Bilotta F, Gelb AW, Stazi E, Titi L, Paoloni FP, Rosa G. Pharmacological perioperative
brain neuroprotection: A qualitative review of randomized clinical trials. Br J Anaesth
2013;110 (suppl 1):i113-20.
Perioperative brain damage resulting in new postoperative neurological deficits like
transient ischaemic attack (TIA), stroke and postoperative cognitive decline (POCD)
are among the most serious adverse complications of surgery and anaesthesia. An increased
risk of perioperative stroke is observed in cardiovascular and neurovascular procedures
and in patients with predisposing risk factors such as previous stroke, carotid stenosis,
patent foramen ovale, atrial fibrillation, infective endocarditis, diabetes, renal
failure and old age. Perioperative brain damage remains a concern because it increases
mortality, lengthens hospitalisation, impairs postoperative quality of life and increases
perioperative costs. Various drugs with different mechanisms of action have been tested
over the years for pharmacological perioperative neuroprotection, though with conflicting
results. This qualitative review of randomised controlled clinical trials (RCTs) addresses
this issue and reports the effects of tested therapies on new postoperative neurological
deficit, POCD and mortality rate.[1]
To identify trials for inclusion in this review, a detailed, systematic research using
Cochrane Central Register of Controlled Trials and MEDLINE was performed. RCTs that
met the following criteria: (i) Used any pharmacological therapy for perioperative
brain neuroprotection, (ii) evaluated pre- and postoperative neurological status,
(iii) measured pre- and postoperative cognitive status and (iv) included adult patients
undergoing elective surgery, were analysed. The details of study population, interventions
and outcomes were extracted using a standardised data extraction form. The outcome
measures in this review were new postoperative neurological deficit defined as stroke,
POCD and mortality.
Of the 5,904 retrieved studies, 25 RCTs (which included, 3,274 patients in the age
range 22-86 years) met the inclusion criteria. The tested therapies were lidocaine,
thiopental, S (+)-ketamine, propofol, nimodipine, GM1 ganglioside, lexipafant, glutamate/aspartate
and xenon remacemide, atorvastatin, magnesium sulphate, erythropoietin, piracetam,
rivastigmine, pegorgotein and 17b-estradiol. New postoperative neurological deficit
was reported in 10 RCTs that tested nine drugs. The incidence was observed to be lower
in studies that tested atrovastatin and magnesium sulphate, was associated with conflicting
results for thiopental and did not differ between treated patients and control group
for the other tested drugs. The POCD was evaluated in 24 RCTs that tested 16 drugs.
The use of lidocaine, ketamine and magnesium sulphate was associated with controversial
results on POCD, and there was no difference between treated patients and control
group for the other tested drugs. The use of remacemide and piracetam, although not
effective in reducing POCD, yielded a better postoperative ‘neurocognitive performance’.
Mortality was evaluated in 16 RCTs that tested 12 drugs and none of these drugs was
associated with a reduction in mortality rate.
In some experimental paradigms, pharmacological brain neuroprotection might reduce
the incidence of new postoperative neurological deficits and POCD, while no benefits
on perioperative mortality are described. However, the methodological inconsistencies
and weakness and the small number of studies do not allow any firm conclusions. There
is no consensus yet on the best neuropsychometric tests for detecting and quantifying
neurological damage and POCD, and also, there is no agreement on the optimal timing
for postoperative testing for research, as well as, day-to-day clinical use. Future
studies need to include a broader range of relevant clinical scenarios using a wider
consensus on the methodological approaches, including timing and dosing of drug administration,
patient selection and perioperative neurological and cognitive testing. The need for
shared methodological approach, when clinical studies on pharmacological neuroprotection
are designed, is recommended.
