Stimulants for disorders of consciousness in the intensive care unit: a randomized, placebo-controlled trial

Abstract

In the intensive care unit (ICU), management of unresponsive patients with brain injury focuses on preventing secondary brain damage. Therapeutic strategies that directly promote the recovery of consciousness are urgently needed. In an investigator-initiated, randomized, placebo-controlled, double-blind, cross-over trial, we studied the effects of apomorphine and methylphenidate in ICU patients with acute disorders of consciousness (DoC). We hypothesized that these stimulants would improve consciousness biomarkers assessed by automated pupillometry (primary outcome) and clinical signs of consciousness (secondary outcome). We randomized 50 ICU patients with DoC (14 female; mean age 63 ± 10 years; 48 with non-traumatic brain injuries) to strata consisting of three consecutive treatment sessions during which apomorphine, methylphenidate or placebo were administered. In total, we administered 112 study medications, including 36 doses of apomorphine, 39 doses of methylphenidate and 37 doses of placebo. Missing administrations were due to death, ICU discharge or spontaneous consciousness recovery. Plasma concentrations of stimulants confirmed drug exposure. We found no adverse events related to the trial drugs. Pupillometry recordings of sufficient quality (n = 590) were available from 48 (96%) patients. A pupillary response to a verbal arithmetic command (i.e. ≥3 pupillary dilations on five verbal arithmetic tasks) was identified during 70 (12%) of these recordings. Seven (15%) patients without any other observable response to spoken commands also passed a stricter threshold of ≥4 pupillary dilations, suggesting cognitive motor dissociation. Apomorphine [odds ratio (OR) 1.35, 95% confidence interval (CI): 0.93 to 1.96] and methylphenidate (OR 1.29, 95% CI: 0.89 to 1.86) did not significantly increase pupillary responses. However, after study drug administration, 10 (20%) patients showed improved clinical arousal at least once. Signs of arousal were noted after one dose of placebo, four doses of apomorphine (OR 5.04, 95% CI: 0.56 to 120.7) and seven doses of methylphenidate (OR 9.96, 95% CI: 1.36 to 235.8). Changes toward higher consciousness level categories were observed once after placebo, four times after apomorphine (OR 5.67, 95% CI 0.63 to 169.46) and three times after methylphenidate (OR 3.41, 95% CI 0.34 to 88.00). In a post hoc analysis, patients with greater pupillary responsiveness showed better arousal, suggesting that this condition may predict stimulant drug effects. In conclusion, while pupillometry revealed no direct drug effects on overall pupillary responses, stimulants may have triggered clinical arousal in some patients, particularly in those with greater pupillary responsiveness. These findings require replication but should guide future pharmacological trials aimed at improving consciousness recovery after brain injury.

Keywords: apomorphine; brain injury; clinical trial; coma; consciousness; methylphenidate; pupillometry.

Figure 1

Study overview. In an investigator-initiated, randomized, placebo-controlled, double-blind, cross-over trial, we investigated the effects of apomorphine and methylphenidate on clinical consciousness levels and consciousness biomarker in acute DoC patients with traumatic or non-traumatic brain injury in the ICU. This figure depicts the study design (A) and study outcomes (B). DoC = disorders of consciousness; ICU = intensive care unit. Created in BioRender. Kondziella, D. (2025) https://BioRender.com/niebd75.

Figure 2

Swimmer plot of time in the ICU for 50 DoC patients. Patients are ordered according to the type of brain injury and length of ICU stay. The plot shows key events during the time course of the study, including day of study enrolment, study drug administrations and functional status at ICU discharge and at 3 months (alive versus dead). Improved arousal during study drug application is highlighted (green circles). Of 50 patients enrolled in the study, 10 showed clinically improved arousal at least once after administration of a study drug (Patients 20 and 21 showed improvement twice). A = apomorphine; M = methylphenidate; P = placebo. Inset: Selected neuroimaging pathologies, including cortical and/or subcortical injury related to herpes encephalitis (coronal FLAIR, Patient 3), post-cardiac arrest encephalopathy (axial DWI, Patient 4), carbon monoxide poisoning (axial DWI, Patient 8), traumatic brain injury (axial CT, Patient 10), intracranial mesencephalic haemorrhage (axial T1, Patient 20), ischaemic stroke from a basilar artery occlusion (axial DWI, Patient 34), cerebral microbleeds associated with extracorporeal membrane oxygenation after major thoracic surgery (axial SWI, Patient 39), obstructive hydrocephalus with cerebral metastasies (axial T2, Patient 43), aneurismal subarachnoid haemorrhage with subdural extension (axial CT, Patient 46) and intracerebral haemorrhage from an arteriovenous malformation with obstructive hydrocephalus (axial CT, Patient 50). DWI = diffusion weighted imaging; FLAIR = fluid attenuated inversion recovery; ICU = intensive care unit; SWI = susceptibility weighted imaging.

Figure 3

Drug responses, pupillary dilations and clinical outcomes. Improved arousal with a study drug was mostly seen in patients alive at ICU discharge and in those with four or five pupillary dilations during mental arithmetic tasks, including patients fulfilling CMD criteria. Numbers indicate Patient IDs. CMD = cognitive motor dissociation; ICU = intensive care unit.

Figure 4

Plasma concentration of stimulant drugs. This figure shows box plots of drug levels and a superimposed strip chart of individual data-points. Plasma concentrations of methylphenidate remained stable for a longer period than levels of apomorphine.

Figure 5

Automated pupillometry and the effects of stimulant drugs during mental arithmetic. Representative pupillometry data of four DoC patients at baseline (T0), revealing the count of statistically significant pupillary dilations during mental arithmetic tasks (A). The data are graphically represented in box plots (left) and scatter plots (right). Mental arithmetic = green; rest = yellow; tick symbol (✓) = significant pupillary dilation (P < 0.0001). No pupillary dilations were observed in the coma patient and the UWS patient. In contrast, the MCS minus patient and the MCS plus patient responded with pupillary dilations during ≥4 of 5 mental arithmetic tasks. This meant the MCS minus patient (Patient 16 in Fig. 3 and Supplementary Table 5) fulfilled CMD criteria. Stimulants had no statistically significant effects on the number of pupil dilations during mental arithmetic (B). CMD = cognitive motor dissociation; DoC = disorders of consciousness; MCS = minimally conscious state.

Figure 6

Clinical effects of stimulant drugs on arousal and consciousness level categories. (A) Fifty DoC patients received 112 administrations of a stimulant drug or placebo. Numerically increased odds ratios for improved arousal (B) and for a shift towards a higher consciousness level category (C) were seen after administration of methylphenidate and apomorphine. DoC = disorders of consciousness; ICU = intensive care unit.