Carvedilol for heart failure, with care

these patients included fentanyl 50 )JLg/kg plus 60 )JLg/kg hourly. This dose of opioid inhibits the endocrine response to pelvic surgery, and to cardiac surgery until bypass,’ and

Aminoacid infusions to prevent post-

operative hypothermia Body temperature falls customarily during anaesthesia and surgery because heat is lost to the environment and the threshold to initiate heat conservation is reduced, although physiological responses are as active as normal when triggered. After surgery patients are uncomfortable when cold, and they shiver at a time when oxygen supply may not match demand. Adverse effects of hypothermia (core are ascribed to coagulation, drug temperature <35°C) and action, metabolism, healing.’1 There is a myriad of heaters, condensers, insulators, convectors, and reflectors for preventing body temperature from falling during anaesthesia. By contrast, few drugs are used primarily to affect temperature. Aspirin and paracetamol are antipyretics, and dantrolene is effective in controlling malignant hyperpyrexia. To these, aminoacid infusion has been proposed as treatment for preventing

postoperative hypothermia. All nutrients raise resting energy expenditure and the rise caused by glucose and aminoacids is additive, which suggests separate underlying mechanisms.2 The thermic effect of aminoacids is high and may account for 30-40% of the energy infused.3 In a series of studies at the Karolinska Hospital, nutrients given orally and a mixture of 19 aminoacids given intravenously at 240 kJ/ h (Vamin, 18 g nitrogen per litre, 126 mL/h, Pharmacia, Stockholm) increased pulmonary oxygen uptake and cardiac output, and raised mixed venous temperatures by 02° to 0-7°C. Aminoacid infusion during abdominal surgery under Nz0/OZ/isoflurane anaesthesia supplemented by fentanyl 3 p,g/kg and atracurium, reduced the fall in blood temperature and and that of pulmonary oxygen uptake during surgery. Once awake, unlike controls, patients given aminoacids did not shiver and had pulmonary oxygen uptakes and cardiac outputs above baseline: also, their baseline temperatures were restored more quickly.4 In a study in patients undergoing hysterectomy, starting aminoacid infusion 1-2 h before the operation prevented any significant fall in rectal temperature during or after surgery done under the same anaesthetic regimen as for the abdominal surgery patients except with enflurane in stead of isoflurane.’ In both studies, patients had no intercurrent disease, surgery lasted about 90 min, blood transfusion was required only once, and the minimum core temperatures in the control groups were 356° and 360°C, respectively, and returned to preoperative values within 100 min. Access to a central vein would not normally be required by these patients but was needed for delivering the aminoacids. Aminoacid infusion seems to prevent postoperative hypothermia, but the authors caution its use in patients without the pulmonary and cardiovascular reserve for fulfilling the increases in pulmonary oxygen uptake and cardiac output. In renal, hepatic, and metabolic disease the fluid and aminoacid load may not be tolerated. Its suitability in children and the elderly is not established. No thermic effect or change in energy substrate handling was seen when nitrogen 0- 15-0-22 g/kg daily, of of which 20-50% were branched aminoacids, was infused for over 6 h after cardiac surgery.6 This is about a fifth to a quarter of the rate of infusion of nitrogen described above, but the total doses are similar. However, anaesthesia for

thermic response. The thermic response to aminoacids in critically ill patients is smaller in non-septic trauma patients than in patients with sepsis in whom there are greater rates of protein breakdown and synthesis.8 The use of aminoacids to prevent anaesthesia-induced and postoperative hypothermia is a practical application of an established phenomenon. In the patients studied at the Karolinska Hospital, the degree of hypothermia to be overcome, the need for central venous access, cost, and contraindications to the volume and aminoacid load in patients with intercurrent disease would preclude advocacy of widespread use of the technique. However, in two recent studies, benzodiazepine premedication5 and balanced anaesthesia with volatile anaesthetic agents4 have been found to augment the thermic response to aminoacids. Further observations using the technique may help in elucidating the mechanisms of heat loss during anaesthesia and surgery, and in devising a suitable treatment for patients at risk of severe postoperative hypothermia or those least able to withstand its effects. may obtund

a

David J R Duthie Department of Anaesthesia, Papworth Hospital, Cambridge, UK Sessler DI. Perianaesthetic thermoregulation and heat balance in humans. FASEB J 1993; 7: 638-44. 2 Carlson GL, Gray P, Arnold J, Little RA, Irving MH. Thermogenic hormonal and metabolic effects of a TNP mixture. Influence of glucose and amino acids. Am J Physiol 1994; 266: E848-51. 3 Jéquier E. The influence of nutrient administration on energy expenditure in man. Clin Nutr 1986; 5: 181-86. 4 Selidén E, Brundin T, Wahren J. Augmented thermic effect of amino acids under general anaesthesia: a mechanism useful for prevention of anaesthesia-induced hypothermia. Clin Sci 1994; 86: 611-18. 5 Selldén E, Bränström R, Brundin T. Preoperative infusion of amino acids prevents postoperative hypothermia. Br J Anaesth 1996; 96: 227-34. 6 Hersio K, Takala J, Kari A, Huttunen H. Changes in whole body and tissue oxygen consumption during recovery from hypothermia: effect of amino acid infusion. Crit Care Med 1991; 19: 503-08. 7 Hall GM, Young C, Holdcroft A, Alaghband-Zadeh J. Substrate mobilisation during surgery: a comparison between halothane and fentanyl anaesthesia. Anaesthesia 1978; 33: 924-30. 8 Giovanni I, Chiarla C, Boldrini G, Castiglioni GC, Castagneto M. Calorimetic response to amino acid infusion in sepsis and critical illness. Crit Care Med 1988; 16: 667-70. 1

Carvedilol for heart failure, with care Despite the introduction of angiotensin-converting enzyme (ACE) inhibitors, case-fatality rates in patients with heart failure remains high, ranging from 10% to 40% depending on severity. Additional therapies are required to reduce the morbidity and mortality associated with heart failure. Clinicians have generally been taught to avoid ß-blocking agents in patients with heart failure. Fortunately, not everyone agreed-indeed these agents were used by some physicians even before ACE inhibitors, antagonists of another neuroendocrine system, became available.’ The association between heightened chronic sympathetic activation and poor prognosis in heart failure is well documented. Chronic sympathetic activation has adverse effects on myocardial function, causes vasoconstriction, is arrhythmogenic, and increases renal renin secretion. These effects suggest that chronic sympathetic activation is causally related to prognosis in heart failure, thus providing a rationale for (3-blockers. The benefits of

1199

P-blockade in patients with left-ventricular dysfunction after myocardial infarction’ support the case too. In several countries p-blockers are already approved for the of heart failure. Carvedilol is a non-selective (3-blocking agent with many additional properties, including vasodilation mediated by a’-adrenoceptor antagonism,4 and antioxidant5 and antiproliferative6 activities. Five large randomised, placebo-controlled studies, four linked ones in the USA and one by an Australia/New Zealand (ANZ) group, have evaluated carvedilol in more than 1500 patients with heart failure over 6-18 months. Most patients were already receiving diuretics, ACE inhibitors, and digoxin. The USA trials’-" recruited 1094 patients, mean age 58, with New York Heart Association (NYHA) class II-IV heart failure of various aetiologies. Patients were assigned to one of four trials according to their performance on a 6minute walk test. The trials had a common entry protocol, and an independent committee monitored mortality. In patients with mild heart failure carvedilol reduced the frequency of worsening heart failure and hospital admission for heart failure. Patients with moderately severe disease benefited similarly. Symptoms were improved by carvedilol in patients with moderate and severe heart failure, indicating that the drug does more than merely slow down disease progression. Carvedilol increased left-ventricular ejection fraction (LVEF), another marker of poor prognosis in heart failure, by about 7%; an increase of around 2% would be expected with an ACE inhibitor. In common with other p-blockers, carvedilol did not generally improve exercise capacity. The benefits of p-blockers on myocardial function may be offset by a reduction in heart rate during more strenuous exercise, but the relevance of maximum exercise testing to everyday life for patients with heart failure has been questioned. The ANZ triall2 recuited 415 patients, mean age 67, all of whom had ischaemic heart disease. Hospital admissions were reduced in patients receiving carvedilol but the drug did not improve symptoms or the frequency of worsening heart failure. 90% of these patients had NYHA class I or II heart failure, and it may be difficult to demonstrate improvement in patients with such mild disease. There was a consistent increase in LVEF. Longer-term trials are required to show whether carvedilol can prevent the progression to overt heart failure in patients with few

treatment

symptoms. The four US trials, combined in a prospectively planned stratified analysis, showed a significant reduction in mortality of 67% in the carvedilol groups compared with placebo at a mean of 8-7 months (8-2% vs 29%).13 Neither the cause nor the severity of the heart failure seemed to influence the mortality benefit of carvedilol, which was dose related (patients receiving 25 mg twice daily fared better than did those on 6-25 mg twice daily). By 18 months of follow-up in the ANZ trial there were few deaths and the reduction in mortality for carvedilol of 23% (12-5% vs 9-7%) was not significant.’4 However, the primary end-point at 18 months, death or hospital admission, fell by 41 %. Some of the ancillary properties of carvedilol may contribute to its beneficial effects in heart failure. Vasodilation would be expected to improve haemodynamics, any harmful effect of sympathetic activation due to a-blockade being prevented by concomitant ß-blockade. The anti-

1200

activity might protect the heart from ischaemia or reperfusion injury, and a reduction in lipid oxidation could have important effects on the progression of atherosclerosis. Antiproliferative effects might retard vascular smoothmuscle-cell hypertrophy, with important consequences for vascular structure and impedance. Carvedilol, metoprolol, and bisoprolol, all non-selective ß-blockers, delay the worsening of heart failure. However, P2-receptor blockade, by additional myocardial effects and by preventing sympathetically-mediated hypokalaemia, may have advantages in the setting of heart failure. Few other ß-blocking agents share the ancillary properties of oxidant

carvedilol and we need to find out whether the benefit of carvedilol on prognosis is a class effect shared by other ß-blockers or not. The effects of carvedilol in elderly patients (over 75) with heart failure, a large population not adequately considered in clinical trials, need to be established. Head-to-head comparisons with ACE inhibitors are required too, as is confirmation that larger doses of carvedilol are tolerated well and are more effective than smaller doses. But those trials are for future research.What about the clinician who, on his or her own initiative and responsibility, wishes to use carvedilol for patients with heart failure now? Carvedilol is licenced for hypertension and angina but not for heart failure, although regulatory approval is being sought. In the large trials discussed above carvedilol was initiated at twice-daily doses of 3-125 mg to 6-25 mg and then titrated up every 1 or 2 weeks, generally to a maintenance dose of 25 mg twice a day. However, the smallest tablet on the market is 12-5 mg. Hypotension and worsening heart failure are more likely if carvedilol is initiated at too high a dose or titrated too quickly. Carvedilol is contraindicated in asthma, and it may be inadvisable to give it to patients with a very low blood pressure or bradycardia.Nonetheless, carvedilol does otherwise seem to be safe; about 95% of patients tolerate the initiation of therapy. Even in those patients who deteriorate at first, long-term treatment has proved beneficial.’S There are powerful reasons for considering treatment with carvedilol for all grades of heart failure. However, having proved itself in clinical trials, the drug must now be shown to be a safe and effective tool in the hands of busy clinicians. As with ACE inhibitors, care will be required. John G F Cleland, Karl

Swedberg

Clinical Research Initiative in Heart Failure, University of Glasgow, UK; and Department of Medicine, Ostra Hospital, University of Goteborg, Sweden 1

2

3

4 5

6 7

8

Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979; i: 1374-76. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: 819-23. Held P. Effects of beta blockers on ventricular dysfunction after myocardial infarction: tolerability and survival effects. Am J Cardiol 1993; 71: 39C-44C. Cubeddu LX, Feunmayor N,Varin F, et al. Clinical pharmacology of carvedilol in normal volunteers. Clin Pharmacol Ther 1987; 41: 31-44. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta-adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992; 263: 92-98. Sung C-P, Arleth AJ, Ohlstein EH. Carvedilol inhibits vascular smooth muscle cell proliferation. J Cardiovasc Pharmacol 1993; 21: 221-27. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits disease progression in patients with mild heart failure. Circulation 1995; 92: I-394 (abstr). Bristow MR, Gilbert EM, Abraham WT, et al. Multicenter Oral Carvedilol Heart Failure Assessment (MOHCA): a six-month dose-

response evaluation in class II-IV

patients. Circulation 1995;

92: I-142

(abstr). 9 Packer M, Colucci WS, Sackner-Bernstein JD, et al. Prospective randomised evaluation of carvedilol on symptoms and exercise tolerance in chronic heart failure: results of the PRECISE trial. Circulation

1995; 92: 1-143 (abstr). 10 Cohn JN, Fowler MB, Bristow MA, et al. Effect of carvedilol in severe chronic heart failure. J Am Coll Cardiol 1996; 27: 169A (abstr). 11 Fowler MB, Gilbert EM. Cohn JN, et al for the Carvedilol Heart Failure Study Group. Effects of carvedilol on cardiovascular hospitalisation in patients with chronic heart failure. JACC 1996; 27 (suppl A): 169A. 12 Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator &bgr;-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation 1995; 92: 212-18. 13 Packer M, Bristow MR, Cohn JN, et al. Effect of carvedilol on the survival of patients with chronic heart failure. Circulation 1995; 92: I-142 (abstr). 14 Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator &bgr;-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation 1995; 92: 1394 (abstr). 15 Sackner-Bernstein JD, Krum H, Goldsmith RL, et al. Should worsening heart failure early after initiation of beta-blocker therapy for chronic heart failure preclude long-term treatment? Circulation 1995; 92: 1-395 (abstr).

Mosquitoes, models,

and

dengue

Vectorborne infectious diseases remain a formidable public health challenge. Dengue virus is an arthropodborne agent of global significance, reflected by a striking expansion in the Americas over the past decade (figure).1,2 This virus is carried by the mosquito Aedes aegypti, which has successfully exploited increased movement of the world’s people into urban centres. This mosquito is domestically adapted, infesting objects near human dwellings, such as tyres, cans, and water jars. The female mosquito’s predilection for human blood and habits of multiple, interrupted feeding facilitate dengue transmission in crowded settings. The rate at which dengue spreads depends on a complex interplay of factors, including numbers of infected and of susceptible human hosts, strain of the virus, size of mosquito population and feeding habits, time from infection to ability to transmit the virus (for both vector and host), and likelihood of virus transmission from man to mosquito to man. One simulation model incorporates many important variables to help describe and predict dengue transmission in an urban environment.4 Public health officials may wish to use such models to assist with planning or for evaluating the potential impact of different intervention strategies. Since temperature may affect vector distribution, size, feeding habits, and extrinsic incubation period,4,5 models can also be used to help evaluate the impact of environmental changes such as global warming. The application of such models reflects how increasingly sophisticated techniques are being used to study infectious diseases. Another example is molecular epidemiology by nucleic acid sequence analysis. This has been used to help identify how strains of dengue virus from different parts of the world are genetically related:6 for example, the dengue type 3 strain isolated from Panama and Nicaragua in 1994 proved to be identical to a type that caused major dengue haemorrhagic fever epidemics in Sri Lanka and India in the 1980s.7 However, while we continue to make use of these advanced techniques we must not lose sight of three important priorities, relevant to dengue and other

Figure: All cases of dengue (and cases of dengue haemorrhagic fever) as at November, 1995, for South and Central America Restricted to 14 countnes with more than 500 countries in region 199 257 (5526).

cases.

Total for 31

is the need to strengthen surveillance activities.8,9 Surveillance for dengue includes determining the number of infected and diseased people as well as the size of the vector population (eg, by larval sampling).1O Even as we create complex models, we should remember that good models require good data. There is no substitute for the actual data when monitoring the spread of infectious diseases and predicting future trends. A strong system of laboratory-based surveillance is critical. Basic diagnostic capabilities, such as viral isolation and serology, remain necessary despite the availability of advanced molecular techniques. Second, prevention and control demands dedicated and sustained involvement at the local level. Removing larval breeding sites such as discarded tyres and other containers that may hold water remains vital to dengue control, but success requires public education and community participation.11, 12 If local communities are not involved in developing priorities in control programmes, they are less likely to be enthusiastic about implementation. Third, is a strong public health infrastructure, international, national, and local, to ensure support for surveillance and control activities.8,9 Government needs to recognise that this infrastructure is essential as part of a country’s defence against microbial threats to health and the economy. The rise in dengue serves as a metaphor for the state of our global society. Factors contributing to this epidemic include international travel in a shrinking planet (leading to introduction of different dengue strains from one part of the world to another), urbanisation, population growth, crowding, poverty (with inadequate water and waste management systems), a weakened public health infrastructure, and limited support for sustained disease-control

emerging infections. First,

1201