PULSE CORTICOSTEROIDS AND CYCLOPHOSPHAMIDE IN PARAQUAT POISONING

To the Editor:

The use of pulse corticosteroids and cyclophosphamide in the acute treatment of paraquat poisoning showed substantial promise in two observational studies (1, 2) but not in a third (3). Lin and colleagues should be applauded for publishing the first randomized clinical trial to evaluate this intervention in the Journal last year (4). However, the presentation of their analysis had a major flaw that throws doubt on their conclusion that the treatment is beneficial.

The only analysis presented was a post hoc analysis, dividing those randomized into two groups on the basis of survival over the first week. An intention-to-treat analysis including all those randomized suggests that although there may be significant benefit, this is not conclusively proven (Table 1). Overall survival in the control group was 18% (12/65) compared with 32% (18/56) in the treatment arm and the study was underpowered to detect this magnitude of treatment effect in the total group (320 patients required for  = 0.05 and  = 0.8). Alternatively, further trials are required to identify and enroll the moderately poisoned group that is most likely to benefit prospectively, rather than retrospectively, as in this trial. It is possible that the group with an intermediate prognosis can be identified based on paraquat concentrations or changes in renal function (5, 6). This prospectively stratified sub-group would not only lead to unbiased analysis of the effect of the severity of the poisoning on the effects of treatment but would also clarify for clinicians which patients should be given this treatment.

Royal Adelaide Hospital, Adelaide, Australia

1. Lin JL, Wei MC, Liu YC. Pulse therapy with cyclophosphamide and corticosteroids in patients with moderate to severe paraquat poisoning: a preliminary report. Thorax 1996; 51: 661-663 [Abstract].

2. Addo E, Ramdial S, Poon-King T. High dosage cyclophosphamide and dexamethasone treatment of paraquat poisoning with 75% survival. West Indian Med J 1984; 33: 220-226 [Medline].

3. Perriens JH, Benimadho S, Kiauw IL, Wisse J, Chee H. High-dose cyclophosphamide and dexamethasone in paraquat poisoning: a prospective study. Hum Exp Toxicol 1992; 11: 129-134 [Medline].

4. Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat-poisoned patients. Am J Respir Crit Care Med 1999; 159: 357-360 [Free Full Text].

5. Ragoucy-Sengler C, Pileire B. A biological index to predict patient outcome in paraquat poisoning. Hum Exp Toxicol 1996; 15: 265-268 [Medline].

6. Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning. QJM 1999; 92: 573-578 [Abstract/Free Full Text].

From the Authors:

We appreciate and agree with Dr. Buckley's comments on our study (1). Our work demonstrated the use of pulse corticosteroid and cyclophosphamide to successfully treat patients with moderate-to-severe paraquat (PQ) poisoning (1, 2) and prevent lethal hypoxemia of PQ-poisoned patients with pulmonary fibrosis. In addition, pulse therapy may be not effective in treating patients with fulminant PQ poisoning who died of multiple organ failure within one week of intoxication.

Our study is designed as a prospectively controlled trial and carried out as such. We could not help performing a post-hoc analysis in this study because no paper suggested an index to accurately predict the clinical severity of PQ-poisoned patients up till now. Some authors reported (3, 4) the use of serum PQ level to predict mortality and survival but not to predict which patients would have fulminant or moderate-to-severe intoxication. One paper (5) suggested the increase of serum creatinine (mg/dl)/dt (per hour) is an index of severity of PQ poisoning. However, serum creatinine is a bad index of progressive renal damage (6). Hence, the accuracy of this index needs further evaluation.

Dr. Buckley combined the two groups of patients and analyzed the data in his table. The analysis is not complete and the results are inconclusive because he did not prove equal distribution of basal data of two study groups after combination and include the patients with mild PQ poisoning.

I agree with his comment that 320 study subjects are needed to obtain adequate power in studying therapy of patients with PQ poisoning (p = 0.05). However, the statistical power of the results of pulse therapy in treating patients with moderate-to-severe poisoning (p = 0.0084) (1) is adequate (> 0.8), although the sample size may be relatively smaller in our study. However, whether pulse therapy is effective in treating patients with PQ poisoning is still an open question. Further study to reassess the efficiency and limitation of pulse therapy is needed.

Chang Gung Memorial Hospital, Taipei, Taiwan

1. Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquat poisoned patients. Am J Respir Crit Care Med 1999; 159: 357-360 .

2. Lin JL, Wei MC, Liu YC. Pulse therapy with cyclophosphamide and corticosteroids in patients with moderate to severe paraquat poisoning: a preliminary report. Thorax 1996; 51: 661-663 .

3. Hart TB, Nevitt A, Whitehead A. A new statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet 1984; ii: 330-332 .

4. Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning. QJM 1999; 92: 573-578 .

5. Ragoucy-Sengler C, Pileire B. A biological index to predict patient outcome in paraquat poisoning. Hum Exp Toxicol 1996; 15: 265-268 .

6. Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Annu Rev Med 1988; 39: 465-490 [Medline].