Analgesia and sedation are core components of intensive care unit (ICU) care. They are used to relieve pain and anxiety, prevent harmful physiological stress responses, improve tolerance of invasive devices and mechanical ventilation, and reduce noxious stimulation. Contemporary ICU practice has moved away from deep continuous sedation toward analgesia-first care, lighter sedation targets, delirium prevention, early mobilization, and patient-centred comfort strategies.
Patients admitted to the ICU after neurosurgical craniotomy pose a specific challenge. Postoperative agitation after intracranial surgery may lead to unplanned extubation, catheter or drain removal, injury, hypertension, coughing, increased sympathetic activation, and potentially adverse neurological consequences. The incidence of agitation after elective intracranial operations was 29%, which was higher than that previously observed in other surgical populations. Neurosurgical patients may be more vulnerable to stress caused by agitation, due to longer anesthesia duration, delayed extubation and pain and post-craniotomy frontal pneumocephalus. Brain lesions and intracranial manipulations in neurosurgical patients might affect the brain regions which involves cognition and emotion, and are assumed to influence postoperative cognition. At the same time, excessive hypnotic sedation may obscure level of consciousness, pupillary and focal neurological examinations, early seizures, intracranial hypertension, or surgical complications. Previous neurosurgical studies have reported postoperative agitation and delirium after craniotomy were not rare, and risk factors including longer anesthesia duration, delayed extubation, pain, and postoperative pneumocephalus have been reported.
However, the investigations of analgesia and sedation in neurosurgical populations have been inadequate. Most of the researches about analgesia and sedation in general ICU were excluded the neurosurgical patients. These patients are special for its cruciality of evaluating the consciousness and neurological signs examination. The analgesia and sedation management is difficult and complex. Several general ICU studies support interest in minimizing routine hypnotic sedation. In a single-centre randomized trial, a protocol of no sedation with morphine boluses increased ventilator-free days and shortened ICU and hospital stay compared with sedation and daily interruption, although agitated delirium was more frequent. In the larger multicentre NONSEDA trial, mortality at 90 days did not differ significantly between nonsedation and light sedation with daily interruption, and many patients in the nonsedation group still required sedatives during ICU stay, most commonly because of delirium. Related NONSEDA substudies have also emphasized that the effects of nonsedation on physical function and cognition require dedicated evaluation.
These findings cannot be directly transferred to post-craniotomy neurocritical care. Reviews, consensus statements and observational studies in neurocritical care emphasize with brain-injured patients have unique sedation indications, including control of intracranial pressure, seizures, cerebral oxygen consumption, ventilator synchrony, and severe agitation. Observational data from brain-injury ICUs show wide variation in sedative and analgesic practice and support structured use of sedation and pain scales. Expert consensus also supports administering analgesics before sedatives when clinically appropriate, but acknowledges the limited high-quality evidence in this population. Therefore, an analgesia-first strategy without routine hypnotic sedatives should be evaluated cautiously with explicit neurological safety monitoring and rescue criteria.
Remifentanil is a short-acting opioid with rapid onset and offset because it is metabolized by non-specific blood and tissue esterases. These pharmacological features make it suitable for titrated analgesia when repeated neurological assessment is needed. We therefore designed this single-arm exploratory study to estimate the feasibility and safety of a remifentanil-based analgesia-first strategy without routine hypnotic sedatives in selected adult patients admitted to ICU after neurosurgical craniotomy.
Age 18-85 years;
Admission to the ICU after neurosurgical craniotomy;
Anticipated ICU stay greater than 24 hours according to the treating team at ICU admission or screening;
The Richmond Agitation-Sedation Scale (RASS) score ≥ +1, indicating restlessness or agitation requiring clinical management;
Need for deep sedation or therapeutic coma, including (partial pressure of oxygen(PaO2)/fraction of inspired oxygen(FiO2): PaO2/FiO2≤100 mmHg, neuromuscular blockade requiring unconsciousness, status epilepticus, mandatory immobility for surgical or procedural safety, severe traumatic brain injury and intracranial hypertension, therapeutic hypothermia and any clinical condition requiring RASS < -2) [15, 16];
Medullary lesion, brainstem condition, or other disorder associated with impaired respiratory drive in which opioid analgesia is judged unsafe by the treating physician [17];
Inability to assess the RASS score or neurological status because of coma, severe aphasia, status epilepticus, severe cognitive dysfunction, schizophrenia, mania, or aother psychiatric or neurological condition that precludes reliable assessment.;
Use of sedatives or opioid analgesics ≥ 1 week before enrollment;
Single group
analgesia-first strategy without hypnotic sedatives
DrugThe study intervention is an analgesia-first strategy without routine hypnotic sedatives. The strategy does not imply absence of all sedative effect; remifentanil may influence arousal, and the RASS target includes light sedation. Routine hypnotic sedatives are avoided unless rescue sedation is clinically required. RASS and CPOT will be assessed routinely, with target RASS -2 to +1 and CPOT 0-1 . Reversible causes of discomfort will first be evaluated and treated, including hypoxia, airway obstruction, ventilator dyssynchrony, pain, urinary retention, nausea, tube irritation, environmental stressors, and neurological deterioration. Non-pharmacological measures such as reassurance, communication, family support when appropriate, sleep protection, and mobilization when safe will be used before pharmacological escalation.
The rate of successful protocol management during the first 24 hours after initiation of the analgesia-first strategy
Successful protocol management requires no rescue hypnotic sedative use, no protocol discontinuation for safety, and adequate RASS control according to the following operational rule: at least 80% of scheduled RASS assessments during the first 24 hours must be within the target range of -2 to +1, with no sustained RASS \> +1 lasting more than 30 minutes despite protocolized treatment and no RASS +3 or +4 at any scheduled or clinically indicated assessment.
The incidence rate of adverse events
Adverse events include accidental extubation, accidental catheter or drain removal, significant agitation, delirium, severe hypotension, severe bradycardia, respiratory depression, vomiting or aspiration risk, opioid-induced rigidity, seizure, neurological deterioration, suspected or confirmed intracranial hypertension, emergent neurosurgical intervention, and urgent unplanned CT or MRI for suspected neurological worsening.
Dosage of remifentanil
total remifentanil dose (mg)
ICU length of stay
ICU length of stay (days)
ICU cost
ICU cost (yuan)
Dosage of sedative drugs
rescue sedative dose (mg)
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