American Journal of Emergency Medicine xxx (2014) xxx–xxx
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Original Contribution
Body mass index as a prognostic factor in organophosphate-poisoned patients Koo Young Jung, MD, PhD a,⁎, Duk Hee Lee, MD, PhD b, Yoon Hee Choi, MD, PhD a, Young Jin Cheon, MD, PhD a a b
Department of Emergency Medicine, Ewha Womans University, Seoul, Korea Department of Emergency Medicine, College of Medicine, Eulji University, Eulji Hospital, Seoul, Korea
a r t i c l e
i n f o
Article history: Received 23 January 2014 Received in revised form 9 April 2014 Accepted 11 April 2014 Available online xxxx
a b s t r a c t Organophosphate poisoning is a serious clinical entity and considerable morbidity and mortality. Several factors have been identified to predict outcomes of organophosphate poisoning. Organophosphates are lipophilic and therefore predicted to have a large volume of distribution and to rapidly distribute into tissue and fat. Thus, toxic effects of organophosphate would be expected to last longer in obese patients. We investigated the relationship between obesity and clinical course in 112 acute organophosphate-poisoned patients from an initial medical record review of 234 patients. One hundred twenty-two patients were excluded: 6 were children, 14 had an uncertain history of exposure and of uncertain agent, 10 were transferred to another hospital, 67 were discharged from the emergency department because their toxicity was mild, 21 had carbamate poisoning, and 4 did not have height or weight checked. Clinical features, body mass index, Glasgow Coma Scale, laboratory findings, serum cholinesterase activity, electrocardiogram finding, management, and outcomes were examined. The lipid solubility of the implicated organophosphate was characterized by its octanol/water coefficient. Forty of 112 patients were obese. Obese patients who were poisoned by high lipophilicity organophosphate compounds had a need for longer use of mechanical ventilation, intensive care unit care, and total length of admission. Body mass index can provide a guide to physicians in predicting clinical course and management in organophosphate-poisoned patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Organophosphate pesticides are widely used in agricultural setting throughout the world. Organophosphate pesticides are responsible for extensive morbidity and mortality because of their wide use and ready availability [1]. Organophosphate compounds were first introduced in the 1930s for use as pesticides. Since then, more than 50,000 organophosphorus compounds have been synthesized and commercially produced [2,3]. Organophosphate pesticides are responsible for up to 3 million cases of toxicity each year [4]. An estimated 200,000 individuals die in rural Asia where intentional selfharm is common. An estimated 3000 to 6000 ventilators are required in Asia alone to provide mechanical ventilation for organophosphatepoisoned patients [5]. Many reports in the literature have described the various factors that predict the outcome in acute organophosphate-poisoned patients. The recognized predictors of poor outcomes include the initial blood pressure, Glasgow Coma Scale (GCS), serum cholinesterase level, ⁎ Corresponding author at: Department of Emergency medicine, Ewha Womans University, Mok-dong 911-1, Yang-ChoenKu, Seoul 158-710, South Korea. Tel.: +82 2 2650 5296, +82 10 8880 5296(Mobile). E-mail addresses: [email protected] (K.Y. Jung), [email protected] (D.H. Lee).
Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and electrocadiographic findings (the prolongation of the QT interval) [6–8]. We investigated the parameters that assist clinicians in predicting the clinical outcome of organophosphate-poisoned patients. Obesity has dramatically increased worldwide in recent years and is a well-recognized health problem [9,10]. If the current trends persist, up to 58% of the world's adult population will be either overweight or obese by 2030 [11]. With the rise in obesity, clinicians will inevitably encounter obese patients in their practice. Obesity can affect the pharmacokinetics of drugs in humans. However, information regarding the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs remains limited [12–14]. It is widely believed that individuals with an abnormal body mass index (BMI) have poor outcomes. In a recent, large-cohort study of intensive care unit (ICU) patients in Europe, increased morbidity, but not mortality, was associated with higher BMI in patients [15]. Akinnusi et al [16] reported that obesity in critically ill patients is not associated with excess mortality but is significantly related to prolonged durations of both mechanical ventilation and the ICU length of stay. However, few data are available concerning the morbidity and mortality associated with obesity in organophosphate-poisoned patients. From a toxicologic perspective, the recognition of the impact of obesity is an important factor in the treatment and clinical course of these patients.
http://dx.doi.org/10.1016/j.ajem.2014.04.030 0735-6757/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
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K.Y. Jung et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx
We investigated the relationship between obesity and the clinical course in acute organophosphate-poisoned patients. 2. Methods Patients who were included in the study were treated following the standard guidelines for the treatment of organophosphate poisoning in our hospital. Activated charcoal was administered after gastric lavage for all patients. Both atropine and pralidoxime (PAM) were administered in accordance with hospital protocol. The PAM was administered first as a loading dose of 1 g for 30 minutes, after which it was infused continuously at 800 mg/h. The patient then either underwent endotracheal intubation or was admitted to the ICU, in compliance with general standards, after obtaining consent from a guardian. We analyzed the data for the following variables: demographic factors (date of arrival, sex and age of patient, height, weight, and BMI), medical history, history of intoxication (ingredients of the organophosphate, lipid solubility of the organophosphate, time and route of exposure, amount ingested, suicidal intention), clinical manifestations, GCS, initial vital signs (respiratory rate, heart rate, systolic blood pressure), initial blood tests (white blood cell count, hematocrit, platelet count, serum blood urea nitrogen, creatinine, sodium and potassium concentration, amylase, arterial blood gas analysis), serum cholinesterase activity, electrocardiographic results (corrected QT [QTc] interval), treatments received (duration of atropine and PAM administration, whether endotracheal intubation performed, total duration of mechanical ventilation, total duration of ICU stay, total duration of admission), mortality, and APACHE II score. The logarithm of the partition coefficient for the n-octanol and water, log P, reflects the equilibrium partitioning a molecule between a nonpolar and a polar phase. The lipophilicity can be measured by log P [17]. Cross-tabulation was performed for noncontinuous variables using the PASW (SPSS, Chicago, IL) version 18, and Student t test was used for continuous variables. Multivariate linear regression and multivariate logistic regression analyses (as appropriate) were used to analyze the variables. A P value less than .05 was considered statistically significant. 3. Results We reviewed the medical records of 234 patients. One hundred twenty-two of these patients were excluded. The following patients were excluded from the study for a variety of reasons. There were 6 children. Fourteen patients had an uncertain history of exposure and uncertain agents of exposure. Ten patients were transferred to another hospital. Sixty-seven patients were discharged from the emergency department because their toxicity levels were mild. Twenty-one patients were exposed to carbamate poisoning. The height or weight was not recorded for 4 patients. A total of 112 subjects were enrolled. The substances responsible for the poisonings were chlorpyrifos (n = 20, log P = 5.05), methidathion (n = 17, log P = 2.35), dichlorvos (n = 12, log P = 1.56), phosphamidon (n = 10, log P = 0.795), malathion (n = 9, log P = 2.75), dimethoate (n = 9, log P = 0.76), parathion (n = 4, log P = 3.83), fenithrothion (n = 4, log P = 3.37), phentoate (n = 3, log P = 3.69), chlorfluazuron (n = 2), and others (log P = octanol/water coefficient) [17] (Table 1). In Asians, a BMI less than 18.5 kg/m2 is defined as underweight; 18.5 to 22.9 kg/m 2, normal weight; 23.0 to 24.9 kg/m2, overweight; 25 to 29.9 kg/m2, obese; and more than 30 kg/m2, morbidly obese [18,19]. In this study, we set a BMI of 25 kg/m 2 as the standard to distinguish the normal BMI group from the abnormal BMI group. Therefore, “obese patients” were defined as those with a BMI greater than 25 kg/m 2. There were 112 patients with 32 different lipid solubilities of organophosphate substances. The separation point for the low and high lipophilic groups is the median of the lipid solubility of the organophosphates.
Table 1 Types of poisoning agents Organophosphates
Relative lipophilicity
(log P)a
Frequency
Chlorpyrifos Methidathion Dichlorvos Phosphamidon Malathion Dimethoate Parathion Fenithrothion Phentoate Chlorfluazuron Others Total
+++++ +++ ++ + +++ + ++++ ++++ ++++
(5.05) (2.35) (1.56) (0.795) (2.75) (0.76) (3.83) (3.37) (3.69)
20 17 12 10 9 9 4 4 3 2 22 112
a
Derived from log P = octanol/water coefficient.
3.1. General characteristics of low and high lipophilicity groups in obese and nonobese patients in organophosphate poisoning Of the 112 enrolled patients, 41 were obese (BMIs N25 kg/m 2). The mean BMI of the obese patients with low lipophilicity agents was 26.38 ± 2.01 25 kg/m 2, and the mean BMI of the patients with high lipophilicity agents was 26.02 ± 1.55 25 kg/m 2 (P = .414). The low and high lipophilicity groups were compared in the obese and nonobese groups, respectively. There were no significant differences in the age, sex, time interval from poisoning to hospital arrival, amount of organophosphate ingested, initial saturation, QTc interval, APACH II score, or GCS (Tables 2 and 3). 3.2. Clinical outcomes between the low and high lipophilicity groups of obese patients and nonobese patients in organophosphate poisoning In the nonobese patients, the duration of the mechanical ventilation, ICU care, and total admission stay were not significantly longer in the high lipophilic group compared with the low lipophilic group. In the obese patients, the duration of the mechanical ventilation (P = .001), ICU care (P = .002), and total admission stay (P = .006) were significantly longer in the high lipophilic group compared with the low lipophilic group (6.70 ± 5.23 days vs 13.54 ± 6.78 days, 9.01 ± 5.78 days vs 17.18 ± 14.65 days, and 13.88 ± 8.73 days vs 24.04 ± 15.17 days, respectively). There was no statistically significant difference in Table 2 Characteristics of high and low lipophilicity groups in nonobese patients with organophosphate poisoning Characteristic
Nonobese patient (n = 72)
P
Low lipophilicity High lipophilicity (n = 32) (n = 40) Age (y), mean ± SD Male/Female, n BMI (kg/m2), mean ± SD Time interval from poisoning to hospital (min), mean ± SD Ingested amount (mL), mean ± SD Lipid solubility of organophosphatea SBP (mm Hg), mean ± SD Saturation (%), mean ± SD Laboratory result WBC (/μL), mean ± SD Sugar (mg/dL), mean ± SD Amylase (IU/L), mean ± SD APACHEII score, mean ± SD QTc (ms), mean ± SD GCS, mean ± SD
47.54 ± 14.66 18:14 22.59 ± 2.47 247.25 ± 301.06
50.10 ± 16.35 20:20 22.84 ± 2.04 258.50 ± 368.35
.465 .623 .603 .982
231.55 ± 376.58 1.60 ± 0.80 120.07 ± 30.38 85.11 ± 19.00
187.78 ± 248.23 4.25 ± 0.85 133.00 ± 37.24 89.06 ± 19.75
.676 .000 .314 .578
12.312.76 ± 7,283.15 212.50 ± 122.63 237.68 ± 280.61 17.32 ± 11.81 443.26 ± 35.46 9.53 ± 4.85
12,623.42 ± 9,486.75 165.78 ± 80.84 135.10 ± 149.95 13.73 ± 10.03 432.93 ± 25.73 12.21 ± 3.54
.877 .253 .215 .353 .184 .148
Statistical significance was defined as a P value b.05. Abbreviations: SBP, systolic blood pressure; WBC, white blood cell. a Derived from log P = octanol/water coefficient.
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
K.Y. Jung et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx Table 3 Characteristics of high and low lipophilicity groups in obese patients with organophosphate poisoning Characteristic
Age (y), mean ± SD Male/Female, n BMI (kg/m2), mean ± SD Time interval from poisoning to hospital (min), mean ± SD Ingested amount (mL), mean ± SD Lipid solubility of organophosphatea SBP (mm Hg), mean ± SD Saturation (%), mean ± SD Laboratory result WBC (/μL), mean ± SD Sugar (mg/dL), mean ± SD Amylase (IU/L), mean ± SD APACHEII score, mean ± SD QTc (ms), mean ± SD GCS, mean ± SD
Obese patient (n = 40) High lipophilicity (n = 21)
53.78 ± 16.76 12:7 26.38 ± 2.01 165.43 ± 183.64
55.00 ± 14.13 12:9 26.02 ± 1.55 165.04 ± 220.71
.825 .944 .414 .696
310.36 ± 303.78
318.26 ± 291.04
.671
1.42 ± 0.84
4.11 ± 0.77
.000
134.50 ± 59.58 87.85 ± 13.71
149.52 ± 30.84 86.11 ± 7.06
.594 .224
15 529.23 ± 8597.90 180.54 ± 67.88 174.60 ± 149.52 13.77 ± 6.80 445.42 ± 18.34 12.01 ± 3.83
14 216.53 ± 7824.55 184.31 ± 72.78 164.62 ± 188.55 16.60 ± 7.41 438.83 ± 38.21 10.72 ± 4.72
.541 .795 .884 .283 .577 .678
Statistical significance was defined as a P value b.05. Abbreviations: SBP, systolic blood pressure; WBC, white blood cell. a Derived from log P = octanol/water coefficient
the intubation requirements or mortality between the low and high lipophilic organophosphates in the obese patients, although both of these groups had significantly higher rates of intubation and mortality than did the nonobese patients (Tables 4 and 5). 4. Discussion Organophosphate poisoning is a serious clinical entity and causes considerable mortality and organophosphate -induced delayed neuropathy in survivors. The estimated mortality after organophosphate ingestion ranges from 11% to 23% [7,20]. A recent study has demonstrated that obese and nonobese individuals may have a significantly different drug plasma concentration but similar tissue concentrations [21]. After the administration of a drug, the drug's distribution into the various tissues of the body depends on several factors that are primarily related to the physiochemical attributes of the drug: the molecular size, degree of ionization, lipid solubility, and ability to cross biological membranes
Table 4 Clinical outcomes of high and low lipophilicity groups in nonobese patients with organophosphate poisoning Nonobese patient (n = 72)
Initial SChE activity (mU/mL), median (range) SChE activity within 48 h of intoxication (mU/mL), median (range) PAM use (d), mean ± SD Intubation requirement, n Mechanical ventilation (d), mean ± SD ICU (d), mean ± SD Total admission (d), mean ± SD Mortality (n)
Table 5 Clinical outcomes of obese patients with organophosphate poisoning Obese patients (n = 40)
P
Low lipophilicity (n = 19)
P
Low lipophilicity (n = 32)
High lipophilicity (n = 40)
2160 (92-7261)
2015 (374-8222)
4001 (231-8519)
3582 (1340-5463)
4.39 ± 2.91 20 3.97 ± 2.88
4.84 ± 3.09 24 6.07 ± 7.91
.402 .699 .310
6.47 ± 7.25 10.93 ± 16.25
9.39 ± 10.24 13.26 ± 11.24
.480 .641
5
3
.569
Statistical significance was defined as a P value b.05. Abbreviation: SChE, serum cholinesterase.
3
Initial SChE activity(mU/mL), median (range) SChE activity within 48 h of intoxication (mU/mL), median (range) PAM use (d), mean ± SD Intubation requirement, n Mechanical ventilation (d), mean ± SD ICU (d), mean ± SD Total admission (d), mean ± SD Mortality (%)
P
Low lipophilicity (n = 19)
High lipophilicity (n = 21)
1926 (572-9261)
3012 (580-10544)
2952 (894-10079)
2115 (974-10790)
7.56 ± 4.83 16 6.70 ± 5.23
10.98 ± 5.69 19 13.54 ± 6.78
.769 .565 .002
9.01 ± 5.78 13.88 ± 8.73 4
17.18 ± 14.65 24.04 ± 15.17 5
.002 .006 1.000
Statistical significance was defined as a P value b.05. Abbreviation: SChE, serum cholinesterase.
[22]. The volume of distribution (Vd) of lipophilic drugs is usually altered to some extent in the obese individual [9]. Obese individuals have an increased absolute amount and proportion of adipose tissue compared with nonobese individuals. In the obese patient, the volume of the distribution of lipophilic drugs is markedly increased. Thus, the elimination half life may also be altered in obese patients. Most organophosphates have moderate to high lipid solubility [23]. Therefore, organophosphates have a high affinity for adipose tissue and a low tendency to remain in the vascular compartment. Several studies have evaluated the impact of obesity on the volume of distribution. Early work with barbiturates clearly demonstrated the close relationship between lipid solubility and drug distribution [24]. Although a few exceptions exist, lipid solubility is the most important variable in predicting the effect that obesity may have on drug distribution [25]. Drug lipophilicity is an imperfect measure for predicting drug distribution in obese individuals; however, for most drugs that are studied, lipophilicitiy contributes substantially to the variances in the calculated peripheral compartment volumes of distribution. For example, the absolute Vd of the relatively hydrophilic drug, daptomycin (an antibacterial agent), increases by approximately 2 to 4 L in the obese patients [26]. In contrast, the analogous increase for a highly lipophilic drug, docetaxel (an anticancer agent), is greater than 400 L [27]. Organophosphates have an affinity for adipose tissue and are therefore predicted to have a large volume of distribution. Adipose tissue gradually accumulates the highest concentrations of an organophosphate [28,29]. When large amounts of organophosphates are ingested with the intent of self-harm, the organophosphates are widely distributed and are later slowly released from the fatty tissue to the vascular compartment. Therefore, the effects of organophosphates are longer lasting in obese patients. The lipophilicities of organophosphates differ and the time to the peak serum concentration after the ingestion of organophosphate pesticides is unknown [2]. Therefore, the duration of toxicity persists because of the large volume of distribution. For example, methyl parathion has a relatively moderate lipophilicity, but its measurement has been reported in the body 48 days after ingestion [30]. This study excluded carbamates because most of them undergo hydrolysis, hydroxylation, and conjugation in the liver and intestinal wall, with 90% of carbamates excreted as metabolites in the urine within 3 to 4 days [31]. This study compared the clinical courses of obese and nonobese patients and used BMI to distinguish the 2 groups. Commonly used direct measures include underwater weighing, skin-fold measurement, bioelectrical impedance analysis, and dual-energy x-ray absorptiometry. Although these direct methodologies are useful for determining an individual's body composition, they are not readily
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
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available to most health care providers. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on the patient's attributes such as height, bodyweight, and sex. The weight and size descriptors used in pharmacokinetic studies and clinical practice include the following: BMI, body surface area, ideal body weight, lean body weight, and the newly described predicted normal weight. Body mass index is calculated by dividing the total body weight in kilograms by the square of the height in meters (ie, kg/m 2). Using the definitions of the National Institutes of Health and the World Health Organization, overweight is defined as a BMI of 25 to 29.9 kg/m 2, obese as a BMI of 30 to 39.9 kg/m 2, and morbidly obese as a BMI more than 40 kg/m 2. However, the current World Health Organization criteria classifying overweight and obesity in adults using BMI may not be appropriate for Asian or Pacific Island populations. For these populations, overweight is defined as a BMI of 23.0 to 24.9 kg/m 2, obese as a BMI of 25 to 29.9 kg/m 2, and morbidly obese as a BMI more than 30 kg/m 2 [18,19]. Indeed, it has been demonstrated that the increased risks associated with obesity occur at lower BMIs in Asians. This study divided patients into 2 groups according to the classification for Asians. Obese patients were defined as those with a BMI greater than 25 kg/m 2. Many factors that identify severely poisoned patients and that correlate with mortality have been reported. Their applications in therapy have not yet been studied. Because there was no statistical significance in mortality between the low and high lipophilic organophosphates, we analyzed only the survivors. In this study, the high lipophilicity group in the obese patients required longer duration of mechanical ventilation, ICU care, and total admission stay. A high BMI was significantly associated with a poor course in organophophate poisoning. Our results revealed that the obese organophosphate-poisoned patients required more intensive hospital management and a longer period of stay. Therefore, consideration of a patient's BMI can provide a guide to physicians in predicting the clinical course and reevaluating organophosphate -poisoned patients. Serum acetylcholinesterase (SChE) activity is often tested in organophosphate-poisoned patients. There were many controversial reports in the literature on the relationship between the severity of poisoning and the plasma cholinesterase level [20]. We checked the SChE levels to establish organophosphate poisoning and to predict the degree of toxicity. We routinely tested the SChE level twice in our center. The first blood sample was obtained as soon as the patient arrived. The second sampling was performed at the time suspected to be 48 hours after the organophosphate exposure. The SChE levels were decreased in the organophosphate poisoning groups (Tables 4 and 5). In some cases, we checked SChE again when the patient's condition did not improve as the physician expected. We did not check the serial SChE level during the entire hospitalization period. This study had several limitations. Only 112 of the 234 patients were enrolled. A prospective, multicenter study over a longer period could supplement this information. Another limitation is the various organophosphates involved in toxic exposure among the patients who were enrolled. In addition, prospective studies using a body fat analyzer to accurately measure obesity are needed. If the serial SChE levels of all of the patients during their entire hospitalization periods had been assessed, we also might conduct an analysis of the relationship between the SChE level and the clinical course. 5. Conclusions Most organophosphates are lipophilic and are therefore predicted to have large volumes of distribution. The concentration of organophosphate in the vascular compartment has a longer duration in obese patients. Thus, obese patients who are poisoned with an
organophosphate from the high lipophilic group have a longer toxic effect. In this study, the duration of both the mechanical ventilation and the ICU stay was longer in obese patients than in nonobese patients. The consideration of a patient's BMI can provide a guide to physicians in predicting the clinical courses and management of organophosphate-poisoned patients. References [1] Ahn JM, Nam KB, Lim JW, et al. Marked prolongation of QT interval and complete heart block caused by organophosphate poisoning. J Korean Soc Emerg Med 2006;70:S216–9. [2] Nelson LS, Lewin NA, Howland MA, et al. Goldfrank's toxicologic emergencies. 9th ed. McGraw Hill; 2011 1450–66. [3] Kim KW, Yoon SK, Jung YS, et al. Organophosphate pesticides. Clinical toxicology. 1st ed. Seoul: Koon Ja; 2006 182–207. [4] Thiermann H, Eyer F, Felgenhauer N, et al. Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds. Toxicol Lett 2010;197 (3):236–42 [Epub 2010 Jun 11]. 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Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Body mass index as a prognostic factor in organophosphate-poisoned patients Koo Young Jung, MD, PhD a,⁎, Duk Hee Lee, MD, PhD b, Yoon Hee Choi, MD, PhD a, Young Jin Cheon, MD, PhD a a b
Department of Emergency Medicine, Ewha Womans University, Seoul, Korea Department of Emergency Medicine, College of Medicine, Eulji University, Eulji Hospital, Seoul, Korea
a r t i c l e
i n f o
Article history: Received 23 January 2014 Received in revised form 9 April 2014 Accepted 11 April 2014 Available online xxxx
a b s t r a c t Organophosphate poisoning is a serious clinical entity and considerable morbidity and mortality. Several factors have been identified to predict outcomes of organophosphate poisoning. Organophosphates are lipophilic and therefore predicted to have a large volume of distribution and to rapidly distribute into tissue and fat. Thus, toxic effects of organophosphate would be expected to last longer in obese patients. We investigated the relationship between obesity and clinical course in 112 acute organophosphate-poisoned patients from an initial medical record review of 234 patients. One hundred twenty-two patients were excluded: 6 were children, 14 had an uncertain history of exposure and of uncertain agent, 10 were transferred to another hospital, 67 were discharged from the emergency department because their toxicity was mild, 21 had carbamate poisoning, and 4 did not have height or weight checked. Clinical features, body mass index, Glasgow Coma Scale, laboratory findings, serum cholinesterase activity, electrocardiogram finding, management, and outcomes were examined. The lipid solubility of the implicated organophosphate was characterized by its octanol/water coefficient. Forty of 112 patients were obese. Obese patients who were poisoned by high lipophilicity organophosphate compounds had a need for longer use of mechanical ventilation, intensive care unit care, and total length of admission. Body mass index can provide a guide to physicians in predicting clinical course and management in organophosphate-poisoned patients. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Organophosphate pesticides are widely used in agricultural setting throughout the world. Organophosphate pesticides are responsible for extensive morbidity and mortality because of their wide use and ready availability [1]. Organophosphate compounds were first introduced in the 1930s for use as pesticides. Since then, more than 50,000 organophosphorus compounds have been synthesized and commercially produced [2,3]. Organophosphate pesticides are responsible for up to 3 million cases of toxicity each year [4]. An estimated 200,000 individuals die in rural Asia where intentional selfharm is common. An estimated 3000 to 6000 ventilators are required in Asia alone to provide mechanical ventilation for organophosphatepoisoned patients [5]. Many reports in the literature have described the various factors that predict the outcome in acute organophosphate-poisoned patients. The recognized predictors of poor outcomes include the initial blood pressure, Glasgow Coma Scale (GCS), serum cholinesterase level, ⁎ Corresponding author at: Department of Emergency medicine, Ewha Womans University, Mok-dong 911-1, Yang-ChoenKu, Seoul 158-710, South Korea. Tel.: +82 2 2650 5296, +82 10 8880 5296(Mobile). E-mail addresses: [email protected] (K.Y. Jung), [email protected] (D.H. Lee).
Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and electrocadiographic findings (the prolongation of the QT interval) [6–8]. We investigated the parameters that assist clinicians in predicting the clinical outcome of organophosphate-poisoned patients. Obesity has dramatically increased worldwide in recent years and is a well-recognized health problem [9,10]. If the current trends persist, up to 58% of the world's adult population will be either overweight or obese by 2030 [11]. With the rise in obesity, clinicians will inevitably encounter obese patients in their practice. Obesity can affect the pharmacokinetics of drugs in humans. However, information regarding the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs remains limited [12–14]. It is widely believed that individuals with an abnormal body mass index (BMI) have poor outcomes. In a recent, large-cohort study of intensive care unit (ICU) patients in Europe, increased morbidity, but not mortality, was associated with higher BMI in patients [15]. Akinnusi et al [16] reported that obesity in critically ill patients is not associated with excess mortality but is significantly related to prolonged durations of both mechanical ventilation and the ICU length of stay. However, few data are available concerning the morbidity and mortality associated with obesity in organophosphate-poisoned patients. From a toxicologic perspective, the recognition of the impact of obesity is an important factor in the treatment and clinical course of these patients.
http://dx.doi.org/10.1016/j.ajem.2014.04.030 0735-6757/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
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K.Y. Jung et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx
We investigated the relationship between obesity and the clinical course in acute organophosphate-poisoned patients. 2. Methods Patients who were included in the study were treated following the standard guidelines for the treatment of organophosphate poisoning in our hospital. Activated charcoal was administered after gastric lavage for all patients. Both atropine and pralidoxime (PAM) were administered in accordance with hospital protocol. The PAM was administered first as a loading dose of 1 g for 30 minutes, after which it was infused continuously at 800 mg/h. The patient then either underwent endotracheal intubation or was admitted to the ICU, in compliance with general standards, after obtaining consent from a guardian. We analyzed the data for the following variables: demographic factors (date of arrival, sex and age of patient, height, weight, and BMI), medical history, history of intoxication (ingredients of the organophosphate, lipid solubility of the organophosphate, time and route of exposure, amount ingested, suicidal intention), clinical manifestations, GCS, initial vital signs (respiratory rate, heart rate, systolic blood pressure), initial blood tests (white blood cell count, hematocrit, platelet count, serum blood urea nitrogen, creatinine, sodium and potassium concentration, amylase, arterial blood gas analysis), serum cholinesterase activity, electrocardiographic results (corrected QT [QTc] interval), treatments received (duration of atropine and PAM administration, whether endotracheal intubation performed, total duration of mechanical ventilation, total duration of ICU stay, total duration of admission), mortality, and APACHE II score. The logarithm of the partition coefficient for the n-octanol and water, log P, reflects the equilibrium partitioning a molecule between a nonpolar and a polar phase. The lipophilicity can be measured by log P [17]. Cross-tabulation was performed for noncontinuous variables using the PASW (SPSS, Chicago, IL) version 18, and Student t test was used for continuous variables. Multivariate linear regression and multivariate logistic regression analyses (as appropriate) were used to analyze the variables. A P value less than .05 was considered statistically significant. 3. Results We reviewed the medical records of 234 patients. One hundred twenty-two of these patients were excluded. The following patients were excluded from the study for a variety of reasons. There were 6 children. Fourteen patients had an uncertain history of exposure and uncertain agents of exposure. Ten patients were transferred to another hospital. Sixty-seven patients were discharged from the emergency department because their toxicity levels were mild. Twenty-one patients were exposed to carbamate poisoning. The height or weight was not recorded for 4 patients. A total of 112 subjects were enrolled. The substances responsible for the poisonings were chlorpyrifos (n = 20, log P = 5.05), methidathion (n = 17, log P = 2.35), dichlorvos (n = 12, log P = 1.56), phosphamidon (n = 10, log P = 0.795), malathion (n = 9, log P = 2.75), dimethoate (n = 9, log P = 0.76), parathion (n = 4, log P = 3.83), fenithrothion (n = 4, log P = 3.37), phentoate (n = 3, log P = 3.69), chlorfluazuron (n = 2), and others (log P = octanol/water coefficient) [17] (Table 1). In Asians, a BMI less than 18.5 kg/m2 is defined as underweight; 18.5 to 22.9 kg/m 2, normal weight; 23.0 to 24.9 kg/m2, overweight; 25 to 29.9 kg/m2, obese; and more than 30 kg/m2, morbidly obese [18,19]. In this study, we set a BMI of 25 kg/m 2 as the standard to distinguish the normal BMI group from the abnormal BMI group. Therefore, “obese patients” were defined as those with a BMI greater than 25 kg/m 2. There were 112 patients with 32 different lipid solubilities of organophosphate substances. The separation point for the low and high lipophilic groups is the median of the lipid solubility of the organophosphates.
Table 1 Types of poisoning agents Organophosphates
Relative lipophilicity
(log P)a
Frequency
Chlorpyrifos Methidathion Dichlorvos Phosphamidon Malathion Dimethoate Parathion Fenithrothion Phentoate Chlorfluazuron Others Total
+++++ +++ ++ + +++ + ++++ ++++ ++++
(5.05) (2.35) (1.56) (0.795) (2.75) (0.76) (3.83) (3.37) (3.69)
20 17 12 10 9 9 4 4 3 2 22 112
a
Derived from log P = octanol/water coefficient.
3.1. General characteristics of low and high lipophilicity groups in obese and nonobese patients in organophosphate poisoning Of the 112 enrolled patients, 41 were obese (BMIs N25 kg/m 2). The mean BMI of the obese patients with low lipophilicity agents was 26.38 ± 2.01 25 kg/m 2, and the mean BMI of the patients with high lipophilicity agents was 26.02 ± 1.55 25 kg/m 2 (P = .414). The low and high lipophilicity groups were compared in the obese and nonobese groups, respectively. There were no significant differences in the age, sex, time interval from poisoning to hospital arrival, amount of organophosphate ingested, initial saturation, QTc interval, APACH II score, or GCS (Tables 2 and 3). 3.2. Clinical outcomes between the low and high lipophilicity groups of obese patients and nonobese patients in organophosphate poisoning In the nonobese patients, the duration of the mechanical ventilation, ICU care, and total admission stay were not significantly longer in the high lipophilic group compared with the low lipophilic group. In the obese patients, the duration of the mechanical ventilation (P = .001), ICU care (P = .002), and total admission stay (P = .006) were significantly longer in the high lipophilic group compared with the low lipophilic group (6.70 ± 5.23 days vs 13.54 ± 6.78 days, 9.01 ± 5.78 days vs 17.18 ± 14.65 days, and 13.88 ± 8.73 days vs 24.04 ± 15.17 days, respectively). There was no statistically significant difference in Table 2 Characteristics of high and low lipophilicity groups in nonobese patients with organophosphate poisoning Characteristic
Nonobese patient (n = 72)
P
Low lipophilicity High lipophilicity (n = 32) (n = 40) Age (y), mean ± SD Male/Female, n BMI (kg/m2), mean ± SD Time interval from poisoning to hospital (min), mean ± SD Ingested amount (mL), mean ± SD Lipid solubility of organophosphatea SBP (mm Hg), mean ± SD Saturation (%), mean ± SD Laboratory result WBC (/μL), mean ± SD Sugar (mg/dL), mean ± SD Amylase (IU/L), mean ± SD APACHEII score, mean ± SD QTc (ms), mean ± SD GCS, mean ± SD
47.54 ± 14.66 18:14 22.59 ± 2.47 247.25 ± 301.06
50.10 ± 16.35 20:20 22.84 ± 2.04 258.50 ± 368.35
.465 .623 .603 .982
231.55 ± 376.58 1.60 ± 0.80 120.07 ± 30.38 85.11 ± 19.00
187.78 ± 248.23 4.25 ± 0.85 133.00 ± 37.24 89.06 ± 19.75
.676 .000 .314 .578
12.312.76 ± 7,283.15 212.50 ± 122.63 237.68 ± 280.61 17.32 ± 11.81 443.26 ± 35.46 9.53 ± 4.85
12,623.42 ± 9,486.75 165.78 ± 80.84 135.10 ± 149.95 13.73 ± 10.03 432.93 ± 25.73 12.21 ± 3.54
.877 .253 .215 .353 .184 .148
Statistical significance was defined as a P value b.05. Abbreviations: SBP, systolic blood pressure; WBC, white blood cell. a Derived from log P = octanol/water coefficient.
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
K.Y. Jung et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx Table 3 Characteristics of high and low lipophilicity groups in obese patients with organophosphate poisoning Characteristic
Age (y), mean ± SD Male/Female, n BMI (kg/m2), mean ± SD Time interval from poisoning to hospital (min), mean ± SD Ingested amount (mL), mean ± SD Lipid solubility of organophosphatea SBP (mm Hg), mean ± SD Saturation (%), mean ± SD Laboratory result WBC (/μL), mean ± SD Sugar (mg/dL), mean ± SD Amylase (IU/L), mean ± SD APACHEII score, mean ± SD QTc (ms), mean ± SD GCS, mean ± SD
Obese patient (n = 40) High lipophilicity (n = 21)
53.78 ± 16.76 12:7 26.38 ± 2.01 165.43 ± 183.64
55.00 ± 14.13 12:9 26.02 ± 1.55 165.04 ± 220.71
.825 .944 .414 .696
310.36 ± 303.78
318.26 ± 291.04
.671
1.42 ± 0.84
4.11 ± 0.77
.000
134.50 ± 59.58 87.85 ± 13.71
149.52 ± 30.84 86.11 ± 7.06
.594 .224
15 529.23 ± 8597.90 180.54 ± 67.88 174.60 ± 149.52 13.77 ± 6.80 445.42 ± 18.34 12.01 ± 3.83
14 216.53 ± 7824.55 184.31 ± 72.78 164.62 ± 188.55 16.60 ± 7.41 438.83 ± 38.21 10.72 ± 4.72
.541 .795 .884 .283 .577 .678
Statistical significance was defined as a P value b.05. Abbreviations: SBP, systolic blood pressure; WBC, white blood cell. a Derived from log P = octanol/water coefficient
the intubation requirements or mortality between the low and high lipophilic organophosphates in the obese patients, although both of these groups had significantly higher rates of intubation and mortality than did the nonobese patients (Tables 4 and 5). 4. Discussion Organophosphate poisoning is a serious clinical entity and causes considerable mortality and organophosphate -induced delayed neuropathy in survivors. The estimated mortality after organophosphate ingestion ranges from 11% to 23% [7,20]. A recent study has demonstrated that obese and nonobese individuals may have a significantly different drug plasma concentration but similar tissue concentrations [21]. After the administration of a drug, the drug's distribution into the various tissues of the body depends on several factors that are primarily related to the physiochemical attributes of the drug: the molecular size, degree of ionization, lipid solubility, and ability to cross biological membranes
Table 4 Clinical outcomes of high and low lipophilicity groups in nonobese patients with organophosphate poisoning Nonobese patient (n = 72)
Initial SChE activity (mU/mL), median (range) SChE activity within 48 h of intoxication (mU/mL), median (range) PAM use (d), mean ± SD Intubation requirement, n Mechanical ventilation (d), mean ± SD ICU (d), mean ± SD Total admission (d), mean ± SD Mortality (n)
Table 5 Clinical outcomes of obese patients with organophosphate poisoning Obese patients (n = 40)
P
Low lipophilicity (n = 19)
P
Low lipophilicity (n = 32)
High lipophilicity (n = 40)
2160 (92-7261)
2015 (374-8222)
4001 (231-8519)
3582 (1340-5463)
4.39 ± 2.91 20 3.97 ± 2.88
4.84 ± 3.09 24 6.07 ± 7.91
.402 .699 .310
6.47 ± 7.25 10.93 ± 16.25
9.39 ± 10.24 13.26 ± 11.24
.480 .641
5
3
.569
Statistical significance was defined as a P value b.05. Abbreviation: SChE, serum cholinesterase.
3
Initial SChE activity(mU/mL), median (range) SChE activity within 48 h of intoxication (mU/mL), median (range) PAM use (d), mean ± SD Intubation requirement, n Mechanical ventilation (d), mean ± SD ICU (d), mean ± SD Total admission (d), mean ± SD Mortality (%)
P
Low lipophilicity (n = 19)
High lipophilicity (n = 21)
1926 (572-9261)
3012 (580-10544)
2952 (894-10079)
2115 (974-10790)
7.56 ± 4.83 16 6.70 ± 5.23
10.98 ± 5.69 19 13.54 ± 6.78
.769 .565 .002
9.01 ± 5.78 13.88 ± 8.73 4
17.18 ± 14.65 24.04 ± 15.17 5
.002 .006 1.000
Statistical significance was defined as a P value b.05. Abbreviation: SChE, serum cholinesterase.
[22]. The volume of distribution (Vd) of lipophilic drugs is usually altered to some extent in the obese individual [9]. Obese individuals have an increased absolute amount and proportion of adipose tissue compared with nonobese individuals. In the obese patient, the volume of the distribution of lipophilic drugs is markedly increased. Thus, the elimination half life may also be altered in obese patients. Most organophosphates have moderate to high lipid solubility [23]. Therefore, organophosphates have a high affinity for adipose tissue and a low tendency to remain in the vascular compartment. Several studies have evaluated the impact of obesity on the volume of distribution. Early work with barbiturates clearly demonstrated the close relationship between lipid solubility and drug distribution [24]. Although a few exceptions exist, lipid solubility is the most important variable in predicting the effect that obesity may have on drug distribution [25]. Drug lipophilicity is an imperfect measure for predicting drug distribution in obese individuals; however, for most drugs that are studied, lipophilicitiy contributes substantially to the variances in the calculated peripheral compartment volumes of distribution. For example, the absolute Vd of the relatively hydrophilic drug, daptomycin (an antibacterial agent), increases by approximately 2 to 4 L in the obese patients [26]. In contrast, the analogous increase for a highly lipophilic drug, docetaxel (an anticancer agent), is greater than 400 L [27]. Organophosphates have an affinity for adipose tissue and are therefore predicted to have a large volume of distribution. Adipose tissue gradually accumulates the highest concentrations of an organophosphate [28,29]. When large amounts of organophosphates are ingested with the intent of self-harm, the organophosphates are widely distributed and are later slowly released from the fatty tissue to the vascular compartment. Therefore, the effects of organophosphates are longer lasting in obese patients. The lipophilicities of organophosphates differ and the time to the peak serum concentration after the ingestion of organophosphate pesticides is unknown [2]. Therefore, the duration of toxicity persists because of the large volume of distribution. For example, methyl parathion has a relatively moderate lipophilicity, but its measurement has been reported in the body 48 days after ingestion [30]. This study excluded carbamates because most of them undergo hydrolysis, hydroxylation, and conjugation in the liver and intestinal wall, with 90% of carbamates excreted as metabolites in the urine within 3 to 4 days [31]. This study compared the clinical courses of obese and nonobese patients and used BMI to distinguish the 2 groups. Commonly used direct measures include underwater weighing, skin-fold measurement, bioelectrical impedance analysis, and dual-energy x-ray absorptiometry. Although these direct methodologies are useful for determining an individual's body composition, they are not readily
Please cite this article as: Jung KY, et al, Body mass index as a prognostic factor in organophosphate-poisoned patients, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.030
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available to most health care providers. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on the patient's attributes such as height, bodyweight, and sex. The weight and size descriptors used in pharmacokinetic studies and clinical practice include the following: BMI, body surface area, ideal body weight, lean body weight, and the newly described predicted normal weight. Body mass index is calculated by dividing the total body weight in kilograms by the square of the height in meters (ie, kg/m 2). Using the definitions of the National Institutes of Health and the World Health Organization, overweight is defined as a BMI of 25 to 29.9 kg/m 2, obese as a BMI of 30 to 39.9 kg/m 2, and morbidly obese as a BMI more than 40 kg/m 2. However, the current World Health Organization criteria classifying overweight and obesity in adults using BMI may not be appropriate for Asian or Pacific Island populations. For these populations, overweight is defined as a BMI of 23.0 to 24.9 kg/m 2, obese as a BMI of 25 to 29.9 kg/m 2, and morbidly obese as a BMI more than 30 kg/m 2 [18,19]. Indeed, it has been demonstrated that the increased risks associated with obesity occur at lower BMIs in Asians. This study divided patients into 2 groups according to the classification for Asians. Obese patients were defined as those with a BMI greater than 25 kg/m 2. Many factors that identify severely poisoned patients and that correlate with mortality have been reported. Their applications in therapy have not yet been studied. Because there was no statistical significance in mortality between the low and high lipophilic organophosphates, we analyzed only the survivors. In this study, the high lipophilicity group in the obese patients required longer duration of mechanical ventilation, ICU care, and total admission stay. A high BMI was significantly associated with a poor course in organophophate poisoning. Our results revealed that the obese organophosphate-poisoned patients required more intensive hospital management and a longer period of stay. Therefore, consideration of a patient's BMI can provide a guide to physicians in predicting the clinical course and reevaluating organophosphate -poisoned patients. Serum acetylcholinesterase (SChE) activity is often tested in organophosphate-poisoned patients. There were many controversial reports in the literature on the relationship between the severity of poisoning and the plasma cholinesterase level [20]. We checked the SChE levels to establish organophosphate poisoning and to predict the degree of toxicity. We routinely tested the SChE level twice in our center. The first blood sample was obtained as soon as the patient arrived. The second sampling was performed at the time suspected to be 48 hours after the organophosphate exposure. The SChE levels were decreased in the organophosphate poisoning groups (Tables 4 and 5). In some cases, we checked SChE again when the patient's condition did not improve as the physician expected. We did not check the serial SChE level during the entire hospitalization period. This study had several limitations. Only 112 of the 234 patients were enrolled. A prospective, multicenter study over a longer period could supplement this information. Another limitation is the various organophosphates involved in toxic exposure among the patients who were enrolled. In addition, prospective studies using a body fat analyzer to accurately measure obesity are needed. If the serial SChE levels of all of the patients during their entire hospitalization periods had been assessed, we also might conduct an analysis of the relationship between the SChE level and the clinical course. 5. Conclusions Most organophosphates are lipophilic and are therefore predicted to have large volumes of distribution. The concentration of organophosphate in the vascular compartment has a longer duration in obese patients. Thus, obese patients who are poisoned with an
organophosphate from the high lipophilic group have a longer toxic effect. In this study, the duration of both the mechanical ventilation and the ICU stay was longer in obese patients than in nonobese patients. The consideration of a patient's BMI can provide a guide to physicians in predicting the clinical courses and management of organophosphate-poisoned patients. References [1] Ahn JM, Nam KB, Lim JW, et al. Marked prolongation of QT interval and complete heart block caused by organophosphate poisoning. J Korean Soc Emerg Med 2006;70:S216–9. [2] Nelson LS, Lewin NA, Howland MA, et al. Goldfrank's toxicologic emergencies. 9th ed. McGraw Hill; 2011 1450–66. [3] Kim KW, Yoon SK, Jung YS, et al. Organophosphate pesticides. Clinical toxicology. 1st ed. Seoul: Koon Ja; 2006 182–207. [4] Thiermann H, Eyer F, Felgenhauer N, et al. Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds. Toxicol Lett 2010;197 (3):236–42 [Epub 2010 Jun 11]. 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