Paediatrics (seek Paediatrician & Pain Team advice)

Ketamine is an anaesthetic and analgesic agent administered by the intravenous (usually) or subcutaneous routes. It has significant analgesic properties unlike other currently used intravenous anaesthetic agents. Ketamine has analgesic effects at doses far below that which can produce hypnosis or anaesthesia. Dysphoric effects may be problematic & illicit use has lead to restrictions on its clinical use.

PURPOSE AND SCOPE

Outlines the procedure for the safe administration of ketamine infusions for analgesia. The clinical areas who may prescribe low dose ketamine include: Acute Pain Service, Chronic Pain Service, Palliative Care and Neurology.
This procedure excludes local guidelines for ketamine for the treatment of depression or use in the Operating Suite, Emergency Department, and Intensive Care Unit, where higher doses would be prescribed for treatment of bronchospasm, sedation or anaesthesia.

RESPONSIBILITIES

Acute Pain Service, Chronic Pain Service, Palliative Care, and Neurology.

PROCEDURE

Patients must have been referred to the above responsible services.

Ketamine
NMDA (N-methyl-D-aspartate) receptor antagonist; traditionally known as an anaesthetic agent. At low doses (sub-anaesthetic), it has other potentially beneficial effects, particularly with respect to pain management (anti-hyperalgesic effects).

Ketamine can attenuate tolerance to opioids in patients on chronic opioid therapy and it can also decrease central sensitization which is responsible for the maintenance of chronic pain states

Ketalar and other generic brand names are available

ACTION
Ketamine is a non-competitive antagonist of the calcium channel of NMDA receptors in spinal cord. The NMDA receptor is important in the aetiology and perseverance of chronic pain. NMDAR activation and upregulation in the dorsal horn of the spinal cord (sensitization), causes enhanced signal transmission in the pain circuitry resulting in allodynia, hyperalgesia and chronic pain. Ketamine binds to the NMDAR, causing it to remain in the resting state. This reduces the degree of sensitisation in the dorsal horn of the spinal cord and helps restore the physiological balance between pain inhibition and facilitation.

PHARMACOLOGY

• Lipid soluble drug, with relatively short duration of action due to redistribution

• Variable clinical effect based on concentration. Use in pain management is targeted at low doses where anti-hyperalgesic effects prominent (a form of analgesia in the setting of poorly controlled pain and analgesic use)

• Potent analgesic itself at moderate doses (> 0.3mg/kg approx.), hence useful for procedural pain in this dose range

• Produces amnesia and dissociative anaesthesia at higher doses (> 0.5 mg/kg)

• With persistent use (greater than 48 hrs), metabolism of ketamine is induced, possibly requiring dose escalation to maintain effect

INDICATIONS

Ketamine may be indicated for

• Pain that does not respond to other forms of analgesia

• Reduction in the total amount of other analgesics needed in order to reduce their side effects or improve the overall quality of analgesia

• Severe neuropathic pain

• For opioid reduction in the setting of opioid tolerance and dependence which is causing impairment of function and/or poorly controlled chronic pain

• Opioid-induced hyperalgesia seen occasionally in palliative care in association with escalating ('wind-up') pain after multiple escalations in opioid especially morphine doses

• Significant vascular/ischemic limb pain

There is little evidence that ketamine is useful in the routine treatment of most types of cancer pain (Hardey et al 2012)

CONTRAINDICATIONS

Use with caution in patients with

• increased intraocular pressure (e.g. glaucoma) and intra cranial pressure (head injury).

• psychiatric illness (e.g. schizophrenia and acute psychosis).

• acute intermittent porphyria.

• seizures (not medically controlled).

• hyperthyroidism.

• pulmonary or upper respiratory infection (ketamine sensitises the gag reflex, potentially causing laryngospasm).

• Ketamine prescription in pain management will be limited to specific patients referred to the Departments of Anaesthesia, Acute/Chronic Pain Service, Intensive Care, Palliative Care and Neurology Service.

• Ketamine use will be initiated in the hospital setting only.

• The dose, administration and parameters will be determined and prescribed by the above responsible services.

• Registered Nurses must have current competency with intravenous analgesia infusions or syringe drivers (subcutaneous infusions) to manage ketamine infusions.

• Ketamine is prescribed on the Intravenous analgesia infusion chart or the continuous subcutaneous Infusion chart.

As information often changes in this area. Prescribers to refer to the Royal Womens Pregnancy and Breastfeeding Medicines Guide (available on the intranet) as your source.

Precautions

• If the patient is receiving other medication that may cause sedation (for example, antihistamines, benzodiazepines, opioids or anticonvulsants), they may be at increased risk of sedation and respiratory depression.

• Some patient's receiving ketamine infusions experience dysphoria (hallucinations and/or vivid dreams). Patients, parents and staff should be made aware of this side effect. If dysphoria is problematic or distressing, the ketamine infusion rate may need to be reduced or the infusion ceased.

• Ketamine can cause an increase in BP and heart rate; administration with other drugs that also have these effects may result in increased adverse effects; monitor combinations carefully.

Concurrent drugs

• Paracetamol, opioids, local anaesthetics, tramadol and NSAIDs may be used concurrently with ketamine infusions and may help to improve analgesia and reduce side effects.

• If opioid infusions are running in conjunction with a ketamine infusion, the opioid requirements may be reduced. The opioid infusion rate may need to be decreased to avoid over sedation or respiratory depression.

• Theophyline (decreases seizure threshold).

1. PRESCRIPTION

• Intravenous Ketamine is prescribed on the MEDICATION PAIN CONTROL-INTRAVENOUS chart & observations are recorded on the OBSERVATIONS ANALGESIA INFUSION chart.

• Subcutaneous Ketamine is prescribed on the CONTINUOUS SUBCUTANEOUS INFUSION chart, and observations recorded on the syringe driver chart.

• Changes in dose maybe initiated by the prescribing team.

2. DOSE

Intravenous route.

A. via CADD intravenous infusion device

Equipment

CADD Solis grey pump

Anti-reflux (one way) Heidelberg Extension Set.

Hydration fluid at minimum of 5ml /hr

Dose

Ketamine 200 mg diluted with 98mL of sodium chloride 0.9%.
Total volume = 100mL
Concentration = 2mg/mL concentration

Ketamine may be given through the same IV line as Opioid analgesia. Use 3 way tap on Heidleberg Extension Set side port with clamp.

Usual dosing regime:

• Loading dose 0.05-0.1 mg/kg followed by:

• Usual dose is 0.1 to 0.3 mg/Kg/hr

• Infusion can be titrated to effect 0.05-0.3 mg/kg/hr

• Thus a 70kg patient could receive 3.5- 7mg loading dose followed by an infusion range of 3.5 - 21 mg /hour

• In obese patients dosing should be based on Ideal Body Weight (IBW)

• Adverse side effects especially hallucinations and fear/panic are dose dependent

• Maximum dose for adult on CADD Solis pump limited to 24 mg/hr

B. Via Alaris intravenous Pump

Please follow critical care guard rail library, this library is accessible to critical care areas ONLY.

Subcutaneous infusion via Niki T34 syringe driver
Ketamine dose as per the prescription on the continuous subcutaneous infusion order form.
Suggested usual starting dose range:

• 100mg/24hrs, or up to 400mg/24hr if prescribed by Acute Pain Service or Persistent Pain consultant

• Dose increased by 50 - 100mg /24hr, no more frequently than every 24hrs

• Usual maximum dose: 600mg/24hrs

• Ideal infusion duration is 5 days, not more frequently than 6 months

Consider adding dexamethasone 1mg to each syringe dose being prescribed to prevent, minimise skin irritation, as mentioned below in the "Management of adverse effects".

Equipment
Access: A 23 or 25G butterfly needle should be sited, preferably on the abdomen or lower chest

Infection control/security: Butterfly is covered by an Opsite dressing

Delivery: Managed as per Syringe Driver NIKI T34 CPP0166

Both intravenous and subcutaneous route ketamine infusion and lines must be labelled in accordance with CPP0222 Labelling of Injectable Medicines and Lines

Ketamine is a drug that requires independent double checking practices

4. CEASING the ketamine

• The decision to cease the ketamine infusion should be made in consultation with the prescribing team.

• Intravenous Ketamine requires downward titration at a rate of 2mg/hour with cessation dose level documented or unless specifically charted by Acute Pain service Medical staff.

• Any remaining ketamine must be disposed of according to CPP0481 Medications-drug register and documentation standard.

Intravenous route

Patient vital sign monitoring as per instructions on analgesia observation infusion chart. including monitoring for troublesome hallucinations.

Subcutaneous route

Four hourly vital sign monitoring including monitoring for signs of troublesome hallucinations.

For Palliative Care patients : monitoring as deemed appropriate by the palliative care team.

Report adverse clinical signs to prescribing team

When patients are admitted to areas not familiar with the CADD pump, nurses have access to qualified staff to undertake any equipment setup, bag change and any other troubleshooting through the CNC (Pain Management) or out-of-hours the on call anaesthetic Registrar, *280 or by calling on staff from the surgical floors.

The availability of this support should be handed over from shift to shift.

• Program pump / syringe driver according to the infusion orders

• This drug requires independent double checking practices.

Adverse effects are reported in 40% of patients dosed with continuous subcutaneous infusion

Psychotropic side effects are common, ranging from drug high to de-realization/depersonalization, hallucinations and fear/panic attacks. These symptoms resemble psychotic episodes in schizophrenia, but disappear rapidly upon termination of the infusion. These effects are dose-dependent. The impact of these side effects on patients is variable. When unacceptable psychotropic effects occur, the ketamine infusion rate may be lowered or a benzodiazepine or a2-adrenergic receptor agonist (clonidine) can be added.

Effects on the cardiovascular system are moderate and well-tolerated. However, care is required in patients with cardiovascular disease (e.g. patients with ischemic heart disease and hypertension).

Finally, there is concern for the possibility of neurotoxicity and potential for abuse through long-term or repetitive ketamine use. Although indications for these concerns were derived from animal studies at relatively high ketamine doses, these issues remain understudied in humans.

Management of adverse effects:

• Hallucinations, vivid dreams or delirium (acute confusion)

  • Contact prescribing team (as appropriate)

  • Consider reducing the ketamine dose

  • Clonidine or Haloperidol may be prescribed by: Acute Pain Service , Persistent Pain Service, Neurology and Palliative Care

• Skin reaction: Rotate site (subcutaneous). Also consider adding 1mg of dexamethasone to the Syringe driver.

• Respiratory depression - stop ketamine, supportive measures and inform prescribing team.

Presentation

• Vials, 200 mg (base)/2 mL

• Ketamine is a racemic mixture. It is formulated as an acid (pH 3.5 to 5.5) solution for intravenous or intramuscular injection.

• Ketamine can be an irritant and should be diluted with sodium chloride 0.9%, glucose 5% or water for injection.

Storage

• Store below 30deg. C.

• Protect from light.

• Ketamine must be stored in accordance with the Controlled Drugs Policy and recorded as per CPP0481 Medication-drug register and documentation standards.

• Do not use if the solution is coloured and/or contains particulate matter.

COMPATABILITIES within syringe drivers

• Both clonidine and midazolam are compatible with ketamine in solution and may be combined with ketamine to minimise its side effects. However, clonidine and midazolam are not compatible with each other.

• Ketamine is compatible in subcutaneous syringe drivers with the following drugs:
  - morphine
  - hydromorphone
  - fentanyl
  - sufentanil
  - metoclopramide
  - haloperidol
  - midazolam
  - levomepromazine
  A second syringe driver would only be necessary if more than 3 drugs need to be administered

• As mentioned above, subcutaneous infusion sites readily become inflamed then dexamethasone 0.5-1mg can be added to the ketamine infusion.

• Refer to the Palliative Care Subcutaneous Infusion Sheet for a full list of compatibilities.