New England Journal of Medicine
|Abstracted by: Dr J Groves (Consultant Anaesthetist, University of the
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
- Selective inhibition of gastrointestinal opioid receptors by ADL 8-2698
may speed postoperative recovery of gastrointestinal function & shorten
- 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.
- 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 &
- Frequency of vomiting was 23% in placebo group, 26% in 1mg group but
zero in the 6 mg group.
- 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.
Selective postoperative inhibition of gastrointestinal opioid receptors
N Engl J Med 27 September 2001; vol 345; number 13: p 935-940.
Clinical Study |
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
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.
- 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.
- 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.
- 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
- Although exercise time was significantly improved in the reinnervation
group, it does not return to normal levels.
2. Effect of sympathetic reinnervation on cardiac performance after heart
N Engl J Med 6 September 2001; vol 345; number 10: p 731-738.
Clinical Study |
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.
- 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.
- Emphysema patients were randomly assigned to undergo lung-volume-
reduction surgery or receive medical treatment.
- Results were reviewed by an independent data & safety monitoring
- Identification of a subset of high-risk patients lead to stopping the
enrolment of these patients into the trial.
- 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
- High-risk was defined as
- very low FEV1 (< than 20% of predicted)
- 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
- Mortality & morbidity
- No deaths 30 days after randomisation in the medical group.
- 30-day mortality was 16% in the surgical group, if all 3 high-risk
factors present, mortality rose to 25%.
- Overall mortality – 0.43 deaths/person-year (surgical) and 0.11
deaths/ person-year (medical)
- At 6 months: surgical group had more deaths, where as in the
medical group more patients were unable to undergo testing due
- 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.
- 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.
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 |
Clinical Study |
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!