Just recently a 75-year-old gentleman was admitted to our unit as he remained unresponsive after short procedural sedation with Propofol. Although he was hemodynamically stable and showed proper spontaneous breathing at any time, the intervention team was concerned about his condition.
On arrival to our ICU, the patient was noted to be still unresponsive. He showed no reaction to painful stimulation. The Pupils were rather wide, but symmetrical in size and showed a prompt response to light. Brain stem reflexes were present and peripheral reflexes were triggerable. His breathing pattern was regular, and saturation levels were above 96% on room air. A blood gas analysis showed a normal pH and normal CO2-levels.
As usual, the common reflexes started to kick in, and some suggested to go for a CT-scan of his head to out-rule some significant complications. Luckily enough, close observation revealed some slow improvement of his alertness, and we considered the possible diagnosis of a central anticholinergic syndrome (CAS).
After the application of 1mg of physostigmine (2x0.5mg) intravenously the patient almost promptly awoke and had an uneventful stay on our unit.
This case just reminded me of these many patients in anaesthesia that inexplicably show delayed awakening after sedation or a general anaesthetic.
In fact, it is estimated that the incidence of central anticholinergic syndrome is around 8- 12 % following general anaesthetic and lesser with regional anaesthesia.
What is a Central Anticholinergic Syndrome?
Classically the central anticholinergic syndrome (CAS) describes a condition where a substance causes a competitive antagonism of acetylcholine (ACh) at peripheral and central muscarinic receptors. Initially, these were plants containing atropine, hyoscyamine and scopolamine.
There are four muscarinic receptors:
- M1 mainly in the central nervous system (responsible for delirium when antagonised)
- M2 in the brain and heart
- M3 in the salivary glands and
- M4 in the brain and lungs
The PERIPHERAL SYNDROME presents with:
- Dry mouth
- Difficulty swallowing (lack of saliva)
- Photophobia and blurred vision (due to dilated pupils)
- Dry skin, fever
- Reduced bowel sounds and urinary retention
The CENTRAL SYNDROME presents with:
- Agitation, agitated delirium, visual and auditory hallucinations
- Hypoactive delirium may also occur, this seems to be more common though in the postoperative setting
The clinical diagnosis of a CAS is more straightforward when typical peripheral symptoms accompany central signs.
The Problem with the "Silent" Postoperative CAS
The clinical diagnosis of a CAS is often straight forward when typical central symptoms accompany peripheral symptoms. The problems are patients in the postoperative setting, in which the patient often presents with somewhat atypical central symptoms and often minimal or even no peripheral symptoms at all.
Especially in this setting, the anticholinergic syndrome may be accompanied by sedation or coma. The mechanisms causative for this phenomenon are not well understood but might include greater tolerance at peripheral receptors, longer persistence at central receptors or greater CNS susceptibility due to age or disease.
Postoperative CAS is often associated with atypical central symptoms and minimal or even no peripheral signs at all! Sedation and coma are often observed in this setting.
What Drugs Cause CAS?
Common anticholinergics agents should be more accurately referred to as antimuscarinics, as these agents do not generally block nicotinic receptors.
The Problem is that many currently used drugs in anaesthesia and critical care are also known to cause this syndrome.
Benzodiazepines, opioids, phenothiazines, butyrophenones, ketamine, etomidate, propofol, nitrous oxide, and volatile inhaled anaesthetics!
How Can I Diagnose a "Silent" Postoperative CAS?
The fact that postoperative CAS often lacks the presence of peripheral symptoms makes the diagnosis challenging. The different presentation of the syndrome ranging from somnolence, confusion, amnesia, delayed recovery, stupor, coma to agitation, hallucinations, dysarthria, ataxia, delirium makes it difficult to diagnose accurately.
It is, therefore, a diagnosis of exclusion! The most helpful tool you have is physostigmine!
The prompt arousal of a patient after the application of intravenous physostigmine is highly suggestive of a postoperative central anticholinergic syndrome.
How to Use Physostigmine
When dealing with prolonged somnolence or unexplained agitation following any form of anaesthesia, make sure to check and monitor vital signs and provide basic or advanced life support if necessary.
Exclude common causes first (e.g. overhang of sedatives or opioids, persistent muscular paralysis, hypoxemia, hypercapnia, hypoglycemia and other).
If common causes can be excluded and CAS is a probable diagnosis, you should consider the application of intravenous physostigmine.
Physostigmine in recommended doses is considered safe! Possible adverse effects are considered unlikely. Studies found cholinergic symptoms sometimes to be mild, and these adverse effects are more an indication of probable excessive doses rather than an established safety concern.
For postoperative CAS a dose of 1mg of physostigmine i/v is recommended.
This dose can be divided into two doses of 0.5mg i/v if required.
The maximum dose recommended in this setting is 2mg i/v.
As posted on BIJC before, Asad et al. had performed a systematic review on the usage of ketamine as a continuous infusion (>24h) in intensive care patients. The same authors have now published a narrative review providing a more depth discussion about the pharmacological and pharmacokinetic properties of ketamine. Also they present recommendations for dosing and monitoring in an ICU setting.
The Goodies of Ket
Current evidence shows that Ketamine...
- Has no adverse effects on the gastrointestinal tract (bleeding) and does not cause acute kidney injury (compared to nonsteroidal anti-inflammatory drungs, NSAID's)
- Does not negatively influence bowel motility (in contrast to opioids)
- Preserves laryngeal protective reflexes
- Lowers airway resistance
- Increases lung compliance
- Is less likely to cause respiratory depression
- Is sympathomimetic, facilitates adrenergic transmission and inhibits synaptic catecholamine reuptake, therefore increasing heart rate and blood pressure
The Concerns of Ket
- Might increase pulmonary airway pressure and therefore aggravate pulmonary hypertension
- Might cause well known psychotomimetic effects which are of concern in the critically ill patient as this might predispose to delirium
- Interacts with benzodiazepines via the P450 pathway which could result in drug accumulation and prolonged recovery
Concerns Proven Wrong
- Ketamine need not to be avoided in patients at risk for seizures, particularly when used for analgosedation for short periods in the ICU setting
- Current evidence shows no increased intracranial pressure or associated adverse neurologic outcomes associated with ketamine administration in critically ill patients
The use of ketamine for analgosedation in the ICU continues to lack high-level evidence.However, it is effectively used around the globe and remains an attractive alternative agent for appropriately selected patients. Taking current knowledge and evidence into account this is especially true for patients with severe pain unresponsive to conventional therapies.
Taking precautions and contraindications into account ketamine is considerably safe and even avoids potentially adverse side effects of other agents used.
Erstad BL, J Crit Care, Oct 2016, Vol 35, p 145-149
Dexmedetomidine has shaken up the usual sedatives in ICU but remains a matter of debate among intensivists. One question is whether the higher costs compared to midazolam are justified by clinical advantages. There is research available suggesting that dexmedetomidine might be an attractive alternative to standard sedatives especially in regards of time to extubation and costs (Turinen et al., Jacob et al.). This seems to hold true for moderate to light sedation of intubated patients.
I've stepped over this prospective, double-blind, randomised trial by Riker et al. in which 68 centres in 5 countries recruited intubated 366 patients to received moderate to light sedation with either dexmedetomidine or midazolam. All patients received daily arousal assessment.
Their primary end point was the percentage of time within the target sedation range (RASS score −2 to +1) and this did not differ between the two groups.
Looking at the secondary endpoints though make things a lot more interesting. Just before the beginning of the sedation period both groups had a similar prevalence of delirium. During study drug administration though, the effect of dexmedetomidine treatment on delirium was significant. A reduction of 24.9% with dexmedetomidine is rather impressive (see figure below). This effect was even greater in patients who were CAM-ICU-positive at baseline.
Finally patients on dexmedetomidine had shorter time to extubation (1.9 days in average) while their length of stay on ICU did not differ.
From a safety point of view the most common adverse effect of dexmedetomidine was bradycardia. It's noteworthy that patients on midazolam had more episodes of hypotension and tachycardia.
THE BOTTOM LINE
- This is another study indicating that dexmedetomidine seems to be beneficial in regards of delirium in mechanically ventilated patients and might speed up time to extubation
- Dexmedetomidine is safe in patients where moderate to light sedation is the aim
Riker et al. JAMA. 2009;301(5):489-499. doi:10.1001/jama.2009.56 OPEN ACCESS
Read more HERE on BIJC
Ketamine's success seems unstoppable:
+++ Anaesthesiologists are opening private clinics for off-label infusions of ketamine for depression http://bit.ly/1IGYTcI +++ Dr. Jim Roberts says #ketamine is an ideal treatment for excited #delirium: http://emn.online/Dec15InFocus +++ Major #ketamine treatment trial to start in 2016 http://m.huffpost.com/au/entry/8501942 +++ More impressed every day with low dose ketamine for pain management! https://www.youtube.com/watch?v=DgckjVVBb48 ...
Intravenous ketamine is also used in critical care units and to my knowledge most clinicians use ketamine as an adjunct to other sedatives. This might be for patients on mechanical ventilation, intubation procedures or simply as an additive to a patient-controlled analgesia pump. I personally think ketamine is one of the essentials in ICU's, but what does the evidence say.
Asad et al. have performed a systematic review on the usage of ketamine as a continuous infusion (>24h) in intensive care patients. The aim was to find evidence in favour for the utilisation of ketamine in the ICU.
As a result of this review - current evidence suggests that:
- In critically ill postoperative patients ketamine has the potential to reduce the cumulative morphine consumption at 48h compared to morphine only
- Several trials show the potential safety of ketamine in regards of cerebral haemodynamics in patients with traumatic brain injury, improved gastrointestinal motility and decreased vasopressor requirements
- One observational study and case reports suggest that ketamine is safe, effective and may have a role in patients who are refractory to other therapies
Our conclusion: THUMBS UP for ketamine in the ICU
Asad E. et al. J Intensive Care Med December 8, 2015
Ketamine - a drug with various actions and just as many opinions on it. One concern often mentioned is that ketamine might cause a raise in intracranial pressure (ICP) and therefore is often avoided in this group of patients. In May's Journal of Anaesthesia Wang et al. looked at the existing evidence on this topic. They ended up with 5 trials meeting their inclusion criteria on administration of ketamine and the ICP levels within the first 24h as a primary outcome.
To make it short: Ketamine does not increase ICP in comparison to opioids. They conclude that ketamine should not be discouraged on the basis of ICP-related concerns.
Wang et al. J Anaesth. 2014 May 24
Since the FDA’s approval of Propofol in 1993 it has become one of the most important drugs used in anaesthesia. It’s properties (short induction time, short half life) have made it an ideal agent for the use in theatre. Also in critical care Propofol was increasingly used for long term sedation and it’s anti-epileptic properties have been welcomed by intensivists treating patients with status epilepticus. In 1992 T.J. Parke et al. published for the first time an article in the BMJ describing 5 children who developed increasing metabolic acidosis, brady-arrhythmia and progressive myocardial failure while sedated with Propofol - today often referred as the Propofol Infusion Syndrome (PRIS). This rare complication shows a complex pathophysiology which is still not fully understood and still continues to be controversially discussed.
While initially described in children and traumatic brain injury it is also increasingly reported in other critically ill patients. If you are interested in some background information on this syndrome this recent case report by Mayette et al., published in the Annals of Intensive Care, provides an interesting insight in this topic.
Parke et al. BMJ. 1992;305:613
Mayette M. et al. Ann Intensive Care. 2013 Sep 23;3(1):32
Take Home Message: Risk factors for PRIS appear to be...