Uses of Ketamine in the Paediatric Population

Abstract

General anesthesia in pediatric patients can vary from light sedation to complete anesthesia with unconsciousness, amnesia and muscle relaxation. A wide variety of procedures are done under general anesthesia in children ranging from surgeries done for correction of congenital defects, cardiac surgeries, scoliosis surgery, hernia surgery etc. to procedures done outside the operating room (OR) for diagnostic and therapeutic purposes. Non-Operating room Anesthesia (NORA) may include painless procedures like CT scan, MRI, radiotherapy for cancer treatment etc. or painful procedures like biopsy, lumbar puncture, securing IV access, insertion of central line etc. done in ICU which requires a cooperative child. Ketamine has an important role in the pediatric population, both as an induction agent and as a sedative-analgesic drug especially in countries where newer drugs are not readily available. Ketamine helps to alleviate separation anxiety. Even procedures done under regional techniques in some older children require use of sedation. Ketamine can be administered through various routes-IV, IM, intranasal etc. It can be used along with other groups of drugs like Benzodiazepines, Barbiturates, Alpha 2 agonists, Propofol etc. Thus Ketamine is a versatile drug with various indications for use in the pediatric population which will be discussed in the current chapter.

1. Introduction

Ketamine was first synthesised in 1962 and put into clinical practice in 1970.It has a chiral structure and consists of two optical isomers S (+) and R (−) forms. Ketamine is commonly used for anaesthesia in the paediatric population. A recent survey identified standard induction agents used in children varied from Etomidate in 26.9% (7/26), propofol in 19.2% (5/26), a combination of benzodiazepines and ketamine in 19.2% (5/26), and barbiturates in 11.5% (3/26) [1]. The use of anaesthesia in paediatric age group outside the OR includes dental offices, endoscopy suites, cardiac catheterization laboratory, radiology facilities, radiation oncology departments, paediatric intensive care units (PICUs), and emergency departments. Patients aged less than 3 years routinely require anaesthesia prior to any procedure. By 7 years of age however most children can tolerate non-painful exams and treatments without anaesthesia support [2, 3]. In the OR Ketamine may be used for sedating the child prior to inducing GA in order to decrease anxiety due to parental separation. However the psychological side effects of Ketamine as well as availability of other agents made Ketamine less popular as an induction agent. Induction technique preferred in children is usually inhalational route especially with the availability of Sevoflurane.

2. Ketamine for conscious sedation

The American Society of Anaesthesiology (ASA) defines four levels of sedation (Table 1): minimal (anxiolysis), moderate (conscious), deep (purposeful response to vigorous stimulation), and general anaesthesia (unresponsive). A variety of pharmacologic agents are available to sedate and anaesthetise patients. Conscious sedation can be defined as, “A controlled state of depressed consciousness that allows the protective reflexes to be maintained, retaining the patient’s ability to maintain a patent airway independently and continuously and allows appropriate response by the patient to physical stimulation or verbal command.” A patient can progress from one level to another during sedation given in various doses. Hence continuous monitoring and vigilance is of utmost importance. The drugs used must be titrated to achieve the desired effect, prevent overdose and sudden loss of consciousness. Prior to even short procedures requiring sedation, the child must be evaluated thoroughly –check for any comorbidities like seizure history, previous surgeries, allergic reactions, birth history, developmental milestones attained etc. Airway should be examined to anticipate any difficult airway-enlarged tonsils, congenital defects etc. The blood investigations necessary should be ordered as per need just like prior to a child for major surgical procedure. Adequate fasting guidelines should be explained and ensured. An understanding of the pharmacodynamics and pharmacokinetic effects of sedating drugs which are going to be used is essential. Appropriate sized airway equipment, venous access, appropriate intraoperative monitoring equipment, properly equipped staff in recovery area and proper discharge criteria should also be checked. Sedation drugs can be administered through various routes—oral, nasal, intramuscular, intravenous (IV), subcutaneous, and inhalational routes.

	Mild	Moderate	Deep sedation	General anaesthesia
Response to verbal stimulus	Normal	Only responds purposefully	Response seen only on repeated painful stimulation	No response even to painful stimulus
Airway	Not affected	Usually able to maintain airway without intervention	May not be able to maintain airway reflexes	Airway adjuncts like supraglottic airway device or endotracheal intubation required
Spontaneous Ventilation	Maintains spontaneous respiration	Adequate	May be inadequate	Frequently inadequate
Cardiovascular Function	No cardiovascular depression	Usually normal	Usually normal	Cardiovascular depression may occur

Table 1.

ASA levels of sedation.

For conscious sedation drugs are used in sub anaesthetic doses and titrated to obtain adequate effect. Various drugs have been used for conscious sedation in paediatric age group which includes Ketamine. The doses of drugs used for Conscious sedation is given in Table 2.

Drug	Route of administration
Midazolam	IV/Intranasal
Ketamine	IV/IM/rectal/oral/intranasal
Dexmedetomidine	IV
Propofol	IV
Ketofol	IV
Opioids (Fentanyl/Remifentanyl)	IV

Table 2.

Drugs used for conscious sedation.

3. Clinical effects of ketamine

Ketamine is a phencyclidine derivative which acts as an N-methyl-D-aspartate (NMDA) receptor antagonist at the dorsal horn of the spinal cord [2, 4]. It induces dissociative amnesia and analgesia [5]. Ketamine has the advantage of various routes of administration available for use. Administration routes include intravenous (1–2 mg/kg), intramuscular (2–10 mg/kg), oral (3–6 mg/kg), intranasal (2–4 mg/kg), and rectal (5–10 mg/kg) (Refer Table 3) [6]. Ketamine has many advantages over other drugs especially due to its relative cardiovascular steadiness and restricted effect on the respiratory mechanics. Recovery occurs within 30–120 min, and this allows the patient to be discharged on the same day as the procedure. It has a dose dependent cardiovascular stimulant effect. In children with congenital heart disease, it causes only minor increases in heart rate and mean pulmonary artery pressure during cardiac catheterization procedures [1]. It has various effects on the other systems in the body some of which are listed in Table 4.

Route	Dose
IV	1–2 mg/kg
IM	2–10 mg/kg
Oral	3–6 mg/kg
Intranasal	2–4 mg/kg
Sedation	0.2–0.75 mg/kg IV or 2–4 mg/kg IM

Table 3.

Dosages of ketamine.

Organ system	Effect
Cardiovascular	Increases heart rate, blood pressure, cardiac output
Respiratory	Increases the oral secretions, bronchodilator, maintains the airway reflexes
Neurologic	Dissociative anaesthesia; Increase in intracranial pressure, excitatory effects on thalamus and limbic systems, increase in intraocular pressure, increase in cerebral metabolism, increase in cerebral oxygen consumption; Emergence delirium

Table 4.

Effects of ketamine on various systems.

Adverse reactions associated with ketamine include dreams, hallucinations, delirium, agitation, vomiting, increased salivation, and laryngospasm [7]. It causes increase in intraocular and intracranial pressures after its administration. Hence it is not used in patients with glaucoma, open globe injuries, or elevated intracranial pressure [5]. Clinically, ketamine is frequently used to facilitate short, painful procedures in the emergency department [4, 8]. Sedation can be achieved with minimal respiratory depression. However when higher doses are used, one can easily induce general anaesthesia [5].

Ketamine causes hyper salivation and thus needs to be administered with an antisialagogue like Atropine or glycopyrrolate. To prevent hallucinations and delirium it is often combined with short acting benzodiazepines like midazolam.

4. Ketofol

The combination of ketamine and propofol, known as ketofol is also a popular drug used for procedural sedation. The two drugs when combined act synergistically and thus helps to decrease the dose of each drug independently. The side effects of ketamine which includes vomiting, laryngospasm, and emergence delirium, can be decreased by adding propofol. In the same way using ketamine along with propofol decreases the risk of propofol-induced respiratory depression and hypotension. The combination also provides for analgesia [9]. There is no standard combination mentioned but usually Ketamine and Propofol are mixed in a 1:1 ratio (mg) [10]. According to a prospective randomised controlled study involving paediatric patients undergoing cardiac catheterization, using a propofol: ketamine combination in the ratio of 10:2 (mg) preserved mean arterial pressure without affecting recovery time [11]. Studies which have compared ketofol with propofol have shown that ketofol produces consistent depth of sedation. Patient satisfaction scores were also found to be similar. Propofol causes pain on injection but the combination of propofol with Ketamine reduces pain on injection. The risk of airway and respiratory complications were similar in both groups [12, 13, 14, 15]. Ketofol decreases the requirements of both opioids and propofol. Ketofol is thus an acceptable choice for short procedures in the emergency department or critical care setting [10]. The efficacy, safety, pharmacokinetics, and pharmacodynamics require further evaluation with additional prospective trials in the paediatric population.

With currently available IV anaesthetic agents such as Propofol, barbiturates, opioids etc. which are used frequently in combination with Ketamine for procedures done outside the OR, the complication rates has declined from 23% [16] seen in the 1980s to 1–2%. This is somewhat similar to the complication rates in the ORs [17, 18, 19]. A current study by Owusu-Agyemang et al. [3] showed that use of propofol either alone or in combination with Dexmedetomidine and Fentanyl lowered complication rates to 0.05%.Some newer drugs like Fospropofol have been approved by FDA for sedation purposes. Some drugs like Remimazolam and other Etomidate derivatives are still in clinical trial stages. Some centres have seen the resurgence of inhalational anaesthetic nitrous oxide.

5. Ketamine use in cancer pain management

Cancer pain management, especially in terminal stages, can be challenging. Cancer pain is mediated through various pathways, including visceral, nociceptive, neuropathic and central. Currently used agents have limited role in addressing each component and have significant adverse events. The safety profile of Ketamine has been evaluated in a number of trials. The WHO ladder for pain management includes acetaminophen, non-steroidal anti-inflammatory drugs, weak opioids like tramadol and the strong opioids like morphine for cancer pain management. In addition to this, topical local anaesthetics like lignocaine can also be used. However US FDA approval for many of these medications is lacking for use in the paediatric age group.

Safety and efficacy as an anaesthetic and analgesic has been well documented; however, ketamine has not yet been approved as an analgesic agent by the US FDA. This may prevent its free use by many for cancer pain management [20, 21, 22, 23]. When Ketamine is used in doses <1 mg/kg it has minimal depressant effects on cardiovascular and respiratory systems as it produces only minimal sedation (Refer Table 1) [20, 24]. However it produces analgesia and modulate central sensitization, hyperalgesia, and opioid tolerance. Hence the National Comprehensive Cancer Network guidelines has recommended considering oral or intravenous (IV) ketamine for pain not responding to other analgesics [20, 25]. Ketamine has been used through various routes of administration-IV, IM, oral, sublingual Intranasal rectal and even epidural in patients with malignancy. The bioavailability of intranasal Ketamine was found to be 45–50% [26, 27].

A review of five studies of ketamine for cancer pain in children showed that patients treated with oral and IV ketamine had only few adverse events reported. However, these studies were all retrospective. Participants’ cancer diagnoses include acute myelogenous leukaemia, myelodysplastic syndrome, osteosarcoma, metastatic giant malignant mesenchymal tumour, glioblastoma multiforme, neuroblastoma, Ewing sarcoma, spindle cell sarcoma, synovial cell sarcoma, and Wilm’s tumour [28]. There are several very small case series or individual case reports of children being treated with ketamine for pain with promising results. For example, at Melbourne, a protocol for IV ketamine administration is being used to treat children who have been unresponsive to two doses of morphine. Additional dose of ketamine (0.1 mg/kg) given as a bolus has helped to achieve effective pain control. These doses have not been associated with hallucinations or dysphoria. However, this report does not enumerate percentages of patients with adequate pain control after treatment with ketamine [29]. A prospective phase I trial of oral ketamine in the dose of 0.25–1 mg/kg given in divided doses in children with chronic noncancer pain has been undertaken [30].

Children with severe cancer pain have been treated with ketamine in doses of 3 mg/kg/day given orally [31] and 0.1–1 mg/kg/h given intravenously. In a retrospective review, 8 of the 11 (73%) children and adolescents had decreased need for opioids and improved pain control [32]. The results of these reports suggest that pain control may be achieved with the use of ketamine in children with cancer pain. These doses were well tolerated by the children between 3 and 17 years of age with cancer pain without nausea, sedation, hallucination, respiratory distress, or psychotomimetic effects.

6. Side effects of ketamine

The common side effects of ketamine include nausea, vomiting, occurrence of bizarre dreams, hallucinations, emergence agitation, seizures. It causes tachycardia and hypertension and thus is contraindicated in patients with cardio vascular illnesses. It also increases in intra ocular pressure and is thus contraindicated in open eye injuries.

Some studies have shown lorazepam given along with Ketamine to decrease the psychotomimetic side effects of ketamine [32]. Ketamine administered through the epidural route in children has shown to produce fewer side effects due to Ketamine. This also decreased the opioid consumption during the procedure [33]. The neurotoxicity caused due to Ketamine appears to be less in children than in adults. There are a few case reports of laryngospasm caused when Ketamine is given intramuscularly or in higher doses [33, 34]. One case report of a ketamine infusion for a child reports mycolonic movements in the child [35]. The report is unclear as to whether this was related to ketamine or the child’s spinal cord tumour. There have been occasional incidences of reversible cystitis with chronic exposure to ketamine [36, 37].

The incidence of respiratory complications has been found to be higher with the use of intramuscular administration of Ketamine as compared to intravenous use. An increased incidence of laryngospasm has been reported especially due to the higher dose of ketamine required for effect as well as delayed absorption of intramuscularly administered drug. The incidence of respiratory adverse events was 2.4% with IM ketamine [34].

A retrospective study evaluated the usefulness of combining intranasal Dexmed (2 mcg/kg) and Ketamine (1 mg/kg) for procedural sedation found it to be useful in 93% of patients. The onset of sedation was 15 min and duration was found to be 62 min. Minor complications like nausea and vomiting only were observed in the study in 0.3% of the patients.

More than 11,000 cases have been reported of its use in children with no fatalities being described in the literature by Green et al. [5] the most frequently cited disadvantage is the emergence phenomenon, seen more commonly in adults where the incidence is 5–50% while in children it has been found to be 0–5%. Ketamine increases the salivary and tracheobronchial mucus gland secretions, and hence needs to be combined with an antisialagogue during GA. Emesis is the one of the most common side effect of ketamine. In a review by Green the incidence of vomiting was found to be 10% and more commonly seen in children undergoing dental procedures. Atropine has been found to decrease the emesis by reducing the salivary secretions. Laryngospasm was reported in 0.4% of cases. Laryngospasm was managed with 100% oxygen and positive pressure ventilation using bag and mask [38].

7. Ketamine in burns contracture release

In his study, Embu has described various techniques for burns contracture release. Some case were done with intermittent doses of Ketamine while patients were spontaneously breathing. Some patients were maintained on inhalational anaesthetic after Ketamine induction-either via face mask or LMA (laryngeal mask airway). After adequate surgical release, the patients were intubated by direct laryngoscopy. No airway complications were reported in the study. However, maintaining anaesthesia with an inhalation agent via facemask was found to be technically difficult owing to the proximity to the sterile surgical field [39].

Agarwal et al. have reported use of tumescent local anaesthesia for the release of neck contracture due to burns in 30 patients. 0.5–1.0 mg/kg of IV ketamine were used in these children at the start of the case. They were maintained on ketamine during the procedure also as intermittent IV boluses (dose has not been specified). No airway complications had been reported. All patients were maintained on spontaneous ventilation throughout the case [40].

8. Ketamine as an adjunct

Preservative-free ketamine added to caudal bupivacaine has been shown to improve the duration of analgesia, without affecting the analgesic intensity in a study done by Martindale et al. [41]. In a recent survey conducted among paediatric anaesthetists in UK by Sanders 32% had reported using epidural ketamine [42]. It is used in a dose of 0.25–1 mg/kg as an additive to bupivacaine or Ropivacaine.

9. Effects of use of ketamine on Perfusion Index (PI)

Children often are given regional anaesthesia for pain management following General anaesthesia (GA) in contrast to adult patients. Hence it is difficult to assess the usefulness of the regional technique except by use of surrogate indicators like tachycardia, hypertension. Perfusion Index is a newer technique to detect effectiveness of regional anaesthetic under GA.

Studies have demonstrated that PI can provide an early and reliable indication of the onset of epidural anaesthesia. Intravascular injection of epinephrine-containing local anaesthetic test dose can also be identified in the adult population [6, 8]. However, caudal blocks in paediatric patients are mostly performed under sedation or general anaesthesia, using ketamine or sevoflurane [9, 10]. Data has shown that ketamine itself can affect PI. Thus it is difficult to predict the onset of caudal block using PI in the paediatric patients who have been sedated using Ketamine. A previous study has shown that intravenous ketamine used in paediatric patients produced a fast and long-lasting decrease in peripheral PI. However the study also showed that caudal block reversed the decrease of PI measured in the toe, caused by ketamine anaesthesia in paediatric population. The PI was found to increase beyond the preinduction level. The study also showed that PI response criterion achieved 100% sensitivity and specificity in detecting the effects of caudal anaesthesia under IV ketamine anaesthesia in paediatric patients. However, neither HR nor MAP criteria were 100% reliable. Furthermore, the changes of PI caused by caudal block under ketamine anaesthesia were much earlier than those of HR and MAP.

Ketamine being a widely used intravenous anaesthetic in paediatric patients, it has been shown to produce an immediate and long-lasting decrease in peripheral PI due to its sympathomimetic effects through its effects on both central and peripheral mechanisms [17, 18]. In this study, a drop in PI was observed within one minute after the injection of ketamine (2.36 ± 0.79 to 1.58 ± 0.61) and after 30 min PI it had decreased to 0.80 ± 0.26, which was far below the baseline value of PI. The changes of MAP lasted about 15 min, and the changes of HR lasted about 5 min following ketamine injection. Caudal block not only reversed the decrease of PI on the toe caused by ketamine anaesthesia in paediatric patients, but also increased PI far beyond the preinduction PI value [43].

10. Use of ketamine in ICU

The sensory association areas of the cortex, components of the limbic system, and thalamus are directly depressed by ketamine. Consequently, higher central nervous system (CNS) centres are unable to receive or process sensory information and its emotional significance cannot be assessed. The result of ketamine administration is anaesthesia, analgesia, suppression of fear and anxiety, and amnesia, which appear to be ideal for the uncooperative child patient.

Ketamine is commonly used for sedation and analgesia during painful procedures because it maintains the cardiovascular and respiratory systems while providing effective sedation, analgesia, and amnesia. However Ketamine-induced emergence reactions like hallucinations, delusions, nightmares, and agitation are shown to be less in children [44]. Ketamine can be used prior to invasive procedures in the ICU like Lumbar puncture, central line insertions. It can be used in management of children with status asthamaticus.

Ketamine has many advantages due to which it is used for sedation in the paediatric population viz. a relatively short duration of action, multiple routes of administration, preservation of airway reflexes, and sympathomimetic properties including increase heart rates and blood pressure. Sedation can be achieved without much respiratory depression. However ketamine has various adverse effects too. These include hallucinations, emergence delirium, agitation, nausea and vomiting, hyper salivation, and laryngospasm. This can cause distress to both the child and parent. Reports of patients developing random movements of the extremities has been reported which renders this drug less than ideal for procedures where the patient must lie perfectly still like in the MRI suite. Thus, ketamine is used along with other sedative agents to counterbalance the side effects and enhance the beneficial effects for each drug rather than as a sole sedative agent for MRI. Ketamine can prevent the cardiorespiratory depression effect of propofol and prolonged recovery of dexmedetomidine by reducing the dose requirements of each drug when used for sedation in children in MRI suite [44, 45, 46, 47, 48].

Exposure to ketamine and other anaesthetic agents during early stages of postnatal brain development increases central nervous system neuronal apoptosis in animals receiving significantly larger and more prolonged doses than used for procedural sedation [49]. No evidence of neuronal injury after a single ketamine based sedation has been seen in small children but repeated use of ketamine for procedures may have detrimental effects. [50, 51].

11. Other uses of ketamine

Ketamine has been used as an induction agent in children with cyanotic congenital heart conditions like Tetralogy of Fallot. This is due to its effect in increasing the systematic vascular resistance and thus decreasing the incidence of righto left shunt. However it can increase the infundibular spasm. Thus it is combined with opioids or propofol. Another recently described alternative to this is Etomidate combined with Ketamine [52].

12. Conclusion

Recent studies have explored the use of Ketamine in other situations in adult population as well like prevention of postoperative sore throat, treatment of status epilepticus, alcohol withdrawal syndrome, status asthamaticus etc. There has been an increased usage of Ketamine in the acute pain setting to prevent excessive opioid use but these require further studies in the paediatric population. Thus Ketamine is a very useful drug in the paediatric age group which may be combined with other drugs to alleviate its side effects and achieve anaesthesia as well as analgesia.