Use of Oral Ketamine in Palliative Care

*Mateja Lopuh*

### **Abstract**

Ketamine, an N-methyl-D-Aspartate receptor antagonist, has been used for more than 50 years. From its initial potential as an anesthetic drug, its use has increased in the fields of pain medicine, psychiatry, and palliative care. It is available in different formulations, of which oral use is promising due to its active metabolite, norketamine which reaches 2–3 times higher levels when administered orally in comparison with parenteral use. Oral use is also more feasible and easier to use in settings, where medical staff is not that present, such as home care or hospices. Oral solution of ketamine has not yet been officially licensed for use although there have been several reports which recommend its use in neuropathic pain, severe depression, airway obstruction, and anxiety. Palliative care is defined as total care for patients whose diseases do not respond to curative treatment. It encompasses good control of physical symptoms, and psychological, social and spiritual problems. Patients often experience pain, despite high doses of opioids, depression and anxiety, and dyspnea. Oral ketamine does not have the side effects of opioids therefore it represents a good alternative. It may also reduce the need for high opioid doses and be more suitable for patients who wish to avoid the necessary sedation.

**Keywords:** oral ketamine, neuropathic pain, opioids, symptom control, palliative care

#### **1. Introduction**

Ketamine is a potent noncompetitive NMDA receptor antagonist. It is primarily marketed as a general anesthetic, but it also shows analgesic properties at lower, subanesthetic doses [1]. It is used as a chlorhydrate in a slightly acid aqueous solution. It is a racemic mixture of two enantiomers of equal quantity of which only the S (+) enantiomer is active and is two times stronger than the racemic mixture and four times stronger than the R (−) enantiomer. In equianalgesic doses, the S-enantiomer is associated with lower levels of undesirable effects.

Ketamine metabolism is characterized by low binding to plasma proteins, about 10–30%. It is highly liposoluble and has therefore an extensive distribution. The central compartment volume is 70 liters and the distribution volume at steady state is around 200 liters. Oxidation is the primary process in the metabolism of ketamine, resulting in norketamine (80%), which is an active metabolite that itself is principally hydroxylated in 6-hydroxy-norketamine and finally excreted in bile and urine after glucuronoconjugation. Ketamine elimination clearance is dependent on the liver blood flow, half time is 2–3 hours, and it may be 20% higher in women than men [2].

Ketamine is commonly administered via the intravenous, intramuscular, subcutaneous, or oral route. The subcutaneous route appears to be very practical because it avoids potential delays in treatment caused by the inability to establish intravenous access, has a rapid onset of action, and can be used by less skilled personnel, too [3].

The oral route availability of ketamine is incomplete and erratic. Only about 16–20% of an oral dose reaches systemic circulation due to extensive hepatic firstpass elimination. The bioavailability of intranasal ketamine was found to be 50%. Peak plasma concentrations are being reported within 30 minutes of oral administration. Norketamine as an active metabolite reaches 2- or 3-times higher levels when ketamine is administered orally than parenterally and the duration of action of oral ketamine is longer. To achieve a good analgesic effect, doses of oral ketamine can be one-third of the parenteral one, due to the active effect of norketamine [3]. In chronic use, norketamine may be the main analgesic agent. Because of norketamine accumulation the need for ketamine when given for a longer period of time, decreases over time. Norketamine is 33% as potent as the parent compound [4].

In palliative care patients often exhibit a variety of symptoms. They float between the desire to keep autonomy for as long as possible and the wish to avoid the unnecessary suffering, caused by poorly relieving symptoms. Many patients are afraid of opioids, especially morphine, and are reluctant to use them. Some physicians still believe that morphine accelerates death, and they would only use it when patients already entered the dying phase. Ketamine with its analgesic properties may be a good option to keep the opioid levels low as long as possible.

Ketamine has not yet been widely used in palliative care probably because it has always been marketed as an anesthetic drug and therefore reserved for use in the operating theaters. Even its use has not been very prominent due to the psychomimetic side effects when used in anesthetic dosage. Its domains of use expanded in pain medicine, where the doses can be lower, but it was used parenterally, therefore intravenous or subcutaneous access was needed. Longer subcutaneous use often resulted in necrosis of subcutaneous tissue and reduced flow from elastomeric pumps.

Oral and nasal use of ketamine has not been officially licensed although several papers have already been published which suggest that both routes are safe and feasible. These two routes seem to offer advantages over the intravenous and subcutaneous approaches as they allow the patient to be self-sufficient and autonomous in drug administration.

Some pharmacokinetics data are summarized in **Table 1**.

Palliative care may expand over the whole trajectory of the incurable disease. Ketamine is used as a co-analgesic in poorly controlled pain, especially neuropathic pain, to reduce the dose of opioids, to relieve anxiety and depression, severe epileptic seizures, and as bronchodilator. The long-term use of ketamine has not been studied extensively. In palliative care, the studies are limited because symptoms accumulate in the course of the disease and that makes the observation of side effects more difficult.


**Table 1.** *Pharmacokinetics of ketamine.*


**Table 2.**

*Suggested useful mechanisms of ketamine action.*

This chapter focuses on the oral/nasal route of ketamine administration in patients with palliative diseases, its useful properties in clinical practice, and its side-effects. Some suggestions are given about the formulation of the drug and the dosage regimens.

#### **2. Clinical uses of ketamine**

Ketamine is approved as a general anesthetic agent. At subanesthetic doses, it can be considered for use in a palliative care setting for pain refractory to opioids and as an adjuvant analgesic. Ketamine was approved by FDA for antidepressant use in 2019 as a nasal spray. Ketamine has no reversal agent [5].

Ketamine can be used in the intensive care units as a sedative and analgesic drug. It can be safely used in patients with traumatic brain injury as it does not raise the intracranial blood pressure, caution is needed when used with raised intraocular pressure. When used as an analgesic drug, it may reduce pain scores, opioid consumption, and postoperative nausea and vomiting.

In chronic, non-cancer pain, ketamine can be used as add-on therapy when other therapeutic options have failed. The long-term effects remain controversial.

In cancer pain, ketamine is considered an essential adjuvant drug but the evidence for its efficiency is low [6, 7].

Ketamine has proven to be efficient in treating major depression, bipolar disorders, and suicidal behavior. It acts very fast, and relieves depression in less than 2 hours. In the approved nasal spray only the S (+) enantiomer is used [8, 9].

Other uses of ketamine with the low level of evidence are alcohol withdrawal, status epilepticus, and persistent bronchospasm in critical care settings [8].

Suggested mechanisms of ketamine action are summarized in **Table 2**.

#### **3. Oral formulations**

Ketamine is not licensed for oral use. Physicians should properly inform the patients about the advantages and possible side-effects of the drug and the route of administration.

A parenteral formulation is utilized for oral formulations of ketamine. Use generic ketamine 50 mg/ml 10 ml vials and purified water. Alternatively, one can use flavored syrup instead of water, but most patients find it too sweet.

To prepare 100 ml of oral solution with a concentration of 50 mg/ 5 ml use two 10 ml vials of ketamine 50 mg/ml for injections and 80 ml of purified water. The solution can be refrigerated with an expiry date of 1 week from manufacture [1].

It is useful to provide the patient with a syringe to ease the administration of ketamine.

#### **4. Nasal route**

Ketamine is not licensed for nasal use. Physicians should properly inform the patients about the advantages and possible side-effects of the drug and the route of administration.

The nasal route appears very promising as it allows the patient to self-administer the drug when needed due to the rapid onset of action which is similar to intramuscular injection. As the capacity of the human nostrils is 0.2 ml, a greater volume may be swallowed or may run out of the nose. Ketamine may be administered via MAD which delivers a mist of atomized medication or via metered-dose nasal spray. The concentration of ketamine, commercially available is 100 mg per ml or 10 m per ml. Up to 40 mg can be reliably delivered intranasally. Higher doses are ingested [10].

Patients can be prescribed oral ketamine basal treatment and use nasal formulation for treating breakthrough pain.

#### **5. Regimens for switching from parenteral to oral administration**

Ketamine has been predominantly used parenterally as a co-analgesic in addition to opioids and co-adjuvant drugs. Oral use has obvious advantages: it is not necessary to carry the pump around, which needs frequent refilling and it avoids inflammation on the site of subcutaneous administration. It has been proven in studies that a 1:1 dose ratio is safe and effective in switching from parenteral to oral administration [11]. Another report suggested switching to one-third of the parenteral dose as a result of the effect of norketamine. Oral ketamine may in fact be a more potent analgesic and produce adverse effects less frequently than parenteral ketamine. After oral administration of 0.5 mg/kg ketamine approximately 20% is absorbed and its analgesic action seems to be mediated by its first metabolite norketamine, which has a half-life of 12 hours [12].

A good therapeutic response to parenteral ketamine suggests a greater likelihood of benefit from oral dosing. Patients who could benefit from switching to oral use of ketamine are those whose pain has been stable for 48 hours after subcutaneous infusion of ketamine, patients who wanted to be discharged home and had good pain control with ketamine, patients with a life expectancy longer than 2 weeks, and patients who could swallow or had a possibility to be tube fed.

When switching from parenteral to the oral route, benzodiazepines are discontinued [12].

The usual starting dose is 10–25 mg three or four times daily plus when needed. The dose can be increased in steps of 10–25 mg up to 100 mg three times daily [13].

Authors of the so far published studies differ in their recommendations about oral ketamine initiation. Some recommend one should always begin first with

parenteral application and then switch to oral ketamine. The parenteral route could be either intravenous or subcutaneous. When used as an adjuvant to oral morphine, patients begin as well with oral ketamine [14, 15]. For the patient, who are, due to advanced disease, unable to swallow, the nasal route is more suitable [10].

## **6. Useful properties in the palliative care setting**

## **6.1 Analgesic properties**

Ketamine is considered one of the World Health Organization's essential drugs for the management of refractory pain and is associated with reduced opioid consumption and reduced opioid tolerance. It can be used in the treatment of acute and chronic pain as a co-analgesic and for alleviating the breakthrough pain episodes. Prescribing subanesthetic doses of ketamine can reduce postoperative morphine necessity and so diminish the side-effects of morphine.

The use of ketamine in the treatment of pain as an adjuvant analgesic is not licensed but the evidence for its efficiency is considerable. Its use has been recommended in the Scottish Palliative Care Guidelines and the Palliative Care Formulary. When used, a prescribing physician should notify the patient.

Ketamine is indicated for the treatment of neuropathic pain which has not responded to other medications, including strong opioids, anticonvulsants (gabapentin), and tricyclic antidepressants, including a trial of high dose dexamethasone.

Experimental data provide evidence that norketamine is effective in preventing central sensitization and in reversing an established hyperalgesia.

Although clinical evidence has been adding up, there are just a few comparative studies, and the majority of evidence is in the form of case reports [16–18].

A usual starting dose of oral ketamine is 10 mg four times daily initially, increasing to a maximum of 100 mg four times daily according to the response. Frail patients may be started at a lower oral dose: 25–30 mg over 24 hours. The maximum reported dose is 200 mg three times daily. It is possible to withdraw ketamine for several weeks after good pain control is achieved and restart the regimen when the pain returns.

Occasionally oral ketamine or sublingual/buccal ketamine is used as required. Usual dose is 2.5–5 mg (using 50 mg/5 ml solution). This dose is an individual decision.

There is no time limit to the treatment, but the success of pain relief should be regularly assessed, and the dose adjusted when needed [19–21].

#### **6.2 Antidepressant and anxiolytic actions**

Ketamine can produce rapid relief of major depression, bipolar disorders, and suicidal ideation. The mechanism for this effect is not yet fully understood but the major depressive disorder is associated with synaptic downregulation in the prefrontal cortex and hippocampus and it is believed that ketamine causes a glutamate surge that leads to a series of events resulting in synaptogenesis and reversal of the negative effect of depression and chronic stress. It appears that ketamine normalizes depression-related prefrontal dysconnectivity.

The rapid effect of ketamine on stress, anxiety, and depression may be of huge importance for the treatment of psychiatric conditions of patients in palliative care. Anxiety and depression are related to lower quality of life [22–24].

The positive psychological effect of ketamine is attributed to an induction of neuroplasticity which reverses the negative effect of stress and depression on neural cells and synapses [25].

There are various dosage regimens described in studies, in one case report patients received a bolus of one single dose of ketamine racemate (0.5 mg/kg). The reduction in anxiety was more pronounced in the first 4 days. After daily oral administration over 28 days of ketamine racemate, a significant effect was sustained with a large effect size for anxiety and depression. There was a significant response after the first 3 days [25, 26].

FDA-approved nasal spray formulation for the treatment of anxiety and depression [27, 28].

#### **6.3 Bronchodilatatory effects**

Ketamine produces bronchodilation, allowing secure induction of anesthesia in a patient with a life-threatening asthma and intense acute bronchial constriction. It is reported that ketamine doses of 0.1–0.2 mg/kg followed by 0.15–2.5 mg/kg/h can be used in patients with refractory bronchospasm and intensive status of asthma. The proposed mechanism of action is inhibition of inflammatory cascade and reduction in markers of inflammation and bronchodilation [29].

#### **6.4 Topical ketamine in the treatment of mucositis pain**

Ketamine oral rinse significantly reduced radiation-induced mucositis pain and hyperalgesia in a patient with head and neck cancer and so preserved the possibility of oral intake. It is speculated that the analgesia could be produced locally and systemically due to the absorption across the oral mucosa. The possibility of systemic absorption may result in psychomimetic and sedative effects. In the published paper the dose of 20 mg was arbitrarily chosen, being twice as the usual empiric starting dose for sublingual administration. As the literature is scarce on data for the topical use of ketamine further studies are needed before its use can be routinely recommended [30].

#### **6.5 Refractory status epilepticus**

Evidence suggests that the activity as well as the number of NMDA receptors is increased in refractory status epilepticus. Ketamine reduces the NMDA receptorinduced neurotoxicity and also has a neuroprotective role. On the other hand, evidence also shows that ketamine, at usual doses, has an epileptogenic potential and should be avoided in patients with epilepsy. From the so far published studies, no conclusive results can be drawn and further clinical trials are needed to assess the safety and efficiency of ketamine in both adult and pediatric populations [31].

#### **7. Side effects of ketamine use**

Side effects of ketamine use are dose-dependent. They are more common when ketamine is used as an anesthetic. Very common side effects are vivid dreams, hallucinations, dysphoria, and sedation. Incidence of psychotic effects can be reduced by using haloperidol or benzodiazepines. Sometimes can be enough just to reduce the dose of ketamine. Among less common side effects are cardiovascular side effects which are normally not serious. An increase in blood pressure and heart rate may occur. There are several reports about urinary tract symptoms that might require

discontinuation of ketamine infusion. The bladder is most severely affected. There is a strong correlation between higher age (older than 30 yrs), longer duration of use (more than 24 months), and co-use of illicit drugs.

Other side effects include increased muscle tone, involuntary movements, dizziness and nausea, liver toxicity, and neuropsychiatric toxicities [32, 33].

## **8. Recommendations for use of ketamine in palliative care**

Palliative care aims to relieve symptoms of the advanced incurable disease and improve the quality of life throughout illness and in the bereavement period so that the patients and families can realize their full potential to live even the life is approaching its end.

Patients in palliative care may report a variety of symptoms among which poor pain control merits full attention. The concept of total pain is applicable as pain may occur on a physical, psychological, social, and spiritual level. Physical pain and psychological distress are connected. About two-thirds of patients with advanced cancer suffer from pain and more than half of those experience moderate to severe pain. Following the WHO cancer pain relief guidelines, one can achieve acceptable pain relief in over 50% of treated patients. About 50% of the patient may have poor pain control.

Many of the symptoms in palliative care require a pharmacological approach and drug prescription. Most strong analgesics have a strong sedative effect and therefore impact patients' cognition. Many patients, who list as their value being able to think clearly, are reluctant to use them. Some are also afraid of the addiction potential of these drugs.

Having in mind that many patients in palliative care have psychiatric symptoms and sometimes they cannot wait for the classic antidepressant drugs to act, ketamine is promising due to its rapid action. Up to 42% of hospice patients have symptoms of depression and up to 70% have symptoms of anxiety. Untreated psychiatric symptoms are associated with significant morbidity and mortality, when left untreated, these symptoms can also interfere with their ability to make decisions and make realistic goals.

Oral ketamine may prove particularly useful for hospice patients who wish to remain home instead of receiving treatment in the hospital. To fasten the onset of oral ketamine, it was suggested to start patients on parenteral dosing before switching to oral administration. Another alternative to oral ketamine is an intranasal spray, which has been approved for the treatment of depression, but it might be more difficult to use [33–36].

## **9. Summary**

Although ketamine has been in clinical practice for many years, it has been predominantly used as an anesthetic drug. Newer insight into its action shows its effectiveness in treating pain, anxiety, depression, bronchial spasm, refractory status epilepticus, and radio-induced mucositis.

This is especially important in the palliative setting, where patients commonly have pain combined with some other symptoms. They usually become refractors to high doses of opioids, with a detrimental quality of life.

Ketamine has a sparing effect on opioid consumption which may prolong their analgesic effect, reduce their dose and make pain treatment effective again. It can be used as an adjuvant as a baseline treatment or/and s a breakthrough medication.

Besides it, rapid relief of anxiety with just a single dose of ketamine is promising as well as the fact that the effect is sustainable.

Oral and nasal routes appear to be a good alternative for patients who are not institutionalized and who wish to avoid painful injections. Further studies are needed to define a suitable dosing protocol for ketamine.

## **Author details**

Mateja Lopuh Center for Interdisciplinary Pain Treatment and Palliative Care, Mobile Palliative Care Unit, General Hospital Jesenice, Slovenia

\*Address all correspondence to: mateja.lopuh@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Use of Oral Ketamine in Palliative Care DOI: http://dx.doi.org/10.5772/intechopen.104875*

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## **Chapter 16** The Role of Ketamine in Trauma

*Mihai Octavian Botea and Erika Bimbo-Szuhai*

*"I would especially commend the physician who, in acute diseases, by which the bulk of mankind are cutoff, conducts the treatment better than others."*

*Hippocrates*

## **Abstract**

Early and effective pain control in trauma patients improves outcomes and limits disability, but analgesia is often missed in the unstable patient, or hemodynamically depressing medications are avoided for fear of losing stability. This chapter outlines the role of ketamine in managing traumatic emergencies in both out-of-hospital and hospital environment, and beyond. Low-dose ketamine also called a sub-dissociative dose is safe, efficient and effective analgesic that can be considered for trauma patients, pediatric or adults, as an alternative to opioids or in combination with opioids for on additive or synergistic effect, with minimal impact on hemodynamic stability. Ketamine at higher doses is also an excellent drug for induction of anesthesia in rapid sequence induction (RSI), post-intubation sedation maintenance or procedural sedation in the trauma patient. Also, can be used for acute agitation and excited delirium. In this chapter, we are describing this drug focusing on a deeper understanding of the safety and efficacy of this agent and, if supported, to encourage physicians to consider ketamine for pain control in trauma and beyond. Also, we are presenting the current literature surrounding ketamine's evidences in the trauma condition to establish its utility and profile of safety for these patients.

**Keywords:** ketamine, analgesia, anesthesia, shock, trauma

## **1. Introduction**

Trauma is one of the leading causes of death worldwide [1] with 5.8 million lives lost each year as a direct result of injury [2], and it is a major economic burden to society in both Europe and United States [1, 3]. Trauma management is demanding for clinicians, often a life-threatening and most of the time a painful condition. Early and effective pain control in trauma is essential not only for acute status control, but has also been associated with a lesser incidence of chronic pain, as well as a shorter period of recovery [1, 2]. Many factors influence the selection of analgesics, and we have available a generous options of pain killers, but in reality, an adequate pain control is often difficult to achieve. According to many reports, trauma patient analgesia is remaining an undermanaged condition [3–5]. Opioid analgesics are often appropriate first-line pain killers for acute pain but come with hemodynamic and respiratory depression, as well as concerns about the addiction risks. Ketamine

is a dissociative and analgesic drug that can be used alone or in combination with other analgesic medication. The terms low-dose, analgesic, pain control and subdissociative dose can be used interchangeably.

#### **2. Pharmacologic properties**

Ketamine is an agent with attractive pharmacological and pharmacokinetic characteristics. Ketamine is a potent dissociative agent with an evolving role in the management of both pediatric and adult trauma patients due to its sedative, analgesic and anesthetic properties, beside its sympathomimetic effect. Ketamine is a derivate of phenylcyclidine with a hallucinogenic property, beside its primarily antagonist activity on N-methyl-D-aspartate receptors although it also acts on opioid (μ), and muscarinic receptors, and sodium channels. Its action is targeting the central nervous system *via* the thalamo-cortical tracts. This drug inhibits presynaptic reuptake of catecholamines, with an onset time of 30 s. For being highly lipophilic, ketamine has a distribution half-life of 10 min, for a short duration of action after an initial bolus. Ketamine is the least protein bound from the i.v. anesthetics (25%) suffering a liver metabolization, generating active compounds (norketamine and hydroxynorketamine), and is eliminated mainly in the urine with an elimination half-life of 1.5–3 h.

The sedative and analgesic effects of this drug begin to wear off in 10–15min.

For many years, ketamine was considered to be a harmful drug to use for airway management or in multiple trauma conditions, especially where a traumatic brain injury component was involved, due to fears of increasing intracranial pressure (ICP) [6]. But recent studies show which can be a real helpful drug, in certain conditions like the combative trauma patient who needs airway management or other situations like improving pain control or anesthesia induction in a hemodynamically unstable trauma patient [6]. Recent experiences show that do not raise intracranial pressure as was once assumed and does raise blood pressure improving cardiovascular stability, unlike most sedating drugs [6]. Also, a drug should be considered extremely helpful for acute invasive procedures that need to be performed under sedation [7, 8], offering a great advantage of analgesia and respiratory stability at the same time. Ketamine is known an optimal drug in various emergency settings. Also, away from the emergency room, studies have been performed to assess the safety and efficacy of ketamine for trauma patients, showing that ICU patients with a sub-dissociative ketamine infusion needed fewer opioid analgesics and had a better hemodynamic stability [9]. In this chapter, we present the current literature surrounding the safety and efficacy of ketamine in the trauma condition to establish its utility for these patients.

#### **3. Systemic effects**

Ketamine has minimal effects on the respiratory drive and protective reflexes of the protective airway reflexes are maintained, thus allowing to keep spontaneous ventilation. However, administering high doses that would be used for anesthetic effect there is a risk of respiratory depression [5, 9]. Ketamine is also responsible for bronchodilation, increased salivation, pulmonary vasodilation and increased cardiac output, through increasing mean arterial pressure and heart rate. Its profile on hemodynamics is favorable, making this agent a unique drug, a considerable option especially in approaching a shocked trauma patient. Also, its depressant effects on the gastrointestinal system are very minimal. Ketamine could have an antiplatelets

action by inhibiting phosphoinositide breakdown and mobilization of Ca2+ in those platelets stimulated by collagen [10].

## **4. Cerebral effects**

The physiological mechanisms lead to neuroprotection, vasodilation and increased cerebral blood flow.

In particular, new clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following traumatic brain injury (TBI). This is fundamental as SD has been suggested as an important mechanism for secondary brain injury and delayed cerebral ischemia [10].

Ketamine has been recently discovered to be a "glutamate modulator." Its action is exerted at two levels: (a) presynaptic, inhibiting the release of glutamate and (b) post-synaptic, performing as a competitive blocker of NMDA receptors, also inhibiting calcium entrance into cells and the production of nitric oxide and oxygen-free radicals, modulating glucose metabolism and the generation of mitochondrial ATP, and also, inhibiting the apoptotic phenomenon. Furthermore, it inhibits the production and release of cytokines not only by the microglia but also by interleukin-8, tumor necrosis factor, Ca++, K+, oxygen-free radicals, adenosine triphosphate.

The cerebral metabolic rate of oxygen is increased, although in a heterogeneous action, more in insula and the frontal lobes, while decreasing in the temporal lobes, pons and cerebellum. Cerebral blood flow does not follow the same pattern. Probably, a dose-dependent uncoupling mechanism is implied. Intracranial pressure remains unaffected or even sometime decreased, being associated with increases in cerebral perfusion pressure.

Cerebral oxygenation remains unchanged. Moreover, ketamine does not compromise the autoregulatory mechanisms or the carbon dioxide (CO2) reactivity of the cerebral vasculature [10, 11].

It is important to promote recent findings that NMDA receptors have different protein subpopulations in their composition, capable of triggering various pathways that stimulate proliferation, synaptogenesis or neuronal regeneration, depending on which protein is activated [12].

Extensive studies have shown that after stroke or traumatic brain injury, NMDA receptors remain hypofunctional, which could be responsible for cognitive impairments. Activating and stimulating these receptors by alternative pathways (glycine/serine) is a promising strategy [12].

## **5. Summary of evidence**

## **5.1 What is the efficacy of ketamine for analgesia?**

There are convincing evidences demonstrating the efficacy and safety of ketamine as an analgesic for trauma patients.

In a very recent meta-analysis published in 2020, where controlled human studies were included, Mahmoud Yousefifard performed extensive search conducted in electronic databases gathering data to the end of 2018. The efficacy and side effects of ketamine administration in prehospital pain management were compared with those of opioid analgesics. Data from seven articles were included in the present meta-analysis. Ketamine administration was not much more effective than administrating morphine or fentanyl in prehospital pain management of trauma patients.

However, co-administration of ketamine + morphine was considerably more effective than ketamine alone, in alleviating pain in prehospital settings. Finally, it was concluded that ketamine alone had less side effects than morphine alone. However, co-administration of ketamine + morphine increases the risk of side effects compared with when morphine is prescribed alone [13].

In 2020, Gaël de Rocquigny published a systemic review in regarding the use of ketamine for prehospital pain control on the battlefield [14]. This included a database searching for studies on ketamine use in combating prehospital settings, at the point of injury or during evacuation. Eight studies were included with 2029 casualties receiving ketamine. Ketamine use increased from 3.9% during the period preceding its addition to the Tactical Combat Casualty Care guidelines in 2012 to 19.8% after this guidelines release. It was the analgesic of choice (up to 52% of casualties) in one of the studies. Ketamine has been preferred to be given during tactical medical evacuation when no analgesic was administered at the point of injury. Pain score decreased from moderate or severe to mild or none, often after only one dose. In one study, ketamine administration during tactical evacuation was associated with increased systolic blood pressure as opposed to those situations when morphine was given. Incoherent speech, hallucinations and extremity movements were the most seen adverse events reported. However, all studies tend to strengthen the belief in the efficacy and safety of ketamine when given at 50-mg to 100-mg intravenous for prehospital analgesia in combat casualties. So, from these army studies, we can easily extrapolate these findings and apply to the civil medicine.

In 2018, Mary K. Walters published a study on the ketamine as an analgesic adjuvant in a trauma patient with rib fractures. This was a retrospective study, based on case-control chart review assessing ICU adult patients with a diagnosis of ≥1 rib fracture and an Injury Severity Score > 15. Patients received standardof-care analgesia with the physician's choice medication with or without ketamine as a continuous, fixed, intravenous infusion at 0.1 mg/kg/h. The authors pointed out that low-dose ketamine appears to be a safe and effective adjuvant option to reduce pain and decrease opioid use in rib fracture [15].

In 2019, Thomas Carver published a prospective, randomized, double-blind placebo-controlled trial on ketamine infusion for pain control in multiple rib fractures. This level II of evidence study included adult patients with three or more rib fractures admitted to a Level I Trauma Center. Other exclusion criteria were Glasgow Coma Scale score less than 13 and chronic opiate use. The experimental arm received lowdose ketamine (LDK) at 2.5 μg/kg/min, while the placebo cohort received an equivalent rate of 0.9% normal saline. The primary outcome was reduction in numeric pain score (NPS) during the first 24 h. From the secondary outcomes studied, oral morphine equivalent (OME) utilization was included. The average Injury Severity Score (ISS) was 14. Low-dose ketamine failed to decrease NPS or OME within the overall cohort, but a decrease in OME was observed among patients with an ISS greater than 15. This study authors also conclude that confirmatory studies are necessary to determine whether LDK is a useful adjunct among severely injured patients [16].

In 2017, Babak Mahshidfar conducted a randomized double-blinded clinical trial to compare low-dose ketamine (LDK) with morphine for pain relief in trauma patients. He enrolled 300 trauma patients from the emergency room of two university hospitals. The patients were randomly divided into two groups. The first group was administered i.v. 0.2 mg/kg of ketamine, while the second group received 0.1 mg/kg of i.v. morphine. The results of this study suggest that LDK, at a dose of 0.2 mg/kg, in the earlier minutes leads to significant reduction of pain when compared with that of intravenous morphine. It also created fewer complications than morphine [17].

In 2014, Joshua P Miller performed an institutional review board-approved, randomized, prospective, double-blinded trial at a tertiary, Level 1 Trauma Center. The

#### *The Role of Ketamine in Trauma DOI: http://dx.doi.org/10.5772/intechopen.103655*

study was focused on low-dose ketamine vs. morphine for acute pain control in the ED. They enrolled adult patients with acute abdominal, flank, low back or extremity pain. Subjects were consented and randomized to intravenous LDK (0.3 mg/kg) or intravenous MOR (0.1 mg/kg). The primary outcome was the maximum change in NRS scores. Low-dose ketamine compared with MOR for acute pain did not produce a greater reduction in NRS pain. But it is assumed that LDK induced a significant analgesic effect within 5 min and provided a moderate reduction in pain for 2 h. The time to achieve maximum reduction in NRS pain scores was at 5 min for LDK and 100 min for MOR. Vital signs, adverse events, clinician and nurse satisfaction scores were similar between groups [18].

In 2012, Paul A. Jennings proved that intravenous morphine plus ketamine provides analgesia superior to that of intravenous morphine alone. This is a prehospital study, randomized, prospective and controlled study. Patients with traumatic condition and a verbal pain score of greater than 5 after 5 mg of i.v. morphine were eligible for enrollment. Patients included in the ketamine group were administered a bolus of 10 or 20 mg, followed by 10 mg every 3 min. The second group patients received just morphine 5 mg i.v. every 5 min until pain free. Pain scores were regularly assessed until hospital arrival. The study conclusion was intravenous morphine plus ketamine for out-of-hospital adult trauma patients providing analgesia superior to that of intravenous morphine alone but was associated with an increase in the rate of minor adverse effects [19].

In 2017, Benov and colleagues published a review of data cases from 17 years of time frame from the military prehospital trauma registry of the Israeli Defense Forces. This included data from 141 solders patients, victims of explosion, who had received ketamine for analgesia. This review made a relatively conclusive statement: "Ketamine in subanesthetic doses is almost an ideal analgesic exhibited through its profound pain relief, its margin of safety, and its role in potentiation of opioids and prevention of opioid hyperalgesia" [20].

In 2007, Michel Galinski investigated the morphine consumption associated with ketamine for severe acute pain in emergency setting, where patients with a visual analog scale (VAS) score of minimum 60/100 were included. The K group patients received 0.2 mg/kg of i.v. ketamine over 10 min, while the P group patients received sodium chloride, as the control group. The patients from both groups were given an initial intravenous morphine dose of 0.1 mg/kg, plus as required doses were supplemented with 3 mg every 5 min. Efficient analgesia was defined as a VAS score not exceeding 30/100. The goals of this study were to assess morphine consumption and VAS at 30 min. They concluded that morphine consumption was much less in the K group vs. the P group. The VAS score at T30 did not differ significantly between the two groups [21]. We could assume the fact that the VAS score at T30 was similar for the two groups due to the fact that the time action for the ketamine dose is roughly around 10–15 min, and the K group received just an initial dose. So probably I would have been better also to have a VAS score at T15, for example, for more realistic and objective findings.

In 2019, Sheila C. Takieddine investigated whether ketamine administered *via* patient-controlled analgesia (PCA) provides adequate analgesia while reducing opioid consumption in the traumatically injured patient. Non-intubated trauma patients in intensive care, who were receiving PCA, were randomized to ketamine or hydromorphone PCA plus opioid analgesics for breakthrough pain. They concluded that ketamine PCA led to lower cumulative opioid consumption and lower oxygen supplementation requirements, though hallucinations occurred more frequently with the use of ketamine. They also concluded that additional studies are needed to investigate the tolerability of ketamine as an alternative to traditional opioid-based PCA [22].

In 2017, Kaitlin A. Pruskowski conducted a study to investigate the efficiency of the initiation of a ketamine continuous infusion in critically ill trauma patients for sedation and analgesic purposes. The secondary goals were to find out the patient population in which ketamine was administered, assess the time patients reached their goal level of sedation and find out the dosing required as adjunctive sedative agents. This retrospective chart review was investigated for 19-month period. This study was focused on the critically ill mechanically ventilated trauma patients. The study concluded that the use of ketamine in critically ill mechanically ventilated adult trauma patients was associated with decreased opioid use but it was also associated with the increased use of dexmedetomidine and ziprasidone to achieve and maintain sedation [23].

In 2014, Kim Phung Tran published a prospective study aiming to compare the analgesic effects and side effects of ketamine and morphine in out-of-hospital environment. The conclusion of this research was that ketamine had a pain control effect similar to morphine, and also accompanied by a lower risk of airway patency issues. The side effects as agitation and hallucinations were higher in incidence in the ketamine group. These conclusions are to be well appreciated as utility and application, particularly in rough and low-resource environments [24].

Bredmose PP conducted in 2009 another prospective study in the field of prehospital care investigating ketamine for analgesia and procedural sedation. This study evaluated the role of ketamine for analgesia and sedation in 1030 trauma patients in a prehospital trauma service led by physicians. Ketamine administration was the first choice in awake non-trapped victims with blunt trauma for analgesia and procedural sedation. This study data interpretation did not point out concerns for loss of airway, oxygen desaturation or clinically significant emergence reactions associated with ketamine use. Ketamine could be considered relatively safe when administered by physicians in out-of-hospital trauma care [25].

Still remaining in the prehospital field, it is advocated that there are many features of ketamine that seem to make it an ideal drug for prehospital use, including disaster surgery where extra personnel and advanced monitoring are not available.

In light of these premises, James E. Svenson performed a retrospective study of all patients transported by a regional aeromedical program. Data were collected from 40 patients, where ketamine was used. The study included pediatric and adult patients with age between 2 months and 75 years old. The indications for administration varied, from trauma to medical conditions. Shock status with need for analgesia, combativeness or agitation, intact airway concerns, or pain unresponsive to opioid drugs were the most common indications for use. Ketamine was administered either intravenously or intramuscularly (when no intravenous access was available). Minimal or no adverse effects [26] were reported.

In 2019, Kugler, Nathan published a level I of evidence study, randomized, doubleblind placebo-controlled prospective trial enrolling elderly patients (age, ≥65 years) with three or more rib fractures presented to a Level I trauma center. The exclusion criteria were Glasgow Coma Scale score less than 14 and/or chronic opiate medication. Patients were randomized in two groups, either low-dose ketamine (LDK) at 2 μg/kg/min or an equivalent rate of 0.9% natrium chloride. This study conclusion is that low-dose ketamine failed to affect NPS or OME within the overall cohort, but a decrease in OME was observed in those with an Injury Severity Score greater than 15. Also, in this view, it is recommended that additional studies are necessary to confirm whether LDK benefits severely injured elderly patients [27].

#### **5.2 What is the clinical evidence of ketamine in RSI and sedation?**

One of other benefits of using ketamine in trauma is that could be an option for rapid sequence intubation (RSI) induction and maintaining sedation. Ketamine

#### *The Role of Ketamine in Trauma DOI: http://dx.doi.org/10.5772/intechopen.103655*

has emerged as an alternative for RSI induction, because the conventional propofol makes hemodynamics vulnerable and induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, where clinical significance on trauma patients is uncertain.

Cameron P. Upchurch in 2017 published the four-year retrospective study comparing etomidate and ketamine for induction during rapid sequence intubation of adult trauma patients. In this analysis spanning an institutional protocol switch from etomidate to ketamine as the standard rapid sequence intubation induction agent for adult trauma patients, patient-centered outcomes were similar for patients who received etomidate and ketamine [28].

In 2019, Josefine Baekgaard investigated whether ketamine should be preferred over other induction agents for RSI in trauma patients. Library was systematically searched for studies reporting RSI of adult trauma patients with ketamine compared with another induction agent (etomidate, propofol, thiopental or midazolam). Extremely few studies have compared induction agents for RSI in trauma patients. Only four studies were included. The review conclusion was that no significant differences have been found in mortality, length of hospital stay or a number of blood transfusions after induction with ketamine compared with other induction agents, but a clinically relevant benefit or harm cannot be excluded [29].

In 2021, Lucy Stanke aiming to bring more evidences in the prehospital field of RSI drug comparison published a retrospective study to evaluated adult patients undergoing prehospital RSI over 13 months within a regional emergency transport medicine service. The purpose of this study was to evaluate hemodynamic changes after the administration of ketamine versus etomidate in prehospital RSI. The analysis emphasized that no cardiovascular differences were reported between patients who received ketamine versus etomidate for out-of-hospital RSI. None of these two drugs was associated with an increased requirement for additional hypnotics, and neither drug was associated with an increased first-attempt tracheal intubation success rate. This study also concluded that more studies, on larger cohorts and prospective designs, are needed to identify patients who may benefit from either ketamine or etomidate [30].

During emergency situations where RSI of anesthesia is required like in shocked or hypotensive patients (e.g., massive hemorrhage due to ruptured major vessels, pelvic fracture or other polytrauma conditions), prior resuscitation is often suboptimal and comorbidities (particularly cardiovascular) may be extensive, making challenges even worst. The induction drugs with the most favorable pharmacological properties offering a hemodynamic stability appear to be etomidate and ketamine. However, etomidate has been withdrawn from use in some countries and is known to impair steroidogenesis. Ketamine has been traditionally contra-indicated in the presence of head trauma, but we argue in this article that any adverse effects of the drug on intracranial pressure or cerebral blood flow are in fact attenuated or reversed by a better cardiovascular stability, sedation and controlled ventilation conferred by the drug. Ketamine represents a very rational option for RSI in hemodynamically compromised patients [31].

#### **5.3 What is the clinical evidence of ketamine in traumatic brain injury?**

For many years, the use of ketamine was restricted in TBI patients based on evidence from the 70s that suggested its detrimental effect on intracranial pressure. New research in healthy volunteers or in patients without neurological comorbidities scheduled for general surgery demonstrated that intracranial pressure, cerebral blood flow and cerebral perfusion pressure increase during anesthesia with variable doses of ketamine and no neurological side effects or sequels were noticed [32, 33]. Other series of studies with small numbers of patients with different central nervous system pathologies that had in common abnormal cerebral spinal fluid circulation reported similar findings, emphasizing the absence of side effects [34–39]. Other recent systematic studies with various degrees and types of limitations reported that in heterogeneous acute brain populations (subarachnoid hemorrhage, tumors, TBI), ketamine induces only temporary variations in intracranial pressure without modifying cerebral perfusion pressure and has no detrimental effect on outcome, intensive care unit stay or mortality [36–38]. When assessing populations of severe acute bran injury, ketamine was not associated with an increase of intracranial pressure in sedated and normocapnic mechanically ventilated patients; furthermore, ketamine may decrease intracranial pressure in some individualized situations [39]. Other recent updates of ketamine administration in TBI led to similar findings [40].

As regards the ketamine use in acute phase of severe traumatic brain injury (TBI), in 2021, Daniel Agustin Godoy stated that ketamine is "an old drug for new uses," having more and more evidences of its benefits even in this condition. In the acute phase of severe acute brain injury, it is paramount to prevent and avoid secondary insults that can further complicate a primary brain injury [41]. Managing a goal-driven sedation and optimal pain control is a cornerstone of improving patient survival, satisfaction and minimizing distress. Without an optimal sedation, there are rising consequences including delayed recovery, difficult weaning from mechanical ventilation, higher complication rate and prolonged hospital staying [42].

Several different classes of hypnotic drugs are used in the management of patients with TBI [43–45]. These drugs are used at induction of anesthesia, to provide and keep sedation, to reduce elevated intracranial pressure, to control seizures and facilitate mechanical ventilation [46, 47]. To date, it is unclear which agent or combination of drugs is the most effective in achieving these goals. Ketamine is a versatile agent with attractive pharmacological and pharmacokinetic properties.

Controversies concerning the optimal sedation management persist, especially in critically TBI, who were systematically excluded from large randomized studies [44]. Different from other agents, ketamine does not depress respiratory activity or airway reflexes (except at very high doses) and may have potential neuroprotective effects, as well as a potential in decreasing seizures and non-convulsive epileptic activity [48, 49]. These properties make from ketamine a realistic choice when profound analgesia and sedation are required.

But there are still some restrictions in severe traumatic brain injury, and certain conditions would contraindicate ketamine administration, such as loss of cerebral autoregulation, hydrocephalus or the concomitant presence of untreated brain aneurysms [40, 50, 51].

#### **5.4 What is the ketamine evidence in eye pathology?**

Ketamine induces intraocular pressure (IOP) changes bur, which are mild and without clinical significance [52, 53]. The current guidelines do not limit the use of ketamine in known or suspected open globe injuries [54].

Ketamine is not recommended to be used for procedural sedation in eye examination as one of the known side effects of this drug is nystagmus.

#### **6. When not to use ketamine?**

An absolute contraindication is hypersensitivity to this drug [40]. Due to hepatic metabolism and mainly kidney elimination, it should not be administrated in the context of liver failure and/or renal failure [40, 50, 51]. Other relative contraindications are those conditions where high blood pressure triggers potentially dangerous

#### *The Role of Ketamine in Trauma DOI: http://dx.doi.org/10.5772/intechopen.103655*

complications such as diastolic cardiac dysfunction, coronary ischemia or aortic dissection [40, 55]. In severe alcoholism, toxicity of ketamine has been described [40]. Use of ketamine in pediatrics is restricted to children younger than 3 months of age. There was reported higher incidence of airway complications like laryngospasm in very young patients [52].

Concerning the TBI, there are only a few contraindications nowadays. These were presented in a previous section.

Nevertheless, ketamine attributes to psychotomimetic effects, which could be the main reserve for not being a first choice when sedation is required [48, 49].

## **7. When to use ketamine?**

In this section, indications for ketamine use will be divided in four general situations: analgesia, procedural sedation, induction of anesthesia/RSI and acute agitation/excited delirium [56].

*Analgesia*


## *Procedural sedation*


## *Induction of anesthesia/rapid sequence intubation*

• Is an optimal choice in shocked trauma patients for RSI due to its analgesic and sedative features and also for its cardiovascular stability?

## *Acute agitation/excited delirium*

• Ketamine may be used in trauma conditions when fast control of agitation is required such as in patients with delirium or when rapid control is essential to diminish the risk of injury to staff, family or the patients themselves.

## **8. Dosing**

The dose considerations of ketamine in adults can be either body weight-based or non-weight-based. For a better accuracy in dose calculations in pediatrics, the dose should always be weight or length based using a standardized measuring tape.

There are no standard recommendations for the ketamine dose. What follows are dose recommendations based on literature review and expert opinion.

*Analgesia dosing recommendations* Intermittent dose:


Adult continuous infusion dose:

• 0.1–0.4mg/kg/hour i.v.

Adult non-weight-based analgesic dosing:

50mg i.m., repeat as required every 30–60min for pain control or until nystagmus develops indicating approach of the dissociative state.

20mg slow i.v./i.o. push over 1min, repeat as required every 20min for desired analgesia or until nystagmus appears indicating reaching the dissociative state.

## **Procedural sedation**

• 1mg/kg i.v. (maximum 100mg per dose)

Induction of anesthesia/RSI

• 2mg/kg i.v. (maximum 200mg)

## **Acute agitation/excited delirium**


#### **Other observations**


• In some expert's opinion doses between 0.5 and 0.9mg/kg i.v. are not efficacious for sedation and could trigger a sense of unreality that can lead to issues in patient management.

## **9. Safety profile**

Ketamine can induce a transient apnea in high doses or with fast administration. These conditions are associated with higher intubation rate. Patients given ketamine should be kept under observation for the risk of respiratory failure, and clinicians using ketamine, especially in high doses, should be ready to take over airway control.

There is a lack of safety data to support recommendations in what concerning the use of ketamine in pregnancy and during breast feeding [62].

Another previous controversy, but recently cleared, ketamine use can be considered in trauma patients with schizophrenia as there does not seems to be a higher incidence of psychosis in these kinds of conditions [63, 64].

## **10. Complications and side effects**

Fast IV administration can trigger transient apnea. Ketamine should be given in a slow bolus, over 1min or more unless being used in RSI where it is followed shortly by a muscle relaxing drug and intubation. Transient apnea following i.m. administration appears to be extremely rare [43].

Reported side effects are laryngospasm, hypersalivation, nausea, dizziness, nystagmus, dysphoria and emergence agitation. Most of the time, these side effects are transient and self-limited and do not require any intervention or rescue. If laryngospasm occurs, it can be managed with repositioning or jaw thrust and positive pressure ventilation. In rare instances, intubation may be necessary.

Emergence reactions are notable to be rare. When appears, these can be safely managed with benzodiazepine use. Pre-medicating with benzodiazepines is not recommended.

## **11. Co-administration with other drugs**

When used in concomitantly, ketamine increases the pain control effects of opioids. The administration of ketamine and opioids in combination improves analgesia with lesser doses of opioids thus decreasing the chance of opioid-induced adverse effects on cardiovascular and respiratory system [65].

Combining ketamine with opioid medication has been reported to block opioidinduced hyperalgesia and acute opioid tolerance.

When used in concomitantly, ketamine increases the sedative effects of benzodiazepines with its risk for respiratory depression. Extra caution should be sought, and airway monitoring should be considered.

Benzodiazepines should not be used prophylactically to prevent emergence reactions and should only be considered to manage an emergence reaction if the patient is a danger to themselves or staff. Suboptimal sedation requesting additional ketamine versus a true emergence reaction should be taken into consideration before the benzodiazepine administration.

### **12. Considerations with non-prescribed drugs**

Ketamine increases the sedative effects of alcohol, and it is essential to anticipate the risks of respiratory decompensation when ketamine is administered to an acutely intoxicated patient [57].

Ketamine should be excluded if cocaine use is suspected as ketamine's sympathomimetic effects could superimpose over the cardiovascular toxicity of cocaine [18].

### **13. Geriatrics**

In the literature, there are not sufficient data in what concerning the use of ketamine in the geriatrics. It is advisable to decrease the dose when using ketamine in the elderly since NMDA receptor binding is slowed with age.

### **14. Pediatrics**

Ketamine is an alternative option to opioids and benzodiazepines for analgesia and sedation in the pediatric trauma patient over the age of 3 months.

Because of possible negative consequences on the developing brain in kids who have received repeated or prolonged exposure to drugs that block NMDA receptors, the use of ketamine in infants less than 3 years of age should be assessed within the context of the benefits and risks of the procedure [19].

Before ketamine use, it is first to take into account the adjunct measures for analgesia such as fractures immobilization or dislocations reductions.

Precautions should be taken when using ketamine out of hospital in the headinjured child. Adverse effects of ketamine in the children with head injuries have not been reported in the literature, though evidence on this topic is limited [66].

#### **15. Conclusion**

Analgesia and sedation are dynamic processes that must meet specific goals, be controlled and be easily modified according to the progress of patient's condition. Knowledge of drug pharmacology and its safety margin and profile are paramount to limit their side effects. Setting a goal-directed strategy, establishing local protocols of administration and monitoring treatment are the cornerstone of an efficient analgesia and sedation strategy. These qualities contribute to fulfilling an optimal and safe level of sedation, looking to balance the deleterious effects of under or over sedation [12].

Further studies on the use of ketamine in the adult and pediatric trauma patient population are required.

*The Role of Ketamine in Trauma DOI: http://dx.doi.org/10.5772/intechopen.103655*

## **Author details**

Mihai Octavian Botea\* and Erika Bimbo-Szuhai Pelican Clinic Hospital, University of Oradea, Oradea, Romania

\*Address all correspondence to: drmob78@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 17**
