Sedation and analgesia are critical skills for practitioners in the prehospital setting. Safe, effective, and predictable medications are required to achieve these aims. This is particularly true when prehospital personnel operate on written protocols or algorithms. Opioids and benzodiazepines are most commonly used, but can be limited by adverse effects such as excessive sedation, hypotension, or respiratory depression. Ketamine, a rapid-acting anaesthetic agent, has a unique set of properties that set it apart from most other sedatives. Studies have shown a variety of potential uses for ketamine in the emergency department, and further studies are suggesting that some of these uses may be expanded to paramedics in the prehospital setting.
History
Ketamine was developed by Parke-Davis in 1962 in an attempt to develop a safer alternative to phencyclidine (PCP). It was initially used medically on American soldiers in Vietnam. Ketamine has subsequently been used as an analgesic and anaesthetic since the late 1970s. It has been used in combat, wilderness, and disaster situations, particularly in developing countries or other circumstances where advanced anaesthesia resources and monitoring are not available (Bonanno, 2002).
In 1970, conflict between the Palestinian Liberation Army and Jordanian army overwhelmed local hospitals with injuries. A British field hospital established in the area frequently used ketamine for patients requiring painful burn care. It was often administered intramuscularly due to poor intravenous (IV) access, yet a single dose still provided sufficient time for necessary cares to be administered. The patients’ airway reflexes were maintained with ketamine, allowing nursing staff to monitor them and anaesthetists to focus their attention on more critical patients (Mercer, 2009). Even today, ketamine is regularly used as an anaesthetic for surgery in the developing world.
Ketamine has been used in the emergency department to facilitate painful or anxiety-provoking procedures such as fracture reduction or wound repair, especially in the paediatric population since the 1990s (Green et al, 1990). Numerous studies in this setting have documented its use and safety profile in this setting. It is also used, although less commonly, in adult patients for similar painful procedures.
Shortly after its introduction to clinical use, ketamine found its way onto the streets. It has most recently been adopted by rave culture and is known by such names as K, Special K, Vitamin K, or Jet. Various forms have been injected, ingested, inhaled, and smoked. When used recreationally, ‘out of body’ experiences, vivid hallucinations, and dreams are reported (Graeme, 2000).
Pharmacology
Ketamine is a derivative of PCP and is known as a ‘dissociative anaesthetic’ as a result of its disruption of communication between the cerebral cortex and limbic system in the brain. Ketamine does not produce a true sedation like that of benzodiazepines or barbiturates, but a ‘trance’ state in which pain amnesia and analgesia are achieved by depressing the brain's ability to perceive sensory stimuli and develop memory. It blocks N-methyl-D-aspartate (NMDA) glutamate receptors, which cause most of its central effects (Aroni et al, 2009).
Ketamine also activates certain subtypes of opioid receptors accounting for its mild analgesic properties. Ketamine has mild sympathomimetic effects, causing the release of norepinephrine and epinephrine; blood pressure and heart rate are usually elevated as a result. Sympathetic nervous system stimulation also causes dilation of the bronchioles. Perhaps its most unique attribute is the preservation of spontaneous respirations and airway reflexes, allowing for a variety of potential uses in emergency medical services (EMS).
An additional benefit of ketamine, especially in the prehospital setting, is its rapid onset and short duration of action (Porter, 2004). When administered intravenously, effects are observed within a minute. Although the onset is slightly longer by other routes, the elimination half-life is 2.5 hours, anaesthesia is maintained for only 10–15 minutes. Ketamine is usually administered by the IV or intramuscular (IM) route. It can be administered intranasally or intraosseously, but there is limited study of its use by these routes (Helm et al, 1996; Reid et al, 2011). Injection solutions are available in 10 mg/ ml, 50 mg/ml, and 100 mg/ml concentrations. The 100 mg/ml solution can be given directly via the IM route, but must be diluted to 50 mg/ml before IV administration.
Dosing is described in Table 1. There is a dose-related analgesic effect at lower doses, but once a dissociative state is achieved, there is no increase in the ‘depth’ of dissociation with higher or repeated doses (Svenson and Abernethy, 2007).
| Use | Intravenous | Intramuscular |
|---|---|---|
| Analgesia | 0.2 to 0.5 mg/kg | 0.5 to 1.0 mg/kg |
| Dissociative sedation/intubation | 1.0 to 2.0 mg/kg | 4.0 to 5.0 mg/kg |
| Time to dissociative state | 60 seconds | 3–5 minutes |
| Duration of dissociative state | 10–15 minutes | 20–30 minutes |
Adverse effects
Ketamine has a wide margin of safety; airway responses are maintained, compared with patients who are excessively sedated with narcotics and benzodiazepines (Strayer and Nelson, 2008). The most common respiratory effect is laryngeal spasm, but even this is rare and occurs in 0.3%. Risk factors include younger age and active respiratory infections (Melendez and Bachur, 2009). The effect is transitory, and airway repositioning and positive pressure ventilation with a bag valve mask are usually the only interventions needed. Sympathomimetic effects produce mild increases in blood pressure, heart rate, cardiac output, and myocardial oxygen consumption.
These increases may not be accompanied by parallel increases in coronary perfusion, such that ketamine could theoretically provoke ischemia in patients with coronary artery disease (Green and Li, 2000). As such, advanced age (and the potential for unknown coronary disease), known cardiac disease, or hypertension may be relative contraindications for the use of ketamine. Vomiting occurs in approximately 10% of patients although often after the dissociative effects have abated and the patient is more alert (Roback et al, 2005). Ketamine has been known to increase salivary and bronchial secretions, prompting pretreatment with atropine; however, ketamine has been given safely without it (Mistry and Nahata, 2005).
‘Emergence phenomenon’ is a relatively unique adverse effect to ketamine. Characterized by confusion, agitation, hallucinations, or dysphoria (or even euphoria), it may range from mild to serious and occurs during recovery from the dissociated state. While not physiologically dangerous, a serious reaction may be distressing to the patient, onlookers, or providers. An agitated patient could be dangerous in the relatively confined space of an ambulance or helicopter, and this should be considered before administration. However, the number and incidence of these reactions may be lower and less intense than what has been traditionally reported in paediatric and young adult populations (Green and Sherwin, 2005; Mistry and Nahata, 2005). A literature review by Strayer and Nelson (2008) describes the incidence of distressing emergence phenomena as 10–20% in adults, but there is no consistent data in the literature. Risk factors are not well studied, but patients with previous psychosis or schizophrenia have had significant emergence reactions and should not be given ketamine (Green and Li, 2000). Historically, it has also been noted that maintaining a calm environment free of excessive stimulation during recovery may also be of benefit, although tranquillity is often the antithesis of the prehospital environment. Significant reactions can be managed with benzodiazepines if they occur.
‘While opioids remain a primary method of pain control, the analgesic and anaesthetic effects of ketamine could be used to either substitute or supplement standard opiates’
Co-administration of ketamine with low-dose benzodiazepines has been shown to prevent emergence phenomena, as has administration just prior to emergence (Strayer and Nelson, 2008). Chudnofsky et al (2000) studied the combination of ketamine and midazolam, and concluded that respiratory depression with the additional sedation was rare, suggesting that the original appeal of ketamine's airway protection may not be lost with the co-administration of midazolam.
Ketamine and intracranial pressure
Early studies demonstrated an increase in intracranial pressure (ICP) with ketamine, and it has been historically contraindicated in patients with suspected head injuries. More recent studies in both humans and animal models suggest that ketamine may actually be beneficial in head trauma. ICP does increase with administration of ketamine, but this increase appears to be associated with improved cerebral perfusion (Sehdev et al, 2006).
Additionally, the action on NMDA receptors in the brain may actually confer neuroprotective effects by inhibiting cell-destroying enzymes and free radicals (Marcoux et al, 1988). Given that both hypotension and hypoxia contribute to poor outcomes in patients with head injury, the stimulant effects of ketamine on blood pressure and maintained respiratory drive may be advantageous (Chestnut et al, 1993).
Prehospital uses
There are many features of ketamine that seem to make it an ideal drug for prehospital use. It provides effective analgesia and amnesia to pain and events. Airway responses are protected, and there is no cardiovascular depression. Furthermore, it has a rapid onset, short duration, and is titratable. It may also allow for reduced doses of medications that cause more central nervous system (CNS) and respiratory depression. Over the past decade, there has been increasing experience with ketamine in prehospital care for multiple indications in both paediatric and adult patients.
While opioids remain a primary method of pain control, the analgesic and anaesthetic effects of ketamine could be used to either substitute or supplement standard opiates. Johansson et al (2009) found that patients who were given a low dose of ketamine (0.2 mg/ kg), in combination with morphine, required overall lower doses of morphine before arrival at the emergency department, compared to those receiving morphine alone. Patients receiving ketamine also had significantly better improvement in pain scores than those receiving morphine alone, and there was no difference in level of sedation.
Morphine-sparing effects
A randomized control trial in an emergency department setting also found ketamine provided morphine-sparing effects compared to placebo (Galinski et al, 2007). At higher doses, the dissociative state achieved by ketamine has been used in situations of severe pain from burns not relieved by narcotics, for fracture reduction, and to facilitate safe extrication of trapped patients with significant or painful injuries (Svenson and Abernethy, 2007). Bredmose et al (2009b) reviewed the use of ketamine in paediatric trauma by the London helicopter emergency medical service (HEMS) for children less than a year old to 15 years old and found it to have a satisfactory safety profile. Porter (2004) reviewed a series of cases where ketamine was safely given on scene to facilitate extrication, splinting of fractures, or to manage severe pain.
Cottingham and Thomson (1994) described various cases of patients where significant analgesia was required to extricate patients who were trapped and in such positions where airway management would have been very difficult if they had become overly sedated. Ketamine facilitated safe extrication of each of these patients. Even in situations where IV access cannot be immediately obtained, such as an uncooperative or trapped patient in a confined space, a dissociative state can be achieved relatively rapidly with IM administration. Unlike opioids, which may exhibit dose-dependent and additive respiratory depression, ketamine may be administered in repeated doses more safely in trapped trauma patients, as there is no additive effect that may lead to respiratory complications (Green and Krauss, 2004).
Ketamine's activation of the sympathetic nervous system may confer additional benefit by helping to maintain the blood pressure of a more seriously ill trauma patient, where other sedatives may cause further hypotension and worsen a shock state (Morris et al, 2009).
Ketamine has been used safely in the prehospital setting in head trauma, including combative patients, as both a sedative and an induction agent for intubation (Svenson and Abernethy, 2007; Melamed et al, 2007). However, bearing in mind the previous concerns over intracranial pressure elevation, there is currently no research comparing outcomes in head-injured patients who have been given ketamine versus other medications in the field. When given alone or with benzodiazepines, ketamine may be effective for chemical restraint and sedation, and could help avoid the need to intubate an uncontrollable patient with paralytics and sedatives that depress respiratory drive. The relatively brief duration of action will be less confounding to neurological examinations needed to classify severity of brain injuries on arrival to the hospital.
An alternative to other medications
Similarly, ketamine provides a safe alternative to other sedating medications in patients that are violent or experiencing agitated delirium as a result of drug ingestion or encephalopathy. Hick and Ho (2005) and Roberts and Geeting (2001) describe situations in the prehospital and hospital settings in which a severely agitated patient was at significant risk of harming themselves or others and IM ketamine injections calmed them adequately to provide further care. These patients are often suffering from a severe metabolic acidosis, and continued agitation or struggling with restraint attempts by law enforcement or medical personnel has been known to increase risk of cardiac arrest (Hick and Ho, 2005). Rapid, predictable sedation is critical to facilitate the safety of everyone involved.
While ketamine is most often used for anaesthesia when no airway intervention is planned, it has also been reliably used as an induction agent for intubation for both medical and trauma patients. Sibley et al (2010) studied the use of ketamine for intubation by a Canadian helicopter service and concluded that it not only was safe, but ideal for use by non-physician providers. Other retrospective studies have shown similar success using ketamine in this manner (Svenson and Abernethy, 2007; Bredmose et al, 2009b). Induction with ketamine maintains the patient's spontaneous respiration and may aid pre-oxygenation. This makes it a particularly appealing induction agent to prevent hypoxia when an intubation is predicted to be difficult.
In the rapidly declining asthmatic or chronic obstructive pulmonary disease (COPD) patient requiring intubation, ketamine would be an ideal induction agent (L'Hommedieu and Arens, 1987). Ketamine has bronchodilatory effects via catecholamine release and inhibition of vagal tone, which can reduce bronchospasm (Aroni et al, 2009). Case studies in an emergency department have suggested that dissociative doses of ketamine, followed by continuous infusion as a bronchodilator, may help avoid intubation, though this longer-term use is less practical for EMS (Denmark et al, 2006). Use in non-invasive ventilation has not been studied, although theoretically it could be beneficial to help relieve not only bronchospasm, but also the anxiety and discomfort sometimes caused by continuous positive airway pressure/ bi-level positive airway pressure (CPAP/BiPAP). It has been used safely with BiPAP in a patient with COPD during surgery to avoid intubation (Kapala et al, 2009).
Patient monitoring when using ketamine
The unique properties of ketamine have garnered much appeal for its use in disaster and wartime settings, when there is limited access to qualified personnel to provide continuous monitoring of sedated patients. Nevertheless, providers must remain vigilant to monitor patients closely when ketamine is administered. The dissociative state achieved by ketamine gives the patient an appearance of being in a trance. Eyes often remain open with notable nystagmus.
Although patients often appear awake, successful dissociation is manifested by a diminished or absent response to painful stimuli. It is important to warn members of the emergency services, family, and bystanders, as this can be particularly distressing to onlookers; reassurance is necessary that this is normal and that the patient will be amnesic and unaware (Porter, 2004). While airway reflexes are maintained more than for any other anaesthetic agent, attention still must be given to ensure that the airway remains patent.
Laryngeal spasm or hypoxia should be immediately addressed with airway repositioning or positive pressure ventilation with a bag valve mask. Continuous pulse oximetry, end-tidal CO2 monitoring, frequent vital signs, and cardiac monitoring should be maintained whenever possible. Critical airway equipment including suction, oxygen, bag-valve masks, and intubation or other secure airway supplies must be on hand. Whenever possible, IV access should be obtained for ketamine use incase other medications are urgently needed.
There is generally no recollection of any events during this period once the effects are gone. However, patients need to be watched for agitation or other evidence of emergence phenomena. Providers may want to have benzodiazepines available should a significant reaction occur; if there is considerable concern for this, pretreatment with midazolam could be considered. Whenever possible, a quiet environment should be maintained to avoid over-stimulating the patient.
Conclusion
Ketamine is an anaesthetic agent unlike any other currently in use. Since its initial use, it has proven to be effective, particularly in developing countries, war zones, or other austere environments where advanced anaesthesia care and monitoring are not available. In the prehospital setting, its documented use has been largely limited to case studies and retrospective reviews involving physicians; further studies could help establish a more definitive role. However, with sufficient training, ketamine is not only safe to be administered by paramedics, but for a variety of situations it may be the ideal choice.