Acute organophosphorus pesticide poisoning (AOPP) is a major health issue worldwide, and is particularly severe in developing countries.1-3 According to a report by the World Health Organization,4 more than 500 000 people worldwide die of suicide every year; 60% of these suicides are attributed to self-poisoning with pesticides.3 Around 60% of these self-poisoning cases (>200 000 per year) involve organophosphorus pesticides.5 AOPP causes death mainly by inducing acute respiratory failure, which occurs and develops rapidly, causing respiratory arrest. If not treated in a timely manner, death can result. Early evaluation of respiratory function remains difficult; only a few parameters are known to be useful for assessment,6-8 including portable chest roentgenography and chest computed tomography.
Several studies have suggested that there is no clear benefit, or that there may even be harm, in using a pulmonary artery catheter in critically ill patients.9-11 As an alternative to the more invasive pulmonary artery catheter, use of the transpulmonary thermodilution method pulse-induced contour cardiac output (PiCCO) has been suggested.12 The PiCCO monitor measures cardiac output and the global end-diastolic volume indexed for body surface area as well as parameters of cardiac performance, such as the cardiac function index and the global ejection fraction. PiCCO also provides an estimate of extra-vascular lung water (EVLW) and calculates the pulmonary vascular permeability index (PVPI),13,14 allowing for differentiation between types of pulmonary edema. EVLW indexed to body weight (EVLWI) can be an independent foresight factor of disease classification, prognosis, and death prediction in critically ill patients, such as those with sepsis, septic shock, and acute respiratory distress syndrome.8,15-17
The PiCCO method has been validated mainly in surgical patients and, to a lesser extent, in patients with AOPP. In this study, we induced severe acute dichlorvos poisoning (SADP) in a porcine model and treated the animals with atropine. The EVLWI was calculated, and the ratio of EVLW to pulmonary blood volume was used as the PVPI. We monitored EVLWI and PVPI by PiCCO plus to evaluate respiratory status. Our objective was to test the hypothesis that EVLWI is an appropriate parameter for evaluation of early SADP-induced respiratory function.
This study was conducted at the Animal Laboratory of Beijing Chaoyang Hospital (Capital Medical University, Beijing, China) with approval from the Medical Ethics Committee of the hospital. Twenty-three-month-old female pigs ((32±3) kg) were used in the study.
Anesthesia and mechanical ventilation
After intramuscular injection of midazolam (2 mg/kg; Nhwa Pharmaceutical, Xuzhou, Jiangsu, China), anesthesia was induced and maintained by intravenous infusion of propofol (0.2 mg×kg−1×h−1; Beijing Fresenius Kabi, Beijing, China). All animals received maintenance fluids (0.9% NaCl, 7 ml×kg−1×h−1). Animals were intubated (6.5F), and mechanical ventilation was administered with a tidal volume of 10 ml/kg, a constant fraction of inspired oxygen (FiO2) of 0.21, and an inspiration/expiration ratio of 1:2 without positive end expiratory pressure (Servo 900C; Siemens, Germany). Respiration was adjusted to obtain an arterial partial pressure carbon dioxide (PaCO2) of 35–45 mmHg.18,19
Electrocardiograms were monitored. A central venous catheter (7F, CS-17702-LF; Arrow International Inc., USA) was inserted into the right external jugular vein and advanced to the right atrium. A thermistor-topped arterial PiCCO catheter (Pulsiocath 5F, 20 cm, PV2015L20; Pulsion Medical Systems AG, Munich, Germany) was placed in the descending aorta via the left femoral artery and connected to a PiCCO Plus monitor.
Animals were randomly allocated to the dichlorvos (n=7), atropine (n=7), or control group (n=6). In the dichlorvos group, the pigs received 80% emulsifiable dichlorvos (100 mg/kg; Dacheng Pesticide Co., Zibo, Shandong, China) via a gastric tube. In the atropine group, the pigs underwent similar administrations of dichlorvos followed by intravenous injections of atropine 30 minutes later (KingYork Amino Acid Co., Tianjin, China). The atropine dose was 0.5 mg initially, doubled every 5 minutes to rapidly attain atropinization, and then maintained.1,20,21 The control group did not receive dichlorvos or atropine, but saline solution only.
Pupillary status, salivation, and muscular fasciculation in all the animals were continuously monitored for 2 hours. Hemodynamic parameters were recorded at 0, 0.5, 1, 2, 4, and 6 hours. At each time point, arterial blood was drawn for blood gas analysis, and venous blood was drawn to determine acetylcholinesterase (AchE) levels.
Volumetric variables were measured using the single-indicator transpulmonary thermodilution technique. The PiCCO values were obtained by repeated injections of 10-ml boluses of ice-cold normal saline via the central line. The mean value of three consecutive measurements was used for the analysis. If the difference between the three obtained values for the cardiac index was greater than 10%, two additional measurements were performed. Finally, the mean of all consecutive measurements was used. The PiCCO method and definitions of intrathoracic blood volume and EVLWI are described in more detail elsewhere.22
The experiment was terminated after 6 hours, and animals were euthanized with a lethal dose of potassium chloride. The left lung was removed for measurement of lung wet-to-dry weights. The entire mass of the left lung tissue was weighed to measure the wet weight, then dried at 80°C for 72 hours to obtain the dry weight. The wet-to-dry ratio was calculated and expressed as a relative value.23 Pathological changes in the right middle lobe tissues preserved in 10% formaldehyde and 4% paraformaldehyde were observed under a light microscope (OLYMPUS, Japan). Changes in tissue ultramicrostructure were observed under a transmission electron microscope (H-600; Hitachi, Japan). All pictures were analyzed by an experienced pathologist, who was blinded to information regarding the animal groups.
Statistical analysis was performed with SPSS 13.0 (SPSS Inc., USA), and the distribution of data was checked. Results are expressed as the mean±standard deviation (SD). A repeated-measures analysis of variance was used to analyze the evaluation of parameters. The Student-Newman-Keuls test was used for comparisons between times of statistical significance in the analysis of variance. Pearson’s correlation coefficients were calculated between EVLWI and PaO2/FiO2 and between EVLWI and PVPI; for all tests, P <0.05 was considered statistically significant.
Animal characteristics after SADP induction
In the dichlorvos group, one pig died 45 minutes after dichlorvos administration because spontaneous respiration stopped and pulse oxygen saturation (SpO2) gradually dropped from 100% to 0; the remaining six pigs survived the experiment. These pigs exhibited pinpoint pupils, excessive salivation, and spasm of limb muscles (scored following De Bleecker et al24). In the atropine group, one pig died at 25 minutes of the same cause as that of the other pig in the dichlorvos group; the remaining six pigs survived the experiment. These animals displayed similar pinpoint pupils, excessive salivation, and spasm within the first 30 minutes. After treatment with atropine, these pigs clearly showed recovery of pupil diameters, decreased salivation, and disappearance of spasms. In the control group, these changes were not observed (Table 1).
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Table 1. Pupillary status, salivation volume, and muscular spasm scores (n=6)
Arterial blood gas analyses and AchE levels
In the dichlorvos group, arterial blood gas analysis revealed that arterial oxygen saturation (SaO2) and PaO2/FiO2 were decreased. The rates of decrease were particularly sharp within the first hour, but had slowed by the sixth hour. PaCO2 was decreased in the first hour, then gradually increased until the experiments were completed. In the atropine group, SaO2 and PaO2/FiO2 underwent similar changes within the first hour, then demonstrated gradual improvement. The animals in the control group did not exhibit any obvious changes with respect to these parameters. The differences in SaO2 and PaO2/FiO2 within groups were statistically significant (P <0.01, Table 2). In the dichlorvos group, AchE levels were markedly decreased in the first hour and continued to decrease over the course of the experiment. In the atropine group, AchE levels were decreased in the first hour, then gradually improved following atropine treatment. There were no evident changes in the control group.
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Table 2. Changes in RR, SaO2, PaCO2, and PaO2/FiO2 (n=6)
PiCCO parameter changes
In the dichlorvos group, EVLWI and PVPI were increased within the first few hours and continued to increase at a steady rate. In the atropine group, the EVLWI and PVPI increased initially, with the peak level at the 1-hour mark, then started to decrease. The control group exhibited negligible changes. The differences in EVLWI and PVPI were statistically significant between the dichlorvos and control groups (P=0.001 and 0.010 respectively), as well as between the dichlorvos and atropine groups (P=0.01 and 0.01 respectively). However, the differences in EVLWI and PVPI were not statistically significant between the atropine and control groups (P=0.157 and 0.360 respectively). Next, we analyzed the correlation between EVLWI and PaO2/FiO2 and between EVLWI and PVPI. In the dichlorvos group, EVLWI was negatively correlated with PaO2/FiO2 (r=−0.823, P=0.001) and positively correlated with PVPI (r=0.628, P=0.001, Figure 1A). In the atropine group, EVLWI was also negatively correlated with PaO2/FiO2 (r=−0.811, P=0.001) and positively correlated with PVPI (r=0.441, P=0.007, Figure 1B). In the control group, EVLWI was not correlated with PaO2/FiO2 or PVPI.
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Figure 1. Correlation between EVLWI and PaO2/FiO2, PVPI in the dichlorvos group (A) and atropine groups (B). A: r=−0.823 and P=0.001 (left), and r=0.628 and P=0.001 (right). B: r= −0.811 and P=0.001 (left), and r=0.441 and P=0.007 (right). (n=6, each).
Lung wet-to-dry weight ratio
Compared with the control animals, the lung water content and wet-to-dry weight ratio were higher in the dichlorvos group (6.32±2.08 vs. 2.83±0.65, P=0.000). After atropine treatment, the lung wet-to-dry ratio was significantly reduced (3.65±0.55 vs. 2.83±0.65, P=0.288).
Histopathological and micropathological changes
Hematoxylin and eosin staining of tissue sections revealed many histopathological changes. In the control group (Figure 2A1), alveolar structures retained their integrity with no increase in thickness of the alveolar septum and a lack of edema in the interstitial lung tissue. In the dichlorvos group (Figure 2B1), interstitial and alveolar edema was severe. There was a large amount of infiltration by inflammatory cells and fluid in the alveolar septae. In the atropine group (Figure 2C1), alveolar structures exhibited normal integrity and there was a mild increase in alveolar wall thickness. There was mild edema of the interstitial lung tissue, but no edema in the alveolar space.
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Histopathological changes (hematoxylin and eosin staining) in tissue sections from the control (A1)
, dichlorvos (B1)
and atropine groups (C1)
Alveolar structures retain their integrity; the alveolar septum does not have increased thickness. There is no evident edema in the lung (original magnification
Interstitial and alveolar edema. Infiltration of inflammatory cells and fluid in the alveoli (original magnification ´400). C1:
Alveolar structures are intact with increased thickness of the alveolar wall. There is mild edema in the lung interstitial space, but no edema in the alveolar space (original magnification ´400). Micropathological changes in the control (A2
), dichlorvos (B2
) and atropine groups (C2
Type II epithelial cells have no marked structural change with normal lamellar bodies present (black arrow). The cell nucleus was not obviously abnormal (white arrow, original magnification ´20 000). B2
: A large amount of cell debris and fluid was found in alveolar spaces, and type II epithelial cells exhibited altered morphology and contained vacuole-like lamellar bodies inside the cell. Mitochondrial cristae were no longer evident or had swollen (black arrow). The nucleus showed significant autolysis (white arrow, original magnification ´20 000). C2
: Lamellar bodies in type II epithelial cells have vacuole-like changes (black arrow). There was a large amount of chromatin condensation in the nucleus (white arrow, original magnification ´20 000).
Changes were also seen in the ultramicrostructure. In the control group (Figure 2A2), type II epithelial cells exhibited no marked structural changes and normal lamellar bodies; the cell nucleus was not obviously abnormal. In the dichlorvos group (Figure 2B2), there was a large amount of cell debris and fluid in the alveolar spaces, and type II epithelial cells had an altered morphology with vacuole-like lamellar bodies inside. The structure of the blood-gas barrier was irregular because of erosion. Mitochondrial cristae were no longer apparent or had become seriously swollen, and the nucleus exhibited massive amounts of autolysis. In the atropine group (Figure 2C2), lamellar bodies in type II epithelial cells had vacuole-like changes with chromatin condensation in the nucleus.
According to reports25,26 and our pre-experimental results (three doses: 50, 75, and 100 mg/kg), and based on the animal serum cholinesterase changes in muscarinic, nicotinic, and nervous system poisoning, we finally chose 100 mg/kg as the toxic dose of SADP. This model approached the SADP standard.
In this study, SADP pigs demonstrated changes in early respiratory status and EVLWI. The poisoned pigs exhibited respiratory stimulation followed by rapid suppression and increased tracheal and esophageal secretion. The respiratory rate was faster in the first 30 minutes, then decreased. Two pigs, one at the 25-minute mark in the atropine group and another at the 45-minute mark in the dichlorvos group, died of asphyxia. Rapid inhibition of the respiratory center may have led to these deaths. Arterial blood gas analyses revealed decreased SaO2 and PaO2/FiO2, but PaCO2 decreased in the first 30 minutes, then increased again. This was in accordance with the mechanisms proposed by Gaspri and Paydarfar27 who stated that dichlorvos poisoning can result in a sequential “two-hit” insult characterized by rapid central apnea followed by delayed secondary respiratory failure. Gaspri and Paydarfar27 suggested that the former insult was attributed to rapid loss of respiratory effort and resulted in a decreased respiratory rate and apnea. The latter insult could be attributed to decreases in the ratio of expiratory to inspiratory volume, widening of the alveolar-arterial gradient, or a prominent increase in airway secretion, thereby causing apnea. In the dichlorvos group, there was a substantial increase in EVLWI, peaking at 13.17 ml/kg; PVPI showed similar changes. There was a high correlation between EVLWI and PVPI and between EVLWI and PaO2/FiO2 (Figure 1A). The relationships between EVLWI and oxygenation indices were studied by Hachenberg et al28 who found no correlation between EVLW and any of the oxygenation indices. Venous admixture (QVA/QT) may have also been influenced by the infusion of nitroglycerin after extracorporeal circulation and in the postoperative course. Nitroglycerin may directly impair oxygenation in edematous lungs by release of hypoxic pulmonary vasoconstriction. Changes in lung water may cause intrapulmonary shunts in cardiac surgical patients, which is potentially aggravated by potent vasodilators. Development of atelectasis after induction of anesthesia or during cardiac surgery largely influences oxygenation. Likewise, an improvement in gas exchange in the postoperative course may be related to aeration of collapsed lung tissue. In the present study, however, the increase in EVLWI was associated with an acute deterioration in oxygenation (PaO2/FiO2). The lung wet-to-dry ratio and histopathology results were altered in the dichlorvos group. Increased permeability due to endothelial cell injury may lead to lung edema after poisoning. Resolution of pulmonary edema may depend not only on Starling forces and lymphatic drainage, but also on active transport of sodium and water out of the alveolar and interstitial compartments. An intact epithelial barrier function seems to be an important factor for this mechanism. These patterns were similar to those observed by Eddleston et al29 who reported that the early phase of respiratory failure was characterized by early acute mixed central and peripheral respiratory failure followed by late peripheral respiratory failure.
Khan et al30 reported that measurement of EVLW by transpulmonary single thermodilution was a useful adjunct to assess lung vascular injury, cardiogenic edema, and overhydration. Because of these advantages, transpulmonary single thermodilution was used in this study to monitor EVLWI and PVPI.15-17 The findings showed that EVLWI and PVPI were indicators of lung vascular injury and had substantially increased from the time of poisoning, with baseline levels of 8.22 and 2.52 mg/kg and peak levels of 13.17 and 3.44 mg/kg at 6 hours, respectively. These increases indicate that dichlorvos severely affected permeability of the pulmonary vessels and alveoli, resulted in extensive leakage of visible components from the vessels, and led to pulmonary edema. This was further demonstrated by the changes observed in lung histopathology. Moreover, Sakka et al8 found that an EVLWI above 15 ml/kg was associated with a mortality rate of 65%, whereas an EVLW below 10 ml/kg was associated with a mortality rate of less than 33%. Meanwhile, Kuzkov et al16 found that EVLWI could be used to indicate the severity of sepsis-induced acute lung injury and predict its occurrence. Therefore, EVLWI is an important index in the evaluation of critically impaired pulmonary functions. In this study, in the dichlorvos group, EVLWI and PVPI increased sharply within the first hour and continued to increase thereafter. In comparison, in the atropine group, these parameters increased within the first hour, but then decreased. Further analyses of the correlations between EVLWI and PaO2/FiO2 and between EVLWI and PVPI revealed that EVLWI had a positive relationship with PVPI but a negative relationship with PaO2/FiO2 in both the dichlorvos and atropine groups. These patterns indicate that dichlorvos poisoning affected the functions of pulmonary vessels and alveoli. The changes in EVLWI and PVPI reflected the changes in extravascular lung water at the 1-hour mark, and they were superior to the changes shown by chest radiography.6,7 These results indicate that EVLWI is a valuable and important parameter for evaluation of the SADP-induced pulmonary status.
The main purpose for EVLWI measurement is early diagnosis and monitoring of poisoning pulmonary edema (PPE). Clinical signs of PPE, such as dyspnea, hypoxemia, and markedly reduced lung compliance, are usually delayed for 1–3 days after induction; however, these signs are also nonspecific. In the earlier stages, edema is mainly interstitial and difficult to detect by chest radiography.6,7 Early EVLWI measurement may therefore be useful to identify patients at risk of respiratory failure.
Dichlorvos is a powerful inhibitor of AchE. By inhibiting cholinergic synapses, it causes massive accumulation of acetylcholine, eventually resulting in cholinergic receptor paralysis.20 Atropine is a classical antagonist for all subtypes of cholinergic receptors,1,20 including the M1, M2, M3, M4, and M5 subtypes. The clinical recommendations for atropine administration include more than 30 regimens with doses varying over a wide range, some of which require hours to attain atropinization.21 In this study, we chose the regimen recommended by Eddleston et al21 which was reported to rapidly reverse bronchospasm and prevent increased airway secretion. The objective of atropinization was to clear the lungs, raise the systolic blood pressure, and increase the heart rate to 80–100 beats per minute. According to Eddleston’s recommendation, atropine (0.5 mg) was intravenously bolus-injected for 30 minutes following induction of dichlorvos poisoning in pigs. The dose was doubled every 5 minutes to attain rapid atropinization. This regimen generated excellent results, including an atropinization time of 9–22 minutes and an atropinization dose of 1.5–15.5 mg. At 30 minutes after atropine administration, the pupillary status had recovered; salivation and muscular spasms were reduced; breath had stabilized; and PaCO2, SaO2, and PaO2/FiO2 were improved. At 2 hours post-administration, the pupillary status was normalized, salivation was limited, and muscular spasms were no longer apparent. From 1 to 6 hours, the EVLWI and PVPI decreased and gradually normalized. These patterns indicate that atropine effectively antagonized cholinergic receptors to relieve pulmonary vessel and alveoli injuries, reduced vascular exudation and alveolar secretion, and alleviated PPE.
Furthermore, in the dichlorvos group, the lung wet-to-dry ratio significantly increased and the corresponding EVLW and PVPI peaked. After atropine intervention, the lung wet-to-dry ratio significantly decreased, but EVLW and PVPI tended to rise first (from 0 to 1 hours), then fall (from 1 to 6 hours); EVLW and PVPI fell to the lowest values at the 6-hour mark. The lung wet-to-dry ratio was stable, and EVLW and PVPI showed no significant changes in the control group. Similar changes were found in the common pathology and ultrastructural pathology of the lung tissues. Alveolar congestion and edema, significantly increased exudation, and inflammatory cell aggregation were observed in the dichlorvos group. Mitochondrial structure disorder, nuclear shrinkage, lamellar body changes, and blood-gas barrier damage were observed in ultrastructural pathology. After atropine therapy, alveolar damage was obviously alleviated with the exception of slight congestion and edema. Exudation of inflammatory cells was obviously decreased. Mitochondrial structure was relatively clear, nuclei had no apparent shrinkage, and the blood-gas barrier was basically integrated in ultrastructural pathology. In the control group, the alveolar structure was normal, and no congestion, edema, or exudation were found. The ultrastructure was normal. The changes in EVLW and PVPI can be easily interpreted by studying the changes in the lung wet-to-dry ratio and lung pathology. Therefore, the use of EVLWI as a parameter for pulmonary function changes after dichlorvos poisoning was further supported.
Gravimetric methods provide the most precise measure of lung water. Unfortunately, the wet-to-dry lung weight method does not distinguish between EVLW and pulmonary blood volume, and effectively overestimates EVLW. Notably, the use of postmortem gravimetry as the reference method for evaluating pulmonary edema also has limitations.31,32 For example, this method allows only one measurement, and therefore cannot follow variations over time. The application of gravimetry is limited almost exclusively to experimental studies. Comparison of gravimetry measurements with results of other techniques for determination of EVLWI can be influenced by the duration from death to lung removal and by pathophysiological changes in the lungs after cardiac arrest. Therefore, the gravimetry technique can underestimate the real value of EVLWI because of partial reabsorption of fluid before lung excision. The number of animals employed in this study was relatively small, they were only monitored for 6 hours, and two of the pigs died during the course of the experiment. Therefore, this study only assessed the pulmonary function changes within a limited period after poisoning. Although measurement of EVLWI seems valuable in the clinical setting, particularly since single transpulmonary thermodilution was shown to be sufficiently accurate for the estimation of EVLWI, we suggest that further experimental studies are necessary to evaluate the PiCCO plus method in AOPP models.
In conclusion, this study demonstrated that EVLWI is a valuable parameter for evaluation of respiratory functions, particularly in the early stages following acute dichlorvos poisoning. Atropine treatment significantly improved the respiratory functions in the poisoned pigs.
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