Analgesia and sedation for intratracheal intubation in the neonatal period: an integrative literature review

Naujorks, Silvia; Knob, Gabriele H.; Dotto, Patrícia P.; Henn, Roseli; Zamberlan, Cláudia

doi:10.1016/j.jped.2022.10.003

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REVIEW ARTICLE • J. Pediatr. (Rio J.) 99 (2) • Mar-Apr 2023 • https://doi.org/10.1016/j.jped.2022.10.003 copy

Analgesia and sedation for intratracheal intubation in the neonatal period: an integrative literature review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective:

to assess evidence available in the literature about the use of sedation and analgesia for intratracheal intubation of newborns.

Data sources:

by means of an integrative literature review, the authors looked for evidence related to the theme from the last ten years, indexed in the Pubmed, Medline, Lilacs, Scielo, and Scopus databases, by combining the descriptors: newborn, intratracheal intubation, and analgesia. Articles in Portuguese, English, and Spanish that met the research purpose were included.

Data summary:

After applying the eligibility criteria, ten articles on the topic were obtained, predominantly narrative reviews, retrospective studies, observational studies, and only one non-randomized clinical trial, which characterizes the literature related to the topic as having a low level of scientific evidence. There is still no consensus in the literature on which medications and indications are for use in non-elective intubations, despite the ethical recommendation.

Discussion:

pain and its deleterious effects should not be neglected. Neonatal Intensive Care Units should have their own protocols regarding sedation and analgesia for intubation considering the individual characteristics of each patient. There is an ethical recommendation regarding the use of sedation and analgesia for intubation since it is a known painful procedure.

KEYWORDS
Newborn; Pain; Intratracheal intubation

No.	Title	Year and Country	Author	Magazine	Method/Results/Conclusion	Evidence Level
1.	Propofol for endotracheal intubation in neonates: a dose-finding trial	2020; The Netherlands	Kort et al.⁷7 de Kort EH, Prins SA, Reiss IK, Willemsen SP, Andriessen P, van Weissenbruch MM, et al. Propofol for endotracheal intubation in neonates: a dose-finding trial. Arch Dis Child Fetal Neonatal Ed. 2020;105:489-95.	Archives of Disease in Childhood: Fetal and Neonatal Edition	Anon-randomized, multicenter, prospective, dose-ranging clinical trial that had the primary objective of finding the optimal dose of propofol for elective intubation in newborns that would produce sufficient sedation without side effects at each gestational age. They used doses of 1 -2.5 mg/kg IV. The ideal dose cannot be established, with the need for high doses of the medication for sedation and a high risk of hypotension, and its use is recommended with caution in this population.	II
2.	Adequate analgesia and sedation should be given to neonates during non-emergency endotracheal intubation	2020; Germany	Tippmann et al.⁸8 Tippmann S, Kidszun A. Adequate analgesia and sedation should be given to neonates during non-emergency endotracheal intubation. Acta Paediatr. 2020;109:17-9.	Acta Paediatrica, International Journal of Paediatrics	Narrative review on the possible reasons for not using premedication for intubation in neonates. It concludes that: the cerebral alterations induced by painful procedures, the low success rate of intubation with increased risk of intracranial hemorrhage with each new attempt, combined with the fact that there is no evidence that contraindicates premedication, make its use ethically unquestionable. It mentions the lack of sedation in the use of morphine, which is widely used for this purpose. Importance of protocols.	V
3.	Premedication practices for tracheal intubation in neonates transported by French medical transport teams: a prospective observational study	2019; France	Carbajal et al.⁹9 Carbajal R, Lode N, Ayachi A, Chouakri O, Henry-Larzul V, Kessouos K, et al. Premedication practices for tracheal intubation in neonates transported by French medical transport teams: a prospective observational study. BMJ Open. 2019;9:e034052.	BMJ Open	A multicenter, observational, prospective study that observed for two months several neonatal transport teams in the Paris region as to whether or not sedation and analgesia were used when intubation was necessary. It found that more than 70% of intubations were performed after premedication; such complications were more frequent when more than one intubation attempt was made, and that there was no agreement on the drugs to be used (the most frequent association being sufentanil + midazolam).	III
4.	Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing ventilation and endotracheal intubation	2019; Italy	Ancora et al.¹⁰10 Ancora G, Lago P, Garetti E, Merazzi D, Levet OS, Bellieni CV, et al. Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation. Acta Paediatrica. 2019;108: 208-17.	Acta Paediatrica, International Journal of Paediatrics	A systematic review, using the GRADE system to assess the quality of the literature on pain and stress management of newborns on mechanical ventilation or during intubation. Publications from 1986 to 2017 were used, from which strong recommendations were extracted. This would reduce pain, facilitate the procedure, and reduce side effects of the procedure. There is no consensus about the best combination of drugs and doses for this, but some indications according to gestational age, hemodynamic status, and extubation plans. It highlights the favorable pharmacokinetic profile of remifentanil and ketamine, despite few studies in NBs yet. It advises against the use of morphine as monotherapy. It also cites Drugs such as propofol, fentanyl and midazolam combined. He mentioned the possibility of using antagonist drugs to reverse sedation and analgesia after the procedure.	II
5.	Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit	2019; USA	Ku et al.¹¹11 Ku LC, Simons C, Smith PB, Greenberg RG, Fisher K, Hornik CD, et al. Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit. J Neonatal-Perinatal Med. 2019;12:143-8.	Journal of Neonatal-Perinatal Medicine	A retrospective, observational study that analyzed the use of intranasal fentanyl and midazolam for analgesia and sedation of neonates in a given US ICU from 2009 to 2015. As a result, its use in RNT and PMT was shown to be safe and well tolerated in this small cohort of 17 patients, and was used for several procedures, including intubation. The dose used was 0.1-0.2 mg/kg midazolam and 1-2 ug/kg/dose fentanyl, and could be repeated.	III
6.	Premedication for endotracheal intubation in the neonate	2018, USA	McPherson¹²12 McPherson C. Premedication for endotracheal intubation in the neonate. Neonatal Netw. 2018;37:238-47.	Neonatal Network	Literature review article on the use of premedication prior to neonatal endotracheal intubation with a description of the main pharmacological agents available. It is concluded that analgesia should be given in all cases, with strong consideration given to the use of a sedative, vagolytic, and muscle relaxant based on patient demographics and physician comfort. To ensure safety and optimize logistics, each neonatal unit should develop its own premedication protocol.	V
7.	Respiratory care for the ventilated neonate	2018; Portugal	Rocha et al.¹³13 Rocha G, Soares P, Gonçalves A, Silva AI, Almeida D, Figueiredo S, et al. Respiratory care for the ventilated neonate. Can Respir J. 2018;2018:7472964.	Canadian Respiratory Journal	Review article on the care and monitoring of neonatal patients on mechanical ventilation. Cites the use of intranasal midazolam/ketamine for intubation in the delivery room and for performing MIST (minimal invasive surfactant therapy). Cites the need for more studies to compare the risks and benefits.	V
8	Ketamine and atropine decrease pain for preterm newborn tracheal intubation in the delivery room: an observational pilot study	2013, France	Barois and Tourneux¹⁴14 Barois J, Tourneux P. Ketamine and atropine decrease pain for preterm newborn tracheal intubation in the delivery room: an observational pilot study. Acta Paediatr. 2013;102: e534-8.	Acta Paediatrica	An observational and prospective study of the feasibility and efficacy of inserting a short venous catheter for analgesia in intubating premature infants in the delivery room. Patients were screened at the discretion of the attending physician to receive ketamine (1.8 +- 0.9 mg/kg) and atropine (20 ucg/kg) 1 min before intubation, when this was indicated. As a result, these medications proved to be effective in reducing pain and preventing vagal bradycardia during intubation, being easy to use and without major side effects observed, allowing the use of surfactant in the first 30 min of life in 79.5% of cases when indicated.	II
9	Premedication for neonatal endotracheal intubation	2013, France	Durrmeyer et al.¹⁵15 Durrmeyer X, Daoud P, Decobert F, Boileau P, Renolleau S, Zana-Taieb E, et al. Premedication for neonatal endotracheal intubation. PediatrCrit Care Med. 2013;14:e169-75.	Pediatric Critical Care Medicine	An observational and prospective study, which described the frequency and nature of premedication used before intratracheal intubation in certain neonatal units in France. A premedication use rate of 56% was found, being mainly composed of opioids (67%) and midazolam (53%). It concluded that the use of premedication for intubation has increased but remains inconsistent and not systematized. It also described that the medications when used were either not recommended or not described by the American Academy of Pediatrics (AAP).	III
10	Premedication for Tracheal Intubation	2013, Italy	Biban and Gaffuri¹⁶16 Biban P, Gaffuri M, Biban P, Gaffuri M. Premedication for tracheal intubation: any good reason for treating newborn infants differently? Pediatr Crit Care Med. 2013;14:441-2.	Pediatric Critical Care Medicine	Article with a narrative about possible reasons for not using premedication for intubation of neonates, among them: lack of guidelines, adverse effects of medications, lack of large studies of medications in this period. It reports the progressive increase over the years in the use of analgesia for intubation, and in the use of institutional protocols.	V

DRUGS	PHARMACOLOGY	CLINICAL CHARACTERISTICS
Analgesics Morphine (10 mg/mL)	IV use at a dose of 0.1-0.2 mg/kg. Action time of 5-10 min, with an elimination half-life of up to 10 hours in premature infants.	Little used for intubation, according to the selected studies, due to its long action time and its long half-life, combined with its respiratory depressant effect.
Fentanyl (0.05 mg/mL)	IV and intranasal use at a dose of 2 mcg/kg. When IV, it has an action time of 1 min and an elimination half-life of 9.5 hours. When intranasal, it has an action time of 5-10 min.	A synthetic opioid that is fast acting, but has a relatively long half-life. Produces chest tightness when given quickly (less than 3 min). Intranasal use for intubation in the delivery room is well described.
Remifentanil (20 mcg/mL)	IV and intranasal use at a dose of 2 mcg/kg. When IV, it has an action time of 1 min and an elimination half-life of 5.4 h. When intranasal, it has an action time of 3-4 min.	A synthetic opioid that is fast acting, and short half-life. Produces chest tightness when given quickly (less than 3 min). Produces better intubation conditions when compared to morphine, with good use in brief intubations, such as for INSURE, MIST, and LISA procedures.
Sedatives Midazolam (15 mg/3 mL)	IV and intranasal use at a dose of 0.05-0.2 mg/kg. When IV, it has an action time of 1-2 min and half-life of 6.3 h in PMT. When intranasal, it has an action time of 5 min.	Its use should be limited to PMT>34 weeks due to hypotension and associated brain injury. It should never be used alone for intubation. It can be used intranasally in patients without venous access, especially in the delivery room. Midazolam associated with sufentanil were the most frequently used medications in a French study.
Propofol (10 mg/mL)	IV use at a dose of 1-2.5 mg/kg. It has an immediate action time and a half-life of 13 min.	It produces analgesia and sedation. In a recent clinical dosing trial, it was not possible to find the optimal dose that leads to adequate sedation and analgesia without side effects. It produces hypotension in more than 59% of the patients. Its use in the neonatal population should be with caution.
Ketamina (50 mg/mL)	IV use at a dose of 1-2 mg/kg e nasal 2mg/kg When IV, it has an action time of less than 1 minute and half-life of 15 a 30 min. When intranasal, it has an action time of 5 a 8 min.	It produces analgesia and sedation, without major side effects reported in the selected articles. Among its advantages: advantageous pharmacokinetic profile, stability of the cardiovascular and respiratory system, it has a bronchodilator effect.
Vagolytics Atropine (0.25 mg/mL or 0.5 mg/mL)	IV use at a dose of 0.02 mg/kg, with an action time of 1 minute and a half-life of 2 h.	It eliminates vagal bradycardia during intubation, increasing HR by about 12%. Its use in the neonate is controversial.
Muscle Relaxant Pancuronium (2 mg/mL)	IV use at a dose of 0.1 mg/kg, with an action time of 2-5 min and a half-life of 2-3 h.	Non-depolarizing neuromuscular blocker. It does not have ideal pharmacokinetics because it has a slow action time and a long half-life. It is usually used in combination with atropine. When used by an experienced professional, it increases intubation success rates.
Rocuronium (10 mg/mL)	IV use at a dose of 1 mg/kg, with an action time of 1 -3 min and a half-life of 40-60 h.	Non-depolarizing neuromuscular blocker. Its use in association with an opioid and atropine is associated with increased intubation success rates.
Vecuronium (4 mg/mL or 10 mg/mL)	IV use at a dose of 0.1 mg/kg, with an action time of 2-3 min and a half-life of 50-70 h.	Non-depolarizing neuromuscular blocker. It produced good intubation conditions associated with morphine in a small study of 13 neonates.
Succinylcholine (1 to 2 mg/mL)	IV use at a dose of 2-4 mg/kg, with an action time of 1 min and a half-life of 6-8 h.	Depolarizing neuromuscular blocker. It has the ideal pharmacokinetics for the procedure, with a short action time and short half-life. It can rarely produce hyperpotassemia, malignant hyperthermia, and bradycardia.

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[1] * Corresponding author. E-mail: silvianaujorks@gmail.com (S. Naujorks).