RU2293333C2 - Method for monitoring critical states development associated with inflammatory systemic response syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves determining myoglobin and troponin-I Troponin-I level being equal to 0.2-1 ng/ml and/or myoglobin level being equal to 60-800 ng/ml with the exception of the first 4 days after direct massive muscle tissue injury, polyorganic insufficiency development conclusion is drawn in septic and aseptic diseases associated with inflammatory systemic response syndrome. Troponin-I level being from 0.2 to 1 ng/ml shows myocardial microinjuries development. Troponin-I level being from 1 to 10 ng/ml, points out to focal destructive myocardial changes availability. Troponin-I level being higher than 10 ng/ml, large focus myocardial infarction development as secondary complications. Myoglobin level being higher than 800 ng/ml, unfavorable prognosis of septic and aseptic diseases associated with inflammatory systemic response syndrome.

EFFECT: high accuracy of monitoring.

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Description

The invention relates to medicine, specifically to the medicine of critical conditions.

Systemic inflammatory reactivity (SVR) is a typical pathological process underlying the pathogenesis of many diseases and more particular syndromes and pathological conditions of various nature. First of all, sepsis, severe injuries of various localization and etiology, crash syndrome, severe necrosis (strokes, heart attacks) and many other critical conditions are currently being considered from the perspective of SVR syndrome. The final stage in the development of SVR is systemic disorders of microcirculation, organ, and then multiple organ failure (PON), shock conditions. Diagnosis and, especially, timely prediction of PON syndrome is the central task of the clinic of emergency conditions [1]. At the same time, if the first task is to some extent solved by using a number of standard scales for assessing PN, then additional conditions are required to solve the problem of reliable prediction of PN before the deployment of the clinical picture of the critical condition, and, first of all, introducing new technologies into medical practice and clinical laboratory analysis methodologies. Markers of organ damage associated with systemic microcirculatory disorders and other pathogenetic links of systemic inflammation occupy a special place in the system for diagnosing and predicting PON [2, 3, 4]. In this regard, you can take a fresh look at the well-known clinical and laboratory methods for diagnosing myocardial infarction - determining in the blood plasma “cardiac markers” - troponin-1 and myoglobin. At the same time, the accumulation of myoglobin in the blood can be associated with various destructive processes that occur not only in the myocardium, but also in the skeletal muscle system. Therefore, this marker can be used to identify systemic destructive processes when concretizing reference intervals of its concentrations and the scope of the method. In addition, high concentrations of myoglobin in the blood, approaching 1000 ng / ml, can themselves become factors in systemic damage, initiating coagulopathy and systemic oxidative stress by the Fanton reaction mechanism. In turn, reference ranges of concentrations of the myocardial-specific isoform of troponin-1, lying between the “normal” and “heart attack” zones, can record the level of microdamage to heart tissues - as one of the key target organs of the systemic destructive process.

Assessment of PON using existing SOFA scales and others. The main clinical and laboratory criteria in these scales are the excess of certain quantitative thresholds for blood levels of total bilirubin (a marker of functional liver failure), creatinine (kidney), and the degree of thrombocytopenia (as one of the markers of DIC) . These signs are considered in cooperation with clinical criteria and special research methods (blood gas research, etc.), since the confirmation of PON by these clinical and laboratory criteria in most cases does not exceed 10-30%. To a lesser extent, these criteria are suitable for predicting PON. The clinical criteria for PON primarily reflect changes in the system of macrohemodynamics, which far from fully characterize changes in the system of microhemodynamics, according to many experts, the main driving force of the pathokinesis of systemic inflammation.

Laboratory diagnosis of myocardial infarction by “cardiac markers” is highly sensitive and specific (certain reference intervals of myocardial-specific troponins) to a specific nosology, but is not intended to diagnose and predict complications of a different nature, which also lead to damage to the myocardium and muscle tissue in general, but of a different nature, for example, systemic microcirculatory disorders and related micro-membrane damage in tissues having a rich vascular network.

The other side of this issue is that under normal clinical conditions, “cardiac markers” are tested in individuals with obvious risk factors for myocardial infarction. Meanwhile, according to our data, for example, in severe injuries and postoperative complications, the probability of myocardial infarction in people who do not have obvious premorbid risk factors (relatively young age, no history of IHD) is at least 1%. Heart attacks in these cases are not always diagnosed in a timely manner or are not diagnosed at all (especially small focal heart attacks). Diagnosis of a heart attack in these cases is difficult due to the lack of appropriate examination protocols for resuscitation patients, their general condition and, as a rule, according to our data, high plasma myoglobin levels, without a direct dependence on the state of the myocardium (systemic disorders in muscle tissue).

Analyzing these methods, we can say that the current level of equipment of large clinical bases: the presence of enzyme-linked immunosorbent, immunochemiluminescent assay analyzers, etc. allows us to assess the level of microcirculatory lesions associated with the development of SVR syndrome of muscle tissue in general and myocardium, in particular, and also diagnose they have focal changes in the myocardium of a necrotic or infectious nature (septic endomyocarditis). However, the currently existing methodological approaches and examination protocols for patients do not allow to fully solve this problem.

Known methods described in Russian and foreign literature for the diagnosis of PON used in critical conditions in obstetrics, as well as the use of "cardiac markers" of myoglobin and troponins-1 and T for the diagnosis of myocardial infarction [2].

The closest analogue of the invention is a method for predicting the development of PON in the third trimester of pregnancy according to the results of studies of acute phase proteins, the level of fibronectin, the hemostatic system, the level of peripheral blood fetal erythrocytes, the hemodynamic system indicator — the structural point of blood pressure described in RF patent No. 2189045. The authors calculate the diagnostic index F by the formula F = K1 0.0018-K2 0.2021865 + K3 0.42014-K4 0.00301 + K5 0.01114 + 0.04018, where K1 is the structural point of blood pressure, conv. units; K2 - the level of D-dimers, ng / ml, K3 - the number of active platelets, 10 ⁹ / l; K4 - the number of fetal red blood cells in peripheral blood,%; K5 - fibronectin level, g / l. And with F less than 0.05, the absence of a threat of development of multiple organ failure is judged, and with F more than 0.05, the development of multiple organ failure is predicted. Moreover, if F is 0.07-0.1, damage to two life support systems is predicted: cardiovascular, hepatolienal, if F is 0.1-2, damage to three systems is predicted: cardiovascular, hepatolienal, hemostasis and maximum risk the development of thrombohemorrhagic complications, if F is 0.2-0.4, the development of irreversible conditions with a fatal outcome is predicted. The method allows you to timely identify the risk group for the development of this syndrome and monitor the patient's condition during gestation.

This method is used only in obstetrics and cannot be illustrated by the clinical practice of other areas of medicine.

The objective of the invention is to monitor the development of critical conditions of various origins associated with the systemic inflammatory response syndrome. The technical result consists in the timely determination of systemic microcirculatory damage to muscle tissue, microcirculatory and local myocardial damage, which determine the development of PON in critical conditions associated with CBP syndrome (sepsis, severe trauma). The method allows timely identification of risk groups for the development of critical complications and the likelihood of a fatal outcome, the development of complications and to resolve the issue of the need for preventive pathogenetic, and in some cases etiological, therapy, for example, when choosing tactics of antibacterial therapy.

The essence of the method lies in the fact that the blood plasma of the patient determines the content of myoglobin and troponin-1, and at a level of troponin-1 0.2-1 ng / ml and / or myoglobin level of 60-800 ng / ml except for the first 4 days after direct massive damage to muscle tissue concludes the development of PON in septic and aseptic diseases associated with SVR, while the level of troponin-1 from 0.2 to 1 ng / ml indicates the development of microdamage to the myocardium, the level of troponin-1 is 1-10 ng / ml indicates the presence of focal destructive changes in the myocardium, ur Wen troponin-1 above 10 ng / ml indicates the development of myocardial infarction macrofocal as secondary complications myoglobin index above 800 ng / ml indicates poor prognosis of septic and aseptic diseases associated with CBP.

The method is based on determining the level of troponin-1 and myoglobin in the blood plasma, followed by determining whether the results obtained belong to one or another reference interval of signs characterizing the patient's condition. Using mathematical processing of the obtained results by the linear method of learning to recognize the obtained images, a stable stochastic relationship between the levels of "cardiac markers" in the blood plasma and the severity of the systemic inflammatory reaction and signs of PON during the development of critical conditions of various etiologies is revealed. For each factor, biologically significant reference intervals are determined:

For troponin-1:

1. 0.2-1.0 ng / ml - PON development is predicted at a specificity level of 87%, at a sensitivity level of 92%, and efficiency is 82%.

2. 1.0-10 ng / ml - predict the presence of focal changes in the myocardium (small focal infarction, septic endocarditis, etc.), specificity and sensitivity of more than 50%.

3. More than 10 ng / ml - they diagnose secondary thrombophilic complications according to the variant of myocardial infarction, in approximately 3% of cases of critical conditions associated with the systemic inflammatory reaction syndrome of various origins, including those who do not have premorbid risk factors for myocardial infarction, with a specificity level of 100%, sensitivity: with a single study of more than 50%, with daily monitoring - 100%.

For myoglobin:

1. 60-800 ng / ml - predict the development of PON, with the exception of the first 4 days after direct massive damage to muscle tissue (amputations and fractures of the extremities, myocardial infarction, etc.), with a sensitivity level of more than 50%, efficiency - more than 70% .

2. More than 800 ng / ml - more than 80% of PONs are predicted during the development of critical conditions of various origins associated with the systemic inflammatory response syndrome. Mortality at given concentrations of myoglobin is more than 50%.

Plasma concentrations of myoglobin and troponin-1 were quantified by the immunochemiluminescent method (closed automatic system "Immulite", DPC). To perform the method, 2 ml of venous blood is taken by puncture of a vein on the upper limb using a special vacuum tube with a stabilizer - 3.8% sodium citrate solution. The ratio of blood and stabilizer is 9/1. Plasma is obtained by centrifugation at a speed of 1500 rpm for 10 minutes.

Limitations of using the method:

1. The first 4 days from the onset of myocardial infarction, the indicators to a greater extent reflect the level of local, but not systemic changes; in the future, it is necessary to compare the dynamics of changes in the level of troponin-1 and myoglobin.

2. According to our data, changes in myoglobin concentrations within interval No. 2 are characteristic in the first two days after massive dissection of muscles during operations (amputation of limbs), gangrene, and when expressed purulent-inflammatory processes in skeletal muscles occur, a change in myoglobin level will reflect the dynamics not only systemic, but also local destructive processes.

Example 1. Patient T., 32 years old. Caesarean section, blood loss of more than 1 liter, shock, DIC. After 6 days - a fatal outcome. It was monitored 8 times: the level of troponin-1 at the end of the first day was 246 ng / ml, then decreased to 8.6 ng / ml on the fifth day, myoglobin level, on the contrary, increased from 682 ng / ml to> 800 ng / ml (upper boundary of reliable determination of the device), despite a shorter half-life. The development of CBP syndrome throughout the process has been confirmed hereinafter by a high level of pro-inflammatory cytokines (IL-6.8, TNFα) and C-reactive protein in the blood. The presence of large-focal myocardial infarction was confirmed by pathological and anatomical research, monitoring of “cardiac” markers revealed secondary myocardial infarction (primarily by troponin-1) and, at the same time, the increasing nature of systemic microcirculatory disorders (by myoglobin).

Example 2. Patient III, termination of pregnancy for social reasons, there are no significant premorbid changes. Amniotic fluid embolism, fulminant form of DIC, the level of cytokines increased several thousand times. Fatal outcome on the third day. After 5 hours: troponin-1 level - 0.96 ng / ml myoglobin -> 800 ng / ml, after 14 hours: troponin-1 normal (<0.2 ng / ml), the same myoglobin level (> 800 ng / ml). This example shows, firstly, that even an episodic increase in troponin-1 within the interval No. 2 is an unfavorable sign during the development of a critical process, and secondly, the expediency of using the definition of both factors that are mutually complementary.

Example. 3. Patient A. Perforated ulcer, peritonitis, after a day, the increase in the level of cytokines is moderate, there are no manifestations of coagulopathy, despite this, PON develops. At the same time, myoglobin level is 256 ng / ml, troponin-1 is normal. After 7 days, the condition improved, cytokine levels decreased, myoglobin level - 91.9 ng / ml, troponin-1 - 98 ng / ml. Diagnosed with secondary myocardial infarction. In this case, the initial high level of myoglobin, relatively high for uncomplicated sepsis, indicates the possibility of the development of secondary complications, and monitoring of the level of troponin-1 made it possible to timely diagnose the development of secondary myocardial infarction.

Example. 4. Patient 9, diagnosis: peritonitis, sepsis, the level of cytokines is high in IL-6, in the rest is moderate, markers of DIC syndrome (D-dimers, etc.) are detected; myoglobin level: on the first day - 53.4 ng / ml, on the third - 106 ng / ml, on the seventh - 419 ng / ml; corresponding troponin-1 levels: normal, normal, 1.5 ng / ml. In this case, both factors indicate the unfavorable dynamics of the development of the infectious variant of the CBP syndrome.

Example 5. Patient m73. Severe pneumonia, sepsis. At the time of hospitalization: troponin-1 - 0.36 ng / ml, myoglobin - 540 ng / ml, cytokine levels are increased hundreds of times, markers of DIC are detected. On the very first day of hospitalization, signs of PON appeared (SOFA 8 points). This example can be considered as a classic manifestation of an infectious systemic inflammation, “cardiac markers” confirm the presence of severe sepsis in the patient.

Example 6. Patient M. Severe pneumonia, sepsis, DIC, the outcome is unfavorable. On the first day of hospitalization - a relatively moderate cytokinemia (increase only several times), a more noticeable increase in C-reactive protein, the level of troponin-1 - 7.6 ng / ml, myoglobin - 280 ng / ml. In this case, the level of myoglobin, unlike cytokines, confirms the severity of the development of the process, and the level of troponin-1 indicates in favor of focal myocardial damage. Pathological and anatomical conclusion - septic endocarditis.

Example 7. Patient A. Atherosclerotic stenosis of the femoral artery, high amputation of the lower limb. Myoglobin level: 2 days after surgery - 99 ng / ml, after 4 days -> 800 ng / ml. Troponin-1 levels are normal. The severity of the cytokine profile relative to the norm on average increased from several times to several tens of times. In this case, the dynamics of changes in the level of myoglobin confirms the negative dynamics of the postoperative process as a whole and the high probability of transformation of the aseptic process into septic.

Example 8. Patient 27, Atherosclerotic stenosis of the femoral artery, high amputation of the lower limb. 2 days after surgery: the levels of pro-inflammatory cytokines are increased from several times to several tens of times (IL-8), C-reactive protein - 8 times, troponin-1 - normal, myoglobin - 308 ng / ml; after 4 days: IL-6, TNF - normal, IL-8 increased 3 times, the level of C-reactive protein increased 2.5 times, troponin-1 - normal, myoglobin level - 13 ng / ml. In this case, there is a positive dynamics in the development of SVR in the postoperative period; monitoring of the level of myoglobin allows you to further objectify this conclusion.

Thus, our proposed method allows us to timely identify the risk group for the development of these complications and solve the problem of the need for preventive pathogenetic, and in some cases etiological, therapy, for example, when choosing tactics for antibacterial therapy.

Table 1
Suggested Reference Troponin-1 Concentration Ranges (ng / ml) for Monitoring Critical Diseases Associated with Systemic Inflammatory Reactivity Syndrome No. Range Justification Value one <0.2 The absolute norm in people under 60 years of age, the probability of exceeding this threshold in patients with hr. CHD (over 75 years old); active rheumatoid arthritis, systemic lupus erythematosus, and also within 2-4 days after planned amputations of most of the lower limb (femoral artery stenosis, age 57-68 years) in all cases <1-4% (total, p-236) It can be considered as a reference value for the norm and for the majority of life-critical diseases 2 0.2-1 It precedes or accompanies the development of PON with severe trauma and sepsis> 25% (p-61), too, but with a fatal outcome> 35% (p-15) It can be considered as a marker of organ dysfunction in critical diseases of various origins. 3 1-10 The presence of focal changes in destructive changes in the myocardium is detected with sepsis and severe injuries, in about 3-4% of cases Marker of small focal myocardial destructive processes four > 10 3 cases of secondary, in relation to the development of SVR, myocardial infarction (patients: 32 and 38 years old - injuries, and 43 years old - sepsis) A known method for the diagnosis of large focal myocardial infarction, which, in critical cases of CBP syndrome, can develop as a secondary complication.

table 2
Suggested reference ranges of myoglobin concentration (ng / ml) for monitoring critical diseases associated with systemic inflammatory reactivity syndrome No. Range Justification Value one <25 The absolute norm in healthy people under 50 Reference interval for healthy people 2 25-60 It is typical in individuals older than 75 years (approximately 40%) and patients with systemic autoimmune diseases (15-20%), 4 days after the planned high amputation of the lower extremities in most cases The identification of these concentrations, in most cases, does not allow us to judge the degree of criticality of the process, but may be useful for monitoring various chronic diseases and in gerontology 3 60-800 In more than 80% of cases, it predicts or confirms PON with sepsis and trauma, taking into account the massiveness of direct damage to muscle tissue, as well as the presence of myocardial infarction It is an obvious “risk zone” of developing PON, and can also act as an additional criterion for PON in sepsis and aseptic diseases associated with SVR four > 800 Critical level: out of 7 patients with severe injuries - fatal outcome in 5 cases It is a zone of poor prognosis for the development of critical diseases, including injuries of any etiology.

Information sources

1. Medvinsky I.D., Yurchenko L.N., Cherdantseva G.A., Mazurov V.D. A method for predicting the development of PON in the III trimester of pregnancy. - RF patent No. 2189045.

2. Bebeshko S.Ya., Podzemelnikov E.V. A method for the diagnosis of unstable angina and small focal myocardial infarction. - RF patent No. 2220421.

3. Nikitin Yu.P. and others. Serum myoglobin in patients with myocardial infarction and unstable angina pectoris. Therapeutic Archive. - M .: Medicine, 1983, No. 11, p.13-17.

4. Pimenov L.T. et al. Experience of radioimmunological determination of blood myoglobin in patients with coronary heart disease. Clinical medicine. - M .: Medicine, 1982, No. 5, p. 37-42.

Claims (1)

A method for monitoring the development of critical conditions associated with a systemic inflammatory response syndrome (SVR), including a blood test, characterized in that the blood plasma of the patient determines the content of myoglobin and troponin-I and at a level of troponin I of 0.2-1 mg / ml and / or a myoglobin level of 60-800 mg / ml, with the exception of the first 4 days after direct massive damage to muscle tissue, concludes the development of multiple organ failure in septic and aseptic diseases associated with CBP, while the level of troponin I from 0.2 to 1 mg / ml indicates the development of myocardial microdamage, the level of troponin I 1-10 mg / ml indicates the presence of focal destructive changes in the myocardium, the level of troponin I above 10 mg / ml indicates the development of large focal myocardial infarction as secondary complications, an indicator of myoglobin above 800 mg / ml indicates an unfavorable prognosis of the development of septic and aseptic diseases associated with SVR.