**5.4 Paracetamol**

Paracetamol (acetaminophen) is a non-opioid drug commonly used drug to treat mild to moderate pain management (peak onset for analgesia from 5 to 10 min to 1 hour after IV single injection) and fever (peak onset antipyretic effect within 30 min after IV single infection) and pain profile with duration (4–6 hours for analgesia). It is successfully used for postoperative pain or as "rescue" treatment post-operatively, as reported in ELBW, and additionally, for narcotic and morphine-sparing effect, respectively [43]. At the same time, the administration of paracetamol only for procedural indications in neonates is under discussion [44]. Paracetamol is recommended for ELBW neonates intravenously post-operatively on a regular schedule as a slow bolus injection over 15 minutes, although evidence of paracetamol dosing for pain relief is also known for oral and rectal administration in younger neonates than 32 weeks of postmenstrual age (PMA). Concerns about adverse effects are justified (circulatory, hepatic, renal, respiratory, etc.), and dosing must be adjusted to the appropriate age of the neonate even though the production of hepatotoxic metabolites is lower due to reduced CYP450 activity [45]. Dosing: the loading dose of paracetamol for premature neonates is 20 mg/ kg, and the maintenance dose (MD) is based on PMA: in neonates less than 32 weeks (PMA), the maintenance dose will be 7.5 mg/kg every 8 hours, in neonates ≥32 weeks of PMA 10 mg/kg every 8 hours [31]. Similarly, the Kinderformularium database recommends paracetamol dosing for premature neonates PMA < 32 weeks as a starting dose: 12 mg/kg/dose, once, and MD as 24 mg/kg/day in 4 doses intravenously [42].

#### **5.5 Midazolam**

Midazolam is, among other sedative drugs, still commonly used benzodiazepine with rapid onset action (within 1–5 min after IV single injection, maximum 5–7 min) and short duration (20-30 min after IV single injection) and widely used for sedative (acute/prolonged), anxiolytic and anticonvulsive effects and amnesia before induction of anaesthesia and procedural sedation used as intermittent dosing or continuous IV infusion. Adverse effects include cardiovascular (hypotension), seizure likeactivity, myoclonic jerks in preterm neonates, nystagmus, agitation or bronchospasm. Dosing: sedation IV 0.05–0.15 mg/kg may be repeated every 2–4 hours, continuous IV infusion 0.01 to 0.06 mg /kg/hour, and the dose should be titrated to achieve the desired effect [46]. The Kinderformularium database recommends midazolam dosing for preterm neonates < 32 weeks GA: initial dose up to 8 weeks postnatal age (PNA) is 0.05 mg/kg/dose over 30 minutes to avoid the risk of hypotension if given more rapidly, and MD: 0.03 – 0.1 mg/kg/hour, continuous infusion [42].

#### **5.6 Dexmedetomidine**

An alfa (α-2) adrenergic agonist with rapid onset action (its onset of action is less than 5 minutes, and the peak effect occurs within 15 minutes) used for sedation, *Multimodal Pain Management in Extremely Low Birth Weight Neonates after Major… DOI: http://dx.doi.org/10.5772/intechopen.111519*

reversible hypnotic effect and added on analgesia profile for procedural sedation and is increasingly used post-operatively in neonates. The various reported side effects are hypotension, hypertension, nausea, vomiting, bradycardia, atrial fibrillation, and pyrexia, but no respiratory depression effects and less anaesthetics and fentanyl consumption were reported in some patient cohorts after abdominal surgery treated with dexmedetomidine perioperatively [47]. Dosing: initial bolus IV 0.00005–0.001 mg/kg over 10 min and continuous infusion 0.0002–0.0008 mg/kg/hour (max. 0.0012 mg/ kg/hour). For example, the Kinderformularium database recommends dexmedetomidine dosing for preterm neonates < 37 weeks GA: LD 0.0002–0.0003 mg/kg/dose over 10 min and MD: 0.0002–0.0003 mg./kg/hour, continuous infusion dose based on effect and side effects. Max: 0.001 mg/kg/hour [42]. Use of LD (starting dose) depends on any concomitant use of other sedatives and the current and desired level of sedation.

#### **5.7 Clonidine**

An alfa (α-2)-adrenergic agonist with a rapid onset action and short duration (the peak action occurs in 10 minutes and lasts for 3–7 hours after IV single dose) that is used for its anxiolytic and sedative effects and safety profile (preventing respiratory depression or haemodynamic instability), treatment for NAS, although, withdrawal symptoms were reported similar but less likely to benzodiazepines and opioids [48]. There are various and unknown mechanisms related to its sedative and add-on analgesic effects. Dosing: 0.001–0.003 mg/kg over 10 min (max. 0.0012 mg/kg/day for intermittent dosing) or LD of 0.001 mg/kg over 10 min and 0.0005–0.001 mg/kg/ hour [49, 50] in a term neonate. Also, the Kinderformularium database recommends clonidine dosing for term neonates only: LD 0.0005 mg/kg/hr., continuous infusion and MD up to a maximum of 0.003 mg/kg/hour, continuous infusion. If a rapid effect is desired, a loading dose of 0.001 mg/kg can be given in 15 minutes. Clonidine is reported to have a risk of rebound phenomenon after its discontinuation, so prevention of this phenomenon is recommended by slow weaning.

#### **5.8 Ketamine**

A general anaesthetic drug with a direct action on the cortex and limbic system with a rapid onset of action (within 30 seconds after IV injection), peak onset of action (5–6 min), and a medium-long duration following the IV single dose (5–10 minutes for anaesthesia) or over 15–30 min for analgesia after IM administration. Adverse effects are described among others (arrhythmias, bradycardia, tachycardia, hyper/hypotension, increased salivation, vomiting, tonic-clonic movements, airway obstructions, respiratory depression and hallucinations, etc., difficult to objectify in ELBW neonates) [51]. Dosing: LD 0.5–1.0 mg/kg (maximum 2 mg/kg) while using more smaller doses followed by IV continuous infusion 0.25 mg/kg/hour is more recently recommended [27] for a term neonate. The Kinderformularium doses are LD at induction of anaesthesia: 0.5–1 mg/kg/dose once and MD 0.5–3 mg/kg/hour continuous infusion [42]. Alternative: intermittent administration: 0.25–0.5 mg/kg/dose every 10–15 minutes [52].

#### **5.9 Chloral hydrate**

A hypnotic and sedative with CNS depressant properties similar to barbiturates. The onset of action is 10–20 minutes, peak effect within 30–60 min, and duration 4–8 hours. Adverse effects are described as CNS symptoms (paradoxical excitement), EEG is not influenced, withdrawal syndrome is known for its prolonged use, and warnings are reported in the paediatric population [53–55]. It is used orally and rectally in neonates and is common for procedural sedation. The risk of accumulation is known after 3 days in preterm and 7 days in term neonates, and hypoxia may occur within 24 hours of administration in some reports. Dosing: 25–75 mg/kg max. á 12 h is administered orally/rectally in full-term neonates only 30 mg/kg/dose, once, and if necessary, repeat after 30 minutes with 15–30 mg/kg/dose [56, 57].
