|Journals Reviewed: BJA 1999 & 2000, Anesthesia & Analgesia 1999
|Abstracted by: Dr N Lowery; MB BCh (Registrar, University of the
Summary of abstracts
As anaesthesiologists, we often play a vital role in organ preservation. We are often called
upon to anaesthetise patients with organ disease and dysfunction, and need to be aware
that there are certain steps we can take to protect the organs in question. What follows
are three articles dealing with this topic as it relates to our theatre practice, highlighting
(You may wish to briefly browse our editorial comment
1. PROTECTIVE EFFECT OF ANAESTHETICS IN REVERSIBLE AND
IRREVERSIBLE ISCHAEMIA-REPERFUSION INJURY
Summary: Many studies have shown that inhalation anaesthetics such as isoflurane,
enflurane and halothane have potent cardioprotective effects. The cardioprotective effects
can be attributed to several factors: preservation of energy levels during ischaemia;
alteration of intracellular calcium concentrtations; inhibition of free radicals; and
interactions with KATP channels.
Potent inhalation agents also have preconditioning effects which may be beneficial,
particularly in patients who are susceptible to myocardial infarction during and after
The article in brief:
Ischaemia and subsequent reperfusion of the myocardium can lead to reversible or
irreversible injury depending on the severity and duration of the preceding ischaemia.
Some anaesthetics, particularly potent inhalational agents, can afford protection against
Reversible ischaemia-reperfusion injury:
Reperfusion injury is defined as cell injury due to reperfusion itself and not the preceding
ischaemia. Manifestation of reversible reperfusion injury include arrhythmia, post
ischaemic contractile dysfunction (stunning) and coronary vascular injury.
Stunning is a fully reversible yet prolonged depression of mechanical function following
brief periods of ischaemia even after myocardial blood flow has been restored.
Mechanisms behind stunning:
- Free radical formation (superoxide, hydroxyl and hydrogen peroxide
- Calcium overload – Considered to be the ultimate culprit in stunning
- Abnormalities of microvasculature
Anaesthetics and reversible ischaemia-reperfusion injury
A. Halogenated anaesthetics
- Preservation of myocardial energy stores - possibly caused by negative inotropic and
chronotropic effects. Actual mechanism of ATP preservation not known
- Alterations in calcium fluxes. Volatiles depress calcium influx through L-type
channels and Na+ - Ca2+ exchange, and could be one of the mechanisms that protects
against calcium overloading.
- Inhibition of free radicals. Effect of free radicals inhibited by halothane, isoflurane
and enflurane. Halothane shown to inhibit production of hydroxyl radical.
Mechanism not known, but may involve decreased intracellular calcium levels.
- Effect on K ATP channels. Channel opening before ischaemia can protect ischaemic
heart, attributed to shortening of action potential duration or attenuation of
membrane depolarisation. Volatiles cause channel opening, possibly mediated via
adenosine type-1 receptors
B. Intravenous anaesthetics
Little evidence of cardioprotection. Some work to suggest that propofol may have
protective effects following global ischaemia
Protection against irreversible injury
Volatile anaesthetics shown to have a preconditioning effect, reducing infarct size by up
to 50% (isoflurane)
Protective effects of anaesthetics in reversible and irreversible ischaemia-reperfusion injury.
Brit J Anaes 1999 Apr 82(4) 622-32.
S. Ross and P. Foex |
2. DOES BEATING HEART SURGEY AFFORD ANY CEREBRAL PROTECTION?
Off-pump coronary artery bypass (OPCAB) is currently very topical in anaesthesia
literature. One of the many problems associated with coronary artery bypass grafting
(CABG) is the so-called "cognitive carnage" associated with cardiopulmonary bypass
(CPB). Studies suggest that this may be due to the high number of emboli associated with
CPB. In a recent study by Watters et al, OPCAB was shown to be associated with fewer
cerebral emboli than with CPB, but does this mean less cognitive deficit?
Watters et al demonstrate in this study that OPCAB is associated with fewer emboli as
detected by transcranial doppler (TCD) , and suggest that future studies may show that it
is associated with a better neurological outcome
- Comparative study
- Non randomised
- Non blinded
20 patients were scheduled for CABG, and choice of technique (OPCAB vs CPB) was at
the surgeons' discretion(n = 10 in both groups). Anaesthesia was the same in both groups
(fentanyl and propofol). A 2 MHz Bidirectional TCD was applied to the right temple to
detect emboli in the region of the middle cerebral artery. Emboli were recorded from the
time of pericardial incision to last aortic manipulation. Data was analysed using the
Microembolus count (median and range) in the OPCAB group was 3 (0-18), compared to
79 (38-876) in the CPB group (p <0.001), demonstrating that OPCAB was associated with
- Measurable endpoints (emboli counts)
- Elegant, simple design
- Appropriate use of statistics (Mann-Whitney U test for nonparametric data)
- Non-randomised – biggest criticism! (although some may argue that surgeons’ choice
is sufficient randomisation!)
- Although it answers the question it sets out to, it does not give us information
regarding neurological outcome – no doubt a trial for later consideration!
REDUCED CEREBRAL EMBOLIC SIGNALS IN BEATING HEART
CORONARY SURGERY DETECTED BY TRANSCRANIAL DOPPLER
BJA 2000 84(5) 629-31 |
Clinical Study |
Watters MPR, Cohen AM et al |
3. PROPOFOL AS AN ANTIOXIDANT?
Propofol has a structure similar to known antioxidants (such as tocopherol). The ability of
propofol to inhibit the formation of lipid peroxides has been found in various media in
which free radicals are produced. De La Cruz et al take an in depth look at propofol’s
Propofol can protect against lipid peroxidation, claims Cruz et al. Lets take a closer look
at their study.
- Randomised (at least partly)
- Non blinded
60 Patients (ASA 1 and 2) undergoing surgery (not open abdominal surgery) and 12
healthy volunteers were studied. The 60 patients undergoing surgery were allocated to 1
of 3 groups. Allocation to groups 1 and 2 was random, while allocation to group 3 was based
upon length of surgery (greater than 1 hour)
Induction with thiopentone 4mg/kg
Induction with propofol 2mg/kg
- Induction propofol 2mg/kg
- Infusion: 10mg/kg for first 10min, 8mg/kg for next 10 mins then 6mg/kg for rest of operation
- Healthy volunteers
- No anaesthetic
- Intralipid 10% iv
The following were measured as indicators of free radical damage within platelets:
- Thiobarbituric acid (measure of lipid peroxidation)
- Glutathione, reduced and oxidised
- Glutathione peroxidase
- Glutathione reductase
- Glutathione transferase
Samples were drawn pre-induction, 5 mins post-induction and, in the case of group 3, 60
mins after the first dose of propofol and analysed for the above substances.
All statistical analyses done with Social Program for Statistical Sciences (SPSS). One
way analysis of variance and post hoc Bonferroni adjustment used to compare differences
within groups. Kruskal-Wallis test used to compare differences among groups.
Considered significant when p < 0.05
No difference between all groups preinduction. No statistical differences between group 1
and 4 post induction, but groups 2 and 3 were significantly different from groups 1 and 4.
Propofol significantly inhibited lipid peroxidation in platelets, whereas administration of
intralipid (group 4) had no significant on this value.
Platelet glutathione was significantly higher in patients given bolus propofol
Oxidised glutathione was significantly lower after propofol was given whereas intralipid
had no effect on this value.
Glutathione peroxidase levels were lower, G. transferase levels higher after propofol
administration. G reductase levels not significantly different.
Propofol infusion was associated with even lower levers of oxidised glutathione than
Propofol does have antioxidant effects in human platelets. This effect may be beneficial in
protection against free radical injury. Although this study looked only at platelets
(specifically, platelet membranes), in vitro studies demonstrate that propofol has
antioxidant effects in other organs too (brain, liver, lung, vessel wall, kidney and heart)
Whether this is of clinical value remains to be seen
- Some randomisation
- Clearly defined exclusion criteria
- Measurable endpoints
- Non blinded. Probably not necessary, as analysis done by laboratory, who will be
- Statistical analysis. This is the part that bothers me most. ANOVA is a good start, to
detect if there is a difference between groups, but the Bonferroni puzzles me. It is a
little unclear as to which comparisons were made, but appears that all possible
comparisons between groups were made. This renders the Bonferroni insenstive, as
the value to reach significance decreases as the number of comparisons increases, and
results may be called insignificant when in fact they actually are. A better test here
may be the Student-Newman-Keuls test, as this gives a more accurate result when
considering multiple comparisons. They then use the Kruskal-Wallis test for between
group comparisons – previously they have used a parametric test and now they are
using a non parametric test. Lastly, they are using repeated measurements on the
various groups - would not a repeated measures (2 way analysis of variance) test be
more appropriate? Perhaps our editor could help me untangle this conundrum.
THE EFFECT OF PROPOFOL ON OXIDATIVE STRESS IN PLATELETS
FROM SURGICAL PATIENTS
Anesth Analg 1999 89 1050-5 |
'Randomised clinical trial'
De La Cruz JP, Zanca A et al |
Doctor Lowery is just possibly shooting at the wrong target.
- He seems to be confusing the use of a post-hoc Bonferroni (administered after an ANOVA) with
the Bonferroni correction used with multiple tests. The idea behind the post-hoc Bonferroni is that
the ANOVA tells us that there is a sample that differs from the rest - the Bonferroni identifies the
difference and corrects for any potential Type I error.
Many would regard the Bonferroni as being very conservative in the current setting - so where the
authors found significant differences, we should accept them. In a similar
vein, we could counter Dr Lowery's later proposal that we use a repeated
measure ANOVA with the argument that a conservative approach is desirable!
- Quite frankly, we're not sure whether the Newman-Keuls (perhaps the least conservative
of all the post-hoc tests) is the right idea. We would prefer a
Tukey (just to keep things honest)!
- The use of a non-parametric test (K-W) is another example of the authors' extreme conservatism -
in a statistical world where authors are striving for the magical achievement of significance, it
seems a bit harsh to shoot the conservatives!
As an aside it might be mentioned that in the past there has been much breast-beating by statisticians
where parametric tests have been used on populations that are non-normal. At least some of this may
be unjustified. Monte Carlo simulations have shown that even in extreme cases, the errors usually
introduced by non-normal population structure are often far smaller than we previously anticipated.
Of greater concern than the above statistical peccadilloes is the study design! Was it really necessary
for the authors to have four groups (resulting in much of our statistical travail)? We get the impression that
the study design went something along the following lines:
- "We now have the facility to do all sorts of fancy tests of oxidative stress;
- Let's look at the cases in theatre - hmm, the TIVAs really don't fit in so we'll make them a separate
- What about some normals - just for the hell of it?"
We get the feeling that a simple study where patients were randomised into two groups would probably
have done the trick, and still constituted a SPU (smallest publishable unit).
One other small point - it's often better to acquire (and easier to prove)
written consent than the verbal consent obtained in this study!