Sedation and analgesia strategies in the neuro intensive care unit

Abstract

Intensivists are often plagued with the challenges of managing critically ill patients in the neurocritical intensive care unit (neuro ICU); one such challenge is the level of illness and the need for sedation, inhibiting the provider’s ability to adequately assess the patient. Most sedatives alter neurological and physical exam findings, only compounding potential barriers to providing the best care for each patient. It is important to emphasize that even in the altered mentation of these patients, physical and neurological exams reign supreme as diagnostic tools and should be used in conjunction with multimodal neuromonitoring methods, rather than labs or imaging alone. Additionally, selecting the appropriate analgesic(s) and sedative(s) based on these findings are highly important when determining the best course of individualized management. Thus, providers in the neuro ICU should be highly familiar with the appropriate analgesic and sedative options available in order to determine not only which may be best for each patient, but to also better understand how each drug may impact assessment findings. This comprehensive review aims to provide a structured overview of the pertinent sedatives commonly used in neuro ICUs, their risks and benefits, and how providers can best utilize each in practice to further improve patient outcomes. The novel contribution of this work provides comparative drug tables, dosing guidance for pediatric and very elderly (> 85-years-old) populations, and an exploration into the future possibilities of utilizing artificial intelligence and the human gut microbiome to further enhance the prospects of precision medicine.

Key Words: Anesthesia; Dexmedetomidine; Critical care; Hemodynamic monitoring; Intensive care unit outcomes; Intensive care; Medical intensive care unit; Multidisciplinary critical care; Neurocritical care; Neuro intensive care unit

Core Tip: It can be challenging for providers to manage critically ill patients in the neuro intensive care unit (ICU) due to the many factors hindering their ability to adequately assess the patient, such as altered baseline mental status as well as the addition of analgesics and sedatives. Relying on labs and imaging findings alone are often inadequate to assess patients and these multimodal neuroimaging methods should always be used adjunctively with comprehensive and thorough physical and neurological exams. This paper provides a structured overview of commonly used sedatives in the neuro ICU to assist intensivists in developing more individualized management decisions for each patient in hopes to further improve patient outcomes.

INTRODUCTION

Managing critically ill patients who present to the neurocritical intensive care unit (neuro ICU) can often present challenges for finding treatments that maintain the right balance between managing patients’ systemic condition as well as their neurological condition[1]. Many patients who are seen in the neuro ICU require highly accurate neurologic assessments and require careful consideration to be given to the treatments administered or withheld[1]. Because of the particular level of care needed for these patients, neuro ICU care has drastically improved resuscitation and management methods which have led to significantly lowered mortality in patients presenting with conditions such as traumatic brain injuries (TBI), status epilepticus, or elevated intracranial pressure (ICP)[2,3]. This improvement in care can be attributed to more invasive and careful intracranial and hemodynamic monitoring, additional nutritional support, tracheostomies, and reduced intravenous sedation compared to patients in a traditional intensive care unit (ICU)[2,3]. In these critically ill patients, the primary goal is to avoid the over- or underuse of any treatments that will lead to poorer outcomes, and there are many sedation and analgesia strategies that, if done carefully, can be utilized to drastically improve patient outcomes[4].

Many intensivists working in neuro ICUs will generally use sedation and analgesia as a primary treatment strategy rather than as adjunctive measures with the goal of decreasing cerebral metabolic rates, lowering ventilator asynchrony, decreasing ICP, controlling seizures, and reducing symptoms of anxiety[4,5]. If not well controlled, pain can worsen agitation or delirium, have damaging impacts on ICP, trigger post-traumatic stress disorder, raise anxiety, and lead to worse outcomes for the patient[4]. By managing these patients with proper sedation and analgesia strategies, the risk for these effects can be minimized[4,6].

However, because of these exact strategies, there are often additional challenges in proper assessment of these critically ill patients who, by nature of their disease, are already difficult to assess[7,8]. Just about any sedative treatment given in an ICU setting will decrease the effectiveness of a neurologic exam[7,8]. Although more challenging, neurologic and physical exams should still reign as the primary method of assessing management options; however, it is imperative that providers consider this when making an appropriate decision for treatment as well as being aware of what treatments may have already been administered prior to the assessment[1,7,8]. Many patients in the neuro ICU can be seen with a deterioration in neurologic function within 10 days as well as secondary deteriorations later in their course of care[7,8]. In understanding this, providers must be aware of all factors at play when considering next steps for each patient[7,8].

Due to the frequent unreliable nature of the bedside exams, many intensivists will opt for utilizing imaging strategies to their advantage[1,7]. Although this should be encouraged as multimodal neuromonitoring has been implicated in improved patient outcomes, it is important to note that providers should be wary of using this as their only, or rather primary method in making management decisions while a patient is in the neuro ICU[7]. While laboratory and imaging results can provide valuable insight to a critically ill patient’s condition, neglecting a thorough, careful physical and neurologic exam can lead to crucial information about the patient’s condition to be missed or misidentified[7,9].

Eventually, providers will have to make management decisions[7,9]. Every drug used for these purposes will sedate patients and can cause their own host of potential problems and risks; however, it is imperative that when making these decisions, providers are aware of the potential benefits and downsides to each option in order to make the best individualized decision for the management of each patient[7]. The purpose of this paper is to provide an overview of available options to achieve appropriate sedation and analgesia strategies for patients in the neuro ICU in an effort to provide clinicians with a guide to making more informed, individualized decisions for their patients in the future.

OPIOID AGONISTS

Opioid agonists are a form of sedative analgesia that can be used in neurological patients admitted to the ICU. Opioid agonists act on opioid receptors that are located centrally and peripherally across the nervous system and mainly act to modulate pain signals, hence their role in analgesia. In addition, opioids are also known to produce a sedating effect in patients. Exogenous opioid agonists exert their effect by binding to μ (mu), δ (delta) and κ (kappa) opioid receptors (with varying binding affinities), otherwise notated as Mu-Opioid Peptide, Delta-Opioid Peptide, and Kappa-Opioid Peptide respectively[10]. These receptors are G protein coupled receptors, which when activated, initiate an intracellular signaling cascade that reduces intracellular cyclic adenosine monophosphate concentration, hyperpolarizes the cell, and reduces neurotransmitter release - thereby reducing pain signal transmission[10]. The effect of sedation is one of the downstream effects of opioid receptor stimulation, and is caused by the disinhibition of GABAergic neurons at the level of the midbrain and brainstem, inhibiting cholinergic neurons at the level of the brainstem[11]. These neurophysiological changes reduce nociception, reduce arousal and promote sedation[11]. The importance of opioids in the ICU setting is underscored by the fact that they can have widespread cortical, subcortical, and brainstem effects that make them potent enough to significantly modulate pain and sedation[11].

The duration of action for the sedative opioids differs between each drug. Morphine, oxycodone, and hydromorphone can provide between 3-12 hours of analgesia and sedation, with oral extended-release formulations providing up to 48 hours of analgesia[12-14]. Intrathecal preparations of opioids have been shown to be effective in providing relief for 1-3 hours with fentanyl and 18-24 hours with morphine[15]. On the other hand, remifentanil has a very short half-life of about 3-10 minutes when compared to the other opioids, even after a prolonged infusion[16]. This feature in particular has made remifentanil useful in patients with traumatic brain injuries and other patients who need frequent reevaluation by providers[16,17].

Opioid agonists are used to provide analgesia to patients and are commonly combined with nonsteroidal anti-inflammatory drugs (NSAIDs) to provide adequate relief for patients with either chronic or acute pain, especially when pain is not controlled by other methods of analgesia[13]. For patients in the neurological ICU, these medications are frequently utilized with other sedatives as an intravenous infusion in order to reduce the severity of pain experienced postoperatively and after the placement of interventional lines tubes such as central venous catheters, intraventricular pressure catheters, and endotracheal tubes for intubated patients[18-20].

Short acting opioids, namely fentanyl, are frequently used for procedural sedation in conjunction with other agents, as it provides both analgesic and a depressant effect on the patient[21]. However, it must be noted that opioids have a limited ability to provide deep sedation and amnestic effects; therefore, the length and invasiveness of the procedure must be taken into consideration when selecting the appropriate sedative agent[21]. In addition, the additive effects of other sedative and analgesic agents must be considered in the treatment of the patient and in the selection of opioids in the postoperative period, as these can complicate and prolong recovery time[22,23]. This has especially been a concern for patients who have had preoperative exposure to opioids or intraoperative exposure to fentanyl, as the quality of postoperative assessments may be limited[22,23]. Of greatest concern is the masking of intracranial events, such as increased intracranial pressure, due to opioid induced sedation, miosis, and respiratory depression[22,23]. This consideration is especially important when patients undergo life-saving surgical interventions such as mechanical thrombectomy, arteriovenous embolization, decompressive hemicraniectomy, suboccipital decompression and craniotomies for penetrating traumatic brain injury[22].

Withstanding the possible pitfalls of opioid use in these patients, analgosedation is the underlying concept driving the use of these agents in neuro ICU patients[24]. This is especially true in incapacitated or intubated patients where assessment of pain may be difficult, where sedatives such as benzodiazepines and propofol have been favored; however, they can be associated with oversedation, delayed extubation, and an increased risk of delirium[24-26]. As a result, to directly alleviate the pain of interventions and conditions that may warrant a patient’s presence in the neuro ICU, analgosedation has been used as a framework to avoid the judicious use of sedatives and its effects[24-25,27,28]. It involves prioritizing the treatment of pain with analgesics (opioids) and only use sedatives when necessary[20,24,29]. This method of pain and sedation management with opioids has been shown to be a viable option for patients in the ICU setting, and reduces the rate of drug-related adverse events, increases pain control, and reduces the time on mechanical ventilation[29].

In patients with acute brain injury, hemodynamic instability and fluctuations in ICP can be observed[20,30]. In cases like these, opioids such as remifentanil and sufentanil can be used in the acute setting for analgesia[20]. Due to these specific drugs’ short half-life, they allow for frequent reevaluations of neurological status, even after prolonged infusion, mitigating the concern for masking of symptoms that was elucidated earlier[16,20]. Although, it must be noted that these agents should be administered as an infusion to avoid the alterations in intracranial pressure, mean arterial pressure, and cerebral perfusion pressure that would be observed in a bolus administration[31]. In the specific instance of paroxysmal sympathetic hyperactivity, the sympathetic nervous system becomes dysregulated due to a disruption of the excitatory and inhibitory pathways of the brain and produces symptoms of tachycardia, hypertension, and hyperthermia[32,33]. The clinical syndrome is most frequently observed in patients after acute traumatic brain injury, but is also occasionally seen in patients with hypoxic brain injury and intracranial hemorrhage[34]. Although no treatment guidelines exist for the management of this condition, the consensus by clinicians is that opioids have been a mainstay of treatment for the reduction of allodynia and pain from otherwise noxious stimuli alongside gabapentinoids[32].

Fentanyl is also used in combination with other drugs to supplement the effects of other anesthetics used in the process of inducing and maintaining general anesthesia[35]. When used with propofol, fentanyl has been shown to reduce the incidence of propofol-related injection pain and the synergistic effects of this drug combination is further emphasized by studies showing that there is reduced incidence of fentanyl-induced cough when these drugs are used together[35]. This synergistic relationship is especially useful in delicate procedures, such as laryngoscopy and intubation, whereby failure to suppress the natural cough reflex can cause an increase in ICP[36]. This effect of cough reflex suppression is also crucial in the emergence and immediate postoperative period of neurosurgical patients where ICP is ideally controlled[36]. Furthermore, use of opioids such as fentanyl, in conjunction with propofol, allows for brief intraoperative awakening periods to assess the patient to guide surgeons when operating in sensitive cortical areas, as well as provide metabolic suppression and neuroprotection[36].

Historically, opioids and benzodiazepines have been used together due to their synergistic effects to induce analgesia and sedation by acting on different neurological pathways[37]. However, concurrent use of these drugs has been associated with iatrogenic withdrawal syndrome (IWS), a condition associated with lacrimation, diarrhea, tachycardia, hypertension, and tachypnea[38,39]. Patients who are continuously exposed to this drug combination during their hospital stay tend to develop a physical dependence, and are then at increased risk of developing IWS once attempts are made to wean patients off the drugs[38]. It has been observed that patients with IWS tend to have a longer time on mechanical ventilation compared to patients without IWS[38,40]. Furthermore, IWS has also been observed to statistically increase the patients’ ICU and hospital length of stay[38,40]. The risks associated with the development of IWS should prompt providers to look for alternative options for sedation and analgesia, further supporting the paradigm shift to analgesia-first sedation[38]. Schematic of the molecular mechanism showing the primary targets of opioid agonists[41] (Figure 1).

Figure 1 Schematic of the molecular mechanism showing the primary targets of opioid agonists[41]. AC: Adenylate cyclase; cAMP: Cyclic adenosine monophosphate; GDP: Guanosine diphosphate; Glu: Glutamate; GTP: Guanosine-5′-triphosphate; PKA: Protein kinase A. Citation: Marcianò G, Vocca C, Evangelista M, Palleria C, Muraca L, Galati C, Monea F, Sportiello L, De Sarro G, Capuano A, Gallelli L. The Pharmacological Treatment of Chronic Pain: From Guidelines to Daily Clinical Practice. Pharmaceutics 2023; 15: 1165 Copyright© The Authors 2023. Published by MDPI, Basel, Switzerland (https://www.mdpi.com/openaccess).

GAMMA-AMINOBUTYRIC ACID AGONISTS

The enhancement of GABAergic transmission remains a cornerstone in the management of agitation and seizures in critically ill neurologic patients. Benzodiazepines are among the most commonly prescribed psychotropic medications, exerting their effects by modulating GABA_A receptor-mediated inhibitory neurotransmission throughout the central nervous system[42]. The most commonly used benzodiazepines for controlling agitation and seizures in critically ill neurologic patients in the neuro ICU are lorazepam, midazolam, and diazepam[43]. Lorazepam is frequently used due to its efficacy and relatively longer duration of action when administered intravenously[44]. Midazolam is preferred for its rapid onset and versatility in administration routes, including intramuscular, buccal, and intranasal, which is particularly useful when intravenous access is not immediately available[45]. Diazepam is also utilized, especially in settings where rectal administration is feasible, although it has a shorter duration of action compared to lorazepam[46].

Benzodiazepines are especially useful in scenarios requiring seizure control, including status epilepticus, as well as short-term procedural sedation[44]. They are often favored in patients at risk for elevated intracranial pressure due to their minimal cardiovascular impact at therapeutic doses[47]. However, prolonged use of 24–48 hours of continuous dosing is discouraged, as multiple studies have linked benzodiazepine use to increased ICU delirium, delayed extubation, and longer ICU length of stay[48]. Other concerns of prolonged benzodiazepine use include long-term neuropsychiatric sequelae (post-traumatic stress disorder, depression, anxiety, and cognitive impairments), withdrawal syndromes, and risk of dependence[49-51].

Pentobarbital is considered a third-line agent for the treatment of super-refractory status epilepticus, defined as seizures that persist for more than 24 hours despite administration of anesthetic agents, and requires management in specialized intensive care units with continuous electroencephalogram (EEG) monitoring[52]. In contrast to benzodiazepines, which increase the frequency of chloride channel opening events, pentobarbital enhances GABAergic transmission by prolonging and potentiating the action of GABA on GABA_A receptors, leading to increased chloride ion influx and hyperpolarization of the neuron, which reduces neuronal excitability[53].

Overall, while benzodiazepines remain indispensable for seizure management and acute sedation in hemodynamically stable patients, their utility in prolonged ICU sedation has diminished due to excessive sedation and significantly extended recovery[54]. This is particularly true when sedation is maintained continuously without routine interruption or timely de-escalation[54]. Additionally, the use of benzodiazepines in critically ill patients requiring extended mechanical ventilation has been associated with higher in-hospital and one-year mortality compared to non-benzodiazepine sedatives[55]. There is a shift in favor towards the use of alternative sedatives such as propofol, that offer superior safety and recovery profiles[56].

Propofol is a phenol-derivative intravenous anesthetic agent widely used in critical care for its rapid onset, short duration, and predictable recovery profile[57]. Its mechanism of action involves potentiation of the GABA-A receptor and inhibition of N-methyl-D-aspartate (NMDA) receptors, leading to profound hypnotic and sedative effects[58]. These pharmacologic properties, coupled with its high lipid solubility, contribute to its rapid redistribution and metabolism, primarily in the liver, with additional extrahepatic clearance[59]. A notable advantage of propofol in neurocritical care is its ability to reduce cerebral metabolic rate (CMRO2) and ICP, making it a preferred agent for patients with TBI, intracranial hemorrhage, or refractory seizures[60].

The short context-sensitive half-time of propofol allows clinicians to perform frequent neurologic assessments, a critical consideration in neuro ICU management. However, propofol can cause significant dose-dependent hypotension and bradycardia, necessitating caution in patients with cardiovascular instability[61]. Moreover, while it has anti-epileptic and anti-emetic properties, it lacks analgesic effects, and thus must be combined with opioids or adjuncts when pain control is required[62]. In addition, as a lipophilic agent, in patients with greater adiposity, there is risk that this medication can accumulate, potentially leading to oversedation in obese patients[63]. Thus, proper management of the sedation and an understanding of the drug’s pharmacokinetics is key.

One rare, but major and often fatal adverse effect of propofol is propofol infusion syndrome (PRIS), characterized by metabolic acidosis, rhabdomyolysis, cardiac failure, and renal dysfunction[64]. PRIS is typically associated with high-dose (> 4 mg/kg/hours), long-term (> 48 hours) infusions, especially in patients with critical illness or those receiving concomitant catecholamines and corticosteroids[65]. Although the incidence of PRIS is low (2.9%), its high mortality (36.8%) underscores the importance of early recognition and risk mitigation[66]. Additional side effects include hypertriglyceridemia, requiring regular lipid monitoring (twice weekly) during prolonged infusions of ≥ 48 hours[67].

Given its rapid titratability, ICP-lowering effect, and favorable pharmacokinetics, propofol remains a cornerstone for sedation in neurocritical care, especially when frequent neurologic assessments are needed; however, clinicians must remain vigilant regarding its hemodynamic effects and the potential for rare but severe complications such as PRIS[66]. Schematic of the molecular mechanism showing the primary targets of GABA_A agonists[68] (Figure 2).

Figure 2 Schematic of the molecular mechanism showing the primary targets of GABA_A agonists[68]. Citation: Paramsothy J, Gutlapalli SD, Ganipineni VDP, Mulango I, Okorie IJ, Arrey Agbor DB, Delp C, Apple H, Kheyson B, Nfonoyim J, Isber N, Yalamanchili M. Propofol in ICU Settings: Understanding and Managing Anti-Arrhythmic, Pro-Arrhythmic Effects, and Propofol Infusion Syndrome. Cureus 2023; 15: E40456 Copyright© The Authors 2023. Published by Springer Nature (https://www.cureus.com/author_guide#!/policies-and-procedures/copyright-and-licensing).

ALPHA-2 ADRENERGIC AGONISTS

α-2 adrenergic agonists are commonly used as adjuncts for sedation and to reduce anesthetic requirements for ICU patients, especially for those who require neurocritical care[69]. The α-2 receptors constitute a family of G-protein–coupled receptors with 3 pharmacological subtypes: Α-2A, α-2B, and α-2C; where α-2A and -2C subtypes are found mainly in the central nervous system[70]. Stimulation of these receptor subtypes may be responsible for sedation, analgesia, and sympatholytic effects[71].

Two such α-2 adrenergic agonists used commonly are clonidine and dexmedetomidine. Clonidine is a mixed α-1 and α-2 adrenoceptor agonist with predominance on the α-2 receptor, whereas dexmedetomidine is a dose-dependent, highly-selective and potent α-2-adrenergic agonist with even greater affinity for the α-2 receptor than clonidine[70,72,73]. Clonidine can be administered in a variety of ways including intravenously, transdermally, and orally, with oral administration having rapid absorption and reaching peak plasma concentration within 60-90 minutes[72]. The onset of action of dexmedetomidine differs between methods of administration, with the intravenous route being 15 minutes, and intranasal route being 47.5 minutes, on average[74]. Clonidine is a relatively safe and versatile drug used as an adjuvant to other analgesics which is often used in acute pain management in the perioperative period[72]. Dexmedetomidine has clinical applications that include sedation and general anesthesia as well as prolonged sedation in hospitalized patients, such as those in the cardiac ICU or ICU, and reduced emergence delirium[71].

Dexmedetomidine is a preferred sedative for those receiving neurocritical care due to its ability to provide an arousable state in patients without the concerning effects of respiratory depression as well as hemodynamic maintenance in those with acute brain injuries[75,76]. Dexmedetomidine also has a role as a neuroprotective agent through its ability to bind to imidazoline receptors, acting as a sympatholytic, and its ability to inhibit inflammation and apoptosis[70]. However, some concerning adverse effects of dexmedetomidine are due to its α-1 receptor activation at higher doses, causing vasoconstriction and resulting hypertension, whereas its peripheral α-2 receptor activation can result in reflex bradycardia[70,72]. Due to these hemodynamic effects, clinicians caution against using dexmedetomidine in patients over 50 years of age with underlying cardiac disease, risk of cardiac complications, or those with accompanying bradyarrhythmias[72,77]. Clonidine’s adverse effects are primarily related to its activation of the α-2 receptor, including bradycardia and orthostatic hypotension; sudden withdrawal of clonidine can lead to rebound hypertension and hypertensive crisis because of this[72].

In the pediatric population, dexmedetomidine is generally given alone and at higher doses to gain an appropriate sedative effect, and the incidence of bradycardia in those patients was found to be estimated at 3% when used as a sole sedative[78]. Additionally, in pediatric populations, dexmedetomidine infusions are found to significantly decrease the incidence of postoperative acute kidney injury through its features of anti-inflammation to prevent inflammation-induced impairment[79].

With any sedative or anesthetic, emergence delirium is of concern, thus, patients in the ICU are given dexmedetomidine as these patients often experience decreased delirium duration than those who are given other commonly used sedatives[80,81]. For patients in the neuro ICU, early neurological assessment is important, and dexmedetomidine allows this through its neuroprotective effects by decreasing time to extubation in mechanically ventilated patients as well as better maintenance of intracranial hemodynamic stability[82]. Schematic of the molecular mechanism showing the primary targets of α-2 agonists[83] (Figure 3).

Figure 3 Schematic of the molecular mechanism showing the primary targets of α-2 agonists[83]. Citation: Bargnes V 3rd, Oliver B, Wang E, Greenspan S, Jin Z, Yeung I, Bergese S. Taming Postoperative Delirium with Dexmedetomidine: A Review of the Therapeutic Agent's Neuroprotective Effects following Surgery. Pharmaceuticals (Basel) 2023; 16: 1453 Copyright© The Authors 2023. Published by MDPI, Basel, Switzerland (https://www.mdpi.com/openaccess).

NMDA AND GLUTAMATE RECEPTOR ANTAGONISTS

Ketamine is a rapid-acting phencyclidine derivative anesthetic that is known for its profound sedative and analgesic properties[84,85]. This drug primarily acts by modulating the function of NMDA receptors, acting as a non-competitive inhibitor[84,86]. The drug is also known to act on norepinephrine, serotonin, and opioid receptors to modulate pain signals, hence its analgesic properties[85,86].

This drug’s rapid onset of 10-30 seconds and duration of action of 5-15 minutes, makes it suitable for use as a sedative for short-term procedural sedation and rapid sequence intubation[87]. It has the advantage of being a suitable anesthetic for patients at risk of bronchospasm, such as those suffering from status asthmaticus, due to its bronchodilatory effects[88]. In an ICU setting, it can also be used for managing acute pain in situations such as trauma and abdominal pain when refractory to standard opioid treatment[88]. Furthermore, patients that suffer from conditions that cause chronic pain like sickle cell and cancer also benefit from the use of ketamine for pain relief[88]. The application of this drug also extends to the management of treatment resistant status epilepticus, due to its inhibition of NMDA receptors which are activated by glutamate, the brain’s primary excitatory neurotransmitter[87,89].

Ketamine has shown profound utility in the management of acute brain injury, where the goal is to mitigate the effects of primary injury and prevent secondary injury[90]. The role of ketamine in this instance, relates to the prevention of cortical spreading depolarization[90,91]. Cortical spreading depression is a term used to describe a pathological progression of electrical activity propagating outwards from the focus of injury in patients with traumatic brain injury, intracranial hemorrhage, acute ischemic stroke/infarction and other forms of acute brain injury[90,91]. This wave of progressive widespread depolarization of neurons functionally expands the lesion, leading to energy and electrochemical imbalance[90,91]. Sedative agents have been shown to alter the propagation of these electrical signals, with ketamine having the lowest incidence of spreading depolarizations when compared with propofol, midazolam and opioids[91]. Furthermore, this neuroprotective effect has also been associated with anti-inflammatory and anti-apoptotic effects in this patient population[90,92,93]. In patients with acute brain injury, ketamine use has been shown to maintain cerebral hemodynamics while reducing ICP and maintaining or increasing cerebral perfusion pressure, thereby proving its utility in acute brain injury[91].

The clinical and pharmacologic advantages of ketamine extend its utility and makes it a versatile drug with potential applications in the neuro ICU setting. Unlike other sedatives like propofol, ketamine does not induce hypotension and bradycardia, and thus maintains general hemodynamic stability[94]. In comparison to propofol and dexmedetomidine, ketamine has been shown to be significantly less likely to induce clinically relevant hypotension and bradycardia[95]. Moreover, the drug may even generally increase heart rate, mean arterial pressure and systolic blood pressure and may be associated with an overall decreased need for vasopressors in mechanically ventilated patients[96,97]. Such clinical advantages make ketamine an attractive option as an analgosedative and induction agent and in hypotensive patients with traumatic brain injury, in whom the maintenance of systemic blood pressure and cerebral perfusion pressure is paramount[85-86,98].

Ketamine also allows for the patient to continue breathing spontaneously and maintain airway reflexes despite the use of the dissociative dose of the drug[82]. This is in stark contrast to other sedatives such as opioids, which can induce a stuporous state accompanied by respiratory depression[13,88]. This unique property of ketamine allows for its use in delayed sequence intubation, used in patients in whom there would be difficulty in preoxygenation for rapid sequence intubation (RSI) (preoxygenation for the anticipated apneic phase of RSI) due to delirium, agitation or head trauma[82,99]. An improvement in oxygen is even noted prior to intubation, after the patient has been sedated with ketamine[82,99]. This property also extends its use to intubation of patients who may have anatomically difficult airways, thus allowing these patients to breathe without assistance while sedated and proving its adequacy for these situations[82,99].

Notably, in patients post-spinal surgery, ketamine has been shown to reduce standardized pain scores and reduce the need for opioid analgesia within the first 24 hours of the postoperative period[100]. However, this effect of reducing the requirements of opioids needed for analgesia has also been observed beyond the first 24 hours of administration in critically ill patients admitted to the ICU, thus supporting its value for patients in a neurocritical care setting[101].

Conversely, the dissociative state can be viewed as a drawback of the drug. Ketamine has been observed to display a dose-dependent ability to induce a dissociative amnesia as well as other psychotropic symptoms such as hallucinations, disorientation, and sensory illusions, thus limiting its ability to be widely used as an analgesic[85,88,98,101]. These effects have been observed even at small doses (0.1 mg/kg)[98]. The dissociative state observed, accompanied by somatosensory hallucinations and space–time distortion, have made ketamine a popular drug of abuse, and therefore can be a potentially contentious choice, especially among certain patient populations[98].

Though the drug may have an overall favorable side effect profile, ketamine has been shown to produce the highest rates of agitation and vomiting in patients who undergo procedural sedation, with the lowest chance of agitation occurring when ketamine is combined with propofol to form an admixture called “ketofol”[102,103]. Additionally, with continuous ketamine infusion, patients have also been observed to experience increased pharyngeal secretions, agitation and dissociation[101]. Schematic of the molecular mechanism showing the primary targets of NMDA and Glutamate Receptor Antagonists[104] (Figure 4). A summary of all drug classes and important drugs discussed are included in Table 1[105-117].

Figure 4 Schematic of the molecular mechanism showing the primary targets of N-methyl-D-aspartate and Glutamate Receptor Antagonists[104]. Citation: Mario A, Ivana L, Claudia MM, Antonello B, Francesco P, Tommaso C, Madia L. Can ketamine therapy overcome treatment-resistant depression in Alzheimer's disease and older adults? Preclinical and clinical evidence. Biomed Pharmacother 2025; 188: 118199 Copyright© The Authors 2025. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/Licenses/by-nc-nd/4.0/).

Table 1 Summary of drugs.

Drug	MoA	Adult dosing1	Contraindications2	Pros	Cons	AEs
Morphine (IV)[105]	μ, δ, & κ opioid receptor agonist	2-10 mg (loading); 2-4 mg/1-2 hours or 4-8 mg/3-4 hours (maintenance)	Hypersensitivity; Epidural/intrathecal infusion site infection; Concomitant anticoagulant therapy; Uncontrolled bleeding; Upper airway obstruction	Widespread cortical, subcortical, and brainstem effects, making them potent enough to significantly modulate pain and sedation; Can be combined with NSAIDs to provide pain relief when not controlled by other methods; Often favored over sedatives in the ICU setting as it reduces the rate of drug-related adverse events, increases pain control, and reduces time on mechanical ventilation; Short half-lives allow for frequent reevaluations of neurological status	Limited ability to provide deep sedation and amnesic effects; Widespread list of more commonly experienced adverse effects compared to other sedatives or analgesics; Can complicate and prolong postoperative recovery times; The nature of these drugs’ effects can mask intracranial events; Can be challenging to manage in patients with acute brain injuries	Constipation and/or diarrhea; Neurotoxicity; Pruritus; Respiratory depression and/or apnea; Withdrawal; Profound drowsiness and/or dizziness; Headaches; Nausea and/or vomiting; Arthralgias; Peripheral edema; Dehydration; Hypokalemia; Abdominal pain and/or anorexia; Anemia; Insomnia; Asthenia and/or fatigue
Oxycodone (oral)[106]		5-10 mg/4-6 hours	Hypersensitivity; Respiratory depression; Hypercapnia; Bronchial asthma; GI obstruction
Hydromorphone (IV)[107]		0.5-2 mg/1 hour (initial); 0.25-4 mg/1 hour	Hypersensitivity; Respiratory depression; Hypercapnia; Bronchial asthma; GI obstruction
Fentanyl (IV)[108]		0.025-0.1 mg or 0.001-0.002 mg/kg (loading); 0.025-0.050 mg or 0.00035-0.0005 mg/kg/0.5-1 hour	Hypersensitivity; Respiratory depression; Bronchial asthma; GI obstruction; Patients requiring short-term therapy; Management of acute or intermittent pain, postoperative or mild pain; Patients who are not opioid tolerant
Remifentanil (IV)[109]		0.0015 mg/kg (loading); 0.0005-0.015 mg/kg/1 hour (maintenance)	Hypersensitivity Intrathecal or epidural administration
Lorazepam (IV)[110]	GABAA receptor agonist	0.02-0.04 mg/kg (initial); 0.02-0.06 mg/kg/2-6 h (maintenance)	Hypersensitivity; Acute narrow-angle glaucoma; Sleep apnea; Intra-arterial injection; Premature infants; Severe respiratory insufficiency	Lorazepam has high efficacy and longer duration of action; Midazolam has a rapid onset and versatility in route of administration; Diazepam has a shorter duration of action and can be used rectally; Useful in controlling seizures; Minimal cardiovascular effects	High-dose midazolam is only used to break seizures; Prolonged use (24-48 hours) can increase delirium, delay extubation, longer LOS, and long-term neuropsychiatric effects; Should not typically be used in hemodynamically unstable patients	Profound drowsiness; Nausea and/or vomiting; Respiratory depression and/or apnea; Anterograde amnesia; Paradoxical reactions (e.g., aggression); Propylene glycol toxicity; Withdrawal
Midazolam (IV)[111]		0.5-5 mg or 0.01-0.05 mg/kg/10-15 minutes	Hypersensitivity; Intrathecal or epidural injections; Premature infants; Acute narrow-angle glaucoma; Concurrent use with protease inhibitors; Concurrent use with fosamprenavir
Diazepam (IV)[112]		5-10 mg (initial); 0.03-0.1 mg/kg/0.5-6 hour (maintenance)	Hypersensitivity; Acute narrow-angle glaucoma; Untreated open-angle glaucoma; Infants < 6 months; Myasthenia gravis; Severe respiratory impairment; Severe hepatic impairment; Sleep apnea
Pentobarbital (IV)[113]		10 mg/kg + 5 mg/kg/h × 3 (loading); 1-4 mg/kg/h (maintenance)	Hypersensitivity; Porphyria	Used for treatment of super-refractory status epilepticus (SRSE)	Third-line agent that carries many potential adverse effects with little utility in neuro ICU settings	Bradycardia and/or hypotension; Gastrointestinal upset and hepatotoxicity; Respiratory effects
Propofol (IV)[114]		0.005-0.050 mg/kg/min or 0.3-3 mg/kg/h	Hypersensitivity; Hypersensitivity to eggs, egg products, soybeans, or soy products	Widely used in critical care due to its rapid onset, short duration, and predictable recovery profile; Able to reduce cerebral metabolic rate and ICP; Allows for frequent neurologic reevaluation; Has anti-epileptic and anti-emetic properties	Should not typically be used in patients with hemodynamic instability; Lacks analgesic effects by itself and must be adjunctive with another drug for pain control; Risk for drug accumulation, especially in obese patients	Cardiac conduct disturbances (e.g., prolonged QT interval); Hypersensitivity reactions; Hypertriglyceridemia; Hypotension; Propofol-related infusion syndrome (PRIS)
Dexmedetomidine (IV)[115]	α-2 receptor agonist	0.0002-0.0015 mg/kg/h	Hypersensitivity	Can provide an arousable state without concerning respiratory effects; Neuroprotective, allowing for better neurological assessment	Hemodynamic effects can limit the patient population for its use	Bradycardia and/or hypotension; Hypertension; Tachyphylaxis; Tolerance and withdrawal
Clonidine (IV)[116]		0.05-0.15 mg/6-8 hours	Hypersensitivity; Epidural injection site infection; Concurrent anticoagulant therapy; Bleeding diathesis; Administration above the C4 dermatome	Many different routes of administration; Relatively safe and versatile drug	Sudden withdrawal can lead to rebound hypertension and hypertensive crisis	Bradycardia and/or hypotension; Withdrawal
Ketamine[117]	NMDA & glutamate receptor antagonist	0.1-0.5 mg/kg (initial); 0.2-0.5 mg/kg/h (maintenance)	Hypersensitivity; Increased blood pressure; Infants < 3 months; Known or suspected schizophrenia	Very rapid onset and short duration of action; Can be used for procedural sedation; Good option for patients at risk of bronchospasm, those refractory to opioid treatment, and those with conditions that cause chronic pain; Can be used for treatment-resistant status epilepticus; Prevents cortical spreading depolarization, making it a great drug for TBIs; Better hemodynamic stability than many other ICU drugs	Causes a profound dissociative state in patients; Can cause many somatosensory effects, even at small doses, having made it a popular drug of recreational abuse; Produces the highest rate of agitation and vomiting in patients who undergo procedural sedation with this drug	Laryngospasm; Cardiovascular instability; Dependence & tolerance; Prolonged emergence from anesthesia; Vivid dreams, hallucinations, and/or delirium; Genitourinary effects; Respiratory depression or apnea

¹Adult dosing is listed for ICU-level patients without evidence of kidney or liver disease.

²Based on United States labeling.

GI: Gastrointestinal; ICP: Intracranial pressure; ICU: Intensive care unit; IV: Intravenous; LOS: Length of stay; NSAIDs: Non-steroidal anti-inflammatory drugs; PRIS: Propofol-related infusion syndrome; SRSE: Super-refractory status epilepticus; TBI: Traumatic brain injury; NMDA: N-methyl-D-aspartate.

Limitations

Although the information presented in this paper is supported by the literature, it should be noted that most of the evidence provided has been extrapolated from mixed, non-neuro ICU populations. Additionally, much of the dose-dependent response data for children and the very elderly populations are scarce, thus making it difficult to provide thorough evidence to support concrete conclusions for these individuals. Lastly, as made evident by the gap in the available literature, pharmacoeconomic evaluations and long-term neurocognitive outcomes are lacking, which creates a missing piece of insight that could be provided for many of the drugs discussed.

Future directions

Due to the complex nature of patient care in the neuro ICU, management with sedation should be focused on two major endpoints: Reduction of post-ICU post-traumatic stress disorder and delirium. In understanding the pharmacokinetics of the different drugs, there are some benefits that providers can have in the selection of appropriate medications; however, further research should be aimed at better preventing these negative outcomes through the use of appropriate sedation and considering which sedation classes may have the greatest benefit in a given patient. With the rapidly evolving field of understanding the human gut microbiome, there are early statements on utilizing the patient’s specific microbial profile for the individualized selection of agents and the titration of dosing for anesthetic agents[118]. This can and should be utilized along with pharmacogenetics in the development of a patient-specific drug profile to ensure that they are receiving the best possible care.

One particularly interesting area is the use of different genetic and proteomic markers in the selection of the best medications for patients. Every human body and disease state is different, and this principle applies to patients suffering from neurologic diseases. As a result, understanding the specific biochemical makeup of each patient and being able to utilize this information can aid in the selection of appropriate drugs. Some of these markers include CYP2B6, UGT2B7, and CYP2A6 which are genetic polymorphisms of enzymes that play a role in the metabolism of different drugs[119-121]. Some of these are known to increase the rate of processing of different anesthetic agents while others are known to decrease processing abilities[119-121]. In understanding the particular patient’s disease state, instances such as these can be utilized as a part of the individualized approach in the treatment of these patients with anesthetic agents.

Lastly, with the emergence of generative artificial intelligence (AI) software, there is potential for improved understanding of the entirety of the patient’s physiology. As, unlike humans, AI is able to factor all the major pieces of data simultaneously, and therefore could be able to help the physician make more adequate sedation choices that otherwise may not be considered as highly[118]. Again, much of the benefits of AI have yet to be realized in this emerging field. Nevertheless, within the neuro ICU, devices such as the Ceribell(R) and its AI tool for the detection of status epilepticus are already in use. Thus, tools which aid in the selection of medications could be easily added as a part of standard practice in the coming future[122]. Other concepts in the literature regarding AI should also be considered as in anesthesia, there have been a number of benefits elucidated. One such example discusses how the use of machine learning could potentially increase benefits to three of the major stakeholders of human healthcare: The patients, the healthcare teams, and the overall health system through health monitoring, prehabilitation, early detection, prediction, and diagnostic tools, and through finding areas which humans would not normally look to improve quality and efficiency[123].

In a neuro ICU setting, this could also be true specifically for that of closed loop anesthesia – a machine learning tool for early detection, prediction, and treatment. Closed loop anesthesia works through setting pre-determined targets as bursts of waves on EEG with burst suppression protocols in order to break recalcitrant status epilepticus or intracranial pressures values of a patient that is actively in the process of herniating[123-125]. The process then allows the machine to work with the individual case to make minute by minute increases or decreases in the amount of anesthesia administered based on the predetermined values that the clinician is chasing[123-125]. This can also be utilized in the minute-by-minute dosing of medications with changes in the anesthesia being administered based on the level of brain activity and ventilator compliance, which would serve incredibly valuable to intensivists in the neuro ICU[123-125]. This would allow for the integration of EEG monitoring and the administration of drugs to ensure that the patient is sedated enough to ward off either seizure or ventilator non-compliance[123-125]. These steps can potentially be utilized as either a bridge to neurosurgical intervention or instead in patients who might be able to avoid the surgical intervention if their case is managed well, such as can be the case in lowering the ICP with anesthesia[126,127]. This closed loop system with machine learning can be utilized in conjunction with other precision medicine principles such as pharmacogenetics, microbiome characterization, and proteome characterization to ensure in which the minute-by-minute changes in the patient and their overall status are considered. This is another promising area of future research and one that could potentially provide enormous benefits for patients within the neuro ICU.

CONCLUSION

It can be challenging for providers to manage critically ill patients in the neuro ICU due to the many factors hindering their ability to adequately assess the patient, such as altered baseline mental status as well as the addition of analgesics and sedatives. Relying on labs and imaging findings alone are often inadequate to assess patients and these multimodal neuroimaging methods should always be used adjunctively with comprehensive and thorough physical and neurological exams. This paper provided a structured overview of commonly used sedatives in the neuro ICU to assist intensivists in developing more individualized management decisions for each patient in hopes to further improve patient outcomes.

ACKNOWLEDGEMENTS

The authors would like to thank the Caribbean Research Group for providing the opportunity to develop this work and for creating a space for young, aspiring researchers to gain writing and publishing experience. The authors would also like to acknowledge the original work proposed by past CRG member, Neonika Fernandes, for starting the idea for this project and allowing the team the opportunity to see it come to fruition.