Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury

Abstract

Objective: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury.

Methods: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days.

Results: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079).

Conclusions: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.

Keywords: acquired brain injury; consciousness; epilepsy; stroke; subarachnoid haemorrhage.

Figure 1

Flow chart of study participants. Overall, 302 patients with different NTBI and mechanical ventilation ≥7 days were recruited between 1 January 2012 until 31 December 2015; 102 with IS, 113 patients with ICH, 42 with SAH, 16 with CABM and 29 with SE. After exclusion of eight patients because of missing data on amantadine treatment, the study sample consisted of 294 patients. In the control group, patients were randomised (1:1:1) to one of the three categories of treatment initiation (early, delayed and late) and patients who were not eligible for amantadine treatment at respective time points (GCS>6 at each day of the corresponding categories of treatment initiation: day 1 until day 5 for early treatment initiation group, day 6 until day 10 for delayed group and day 11 until day 15 for late group) were excluded. Afterwards, there were 84 patients in the amantadine group and 100 patients in the control group. Patients in the SE registry could be included repeatedly for separate episodes of SE, but patients included in outcome analysis of amantadine treatment were all different individual patients. CABM, community-acquired bacterial meningitis; ICH, intracerebral haemorrhage; IS, ischaemic stroke; NTBI, non-traumatic brain injury; SAH, subarachnoid haemorrhage; SE, status epilepticus; UKER, Universitätsklinikum Erlangen;.

Figure 2

Subgroup analyses. Subgroup analyses were conducted for the primary outcome, improvement of consciousness at day 5, using multivariable regression analyses adjusted for age, GCS at treatment initiation and duration of ventilation until weaning initiation (without the subgroup-defining variable). Early treatment was defined as administration of the first dose of amantadine within 3±2 days after weaning initiation; delayed treatment was defined as treatment initiation within 8±2 days; late treatment was defined as treatment initiation within 13±2 days. CABM, community-acquired bacterial meningitis; GCS, Glasgow Coma Scale; ICH, intracerebral haemorrhage; IS, ischaemic stroke; SAH, subarachnoid haemorrhage; SE, status epilepticus.

Figure 3

Exploratory analyses regarding the time course of consciousness. Illustration of the time course of consciousness from 5 days before amantadine treatment initiation (shown in light grey) until 10 days thereafter, d0 represents the day of amantadine treatment initiation. (A) For exploratory illustration, mean values of GCS were calculated for amantadine group (square) and control group (circle). Points represent the mean and thin lines the SD. (B) For exploratory illustration, mean differences of GCS values between amantadine group and control group were calculated. Points represent the mean difference and thin lines the 95% CI. Patients discharged from hospital before respective days of GCS assessment were not accounted for (secondary outcome analysis of GCS at day 5 and GCS at day 10 included GCS at hospital discharge for these patients). GCS, Glasgow Coma Scale; NTBI, non-traumatic brain injury.