binds the β- adrenergic receptors on the cell membrane and directly elevates the glycolytic flux. It also stimulates the ubiquitous sodium-potassium pump in breaking down adenosine triphosphate (ATP).  Hydrolysis of adenosine triphosphate into adenosine triphosphate (ADP) occurs through the stimulation of phosphofructokinase, which reactivates the glycolysis process. This reactivation elevates the glycolytic flux, where the conversion of pyruvate supersedes the conversion of pyruvate into acetyl-CoA into lactate by lactate dehydrogenase (LDH) (Sebastien Gibot, 2012).

Reduced clearance of produced lactate is also a contributory mechanism in high levels of lactate found in sepsis and septic shock patients. High levels of lactase (hyperlactatemia) can be as a result of dysfunctionalities of the hepatic-lactate clearing mechanism caused by the inhibition of pyruvate dehydrogenase (PDH) in the kidneys. Further liver complications also compromise the clearance of lactate from the body contributing to lactate accumulation and hyperlactatemia. A reduction of the blood flow to the liver, approximately 25 percent, is a great contributor to the decrease in clearing accumulated lactate. Reduced liver blood flow leads to low levels of lactate delivery for metabolism to produce energy for hepatic processes. Under reduced oxygen deliveries, aerobic glycolysis becomes the primary source of hepatic energy as the liver ceases to utilize lactate for gluconeogenesis and starts producing lactate (Seung Mok Ryoo & Won Young Kim, 2018).

Clinical Significance of Lactate

Lactate as a Prognosis Marker of Sepsis and Septic Shock

The accumulation of lactate and protons in the body’s fluid system results in hyperlactatemia and lactate acidosis. The conversation of pyruvate to glucose creates a glycolytic flux that generates hydrogen ions, but the conversion of pyruvate back to glucose utilizes the hydrogen ions. Therefore, an elevated production of lactate that leads to hyperlactatemia does not singly cause lactate acidosis, but the hydrolysis of hydrogen ions becomes the cause of acidosis.

Irrespective of the source of lactate production, high levels of lactate in the body correlates to adverse disease outcomes. Accumulation of lactate can result in the lessening of cardiac ability to contract and expand. It also leads to the reduction of hypo-responsiveness of vascular vessels to vasopressors through various inhibitory mechanisms.

High levels of lactate in the blood, greater than 4mmol/L, have been associated with high mortality, and it is contributory to the worsening of underlying health complications. The Third International Consensus definition of sepsis involves a serum lactate concentration of greater than two mmol/L. Furthermore, the Surviving Sepsis Campaign (SCC) endorsed the normalization of lactate in patients with hyperlactatemia as a biomarker of global tissue hypoperfusion (Seung Mok Ryoo & Won Young Kim, 2018).

Lactate- guided Sepsis and Septic Shock Management

Since the proposal of EGDT, oxygen saturation in the venous (ScvO2), has been the gold standard biomarker that monitors delivery and consumption of oxygen. However, the use of venous oxygen saturation as a therapeutic biomarker has displayed a failure of improvement in clinical outcomes compared to lactate monitoring methodologies (Paul et al. 2009).

Lactate serves as an indicative biomarker for global tissue hypoxia and anaerobic glycolysis, therefore, displaying the severity of illness and the clearance of lactate. SCC guidelines recommend resuscitation to balance and normalize high lactate levels in septic patients. The recommended bundle therapy for the management of sepsis and septic comprised of 4 procedures that are the first line of treatment executed within three hours and three methods performed within 6 hours. The 3-hour therapy bundle involves the measurement of levels of circulating lactate, and the 6-hour package also permitted the re-measurement of levels of lactate if the previous lactate level was high (Seung Mok Ryoo & Won Young Kim, 2018)

The SCC noted that lactate measurements are not indicative biomarkers for the evaluation of an individual’s severity of sickness or response to administered therapies. Even though serum lactate measurements are widely known, they are not universally available, mainly in the developing world. However, a randomized control trial evaluated lactate guided resuscitation in septic patients and observed that mortality significantly reduced in patients who received lactate guided resuscitation compared to those who failed to receive lactate monitoring before resuscitation (Paul et al. 2009).

Lactate as a Risk- Stratification Biomarker

Measurement and monitoring of lactate levels may assist in triage decision making in the identification of patients in the field who need emergency interventions and intensive in-hospital treatment. Patients with high levels of lactate levels in their blood may benefit from pre-hospital triage decisions, even though they do not display respiratory distress, shock, or mental alteration (Seung Mok Ryoo & Won Young Kim, 2018).

Lactate-Lactate Clearance Rate in Septic Patients

Frequent measurements of serum lactate in septic patients after resuscitation can serve as a secondary biomarker that indicates the patient’s therapeutic response. These measurements can also serve as a predictive indicator for the onset of septic shock and mortality depending on the lactate concentration value. Additionally, the assessment of lactate clearance from the bloodstream through measurements has demonstrated to be a vital indicator of mortality and morbidity. Septic patients who manage to clear a previous high level of lactate within the first 24 hours have much more significant outcomes than those patients who have continuously elevated levels of lactate (Paul et al. 2009).

If increased levels of circulating lactate levels can aid in the determination of patients whose state of health progresses to clinically substantial outcomes after sepsis, then it may be a great tool in assisting pre-hospital triage. The measurement and monitoring of lactate levels provide a platform for early diagnosis for more aggressive initial resuscitation procedures.

Lactate as a Catecholamine Marker

Lactate can also be used as a biomarker of released endogenous catecholamine, therefore making it beneficial in the identification of patients who display signs of occult shock. Lactate production is a biochemical aspect of tissue hypoperfusion and is fundamental in the recognition and identification of cryptic shock patients who need early goal-directed therapy (EGDT). These signs include maintained blood pressure as a result of a vigorous response to endogenous catecholamine. Patients with occult shock also display deceptive “positive” vital signs, concealing the catecholamine-dependent state of the trauma of the vitals. High levels of lactate, therefore, identify secret shock patients as patients with a high risk of mortality or decompensation. (Sebastien Gibot, 2012).

Lactate as a target for Early Resuscitation in Sepsis

The Surviving Sepsis Campaign (SCC) recommended guidelines on patients with high lactate levels, above 4.0 mmol/L, to receive aggressive fluid resuscitation to reduce the probability of early mortality. The main goal of resuscitation is the restoration of microcirculatory perfusion. Therefore, elevated levels of lactate can be an indicative consequence of insufficient delivery of oxygen in the organs, causing tissue hypoperfusion. Resuscitation improves hypoperfusion by improving the delivery of oxygen to balance and meet oxygen demand hence restoring oxygenation in the tissues. Following the commencement of resuscitation, the high levels of lactate should decrease as the equilibrium of oxygen delivery and demand is achieved and maintained. Regular measurement and monitoring of lactate levels should hence part of resuscitation procedures (Lori et al., 2016).

Measurement of Lactate

Lactate measurement is a sensitive but non-specific blood marker for an indication of tissue hypoxia. Point of care (POC) measurement of lactate has assisted as a clinical diagnostic tool for the assessment, evaluation, and monitoring of acute and critical septic patients. The gold standard sample for the measurement of lactase is arterial blood. Blood gas and point of care analyzers utilize a well-validated procedure to measure the amounts of lactase in the bloodstream (Paul et al. 2009).

Serum lactate concentrations that are higher than 4mmol/L indicate abnormalities in healthy individuals but are usually in acute or critical patients in the hospital. The level of lactate that is greater than 4mmol/L is generally accompanied by a systemic inflammatory response and often results in significant hospital admission rates and mortality rates. In healthy individuals, the concentration of serum lactate at an approximate range of between 0.5-1.5 mmol/L (Lori et al., 2016).

The measurement of lactase in pre-hospital settings, that is, before arrival to the hospital and in emergency vehicles, could be vital in providing emergency staff with sufficient information on pending septic shock and organ dysfunction despite the availability and utilization of standard hemodynamic factors. Pre-hospital lactate measurement and monitoring can as a predictive tool for emergency dispatch who attended to septic patients with neurological, respiratory, and circulatory disorders before fluid resuscitation. (Paul et al. 2009).

Hand-held point-of-care finger stick lactate monitors assess lactate concentration circulating in the blood. They utilize test strip technology similar to those that measure sugar levels. This lactate monitoring devices can process little microliter aliquots of blood from septic patients. They give out a rapid result within a short period while avoiding vascular punctures that result in significant volume draws of blood. Hand-held lactate monitoring devices enable earlier recognition and triage, providing resuscitation guides for septic patients (Sebastien Gibot, 2012).

An example of a point of contact hand-held lactate analyzer is the Stat Strip from Nova Biomedical Corporation. It has a 0.6 microliter sample size, 0.3 to 20 mmol/L detection range, and presents results in ten seconds. Analysis and performance of real-time capillary lactate POC testing enable fast targeted interference to improve the clearance of lactate. Small microliter sample size and quick results improvement time aid in creating the serial lactate values acquisition beneficial, possible, and can preserve blood in prior anemia patients (Lori et al., 2016).

Pre-Hospital Care for Septic Patients

Accelerated identification and definitive treatment of sepsis have shown to improve clinical outcomes. The development, endorsement have supported this, and implementation of SCC guidelines have reduced sepsis mortalities. The critical management of lactate accumulation in septic patients is the treatment of the leading underlying cause of infectiioThis involves early administration of appropriate antibiotics and fluids (Sebastien Gibot, 2012),

More than 60% of patients presented in emergency rooms with sepsis and septic manifestations arrive via emergency service transportation. Therefore, paramedics and emergency medical service staff, play a vital part in the early recognition and management of sepsis and septic shock (Paul et al. 2009).

The roles of EMS in the identification and management of suspected septic patients have towards the improvement of related education and hospital treatment and management of sepsis. Recently, much attention has shifted to the expansion of pre-hospital diagnostic procedures, including point-of-care testing of lactate levels in the blood. Paramedics in a pre-hospital setting should provide an exhaustive assessment on a septic patient, appropriate breathing and respiratory management, fluid resuscitation, and a high flow of oxygen (Sebastien Gibot 2012).

Pre-hospital Monitoring of Lactate in Septic Patients

In the setting of pre-hospital, the severity of septic shock assessment is necessary to select the best in-hospital care level. Since faulting of clinical signs is possible, there is a need for an extra element to improve the assessment and to choose in-hospital admittance in the emergency department or the intensive care unit. Point of care medical tools producing levels of blood lactate as the setting of pre-hospital may give a valuable and laid-back element for the decision-making and severity assessment (Paul et al. 2009).

Recognition of emergency medical services (EMS) and pre-hospital notification are proving to be effective in decreasing hostile effects allied to stroke. Therefore a case can be made for the EMS role in the timely detection and care of severe sepsis patients (Lori et al., 2016).).  The primary focus of the EMS role in the discovery of sepsis is on escalating pre-hospital diagnostics and refining provider education. Currently, the attention is on the point-of-care testing of blood lactate. The blood lactate value as a tool for risk stratification in sepsis is demonstrated in settings of the emergency department. Several studies established the practicability of portable lactate meter use in the pre-hospital setting and ED triage. But a single study addresses the devices’ use by providers of pre-hospital to assist in the knowledge and timely treatment of adult sepsis patients (Sebastien Gibot, 2012).

The assessment of pre-hospital focuses on significant sign evaluations and monitoring of serum lactate and the use of end-tidal carbon dioxide to conquer sepsis. Management of pre-hospital concentrates on resuscitation of fluids and infusions of vasopressor to develop the perfusion status of the patients. In majority of EMS systems, the arterial blood gases and lab values inclusion are not practical. As an alternative, providers use the BAS 90-30-90 scales and the Robson screening tool, recognized worldwide by pre-hospital systems. These scales bring up the patients’ clinical signs suspected of suffering an active infection. (Paul et al. 2009).

The BAS 90-30-90 scale employs an approach that is objective for assessing possible septic patients. The Robson screening tool includes two parts to aid in identifying and isolating septic shock patients, thus initiating the management of pre-hospital. Existing research recommends that Robson screening tools are most likely to detect septic patients in the field. Still, many protocols of pre-hospital in the US employ a blend of the two scales to assess perfusion rank and the possibility for infection. The capnography use is every day in most US services, whereas ultrasound and lactate meters are scarce. Capnography, a recognized device in EMS, offers valuable information about perfusion and ventilation. The monitoring of capnography helps evaluate the effectiveness of therapies created to develop perfusion (Lori et al., 2016).

In the pre-hospital setting, there is a limitation to the available tools for assessing the success of the efforts of fluid resuscitation. Trending fingerstick levels of lactate acid is useful depending on the availability of equipment and that time allows. Even though they help demonstrate the patients’ standard before fluid resuscitation, their use in the medical setting and EMS is not FDA-cleared. Paramedics frequently question on when it is suitable to use vasopressors. If the patient is not responding to aggressive fluid resuscitation, protocols of paramedic usually recommend use of vasopressors. The vasopressor to choose in septic shock is norepinephrine. This vasopressor works primarily by vasoconstriction with less side effects on the heart compared to dopamine. (Lars W et. al 2014),

Epinephrine can be used instead of or together with norepinephrine.

On the other hand, providers need to be alert that infusions of epinephrine may kindle aerobic metabolism of skeletal muscle, possibly increasing levels of lactate and interfering through the lactate use as a marker. Injections of antimicrobials in an hour of arrival is an objective for septic patients. The completion of the infusion preceding to inter-facility transport is dependent on the antimicrobial. Conversely, if it has not, providers might transport the infusions of antimicrobials. If the initiation of the injection is recent, providers should assess for allergic reaction signs and be ready to dismiss the infusion if necessary (Lars W et al., 2014),

It is therefore vital for providers of EMS to recognize that it is their own care but the entire healthcare process happens from the period the patient calls 911 to the period the patient is discharged back home. Regularly, septic patients are critically ill, but the description of its symptoms to a dispatcher may result into these calls being regarded as non-priority. In the setting of a pre-hospital, the septic patient needs to receive fluid resuscitation, oxygen at high-flow, proper management of airway, and a comprehensive evaluation. In the case of a hypotensive patient after being correctly fluid resuscitated, there is a need to consider the use of dopamine (Lori et al., 2016).

A proven test that is useful for the pre-hospital sepsis diagnosis is a measurement of lactate. The hypoperfusion in sepsis decreases delivery of oxygen to the tissues, which leads to lactate levels increase. Handheld POC monitors of lactate can offer measurement that is accurate and rapid of the blood lactate level of the patient (Lars W et al., 2014),). Lactate measuring tools permit healthcare staff acquire bedside assessment data of the patient instead of waiting for the laboratory results. Besides, levels of lactate continuously rise in the whole sample, which can lead to incorrectly raised capacities in the case of a delay in laboratory handling.

Better management of pre-hospital can make a weighty difference in the result of a septic patient. Timely identification and treatment can considerably decrease the patients’ mortality, stay in the hospital and stay in the ICU stays. EMS is not complete in the pre-hospital setting because, as the health industry grows, the expectation towards the paramedics’ increases too. They are to transport developed equipment for diagnostics, ventilators, and compound infusions. Septic patients mainly can be challenging to manage and evaluate in the pre-hospital arena (Paul et al. 2009).

Recommendations

Pre-hospital monitoring of lactate will stimulate better sepsis knowledge in adults and better the quality of care. It can be used to start off a particular treatment system like intravenous antibiotics. This will decrease the quantity of admitted patients to intensive care unit, thus reducing the National Health Service costs and mortality. The advancement of pre-hospital care requires the primary phase to avoid the late diagnosis, and responsibility is limited to time. Patients’ screening for severe sepsis can be done when on route to the hospital. Timely recognition and quick administration of antibiotics and fluid resuscitation as inclusive of the quantifiable resuscitation procedure are essential for improving results from septic shock. Unfortunately, providers of EMS regularly fail to detect the early warning sepsis signs. This failure is as a result of a partial evaluation. Addition of ETCO₂ and temperature monitoring might provide field workers with impartial evidence with which to create a more precise field diagnosis (Lori et al, 2016). There is still less strong evidence addressing the effect of pre-hospital interventions on sepsis outcomes. Most available indications are of low quality and indicate that the pre-hospital interventions have limited impact on outcomes in sepsis beyond improving process outcomes and expediting the passage of patients though the emergence care pathway.

Evidence indicating that pre-hospital antibiotic therapy and fluid resuscitation improve outcomes of patients is still lacking. The POC hand-held device produces timely, efficient and accurate lactate measurements with the possibility of affecting the medical decision making sooner. But this does not mean it’s the best pre-hospital lactate monitoring device.  Therefore, there is a need to increase awareness of EMS and to apply the new tools, thus enhancing the pre-hospital evaluation for sepsis. Extra research studies using vast numbers of sepsis patients and stronger means are needed.

Conclusion

Pre-hospital lactate monitoring can be a clinical tool for identification of the high level of lactate production and a low rate of clearance from a patient’s blood system. It can provide the earliest form for the identification of septic patients, therefore, play a significant role in making triage decisions and interventions. Lactate readings are also indicative of underlying health complications such as global tissue hypoxia, tissue hypoperfusion, and organ dysfunction. Early identification and management of lactate levels in septic patients with previously high lactate levels have shown to contribute to clinically significant outcomes and low mortality rates.

References

Alaap Mehta, Ali Khalid & Manta Swaroop (2019). Sepsis and Septic Shock. Intechopen. doi:  10.5772/intechopen.86800

Lars W et al. (2014), Etiology and therapeutic approach to elevated lactate, Mayo Clinical Proceedings, 88(10): 1127-1140  doi: 10.1016/j.mayocp.2013.06.012

Lori L et al., (2016), Pre-hospital lactate measurement by emergency medical services in patients meeting Sepsis criteria, Western Journal of Emergency Medicine; 17(5): 648-655. doi: 10,5811/westjem.2016.6.30233

Nguyen HB et al, (2004), Early Lactate Clearance is associated with improved outcome in severe sepsis and septic shock, Critical Care Medicine doi: 10.1097/01.CCM.0000132904.35713.A7

Paul A, van Beest et al. (2009) Measurement of Lactate in a pre-hospital setting is related to outcome, European Journal of Emergency Medicine 16:318-322

Sebastien Gibot (2012), 0n the origins of lactate during sepsis, Critical Care, 16(5): 151. doi: 10.1186/cc11472

Seung Mok Ryoo & Won Young Kim (2018), Clinical Applications of Lactate testing in patients with Sepsis and Septic Shock, Journal of Emergency and Critical Care Medicine 2:14. Retrieved from http://dx.doi.org/10/21037/jeccm.2018.01.13

Su Mi Lee & Won Suk An (2016), New Clinical Criteria for Septic Shock: Serum Lactate level as a new emerging sign, Journal of Thoracic Disease 8(7):1388-1390. doi: 10.21037/jtd.2016.05.55