Effect of low-molecular-weight heparin on serum concentrations of potassium

THE LANCET

Mania SIR—In an otherwise outstanding review of our current understanding of all aspects of mania (April 19, p 1157),1 Ian Daly suggests that “lithium remains the treatment of choice in mania” and that “there is not enough evidence to advocate the more widespread use of anticonvulsants as first-line agents”. I feel that these statements underestimate the quantity and quality of the data in favour of the use of sodium valproate in bipolar disorder. Sodium valproate has been demonstrated in two double-blind, placebo-controlled studies to be at least as effective as lithium in the treatment of acute mania.2,3 In the second study (of 179 patients at nine centres), lithium was no better than placebo in the treatment of patients with mixed mania (a group that accounts for 40–50% of all hospitalised manic patients) or rapid cycling bipolar disorder, whereas sodium valproate was highly effective for both groups. The two treatments were equally effective in the treatment of classic so-called euphoric mania. In both studies, use of sodium valproate was associated with fewer adverse effects and a lower rate of treatment discontinuation than use of lithium. Several open and chart-review studies also suggest that sodium valproate is more effective than lithium in patients with comorbid substance abuse, neurological or electroencephalographic abnormalities, and secondary mania. In addition to the equal or greater efficacy of sodium valproate, it is also associated with significantly shorter lengths of stay than lithium,4 probably because its higher tolerability allows the use of aggressive loading strategies to produce therapeutic blood concentrations within 24 h. This results in major cost savings (of the order of $4000–6000 per year) when compared with the use of lithium. With respect to prophylaxis, one 18month, open, follow-up study showed equal efficacy for lithium and valproate but significantly higher patient satisfaction with valproate.5 Preliminary analysis of unpublished data from a large, 12-month, randomised, doubleblind, multicentre study seems to confirm this finding (C Bowden, personal communication). Thus, the evidence clearly shows that sodium valproate is as effective as lithium in classic euphoric mania, more effective than lithium in most other types of mania, results in shorter lengths of hospital stay, is better tolerated, and is probably at least as effective as lithium in prophylaxis. These data are reflected in four recently published treatment algorithms and expert consensus guidelines, all of

292

which recommend sodium valproate or lithium as first-line treatment in euphoric mania, and sodium valproate alone as the agent of choice in patients with mixed mania, rapid cycling, comorbid substance abuse, or associated neurological abnormalities. James G Longhurst Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06519, USA

1 2

3

4

5

Daly I. Mania. Lancet 1997; 349: 1157–60. Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A double-blind comparison of valproate, lithium in the treatment of acute mania. Am J Psychiatry 1992; 149: 108–11. Bowden CL, Brugger AM, Swann AC, et al, for the Depakote Mania Study Group. Efficacy of divalproex versus lithium, placebo in the treatment of mania. JAMA 1994; 271: 918–24. Frye MA, Altshuler MD, Szuba MP, Finch NN, Mintz J. The relationship between antimanic agent for treatment of classic or dysphoric mania and length of hospital stay. J Clin Psychiatry 1996; 57: 17–21. Lambert PA, Venaud D. Etude comparative du valpromide versus lithium dans la prophylaxie des troubles thymiques. Nervure 1992; 9: 1–9.

Author’s reply SIR—The recent paper by A Swann and colleagues1 firmly clarifies and extends the tentative conclusions from earlier, mostly uncontrolled trials, which indicated that valproate may be of particular benefit in the treatment of mixed manic states. These findings are clear and impressive and will continue to appropriately influence treatment guidelines. Interesting questions remain. Will controlled trials establish the superiority of valproate over and above the other anticonvulsants used in this disorder? Is observed heterogeneity in presentation with seemingly differential drug treatment response restricted to acute episodes, or will it persist during prophylaxis? Despite these findings, inasmuch as lithium is the standard thymoleptic agent with proven benefit in both acute treatment and prophylaxis, the results from adequate controlled trials of valproate versus lithium are as follows. First, two controlled trials, one small in number, the other a large multicentre trial, have established similar efficacy for the two agents in the treatment of acute mania.2,3 Second, no study has yet been published comparing valproate with lithium in prophylaxis. In these circumstances, there is simply insufficient evidence to recommend valproate as the drug of first choice in the treatment of manic states, or to recommend its routine use in prophylaxis. Ian Daly Clondalkin Mental Health Service, Eastern Health Board, Unit 1A, Clondalkin, Dublin 22, Ireland

1

2

3

Swann AC, Bowden CL, Morris D, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 1997; 54: 37–42. Freeman TW, Clothier JL, Pazzaglia P, et al. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992; 149: 108–11. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex versus lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 1994; 271: 918–24.

Effect of low-molecularweight heparin on serum concentrations of potassium SIR—Corina Canova and colleagues (May 17, p 1447)1 report a significant rise in serum concentrations of potassium in 81 patients receiving lowdose, low-molecular-weight heparin. The highest rise (from 5·11 to 5·70 mmol/L) occurred in a patient in a subgroup with renal failure (creatinine clearance 10–49 mL/min). On the basis of their observations, the investigators recommend that “potassium should be monitored during the administration of low-molecular-weight heparin at least in patients with concentrations greater than 5 mmol/L”. The following case suggests that this advice may be inadequate. An 86-year-old woman sustained a fractured tibia and required hospital admission. On admission, subcutaneous enoxaparin 20 mg daily was started as treatment against thromboembolic disease. Baseline biochemical values were: sodium 143 mmol/L, potassium 4·3 mmol/L, urea 21·7 mmol/L, and creatinine 179 µmol/L. She had a history of chronic pyelonephritis, and creatinine clearance was reduced at 18 mL/min. She did not have diabetes and her only medication that could potentially affect serum concentrations of potassium was salbutamol 400 µg daily via an inhaler device. Her mobility remained poor and required continuation of enoxaparin. 35 days after admission, measurement of urea and electrolytes was repeated: sodium 139 mmol/L, potassium 6·1 mmol/L, urea 16·7 mmol/L, and creatinine 202 µmol/L. A repeat sample confirmed significant hyperkalaemia (6·7 mmol/L), and T-wave changes were evident on the electrocardiogram. She was promptly treated with intravenous insulin and dextrose. She then required calcium polysterene sulphonate to maintain a serum concentration of potassium below 5 mmol/L until her mobility improved and enoxaparin could be withdrawn (58 days after admission). After 6 weeks on enoxaparin, her serum concentration of

Vol 350 • July 26, 1997

THE LANCET

aldosterone and plasma renin activity (PRA) were 646 pmol/L and 2·0 ng mL⫺1 h⫺1, respectively (measured after 12 h in supine position). 4 days after enoxaparin had been discontinued, her serum concentration of aldosterone had increased to 747 pmol/L and PRA had decreased to 0·8 ng mL⫺1 h⫺1. This patient was subsequently discharged, but was readmitted 2 weeks later because of pneumonia and dehydration. Although her initial response to therapy was good, she remained immobile; after 10 days it was decided that low-dose enoxaparin was warranted. Her mean serum concentration of potassium during the week before administration of enoxaparin was 4·85 mmol/L. 2 days after rechallenge with enoxaparin serum potassium rose to 5·4 mmol/L and remained above 5 mmol/L until treatment with calcium polysterene sulphonate was started 3 days later. Her serum concentration of aldosterone before enoxaparin was 611 pmol/L and PRA was <0·2 ng mL⫺1 h⫺1. After 9 days of enoxaparin therapy, serum aldosterone remained similar (615 pmol/L) but PRA increased (1·5 ng mL⫺1 h⫺1). This case shows that low-dose, lowmolecular-weight heparin can cause clinically important hyperkalaemia even when the baseline serum concentration of potassium is well below 5 mmol/L. Heparin-induced hyperkalaemia is most likely in patients with chronic renal failure or diabetes, or during concomitant administration of drugs which affect potassium balance, such as angiotensin-converting-enzyme inhibitors.2 Previous reports indicate that low-dose unfractionated heparin has resulted in serum concentrations of potassium of more than 6 mmol/L in patients with one or more of the above risk factors.3–5 We suggest that serum potassium should be monitored in all patients during treatment with lowdose heparin, either unfractionated or of low molecular weight, particularly in those at risk of hyperkalaemia, irrespective of the initial potassium concentration. *M I Wiggam, T R O Beringer Department of Health Care for the Elderly, Royal Victoria Hospital, Belfast BT12 6BA, UK

1

2

3

4

5

Canova CR, Fischler MP, Reinhart WH. Effect of low-molecular-weight heparin on serum potassium. Lancet 1997; 349: 1447–48. Oster JR, Singer I, Fishman LM. Heparininduced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575–86. Edes TE, Sunderajan EV. Heparin-induced hyperkalemia. Arch Intern Med 1985; 145: 1070–72. Busch EH, Ventura HO, Lavie CJ. Heparininduced hyperkalemia. South Med J 1987; 80: 1450–51. Edes TE. Heparin-induced hyperkalemia. Postgrad Med 1990; 87: 104–05.

Vol 350 • July 26, 1997

Relation between endothelial-cell activation and infection, inflammation, and infarction SIR—Patrick Vallance and colleagues (May 10, p 1391)1 postulate that acute infection or inflammation increased the risk of acute cardiovascular events by causing endothelial-cell dysfunction. The changes they describe, however, are recognised as those of endothelialcell activation. Pober2 described how stimulation of the endothelium by certain agents such as interleukin-1 resulted in a series of changes to the endothelium allowing it to participate in the inflammatory response. To emphasise that this process did not represent sublethal injury with consequent dysfunction, Pober used the term endothelial-cell activation (ECA) to describe these events, which has now become widely accepted. ECA can be induced by a wide range of agents, for example, certain bacteria, viruses, and cytokines such as interleukin-1 and tumour necrosis factor, physical and oxidative stress, oxidised low density lipoproteins, immune complexes, and B and T cell activation. It may have a central pathophysiological role in many conditions including atherosclerosis, diabetes, the systemic inflammatory response syndrome, ischaemia/ reperfusion injury, transplant rejection, and the vasculitides. The five core changes of ECA are: loss of vascular integrity; expression of leucocyte adhesion molecules;3 change in phenotype from antithrombotic to prothrombotic; cytokine production; and upregulation of HLA molecules. There are two stages of ECA. The first, endothelial-cell stimulation, or ECA type I, does not require de novo protein synthesis of gene upregulation and occurs in seconds. Effects include the retraction of endothelial cell from one another, expression of P-selectin, and release of von Willebrand factor. The second response, ECA type II, requires hours for the stimulating agent to cause an effect through gene transcription and then protein synthesis. The genes include those for E-selectin, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, proinflammatory cytokines including interleukin-6 (thus potentially regulating the acute phase response), and inducible nitric oxide synthetase. We agree with Vallance and colleagues that clinical studies in defined groups of patients are required to test the hypothesis that ECA due to acute infection or inflammation may be a risk factor for cardiovascular disease. As yet the story is incomplete, since

some mechanisms of ECA have only been observed in vitro or in animal models. The diverse effects of ECA have been shown to share a common intracellular control mechanism through the activation of the transcription factor nuclear factor ␬B(NF-␬B). Some of the antiinflammatory effects of glucocorticoids4 and aspirin,5 the same agents that Vallance et al say give protection against temporary ECA, have been shown to act through the inhibition of NF-␬B. As a transcriptional activator of the genes of ECA, NF-␬B itself is an ideal target. Fundamental approaches to switching off NF-␬B are being explored. *Beverley J Hunt, Karen M Jurd Department of Haematology, St Thomas’ Hospital, London SE1 7EH, UK

1

2

3

4 5

Vallance P, Collier J, Bhagat K. Infection, inflammation and infarction: does acute endothelial cell dysfunction provide a link? Lancet 1997; 349: 1391–92. Pober JS. Cytokine-mediated activation of vascular endothelium. Am J Pathol 1988; 133: 426–33. Adams DH, Shaw S. Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet 1994; 343: 831–36. Marx J. How the glucocorticoids suppress immunity. Science 1995; 270: 232–33. Kopp E, Ghosh S. Inhibition of NF-␬B by sodium salicylate and aspirin. Science 1994; 265: 956–59.

SIR—Patrick Vallance and colleagues 1 suggest a link between the clinical symptoms of cardiovascular disease, such as angina, and endothelial-cell dysfunction, focusing on the loss of control of vasodilation mediated by substances such as nitric oxide. They briefly ask how might inflammation or infection alter the risk associated with atheroma, including the alteration of clotting factors such as fibrinogen. We believe that the alternative aspect of the physiology of the endothelium—ie, its role in thrombosis and haemostasis—is of equal, if not greater, importance. In addition to its vasomotor function, the endothelial cell is important in the regulation of blood clotting, for example, the production of prostacyclin, coagulation factor V, tissue plasminogen activator, and von Willebrand factor. Furthermore, the endothelial cell membrane component, thrombomodulin, affects the biology of thrombin and the anticoagulant protein C.2 In addition to fibrinogen, some endothelial products have prognostic value in cardiovascular disease and stroke. Epidemiological studies indicate that increased concentrations of tissue plasminogen activator and von Willebrand factor both predict adverse cardiovascular

293