**2. Clinical endpoints in neonatal postoperative pain studies**

In general, clinical endpoints of pain studies are recommended to demonstrate that the introduction of validated pain together with sedation instruments while adjusting the age-appropriate dosage of analgesics and sedative drugs according to postmenstrual age (PMA) or postnatal age (PNA), and body weight leads to the


*Multimodal Pain Management in Extremely Low Birth Weight Neonates after Major… DOI: http://dx.doi.org/10.5772/intechopen.111519*


*GW—gestational week, M—month, HR—heart rate, BP—blood pressure, COVERS—crying, oxygen requirement, vital signs, expression, resting, signalling distress, RDS—respiratory distress syndrome, CLD—chronic lung disease, VP—ventriculoperitoneal shunt.*

#### **Table 1.**

*Studies that reported postoperative pain management in preterm neonates – the list of validated scales in postoperative pain profile.*

achievement of goals in the paediatric population [6]. More recently, the Neonatal Face Coding Score (NFCS) [7], the Children's & Infants' Postoperative Pain Scale (CHIPPS) [8], the Pain Assessment Tool (PAT) [9], the Modified Postoperative Comfort Score (PCS) = Clinical Scoring System [10], the CRIES scale [11] and the Multidimensional Assessment of Pain Scale (MAPS) [12] were validated for the treatment of postoperative pain in preterm neonates, of which only the PAT scale for extremely low birth weight neonates (ELBW, less than 1000 g, less than 28 weeks of gestation), respectively (**Table 1**). Therefore, in the ELBW cohort, it is also recommended that pain management, including assessment, re-evaluation, prevention, and treatment of a given pain profile (postoperative pain lasting 0–48 hours after surgery) adopted from other preterm neonates, seems to be best described by clinical goals. Primary endpoints are efficacy parameters (excessive, optimal or failed management) as measured by a validated postoperative score (PAT) or some validation processes are needed to be implemented using the COMFORTneo scale or the Numerical Rating Scale (NRS) for a given pain profile, and the effect of paracetamol on opioid consumption during the first 48 hours after surgery also. Secondary endpoints are, for example, safety parameters of the analgesic drugs (e.g., paracetamol hepatotoxicity or bradycardia <80/min, and hypotension defined as mean blood pressure < 10th percentile for opioids). Tertiary endpoints are parameters of long-term morbidity (e.g., intraventricular haemorrhage—IVH, periventricular leukomalacia—PVL, the severity of chronic lung disease, postnatal restriction of growth, prolonged pulmonary ventilatory support, abdominal discomfort, enteral nutrition and breastfeeding, length of hospital stay, and mental and psychomotor development in 12–24 months or death), and more recently, the correlation between total cumulative opioid dose from birth to the period of developmental equivalent assessment of cognitive, language, motor and executive functions at early-school age or later (**Figure 1**) [13].

*Multimodal Pain Management in Extremely Low Birth Weight Neonates after Major… DOI: http://dx.doi.org/10.5772/intechopen.111519*

#### **Figure 1.**

*Multimodal pain management in extremely low birth weight infants after major abdominal surgery and team involvement. Primary objectives are postoperative pain/sedation efficacy parameters (pain lasting 0–48 hours after surgery). Secondary objectives are safety parameters of the analgesics and sedative drugs used (pain lasting 0–48 hours after surgery). Tertiary objectives are parameters of long-term (monitoring parameters evaluated for 12–24 months) and early-school age (5 years of age).*

### **3. Pain scales validated in ELBW population**

#### **3.1 Pain assessment tool (PAT)**

The PAT scale is a scoring system developed and evaluated by Hodgkinson in 1994, originally in a group of 20 term neonates following surgery. The study found that PAT effectively quantified neonates' pain and reflected nurses' perceptions of it [14]. The scale incorporates both behavioural and physiological items and includes a score based on the caregiver's judgement to capture individual reactions and evaluations of the nurse who cared for the patient over time. The tool has ten parameters (see **Table 1**) that are scored on a scale of 0 to 2, with minimum and maximum scores of 0 and 20. Scores greater than 5 indicate some non-pharmacological methods to provide adequate comfort, and scores greater than 10 require adjustment of the analgesia. Later, Spence and O'Sullivan demonstrated that the PAT is a reliable

and valid tool in various groups of NICU patients (both surgical and nonsurgical, preterm and term). The PAT is a clinician-friendly Pain Assessment Tool for all groups of critically ill infants in the NICU; moreover, according to the literature, it is the only scale validated for the postoperative pain profile in extremely low birth weight neonates [9, 15]. However, we find certain limitations in the small sample size of the studied surgical ELBW patients and in the possible impact of the variability of physiological thresholds across gestational/postmenstrual ages (e.g. chronic lung disease and oxygenation requirements).

#### **3.2 COMFORTneo**

In 2004, a modified COMFORT-behavioural scale (COMFORTneo) was created and validated in a population of preterm infants to provide the following definition: behavioural distress encompasses all behaviours of negative affect associated with pain, anxiety and fear. And distress may occur in the absence of pain [16]. The COMFORTneo scale consists of 6 behavioural items: alertness; calmness/agitation; muscle tone assessment by observation of movements of extremities, crying/respiratory response in ventilated patients, body movements and facial expressions. Total scores range from 6 to 30 (1 to 5 for each item) and the cutoff score reflecting pain/ distress is ≥14. A score ≤ 9 reflects possible oversedation. Testing of internal consistency of the scale was good and concurrent validity with the NRS (Numeric rating scale) was adequate in terms of persistent or prolonged pain and sedation in neonates from the 23rd to 43rd weeks of gestational age. COMFORTneo scale and physiological measurements could be clinically useful pain instruments for the neonatal intensive care unit (NICU) environment and critically ill neonates in the postoperative period.

#### **3.3 Numerical rating scale (NRS)**

The NRS quantifies pain on a scale from 0 to 10 based on an individual patient's pain experience; the assessment of pain intensity is as follows: no pain = 0, mild pain = 1–3, moderate pain = 4–6, and severe pain ≥7. Various pictorial adaptations of the NRS mimicking facial expressions are used in young children. For non-verbal individuals, the quantification of pain rests in the hands of caregivers or parents according to the typical patient's pain behaviour. The tool's accuracy depends on the parents and nurse's ability to observe and describe the patient's response to pain in an individual way [17]. As some validation studies show, this simple tool is a good instrument to specify the nature of discomfort (pain or stress) as an additional tool along with validated behavioural and multidimensional scales in the population of preterm neonates [3]. The NRS is a useful instrument in the multimodal assessment of pain in premature neonates; moreover, the possibility of parental involvement in pain management improves current practice in NICUs.

### **4. Adjuvant objective methods in neonatal pain studies**

#### **4.1 Near-infrared spectroscopy (NIRS)**

Cortical activity specifically associated with the affective component of nociception, i.e. with the negative emotional experience of pain (e.g. the area of the cingula, insula, prefrontal cortex), does not always have to be correlated with the *Multimodal Pain Management in Extremely Low Birth Weight Neonates after Major… DOI: http://dx.doi.org/10.5772/intechopen.111519*

discriminative-executive component, which we can assess from the behaviour of the neonates [18, 19]. NIRS is a non-invasive method of optical measurement of local changes in tissue oxygenation in real time. Roué described the most significant correlation between pain and changes in NIRS parameters in 113 full-term healthy neonates during venipuncture. The other measurements performed in this study (skin conductance, heart rate, cortisol in saliva) rather represented a prolonged stress reaction to pain [20]. Bartocci demonstrated primary and secondary somatosensory cortex activation after venipuncture in premature neonates (28-36th gestational weeks), with an intensity inversely proportional to gestational age [21]. Other CNS centres participating in the discriminative and affective components of nociception were also studied using this method. Yuan demonstrated a correlation between pain and NIRS changes in the prefrontal cortex during circumcision in healthy mature neonates [22]. NIRS is a non-invasive objective method that could most closely correlate with the cortical response to a painful stimulus.

#### **4.2 Physiological functions**

Heart and respiratory rate, SpO2 and blood pressure are measured continuously as a part of standard postoperative monitoring of vital functions. Physiological responses to pain stimuli and their correlations were described in multivariate analyses. In full-term infants, physiological measurements were not necessarily well-correlated with behavioural responses. A positive correlation was found between SpO2 and NIRS parameters (HbO2) [20]. Different findings were described in neonates between 28 and 36 weeks of gestation. Preterm infants were more likely to exhibit desaturation or apnoea in response to a painful or stressful stimulus [21]. Therefore, these different pain response profiles should be considered in future research.

#### **4.3 Skin conductance measurement (SCM)**

Changes in electrical skin conductance measured on the palmar side of the hands and soles appear suitable for objective pain evaluation [23, 24]. The activation of the sympathetic nervous system by painful stimuli leads to the activation of eccrine sweat glands and an increase in electrical skin conductivity. These changes could be detected in infants <28 + 0 of gestational age and seem to be able to differentiate between pain and discomfort [25]. Surprisingly, it seems that conductance parameters do not correlate with gestational age, and their changes have been described in neonates as early as 22 gestational weeks. The major limitation of the method is the inability to determine basal skin conductance in this population [26].

#### **5. Pharmacological treatment in neonatal postoperative pain studies**

Pharmacological treatment of pain together with sedation in the postoperative period is governed by international recommendations for the treatment of moderate to severe pain (postoperative pain profile lasting for 48 hours) for mechanically ventilated neonates, and a combination of systemic analgesics (opioids and nonopioids) and sedatives or regional anaesthesia (levobupivacaine) for some surgeries are selected [27]. Pharmacological treatment includes slow IV boluses, intermittent dosing or using continuous infusion with the commonly used opioid—morphine, and synthetic opioids—fentanyl, or sufentanil in some intensive care units, the effects of

which are expressed as morphine potency. Therefore, morphine-equivalent doses are also calculated to achieve an analgesic effect, but the dosage will vary according to the postnatal age (PNA) of the neonate; for example, in neonates younger than 10 days, it is recommended to reduce the initial dose of morphine or sufentanil [28, 29]. More recently, alpha agonists (dexmedetomidine and clonidine) can also be considered, as well as intravenous paracetamol, recommended to be given to all patients regularly and in a dose corresponding to the postmenstrual age (PMA) with an initial loading dose and a maintenance dose (see paracetamol) [30, 31]. Adjusting the dosage of analgesics and sedative drugs is guided by the scale of pain and sedation and doses should be titrated to appropriate effects. In case of PAT score > 10 or COMFORTneo and NRS scores indicating discomfort (≥ 14 or more ≥4), the rate of opioid infusion is increased in individual steps by a certain percentage (%) up to the maximum ageappropriate dose to achieve the desired effect. As a rescue ("rescue") analgesic treatment in case of severe pain (i.e. PAT >10, COMFORTneo ≥ 22, NRS ≥ 7), a bolus of opioids or a second-choice drugs (e.g. ketamine, dexmedetomidine, clonidine or propofol) are used intravenously so that the target values of PAT (≤10), COMFORTneo (9–13) points and NRS (0–3 points) are achieved. On the contrary, for COMFORTneo scores corresponding to excessive sedation (<9) and NRS ≤3, the opioid infusion rate should be reduced, for example by a certain percentage (%) based on assessment. The analgesic/sedation concept in ELBW after abdominal surgery has its pharmacological aspects that strongly correlate with changes in drug disposition, which are the consequences of, for example, extreme immaturity, period of peri−/postoperative stress (metabolic, hormonal, etc.) related to abdominal causes of surgery (e.g. NEC, spontaneous intestinal perforation—SIP) or inflammation (changes in CYP 450 activity) or physiological changes in ventilation, circulation, renal and hepatic functions and as expected increased permeability of the blood-brain barrier to analgesics and sedatives in ELBW neonates. In this vulnerable population, therefore, measuring the effectiveness and safety of the drugs used is extremely important. In the following section, drugs are selected with a focus on drug characteristics, clinical indication, reported efficacy and safety and drug dosage in premature and ELBW neonates, respectively, after abdominal surgery. Complex therapy includes non-pharmacological interventions, sucrose, the most used intravenous analgosedative drugs (except ibuprofen), and significantly less used epidural analgesics; therefore, the knowledge about analgosedative use still missing in this population will be summarized.

#### **5.1 Morphine**

A natural opiate alkaloid with a rapid and prolonged peak onset of action (20 minutes after IV single injection) acting, for example 3–5 hours after IV single injection used in neonates for postoperative pain, for specific conditions such as necrotizing enterocolitis (NEC) and neonatal abstinence syndrome (NAS) [32, 33]. Pharmacodynamics is highly dependent on the dosage form and route of administration (epidural, intravenous, subcutaneous, intramuscular, oral or rectal) with a broad peak of onset of action after administration lasting between 20 and 90 min and a duration of 3–20 hours. However, ELBW neonates lack reports on efficacy and safety (e.g. evidence of benefits for poor neurologic outcomes) [34, 35]. Respiratory depression and hypotension have been described with continuous infusion. Therefore, lower doses are generally recommended in premature neonates. Dosing: analgesia [36, 37], 0.05–0.1 mg/kg/dose every 4–6-8 hours for intermittent dosing while for continuous IV infusion initial dose 0.01 mg/kg/dose is titrated to the maximum

*Multimodal Pain Management in Extremely Low Birth Weight Neonates after Major… DOI: http://dx.doi.org/10.5772/intechopen.111519*

0.03 mg/kg/hour (some authors suggested 0.015–0. 020 mg/kg/hour). Initial IV infusion rates of 0.010 mg/kg/hour are acceptable for neonates younger than 1 week. Neonates older than 1 week tolerate 0.015 mg/kg/hour, whereas older infants may tolerate 0.020–0.040 mg/kg/hour. Supplemental IV boluses of as much as 0.050 mg/ kg may be administered for episodes of breakthrough pain in mechanically ventilated neonates who are receiving morphine by means of continuous infusion. For example, Kinderformularium recommends morphine dosing for preterm neonates < 37 weeks GA as an initial dose of 0.050–0.100 mg/kg followed by continuous infusion of 0.003–0.020 mg/kg/hour continuous infusion.

#### **5.2 Fentanyl**

Fentanyl is a synthetic effective opioid with high potency to morphine, a rapidacting onset (peak onset 3–4 min after IV single injection) with medium-long duration (30 min after IV single injection) used for acute procedural, postoperative, and prolonged pain profile, and specific conditions (ECMO) in neonates. Adverse effects include apnoea, increased chest rigidity and respiratory depression that more often described when fentanyl is administered as an IV bolus of 0.001–0.002 mg/kg than when it is given as a continuous IV infusion of 0.001–0.002 mg/kg/hour while fentanyl causes less likely systemic hypotension than morphine. The first report of a cohort of very preterm neonates (23–30 gestational age) evaluated the association between cumulative neonatal exposure to fentanyl by neurodevelopmental and socioemotional outcomes in children at 5 years of age. However, according to the authors, the conclusions of this study were still ambiguous [38]. Dosing: analgesia [39], intermittent slow IV push 0.0005–0.003 mg/kg/dose, continuous infusion 0.0005–0.002 mg/kg/hour; sedation, slow IV push 0.001–0.004 mg/kg/dose may be repeated every 2–4 hours, continuous analgesia/sedation initial 0.001–0.002 mg/kg then 0.0005–0.001 mg/kg/hour. The mean required dose is 0.00064 mg/kg/hour <34 GA. During ECMO IV push 0.005–0.010 mg/kg and 0.001–0.005 (max 0.020) mg/ kg/hour were reported due to known drug tolerance in this population. Additionally, the Kinderformularium database recommends fentanyl dosing for preterm neonates < 37 weeks GA: an initial dose of 0.0005–0.003 mg/kg followed by continuous infusion 0.005–0.003 mg/kg/hour continuous infusion.

#### **5.3 Sufentanil**

A synthetic, short-acting opioid agonist with a rapid onset of action (peak onset 5–6 min after IV single injection) and with a medium-long duration (30 min after IV single injection) more potent than fentanyl or morphine used for general and intraoperative anaesthesia, and analgesia/sedation in mechanically ventilated neonates and neonatal ECMO. Adverse effects are somewhat similar to those reported with fentanyl (bradycardia, hypotension, hypertension, cardiac arrhythmia, CNS depression, respiratory depression, chest wall rigidity, seizures and burst-suppression EEG pattern). Sufentanyl doses are not validated for premature neonates. Dosing: analgesia/sedation, in mechanically ventilated premature neonates 26–34 weeks IV loading dose 0.0005 mg/kg over 10 minutes followed by 0.002 mg/kg/hour continuous infusion [40], or in ventilated full-term neonates, sufentanil LD of 0.002 mg/kg and MD of 0.00029 mg/kg/hour was reported, but dosage regimen was recommended to be verified in clinical trials for analgesia in full-term neonates [41]. A 0.0005 mg/ kg IV bolus and a continuous infusion of 0.0002 mg/kg/hour for 24 hours have been

recommended for postoperative anaesthesia (Anand 1992). The Kinderformularium database recommends the dosage of sufentanil for young infants and children (from 1 month to 18 years)—an initial dose of 0.0002—0.0005 mg/kg (maximum 0.001 mg/ kg) and a loading dose (LD) in ventilated patients: 0. 0003–0.002 mg/kg/dose slowly IV over 30 seconds. If necessary, additional doses of 0.0001–0.001 mg/kg/dose can be given up to a maximum (cumulative) dose of 0.005 mg/kg in major procedures [42].
