Jude Joseph Fleming

Clinical profile and outcome of patients hospitalized with dimethyl and diethyl organophosphate poisoning.

The two major classes of organophosphate compounds, dimethyl and diethyl organophosphates, have different toxicokinetic properties. This study evaluated the clinical profile and outcomes in patients admitted with poisoning with these two classes of organophosphates. Methods. This retrospective study spanned 6 years (2002–2007). Patients were treated with atropine and supportive care including ventilation, as required, and followed up until death or hospital discharge. Oximes were not administered. Of the 422 charts retrieved, 396 fulfilled inclusion criteria. Data on the clinical profile, ventilation, length of hospital stay, incidence of intermediate syndrome and mortality were extracted. Results. The mean (±standard deviation) age was 31.4 ± 12.7 years with a male preponderance (2.6:1). The median (interquartile range (IQR)) admission pseudocholinesterase level of 317 (222–635) U/L indicated significant inhibition of cholinesterase activity. The median lag-time to presentation to our hospital was 5 (IQR 3–8.5) hours. Oximes were administered at a primary center in 33 patients (8.3%). Dimethyl organophosphate was ingested by 141 patients, diethyl organophosphate by 108, S-alkyl organophosphate by 2, and an un-identified organophosphate by 145 patients. Ventilation was required in 260 patients (65.7%); the median duration of ventilation being 7.5 (IQR 3–12) days. Overall mortality was 13.1%. There was a significant difference between dimethyl and diethyl organophosphate compounds in ventilatory requirement (76% vs. 56%, adjusted odds ratio (OR) 2.37, 95% CI 1.01–5.57, p = 0.047), duration of ventilation (11 (4–15) vs. 5 (2–9) days, adjusted OR 1.12, 95%CI 1.04–1.21, p = 0.002) and incidence of intermediate syndrome (72/125 (58%) vs. 24/92 (26%), adjusted OR 2.84, 95%CI 1.38–5.86, p = 0.004). Mortality was similar in the two groups (20/141 (14%) vs. 7/108 (6%), dimethyl vs. diethyl organophosphate, adjusted OR 1.29, 95%CI 0.43–3.94, p = 0.65). Conclusions. Patients admitted with dimethyl organophosphate poisoning have a worse outcome compared with diethyl organophosphate poisoning for clinically relevant patient outcomes.

Bioscavenger therapy for organophosphate poisoning – an open-labeled pilot randomized trial comparing fresh frozen plasma or albumin with saline in acute organophosphate poisoning in humans

Introduction. Traditional treatment of organophosphate poisoning (OP) with oximes has had limited success. Fresh frozen plasma (FFP) or albumin, acting as bioscavengers to mop up free organophosphate, has been recently proposed as a treatment modality. In this pilot open-label, three-arm, randomized controlled study exploring proof of concept, we evaluated if bioscavenger therapy had a role in OP. Patients and methods. Sixty patients with significant poisoning presenting within 12 hours, with suppression of pseudocholinesterase activity to < 1,000 U/L, were randomized to receive FFP (8 bags, 250 mL each over 3 days), 20% human albumin (4 × 100 mL over 3 days), or saline (2,000 mL over 3 days) in addition to atropine and supportive care. Pseudocholinesterase and organophosphate levels were measured pretreatment, post-infusion (Day 2, Day 3), and predischarge and expressed as mean ± standard error. The incidence of intermediate syndrome, need for mechanical ventilation, atropine requirement, and mortality were assessed. Results. Twenty patients received albumin and 19 patients each FFP or saline. FFP increased pseudocholinesterase levels (250 ± 44–1,241 ± 364 U/L) significantly (p = 0.007). Small, nonsignificant increases were observed with saline (160 ± 30–259 ± 78) and albumin (146 ± 18–220 ± 61). Organophosphate levels reduced in all 3 arms; no clear-cut trends were observed. We observed more cases of intermediate syndrome with FFP [10/19 (53%) vs. 5/20 (25%) vs. 5/19 (26%), FFP, albumin, and saline arms (p = 0.15)]. The interventions did not affect ventilatory requirements (14/19 vs. 15/20 vs. 14/19) or prevent delayed intubation. There were no differences in mean (±standard error) atropine requirement (in milligrams) in the first 3 days (536 ± 132 vs. 361 ± 125 vs. 789 ± 334) and duration (in days) of ventilation (10.0 ± 2.1 vs. 7.1 ± 1.5 vs. 7.5 ± 1.5) or hospital stay (12.4 ± 2.2 vs. 9.8 ± 1.4 vs. 9.8 ± 1.6). Two patients developed adverse effects with FFP. Mortality was similar (4/19 vs. 5/20 vs. 2/19, p = 0.6). Conclusions. Despite significant increase in pseudocholinesterase levels with FFP, this pilot study did not demonstrate favorable trends in clinical outcomes with FFP or albumin.

Electrolytes assessed by point-of-care testing - Are the values comparable with results obtained from the central laboratory?

Background and Aims: When dealing with very sick patients, the speed and accuracy of tests to detect metabolic derangements is very important. We evaluated if there was agreement between whole blood electrolytes measured by a point-of-care device and serum electrolytes measured using indirect ion-selective electrodes. Materials and Methods: In this prospective study, electrolytes were analyzed in 44 paired samples drawn from critically ill patients. Whole blood electrolytes were analyzed using a point-of-care blood gas analyzer and serum electrolytes were analyzed in the central laboratory on samples transported through a rapid transit pneumatic system. Agreement was summarized by the mean difference with 95% limits of agreement (LOA) and Lin’s concordance correlation (p c). Results: There was a significant difference in the mean (±standard deviation) sodium value between whole blood and serum samples (135.8 ± 5.7 mmol/L vs. 139.9 ± 5.4 mmol/L, P < 0.001), with the agreement being modest (pc = 0.71; mean difference −4.0; 95% LOA −8.78 to 0.65). Although the agreement between whole blood and serum potassium was good (pc = 0.96), and the average difference small (−0.3; 95% LOA −0.72 to 0.13), individual differences were clinically significant, particularly at lower potassium values. For potassium values <3.0 mmol/L, the concordance was low (pc = 0.53) and the LOA was wide (1.0 to −0.13). The concordance for potassium was good (pc = 0.96) for values ≥3.0 (mean difference −0.2; 95% LOA −0.48 to 0.06). Conclusions: Clinicians should be aware of the difference between whole blood and serum electrolytes, particularly when urgent samples are tested at point of care and routine follow-up electrolytes are sent to the central laboratory. A correction factor needs to be determined at each center.

Agreement between paired blood gas values in samples transported either by a pneumatic system or by human courier

Abstract Background: Rapid accurate assessment of metabolic derangements is crucial in the critically ill. We evaluated if arterial blood gas (ABG) samples transported through a pneumatic tube system (PTS) agreed with values transported by a human courier. Methods: In this prospective study of 50-paired ABG samples, the couriered reference ABG was compared with those transported by PTS. Agreement was summarised by the mean difference with 95% limits of agreement (LOA) and Lins concordance correlation (pc). Results: The mean (±SD) time from sampling to analysis was 35.7±23.2 (courier) and 38.6±22.1 (PTS) minutes. Agreement was good between courier and PTS for pH, PaCO2, bicarbonate, oxygen saturation and PaO2 values (pc>0.97). Although the mean difference in PaO2 values between PTS and courier was small (–0.9 mm Hg) and the agreement was good, individual differences were clinically significant (95% LOA –40.8 to 39.0). For PaO2 <160 mm Hg, analysis of PTS samples yielded erroneously high PaO2 values and vice versa for PaO2>160 mm Hg compared to manual courier. This suggested exaggerated oxygen movement between the blood sample and air in the PTS. Conclusions: In this study, analysis of samples transported through the PTS resulted in clinically unacceptable PaO2 values. Delay in transport and analysis of ABG samples should be avoided and samples transported manually if they cannot be assessed on-site.

Zinc and Zinc Related Enzymes in Precancerous and Cancerous Tissue in the Colon of Dimethyl Hydrazine Treated Rats

Trace element zinc deficiency or excess is implicated in the development or progression of some cancers. The exact role of zinc in the etiology of colon cancer is unclear. To cast light on this question, an experimental model of colon carcinogenesis was applied here. Six week old rats were given sub cutaneous injections of DMH (30 mg/kg body weight) twice a week for three months and sacrificed after 4 months (precancer model) and 6 months (cancer model). Plasma zinc levels showed a significant decrease (p<0.05) at 4 months and a greater significant decrease at 6 months (p<0.01) as compared with controls. In the large intestine there was a significant decrease in tissue zinc levels (p<0.005) and in CuZnSOD, and alkaline phosphatase activity (p<0.05) in the pre-cancerous model and a greater significant decrease in tissue zinc (p<0.0001), and in CuZnSOD and alkaline phosphatase activity (p<0.001), in the carcinoma model. The tissue zinc levels showed a significant decrease in the small intestine and stomach (p<0.005) and in liver (p<0.05) in the cancer model. 87% of the rats in the precancer group and 92% rats in the cancer group showed histological evidence of precancerous lesions and carcinomas respectively in the colon mucosa. This study suggests that the decrease in plasma zinc, tissue zinc and activity of zinc related enzymes are associated with the development of preneoplastic lesions and these biochemical parameters further decrease with progression to carcinoma in the colon.

Measurement of renal function in kidney donors using serum cystatin C and β2-microglobulin:

Background: The usefulness of serum cystatin C and serum β 2-microglobulin (B2M) as markers of glomerular filtration rate (GFR) were compared in kidney donors before and after nephrectomy. Methods: Blood samples were taken from 28 donors (15 women and 13 men) for serum creatinine, urea, cystatin C and B2M estimation a median of 7 days before and 10 days after nephrectomy. Results: Estimated GFR decreased from a median of 86.2 mL/min/1.73 m2 to 60.3 mL/min/1.73 m2, a median decrease of 28.6%. Serum creatinine increased by 40% and urea by 30.4%; serum cystatin C increased by 31.2% and serum B2M increased by 65.6%. Using published data on biological variation, critical values were calculated. An increase in serum creatinine above 18 µmol/L detected the decline in renal function in 26/28 (92.9%) subjects. Increases in serum B2M greater than a critical value of 0.94 mg/L detected 24/28 (85.7%) of these subjects, but the critical value of 0.59 mg/L for cystatin C detected only 8/28 (28.6%). Conclusion: Using critical values, serial measurement of serum creatinine was better than serum B2M in detecting reduced renal function. Because of its large intraindividual variation, serial serum cystatin C estimation was very poor in detecting reduced renal function.

Usefulness of ferroxidase activity of ceruloplasmin in the diagnosis of Wilson’s disease

Serum ceruloplasmin is one of the most commonly used screening tests for Wilson’s disease. However immunological assays for ceruloplasmin are not recommended for diagnosis and management of Wilson’s disease through calculation of free copper index. Enzymatic methods using non-physiological substrates have toxicity and stability problems, making them difficult to automate. Ferroxidase assays may be a satisfactory alternative for measuring serum ceruloplasmin. The o-dianisidine hydrochloride manual method for estimation of serum ceruloplasmin enzyme activity was compared with an automated method using the ferroxidase activity of ceruloplasmin in measurement in a double blind study in 91 consecutive patients screened for Wilson’s disease. The o-dianisidine and ferroxidase methods both successfully identified 7 patients with Wilson’s disease. Values for these 7 patients in the o-dianisidine and ferroxidase methods were median 5.0 (range 0–16.0 U/L) and median 45.0 (range 4–166 U/L) respectively. There were 7 other positive values (<62 U/L) with the o-diansidine method and 2 (<200 U/L) with the ferroxidase method, where WD was not confirmed. ROC curves for both methods showed area under the curve of 0.998 for o-dianisidine and 0.997 for ferroxidase. Using literature cut off values of 62 U/L and 200 U/L respectively both methods had 100% sensitivity and specificity was 91.7% (o-dianisidine) and 97.6% (ferroxidase). For the o-dianisidine assay, specificity was improved to 98.8% using a cut off of 22.5 U/L. In the 84 persons (46 adults and 38 children) in whom the diagnosis of Wilson’s disease was not established, the mean value for ceruloplasmin activity by the o-dianisidine and ferroxidase methods was 124.7 ± 48.7 U/L and 571.4 ± 168.1 U/L respectively. There were no significant differences between sex or age of patients (p > 0.29). In a subsequent evaluation with 372 specimens, the Pearson correlation coefficient between the assays was 0.908, p < 0.01, slope 4.06, intercept 265.8, with the manual assay as the x-axis. The ferroxidase assay is a suitable replacement for the o-dianisidine assay in detecting patients with Wilson’s disease.

Protective role of aspirin, vitamin C, and zinc and their effects on zinc status in the DMH-induced colon carcinoma model.

Chemoprotection refers to the use of specific natural or synthetic chemical agents to suppress or prevent the progression to cancer. The purpose of this study is to assess the protective effect of aspirin, vitamin C or zinc in a dimethyl hydrazine (DMH) colon carcinoma model in rats and to investigate the effect of these supplements on changes associated with colonic zinc status. Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) and group 3 (zinc), each being subdivided into two groups and given subcutaneous injection of DMH (30 mg/kg body wt) twice a week for 3 months and sacrificed at 4 months (A-precancer model) and 6 months (B-cancer model). Groups 1, 2, 3 were simultaneously given aspirin, vitamin C, or zinc supplement respectively from the beginning till the end of the study. It was observed that 87.5% of rats co-treated with aspirin or vitamin C showed normal colonic histology, along with a significant decrease in colonic tissue zinc at both time points. Rats co-treated with zinc showed 100% reduction in tumor incidence with no significant change in colonic tissue zinc. Plasma zinc, colonic CuZnSOD (copper-zinc superoxide dismutase) and alkaline phosphatase activity showed no significant changes in all 3 cotreated groups. These results suggest that aspirin, vitamin C or zinc given separately, exert a chemoprotective effect against chemically induced DMH colonic preneoplastic progression and colonic carcinogenesis in rats. The inhibitory effects are associated with maintaining the colonic tissue zinc levels and zinc enzymes at near normal without significant changes.

Interference in autoanalyzer analysis.

This paper presents certain simple procedures for assessing the most common types of interference, due to haemolysis, icterus or lipaemic serum in 19 routine Clinical Chemistry tests and suggests steps to overcome the problem in some tests. A change in the measured concentration, to be analytically significant, had to exceed 2.8 X % coefficient of variation (cv) of the intra-assay analytical variation of each assay. Haemolysis caused interference in 10 of the 19 assays investigated. A haemolysate haemoglobin concentration of 0.29 g/dl, visible to the eye, caused an analytically significant increase in creatinine kinase MB subunit (CKMB), lactate dehydrogenase (LDH), total protein, triglyceride, uric acid and urea, and a significant decrease in alkaline phosphatase (ALP), and total bilirubin. A higher concentration of haemoglobin (0.68 g/ dl) caused an additional significant increase in CK, and a decrease in direct bilirubin. Addition of bilirubin caused interference in all the peroxidase linked reactions as well as in the creatinine assay. At a serum concentration of 5.2 mg/dl it caused a decrease in creatinine, glucose, triglyceride and uric acid. At a higher concentration (15.9 mg/dl) it also decreased cholesterol. Lipaemia interference affected the least number of assays. An added triglyceride of 537–561 mg/dl caused an increase in glucose, uric acid, and amylase. At a level of 1122 mg/dl it also increased CKMB, and at a value of 2244 mg/dl it increased total and direct bilirubin. At the highest levels of haemolysis and lipaemia, the serum glutamate oxaloacetate transaminase (GOT) and giutamate pyruvate transaminase (GPT) gave erratic results. Overall uric acid and CKMB were the analytes most susceptible to interference, while serum caicium and phosphate did not suffer from any. The interference depends on the exact assay conditions used and the susceptibility of each individual laboratorys tests should be determined by them. The reasons for the interferences described are discussed.

Estimation of Monocrotophos renal elimination half-life in humans

Abstract Introduction. Monocrotophos, implicated in about 1/4th of organophosphate poisonings in our centre, is associated with the highest mortality (24%). Yet data on its pharmacokinetics in humans is limited. We estimated the renal elimination half-life of monocrotophos. Patients and Methods. Consecutive patients presenting with monocrotophos overdose over a 2-month period who had normal renal function were recruited. Monocrotophos in plasma and urine were quantitated by high-performance liquid chromatography. Urine was obtained from catheterised samples at 0–2, 2–4, 4–6, 6–8, 8–12 and 12–24 h. Plasma specimens were collected at the time of admission, and at the midpoint of the urine sample collections at 1, 3, 5, 7, 10, 15 and 21 h. Renal elimination half-life was calculated from the cumulative amount excreted in the urine. Results. The cohort of 5 male patients, aged 35.8 ± 2.94 years, presented with typical organophosphate (cholinergic) toxidrome following intentional monocrotophos overdose. All patients required mechanical ventilation; one patient died. Plasma data was available from 5 patients and urine data from 3 patients. The median renal elimination half-life was 3.3 (range: 1.9–5.0 h). Plasma monocrotophos values, as natural log, fell in a linear fashion up to around 10 h after admission. After the 10-hour period, there was a secondary rise in values in all the 3 patients in whom sampling was continued after 10 h. Conclusion. A renal elimination half-life of 3.3 h for monocrotophos is consistent with a water-soluble compound which is rapidly cleared from the plasma. The secondary rise in plasma monocrotophos values suggests possible re-distribution. Determining the elimination profile of this compound will help develop better strategies for treatment.