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Neutrophil-Lymphocyte Ratio in Patients with Pesticide Poisoning
The Journal of Emergency Medicine, Vol. 47, No. 3, pp. 286–293, 2014 Copyright Ó 2014 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2014.01.034
Selected Topics: Toxicology
NEUTROPHIL-LYMPHOCYTE RATIO IN PATIENTS WITH PESTICIDE POISONING Zerrin Defne Dundar, MD,* Mehmet Ergin, MD,* Ramazan Koylu, MD,† Rasit Ozer, MD,* Basar Cander, MD,* and Yahya Kemal Gunaydin, MD† *Emergency Medicine Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey and †Emergency Medicine Clinic, Konya Training and Research Hospital, Konya, Turkey Reprint Address: Zerrin Defne Dundar, MD, Emergency Medicine Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
, Abstract—Background: Pesticides are highly toxic to human beings, and pesticide poisoning is associated with high morbidity and mortality. The identification of powerful prognostic markers is important for the management of patients with pesticide poisoning in emergency settings. Objective: To investigate the prognostic value of the neutrophil-lymphocyte ratio and hematological parameters measured in patients with pesticide poisoning within the first 24 h after admission to the emergency department (ED). Methods: All patients ($15 years old) admitted to the ED from July 2008 through February 2013 due to pesticide poisoning were enrolled in the study. The written and electronic medical charts of patients were reviewed. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were calculated for each patient using absolute neutrophil, lymphocyte, and platelet counts. Mechanical ventilation requirement and mortality were used as the primary endpoints. Results: A total of 189 patients were included in the study. The mechanically ventilated patients had significantly higher leukocyte and neutrophil counts, and neutrophil-lymphocyte and platelet-lymphocyte ratios (p < 0.001, p < 0.001, p < 0.001, p = 0.003, respectively), whereas they had significantly lower lymphocyte counts compared to nonventilated patients (p = 0.011). Survivors had significantly higher leukocyte and neutrophil counts, and neutrophil-lymphocyte ratios (p < 0.001, p < 0.001, p = 0.002, respectively), whereas there was no significant difference between groups in terms of lymphocyte counts (p = 0.463), compared to nonsurvivors. Conclusion: Leukocyte counts, neutrophil counts, and neutrophil-lymphocyte ratios measured within the first 24 h after admission to the
ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning. Ó 2014 Elsevier Inc. , Keywords—pesticide; poisoning; cholinesterase; neutrophil-lymphocyte ratio
INTRODUCTION Pesticides are highly toxic chemical substances designed to kill living organisms including insects, rodents, and fungi. They are widely used and their sales are not controlled by governments in developing agricultural countries (1,2). The number of intentional and unintentional pesticide poisoning cases has increased in recent years. Annually, approximately 250,000–300,000 deaths occur due to pesticide poisoning worldwide, and 70–80% of pesticide poisonings are suicidal (2). The identification of powerful prognostic markers are important for the management of patients with pesticide poisoning in emergency settings. Pesticides have many subgroups with different mechanisms of action, for example, organophosphates, organochlorines, pyrethroids, and carbamates. Although their mechanisms of action are different, in almost all acute pesticide poisoning, a general inflammatory response occurs in the body due to oxidative stress (3,4). As a result of this inflammatory response, major laboratory abnormalities, such as leukocytosis and hyperglycemia, can be identified in patients with pesticide poisoning
RECEIVED: 25 July 2013; FINAL SUBMISSION RECEIVED: 22 November 2013; ACCEPTED: 28 January 2014 286
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(5–8). When the differential count of leukocytes is evaluated during the acute inflammatory response to oxidative stress, it is characterized by an increase in neutrophil counts, an increase in monocyte counts, and a decline in lymphocyte counts (9,10). The ratio of neutrophil-lymphocyte also can be used as an additional inflammatory marker. In recent studies, it has been reported that the neutrophil-lymphocyte ratio is a sensitive inflammatory and prognostic marker in various clinical conditions including sepsis, cardiac disorders, stroke, and acute appendicitis (9–13). Due to the similar inflammatory mechanism in the pathophysiology of pesticide poisoning, the counts of leukocytes, neutrophils, and lymphocytes, and the neutrophillymphocyte ratio can be used as prognostic markers in predicting the severity of pesticide poisoning. The aim of this retrospective study is to investigate the prognostic value of the neutrophil-lymphocyte ratio and other hematological parameters measured within the first 24 h after admission to the emergency department (ED) in patients with pesticide poisoning. MATERIALS AND METHODS The study was conducted in compliance with the guidelines of the Declaration of Helsinki and was approved by the local ethics committee. Patients This retrospective observational study was conducted in the EDs of a university hospital and a training and research hospital. All patients ($15 years old) admitted to both EDs for pesticide poisoning from July 2008 through February 2013 were enrolled in the study. The diagnosis of acute pesticide poisoning was based on the history of exposure to or contact with a pesticide, the presence of characteristic clinical signs and symptoms of pesticide poisoning, improvement of signs and symptoms with administration of atropine and oximes, and decreased serum cholinesterase activity for organophosphate poisoning. Patients with pregnancy, cancer, hematological disease, or trauma were excluded from the study. Treatment Protocol All patients were treated with standard protocols. Initial decontamination procedures were carried out, including removal of all clothing, washing the entire body with soap and water, gastric lavage, and activated charcoal. The patients with cholinergic symptoms such as lacrimation, salivation, diaphoresis, and with decreased serum cholinesterase levels were treated with intravenous atropine and pralidoxime.
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Study Protocol The written and electronic medical charts of patients were reviewed. Demographic data, type of pesticide, route of exposure, physical examination findings, serum cholinesterase levels, and complete blood count (CBC) results (leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, basophil, platelet counts, and hemoglobin) within the first 24 h after admission to the ED, mechanical ventilation requirement, length of stay in hospital, and outcomes were recorded using standard data collection forms. The data collection forms were completed by one investigator at each of the two centers, and the accuracy of the data was verified by a third independent investigator. Neutrophil-lymphocyte ratio and plateletlymphocyte ratio were calculated using absolute neutrophil, lymphocyte, and platelet counts. Mechanical ventilation requirement and mortality were used as the primary endpoints. Patients were divided into two subgroups, mechanically ventilated and nonventilated, for analysis. Patients were also divided into two subgroups, survivors and nonsurvivors. The hematological parameters were compared between the groups. Statistical Analysis All statistical analyses were performed using SPSS 16.0 software (SPSS Inc, Chicago, IL). Descriptive statistics were computed for all variables. Quantitative variables were expressed as mean 6 standard deviation and categorical variables were expressed as number of cases (percentage). All data were analyzed for normality. The differences between the groups were compared using the Student’s t-test for normally distributed quantitative variables and the Mann-Whitney U test for nonnormally distributed quantitative variables. The control for multiple comparisons was made by using Bonferroni correction, and p value <0.005 was considered significant. The differences between the groups were determined using the chi-squared test and Fischer’s exact test for categorical variables. Receiver operating characteristic (ROC) analyses were used to determine the power of parameters in predicting mechanical ventilation requirement and mortality. The optimal cut-off values for each parameter were determined by using Youden’s index (sensitivity + specificity 1). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rate were calculated for those cut-off values. RESULTS In this retrospective study, the charts of 209 patients admitted to EDs due to pesticide poisoning from July
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2008 through February 2013 were reviewed. Nineteen patients were excluded from the study. Eleven had no measured serum cholinesterase level, 3 were pregnant, 2 were victims of trauma, 1 had a diagnosis of cancer, and 2 had coexisting hematological diseases. A total of 189 patients were included in the study for evaluation. The median age of patients was 38.0 (25.5–54.0) years, and 106 (56.1%) of the 189 patients were men. The route of exposure was oral ingestion in 102 (54.0%) patients, inhalation in 74 (39.2%) patients, and transdermal in 13 (6.9%) patients. The most common pesticides identified in the poisonings were organophosphates (43.6%), pyrethroids (24.8%), and carbamates (5.3%). However, the type of pesticide could not be determined in 50 (26.5%) patients. The mean length of stay in the hospital was 4.25 6 4.63 days. Twenty patients (10.6%) required mechanical ventilation support during the treatment period. The mechanically ventilated patients had significantly higher leukocyte and neutrophil counts, and neutrophillymphocyte and platelet-lymphocyte ratios (p < 0.001, p < 0.001, p < 0.001, and p = 0.003, respectively), whereas they had significantly lower lymphocyte counts compared to nonventilated patients (p = 0.011). The
comparisons of parameters between mechanically ventilated and nonventilated patients are shown in Table 1. Nine (4.8%) of the patients died during their intensive care unit follow-up period. Survivors had significantly higher leukocyte and neutrophil counts, and neutrophillymphocyte ratios (p < 0.001, p < 0.001, and p = 0.002, respectively), whereas there was no significant difference between groups in lymphocyte counts (p = 0.463), compared to nonsurvivors. The comparisons of parameters between survivors and nonsurvivors are shown in Table 2. The area under the ROC curve of neutrophillymphocyte ratio was 0.844 (95% confidence interval [CI] 0.751–0.937, p < 0.001) for predicting mechanical ventilation requirement (Figure 1). The optimal cut-off value was 8.4. Any neutrophil-lymphocyte ratio values higher than 8.4 had a sensitivity of 85% and a specificity of 75% (Table 3). The area under the ROC curve of neutrophillymphocyte ratio was 0.799 (95% CI 0.728–0.871, p = 0.002) for predicting mortality (Figure 2). The optimal cut-off value was 7.1. Any neutrophil-lymphocyte ratio values higher than 7.1 had a sensitivity of 100% and a specificity of 66% (Table 4).
Table 1. The Comparisons of Parameters between Mechanically Ventilated and Nonventilated Patients
Age, years Gender Male Female Type of pesticide Organophosphate Pyrethroid Carbamate Organochlorine Chlorophenoxy Acaricide Phenylpyrrole Phosphonate Fungicide Unknown Route of exposure Oral ingestion Inhalation Transdermal Glasgow Coma Scale score Serum cholinesterase, U/L Leukocyte, K/uL Neutrophil, K/uL Lymphocyte, K/uL Monocyte, K/uL Eosinophil, K/uL Basophil, K/uL Platelet, K/uL Hemoglobin, g/dL Neutrophil-lymphocyte ratio Platelet-lymphocyte ratio Length of stay in hospital, days
p Value
Mechanically Ventilated (n = 20)
Nonventilated (n = 169)
46.7 6 20.8
41.0 6 18.5
0.205
10 (50.0) 10 (50.0)
96 (56.8) 73 (43.2)
0.562
16 (80.0) 1 (5.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) 1 (5.0)
67 (39.6) 27 (16.0) 10 (5.9) 7 (4.1) 4 (2.4) 3 (1.8) 0 (0.0) 1 (0.9) 1 (0.9) 49 (29.0)
0.010
20 (100.0) 0 (0.0) 0 (0.0) 8.9 6 4.6 2064 6 3309 21.0 6 9.4 18.4 6 8.7 1.6 6 1.3 0.9 6 0.6 0.0 6 0.1 0.1 6 0.1 287.1 6 104.3 13.8 6 2.1 16.6 6 10.1 255.0 6 127.4 11.9 6 8.3
82 (48.5) 74 (43.8) 13 (7.7) 14.8 6 1.1 5676 6 3854 11.1 6 4.5 8.5 6 4.5 1.9 6 1.0 0.6 6 0.4 0.1 6 0.1 0.1 6 0.1 244.8 6 58.9 14.0 6 1.8 6.4 6 5.6 167.6 6 113.8 3.4 6 2.9
<0.001 <0.001 <0.001 <0.001 <0.001 0.011 0.003 <0.001 0.726 0.090 0.548 <0.001 0.003 <0.001
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Table 2. The Comparisons of Parameters between Survivors and Nonsurvivors
Age, years Gender Male Female Type of pesticide Organophosphate Pyrethroid Carbamate Organochlorine Chlorophenoxy Acaricide Phenylpyrrole Phosphonate Fungicide Unknown Route of exposure Oral ingestion Inhalation Transdermal Glasgow Coma Scale score Serum cholinesterase, U/L Leukocyte, K/uL Neutrophil, K/uL Lymphocyte, K/uL Monocyte, K/uL Eosinophil, K/uL Basophil, K/uL Platelet, K/uL Hemoglobin, g/dL Neutrophil-lymphocyte ratio Platelet-lymphocyte ratio Length of stay in hospital, days
p Value
Nonsurvivors (n = 9)
Survivors (n = 180)
49.1 6 25.5
41.2 6 18.4
0.364
4 (44.4) 5 (55.6)
102 (56.7) 78 (43.3)
0.473
7 (77.8) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0)
76 (42.2) 27 (15.0) 10 (5.6) 8 (4.4) 4 (2.2) 3 (1.7) 0 (0.0) 1 (0.6) 1 (0.6) 50 (27.8)
0.002
9 (100.0) 0 (0.0) 0 (0.0) 8.4 6 5.4 1667 6 3025 21.0 6 11.2 18.4 6 10.0 1.7 6 1.0 0.8 6 0.3 0.04 6 0.08 0.1 6 0.1 310.0 6 119.6 13.1 6 2.07 11.8 6 3.6 217.2 6 102.2 5.7 6 4.0
93 (51.7) 74 (41.1) 13 (7.2) 14.4 6 2.0 5449 6 3919 11.7 6 5.3 9.1 6 5.31 1.9 6 1.1 0.6 6 0.4 0.08 6 0.08 0.1 6 0.1 246.3 6 61.3 14.0 6 1.8 7.3 6 7.1 174.8 6 118.7 4.2 6 4.7
0.003
DISCUSSION Pesticides are highly toxic to human beings, and pesticide poisonings are associated with high morbidity and mor-
Figure 1. The receiver operating characteristic curves of neutrophil-lymphocyte and platelet-lymphocyte ratios for predicting mechanical ventilation requirement. nlr = neutrophil-lymphocyte ratio; plr = platelet-lymphocyte ratio.
<0.001 0.005 <0.001 <0.001 0.463 0.068 0.014 0.863 0.096 0.117 0.002 0.136 0.129
tality (14–16). The general supportive treatments given to poisoned patients, particularly respiratory and cardiovascular support, are crucial (17,18). It is important to decide on admission to the ED which patient should be followed in the intensive care unit and also to estimate which patient can be expected to have a better prognosis during the follow-up period. Another problem during the clinical management of patients with pesticide poisoning is often the failure to identify the type of pesticide in the poisoning. In our country, it has been reported that 70% of pesticide poisonings are suicidal (8,18). Particularly in the absence of witnesses, it becomes impossible to identify when, how much, and which pesticides to which the patient was exposed. In such cases, the severity of poisoning should be evaluated by objective criteria on admission to the ED. Complete blood count is performed in almost all patients with pesticide poisoning on admission to the ED. It is also important to note that the test results are available in 5–10 min, and the CBC is inexpensive and easy to interpret. In our study, we found that the more severely poisoned patients had leukocytosis, neutrophilia, monocytosis, and lymphocytopenia within the first 24 h after admission to the ED. Oxidative stress is the major mechanism in the
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Table 3. The Receiver-Operating Characteristic Analysis of Parameters in Predicting Mechanical Ventilation Requirement
Leukocyte Neutrophil NLR PLR
AUC (95% CI)
p Value
Cut-off
Sens.
Specif.
PPV
NPV
AR
0.862 (0.762–0.962) 0.867 (0.775–0.960) 0.844 (0.751–0.937) 0.704 (0.569–0.838)
<0.001 <0.001 <0.001 0.003
12.9 11.3 8.4 217.5
90% 85% 85% 60%
76% 79% 75% 80%
31% 32% 29% 26%
99% 98% 98% 94%
77% 79% 76% 78%
AUC = area under the curve; CI = confidence interval; Sens. = sensitivity; Specif. = specificity; PPV = positive predictive value; NPV = negative predictive value; AR = accuracy rate; NLR = neutrophil-lymphocyte ratio; PLR = platelet-lymphocyte ratio.
pathophysiology of most toxins and diseases (3,19–21). In experimental and clinical studies, it has been reported that the production of free radicals is increased in pesticide poisonings (14,22,23). More severe pesticide poisonings will lead to an increased production of free radicals. When the production of free radicals exceeds the antioxidant capacity of the patient, there will be noticeable changes on the CBC due to the oxidative stress (23–25). Leukocytosis, neutrophilia, lymphocytopenia, and monocytosis can be detected on CBC in the acute period of the clinical course when the oxidative stress is increased (9–11). In experimental and clinical studies, it has been reported that leukocytosis and neutrophilia can be seen in the early stages of pesticide poisoning, and leukopenia and lymphocytopenia develop in the later stages (8,23,24,26,27). Although the difference in lymphocyte counts between mechanically ventilated and nonventilated patient groups seems to be statistically nonsignificant after Bonferroni correction in our study, decreased lymphocyte count was expected due to the underlying pathophysiological mechanism, increased oxidative stress. We consider that the significant difference found by Student’s t-test was more reliable in
Figure 2. The receiver operating characteristic curves of neutrophil-lymphocyte and platelet-lymphocyte ratios for predicting mortality. nlr = neutrophil-lymphocyte ratio; plr = platelet-lymphocyte ratio.
catching the changes in lymphocyte counts. Our other findings are also consistent with the current literature. In our study, we found that more severely poisoned patients had increased platelet levels, but this increase was not statistically significant. Whereas some experimental studies have reported increased platelet levels in subacute and chronic pesticide poisoning, others have reported findings of thrombocytopenia (26,28,29). From the literature, it would be reasonable to conclude that thrombocytopenia appears after the oxidative stress negatively affects the platelet membranes, as in all blood cells. Thrombocytopenia is frequently observed in nonpoisoning clinical conditions such as sepsis and pneumonia, where the oxidative stress is increased (9,10,26,28). These results should be confirmed by further prospective and controlled studies. In our study, neutrophil-lymphocyte and plateletlymphocyte ratios were significantly higher in the more severely poisoned patients. Previous studies have reported that the neutrophil-lymphocyte ratio is a strong indicator of inflammation and prognosis in many diseases (9–13). In experimental studies, it has been shown that the neutrophil-lymphocyte ratio increases in pesticide poisonings (26,28,30). In our study, we found that the neutrophillymphocyte ratio was a strong prognostic indicator for predicting both the mechanical ventilation requirement and mortality. However, our findings also showed that the leukocyte counts alone and the neutrophil counts alone had the same prognostic strength. All three parameters should be reevaluated in large-scale prospective studies. In this study, we found no differences between the ED admission hemoglobin levels of the most severely poisoned patients vs. those less severely poisoned. In the literature, it is reported that varying hemoglobin levels are seen depending on whether the poisoning is acute, subacute, or chronic in patients poisoned with different pesticide groups (14,24). It has been typically reported that erythrocyte fragility is increased due to the lipid peroxidation of the erythrocyte membrane in cases of severe poisoning, with increased oxidative stress burden, and that the red blood cell life span was shortened (26– 28,30). It has been reported that another mechanism that may be responsible for the fall in hemoglobin levels is the direct inhibition of hemoglobin synthesis by the
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Table 4. The Receiver-Operating Characteristic Analysis of Parameters in Predicting Mortality
Leukocyte Neutrophil NLR
AUC (95% CI)
p Value
Cut-off
Sens.
Specif.
PPV
NPV
AR
0.846 (0.752–0.941) 0.857 (0.772–0.942) 0.799 (0.728–0.871)
<0.001 <0.001 0.002
14.1 12.2 7.1
89% 89% 100%
77% 78% 66%
16% 17% 12%
99% 99% 100%
77% 78% 68%
AUC = area under the curve; CI = confidence interval; Sens. = sensitivity; Specif. = specificity; PPV = positive predictive value; NPV = negative predictive value; AR = accuracy rate; NLR = neutrophil-lymphocyte ratio.
pesticides (26). However, it also has been reported that the sensitivity of erythrocytes and lymphocytes to oxidative stress in pesticide poisoning depends on the balance between oxidative stress and antioxidant defense capacity (14,23,25). In our study, we consider that the normal hemoglobin levels of patients with pesticide poisoning measured within the first 24 h were possibly due to nondepleted antioxidant capacity of erythrocytes in the early period of poisoning. Limitations
4. 5.
6. 7. 8.
This is a retrospective study, with a relatively low number of nonsurvivor cases. We could not analyze the pesticide subgroups due to the low number of cases. We also could not objectively evaluate the reliability of the history given by the patients concerning the type and times of pesticide exposure. Therefore, the prognostic value of the neutrophil-lymphocyte ratios in pesticide poisoning patients should be evaluated in large-scale prospective studies. CONCLUSION In this study, we found that the patients with more severe pesticide poisoning had increased leukocyte, neutrophil, and platelet counts. Those patients also had decreased lymphocyte counts and unchanged hemoglobin levels. These findings suggest that complete blood count results are associated with oxidative stress rather than bone marrow depression in acute pesticide poisoning. Leukocyte counts, neutrophil counts, and neutrophillymphocyte ratios measured within the first 24 h after admission to the ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning.
9.
10. 11. 12. 13. 14. 15. 16. 17.
18. 19.
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Neutrophil-Lymphocyte Ratio in Poisoning
ARTICLE SUMMARY 1. Why is this topic important? Pesticides are highly toxic to human beings, and pesticide poisonings are associated with high morbidity and mortality. The identification of powerful prognostic markers is important for the management of patients with pesticide poisoning in emergency settings. 2. What does this study attempt to show? In this study, we aimed to evaluate the prognostic value of the neutrophil-lymphocyte ratio and hematological parameters measured within the first 24 h after admission to the emergency department (ED) in patients with pesticide poisoning. 3. What are the key findings? Patients more severely poisoned with pesticides had higher leukocyte and neutrophil counts than those less severely poisoned. The more severely poisoned also had higher neutrophil-lymphocyte ratios. However, they had lower lymphocyte counts. 4. How is patient care impacted? Leukocyte counts, neutrophil counts, and neutrophillymphocyte ratios measured within the first 24 h after admission to the ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning.
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http://dx.doi.org/10.1016/j.jemermed.2014.01.034
Selected Topics: Toxicology
NEUTROPHIL-LYMPHOCYTE RATIO IN PATIENTS WITH PESTICIDE POISONING Zerrin Defne Dundar, MD,* Mehmet Ergin, MD,* Ramazan Koylu, MD,† Rasit Ozer, MD,* Basar Cander, MD,* and Yahya Kemal Gunaydin, MD† *Emergency Medicine Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey and †Emergency Medicine Clinic, Konya Training and Research Hospital, Konya, Turkey Reprint Address: Zerrin Defne Dundar, MD, Emergency Medicine Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
, Abstract—Background: Pesticides are highly toxic to human beings, and pesticide poisoning is associated with high morbidity and mortality. The identification of powerful prognostic markers is important for the management of patients with pesticide poisoning in emergency settings. Objective: To investigate the prognostic value of the neutrophil-lymphocyte ratio and hematological parameters measured in patients with pesticide poisoning within the first 24 h after admission to the emergency department (ED). Methods: All patients ($15 years old) admitted to the ED from July 2008 through February 2013 due to pesticide poisoning were enrolled in the study. The written and electronic medical charts of patients were reviewed. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were calculated for each patient using absolute neutrophil, lymphocyte, and platelet counts. Mechanical ventilation requirement and mortality were used as the primary endpoints. Results: A total of 189 patients were included in the study. The mechanically ventilated patients had significantly higher leukocyte and neutrophil counts, and neutrophil-lymphocyte and platelet-lymphocyte ratios (p < 0.001, p < 0.001, p < 0.001, p = 0.003, respectively), whereas they had significantly lower lymphocyte counts compared to nonventilated patients (p = 0.011). Survivors had significantly higher leukocyte and neutrophil counts, and neutrophil-lymphocyte ratios (p < 0.001, p < 0.001, p = 0.002, respectively), whereas there was no significant difference between groups in terms of lymphocyte counts (p = 0.463), compared to nonsurvivors. Conclusion: Leukocyte counts, neutrophil counts, and neutrophil-lymphocyte ratios measured within the first 24 h after admission to the
ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning. Ó 2014 Elsevier Inc. , Keywords—pesticide; poisoning; cholinesterase; neutrophil-lymphocyte ratio
INTRODUCTION Pesticides are highly toxic chemical substances designed to kill living organisms including insects, rodents, and fungi. They are widely used and their sales are not controlled by governments in developing agricultural countries (1,2). The number of intentional and unintentional pesticide poisoning cases has increased in recent years. Annually, approximately 250,000–300,000 deaths occur due to pesticide poisoning worldwide, and 70–80% of pesticide poisonings are suicidal (2). The identification of powerful prognostic markers are important for the management of patients with pesticide poisoning in emergency settings. Pesticides have many subgroups with different mechanisms of action, for example, organophosphates, organochlorines, pyrethroids, and carbamates. Although their mechanisms of action are different, in almost all acute pesticide poisoning, a general inflammatory response occurs in the body due to oxidative stress (3,4). As a result of this inflammatory response, major laboratory abnormalities, such as leukocytosis and hyperglycemia, can be identified in patients with pesticide poisoning
RECEIVED: 25 July 2013; FINAL SUBMISSION RECEIVED: 22 November 2013; ACCEPTED: 28 January 2014 286
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(5–8). When the differential count of leukocytes is evaluated during the acute inflammatory response to oxidative stress, it is characterized by an increase in neutrophil counts, an increase in monocyte counts, and a decline in lymphocyte counts (9,10). The ratio of neutrophil-lymphocyte also can be used as an additional inflammatory marker. In recent studies, it has been reported that the neutrophil-lymphocyte ratio is a sensitive inflammatory and prognostic marker in various clinical conditions including sepsis, cardiac disorders, stroke, and acute appendicitis (9–13). Due to the similar inflammatory mechanism in the pathophysiology of pesticide poisoning, the counts of leukocytes, neutrophils, and lymphocytes, and the neutrophillymphocyte ratio can be used as prognostic markers in predicting the severity of pesticide poisoning. The aim of this retrospective study is to investigate the prognostic value of the neutrophil-lymphocyte ratio and other hematological parameters measured within the first 24 h after admission to the emergency department (ED) in patients with pesticide poisoning. MATERIALS AND METHODS The study was conducted in compliance with the guidelines of the Declaration of Helsinki and was approved by the local ethics committee. Patients This retrospective observational study was conducted in the EDs of a university hospital and a training and research hospital. All patients ($15 years old) admitted to both EDs for pesticide poisoning from July 2008 through February 2013 were enrolled in the study. The diagnosis of acute pesticide poisoning was based on the history of exposure to or contact with a pesticide, the presence of characteristic clinical signs and symptoms of pesticide poisoning, improvement of signs and symptoms with administration of atropine and oximes, and decreased serum cholinesterase activity for organophosphate poisoning. Patients with pregnancy, cancer, hematological disease, or trauma were excluded from the study. Treatment Protocol All patients were treated with standard protocols. Initial decontamination procedures were carried out, including removal of all clothing, washing the entire body with soap and water, gastric lavage, and activated charcoal. The patients with cholinergic symptoms such as lacrimation, salivation, diaphoresis, and with decreased serum cholinesterase levels were treated with intravenous atropine and pralidoxime.
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Study Protocol The written and electronic medical charts of patients were reviewed. Demographic data, type of pesticide, route of exposure, physical examination findings, serum cholinesterase levels, and complete blood count (CBC) results (leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, basophil, platelet counts, and hemoglobin) within the first 24 h after admission to the ED, mechanical ventilation requirement, length of stay in hospital, and outcomes were recorded using standard data collection forms. The data collection forms were completed by one investigator at each of the two centers, and the accuracy of the data was verified by a third independent investigator. Neutrophil-lymphocyte ratio and plateletlymphocyte ratio were calculated using absolute neutrophil, lymphocyte, and platelet counts. Mechanical ventilation requirement and mortality were used as the primary endpoints. Patients were divided into two subgroups, mechanically ventilated and nonventilated, for analysis. Patients were also divided into two subgroups, survivors and nonsurvivors. The hematological parameters were compared between the groups. Statistical Analysis All statistical analyses were performed using SPSS 16.0 software (SPSS Inc, Chicago, IL). Descriptive statistics were computed for all variables. Quantitative variables were expressed as mean 6 standard deviation and categorical variables were expressed as number of cases (percentage). All data were analyzed for normality. The differences between the groups were compared using the Student’s t-test for normally distributed quantitative variables and the Mann-Whitney U test for nonnormally distributed quantitative variables. The control for multiple comparisons was made by using Bonferroni correction, and p value <0.005 was considered significant. The differences between the groups were determined using the chi-squared test and Fischer’s exact test for categorical variables. Receiver operating characteristic (ROC) analyses were used to determine the power of parameters in predicting mechanical ventilation requirement and mortality. The optimal cut-off values for each parameter were determined by using Youden’s index (sensitivity + specificity 1). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rate were calculated for those cut-off values. RESULTS In this retrospective study, the charts of 209 patients admitted to EDs due to pesticide poisoning from July
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2008 through February 2013 were reviewed. Nineteen patients were excluded from the study. Eleven had no measured serum cholinesterase level, 3 were pregnant, 2 were victims of trauma, 1 had a diagnosis of cancer, and 2 had coexisting hematological diseases. A total of 189 patients were included in the study for evaluation. The median age of patients was 38.0 (25.5–54.0) years, and 106 (56.1%) of the 189 patients were men. The route of exposure was oral ingestion in 102 (54.0%) patients, inhalation in 74 (39.2%) patients, and transdermal in 13 (6.9%) patients. The most common pesticides identified in the poisonings were organophosphates (43.6%), pyrethroids (24.8%), and carbamates (5.3%). However, the type of pesticide could not be determined in 50 (26.5%) patients. The mean length of stay in the hospital was 4.25 6 4.63 days. Twenty patients (10.6%) required mechanical ventilation support during the treatment period. The mechanically ventilated patients had significantly higher leukocyte and neutrophil counts, and neutrophillymphocyte and platelet-lymphocyte ratios (p < 0.001, p < 0.001, p < 0.001, and p = 0.003, respectively), whereas they had significantly lower lymphocyte counts compared to nonventilated patients (p = 0.011). The
comparisons of parameters between mechanically ventilated and nonventilated patients are shown in Table 1. Nine (4.8%) of the patients died during their intensive care unit follow-up period. Survivors had significantly higher leukocyte and neutrophil counts, and neutrophillymphocyte ratios (p < 0.001, p < 0.001, and p = 0.002, respectively), whereas there was no significant difference between groups in lymphocyte counts (p = 0.463), compared to nonsurvivors. The comparisons of parameters between survivors and nonsurvivors are shown in Table 2. The area under the ROC curve of neutrophillymphocyte ratio was 0.844 (95% confidence interval [CI] 0.751–0.937, p < 0.001) for predicting mechanical ventilation requirement (Figure 1). The optimal cut-off value was 8.4. Any neutrophil-lymphocyte ratio values higher than 8.4 had a sensitivity of 85% and a specificity of 75% (Table 3). The area under the ROC curve of neutrophillymphocyte ratio was 0.799 (95% CI 0.728–0.871, p = 0.002) for predicting mortality (Figure 2). The optimal cut-off value was 7.1. Any neutrophil-lymphocyte ratio values higher than 7.1 had a sensitivity of 100% and a specificity of 66% (Table 4).
Table 1. The Comparisons of Parameters between Mechanically Ventilated and Nonventilated Patients
Age, years Gender Male Female Type of pesticide Organophosphate Pyrethroid Carbamate Organochlorine Chlorophenoxy Acaricide Phenylpyrrole Phosphonate Fungicide Unknown Route of exposure Oral ingestion Inhalation Transdermal Glasgow Coma Scale score Serum cholinesterase, U/L Leukocyte, K/uL Neutrophil, K/uL Lymphocyte, K/uL Monocyte, K/uL Eosinophil, K/uL Basophil, K/uL Platelet, K/uL Hemoglobin, g/dL Neutrophil-lymphocyte ratio Platelet-lymphocyte ratio Length of stay in hospital, days
p Value
Mechanically Ventilated (n = 20)
Nonventilated (n = 169)
46.7 6 20.8
41.0 6 18.5
0.205
10 (50.0) 10 (50.0)
96 (56.8) 73 (43.2)
0.562
16 (80.0) 1 (5.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) 1 (5.0)
67 (39.6) 27 (16.0) 10 (5.9) 7 (4.1) 4 (2.4) 3 (1.8) 0 (0.0) 1 (0.9) 1 (0.9) 49 (29.0)
0.010
20 (100.0) 0 (0.0) 0 (0.0) 8.9 6 4.6 2064 6 3309 21.0 6 9.4 18.4 6 8.7 1.6 6 1.3 0.9 6 0.6 0.0 6 0.1 0.1 6 0.1 287.1 6 104.3 13.8 6 2.1 16.6 6 10.1 255.0 6 127.4 11.9 6 8.3
82 (48.5) 74 (43.8) 13 (7.7) 14.8 6 1.1 5676 6 3854 11.1 6 4.5 8.5 6 4.5 1.9 6 1.0 0.6 6 0.4 0.1 6 0.1 0.1 6 0.1 244.8 6 58.9 14.0 6 1.8 6.4 6 5.6 167.6 6 113.8 3.4 6 2.9
<0.001 <0.001 <0.001 <0.001 <0.001 0.011 0.003 <0.001 0.726 0.090 0.548 <0.001 0.003 <0.001
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Table 2. The Comparisons of Parameters between Survivors and Nonsurvivors
Age, years Gender Male Female Type of pesticide Organophosphate Pyrethroid Carbamate Organochlorine Chlorophenoxy Acaricide Phenylpyrrole Phosphonate Fungicide Unknown Route of exposure Oral ingestion Inhalation Transdermal Glasgow Coma Scale score Serum cholinesterase, U/L Leukocyte, K/uL Neutrophil, K/uL Lymphocyte, K/uL Monocyte, K/uL Eosinophil, K/uL Basophil, K/uL Platelet, K/uL Hemoglobin, g/dL Neutrophil-lymphocyte ratio Platelet-lymphocyte ratio Length of stay in hospital, days
p Value
Nonsurvivors (n = 9)
Survivors (n = 180)
49.1 6 25.5
41.2 6 18.4
0.364
4 (44.4) 5 (55.6)
102 (56.7) 78 (43.3)
0.473
7 (77.8) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0)
76 (42.2) 27 (15.0) 10 (5.6) 8 (4.4) 4 (2.2) 3 (1.7) 0 (0.0) 1 (0.6) 1 (0.6) 50 (27.8)
0.002
9 (100.0) 0 (0.0) 0 (0.0) 8.4 6 5.4 1667 6 3025 21.0 6 11.2 18.4 6 10.0 1.7 6 1.0 0.8 6 0.3 0.04 6 0.08 0.1 6 0.1 310.0 6 119.6 13.1 6 2.07 11.8 6 3.6 217.2 6 102.2 5.7 6 4.0
93 (51.7) 74 (41.1) 13 (7.2) 14.4 6 2.0 5449 6 3919 11.7 6 5.3 9.1 6 5.31 1.9 6 1.1 0.6 6 0.4 0.08 6 0.08 0.1 6 0.1 246.3 6 61.3 14.0 6 1.8 7.3 6 7.1 174.8 6 118.7 4.2 6 4.7
0.003
DISCUSSION Pesticides are highly toxic to human beings, and pesticide poisonings are associated with high morbidity and mor-
Figure 1. The receiver operating characteristic curves of neutrophil-lymphocyte and platelet-lymphocyte ratios for predicting mechanical ventilation requirement. nlr = neutrophil-lymphocyte ratio; plr = platelet-lymphocyte ratio.
<0.001 0.005 <0.001 <0.001 0.463 0.068 0.014 0.863 0.096 0.117 0.002 0.136 0.129
tality (14–16). The general supportive treatments given to poisoned patients, particularly respiratory and cardiovascular support, are crucial (17,18). It is important to decide on admission to the ED which patient should be followed in the intensive care unit and also to estimate which patient can be expected to have a better prognosis during the follow-up period. Another problem during the clinical management of patients with pesticide poisoning is often the failure to identify the type of pesticide in the poisoning. In our country, it has been reported that 70% of pesticide poisonings are suicidal (8,18). Particularly in the absence of witnesses, it becomes impossible to identify when, how much, and which pesticides to which the patient was exposed. In such cases, the severity of poisoning should be evaluated by objective criteria on admission to the ED. Complete blood count is performed in almost all patients with pesticide poisoning on admission to the ED. It is also important to note that the test results are available in 5–10 min, and the CBC is inexpensive and easy to interpret. In our study, we found that the more severely poisoned patients had leukocytosis, neutrophilia, monocytosis, and lymphocytopenia within the first 24 h after admission to the ED. Oxidative stress is the major mechanism in the
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Table 3. The Receiver-Operating Characteristic Analysis of Parameters in Predicting Mechanical Ventilation Requirement
Leukocyte Neutrophil NLR PLR
AUC (95% CI)
p Value
Cut-off
Sens.
Specif.
PPV
NPV
AR
0.862 (0.762–0.962) 0.867 (0.775–0.960) 0.844 (0.751–0.937) 0.704 (0.569–0.838)
<0.001 <0.001 <0.001 0.003
12.9 11.3 8.4 217.5
90% 85% 85% 60%
76% 79% 75% 80%
31% 32% 29% 26%
99% 98% 98% 94%
77% 79% 76% 78%
AUC = area under the curve; CI = confidence interval; Sens. = sensitivity; Specif. = specificity; PPV = positive predictive value; NPV = negative predictive value; AR = accuracy rate; NLR = neutrophil-lymphocyte ratio; PLR = platelet-lymphocyte ratio.
pathophysiology of most toxins and diseases (3,19–21). In experimental and clinical studies, it has been reported that the production of free radicals is increased in pesticide poisonings (14,22,23). More severe pesticide poisonings will lead to an increased production of free radicals. When the production of free radicals exceeds the antioxidant capacity of the patient, there will be noticeable changes on the CBC due to the oxidative stress (23–25). Leukocytosis, neutrophilia, lymphocytopenia, and monocytosis can be detected on CBC in the acute period of the clinical course when the oxidative stress is increased (9–11). In experimental and clinical studies, it has been reported that leukocytosis and neutrophilia can be seen in the early stages of pesticide poisoning, and leukopenia and lymphocytopenia develop in the later stages (8,23,24,26,27). Although the difference in lymphocyte counts between mechanically ventilated and nonventilated patient groups seems to be statistically nonsignificant after Bonferroni correction in our study, decreased lymphocyte count was expected due to the underlying pathophysiological mechanism, increased oxidative stress. We consider that the significant difference found by Student’s t-test was more reliable in
Figure 2. The receiver operating characteristic curves of neutrophil-lymphocyte and platelet-lymphocyte ratios for predicting mortality. nlr = neutrophil-lymphocyte ratio; plr = platelet-lymphocyte ratio.
catching the changes in lymphocyte counts. Our other findings are also consistent with the current literature. In our study, we found that more severely poisoned patients had increased platelet levels, but this increase was not statistically significant. Whereas some experimental studies have reported increased platelet levels in subacute and chronic pesticide poisoning, others have reported findings of thrombocytopenia (26,28,29). From the literature, it would be reasonable to conclude that thrombocytopenia appears after the oxidative stress negatively affects the platelet membranes, as in all blood cells. Thrombocytopenia is frequently observed in nonpoisoning clinical conditions such as sepsis and pneumonia, where the oxidative stress is increased (9,10,26,28). These results should be confirmed by further prospective and controlled studies. In our study, neutrophil-lymphocyte and plateletlymphocyte ratios were significantly higher in the more severely poisoned patients. Previous studies have reported that the neutrophil-lymphocyte ratio is a strong indicator of inflammation and prognosis in many diseases (9–13). In experimental studies, it has been shown that the neutrophil-lymphocyte ratio increases in pesticide poisonings (26,28,30). In our study, we found that the neutrophillymphocyte ratio was a strong prognostic indicator for predicting both the mechanical ventilation requirement and mortality. However, our findings also showed that the leukocyte counts alone and the neutrophil counts alone had the same prognostic strength. All three parameters should be reevaluated in large-scale prospective studies. In this study, we found no differences between the ED admission hemoglobin levels of the most severely poisoned patients vs. those less severely poisoned. In the literature, it is reported that varying hemoglobin levels are seen depending on whether the poisoning is acute, subacute, or chronic in patients poisoned with different pesticide groups (14,24). It has been typically reported that erythrocyte fragility is increased due to the lipid peroxidation of the erythrocyte membrane in cases of severe poisoning, with increased oxidative stress burden, and that the red blood cell life span was shortened (26– 28,30). It has been reported that another mechanism that may be responsible for the fall in hemoglobin levels is the direct inhibition of hemoglobin synthesis by the
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Table 4. The Receiver-Operating Characteristic Analysis of Parameters in Predicting Mortality
Leukocyte Neutrophil NLR
AUC (95% CI)
p Value
Cut-off
Sens.
Specif.
PPV
NPV
AR
0.846 (0.752–0.941) 0.857 (0.772–0.942) 0.799 (0.728–0.871)
<0.001 <0.001 0.002
14.1 12.2 7.1
89% 89% 100%
77% 78% 66%
16% 17% 12%
99% 99% 100%
77% 78% 68%
AUC = area under the curve; CI = confidence interval; Sens. = sensitivity; Specif. = specificity; PPV = positive predictive value; NPV = negative predictive value; AR = accuracy rate; NLR = neutrophil-lymphocyte ratio.
pesticides (26). However, it also has been reported that the sensitivity of erythrocytes and lymphocytes to oxidative stress in pesticide poisoning depends on the balance between oxidative stress and antioxidant defense capacity (14,23,25). In our study, we consider that the normal hemoglobin levels of patients with pesticide poisoning measured within the first 24 h were possibly due to nondepleted antioxidant capacity of erythrocytes in the early period of poisoning. Limitations
4. 5.
6. 7. 8.
This is a retrospective study, with a relatively low number of nonsurvivor cases. We could not analyze the pesticide subgroups due to the low number of cases. We also could not objectively evaluate the reliability of the history given by the patients concerning the type and times of pesticide exposure. Therefore, the prognostic value of the neutrophil-lymphocyte ratios in pesticide poisoning patients should be evaluated in large-scale prospective studies. CONCLUSION In this study, we found that the patients with more severe pesticide poisoning had increased leukocyte, neutrophil, and platelet counts. Those patients also had decreased lymphocyte counts and unchanged hemoglobin levels. These findings suggest that complete blood count results are associated with oxidative stress rather than bone marrow depression in acute pesticide poisoning. Leukocyte counts, neutrophil counts, and neutrophillymphocyte ratios measured within the first 24 h after admission to the ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning.
9.
10. 11. 12. 13. 14. 15. 16. 17.
18. 19.
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Neutrophil-Lymphocyte Ratio in Poisoning
ARTICLE SUMMARY 1. Why is this topic important? Pesticides are highly toxic to human beings, and pesticide poisonings are associated with high morbidity and mortality. The identification of powerful prognostic markers is important for the management of patients with pesticide poisoning in emergency settings. 2. What does this study attempt to show? In this study, we aimed to evaluate the prognostic value of the neutrophil-lymphocyte ratio and hematological parameters measured within the first 24 h after admission to the emergency department (ED) in patients with pesticide poisoning. 3. What are the key findings? Patients more severely poisoned with pesticides had higher leukocyte and neutrophil counts than those less severely poisoned. The more severely poisoned also had higher neutrophil-lymphocyte ratios. However, they had lower lymphocyte counts. 4. How is patient care impacted? Leukocyte counts, neutrophil counts, and neutrophillymphocyte ratios measured within the first 24 h after admission to the ED are useful and easy-to-use parameters for estimating prognosis in the follow-up of patients with pesticide poisoning.
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