Intranasal Midazolam for the Emergency Management of Hypercyanotic Spells in Tetralogy of Fallot Jesus Vallejo Montero, RN,* Esther Moreno Nieto, RN,† Inmaculada Rubio Vallejo, PharmD,‡ and Sergio Vallejo Montero, RN† Abstract: The case of a 2-month-old boy with previously diagnosed tetralogy of Fallot who was brought to the emergency department with a hypercyanotic spell is described. Because partly of the difficulty of intravenous placement, especially in an infant crying with marked hypernea and deeply cyanotic, intranasal midazolam was administered. Before 3 minutes of hypernea terminated increasing the oxygen saturation successfully and intravenous line was easily placed with the baby remaining in calm. Sedation is an important step in the management of patients with cyanotic spells. Intranasal midazolam offers an alternative use as an initial method of calming the child that was effective in a patient with a severe cyanotic spell because of tetralogy of Fallot in the emergency department. Key Words: tetralogy of Fallot, cyanosis, sedation, midazolam, intranasal (Pediatr Emer Care 2015;31: 269–271)


etralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (7%-10% of all cases).1 The 4 characteristic morphologic abnormalities are: interventricular communication, subpulmonary stenosis (right ventricular outflow tract obstruction), biventricular origin of the aortic valve, and concentric right ventricular hypertrophy. These anatomic abnormalities result in decreased pulmonary blood flow, leading to hypoxia and cyanosis. Hypercyanotic spell is a pediatric cardiac emergency. Sudden desaturation will occur during a hypercyanotic spell characterized by severe reduction in pulmonary blood flow. It occurs because of an imbalance between pulmonary and systemic vascular resistance favoring decreased pulmonary flow and increased right-toleft shunting. Hypoxemia, metabolic acidosis, hyperpnoea, increased systemic venous return, catecholamines, and pulmonary vasoconstriction are thought to be involved in an interaction that results in a self-perpetuating cycle. Management of a hypercyanotic spell consists of calming the child by relieving pain and anxiety to reduce heart rate and systemic oxygen consumption and manoeuvres to increase the amount of blood exiting the right ventricle to the pulmonary vasculature instead of the aorta. Midazolam is one of the most widely used sedative agents in pediatric patients. Intranasal route has been frequently used in children undergoing dental procedures, laceration repairs, and for the rapid sedation of patients in which intravenous (IV) access was not possible and for the emergency treatment of seizures. Its

From the *Department of Emergency Medicine, Hospital SAS Jerez de la Frontera, †Emergency Medical Service, SAS, Chiclana de la Frontera; and ‡Facultad de Farmacia, Sevilla, Spain. Disclosure: The authors declare no conflict of interest. Reprints: Jesus Vallejo Montero, RN, Servicio De Urgencias, Hospital SAS Jerez de la Frontera, Carretera de Circunvalación, N-IV KM 638, 11407 Jerez de la Frontera, Cádiz, Spain (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161

effective sedative properties, short duration, and cardiorespiratory stability make it useful in cardiac patients.2–4

CASE A 2-month-old boy was brought to the emergency department (ED) by the critical care transport team for turning blue when crying. He was diagnosed with TOF antenatally and was born at term. An echocardiogram 1 day after he was born confirmed the diagnosis. The patient was taking propranolol to prevent hypoxic spells while he was waiting for a definitive surgical intervention. He remained free of symptoms with a normal growth and development follow-up by his pediatric cardiologist. On presentation, the baby was agitated, tachycardic, tachypneic, and profoundly cyanotic. Heart rate was 184 beats per minute, respiratory rate was 60 breaths per minute, oxygen saturation shown on pulse oximetry (SpO2) was 54%, blood pressure could not be taken by patient agitation. Capillary refill time was below 2 seconds. The patient received 100% FiO2 in a nonrebreather, and a bag valve mask apparatus was available at the bedside. The intent of the mother to calm irritability and inconsolable crying, placing the baby in a knee-chest position and giving supplementary oxygen was unsuccessful, and his SpO2 kept diving into the 50s. At this point, obtaining IV access for pharmacologic therapies was important, but IV access was not immediately available because the child was crying and moving during each attempt. In order to reduce stress and anxiety and to facilitate the procedure, Midazolam standard 5 mg ml solution commercially available for IV use (DORMICUM, Roche Farma, S.A.) was dripped by syringe into both nostrils in equal doses. Instillation of midazolam 0.2 mg kg caused rapid sedation, and calming of the patient, anxiolysis with sleepy (eyes open, less active) was observed. Before 3 minutes the hypernea terminated, heart rate 132 beats per minute, blood pressure 82/45 mm Hg, respiratory rate 28 breaths per minute, increasing the SpO2 at levels from 52% to 100%. Then, with a good sedation level and less movement, IV line was easily placed in the ED, and he was given 20 mL/kg normal saline bolus. The patient was admitted in the pediatric intensive care unit and 3 days later underwent to corrective surgical procedure. No adverse events occurred with the use of intranasal midazolam (INM).

DISCUSSION Hypercyanotic spell is an important complication of TOF and requires prompt management to break the hypoxic cycle.1 The clinical features are central cyanosis, irritability (because of cerebral hypoxia), hyperpnoea secondary to metabolic acidosis, and signs of the trigger (anxiety, fever).

Pediatric Emergency Care • Volume 31, Number 4, April 2015

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Pediatric Emergency Care • Volume 31, Number 4, April 2015

Vallejo et al

The mechanism of cyanotic spells is not clear. Increases in infundibular contractility or hyperpnoea, peripheral vasodilatation, and right ventricular mechanoreceptor stimulation are some of the proposed mechanisms.5 The aim of therapy is to redress this imbalance by relieving pain and anxiety, increase systemic vascular resistance, and increase pulmonary blood flow. To keep the child calm and to avoid painful procedures without sedating the patient, the arms of the mother often seems to be the best place for the infant. Initially, the infant should be positioned with the knees to the chest in an effort to increase systemic vascular resistance and promote systemic venous return to the right heart. Compression of the femoral arteries or external manual compression of the abdominal aorta also can be attempted.6 If no improvement is seen within a few minutes, immediate IV access to allow prompt administration of fluids and drugs should be obtained. However, to provoke the infant by attempting to start an IV line, especially if not skilled in pediatric IV placement can worse the situation. The safety and efficacy of a sedation protocol based on INM in children who are anxious and uncooperative when undergoing minor painful procedures, such as peripheral line insertion, has been shown.2 Wilton and colleagues first described intranasal use of midazolam as a pre-anaesthetic sedative for children. Its successful use has since been described for sedating preschool children before suture of lacerations in the ED, as a premedicant in young children undergoing short surgical procedures, for the rapid sedation of patients in which IV access was not possible and for the emergency treatment of seizures.2–4 The observed pharmacokinetic-pharmacodynamic properties suggest that INM deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose to facilitate the potential difficulty of IV placement in children. Oxygen is of limited value in cyanotic spell caused by TOF because the problem is reduced pulmonary blood flow. It should be given, but care should be taken not to increase the infant's stimulation. Blow-by O2 is the least objectionable. If it is distressing the child, it should be discontinued. If the infant is still cyanotic, acidosis will result and sodium bicarbonate 1 to 2 mEq/kg IV must be administrated. It reduces the respiratory center stimulation by metabolic acidosis and may diminish the increase in pulmonary vascular resistance caused by hypoxia and acidosis. If these measures are not successful, medical therapy includes: Supportive measures such as volume repletion with crystalloid or colloid fluid bolus of 10 to 20 mL/kg. This maximises preload and should be given prior to the following drugs which may induce hypotension. The β blockers (propranolol IV, 0.015 to 0.02 mg/kg or the shorter-acting Esmolol, 0.5 mg/kg given over 1 minute, and then continued as an infusion) by decreasing cardiac contractility to relax the dynamic muscular stenosis of the right ventricular outflow tract and to allow more time for right ventricular filling, improving pulmonary blood flow Phenylephrine, 0.1-0.5 μg/kg per minute, to increase systemic venous resistance and force more blood to the lungs. An alternative, to α-agonists could be terlipressin 20 μg/kg, a potent vasoconstrictor, reported as effective to reverse hypercyanotic spells.7 Sedation to decrease the release of catecholamines is an important step in the management of patients with cyanotic spells associated with TOF. Morphine, 0.1 to 0.2 mg/kg IV, intramuscularly, or subcutaneously is frequently recommended for sedating awake patients


with hypercyanotic spells to increase the period of right ventricular filling by decreasing the heart rate and promote relaxation of the infundibular spasm. However, morphine often causes both arterial and venodilation, resulting in paradoxical exacerbation of cyanosis. It is commonly known that morphine depresses respiratory center, increasing the risk of repetitive apneas. Ketamine, 0.25 to 1.0 mg/kg, IVor intramuscularly, has dual benefit, it causes sedation and increases systemic venous resistance and may be an alternative to morphine. However, ketamine has relatively high incidence of airway complications Dexmedetomidine infusion, initiating at a very low dose of 0.1 to 0.2 mcg/kg per hour (without a bolus), has been recently shown to be useful in hypercyanotic neonates.8 Midazolam is a water-soluble hypnotic-sedative drug with anxiolytic and amnestic properties, which is the shortest acting in relation to other benzodiazepines. The short duration and cardiorespiratory stability makes it useful in cardiac patients.9 Absorption of intranasal drugs occurs directly into the central circulation due to the rich vascularization of the nasal cavity, bypassing the enterohepatic circulation. Midazolam easily cross the nasal mucosa and the blood-brain barrier, resulting in a rapid rise in both the plasma and the cerebrospinal fluid concentrations.10 The use of atomized spray versus droplet delivery into the nasal cavity has been compared. Drops into the nose are deposited onto the ciliary surface with excess runoff down the oropharynx. In comparison, atomized particles cover more surface area and are better distributed into the nasal mucosa, resulting in better bioavailability and improved sedative effects.2,11 Adverse effects of nasal medications are infrequent. The most commonly reported adverse effects of INM are nasal burning for 30 to 45 seconds and bitter taste. Its safety and anxiolytic effect have been proved in several studies. Although all sedative agents can cause respiratory depression that appears to be dosedependent and increases with coadministration with other sedative agents, and hemodynamic effects by decreasing central sympathetic outflow and systemic vascular resistance. Because INM is directly absorbed into the cerebral spinal fluid, it is not subject to hepatic first-pass metabolism and less likely to accumulate, INM did not result in significant cardiovascular effects and respiratory depression as premedication in normal children and in children with congenital heart disease.2,4,12–14 In our case, the administration of nasal Midazolam provided a good sedation and immediately increased systemic arterial saturation, probably by decreasing sympathetic tone, augmenting pulmonary blood flow. There were no adverse effects.

REFERENCES 1. Bailliard F, Anderson RH. Tetralogy of Fallot. Orphanet J Rare Dis. 2009;4:2. 2. Lane RD, Schunk JE. Atomized intranasal midazolam use for minor procedures in the pediatric emergency department. Pediatr Emerg Care. 2008;24:300–303. 3. Wilton NCT, Leigh J, Rosen DR, et al. Preanesthetic sedation of preschool children using intranasal midazolam. Anesthesiology. 1988;69:972–975. 4. Holsti M, et al. Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care. 2007;23:148–153. 5. Duro RP, Moura C, Leite-Moreira A. Anatomophysiologic basis of tetralogy of Fallot and its clinical implications. Rev Port Cardiol. 2010;29: 591–630. 6. Baele PL, Rennotte M-TE, Veyckemans FA. External compression of the abdominal aorta reversing tetralogy of Fallot cyanotic crisis. Anesthesiology. 1991;75:146–149.

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Pediatric Emergency Care • Volume 31, Number 4, April 2015

7. Azpilicueta Idarreta M, Ibarra de la Rosa I, Tejero Hernández MA, et al. Terlipressin as rescue therapy in hypercyanotic spells of Fallot tetralogy. An Pediatr (Barc). 2010;73:35–38. 8. Senzaki H, Ishido H, Iwamoto Y, et al. Sedation of hypercyanotic spells in a neonate with tetralogy of Fallot using dexmedetomidine. J Pediatr (Rio J). 2008;84:377–380. 9. Hardmeier M, Zimmermann R, Rüegg S, et al. Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers. Clin Pharmacol Ther. 2012;91:856–862. 10. Wermeling DP, Record KA, Kelly TH, et al. Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers. Anesth Analg. 2006;103:344–349.

Emergency Management of Hypercyanotic Spells

11. Warrington SE, Kuhn RJ. Use of intranasal medications in pediatric patients. Orthopedics. 2011;34:456–459. 12. Knoester PD, Jonker DM, van der Hoeven RTM, et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in health volunteers. J Clin Pharmacol. 2002;53: 501–507. 13. Audenaert SM, Wagner Y, Montgomery CL, et al. Cardiorespiratory effects of premedication for children. Anesth Analg. 1995;80:506–510. 14. Gharde Parag, Chauhan Sandeep, Kiran Usha. Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair. Ann Card Anaesth. 2006;9:25–30.

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Intranasal midazolam for the emergency management of hypercyanotic spells in tetralogy of Fallot.

The case of a 2-month-old boy with previously diagnosed tetralogy of Fallot who was brought to the emergency department with a hypercyanotic spell is ...
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