Sub-dissociative Dose Ketamine

Introduction

Pain is one the most common presentation to the emergency department (ED) and therefore, we should be aware of novel treatments options, adjuncts that can be used in addition to conventional therapies. Opioids are among the most commonly used analgesics in ED. Recently, a lot has been written about Low Dose Ketamine or Sub-Dissociative doses  (SDK) of ketamine to treat intractable pain or as a part of multimodal approach. 

Classically, ketamine has been used as an anesthetic agent for procedural sedation or intubation but low dose or sub- dissociative dose ketamine (SDK) may be used as an adjunct to opioids or as a single agent. SDK dosing is anywhere from 0.1-0.3 mg/kg where ketamine acts not as an anesthetic, but rather as an analgesic. Generally,  SDK does not produce many of the potentially adverse respiratory or hemodynamic effects of other analgesics, and may be used as a safe and effective alternative or adjunct to opioids. Ketamine is both hydrophilic and lipophilic which allows administration via various routes. 

It has been found that SDK lowers pain scores and has functionally equivalent efficacy to morphine for short-term analgesia in the ED. WHen used with opioids, SDK also reduces the overall dose of opioid analgesics and the need for re-dosing. 

Mechanism of action - Ketamine

After cell injury, the NMDA/glutamate receptor complex is activated in the dorsal horn of the spinal cord and these receptors are pivotal in developing hyperalgesia, allodynia and ultimately, central sensitization and wind up phenomenon (Wind-up is a frequency-dependent excitability of neurons in the dorsal horn of the spinal cord and the activation of the NMDA/glutamate receptor complex is a necessary step in the development of the wind-up phenomenon), which leads to the development of persistent and neuropathic pain as well as opioid-tolerant pain. SDK non-competitively blocks the NMDA receptors with its antihyperalgesic, antiallodynic and anti-tolerance effects. This mechanism of action of ketamine is responsible for its utility in managing a variety of acute and chronic (neuropathic, malignant, opioid-tolerant, opioid-induced hyperalgesic states) painful conditions as an adjuvant analgesic or single agent.

Ketamine undergoes extensive hepatic metabolism (via cytochrome P450 enzymes) with norketamine being an active metabolite with 1/3 of the potency of ketamine. Ninety percent of the drug is excreted in urine in the form of metabolites with 2-4% of the drug remains unchanged

In theory, patients with severe liver and renal dysfunction may have prolonged clearance and accumulation but there is no data to imply that SDK is unsafe in patients with liver or renal dysfunction

SDK Dosing:

0.1-0.3mg/kg over 15 minutes diluted in 100ml NS for short infusion - No monitoring necessary

0.15-0.2mg/kg/hr (continuous infusion): 100mg Ketamine in 100ml NS, IV pump is

necessary, titrate q30 min by 5mg until the pain is optimized or develop psycho-perceptual effects, monitoring is preferred

• Analgesic dose (0.1-0.3 mg/kg) - At these low doses, ketamine has minimal psycho-perceptual effects and works as a strong analgesic. Typically, these doses do not require monitoring.
• Recreational dose (0.2-0.5 mg/kg) ketamine works as a great analgesic but also leads to distortions of perception. 
• Dissociative dose (>0.7 mg/kg) ketamine - These doses keep them awake but unconscious. Typically this range of dose is used for PSA or intubation. 

Sitiations where SDK can be used:

Acute traumatic and non-traumatic pain

Complex regional pain syndrome

Functional abdominal pain

Migraine headache

Neuropathic and radicular pain

Sickle cell crisis

Chronic pain syndromes. 

Note: SDK does not cause respiratory depression or increase in intra-cranial or intra-ocular pressure. 

Side effects (directly related to speed of administration):

Nausea/Vomiting, Dizziness, Lightheadedness, Feeling of unreality, dysphoria

Emergence reactions - Not seen at low doses

Indications

• Acute pain: traumatic, non-traumatic, brief painful procedures, post-operative pain
• Chronic: central pain (post stroke pain), phantom pain, neuropathic pain, cancer pain
• Opioid-tolerant pain
• Opioid-induced hyperalgesic states

Contraindications

• Allergy to ketamine
• Age <2 months
• History of schizophrenia

Take Home

SDK used alone or in combination with opioids is safe and effective for the treatment of acute pain in the ED and may result in opioid sparing. Its use has been associated with relatively high rates of minor and short lived adverse side effects that can be reduced by utilizing a short-infusion of ketamine via IV of 0.3 mg/kg over 15 min.

References:

1. Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med. 2009 Nov 27;17:61.
2. Galinski M, Dolveck F, et al. Management of severe acute pain in emergencysettings: ketamine reduces morphine consumption. Am J Emerg Med. 2007 May;25(4):385- 90
3. Ahern TL, Herring AA, Anderson ES, Madia VA, et al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201
4. Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial Am J Emerg Med. 2015 Mar;33(3):402-8
5. Motov S, Rockoff B, Cohen V, Pushkar I, et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2015 Mar;22(3):251-7
6. Goltser A, Soleyman-Zomalan E, Kresch F, Motov S. Short (low-dose) ketamine infusion for managing acute pain in the ED: case-report series. Am J Emerg Med. 2015 Apr;33(4):601.e5-7.
7. Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015 Jul;16(7):1402-9.
8. Yeaman F, Meek R, Egerton-Warburton D, Rosengarten P, et al. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014 Jun;26(3):237-42
9. Motov S, Mai M, Pushkar I, Likourezos A, et al. A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED. Am J Emerg Med. 2017 Aug;35(8):1095-1100. doi: 10.1016/j.ajem.2017.03.004. Epub 2017 Mar 3.

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic

Wrist Block (Landmark Technique)

While a majority of injuries on hand can be managed by local infiltration of anesthetics, wrist nerve blocks may be required in instances such as diffuse lesions, deep lacerations, deep contaminated abrasions, hydrofluoric acid and thermal burns. Wrist blocks are also particularly useful when the injured extremity is swollen and local infiltration may lead to severe pain.  

Nerves at the level of the wrist are more easily accessible anatomically and can be blocked more reliably. All three nerves (Median, Radial, Ulnar) lie in the volar aspect of the wrist near easily palpated tendons. However, a full wrist block may have a slow and unreliable onset and can require more time to take effect. 

Right wricrossectionalonal view

1. Median Nerve

Location - Just below the palmaris longus (PL) tendon OR slightly radial to it between the PL and flexor carpi radialis (FCR) tendons. The nerve lies relatively superficially (1cm or less from skin) but deep to the fascia of the flexor retinaculum. 

PL tendon is located by having the patient make a fist with the wrist flexed against resistance. Use a 25-gauge needle and go perpendicular to the skin on the radial border of the palmaris longus tendon just proximal to the proximal wrist crease. Advance the needle slowly until a slight “pop” is felt as the needle penetrates the retinaculum. Inject 3 to 5 mL of anesthetic in the proximity of the nerve at a depth of 1 cm under the tendon.  

https://www.researchgate.net/figure/Peripheral-nerve-blocks-at-the-wrist-A-Median-nerve-block-B-Ulnar-nerve-block-C_fig2_320883196

Caveats - PL may be absent in up to 20% of patients, in which case you inject at about 1 cm in the ulnar direction from the FCR tendon. The superficial position of the median nerve at the wrist is a major cause of failure of this block as the anesthetic is often instilled too deep.

2. Radial Nerve

Nerve block of radial nerve requires an injection in close proximity to the artery and a field block that extends around the dorsal aspect of the wrist. Radial nerve follows the radial artery into the wrist but gives off sensory nerve branches proximal to the wrist. These branches wrap around the wrist and fan out to supply the dorsal and radial aspect of the hand.

Insert a 25-gauge needle and inject 2-5ml of LA immediately lateral to the palpable artery at the level of the proximal palmar crease. Inject another 5 to 6 mL of anesthetic subcutaneously from the initial point of injection to the dorsal midline. Withdraw the needle and reposition it to complete the block.

3. Ulnar NerveThe ulnar nerve follows the ulnar artery into the wrist, where they both lie deep to the flexor carpi ulnaris (FCU) tendon (The nerve lies between the tendon and the artery). The FCU tendon is palpated just proximal to the prominent pisiform bone by having the patient flex the wrist against resistance. 

Use a lateral approach to ulnar nerve block rather than volar approach due to risk of ulnar arterial puncture. Use a 25-gauge needle and inject on the ulnar aspect of the wrist at the proximal palmar crease and deposit a wheal of anesthetic horizontally under the flexor carpi ulnaris tendon. Then direct the needle toward the ulnar bone at a point deep to the flexor carpi ulnaris tendon and inject 3 to 5 mL of anesthetic solution as the needle is withdrawn. Block the dorsal cutaneous branches by subcutaneously injecting 5 to 6 mL of anesthetic from the lateral border of the flexor carpi ulnaris tendon to the dorsal midline. 

Images from:

Roberts and Hedges’ Clinical Procedures in Emergency Medicine

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic

Procedural Sedation in ED

Procedural Sedation and Analgesia (PSA) is the administration of sedatives and analgesics or dissociative anesthetics to induce a depressed level of consciousness while maintaining cardiorespiratory function so that a medical procedure can be performed with little or no patient reaction or memory. 

PSA Terminology and levels of Sedation

Minimal sedation (anxiolysis): A drug-induced state during which patients respond normally to verbal commands. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular function is unaffected.

Moderate sedation (formerly conscious sedation): A drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Reflex withdrawal from a painful stimulus is not considered a purposeful response. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

Deep sedation: A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully after repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

Dissociative sedation: A trancelike cataleptic state induced by the dissociative agent ketamine and characterized by profound analgesia and amnesia with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability.

General anesthesia: A drug-induced loss of consciousness during which patients cannot be aroused, even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Patients frequently need assistance in maintaining a patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardio- vascular function may be impaired.

Evaluation before PSA

• ASA Grading
• Inspect Airway for difficulty (short neck, micrognathia, large tongue, trismus, morbid obesity, a history of difficult intubation, or anatomic anomalies of the airway and neck)
• Last Ate/Drank
• Systemic Disease (Most agents can cause vasodilatation and hypotension, particularly in patients with pre-existing hypovolemia)
• Medications
• Allergies
• Prior Sedation
• Estimated Weight 

PSA ideally needs 2 Doctors and 1 Nurse 

There is no evidence that the risk of aspiration during procedural sedation is increased with recent oral intake. Current guidelines regarding the safe fasting period prior to procedural sedation are based on expert consensus. Recent food intake is not an absolute contraindication. However, f the risk of aspiration is concerning, waiting 3 hours after the last oral intake before performing procedural sedation is associated with a low risk of aspiration, regardless of the level of sedation.

Equipment, Drugs and Preparation (Prepare as you do for Intubation)

• Suction/O2
• BMV
• OPA/NPA
• Laryngoscopes 
• ET Tube/Stylet
• Bougie
• LMA
• Defibrillator
• Difficult Airway Equipment 

Drugs

• Analgesics (Fentanyl/Morphine/Ketamine/NO)
• Sedatives (Propofol, Midazolam, Etomidate)
• Anti-emetics
• Reversal Agents
• IV Fluids

Monitoring during PSA

Type of monitoring and Number of Providers

Interactive monitoring i.e. direct observation of the patient to assess the depth of sedation and observe for hypoventilation or apnea, upper airway obstruction, laryngospasm, vomiting, or aspiration. 

Electronic monitoring i.e. using equipment to assess arterial oxygenation, ventilation, blood pressure, and cardiac rate and rhythm. Moderate and deep sedation require constant observation and continuous monitoring. 

• Consciousness level
• Resp Rate and Effort
• ECG
• Blood Pressure
• SpO2
• ETCO2

Pulse oximetry is not a substitute for monitoring ventilation, as hypoventilation or apnea develop before oxygen saturation decreases, especially in patients who receive supplemental oxygen.

Ventilation can be electronically monitored using capnography. The end-tidal carbon dioxide correlates with the arterial partial pressure of carbon dioxide so that an end-tidal carbon dioxide above 50 mm Hg (6.6kPa) or an increase in end-tidal carbon dioxide >10 mm Hg (1.33 kPa) indicates hypoventilation. A flat-line capnogram can be due to apnea, upper airway obstruction, or complete laryngospasm. Normalization of the waveform after chin lift, jaw thrust, or oral airway placement confirms that apnea was due to upper airway obstruction. Capnography during procedural sedation allows the early recognition of adverse events. Because the risk of respiratory depression increases with the depth of sedation, capnography should be considered for moderate sedation and is recommended for prolonged deep sedation.

Sequence of Events 
1. Give Analgesics (morphine/fentanyl) first. 

2. Preoxygenate: Supplemental oxygen reduces the incidence of hypoxemia and has no adverse clinical effects. In morbidly obese patients, BiPAP may be useful to facilitate adequate sedation while averting hypoventilation. Connect appropriate monitoring equipment to the patient.

3. Give Sedative Agent
Once administered, observe and monitor the patient until the peak effect of the initial sedative dose has been reached. Once the patient has achieved the target sedation level, do the procedure and give additional doses in small increments if needed. 

Complications

• Aspiration
• Hypoxia
• Hypotension
• Allergic Reaction
• Agitation
• Vomiting
• Delayed Recovery

Issues arise due to using an inappropriate agent or giving an incorrect dose or administering through a wrong route and poor use of adjunctive agents. Time of onset from injection to the initial observed effect must be appreciated bby the provider, especially when using drugs in combination, to avoid stacking of drug doses and oversedation.

Sample Discharge Instructions

Here is a full checklist for PSA done by @emupdates
RCEM ED Sedation Proforma 


Key Points

• Pulse oximetry measures the percentage of hemoglobin that is bound to oxygen and is not a substitute for monitoring ventilation because of the variable lag time between the onset of hypoventilation or apnea and a change in the oxygen saturation of hemoglobin molecules.
• The emotional state of a patient on induction strongly correlates with the degree of distress on emergence and in the days immediately after the procedure.
• There is no universally correct or preferred medication or drug regimen. Many options are acceptable and successful. The best choice is an agent whose pharmacologic properties are familiar to the operator and that is used frequently by the operator, is easily titratable, and has a short duration of action or is readily reversible. 
• Clinicians must have a thorough knowledge of the pharmacokinetics, dosing, administration, and potential complications of the PSA agents that they use. 

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh
     Department of Emergency Medicine

     Edinburgh
     Scotland

     @EMDidactic