Clinical Toxicology (2014), 52, 873–879 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2014.944976
CRITICAL CARE
Features of myocardial injury in severe organophosphate poisoning Y. S. CHA, H. KIM, J. GO, T. H. KIM, O. H. KIM, K. C. CHA, K. H. LEE, and S. O. HWANG
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Department of Emergency Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
Background. In organophosphate (OP) poisoning cardiac complications may occur. However, the current body of knowledge largely consists of limited studies, and case reports are mainly on electrocardiogram (ECG) abnormalities. As definite myocardial injury is difficult to assess through ECG, we investigated the prevalence of myocardial injury through cardiac biochemical markers such as troponin I (TnI) in severe OP poisoning. Methods. We conducted a retrospective review of 99 consecutive OP insecticide poisoning cases that were diagnosed and treated at the emergency department of the Wonju Severance Christian Hospital between March 2008 and December 2013. Results. Based on Namba classification for OP poisoning, there were no patients with mild toxicity, 9 patients (9.1%) with moderate toxicity and 90 patients (90.9%) with severe toxicity. On ECG, normal sinus rhythm was most common, and ST depression and elevation were seen in 11 patients (11.1%). Elevation of TnI within 48 h was seen in 34 patients (34.3%). The median peak level and peak time of TnI were 0.305 (IQR, 0.078–2.335) ng/mL and 15 (IQR 6.9–34.4) hours, respectively. There were differences between patients with normal TnI and elevated TnI in terms of age (yrs), number of patients who were exposed to OP via the oral route, and initial Glasgow Coma Scale (GCS; 58 ⫾ 17 vs. 66 ⫾ 16, p ⫽ 0.015, 56 [87.5%] vs. 33 [97.1%], p ⫽ 0.048 and 12.0 [IQR, 8.0–15.0] vs. 9.0 [IQR, 5.8–12.0], p ⫽ 0.019). Conclusions. OP can cause direct myocardial injury during the acute early phase in severe OP poisoning. Monitoring of TnI may be needed in severe OP poisoning. Keywords
Organophosphate; Myocardial injury; Troponin I
Introduction
the current body of knowledge largely consists of limited studies and case reports based mainly on electrocardiogram (ECG) abnormalities. In addition, no studies have evaluated cardiac biochemical markers. It is difficult to diagnose definite myocardial injury based on ECG alone. Therefore, we investigated the prevalence of myocardial injury through cardiac biochemical markers such as troponin I (TnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) in severe OP poisoning.
Organophosphate (OP) insecticides irreversibly inhibit acetylcholinesterase and cause accumulation of acetylcholine (Ach) and overstimulation of cholinergic synapses in the central nervous system, somatic nerves, parasympathetic nerve endings, and sweat glands.1,2 Even though the most common complication is the respiratory failure, cardiac complications may also occur after OP poisoning.2,3 Generally, cardiac complications from OP are known by the three phases in a study by Ludomirsky et al.4 An initial intense sympathetic phase is followed by a second prolonged parasympathetic phase that is usually accompanied by hypoxemia, often manifests as ST–T changes, and shows A–V conduction disturbances which can degenerate to ventricular fibrillation (VF). The third phase of QT prolongation is followed by Torsade de Pointes (TdP) and VF. Cardiac complications, such as various arrhythmias, conduction disturbances, hypertension-hypotension, and myocardial damage, have been reported with OP poisoning.5–7 However,
Methods Study design and data This is a retrospective and observational study of consecutive patients who were diagnosed with acute OP insecticide poisoning between March 2008 and December 2013 in the emergency department (ED) of The Wonju Severance Christian Hospital, Wonju College of Medicine, Yonsei University. Poisoning with OP was confirmed by patient or guardian statements, and verification of the agent was performed by an emergency physician who transcribed the bottle label into patient records. Levels of serum pseudocholinesterase were also used to confirm OP poisoning. OP was classified into Class I, II, or III based on the WHO classification scheme.8
Received 13 March 2014; accepted 9 July 2014. Address correspondence to Hyun Kim, MD, Department of Emergency Medicine, Wonju College of Medicine, Yonsei University, 162 Ilsandong, Wonju 220-701, Republic of Korea. Tel: ⫹ 82-33-741-1614. Fax: ⫹ 82-33-742-3030. E-mail: [email protected]
873
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874 Y. S. Cha et al. In the absence of sufficient information, patients were left unclassified. Data were retrospectively collected from medical records and reviewed. The following parameters were assessed: age, gender, the ingested amount of OP, class of OP, cause of poisoning, elapsed time from ingestion to arrival at the ED, route of poisoning, initial mental status (Glasgow Coma Scale [GCS]), ECG, initial vital signs, and mortality, etc. We defined the amount of OP ingested as follows: “a little” or “a spoonful” was taken to be 5 mL, “a mouthful” was presumed to be 25 mL, “a small cup” was presumed to be 100 mL, and “a bottle” was presumed to be 300 mL.9 We assessed atropine dosage for 48 h and duration of atropine used, as this drug may affect the heart. We evaluated arterial blood gas, serum lactate, complete blood count, electrolyte levels (sodium, potassium), blood urea nitrogen, creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, and serum pseudocholinesterase in the ED. CK-MB, TnI, and BNP were investigated as cardiac biochemical markers in the ED. In case of elevated TnI, it has been followed up after admission. We used high sensitivity TnI (Siemens Healthcare Diagnostics Inc., Newark, DE, USA). The corrected QT interval (QTc) on the ECG was calculated using Bazett’s formula, and prolonged QTc interval was defined as more than 440 ms.10 Clinical courses were defined as respiratory failure requiring mechanical ventilation, hypotension (systolic blood pressure ⬍ 90 mm Hg), pneumonia, GCS less than 15, and death. We investigated the prevalence of TnI elevation within 48 h and if TnI was elevated, we also evaluated peak level of TnI and time when it was reached peak level. We compared the general characteristics of groups with or without TnI elevation and intensive care unit (ICU) admission length and total admission length were used to compare prognosis between the two groups. The study was approved by the institutional review board committee of Wonju College of Medicine, Yonsei University (approval number YWMR-14-5-003)
(0 patients), poisoning with any additional material except for alcohol (10 patients), acute coronary syndrome and end-stage renal disease (3 patients), cardiac arrest upon ED arrival (7 patients), and insufficient data (4 patients; Fig. 1). Between 2008 and 2013, the total number of patients who visited our hospital ED ranged from 29,326 and 40,465 patients annually. There were 64 men (64.6%), with ages ranging from 22 to 90 years with a mean of 61 ⫾ 17 years. The median ingested amount of OP was 100 (IQR 50–200) cc, and 80 patients (80.8%) had been exposed to OP with suicidal intention. Absorbed OP included chloropyrifos, dichlorvos, diazinon, parathion, methidathion, phenothoate, etc. Totally 15 patients (15.2%) and 39 patients (39.4%) were poisoned by Classes I and II, respectively. No patients were poisoned by Class III. Using Namba classification for OP poisoning,11 0 patients had mild toxicity, 9 patients (9.1%) had moderate toxicity, and 90 patients (90.9%) had severe toxicity (Table 1). The average initial GCS was 11 (IQR 7–15), and 35 patients (35.4%) had co-ingested alcohol. Fifteen patients (15.2%) had initial hypoxia (PaO2 ⬍ 60 mmHg) and 17 patients (17.5%) had shock (systolic blood pressure ⬍ 90 mmHg). Ninty-seven patients (98%) received pralidoxime and 90 patients (90.9%) received atropine. Atropine dosages for 48-h and duration of atropine used were 102.6 (IQR 40.0–172.0) mg and 4.0 (IQR 2.0–7.5) days, respectively (Table 1). On ECG, normal sinus rhythm was most common when analyzing rate, and ST depression and elevation were seen in 11 patients (11.1%). Of these, ST abnormalities in 10 patients were normalized with treatment. QT prolongation
Statistical analysis Statistical analyses were performed using SPSS software for Windows (V.20.0 K, SPSS, Chicago, IL, USA). Nominal data are presented as frequencies and percentages, and continuous variables are presented as mean and standard deviation (SD) and median and interquartile range (IQR) after investigating for normality using the Shapiro–Wilk test. The chi-square test or Fisher’s exact test were used for comparison of nominal variables, while the two-sample t-test and Mann–Whitney U-test were used to compare continuous variables. P values less than 0.05 were considered statistically significant.
Results General and laboratory characteristics of patients with OP poisoning A total of 123 consecutive patients were identified for this study. Exclusion criteria were age below 18 years
Fig. 1. Numbers of Patients assessed, excluded, and included. ED: Emergency Department. Clinical Toxicology vol. 52 no. 8 2014
Myocardial injury in organophosphate poisoning 875 Table 1. Characteristics and laboratory findings of patients poisoned with organophosphate according to the presence of elevated troponin I.
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Characteristics Age (years) Male ED arrival time (minutes) Amount (cc) Route (oral) Intentional poisoning Coingested with alcohol Class of organophosphate Class I Class II Class III Unclassified Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (per minute) Respiratory rate (per minute) Initial GCS Initial hypoxia (PaO2 ⬍ 60mmHg) Initial shock (systolic BP ⬍ 90mmHg) Namba classification Mild Moderate Severe Gastric lavage Activated charcoal Use of pralidoxime Use of atropine Atropine dosage for 48 h (mg) Total atropine dosage (mg) Duration of atropine (days) Laboratoty findings Initial CK (U/L) Pseudocholinesterase(U/L) Lactate (mmol/L) BUN (mg/dL) Cr (mg/dL) Glucose (mg/dL) Amylase (U/L) Clinical courses Respiratory failure requiring mechanical ventilation Shock (systolic BP ⬍ 90mmHg) Use of adrenergic agents Pneumonia GCS ⬍ 15 Outcomes Total admission days ICU admission days
Total (n ⫽ 99)
Non-elevation of troponin I group (n ⫽ 65; 65.7%)
Elevation of troponin I group (n ⫽ 34; 34.3%)
61 ⫾ 17* 64 (64.6%) 156 (77–290)† 100 (50–200)† 89 (89.9%) 80 (80.8%) 35 (35.4%)
58 ⫾ 17* 45 (69.2%) 160 (75–271)† 100 (35–138)† 56 (87.5%) 51 (79.7%) 25 (46.3%)
66 ⫾ 16* 19 (55.9%) 154 (77–369)† 150 (50–300)† 33 (97.1%) 29 (87.9%) 10 (37.0%)
15 (15.2%) 39 (39.4%) 0 (0.0%) 45 (45.5%) 132 ⫾ 41* 78 ⫾ 22* 96 ⫾ 20* 20 (18–20)† 11 (7–15)† 15 (15.2%) 17 (17.5%)
8 (12.3%) 28 (43.1%) 0 (0.0%) 29 (44.6%) 133 ⫾ 36* 79 ⫾ 19* 95 ⫾ 17* 20 (18–22)† 12.0 (8.0–15.0)† 10 (15.4%) 8 (12.7%)
7 (20.6%) 11 (32.4%) 0 (0.0%) 16 (47.1%) 130 ⫾ 49* 78 ⫾ 28* 98 ⫾ 25* 20 (18–20)† 9.0 (5.8–12.0)† 5 (14.7%) 9 (26.5%)
p value 0.015 0.187 0.816 0.221 0.048 0.315 0.428 0.429
0.706 0.937 0.597 0.897 0.019 0.929 0.089 0.026
0 (0.0%) 9 (9.1%) 90 (90.9%) 25 (25.3%) 70 (70.7%) 97 (98%) 90 (90.9%) 102.6 (40.0–172.0)† 195.3 (50.0–406.1)† 4.0 (2.0–7.5)†
0 (0.0%) 9 (13.8%) 56 (86.2%) 16 (25.4%) 48 (78.7%) 64 (98.5%) 60 (92.3%) 101.0 (35.5–170.0)† 172.5 (40.3–367.5)† 3.0 (2.0–4.3)†
0 (0.0%) 0 (0.0%) 34 (100%) 9 (27.3%) 22 (66.7%) 33 (97.1.0%) 30 (90.9%) 112.0 (43.0–216.3)† 220.0 (105.3–466.8)† 4.0 (3.0–12.0)†
0.842 0.202 1.000 1.000 0.610 0.181 0.026
145.0 (97.8–226.0)† 335 (285–1224)† 3.55 (2.34–5.72)† 16.0 (11.1–20.0)† 0.9 (0.6–1.0)† 167 (130–240)† 94.0 (60.0–205.0)†
146.0 (80.5–218.0)† 390 (296–1765)† 3.39 (2.10–5.12)† 15.8 (12.0–19.0)† 0.78 (0.60–0.91)† 158 (121–235)† 85 (55–181)†
136.5 (102.5–228.0)† 301 (259–484)† 4.58 (2.72–7.35)† 16.0 (11.0–21.0)† 0.91 (0.70–1.23)† 194 (154–280)† 130 (65–228)†
0.771 0.028 0.053 0.732 0.015 0.015 0.086
77 (77.8%) 19 (19.2%) 12 (63.2%) 37 (37.4%) 73 (73.7%)
46 (70.8%) 10 (15.4%) 5 (50.0%) 18 (27.7%) 44 (67.7%)
10 (4–21)† 6 (2–14)†
9.0 (4.0–19.0)† 5.0 (2.0–12.0)†
31 (91.2%) 9 (26.5%) 7 (77.8%) 19 (55.9%) 29 (85.3%)
0.020 0.184 0.350 0.006 0.059
15.5 (5.0–21.0)† 9.0 (3.8–18.0)†
0.347 0.041
ED, Emergency Department; BP, Blood Pressure; BUN, Blood Urea Nitrogen; Cr, Creatinine; CK, creatine kinase; GCS, Glasgow Coma Scale; ICU, Intensive Care Unit. *Mean ⫾ Standard deviation. †Median (interquartile range).
was seen in 69 patients (69.7%). On cardiac biochemical markers analysis, the median initial levels of TnI, CK-MB, and BNP were 0.015 (IQR 0.009–0.022) ng/mL, 1.91 (IQR 1.01–3.91) ng/mL, and 18.3 (IQR 7.9–55.1) pg/mL, respectively (Table 2). Serum lactate was 3.55 (IQR 2.34–5.72) mmol/L. Median hemoglobin was 14.2 (IQR 13.3–15.3) and serum pseudocholinesterase was 335 (IQR 285–1224) U/L (Table 1). Copyright © Informa Healthcare USA, Inc. 2014
Clinical courses after OP poisoning included respiratory failure requiring ventilator care (77 patients, 77.8%), shock (systolic blood pressure ⬍ 90 mm Hg; 19 patients, 19.2%), pneumonia (37 patients, 37.4%), and GCS below 15 (73 patients, 73.7%). In shock patients, adrenergic agents were used to 12 patients (63.2%). Total admission length and ICU admission length were 10 (IQR 4–21) and 6 (IQR 2–14) days, respectively. Eighteen patients (18.2%) died after admission
876 Y. S. Cha et al. Table 2. Characteristics of electrical and myocardial injury.
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Characteristics ECG Rate Normal sinus rhythm Sinus tachycardia Sinus bradycardia ST and T wave change Normal ST depression ST elevation ST change normalization QT prolongation (⬎ 440ms) Normal Prolongation PR prolongation (⬎ 120ms) Normal Prolongation Laboratoty findings Initial troponin I (ng/mL) Initial CK-MB (ng/mL) Initial BNP (pg/mL)
Total (n ⫽ 99)
Non-elevation of troponin I group (n ⫽ 65; 65.7%)
Elevation of troponin I group (n ⫽ 34; 34.3%)
57 (57.6%) 37 (37.4%) 3 (3.0%)
40 (63.5%) 20 (31.7%) 3 (4.8%)
17 (50.0%) 17 (50.0%) 0 (0%)
86 (86.9%) 7 (7.1%) 4 (4.0%) 10 (90.9%)
57 (90.5%) 4 (6.3%) 2 (3.2%) 6 (100%)
29 (85.3%) 3 (8.8%) 2 (5.9%) 4 (80.0%)
0.455
28 (28.3%) 69 (69.7%)
45 (71.4%)
24 (70.6%)
0.931
89 (89.9%) 3 (3.0%)
2 (3.2%)
1 (3.3%)
1.000
p value 0.126
0.673
0.015 (0.009–0.022)† 0.015 (0.008–0.015)† 1.68 (0.98–3.64)† 1.91 (1.01–3.91)† 15.8 (6.1–50.5)† 18.3 (7.9–55.1)†
0.048 (0.015–0.125)† ⬍ 0.001 2.22 (1.06–4.03)† 0.569 21.3 (14.6–105.2)† 0.052
ECG, electrocardiogram; CK-MB, creatine kinase MB; BNP, B-type natriuretic peptide. †Median (interquartile range).
(Table 1). Causes of mortality were acute kidney injury (3 patients, 16.7%), respiratory failure (4 patients, 22.2%), and multi-organ failure (11 patients, 61.1%), respectively.
TnI and patients with elevated TnI (Table 1) and also presence of shock or hypoxia statistically did not relate to the elevated TnI (Table 3). Serum lactate was 3.39 (IQR 2.10–5.12) mmol/L in patients with normal TnI and 4.58 (IQR 2.72–7.35) mmol/L in patients with elevated TnI (p ⫽ 0.053). Serum creatinine (Cr) and glucose were (0.78 [IQR 0.60–0.91] mg/dL vs. 0.91 [IQR 0.70–1.23] mg/dL, p ⫽ 0.015) and (158 [IQR 121–235] mg/dL vs. 194 [IQR 154–280] mg/dL, p ⫽ 0.015) in the normal TnI and elevated TnI groups, respectively. Serum pseudocholinesterase was 390 (IQR 296–1765) mg/ dL in the normal TnI group and 301 (IQR 259–484) mg/ dL in elevated TnI group (p ⫽ 0.028; Table 1). There were no differences in arterial blood gas, complete blood count, electrolyte (sodium, potassium), and liver function test (AST and ALT; data not shown). Forty-six (70.8%) patients with normal TnI and 31 patients (91.2%) with elevated TnI had respiratory failure requiring ventilator care (p ⫽ 0.020). Pneumonia occurred in 18 (27.7%) and 19 patients (55.9%) in the normal versus elevated TnI groups (p ⫽ 0.006), respectively. The incidence of shock, use of adrenergic agents in shock, and GCS below 15 did not differ between the two groups (Table 1).
General and laboratory characteristics according to the presence of elevation of TnI Elevation of TnI was seen in 34 patients (34.3%) and myocardial injury found only in severe group patients (34 patients, 100%; Table 3). Patients with normal TnI versus elevated TnI differed in terms of age (yrs), number of patients who were exposed to OP by the oral route, and initial GCS (58 ⫾ 17 vs. 66 ⫾ 16, p ⫽ 0.015, 56 [87.5%] vs. 33 [97.1%], p ⫽ 0.048 and 12.0 [IQR 8.0–15.0] vs. 9.0 [IQR 5.8–12.0], p ⫽ 0.019). There were no differences in gender, ED arrival time after poisoning, amounts of toxin ingested, cause of poisoning, co-ingestion of alcohol, class of OP, or initial vital signs. Monocrotophos (2 patients, 66.7%) in Class I agents, dichlorvos (3 patients, 60.0%), and fenitrothion (5 patients, 45.5%) in Class II agents induced the higher rate of myocardial injury among the various OP. There were no statistical differences in initial hypoxia, initial shock, and 48-h and total atropine dosage between patients with normal Table 3. Myocardial injury according to severity, shock, and hypoxia. Severity (p ⫽ 0.026) Troponin I
Severe
Elevation
34 (100%)
Non-severe OR (95%CI)* 0 (0.0%)
Non-elevation 56 (86.2%) 9 (13.8%)
Shock (p ⫽ 0.184) Shock
Non-shock
OR (95%CI)*
Hypoxia (p ⫽ 0.929) Hypoxia
9 (47.4%) 25 (31.3%) 1.980 5 (3.3%) (0.716–5.475) 10 (52.6%) 55 (68.8%) Reference 10 (66.7%)
Non-hypoxia
OR (95%CI)*
29 (34.5%)
0.948 (0.296–3.036) Reference
55 (65.5%)
*Odds Ratio (95% Confidence Interval). Clinical Toxicology vol. 52 no. 8 2014
Myocardial injury in organophosphate poisoning 877
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The average ICU admission length was 5.0 (IQR 2.0–12.0) and 9.0 (IQR 3.8–18.0) days in the normal and elevated TnI groups, (p ⫽ 0.041), respectively (Table 1). Electrical and myocardial injury in OP poisoning ST depression and elevation were more common in patients with elevated TnI ([6 patients, 9.5%] vs. [5 patients, 14.7%]), but there was no statistical difference (p ⫽ 0.673). ST abnormalities in one patient with elevated TnI were not normalized (Table 2). Out of 34 patients, 18 (52.9%) patients had elevated initial TnI in the ED. The median peak TnI level and peak time were 0.305 (0.078–2.335) ng/mL and 15 (IQR 6.9– 34.4) hours, respectively (Table 4). Although CK-MB and BNP were higher patients with elevated TnI than in patients with normal TnI (1.68 [IQR 0.98–3.64] vs. 2.22 [IQR 1.06– 4.03], p ⫽ 0.569 and 15.8 [6.1–50.5] vs. 21.3 [14.6–105.2], p ⫽ 0.052), there was no statistical difference (Table 2).
Discussion TnI is used to detect myocardial injury, as it is expressed in cardio-specific isoforms.12 Experimental data strongly suggest that TnI leaks out of the cell only after membrane disruption following myocardial cell death.13 With the highsensitivity troponin assays which we used, circulating TnI can be found in the plasma as a result of transient ischemia or inflammatory myocardial injury.14 Thirty-four patients (34.3%) in our study had elevated TnI, and the median peak TnI levels were 0.305 (0.078–2.335) ng/mL. Our study included early elevation of TnI within two days, and 18 of 34 patients with increased TnI within 48 h had initially elevated TnI in the ED (Table 4). Although hypoxia, shock, and electrolyte imbalance may affect cardiac toxicity,15 we found no statistical difference between the two groups in terms of initial hypoxia, initial shock, sodium, and potassium (Table 1). Although ECG abnormalities, such as rhythm disturbances, have been documented as cardiac complications of OP, it is difficult to confirm myocardial injury with only ECG studies. In addition, sinus tachycardia, the most common ECG abnormality seen in our study, is a non-specific ECG abnormality with many causes. Fewer patients had ST change (11.1%), which corresponds with myocardial ischemia, than TnI elevation (34.3%). Both TnI elevation and ischemic ECG changes were only seen in 5 patients. Therefore, it is not accurate to evaluate myocardial injury Table 4. Characteristics of troponin I in elevation of troponin I group. Characteristics
Elevation of troponin I group
Elevation of troponin I for 48 h Elevation of initial troponin I Peak level of troponin I (ng/mL) Peak time of troponin I (hours) †Median
(interquartile range).
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34 (34.3%) 18 (18.2%) 0.305 (0.078–2.335)† 15.0 (6.9–34.4)†
with only ECG abnormalities. In an autopsy study,16 myocardial injury was reported in patients who died of OP. However, we cannot distinguish whether myocardial injury was caused by primary OP or was the effect of multiple organ failure during treatment. Previous studies have not examined biochemical markers of myocardial injury in humans. In a study by Saadeh et al.,17 increased CK and lactate dehydrogenase levels with ST-segment elevation were found in 5 of 11 patients. However, other cardiac biochemical markers such as TnI, which is highly specific for myocardial injury, were not studied. In a rat study, there was no elevation of cardiac biomarkers, including TnI, by dichlorvos poisoning.18 However, the result of our human study was that elevation of TnI was caused by OP in 34.3% patients. Previously, the time interval to cardiac damage was unknown. However, we showed that myocardial injury is caused during the acute early phase, because we analyzed TnI within 2 days. Of course, the severity of poisoning in our study was very high (Table 1). Most patients (90.9%) belonged to severe class by Namba classification. This was considered due to unconsciousness, severe cholinergic symptoms, and low serum pseudocholinesterase activity. Therefore, we concluded that OP can cause direct myocardial injury apart from rhythm disturbances in severe OP poisoning. However, the median maximum of TnI level was 0.305 ng/mL and this was relatively low compared to other myocardial injuries, such as myocardial infarction and myocarditis.19 The protocol for pralidoxime administration at our hospital is to infuse 1–2 g over 20–30 min followed by 0.5 g/h for 48 h. For atropine, an initial intravenous bolus of 1–3 mg depending on the severity of symptoms and continuous infusions will be needed for patients severely poisoned by very fat-soluble OP that continue to redistribute from the fat and freshly inhibit serum cholinesterase. Applying the atropine regimen may result in myocardial injury due to atropineinduced tachycardia so the usage of atropine was paused in case of the pulse rate increasing to over 120 bpm.20,21 In our study, totally 34 patients showed elevated TnI. Among the TnI-elevated patients, 18 patients (52.9%) had elevated TnI at initial ED assessment before atropine usage. Also, there was no statistical difference between the two groups in terms of atropine dosage for 48 h (Table 1). Therefore, we could exclude effects of subsequent myocardial injury, induced by atropine. To exclude the effect of shock and hypoxia among the myocardial injury patients, the TnI elevation within nonshock and non-hypoxia patients were evaluated (Table 3). In non-shock and non-hypoxia patients, myocardial injury were 31.3% patients and 34.3%, respectively, and this result was similar to the total myocardial injury percent (34.3%). Among the myocardial injury patients, 18 patients (52.9%) had elevated TnI at initial ED assessment, use of adrenergic agents did not actually related to the myocardial injury. Therefore, we could exclude effects of subsequent myocardial injury, induced by shock, adrenergic agents, and hypoxia. Initial GCS scores differed between groups. Patients with elevated TnI tended to be older, which may be because older
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878 Y. S. Cha et al. patients have poor decreased physiologic defense mechanisms to OP poisoning. In addition, patients with elevated TnI had more complications including respiratory failure requiring ventilator care and pneumonia; they also had longer stays in the ICU than the patients with normal TnI. We found a difference in serum glucose between patients with normal and the elevated TnI. Hyperglycemia may be caused by pancreatic injury in OP.3,22–23 Although Cr was normal in both groups, patients with elevated TnI had higher Cr levels and lower pseudocholinesterase levels than patients with normal TnI. We found no statistical differences in ECG analysis between patients with normal and elevated TnI (Table 2). Sinus tachycardia was more than sinus bradycardia. Anand et al.16 confirmed that sinus tachycardia is the most common abnormality, and observed tachycardia in 26 of 36 patients on admission. Sinus tachycardia may be caused by intense sympathetic stimulation, nicotinic stimulation of ganglionic sites by excess ACh, atropine administration, hypoxia, dehydration, and shock.16 In our study, 11 patients (11.1%) had ST changes, and this change persisted in one patient, suggesting long-lasting myocardial damage.24 Anand et al.,16 found a higher proportion of ST changes (19.4%, 7 patients of 36 patients) than our study. There was QT prolongation in 69.7% of patients in our study. Although TdP can occur in patients with OP poisoning in the setting of prolonged QTc intervals,25–27 TdP did not occur in our study. The clinical usefulness of BNP assays has been confirmed for screening of heart disease, stratification of patients with congestive heart failure, detection of left ventricular systolic and/or diastolic dysfunction, and differential diagnosis of dyspnea.28,29 In our study, even though BNP was higher in patients with elevated TnI, there was no statistical difference between the two groups (p ⫽ 0.052) and BNP values of both groups were within the normal range (⬍ 100 pg/mL). This may mean that myocardial injury related to OP is not enough to cause ventricular dysfunction. This study had some limitations. First, it was a retrospective study and involved only one hospital. As a result, not all relevant assessment parameters could be included. In particular, the ingested amount of toxin and the ED arrival time after ingestion may be overestimated or underestimated. Second, since the exact percentages of OP, solvent, and surfactant are unknown, their clinical influence could not be predicted. Third, GCS can be affected by co-ingestion of alcohol as well as by OP insecticides. In our study, 35.4% of patients co-ingested alcohol with OP. However, there was no difference in the incidence of alcohol co-ingestion between the two groups (Table 1). The prevalence of TnI elevation was 37.0% in the 17 of 46 patients who ingested OP alone; we could not investigate alcohol co-ingestion in 18 patients. There was no significant difference compared to all patients (34.3% in 99 patients). Even when we eliminated the effects of alcohol, patients with elevated TnI had lower initial GCS scores than patients with normal TnI (9.0 [IQR 3.5–12.5] ng/mL vs. 11.0 [IQR 6.5–15.0] ng/mL, respectively, [p ⫽ 0.225]). However, not evaluating the
presence of alcohol co-ingestion by serum ethanol level in all included patients was a limitation of our study. Further studies are required to clarify these details.
Conclusions OP can cause direct myocardial injury during the acute early phase in severe OP poisoning. Monitoring of TnI may be needed in severe OP poisoning.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
Contributorship Conception and design of the study: Hyun Kim, Yong Sung Cha Acquisition of data: Jin Go, Kyoung Chul Cha, Oh Hyun Kim, Tae Hoon Kim Drafting the article: Yong Sung Cha Revising draft critically for important intellectual contents: Hyun Kim, Kang Hyun Lee, Sung Oh Hwang Final approval of the version: Hyun Kim
References 1. Linden CH, Lovejoy FH Jr. Poisoning and drug overdosage. In: Harrison TR, Fauci A, Braunwald E, Isselbacher K, Wilson J, Martin J, et al., eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill, Health Professions Division; 1998:2523–2543. 2. Roth A, Zellinger I, Arad M, Atsmon J. Organophosphates and the heart. Chest 1993; 103:576–582. 3. Karalliedde L. Organophosphorus poisoning and anaesthesia. Anaesthesia 1999; 54:1073–1088. 4. Ludomirsky A, Klein HO, Sarelli P, Becker B, Hoffman S, Taitelman U, et al. Q-T prolongation and polymorphous (“torsade de pointes”) ventricular arrhythmias associated with organophosphorus insecticide poisoning. Am J Cardiol 1982; 49:1654–1658. 5. Karki P, Ansari JA, Bhandary S, Koirala S. Cardiac and electrocardiographical manifestations of acute organophosphate poisoning. Singapore Med J 2004; 45:385–389. 6. Brill DM, Maisel AS, Prabhu R. Polymorphic ventricular tachycardia and other complex arrhythmias in organophosphate insecticide poisoning. J Electrocardiol 1984; 17:97–102. 7. Wang MH, Tseng CD, Bair SY. Q-T interval prolongation and pleomorphic ventricular tachyarrhythmia (‘Torsade de pointes’) in organophosphate poisoning: report of a case. Hum Exp Toxicol 1998; 17:587–590. 8. World Health Organization. The WHO recommended classification of pesticides by hazard and guidelines to classification: 2004 [Online] 2004; Available at: http://apps.who.int/iris/bitstream/10665/43138/1/ 9241546638.pdf Accessed on January 01 2014. 9. World Health Organization. Safety of pyrethroids for public health use [Online] 2005; Available at: http://apps.who.int/iris/ handle/10665/69008 Accessed on May 17 2008. 10. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007; 100:609–615. 11. Namba T, Nolte CT, Jackrel J, Grob D. Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med 1971; 50:475–492. Clinical Toxicology vol. 52 no. 8 2014
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Myocardial injury in organophosphate poisoning 879 12. Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. non-coronary disease. Eur Heart J 2011; 32:404–411. 13. Fishbein MC, Wang T, Matijasevic M, Hong L, Apple FS. Myocardial tissue troponins T and I. An immunohistochemical study in experimental models of myocardial ischemia. Cardiovasc Pathol 2003; 12:65–71. 14. Mingels AM, Jacobs LH, Kleijnen VW, Laufer EM, Winkens B, Hofstra L, et al. Cardiac troponin T elevations, using highly sensitive assay, in recreational running depend on running distance. Clin Res Cardiol 2010; 99:385–391. 15. Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: the present and the future. J Am Coll Cardiol 2006; 48:1–11. 16. Anand S, Singh S, Nahar Saikia U, Bhalla A, Paul Sharma Y, Singh D. Cardiac abnormalities in acute organophosphate poisoning. Clin Toxicol (Phila) 2009; 47:230–235. 17. Saadeh AM, Farsakh NA, al-Ali MK. Cardiac manifestations of acute carbamate and organophosphate poisoning. Heart 1997; 77:461–464. 18. Kose A, Gunay N, Yildirim C, Tarakcioglu M, Sari I, Demiryurek AT. Cardiac damage in acute organophosphate poisoning in rats: effects of atropine and pralidoxime. Am J Emerg Med 2009; 27:169–175. 19. Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation 2011; 124:2350–2354. 20. American Heart Association Guidelines: management of symptomatic bradycardia and tachycardia. Circulation 2005; 112:IV67. 21. Eddlestone M, Dawson A, Karalliedde L, Dissanayake W, Hittarage A, Azher S, Buckley NA. Early management after
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self-poisoning with an organophosphorus or carbamate pesticide-a treatment protocol for junior doctors. Crit Care 2004; 8: R391–R397. Sahin I, Onbasi K, Sahin H, Karakaya C, Ustun Y, Noyan T. The prevalence of pancreatitis in organophosphate poisonings. Hum Exp Toxicol 2002; 21:175–177. Lee WC, Yang CC, Deng JF, Wu ML, Ger J, Lin HC, et al. The clinical significance of hyperamylasemia in organophosphate poisoning. J Toxicol Clin Toxicol 1998; 36:673–681. Chhabra M, Sepaha G, Jain S, Bhagwat R, Khandekar J. ECG and necropsy changes in organophosphorus compound (malathion) poisoning. Indian J Med Sci 1970; 24:424–429. Kiss Z, Fazekas T. Arrhythmias in organophosphate poisonings. Acta Cardiol 1979; 34:323–330. Chuang FR, Jang SW, Lin JL, Chern MS, Chen JB, Hsu KT. QTc prolongation indicates a poor prognosis in patients with organophosphate poisoning. Am J Emerg Med 1996; 14:451–453. Bar-Meir E, Schein O, Eisenkraft A, Rubinshtein R, Grubstein A, Militianu A, et al. Guidelines for treating cardiac manifestations of organophosphates poisoning with special emphasis on long QT and Torsades De Pointes. Crit Rev Toxicol 2007; 37:279–285. Ozturk MA, Kelestimur F, Kurtoglu S, Guven K, Arslan D. Anticholinesterase poisoning in Turkey–clinical, laboratory and radiologic evaluation of 269 cases. Hum Exp Toxicol 1990; 9:273–279. Sivagnanam S. Potential therapeutic agents in the management of organophosphorus poisoning. Crit Care 2002; 6:260–261.
CRITICAL CARE
Features of myocardial injury in severe organophosphate poisoning Y. S. CHA, H. KIM, J. GO, T. H. KIM, O. H. KIM, K. C. CHA, K. H. LEE, and S. O. HWANG
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Department of Emergency Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
Background. In organophosphate (OP) poisoning cardiac complications may occur. However, the current body of knowledge largely consists of limited studies, and case reports are mainly on electrocardiogram (ECG) abnormalities. As definite myocardial injury is difficult to assess through ECG, we investigated the prevalence of myocardial injury through cardiac biochemical markers such as troponin I (TnI) in severe OP poisoning. Methods. We conducted a retrospective review of 99 consecutive OP insecticide poisoning cases that were diagnosed and treated at the emergency department of the Wonju Severance Christian Hospital between March 2008 and December 2013. Results. Based on Namba classification for OP poisoning, there were no patients with mild toxicity, 9 patients (9.1%) with moderate toxicity and 90 patients (90.9%) with severe toxicity. On ECG, normal sinus rhythm was most common, and ST depression and elevation were seen in 11 patients (11.1%). Elevation of TnI within 48 h was seen in 34 patients (34.3%). The median peak level and peak time of TnI were 0.305 (IQR, 0.078–2.335) ng/mL and 15 (IQR 6.9–34.4) hours, respectively. There were differences between patients with normal TnI and elevated TnI in terms of age (yrs), number of patients who were exposed to OP via the oral route, and initial Glasgow Coma Scale (GCS; 58 ⫾ 17 vs. 66 ⫾ 16, p ⫽ 0.015, 56 [87.5%] vs. 33 [97.1%], p ⫽ 0.048 and 12.0 [IQR, 8.0–15.0] vs. 9.0 [IQR, 5.8–12.0], p ⫽ 0.019). Conclusions. OP can cause direct myocardial injury during the acute early phase in severe OP poisoning. Monitoring of TnI may be needed in severe OP poisoning. Keywords
Organophosphate; Myocardial injury; Troponin I
Introduction
the current body of knowledge largely consists of limited studies and case reports based mainly on electrocardiogram (ECG) abnormalities. In addition, no studies have evaluated cardiac biochemical markers. It is difficult to diagnose definite myocardial injury based on ECG alone. Therefore, we investigated the prevalence of myocardial injury through cardiac biochemical markers such as troponin I (TnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) in severe OP poisoning.
Organophosphate (OP) insecticides irreversibly inhibit acetylcholinesterase and cause accumulation of acetylcholine (Ach) and overstimulation of cholinergic synapses in the central nervous system, somatic nerves, parasympathetic nerve endings, and sweat glands.1,2 Even though the most common complication is the respiratory failure, cardiac complications may also occur after OP poisoning.2,3 Generally, cardiac complications from OP are known by the three phases in a study by Ludomirsky et al.4 An initial intense sympathetic phase is followed by a second prolonged parasympathetic phase that is usually accompanied by hypoxemia, often manifests as ST–T changes, and shows A–V conduction disturbances which can degenerate to ventricular fibrillation (VF). The third phase of QT prolongation is followed by Torsade de Pointes (TdP) and VF. Cardiac complications, such as various arrhythmias, conduction disturbances, hypertension-hypotension, and myocardial damage, have been reported with OP poisoning.5–7 However,
Methods Study design and data This is a retrospective and observational study of consecutive patients who were diagnosed with acute OP insecticide poisoning between March 2008 and December 2013 in the emergency department (ED) of The Wonju Severance Christian Hospital, Wonju College of Medicine, Yonsei University. Poisoning with OP was confirmed by patient or guardian statements, and verification of the agent was performed by an emergency physician who transcribed the bottle label into patient records. Levels of serum pseudocholinesterase were also used to confirm OP poisoning. OP was classified into Class I, II, or III based on the WHO classification scheme.8
Received 13 March 2014; accepted 9 July 2014. Address correspondence to Hyun Kim, MD, Department of Emergency Medicine, Wonju College of Medicine, Yonsei University, 162 Ilsandong, Wonju 220-701, Republic of Korea. Tel: ⫹ 82-33-741-1614. Fax: ⫹ 82-33-742-3030. E-mail: [email protected]
873
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874 Y. S. Cha et al. In the absence of sufficient information, patients were left unclassified. Data were retrospectively collected from medical records and reviewed. The following parameters were assessed: age, gender, the ingested amount of OP, class of OP, cause of poisoning, elapsed time from ingestion to arrival at the ED, route of poisoning, initial mental status (Glasgow Coma Scale [GCS]), ECG, initial vital signs, and mortality, etc. We defined the amount of OP ingested as follows: “a little” or “a spoonful” was taken to be 5 mL, “a mouthful” was presumed to be 25 mL, “a small cup” was presumed to be 100 mL, and “a bottle” was presumed to be 300 mL.9 We assessed atropine dosage for 48 h and duration of atropine used, as this drug may affect the heart. We evaluated arterial blood gas, serum lactate, complete blood count, electrolyte levels (sodium, potassium), blood urea nitrogen, creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, and serum pseudocholinesterase in the ED. CK-MB, TnI, and BNP were investigated as cardiac biochemical markers in the ED. In case of elevated TnI, it has been followed up after admission. We used high sensitivity TnI (Siemens Healthcare Diagnostics Inc., Newark, DE, USA). The corrected QT interval (QTc) on the ECG was calculated using Bazett’s formula, and prolonged QTc interval was defined as more than 440 ms.10 Clinical courses were defined as respiratory failure requiring mechanical ventilation, hypotension (systolic blood pressure ⬍ 90 mm Hg), pneumonia, GCS less than 15, and death. We investigated the prevalence of TnI elevation within 48 h and if TnI was elevated, we also evaluated peak level of TnI and time when it was reached peak level. We compared the general characteristics of groups with or without TnI elevation and intensive care unit (ICU) admission length and total admission length were used to compare prognosis between the two groups. The study was approved by the institutional review board committee of Wonju College of Medicine, Yonsei University (approval number YWMR-14-5-003)
(0 patients), poisoning with any additional material except for alcohol (10 patients), acute coronary syndrome and end-stage renal disease (3 patients), cardiac arrest upon ED arrival (7 patients), and insufficient data (4 patients; Fig. 1). Between 2008 and 2013, the total number of patients who visited our hospital ED ranged from 29,326 and 40,465 patients annually. There were 64 men (64.6%), with ages ranging from 22 to 90 years with a mean of 61 ⫾ 17 years. The median ingested amount of OP was 100 (IQR 50–200) cc, and 80 patients (80.8%) had been exposed to OP with suicidal intention. Absorbed OP included chloropyrifos, dichlorvos, diazinon, parathion, methidathion, phenothoate, etc. Totally 15 patients (15.2%) and 39 patients (39.4%) were poisoned by Classes I and II, respectively. No patients were poisoned by Class III. Using Namba classification for OP poisoning,11 0 patients had mild toxicity, 9 patients (9.1%) had moderate toxicity, and 90 patients (90.9%) had severe toxicity (Table 1). The average initial GCS was 11 (IQR 7–15), and 35 patients (35.4%) had co-ingested alcohol. Fifteen patients (15.2%) had initial hypoxia (PaO2 ⬍ 60 mmHg) and 17 patients (17.5%) had shock (systolic blood pressure ⬍ 90 mmHg). Ninty-seven patients (98%) received pralidoxime and 90 patients (90.9%) received atropine. Atropine dosages for 48-h and duration of atropine used were 102.6 (IQR 40.0–172.0) mg and 4.0 (IQR 2.0–7.5) days, respectively (Table 1). On ECG, normal sinus rhythm was most common when analyzing rate, and ST depression and elevation were seen in 11 patients (11.1%). Of these, ST abnormalities in 10 patients were normalized with treatment. QT prolongation
Statistical analysis Statistical analyses were performed using SPSS software for Windows (V.20.0 K, SPSS, Chicago, IL, USA). Nominal data are presented as frequencies and percentages, and continuous variables are presented as mean and standard deviation (SD) and median and interquartile range (IQR) after investigating for normality using the Shapiro–Wilk test. The chi-square test or Fisher’s exact test were used for comparison of nominal variables, while the two-sample t-test and Mann–Whitney U-test were used to compare continuous variables. P values less than 0.05 were considered statistically significant.
Results General and laboratory characteristics of patients with OP poisoning A total of 123 consecutive patients were identified for this study. Exclusion criteria were age below 18 years
Fig. 1. Numbers of Patients assessed, excluded, and included. ED: Emergency Department. Clinical Toxicology vol. 52 no. 8 2014
Myocardial injury in organophosphate poisoning 875 Table 1. Characteristics and laboratory findings of patients poisoned with organophosphate according to the presence of elevated troponin I.
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Characteristics Age (years) Male ED arrival time (minutes) Amount (cc) Route (oral) Intentional poisoning Coingested with alcohol Class of organophosphate Class I Class II Class III Unclassified Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse rate (per minute) Respiratory rate (per minute) Initial GCS Initial hypoxia (PaO2 ⬍ 60mmHg) Initial shock (systolic BP ⬍ 90mmHg) Namba classification Mild Moderate Severe Gastric lavage Activated charcoal Use of pralidoxime Use of atropine Atropine dosage for 48 h (mg) Total atropine dosage (mg) Duration of atropine (days) Laboratoty findings Initial CK (U/L) Pseudocholinesterase(U/L) Lactate (mmol/L) BUN (mg/dL) Cr (mg/dL) Glucose (mg/dL) Amylase (U/L) Clinical courses Respiratory failure requiring mechanical ventilation Shock (systolic BP ⬍ 90mmHg) Use of adrenergic agents Pneumonia GCS ⬍ 15 Outcomes Total admission days ICU admission days
Total (n ⫽ 99)
Non-elevation of troponin I group (n ⫽ 65; 65.7%)
Elevation of troponin I group (n ⫽ 34; 34.3%)
61 ⫾ 17* 64 (64.6%) 156 (77–290)† 100 (50–200)† 89 (89.9%) 80 (80.8%) 35 (35.4%)
58 ⫾ 17* 45 (69.2%) 160 (75–271)† 100 (35–138)† 56 (87.5%) 51 (79.7%) 25 (46.3%)
66 ⫾ 16* 19 (55.9%) 154 (77–369)† 150 (50–300)† 33 (97.1%) 29 (87.9%) 10 (37.0%)
15 (15.2%) 39 (39.4%) 0 (0.0%) 45 (45.5%) 132 ⫾ 41* 78 ⫾ 22* 96 ⫾ 20* 20 (18–20)† 11 (7–15)† 15 (15.2%) 17 (17.5%)
8 (12.3%) 28 (43.1%) 0 (0.0%) 29 (44.6%) 133 ⫾ 36* 79 ⫾ 19* 95 ⫾ 17* 20 (18–22)† 12.0 (8.0–15.0)† 10 (15.4%) 8 (12.7%)
7 (20.6%) 11 (32.4%) 0 (0.0%) 16 (47.1%) 130 ⫾ 49* 78 ⫾ 28* 98 ⫾ 25* 20 (18–20)† 9.0 (5.8–12.0)† 5 (14.7%) 9 (26.5%)
p value 0.015 0.187 0.816 0.221 0.048 0.315 0.428 0.429
0.706 0.937 0.597 0.897 0.019 0.929 0.089 0.026
0 (0.0%) 9 (9.1%) 90 (90.9%) 25 (25.3%) 70 (70.7%) 97 (98%) 90 (90.9%) 102.6 (40.0–172.0)† 195.3 (50.0–406.1)† 4.0 (2.0–7.5)†
0 (0.0%) 9 (13.8%) 56 (86.2%) 16 (25.4%) 48 (78.7%) 64 (98.5%) 60 (92.3%) 101.0 (35.5–170.0)† 172.5 (40.3–367.5)† 3.0 (2.0–4.3)†
0 (0.0%) 0 (0.0%) 34 (100%) 9 (27.3%) 22 (66.7%) 33 (97.1.0%) 30 (90.9%) 112.0 (43.0–216.3)† 220.0 (105.3–466.8)† 4.0 (3.0–12.0)†
0.842 0.202 1.000 1.000 0.610 0.181 0.026
145.0 (97.8–226.0)† 335 (285–1224)† 3.55 (2.34–5.72)† 16.0 (11.1–20.0)† 0.9 (0.6–1.0)† 167 (130–240)† 94.0 (60.0–205.0)†
146.0 (80.5–218.0)† 390 (296–1765)† 3.39 (2.10–5.12)† 15.8 (12.0–19.0)† 0.78 (0.60–0.91)† 158 (121–235)† 85 (55–181)†
136.5 (102.5–228.0)† 301 (259–484)† 4.58 (2.72–7.35)† 16.0 (11.0–21.0)† 0.91 (0.70–1.23)† 194 (154–280)† 130 (65–228)†
0.771 0.028 0.053 0.732 0.015 0.015 0.086
77 (77.8%) 19 (19.2%) 12 (63.2%) 37 (37.4%) 73 (73.7%)
46 (70.8%) 10 (15.4%) 5 (50.0%) 18 (27.7%) 44 (67.7%)
10 (4–21)† 6 (2–14)†
9.0 (4.0–19.0)† 5.0 (2.0–12.0)†
31 (91.2%) 9 (26.5%) 7 (77.8%) 19 (55.9%) 29 (85.3%)
0.020 0.184 0.350 0.006 0.059
15.5 (5.0–21.0)† 9.0 (3.8–18.0)†
0.347 0.041
ED, Emergency Department; BP, Blood Pressure; BUN, Blood Urea Nitrogen; Cr, Creatinine; CK, creatine kinase; GCS, Glasgow Coma Scale; ICU, Intensive Care Unit. *Mean ⫾ Standard deviation. †Median (interquartile range).
was seen in 69 patients (69.7%). On cardiac biochemical markers analysis, the median initial levels of TnI, CK-MB, and BNP were 0.015 (IQR 0.009–0.022) ng/mL, 1.91 (IQR 1.01–3.91) ng/mL, and 18.3 (IQR 7.9–55.1) pg/mL, respectively (Table 2). Serum lactate was 3.55 (IQR 2.34–5.72) mmol/L. Median hemoglobin was 14.2 (IQR 13.3–15.3) and serum pseudocholinesterase was 335 (IQR 285–1224) U/L (Table 1). Copyright © Informa Healthcare USA, Inc. 2014
Clinical courses after OP poisoning included respiratory failure requiring ventilator care (77 patients, 77.8%), shock (systolic blood pressure ⬍ 90 mm Hg; 19 patients, 19.2%), pneumonia (37 patients, 37.4%), and GCS below 15 (73 patients, 73.7%). In shock patients, adrenergic agents were used to 12 patients (63.2%). Total admission length and ICU admission length were 10 (IQR 4–21) and 6 (IQR 2–14) days, respectively. Eighteen patients (18.2%) died after admission
876 Y. S. Cha et al. Table 2. Characteristics of electrical and myocardial injury.
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Characteristics ECG Rate Normal sinus rhythm Sinus tachycardia Sinus bradycardia ST and T wave change Normal ST depression ST elevation ST change normalization QT prolongation (⬎ 440ms) Normal Prolongation PR prolongation (⬎ 120ms) Normal Prolongation Laboratoty findings Initial troponin I (ng/mL) Initial CK-MB (ng/mL) Initial BNP (pg/mL)
Total (n ⫽ 99)
Non-elevation of troponin I group (n ⫽ 65; 65.7%)
Elevation of troponin I group (n ⫽ 34; 34.3%)
57 (57.6%) 37 (37.4%) 3 (3.0%)
40 (63.5%) 20 (31.7%) 3 (4.8%)
17 (50.0%) 17 (50.0%) 0 (0%)
86 (86.9%) 7 (7.1%) 4 (4.0%) 10 (90.9%)
57 (90.5%) 4 (6.3%) 2 (3.2%) 6 (100%)
29 (85.3%) 3 (8.8%) 2 (5.9%) 4 (80.0%)
0.455
28 (28.3%) 69 (69.7%)
45 (71.4%)
24 (70.6%)
0.931
89 (89.9%) 3 (3.0%)
2 (3.2%)
1 (3.3%)
1.000
p value 0.126
0.673
0.015 (0.009–0.022)† 0.015 (0.008–0.015)† 1.68 (0.98–3.64)† 1.91 (1.01–3.91)† 15.8 (6.1–50.5)† 18.3 (7.9–55.1)†
0.048 (0.015–0.125)† ⬍ 0.001 2.22 (1.06–4.03)† 0.569 21.3 (14.6–105.2)† 0.052
ECG, electrocardiogram; CK-MB, creatine kinase MB; BNP, B-type natriuretic peptide. †Median (interquartile range).
(Table 1). Causes of mortality were acute kidney injury (3 patients, 16.7%), respiratory failure (4 patients, 22.2%), and multi-organ failure (11 patients, 61.1%), respectively.
TnI and patients with elevated TnI (Table 1) and also presence of shock or hypoxia statistically did not relate to the elevated TnI (Table 3). Serum lactate was 3.39 (IQR 2.10–5.12) mmol/L in patients with normal TnI and 4.58 (IQR 2.72–7.35) mmol/L in patients with elevated TnI (p ⫽ 0.053). Serum creatinine (Cr) and glucose were (0.78 [IQR 0.60–0.91] mg/dL vs. 0.91 [IQR 0.70–1.23] mg/dL, p ⫽ 0.015) and (158 [IQR 121–235] mg/dL vs. 194 [IQR 154–280] mg/dL, p ⫽ 0.015) in the normal TnI and elevated TnI groups, respectively. Serum pseudocholinesterase was 390 (IQR 296–1765) mg/ dL in the normal TnI group and 301 (IQR 259–484) mg/ dL in elevated TnI group (p ⫽ 0.028; Table 1). There were no differences in arterial blood gas, complete blood count, electrolyte (sodium, potassium), and liver function test (AST and ALT; data not shown). Forty-six (70.8%) patients with normal TnI and 31 patients (91.2%) with elevated TnI had respiratory failure requiring ventilator care (p ⫽ 0.020). Pneumonia occurred in 18 (27.7%) and 19 patients (55.9%) in the normal versus elevated TnI groups (p ⫽ 0.006), respectively. The incidence of shock, use of adrenergic agents in shock, and GCS below 15 did not differ between the two groups (Table 1).
General and laboratory characteristics according to the presence of elevation of TnI Elevation of TnI was seen in 34 patients (34.3%) and myocardial injury found only in severe group patients (34 patients, 100%; Table 3). Patients with normal TnI versus elevated TnI differed in terms of age (yrs), number of patients who were exposed to OP by the oral route, and initial GCS (58 ⫾ 17 vs. 66 ⫾ 16, p ⫽ 0.015, 56 [87.5%] vs. 33 [97.1%], p ⫽ 0.048 and 12.0 [IQR 8.0–15.0] vs. 9.0 [IQR 5.8–12.0], p ⫽ 0.019). There were no differences in gender, ED arrival time after poisoning, amounts of toxin ingested, cause of poisoning, co-ingestion of alcohol, class of OP, or initial vital signs. Monocrotophos (2 patients, 66.7%) in Class I agents, dichlorvos (3 patients, 60.0%), and fenitrothion (5 patients, 45.5%) in Class II agents induced the higher rate of myocardial injury among the various OP. There were no statistical differences in initial hypoxia, initial shock, and 48-h and total atropine dosage between patients with normal Table 3. Myocardial injury according to severity, shock, and hypoxia. Severity (p ⫽ 0.026) Troponin I
Severe
Elevation
34 (100%)
Non-severe OR (95%CI)* 0 (0.0%)
Non-elevation 56 (86.2%) 9 (13.8%)
Shock (p ⫽ 0.184) Shock
Non-shock
OR (95%CI)*
Hypoxia (p ⫽ 0.929) Hypoxia
9 (47.4%) 25 (31.3%) 1.980 5 (3.3%) (0.716–5.475) 10 (52.6%) 55 (68.8%) Reference 10 (66.7%)
Non-hypoxia
OR (95%CI)*
29 (34.5%)
0.948 (0.296–3.036) Reference
55 (65.5%)
*Odds Ratio (95% Confidence Interval). Clinical Toxicology vol. 52 no. 8 2014
Myocardial injury in organophosphate poisoning 877
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The average ICU admission length was 5.0 (IQR 2.0–12.0) and 9.0 (IQR 3.8–18.0) days in the normal and elevated TnI groups, (p ⫽ 0.041), respectively (Table 1). Electrical and myocardial injury in OP poisoning ST depression and elevation were more common in patients with elevated TnI ([6 patients, 9.5%] vs. [5 patients, 14.7%]), but there was no statistical difference (p ⫽ 0.673). ST abnormalities in one patient with elevated TnI were not normalized (Table 2). Out of 34 patients, 18 (52.9%) patients had elevated initial TnI in the ED. The median peak TnI level and peak time were 0.305 (0.078–2.335) ng/mL and 15 (IQR 6.9– 34.4) hours, respectively (Table 4). Although CK-MB and BNP were higher patients with elevated TnI than in patients with normal TnI (1.68 [IQR 0.98–3.64] vs. 2.22 [IQR 1.06– 4.03], p ⫽ 0.569 and 15.8 [6.1–50.5] vs. 21.3 [14.6–105.2], p ⫽ 0.052), there was no statistical difference (Table 2).
Discussion TnI is used to detect myocardial injury, as it is expressed in cardio-specific isoforms.12 Experimental data strongly suggest that TnI leaks out of the cell only after membrane disruption following myocardial cell death.13 With the highsensitivity troponin assays which we used, circulating TnI can be found in the plasma as a result of transient ischemia or inflammatory myocardial injury.14 Thirty-four patients (34.3%) in our study had elevated TnI, and the median peak TnI levels were 0.305 (0.078–2.335) ng/mL. Our study included early elevation of TnI within two days, and 18 of 34 patients with increased TnI within 48 h had initially elevated TnI in the ED (Table 4). Although hypoxia, shock, and electrolyte imbalance may affect cardiac toxicity,15 we found no statistical difference between the two groups in terms of initial hypoxia, initial shock, sodium, and potassium (Table 1). Although ECG abnormalities, such as rhythm disturbances, have been documented as cardiac complications of OP, it is difficult to confirm myocardial injury with only ECG studies. In addition, sinus tachycardia, the most common ECG abnormality seen in our study, is a non-specific ECG abnormality with many causes. Fewer patients had ST change (11.1%), which corresponds with myocardial ischemia, than TnI elevation (34.3%). Both TnI elevation and ischemic ECG changes were only seen in 5 patients. Therefore, it is not accurate to evaluate myocardial injury Table 4. Characteristics of troponin I in elevation of troponin I group. Characteristics
Elevation of troponin I group
Elevation of troponin I for 48 h Elevation of initial troponin I Peak level of troponin I (ng/mL) Peak time of troponin I (hours) †Median
(interquartile range).
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34 (34.3%) 18 (18.2%) 0.305 (0.078–2.335)† 15.0 (6.9–34.4)†
with only ECG abnormalities. In an autopsy study,16 myocardial injury was reported in patients who died of OP. However, we cannot distinguish whether myocardial injury was caused by primary OP or was the effect of multiple organ failure during treatment. Previous studies have not examined biochemical markers of myocardial injury in humans. In a study by Saadeh et al.,17 increased CK and lactate dehydrogenase levels with ST-segment elevation were found in 5 of 11 patients. However, other cardiac biochemical markers such as TnI, which is highly specific for myocardial injury, were not studied. In a rat study, there was no elevation of cardiac biomarkers, including TnI, by dichlorvos poisoning.18 However, the result of our human study was that elevation of TnI was caused by OP in 34.3% patients. Previously, the time interval to cardiac damage was unknown. However, we showed that myocardial injury is caused during the acute early phase, because we analyzed TnI within 2 days. Of course, the severity of poisoning in our study was very high (Table 1). Most patients (90.9%) belonged to severe class by Namba classification. This was considered due to unconsciousness, severe cholinergic symptoms, and low serum pseudocholinesterase activity. Therefore, we concluded that OP can cause direct myocardial injury apart from rhythm disturbances in severe OP poisoning. However, the median maximum of TnI level was 0.305 ng/mL and this was relatively low compared to other myocardial injuries, such as myocardial infarction and myocarditis.19 The protocol for pralidoxime administration at our hospital is to infuse 1–2 g over 20–30 min followed by 0.5 g/h for 48 h. For atropine, an initial intravenous bolus of 1–3 mg depending on the severity of symptoms and continuous infusions will be needed for patients severely poisoned by very fat-soluble OP that continue to redistribute from the fat and freshly inhibit serum cholinesterase. Applying the atropine regimen may result in myocardial injury due to atropineinduced tachycardia so the usage of atropine was paused in case of the pulse rate increasing to over 120 bpm.20,21 In our study, totally 34 patients showed elevated TnI. Among the TnI-elevated patients, 18 patients (52.9%) had elevated TnI at initial ED assessment before atropine usage. Also, there was no statistical difference between the two groups in terms of atropine dosage for 48 h (Table 1). Therefore, we could exclude effects of subsequent myocardial injury, induced by atropine. To exclude the effect of shock and hypoxia among the myocardial injury patients, the TnI elevation within nonshock and non-hypoxia patients were evaluated (Table 3). In non-shock and non-hypoxia patients, myocardial injury were 31.3% patients and 34.3%, respectively, and this result was similar to the total myocardial injury percent (34.3%). Among the myocardial injury patients, 18 patients (52.9%) had elevated TnI at initial ED assessment, use of adrenergic agents did not actually related to the myocardial injury. Therefore, we could exclude effects of subsequent myocardial injury, induced by shock, adrenergic agents, and hypoxia. Initial GCS scores differed between groups. Patients with elevated TnI tended to be older, which may be because older
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878 Y. S. Cha et al. patients have poor decreased physiologic defense mechanisms to OP poisoning. In addition, patients with elevated TnI had more complications including respiratory failure requiring ventilator care and pneumonia; they also had longer stays in the ICU than the patients with normal TnI. We found a difference in serum glucose between patients with normal and the elevated TnI. Hyperglycemia may be caused by pancreatic injury in OP.3,22–23 Although Cr was normal in both groups, patients with elevated TnI had higher Cr levels and lower pseudocholinesterase levels than patients with normal TnI. We found no statistical differences in ECG analysis between patients with normal and elevated TnI (Table 2). Sinus tachycardia was more than sinus bradycardia. Anand et al.16 confirmed that sinus tachycardia is the most common abnormality, and observed tachycardia in 26 of 36 patients on admission. Sinus tachycardia may be caused by intense sympathetic stimulation, nicotinic stimulation of ganglionic sites by excess ACh, atropine administration, hypoxia, dehydration, and shock.16 In our study, 11 patients (11.1%) had ST changes, and this change persisted in one patient, suggesting long-lasting myocardial damage.24 Anand et al.,16 found a higher proportion of ST changes (19.4%, 7 patients of 36 patients) than our study. There was QT prolongation in 69.7% of patients in our study. Although TdP can occur in patients with OP poisoning in the setting of prolonged QTc intervals,25–27 TdP did not occur in our study. The clinical usefulness of BNP assays has been confirmed for screening of heart disease, stratification of patients with congestive heart failure, detection of left ventricular systolic and/or diastolic dysfunction, and differential diagnosis of dyspnea.28,29 In our study, even though BNP was higher in patients with elevated TnI, there was no statistical difference between the two groups (p ⫽ 0.052) and BNP values of both groups were within the normal range (⬍ 100 pg/mL). This may mean that myocardial injury related to OP is not enough to cause ventricular dysfunction. This study had some limitations. First, it was a retrospective study and involved only one hospital. As a result, not all relevant assessment parameters could be included. In particular, the ingested amount of toxin and the ED arrival time after ingestion may be overestimated or underestimated. Second, since the exact percentages of OP, solvent, and surfactant are unknown, their clinical influence could not be predicted. Third, GCS can be affected by co-ingestion of alcohol as well as by OP insecticides. In our study, 35.4% of patients co-ingested alcohol with OP. However, there was no difference in the incidence of alcohol co-ingestion between the two groups (Table 1). The prevalence of TnI elevation was 37.0% in the 17 of 46 patients who ingested OP alone; we could not investigate alcohol co-ingestion in 18 patients. There was no significant difference compared to all patients (34.3% in 99 patients). Even when we eliminated the effects of alcohol, patients with elevated TnI had lower initial GCS scores than patients with normal TnI (9.0 [IQR 3.5–12.5] ng/mL vs. 11.0 [IQR 6.5–15.0] ng/mL, respectively, [p ⫽ 0.225]). However, not evaluating the
presence of alcohol co-ingestion by serum ethanol level in all included patients was a limitation of our study. Further studies are required to clarify these details.
Conclusions OP can cause direct myocardial injury during the acute early phase in severe OP poisoning. Monitoring of TnI may be needed in severe OP poisoning.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
Contributorship Conception and design of the study: Hyun Kim, Yong Sung Cha Acquisition of data: Jin Go, Kyoung Chul Cha, Oh Hyun Kim, Tae Hoon Kim Drafting the article: Yong Sung Cha Revising draft critically for important intellectual contents: Hyun Kim, Kang Hyun Lee, Sung Oh Hwang Final approval of the version: Hyun Kim
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