Octreotide infusion versus injection sclerotherapy

satisfactory urine output was maintained, and there was further improvement in ventilatory function evidenced by blood gas analysis (Pa02 15 6 kPa, PaC02 52 kPa, FI02 04, PEEP +4cmH20), peak airway pressure of 25 cmH2O, and radiological appearance. The patient was ventilated for a further 72 hours during which neurological status returned to normal enabling extubation. The patient was discharged from hospital 2 days later with no detectable neurological deficit and with antibiotic cover continued for 10 days. Synthetically-derived surfactants have been used for some time in treating neonatal respiratory distress syndrome and more recently have been shown to improve gas exchange and decrease mortality rates when administered to patients with adult respiratory distress syndrome.1 The pathophysiology of near drowning includes hypoxia due to diffuse atelectasis induced by surfactant inactivation from freshwater aspiration.2 The mainstay of treatment is positive pressure ventilation with positive end-expiratory pressure. There have been no previous reports of the near

use

of exogenous surfactant in the

treatment

of

discarded.2 Most trials are too small. For example, a review of 44 trials with non-significant results and published in dermatological journals showed that half were compatible with a 50% benefit, but only in 1 were confidence intervals reported.2 Additionally, small trials are more likely to be published if they are significant.3 Lastly, one large trial is usually preferable to a meta-analysis of several small trials of

varying quality. If trials of low power are done, as by Sung et al, the results should be interpreted cautiously, and trials that set out to establish equivalence should be designed and analysed

accordingly.4 Douglas G Altman Medical Statistics Laboratory, Imperial Cancer Research Fund, PO Box 123, Lincoln’s Inn Fields, London WC2A 3PX, UK

1

2

drowning in human beings. 3

M McBrien, JJ Katumba, A I Mukhtar Departments of Anaesthesia and Paediatrics, Kettering & Kettering, Northamptonshire NN16 8UZ, UK

1

2

District General

Hospital,

Weg J, Reines H, Balk R, et al. Safety and efficacy of an aerosolized surfactant (Exosurfa) in human sepsis induced ARDS. Chest 1991; 100: 137. Gonzalez Rothi RJ. Near drowning: consensus and controversies in pulmonary and cerebral resuscitation. Heart Lung 1987; 16 (5): 474-82.

Octreotide infusion

versus

injection

sclerotherapy SiR-Sung and colleagues (Sept 11, p 637) present the results of a randomised trial comparing octreotide with injection sclerotherapy in the treatment of acute variceal bleeding. They estimate that 1800 patients would be needed to have 80 % power to detect a difference in success rates of 85% and 90%. (The correct figure is 1450.) They could not do such a large trial so they "arbitrarily set a target of 100 patients". They did not give the power of their trial, but it was in fact only 5%. Thus, if the true success rates of the two treatments were indeed 85% and 90%, their trial had only a 1 in 20 chance of obtaining a significant result. We can question the value of a trial with such low power, especially when it seems that the investigators were really hoping to establish equivalence. The observed overall success rates were 84% for the octreotide group and 90%for the sclerotherapy group (p 0-55), which are remarkably close to the predicted values. The 95% CI for the difference in success rates is - 7-3-19-5% (wrongly given in the text and abstract as 0-195%). The original power calculation seems to have been based on the premise that a difference of five percentage points in success rates was clinically important. The 95% CI includes differences larger than this in both directions, and so Sung and colleagues’ conclusion that they have shown octreotide to be as effective as endoscopic sclerotherapy cannot be supported by their results. Nor can they reasonably claim that the treatment is safe on the basis of only 49 patients. Nicholl (Sept 29, p 809) questions whether previous =

arguments about the power of trials still hold in the age of meta-analysis. There is sometimes a case for doing small trials of low statistical power! but it is unwise to suggest, as some have, that because of meta-analysis we can drop previous advice about sample size. Many trials will not be replicated and so will never be incorporated into a meta-analysis. Further, the publication of a small trial showing a non-significant effect may discourage replication, and valuable treatments might be

1486

4

MacRae KD. The value of small clinical trials. Recent Res Cancer Res 1988; 111: 191-94. Williams HC, Seed P. Inadequate size of ’negative’ clinical trials in dermatology. Br J Dermatol 1993; 128: 317-26. Dickersin K. The existence of publication bias and risk factors for its occurrence. JAMA 1990; 263: 1385-89. Makuch R, Johnson M. Issues in planning and interpreting active control equivalence studies. J Clin Epidemiol 1989; 42: 503-11.

SiR-We were surprised that Sung and colleagues estimate the size needed to achieve a statistical power of 80% and 5 % type I error with a two-tailed test to be almost 900 patients, and that they postulate that octreotide infusion and emergency sclerotherapy were equally effective in controlling variceal haemorrhage. Although no value is universally accepted, a statistical power ranging from 80-90% is regarded as appropriate.’ If one does not achieve that aim, a type II error

sample

can occur.

Sung and colleagues study is clearly powerless, as they point Their sample size is far from the target of 900 individuals needed for an acceptable type II error. Therefore, no out.

conclusion on the equal effectiveness of both treatments should be made. Moreover, their conclusion in the summary is different from that at the end of the discussion, in which no statement about the equal effectiveness of octreotide and emergency sclerotherapy was made. Finally, we do not refute the hypothesis that octreotide infusion and emergency sclerotherapy might be equally effective, but we think that this study cannot prove it. Julio

Mayol Martinez, Jesus Alvarez Fdez-Represa

Servicio de

1

Cirugia I, Hospital Universitario San Carlos, 28040 Madrid, Spain

Murray GD. Statistical aspects of research methodology. Br J Surg 1991; 78: 777-81.

SIR—Sung and colleagues’ results confirm those of an earlier studyl-namely, that vasoactive medical treatment and emergency sclerotherapy were equally effective in controlling variceal haemorrhage. I would, however, like to make the following comment. In common with other studies on the treatment of acute variceal bleeding, not all the patients treated were bleeding on admission to the study. Although tables 1 and 2 show that only 37% in the sclerotherapy group and 51% in the octreotide group were bleeding at emergency endoscopy, the summary and figures 1 and 2 are misleading on this point. Since in patients with "signs of recent bleeding" the haemorrhage had obviously already ceased, the bleeding cannot be claimed to have been stopped by the treatment. Therefore, bleeding was controlled by emergency sclerotherapy, not in 90% as reported, but in 78 % (14 of 18), and in the octreotide group not in 84% but in 68% (17 of 25).

To avoid false conclusions,

only patients who

are

actually

bleeding should be included bleeding treatment.2,3

in future studies

on

variceal

S Walker Department of Gastroenterology, Robert-Bosch-Krankenhaus, D-70376 Stuttgart, Germany Shields R, Jenkins SA, Baxter JN, et al. A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices. J Hepatol

1

1992; 16: 128-37. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleeding esophageal varices: a placebo-controlled, double-blind study. Hepatology 1986; 6: 112-15. 3 Walker S, Kreichgauer HP, Bode JC. Terlipressin versus somatostatin in bleeding esophageal varices: controlled, double-blind study. Hepatology 1992; 15: 1023-30.

2

SiR-Although I accept Sung and colleagues’ conclusion that octreotide infusion and emergency sclerotherapy are equally effective in controlling variceal naemorrhage, there is at least one point that does not fully reflect the content of the report from which it is taken. This point is the reference to an article by Walker2 who, by contrast with Sung and colleagues’ statement, specifically comment that "Terlipressin appears to be the substance of choice in the treatment of bleeding oesophageal varices by medication". Walker also refers to the study by Soderlund et al2 in which terlipressin was evaluated in a double-blind, randomised, placebo-controlled trial. Not only was there a significant decrease in hospital mortality (10% vs 38%) but also there was an increased one month survival (90% vs 62%, p < 005): "The latter effect has previously not been observed for any vasoactive therapy". Clearly these improved survival rates make terlipressin a vital component of the treatments available for these lifethreatening situations and not a compound whose efficacy should be left in doubt.

terlipressin (triglycyllysine vasopressin) in the treatment of oesophageal varices, this drug was claimed to have no effect on smooth muscle and does not affect the heart or the haemostatic mechanisms of the body.1 In a controlled trial in the treatment of oesophageal varices, terlipressin proved better than vasopressin. Soderlund et aP also confirmed that terlipressin significantly improved the results of variceal haemorrhage, compared with placebo. On the other hand, D’Heygere et al3 reported a success rate of only 46% in controlling variceal haemorrhage with terlipressin. A controlled study of terlipressin versus vasopressin in Taiwan with a larger number of patients did not show much difference in therapeutic effect.4 However, Freeman’s study and the Taiwan study had small sample sizes and therefore their conclusions should be viewed with some caution. Side-effects, including chest pain, bradycardia, and electrocardiographic changes, have also been reported.2,5 Since data on the combination of terlipressin with nitrates are limited, this new treatment should be compared with somatostatin, or its analogue octreotide, infusion in a prospective randomised manner.

Joseph J Y Sung Department of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong 1

2

3 4

5

Freeman JG, Cobden I, Lishman AH, et al. Controlled trial of terlipressin versus vasopressin in the early treatment of oesophageal varices. Lancet 1982; i: 66-68. Söderlund C, Magnusson I, Törngren S, Lundell L. Terlipressin controls acute bleeding oesophageal varices: a double-blind, randomized, placebo controlled trial. Scand J Gastroenterol 1990; 25: 622-30. D’Heygere F, Burroughs AK, Sherlock S, et al. Prospective evaluation of glypressin for variceal bleeding in cirrhotics. Gut 1986; 27: 1247. Chiu KW, Sheen IS, Liaw YF. A controlled study of glypressin versus vasopressin in the control of bleeding from oesophageal varices. J Gastroenterol Hepatol 1990; 5: 549-53. Chen SC, Lin ZY, Lu SN, et al. The effect of pitressin and glypressin in variceal bleeding: a preliminary clinical trial. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 1990; 6: 551-55.

Brian Donovan Ferring Laboratories, Greville House, Feltham, Middlesex TW14 9PX, UK

Inhibition of nitric oxide

1

SiR-Haynes and colleagues (Oct 9, p 931) show that inhibition of nitric oxide (NO) synthesis with NG-monomethyl-Larginine (L-NMMA, 3 mg/kg) in the systemic circulation is associated with an increase in mean systemic arterial pressure. This work suggests that resting systemic blood pressure is at least in part maintained by NO production. We have reportedl that the intracoronary infusion of increasing concentrations of L-NMMA (4, 10, and 25 mol/ min) caused a significant decrease iri distal epicardial coronary artery diameter (up to 5-9 [SE 2-1]%) and coronary blood flow (up to 5-7 [1,9]%) in 12 patients with angiographically-normal coronary arteries and with no risk factors for coronary artery disease, indicating that resting coronary artery and resistive vessel tone and blood flow are at least in part maintained by basal NO production. The total dose of L-NMMA was 50 mg (0-6--0-8 mg/kg). Unlike Haynes and co-workers we recorded no change in systemic arterial pressure or heart rate, perhaps because the total dose of L-NMMA was insufficient to have a systemic effect. No evidence of myocardial ischaemia was detected. We have subsequently investigated a further three patients with angiographically-normal coronary arteries with a higher maximum dose of intracoronary L-NMMA (4, 10, 25, and 100 pmol/min) up to a total dose of 170 mg (20-26 mg/kg) over 20 min. In all 3 patients, epicardial coronary artery diameter and coronary blood flow were decreased, by 7-8 (1-0)% and 10-2 (24)°,’°, respectively. There was no change in either the heart rate or the systemic arterial blood pressure measured by continuous direct intra-arterial recording during or after the infusion of L-NMMA.

2

Walker S. Vasoconstrictor therapy in bleeding esophageal varices. Hepatogastroenterol 1990; 37: 538-43. Söderlund C, Magnusson J, Törngren S, Lundell L. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices: a double-blind randomised, placebo-controlled trial. Scand Gastroenterol 1990; 25: 622-30.

J

Authors’ reply SiR-The

comments

by Altman and Martinez are well taken.

in Statistical methods that the power of statistics is a limitation in this study and a type II error cannot be eliminated. Unfortunately, a single-centre study is unlikely to achieve the number that could satisfy the statistical requirement, since both forms of treatment are effective and the expected success rates are very close. We agree that although, "... our study suggests that octreotide is as effective as endoscopic sclerotherapy", further investigations, probably with a multicentre trial, are needed to confirm its efficacy. We agree with Walker that acute variceal bleeding seen at endoscopy was controlled by emergency sclerotherapy in 78% and by octreotide infusion in 68% in our study. Previous reports have shown that, at the time of endoscopy, only 29-50% of patients are actively bleeding, the rest having stopped spontaneously. Yet the incidence of early rebleeding in patients with cirrhosis is very high (range 20-60%). When studying the efficacy of treatments for variceal haemorrhage, we believe that both the control of acute bleeding and prevention of early recurrence are important indices to look at. With respect to Donovan’s comments on the use of

My colleagues and I

state

synthesis

1487