Mechanical ventilation (MV) is a common intensive care intervention (approximately 20 million patients per annum(1) worldwide). Patients requiring MV experience high mortality and morbidity. MV accounts for much intensive care unit (ICU) resource utilisation(2).
Most patients requiring MV are medically sedated. Optimizing sedation and analgesia is fundamental to the management of critically ill patients. There is a consistent association between deep sedation and negative prognostic markers(3, 4), driving international guidance aimed at improving outcomes(3, 5).
Providing adequate sedation, maintaining comfort, reducing pain, and minimising agitation / delirium have been identified as top priorities for ICU research by both patients and clinicians(6).
Ketamine is an N-methyl D-aspartic acid (NMDA) receptor antagonist that has be used since the 1970s to provide cataleptic, amnesic, analgesic, and dose dependant anaesthetic effects(7).
Ketamine has been particularly successful in military(8) and pre-hospital(9) settings owing to its ability to stimulate the sympathetic nervous system, resulting in increased heart rate and blood pressure(10).
Over this time ketamine has also become increasingly popular as an anaesthetic agent for emergency surgical procedures in hypotensive patients(11, 12).
More diverse effects of ketamine include: providing anti-inflammatory effects in sepsis(13), bronchodilation(14), neuroprotective properties(15, 16), tumour inhibition(17, 18), and antidepressant effects(19).
Although having been around for 50 years, ketamine, particularly as a continuous infusion, has not become a routine sedative option to facilitate MV.
In a survey of ICUs in the UK, propofol in combination with either alfentanil or fentanyl was the most common sedation-analgesia regime used with 92.2% of units using propofol as their first choice agent(20). A third of units reported using other non-ketamine sedative agents either ‘frequently’ or ‘very frequently’, these included benzodiapines e.g. midazolam (29.4%), clonidine (35.3%), and dexmedetomidine (11.8%).
Adverse features of sedatives
Hypotension is a common adverse effect of most sedative agents. It is thought that the predominant mechanism behind this is attenuation of external stimulation, reduced sympathetic tone, and vasodilation(21).
During induction of anaesthesia propofol has been shown to cause a 12% reduction in Mean Arterial Pressure (MAP), a 13% decrease in cardiac output (CO), and an 18% reduction in left ventricular stroke work index.(22)
In the 2009 SEDCOM study comparing dexmedetomidine and midazolam, hypotension occurred in a total of 56% patients and required intervention in 28%(23).
More recently, in 2019, the SPICE 3 study also found a significantly increased incidence of hypotension, bardycardia, and asystole wuth dexmedetomidine(24).
Maintaining patients’ blood pressure is a fundamental part of ICU care, and the American College of Critical Care Medicine (ACCM) suggests a MAP of between 60-65mmHg is necessary to perfuse vital organs(25). Hypotension has been consistently linked to poor outcomes, conversely studies have shown that maintaining MAP ≥ 65mmHg in ICU patients with sepsis can reduce the incidence of acute kidney injury (AKI) by 7%, myocardial injury by 4.5%, and overall in-hospital mortality by 11.4%(26).
These findings are in keeping with the consensus guidelines ‘Surviving Sepsis’, which recommend that, following sufficient fluid resuscitation, vasopressor medications should be initiated if MAP is below 65mmHg(27). This is often extended to other causes of hypotension and a target MAP of ≥ 65mmHg is generally considered reasonable.
Whilst hypotension and shock may be a feature of a patient’s illness, there may be a subset of patients who suffer exacerbation or perpetuation of hypotension through administration of sedative medications. Through stimulation of the sympathetic nervous system, Ketamine has the ability to induce anaesthesia without significant cardiovascular consequences; we hypothesise that these benefits may extend to sedation on ICU, however it was unclear if there was pre-existing literature to support this.
Delirium is common during critical illness and result in higher mortality rates, longer ICU stays, and worse long-term outcomes(28, 29). Research into causative factors has been largely unsuccessful at reducing delirium incidence, however it is widely accepted that sedation particularly using benzodiazepines significantly increases risk(3, 5, 30).
Reluctance to adopt frequent use of ketamine often relates to possible ‘emergence reactions’. Emergence reactions are psychomotor symptoms experienced by some patients when waking from ketamine-induced anaesthesia. The incidence of these reactions vary in the literature from 5–30%.(31)
These reactions, which can vary from mild manifestations such as floating sensations, disorientation, excitement, dysphoria, vivid dreams, and amnesia, up to more marked reactions including frank delirium, hallucinations, and agitation(31–33) are well documented in the context of general anaesthesia, however, to our knowledge have not been examined in the context of critically unwell sedated patients on ICU. As part of this scoping review we aimed to define exactly what is known with regards to delirium and ketamine use in ICU, and what, if any, gaps existed in the literature.
Adverse features of ICU
Depression and PTSD
Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are common amongst the survivors of ICU, with the prevalence of MDD ranging in the literature from 17–43%(34, 35) and PTSD ranging from 21–35%(34, 36).
Associations between perceived risk factors and PTSD have been extensively examined with varied results(35). Duration of ICU delirium, early post-ICU depressive symptoms, the use of benzodiazepines, and physical and cognitive impairment during recovery and rehabilitation have all been identified as significant risks for developing MDD(36–38).
Ketamine was recently licensed for MDD treatment following reviews that highlighted transient psychotomimetic effects with single-dose administration(39, 40). This warrants further investigation to establish whether any literature exists relating to either depression post-ICU or patient centred outcomes (e.g. QALY or EQ5D) and ketamine sedation on ICU.