• Users Online: 370
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 38-43

Positive cumulative fluid balance in the first 72 h is associated with adverse outcomes following heat stroke


Emergency Intensive Care Unit, Beijing Lu He Hospital, Capital Medical University, Beijing, China

Date of Submission10-Feb-2020
Date of Decision07-Apr-2020
Date of Acceptance02-Jun-2020
Date of Web Publication06-Jul-2020

Correspondence Address:
Dr. Gang Ye
Beijing Lu He Hospital, Capital Medical University, Beijing
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ed.ed_3_20

Rights and Permissions
  Abstract 


Objective: The objective of the study was to determine the association between positive cumulative fluid balance following heat stroke (HS) and its impact on patient outcomes.
Methods: A retrospective chart review of HS patients admitted to the emergent intensive care unit (ICU), Beijing Lu He Hospital, Capital Medical University, from 2015 to 2018 was conducted.
Results: Forty-nine surviving HS patients met the inclusion criteria. Patients were divided into two groups based on the median duration of mechanical ventilation (MV). Patients with MV for more than 6 days were placed in the longer length of the MV group. Patients with MV for <6 days were placed in the shorter MV group. There were significant differences between the two groups regarding the fluid balance on day 2 (3040 ml vs. −533 ml, P = 0.017) and persistent cumulative fluid overload in the first 72 h (6112 ml vs. −46 ml, P = 0.04). Patients with a higher cumulative fluid overload in the first 72 h were more likely to receive a longer duration of MV (10.7 days vs. 3.2 days, P < 0.001) and ICU length of stay (22.5 days vs. 6.2 days, P < 0.001). Spearman analysis of fluid overload in the first 72 h and MV time showed that the correlation coefficient was 0.662. Binary logistic regression analysis showed that the positive cumulative fluid balance in the first 72 h (odds ratio [OR] = 1, 95% confidence interval [95% CI] = 0.99–1.01] and alanine aminotransferase (OR = 0.978, 95% CI = 0.95–0.99) were both independent risk factors for prolonged MV in patients with HS (P = 0.025, P = 0.026). There were also differences between groups regarding creatine kinase-MB (P = 0.01) and Glasgow Coma Scale scores (P = 0.033). The patients with a higher cumulative fluid overload in the first 72 h had larger sequential organ failure assessment cores. Based on the receiver operating characteristic analysis, the cumulative fluid overload in the first 72 h predicted the need for invasive MV with the area under the curve of 0.869 (P < 0.0001, 95% CI: 0.779–0.958) at a cutoff value >1685 ml (sensitivity: 86%; specificity: 78%).
Conclusions: Fluid overload in the first 72 h was a predictor of prolonged MV and ICU length of stay in surviving HS patients. Maintaining cautious about fluid resuscitation for HS patients may be critical for improving patient outcomes.

Keywords: 72 h, heat stroke, mechanical ventilation, persistent cumulative fluid overload


How to cite this article:
Yin X, Ye G. Positive cumulative fluid balance in the first 72 h is associated with adverse outcomes following heat stroke. Environ Dis 2020;5:38-43

How to cite this URL:
Yin X, Ye G. Positive cumulative fluid balance in the first 72 h is associated with adverse outcomes following heat stroke. Environ Dis [serial online] 2020 [cited 2020 Oct 25];5:38-43. Available from: http://www.environmentmed.org/text.asp?2020/5/2/38/289029




  Introduction Top


Heat stroke (HS) is a life-threatening condition characterized by a body core temperature (Tc) of more than 40° or with central nervous system (CNS) dysfunction.[1] Two types of HS have been identified: one occurs with exposure to a high environmental Tc and is called nonexertional HS and the other results from strenuous exercise and is termed exertional HS. Thermoregulatory failure and an exaggerated acute-phase response may lead to disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS).[2] Mortality ranges from 10% to 64% and increases with delays in patient cooling.[3],[4]

Currently, no effective well-defined treatment measures are available to curb the deteriorating condition of HS patients. HS patients may suffer from severe electrolyte losses, thus timely and effective fluid resuscitation is essential. Rapid and effective cooling is the basis of treatment unless the patient requires cardiopulmonary resuscitation.[5],[6] The usual practice is to control the target temperature from 38.5°C to 38.0°C to reduce the risk of clinical deterioration.[5] Early investigations regarding the standard treatment of HS included surface cooling methods combined with rapid intravenous infusion of 3–4 L of crystalloids.[7],[8] Hongjun et al. reported that aggressive fluid resuscitation needs to be performed on HS patients enrolled in the intensive care unit (ICU).[9] Conversely, some researchers have put forward the concept of more moderate fluid resuscitation in the early stage of HS, and the study suggested that during acute cooling treatment, caution should be exercised when providing intravenous fluids of more than 1 L to HS patients. They thought that rehydrating patients with high central venous pressure heavily may allow them to develop acute heart failure and pulmonary edema.[10]

As such, we designed the study to investigate the relationship between different fluid resuscitation strategies in HS survivors and their prognosis. Specifically, we investigated whether liquid overload was associated with a longer duration of mechanical ventilation (MV) and additional complications.


  Methods Top


Setting and study population

The study was conducted at the emergent ICU (EICU), Beijing LuHe Hospital, Capital Medical University. Eighty-two cases of patients with severe heat stoke admitted in our department from July 2015 to July 2018 were included, 33 patients were excluded, 27 patients dead, 3 transferred, 1 giving up treatment, and 2 nonintubated. HS survival patients were divided into two groups based on the median duration of MV. Patients with MV for more than 6 days were placed in the longer length of MV (LLMV) group. Patients with MV for no more than 6 days were placed in the shorter MV (SMV) group. Forty-nine mechanically ventilated HS patients were divided into the LLMV group (17 cases) and the SMV group (32 cases). Schematic of patient selection is shown in [Figure 1].
Figure 1: Inclusion criteria for the patient

Click here to view


After admission to the ICU, all patients were equipped with sterile thermometer catheters to monitor their bladder temperature. Cooling by alcohol sponge bath, carpet and ice compress bag, or continuous renal replacement therapy was started. The cooling was stopped when the Tc of the patient dropped to 38°C. The initial fluid resuscitation goal was to achieve a mean arterial pressure of 65 mmHg or higher or to decrease lactate levels. Recovery after 24 h was not standard. Any further resuscitation was performed by an experienced clinician.

Observation parameters

Statistical analysis was performed on the data of all patients during hospitalization. The gender, age, body weight, body Tc, duration of hyperthermia, and EICU length of stay were recorded. The worst clinical biochemical indexes were extracted from patient records within 24 h of EICU admission. The fluid overload (fluid overload = daily input − daily output (milliliters) on day 1, day 2, day 3, and in the first 72 h was determined for both study cohorts and the sequential organ failure assessment (SOFA) scores. We derived an optimum threshold of cumulative fluid overload for predicting longer MV. The optimum threshold was defined by receiver operator characteristic (ROC) curve analysis followed by Youden's J statistic, which simultaneously maximizes the sensitivity and specificity of the categorization.

Statistical analysis

SPSS 22.0 statistical software (SPSS 22.0; IBM, Chicago, IL, USA) was used for the statistical analysis. Data were expressed as the frequency and percentage for categorical variables and the mean ± standard deviation for continuous variables. Continuous variables were indicated as median (25%–75%) and compared through Mann–Whitney U-test. Categorical variables were indicated as number (%) and compared through Fischer's exact test. All statistical tests were two-sided and significance was defined as P < 0.05. Baseline correlations were assessed by Pearson or Spearman correlation coefficients. Receiver operating characteristic (ROC) analysis was performed to detect the sensitivity and specificity of the test.


  Results Top


A total of 49 HS patients from the original 82 patients were included in the study [Figure 1]. Patients' demographic data and clinical data were recorded and analyzed [Table 1]. Forty-five patients were building workers, and baseline patient characteristics were similar. MV duration and EICU length were statistically significant between the two groups (all P < 0.001). Glasgow Coma Scale (GCS) score was statistically significant between the LLMV and SMV groups (P = 0.033). In addition, a statistically significant relationship between the two groups was also observed in alanine aminotransferase (ALT) and creatine kinase-creatine phosphokinase isoenzyme (CK-MB) levels (P = 0.013, P = 0.01). No statistically significant relationship between the two groups regarding other clinical biochemical indexes was identified. (all P > 0.05). A statistically significant trend was evident in fluid overload on day 2 and persistent cumulative fluid overload in the first 72 h between the two groups (P = 0.017, P = 0.04). No statistically significant trend was evident in fluid overload on day 1 and day 3 [Table 1] and [Figure 2]. Spearman analysis of fluid overload in the first 72 h and MV time showed that the correlation coefficient was 0.662, the correlation coefficient between CK-MB and MV time was 0.643, and between ALT and MV time was 0.491. Binary logistic regression analysis showed that the positive cumulative fluid balance in the first 72 h (odds ratio [OR] = 1, 95% confidence interval [95% CI] = 0.99–1.01) and ALT (OR = 0.978, 95% CI = 0.95–0.99) were both independent risk factors for prolonged MV in patients with HS (P = 0.025, P = 0.026). In a post hoc analysis, all SOFA measurements during the first 72 h between two groups were taken into account. No statistical significance was observed on day 1. SOFA scores were statistically significant between the LLMV and SMV groups on day 2 (P = 0.021) and day 3 (P = 0.002) [Table 2]. It has been found that fluid overload was notably higher among patients in the LLMV group in the first 72 h. The 72 h cumulative fluid overload values were used as a potential risk factor to predict weaning from ventilation. Based on the ROC analysis, the optimum threshold of cumulative fluid overload was predictive of invasive MV with an area under the curve of 0.869 (P < 0.0001, 95% CI: 0.779–0.958) at a cutoff value >1685 ml (sensitivity: 86%; specificity: 78%) [Figure 3].
Table 1: Comparison of clinical biochemical indexes and clinical data affecting patients' duration of mechanical ventilation

Click here to view
Figure 2: Mean cumulative fluid overload over the first 5 days of emergent intensive care unit stay (longer length of mechanical ventilator group vs. shorter mechanical ventilator group). X-axis represents the days 1–5 for patients admitted to the hospital. The y-axis is the mean cumulative fluid overload per day in each group in the first 5 days of emergent intensive care unit stay. Mean cumulative fluid overload of longer length of mechanical ventilator group becomes significantly higher than those of shorter mechanical ventilator group on day 2

Click here to view
Table 2: Comparison of sequential organ failure assessment scores for the 1st 3 days between the two groups

Click here to view
Figure 3: Receiver operating characteristic for the optimum threshold of cumulative fluid overload in predicting invasive mechanical ventilation need. AUC = 0.869 (P < 0.0001, 95% CI: 0.779–0.958) at cutoff value > 1685 ml (sensitivity: 86%; specificity: 78%). AUC: Area under the curve, CI: Confidence interval, IMV: Invasive mechanical ventilator, ROC: Receiver operating characteristic

Click here to view



  Discussion Top


HS is an acute medical emergency and sometimes maybe fatal; thus, it is paramount to begin treatment immediately, such as cooling measures and fluid resuscitation to avoid progression to tissue damage and death. Dehydration and electrolyte loss can lead to a decrease in cardiac output and can lead to low blood pressure. Thus, patients are commonly subjected to rapid infusion with large volumes of fluids. The inflammatory response associated with HS is similar to the systemic inflammatory response syndrome (SIRS);[1],[6] SIRS can lead to DIC, multiple organ failure, and death. In one study of exertional HS patients, 84% met the diagnostic criteria for SIRS, and the length of hospital stay was prolonged.[11] The hemodynamic characteristics of most patients are high cardiac index, low systemic vascular resistance, and normal low filling pressure, and shock is distributed. Myocardial failure and a hypodynamic state may occur in the elderly.[12]

Few studies have been conducted regarding resuscitation strategies in HS patients. There was a literature reported that the fluid resuscitation volume was about 9 ml/kg/h in the first 6 h, and the fluid overload in the first 48 h reached 6 L. With resuscitation, more than 77% of patients experienced increased extravascular lung water.[13] It has been found that fluid overload on day 2 and fluid overload in the first 72 h were independent predictors of prolonged MV [Table 1]. The fluid balance in the first 72 h was 6112 ml and −46 mL in the LLMV and SMV groups, respectively. Obviously, the fluid balance in the SMV groups was far below LLMV. A previous study indicated that caution should be exercised when administering intravenous fluids of more than 1 L to HS patients during the cooling period.[10] Most patients had normal blood pressure, blood volume, and cardiac output, and some even had increased cardiac output.[14],[15] For surviving HS patients, it was concluded that the LLMV group patients' positive cumulative fluid balance may cause pulmonary edema, which leads to prolonged MV. During the study, it has been observed that with the decrease in body temperature in survival patients, the urine volume showed the tendency to increase. For HS patients, providing invasive hemodynamic monitoring (e.g., Pulse-indicated continuous cardiac output (PICCO)) in the process of rehydration may avoid the liquid overload. However, for patients without invasive monitoring further fluid resuscitation needs to be taken with caution as soon as there is an increase in urine volume and a decrease in lactic acid during the process of rehydration.

When comparing and analyzing clinical biochemical indexes and clinical data, CK-MB and GCS scores showed statistically significant difference between the two groups. Patients with elevated serum CK-MB often suffer from cardiac insufficiency. Although N-terminal pro-brain natriuretic peptide (NT-proBNP) showed no statistically significant difference, this level was elevated in both the groups at 1353 ng/ml and 1586 ng/ml in the LLMV and SMV groups, respectively. The plasma level of NT-proBNP was significantly increased in the two groups, which indicated that HS patients had already undergone heart dysfunction. Echocardiographic findings and myocardial marker levels for HS patients have also been reported.[16],[17] The pathophysiology of HS includes major cardiovascular involvement, which has been well-documented for decades.[18],[19] Myocardial ischemia has been reported in HS patients, and the increased oxygen demand due to high fever, tachycardia, and a significantly high cardiac output state, or hypotension, were considered to be causative factors.[9] One previous investigation using a rat model of HS reported that troponin I (cTnI) showed a 40-fold increase over control animals, which was consistent with cardiorenal failure.[20] cTNI generally reaches the peak level at 6–18 h[21],[22] in HS patients suffering from myocardial injury. The markers of myocardial injury in the LLMV group were higher than those in the SMV group, suggesting that the myocardial injury was more severe in the LLMV group. Thus, fluid overload may further exacerbate cardiac dysfunction in HS patients. Animal experiments have revealed that an increase in cerebral temperature of even 1°C above the normal 37°C for 60 min can cause neurologic deterioration and measurable histopathological lesions.[23] Research has also confirmed that brain temperature is 0.5°C–2°C warmer than Tc.[24],[25] Cooling therapies seem to play a more significant role in HS patient outcomes when the body Tc is dropped to 38.0°C within 2 h after HS onset.[4] It has been reported that the average GCS score at admission for the survival HS patients was 6 points,[26] which is consistent with the observed results in this study. GCS score was statistically significant between the LLMV and SMV groups. Patients with higher GCS scores may have experienced longer duration of hyperthermia than those of low GCS scores. The brain is so extremely sensitive to heat treatment that the CNS disorders are inevitable in HS patients.[27] People with severe exertional HS may develop seizures and sphincter incontinence.[28] In the early stage, the CNS injury caused by HS may be multifactors. HS itself can cause brain cell toxicity, and heat stress can increase brain metabolism, and heat release from the skin, as well as quickly, reduces blood flow to the brain. Heat stress can also directly inhibit the heart tissue, resulting in a decline in cardiac output. In addition, diseases such as inflammation, dehydration, and low blood pressure can also lead to cerebral ischemia and hypoxia, thus resulting in brain injury.

By analyzing, patients in the LLMV group had higher SOFA scores. MV was required more frequently in the LLMV group. Although the total fluid balance was not statistically significant between the two groups on day 1, MODS may peak within 24–48 h in exertional HS patients. If patients got treated promptly, their clinical symptoms became mild in most cases and subsided within a few days.[5] If HS patients were admitted with unstable hemodynamics, aggressive fluid treatment was necessary. When patients' condition improved after timely treatment, excessive fluid resuscitation might contribute to edema of organs, which was unfavorable for patient recovery. The data on HS patients collected by our group show that HS occurs suddenly and sometimes without prodrome, so fluid depletion in these patients should not always be considered. Thus, fluid administration should be based on the fluid responsiveness status of each patient during the intervention period.

This study has several limitations, including its retrospective nature and small sample size. In addition, it did not control for differences in resuscitation protocols. Furthermore, the volume of fluid resuscitation given to patients with HS prior to admission to the ICU was not counted, which may lead to an underestimation of the volume of fluid resuscitation during the study. Last but not least, although we have shown a link between positive cumulative fluid balance and adverse outcomes, invasive monitoring data were of absence in the study. The findings suggest an association between cumulative fluid overload in the first 72 h and adverse outcomes for HS patients. This association warrants further study in HS patients.


  Conclusions Top


In this study, we found that fluid overload in the first 72 h may be an independent predictor of prolonged MV usage and duration of EICU stay in HS patients. The results revealed that maintaining cautious about fluid resuscitation may be critical for improving HS patient recovery and minimizing the impact of fluid overload on clinical outcomes following HS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bouchama A, Knochel JP. Heat stroke. N Engl J Med 2002;346:1978-88.  Back to cited text no. 1
    
2.
Grogan H, Hopkins PM. Heat stroke: Implications for critical care and anaesthesia. Br J Anaesth 2002;88:700-7.  Back to cited text no. 2
    
3.
Yaqub B, Al Deeb S. Heat strokes: Aetiopathogenesis, neurological characteristics, treatment and outcome. J Neurol Sci 1998;156:144-51.  Back to cited text no. 3
    
4.
Pease S, Bouadma L, Kermarrec N, Schortgen F, Régnier B, Wolff M. Early organ dysfunction course, cooling time and outcome in classic heatstroke. Intensive Care Med 2009;35:1454-8.  Back to cited text no. 4
    
5.
Shapiro Y, Seidman DS. Field and clinical observations of exertional heat stroke patients. Med Sci Sports Exerc 1990;22:6-14.  Back to cited text no. 5
    
6.
Huisse MG, Pease S, Hurtado-Nedelec M, Arnaud B, Malaquin C, Wolff M, et al. Leukocyte activation: The link between inflammation and coagulation during heatstroke. A study of patients during the 2003 heat wave in Paris. Crit Care Med 2008;36:2288-95.  Back to cited text no. 6
    
7.
Khogali M, Amar M, AI-Habashi S, El-Saycd H, EI-Sayed S, Mutwali A, et al. Management and therapy regimen during cooling and in recovery room at different heat stroke treatment centres. In: Khogali M, Hales JR, editors. Heat Stroke and Temperature Regulation. Australia: Academic Press; 1983. p. 149-56.  Back to cited text no. 7
    
8.
Khogali M. Health disorders with special reference to Makkah Pilgrimage (The Hajj) Monograph. Published by Ministry of health. Kingdom of Saudi Arabia. Hajj 1983:41.  Back to cited text no. 8
    
9.
Hongjun K, Qing S, Yan Z, Liang P, Hui L, Feihu Z. Fluid resuscitation and standard drug treatment strategies in heatstroke Chinese patients. Drug Res (Stuttg) 2015;65:18-23.  Back to cited text no. 9
    
10.
Seraj MA, Channa AB, al Harthi SS, Khan FM, Zafrullah A, Samarkandi AH. Are heat stroke patients fluid depleted? Importance of monitoring central venous pressure as a simple guideline for fluid therapy. Resuscitation 1991;21:33-9.  Back to cited text no. 10
    
11.
Zeller L, Novack V, Barski L, Jotkowitz A, Almog Y. Exertional heatstroke: Clinical characteristics, diagnostic and therapeutic considerations. Eur J Intern Med 2011;22:296-9.  Back to cited text no. 11
    
12.
Bouchama A, Dehbi M, Chaves-Carballo E. Cooling and hemodynamic management in heatstroke: Practical recommendations. Crit Care 2007;11:R54.  Back to cited text no. 12
    
13.
Akhtar MJ, al-Nozha M, al-Harthi S, Nouh MS. Electrocardiographic abnormalities in patients with heat stroke. Chest 1993;104:411-4.  Back to cited text no. 13
    
14.
AI-Harthi SS, Sharaf El-Deen MS, Aktar I, Nozha M. Hemodynamic changes and intravascular hydration state- in heat stroke. Ann Saudi Med 1989;9:378-83.  Back to cited text no. 14
    
15.
Knoechel JP. Environmental beat illness – An eclectic review. Arch. Intern Med 1974;133:841-63.  Back to cited text no. 15
    
16.
al-Harthi SS, Nouh MS, al-Arfaj H, Qaraquish A, Akhter J, Nouh RM. Non-invasive evaluation of cardiac abnormalities in heat stroke pilgrims. Int J Cardiol 1992;37:151-4.  Back to cited text no. 16
    
17.
Madsen LH, Christensen G, Lund T, Serebruany VL, Granger CB, Hoen I, et al. Time course of degradation of cardiac troponin I in patients with acute ST-elevation myocardial infarction: The ASSENT-2 troponin substudy. Circ Res 2006;99:1141-7.  Back to cited text no. 17
    
18.
Stauss HM, Morgan DA, Anderson KE, Massett MP, Kregel KC. Modulation of baroreflex sensitivity and spectral power of blood pressure by heat stress and aging. Am J Physiol 1997;272:H776-84.  Back to cited text no. 18
    
19.
Schochina M, Horowitz M. Central venous pressure, arterial pressure and hypovolemia: Their role in adjustment during heat stress. J Therm Biol 1989;14:109-13.  Back to cited text no. 19
    
20.
Quinn CM, Duran RM, Audet GN, Charkoudian N, Leon LR. Cardiovascular and thermoregulatory biomarkers of heat stroke severity in a conscious rat model. J Appl Physiol (1985) 2014;117:971-8.  Back to cited text no. 20
    
21.
Clements P, Brady S, York M, Berridge B, Mikaelian I, Nicklaus R, et al. Time course characterization of serum cardiac troponins, heart fatty acid-binding protein, and morphologic findings with isoproterenol-induced myocardial injury in the rat. Toxicol Pathol 2010;38:703-14.  Back to cited text no. 21
    
22.
Jørgensen PH, Nybo M, Jensen MK, Mortensen PE, Poulsen TS, Diederichsen AC, et al. Optimal cut-off value for cardiac troponin I in ruling out Type 5 myocardial infarction. Interact Cardiovasc Thorac Surg 2014;18:544-50.  Back to cited text no. 22
    
23.
Del Bene VE. Temperature. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. Boston: Butterworths Butterworth Publishers, a Division of Reed Publishing; 1990.  Back to cited text no. 23
    
24.
Wass CT, Lanier WL, Hofer RE, Scheithauer BW, Andrews AG. Temperature changes of > or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 1995;83:325-35.  Back to cited text no. 24
    
25.
Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS. Brain temperature exceeds systemic temperature in head-injured patients. Crit Care Med 1998;26:562-7.  Back to cited text no. 25
    
26.
Yang M, Li Z, Zhao Y, Zhou F, Zhang Y, Gao J, et al. Outcome and risk factors associated with extent of central nervous system injury due to exertional heat stroke. Medicine (Baltimore) 2017;96:e8417.  Back to cited text no. 26
    
27.
Leon LR, Bouchama A. Heat stroke. Compr Physiol 2015;5:611-47.  Back to cited text no. 27
    
28.
Epstein Y, Yanovich R. Heatstroke. N Engl J Med 2019;380:2449-59.  Back to cited text no. 28
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed646    
    Printed52    
    Emailed0    
    PDF Downloaded86    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]