Pharmacological perioperative brain neuroprotection: A qualitative review of randomized clinical trials

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.

No conflict of interest has been declared by the author(s).

• REFERENCE

• 1 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 (Suppl. 01) i113-20