the first patient was a 31-year - old caucasian woman admitted to our facility after sustaining 65% tbsa thermal injuries in a residential fire .
the patient received lactated ringers during initial resuscitation titrated to a combined endpoint of urine output and tissue perfusion according to clinical judgment supported by a computer - based clinical decision support system .
given circumferential burns and decreased pulses , escharotomies were performed on her right upper extremity and bilateral lower extremities .
albumin was started at 8 hours post - burn at 0.4  ml / kg/%tbsa/24 hours when she was transiently hypotensive ( mean arterial pressure [ map ] 4050 for 30 minutes ) .
mg / kg / hr was initiated 11 hours post - burn as a rescue therapy to reduce oxidative stress and overall fluid requirements .
she received a total of 101  g of ascorbic acid in 18 hours ( table 1 ) .
before it could be initiated , she became progressively hypotensive and developed heart block leading to pulseless electrical activity . despite cardiopulmonary resuscitative efforts , the patient died on hospital day 2 . at autopsy
, there was mild cerebral edema , and birefringent calcium oxalate crystals were identified in her intratubular spaces in both kidneys .
patient demographics and vitamin c dosages the second patient was a 20-year - old man with 67% tbsa thermal injuries sustained from a reported industrial accident at a steel plant . on arrival , he was awake with a glasgow coma scale of 15 .
vitamin c infusion at 66  mg / kg / hr was initiated at 8 hours post - burn to help reduce oxidative stress and total resuscitative volume .
in addition , he received an additional 200  mg of ascorbic acid in his total parenteral nutrition .
his hospital course was complicated by bilateral lower extremity and right upper extremity escharotomies for circumferential burns .
he then developed primary metabolic acidosis , refractory shock , and aki requiring continuous venovenous hemofiltration .
he ultimately required a left above - the - knee amputation for progressively necrotic tissue . with worsening lactic acidosis and fever despite broad spectrum antibiotics ( started 24 hours post - burn ) ,
an exploratory laparotomy was performed to identify necrotic bowel , and none was identified . on hospital day 3 , his pupils were fixed and dilated with brain imaging showing cerebral edema and tonsillar herniation .
autopsy showed evidence of early cerebellar herniation with ischemic necrosis of the brainstem , cerebellum , and upper cervical spinal cord .
calcium oxalate crystals were identified in the intratubular space in both kidneys ( figure 1 ) . high power
preclinical studies have demonstrated the role of free radicals in the development of edema and increased vascular permeability after thermal injury .
other mediators of vascular permeability in burn patients include histamine , prostaglandins , catecholamines , and thromboxane .
histamine released from mast cells in injured tissue results in upregulation of xanthine oxidase activity and free radical formation .
local antioxidant activity is altered in the injured tissue and damaged neutrophils contribute to the formation of more free radicals .
for this reason , antioxidants , such as ascorbic acid , were investigated to decrease the amount of resuscitative volumes and secondary injury caused by free radicals .
ascorbic acid was shown to have free radical scavenging effects , an antihistamine effect , and helped to regulate collagen denaturation .
more recent studies have shown high - dose vitamin c infusions to reduce post - burn lipid peroxidation , vascular permeability , edema , and fluid resuscitative volumes .
animal studies were performed to analyze the effect of high - dose vitamin c on resuscitative volume and edema formation .
the water content of the burned skin in the vitamin c group was markedly decreased , suggesting reduced post - burn capillary permeability .
another animal study was performed to test the hypothesis that there is evidence of increased negative interstitial hydrostatic pressure in burn injured tissue .
this is suggested as a major pathophysiological mechanism necessary to cause such a rapid and massive edema formation after thermal injury .
tanaka et al investigated high - dose vitamin c and its effect on counteracting the increased negativity of interstitial pressure in rats .
they showed a marked attenuation of post - burn interstitial pressure by high - dose vitamin c with moderate decrease in the total body weight . in sheep , there was a significant decrease in the resuscitative volume in those sustaining a 40% tbsa after infusion of high - dose vitamin c. even in delayed initiation of high - dose vitamin c ( 2 and 6 hours post - burn ) , there was still a decrease in the fluid volume required in thermally injury guinea pigs .
despite the delayed initiation of high - dose vitamin c and decrease in resuscitation volume , they found that the 24-hour fluid requirement to be reduced to 32.5% of the parkland formula . a randomized
, prospective study was performed utilizing a continuous ascorbic acid ( 66  mg / kg / hr ) infusion on burn patients with 30% tbsa for 24 hours .
they found a 45% decrease in the volume required for resuscitation in the high - dose vitamin c treatment group ( 5.5 vs 2.1  ml / kg for control p < 0.01 ) .
there was a 3-fold weight gain in the control group compared with the ascorbic acid group .
ultimately , the vitamin c treatment group required fewer days on mechanical ventilation ( p < 0.05 ) . of note
in the retrospective review by kahn et al , their institute did not give the high - dose vitamin c if there was a delay in transfer or if there was baseline renal impairment .
careful attention was also paid to the patients volume status as ascorbic acid is hyperosmolar and can cause osmotic diuresis .
they carefully followed hematocrit , decreased central venous pressure , decreased urine output , or maps . ultimately , they found infusion of high - dose vitamin c safe and efficacious . in the above - mentioned studies ,
vitamin c supplementation is recommended in burn patients with typical doses from 500 to 1500  mg / d .
this is for increased requirements because of stress and need for wound healing . in the average person ,
one review of the literature reports that ingestion of up to 10  g / d of ascorbic acid orally does not pose a health risk to humans and another stated up to 2  g / d can be tolerated .
given the positive effects of high - dose vitamin c infusions in animal and human studies , literature proposes a continuous ascorbic acid infusion at 66  mg / kg / hr for the initial 24 hours of burn resuscitation .
vitamin c supplementation , both high and low doses , contributing to renal failure secondary to calcium oxalate deposits has been reported in the literature .
in addition to being part of a daily multivitamin , vitamin c is also being used as an alternative medicine in cancer , amyloidosis , and nephropathy .
ascorbic acid can induce oxalate nephropathy , worsen renal injury , and delay kidney recovery .
oxalate nephropathy , or aki as a result of calcium oxalate accumulation , can occur in both primary and secondary hyperoxaluria .
primary hyperoxaluria is because of a group of autosomal recessive inheritance , whereas secondary hyperoxaluria is because of increased oxalate intake , increased absorption of oxalate , or increased production of oxalate .
increased production of oxalate is typically because of increased ingestion of oxalate precursors , such as ethylene glycol , and more rarely , vitamin c. two patients identified in the literature were given 45 and 60  g intravenously of ascorbic acid as an alternative therapy in amyloidosis and cancer , respectively .
both patients subsequently developed acute renal failure and showed birefringent crystals on polarized light microscopy consistent with calcium oxalate nephropathy .
these patients had normal native renal function before the administration of vitamin c. oxalate nephropathy has been described in non - burn patients even at low doses .
of note , these patients received anywhere from 500  mg to 6.5  g orally .
all of the patients reported taking the dosages of vitamin c for months and had normal renal function prior .
review of the literature identified one other case report of vitamin c - associated nephropathy in a burn patient .
the patient sustained 40% tbsa and was given vitamin c supplementation of 1  g / d intravenously .
renal biopsy showed extensive calcium oxalate deposits within his tubules . only after decreasing the vitamin c dosage to 0.2  g / day and increasing the dialyzate flow
the author proposed that the aki was initially caused by volume loss from his burn injury and potentially exacerbated by amikacin .
he argues that the vitamin c supplementation either potentiated his renal injury or delayed its resolution .
overall , this shows oxalate nephropathy , and calcium oxalate crystals can form in the presence of normal renal function and by taking low doses .
the finding of calcium oxalate crystals in renal tubules of burn patients has not been previously reported .
others have reported patients developing aki following vitamin c infusion for adjuvant treatment of amyloidosis and cancer and subsequently found calcium oxalate nephropathy on renal biopsy .
all of these patients had normal renal function before the start of vitamin c. in these patients , calcium oxalate nephropathy was described as a clinically significant morbidity .
second , our patients had significant burns and were at risk for renal failure . in regard
to its delayed initiation , both tanaka et al and sakurai et al described a beneficial effect of high - dose vitamin c in guinea pigs , even after its infusion was postponed by 6 hours .
in addition , in these studies , no lab abnormalities were noted despite their high - dose vitamin c infusion delay .
for this reason , we used high - dose vitamin c as a rescue therapy to help attenuate the total volume of resuscitation and possible reduce the systemic inflammatory response .
of note , the initial studies in utilizing vitamin c were in accordance with the parkland formula .
however , in 1991 , matsuda et al showed that with high - dose vitamin c the total 24-hour resuscitation was able to be reduced from 4 to 1  ml / kg/%tbsa . in the article by sakurai et al , they resuscitated with lactated ringer s solution according to the parkland formula for only the first 6 hours , and then reduced the volume by 25% of the parkland formula once the high - dose vitamin c was initiated .
tanaka et al initiated resuscitation with the parkland formula for 0.5 to 2 hours post - injury and then reduced the volume to 25% of the parkland formula .
despite the delayed initiation of high - dose vitamin c and decrease in resuscitation volume , they found the 24-hour fluid requirement to be reduced to 32.5% of the parkland formula .
although our patients did receive a lower volume of resuscitation compared to the parkland formula ( table 1 ) , they did not have profound diuresis , and their laboratory findings did not show evidence of hemoconcentration after the initiation of vitamin c ( table 1 ) .
our resuscitation practices are guided by a computerized clinical decision support system with initial crystalloid rate determined by the isr rule of 10s formula .
as expected , the initiation of vitamin c resulted in increased urine output ( table 1 ) .
lactate was also monitored serially and rose in both patients consistent with worsening tissue perfusion , despite apparent adequacy of volume resuscitation and oxygen delivery evidence by elevated scvo2 ( table 1 ) .
the first patient had normal renal function ( cr 0.8  mg / dl ) at the time of high - dose vitamin c infusion .
ten hours after high - dose vitamin c was started , her cr increased to 1.40  mg / dl and was associated with an increase in urine output .
our second patient had renal impairment before high - dose vitamin c infusion , and it only worsened during his hospital course .
it is difficult to ascertain the exact cause for the renal impairment in our patients .
both are likely secondary to the extent of burns ; however , given the presence of calcium oxalate crystals in their renal tubules , oxalate nephropathy can not be ruled out .
it is expected that the aki in thermally injured patients is related to hypotension and shock leading to acute tubular necrosis . however , at autopsy , microscopic evaluation of acute tubular necrosis was hindered by diffuse postmortem autolysis of renal tubules .
therefore , with the presence of calcium oxalate crystals on postmortem analysis , the crystals either caused the aki or were a possible contributor .
knowing oxalate nephropathy can occur when high - dose vitamin c is used as an adjunct to burn resuscitation should be a cause for legitimate concern .
it is not our intent to put a moratorium on high - dose vitamin c therapy as burn centers with lots of experience using this resuscitative adjunct have reported overall success without any reports of this particular complication .
it may be that the benefits of high - dose vitamin c outweigh potential complications .
only a well - designed prospective clinical trial could answer this question while keeping in mind to deliberately monitor for this complication given our findings .
this report identifies a known complication of vitamin c therapy in 2 patients receiving high - dose vitamin c as a rescue therapy in complicated burn resuscitations . currently , there is much enthusiasm in the burn community about high - dose vitamin c infusions , and there are data supporting its use as an adjunct to complicated burn resuscitations . in other patient populations ,
high - dose vitamin c becomes a standard of care in burn units , further prospective research is necessary to determine the prevalence of adverse - effects , the optimal dose , timing , and the appropriate patient population for this therapy .
 fluid resuscitation is the foundation of management in burn patients and is the topic of considerable research . 
 one adjunct in burn resuscitation is continuous , high - dose vitamin c ( ascorbic acid ) infusion , which may reduce fluid requirements and thus decrease the risk for over resuscitation . 
 research in preclinical studies and clinical trials has shown continuous infusions of high - dose vitamin c to be beneficial with decrease in resuscitative volumes and limited adverse effects . 
 however , high - dose and low - dose vitamin c supplementation has been shown to cause secondary calcium oxalate nephropathy , worsen acute kidney injury , and delay renal recovery in non - burn patients . to the best of our knowledge , 
 the authors present the first case series in burn patients in whom calcium oxalate nephropathy has been identified after high - dose vitamin c therapy . 
CASE REPORTS
DISCUSSION
CONCLUSION
ACKNOWLEDGMENTS