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Monday 20 May 2019
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Sedation in neurocritical care

Sedation is one of the main facilities in the intensive care unit (ICU). However, it is well known that no sedation, or minimising it, results in better outcomes, such as decreased length of hospital stay, shorter duration of mechanical ventilation, reduced healthcare costs and a reduced need for additional examinations to determine brain function. It is also related to early mobilisation of the patient, but it is unclear if it decreases delirium. Most of the review studies supporting this evidence are based on populations with non-acute brain injury. Traditionally, these patients were kept under sedation in the early phase to prevent the secondary insult.1,2
 
Sedation in the ICU has different roles. The drugs used are intravenous, such as propofol and midazolam.2 The objective is to control pain and anxiety, reduce agitation and achieve patient–ventilator synchrony. Nonetheless, there are situations where sedation has specific roles such as in patients with high intracranial pressure (ICP), those requiring muscular relaxation for any reason, and those with a status epilepticus.2
 
The trend now is to interrupt sedation as soon as possible and avoid it during the day. However, these two new settings have to be analysed and compared with the benefit they may have concerning the risk of exacerbating intracranial hypertension in patients with reduced brain compliance.1
 
The ideal sedative drug should be able to decrease ICP and maintain an appropriate cerebral perfusion without interfering with its autoregulation. Additionally, it should decrease the cerebral metabolic rate of oxygen and have neuroprotective and anticonvulsant properties. 
 
In regard to its pharmacological properties, it should have a predictable response, rapid onset and wake-up, and minimum secondary effects.2
 
There are no management of sedation guidelines in neurocritical patients. Each ICU bases its decisions on its own experiences and follows basic recommendations that are well accepted in the scientific community; however, we need to establish algorithms for the management of sedation these patients. 
 

Need for sedation 

Sedation in neurocritical patients is essential to relieve pain, anxiety, reduce ICP, decrease oxygen consumption, tolerate therapeutic manoeuvres, and improve adaptation to mechanical ventilation. However, it has its drawbacks. It prevents frequent neurological evaluation, thus decreasing prognostic capacity because clinicians are incapable of detecting changes in the brain state. 
 
By contrast, sedation is part of management in certain other conditions; targeted temperature management, elevated ICP and refractory status epilepticus.1 It is a first-line treatment when ICP is high, together with other measures. In most cases, elevated ICP develops within 48 hours of the brain insult; however, it can develop earlier than this. 
 
Prolonged deep sedation might possibly worsen cognitive results after its cessation and contribute to polyneuropathy in critical patients. Unless deep sedation or general anaesthesia is necessary, analgesia must precede sedation. Nowadays, there is a new trend to base sedation on opioids.3
 
The guidelines for sedoanalgesia in massive cerebral infarction establish the following recommendations:4
  • Analgesia and sedation are recommended if signs of pain, anxiety, or agitation arise (strong recommendation, very low quality of evidence)
  • The lowest possible sedation intensity and earliest possible sedation cessation is recommended, while avoiding physiological instability and discomfort (strong recommendation, very low quality of evidence)
  • The routine use of daily wake-up trials is not recommended. Caution is particularly warranted in patients prone to ICP crisis. Neuromonitoring of at least ICP and CPP is recommended to guide sedation, and daily wake-up trials should be abandoned or postponed at signs of physiological compromise or discomfort.
 

Sedation assessment

Neurophysiological monitoring should be considered a routine practice for neurocritical patients requiring sedation. Over-sedation increases the risk of infection, delays the removal of mechanical ventilation, and increases the length of stay in ICUs. On the other hand, infrasedation causes agitation, anxiety, and risk of accidents such as self-extubation, pulling out of catheters, discomfort, or ventilator asynchronies5 and has prevented neurologic deterioration.6,7
 
A number of scales to evaluate arousal, deep of sedation and response to stimuli are available:8
  • Ramsay Scale: evaluates consciousness
  • Richmond Agitation Sedation Scale (RASS): examines cognition 
  • Sedation Agitation Scale (SAS) and Motor Activity Assessment Scale (MAAS): monitor sedation and arousal. 
Their use can reduce the amount of sedatives given to achieve a specific sedation target, decreasing the number of days on mechanical ventilation and cost of hospital stay; however, no validation is available in the neuro-ICU environment.2 The Nociception Coma Scale has emerged as a valid tool to assess pain in patients with disorders of consciousness.9
 
When it is not possible to use these scales, for example, in patients who require muscular relaxation, then an electrophysiological endpoint must be used instead. One example is bispectral index (BIS) monitoring,10 which has made adjustments of sedation possible. A study showed that BIS values significantly correlated with RASS and SAS scores in patients with acute brain injury.11 In another study, the BIS reliably assessed sedation levels during continuous propofol infusion in the same type of patients.12
 
BIS was initially developed for monitoring the depth of general anaesthesia in patients without brain pathology. It is thought that the ABI (acute brain injury) may influence the BIS algorithm because of EEG changes related to the pathology itself rather than to the sedative state.The approach to sedation should first consider the severity of acute brain injury and the cerebral physiological state, mainly ICP. Figure 1 shows a possible algorithm for the management of sedation in neurointensive care units.
 
Figure 1: Algorithm for the management of sedation in the neurointensive care units
 
The first things to consider are appropriate control of pain, control of agitation and promoting ventilator synchrony. In patients with intracranial hypertension, the targets for sedation and analgesia should be titrated to control ICP and brain tissue oxygen pressure.1
 

Need to wake up

For the clinical assessment of neurocritical patients, interruption of continuous sedation (IS) is therefore necessary. This is usually short-term, aimed at evaluating the patients and planning further management strategies, including the definitive sedation interruption once the clinical concern and IS does not provoke patients’ distress and metabolic imbalance.2 Withdrawal of sedation and IS by daily wake-up tests might appear beneficial to these patients by allowing clinical neuro-monitoring and timely detection of warning neurological signs.13 Daily IS trials have the potential to reduce mechanical ventilation duration and the need for tracheostomy.14 These potential benefits, however, must be balanced against the risk of further cerebral haemodynamic deterioration when sedation is stopped abruptly.15 Cerebral hypoperfusion and raised ICP might result in an imbalance of energy supply and demand, especially for the injured brain and, therefore, aggravate the risk for metabolic distress and brain tissue hypoxia.16–22 IS might lead to significant ICP elevation and CPP reduction, which are more relevant in the first days after ABI than after 4–5 days.23
 
Avoidance of IS is recommended in all patients at risk of, or having, elevated ICP. In these patients, sedation should never be stopped abruptly but withdrawn progressively, titrating the sedation dose to ICP targets. In all other ABI patients, withdrawal should proceed as in the general ICU and daily IS in not contraindicated.1
 
Given that little knowledge is available about the benefits of IS in ABI, it is important to implement multi-modal monitoring in neurocritical care in order to omit IS in those patients who will potentially be harmed by the procedure.2
 

Sedative drugs available 

The ideal drug for sedation should have a rapid onset and rapid recovery, in order to evaluate the neurological state, as well as a predictable clearance independent of end-organ function (avoiding accumulation). It should be easy to achieve adequate levels of sedation and it would have to reduce ICP by reducing cerebral blood and cerebral vasoconstriction. As it reduces cerebral blood flow, it should decrease the metabolic rate of oxygen consumption at the same time. In addition, cerebral autoregulation should also be maintained, while having minimal cardiovascular depressant effects.24
 

Propofol 

Propofol has a rapid onset and cessation of sedation. However, it also can unpredictably accumulate after long-term use and cause prolonged sedation.25 Cerebral blood flow and ICP are decreased.26–28 Standard- and high-dose propofol infusion (2mg/kg induction bolus followed by 150–200mg/kg/min infusion) can be used as an anticonvulsivant.29–32 Propofol infusion syndrome should be detected promptly in order to start adequate treatment. The hypotension related to propofol is multifactoral, and severe propofol-associated hypotension occurred in 26.2% of patients in some studies.33–36 Weaning from mechanical ventilation occurs earlier than with midazolam.37
 

Opioids

In general, opioids decrease the cerebral metabolic rate of oxygen, cerebral blood flow and ICP, as long as normocapnia is maintained by mechanical ventilation.2 However, Roberts et al found that morphine, fentanyl, sufentanil and alfentanil significantly increased ICP and decreased CPP and MAP after bolus administration.38
 

Remifentanil 

Remifentanil is a mu-opioid agonist with analgesic effects and a rapid onset and a short duration of action. It can cause decreases in both cerebral metabolic rate and ICP, with minimal changes in CPP and cerebral blood flow.39 It can facilitate frequent awakening to evaluate neurological and respiratory parameters.40
 

Benzodiazepines

Use of benzodiazepines increases the incidence of delirium significantly. Midazolam is an appealing sedative option for its rapid onset and short duration of effect with bolus administration, making it ideal for procedural sedation. It is also a very important drug in refractory status epilepticus. Benzodiazepines increase the seizure threshold and are useful antivonvulsivants.41,42 Midazolam accumulates in adipose tissue because of its high lipid solubility, thereby prolonging time to awakening.43
 

Barbiturates 

The use of barbiturates has been limited owing to their undesirable side effect profile, for example, immunosupressant properties and negative ionotropic effects. Pentobarbital is an extended drug used for refractory status epilepticus or elevated ICP.44–46 They are considered second-line therapy for the control of ICP, after propofol. 
 

Dexmedetomidine 

Dexmedetomidine is an alpha-2 agonist acting on the central nervous system, with a rapid onset and termination of activity. It offers mild to moderate sedation without significant respiratory depression, analgesic effects and less delirium than with benzodiazepines.47 Side effects include bradycardia and hypotension, with bradycardia being the most typical haemodynamic effect.48
 
Grof and Bledsoe demonstrated that neurocritically ill patients may require high doses of dexmedetomidine to achieve desired levels of sedation and to wean off adjunctive analgesic and/or sedative agents. Infusions may be started at doses from 0.4–1mg/kg/hour in neurocritical care patients to achieve target levels of sedation.44
 
In a study by Erdman et al, limiting dose titration to every 30 min and omitting a bolus dose resulted in no significant difference in the prevalence of hypotension or bradycardia between dexmedetomidine and propofol.49
 
It also appears to shorten time to extubation and enhance arousability and the patient’s ability to communicate with caregivers. Dexmedetomidine may reduce delirium after long-term sedation as compared with midazolam,50 and also reduce the overall neurocognitive adverse events of sedation, such as agitation, anxiety, and delirium, compared with propofol.51
 
However, safety and efficacy of this drug have not been evaluated in some ICU patient groups, such as patients with acute neurologic disorder (for example, stroke and head trauma).2
 

Newer alternatives

Inhalative sedation in the ICU is starting to spread all over Europe and has been recommended as an alternative in a German consensus guideline.52 The device used is called AnaConDa (Anaesthetic Conserving Device), which makes possible the administration of anaesthetic agents (isoflurane and sevoflurane)  in any ventilator commonly found in the ICU.53–55
 
Isoflurane, sevoflurane and desflurane have shown some benefits compared with intravenous sedation. They have a low metabolism and, due to their low solubility, are eliminated quickly and offes shorter and more predictable wake-up times than intravenous agents.54-58 They can also prevent the development of bronchospam,53,55 have cardioprotective effects54 and are haemodynamically more stable than intravenous drugs.55
 
Some volatile anesthetics abolish cerebral autoregulation at high doses; it has been reported that at 1.0 MAC sevoflurane, the autoregulation of cerebral blood flow remained intact, but that this was impaired at 2.0 MAC. They also have a direct neuroprotective effect in periods of in vitro59 and in vivo60 ischaemia or administered prior to it (anaesthetic conditioning).61 Preconditioning has been described in in vitro62 and in vivo63 models of cerebral ischaemia. Sevorane also has a role in post-conditioning; its application could be of interest once cerebral ischaemia has occurred.
 
Lee et al64 found that isoflurane post-conditioning reduced brain injury due to ischaemia in rats. However, at 0.5 MAC, adequate neuroprotection is not obtained, which means that the effect of sevoflurane post-conditioning in focal ischaemic lessions is dose-dependent.65
 
In a prospective study of sevoflurane sedation in patients with acute stroke or subarachnoid haemorrhage, sufficient sedation levels without clinically relevant ICP increases were achieved in 68% of patients.66 However, serious adverse events observed in the remaining 32% raise considerable safety concerns. Mean arterial pressure (MAP) had to be stabilised actively to maintain CPP. Based on these observations, it was concluded that that the alleged neuroprotective potential of sevoflurane do not outweighs the risk of adverse events and sevoflurane sedation should probably not be used in this specific patient population.66
 
Volatile sedation has historically been considered unsafe in neurocritical care units around the world. However, as previously mentioned and suggested in several studies, the potential neuroprotective benefit of inhalative sedation has to be more studied. 
 
As well as inhalative sedatives, the use of ketamine has also been debated because of the concern raised by early studies that it was associated with increased ICP.67 In studies examining the cerebral haemodynamic effects of ketamine after acute brain injury, ICP was reduced and CPP remained stable or increased, without significant changes in cerebral haemodynamics.68 A systematic review concluded that ketamine was not associated with an increased risk of ICP elevation, as said previously.69
 
Ketamine is a short-acting NMDA receptor antagonist with a rapid onset of action. It does not alter systemic haemodynamics or respiratory drive, therefore it can be used in non-intubated patients. At doses of 1–5mg/kg/hour, it can be used as an adjunct to other sedatives to improve their effects and thus limit drug requirements. 
 

Conclusions

Sedation and analgesia is frequently used in the management of critically ill patients and is related to a longer hospital stay and more difficult weaning from mechanical ventilation. However, in neurointensive care units, it is also a therapeutic strategy. Therefore studies have been developed to achieve efficient sedation and avoid the adverse effects as much as possible. 
 
Midazolam and propofol are the most frequently used first-line sedatives; however, use of benzodiazepines is less common because 
of their deleterious effects, such as prolonging mechanical ventilation time and increasing awakening times. 
 
New trends, such as inhalative sedation or ketamine, are beginning to garner more attention, but more studies are required to fully confirm their use.
 

References

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