Continuing Education Activity

Endotracheal intubation is indicated in many clinical settings, such as impending respiratory failure and when protecting the patient airway. The following describes the most common medications used for rapid sequence intubation of the pediatric patient in an emergency setting. It represents a reasonable approach for individuals who are not anesthesia or critical care specialists. The process of endotracheal intubation is not reviewed; however, the following are a few critical points regarding the procedure. In most cases, endotracheal intubation is a semi-urgent procedure. Commonly used premedications including fentanyl, midazolam, and atropine; induction agents including etomidate and ketamine; paralytics including rocuronium and succinylcholine; and reversal agents including naloxone, flumazenil, and paralytics are reviewed. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of agents used to facilitate tracheal intubation, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives:

• Explain how the various agents used to facilitate intubation are useful in the process of intubating a patient.
• Review the various mechanisms of action of common intubation medications.
• Identify the most prevalent adverse effects associated with the various intubation medications.
• Summarize interprofessional team strategies for improving care coordination and communication to properly use medications to facilitate tracheal intubation to improve patient outcomes.

Indications

Endotracheal intubation is indicated in many clinical settings, such as impending respiratory failure and when protecting the patient airway. The following describes the most common medications used for rapid sequence intubation of the pediatric patient in an emergency setting. It represents a reasonable approach for individuals who are not anesthesia or critical care specialists. The process of endotracheal intubation is not reviewed; however, the following are a few critical points regarding the procedure.[1][2]

In most cases, endotracheal intubation is a semi-urgent procedure. A good bag-mask technique can be used to effectively oxygenate and ventilate the patient while appropriate staff and equipment are assembled. Suction, oxygen, and airway equipment, medications, and monitors are gathered and checked, and intravenous (IV) access assured. A brief “pre-assessment” of the patient including potential airway problems, aspiration risk, and comorbid conditions should precede attempted intubation. For example, a child who is intubated for croup may require an endotracheal tube that is smaller than usual due to airway inflammation. Commonly used premedications including fentanyl, midazolam, and atropine; induction agents including etomidate and ketamine; paralytics including rocuronium and succinylcholine; and reversal agents including naloxone, flumazenil, and paralytics are reviewed.[3]

Mechanism of Action

Oxygen is arguably the most important drug to consider when intubating a child. A period of “preoxygenation" should precede attempts at intubation.” Providing 100% Fi02 via bag-mask ventilation increases the amount of oxygen dissolved in the blood (pO2) and bound to hemoglobin. This provides an “oxygen reservoir” that patients can use if there are periods of decreased oxygen delivery to the lungs during the process of intubation.

Fentanyl is a synthetic opioid that binds to opiate receptors resulting in decreased pain. Endotracheal intubation results in sympathetic nervous stimulation that can cause significant increases in blood pressure. Fentanyl can be given prior to induction agents reduce increases in blood pressure in patients with increased cranial pressure or in other clinical settings where a rapid rise in blood pressure is undesirable. Its rapid onset and metabolism relative to other opiates make it a common choice for premedication.

Midazolam is a fast acting benzodiazepine that provides anxiolysis and some amnesia, facilitating endotracheal intubation. Like fentanyl, it can be given before induction agents to facilitate endotracheal intubation.

Atropine occasionally is used as a premedication. Its anticholinergic effects reduce ACH-mediated bradycardia that can accompany endotracheal intubation.

Etomidate is a sedative-hypnotic agent commonly used for rapid sequence induction. It is an imidazole compound that acts at the level of the reticular-activating system to produce anesthesia. It appears to depress central nervous system (CNS) function via GABA.[4]

Ketamine induces a dissociative state resulting in sedation, amnesia, and analgesia. Its effect is at least in part due to non-competitive blockade of N-methyl-d-aspartate (NMDA) receptors in the cortex and limbic systems.

Rocuronium is a nondepolarizing skeletal muscle relaxant. It works as a cholinergic receptor antagonist, inhibiting depolarization.

Succinylcholine is a depolarizing muscle relaxant that combines with cholinergic receptors at the motor endplate to produce depolarization, preventing neuromuscular transmissions as long as it remains bound to the receptor site.[5]

Administration

Fentanyl can be administered via intravenous, intraosseous, intramuscular, intranasal, sublingual, transdermal, and oromucosal routes. When given IV, it is usually administered over 30 to 60 seconds to reduce the risk of respiratory depression. When given IV, effects begin within 2 to 3 minutes with a duration of action lasting 30 to 60 minutes.

Midazolam can be administered via IV, intraosseous (IO), intramuscular (IM), intranasal (IO), and oral routes. Its onset of action is about 2 minutes after IV injection with maximal effects occurring in 5 to 10 minutes. It is usually given over 2 minutes (IV).

Atropine is occasionally used as a premedication. Its anticholinergic effects reduce ACH-mediated bradycardia that can accompany endotracheal intubation.

Etomidate is given IV over 30 to 60 seconds. Its actions are seen within 1 minute of IV administration.

Ketamine is given via IV, IM, and IO routes when used for induction. The onset of action is within 30 seconds of IV administration, with anesthetic effects lasting 5 to 10 minutes. IM dosing has an onset of action ranging from 3 to 4 minutes with anesthetic effects lasting 12 to 25 minutes.

Rocuronium onset is about 1 to 2 minutes after IV administration, and duration of action is 30 to 60 minutes. It is minimally metabolized in the liver and may have a longer duration of action in the setting of hepatic dysfunction.

Succinylcholine is preferably given via the IV route, though it can be given IM. When given IV, the onset of action is 30 to 60 seconds, with a duration of action 8 to 15 minutes.

Adverse Effects

Oxygen used short-term as a supplement in ventilated patients has few adverse effects. Neonates with suspected ductal-dependent cardiac lesions are an exception to this rule since high concentrations of supplemental oxygen could result in the closure of a patient ductus arteriosus. Consult with a pediatric cardiologist or pediatric critical care specialist before withholding supplemental oxygen. The concentration of supplemental oxygen is adjusted to maintain the desired oxygen saturation based on the clinical setting.

Fentanyl can cause respiratory depression and decreased blood pressure. In the setting of sepsis or other conditions that can reduce blood pressure, other agents should be considered. Sinus tachycardia, hypertension, palpitations, and bradycardia also are reported. Chest wall rigidity is an uncommon but serious adverse effect of fentanyl that can make it exceedingly difficult to ventilate patients. Paralytic medications may be needed to allow for effective ventilation in the setting of fentanyl-induced muscle rigidity. Fentanyl exposes patients to the risk of opioid addiction. The risk of CNS depression is increased with concomitant use of other CNS depressing agents like benzodiazepines or ethanol. As with other medications, allergic reactions can occur.

Midazolam can decrease respiratory drive and reduce blood pressure. Common adverse effects include hiccups, nausea, vomiting, coughing, headache, drowsiness, pain during injection, and "oversedation." In the setting of sepsis or other conditions that can reduce blood pressure, other agents should be considered. As with other medications, allergic reactions can occur.

Etomidate can cause elevated or decreased blood pressure, apnea, laryngospasm, tachycardia, bradycardia, hypoventilation, myoclonia, adrenocortical insufficiency, and hypoaldosteronism. It can also cause injection site reactions, nausea, vomiting, and hiccups. As with other medications, allergic reactions can occur.

Ketamine increases myocardial oxygen consumption, raising concerns for its use in patients with coronary artery disease. There are concerns that ketamine may increase intracranial or intraocular pressure, so in the setting of possible increased intracranial or intraocular pressure, other agents may be preferred. Common adverse effects of ketamine include rash, diplopia, vomiting, involuntary movements of the head and extremities, increased secretions and emergence reactions, hypertension, and allergic reactions. One of the most concerning potential adverse effects of ketamine is laryngospasm, which may be severe. Ketamine is usually given over 60 seconds to reduce the risk of respiratory depression, apnea, and increased pressor response. As with other medications, allergic reactions can occur.

Rocuronium may require dosing adjustments in patients with hepatic or renal impairment. Certain pathologic states like acid/base imbalances, dehydration, hypothermia and electrolyte abnormalities can increase the risk of a prolonged neuromuscular block with rocuronium. Patients with a family history of malignant hyperthermia should be treated with extreme caution as rocuronium may contribute to this reaction, especially in the presence of halogenated anesthetics. As with other medications, allergic reactions can occur. It is important to assure adequate sedation in paralyzed patients. Some sedating medications may where off before paralytics, especially when repeated doses are given.

Succinylcholine can trigger malignant hyperthermia in susceptible individuals. There are rare reports of rhabdomyolysis with hyperkalemia, ventricular dysrhythmias, and death in children found to have undiagnosed skeletal muscle myopathy. It may cause increased intraocular pressure, increased intracranial pressure, flushing, hypotension, and bronchoconstriction. As with other medications, allergic reactions can occur. It is important to assure adequate sedation in paralyzed patients. Some sedating medications may wear off before paralytics, especially when repeated doses are given.[6]

Contraindications

Fentanyl should not be used if there is a known allergy to opiates. Concomitant use of fentanyl with a cytochrome P450 3A4 inhibitor may result in increased fentanyl plasma concentrations. Patients who recently had a P450 3A4 inducer discontinued may have increased concentrations of plasma fentanyl.

Midazolam should not be used if there is a known allergy to benzodiazepines. It can reduce blood pressure, so it is not recommended in the setting of shock.

Etomidate should not be used in the setting of sepsis or adrenal insufficiency. It is extensively metabolized in the liver, so caution should be used when administering etomidate to patients with hepatic disease. It should not be used if there is a known allergy to the drug.

Ketamine should not be used if there is a known allergy to the drug or in patients a history of psychosis.[6]

Rocuronium should not be used if there is a known allergy to the drug. Caution should be used in patients with neuromuscular disease, malnutrition or hepatic impairment.

Succinylcholine is contraindicated in patients with a personal or family history of malignant hyperthermia and patients with skeletal myopathies like muscular dystrophy. In the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle or upper motor neuron injury succinylcholine can cause severe hyperkalemia which may result in cardiac arrest, making it contraindicated in these clinical settings. It should not be used in patients with a known allergy to the drug.[6]

Monitoring

Preparation is the key to a safe and successful endotracheal intubation. Providers should monitor heart rate and rhythm, blood pressure, oxygen saturation, and preferably, end-tidal throughout the procedure. A provider skilled in airway management including bag-mask ventilation should be at the bedside monitoring the patient. Equipment should be checked at the bedside before attempting endotracheal intubation.

Equipment includes suction, appropriate-sized bag and mask, oxygen source, appropriate size endotracheal tubes including a size larger and one size smaller, laryngoscope and appropriate-sized laryngoscope blades (including one size smaller and one size larger), endotracheal tube-securing equipment (tape or other), stethoscope, appropriate sized nasogastric tubes, and in most cases, x-ray equipment to confirm appropriate placement.

IV or IO access should be obtained before intubation attempts, and the appropriate drug should be drawn up and available before attempting intubation. Patients should be bagged with 100% oxygen to create an oxygen reservoir in the blood before attempting intubation. Once the endotracheal tube is in place, tube placement should be confirmed with a CO2-detecting device, auscultation of good breath sounds bilateral, confirmation of chest rise with bagging, the absence of "breath sounds" over the stomach, and appropriate clinical response (O2 saturation, HR, BP, end-tidal CO2). Tube position should be confirmed via x-ray as well.

Toxicity

Naloxone binds to opioid receptors. When opioids are present, it competes with opioids for receptor sites, thus acting a reversal agent for opioids like fentanyl and morphine. It can be given by the IV, IM, IO, subcutaneous (SQ) and nasal route. When administered by IV, the onset of action is about 2 minutes. Onset is less rapid when given IM or SQ. In opioid-addicted individuals, it can cause withdrawal symptoms. Some narcotics have longer half-lives than naloxone with the return of opioid effects once naloxone wears off.

Flumazenil competitively inhibits the actions of benzodiazepines at the side of the GABA/benzodiazepine receptor complex, acting as a reversal agent for benzodiazepines like midazolam. Some benzodiazepines have longer half-lives than flumazenil. Return of benzodiazepine effects may return after flumazenil has been metabolized.[7]

Sugammadex is a reversal agent for rocuronium. It binds to rocuronium and renders it unavailable to bind to the ACH receptor at the neuromuscular junction. It can also bind to vecuronium and pancuronium. Sugammadex's effects can wear off before rocuronium has been completely metabolized, so the paralytic effects of rocuronium may return after sugammadex has been metabolized, especially when repeated doses of rocuronium are used.[8]

Enhancing Healthcare Team Outcomes

Team members participating in an endotracheal should have clearly defined rolls and responsibilities. Advanced planning to assure all of the needed supplies and personnel are available when emergent intubation is needed.[9] Depending upon the facility and resources available, ideally the should be a team leader who will perform the actual intubation, a nurse to place the IV and provide medications, and a respiratory therapist to provide bag mask valve ventilation before intubation, and who will continue ventilation using the ET tube manually until a ventilation can be provided by a mechanical ventilator.  Additional staff may include a pharmacist to draw up medications, social work or a chaplin to support the family, and additional nursing staff.  It is vital that all healthcare workers know the indications and contraindications of medications used during the procedure. In addition, it is important to have an intravenous line before attempting endotracheal intubation. Oxygen saturation, heart rate and rhythm, respiratory rate, blood pressure, and end-tidal CO2 monitoring (if available) should be continued before and after intubation.  Team members participating in an endotracheal should have clearly defined rolls and responsibilities. Advanced planning to assure all of the needed supplies and personnel are available when emergent intubation is needed.[9] An interprofessional approach to intubation will provide the best and safest patient care. [Level V]