Management of PQ poisoning is a medical challenge due to its high toxicity without effective antidote. PQ is rapidly distributed to lung, liver, kidney and muscle upon ingestion and selectively accumulates in the lungs, leading to irreversible pulmonary fibrosis and resulting in death within days up to a month. The clinical manifestations depend upon the quantity ingested. Large amounts of liquid concentrate (> 50–100 ml of 20% ion w/v) could result in fulminant organ failure and death within several hours to a few days, while smaller quantities could be harmful to the key target organs (kidneys and lungs) and develop over the next 2–6 days with the mortality rate still over 50%.
In the present study, our retrospective analysis revealed that the mortality rate was 44.55%, a little better than the previous reports. Most baseline variables had no significant differences between the survivor and non-survivor group. However, patients in the survivor group ingested less amount of PQ, which is consistent with previous reports. We also found patients presented with lower serum creatinine level and higher glomerular infiltration rate at admission, developed lower incidence of acute kidney injury in the survivor group (Table 1). Cox regression survival analysis revealed that patients with abnormal renal function at admission or developed AKI after admission were high-risk population for mortality (Table 2). In the present study, 54.50% patients presented with normal renal function at admission and 45.22% patients among them developed AKI. The AKI incidence rate was similar with a previous study (51.4% reported by Hong et al. in 2009). In their study, AKI developed fully at the fifth day after PQ ingestion and normalized within 3 weeks without exception; Serum uric acid level could be a marker for mortality and acute kidney injury in patients with acute PQ intoxication[15, 16]. We could not characterize the evolution of AKI in present study because six patients who had impaired renal function at discharge did not have further renal function examinations. We could not find the association between serum uric acid level and AKI development or prognosis, but Cox regression analysis demonstrated that the amount of PQ ingested was the only independent risk factor for the development of AKI [HR 1.042, 95% CI (1.016–1.069), p = 0.002].
The percentage of abnormal pulmonary CT imaging in the survivor group was lower than the non-survivor group (41.88% vs 57.45%, p = 0.025) in our study, the lesions were consisted of pulmonary segment involvement, effusion, consolidation and fibrosis, or rapid lesion progression. Previous study reported that CT imaging could be a prognostic indicator for patients with pulmonary injury from acute PQ poisoning. However, Cox regression analysis in the present study could not identify it as an independent risk factor for the prognosis. Further study should put emphasis on unified grouping of pulmonary lesion and identify characteristic early features.
Another interesting finding was that 12 Patients who ingested PQ combined with alcohol had a higher survival rate than those ingested PQ alone. PQ induced redox cycling rapidly oxidizes NADPH and leads to secondary changes on cellular metabolism and impairs defenses against oxidative stress. Previous animal studies and medical case reports drew different conclusions about the impact of ethanol on PQ poisoning. Ethanol may decrease PQ toxicity partly through competitive consumption of NADPH and oxygen during the metabolism process [19–23]. The acute and chronic ethanol ingestion may have different impact on PQ metabolism. Further detailed studies are needed.
As to the therapy regimen, the survivors in the present study were treated with higher dosage of methylprednisolone, aspirin and rapamycin. The frequency of hemoperfusion was more in the survivor group. In the past decades, attempts to reduce absorption by gastric lavage, administration of Fueller’s earth and skin decontamination have been used routinely. Early hemoperfusion is suggested in the aim of eliminating plasma PQ [9, 25]. A combination of glucocorticoid and cyclophosphamide was reported to be beneficial. The survival benefit of additional immunosuppressive treatment has been demonstrated in the combination of methylprednisolone, cyclophosphamide and daily dexamethasone . Intravenous anti-oxidants such as N-Acetylcysteine, L-Glutathione, vitamin C, vitamin E and thioctic acid have been used with various success[7, 27]. Our previous animal study revealed that rapamycin has significant inhibitory effects on progressive pulmonary fibrosis in the PQ intoxication mice model which may be partly ascribed to the inhibition of TGF-β1, however, the results in clinical settings differed[29, 30]. Some other potential agents, such as docosahexaenoic acid, naringin and lysine acetylsalicylate have been shown to ameliorate PQ-induced pulmonary fibrosis in animal models. Our results demonstrated positive effects of the therapy regimen consisted of cyclophosphamide, methylprednisolone, vitamin C, aspirin and rapamycin combined with hemoperfusion, higher dose of methylprednisolone and aspirin were protective factors for survival.
Ananieva et al. reported that salicylic acid (SA) mediates tolerance in barley plants to PQ, exogenous treatment with SA could antagonize PQ toxicity via elicitation of an antioxidative response in barley plants over ten years ago. Recent studies have shown that salicylates, including sodium salicylate (NaSAL)[35, 36] and lysine acetylsalicylate (LAS) may form complexes with PQ, prevent its toxicity through anti-inflammatory, anti-oxidant and anti-thrombogenic properties. LAS (also named Aspirin-DL-Lysine) has been shown to be a promising intravenous antidote for the treatment of PQ poisoning in animal studies. To our knowledge, there have been no published human studies about the SA therapy in PQ poisoning. The present study firstly reported beneficial effect of oral aspirin therapy in PQ poisoning patients. Because LAS are not available in our hospital, we used oral aspirin in 72 patients (34.12%) with a mean daily dosage of 110.58 mg. Patients treated with aspirin had superior survival (73.61% vs 46.04%, log rank test, p < 0.001). Larger trials will be needed to verify the effect of aspirin on survival in patients with PQ poisoning.
Previous study showed that the addition of high-dose vitamin C to the treatment can reduce the development of acute kidney injury and mortality in PQ poisoning patients . The optimal dosage of vitamin C is unknown. Hong et al. suggested that the loading and maintenance dosages should be 2278 mg and 146 mg/h based on pharmacokinetic data in patients with PQ intoxication. A much larger dose (1.5 g/kg or daily 10 g) of vitamin C recommended as the upper limit has been beneficial for the treatment of pancreatitis and advanced malignancies[37, 38]. In the present study, the median daily dosage of vitamin C was 3000 mg. Further investigation is needed to determine the optimal dosage of vitamin C.
There are some limitations in present study. First, we used the amount of PQ ingestion as a variable. It’s not accurate because sometimes the patient provided mistake information. We used semi-quantitative urine PQ test instead of quantitative dithionite concentration determination. As we know, 90% of the absorbed PQ is rapidly excreted unchanged in urine within 12–24 h after ingestion, the urine test has a good correlation between PQ concentration and intensity of the blue color formed. However, due to the different time interval between ingestion and admission, we could not decide the therapy intensity according to the urine semi-quantitative results alone. Second, the dosage of aspirin was determined according to our own experience; further studies are needed to verify the conclusion and illuminate the optimal dosage.