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Fluid therapy and high-dose metoclopramide
- Gareth L Ackland (12 August 2006)
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Single dose metoclopramide and movement disorders
- Jane E Alty (14 August 2006)
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Post operative nausea and vomiting – a complex issue
- Lini Cherian, Boby J Sebastian (14 August 2006)
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Author's reply: Fluid therapy and high-dose metoclopramide
- Götz Gelbrich (16 August 2006)
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Author's reply: Single dose metoclopramide and movement disorders
- Götz Gelbrich (16 August 2006)
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High dose metoclopromide, cardiovascular side effects and method of administration
- Arun Sehgal (16 August 2006)
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First do no harm
- John M Roberts (16 August 2006)
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Post operative vomiting
- Janet Metcalfe (16 August 2006)
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PONV prevention in context
- John B Carlisle (16 August 2006)
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Anaesthetic techniques might be an important confounding factor
- Hamzeh Hussein, Dr. W Fawcett- Lead Clinician/ consultant anaesthetist (17 August 2006)
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Reply to author: single dose metoclopramide and movement disorders
- Jane E Alty (17 August 2006)
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Author's reply: High dose metoclopromide, cardiovascular side effects and method of administration
- Götz Gelbrich (17 August 2006)
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Author's reply: First do no harm
- Götz Gelbrich (17 August 2006)
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Change in current practice
- Adam K Yamamoto (17 August 2006)
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Higher dose metoclopramide is a cheap combination anti-emetic
- Kevin D Johnston (17 August 2006)
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Author's reply: Post operative vomiting
- Götz Gelbrich (18 August 2006)
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Author's reply: Higher dose metoclopramide is a cheap combination anti-emetic
- Götz Gelbrich (18 August 2006)
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Author's reply: Anaesthetic techniques might be an important confounding factor
- Götz Gelbrich (18 August 2006)
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Re: Author's reply: High dose metoclopromide, cardiovascular side effects and method of administration
- Arun Sehgal (22 August 2006)
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Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: The Concerns of The Orthopaedic Surgeon.
- Louisa N Banks, Martyn Lovell (Orthopaedic Consultant) Shashi Godey (Orthopaedic Clinical Fellow) (30 August 2006)
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Author's reply: The Concerns of The Orthopaedic Surgeon.
- Götz Gelbrich (2 September 2006)
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Re: Author's reply: The Concerns of The Orthopaedic Surgeon.
- Louisa N Banks, Martyn Lovell, Shashi Godey (7 September 2006)
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Author's reply II: The Concerns of The Orthopaedic Surgeon.
- Götz Gelbrich (9 September 2006)
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Gareth L Ackland, Lecturer, Anaesthesia University College Hospital
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The prevention of postoperative nausea and vomiting by high-dose metoclopramide combined with dexamethasone appears to be an effective strategy. However, an important confounding factor has not been addressed by the authors. Several studies have established that adequate intravascular volume/ supplemental fluid therapy reduces PONV (1-3), even in very high-risk patient groups (4). Given the cumulatively higher incidence of hypotension and tachycardia associated with higher-dose metoclopramide , one would expect the anesthesiologist (blinded to the anti-emetic therapy) to administer greater volumes of fluid to these patients. If so, the larger volumes of fluid administered to the higher- dose metoclopramide patient groups could also contribute, if not wholly explain, the apparent beneficial effect of metoclopramide in reducing PONV. In the absence of a detailed description by the authors in the Methods section as to what defined hypotension and tachycardia, together with the anesthesiology strategy to combat these changes, it is difficult to be sure whether the beneficial effect reported is directly due to high- dose metoclopramide. 1. Maharaj et al. Preoperative intravenous fluid therapy decreases postoperative nausea and pain in high risk patients.Anesth Analg. 2005 ;100(3):675-82 2. Moretti EW et al.Intraoperative colloid administration reduces postoperative nausea and vomiting and improves postoperative outcomes compared with crystalloid administration. Anesth Analg. 2003;96(2):611-7 3. Magner JJ et al. Effect of intraoperative intravenous crystalloid infusion on postoperative nausea and vomiting after gynaecological laparoscopy: comparison of 30 and 10 ml kg(-1).Br J Anaesth. 2004;93(3):381-5. 4.Goodarzi M et al. A prospective randomized blinded study of the effect of intravenous fluid therapy on postoperative nausea and vomiting in children undergoing strabismus surgery. Paediatr Anaesth. 2006;16(1):49-53 Competing interests: None declared |
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Jane E Alty, Specialist Registrar in Neurology York Hospital, York, YO31 8HE
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EDITOR- Wallenborn et al have shown that the addition of metoclopramide to dexamethasone is effective in preventing postoperative nausea and vomiting.[1] Metoclopramide is associated with a significantly higher prevalence of extrapyramidal movement disorders, even after a single dose, and it was therefore surprising to see so few adverse events in this study. One explanation may be that the symptom of akathisia (a subjective sensation of inner restlessness) was not specifically enquired about and previous studies have shown that this is rarely spontaneously volunteered.[2] Certain groups of patients seem particularly vulnerable to the acute extrapyramidal effects of metoclopramide. A prospective study of 2557 patients receiving first prescriptions for metoclopramide showed that females and those aged less than 30 years have a higher risk of developing akathisia and dystonia.[3] Recently a genetic predisposition to acute dystonia associated with metoclopramide has been reported.[4] It may therefore be prudent to enquire specifically about a family history of drug related dystonic reactions. On a practical note, the risk of akathisia may be reduced by slowing the rate of infusion of metoclopramide. A prospective, double blind, randomised clinical study of 300 patients compared two rates of intravenous infusion of metoclopramide. The incidence of akathisia was significantly higher in the bolus group (24.7%) than in the slow infusion (over 15 minutes) group (5.8%).[5] In summary, there are several additional factors to consider before introducing a regimen of metoclopromide and dexamethasone as routine practice. Single dose metoclopramide carries substantial morbidity and particular caution should be taken with young female patients. Competing interests: None declared References: 1.Wallenborn J, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbach A et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind muticentre trial. BMJ 2006; 333:324-7. 2.Fleishman SB, Lavin MR, Sattler M, Szarka H. Anti-emetic induced akathisia in cancer patients receiving chemotherapy. Am J Psychiatry 1994 May; 151(5):763-5. 3.Bateman DN, Darling WM, Boys R, Rawlins MD. Extrapyramidal reactions to metoclopramide and prochlorperazine. Q J Med. 1989 Apr;71(264):307-11. 4.van der Padt A, van Schaik RH, Sonneveld P. Acute dystonic reaction to metoclopromide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms. Neth J Med. 2006 May;64(5):160-2. 5.Parlak I, Atilla R, Cicek M, Parlak M, Erdur B, Guryay M et al. Rate of metoclopramide infusion affects the severity and incidence of akathisia. Emerg Med J. 2005 Sep;22(9):621-4. Competing interests: None declared |
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Lini Cherian, Anaesthetist not working, Boby J Sebastian
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I read with interest the research article by Wallenborn and co authors on the prevention of post operative nausea and vomiting by metoclopramide combined with dexamethasone. It was a well designed study with large number of subjects. We know that one of the most common and distressing symptoms following anaesthesia and surgery is post operative nausea and vomiting. Many factors affect PONV – 1.patient factors like age, gender, obesity, h/o motion sickness, delayed gastric emptying, smoking. 2.pre operative factors- full stomach or prolonged fasting, anxiety, reasons for surgery [GIT obstruction, raised ICT, abdominal and gynaecological surgery, laproscopic,ENT, and ophthalmic surgery]. 3. anaesthetic factors – choice of premedication,use of opiods,nitrous oxide, and some inhalational agents, intubation, longer procedures and greater depth of anaesthesia. 4.post operative factors – pain, dizziness, early ambulation, hypotension, premature oral intake. (1) The causes of vomiting are many and so is its prevention and treatment. A single drug is usually ineffective and a variety of combinations have been tried. Here the authors have tried varying doses of metoclopramide with dexamethasone for the prevention of PONV. It was found that 25 and 50mg of metoclopramide with 8mg of dexamethasone was markedly effective in preventing early PONV and 50mg combination also prevented late onset PONV. The incidence of side effects like extrapyramidal symptoms, hypotension, tachycardia were low, which is surprising.(2) Hence this combination provides another option for PONV prophylaxis, thanks for the work of Wallenborn and colleagues. So, identification of patients at risk for PONV, optimal PONV prophylaxis,use of anaesthetic agents and techniques with least risk of PONV, goes a long way in preventing the incidence of this distressing problem. Reference. 1.Dr S Islam, Dr P N Jain – Post operative vomiting: a review article.Indian J Anaesthesia 2004;48. 2.J Wallenborn et al – Prevention of post operative nausea and vomiting by metoclopramide combined with dexamethasone: randomized double blind multicentre trial.BMJ ,12 Aug 2006 Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Sir, Thank you for your comment, giving us the opportunity to discuss this issue. Though intraoperative crystalloids and colloids were correlated with hypotension (but not tachycardia) after application of the study medication, the use of fluids was not associated with the dose of metoclopramide. This sounds paradoxically at first glance, but it may be explained by other variables, predicting both the need for fluids during surgery and hypotension after metoclopramide. For example, when adjusting for type and duration of surgery and the patient's age, hypotension was no longer associated with the use of crystalloids, and the correlation with colloids diminished. Furthermore, among the 2741 Patients who had no hypotension or tachycardia after administration of the study medication, the rates of postoperative nausea and vomiting were similar (22.4, 20.0, 17.2 and 13.8 percent in the four arms) to those in the entire sample. Among the remaining 399 patients, the respective rates were 30.4, 25.0, 16.8 and 17.7 percent (be aware of the lower precision of these rates due to the smaller number of cases). These analyses suggest that the potential confounding by the drug side effects and their treatment, if present at all, is marginal. Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Madam, Thank you for your comment. Please note that we treated anaesthetised patients. It is possible that the risk of the induction of a certain adverse event is not the same as in patients who are awake. Secondly, events occuring early after treatment and lasting only a short time will be reported by patients who are awake at the time of administration but will not be reported by patients anasthetised at the time of administration. Thus in principle we should not be surprised when observing different event rates in different patient populations. However, the study of Bateman et al [1] reports 12 cases of extrapyramidal disorder in 2557 patients (0.47 percent). Although the setting of this study is, of course, incomparable to ours, this result is in line with our study which found 15 cases among 2352 patients who received metoclopramide (0.64 percent). The paper of Fleishman et al [2] is based on the telephone follow-up of 24 cancer patients. This is a very small study in a very special group of patients. The doses of metoclopramide are usually much higher. In view of the cancer chemotherapy which is anything but harmless, we can not conclude about the attributability of side effects to antiemetic co- medication from this small cohort study. The rate of extrapyramidal symptoms may not be generalised to other patient populations. As well, the rate of underreporting extrapyramidal symptoms (75 percent in this study) can not be generalised. Severely ill patients may consider certain symptoms unimportant, so they do not spontaneously report on them. For patients with a minor disease, the same symptoms may represent a major part of their entire discomfort; they will possibly tell about them spontaneously and detailed. I do not know data supporting this, but it seems plausible enough to be careful with drawing conclusions from [2]. The study by Parlak et al [3] is interesting, thank you for referring to this paper. We proposed the option of 25 mg metoclopramide intraoperatively plus individual postoperative prophylaxis. Reference [3] should be included into the discussion about the optimal postoperative prophylaxis of late nausea and vomiting. 1. Bateman DN, Darling WM, Boys R, Rawlins MD. Extrapyramidal reactions to metoclopramide and prochlorperazine. Q J Med. 1989;71:307-11. 2. Fleishman SB, Lavin MR, Sattler M, Szarka H. Anti-emetic induced akathisia in cancer patients receiving chemotherapy. Am J Psychiatry 1994;151:763-5. 3. Parlak I, Atilla R, Cicek M, Parlak M, Erdur B, Guryay M et al. Rate of metoclopramide infusion affects the severity and incidence of akathisia. Emerg Med J. 2005;22:621-4. Competing interests: None declared |
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Arun Sehgal, Specialist Registrar - Anaesthesia Norwich, NR4 7UY
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High dose metoclopromide, cardiovascular side effects and method of administration Wallenborn and colleagues have demonstrated that high dose metoclopromide in combination with dexamethasone would be useful in the prevention of postoperative nausea and vomiting and I would like to congratulate them on their work (1). However, the common adverse events of tachycardia and hypotension are significant and appear to be dose dependent. An about 20% chance of tachycardia and hypotension would be concerning in patients with significant cardiovascular disease. There have been reports of arrhythmias associated with use of metoclopromide (2 ,3 ). The method of administration of different doses of metoclopromide is not clear from the description in the Methods section. It would be interesting to know whether the method of administration of high dose metoclopromide as intravenous bolus or slow intravenous injection over few minutes or in an intravenous crystalloid infusion has an influence on the incidence of cardiovascular adverse events. References : 1. Wallenborn et al, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbacn UK, Kuhnast T, Wiegel M, Olthoff D. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ 2006; 333: 324 –7. 2. Baguley WA, Hay WT, Mackie KP, Cheney FW, Cullen BF. Cardiac dysrhythmias associated with the intravenous administration of ondansetron and metoclopramide. Anesth Analg. 1997 Jun;84(6):1380-1. 3. Bevacqua BK. Supraventricular tachycardia associated with postpartum metoclopramide administration. Anesthesiology. 1988;68(1):124- 5. Arun Sehgal Specialist Registrar – Anaesthesia Norwich NR4 7UY Competing interests: None declared |
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John M Roberts, Pediatric anesthesiologist John Hopkins Hospital, Baltimore 21287
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Wallenborn et al's report adds a valuable lesson to the sparse literature on successful PONV therapeutic options. In the US, metoclopramide is only licensed for use in diabetic gastroparesis but many of us have used it off license for sometime. However, we use it with caution as we are all too aware of the risk of oculogyric crises. On a number of occasions I have been called to assist with patients in crises obstructing their airways after a small dose of metoclopramide. This seems particularly prevalent in Afro-Carribean patients and usually on their first or second dose. On one occasion, the patient required intubation due to severe neck dystonia. This leads one to speculate that the case of "inspiratory stridor with cyanosis" quoted in the adverse effects section was infact a case of severe dystonia leading to a compromised airway. I am concerned that high dose metoclopramide recommended in this paper may lead to considerable problems. If a patient were to ask me "what am I most likely to get - PONV or oculogyric crisis?" I could easily say the former, but if they were to ask "what carries the higher risk ?" I would find that hard to answer. We need to quote a risk figure to patients prior to implementing any new treatments and I would struggle to put a figure on it at the moment. Yes, this may reduce PONV, but what will it provoke? Remember the first principal of medical ethics "first do no harm". Competing interests: None declared |
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Janet Metcalfe, recent patient Secretary
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I read this research in my daughters BMJ with great hope. I was recently admitted to my local hospital with bowel obstruction. I was vomiting constantly and thought that all would be well after my surgery. Little did I realise that the effects of a 3 hour anaesthetic would be so serious that my pre-operative vomiting was minor compared to my post- operatice sickness! ANYTHING that reduces the dreadful vomiting and constant feeling of sickness must be a good thing ...I only wish I had known about this magic metoclopramide sooner! Competing interests: None declared |
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John B Carlisle, Consulant anaesthetist Torbay hospital, Devon, UK. TQ2 7AA
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Metoclopramide is one of the drugs that we reviewed in our recent Cochrane meta-anlaysis, 'Drugs for preventing postoperative nausea and vomiting' (PONV).1 We also found that metoclopramide was effective. We found that, when compared with placebo, the average relative risk for PONV was 0.76 - for all doses of metoclopramide, which compares to 0.89, 0.75 and 0.63 for 10mg, 25mg and 50mg of metoclopramide in Wallenborn’s study. We would like to comment on the useful information that Wallenborn’s study provides in this context. Wallenborn has provided the most information linking antiemetic dose with effect. He found that 50mg was 1.2 times more effective than 25mg, and 25mg was about 1.2 times more effective than 10mg. We found a clear pattern of increasing effect in our review for droperidol, but less convincing patterns for other antiemetics, including metoclopramide. Wallenborn did not measure a statistically significant difference between 10mg of metoclopramide and placebo. From our systematic review we think that 10mg of intravenous metoclopramide does have an effect, but not sufficient to be detected at the P=0.05 level in 788 participants with a control PONV risk of 0.23. We included 737 studies involving 103,237 people in our review. We found convincing evidence that nine drugs were effective. But the results for all nine were skewed, probably by publication bias. The results for metoclopramide were skewed the least, as illustrated by a funnel plot that was only mildly asymmetric. As Sweeney comments in his editorial, many clinicians either dismiss metoclopramide or consider it to be a weak antiemetic. This conservative expectation has probably resulted in the least distortion of effect for metoclopramide, perhaps be ‘allowing’ the publication of studies that show little or no antiemetic effect. In comparison we found that the funnel plots for newer agents, either in comparison with placebo or older antiemetics, were markedly skewed. We think that clinicians should be cautious, in both extolling the virtues of new antiemetics and in discarding older drugs, particularly when rare adverse reactions are detected only after a large number are exposed to a new drug. We were unable to find convincing evidence that the antiemetic effect differed amongst the nine drugs: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine, granisetron and ramosetron. In the United Kingdom 10mg of intravenous metoclopramide costs about £0.27. The metoclopramide cost of prophylaxis for 1000 people would be £270, £675 and £1350 at the three doses in this study. This compares to about £5990 for 4mg of ondansetron and £8600 for 1mg of granisetron. Less than 10% of people would benefit from prophylaxis when the control risk for PONV is 0.23 (or 230 out of 1000). Of 1000 people given one of the three metoclopramide doses, 30, 60 and 90 people respectively would avoid PONV, whilst 970, 940 and 910 people would not benefit. The metoclopramide cost for one person to avoid PONV is £9, £11 and £15 respectively. The comparative cost for ondansetron 4mg is about £74, and about £106 for 1mg of granisetron. One might expect extrapyramidal reactions in between two and five of the 1000 people given metoclopramide. Finally we disagree with Sweeney’s suggestion that “A head to head trial of metoclopramide and dexamethasone versus a 5-HT3 antagonist combined with dexamethasone would be the next logical step”. Such a study could only conclude on the relative effect of metoclopramide versus the 5- HT3 antagonist. Our posthoc analysis supported the finding of the IMPACT study - that the effects of different antiemetic drugs appear to be additive.2 Sweeney’s proposed study would add little to all the other studies of metoclopramide and 5-HT3 antagonists. If clinicians remain set on more ‘primary’ research, despite the incomplete synthesis of the research already published, they should concentrate on the detection of rare serious side effects. 1. Carlisle JB, Stevenson CA. Drugs for preventing postoperative nausea and vomiting. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004125. DOI: 10.1002/14651858.CD004125.pub2. 2. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I et al [for the IMPACT investigators]. A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting. New England Journal of Medicine 2004;350(24):2441-51. Competing interests: None declared |
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Hamzeh Hussein, Senoir House Officer- Anaesthetics Department of Anaesthetics and Critical Care Unit, Dr. W Fawcett- Lead Clinician/ consultant anaesthetist
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Dear Editor We read with interest research article by Wallenborn and co-authors (1) on the prevention of post operative nausea and vomiting by metoclopramide combined with dexamethasone. The complexity of care needed for prevention of PONV; makes the condition a real test and a useful marker of the effectiveness of any institution caring for these patients. PONV exhibits a multifactorial aetiology and is influenced by patient, anaesthetic and surgical factors. However, there are an important both stratification and confounding factors which have not been clear by the authors e.g. previous reflux disease, obesity (BMI), delayed gastric emptying and particularly anaesthetic techniques. Several studies have demonstrated that intravenous agents are incriminated to varying degrees. Propofol is associated with less PONV than thiopentone any may have specific anti-emetic properties (2). Nitrous oxide is thought to be associated with PONV possibly as a gut distension and raised pressure in the middle ear (3). Neuromuscular blocking agents are not implicated but reversal with neostigmine has been shown to increase emesis (4). We feel that, as this paper is likely to become a major source of reference for any doctors caring for such patients (including anaesthetists); it should include the details of the use of anaesthetic agents and techniques. References: 1-Wallenborn J, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbach A et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind muticentre trial. BMJ 2006; 333:324-7 2-Recent advances in intravenous anaesthesia Br. J. Anaesth., November 1, 2004; 93(5): 725 – 736 3- G. Verheecke. Early postoperative vomiting and volatile anaesthetics or nitrous oxide Br. J. Anaesth., January 1, 2003; 90(1): 109 - 110 4-C.-R. Cheng, D. I. Sessler et al. Does Neostigmine Administration Produce a Clinically Important Increase in Postoperative Nausea and Vomiting? Anesth. Analg., November 1, 2005; 101(5): 1349 - 1355 Competing interests: None declared |
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Jane E Alty, SpR Neurology York Hospital
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Dear Dr Gelbrich Thank you for your response. Whilst I agree with several of your comments I do think it is important to stress that the half life of metoclpramide is 4-6 hours, and up to 15 hours in those with renal impairment. This means that, despite the patients being anaesthetised, there is still a very real risk of movement disorders manifesting in the post operative period, especially with the high doses being used. Yours sincerely Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Please note that hypotension and tachycardia are attributable to 50 mg metoclopramide in about 9 percent of the patients. Another 9 percent occurred in the control group (due to either dexamethasone or other factors). Furthermore, detailed analysis has shown that metoclopramide was associated with an increase of side effects lasting up to 5 minutes but not with events lasting over 5 minutes. This may be, therefore, a minor problem. We agree that care should be taken in patients with severe heart disease. It is an interesting suggestion to examine whether infusion would solve the problem. In our study, any dose of metoclopramide was expanded to 10 mL by physiological saline and administered by slow intravenous injection. Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Sir, The case with inspiratoric stridor and cyanosis was a patient of the control group, receiving only dexamethasone. The severe adverse event occurred at the time of extubation. I would never claim a drug to be harmless, and everybody should be aware of this. I think the principle "first do not harm" would imply that we confine ourselves to prayer (which is certainly harmless). Instead, I propose the principle to consider the risk-benefit ratio, since a certain risk will always be the price for the benefit. The question is whether the price is fair for the patient. Therefore, I favour to handle desired and adverse effects in the same manner when designing the case report forms for a study and when presenting the results (I hope this can be seen from the long version of our paper at bmj.com). This includes prediction models for both benefit and harm. Since doctors and patients have widely varying opinions about the weight of certain positive and negative treatment effects, everybody should have the possibility to find his or her own (possibly individualised) decision rules for or against a treatment. Competing interests: None declared |
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Adam K Yamamoto, SHO Luton, UK, LU4 0DZ
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The combination of dexamethasone and ondansetron is one which is commonly used for the prevention of postoperative nausea and vomiting (PONV) in UK hospitals. Previous systematic reviews have shown metoclopramide to be ineffective as an antiemetic at a standard dose of 10mg, with ondansetron on the otherhand being efficacious(1)(2). Trials comparing the two agents directly have gone largely in favour of the 5-HT antagonist, but in many of these metoclopramide was tested at the 10mg dose only. The efficacy of metoclopromide over ondansetron when employed in combination with dexamethasone at doses used in the study by Wallenborn and colleagues (3) would provide further support for a return to its use in preventing PONV. Of note, the use of metoclopromide at the maximum dose of 50mg as used in this study would still be approximately 3 times less expensive than the equivalent dose of steroid and 5HT-3 antagonist (4). In view of the increasing financial strain within the NHS and the frequency of surgical procedures, this change in prescribing would be a significant one. 1. Henzi I, Walder B, Tramer MR.Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth. 1999 Nov;83(5):761- 71. 2.Tramer MR, Reynolds DJ, Moore RA, McQuay HJ.Efficacy, dose- response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo- controlled trials. Anesthesiology. 1997 Dec;87(6):1277-89 3. Wallenborn et al, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbacn UK, Kuhnast T, Wiegel M, Olthoff D. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ 2006; 333: 324 –7 4. British National Formulary 2006 Competing interests: None declared |
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Kevin D Johnston, Specialist Registrar in Anaesthetics John Radcliffe Hospital, Oxford, OX3 9DU
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EDITOR ¡V It is interesting how anti-emesis philosophy comes full circle with the observations by Wallenborn et al that higher doses of metoclopramide are effective prophylaxis against postoperative nausea and vomiting (PONV) 1. The authors comment that metoclopramide has a complex mode of action, binding to both dopamine and 5-HT receptors. In fact it has been known for some time that the effectiveness of higher doses of metoclopramide against emesis induced by the chemotherapeutic agent cisplatin is secondary to its properties as a 5-HT3 receptor antagonist. Indeed, the development of selective 5-HT3 receptor antagonists as a new class of drug became possible as a result. In recent years we have seen a vast amount of research into newer more expensive anti-emetics for use in PONV yet most people now accept that until efficacious ¡¥final pathway¡¦ anti-emetics become available, the future of PONV management lies in combining anti-emetic drugs with different receptor actions. Doses of metoclopramide between 1 and 3 mg/kg which have been used in cancer chemotherapy patients 2,3 result in 5-HT3 receptor antagonism in animal studies 4. Clearly doses in the range of 25-50 mg fall somewhat short of this but still the 5-HT3 receptor blocking profile of metoclopramide should not be ignored. It may even be that a cheap and effective drug for PONV with the combined actions of a dopamine and 5-HT3 receptor antagonist has been available for years but never been used at the right dose. On a cautionary note however, Wallenborn¡¦s subjects all received metoclopramide in combination with dexamethasone. Since the additive (even synergistic) effects of combining 5-HT3 antagonists with dexamethasone are becoming more widely appreciated, Is it possible that the differences in effectiveness between doses of metoclopramide in the study may not have been as marked had they been administered in isolation ? 1 Wallenborn J, Gelbrich G, Bulst D et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ 2006; 333:324-7 2 De Mulder PH, Seynaeve C, Vermorken JB et al. Ondansetron compared with high dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double- blind crossover study. Ann Int Med 1990; 113:834-40 3 Harrington RA, Hamilton CW, Brogden RN. Metoclopramide. An updated review of its pharmacological properties and clinical use. Drugs 1983;25:451-94 4 Gullikson GW, Loeffler RF, Virina MA. Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. J Pharmacol Exp Ther 1991;258:103-110 Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Madam, Thank you for your comment reflecting the patient's view, supporting the opinion that postoperative nausea and vomiting (PONV) is not at all a minor point. There are several options for the prophylaxis of PONV (see the response by John B Carlisle). None of them is magic, and so isn't metoclopramide; each of the drugs has its contraindications and side effects. In particular, metoclopramide is contraindicated in case of mechanic obstruction of the bowels. Furthermore, these drugs reduce the rate of PONV, and combinations reduce it drastically, but we can not promise anybody in advance that he or she will definitely be free of PONV when receiving certain drugs. However, both physicians and patients should be aware that PONV is a major side effect of surgery but we do not need to just accept its occurrence. By an appropriate policy of prophylaxis, beginning with clarifying the individual risk profiles of the patients, the majority of PONV can be avoided at reasonable cost and low rate of adverse effects. Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Sir, Indeed, we also suspected that there might be superadditive effects of the combination of dexamethasone with metoclopramide. Unfortunately, to discover such effects (called interaction of factors by the statisticians), one needs much larger sample sizes (for example, the fourfold sample size for a 2-by-2 factorial design, compared to a 2-armed design, when the superadditive gain is of the same size like the effect of a single drug). To demonstrate superaddition of 8 mg dexamethasone and 50 mg metoclopramide, we estimated n=7000 to be needed which would have been infeasible for us. Therefore we dropped interaction and focussed on the issue of highest immediate clinical relevance. The only chance to reduce sample size would be to include only patients at high baseline risk. However, to demonstrate superadditivity requires a factorial design including a placebo group. In view of cheap and effective options of prophylaxis of PONV, we would consider this unethical in a patient population with particular high risk of PONV. As a consequence, we think we need (possibly international) megatrials. Competing interests: None declared |
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Götz Gelbrich, senior biometrician D-04107 Leipzig, Germany
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Sir, Thank you for your comment. We think that part of the variables you mentioned are predictors of PONV, we are still analysing this. The matter is complicated because of the multitude of correlations between the variables involved. To mention only a simple example, body height is associated with PONV, because sex is associated with both height and PONV. In multiple regression analysis, the "influence" of body height on PONV vanishes. However, there are more tricky relationships that can not be clarified by a single regression model. Repeated analysis and discussion is required, and we try to avoid immature statements. However, by confounding we understand the following. The frequencies of a certain (side) effect in the randomised treatment groups may be different. This may induce different concomitant treatment or diagnostic procedures or surveillance of the subjects. If the concomitant treatment affects the primary outcome of interest, the estimate for the effect of the randomised treatment may be biased. As well, additional diagnostics or more intense observation may lead to observation bias. We think that the variables you mentioned are, in part, covariables of PONV, but not confounders in this sense. In particular, anaesthetic procedures may vary due to different house policies in the participating clinics. Since we stratified randomisation by type of surgery and centre, we indirectly stratified also by certain procedural variables of anaesthesia. Thus such variables, possibly affecting PONV, were not statistically associated with the dose of metoclopramide, and hence they were not confounders in the sense described above. Regarding BMI, we presented (see long version on bmj.com) that obesity (as a binary variable) was not significantly related to PONV. We also tried to find any association of BMI and PONV, including nonlinear and even nonmonotoneous relationships, but we did not find any. Competing interests: None declared |
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Arun Sehgal, SpR Anaesthesia Norwich
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Dear Dr Gelbrich Thank you for your response. It is reassuring to know that the tachycardia and hypotension last for less than 5 minutes after high dose metoclopromide. With regards to the incidence of these adverse events, reading the first 2 lines of the adverse events section of your article it appears that the incidence of tachycardia or hypertension is more than 9% with 50mg metoclopromide. Yours sincerely Competing interests: None declared |
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Louisa N Banks, Orthopaedic Registrar Wythenshawe University Hospital, South Manchester, Martyn Lovell (Orthopaedic Consultant) Shashi Godey (Orthopaedic Clinical Fellow)
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Dear Sir/Madam, We enjoyed reading the article on the prevention of postoperative nausea and vomiting by the intraoperative administration of metoclopramide combined with dexamethasone. However, we would like to express reservations about the “safe”, use of dexamethasone given the known risk of osteonecrosis of the femoral head with short-term steroid administration (1,2). Osteonecrosis (avascular necrosis) of the femoral head can be crippling, especially in the younger patient and prevention is obviously preferable. Other concerns with using this regime are that further side-effects of corticosteroid administration include poor healing and thromboemobolism (3), maybe indicating that this combination of drugs wouldn’t be suitable for patients undergoing joint replacement operations who, due to the nature of the surgery are already at increased risk of a deep vein thrombosis and where wound breakdown would be potentially disastrous. Patients on long term therapy with corticosteroids obviously need steroid cover perioperatively to prevent adrenal insufficiency, but in patients where the administration of steroids is of dubious use, the risks and the benefits must be weighed up and alternatives used where appropriate. It may be good practice for physicians and anaesthetists to discuss the administration of steroids with the operating surgeon. References: 1. McKee MD, Waddell JP, Kudo PA, Schemitsch EH, Richards RR. Osteonecrosis of the femoral head in men following short-course corticosteroid therapy: a report of 15 cases. CMAJ January 23, 2001; 164 (2) 205-6. 2. Gunal I, Karatosun V. Avascular necrosis of the femoral heads after single corticosteroid injection CMAJ July 4, 2006; 175 (1). 3. British National Formulary. British Medical Association. Royal Pharmaceutical Society of Great Britain. Competing interests: None declared |
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Götz Gelbrich, senior biometrician KKSL, D-04107 Leipzig
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Ladies and Gentlemen, Thank you for your interest and your comment. We definitely agree that physicians of different specialisation concerned with the treatment of a patient should cooperate, in particular when prescribing drugs. As well, a treatment scheme should include anamnestic issues to clarify risk factors and possible contraindications. However, we do not agree that the references you quoted provide evidence that osteonecrosis was related to low-dose corticosteroids. To understand this, imagine that I consecutively register patients of a heart centre delivered with acute myocardial infarction. My inclusion criteria is that they have driven a black car within the last three years. After a while, I have collected an impressive number of cases. Now I can submit my paper entitled "Myocardial infarction after driving a black car". Your first reference is of this type. The personal thinking of the authors that the number of 15 cases they presented is high is the only argument for the increased risk of osteonecrosis associated with LOW-DOSE corticosteroids. To assess the increased risk for an event associated with an exposure, one needs a 2-by-2 table with exposure (yes/no) in the rows and event (yes/no) in the columns. The authors presented only one out of four cells of this table. Now suppose, a patient presents with acute myocardial infarction. He did not have any risk factors or signs predicting myocardial infarction before. His physician read my article (see above), gets to know that his patient has a black car, and writes a case report. The additional "evidence" coming from this report is of the same type like your second reference. To avoid misunderstanding: I do not claim that osteonecrosis is not associated with low-dose corticosteroids. I only say that evidence should be obtained by appropriate methods. A case-control study could certainly be carried out. Case reports are useful to trigger a systematic observation, but they are not a substitute. Cumulative case reports are not necessarily cumulative evidence; they may be repeated biased observation as well. Competing interests: None declared |
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Louisa N Banks, Registrar in Orthopaedics Wythenshawe Hospital, M23 9LT, Martyn Lovell, Shashi Godey
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We note this response with surprise. The relevance of a black car is nonsensical, if osteonecrosis is associated with corticosteroids, which it is. 15 cases of osteonecrosis is a large number and should not be ignored. We again, take issue with the use of the word 'safe' in the original article. There were three facets to our letter: thromboembolism and poor wound healing were mentioned. Are these to be discounted, or are they red and blue cars ? Competing interests: None declared |
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Götz Gelbrich, senior biometrician KKSL, D-04107 Leipzig
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Ladies and Gentlemen, We warmly recommend the review paper by Salerno and Hermann [1] which contains a section dealing with the safety of low-dose corticosteroids, including the problem of wound healing, as well as other popular concerns against single low-dose corticosteroids. Retching associated with nausea and vomiting may also, by mechanical stress, jeopardise wound healing. Thus avoiding the benefit of a drug may also be harmful. This should be kept in mind when speaking about the safety of the patients. Apfel et al. [2] randomised over 5000 patients, half of them received dexamethasone (4 mg i.v.). They did not report delayed wound healing or increased risk of thrombosis with dexamethasone. Of course, they could not observe whether there is a relationship to osteonecrosis because this would occur beyond the observation time in the study. However, if there is a reason to believe that low-dose corticosteroids may cause osteonecrosis, a follow-up investigation might be initiated right now. This would provide evidence. Other suspected adverse effects could be examined at the same time. Evidence would arise from a statement like this: "In a consecutive review of all cases delivered to our unit, we found 15 patients with osteonecrosis who received and A cases who did not receive low-dose corticosteroids. Among the patients without osteonecrosis, there were B cases who received and C cases who did not receive low-dose corticosteroids. The ratio 15/A is (significantly) larger than the ratio B/C." This would not ensure causality, but at least it can demonstrate a numerical relationship. The collection of case reports by McKee et al. [3] is not evidence as it does not provide information about the numbers A, B and C (where B and C obtained from a well-defined subset of control patients would also be acceptable). What does the matter have in common with black cars? The study in mind "proving" inceased risk of myocardial infarction after driving a black car [4] is, of course, nonsense. I have chosen this example because the nonsense is obvious. In other situations, the nonsense may be less obvious, but an analogy may help to understand the point. When replacing "myocardial infarction" with "osteonecrosis" and "driving a black car" with "low-dose corticosteroid therapy", we obtain reference [3]. The methodology is exactly the same, and hence, nonsensical. References: 1. Salerno A, Hermann R. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am. 2006;88: 1361-72. 2. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350: 2441-51. 3. McKee MD, Waddell JP, Kudo PA, Schemitsch EH, Richards RR. Osteonecrosis of the femoral head in men following short-course corticosteroid therapy: a report of 15 cases. CMAJ 2001;164: 205-6. 4. Gelbrich G. Author's reply: The Concerns of The Orthopaedic Surgeon. Rapid response, bmj.com, 2 Sep 2006. Competing interests: None declared |
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