Anaesthetist Dr Jan Persson from Stockholm has published an updated review of recent ketamine literature. The following interesting facts about our favourite drug are extracted from Dr Persson’s paper:
- Action on multiple receptors earns it the nickname: ‘the nightmare of the pharmacologist’
- Recently ketamine has also been shown to inhibit tumor necrosis factor-alpha (TNF- alpha) and interleukin 6 (IL-6) gene expressions in lipopolysaccharide (LPS)-activated macrophages. It has been speculated that these antiproinflammatory effects may be responsible for antihyperalgesic effects of ketamine
- Ketamine can exist in two forms, or enantiomers; S-ketamine and R-ketamine. The physical properties of the enantiomers are identical, but their interactions with complex molecules, underlying PK/PD parameters, might differ. It has been well established that the elimination clearance of S-ketamine is larger than that of R-ketamine. The S-form has been commercially available for several years, probably based on the perception that it would have a better effect to side-effect ratio. The recent literature calls into question the proposed advantages of the S-enantiomer.
- Ketamine has been shown to induce neuroapoptosis, or neuronal cell death, in newborn animals. This is obviously a concern in paediatrics, where ketamine plays an important role, both in anaesthesia and for sedation/analgesia during painful procedures. The relevance in humans of these effects, however, is unclear, and as pointed out by Green and Cote it does seem unlikely, for various reasons, that such an effect would be of major importance. It does not seem likely, though possible, that a clinically relevant effect would have passed unnoticed.
- Another, somewhat unexpected, side effect that has emerged in recent years is bladder dysfunction. In some cases the bladder effects progress to ulcerative cystitis. Although the reported cases have mainly concerned recreational drug users, they are relevant for long-term analgesic use as well. The mechanisms involved are unknown. This side effect might turn out to be the most serious limitation to long-term analgesic treatment with ketamine.
Curr Opin Anaesthesiol. 2010 Aug;23(4):455-60
Ketamine was used by clinical staff from the The Shock Trauma Air Rescue Society (STARS) in Alberta to facilitate intubation in both the pre-hospital & in-hospital setting (with a neuromuscular blocker in only three quarters of cases). Changes in vital signs were small despite the severity of illness in the study population.
A prospective review of the use of ketamine to facilitate endotracheal intubation in the helicopter emergency medical services (HEMS) setting
Emerg Med J. 2010 Oct 6. [Epub ahead of print]
A paper of great interest for those of us who spend a lot of time teaching the use of ketamine describes its history from initial synthesis in the early 1960s. Ketamine pioneer Edward F. Domino, M.D describes how it was first given to humans in 1964: ‘Our findings were remarkable! The overall incidence of side effects was about one out of three volunteers. Frank emergence delirium was minimal. Most of our subjects described strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs.‘
Domino goes on to list interesting anecdotes in ketamine’s history, like how his wife came up with the term ‘dissociative anaesthetic’ and how physicians and their partners experimenting with ketamine in the 1970s tried communicating with dolphins, fell in love, and froze to death in a forest. The pharmacology of ketamine is described along with its effects on pain and even depression.
Taming the ketamine tiger.
Anesthesiology. 2010 Sep;113(3):678-84 Free Full Text
The College of Emergency Medicine (UK) has updated its guideline on ketamine sedation in children.
The summary is copied below
Full text is available here
Guideline for ketamine sedation of children in Emergency Departments
- Before ketamine is used all other options should be fully considered, including analgesia, reassurance, distraction, entonox, intranasal diamorphine, etc.
- The doses advised for analgesic sedation are designed to leave the patient capable of protecting their airway. There is a significant risk of a failure of sedation if the procedure is prolonged, and the clinician must recognise that the option of general anaesthesia may be preferred in these circumstances.
- There is no evidence that complications are reduced if the child is fasted, however traditional anaesthetic practice favours a period of fasting prior to any sedative procedure. The fasting state of the child should be considered in relation to the urgency of the procedure, but recent food intake should not be considered as an absolute contraindication to ketamine use.
- Ketamine should be only used by clinicians experienced in its use and capable of managing any complications, particularly airway obstruction, apnoea and laryngospasm. The doctor managing the ketamine sedation and airway should be suitably trained and experienced in ketamine use, with a full range of advanced airway skills.
- At least three staff are required: a doctor to manage the sedation and airway, a clinician to perform the procedure and an experienced nurse to monitor and support the patient, family and clinical staff. Observations should be regularly taken and recorded.
- The child should be managed in a high dependency or resuscitation area with immediate access to full resuscitation facilities. Monitoring should include ECG, blood pressure, respiration and pulse oximetry. Supplemental oxygen should be given and suction must be available.
- After the procedure the child should recover in a quiet, observed and monitored area under the continuous observation of a trained member of staff. Recovery should be complete between 60 and 120 minutes, depending on the dose and route used.
- There should be a documentation and audit system in place within a system of clinical governance.
A literature review addresses the myth that ketamine is contraindicated in head injured patients. They summarise articles from the 1970’s which identified an association between ketamine and increased ICP in patients with abnormal cerebrospinal fluid pathways (such as those caused by aqueductal stenosis, obstructive hydrocephalus and other mass effects). In more recent studies no statistically significant increase in ICP was observed following the administration of ketamine in patients with head injury; some of the studies showed a net increase in CPP following ketamine administration. They list ketamine’s stable haemodynamic profile and potential neuroprotective effects as further rationale for its use.
The authors boldly summarise:
‘Based on its pharmacological properties, ketamine appears to be the perfect agent for the induction of head-injured patients for intubation.’
Myth: ketamine should not be used as an induction agent for intubation in patients with head injury
CJEM. 2010 Mar;12(2):154-7
There is a myth that increased muscular tone caused by ketamine leads to an increased failure rate of joint manipulations when this agent is used for procedural sedation in the ED. This is neither borne out by the published evidence nor our own experience of a series of cases, which have been presented by Louisa Chan at a former (UK) College of Emergency Medicine Conference. At the Australasian College of Emergency Medicine Annual Scientific Conference in Melbourne these data were presented by A/Professor Taylor’s team in Victoria, which provide evidence that procedural failure rate is in fact lower with ketamine than with other commonly used sedatives. Here is the abstract reproduced with the kind permission of A/Prof Taylor:
Failure to successfully complete a procedure following emergency department sedation
DMcD Taylor1,2 for the Emergency Department Sedation Study Investigators
1Austin Health; 2University of Melbourne, Melbourne, Australia
Aims: To determine the nature and incidence of, and factors contributing to, failure to successfully complete a procedure fol- lowing sedation in the ED
Methods: Eleven Australian ED enrolled consecutive adult and paediatric patients between January 2006 and December 2008. Patients were included if a sedative drug was administered for an ED procedure. Data collection was prospective and employed a specifically designed form.
Results: Two thousand six hundred and twenty three patients were enrolled (60.3% male, mean age 39.2 years). Failure to successfully complete the procedure occurred in 148 (5.6%) cases. Most failures occurred with attempted reductions of fractured/dislocated shoulders (35 cases), hips (32), ankles (21) and elbows (14). However, failure rates were highest among fractured/dislocated hips (18.5%), digits (13.7%), femurs (11.1%), mandibles (10.2%) and elbows (9.3%). Failure rates for residents/registrars (5.9%), consultants (5.6%) and nurse practitioners (5.9%) did not differ (P = 0.92). Overall, failure rates for the various drugs (used alone or in combina- tion) did not differ (P = 0.07). However, ketamine (used alone or in combination) was associated with a much lower failure rate (2.9%) than all other sedation drugs used (midazolam 5.8%, propofol 6.5%, fentanyl 6.9%, nitrous oxide 7.1%, and morphine 7.8%).
Conclusion: Procedural failure is uncommon although some pro- cedures are at higher risk, especially dislocated hip reduction. Failure rates do not appear to be affected by the designation of the operator or the sedative drug used. However, ketamine use is associated with lower failure rates. For those procedures at higher risk of failure, the provision of optimal conditions (spe- cialist unit assistance, venue, drug selection) may minimise failure rates.
Emergency Medicine Australasia 2010;22(S1):A52-3
A poster presentation at the Australasian College of Emergency Medicine’s Annual Scientific Conference in Melbourne in November 2009 reports 100 cases of pre-hospital ketamine use for analgesia by paramedics in New Zealand – reproduced below with permission of the author:
Ketamine is a safe and effective analgesic for pre-hospital paramedic led pain relief
HM Hussey & BC Ellis
Introduction: There have been a number of reports on the use of ketamine by pre-hospital physicians, with many advocating its use as the ideal pre-hospital analgesic and sedative due to its airway and cardiovascular stability. There however is little published on its use by paramedics. This study aims to review its effectiveness and safety when administered pre-hospital by paramedics.
Method: Prospective observational study of 100 consecutive administrations by St Johns ambulance paramedics in 2008–09 using a specifically designed data sheet. Demographic data, adjuvant analgesics used, ketamine dose, pre and post dose pain scores on VNRS and physiological parameters were collected. In addition paramedics and patients completed a satisfaction rating score.
Results: The mean dose of ketamine used was 30.2 mg and the mean improvement in pain was 5.10. Ketamine was used both as a lone agent and with morphine; excellent analgesia was achieved in both groups. The most common reason for use was limb trauma followed by burns and extractions from scene. There were no episodes of hypotension or airway compromise. 15% of patients had an adverse reaction all mild and mostly comprising minor psychotropic effects. The median satisfaction rating for both paramedics and patients was ‘Good’.
Conclusion: These results back the use of Ketamine by St John’s Ambulance paramedics and the authors support its use by other pre-hospital services as a safe and effective analgesic.
Emergency Medicine Australasia 2010;22(S1):A30
Records of 4252 patients aged 0-19 who received ketamine were reviewed for documented adverse events. Patients were all American Society of Anesthesiology Class I or II. 102 (2.4%) had an ‘adverse event’, defined as the occurrence of hypoxia by oxygen saturation lower than 93% on room air or clinical cyanosis, documentation of laryngospasm, airway obstruction, or apnea diagnosed clinically or by capnography, stridor, respiratory distress, or hypoventilation or hypercarbia as assessed by capnography. Cases with adverse events were compared with controls who had received ketamine without adverse events, but were not otherwise matched.
Of the adverse events, laryngospasm was documented to have occurred in 29/4252 cases (0.7%), hypoxia in 81/4252 (1.9%), and positive pressure ventilation was required in 33/4252 (0.8%). Intubation was required in one patient (0.023%). Compared with controls, patients with adverse events were more likely to have received IM, as opposed to IV, ketamine, although children who received IM ketamine were more likely to be younger than those who received IV ketamine (4.1 vs 7.9 years).
The retrospective design and other methodological limitations make it harder to draw conclusions other than what we know from existing literature, to which this large series adds: ketamine is given to a lot of kids with few adverse effects; larygnospasm is a real but infrequent occurrence that usually responds to simple manouevres; and intubation is extremely rarely required, but nevertheless may be necessary and therefore those physicians using ketamine should have advanced airway skills.
Serious Adverse Events During Procedural Sedation With Ketamine
Pediatr Emerg Care. 2009 May;25(5):325-8
A prospective study of 746 children sedated in the emergency department with iv or im ketamine revealed 2.1% may have experienced ’emergence delirium’ although the authors concede this was difficult to define. In contrast, 291 (38%) reported pleasant altered perceptions. Follow up revealed at least one nightmare in the following weeks in 3.4% of patients, which may be well under the rate reported in the normal unsedated paediatric population.
What is the nature of the emergence phenomenon when using intravenous or intramuscular ketamine for paediatric procedural sedation?
Emerg Med Australas. 2009 Aug;21(4):315-22
Ketamine lowered ICP in brain-injured kids
Ventilated children between the ages of 1 and 16 with traumatic brain injury and elevated intracranial pressure (ICP) were given ketamine and effect on cerebral perfusion pressure (CPP) and ICP was measured. Ketamine decreased ICP while maintaining blood pressure and CPP.
These results refute the notion that ketamine increases ICP. The authors conclude: “Ketamine is a safe and effective drug for patients with traumatic brain injury and intracranial hypertension, and it can possibly be used safely in trauma emergency situations”
Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension
J Neurosurg Pediatr. 2009 Jul;4(1):40-6 (Full text)