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ORIGINAL ARTICLE
Year : 2018  |  Volume : 26  |  Issue : 1  |  Page : 77-82

To evaluate the role of Vitamin C in reducing the resuscitation fluid volume requirement in burned patients


1 Department of Plastic Surgery, Dayanand Medical College, Ludhiana, Punjab, India
2 Intern, Maulana Azad Medical College, New Delhi, India
3 Department of Pharmacology, Dayanand Medical College, Ludhiana, Punjab, India

Date of Web Publication11-Mar-2019

Correspondence Address:
Dr. Sanjeev Uppal
133 H, BRS Nagar, Ludhiana - 141 012, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijb.ijb_21_17

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  Abstract 


Introduction: Free radicals released after burn injury lead to vascular endothelial injury and contribute to capillary leakage which in turn leads to burn edema. Antioxidant therapy (Vitamin C), to scavenge these free radicals, is suggested to limit endothelial injury and hence limit capillary leakage which in turn leads to reduction in fluid requirement to resuscitate the burn patient.
Materials and Methods: This was a prospective, randomized study of 30 burn patients with 20%–60% burns. Fifteen patients were taken in each group. Group A patients were treated with only RL and Group B were treated with RL and adjuvant Vitamin C infusion. Fluid requirement, urine output, fluid balance, body weight gain, Vitamin C, and malondialdehyde (MDA) levels were noted. The two groups were then compared.
Results: Fluid requirement in Group A was 3.74 ± 0.57 ml/kg/% of burns and in Group B was 2.46 ± 0.54 ml/kg/% of burns. Urine output was 1.05 ± 0.28 ml/kg/h in Group A, and in Group B, it was 1.42 ± 0.39 ml/kg/h. Fluid retention and body weight gain were lower in Group B. MDA levels were significantly lower at 36 h in Group B.
Conclusion: Vitamin C, when given as adjuvant therapy in burns, decreases fluid requirement and lowers the MDA levels showing antioxidant effect of Vitamin C.

Keywords: Antioxidant, burn edema, capillary leakage, fluid requirement, free radicals, Vitamin C


How to cite this article:
Tanwar B, Uppal D, Mittal RK, Kaushal S, Garg R, Shah S, Uppal S. To evaluate the role of Vitamin C in reducing the resuscitation fluid volume requirement in burned patients. Indian J Burns 2018;26:77-82

How to cite this URL:
Tanwar B, Uppal D, Mittal RK, Kaushal S, Garg R, Shah S, Uppal S. To evaluate the role of Vitamin C in reducing the resuscitation fluid volume requirement in burned patients. Indian J Burns [serial online] 2018 [cited 2019 Mar 18];26:77-82. Available from: http://www.ijburns.com/text.asp?2018/26/1/77/253848




  Introduction Top


Burn injury still remains a major health problem in developing countries like India. Fluid resuscitation to maintain adequate tissue perfusion while reducing edema in a severely burnt patient still remains a challenge.[1] The postburn edema occurs not only in the burnt area but also in the unburnt area of the body. The cause of this edema in severe burns is initiation of a systemic inflammatory response that leads to endothelial dysfunction. This leads to fluid and protein leakage from the intravascular space to the interstitial space.[2] The resultant phenomenon of “fluid creep” leads to various complications of burn injury such as abdominal compartment syndrome and pulmonary edema.[3],[4]

Local mediators such as histamines, serotonin, prostaglandin, and free radicals produced during burn injury have been implicated in the development of capillary leakage.[5],[6],[7] Recent studies have suggested that free radicals generated as result of burn injury play an important role in tissue injury. Friedl et al. demonstrated that histamine released from mast cells after burn injuries increases xanthine oxidase activity, in turn producing oxygen-free radicals. Endothelium is specifically susceptible to oxidative stress, and these free radicals cause endothelial injury and contribute to altered capillary permeability in turn contributing to burn shock.[8] If we can control this loss of fluid to interstitial space, we may control the burn edema and shock.

Saffle [4] explained that the pathophysiology of burn edema is multifactorial and the greatest edema formation occurs almost immediately postburn within the wound, caused by near total permeability to even very large (350 Š) molecules permitting leakage of fluid which is essentially identical to plasma.

Tanaka et al. investigated patients with >30% total body surface area (TBSA) burns. Two groups were compared. One was treated with only ringer lactate (RL) solution and the other group was treated with high dose of Vitamin C, 66 mg/kg/h as adjuvant therapy, along with RL solution as per the Parkland formula in 24 h, and it was concluded that adjuvant administration of high dose Vitamin C (as antioxidant) during the first 24 h after thermal injury significantly reduced resuscitation fluid volume requirement.[9]

In our study, the effect of high-dose Vitamin C as an antioxidant adjuvant therapy in burns patient and the outcome in terms of fluid requirement, fluid retention, urine output, complications associated with burns, and other morbidities related to burn injury were evaluated. The malondialdehyde (MDA) levels (indicative of free radical injury) were also measured.


  Materials and Methods Top


To evaluate the role of Vitamin C in reducing the resuscitation fluid volume, a randomized, prospective, comparative study on 30 burn-injured patients (with TBSA burnt between 20% and 60%) admitted in the burns ICU of Dayanand Medical College and Hospital, Ludhiana from June 1, 2014 to October 31, 2015 was carried out. Informed consent was taken from each patient and all aspects of the study were performed in accordance with the regulations of the Institutional Review Board.

Randomization was done based on the day of the week on admission, and patients allotted Group A and Group B. The care givers were unblinded. Group A was resuscitated with only RL solution and Group B was given RL and Vitamin C. Resuscitation fluid was calculated as per Parkland's formula, depending on the weight and percentage of burnt body surface area (fluid given before admission to hospital was included in this volume). Vitamin C was given in the form of infusion in dosage of 66 mg/kg/h for first 24 h only, along with a calculated amount of RL. The amount of fluid given in the form of infusion to administer Vitamin C was added to the resuscitation fluid volume.

Blood sample for measuring MDA levels and Vitamin C levels was collected at the time of starting Vitamin C infusion, considering the starting time to be 0 h and were repeated at 10 h, 24 h, and 36 h (10 h after stopping Vitamin C infusion). Various hemodynamic parameters and urine output were recorded hourly. Resuscitation fluid administration rate was adjusted to maintain the hemodynamic stability (systolic blood pressure [BP] above 100 mmHg) and urine output of 0.5–1.0 ml/kg/h. Patients' weight was measured at the time of admission and after 24 h, 48 h, and 96 h. The two groups were compared.

Exclusion criteria

Patients having preexisting hepatic, respiratory, cardiac or renal disease (based on history of medication and organ-specific function tests available at the time of admission), patients having associated injuries other than burns, patients with history of diabetes, patients reporting after 10 h of incident and patients with inhalation injury were excluded.

Method of measuring Vitamin C and malondialdehyde levels

MDA was measured using thiobarbituric acid assay method with spectrophotometer. Vitamin C levels were measured using Shimadzu high-performance liquid chromatography with ultraviolet probe with the following specifications:

Stationary phase: C18 column

Mobile phase: Water: 40%, ACN: 60%

Chromatographic conditions:

  • Flow rate: 1.0 ml/min
  • Oven temperature: 40°C
  • Cooler temperature: 15°C
  • Run time: 4 min
  • Wavelength: 254 nm.


Statistical analysis

Continuous group variables were expressed as the mean ± standard deviation, cat. variables as n (%). t-test was used to compare continuous data of the two groups and Chi-square test was used to find the association between categorical variables. P < 0.05 was taken as statistically significant.


  Results Top


In our study, the mean age in Group A was 35.0 years, and in Group B, it was 40.2 years. It is not statistically significant. The gender difference is also not statistically significant. The mean burnt body surface in Group A was 41.7%, and in Group B, it was 38.8%; the difference is not statistically significant [Table 1].
Table 1: Age, sex, and percentage of burnt surface area of patients in two groups

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In Group A (treated with RL only) patients, the average fluid requirement to achieve hemodynamic stability and adequate urine output in first 24 h was 3.7 ml ± 0.6/kg/% of burn whereas, in Group B (treated with RL and Vitamin C) patients, the fluid requirement was 2.5 ml ± 0.5/kg/% of burn. The difference was statistically significant (P < 0.001) [Table 2] and [Figure 1].
Table 2: Various parameters noted in the two groups in the first 24 h of resuscitation

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Figure 1: Resuscitation fluid required in both groups in the first 4 days in ml/kg/% of burns. RL: Group in which only Ringer lactate was given. Vit C: Group in which along with Ringer lactate, adjuvant therapy of Vitamin C infusion was used (Fluid given in infusion was added to the fluid given)

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In Group A, urine output in first 24 h of resuscitation was 1.1 ml ± 0.3/Kg/h, whereas, in Group B, it was 1.4 ml ± 0.4/Kg/h. The difference was again statistically significant (P = 0.006) [Table 2].

Fluid retention in the body was also calculated, i.e., total fluid intake – total fluid output in first 24 h. In Group A, it was 116.6 ± 39.7 ml, and in Group B, it was 77.2 ± 61.3 ml. This was statistically significant (P = 0.046) [Table 2].

Body weight gain in the two groups was also measured as the percentage increases in body weight in the first 24 h of resuscitation. It was higher in Group A, i.e., 7.5% ± 2.8% whereas, it was 4.1% ± 2.4% in Group B. The difference was statistically significant (P = 0.001) [Table 2] and [Figure 2]. The mean systolic BP of patients of Vitamin C group was higher (104.5 ± 13.9 mmHg) than the RL group (115.9 ± 8.3 mmHg) and P = 0.048 [Table 2].
Figure 2: Percentage of body weight gain in both groups in 4 days

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Weight gain percentage on 1st day was 7.5% in the RL group and 4.1% in the group treated with RL and Vitamin C as adjuvant therapy. The difference was significant (P = 0.001). On subsequent days, the difference was not significant.

MDA level, which is an indicator of free radical mediated injury, was also measured in the two groups for the first 36 h. In Group A, MDA levels were significantly higher (7.1 μmol/L ± 4.1) than Group B (2.0 μmol/L ± 0.01) at 36 h of resuscitation (10 h after stopping Vitamin C infusion) [Table 3] and [Figure 3].
Table 3: Malondialdehyde levels in both groups in the first 36 h in μmol/L

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Figure 3: Malondialdehyde levels in both groups in the first 36 h

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Vitamin C levels in the two groups were also checked for the first 36 h to confirm the delivery of Vitamin C in plasma and also to see the amount of time it takes to pass out of the body. It was noted that Vitamin C levels fell rapidly within hours after stopping infusion [Table 4] and [Figure 4].
Table 4: Vitamin C levels in μg/ml in the two groups at 0, 10, 24, and 36 h of starting IV infusion

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Figure 4: Vitamin C levels in the two groups at 0, 10, 24, and 36 h of starting Vitamin C infusion

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Other observations

While Vitamin C infusion was going on, blood glucose levels tested with glucometer showed high glucose levels; however, the parallel reports from samples sent to biochemistry laboratory showed normal range of glucose levels; these false high levels were due to interference of Vitamin C in the measurement of glucose by strip method.[10]

We also noted some diuretic effect on starting the Vitamin C infusion which lasted for about 10 h of stopping the infusion.

Outcome

In our study, 53.33% of patients of Vitamin C recovered as compared to 40.00% of RL group, none of the patients in the two groups suffered from renal failure. Pneumonia was seen in 26.67% in Vitamin C group and in 40% of RL group [Table 5], but all these differences were not statistically significant.
Table 5: Complications in the two groups

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  Discussion Top


The initial fluid resuscitation in major burn trauma is intravenous infusion of crystalloids solutions to correct hypovolemia and to improve peripheral tissue perfusion.[11] The accepted norms are to monitor the adequacy of resuscitation with urine output of 0.5–1.0 ml/kg/h of body weight and stable hemodynamic status. There have been reports of overresuscitation of burn patients leading to problems such as anasarca, abdominal compartment syndrome, prolonged mechanical ventilation, and pneumonias. This has been termed as “fluid creep” phenomenon. Why does “fluid creep” occur is not clear as per Greenhalgh.[3]

In the early 1970s, the understanding of fluid loss from intravascular compartment to extravascular compartment and resulting in edema was realized, and in an effort to decrease this intravascular loss of fluid, Monafo examined the efficacy of using hypertonic saline solution (240–300 mEq/L of Na) for resuscitation.[10],[12] The concept was based on hypothesis that hypertonic saline would shift water from the intracellular to the intravascular space. The other benefit would be that with a lower volume of resuscitation, there would be less edema and its associated complications. Early formulae developed by Evans and by surgeons at the US Army Burn Center contained significant amount of colloid in their calculations.[13] Colloids were used in an effort to decrease the fluid loss from intravascular compartment to extravascular compartment. Administration of large volume of crystalloid during burn resuscitation decreases plasma protein concentration and further promotes intravascular egress of fluid and edema formation. Replenishment of plasma protein using colloids (either with albumin or plasma) theoretically mitigates this effect.

Fang et al. in their study explained that thermal injury generates free radicals from various cellular populations, and modulations of free radical activity with scavengers may improve outcome.[14]

Horton explained that the free radical-mediated cell injury has been supported by postburn increase in systemic and tissue levels of lipid peroxidation products such as MDA levels. Antioxidant therapy in burn patients has been shown to reduce burn and sepsis-mediated mortality. He concluded in his study that antioxidant strategies designed to scavenge the burst of free radicals have been shown to reduce tissue injury to improve organ function and to improve outcome.[11]

Our study consisting of 30 patients of burns studied the effects of antioxidant, i.e., Vitamin C in reducing the fluid requirement in burns patients. The MDA levels indicating the free radical-induced injury were also measured.

Patients treated with only RL solution (Group A) required 3.74 ± 0.57 ml of fluid/kg/% of burn area, whereas patients who were resuscitated with Vitamin C as adjuvant therapy (Group B) required 2.46 ± 0.54 ml of fluid/kg/% of burn in the first 24 h of resuscitation. This was significantly different (P < 0.001). Fluid required in Vitamin C group was 34.3% lesser as compared to fluid required in RL group.

Tanaka et al. in their study required 5.5 ± 3.1 ml/kg/%of burns in RL group and 3.0 ± 1.7 ml/kg/% of burns in Vitamin C group and demonstrated 45.5% reduction in the initial resuscitation fluid volume in Vitamin C group patients.[15] Whereas Kahn et al. in their study reported fluid requirements in the first 24 h was 7.1 ± 1 ml/kg/% TBSA for RL group and 5.3 ± 1 ml/kg/%TBSA for Vitamin C group (P < 0.05).[16]

Matsuda et al. demonstrated in their experimental model that treatment with high-dose ascorbic acid reduces edema formation and fluid requirements during resuscitation. In their subsequent study, they reported that with a high dose of ascorbic acid therapy, the 24-h fluid resuscitation volume was reduced to 32.5% of the Parkland formula, while maintaining adequate cardiac output values.[17]

Urine output in Group A was also significantly lower (1.05 ± 0.28 ml/kg/h) than in Group B (1.42 ± 0.39 ml/kg/h) despite receiving higher fluid volume (P = 0.006).

Kahn et al. in their study reported urine output of 1.0 ± 0.5 ml/kg/h in RL group and 1.5 ± 0.4 ml/kg/h in Vitamin C group.[16] Tanaka et al. reported urine output of 1.1 ± 0.3 ml/kg/h in RL group as compared to 1.3 ± 0.6 ml/kg/h in Vitamin C group.[15]

Fluid retention which was inferred from the body weight gain was significantly more in Group A (116.6 ml/kg) after 24 h than Group B (77.2 ml/kg). This was statistically significant. Tanaka et al. reported more fluid retention in RL group, which was 162 ± 87 ml/kg as compared to 89 ± 97 ml/kg in Vitamin C group.[15]

Fluid retention in body signifies, to some extent, the fluid lost in third spaces, i.e., loss to extravascular space. This third space loss contributes to burn shock and also is the reason for complications related to burn resuscitation shock. Patients treated with Vitamin C showed less fluid retention. This again is consistent with the logic that Vitamin C prevents loss of fluid to extravascular compartment by having protective effect on capillary endothelium.

Body weight gain (resulting from fluid creep) was also significantly higher in Group A (7.5%) as compared to Group B (4.1%). Tanaka et al. also reported the percentage of weight gain in the first 24 h after injury as 17.8% ± 6.9% in the control group versus 9.2% ± 8.2% in the ascorbic acid group (P < 0.01).[15]

Demling in his study explained that the antioxidants in the early phase of resuscitation help in the prevention of edema by scavenging the free radicals in circulation.[18]

Hemodynamic status of both the groups was equivalent, i.e., BP, pulse, respiratory rate, oxygen saturation, and body temperature. Patients infused with high-dose Vitamin C showed no significant difference in vital parameters and remained stable throughout Vitamin C infusion. Mean systolic BP of RL group was 115.8 ± 8.3 mmHg as compared to Vitamin C which was better 104.5 ± 13.9 mmHg. This observation again suggests decreased capillary leakage and hence maintaining adequate blood pressure, in Vitamin C group.

To substantiate the antioxidant effect of Vitamin C, we did MDA levels (which is quantitative indicator of free radical-induced injury) in both the groups.

Mean MDA levels were similar in both groups at the admission time; the levels remained insignificantly different till first 24 h of resuscitation. In our study, MDA levels were significantly higher in Group A (7.1 μmol/L) as compared to Group B (3.9 μmol/L) by the end of 36 h (i.e., after 10 h of stopping Vitamin C infusion). Tanaka et al. reported serum MDA levels in both groups were above normal on admission, then gradually decreased. Levels of MDA in RL group were higher than those in the ascorbic acid group at 10, 18, 24, 36, and 48 h, however (P = 0.03).[15]

Studies show that free radicals are released when the previously ischemic tissue becomes reperfused. The reperfusion causes release of free radicals into the circulation which further causes endothelial injury.[11] Hence, when free radicals released into the body are scavenged by antioxidants, free radical-induced injury is less and is evident by lower levels of MDA.

Vitamin C levels

Vitamin C levels were found high in blood while Vitamin C infusion was going on, i.e., for the first 24 h. Levels dropped to near preinfusion levels at 36-h postinfusion, i.e., 10 h of stopping the infusion. Tanaka et al. reported serum Vitamin C levels in the ascorbic acid group progressively increased for 10 h, remained elevated for 36 h, and disappeared quickly.[9] SJ Padayathy in his study on pharmacokinetics of Vitamin C oral versus IV use found that high-plasma concentration after Vitamin C dose falls to steady state values within hours of administering Vitamin C dose.[19]


  Conclusion Top


In our study, we found that when high-dose Vitamin C (66 mg/kg/h) is given as adjuvant therapy in resuscitating the burn patients in the first 24 h, it decreases fluid requirement, increases urine output, and decreases fluid retention in body. Vitamin C is safe and is excreted out of body within few hours. We also noticed that the patients treated with Vitamin C showed decreasing trends of MDA levels, indicating reduced free radical-induced injury. Based on our study experience, we found it beneficial as adjuvant therapy in resuscitating burns patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dubick MA, Williams C, Elgjo GI, Kramer GC. High-dose Vitamin C infusion reduces fluid requirements in the resuscitation of burn-injured sheep. Shock 2005;24:139-44.  Back to cited text no. 1
    
2.
Biesalski HK, McGregor GP. Antioxidant therapy in critical care – Is the microcirculation the primary target? Crit Care Med 2007;35:S577-83.  Back to cited text no. 2
    
3.
Greenhalgh DG, Warden GD. The importance of intra-abdominal pressure measurements in burned children. J Trauma 1994;36:685-90.  Back to cited text no. 3
    
4.
Saffle JI. The phenomenon of “fluid creep” in acute burn resuscitation. J Burn Care Res 2007;28:382-95.  Back to cited text no. 4
    
5.
Majno G, Palide GE. Studies on inflammation. The effect of histamine and serotonin on vascular permeability. J Cell Biol 1961;11:571-605.  Back to cited text no. 5
    
6.
Majno G, Shea SM, Leventha M. Endothelial contractions induced by histamine type mediators. J Cell Biol 1969;42:647-72.  Back to cited text no. 6
    
7.
Heggers JP, Loy GL, Robson MM, Del Baccaro EJ. Histological demonstration of prostaglandins and thromboxanes in burned tissues. J Surg Res 1980;28:110-7.  Back to cited text no. 7
    
8.
Friedl HP, Till GO, Trentz O, Ward PA. Roles of histamine, complement and xanthine oxidase in thermal injury of skin. Am J Pathol 1989;135:203-17.  Back to cited text no. 8
    
9.
Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S, et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: A randomized, prospective study. Arch Surg 2000;135:326-31.  Back to cited text no. 9
    
10.
Monafo WW. The treatment of burn shock by the intravenous and oral administration of hypertonic lactated saline solution. J Trauma 1970;10:575-86.  Back to cited text no. 10
    
11.
Horton JW. Free radicals and lipid peroxidation mediated injury in burn trauma: The role of antioxidant therapy. Toxicology 2003;189:75-88.  Back to cited text no. 11
    
12.
Monafo WW, Halverson JD, Schechtman K. The role of concentrated sodium solutions in the resuscitation of patients with severe burns. Surgery 1984;95:129-35.  Back to cited text no. 12
    
13.
Warden GD. Burn shock resuscitation. World J Surg 1992;16:16-23.  Back to cited text no. 13
    
14.
Fang CH, Peck MD, Alexander JW, Babcock GF, Warden GD. The effect of free radical scavengers on outcome after infection in burned mice. J Trauma 1990;30:453-6.  Back to cited text no. 14
    
15.
Tanaka H, Matsuda H, Shimazaki S, Hanumadass M, Matsuda T. Reduced resuscitation fluid volume for second-degree burns with delayed initiation of ascorbic acid therapy. Arch Surg 1997;132:158-61.  Back to cited text no. 15
    
16.
Kahn SA, Beers RJ, Lentz CW. Resuscitation after severe burn injury using high-dose ascorbic acid: A retrospective review. J Burn Care Res 2011;32:110-7.  Back to cited text no. 16
    
17.
Matsuda T, Tanaka H, Williams S, Hanumadass M, Abcarian H, Reyes H, et al. Reduced fluid volume requirement for resuscitation of third-degree burns with high-dose Vitamin C. J Burn Care Rehabil 1991;12:525-32.  Back to cited text no. 17
    
18.
Demling RH. The burn edema process: Current concepts. J Burn Care Rehabil 2005;26:207-27.  Back to cited text no. 18
    
19.
Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann Intern Med 2004;140:533-7.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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