Kyiv City Clinical Hospital of Emergency Medical Care, Department of Intensive Care and Extracorporeal Detoxification, Kyiv, Ukraine
ABSTRACT. In recent years cases of combined poisoning with methadone hydrochloride and ethanol complicated by the development of acute renal failure became more common, and this induced the search for new and more efficient methods of diagnostics and treatment in this category of patients.
Objective: to investigate peculiarities of clinical, biochemical parameters and haematological toxicity indices in patients with combined severe poisoning with methadone hydrochloride and assess their predictive value in formation of complications (acute renal failure). Materials and methods. Complex clinical, biochemical and toxicological study of 77 patients with acute poisoning with methadone hydrochloride, who underwent treatment in 2016–2018 in Kyiv Toxicological Centre, was performed. Haematological toxicity indices (nuclear, haematological, leukocytic, systemic response reactivity, sensitization) were studied 24, 48 and 72 hours following admission. Assessment of the confidence of parameters in the study groups was performed by Student's t-test with the significance level of p<0.05; determination factor R2 was used to verify the degree of influence of toxicity parameters on the treatment duration.
Results. The patient population consisted of 72 (93.51 %) males and 5 (6.4 %) females aged 20 to 42 years. Patients were divided into 3 groups. The first group included 31 patients with methadone hydrochloride mono-poisoning; the second group included 25 patients with combined poisoning with methadone hydrochloride and ethanol; and group 3 included 21 patients with combined poisoning with methadone hydrochloride and ethanol at the background of acute renal failure. It has been established that unlike biochemical and clinical parameters, haematological intoxication indices have a high degree of correlation with the duration of treatment. Within the first 24 hours, high level of haematological toxicity parameters suggested high potential threat of dangerous complications (acute renal failure, sepsis, etc.) that was confirmed by the high level of determination factor (R2 >0.5) between parameters and treatment duration. The level of correlation between treatment duration and parameters of central haemodynamics and biochemical parameters was low (R2<0.5) that did not allow to use them as the predictive ones.
Conclusion. It has been established that estimated haematological toxicity indices are the sensitive markers of the toxic process in combined poisoning with methadone hydrochloride that may form the basis for prediction of early development of acute renal failure and making a decision on early haemodialysis.
Key Words: acute poisoning, haematological toxicity indices, methadone hydrochloride.
Introduction. Previous studies have established that constant increase in the incidence of acute poisoning with methadone hydrochloride (hereinafter — MH) among young people in Kyiv and other cities of the central regions of Ukraine and fatal consequences of such poisonings is the relevant medical and social problem [10-12]. For example, according to the data of Kyiv City Toxicological Centre over the period from 2011 to 2018, the number of MH poisoning increased 150 times, and during the last 5 years — 2.5 times that is a breakthrough event among poisoning of chemical origin.
The peculiarity of the last years is a combined poisoning with MH, in particular in combination with ethyl alcohol [1, 3, 8]. At the background of combined poisoning, life-threatening complications (crush syndrome of soft tissues, acute renal failure, pneumonia, sepsis) that require continuous and expensive treatment [2, 4-7, 18, 19, 21, 22]. In such cases, current methods of evaluation of the toxic process additionally to the standard clinical and laboratory studies may be used via predicted haematological toxicity indices [9, 13-17].
This scientific study was performed in 2018 within the task of the scientific and research work “Scientific justification of safety of pesticides and agrochemicals, novel technologies, substances, materials, devices, environmental objects, food products and food stock for human health; development of the appropriate medical criteria and parameters (sanitary and epidemiological); sanitary and chemical, toxicological and hygienic evaluation, regulation, rationing” (state registration No. 0112U001133). According to the scientific methods, this study is an extension of systemic studies of the toxic process that were performed at the State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety of the Ministry of Health of Ukraine” during 2013–2017, headed by B. S. Sheiman, Doctor of Medical Sciences, Professor. Study results provided the following scientific confirmation: complex evaluation of the mechanism of toxin production, degree of severity of laboratory manifestations of toxaemia, reactions of antitoxic adaptation system in blood plasma, condition of physiological systems of the elimination of toxins and acuity of physiological disorders, allows justifying indications for the selection of methods of efferent therapy (haemodialysis, hemodiafiltration, plasmapheresis, etc.) for replacement of lost detoxification functions of human organs and systems [13-17].
Objective: determine markers of the toxic process (biochemical parameters and haematological toxicity indices) in patients with combined severe MH poisoning and their predictive value.
Materials and methods. For the purpose of study, analysis of annual reports of the Toxicological Department, Toxicological Laboratory, Department of Intensive Care and Extracorporal Detoxification of the Kyiv City Clinical Emergency Care Hospital for the period from 2005 to 2018 was performed. Retrospective evaluation of the total array of observations has established 1,367 cases of acute poisoning with MH (mono and combined poisoning). Detailed analysis of the sample data — 77 patients who underwent treatment during 2016–2018 was performed. Epidemiological, clinical, functional, laboratory and toxicological methods of study were used.
For collection and further processing of the study results, the database was created in Microsoft Excel 2007. Assessment of the confidence of parameter values in the study groups was performed by Student’s t-test with the significance level of p < 0.05; determination factor R2 was used to verify the degree of influence of toxicity parameters on the treatment duration.
The study was divided into 3 stages. During the first stage, retrospective data on the number of MH poisoning, changes over time, age and gender composition of patients, treatment results, reasons of hospital mortality during 2005–2018 was studied and systematised. All patients were diagnosed with severe acute MH poisoning at the time of hospitalization based on present medical history and clinical examination. In all patients, qualitative methods were used for diagnostics of MH in blood and administered a dose of MH was evaluated based on present medical history. Blood concentration of ethanol was measured by quantitative methods (gas chromatography, Chrom-5). Exposure terms of administered substance (time from administration to hospitalization and start of medical care), presence and nature of concomitant diseases were systematised and analysed.
At the second stage of the study, we performed an evaluation of the severity of the condition of victims according to the appropriate international scale (Poisoning Severity Score, hereinafter — PSS) or Persson scale (Persson H.E., 1998), recommended by the European Association of Poisons Centres and Clinical Toxicologists, EAPCCT. International rating scale PSS provides for the evaluation of functions of many organs and systems based on syndrome approach with simultaneous consideration of quantitative (laboratory) and qualitative (clinical) parameters [20]. For example, evaluation of the following organs and systems was performed by PSS: gastrointestinal tract (GIT), nervous system (NS), respiratory system (RS), cardiovascular system (CVS), metabolic parameters (acid-base balance and electrolyte balance, glucose level), liver (AST, ALT), kidneys (proteinuria, urea, creatinine, diuresis), blood (haemolysis, methemoglobinaemia), muscles (blood CPK), skin (irritation, burn, compression), eyes (irritation of mucous membranes, destruction), presence of local lesions (pain, irritation, swelling, necrosis).
During hospitalization and treatment, clinical and laboratory parameters were determined in patients with severe acute poisoning according to the standard procedures approved by Orders of the MoH of Ukraine and unified clinical protocols [9, 17]. Blood sampling for laboratory tests was performed during admission of the patient to the Department of Intensive Care and overtime of treatment in 24, 48 and 72 hours. Abdominal ultrasound, computed tomography of the head and chest X-ray in frontal view was performed once in all patients during the first 6 hours of hospitalization.
During the third stage of the study, haematological parameters were evaluated to assess the nature and degree of severity of the toxic process. Parameters of toxicosis, type of reactogenicity of systemic response and sensitization in patients with acute MH poisoning were studied upon admission to the department and during treatment (in 24, 48, and 72 hours).
Tests were performed using estimated indices (nuclear, haematological and leukocytic intoxication index, index of reactivity of the systemic response and sensitization) and direct methods for determination of toxic substance in biological liquid media of victims.
Leukocytic intoxication index proposed by Ya. Kalf — Kalif was calculated by the formula:
LII (4М+3I+2St+Sg) x (P+1): (L+Мо) x (Е+1),
where M is myelocytes; I is immature; St is stabs; P is plasmocytes; Sg is segmented white blood cells; L is lymphocytes; Mo is monocytes; E is eosinophils.
Haematological intoxication index was calculated by the formula:
HII = LІІ x КESR x КWBC,
where LII — leukocytic intoxication index by Ya. Kalf — Kalif; KESR — correction factor measured by ESR from the table; K WBC — correction factor measured by the number of white blood cells per 1 µL of the blood from the table.
Nuclear intoxication index was calculated by the formula:
NII = (Мо + I + St) : S,
where Mo is monocytes; I is immature; St is stabs; S is segmented white blood cells.
The obtained examination results using calculation methods were further interpreted as follows:
Leukocytic intoxication index (LII) in a healthy human is 1.5 U. Increase over 1.5 specifies toxaemia (of bacterial origin in the majority of cases).
Nuclear intoxication index (NII) in a healthy human is less than 0.1 U. Increase over 0.1 U specifies toxaemia (its severe course with rough damage of cellular structures in the majority of cases).
Haematological intoxication index (HII) in a healthy human is 0.8 U. Increase over 0.8 U specifies toxaemia.
Reactivity index (RI) of systemic response within 13 to 23 U specifies the normal type of response; less than 13 U – hyperergic; over 23 U – delayed.
Sensitization index (SI) less than 2 U specifies the absence of body sensitization; over 2 U — its presence.
The general set was 1,368 cases (N = 1,368), and via a simple random selection, a sample was formed — 77 patients (n = 77), males 72 (93.51 %), females — 5 (6.49 %) aged 20 to 42 years of age that is representative.
In accordance with the obtained results of toxicological examinations for the presence of MH and ethanol in the blood, all patients were distributed into 3 groups — first, second, and third.
The first group included 31 patients with MH mono-poisoning, aged 20 to 40 years of age, out of them, 28 are males (90.32 %) and 3 — females (9.68 %).
The second group included 25 patients with MH and ethanol combined poisoning, aged 24 to 39 years of age, out of them, 23 are males (92.00 %) and 2 — females (8.00 %).
The third group included 21 patients with combined NH poisoning in combination with acute renal failure (ARF), aged 24 to 42 years of age, out of them, 21 are males (29.8 %). Patients of the third group, additionally to the conventional therapy, received additional detoxification measures (haemodialysis) and pharmaceutical correction that were individualised by the results of clinical and laboratory, toxicological and functional studies.
Results. At the first stage of studies, clinical and laboratory parameters of the patients from the first, second and third group were studied. Comparative characteristics of the clinical parameters and results of rationing of the severity of MH poisoning in the study groups upon treatment initiation is provided in Table 1.
Upon analysis of the age of the patient in the groups, it was established that there were no significant differences, and they aged 30.32 to 33.37 years. Also, there was no significant difference in the parameters of a dose of toxic substance — MH that was within 178.75 to 190.51 mg. Blood concentration of ethanol in the patients of the second and third group ranged from 1.31 to 1.51 per mill.
There was no significant difference in the parameters of haemodynamics and respiration in the first, second, and third group. Laboratory examination of the patients’ blood upon admission did not give the significant difference between parameters of white blood cells and biochemical parameters, however, the second group had the highest values of haematocrit and signs of dehydration.
Table 1
Comparative characteristics of the clinical parameters and results of rationing of the severity of MH poisoning in the study groups upon treatment initiation.
Note: 1 — the difference between parameters of the first and second groups is significant (р < 0.05); 2 — the difference between parameters of the second and third groups is significant (р < 0.05).
Scoring of the severity of poisoning by Persson scale was performed at the second stage. It should be noted that there was a significant difference between scores of the severity of poisoning by Persson scale between the first, second and third groups р < 0.05). These parameters were the highest in the third group of patients with severe poisoning complicated by crush syndrome of soft tissues. Also, the above group had the longest treatment duration — over 10 days. The parameter that exceeds 20 points by this scale suggests extremely severe patient’s condition accompanied by many abnormal syndromes. Comparative characteristics of scoring of the patients by PSS is also provided in Table 1.
At the third stage, blood analysis was performed over time, 24, 48 and 72 hours after admission to the Department of Intensive Care and Extracorporal Detoxification. During this stage, estimated haematological parameters were evaluated to assess the nature and degree of severity of the toxic process. Parameters of toxicosis, type of reactogenicity of systemic response and presence of sensitization in patients with severe MH poisoning were studied in the patients of each group. Examination results of the estimated intoxication indices are provided in Table 2.
Table 2
Change in the levels of haematological toxicity indices overtime at the treatment stages in patients with acute MH poisoning (М = 77).
Note: 1 — the difference in the groups in terms of the normal range is significant р < 0.05); LІ — leukocytic index; NІ — nuclear index; HІ — haematological index; RI — reactivity index of the systemic response; SІ — sensitization index.
Condition of the patients in the first group upon admission to the in-patient department was accompanied by the insignificant increase in the parameters of general toxicity (LII, HII, NII levels), moderate hyperergic type of reactivity of the systemic response to the action of aetiological factor and absence of the signs of sensitization. No significant changes in the parameters were observed during treatment. However, signs of body sensitization developed throughout the treatment period.
Condition of the patients in the second group upon admission to the in-patient department was accompanied by the significant increase in the parameters of general toxicity (LII, HII, NII levels), pronounced hyperergic type of reactivity of the systemic response and signs of sensitization. Positive changes occurred during treatment: significant changes over time to the normalization of LII levels were reported in 24 and 48 hours compared to the baseline. However, NII and HII parameters were virtually unchanged during 48 hours; tendency to the normalization of HII, NII, RI levels occurred in 72 hours upon the stable parameter of the sensitization level — SI.
Condition of the patients in the third group upon admission to the in-patient department was accompanied by the critical increase in the parameters of general toxicity (LII, HII, NII levels), hyperergic type of reactivity of the systemic response to the action of aetiological factor and pronounced signs of sensitization. During treatment, positive changes in the studied parameters have occurred: in 48 and 72 hours — insignificant changes in the level of LII and NII over time compared with baseline, in 72 hours — changes to the normalization of HII levels.
Upon investigation of changes in reactivity index (RI) of the systemic response over time, it has been established that the following changes have occurred during treatment: hypoergic type of systemic response to the action of aetiological factor was predominantly reported upon admission to the in-patient department; in 48 and 72 hours from treatment initiation, IR levels gradually normalized.
At the next stage of the study, the special influence of the model factors (estimated intoxication indices) on the variation was a resultant parameter — treatment duration in patients of the third group (combined poisoning with MH + ethanol + ARF) was studied. Fig. 1-7 shows the results of the assessment of determination factor R2 between toxicity indices and treatment duration in patients with MH poisoning complicated with crush syndrome (n = 21). It has been established that values of determination factor between treatment duration and leukocytic intoxication index (LI) (Fig. 1) are R2 = 0.2634 suggesting a low link between parameters. Degree of the relationship between treatment duration and haematological intoxication index (HI) is R2 = 0.5662 suggesting high determination level or close link between parameters (Fig. 2). Degree of the relationship between treatment duration and nuclear intoxication index (NI) is R2 = 0.5267 that also suggests a high determination level or close link between parameters (Fig. 3). Degree of the relationship between treatment duration and sensitization index (SI) is R2 = 0.5459 that also suggests a high determination level or close link between parameters (Fig. 4). Degree of the relationship between treatment duration and reactogenicity index (RI) is R2 = 0.0647 suggests low determination level or a lock of the general link (influence) between parameters (Fig. 5).
Therefore, results of the assessment of the toxicity indices have established that high level of determination between treatment duration and estimated haematological toxicity indices was among the following indices: HІ — R2 = 0.566 (haematological), NІ — R2 = 0.526 (nuclear), and SІ — R2 = 0.545 (sensitization).
Excess of R2 ≥ 0.5 suggests a high level of the possibility of the case, in other words: high values of the above estimated haematological indices predict long-term hospitalization in patients with severe MH poisoning. Alternatively, R2 ≤ 0.5 suggests the lack of the link between parameters (blood pressure, daily diuresis, biochemical parameters), as well as the lack of their predictive value in terms of assessment of anuria and ARF, sepsis and other life-threatening complications.
Figure 1. Degree of relationship (determination factor — R2) between treatment duration and leukocytic intoxication index (LI).
Figure 2. Degree of relationship (determination factor — R2) between treatment duration and haematological intoxication index (HI).
Figure 3. Degree of relationship (determination factor — R2) between treatment duration and nuclear intoxication index (NI).
Figure 4. Degree of relationship (determination factor — R2) between treatment duration and sensitization index (SI).
Figure 5. Degree of relationship (determination factor — R2) between treatment duration and reactogenicity index (RI).
Predictive value of intoxication indices allows forming individualised treatment approach that provides for early initiation of artificial detoxification methods (haemodialysis, haemodiafiltration) and inclines physician for a long-term treatment and rehabilitation even, when at Day 1 of admission to the Intensive Care Department, patient has no obvious clinical signs of acute renal failure and sepsis yet.
Conclusion. It has been established that sensitive markers of the toxic process upon combined poisoning with methadone hydrochloride and ethanol complicated with the development of acute renal failure are estimated haematological intoxication indices (nuclear, haematological, and leukocytic; reactivity index of systemic response and sensitization index) that may form the basis in prediction of the source of somatogenic phase of poisoning and making a decision in terms of early initiation of artificial detoxification methods.
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Надійшла до редакції 20.05.2019 р.