The effects of fresh frozen plasma on cholinesterase levels and outcomes in patients with organophosphate poisoning

OBJECTIVE: The aim of this study is to determine the effects of fresh frozen plasma, as a source of cholinesterase, on butyrylcholinesterase (BuChE; plasma or pseudo cholinesterase) levels and outcomes in patients with organophosphate poisoning. MATERIALS AND METHODS: This prospective study was performed at the Department of Intensive Care of Erciyes University Medical School. Over 2 yrs, patients admitted to the ICU for OP poisoning were entered into the study. OP poisoning was diagnosed on the basis of history and BuChE levels. All patients received atropine. Fresh frozen plasma was given to 12 patients. The study was approved by the Ethical Committee, and verbal informed consent was obtained. RESULTS: Thirty-three patients were included in the study. BuChE levels measured at admission and the pralidoxime and atropine doses administered were not different between groups (p>0.05). Although intermediate syndrome developed in 28.6% of patients receiving pralidoxime, there were no intermediate syndrome cases in patients receiving plasma prior to developing intermediate syndrome. The mortality rates were 14.3% in the pralidoxime group and 0% in the plasma+atropine+pralidoxime group. Two patients received plasma after developing the intermediate syndrome, and one patient who received only atropine died. BuChE levels of fresh frozen plasma were 4069.5 +/- 565.1 IU/L. Every two bags of plasma provided an increase in BuChE levels of approximately 461.7 +/- 142.1 IU/L. CONCLUSION: Fresh frozen plasma therapy increases BuChE levels in patients with organophosphate poisonings. The administration of plasma may also prevent the development of intermediate syndrome and related mortality. Plasma (fresh frozen or freshly prepared) therapy may be used as an alternative or adjunctive treatment method in patients with organophosphate pesticide poisoning, especially in cases not given pralidoxime. Further randomized controlled and animal studies are required to infer a definitive result.     

甲基莲心碱对有机磷中毒小鼠胆碱酯酶的重活化作用

目的　探讨甲基莲心碱 (Nef)对LD10 0 剂量的敌敌畏(DDVP)和敌百虫 (Dip)中毒小鼠胆碱酯酶的重活化作用及其保护效应。方法　将昆明种小鼠分为DDVP或Dip中毒组及Nef、阿托品和氯磷定等各治疗组 ,采用急性毒性试验及DTNB比色法测定小鼠胆碱酯酶 (ChE)活力单位。结果　①Nef(15mg·kg-1,ip)对中毒小鼠有确切的保护作用 ,因为Nef处理的小鼠 2 4h死亡率低于生理盐水组 (P <0 0 1) ,其死亡率接近阿托品 (0 5mg·kg-1,ip)处理组 ,二者间死亡率差异无显著性 (P >0 0 5 ) ,但均低于氯磷定组 ,差异有显著性 (P <0 0 5 )。②Nef与氯磷定对中毒小鼠的ChE活力均有重活化作用 ,二组间ChE活力单位百分率差异无显著性 (P >0 0 5 ) ,但均高于生理盐水对照组及阿托品组 (P <0 0 1)。结论　实验结果表明Nef具有重活化有机磷中毒小鼠体内被抑制的ChE功效 ,并具有与阿托品相似的对抗有机磷中毒的作用 ,其作用机制尚需进一步研究     

血液灌流与血浆置换联合抢救老年重度有机磷中毒的疗效

目的探究老年有机磷中毒重度型应用血浆置换联合血液灌流疗法的临床效果。方法有机磷中毒老年患者100例,按治疗方式的不同分为对照组和治疗组,每组50例。对照组进行血液灌流疗法,治疗组进行血液灌流联合血浆置换疗法,观察两组患者各项生化指标、临床疗效和并发症的情况。结果两组治疗后各项生化指标均有改善,但治疗组的指标水平明显优于对照组;治疗组的阿托品中毒、中间综合征、病死和反跳等并发症的发生率显著低于对照组,差异具有统计学意义（P〈0.05）。结论血液灌流联合血浆置换抢救老年重度有机磷中毒,有效的减少了患者并发症的发生,降低了患者各项生化指标的数值,提高了患者预后的生活水平,值得在临床上推广。     

有机磷中毒患者血胆碱酯酶活性的变化规律及临床意义

目的研究急性有机磷中毒（AOPP）患者全血及血清胆碱脂酶（ChE）活性的变化规律。方法所有51例患者入院后均给予清除毒物、应用双复磷或氯磷定、阿托品及积极的对症支持治疗。分别于治疗前、治疗后6～12、24、48、72、96、120h及出院时抽末梢血测定全血及血清ChE活性,并于同期测定37名均为健康者血ChE活性作为正常对照。结果全血、血清ChE活性在中毒患者治疗前均较正常对照组明显降低（P〈0.01）,治疗后轻度患者的全血ChE活性恢复较快,至出院时基本恢复正常;中、重度患者的全血ChE活性于治疗后24h降至最低,于48h缓慢回升,至出院时仍未恢复至正常水平;3例死亡患者全血ChE活性持续不回升。血清ChE活性值波动较大,分布较离散,恢复相对较快。结论全血ChE活性是对急情有机磷中毒进行早期诊断,判断疗效和估计预后的重要指标,在治疗上具有重要的指导意义。     

Endocrine changes in patients with acute organophosphate poisoning

In critical illness, several drugs and various stressful conditions modify the functions of neurotransmitters which consequently affect the secretion of pituitary hormones. Although the role of neurotransmitters in the regulation of endocrine system is well known, cholinergic actions have been less investigated. In animals, cholinesterase inhibitors were shown to modify the pituitary-thyroid and pituitary-adrenal axes, and to affect prolactin levels. The aim of the present study was to determine the effect of the organophosphate compounds on endocrine system, particularly pituitary hormones. This prospective study was performed in Medical Intensive Care Unit of Erciyes University Medical School Hospital. Twenty-two consecutive patients (ten males and 12 females aged 28+/-8 years) with organophosphate poisoning were included in the study. ACTH (P<0.002), cortisol (P<0.0005) and PRL (P<0.005) levels were significantly higher during poisoning than after resolution of poisoning. FSH levels were significantly lower during poisoning (P<0. 05). Sick euthyroid syndrome was determined in seven patients (31. 8%). Two of them had low fT3 (with normal fT4 and TSH), two had low fT4 (with normal fT3 and TSH) and three had low TSH (with normal fT3 and fT4) levels. Serum levels of these hormones returned to normal values after resolution of poisoning. The present study demonstrated that organophosphate compounds affected PRL, ACTH and cortisol levels, but did not change LH levels. Organophosphate compounds may result in sick euthyroid syndrome. These conditions may be related to the effects of acetylcholine and direct effect of organophosphate compounds.     

The association of blood cholinesterase levels with the susceptibility of animals to sarin and ethyl pyrophosphate poisoning

An association between the blood cholinesterase (ChE) levels and the toxicity of sarin and ethyl pyrophosphate has been established. This has been demonstrated in two types of experiment. In the first, guinea-pigs were given a non-lethal dose of sarin (isopropyl methylphosphonofluoridate) which reduced the blood ChE to 20% of normal, and at intervals, as the ChE level of the blood gradually recovered, separate batches were given a second dose of the same size. A comparison was then made between the blood ChE levels immediately prior to the injection of the second dose and the mortality rate. In the second, a relatively small dose of sarin or ethyl pyrophosphate was given daily to rabbits until the enzyme value fell to a steady level. LD50 values were then determined on such groups and compared with those found in saline treated ones. In both guinea-pigs and rabbits it has been shown that a depression of blood ChE to below 40% indicated an increased toxicity of sarin and ethyl pyrophosphate to these species. The approximate quantitative relation appears to be that susceptibility is increased in the ratio 1.5 when the blood ChE is reduced by half.     

甲氯酚酯治疗儿童急性重度有机磷中毒疗效观察

目的：探讨甲氯酚酯用于儿童急性有机磷农药中毒的临床治疗效果。方法：将近10年我科收治的急性有机磷农药中毒患儿58例,随机分为治疗组30例（女10例）,对照组28例（女9例）,对照组采用洗胃、静脉推注阿托品、解磷定、吸氧、保持呼吸道通畅等常规方法。治疗组在常规治疗的基础上静脉滴注甲氯酚酯（剂量60～100mg/次,2次,d）观察两组儿童的治疗效果。结果：治疗组治愈26例,治愈率86．7％;对照组治愈19例,治愈率67．9％两组比较P〈O．05。结论：在抢救重度有机磷农药中毒时,及时应用甲氯酚酯能明显提高抢救成功率,值得临床推广使用。     

Intermediate syndrome following acute organophosphate poisoning: correlation with initial serum levels of muscle enzymes

Following acute organophosphate poisoning, intermediate syndrome essentially relates to the impairment of neuromuscular transmission due to prolonged inhibition of acetylcholinesterase activity at the muscle end-plate. However, the role of muscle injury in the development of intermedicate syndrome is not clear. The aim of this study was to determine whether the initial serum levels of the muscle enzymes can predict the subsequent development of intermediate syndrome. We reviewed the files of 47 adult patients with organophosphate poisoning between April 2003 and February 2006. The muscle enzymes were obtained within first 24 hr from each patient. Among the patients, 17% (n = 8) had severe poisoning and 83% (n = 39) mild poisoning. In 10 patients (21%), intermediate syndrome was observed. Of the patients with severe poisoning, 63% (n = 5) developed subsequent intermediate syndrome; among those with mild poisoning, 13% (n = 5) developed intermediate syndrome. There was no significant difference in initial serum levels of creatine kinase and aspartate aminotransferase between the patients with severe poisoning and mild poisoning, and there was no difference in initial serum levels of creatine kinase and aspartate aminotransferase between the patients with and without intermediate syndrome. The serum levels of the muscle enzymes measured within the first 24 hr may not predict the subsequent development of intermediate syndrome.     

Role of aliesterase in organophosphate poisoning

Various doses of CBDP (2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin-2-oxide), a metabolite of tri-o-cresyl phosphate, increased dramatically the acute toxicity of soman (pinacolyl methylphosphonofluoridate) in mice. CBDP (5 mg/kg; iv) reduced the soman LD50 value from 136 μg/kg in control to 6.95 μg/kg. The potentiation of soman toxicity following CBDP pretreatment appeared to be due primarily to inhibition of plasma aliesterase activity. Inhibition of liver aliesterase was not of primary importance in the potentiation of soman toxicity following CBDP pretreatment. In addition pretreatment with ISO-OMPA (tetraisopropyl pyrophosphoramide), a selective inhibitor of pseudocholinesterase, had no effect on the acute toxicity of soman. Similarly pretreatment of mice with pyridostigmine, a quaternary carbamate anticholinesterase which does not inhibit aliesterase, resulted in marked inhibition of diaphragm, plasma, and brain acetylcholinesterase had no effect on the acute toxicity of soman. Plasma aliesterase may be a depot for soman poisoning. The acute toxicity of soman by the ip, sc, and iv routes of administration was reduced following pretreatment of mice with phenobarbital (100 mg/kg) for 4 days. The reduced toxicity of soman following phenobarbital pretreatment was due to induction of liver aliesterase activity which subsequently resulted in an increase in plasma aliesterase activity. Thus more soman was probably bound to plasma aliesterase activity resulting in a reduction in acute toxicity of soman.Conversely pretreatment of mice with pentobarbital (70 mg/kg; ip) increased the toxicity of soman. This was probably the result of inhibition of plasma aliesterase by pentobarbital pretreatment combined with the central respiratory depression following pentobarbital administration. Following pentobarbital pretreatment soman inhibition of brain acetylcholinesterase was increased suggesting that plasma aliesterase inhibition alters the distribution of free soman in vivo. In summary, in mice plasma aliesterase appears to be an extremely important detoxification route for soman in vivo.     

The effect of fluvastatin on plasma fibrinogen levels

There are conflicting data with regard to the effect of statins, including fluvastatin, on plasma fibrinogen levels. We undertook the present study to examine the influence of fluvastatin (40 mg/day) on plasma fibrinogen levels in hypercholesterolemic non-smoker patients with normal triglyceride levels (< 2.25 mmol/l) (n = 65). Fluvastatin administration was followed by a significant decrease of plasma fibrinogen levels by 8% (from 3.6 g/l to 3.33 g/l median value, p < 0.02). No correlation was found between the change in lipids and that in fibrinogen levels. Furthermore, there was no correlation between plasma fibrinogen levels and the change in fibrinogen concentration after fluvastatin administration. These results are in contrast with previously published data. However, the majority of the previous studies included patients with ischemic heart disease, unlike our study population. Furthermore, in some of these studies, which Included relatively small numbers of patients, there was a trend towards a decrease in plasma fibrinogen concentration after fluvastatin administration. We conclude that fluvastatin can significantly decrease plasma fibrinogen levels. However, more studies using fluvastatin and other drugs of this class are necessary to clarify this issue.     

The effect of frusemide on indomethacin plasma levels

1 The pharmacokinetic and clinical effects of concurrent oral indomethacin and frusemide administration were determined in eight patients with rheumatoid arthritis.

2 Oral frusemide significantly reduces the plasma level of indomethacin following concurrent administration of the two drugs orally.

3 A profile of pain index, articular index and grip strength following oral indomethacin (50 mg) was determined and although the decrease in articular index was less when frusemide and indomethacin were given together it did not reach statistical significance.

     

Decreased plasma and cerebrospinal fluid glutamine concentrations in a patient with bialaphos poisoning.

A 47-year-old Japanese woman undergoing maintenance hemodialysis (HD) was admitted to our hospital because of poisoning with the herbicide bialaphos. Respiratory arrest and loss of consciousness ensued rapidly, accompanied by convulsions and nystagmus. Treatment with HD and direct hemoperfusion, followed by HD alone, effectively removed bialaphos and its chief toxic metabolite (L-AMPB) from the circulation (bialaphos decreased from 0.33 to < 0.05 microg/ml and L-AMPB from 14 to 0.86 microg/ml). The glutamate concentration improved gradually after the removal of bialaphos and L-AMPB from plasma (plasma glutamate concentration: 250.4 nmol/l on day 5 to 120.6 nmol/l on day 26). Decreased glutamine concentration in cerebrospinal fluid was demonstrated for the first time as well as in plasma, indicating glutamine synthetase inhibition not only in plants but also in humans by bialaphos poisoning.     

Advances in the management of organophosphate poisoning

Organophosphate (OP) poisoning is commonly encountered in agricultural communities. The mainstay of therapy in OP poisoning is the use of atropine. However, several other therapies have been evaluated. Although oxime has been the most studied antidote, results in humans have been disappointing and limited by the lack of well-designed, prospective, randomised controlled trials. The key factor in determining outcomes in OP poisoning appears to be the timing of antidote administration. Other adjuvants, such as magnesium, fresh frozen plasma and haemoperfusion appear promising, and need to be explored further. A multi-faceted approach may be the answer to improving outcomes in OP poisoning. This review evaluates the advances in OP management over the last 20 years.     

Blockade of acetylcholine synthesis in organophosphate poisoning

In spite of worldwide research efforts in the search for the treatment of organophosphate poisoning, the substances with practical antidotal capabilities remain to be discovered. This problem has generally been approached by attempting to reactivate the inhibited acetylcholinesterase. Our approach consisted of reducing the amount of the lethal agent acetylcholine by blocking its synthesizing enzyme cholineacetylase with methyl methane thiol sulfonate (MMTS). We have taken into consideration that we are dealing with acute toxicological problems. This applies for poisoning as well as for treatment, and therefore in the present stage we can only present minimal results. The time from sarin (2 mg/kg) injection to death in rats (controls) was 2:59 min. With a MMTS dosage of 133.5 mg/kg prior to sarin, it was prolonged to 20:55 min (p < 0.01). With the same dosage of MMTS under identical conditions, the time from soman (2 mg/kg) injection to death was prolonged from 6:08 to 14:48 min (p < 0.01). Although MMTS cannot be used as a therapeutic agent, our attempt has demonstrated a utility in treating organophosphate poisoning in mice and rats and points in a direction where further work might be fruitful.     

Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures.

Developing mammals are markedly more sensitive to acute toxicity from exposure to a variety of organophosphorus (OP) pesticides. The present study examined dose-related inhibition of both brain and plasma cholinesterase activity in neonatal and adult rats exposed to sublethal doses of one of three common OP pesticides, methyl parathion, parathion and chlorpyrifos. Effective dose 50 (i.e., ED50 or dose which would inhibit 50% of the cholinesterase activity) values were determined and then correlated with an indicator of acute toxicity, the maximal tolerated dose (MTD). It was found that ED50 estimates for both brain and plasma cholinesterase correlated highly (r = 0.932-0.992) with previously derived MTD values. In no case was there a significant difference between in vivo brain and plasma cholinesterase inhibition across doses in neonatal rats was high (r = 0.962-0.975) but lower in adults (r = 0.700-0.943). The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats. Additionally, under defined experimental conditions, plasma ChE inhibition may be a useful quantitative index for the degree of brain cholinesterase inhibition following OP exposures.     

急诊重症监护室中毒患者临床救治效果观察

目的观察急诊重症监护室中毒患者的临床救治效果。方法急诊重症监护室中毒患者45例,先清除患者体内未吸收的毒物,再给予药品和利尿治疗,并据患者情况予相关对症治疗及心理干预。观察患者的救治效果。结果经救治后,45例患者中救治成功39例,救治成功率为86.67%;死亡6例,病死率为13.33%。结论对中毒患者进行救治时,明确中毒物质,再据具体中毒物质选择正确的抢救方法并进行快速抢救,能有效提高中毒患者的救治成功率,从而确保患者的生命安全并提高其生活质量。