A New England Salmagundi

Journals Reviewed: New England Journal of Medicine
Abstracted by: Dr J Groves (Consultant Anaesthetist, University of the Witwatersrand)

Summary of abstract

Let's see what recent editions of the NEJM has to offer! (You may wish to briefly browse our editorial comment ).


1. Selective inhibition of opioid receptors in the gut

Delay in return of gastrointestinal function & resumption of oral intake can prolong length of hospital stay and can be aggravated by postoperative opioid analgesia. Major causes of ileus include surgical manipulation of bowel & stimulation of opioid receptors by endogenous & exogenous opioids. Gastrointestinal consequences can be moderated by administration of oral naxolone, but significant absorption attenuates the efficacy of systemically administered opioids. An investigational drug called ADL 8-2698, is a selective opioid antagonist with limited oral absorption, minimal access across the blood-brain-barrier & prolonged duration of action.

Hypothesis

  • Selective inhibition of gastrointestinal opioid receptors by ADL 8-2698 may speed postoperative recovery of gastrointestinal function & shorten hospital stay.

Method

  • 79 patients undergoing major abdominal surgery partial colectomy or total abdominal hysterectomy.
  • Randomly assigned into 3 groups. First group to receive a 1 mg capsule of ADL 8-2698, 2nd group = 6 mg and 3rd group a placebo, 2 hours preoperatively & repeated twice daily until first bowel movement, until discharge or for a maximum of 7 days.

Results

  • Time to recovery of GIT function was significantly shorter in the 6 mg ADL 8-2698 group than those receiving the placebo. Median time to the 1st passage of flatus decreased from 70 to 49 hours, the time to 1st bowel movement decreased from 111 to 70 hours and time until discharge decreased from 91 to 68 hours.
  • Dose was important, with 6 mg being more effective than 1 mg.
  • Visual-analogue scores for pain, itching and abdominal cramping were similar in all 3 groups.
  • Significantly less nausea in the 6 mg group compared with the 1 mg & placebo groups.
  • Frequency of vomiting was 23% in placebo group, 26% in 1mg group but zero in the 6 mg group.

Discussion

  • Gastrointestinal opioid receptors play an important part in recovery from postoperative ileus. Ileus contributes to postoperative discomfort & increases morbidity.
  • Large doses of ADL 8-2698 have the potential to antagonise gastrointestinal opioid receptors nearly completely without inhibiting the beneficial effects of systemically administered opioids. This enables recovery of GIT function & toleration of feeds earlier, less nausea & vomiting and discharge from hospital a day earlier.
  • ADL 8-2698 has minimal absorption following oral administration and therefore has no apparent adverse effects.
  • ADL 8-2698 may be less effective in patients treated with epidurally administered local anaesthetics and it is unknown if the same benefit would be observed after other types of surgery.
Article 1: Selective postoperative inhibition of gastrointestinal opioid receptors
N Engl J Med 27 September 2001; vol 345; number 13: p 935-940.
Article type: Clinical Study
Authors: A. Taguchi & others. Washington University, St Louis.

2. Reinnervation of the transplanted heart

Exercise tolerance remains abnormal after heart transplant due to impairment of chronotropic responsiveness & ventricular function. This, in part, can be attributed to surgical interruption of postganglionic sympathetic fibres at the time of cardiac transplantation.

Studies suggest that denervation is not irreversible and partial reinnervation of the allograft is possible. The denervated heart relies on circulating catecholamines to adapt the cardiac output to demand and so exercise capacity is decreased. Reinnervation is important as it affects the sensation of chest pain, regulation of regional blood flow & substrate metabolism.

This study was conducted to determine whether partial restoration of myocardial sympathetic innervation increases the capacity for exercise.

Method

  • 29 cardiac transplant recipients otherwise healthy, no acute rejection and no allograft dysfunction.
  • Quantified the presence & extent of myocardial reinnervation noninvasively using positron-emission tomography (PET) with the catecholamine analogue [11C] hydroxyephedrine (which is taken up & stored in presynaptic sympathetic nerve terminals).
  • Examined the relationship between reinnervation and allograft function at rest and during exercise by measuring global & regional ventricular function using radionuclide angiography.
  • The results were compared with a control group of 10 people, with no clinical or ECG evidence of heart disease. The composition and mean age of the control group were similar to those of the study group.

Results

  • Sympathetic reinnervation, mainly in the anteroseptal wall, was present in 16 of the 29 transplant recipients.
  • At rest, no significant haemodynamic difference between the reinnervation group & the dennervation group.
  • Overall exercise time was significantly longer in the reinnervation group, but less than the controls.
  • Persistent dennervation was associated with shorter mean exercise time and lower peak heart rate.

Discussion:

  • Findings confirm sympathetic reinnervation. The interval between transplant and participation in the study was significantly longer in the reinnervation group and the donors were younger. Reinnervation improved the chronotropic & inotropic response to exercise.
  • A variety of factors other than reinnervation may influence the ventricular performance & exercise capacity in cardiac transplant recipients. Such as, prolonged cold ischaemia of the allograft, episodes of rejection, perimyocytic fibrosis, hypertension induced by immunosuppressants, occult ischaemia, transplant vasculopathy and peripheral deconditioning.
  • Although exercise time was significantly improved in the reinnervation group, it does not return to normal levels.
Article 2: 2. Effect of sympathetic reinnervation on cardiac performance after heart transplantation
N Engl J Med 6 September 2001; vol 345; number 10: p 731-738.
Article type: Clinical Study
Authors: F. M. Bengel & others. University of Munich.

3. Lung volume reduction -- survival reduction?

Lung-volume-reduction surgery is a potentially valuable treatment for patients with advanced emphysema. Surgery involves the removal of 20-35% of emphysematous lung to improve lung mechanics. Generally lung function, exercise capacity and quality of life improve, but results do vary. The surgical mortality ranges from 4-15% and the one-year mortality rate is as high as 17%.

Uncertainty about the risk of lung-volume-reduction surgery, magnitude and duration of benefit and the optimal selection criteria, were the motivation for the multicenter, randomised clinical trial. The National emphysema treatment trial compares lung-volume-reduction surgery with medical treatment.

Goal

  • Compare survival rates and exercise capacity 2 years after lung-volume- reduction surgery with results obtained from medical therapy.
  • Identify optimal selection criteria for surgery.

Methods

  • Emphysema patients were randomly assigned to undergo lung-volume- reduction surgery or receive medical treatment.
  • Results were reviewed by an independent data & safety monitoring board.
  • Identification of a subset of high-risk patients lead to stopping the enrolment of these patients into the trial.

Results

  • 1033 patients where enrolled between January 1998 June 2001. Of these, 140 patients met the criteria for high-risk of death after surgery 70 were randomly assigned to the surgical group & 70 to the medical group.
  • High-risk was defined as
    1. very low FEV1 (< than 20% of predicted)
    2. very low carbon monoxide diffusing capacity (< 20% of predicted) or homogenous emphysema (diagnosed on CT scan)
  • 69 patients in the surgical group underwent Lung-volume-reduction surgery, 1 patient refused.
  • Surgery consisted of either a median sternotomy (47 patients) or video- assisted thoracoscopy (22).
  • 4 patients in the medical group undertook surgery out of the trial 2 of which died.
  • Mortality & morbidity
    1. No deaths 30 days after randomisation in the medical group.
    2. 30-day mortality was 16% in the surgical group, if all 3 high-risk factors present, mortality rose to 25%.
    3. Overall mortality 0.43 deaths/person-year (surgical) and 0.11 deaths/ person-year (medical)
    4. At 6 months: surgical group had more deaths, where as in the medical group more patients were unable to undergo testing due to illness.
  • Survivors of surgery had a small improvement at 6 months in the maximal workload, the distance walked in 6 minutes but the health- related quality of life was similar between the two groups.

Conclusion

  • Caution is warranted in the use of Lung-volume-reduction surgery in patients with emphysema who have low FEV1 and either homogenous emphysema or very low carbon monoxide diffusing capacity.
  • These patients are at high-risk for death after Lung-volume-reduction surgery and are unlikely to derive benefit from the procedure.
Article 3: Patients at high-risk of death after Lung-volume-reduction surgery
N Engl J Med 11 October 2001; vol 345; number 15: p 1075-1083
Article type: Clinical Study
Authors: National Emphysema treatment trial research group.


Editorial - Why do some COPD patients do badly?

We're intrigued by the last article. Not, you understand, because we thought it was a bad article. On the contrary, the authors appear to have done a fine job, carefully (and prospectively) auditing a major trial of lung volume reduction surgery, picking out high-risk candidates right from the start, and then wisely stopping enrolment of such patients when it became clear that they were being harmed by the surgery.

What we are interested in is information not contained in the study. We'd like to know how well the nutritional status of the patients correlated with survival. We have our reasons. The abstract from a recent Japanese study on Lung volume reduction surgery (LVRS), [Jpn J Thorac Cardiovasc Surg 2001 Sep;49(9):552-6] supports what we've known about 'COPD' for some time - that those patients who are malnourished do badly! According to the authors "We found fat-free mass and body weight to be good predictors of unacceptable postoperative complications following bilateral lung volume reduction surgery". Another recent study of LVRS [Lung 2000 Nov-Dec;178(6):381-9] found three quarters of patients to be underweight before surgery, with improvement in fat-free mass in both studies after surgery. Schwebel's recent study of lung-transplantation candidates provides yet more evidence for an association between severe respiratory disease and nutritional depletion [Eur Respir J 2000 Dec;16(6):1050-5]. In another study, fifty three percent of LVRS candidates had subnormal BMIs, and one quarter of these required prolonged ventilatory support, compared with 4% of those with a normal BMI [Chest 1999 Sep;116(3):693-6].

We have recently begun to appreciate that "chronic obstructive airways disease" is more a systemic disease than a lung disease. Systemic inflammation is common, and probably contributes to malnutrition and impaired outcome [Novartis Found Symp 2001;234:242-9]. Inflammatory products such as tumour necrosis factor may be chronically elevated, and contribute to anorexia and loss of muscle mass. Effort tolerance in such patients is often limited more by weakness of skeletal muscles than "breathlessness" per se. This weakness may be due to both loss of skeletal muscle mass, and impaired provision of oxygen to the musculature.

We're not betting people, but would be prepared to wager a small amount that, had the National Emphysema Treatment Trial Research Group provided an indication of nutritional status in their 'high risk' subgroup, these patients would have been nutritionally far worse off than the 'low risk' LVRS candidates. Which brings us to another point .. When are researchers going to start providing complete records of all the raw data from studies, without which, more often than not, such studies become valueless twenty years down the line. Why valueless? Because, years later, someone always thinks up a comparison or test that the authors neglected, and can only be resolved by examining all of the data!

Ed      

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