RU2707061C1 - Method for prediction of functioning of arterial duct in premature newborns - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neonatology, and can be used for prediction of functioning of arterial duct in premature newborns with very low and extremely low body weight. That is ensured by measuring the gestational age, measuring weight and height at birth, determining blood serum concentration in umbilical blood and calculating the prognostic index D by the original calculation formula. If D is more than 0, the presence of arterial duct functioning is predicted for the second-third days of life in premature children. If D is less than 0, the absence of functioning of the arterial duct is predicted.

EFFECT: method enables predicting functioning of arterial duct in premature newborns with high accuracy by determining concentration of hydrogen sulphide in umbilical blood, which enables to determine well-timed therapeutic approach.

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Description

The invention relates to medicine, namely to neonatology and can be used to predict the functioning of the arterial duct by the second or third days of life in deeply premature newborns born with a body weight of less than 1500 g.

Relevance. In connection with the transition to the new criteria for live births recommended by the World Health Organization, the problem of prematurity is central to neonatology and pediatrics (On medical birth criteria, the form of a birth certificate and the procedure for its issuance: Order of the Ministry of Health and Social Development of the Russian Federation of December 27, 2011 No. 1687n, Moscow). The pathology that aggravates the prognosis of life and health of a premature newborn includes the functioning of the ductus arteriosus (Modern views on the open ductus arteriosus in newborns / D.S. Kryuchko, A.G. Antonov, A.A. Lenyushkina, etc. // Pediatrics. - 2011.- T. 90, No. 1. - S. 130-136). The frequency of occurrence of a hemodynamically significant functioning ductus arteriosus (GFAP) is inversely related to gestational age. In children born before 28 weeks, this pathology is observed in 25-70% (open arterial duct in premature babies / Burov A.A., Degtyarev D.N., Ionov O.V. et al. // Neonatology: news, opinions, training. - 2016. - No. 4 (14). - S. 120-128). Clinical manifestations of the functioning of the ductus arteriosus have two main directions: a decrease in systemic blood flow due to "robbing" a large circle of blood circulation and an increase in blood supply to the circulatory system, which subsequently leads to aggravation of the severity of respiratory distress syndrome, metabolic and mixed acidosis, poor absorption of enteral nutrition, and development pulmonary hemorrhage in the first two days after birth, decreased urine output, the risk of developing early intraventricular rovoizliyany. In premature infants, a functioning ductus arteriosus can be associated with a critical clinical condition leading to serious complications, the most common of which are intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy, which requires special conditions for nursing functional children (Modern view arterial duct in premature infants / J.A. Zvyagina, E.G. Tsoi, L.N. Igisheva, D.A. Tronina // Mother and child in Kuzba ce -. 2018. - №4 (75) - pp. 4-12).

The relevance of the claimed method is caused by the need to search for additional early criteria for predicting the functioning of the ductus arteriosus in very premature newborns to develop adequate tactics for their management.

A known method for predicting the state of the cardiovascular system of the newborn. For this, the total peripheral vascular resistance, shock and minute indices are determined in pregnant women, and with their values 1376-1430 dyn.cm ^-5 , 41-48 ml / m ² , 3.35-4.0 l / min / m ^2, respectively, the labile type is diagnosed hemodynamics of the newborn with the closure of fetal communications within 12-24 hours, blood pressure lability and tachycardia; with their values of 1431-1695 dyn.cm ^-5 , 31-40 ml / m ² , 2.4-3.34 l / min / m ^{2, a} persistent hyperkinetic type is diagnosed with the closure of fetal communications on the 4-5th day of life arterial hypertension and a tendency to bradycardia; at values of 2770-1696 dyn.cm ^-5 , 24-30 ml / m ² , 2.04-2.39 l / min / m ^{2, a} persistent hypokinetic type of hemodynamics is diagnosed with the closure of fetal communications on the 5-6th day of life, arterial hypotension and a tendency to tachycardia. (Copyright certificate for the invention No. 1699425 of the USSR. A method for predicting the state of the cardiovascular system of a newborn / L. Titchenko, M. V. Salyaeva, E. Kotikova // Discovery. Inventions. - 1991. - No. 47. - C . 12-13). This method has several disadvantages: only gross hemodynamic deviations are predicted and only in full-term newborns; this method does not allow to predict the closure of a functioning arterial duct; the method is indirect, since blood flow indicators in a pregnant woman are used to predict; it is impossible to predict the state of the cardiovascular system of the newborn in complicated births.

Also known is a method of biochemical assessment of adaptation of cardiac activity in newborns. For this, serum of venous blood is examined, determining the activity of the myocardial isoform of creatine phosphokinase (MV-CPK), the level of triglycerides (TG), low density lipoproteins (LDL) on 3-4 days of life. With an increase in MV-KFK activity from 9.9 to 13.7 U / L, TG from 2.8 to 4.8 mmol / L, LDL from 8.6 to 12.8 g / L, pronounced cardiac adaptation dysfunctions are diagnosed. With values of MV-KFK from 6.5 to 8.1 U / L, TG from 0.8 to 1.6 mmol / L, LDL from 3.9 to 4.7 g / L, a favorable course of the period of adaptation of cardiac activity is diagnosed in newborn babies. (Patent No. 2274867 Russian Federation. Method for biochemical assessment of adaptation of cardiac activity in newborns / Cherkasov NS, Cheremina NI // Inventions. Utility models. - 2006. - No. 11). This method has several disadvantages: the method allows to predict the state of the cardiovascular system only for full-term newborns; it does not accurately predict the closure of a functioning ductus arteriosus; venous blood sampling is required in the newborn.

To calculate the likelihood of closing GZFAP against the background of drug therapy, a mathematical calculation model was built (Savchenko O.A., Krivtsova L.A. Evaluation of the closure factors of the hemodynamically significant functioning arterial duct in newborns with very low and extremely low body weight against the background of drug treatment with peddea / / Siberian Medical Journal. - 2013. - V. 28, No. 4. - S. 59-63). In the course of the analysis, it was found that predictors of closure of GFAP are body weight at birth, systolic and diastolic blood pressure on the 2nd day of life. Get the standard regression equation (Y), which characterizes the mathematical model:

Y ≠ 18.321-9.7732 * C1-0.0288 * C2-0.3571 * C3, where

C1 - body weight at birth, kg;

C2 - systolic blood pressure, mm. Hg. st .;

C3 - diastolic blood pressure, mm. Hg. st .;

To calculate the probability of duct non-closure, an equation was obtained that describes this model: P ≠ [1 / (1 + е- ^у )] * 100,

P is the risk of duct failure,%;

e is the base of the natural logarithm (e = 2.71);

Y is the standard regression equation.

However, this method allows predicting the closure of GZFAP only against the background of drug therapy, a complex mathematical calculation is necessary.

There is a method of calculating the probability of closure of GZFAP on the background of drug therapy with non-steroidal anti-inflammatory drugs using nomograms (Savchenko O.A., Krivtsova L.A., Pavlinova E.B. Functioning ductus arteriosus in premature infants: hemodynamic predictors of success of drug closure // Children's diseases heart and blood vessels. - 2016. - T. 13, No. 3. - S. 133-139). The standard regression equation is obtained: Y = 2.9879 + 1.7815 * C1-0.8095 * C2 + 1.0019 * C3, where Y is a free member of the regression equation; C1 - the normalized value of diastolic blood pressure on the 2nd day (mm. Hg. Art.); C2 is the normalized value of the ratio of the sizes of the left atrium and the aortic root (unit); C3 - normalized value of the speed of blood flow in the open arterial duct (m / s). Based on the data obtained, nomograms have been developed to assess the likelihood of drug closure of GZFAP. On the nomogram mark the point that corresponds to the measured values of diastolic blood pressure and the speed of blood flow in the duct. Based on the ratio of the sizes of the left atrium and the aortic root, a straight line is selected from the nomogram. If the set point is below this line, then the expected probability of closing is less than 50%, if higher, then the probability of closing is more than 50%. The disadvantages of this method is the prediction of the closure of GZFAP only on the background of drug therapy; requires expensive equipment and highly qualified personnel to perform echocardiography.

A known method for postnatal prediction of the persistence of hemodynamically significant open ductus arteriosus in premature infants by assessing gestational age, Apgar score, reflexes of the newborn, the state of the muscular system, skin, swelling, moist rales, pulmonary pattern enhancement on the radiograph, and echocardiographic parameters of the final diastolic size, left atrium and right ventricle per kilogram of the weight of the newborn and calculated prognostically th coefficient by the mathematical formula. With a prognostic coefficient of 10 points or more, a high risk of prolonged persistence of a hemodynamically significant variant of the open arterial duct in premature infants is predicted, and with a prognostic coefficient of 0 to 9 points, a low risk of prolonged persistence of a hemodynamically significant variant of the open arterial duct. (Patent No. 2556793 Russian Federation. Method for postnatal prediction of persistent hemodynamically significant open ductus arteriosus in premature infants / Klimacheva OV, Klimachev A.M., Spivak EM // Inventions. Utility models. - 2015. - No. 20).

However, to perform this method requires expensive equipment and highly qualified personnel to perform echocardiography; this test allows predicting GFAP by 3 days of life; the method requires the evaluation of a large number of parameters.

The technical result of the proposed method is to simplify the method and increase the accuracy of the study when predicting the risk of the functioning of the ductus arteriosus by the second or third days of life in a deeply premature newborn, since when there is a hemodynamically significant ductus arteriosus, it is at the early start of drug therapy that its effectiveness increases.

The technical result is achieved by determining gestational age at birth, measuring weight and height at birth, determining the concentration of hydrogen sulfide in cord blood. Next, calculate the prognostic index D according to our formula. With a value of D less than 0, the absence of a functioning ductus arteriosus is predicted, and with a value of D more than 0, the presence of a functioning ductus arteriosus is predicted by the second or third day of life in deeply born babies born with a body weight of less than 1500 g with an accuracy of 90.4%.

Distinctive features are the measurement of weight and height at birth, the determination of the concentration of hydrogen sulfide in cord blood and the calculation of the prognostic index D by the formula:

D = 12.77705-A1 × 0.099375-A2 × 0.40046-A3 × 0.00012 + A4 × 0.03885, where

12.77705 - CONSTANT;

A1 is the concentration of hydrogen sulfide, µmol / l;

A2 - gestational age in obstetric weeks;

A3 - weight of the newborn, g;

A4 - the growth of the newborn, cm;

And with a value of D greater than 0, the presence of functioning of the arterial duct is predicted by the second or third days of life in deeply premature infants, and with a value of D less than 0, the absence of functioning of the arterial duct is predicted.

The method is as follows. At birth, 1 ml of blood is drawn from the cord vein and the concentration of hydrogen sulfide is determined by the method of QuK., Chen CPLH, Halliwell B. etal. (Hydrogen sulfide is a mediator of cerebral ischemic damage / K. Qu, CPLH Chen, B. Halliwell et al. // Stroke. - 2006. - Vol. 37, No. 3. - P. 889-893). 1 ml of umbilical cord blood was placed in a test tube, 0.25 ml of 1% zinc acetate and 0.45 ml of distilled water were added, shaken and incubated for 10 minutes at room temperature. Then 0.25 ml of a 10% trichloroacetic acid solution is added, centrifuged for 10 minutes at 3000 rpm. The supernatant is completely poured into a clean tube and 0.133 ml of a 20 mmol / L solution of N, N-dimethyl-p-phenyldiamine sulfate prepared in 7.2 mol / L HCl and 0.133 ml of a 30 mmol / L solution of iron chloride III (FeCl ₃ ) are added. prepared in 1.2 mol / L HCl. Then incubated for 20 min at room temperature. After 20 minutes, the extinction is removed on a spectrophotometer at a wavelength of 670 nm against water. The concentration of hydrogen sulfide in the blood serum is calculated according to the calibration graph. To do this, use a solution of sodium hydrosulfide (NaHS) in concentrations of 320, 160, 80 and 40 μmol / l instead of the sample. The selected concentrations of sodium hydrosulfide correspond to 30% of the hydrogen sulfide produced in the body, respectively 96, 48, 24, 12 μmol / L, which are deposited along the ordinate, the resulting extinction along the abscissa. Next, build a linear curve at the points of intersection of values. Also, after birth, the baby’s weight is measured in grams and body length in centimeters. Then, after statistical processing by discriminant analysis, the formula for calculating the prognostic index D is revealed:

D = 12.77705-A1 × 0.099375-A2 × 0.40046-A3 × 0.00012 + A4 × 0.03885, where

12.77705-CONSTANT;

A1 is the concentration of hydrogen sulfide, µmol / l;

A2 - gestational age in obstetric weeks;

A3 - weight of the newborn, g;

A4 - the growth of the newborn, see

If D is less than 0, the absence of a functioning ductus arteriosus is predicted, and if D is greater than 0, the presence of a functioning ductus arteriosus is predicted by the second or third day of life in deeply born babies born with a body weight of less than 1500 g.

The novelty of the proposed method lies in the fact that for the first time the relationship between the risk of the functioning of the ductus arteriosus and the concentration of hydrogen sulfide in cord blood, gestational age, weight and height at birth is traced.

Hydrogen sulfide (H2S) is well known as a toxic gas that blocks the respiratory function of mitochondria in high concentrations. Hydrogen sulfide is involved in the regulation of many physiological processes, both in the transmission of data in the central and peripheral nervous system, and in the regulation of homeostasis, immunity. An important role is played by hydrogen sulfide in the regulation of the cardiovascular system. Intracellular synthesis of hydrogen sulfide is carried out in various cells of the body. Currently, three enzymes for the synthesis of hydrogen sulfide are known: cystotionin-β-synthase (CBS), cystotionin-γ-lyase (CSE) and 3-mercaptopropyrvate sulfur-transferase (3-MST). In smooth muscle cells of blood vessels, the reduction and relaxation of which provides changes in their tone, the synthesis of hydrogen sulfide is carried out by the CSE enzyme. Hydrogen sulfide easily penetrates through the membranes of any cells, interacting directly with intracellular proteins. As a result of numerous experimental studies, it was proved that H ₂ S plays an important role in the regulation of the cardiovascular system, in particular, blood vessels. According to Mathaia et al. hydrogen sulfide is a vasodilator gas (No facilitator required formembrane transport of hydrogen sulfide / JC Mathaia, A. Missnerb, P. Ku et al. // Proc. Natl. Acad. Sci. USA - 2009).

In experiments, it was proved that a hydrogen sulfide donor, sodium hydrosulfide (NaHS), causes relaxation of various departments of the arterial and venous channels. Despite the role of the endothelium in the regulation of vascular tone, its removal did not affect the action of hydrogen sulfide in smooth muscle cells. This allows us to draw conclusions about the direct effect of hydrogen sulfide on smooth muscle cells through special structures in the membrane - potassium channels. Hydrogen sulfide binds to specific proteins, changes their spatial configuration and leads to the opening of the channel. The opening of potassium channels leads to an increase in the output of potassium ions from the cell into the intercellular medium; membrane hyperpolarization and inactivation of calcium channels occur. The cessation of calcium intake into the cell leads to a relaxation of the smooth muscle cell, to a decrease in the tone of blood vessels and blood pressure.

However, the determination of this gas in umbilical cord blood in deeply premature infants during the functioning of the ductus arteriosus was not carried out. The use of gestational age, weight and height at birth increases the reliability of the method.

The proposed method is confirmed by the following examples.

Example 1. Baby M. was born from 1 pregnancy 1 preterm birth in 32 weeks. Pregnancy proceeded against the background of severe preeclampsia, placental insufficiency, chronic fetal hypoxia, fetal growth retardation syndrome, ureaplasmosis (treated). Childbirth is performed by cesarean section. Birth weight 985 g, height 38 cm. Apgar score 5/6. At birth, blood was taken from a cord vein, the concentration of hydrogen sulfide was 10 μmol / L. The predictive index D is calculated by the formula: D = 12.77705-10 × 0.099375-32 × 0.40046-985 × 0.00012 + 38 × 0.03885 = 0.38. The prognostic index predicts the functioning of the ductus arteriosus on the second or third day of life. The condition from birth is regarded as serious. On day 2, ECHO-KG was performed, a functioning arterial duct (FAP) of 2 mm was diagnosed, hemodynamically significant. The drug was closed with the drug ibuprofen for intravenous administration. By the 6th day of life, the FAP closed. By the month of the FAP is not visualized.

Example 2

Baby B. was born from 3 pregnancies of 2 preterm births at 31 weeks 2 days. Pregnancy proceeded against the background of severe preeclampsia, anemia, placental insufficiency, chronic fetal hypoxia of the fetus, placentitis, polyhydramnios. Childbirth is performed by cesarean section. Birth weight 1430 g, height 40 cm. Apgar score 4/6 points. At birth, blood was drawn from the umbilical cord vein, the concentration of hydrogen sulfide was 5 μmol / L. The predictive index D is calculated by the formula: D = 12.77705-5 × 0.099375-31 × 0.40046-1430 × 0.00012 + 40 × 0.03885 = 1.27. The prognostic index predicts the functioning of the ductus arteriosus on the second or third day of life. The condition from birth is regarded as serious. On the 3rd day, ECHO-KG was performed, 1.5 mm phase imaging was diagnosed. No drug closure was performed, as there were contraindications.

By the month of the FAP is not visualized.

Example 3

Baby T. was born from 2 pregnancies of 2 preterm births at 28 weeks. Pregnancy proceeded against the background of complicated obstetric and gynecological history, anemia, colpitis. Prenatal outflow of amniotic fluid, prolonged anhydrous period, premature detachment of a normally located placenta. Birth weight 900 g, height 37 cm. Apgar score 4/5 points. The condition from birth is regarded as serious. At birth, blood was taken from the umbilical cord vein, the concentration of hydrogen sulfide was 74 μmol / L. The predictive index D is calculated by the formula: D = 12.77705-74 × 0.099375-28 × 0.40046-900 × 0.00012 + 37 × 0.03885 = - 4.0. D less than 0 - predict the lack of functioning of the arterial duct. On day 2, ECHO-KG was performed: FAP is not visualized. By 1 month of life, according to ECHO-KG, there is no FAP.

In this way, 83 deep preterm infants with a body weight of less than 1,500 g at birth were examined. The results of the study are shown in the table.

The advantages of the method.

1. To perform the method requires a small number of indicators, data on gestational age, parameters of physical development, concentration of hydrogen sulfide.

2. Small time and financial costs for determining the concentration of hydrogen sulfide.

3. Non-invasiveness for the child.

4. The proposed method has high accuracy, sensitivity, specificity.

5. Prediction of the functioning of the arterial duct on the second or third day of life allows you to timely determine the tactics of the newborn, reduce the implementation of complications by the end of the neonatal period.

Claims (9)

A method for predicting the functioning of the ductus arteriosus in deeply premature infants born with a body weight of less than 1500 g by determining gestational age, characterized in that they measure weight and height at birth, determine the concentration of hydrogen sulfide in cord blood and calculate the prognostic index D by the formula: D = 12.77705-A1 × 0.099375-A2 × 0.40046-A3 × 0.00012 + A4 × 0.03885, Where 12.77705 - CONSTANT; A1 is the concentration of hydrogen sulfide, µmol / l; A2 - gestational age in obstetric weeks; A3 - weight of the newborn, g; A4 - the growth of the newborn, cm; and if the value of D is greater than 0, the presence of the functioning of the ductus arteriosus is predicted by the second or third days of life in deeply premature infants, and when the value of D is less than 0, the absence of functioning of the arterial duct is predicted.