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APACHE score, Severity Index of Paraquat Poisoning and serum lactic acid
concentration in the prognosis of paraquat poisoning of Chinese
Shuyun Xu1，Hai Hu1，Zhen Jiang1，Shiyuan Tang1，Yuangao Zhou2，Jie Sheng1，Jinggang Chen1，
Yu Cao1
1. Department of Emergency, West China Hospital, Sichuan University, No 37 Guoxuexiang /
Wuhou District, Chengdu, Sichuan, 610041, PR China;
2. Department of Laboratory Medicine, Sichuan University, West China Hospital, No 37
Guoxuexiang / Wuhou District, Chengdu, Sichuan, 610041, PR China.
Corresponding authors: Yu Cao, Department of Emergency, West China Hospital, Sichuan
University, No 37 Guoxuexiang / Wuhou District, Chengdu, Sichuan Province, 610041, P. R.
China. E-mail: [email protected]
Tel: +86-28-85164011
Fax: +86-28-85164024
Abstract
Background: Many prognostic indictors had been studied to evaluate the prognosis of paraquat
poisoning. However, the optimal indicator remains unclear.
Objective: To determine the value of the Acute Physiology and Chronic Health Evaluation
(APACHE-II) score, Severity Index of Paraquat Poisoning (SIPP) and serum lactate levels in the
prognosis of paraquat poisoning, we performed a prospective study consisting of 143 paraquat
patients.
Methods: Data were collected from patients (161) at West China Hospital in Chengdu, China,
including the details about the patients’ general conditions, laboratory examinations, and treatment.
Receiver operating characteristic (ROC) curves for predicting inpatient mortality of APACHE II ,
SIPP and lactate were generated. To analyze the best cut-off values for lactate level, APACHE II
and SIPP in predicting the prognosis of paraquat poisoning, the initial parameters on admission
and 7 days survival curves of patients with lactate level ≥ 2.95 mmol/L, SIPP ≥ 15.22 h·mg/L and
APACHE II score ≥ 5.50 at the time of Westchina Hospital (WCH) arrival were compared using
one-way analysis of variance (ANOVA) and log-rank test.
Results: The SIPP (5.45 ± 3.67 versus 11.29 ± 4.31 hr•mg/L ), APACHE II score (2.78 ± 1.89
versus 7.63±2.46) and lactate level (2.78 ± 1.89 versus 7.63 ± 2.46 mmol/l) were significantly
lower in survivors (77) after oral ingestion of paraquat compared with nonsurvivors (66). The
APACHE II score, SIPP and lactate level had different AUC of ROC (0.789, 0.847 and 0.916 ,
respectively) and accuracy (0.64, 0.84 and 0.89, respectively). Respiratory rate (RR), serum
creatinine, PaCO2 and mortality rate at 7 days after admission in patients with lactate level ≥ 2.95
mmol/L were markedly different compared to others (P<0.05).
Conclusions: The predictive value of lactic acid was superior to APACHE II Score and SIPP for
acute oral paraquat poisoning.
Key Words: paraquat poisoning, Receiver operating characteristic, lactate levels;
1. Introduction
Paraquat is an organic heterocyclic contact defoliant and herbicide, which has gained worldwide
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popularity [1-3]. The widespread use of paraquat in the villages of developing countries, such as
China, has led to an increase in the number of paraquat poisoning cases [2]. It is reported that the
number of poisonings cases have reached for an estimated 877 000 every year（World Health
Organization， 2003）, and many health officials consider paraquat a public health threat because
of its high toxicity [4,5]. The ingestion of 40 mg of paraquat ion/kg body weight is associated with a
mortality rate of up to 100% [1]. The clinical manifestations of paraquat poisoning varies
depending on a number of factors, including dosage and route of entry [2, 6], which also affects the
prognosis. There have been reports of survival from mild poisonings with no intervention, but
highly toxic doses (35 mg/kg) are almost always fatal despite aggressive interventions, such as
hemodialysis and renal replacement therapy [7]. Hence, an accurate prognostic indicators is very
necessary. Appropriate prognostic indicators can aid physicians in evaluating the severity of
poisoning and predicting overall outcome. At present, most primary health care institutional
guideline lacks a favorable prognostic indicators for paraquat poisoning. Therefore, most
physicians predict the outcome of the condition by the clinical signs and symptoms [8]. However,
the time to the onset of symptoms after acute paraquat poisoning can require a period of time, and
by then the poisoning can become irreversible or fatal. Thus, a simple and easy to obtain
prognostic indicator for acute paraquat poisoning is crucially important.
Many prognostic indictors had been studied to evaluate the prognosis of paraquat poisoning, but
the optimal indictors remains unclear. The Acute Physiology and Chronic Health Evaluation II
(APACHE II) score is a scoring systems based on 12 parameters of acute physiology and chronic
health [9]. This scoring system is commonly used for the assessment of the severity and prognosis
of diseases [10], especially in the intensive care unit (ICU) [11]. The APACHE II is also used to
predict the severity and prognosis of poisoning, but Chinese physicians rarely use it for acute
paraquat poisoning cases. The Severity Index of Paraquat Poisoning (SIPP) is also a potentially
valuable prognostic indicator, which is calculated by multiplying the time since the ingestion (hr)
of paraquat by the paraquat concentration in plasma (mg/L) [12,13]. Studies have suggested that
patients with a SIPP of less than 10 h·mg/L have a good chance of survival, whereas those
between 10-50 h·mg/L frequently dies because of interstitial pulmonary fibrosis secondary to
paraquat poisoning, and those with values greater than 50 h·mg/L dies rapidly owning to
circulatory collapse [14,15]. Though promising, but the plasma paraquat level is not widely available
in China. Other studies have shown that acidosis was an important prognostic indicator for acute
paraquat poisoning [16, 17], particularly the serum lactic acid concentration, which was the
primary cause of acidosis. To determine the value of the APACHE II, SIPP and serum lactate
concentration in the prognosis of paraquat poisoning, a prospective study consisting of 143
patients with paraquat poisoning was performed.
2 Data and Method
2.1 Study population
Patients with acute oral paraquat poisoning were consecutively selected among those who were
referred to the Emergency Department (ED) of Sichuan University (Chengdu, China) between
January 2011 and January 2012 (n=143) according to the following exclusion criteria:
transcutaneous or intravenous exposure and undetectable levels of paraquat in the blood. In
addition, individuals were also ineligible if they had concomitant diseases including cancer,
cardiac disease, pulmonary disease, renal disease and liver disease, or if the patient refused to
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participate in the study. Signed informed consent was obtained from the patients, family members,
or legal guardians.
2.2 Data collection
All data was collected by experienced emergency doctors, including the details of the patients’
general conditions, laboratory examinations, and treatment. On admission, each patient’s age,
gender and other demographic data, past medical history, amount of paraquat ingested (including
other toxic substances ingested) and poisoned time was documented. On admission, vital signs
were recorded and blood samples were collected for the purpose of the following tests: blood
routine, liver and renal function, other biochemical blood examination, and arterial blood gas
examination. To ensure inter-rater reliability, a 20% sample of data were screened by a second
reviewer. The Glasgow Coma Scale (GCS) score and the APACHE II score was calculated, and
the serum lactate level and plasma paraquat concentration was determined. All specimens were
collected at 1 hour after admission. Complete blood cell count, biochemistry, and lactic acid level
were measured using an autoanalyzer (Roche modular P800, Mannheim, Germany). Plasma
paraquat concentration was measured by high performance liquid chromatographic (HPLC)
system (Shimadzu, Japan). The elapsed time (hours) from ingestion of paraquat to arrival and
serum paraquat levels was recorded to calculate SIPP (mean elapsed time (hour) × serum paraquat
level in the ED (mg/L)). Deaths which occurred in the hospital were recorded, and those
discharged from the hospital was followed by telephone or letter. The 60 days mortality were used
to determine the efficacy of individual prognostic indicators, and the results were summarized by
an expert of toxicology.
2.3 Treatment
As summarized in Table 1, all patients presenting within 6 hours of paraquat ingestion received a
gastric lavage followed by 200ml of 20% mannitol via gastric tube. The patients who presented
within 12 hours of ingestion received hemoperfusion every 12 hours until serum paraquat levels
dropped below 200 ppm. In addition, they also received a pulse therapy daily via intravenous
infusion with 1 gram of methylprednisolone, 400mg of cyclophosphamide (CTX), antioxidants
vitamins C (2g/d) and E (300mg/d), and cysteine (1.2g/d). Supplemental oxygen therapy was
administered if the oxygen partial pressure was less than 50mmHg. Hemodialysis was performed
if the patients had severe metabolic acidosis, hyperkalemia, or heart failure.
2.4 Statistical analysis
Collected data were presented as mean ± standard deviation for continuous variables and
frequency for categorical variables. A P-value of < 0.05 was considered statistically significant,
with all statistical analyses performed using SPSS18.0. Differences in covariates between
survivors and nonsurvivors were tested by Student’s t-test for continuous variables and chi-square
test or Fisher exact probability method for categorical variables. To investigate which prognostic
indicator (APACHE II, SIPP, and serum lactic acid level) were the most valuable predictor of
prognosis for acute paraquat poisoning, receiver operating characteristic (ROC) curves for
predicting inpatient mortality were generated. The area under the curve (AUC), sensitivities,
specificities, cut-off values, accuracy, and an indicator of the predictive value of a test were
calculated using GraphPad Prism V4.0. To analyze the best cut-off values for APACHE II score,
SIPP and lactate level for predicting the prognosis in paraquat poisoning, one-way analysis of
variance (ANOVA) assessed for differences in initial parameters at the time of WCH arrival of
paraquat poisoning patients of lactate level ≥ 2.95 mmol/L, APACHE II score ≥ 15.22 and SIPP ≥
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5.50 h·mg/L. In addition, with one another, the 7 days survival curves of lactate level ≥ 2.95
mmol/L, APACHE II score ≥ 15.22, and SIPP ≥ 5.50 h·mg/L were compared.
3. Result
3.1 Patient characteristics
During the study period, 161 patients fulfilled the acute oral poisoning criteria. Eighteen of these
patients were excluded because of missing data or loss of follow-up. The remaining 143 patients
were included in the study analysis. The median age of the patients in this study was 30.65 ±
12.75 years old. The mean time interval between exposure and WCH arrival (hours) was 8.95 ±
6.15 h. The mean ingested amount of paraquat dichloride (24.5% concentrate neat) as estimated
through history was 65.66 ± 14.01 ml. Forty-seven (32.86%) patients had comorbid diseases, of
which 25 (17.48%) patients had psychiatric conditions. Only 1 patient had concomitant alcohol
ingestion. 77 (53.85%) of patients survived after oral ingestion of paraquat, whereas 66 patients
died within 60 days. The overall 60-day mortality rate was 46.15%. The general characteristics of
all patients, the survivors and nonsurvivors are summarized in Table 1. The SIPP (5.45 ± 3.67
versus 11.29 ± 4.31 hr•mg/L), APACHE II score (2.78±1.89 versus 7.63±2.46) and lactate level
(2.78±1.89 versus 7.63±2.46 mmol/l) in survivors were significantly lower compared to
nonsurvivors.
Table 1. General characteristics of 143 oral paraquat poisoning patients at the time of WCH arrival
Number of patientsa
Age (year)b
Sexa
Time between exposure and WCH arrival
(hours)b
Estimated amount of paraquat dichloride
(24.5% concentrate) exposure (mL)b
Comorbid diseasea
Pyschiatric conditiona
underlying diseasea
Concomitant alcohol ingestiona
Serum lactates (mmol/l)b
APACHE II scoreb
SIPP (hr•mg/L)b
All patients
Survivors
Non-survivors
P
value
143
30.6±12.7
54/89
9.9±5.1
77
28.0±12.9
28/49
11.2±4.3
66
33.6±11.9
26/40
7.4±6.9
0.190
0.666
0.106
65.6±14.1
50.1±21.2
76.9±18.2
0.227
47
25
7
1
5.29±2.54
8.65±4.63
81.07
±
67.42
27
16
5
1
2.78±1.89
5.45±3.67
15.39 ±
10.6
20
9
2
0
7.63±2.46
11.29±4.31
147.85
±
78.56
0.546
0.262
0.35
1.000
<0.001
<0.001
<0.001
Results are expressed as a number of patients or b mean ± SD.
3.2 The prognostic value of lactate level、APACHE II score、SIPP
Of all patients, 143 with a history of acute oral paraquat poisoning were included. Receiver
operating characteristic (ROC) curves were calculated for APACHE II score, SIPP and lactate
level on admission. The APACHE II score, SIPP and lactate level all had different ROC area under
the curves (AUC). The lactate level was as good as the SIPP or APACHE II score (AUC 0.916 vs
4
0.847, 0.789) at predicting the patient outcome, and level of consciousness had the utmost
contribution to the APACHE II score or SIPP (Fig 1 A, Table 2). All 3 predictive indicators was
useful in predicting the outcome in oral paraquat poisoning patients, with patents with lactate level
equal > 2.95 (mmol/l) having a sensitivity of 0.87, specificity of 0.91 and accuracy of 0.89 for
predicting death, SIPP > 15.22(h•mg/L) having a sensitivity of 0.78, specificity of 0.91 and
accuracy of 0.84 for predicting death, and APACHE II score > 5.50 having sensitivity, specificity
and accuracy of 0.95, 0.50 and 0.64, respectively.
Fig. 1.
A: shows the ROC curves comparing lactate level，APACHE II score, SIPP for prediction 60-day
mortality of f acute oral paraquat poisoning mortality.
B: 7 days survival curves after admission of paraquat-poisoning patients of lactate level≥2.95
mmol/L, APACHE II score≥15.22 and SIPP≥5.50 h·mg/L.
Table 2 Comparisons of initial parameters in paraquat poisoning patients with SIPP ≥ 15.22
h·mg/L, APACHE II score ≥ 5.50, and lactate level ≥ 2.95 mmol/L at the time of WCH
arrival
Number of patients
SBP (mmHg)
DBP (mmHg)
HR (/min)
RR (/min)
BT (℃)
Hemoglobin (g/dL)
WBC (×103/mm3)
pH
PaCO2 (mmHg)
PaO2 (mmHg)
5
lactate level≥2.95
mmol/L
SIPP≥15.22 h·mg/L
APACHE II score ≥
5.50
64
117.42±19.42
79.46±20.73
87.68±16. 52
27.08±3.06
36.89±0.44
15.75±2.32
18.28±6.04
7.31±0.08
27.77±4.2
95.23±24.02
59
126.63±20.58
81.0±11.57
83.55±13.62
26.38±3.36
36.86±0.47
14. 47±3.03
16.89±5.97
7.38±0.12
29.63±5.9
91.46±32.13
91
121.72±23.61
80.5±14. 68
95.59±10.09
22.23±2.14
36.94±0.52
16.24±1.83
17.23±6.18
7.45±0.10
32.26±5.0
99.74±30.03
BUN (mg/dL)
Creatinine (mg/dL)
AST (IU/L)
ALT (IU/L)
Total bilirubin (mg/dL)
Amylase (IU/L)
Glucose (mg/dL)
23.84±4.27
2.54±0.3
76.52±9.28
62.38±11.27
1.78±0.65
515.39±162.53
147.37±21.48
21.63±3.68
2.04±0.4
75.95±10.31
63.62±10.68
1.88±0.43
490.51±157.01
159.69±17.83
20.05±4.70
1.84±0.3
77.47±11.25
67.57±8.25
1.84±0.74
413.18±188.22
162.76±23.62
Results are expressed as mean ± SD.
SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; RR, respiratory rate;
BT, body temperature; WBC, total white blood cell; BUN, blood urea nitrogen; AST, aspartate
aminotransferase; ALT, alanine aminotransferase.
3.3 Comparison of best cut-off values for lactate level, APACHE II score and SIPP
The initial parameters of patients with lactate level ≥ 2.95 mmol/L, SIPP ≥ 15.22 h·mg/L and
APACHE II score ≥ 5.50 at the time of WCH arrival are shown in Table 2. On average, respiratory
rate (RR) and serum creatinine amylase values (RR: 27.8 ± 3.0 /min and creatinine: 2.54 ± 0.3
mg/dL) in patients with lactate level ≥ 2.95 mmol/L were higher than patients with SIPP ≥ 15.22
h·mg/L (RR: 26.38±3.3 /min; and creatinine: 2.04±0.4 mg/dL) and APACHE II score ≥ 5.50 (RR:
22.23 ± 2.1 /min and creatinine: 1.84 ± 0.3 mg /dL) at the time of WCH arrival (P<0.05). In
contrast, blood PaCO2 values (27.77±4.2 mmHg) in patients with lactate level ≥ 2.95 mmol/L was
lower than patients with SIPP ≥ 15.22 h·mg/L (29.63±5.9 mmHg) and APACHE II score ≥ 5.50
(32.26 ± 5.0 mmHg) (P<0.05). Further analysis revealed a significant difference in the 7 days
survival curves in patients with lactate level ≥ 2.95 mmol/L, SIPP ≥ 15.22 h·mg/L and APACHE II
score ≥ 5.50 (Fig. 1 B). The paraquat poisoning patients with lactate level ≥ 2.95 mmol/L or SIPP
≥15.22 h·mg/L had a significant higher 7-day mortality after admission, 54 of the 64 deaths
(84.38%) in the patients of lactate level≥2.95 mmol/L and 49 of 59 (83.05%) in the patients of
SIPP≥5.50 h·mg/L compared with 46 of 91 deaths (50.55%) in the patients of APACHE II
score≥5.50, (P<0.05) ( Fig. 1 B)
4. Discussion
For a long time, one of the many problems which puzzled clinical doctors was how to uncover a
good prognostic indictor. A good prognostic indictor is able to identify the high risks patients, and
can facilitate the doctor-patient communications [18], acquired from the blood. In addition, it must
have an appropriate half-life period, not only does it have to respond in the early phase, but also
has to have enough window phase [19], easy to be acquired and expanded, and is helpful for
clinical doctors to predict the prognosis [20]. The number of paraquat poisoning cases in western
China has increased dramatically in recent years. West China Hospital of Sichuan University
(Chengdu, China) is the first-line poisoning treatment referral center in western China, and our
center has developed an algorithms for measurement and diagnosis of paraquat levels to ensure the
consistent intervention measures. Though our practice, we have found that the APACHE II score,
lactic acid and SIPP maybe correlated with the prognosis of paraquat poisoning.
The present study has investigated the correlation of 3 indicators (APACHE II score, lactic acid
and SIPP) and the prognosis of acute paraquat poisoning. The lactic acid had the largest ROC area
under the curves (AUC) compared with SIPP and APACHE II. The lactic acid was more specific
6
and accurate at predicting the prognosis of acute paraquat poisoning. This implies that the
predictive value of lactic acid was superior to SIPP and APACHE II., which accords with our past
clinical observations. The most common clinical manifestations of paraquat poisoning were
anoxia and ARDS (acute respiratory distress syndrome) which are caused by acute lung injury
[21,22], and were the primary cause of death in patients with a short survival. The serum lactic acid
concentration is an indicator of histanoxia, which can reflect the severity of patient's condition. In
addition, because of its sensitivity for anoxia, it can also reflect the severity of paraquat poisoning.
Our results showed that the serum lactate concentration correlates with the prognosis, and
demonstrated that it is a good prognostic indicator, which can indicate physicians of the necessity
for early treatment, and is very important for high risk patients. Through comparisons of initial
parameters and survival curves of patients with lactate level ≥ 2.95 mmol/L, SIPP ≥ 15.22 h·mg/L
and APACHE II score ≥ 5.50 at the time of WCH arrival, we had found that the hypoxic
symptoms were more severe in patients with lactate level ≥ 2.95 mmol/L. In addition, these
patients also had a poorer renal function and shorter survival. These results can explain why the
serum lactic acid concentration was on overall a better indicator than SIPP and APACHE II Score
at predicting the mortality of acute paraquat poisoning.
The results of this study was comparable to the results from past literatures, which concluded that
SIPP was related to prognosis of paraquat poisoning [12-15]. When the cutoff value was 15.22
h·mg/L, the accurancy of SIPP at predicting mortality was 84%. When available, the plasma
paraquat concentration should be tested, and appropriate treatment should be administer
accordingly. Because the plasma paraquat concentration only reflex the distribution in blood, the
tissue damage for patients unable to direct reaction. This may be the reason that the predictive
value of SIPP was lower than serum lactic acid concentration. In addition, the results of our study
also showed that the APACHE II score is not as good a prognostic indicator as lactic acid and SIPP.
The AUC of APACHE II was 0.789, degree of accurancy was only 64%, and the cutoff value was
5.50 , which is not comparable to the result of past literature [23]. Possible reasons for its decrease
in reliability include the fact that acute paraquat poisoning symptoms can take from a few days to
weeks to manifest [23,24], and since the APACHE II score is generally calculated during the early
stages, and therefore it may not be able to truly reflect the severity of the poisoning. As a result,
the APACHE II score may not provide the best prognostic information.
In conclusion, serum lactic acid level, SIPP and APACHE II score all were correlated with
prognosis of acute paraquat poisoning. The elevation of serum lactic acid level had great inferred
value for the severity and prognosis of acute paraquat poisoning. Serum lactic acid ≥ 2.95mmol/L
and SIPP ≥15.22 h·mg/L was a simple and easy to acquire prognostic indicator of acute paraquat
poisoning, and was better than SIPP. In the future, serum lactic acid concentration accompany
with SIPP for predicting the prognosis of acute paraquat poisoning should be the area of interest
for investigators. Because of the delay of symptom after acute paraquat poisoning, APACHE II
score maybe inaccurate at the early course of paraquat poisoning, but whether it can be used to
predict the prognosis at several days after poisoning should also be investigated in the future.
Financial disclosure：No current external funding sources for this study
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