Successful therapy with hemoperfusion and plasma exchange in acute 1,2,3-trichloropropane poisoning

Abstract

1,2,3-trichloropropane (1,2,3-TCP) is commonly used as an intermediate in pesticide and an industrial specialty solvent. Acute 1,2,3-TCP poisoning is rare but a medical emergency. Sporadic cases of toxic hepatic injury from 1,2,3-TCP in humans have been reported. Liver is a target organ for 1,2,3-TCP toxicity, which may ensue in a short period after ingestion. A specific antidote against 1,2,3-TCP is not available. So it is important to distinguish that a patient with 1,2,3-TCP poisoning constitutes a medical emergency. In this case study, the poisoned patient’s clinical condition and laboratory values improved gradually after she received hemoperfusion (HP) and plasma exchange, which indicated that the therapy with HP and plasma exchange were helpful in the treatment of 1,2,3-TCP poisoning.

Introduction

1,2,3-trichloropropane (1,2,3-TCP) is a colorless or pale green flammable liquid. It is soluble in water at a concentration of 1 part per 1000 and is miscible with alcohol and ether. 1,2,3-TCP is commonly used as an intermediate in pesticide and an industrial specialty solvent for the manufacturing of pharmaceuticals, paints, and chemicals. Therefore, it is widely used in agricultural and industrial productions. ¹ The physical, chemical, and toxicological effects of 1,2,3-TCP in animals have been well described in the literature, but there is very few clinical reports about the cases of severe poisoning resulting from accidental ingestion or in a suicide attempt. As far as we know, only one case with clinically significant 1,2,3-TCP-induced hepatotoxity has been reported in English-language publications. ² There is a high risk of mortality when the fulminant hepatic failure occurs by 1,2,3-TCP poisoning. Here, we present our successful experience in the treatment of 1,2,3-TCP-induced acute hepatic failure with hemoperfusion (HP) and plasma exchange.

Case report

A 56-year-old female, previously healthy, accidentally swallowed approximately 20 mL of 1,2,3-TCP in a pure form. Shortly after ingestion, she developed nausea, vomiting, dizziness, and lost her consciousness at about 30 min after ingestion. Then, the patient was transported to a local hospital where she received gastric lavage with large amounts of normal saline and symptomatic treatment. The patient gradually regained her consciousness during the course. For further treatment, the patient was transferred to our emergency department 7.5 hours after ingestion. On admission, she was conscious and her vital signs were as follows: blood pressure 159/92 mmHg; pulse rate 76 beats/min; temperature 36.3°C and respiration rate 19 per minute. Her Glasgow Coma Score was 15 and there was no abnormal indication in her systemic evaluation. Chest radiograph and abdomen ultrasound were negative. Results of serological tests for viral and nonviral infectious hepatitis and tests for auto-antibodies were negative. Toxicological examination showed 9370 ng/mL of 1,2,3-TCP in her blood by gas chromatography–mass spectroscopy (apparatus type, GC/MS6890N-5973I made by Agilent, Santa Clara, CA, USA). The initial laboratory results included complete blood cell count, blood glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, coagulation profile, electrolyte and renal function tests and are listed in Table 1.

Table 1.

Initial laboratory parameter values of the patient

Parameters	Values	Normal ranges
White blood cells (×109 L−1)	4.25	3.5–10
Red blood cells (×1012 L−1)	4.61	3.9–5.2
Hemoglobin (g L−1)	144	116–155
Platelets (×109 L−1)	200	100–300
Potassium (mmol L−1)	3.40	3.50–5.50
Sodium (mmol L−1)	138	135–155
Chlorine (mmol L−1)	102	95–115
Glucose (mmol L−1)	6.60	3.89–6.11
ALT (U L−1)	14	5.0–40.0
AST (U L−1)	11	5.0∼40.0
Total bilirubin (μmol L−1)	8.0	1.7–17.1
Direct bilirubin (μmol L−1)	2.3	0–6.0
Amylase (U L−1)	87	40–110
Creatinine (μmol L−1)	48	44–133
Total protein (g L−1)	83	62–85
Albumin (g L−1)	46	35–55
PT (s)	11.5	11.0–13.0
APTT (s)	32.7	15.0–36.0
INR	1.038	0.8–1.2

ALT: alanine aminotransferase; AST:aspartate aminotransferase; PT:Protrombintime; APTT:Activated Parsiyel tromboplastin time; INR:international normalized ratio.

After admission to the intensive care unit, the patient received general supportive treatment including glutathione, vitamin K, antacids, prophylactic antibiotics, maintenance of the fluid–electrolyte balance and the daily HP for 3 days at 11 hours post ingestion. After the first day of HP, blood concentrations of 1,2,3-TCP decreased by up to 80% of the initial concentration to 1900 ng/mL. However, the 1,2,3-TCP reduction rate was only 12% (pre-HP value was 1900 ng/mL, while post HP value was 1670 ng/mL) after the second day of HP. The patient refused to monitor 1,2,3-TCP level after the third day of HP because of the financial problem. At the same time, a marked elevation in ALT, AST, total bilirubin and direct bilirubin occurred on day 2 after admission, although the initial biochemical parameters were within the reference range. The levels of ALT and AST remained persistently elevated and reached a peak level on day 4 (ALT 5100 U L⁻¹; AST 5290 U L⁻¹). Meanwhile, the patient developed jaundice and hepatic encephalopathy, which were compatible with acute hepatic failure. Abdomen ultrasound showed hepatomegaly. Once the peak of liver enzymes was reached, the levels decreased rapidly with the ensuing plasma exchange of about 2000 mL fresh frozen plasma in the following consecutive 5 days. On day 9 after admission, the ALT level decreased to 276 U L⁻¹ and AST to 94 U L⁻¹. Following this, although the liver enzymes again elevated gradually and reached another peak on day 16 (ALT 724 U L⁻¹; AST 264 U L⁻¹), the patient kept improving and regained her consciousness on day 12. In contrast, her bilirubin levels were persistently elevated after admission, reaching a peak on day 20 (direct bilirubin 351.1 μmol L⁻¹; total bilirub 236.6 μmol L⁻¹) and later the levels went down mildly. The changes in hepatic function were presented in Figure 1.

Figure 1.

The changes in hepatic function of the patient from admission till discharge.

During the period of hospitalization, systemic bleeding complications were not observed. But platelet count decreased markedly after three HP treatments (pre HP value was 200×10⁹ L⁻¹, while the post HP value was 13 × 10⁹ L⁻¹). After supplemented (4 units of platelets), platelet count gradually went up to a normal level (128×10⁹ L^-1 on day 5 after HP). No suggestion of underlying renal injury could be discerned from the few changes in serum creatinine and blood urea nitrogen levels.

When the patient was discharged on day 24 after admission, her ALT level fell to 170 U L⁻¹, AST to 96 U L⁻¹, total bilirubin to 294.3 mg/dL and direct bilirubin to 200.3 mg/dL. One month after discharge, the ALT level fell down to 66 U L⁻¹, AST to 43 U L⁻¹, total bilirubin to 64.1 mg/dL and direct bilirubin to 42.6 mg/dL. After 6 months of follow-up, all laboratory values went back to normal (ALT 32 U L⁻¹; AST 28 U L⁻¹; total bilirubin 12.6 μmol L⁻¹; direct bilirubin 4 μmol L⁻¹). Moreover, during follow-up, the patient was continuously treated with glutathione and prophylactic antibiotics at local hospital.

Discussion

After ingestion, 1,2,3-TCP distributes uniformly throughout the available body compartments for its lipid solvent properties. 1,2,3-TCP is metabolized extensively by liver, with metabolites being excreted in urine, bile and lung (as CO₂). Low vapor pressure (3.4 mmHg, 20°C) and high lipid solubility of 1,2,3-TCP contribute to limited direct pulmonary elimination and account for the relatively long biological half-life of the parent compound. ¹ Thus, some bioaccumulation during 1,2,3-TCP exposure seems likely. Some study on 1,2,3-TCP showed liver was the major target organ upon acute oral exposure at high doses. ³ Interaction with glutathione and metabolic studies of the compounds that are structurally related to 1,2,3-TCP suggest that liver toxic effects of 1,2,3-TCP probably result from cytochrome P-450 activation to active metabolites that bind with critical macromolecues. ¹ It is unclear whether there are other possible idiosyncratic mechanisms of hepatotoxicity for 1,2,3-TCP.

It has been demonstrated in dogs that 1,2,3-TCP ingestion can lead to acute toxicity such as nausea, vomiting, eventual liver and kidney damage. ¹ Reports of oral exposure to 1,2,3-TCP in human are limited to case reports of accidental ingestion and the clinical manifestation including depression of the central nervous system and hepatic injury. ³ In our study, the patient mainly developed acute hepatitis after temporary loss of consciousness and the situation kept deteriorating shortly after ingestion. The precise mechanisms of 1,2,3-TCP-induced depression of the central nervous system are not clear. The active metabolites of 1,2,3-TCP may be responsible for persistently elevated bilirubin levels till the 24th day after admission. Some in vitro experiments showed glutathione or N-acetyl-cysteine had hepatoprotective effects by inhibiting the binding of active metabolites of 1,2,3-TCP to critical macromolecues, ⁴ so the patient was treated with glutathione to prevent hepatic damage. Because a specific antidote against 1,2,3-TCP poisoning was not available, the interest was focused on how to enhance the elimination of 1,2,3-TCP in blood. HP has been used for toxin overdoses for several decades. ^5,6 It has been proven that HP plays a role in the extracorporal elimination of 1,2,3-TCP. ⁷

In our study, we used HP with a styrene/divinylbenzene copolymer which can be used to clear poisons that have a large molecular weight, high lipid solubility, and a strong protein-binding ability. ⁸ During the first HP, the clearance rate of 1,2,3-TCP was high. The rapid reduction of 1,2,3-TCP level in blood suggested that direct removal from the blood may be the main mechanism of HP. After the subsequent HP, the reduction in blood 1,2,3-TCP levels was limited, indicating that the main variable factor of HP for the elimination of 1,2,3-TCP was dependent on the poison plasma levels. However, to what extent the reduction of 1,2,3-TCP in blood can be related to HP alone may be a matter of debate. In fact, limited data are available for the effect of HP on toxicokinetics of 1,2,3-TCP in human, so further investigations are needed, especially involving measurement of efficacy and the efficiency of toxin removal. In addition, it is uncertain whether 1,2,3-TCP in the tissues could be removed through HP. In our study, HP technique failed to prevent progressive deterioration of hepatic function. The bioaccumulation of 1,2,3-TCP in liver as a result of its high lipophilicity and active metabolites possibly can explain the discrepancy between the fast reduction in blood 1,2,3-TCP levels during the first HP and progressive deterioration of hepatic function. This indicates that HP could not remove 1,2,3-TCP and active metabolites in the liver tissue. The reduction in blood levels is not only related to HP but is a complex phenomenon involving redistribution, urinary elimination and metabolic degradation. So the reduction in blood levels is not a good reflection of the body burden of 1,2,3-TCP. Anyway, it is clear that rapidity of 1,2,3-TCP removal in blood is beneficial. So HP should be initiated as soon as possible after ingestion.

Plasma exchange can not only remove the high molecular weight and lipid-soluble toxins by separating and discarding plasma of the hepatic failure patient ⁹ but also compensate with normal fresh frozen plasma to supplement some essential substances such as coagulation factors, albumin, immunoglobin so as to ameliorate the microenvironment of liver and accelerate the liver regeneration and the hepatic function recovery. ¹⁰ However, plasma exchange is not suitable for the early treatment of acute poisoning, because of limitations on the amount of plasma that can be exchanged, especially in view of a high distribution volume and lipid-soluble characteristics of 1,2,3-TCP. In this case, when the liver was damaged to a certain degree, dysfunctional hepatocytes were unable to clear metabolites from the blood, leading to the accumulation of numerous albumin-bound substances that may induce hepatic encephalopathy. For this reason, right after HP, we performed plasma exchange in the following 5 consecutive days. This intervention led to gradual resolution of symptoms including jaundice and hepatic encephalopathy and reduced the growth rate of bilirubin, although the rebounding elevated liver enzymes and progressively elevated bilirubin indicated that the liver was persistently damaged by the long half-life of 1,2,3-TCP. There was a clear link between clinical improvement and the removal of albumin-bound toxins in the form of severely acute hepatic injury. ¹¹ Considering the improvement of hepatic encephalopathy and a tight supply of plasma, the patient was not treated with plasma exchange anymore after day 9. In our study, plasma exchange acted as liver support rather than a detoxification method after the high level of 1,2,3-TCP in plasma had declined later by HP. In addition, in some studies the application of molecular adsorbant recirculating system (MARS) was also preferred as a liver support device in patients with toxin-induced hepatic failure, since MARS can remove efficiently bilirubin, bile acids, tryptophan, romatic aminoacids, middle and short chain fatty acids, and inflammation mediators. ¹²

One limitation of this study is that 1,2,3-TCP levels in blood were not continuously monitored 3 days after admission. The other limitation is that the function of coagulation system particularly in terms of reduced number of platelet failed to reflect the degree of hepatic dysfunction, because it was affected during the course of blood purification.

In summary, the most important factor in managing 1,2,3-TCP poisoned patients is to discern that a patient who has ingested 1,2,3-TCP constitutes a medical emergency. Aggressive HP should be instituted in the early stage in order to accelerate the elimination of plasma 1,2,3-TCP. The use of plasma exchange may improve the outcome of high-risk patients with 1,2,3-TCP -induced hepatic failure.