Intraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment Protocol

Abstract

Background: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IAN_only) treatment protocol for refractory DCI in an observational study.

Methods: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IAN_only). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5).

Results: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IAN_only 0.26±0.20 µg/kg per minute, P<0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P<0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P=0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P=0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P=0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P<0.01).

Conclusions: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Keywords: Glasgow Outcome Scale; brain ischemia; nimodipine; norepinephrine; subarachnoid hemorrhage.

Figure 1.

Classical (iHTN+IAN) and modified (IAN_only) treatment protocols. DCI: delayed cerebral ischemia; ERT: endovascular rescue treatment; iHTN+IAN: patients treated according to the classical protocol; IAN_only: patients treated according to the modified protocol; TCD: transcranial doppler ultrasonography; SBP: systolic blood pressure.

Figure 2.

Primary outcome (noradrenaline demand). (A) Noradrenaline requirements were strongly increased 24 hours after initiation of IAN in patients treated with iHTN+IAN (0.23±0.32 to 0.67±0.56μg/kg/min, Wilcoxon rank sum test, p<0.0001). With IAN_only, demand was still elevated after initiation of IAN (0.21±0.17 to 0.36±0.30μg/kg/min, p<0.05) but the increase was more moderate than with iHTN+IAN (p<0.05). (B) Mean noradrenaline demand displayed as Tukey boxplot. The line in the middle of the box represents the median value, the box edges represent 25^th and 75^th percentiles, the whiskers represent all other values up to 1.5 times the interquartile range, outliers are shown as dots. Noradrenaline demand of the total treatment duration was significantly reduced with IAN_only (iHTN+IAN 0.70±0.54μg/kg/min, IAN_only 0.26±0.20μg/kg/min, p<0.0001).

Figure 3.

Brain tissue oxygenation and intracranial pressure. (A) Brain tissue oxygenation (p_tiO₂) and (B) intracranial pressure (ICP) calculated as means over the total treatment duration (neuromonitoring iHTN+IAN n=21 (72.4%), IAN_only n=11 (55.0%)) with significantly higher p_tiO₂ and lower ICP with IAN_only.