Effects of nicotinic acid upon post-burn oedema: a preliminary report of clinical trials

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Burns, 2, 152-157

Effects of nicotinic acid upon post-burn oedema: a preliminary report of clinical trials C. H. Wells, J. G. Hilton, D. L. Larson and D. F. Sloan Shriners Burns Institute and Departments of Physiology and Biophysics, Pharmacology and Toxicology, and Surgery, University of Texas Medical Branch, Galveston Summary Experimental animal studies indicate that administration of nicotinic acid effectively minimizes plasma extravasation associated with thermal injury. Nicotinic acid was administered to 17 patients with average body surface burns of 52 per cent. This therapy was begun within 10 hours of injury, in a dose of 2-3.6 g/day over the first 2 days, followed by declining dosage rates throughout the final 24-hour treatment period. Oedema formation in these patients was minimal. Only one developed sufficient oedema to require escharotomy. Total fluid requirements in the first 24 hours after initiation of this therapy averaged 2.0 ml/kg for each per cent of the body surface area burned. This modest fluid requirement appeared adequate to meet the patients' needs. Mean arterial blood pressure was 134/88i6/5 on the first day of treatment, 119/77-[-6/4 on the second day, and 120/75 ±6/3 on the third day of treatment. Mean heart rates of 98 i 6,113 ± 6, and 118 ± 6 were observed on the first 3 treatment days respectively. An average urinary output of 72 ml/hour was obtained on the first day, 83 ml/hour on the second day and 118 ml/hour on the third day. Seven of these patients died 5-40 days following cessation of the nicotinic acid therapy. These patients were burned over an average of 74± 6 per cent of their surface area (61 ±7 per cent thirddegree). Small scattered foci of renal papillary necrosis were observed in 2 patients and medullary interstitial nephritis in a third. This complication, if attributable to nicotinic acid therapy, constitutes the only serious adverse reaction observed. Subsequent animal experiments suggest that this pathology may be minimized by the administration of mannitol. The last 7 patients in these trials received mannitol (30 mg/kg bodyweight/hour) throughout the period of nicotinic acid

administration. No further clinical or histopathological evidence of renal papillary necrosis was seen.

INTRODUCTION THB CONTROL of oedema in the first few days following extensive thermal injury is widely recognized as desirable although difficult to achieve. Most fluid replacement r6gimes recommended for use with thermal injury (Cope and Moore, 1947; Evans et al., 1952; Baxter, 1974) are accompanied by substantial oedema formation both in injured and uninjured tissues. Serum albumin and other high-molecular-weight plasma expanders are often used (Evans et al., 1952; Sorensen, 1968; Larson and Wells, 1975) but have not successfully prevented oedema formation in the early phases of burn therapy. Hypertonic saline (Monafo, 1970) has also been used for fluid resuscitation in hopes of controlling oedema. This fluid replacement r6gime successfully diminishes oedema formation but is frequently associated with hypernatraemia and elevations in serum osmolality. Studies of tissue inflammation and oedema formation secondary to thermal or chemical injury have revealed that vasoactive substances, particularly prostaglandins, are involved in various phases of the inflammatory process (Spector and Willoughby, 1959a; Wilhelm and Mason, 1960; Baxter et al., 1963; Arturson et al., 1973). Recent studies have shown nicotinic acid to be effective in minimizing plasma losses in experimental animals in the early post-burn phase (Hilton and Wells, 1976a, b). It is presumed

Wel[s et al. ! Nicotinic Acid and Oedema Formation

that this agent acts through interference with prostaglandin synthesis. In order to evaluate the effectiveness of nicotinic acid in controlling the oedema of thermal injury, the agent was administered to 17 burned adults throughout the first 3 days following injury. These patients had an average burn of 52 per cent of their body surface, with 29 per cent third-degree. All were admitted within 10 hours of injury. All received substantial quantities of resuscitative fluid in the period between injury and hospital admission and had clinically evident oedema upon admission. Treatment with nicotinic acid was begun promptly after admission at a rate of 2-3'5 g/day by continuous intravenous drip. Intravenous fluids were administered as deemed necessary by the patient's clinical course. With the exception of nicotinic acid administration, all patients were treated by the techniques routinely employed in this unit. Ten of the 17 patients survived. The 7 patients who died were burned over an average of 744-6 per cent of their surface area (614-7 per cent third-degree). N o deaths occurred during nicotinic acid treatment or within 5 days of its cessation. Five deaths resulted from sepsis and 1 from a coronary occlusion during the sixth week of the patient's hospital course.

RESULTS A N D D I S C U S S I O N Prior experimental animal studies suggest that accelerated rates of plasma loss observed after some forms of trauma, including thermal injury, are mediated in large measure by various vasoactive substances, particularly prostaglandins (Spector and Willoughby, 1959b; Rocha e Silva and Rosenthal, 1961; Angg/ird and Jonsson, 1970; Kaley and Weiner, 1971; Williams and Morley, 1973; Arturson and Jonsson, 1973). Nicotinic acid has been shown to minimize plasma losses of experimental animals with burns when administered before, or within the first few hours after injury (Hilton and Wells, 1976a, b). While there is little evidence to indicate the means by which this suppression of plasma loss is produced, it has been suggested to be a consequence of nicotinic acid suppression of prostaglandin synthesis. Nicotinic acid inhibits norepinephrineinduced lipolysis (Carlson and Or6, 1962), thereby restricting the availability of substrate (serum-free fatty acid) for prostaglandin synthesis. Nicotinic acid may also facilitate prostaglandin degradation. Nicotinamide adenine dinucleotide (NAD) requires nicotinic acid for its synthesis. N A D is a necessary co-factor for degradation of

1 53

prostaglandins by 15-hydroxydehydrogenase (Angg~ird et al., 1969; Samuelsson et al., 1971). The clinical trials reported here support the conclusions of experimental animal studies concerning nicotinic acid effects upon fluid shifts. In the early post-burn period, patients treated with nicotinic acid developed minimal oedema either in injured or uninjured tissues. The degree of oedema in a typical patient 24 hours after injury may be seen in Fig. 1. This patient suffered third-degree flame injury over 90 per cent of his surface area. Despite this injury, he developed[ minimal oedema, required no escharotomies, remained alert and co-operative, and maintained[ good oral fluid and food intake. All patients who took part in these clinical trials appeared to respond to this therapy. Inhibition of oedema was most marked in uncomplicated second-degree injury and least evident in patients with extensive concurrent contusion or crush injury. The total 24-hour fluid intake of these 17 patients averaged 2.8:k0.3ml/kg body-weight for each 1 per cent surface area burn in the first 24 hours after injury, much of which resulted from vigorous fluid resuscitation before hospital admission. An average of 2 ± 0 . 2 ml/kg for each 1 per cent surface area burn was administered in the first 24 hours of nicotinic acid therapy followed by 2.4:t:0.3 ml/kg body-weight for each 1 per cent surface area burn on the second day of nicotinic acid therapy. Throughout the period of nicotinic acid administration, oral intake comprised a major portion of the patients' fluid administration. Nicotinic acid administration. rates were gradually reduced to zero over the next 24 hours. While fluid administration was less than that generally recommended for an injury of this nature, there was little evidence that it was insufficient to meet the patients' needs (Table I). The average blood pressure of these patients remained at acceptable levels throughout the period of nicotinic acid administration. Mean pulse rate, while slightly higher than that expected[ for uninjured individuals, was approximately that seen in routinely treated patients. N o evidence of hypovolaemic tachycardia was seem Venous haematocrits remained slightly elevated[ throughout the period of nicotinic acid adminis-. tration. The maintenance of good renal function in these patients also suggests an adequate plasma volume. Glomerular filtration rates were measured[ in 10 of these 17 patients. The mean of these values on each of the first 4 days following injury is presented in Table I (creatinine clearance). These clearance values are substantially greater

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Fig. 1. The degree of oedema in a typical patient in the first 24 hours after injury. than those typically observed by us in patients with injury of this magnitude following routine therapy. Urine production (Table I) was also substantially greater than that typically seen in the burn victim. The average blood urea nitrogen levels of these individuals also remained within normal limits. The lack of an appreciable rise in blood urea nitrogen following nicotinic acid administration was unexpected. The maintenance of a stable blood urea nitrogen level depends not only upon adequate urea excretion and consequently upon adequate renal function, but also upon the rate of urea synthesis. Nicotinic acid

has been shown to increase urea synthesis (Trout et al., 1967), particularly in starved animals. The blockade of norepinephrine-induced lipolysis by nicotinic acid appears to facilitate use of alternate energy sources. For this reason urea production from increased protein catabolism could be expected. Although blood urea nitrogen levels were higher on the second and third than on the first day of treatment, this elevation was slight and offered little indication of substantially increased protein catabolism. A suggestion that capillary permeability, while increased above normal, was less than generally

Wells et al. : Nicotinic Acid and Oedema Formation Table I.

~:,; , . ,

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Summary of clinical data First 24hr after injury

Arterial blood pressure Heart rate Haematocrit Fluid volume given (ml/kg ×% burn) Glomerular filtration rate (ml/min) Blood urea nitrogen Serum K Urine production (ml/hr) Serum albumin Albumin administered (g/day)

137/86 4- 9/4 96 ± 4 51 ± 2

First 24hr of treatment

Time after burn Day 2

Day 3

Day 4

134/88-4-6/5 984-6 51 ± 2

119/77 ,-l-6/4 1134-6 52 4-2

120/754-6/3 118±6 47~1

137/75±714 1184-4 40±2

2"9 4- 0.3

2-1 Z: 0'3

15.1 4- 1.3 4-4 4- 0"2

84.7±12.7 15 4- 1"3 4"44- 0"2

88 ml 64.2 4- 9.1

0-2

1"64- 0'2

94.1 ± 1 4 . 9 18'34- 1"7 5 4- 0-2

92.1 ± 1 5 . 5 19 4- 3"1 4"84- 0'2

100"2±11.1 19"44- 4.1 4"64- 0'3

72ml 3.3 4- 0.2

83ml 3.2 4- 0.2

118ml 2.7 ± 0'1

121 ml 2"6 Z: 0"2

51 "5 -4- 9.4

44-4 4- 6-6

observed in patients with this degree of injury can be obtained from consideration of serum albumin levels and albumin administration rates. While many institutions do not use albumin during the first 24 hours after injury, it is routinely administered in our institution at the rate of 12.5 g/1 (1.25 per cent solution) of resuscitation fluid throughout the first few days of intravenous fluid administration. Fluid resuscitation in this unit is conducted at a daily rate of approximately 3 ml/kg body-weight for every 1 per cent of the body surface burned. It may thus be seen that these patients (approximately 70 kg body-weight, 52 per cent burn) would normally receive nearly 140 g of albumin on each of the first few postburn days. This rate of albumin administration typically maintains serum albumin levels between 2 and 2.2 g per cent. The substantially higher serum albumin levels (Table I) observed in patients treated with nicotinic acid, in association with lower albumin administration rates (Table I), may well suggest a lower capillary permeability in these than in routinely treated burn patients. Our experiences with this therapy have revealed no consistent complications. However, a small focus of papillary necrosis was found in a renal papilla of each of two patients. Small areas of diffuse medullary interstitial nephritis were observed in a third patient. While these lesions involved a minute fraction of the papillary tissue of these patients, they were a disturbing finding. Papillary necrosis is not, in our experience, a common consequence of thermal injury. It should be emphasized that the renal papillary lesions observed were minimal and were only identified after unusually careful scrutiny. All papillae had, upon routine autopsy, been reported

2'5~

0"3

1"84-

27.3 ±

4'7

18-4 4- 3-6

to be normal. The lesions were found upon later, careful examination. Despite the uncertainty of attributing these scattered foci of papillary necrosis to nicotinic acid therapy, some thoughts about the possible pathophysiology of the lesions and means of avoiding them have been considered. Nicotinic acid is a thoroughly studied compound that has not, to our knowledge, been previously associated with renal papillary necrosis. Nevertheless, there is reason to suspect that this compound, if acting as an inhibitor of prostaglandin synthesis, might be responsible for such a lesion. Several antipyretic analgesics which are prostaglandin synthetase inhibitors have been shown to produce similar lesions (Gault et al., 1968; Nanra et al., 1973). Prostaglandin synthesis in the renal medulla appears necessary to maintain adequate renal blood flow and to prevent ischaemic tissue necrosis during hypotensive states (McGiff and Itskovitz, 1973; Zins, 1975). Reports of studies utilizing prolonged nicotinic acid administration in high doses (8-10g/day) to schizophrenics (Denson, 1962; Hoffer, 1962; Gallent et al., 1966; Mosher, 1970), in which papillary necrosis was apparently not observed, suggest that this lesion, if attributable to nicotinic acid, must be of a hypoxic rather than toxic nature. The requisite renal papillary hypoxia might develop from the combined effects of stress-induced reductions in blood flow to this tissue and nicotinic acid suppression of renal medullary prostaglandin synthesis. There remains, however, serious doubt that mechanisms of this sort can produce papillary necrosis in man within the relatively brief (3-day maximum) duration of nicotinic acid therapy following burns. T e n to

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twenty weeks are required for the production of such lesions in experimental animals (Nanra et al., 1973). Despite reservations concerning the role of nicotinic acid in the production of these lesions, possible means of preventing ischaemic papillary necrosis have been explored. Studies of renal medullary blood flow viewed cinephotomicrographically in papilla of nicotinic acid treated and untreated immature hamsters indicate mannitol is an effective means of minimizing these post-trauma changes (Hayashi, 1975). Additional studies conducted in our laboratories of renal papillary Poz of normal dogs and dogs with haemorrhagic hypotension with and without nicotinic acid, also indicate that mannitol is an effective means of minimizingchanges in papillary Po~. As a result of these studies, the last 7 patients in this series were given mannitol (0'03 g/kg/hour) intravenously throughout the period of nicotinic acid administration. No further evidence of papillary necrosis has been observed. The osmotic effect of the dose of mannitol administered to these patients was sufficient to account for the solute of approximately 40 ml of urine an hour in a concentration of 300 mosmol/l. The higher urine osmolalities typically observed in patients after severe injury proportionately reduce this urine volume. The dose of mannitol is, therefore, sufficient to have a noticeable effect on urine production but could not be totally responsible for the high urinary output. Throughout the first 2 days of nicotinic acid administration the mean urine production rate of patients without concurrent mannitol administration was 574-7 ml/hour. Those with concurrent mannitol administration produced an average of 107 :/: 18 ml/hour. While the urine production rate of patients treated with nicotinic acid and mannitol was indeed greater than that of those receiving nicotinic acid alone, urine output of both groups was substantially greater than would be expected in individuals receiving traditional therapies. The experiences gained in these initial clinical trials suggest that nicotinic acid therapy of the acute phase of thermal injury effectively minimizes oedema formation. It appears to be a promising addition to the care of the burned patient.

REFERENCES

ANGG)~J~D E. and JONSS0N C-E. (1970) Effiux of prostaglandins in lymph from scalded tissue. Acta PhysioL Scand. 81, 440.

Burns Vol. 2/No. 3

ANGG.;~RDE., MATSCHINSKYR. M. and SAMUELSSONB. (1969) Prostaglandins: enzymatic analysis. Science 163, 479. ARTURSONG., HAMBERCM. and JONSSONC-E. (1973) Prostaglandins in human burn blister fluid. Acta PhysioL Scand. 87, 270. ARTURSON G. and JONSSON C-E. (1973) Effects of indomethacin on the transcapillary leakage of macromolecules and the efflux of prostaglandins in the paw lymph following experimental scalding injury. Ups. £ Med. ScL 78, 181. BAXTER C. R. (1974) Fluid volume and electrolyte changes of the early post-burn period. Clin. Plast. Surg. 1, 693. BAXTERC. R., CRENSHAWC. A., NASCHKEM. D. and SHIRES G. T. (1963) Excretion of serotonin metabolites following thermal injury. Surg. Forum 14, 61. CARLSONL. and OR6 L. (1962) The effect of nicotinic acid on the plasma-free fatty acids demonstration of a metabolic type of sympathicolysis. Acta Med. Scand. 172, 641. COPE O. and MOOREF. D. (1947) The redistribution of body water and the fluid therapy of the burned patient. Ann. Surg. 126, 1010. DENSON R. (1962) Nicotinamide in the treatment of schizophrenia. Dis. Nerv. Syst. 23, 167. EVANS E. I., PUNNELL, O. J., ROBINETT P. W., BATC~ELOR A. and MARTIN M. (1952) Fluid and electrolyte requirements in severe burns. Ann. Surg. 135, 804. GALLENTM., BISHOPM. and STEELEC. (1966) DPN (NAD oxidized form): A preliminary evaluation in chronic schizophrenic patients. Ann. Ther. Resid. 8, 542. GAULT M. H., RUDWALT. C., ENGLES W. D. and DOSSETOR J. B. (1968) Syndrome associated with abuse of analgesics. Ann. Intern. Med. 68, 906. HAYASm M. (1975) Personal communication. HILTONJ. G. and WELLSC. H. (1976a) Nicotinic acid reduction of plasma volume loss following thermal injury. Science (In press). HILTON J. G. and WELLS C. H. (1976b) Effects of nicotinic acid post-burn upon plasma volume loss. Surg. Gynecol. Obstet. (In press). HOFFER A. (1962) Niacin Therapy in Psychiatry. Springfield, II1., Thomas. KALEYG. and WEINERR. (1971) Prostaglandin El: A potential mediator of the inflammatory response. Ann. N. Y. Acad. Sci. 180, 338. LARSON D. L. and WELLS C. H. (1975) Plasma protein shifts in thermal injury. In: Proceedings o f the National Institute o f Health Workshop on Albumin. Bethesda, Maryland, National Institute of

Health, p. 221. McGIFF J. C. and ITSKOVITZH. D. (1973) Prostaglandins and the kidney. Circulation Res. 33, 479. MONAFOW. W. (1970) The treatment of burn shock by intravenous and oral administration of hypertonic lactated saline solution, d. Trauma 10, 575.

Wells et al. : Nicotinic Acid and Oedema Formation

MOSHER L. R. (1970) Nicotinic acid side effects and toxicity: a review. Am. J. Psychiatry 126, 124. NANRA R. S., CHIRAWONG P a n d KINCAID-SMITH P.

(1973) Medullary ischaemia in experimental analgesic nephropathy--the pathogenesis of renal papillary necrosis. N.Z. Med. J. 3, 580. ROCHA E SILVA M. and ROSENTHAL S. R. (1961) Release of pharmacologically active substances from the rat skin in vivo following thermal injury. J. PharmacoL Exp. Ther. 132, 110. SAMUELSSON B., GRANSTR6M E., GREEN K. and HAMBERGM. (1971) Metabolism of prostaglandins. Ann. N. Y. Acad. ScL 80, 138. SORENSEN B. (1968) Saline solutions and dextran solutions in the treatment of burn shock. Ann. N. 1i. Acad. Sci. 150, 865. SPECTOR W. G. and WILLOUCHBYD. A. (1959a) The demonstration of the role of mediators in turpentine

157

pleurisy in rats by experimental suppression of the inflammatory changes. J. Pathol. 77, 1. SPECTOR W. G. and WILLOUGHBY D. A. (1959b) Experimental suppression of the acute inflammatory changes of thermal injury. J. PathoL 78, 121. TROUT D. L., BITTERH. L. and LACKEYW. W. (1967) Effects of nicotinic acid on the choice of substrates utilized during fasting. Bioehem. Pharmacol. 16, 971. WILHELM D. L. and MASON B. (1960) Vascular permeability changes in inflammation: the role of endogenous permeability factors in mild thermal injury. Br. J. Exp. PathoL 41, 487. WILLIAMS T. J. and MORLEYJ. (1973) Prostaglandins as potentiators of increased vascular permeability in inflammation. Nature (Lond.) 246, 215. ZINS G. (1975) Renal prostaglandins. Am. J. Med. 58, 14.

Requests/'or reprints should be addressed to: Dr C. H. Wells, Shriners Burns Institute, Galveston Unit, Galveston, Texas 77550, USA.