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Fatal vitamin C-associated acute renal failure.

SUMMARY

Although daily ingestion of high-dose vitamin C is generally regarded as largely innocuous, fatal nephrotoxicity can occur in some rare circumstances. We report a case where the patient, who chose to forgo any advanced conventional medical intervention (dialysis and mechanical ventilation), had failed to disclose his use of high-dose vitamin C and subsequently died. Intra-renal oxalate crystal deposition was demonstrated at autopsy. Directed enquiry with the family then revealed his high-dose vitamin C usage. Even though fully-informed discussion was limited by incomplete prospective disclosure it remains the prerogative of any competent patient to decline any treatment, including those that may be considered life-saving.

Key Words: vitamin C, ascorbic acid, acute renal failure, mental competency, personal autonomy, autopsy, critical care

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Supra-physiological vitamin C (ascorbic acid) supplementation has been subject to considerable debate and investigation. Popularised by the work of Nobel Prize winner Linus Pauling in the 1970s, vitamin C use has variously been advocated as prophylaxis and/or treatment for many afflictions, ranging from the common cold through to malignancy (1-5). Subsequent studies and metanalyses have not been able to substantiate the claimed benefits (6-8). Although commonly regarded as relatively innocuous, high-dose vitamin C can rarely be associated with significant morbidity and mortality (9-15). A fatal outcome associated with apparent excessive vitamin C supplementation is reported here. As well as highlighting the potential for vitamin C toxicity and the importance of knowing all ingested medicaments, other features include aspects of patient competence to refuse life-preserving therapies and the continuing importance of the post-mortem examination.

CASE HISTORY

A 72-year-old male presented to hospital with a two-week history of generalised malaise and lethargy, along with unsubstantiated reports of intermittent confusion. He had a background history of putative pernicious anaemia and a previous hemicolectomy for diverticular disease. He denied any cardiorespiratory, genitourinary or gastrointestinal symptoms. He stated that he took no regular medications and denied substance ingestion. At times when answering direct questions he appeared evasive, giving the impression that certain details may have been withheld. When directly challenged in this regard, he was no more forthcoming. A degree of dysarthria was noted and attributed to his very dry mouth. Despite this he was clearly not confused or disorientated and his executive function was deemed to be intact.

On examination, he appeared cachectic and was dehydrated and hypothermic (tympanic temperature 32.9[degrees]C). His heart rate was 85 beats/minute with low to normal blood pressure (SBP 95 mmHg) and modestly prolonged capillary refill time. He had moderate tachypnoea with a Kussmaul-type pattern but well maintained oxygen saturations of 100% on 6 1/min supplemental oxygen by facemask. The only focal finding was mild epigastric tenderness without guarding or rebound tenderness. He was oliguric. Blood chemistry revealed creatinine 1358 [micro]mol/l, urea 64 mmol/l, [K.sup.+] 4.1 mmol/l, [Na.sup.+] 140 mmol/l, serum osmolality 353 mOsm/kg. A full blood count result included haemoglobin 94 g/l and WCC 8.3x [10.sup.9]/l. Arterial blood gas analysis revealed pH 7.07, Pa[O.sub.2] 206 mmHg, [P.sub.a]C[O.sub.2] 8 mmHg, actual HC[O.sub.3.sup.-] 2.3 mmol/l and a base deficit of 27 mmol with an arterial lactate of 0.6 mmol/l. Resuscitation with intravenous (IV) crystalloid was commenced while an intensivist consultation was arranged. Following review he was transferred to the intensive care unit (ICU) for on-going management.

Discussion with him centred upon the nature of his problem, its possible causes and consequences, and the proposed immediate management strategies. During this discussion he made it clear that in the interim, he did not wish to have either dialysis or, should it become necessary, tracheal intubation and mechanical ventilation. He stated that he wished to consider these options further and offer a definitive opinion the following day. It was impressed upon him that in the event of a more immediate generalised deterioration he would most likely be unable to offer any revised opinion. The high likelihood of death without advanced therapeutic measures, particularly renal replacement therapy, was also emphasised. He indicated that he understood and accepted this but still refused treatment. He also firmly stated that no contact was to be made with his immediate family members.

In ICU, further IV crystalloid rehydration was provided with a total of six litres in the first eight hours. Given some uncertainty regarding his 'usual' blood pressure, it was decided to commence titrated IV infusions of catecholamines (initially noradrenaline with dopamine later added) with the intent of optimising renal perfusion. Despite these initial measures he remained oligo-anuric even though the urea and creatinine responded favourably, falling to 55 mmol/l and 1015 [micro]mol/l respectively. His acidosis worsened to a nadir of pH 6.97 and he developed an acute confusional state with marked agitation for which titrated IV doses of diazepam and haloperidol were administered. An ultrasound scan excluded obstructive nephropathy and showed normal-sized kidneys that were unusually echogenic in a homogenous distribution. Numerous renal tubular epithelial cells were seen on urine microscopy. A trial bolus-administration of frusemide was unhelpful. He became hypoxaemic with increasing work of breathing and a decreasing level of consciousness. In the absence of clinical or radiographic evidence of fluid overload, non-invasive ventilatory assistance (Fi[O.sub.2] 0.5) was commenced in the belief that this did not contravene his earlier request for limitation. Following a nephrology consultation, his IV fluid therapy was changed to an isotonic bicarbonate solution.

Given his accelerated deterioration, some consideration was given to temporarily overriding the patient's earlier refusal of renal replacement therapy on the grounds that he may not have been fully competent. At this point, his family members made contact and provided further detail. He had long-held firm views regarding the importance of nutritional supplementation in preference to 'conventional' medicine. At the time, this was not recognised as having any potential immediate causal relationship to his acute renal failure. Further, his family members confirmed that the decision to forgo advanced conventional therapeutic interventions was entirely congruent with his character and previously expressed beliefs. Accordingly no further consideration was given to disregarding his initial refusal of escalation. He had now become deeply unconscious and it was apparent that the currently employed measures were not sufficient to reverse his decline. Following discussion with his sister and the wider family, active management was discontinued and palliation instituted. Death followed soon thereafter. At this stage the cause of his acute renal failure remained unknown and his death was referred to the coroner. An autopsy examination was performed. Renal histology revealed that his renal failure had been secondary to extensive oxalate crystal deposition, with the pathologist offering ingestion of an oxalate-containing substance as a possible cause. Subsequent directed enquiry with the family reconfirmed his preference for nutritional supplementation and revealed that he was known to be a firm advocate of regular high-dose vitamin C therapy (in the order of several grams per day). Numerous empty packages of a proprietary vitamin C-containing preparation (whose listed contents included both ascorbic acid and magnesium ascorbate) had been found at his home after his death. It appeared that he had consumed vast additional amounts of vitamin C supplement in the period leading up to his death. With this additional information, a plausible clinical picture emerged.

DISCUSSION

The development of renal failure in association with use of high-dose vitamin C has been described previously but only one other case fatality has been reported (9-15).

Vitamin C is metabolised to oxalate and deposition of oxalate in the kidney is a recognised cause of acute renal failure. Some variability has been demonstrated in the development of vitamin C-associated oxaluria and/or nephrolithiasis but nonetheless caution has been advised in the use of high-dose supplementation or therapy (16,17). While there is little information available regarding the outcome from ascorbic acid induced oxalosis and acute renal failure, renal failure associated with primary hyperoxaluria can be effectively managed medically and carries a reasonable prognosis (18). Although not disclosed by the patient, his reported healthcare preferences and the numerous empty containers of vitamin C-containing supplements support the premise that he had consumed exceedingly high-dose vitamin C in his final few days. His regular gram-sized maintenance dosage may well have been augmented by increased consumption in response to the non-specific symptoms that he had described as a prodrome to his hospital presentation. In addition it is possible that dehydration had contributed to the extensive intrarenal crystallisation of oxalate salts and resulting acute renal failure. Regardless, the presence of oxalate deposition seen in his kidneys at autopsy supports the theory that excessive amounts of vitamin C had provoked his problems.

Although it may frequently be unintentional, many patients who use complementary and alternative medications fail to disclose their usage of such remedies to medical practitioners (17,19-21). In this case, non-disclosure removed any possibility of identifying the relationship between the acute renal failure and vitamin C toxicity. It also precluded a fully informed discussion regarding the anticipated reversibility of oxalate-associated nephropathy and the expected life-preserving role of short-term renal replacement therapy. The patient was described as having been widely read in the area of nutritional supplementation. However it cannot be known if he was aware of the potential toxicity of vitamin C. The physician-patient relationship imposes duties and obligations on both parties, and non-disclosure by a patient, whether involuntary or not, can adversely affect the quality of care that is provided (22,23).

The relevant New Zealand legislation requires that a patient's competence must be assumed unless there are reasonable grounds to believe otherwise (24). This is encompassed within the Code of Health and Disability Services Consumers' Rights which stipulates the patient's right to autonomy (25). Every patient has the right to decline any treatment, but this patient's interim refusal presented a challenge. He had indicated that he wished to deliberate further, but he proved unable to deliver his ultimate decision. The significant implications of his deliberative delay were clearly spelt out to him and he was prepared to accept the associated risks, including death.

Strong consideration was given to temporarily over-riding the patient's interim decision to refuse dialysis on the grounds that his severe uraemia, which can be associated with delirium and acute dementia, may have sufficiently impaired his decision-making faculties and negated the validity of his response (26,27). During this deliberation, the family's additional perspective became available to confirm that a decision to forgo 'conventional' medical intervention was entirely in keeping with his expected response. This allayed any lingering doubts that his 'executive function' was significantly impaired. Accordingly, his wishes were complied with and no dialysis or invasive mechanical ventilation therapies were instituted.

At the time of death, the aetiology of his acute renal failure was unclear. The findings at the coronial post-mortem examination came as a surprise to the clinical team. It was only while communicating the autopsy result to his family that the extreme nature of his vitamin C usage became clear. The autopsy results were entirely compatible with the cause of death being acute renal failure secondary to the nephrotoxic effects of high-dose vitamin C therapy. No other relevant findings were discovered. Had the oxalosis not been revealed by post-mortem histology, additional information would not have been sought from the family and the cause of renal failure would have remained speculative. Even though highly selected, the autopsy still has an important role to play in intensive care medicine (28,29).

CONCLUSION

Ingestion of high-dose vitamin C can result in acute renal failure secondary to renal oxalate deposition. Due to an unusual and complex set of circumstances, this has resulted in a case fatality whose occult cause was only elucidated using additional information gathered at autopsy. The physician-patient relationship imposes mutual obligations, and on this occasion it is likely that patient non-disclosure had an adverse impact on the outcome. That notwithstanding, it remains the prerogative of every competent patient to decline any treatments, including those that can be life-saving.

Accepted for publication on April 30, 2008.

REFERENCES

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G. J. MCHUGH *, M. L. GRABER [[dagger]], R. C. FREEBAIRN [[double dagger]]

Intensive Care Unit, Palmerston North Hospital, Palmerston North, New Zealand

* M.B., Ch.B., F.A.N.Z.C.A., E.D.I.C., Medical Head, Intensive Care.

[[dagger]] M.B., B.S., M.R.C.P (U.K.), Locum Nephrologist, Department of Renal Medicine.

[[double dagger]] M.B., Ch.B., F.A.N.Z.C.A., F.J.F.I.C.M., Medical Director, Intensive Care Services, Hawkes' Bay Hospital, Hastings.

Address for reprints: Dr G. McHugh, Medical Head, Intensive Care, Palmerston North Hospital, Private Bag 11036, Palmerston North, New Zealand.
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Author:McHugh, G.J.; Graber, M.L.; Freebairn, R.C.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8NEWZ
Date:Jul 1, 2008
Words:2847
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