Early haemoperfusion with continuous venovenous haemofiltration improves survival of acute paraquat-poisoned patients

Abstract

Objective

To determine whether haemoperfusion (HP) with continuous venovenous haemofiltration (CVVH) improves the survival of patients with acute paraquat poisoning, compared with those treated using HP alone.

Methods

Medical records of patients with acute paraquat poisoning were analysed. Patients were randomised to undergo HP or HP + CVVH within 24 h of paraquat ingestion. Mortality rate, survival duration and cause of death were recorded.

Results

There were no significant differences in mortality rate between the HP group (n = 458) and the HP + CVVH group (n = 226) (57.4% and 58.4%, respectively). The mean survival duration was significantly longer in the HP + CVVH group than the HP group (8.6 ± 3.1 and 5.1 ± 2.3 days, respectively). Early circulatory collapse was a major cause of death in the HP group. The major cause of death in the HP + CVVH group was late respiratory failure.

Conclusion

Combined therapy with HP and CVVH can prevent early death and prolong survival duration following acute paraquat poisoning, providing the opportunity for further treatment.

Keywords

Continuous venovenous haemofiltration haemoperfusion paraquat poisoning

Introduction

Paraquat (1,1′-dimethyl-4-4′-bipyridinium dichloride) is a widely used herbicide that was introduced to agriculture in 1962, and is responsible for thousands of accidental and intentional deaths each year.¹ Attempts to modify the toxicity of paraquat have proven ineffective, and the clinical outcome of poisoning is therefore determined by degree of exposure.^2–6

The primary mechanism of exposure is ingestion, after which paraquat accumulates primarily in the lungs, resulting in acute pulmonary distress.⁷ The selective accumulation of paraquat in alveolar cells induces the production of large quantities of toxic free radicals such as reactive oxygen species, leading to lipid peroxidation of cell membranes, exhaustion of nicotinamide adenine dinucleotide phosphate and cell death.^8,9 Paraquat also has severe effects on the gastrointestinal tract, kidneys, liver and heart,^7,10 and death is usually due to multiple organ failure.¹

Haemoperfusion (HP) is the first-line treatment in patients with acute paraquat poisoning. HP is most effective when initiated within 2 h of paraquat injection and 4 h of ingestion and administered continuously for 6–8 h.^11,12 HP is of limited value in cases of severe paraquat poisoning, however.^13,14 Repeated pulses of immunosuppression with methylprednisolone and cyclophosphamide may lower mortality rates,⁵ although a multicentre study found that mortality rates remained high in spite of large intercentre variations in treatment (including HP, immunosuppression and antioxidant treatment).⁴ Continuous renal replacement therapy, such as continuous venovenous haemofiltration (CVVH), is used to treat patients with acute renal failure and cardiovascular instability and is believed to eliminate excess cytokines and inhibit abnormal enzyme release.¹⁵ To the best of our knowledge, there have been no large-scale studies investigating the efficacy of HP with CVVH in lowering the mortality rate of paraquat poisoning.

The aim of this retrospective study was to determine whether HP with CVVH improves the survival of patients with acute paraquat poisoning, compared with those treated using HP alone.

Patients and methods

Study population

This retrospective study recruited patients with acute paraquat poisoning admitted to The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China between August 2004 and February 2013. Exclusion criteria were: (i) patient held paraquat in their mouth, but did not swallow; (ii) time to arrival at emergency room >24 h; (iii) refusal to participate; (iv) incomplete treatment. Paraquat poisoning was classified via sodium dithionite test of urine obtained on arrival at the emergency room: dark blue, severe poisoning; blue to light blue, mild-to-moderate poisoning; no blue colour, negative.¹⁶ Acute kidney injury was diagnosed according to the RIFLE classification (class R, class I, or class F).¹⁷

The study was granted an exemption in writing by the Ethics Review Board of the First Affiliated Hospital of Zhengzhou University and the requirement for specific informed consent was waived. Informed consent regarding the risk of acute paraquat poisoning and all treatment modalities was obtained from all patients upon their initial admission. All patient information was securely protected and available only to the investigators.

Treatment

On admission, vital signs were assessed and routine lab tests (including complete blood cell counts, liver and renal function, coagulation function, arterial blood gas and routine urine analysis) were performed. All patients received a unified therapeutic regimen including gastric lavage, fluid replacement, antioxidants (vitamin C, vitamin B and L-glutathione) and immunosuppressants (corticosteroids). To reduce the extent of oxygen free radical-induced organ injury, intravenous dexamethasone (10 mg every 6 h for 3 days) and intravenous vitamin C (3 g/day for 5–7 days) were administered to all patients.

Using the block randomization method, patients were randomly assigned to undergo HP or HP + CVVH. HP comprised one or two courses of 300 g charcoal HP therapy for 6 h (Adsorba; Gambro, Sweden) using an jugular dual-lumen catheter. CVVH was performed immediately after HP using an AK-10 blood pump with polyamide haemofilter (FH-55; Gambro, Stockholm, Sweden), with blood flow rate 100–150 ml/min and effluent filtration rate 1500–2000 ml/h. Duration of CVVH, replacement fluid and net ultrafiltration rates varied according to clinical status. Bicarbonate-based solutions were administered before the haemofilter as replacement solutions, and haemofilters were changed every 24–36 h to prevent decay in membrane permeability and loss of ultrafiltration capacity. Heparin infusion was continued at 300–700 U/h to maintain activated partial thromboplastin time at 50% greater than normal.

Statistical analyses

Data were presented as mean ± SD or n (%). Between-group comparisons were made using χ²-test or Mann–Whitney test, as appropriate. Statistical analyses were performed with SPSS® version 16.0 (SPSS, Inc., Chicago, IL, USA) for Windows®. P-values < 0.05 were considered statistically significant.

Results

The study enrolled 1185 patients, of whom 501 did not meet the eligibility criteria and were excluded. The final analysis included 684 patients (201 males/483 females; mean age 38.4 ± 12.4 years; age range 13–61 years). Figure 1 shows the flow of patients through the study. The total time elapsed from paraquat ingestion to hospital arrival was ≤4 h in 536 (78.4%) patients and >4 h in 148 (21.6%). There were no significant between-group differences in demographic characteristics (Table 1).

Figure 1.

Flow chart indicating enrolment and status of patients.

Table 1.

Demographic and clinical characteristics of patients with acute paraquat poisoning included in a study to compare the efficacy of haemoperfusion (HP) and HP plus continuous venovenous haemofiltration (CVVH).

Characteristic	HP group n = 458	HP + CVVH group n = 226	Statistical significance^a
Age, years	39 ± 15	37 ± 19	NS
Females	302 (65.9)	151 (66.8)	NS
Body mass index, kg/m²	22.4 ± 9.1	23.1 ± 8.5	NS
Tobacco use	147 (32.1)	80 (35.4)	NS
Alcoholism	102 (22.3)	52 (23.0)	NS
Initial serum creatinine, mg/dl	1.36 ± 0.98	1.41 ± 1.12	NS
Peak serum creatinine, mg/dl	2.87 ± 1.23	2.61 ± 0.56	NS
Initial urine paraquat, µg/ml	269.1 ± 281.3	281.3 ± 301.6	NS
Initial PaO₂, mmHg	101.3 ± 25.0	96.8 ± 35.2	NS
Urine dithionite test^b			NS
Negative	5 (0.1)	4 (0.2)
Mild-to-moderate	256 (55.9)	119 (52.7)
Severe	197 (43.0)	103 (45.6)
Time from paraquat ingestion to HP, h	4.8 ± 2.1	5.2 ± 3.7	NS
Duration of HP, h	5.6 ± 2.0	5.3 ± 2.3	NS
Acute kidney injury	386 (84.3)	186 (82.3)	NS
Acute respiratory failure	285 (62.2)	138 (61.1)	NS
Death	263 (57.4)	132 (58.4)	NS
Time from paraquat ingestion to death, days	5.1 ± 2.4	8.6 ± 3.1	P < 0.01
Death within 4 days of PQ ingestion	186 (70.7)	59 (44.7)	P < 0.01
Cause of death			P < 0.01
Circulatory collapse	195 (42.6)	34 (15.0)
Lung fibrosis with hypoxemia	65 (14.2)	0 (0)
Respiratory failure	0 (0)	98 (43.4)

Data presented as mean ± SD or n (%).

χ²-test or Mann–Whitney test

Sodium dithionite test for severity of paraquat poisoning: dark blue, severe; blue to light blue, mild-to-moderate; no blue colour, negative.

NS, not statistically significant (P ≥ 0.05); PaO₂, partial pressure of oxygen.

Data regarding clinical characteristics of patients, stratified according to treatment group, are given in Table 1. There were no significant between-group differences in prognostic factors or mortality rate. The time from paraquat ingestion to death was significantly longer and significantly fewer patients died within 4 days in the HP + CVVH group than the HP group (P < 0.01 for each comparison; Table 1). There was a significant between-group difference in cause of death, with circulatory collapse the major cause of death in the HP group and respiratory failure the major cause of death in the HP-CVVH group (P < 0.01; Table 1).

Discussion

Paraquat is a widely used herbicide that has been used in China since 1960. The in-hospital fatality rate of paraquat poisoning is approximately 55%, with no significant differences between survivors and non-survivors with respect to patient characteristics. Death generally occurs 24–72 h after ingestion, with causes including acute respiratory failure, acute renal failure, acute hepatic failure and multiple organ dysfunction syndrome.^1,18 The present study found that, compared with HP alone, HP + CVVH increases survival time but does not improve the mortality rate of patients with acute paraquat poisoning.

Continuous venovenous haemofiltration has been shown to stabilize the haemodynamic status of patients with severe sepsis and multiorgan failure, but the exact mechanisms underlying its beneficial effects remain unclear.¹⁹ It is possible that CVVH may be effective in eliminating serum cytokines and enzymes,¹⁹ and could therefore benefit patients with acute paraquat poisoning. Significantly more patients in the HP-CVVH group than the HP group survived for longer than 4 days in the present study, and many of these patients died from respiratory failure. This suggests that prophylactic CVVH after HP can reduce the number of early deaths caused by multiorgan failure but does not prevent late pulmonary fibrosis. The extended survival time afforded by CVVH may provide the opportunity for further treatment.

Several small-scale studies have shown that prophylactic CVVH after HP could prolong survival time and prevent early death caused by circulatory collapse, but cannot provide a survival benefit in acute paraquat poisoning.^20,21 The present study included a large cohort of patients who were treated according to a uniform three-step protocol: (i) Fuller’s earth within 24 h following paraquat ingestion to reduce absorption in the gastrointestinal tract; (ii) intensive extracorporeal elimination therapy (HP and CVVH) if urine paraquat test was positive; (iii) intensive antioxidant therapy (N-acetylcysteine, glutathione, vitamin C). HP is known to effectively eliminate paraquat from the blood, in spite of its limited effects on mortality.^22,23 This may be due to the fact that the ingested quantity is commonly many times greater than the lethal dose, and the long delay between ingestion and presentation.

This study has several limitations, most notably the absence of data regarding plasma paraquat concentrations. Plasma paraquat levels peak early in the course of poisoning, then decrease rapidly during the first 10 h after ingestion because of distribution to tissue. An error of 1–2 h in the estimate of ingestion time can move a patient from 30% to 70% on the survival curve.²⁴ In addition, plasma paraquat levels cannot be checked easily and quickly in an emergency situation. In addition, the present study was retrospective and performed in a single centre.

In conclusion, combined therapy with HP and CVVH can prevent early death and prolong survival duration following acute paraquat poisoning, providing the opportunity for further treatment. CVVH had no survival benefit over and above that provided by HP alone. Prophylactic CVVH can prevent early death caused by multiorgan failure, but cannot prevent late pulmonary fibrosis.

Footnotes

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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