Management of Ketamine Extravasation in a Pediatric Patient During Procedural Sedation

Abstract

Ketamine is a commonly used intravenous and intramuscular medication for procedural sedation within pediatric emergency medicine. There is limited availability of data on the rate of absorption and use of subcutaneous ketamine administration. We describe the case of a 12-year-old male who was sedated after extravasation and subsequent absorption of ketamine 1 mg/kg from a peripheral intravenous line (PIV). Despite being an unintended route, absorption of subcutaneous ketamine resulted in satisfactory procedural sedation with no complications. Given limited data on subcutaneous ketamine pharmacokinetics, the aim of this case report is to present the observed absorption of subcutaneous ketamine due to extravasation of PIV during a pediatric procedural sedation.

Introduction

Ketamine is a non-competitive antagonist of the glutamate N-methyl-D-aspartic acid receptor that provides analgesia, sedation, amnesia, and immobilization, while maintaining cardiovascular stability and bronchodilator effects.^1–3 These characteristics make it an attractive agent in emergency medicine for procedural sedation. Common uses of ketamine include procedures that are painful and/or traumatic to the patient yet brief enough to require only minimal sedation (e.g., fracture reduction, chest tube insertion, laceration repair, etc.).^1,3

For procedural sedation in pediatric patients, ketamine can be administered in a variety of routes including intravenously, intramuscularly, and intranasally. Intravenous dosing for pediatric procedural sedation typically ranges from 1 to 2 mg/kg initially given over 30 to 60 seconds followed by 0.5 to 1 mg/kg for subsequent doses every 5 to 15 minutes. The ketamine molecule is lipophilic and hydrophilic, allowing for rapid absorption and distribution into peripheral tissues. Ketamine intravenously has a favorable dose-dependent pharmacokinetic profile with a rapid onset of action within 30 seconds, a typical anesthetic duration of 5 to 10 minutes (full recovery within 1 to 2 hours), and half-life of 10 to 15 minutes. When given intramuscularly, the anesthetic onset is delayed to 3 to 4 minutes with a slightly longer anesthetic duration of action of 12 to 25 minutes (full recovery within 3 to 4 hours).^1,3–6 Literature mentions subcutaneous and intravenous (IV) dosing of ketamine in the setting neuropathic pain management, with optimal doses ranging from 0.125 to 0.3 mg/kg/hr. Other sources cite smaller and larger doses with comparable results between each route.⁷

Although ketamine is a growing topic in scientific research, there is little record of ketamine extravasation, pharmacotoxicity via subcutaneous route, and their management. The following case describes extravasation of ketamine from a peripheral IV line (PIV) during a pediatric procedural sedation.

Case

A 12-year-old, 47-kg white male with past medical history significant for anxiety and migraines, on amitriptyline and paroxetine, presented to the pediatric emergency department for concern for left wrist injury. Patient was playing basketball and sustained a fall on outstretched hand injury resulting in a left distal radius fracture with dorsal angulation of distal fracture fragment. The patient was evaluated by orthopedics and the need was determined for closed reduction with procedural sedation. Intravenous ketamine 1 mg/kg (10 mg/mL; Mylan Pharmaceuticals) was chosen as the anesthetic agent.

Informed consent was obtained from the mother with discussion of risks and benefits of ketamine administration. A PIV was placed by nursing in the right ante-cubital region, and continuous cardiac monitoring and capnography were initiated. Patient was administered entire dose of ketamine and immediately reported pain at the PIV site. Moderate swelling and erythema surrounding the site confirmed suspicions of extravasation. Ketamine was inadvertently injected into the subcutaneous tissue. Clinical discretion of the pediatric emergency medicine team was heightened due to limited published data on subcutaneous ketamine absorption. Warm, dry compresses were applied to the area, and no additional medication was administered for 20 minutes following PIV extravasation. This 20-minute wait period was determined by considering the anesthetic durations of intravenous and intramuscular ketamine.

The patient was mildly tachycardic upon arrival, so this measure was less reliable in identifying systemic toxic effects. Between 15 to 20 minutes post-extravasation of subcutaneous ketamine, the patient developed nystagmus with partial dissociation. At this point, an additional 0.5 mg/kg dose of IV ketamine was given via new PIV with complete dissociation and relaxation of the patient.

In this case, the initial extravasated dose of 1 mg/kg in addition to the subsequent dose of 0.5 mg/kg IV were sufficient for procedural sedation. No further doses of medication were required for completion of the procedure. Patient returned to baseline within 30 minutes of medication administration with no complications or signs of emergence reaction. Swelling and erythema of the extravasated site gradually lessened over the following hours. Few data were available regarding the status of the extravasated site following discharge.

Discussion

Extravasation is the accidental leakage of a known vesicant from an intravascular line into the surrounding tissues.^8–10 It is a common iatrogenic injury in clinical practice where providers must consider local histopathologic and systemic consequences. Toxic potential of the agent, dosage, volume, site of extravasation, and past medical history of the patient determine the extent of injury. It is important to distinguish extravasation from infiltration, as the latter denotes leakage of a non-vesicant. No literature clearly defines ketamine as a known vesicant; however, it supports the type of reaction that one would expect from a known vesicant. Therefore, we classify this case as an extravasation event because of ketamine potential for ischemia and necrosis.⁸

Local clinical features of extravasation commonly present as pain, erythema, edema, and joint stiffness near the affected site, all of which were noted in the case patient. More severe injury may result in blistering, induration, ulceration, and even necrosis. Extravasation injury occurs by multiple mechanisms: vasoconstriction or vasodilation, cytotoxicity, osmotic damage, extremes in pH, high volume resulting in mechanical compression of tissue and nerves, or superimposed infection.^8,9 Ketamine is a weakly acidic solution with an associated pH of 3.5 to 5.5.^9,11 The ideal pH for human tissues ranges from 5.5 to 8.5.⁹ Extravasation of an acidic solution, such as ketamine, may lead to ischemia and necrosis. In early stages (2–4 hours post-injury) erythrocyte sludging may occur, followed by endothelial degenerative changes and lysis of inflammatory cells in the later stages (12–24 hours post-injury).^8–10 As mentioned, subcutaneous dosing of ketamine is safely achieved at 0.125 to 0.3 mg/kg/hr for neuropathic pain. Therefore, the dose at which ketamine is no longer safe for subcutaneous administration is in question.

In the event of extravasation, it is important to immediately discontinue drug administration and aspirate the cannula. The clinician must avoid flushing the cannula, as this will push additional agent into the subcutaneous region and prevent quantification of the extravasated drug. If the extravasation event is not witnessed, distinguishing between a drug reaction and extravasation are important as these etiologies present similarly.^8,9 The majority of extravasation management is conservative due to the relatively low rates of complication.⁹ Emergent treatment options include dry heat with elevation and close monitoring for ischemia.^8,10 Heat promotes vasodilation and reabsorption of extravascular contents by circulation. Dry heat specifically is important to prevent maceration of the compromised tissue.⁸ Elevation decreases swelling and improves lymphatic drainage of the affected site.^8,9 Marking the perimeter of skin change and assessing local injury based on blanching, skin temperature, capillary refill, distal pulses, and signs of skin breakdown or necrosis are important for documenting the injury progression.^8,9 There is no specific decontamination measure for extravasated ketamine, although saline washout is an efficient method for dilution.¹¹ If signs of ischemia and necrosis develop, a surgical consult is recommended.⁹

In addition to local effects of extravasation, systemic drug reaction must be considered because management differs significantly. Systemic sequelae of extravasation could be fatal at high doses, so it is important to be mindful of the distractors of local toxicity. Systemic effects of extravasation are fully dependent on the pharmacology and mechanism of action of the agent administered. Ideally, systemic toxicity will occur only at supra-therapeutic dosing for a given route, but it is still important to consider in the instance of extravasation. Because knowledge of ketamine systemic adverse effects is more readily available than local adverse effects, it is summarized here in brief.

Systemic effects of ketamine toxicity are usually minimal due its dose-dependent nature, first-pass metabolism, short half-life, and preserved cardiorespiratory function.^1–4,12 Depending on the route of administration, dosage, and patient sensitivity, signs of ketamine intoxication commonly last 15 minutes to 2 to 3 hours.¹³ Common sequelae include altered consciousness, agitation, hallucinations, hypersalivation, and lacrimation.^12,14 Severe intoxication may lead to adrenergic hyperactivity: hypertension, hyperthermia, diaphoresis, tachycardia. Monitoring vital signs is recommended to assess for these adrenergic effects. Agitation is managed by limiting stimulation in the patient room and administering benzodiazepines (midazolam, lorazepam, diazepam) or haloperidol. Numerous sources cite the use of atropine for hypersecretion.^1,4 The median lethal dose of ketamine is estimated to be 600 mg/kg for a human based on the safety ratio in rodents.¹⁵ Levels of this magnitude are extremely unlikely in iatrogenic settings. In the event of extreme toxicity, dialysis and hemoperfusion are unlikely to pose any systemic benefit due to the agent's large volume of distribution.¹¹

Preventive measures of infiltration and extravasation include ensuring secure cannula placement and close observation during injections and infusions. Articular sites at risk for dislodgment should be avoided when injecting more cytotoxic agents. Flashback when inserting the needle is a helpful sign for ensuring intravascular placement of the cannula. Resistance, pain, and sudden swelling upon injection are early signs of possible extravasation.⁸

In this case, the initial extravasated dose of 1 mg/kg in addition to the subsequent dose of 0.5 mg/kg IV after 20 minutes were sufficient for procedural sedation. It may be worth postulating that equivalent dosing of subcutaneous and IV ketamine produce comparable results. This case study highlights the importance of timely recognition and treatment of ketamine extravasation and serves as a guideline for providers. Initial steps of management, including dry heat and elevation, are listed to guide the provider in mitigating potential local adverse effects. Possible systemic effects are detailed for the provider to consider following initial management.

There remains a lack of evidence pertaining to ketamine extravasation and its associated toxicity, so we encourage clinicians to contribute findings and outcomes of ketamine extravasation as knowledge becomes available. We also encourage scientists to investigate the maximum dosing cutoff for safe subcutaneous ketamine administration and if there is potential for subcutaneous administration for indications aside from neuropathic pain.

Conclusion

This article details successful procedural sedation of a pediatric patient following ketamine extravasation of IV equivalent dosing. Although emergent treatment of extravasation should include dry heat with elevation and close monitoring for local tissue damage, it is important to be mindful of systemic sequelae: altered consciousness, agitation, hallucinations, hypersalivation, and lacrimation.^8,10 Future studies should focus on elucidating the safe dosing, effects, and pharmacologic potential of subcutaneous ketamine administration

ABBREVIATIONS

IV

intravenous

PIV

peripheral intravenous line